Report Based On The Analysis Of The Ons Survey Of Psychiatric Morbidity Among Adults: Fill & Download for Free

Common Mental Health Disorders: Identification and Pathways to Care.2COMMON MENTAL HEALTH DISORDERS2.1. INTRODUCTIONThis guideline is concerned with the care and treatment of people with a common mental health disorder, including depression, generalised anxiety disorder (GAD), panic disorder, phobias, social anxiety disorder, obsessive-compulsive disorder (OCD) and post-traumatic stress disorder (PTSD). It makes recommendations about the delivery of effective identification, assessment and referral for treatment in primary care. The guideline will also be applicable to secondary care, and relevant (but does not make specific recommendations) for the prison service and non-NHS services such as social services, and the voluntary and independent sectors. A particular purpose of this guideline is to integrate existing NICE guidance on the identification and assessment of common mental health disorders and to provide recommendations to support the development of local care pathways for these disorders.The purpose of this introductory chapter is to provide an overview of the epidemiology and treatment of the common mental health disorders, and to highlight important issues related to identification and assessment of the disorders and the relevant local care pathways within the NHS.This guideline does not cover interventions to treat the disorders and should be used in conjunction with other relevant NICE guidelines, which give evidence of the effectiveness of interventions for the specific disorders, including drug treatments and psychological therapies:Self-harm: the Short-term Physical and Psychological Management and Secondary Prevention of Self-harm in Primary and Secondary Care (NICE, 2004c; NCCMH, 2004b).Obsessive-compulsive Disorder (NICE, 2005a; NCCMH, 2006).Post-traumatic Stress Disorder (PTSD) (NICE, 2005b; NCCMH, 2005).Antenatal and Postnatal Mental Health (NICE, 2007a; NCCMH, 2007).Depression (NICE, 2009a; NCCMH, 2010b).Depression in Adults with a Chronic Physical Health Problem (NICE, 2009b; NCCMH, 2010a).Generalised Anxiety Disorder and Panic Disorder (with or without Agoraphobia) in Adults(NICE, 2011a; NCCMH, 2011a).Self-harm: Longer-Term Management (NICE, 2011c; NCCMH, forthcoming). A NICE guideline on social anxiety disorder is expected in 2013.Go to:2.2. THE DISORDERSThis guideline covers the following common mental health disorders in adults (18 years and older):depression (including subthreshold disorders)anxiety disorders (including GAD, panic disorder, phobias, social anxiety disorder, OCD and PTSD).The guideline will also cover, where relevant, issues relating to comorbidity; however, as no separate NICE guideline addresses comorbid presentations of common mental health disorders, this will not be a key topic of the guideline. Groups not covered include adults with subthreshold mixed anxiety and depression, adults with psychotic and related disorders (including schizophrenia and bipolar disorder), people for whom drug and alcohol misuse are the primary problem, people with eating disorders, and children and people younger than 18 years old.2.2.1. Symptoms and presentationDepressionDepression refers to a wide range of mental health problems characterised by the absence of a positive affect (a loss of interest and enjoyment in ordinary things and experiences), low mood and a range of associated emotional, cognitive, physical and behavioural symptoms. Distinguishing the mood changes between clinically significant degrees of depression (for example, major depression) and those occurring ‘normally’ remains problematic and it is best to consider the symptoms of depression as occurring on a continuum of severity (Lewinsohn et al., 2000).Commonly, mood and affect in a major depressive illness are unreactive to circumstance remaining low throughout the course of each day, although for some people mood varies diurnally, with gradual improvement throughout the day only to return to a low mood on waking. In other cases a person's mood may be reactive to positive experiences and events, although these elevations in mood are not sustained with depressive feelings often quickly re-emerging (Andrews & Jenkins, 1999).Behavioural and physical symptoms typically include tearfulness, irritability, social withdrawal, an exacerbation of pre-existing pains, and pains secondary to increased muscle tension (Gerber et al., 1992). A lack of libido, fatigue and diminished activity are also common, although agitation and marked anxiety can frequently occur. Typically there is reduced sleep and lowered appetite (sometimes leading to significant weight loss), but some people sleep more than usual and have an increase in appetite. A loss of interest and enjoyment in everyday life, and feelings of guilt, worthlessness and deserved punishment are common, as are lowered self-esteem, loss of confidence, feelings of helplessness, suicidal ideation and attempts at self-harm or suicide. Cognitive changes include poor concentration and reduced attention, pessimistic and recurrently negative thoughts about oneself, one's past and the future, mental slowing and rumination (Cassano & Fava, 2002).Generalised anxiety disorderThe essential feature of GAD is excessive anxiety and worry (apprehensive expectation), occurring on more days than not for a period of at least 6 months, about a number of events or activities. The person with GAD finds it difficult to control the anxiety and worry, which is often accompanied by restlessness, being easily fatigued, having difficulty concentrating, irritability, muscle tension and disturbed sleep (Brownet al., 2001).The focus of the anxiety and worry in GAD is not confined to features of another disorder, for example having panic attacks (as in panic disorder) or being embarrassed in public (as in social anxiety disorder). Some people with GAD may become excessively apprehensive about the outcome of routine activities, in particular those associated with the health of or separation from loved ones. Some people often anticipate a catastrophic outcome from a mild physical symptom or a side effect of medication. Demoralisation is said to be a common consequence, with many individuals becoming discouraged, ashamed and unhappy about the difficulties of carrying out their normal routines. GAD is often comorbid with depression and this can make accurate diagnosis problematic (Wittchen et al., 2002).Panic disorderPeople with panic disorder report intermittent apprehension, and panic attacks (attacks of sudden short-lived anxiety) in relation to particular situations or spontaneous panic attacks, with no apparent cause. They often take action to avoid being in particular situations in order to prevent those feelings, which may develop into agoraphobia (Breier et al., 1986).The frequency and severity of panic attacks varies widely. Situational triggers for panic attacks can be external (for example, a phobic object or situation) or internal (physiological arousal). A panic attack may be unexpected (spontaneous or uncued), that is, one that an individual does not immediately associate with a situational trigger.The essential feature of agoraphobia is anxiety about being in places or situations from which escape might be difficult, embarrassing or in which help may not be available in the event of having a panic attack. This anxiety is said to typically lead to a pervasive avoidance of a variety of situations that may include: being alone outside the home or being home alone; being in a crowd of people; travelling by car or bus; being in a particular place, such as on a bridge or in a lift.Obsessive-compulsive disorderOCD is characterised by the presence of either obsessions or compulsions, but commonly both. An obsession is defined as an unwanted intrusive thought, image or urge that repeatedly enters the person's mind. Obsessions are distressing, but are acknowledged as originating in the person's mind and not imposed by an external agency. They are usually regarded by the individual as unreasonable or excessive. Common obsessions in OCD include contamination from dirt, germs, viruses, body fluids and so on, fear of harm (for example, that door locks are not safe), excessive concern with order or symmetry, obsessions with the body or physical symptoms, religious, sacrilegious or blasphemous thoughts, sexual thoughts (for example, of being a paedophile or a homosexual), an urge to hoard useless or worn out possessions, or thoughts of violence or aggression (for example, stabbing one's baby) (Lochner & Stein, 2003).Compulsions are repetitive behaviours or mental acts that the person feels driven to perform. A compulsion can either be overt and observable by others, or a covert mental act that cannot be observed. Covert compulsions are generally more difficult to resist or monitor than overt ones because they can be performed anywhere without others knowing and are easier to perform. Common compulsions include checking (for example, gas taps), cleaning, washing, repeating acts, mental compulsions (for example, repeating special words or prayers in a set manner), ordering, symmetry or exactness, hoarding/collecting and counting (Foa et al., 1995). The most frequent presentations are checking and cleaning, and these are the most easily recognised because they are on a continuum with everyday behaviour. A compulsion is not in itself pleasurable, which differentiates it from impulsive acts such as shopping or gambling, which are associated with immediate gratification.Post-traumatic stress disorderPTSD often develops in response to one or more traumatic events such as deliberate acts of interpersonal violence, severe accidents, disasters or military action. Those at risk of PTSD include survivors of war and torture, of accidents and disasters, and of violent crime (for example, physical and sexual assaults, sexual abuse, bombings and riots), refugees, women who have experienced traumatic childbirth, people diagnosed with a life-threatening illness, and members of the armed forces, police and other emergency personnel (Foa et al., 2008).The most characteristic symptoms of PTSD are re-experiencing symptoms. People with PTSD involuntarily re-experience aspects of the traumatic event in a vivid and distressing way. Symptoms include flashbacks in which the person acts or feels as if the event is recurring; nightmares; and repetitive and distressing intrusive images or other sensory impressions from the event. Reminders of the traumatic event arouse intense distress and/or physiological reactions. As a result, hypervigilance for threat, exaggerated startle responses, irritability, difficulty in concentrating, sleep problems and avoidance of trauma reminders are other core symptoms. However, people with PTSD also describe symptoms of emotional numbing. These include inability to have any feelings, feeling detached from other people, giving up previously significant activities and amnesia for significant parts of the event.Two further common mental health disorders, social anxiety disorder and specific phobias, are briefly described below. However, because no NICE guidelines currently exist for these disorders they will not be discussed in detail in the remainder of this chapter.Social anxiety disorderSocial anxiety disorder, also referred to as social phobia, is characterised by an intense fear in social situations that results in considerable distress and in turn impacts on a person's ability to function effectively in aspects of their daily life. Central to the disorder is a fear of being judged by others and of being embarrassed or humiliated. This leads to the avoidance of a number of social situations and often impacts significantly on educational and vocational performance. The fears can be triggered by the actual or imagined scrutiny from others. The disorder often begins in early adolescence, and although an individual may recognise the problem as outside of normal experience, many do not seek help (Liebowitz et al., 1985).Social anxiety disorder is characterised by a range of physical symptoms including excessive blushing, sweating, trembling, palpitations and nausea. Panic attacks are common, as is the development of depressive symptoms as the problem becomes chronic. Alcohol or drug misuse can develop because people use these substances in an attempt to cope with the disturbing and disabling symptoms. It is also often comorbid with other disorders such as depression (Kessler et al., 1999).Specific phobiasA specific phobia is an unwarranted, extreme and persistent fear of a specific object or situation that is out of proportion to the actual danger or threat (Humphris et al., 1995). The fear and anxiety occur immediately upon encountering the feared object or situation and tend to lead to avoidance or extreme discomfort. The person with a specific phobia recognises that the fear is excessive, unwarranted or out of proportion to the actual risk. Specific phobias result in significant interference with the activities of daily life; they are usually grouped under a number of subtypes including animal, natural environment, blood-injection-injury and situational.2.2.2. Incidence and prevalenceEstimates of the prevalence of common mental health disorders vary considerably depending on where and when surveys are carried out, and the period over which prevalence is measured.The 2007 Office for National Statistics (ONS) household survey of adult psychiatric morbidity in England found that 16.2% of adults aged 16 to 64 years met the diagnostic criteria for at least one disorder in the week prior to interview (McManus et al., 2009). In the three ONS surveys carried out so far, the proportion of adults meeting the criteria for at least one disorder increased between 1993 and 2000 but did not change between 2000 and 2007 (15.5% in 1993, 17.5% in 2000 and 17.6% in 2007). The largest increase in the rate of disorders found between 1993 and 2007 was in women aged 45 to 64 years, among whom the rate went up by about one fifth (McManus et al., 2009).More than half of the adults identified with a common mental health disorder in the ONS survey presented with a mixed anxiety and depressive disorder (9% in the past week). The 1-week prevalence for the other common mental health disorders were 4.4% for GAD, 2.3% for a depressive episode, 1.4% for phobia, 1.1% for OCD and 1.1% for panic disorder (McManus et al., 2009).In the US, Kessler and colleagues conducted the National Comorbidity Survey, a representative household interview survey of 9,282 adults aged 18 years and over, to estimate the lifetime (Kessler et al., 2005a) and 12-month (Kessler et al., 2005b) prevalence rates of mental disorders classified using theDiagnostic and Statistical Manual of Mental Disorders (4th text-revision version; DSM-IV-TR) of the American Psychiatric Association (APA, 2000). A summary of their findings can be seen in Table 1. Of the 12-month cases in the US National Comorbidity Survey, 22.3% were classified as serious, 37.3% as moderate and 40.4% as mild. Fifty-five per cent carried only a single diagnosis, 22% two diagnoses and 23% three or more diagnoses. Latent class analysis identified three highly comorbid classes representing 7% of the population, and the authors concluded that, although mental disorders are widespread, serious cases are concentrated among a relatively small proportion of people with high comorbidity (Kessler et al., 2005b).Table 1Summary of prevalence rates for common mental health disorders.In summary, at any given time common mental health disorders can be found in around one in six people in the community, and around half of these have significant symptoms that would warrant intervention from healthcare professionals. Most have non-specific mixed anxiety and depressive symptoms, but a proportion have more specific depressive disorder or anxiety disorders including panic disorder, phobias, OCD or PTSD.The location, time and duration of the survey are not the only factors to influence prevalence rates. A number of demographic and socioeconomic factors are associated with a higher risk of disorders, including gender, age, marital status, ethnicity and socioeconomic deprivation. These will be discussed below.GenderDepression and anxiety disorders tend to have a higher prevalence in women. Prevalence rates of depression have consistently been found to be between 1.5 and 2.5 times higher in women than men (Waraich et al., 2004). In the ONS survey (McManus et al., 2009) women were more likely than men to have a disorder (19.7 and 12.5%, respectively), with rates significantly higher for women across all categories of disorder except for panic disorder and OCD. The greatest difference between genders was among South Asian adults where the age-standardised rate among women (34.3% of South Asian women) was three times that of men (10.3% of South Asian men). Reasons cited in the 2007 ONS survey (McManus et al., 2009) include the impact of having children (Bebbington et al., 1991), exposure to domestic or sexual violence (Patel et al., 2006), adverse experiences in childhood and women's relative poverty (Patel et al., 1999; Piccinelli & Wilkinson, 2000).AgeIn the 2007 ONS survey (McManus et al., 2009) rates varied by age, with those aged 75 years and over least likely to have a disorder (6.3% of men and 12.2% of women). In women, the rate peaked among 45- to 54-year-olds of whom 25% met the criteria for at least one disorder. Among men, the rate was highest in 25- to 54-year-olds (14.6% of 25- to 34-year-olds, 15.0% of 35- to 44-year-olds and 14.5% of 45- to 54-year-olds).Marital statusWomen across all marital-status categories were more likely than their male counterparts to have disorders in the 2007 ONS survey (McManus et al., 2009), except for divorced people in whom the prevalence for men and women was very similar (26.6% for women and 27.7% for men). Among men, those currently divorced had the greatest likelihood of having a disorder, but variation by other marital status categories was less pronounced. For women the rate of disorder was high for divorced women, but even higher for separated women (33.0%). Men and women who were married or widowed had the lowest observed rates of disorder (10.1% of married men and 16.3% of married women; 10.4% widowed men and 17.4% widowed women).EthnicityIn the 2007 ONS survey (McManus et al., 2009), after age-standardisation of the data, there was little variation between white, black and South Asian men in the rates of any disorder. However, among women rates of all disorders (except phobias) were higher in the South Asian group. The number of South Asian women in the sample was small, so while the differences were pronounced they were only significant for disorders as a whole for GAD and panic disorder.Socioeconomic factorsIn the 2007 ONS survey (McManus et al., 2009), people living in households with the lowest levels of income were more likely to have a disorder than those living in the highest income households. A number of socioeconomic factors significantly affected prevalence rates in the 2000 ONS survey (Singleton et al., 2001): those with a depressive episode were more likely than those without a disorder to be unemployed, to belong to social classes 4 and below, to have no formal educational qualifications, to live in Local Authority or Housing Association accommodation, to have moved three or more times in the last 2 years and to live in an urban environment.An illustration of the social origins of depression can be found in a general practice survey in which 7.2% (ranging 2.4 to 13.7%, depending upon the practice) of consecutive attendees had a depressive disorder. Neighbourhood social deprivation accounted for 48.3% of the variance among practices. Other variables were the proportion of the population having no or only one car and neighbourhood unemployment (Ostleret al., 2001). The evidence therefore overwhelmingly supports the view that the prevalence of common mental health disorders, however it is defined, varies according to gender and social and economic factors.Learning disabilitiesThe rates of common mental health disorders in adults with learning disabilities are generally considered to be higher, but limited data and methodological problems (Smiley, 2005) mean that precise estimates are often not available and so uncertainty remains. In contrast, there is clearer evidence that other mental disorders such as problem behaviour have a higher rate of learning disabilities (Cooper et al., 2007). Rates of mental disorders may vary with the severity of the learning disability, being higher in more severe disability (Whitaker & Read, 2006), and challenges in assessment and diagnosis are considerable especially for those with more severe learning disabilities (Smiley, 2005; Whitaker & Read, 2006). However, some indication of the possible differential incidence of common mental health disorders can be obtained from the following studies. Richards and colleagues (2001) report a four-fold increase in the rates of affective disorders for people with mild learning disability. Rates of problems may also vary with the disorder; for example, Collacott (1999) reports a higher rate of depression in adults with Down's syndrome than in adults with other causes of learning disability. With regard to anxiety disorders, Cooper (1997) reports a rate of 2.5% for OCD in adults with a learning disability, which is higher than in the general adult population.2.2.3. AetiologyThe aetiology of common mental health disorders is multi-factorial and involves psychological, social and biological factors. Many of the common mental health disorders have similar aetiologies. For example,King and colleagues (2008) identified five immutable risk factors for depression. These were younger age, female gender, lower educational achievement, previous history of depression and family history of depression. Brewin and colleagues (2000) and Ozer and colleagues (2003) identified similar risk factors for PTSD, including a previous personal or family history of anxiety disorders or affective disorders, neuroticism, lower intelligence, female gender and a history of previous trauma. The ONS survey (McManus et al., 2009) identified factors that may be associated with increased duration of an episode of depression or anxiety. These can be broadly defined as biological factors, social stresses and life events. These risk factors will now be discussed in general. For information regarding factors for specific disorders, please refer to the relevant NICE guideline (see Section 2.1).There is good evidence for biological factors in the development of many psychological disorders. Biological factors can be biochemical, endocrine and neurophysiological (Goodwin, 2000; Malhi et al., 2005) or genetic (Kendler & Prescott, 1999), and can interact with early trauma ultimately leading to psychological distress (Heim & Nemeroff, 2001).Support for this claim often comes from family-history studies (Angst et al., 2003). A family history of depressive illness has been linked with an increased chance of developing depression (Kendler et al., 2001). Similarly, the risk of GAD in first-degree relatives of patients with GAD was five times that of controls (Noyes et al., 1987). Although specific genes conferring vulnerability to GAD have not yet been reliably identified, the genes involved in the transmission of GAD appear to increase susceptibility to other anxiety disorders such as panic disorder and agoraphobia as well as major depression (Hettema et al., 2001 and 2005; Kendler, 1996). There is some evidence to suggest that personality traits such as neuroticism may have a role in the development of common mental health disorders. Personality traits such as neuroticism have been identified as risk factors for both depression (Fava & Kendler, 2000) and GAD (Hettema et al., 2004). However, the specific role of neurotransmitters and other chemical mediators in the aetiology of common mental health disorders is currently unclear.According to a stress-vulnerability model (Nuechterlein & Dawson, 1984), it is not only biological factors that can trigger the development of a common mental health disorder. Social triggers may also play an important role (Harris, 2000). The ONS survey (McManus et al., 2009) identified perceived financial strain (Weich & Lewis, 1998a), work stress (Stansfeld et al., 1999), poor housing (Weich & Lewis, 1998b) and social isolation (Bruce & Hoff, 1994) as key factors that can influence the development of common mental health disorders. In the UK, an influential study found that social vulnerability factors for depression in women in Camberwell, south-east London, included: having three or more children under the age of 14 years living at home; having no paid employment outside the home; and not having a confiding relationship with another person (Brown & Harris, 1978). The importance of a confiding relationship has been further reiterated by Patten (1991) who found that a lack of such a relationship was a strong risk factor for depression.Negative life events, particularly those relating to health, can also impact on the development of depression and anxiety, although vulnerabilities will vary between individuals (Harris, 2000). The ONS survey identified poor physical health and problems with alcohol use as predictors of anxiety and depression (Salokangas & Poutanen, 1998), while King and colleagues (2008) found that current poorer physical and mental health functional status, based on the 12-Item Short Form Health Survey (SF-12) questionnaire, was linked to the development of depression. However, it is also important to note that depression may lead to secondary disability that compounds, and is difficult to distinguish from, the depression itself.Early life experiences as well as current social stressors must also be considered. A poor parent–child relationship, marital discord and divorce, neglect, and physical and sexual abuse almost certainly increase a person's vulnerability to depression in later life (Fava & Kendler, 2000) and can play a vital role in the development of GAD. Barlow (2000) reported that good parenting experiences are important in providing children with a secure base from which to explore the world. Problems in child–parent attachment have been linked to feelings of diminished personal control of potentially threatening events (Barlow, 2000), which can in turn increase susceptibility to psychological illness.However, when considering the importance of life events it is important to remember that events may not have a causal impact on the development of symptoms. Instead, they may act as a trigger among people who are biologically or psychologically predisposed to a disorder, for example OCD (Gothelf et al., 2004; Khanna et al., 1988). The authors of the ONS survey make the point that although these risk factors are associated with disorders and tend to increase the duration of episodes it is not clear whether or not they cause the onset of an episode.2.2.4. Development, course and prognosisFor many people the onset of common mental health disorders occurs in adolescence or early adult life, but the disorders can affect people at any point. Earlier onset is generally associated with poorer outcomes. Kessler and colleagues (2005a) reported an estimated median age of onset for anxiety disorders of 11 years and for mood disorders of 30 years in their US National Comorbidity sample. Half of all lifetime cases had started by 14 years and three quarters by 24 years. Many anxiety disorders also have a chronic course. This chronic course may be associated with a considerable delay in presenting to services, with consequent significant personal and social impairment. Therefore, Kessler and colleagues (2005a) concluded that interventions aimed at prevention or early treatment needed to focus on young people.DepressionThe average age of the first episode of major depression is the mid-20s and although the first episode may occur at any time, from early childhood through to old age, a substantial proportion of people have their first depressive episode in childhood or adolescence (Fava & Kendler, 2000).Although depression has been understood to be a time-limited disorder lasting on average 4 to 6 months with complete recovery afterwards, it is now clear that incomplete recovery and relapse are common. The World Health Organization (WHO) study of mental disorders in 14 centres across the world found that 50% still had a diagnosis of depression 1 year later (Simon et al., 2002) and at least 10% of patients have persistent or chronic depression (Kessler et al., 2003). At least 50% of people following their first episode of major depression will go on to have at least one more episode (Kupfer, 1991), and after the second and third episodes the risk of further relapse rises to 70 and 90%, respectively (Kupfer, 1991). Early-onset depression (at or before 20 years of age) and depression occurring in old age have a significantly increased vulnerability to relapse (Giles et al., 1989; Mitchell & Subramaniam, 2005). Thus while the outlook for a first episode is good, the outlook for recurrent episodes over the long term can be poor with many patients experiencing symptoms of depression over many years (Akiskal, 1986).Generalised anxiety disorderMost clinical studies suggest that GAD is typically a chronic condition with low rates of remission over the short and medium term. Evaluation of prognosis is complicated by the frequent comorbidity with other anxiety disorders and depression, which worsen the long-term outcome and accompanying burden of disability (Tyrer & Baldwin, 2006). In the Harvard-Brown Anxiety Research Program, which recruited patients from Boston hospitals, the mean age of onset of GAD was 21 years, although many patients had been unwell since their teens. The average duration of illness in this group was about 20 years and despite treatment the outcome over the next 3 years was relatively poor, with only one in four patients showing symptomatic remission from GAD (Yonkers et al., 1996). The proportion of patients who became free from all psychiatric symptomatology was even smaller, at about one in six. In patients who remitted from GAD, the risk of relapse over the next year was about 15% increasing to about 30% in those who achieved only partial symptomatic remission (Yonkers et al., 1996).The participants in the above study were recruited from hospital services and may not be representative of GAD in general. In a naturalistic study in the UK, Tyrer and colleagues (2004) followed up patients with anxiety and depression identified in psychiatric clinics in primary care and found that 12 years later 40% of those initially diagnosed with GAD had recovered, in the sense of no longer meeting criteria for any DSM-III psychiatric disorder. The remaining participants remained symptomatic, but only 3% still had GAD as the principal diagnosis; in the vast majority of patients, conditions such as dysthymia, major depression and agoraphobia were now more prominent. This study confirms the chronic and fluctuating symptomatic course of GAD in clinically-identified patients. It should be noted, however, that the majority of people with GAD in the community do not seek medical help for their symptoms (Wittchen & Jacobi, 2005) and the course of the illness in these circumstances is not established.Panic disorderPanic disorder comprises two main subtypes; panic disorder without agoraphobia and panic disorder with agoraphobia, with different presentations and often different courses. Panic disorder with agoraphobia (about one third of all presentations of panic disorder) is characterised by an avoidance of situations from which escape may not be possible or help not available in the event of a panic attack. Panic disorder with agoraphobia is also more common in women by a factor of approximately two to one. In contrast, panic disorder without agoraphobia is not situation-specific and symptoms may develop with no obvious or apparent cause (Weissman & Merikangas, 1986).The most common age of onset is from the mid-teens to the mid-20s; however, onset may occur at any time. Panic disorder often begins with occasional panic attacks that increase in frequency and which in time lead to a pattern of a generalised avoidance. The course of this disorder often follows a chronic pathway for many people with panic disorder, with agoraphobia likely to have an even more chronic course (Francis et al., 2007).Panic attacks commonly occur in many other disorders including specific phobias and social anxiety disorder, but they can also occur in GAD, drug or alcohol misuse, personality disorders and a number of physical disorders.Obsessive-compulsive disorderThe mean age of onset of OCD is in late adolescence for men and early 20s for women, although age of onset covers a wide range of ages. However, it may take individuals between 10 and 15 years or longer to seek professional help. There is often comorbidity with a range of disorders, especially depression (for example, Abramowitz, 2004; Abramowitz et al., 2003; Apter et al., 2003), and other anxiety disorders (for example, Biederman et al., 2004; LaSalle et al., 2004; Nestadt et al., 2003; Welkowitz et al., 2000).OCD may follow an acute, episodic or chronic course. In one of the largest follow-up studies, Skoog and Skoog (1999) conducted a 40-year prospective study and reported that approximately 60% of people with OCD displayed signs of general improvement within 10 years of illness, increasing to 80% by the end of the study. However, only 20% achieved full remission even after almost 50 years of illness; 60% continue to experience significant symptoms; 10% displayed no improvement; and 10% had deteriorated. A fifth of those who had displayed an early sustained improvement subsequently relapsed, even after 20 years without symptoms. This suggests that early recovery does not eliminate the possibility of very late relapse. Intermittent, episodic disorder was more common during the early stage of illness and predicted a more favourable outcome, whereas chronic illness predominated in later years. Worse outcome was predicted by early age of onset (particularly in males), experiencing obsessions and compulsions or magical thinking, poor social adjustment and early chronic course.Post-traumatic stress disorderThe onset of symptoms in PTSD is usually in the first month after the traumatic event, but in a minority (less than 15%; McNally, 2003) there may be a delay of months or years before symptoms start to appear. PTSD also shows substantial natural recovery in the initial months and years after a traumatic event. Whereas a high proportion of trauma survivors will initially develop symptoms of PTSD, a substantial proportion of these individuals recover without treatment in the following years, with a steep decline in PTSD rates occurring in the first year (for example, Breslau et al., 1991; Kessler et al., 1995). On the other hand, at least one third of people who initially develop PTSD remain symptomatic for 3 years or longer and are at risk of secondary problems such as substance misuse (for example, Kessler et al., 1995). In the 2007 ONS (McManus et al., 2009) survey, screening positive for current PTSD declined with age, from 4.7% of 16- to 24-year-olds to 0.6% of adults aged 75 years or over.2.2.5. Impairment, disability, secondary problemsDepressionApart from the subjective suffering experienced by people who are depressed, the impact on social and occupational functioning, physical health and mortality is substantial. In fact, depressive illness causes a greater decrement in health state than major chronic physical illnesses such as angina, arthritis, asthma and diabetes (Moussavi et al., 2007).Depression is a major cause of disability across the world. In 1990 it was the fourth most common cause of loss of disability-adjusted life years (DALYs) in the world and by 2020 it is projected to become the second most common cause (World Bank, 1993). In 1994 it was estimated that about 1.5 million DALYs were lost each year in the West as a result of depression (Murray et al., 1994). Depressive disorders account for 4.4% of the global disease burden or the equivalent of 65 million DALYs (Murray & Lopez, 1997; WHO, 2002).Emotional, motivational and cognitive effects substantially reduce a person's ability to work effectively, with losses in personal and family income as well as lost contribution to society in tax revenues and employment skills. Wider social effects include: greater dependence upon welfare and benefits with loss of self-esteem and self-confidence; social impairments, including reduced ability to communicate and sustain relationships during the illness with knock-on effects after an episode; and longer-term impairment in social functioning, especially for those who have chronic or recurrent disorders. Some of the features of depression (such as lethargy) may impede access to appropriate healthcare.Depression can also exacerbate the pain, distress and disability associated with physical health problems, and can adversely affect outcomes. Depression combined with chronic physical health problems incrementally worsens health compared with a physical health problem alone or even combinations of physical health problems (Moussavi et al., 2007). In addition, for a range of physical health problems findings suggest an increased risk of death when comorbid depression is present (Cassano & Fava, 2002). In coronary heart disease, for example, depressive disorders are associated with an 80% increased risk both for its development and of subsequent mortality in people with established disease, at least partly because of common contributory factors (Nicholson et al., 2006).Suicide accounts for nearly 1% of all deaths and nearly two thirds are people with depression (Sartorius, 2001); putting it in another way, having depression leads to over a four-times higher risk of suicide compared with the general population, which rises to nearly 20 times in the most severely ill (Bostwick & Pankratz, 2000). Sometimes depression may also lead to acts of violence against others, and may even include homicide. Marital and family relationships are frequently negatively affected, and parental depression may lead to neglect of children and significant disturbances in children (Ramachandani & Stein, 2003).Generalised anxiety disorderLike major depression GAD is associated with a substantial burden of disability, equivalent to that of other chronic physical health problems such as arthritis and diabetes (Wittchen et al., 2002). There is evidence that comorbid depression and anxiety has a worse prognosis and more persistent symptoms than either depression or anxiety disorders alone (Kroenke et al., 2007). There is also evidence that, in the community, anxiety disorders are independently associated with several physical health problems and that this comorbidity is significantly associated with poor quality of life and disability (Sareen et al., 2006), and high associated health and social costs (Simon et al., 1995).Studies have shown that the presence of GAD is also associated with significant impairments in occupational and social functioning. For example, over 30% of patients with GAD showed an annual reduction of work productivity of 10% or more compared with 8% of people with major depression. The figure for people with comorbid GAD and depression was over 45% (Wittchen et al., 2000). A large part of the economic cost of anxiety disorders is attributable to the costs of non-medical psychiatric treatment. Patients with GAD have increased numbers of visits not only to primary care doctors but also to hospital specialists, particularly gastroenterologists (Kennedy & Schwab, 1997; Wittchen et al., 2002). This may be a consequence of the distressing somatic symptoms that many people with GAD experience.GAD also carries a considerable cost in personal suffering and difficulties. In the Harvard-Brown Program, one third of patients had never married and unemployment was higher than average (Yonkers et al., 1996). Suicidal ideation and suicide attempts are significantly increased in GAD, particularly in women, and this increase is still greater in the presence of comorbid major depression (Cougle et al., 2009).Panic disorderPanic disorder has considerable impact on the NHS, such as general practitioners (GPs), society as a whole (in terms of sickness and absence from work, labour turnover and reduced productivity), and individuals and families (Sherbourne et al., 1996). The impact in any of these spheres is difficult to measure accurately and there may be an underestimation of the impact, but it is still substantial. A person with panic disorder may experience severe and enduring physical sensations, which may lead them to think that they have a physical illness; it can be difficult for healthcare professionals to provide adequate reassurance that this is not the case, which may lead to multiple consultations. Their economic wellbeing may also be affected (Edlund & Swann, 1987).Obsessive-compulsive disorderOCD is ranked by the WHO in the top ten of the most disabling illnesses by lost income and decreased quality of life (Bobes et al., 2001). The severity of OCD differs markedly from one person to another. While some people may be able to hide their OCD from their own family, the disorder may have a major negative impact on social relationships leading to frequent family and marital discord or dissatisfaction, separation or divorce (Koran, 2000). It also interferes with leisure activities (Antony et al., 1998) and with a person's ability to study or work, leading to diminished educational and/or occupational attainment and unemployment (Koran, 2000; Leon et al., 1995). The social cost (that is the person's inability to fully function in society) has been estimated as US$5.9 billion in 1990, or 70.4% of the total economic cost of OCD (DuPont et al., 1995).Post-traumatic stress disorderSymptoms of PTSD cause considerable distress and can significantly interfere with social, educational and occupational functioning. It is not uncommon for people with PTSD to lose their jobs either because re-experiencing symptoms, as well as sleep and concentration problems, make regular work difficult or because they are unable to cope with reminders of the traumatic event they encounter while at work (Zatzick et al., 1997). The resulting financial problems are a common source of additional stress and may be a contributory factor leading to extreme hardship, such as home-lessness. The disorder has adverse effects on the person's social relationships, leading to social withdrawal. Problems in the family and break-up of significant relationships are not uncommon.People with PTSD may also develop further, secondary psychological disorders as complications of the disorder. The most common complications are:the use of alcohol, drugs, caffeine or nicotine to cope with their symptoms, which may eventually lead to dependencedepression, including the risk of suicideother anxiety disorders, such as panic disorder, which may lead to additional restrictions in their life (for example, inability to use public transport).Other possible complications of PTSD include somatisation, chronic pain and poor health (Schnurr & Green, 2003). People with PTSD are at greater risk of physical health problems, including circulatory and musculoskeletal disorders, and have a greater number of medical conditions than those without PTSD (Ouimette et al., 2004).The course and prognosis of all common mental disorders are affected by a range of social factors, a number of which have been already discussed above. However, a range of factors related to social exclusion have a specific effect on access to services. This means that a number of groups may have particular problems accessing services including: those involved with the criminal justice system; homeless or precariously housed people; travelling communities; some groups of younger people (including those who have been in care as children and adolescence); people who misuse drugs and alcohol; and those of uncertain immigration status.2.2.6. Economic costsThe ONS report (McManus et al., 2009) makes the point that although common mental health disorders are usually less disabling than major psychiatric disorders such as psychosis, their greater prevalence means that the cumulative cost to society is vast. Mixed anxiety and depression has been estimated to cause one fifth of days lost from work in Britain (Das-Munshi et al., 2008). Even before the recent expansion of the European Union, it was estimated that work-related stress affected at least 40 million workers in its then 15 member states and that it cost at least €20 billion annually. In the UK, it has been suggested that over 40 million working days are lost each year due to stress-related disorders (European Agency for Safety and Health at Work, 2000).Costs of depressionDepression is associated with high prevalence and treatment costs, and as stated above is considered one of the most important risk factors for suicide (Knapp & Illson, 2002). Furthermore, depression has a large impact on workplace productivity. As a result, depression places an enormous burden on both the healthcare system and the broader society.Depression has a major financial impact on health and social services and the wider economy. A review was conducted by the King's Fund in 2006 to estimate mental health expenditure including depression in England for the next 20 years, to 2026 (McCrone et al., 2008). The study estimated the total cost of services for depression in England in 2007 to be £1.7 billion, while lost employment increased this total to £7.5 billion. Based on the estimate that 1.45 million people would have depression in 2026, the authors estimated that the total service cost would be £12.2 billion when accounting for prescribed drugs, inpatient care, other NHS services, supported accommodation, social services and lost employment in terms of workplace absenteeism.One of the key findings from the cost-of-illness literature is that the indirect costs of depression far outweigh the health service costs. A study by Thomas and Morris (2003) suggested that the effect on lost employment and productivity was 23 times larger than the costs falling to the health service. Other studies have also supported these findings. Based on UK labour-market survey data, Almond and Healey (2003)estimated that respondents with self-reported depression/anxiety were three times more likely to be absent from work (equivalent to 15 days per year) than workers without depression/anxiety. Furthermore, a US-based study suggests that depression is a major cause of reduced productivity at work, in terms of ‘work cut-back days’ (Kessler et al., 2001). This reduced workplace productivity is unlikely to be adequately measured by absenteeism rates and further emphasises the ‘hidden costs’ of depression (Knapp, 2003). A recent study conducted by the the Centre for Economic Performance's Mental Health Policy Group estimated that the total loss of output (in terms of lost productivity, absenteeism from work or benefits received) due to depression and chronic anxiety is some £12 billion per year (Layard, 2006).Other intangible costs of illness include the impact on the quality of life of people with depression and their families and carers. Certainly, the cost-of-illness calculations presented here and in Table 2 show that depression imposes a significant burden on individuals and their families and carers, the healthcare system and the broader economy through lost productivity and workplace absenteeism. Furthermore, it is anticipated that these costs will continue to rise significantly in future years. Therefore, it is important that the efficient use of available healthcare resources is used to maximise health benefits for people with depression.Table 2Summary of cost of illness data for depression and anxiety.Costs of anxiety disordersAnxiety disorders place a significant burden on individuals as well as on the healthcare system. Although direct comparisons between studies are difficult to make due to variations in country, health services and year of interest, economic cost has been estimated at over US$40 billion (Andlin-Sobocki et al., 2005; see Table 2 for further information). Estimated costs are incurred by healthcare resource utilisation such as mental health services, medication, hospitalisation, nursing homes and outpatient visits, productivity losses and, to a lesser extent, by provision of other services such as criminal justice services, social welfare administration and incarceration, as well as family care-giving (0.8%) (Andlin-Sobocki et al., 2005).Total healthcare cost is not the only important outcome to consider when investigating cost. Marciniak and colleagues (2005) found that the total medical cost per person with any anxiety disorder was estimated at US$6,475 in 1999. More specifically, when looking at GAD alone, the figure increased to US$2,138 when controlling for demographics and other disease states. This increased cost may be due to factors such as increased outpatient mental health service use or medical specialist service use. Furthermore, people with anxiety tend to miss more days of work or have a short-term disability than controls (Marciniak et al., 2004).Anxiety disorders are associated with a wide range of comorbidities, which result in a substantial increase in the total healthcare costs. Souêtre and colleagues (1994) estimated the total direct and indirect costs incurred by people with GAD with and without comorbidities using data on 999 people participating in a French cross-sectional study. Controlling for confounding variables, the prevalence of healthcare utilisation in terms of hospitalisation, laboratory tests and medications, and the respective medical costs were found to be significantly higher in people with GAD and other comorbidities than those without comorbidities. Moreover, comorbidities were associated with increased absenteeism from work. In particular, comorbid depression (Marciniak et al., 2005; Wetherell et al., 2007; Zhu et al., 2009) and physical pain (Olfson & Gameroff, 2007; Zhu et al., 2009) have been found to have a significant impact on treatment costs incurred by people with GAD.Costs of post-traumatic stress disorderIn 2003 to 2004, social and welfare costs of claims for incapacitation and severe disablement from severe stress and PTSD amounted to £103 million, which is £55 million more than was claimed 5 years previously (Hansard, 2004). Therefore, PTSD presents an enormous economic burden on families, the national health services and society as a whole.Go to:2.3. TREATMENTA number of treatments exist for common mental health disorders. However, because this guideline is predominantly interested in the identification and assessment of these conditions, the treatments will only be discussed briefly. For more information, please see the relevant guideline (see Section 2.1).2.3.1. Pharmacological treatmentsDepressionThere is a wide range of antidepressant drugs available for people with depression. These can be grouped into tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors and a range of other chemically unrelated antidepressants (British National Formulary [BNF] 59; British Medical Association & the Royal Pharmaceutical Society of Great Britain, 2010).Generalised anxiety disorderPlacebo-controlled trials indicate that a wide range of drugs with differing pharmacological properties can be effective in the treatment of GAD (Baldwin et al., 2005). In recent years, antidepressant medications such as SSRIs have been increasingly used to treat GAD (Baldwin et al., 2005).Conventional antipsychotic drugs and the newer ‘atypical’ antipsychotic agents have also been used in the treatment in GAD, both as a sole therapy and as an ‘addon’ to SSRI therapy when the latter has proved ineffective (Pies, 2009). However, the greater side-effect burden of antipsychotic drugs means that presently their use is restricted to people with refractory conditions, with prescribing being guided by secondary care physicians.Panic disorderThere is evidence to support the use of pharmacological intervention in the treatment of panic disorder, in particular with SSRIs. When a person has not responded to an SSRI, other related antidepressants may be of benefit. There is little good evidence to support the use of benzodiazepines. In contrast to a number of other depressive and anxiety disorders, there is little evidence to support the use of pharmacological and psychological interventions in combination.Obsessive-compulsive disorderPharmacological investigations have demonstrated effectiveness in OCD, in particular with SSRIs and related antidepressants (Montgomery et al., 2001; Zohar & Judge, 1996) for moderate to severe presentations, especially if the problem has a chronic course; this may be in combination with psychological interventions.Post-traumatic stress disorderAt present there is no conclusive evidence that any drug treatment helps as an early intervention for the treatment of PTSD-specific symptoms (NCCMH, 2005). However, for people who are acutely distressed and may be experiencing severe sleep problems, consideration may be given to the use of medication. Drug treatments for PTSD should not be used as a routine first-line treatment for adults (in general use or by specialist mental health professionals) in preference to a trauma-focused psychological therapy. Drug treatments should be considered for the treatment of PTSD in adults when a person with the disorder expresses a preference not to engage in a trauma-focused psychological treatment. The SSRI paroxetine is the only drug with a current UK product licence for PTSD.2.3.2. Psychological treatmentsDepressionEffective psychological treatments for depression identified in the NICE Depression guideline (NICE, 2009a) include: cognitive behavioural therapy (CBT), behavioural activation, interpersonal therapy (IPT),behavioural couples therapy and mindfulness-based cognitive therapy. For moderate to severe disorders these are often provided in conjunction with antidepressants. For subthreshold and milder disorders, structured group physical activity programmes, facilitated self-help and CCBT are effective interventions.Generalised anxiety disorderCognitive and behavioural approaches are the treatments of choice for GAD. People who have moderate to severe disorder, particularly if the problem is long-standing, should be offered CBT or applied relaxation. For those with milder and more recent onset disorders, two options are available: facilitated ornon-facilitated self-help based on CBT principles and psychoeducational groups also based on CBT principles.Panic disorderCognitive and behavioural approaches are again the treatments of choice for panic disorder. People who have a moderate to severe GAD, particularly if it is longstanding, should receive between 7 and 14 hours of therapist-provided treatment over a 4-month period. For those with milder and more recent onset GAD, facilitated or non-facilitated self-help based on CBT principle are efficacious treatments.Obsessive-compulsive disorderCBT is the most widely used psychological treatment for OCD in adults (Roth & Fonagy, 2004). The main CBT interventions that have been used in the treatment of OCD are exposure and response prevention (ERP) (for example, Foa & Kozak, 1996; Marks, 1997), different variants of cognitive therapy (Clark, 2004; Freeston et al., 1996; Frost & Steketee, 1999; Krochmalik et al., 2001;Rachman, 1998, 2002 and 2004; Salkovskis et al., 1999; van Oppen & Arntz, 1994; Wells, 2000), and a combination of ERP and cognitive therapy (see Kobak et al., 1998; Roth & Fonagy, 2004). ERP and cognitive therapy have different theoretical underpinnings, but may be used together in a coherent package.Post-traumatic stress disorderGeneral practical and social support and guidance about the immediate distress and likely course of symptoms should be given to anyone following a traumatic incident. Trauma-focused psychological treatments are effective for the treatment of PTSD, either trauma-focused CBT or eye movement desensitisation and reprocessing (EMDR). These treatments are normally provided on an individual outpatient basis and are effective even when considerable time has elapsed since the traumatic event(s).2.3.3. Current levels of treatment of common mental health disordersIt is concerning that, according to the 2007 ONS survey (McManus et al., 2009), only one quarter (24%) of people with a disorder were receiving any treatment for it in the week prior to interview. Treatment received by that 24% was mostly in the form of medication: 14% were taking psychoactive medication only, 5% were in receipt of counselling or therapy and 5% were receiving both medication and counselling/therapy.Use of healthcare servicesOf the people reporting a common mental health disorder in the ONS survey (McManus et al., 2009), 39% had used some type of healthcare service for a mental or emotional problem within the last year, compared with 6% of men and women without a disorder.Primary care servicesGeneral practice services were the most common healthcare service used in the ONS survey. A total of 38% of people with a common mental health disorder contacted their GP for help. Depression and phobias were associated with the highest use of healthcare services for a mental or emotional problem (both 67%), and mixed anxiety and depression was associated with the lowest use (30%) (McManus et al., 2009).Community care servicesAll respondents in the ONS survey (McManus et al., 2009), were asked about community and day care services used in the past year. Community and day care services were used less than healthcare services. Those with phobias made most use of community or day care services (49%), while mixed anxiety and depressive disorder was associated with the lowest rate of community or day care service use (12%).SummaryIn summary, common mental health disorders are associated with a range of symptoms that can lead to significant impairment and disability, and high costs both for the individual with the disorder and for society as a whole.Effective treatments are available that differ depending on the disorder. As a result, early detection, assessment and intervention are key priorities for any healthcare system. This guideline, which is focused on primary care, will provide recommendations on how to best identify and assess common mental health disorders and the key indicators for treatment in order to help improve and facilitate access to care, and the route through care.Go to:2.4. IDENTIFICATION, ASSESSMENT AND PATHWAYS TO CAREGoldberg and Huxley (1992) described a useful model within which to consider issues relating to the identification, assessment and pathway to psychiatric care for people with a common mental health disorder (see Figure 1). They identified five levels of care, with ‘filters’ between them relating to the behaviour of those with the disorders and the behaviours of the healthcare practitioners with whom they came into contact, emphasising that only a small proportion of people with a mental disorder receive specialist psychiatric care.Figure 1Levels and filters model of the pathway to psychiatric care (adapted from Goldberg & Huxley, 1992).The prevalence rates given above are taken from the original model and relate to proportions found in epidemiological surveys conducted before 1980. The Level 1 figures refer to all psychiatric disorders in the population, including psychotic and organic disorders, so the prevalence rates are somewhat higher than those given for the common mental health disorders in Section 2.2.2 above.For Filter 1 (the decision to consult a primary care physician), the key individual is the patient themselves. Level 2 refers to all psychiatric disorders in general practice, even if the GP has not diagnosed the disorder. Filter 2 refers to the detection and diagnosis of psychiatric disorder; Level 3 is ‘conspicuous’ or diagnosed psychiatric disorder within primary care. The third filter is the process of referral to secondary care, and Level 4 and Level 5 refer to the small proportion of patients with illnesses severe enough to need specialist secondary care.2.4.1. Increasing access to careThere are significant concerns about a number of barriers to access to care. These may include stigma (both cultural and self, and stigmatisation), misinformation or cultural beliefs about the nature of mental disorder, social policy or other approaches that limit access to services.Presentation of people with a common mental health disorder to primary careOf the 130 cases of depression (including mild cases) per 1000 population, only 80 will consult their GP. The stigma associated with mental health problems generally (Sartorius, 2002), and the public view that others might view a person with depression as unbalanced, neurotic and irritating (Priest et al., 1996), may partly account for the reluctance of depressed people to seek help (Bridges & Goldberg, 1987). The most common reasons given for reluctance to contact the family doctor include: did not think anyone could help (28%); a problem one should be able to cope with (28%); did not think it was necessary to contact a doctor (17%); thought problem would get better by itself (15%); too embarrassed to discuss it with anyone (13%); and afraid of the consequences (for example treatment, tests, hospitalisation or being sectioned under the Mental Health Act; 10%) (Meltzer et al., 2000).Most anxiety disorders are found more frequently in primary care than in the community except for social anxiety disorder and agoraphobia, both of which involve avoidance of public places such as doctors' surgeries (Bushnell et al., 2005; Oakley Browne et al., 2006; see Table 3). However, even when people with anxiety and depression do consult their GP, their disorder often goes unrecognised, partly because many do not present their psychological symptoms overtly.Table 3Twelve-month prevalence of anxiety disorders in New Zealand (Oakley Browne et al., 2006).Dowrick and colleagues (2010) carried out systematic reviews to identify groups for whom there are particular problems accessing mental health services, and to identify systems for promoting access. Poorer access to care has been found to be associated with lower social class, geographical location, ethnic minority groups, the presence of sensory or other impairments, the presence of learning difficulties, and particular demographic factors including age and gender (for example, older people or younger men).This guideline seeks to identify service developments or changes that may be specifically designed to promote access, both for the general population and for specific outreach groups (see Chapter 4). Particular areas include: community outreach; providing education and information concerning the nature of mental disorder; and new and adapted models of service delivery, which focus on the needs of black and minority ethnic (BME) groups and older people.2.4.2. IdentificationRecognition of depressionOf the 80 people with depression per 1000 population who do consult their GP, 49 are not recognised as depressed, mainly because most such patients are consulting for a somatic symptom and do not consider themselves mentally unwell despite the presence of symptoms of depression (Kisely et al., 1995). People who present with somatic symptoms are especially unlikely to be recognised (Kisely et al., 1995). GPs tend to be better at recognising more severe forms of the disorder (Goldberg et al., 1998; Thompson et al., 2001). With 50% of people with depression never consulting a doctor, 95% never entering secondary mental health services, and many more having their depression going unrecognised and untreated, this is clearly a problem for primary care.Recognition of anxiety disordersAnxiety symptoms are also often not recognised by primary healthcare professionals because, once again, patients may not complain of them overtly (Tylee & Walters, 2007). Cases of anxiety are especially likely to be missed when people frequently attend with multiple symptoms, despite reassurance. Instead, these symptoms are often characterised as possible symptoms of cardiovascular, respiratory, gastrointestinal, neurological or musculoskeletal disease (Blashki et al., 2007).For many people with a common mental health disorder, stigma and avoidance may contribute to under-recognition of their condition. Pessimism about possible treatment outcomes may further contribute to this. However, GPs themselves can contribute to the under-recognition of these conditions.Consultation skillsGPs are immensely variable in their ability to recognise depressive illnesses, with some recognising virtually all of the patients found to be depressed at independent research interview, and others recognising very few (Goldberg & Huxley, 1992; Üstün & Sartorius, 1995).The communication skills of the GP make a vital contribution to determining their ability to detect emotional distress, and those with superior skills allow their patients to show more evidence of distress during their interviews thus facilitating detection (Goldberg & Bridges, 1988; Goldberg et al., 1993).According to Goldberg and colleagues (1980a and 1980b), ten behaviours are associated with greater detection. These include factors such as making eye contact, having good interview skills, asking well-formulated questions and focusing on more than just a symptom count. Attempts to improve GP behaviour have been successful (Ostler et al., 2001; Tiemens et al., 1999), although results are mixed (Kendrick et al., 2001; Thompson et al., 2000) and interventions sometimes fail to impact on patient outcomes despite changes in clinician behaviour (Gask et al., 2004).Case identificationThe fact that common mental health disorders often go undiagnosed among primary care attenders has led to suggestions that clinicians should systematically screen for hidden disorders. However, general screening is not without its problems and is currently not recommended in most countries, including the UK. Instead, targeted case identification, which involves screening a smaller group of people known to be at higher risk based on the presence of particular risk factors, may be a more useful method of improving recognition of psychological disorders in primary care.Whooley and colleagues (1997) found that two questions were particularly sensitive in identifying depression:During the last month, have you often been bothered by feeling down, depressed or hopeless?During the last month, have you often been bothered by having little interest or pleasure in doing things?The current NICE Depression guideline (NICE, 2009a) recommends that GPs be alert to possible depression in at-risk patients and consider asking the above Whooley questions when depression is suspected. If the person screens positive, further follow-up assessments should then be considered. Currently, no equivalent Whooley questions have been recommended for anxiety.The view of the GDG for this guideline was that the development of separate case identification questions for each type of anxiety disorder would very likely be impractical and have no utility for routine use in primary care. The preference was to explore the possibility of a small number of case identification questions with general applicability for a range of anxiety disorders. A potentially positive response would then prompt a further assessment. This is dealt with in Chapter 5.2.4.3. AssessmentSince April 2006, the UK general practice contract Quality and Outcomes Framework Guidance for GMS Contract (QOF) has incentivised GPs for measuring the severity of depression at the outset of treatment in all diagnosed cases, using validated questionnaires (British Medical Association & NHS Employers, 2008). The aim is to improve the targeting of treatment of diagnosed cases, particularly antidepressant prescribing, to those with moderate to severe depression, in line with the NICE guidelines.A number of assessment tools have been identified as potentially useful for the assessment. The NICEDepression guideline (NICE, 2009a), for example, recommends the use of the nine-item Patient Health Questionnaire (PHQ-9) (Spitzer et al., 1999), the depression scale of the Hospital Anxiety and Depression Scale (HADS) (Zigmond & Snaith, 1983) and the Beck Depression Inventory, 2nd edition (BDI-II) (Beck, 1996; Arnau et al., 2001). The rationale for using such instruments is that doctors' global assessments of severity do not agree well with valid and reliable self-report measures of severity in terms of cut-off levels for case identification (Dowrick, 1995; Kendrick et al., 2005; Lowe et al., 2004;Williams et al., 2002), which can result in over-treatment of mild cases and under-treatment of moderate to severe cases (Kendrick et al., 2001 and 2005).However, the QOF guidance, again in line with NICE guidance, also recommends that clinicians consider the degree of associated disability, previous history and patient preference when assessing the need for treatment rather than relying completely on the questionnaire score (British Medical Association & NHS Employers, 2006). This is especially important given that people with mental illness vary in the pattern of symptoms they experience, their family history, personalities, pre-morbid difficulties (for example, sexual abuse), physical illness, psychological mindedness, current relational and social problems and comorbidities – all of which may affect the outcomes of any intervention (for example, Cassano & Fava, 2002; Ramachandani & Stein, 2003).Currently, evidence exists that points practitioners in the direction of well-validated tools. As a result, this guideline will not attempt to recommend specific tools because preferences vary between practices. Instead, this guideline will focus on ways to improve the assessment process, specifically, how to assess the nature and severity of a common mental health disorder, factors that may influence referral for treatment, routine outcome monitoring (ROM) and risk assessment.2.4.4. Pathways to careGiven the complexity of healthcare organisations and the variation in the way care is delivered (inpatient, outpatient, day hospital, community teams and so on), choosing the right service configuration for the delivery of care to specific groups of people has gained increasing interest with regard to both policy (for example, see Department of Health, 1999) and research (for example, evaluating day hospital treatment [Marshall et al., 2001]). Research using randomised controlled trial (RCT) designs has a number of difficulties; for example, using comparators such as ‘standard care’ in the US makes the results difficult to generalise or apply to countries with very different types of ‘standard care’.Stepped careCurrently, much of the UK mental health system is organised around the principles of stepped care. Stepped care (Scogin et al., 2003) is a framework that is increasingly being used in the UK to provide a structure for best-practice clinical pathways to care. It is designed to increase the efficiency of service provision with an overall benefit to patient populations. The basic principle is that patients presenting with a common mental health disorder will ‘step through’ progressive levels of treatment as necessary, with the expectation that many of these patients will recover during the less intensive phases. High-intensity treatments are reserved for patients who do not benefit from low-intensity treatments, or for those who can be accurately predicted not to benefit from such treatments. Thus, stepped care has the potential for deriving the greatest benefit from available therapeutic resources (Bower & Gilbody, 2005) and has been recommended in a number of NICE guidelines including Depression (NICE, 2009a) and Generalised Anxiety Disorder and Panic Disorder (With or Without Agoraphobia) in Adults (NICE, 2011a).A potential disadvantage of a stepped-care approach is that patients who do not benefit from low-intensity treatments may still have to undergo such treatments before a successful outcome is achieved. To maximise the efficiency of care delivery, patients who can be predicted as unlikely to respond to less intensive treatments ideally should be referred straight to higher levels; that is, care should be ‘stratified’ to an extent (Bower et al., 2006). However, prognostic evidence to support such decisions is currently lacking.Improving Access to Psychological Therapies programmeIn 2004 the economist Richard Layard made the case for a major expansion in the availability of psychological treatments, which he suggested could bring a significant reduction in the welfare benefits bill and increased tax contributions of those helped back to work. In 2006 the government established the Improving Access to Psychological Therapies (IAPT) programme, based heavily on the stepped-care approach. Clark and colleagues (2009) reported on the initial success of two demonstration sites in Newham and Doncaster, and the IAPT programme proposes a phased national roll-out by 2013 (to date, over 50% of Primary Care Trusts have an IAPT service). Self-referral to IAPT services is also actively encouraged, with emerging evidence to suggest that it increases access for vulnerable groups, such as BME groups to psychological interventions (Clark et al., 2009). In addition, an analysis of the first full year of operation of the first wave of roll-out sites (October 2008 to September 2009) has recently been published (Glover et al., 2010). Anonymous patient-level data were collected from 32 sites with the aim of evaluating whether the ‘commitments relating to accessibility, the provision of NICE-approved therapies and detailed outcome monitoring were progressing appropriately’. The authors concluded that the large amount of outcome data collected is a remarkable achievement, although there are some limitations and shortcomings that need to be addressed. For example, the analysis suggests that the diagnostic coding frame needs to be extended to include panic disorder and more research needs to be conducted to establish how reliable diagnoses can be obtained. Furthermore, in terms of equality of access, the authors state that ‘older people and men appeared under-represented in relation to expectation based on the patterns of morbidity shown by the psychiatric morbidity survey. The position for people with disabilities is not recorded at all in most sites, making it difficult to see how commissioners and providers can discharge their responsibilities to promote access to services for disabled people under disability discrimination legislation.’ Also, ‘after allowing for all other relevant factors for which data were available, Black people were significantly less likely to receive any treatment or to recover on either the two-scale or the three-scale makers, Asians were less likely to receive high intensity treatment (CBT or counselling), and both were significantly less likely to receive CBT’. More generally, with regard to treatment received, there was evidence to suggest that more needs to be done to ensure that the treatment given for specific diagnoses is aligned to that recommended in NICE guidelines.

Despite declines in smoking rates, number of smokers and cigarettes rises.Of all lifestyle behaviours, smoking caused the most deaths in the last century.In the context of smoking being pleasurable: a stimulating or relaxing activity that can act as a social lubricant, or an anti-social shield signalling ‘stay away’— it seems that ‘cigarette culture’ had a measurable impact on particular populations of people:Smoking is more common in people who are vulnerable to suggestions, cultural motifs, as well as those who self-separate— such as Schizophrenic populations (estimates up to ninety percent);As well as populations that are atypical when it comes to: self-regulation, motivation/reward-feedback loops and circadian rhythms— such as mood-disorders especially bi-polar disorders, or ADHD.In terms of adverse health outcomes: asthmatics, developing babies, military veterans, young women (damage susceptibility suspected), LGBT, or low socio-economic backgrounds (rural or inner-city areas; poor/low education; manual, high-stakes or otherwise monotonous labour with minimal or fixed social interaction patterns etc.), and low(er) social status (e.g. low caste, or even university rank), are at increased risk.Moreover, young people which includes children, from poorer regions and developing nations, seem to be targeted by ‘Big Tobacco’:According to a WHO survey of smoking trends in youths, around half of the 151 countries surveyed showed that a similar number of girls and boys smoked.Strategic Marketing is used to lure consumers with misleading categories, such as "light" or "low tar" cigarettes, which helps expand their customer base: More women than men smoke "light" cigarettes (63% versus 46%), often in the mistaken belief that "light" means "safer";— The things is, "light" smokers may engage in compensatory smoking, inhaling more deeply and more frequently to absorb the ‘right’ amount of nicotine.Another such example would be menthol cigarettes— more than 1/3 of LGBT smokers report that they usually smoke menthol cigarettes, which are easier to use and harder to quit.America’s new tobacco crisis: The rich stopped smoking, the poor didn’tMarketing of menthol cigarettes and consumer perceptionsTobacco smoking and blindness - The ignored epidemicStudy: Young Women Now Have Higher Rates for Lung Cancer Than Men WorldwideWhy Are LGBTQ Americans 33 Percent More Likely to Smoke Than Straight People?An 'epidemic of nicotine addiction' among kids prompts FDA to get tough on e-cigarette makers"I did not intend to stop. I just could not stand cigarettes any more." A qualitative interview study of smoking cessation among the elderly — perhaps, the lack of social regulation of people high on schizophrenic traits (perhaps: due to paranoia and other isolating as well as antisocial behaviour) makes them uniquely vulnerable to cultural motifs...Sweden has managed to effectively reduce smoking as well associated cancers, without prohibition.Only 11% of the total Swedish population (8% of men and 10% of women) smoked daily in 2016.Swedish males reportedly have the lowest rate of lung cancer and lowest rate of tobacco-related morality in Europe.Smoking trends in Europe reveal an interesting pattern in the context of the given country’s sociopolitical climate as well as relative economic status:Smoking related death (malignant cancer of trachea, bronchus & lung) by gender in select European countries (share of all deaths percentage—total, male, female; & rate of death by 100, 000: male, female):Sweden — 4.1, 4.2, 4.0;—————— DR: 41.4, 35.1Denmark — 6.9, 7.1, 6.7;—————— DR: 76.0, 60.2Iceland — 6.8, 6.3, 7.4;—————— DR: 61.4, 61.9Finland — 4.2, 5.6, 2.9;—————— DR: 60.6, 24.2UK — 6.0, 6.6, 5.4; ————————— DR: 71.9, 49.7Germany — 5.0, 6.5, 3.6; —————- DR: 73.0, 33.6Latvia — 3.3, 5.5, 1.3; ———————— DR: 103.6, 15.2Roumania — 4.0, 5.9, 1.9;—————— DR: 95.8, 21.8Turkey — 5.7, 8.9, 1.9; ———————DR: 107.4, 16.9For example: Turkey seems to have a large difference in smoking behaviour by gender, especially compared to Sweden and Iceland. [1]According to macrotrends, countries that share a similar smoking rate (excluding smokeless tobacco use) with Turkey, are the following:Source: Turkey Smoking Rate 2000-2020Russia has the largest adult smoking population in Europe.Among Russians aged 19 to 44 years, 7 in 10 men smoke and 4 in 10 women smoke.Russia sees half a million premature male deaths per year— and circulatory disease (the biggest cause of death) kills at about 4 times the rate that it does in the UK, for both men and women.While the contribution of alcohol to the excess mortality rates is well-rehearsed, tobacco consumption, which accounts for 150,000 of the excess male deaths annually, receives less attention.However, while male smoking prevalence, which stood at 61 percent in 1995, has declined recently (58.3 % in 2016), female smoking has increased from around 9 percent, in 1995, to around 14 percent in 2014.Among males, smoking prevalence has remained at very high levels across cohorts, and with nearly identical life-course trajectories, peaking at around 75 percent for those entering their 20s (i.e. around the age of compulsory military service). Our data suggest that peak prevalence rates have been falling slightly over time, starting in the 1970 cohort.In contrast, for females, smoking prevalence has increased in each successive cohort, with the steepest increases occurring among women born in the 1970s. [2]Moreover, around 15 percent of Russia’s youth smoke (-d in 2016).The European countries with the highest smoking and tobacco use prevalence among youth are: Latvia, Lithuania, Italy, Roumania and Ukraine—with Italy, Hungary, Bulgaria and France having a higher prevalence among girls than boys. [3]Sweden was the only European country to achieve the WHO goal of less than 20% daily smoking prevalence among adults by year 2000.However, Sweden has a high level of use of smokeless tobacco, specifically a moist snuff product called 'snus'.—Germany, a case study: East—WestThe collapse of Germany led to the separation of Germany.After Germany was divided into two parts, East Germany built the Berlin Wall to prevent its citizens from fleeing to the west. The wall physically divided the country into eastern communism and western democracy.The Berlin Institute for Population and Development concluded in a recent study that half of all Germans believe there are more differences between “Ossis” (easterners) and “Wessis” (westerners) than commonalities. [4]The eventual reunification of Germany, has allowed for some of these differences to dissipate. However, states in the former west continue to be considerably richer than those in the former east, which may be due to:Wages in the east continuing to be lower: at €2,800 (2,576 USD) a month, people earn about two-thirds of the average wage in the west;Property in the east being only worth half as much in the west;Cultural factors, such as: owning property generally being taboo in former East Germany, means that families have/had less to pass on to their children.The risk of an east German slipping into poverty is about 25% higher than that of a west German.A study on tobacco consumption, reports on this East-West dynamic:Since the reunification 25 years ago, East Germans have experienced remarkable mortality improvements.Among women, the life expectancy difference has practically disappeared, to 0.1 years in 2013; among men, the gap narrowed to 1.2 years in 2013.”However, the 2017 study suggests that this mortality advantage, of the East-German 50- to 69-year-old age group, will diminish since the mortality improvement in the East in comparison with the West, is suppressed by the increasing prevalence of cigarette smoking!Past smoking behaviours first allowed East German women to reach a lower mortality level than women in the West. Contemporary smoking habits are projected to again reverse the difference within the next 20 years.Because smoking prevalence among women in the East increased after reunification, the low-mortality success story of East German women is anticipated to end as they return to higher overall mortality.This study gives another shocking example of how enduring the consequences of changing smoking habits are.Mainly younger East German cohorts that were exposed to the post-reunification tobacco campaigns and formerly unknown cigarette advertisements will experience higher mortality from smoking-related diseases. Source: The German East-West Mortality Difference: Two Crossovers Driven by SmokingAcross the world, tobacco consumption — like waterOn 31st May every year since 1988, the World Health Organization (WHO), together with its 23 global partners, observes ‘World No Tobacco Day’.Throughout Southeast Asia, East Asia (mainly Taiwan), and the Indian subcontinent—chewing tobacco is popular alternative to cigarettes:Paan is a preparation combining betel leaf with areca nut, and optionally, little pastes of lime, and some sweets.The origin and diffusion of betel chewing originates from and is closely tied to the Neolithic expansion of the Austronesian peoples.It is chewed for its stimulant and psychoactive effects. After chewing it is either spat out or swallowed.Tobacco became an optional addition to paan, soon after its introduction from the Western Hemisphere.Health risk: Studies suggest that areca-nut paan with and without tobacco increase oral cancer risk by 9.9 and 8.4 times, respectively.However, Paan is losing its appeal to farmers because of falling demand, as consumers prefer chewing tobacco formulations such as gutka over paan.Gutka is a chewing tobacco preparation made of crushed areca nut, tobacco, catechu, paraffin wax, slaked lime and sweet or savoury flavourings.Approx. 40% of the tobacco consumed in India is in smokeless form.The most important carcinogens in chewing tobacco are a class of compounds called Nicotine-derived Nitrosamines. These are to a certain extent produced by the tobacco plant itself, and are amplified by the drying and curing process.As tobacco contains a lot of tar products, which consists of a lot of poly-aromatic hydrocarbons (known carcinogens), means that chewing tobacco causes natural occurring tar products to be ingested—though it is still worse to burn these products and inhale into the lungs.However, Sweden has the highest tobacco use in the West and the lowest cancer rate— since they mainly use snus, which is pasteurised— not fire cured.Mu‘assel (Arabic: معسل‎, meaning "honeyed"), is a syrupy tobacco mix containing molasses (black treacle) and vegetable glycerol which is smoked in a hookah, a type of water-pipe.“Shisha”— as it was known before it spread to the Middle East, with Hookah originating in India — is the Hindi and ancient Sanskrit word for “Glass”.In earlier times, hookahs were used by the people of the Indian subcontinent to smoke opium or hashish. Flavoured tobacco (Mu’assel) first started being used in the beginning of 20th century.In many places in the Arab world, the smoking of shisha is a part of traditional culture, and is considered a social custom.However, hookah smoke contains high levels of toxic compounds, including tar, CO, heavy metals and cancer-causing chemicals.Smoking shisha involves burning wood, coal or charcoal to heat up specially prepared tobacco (shisha).An hour of smoking a shisha contains an average of 200 puffs while a single cigarette is around 20 puffs.Tobacco is derived from the leaves of the genus Nicotiana— a plant indigenous to the Americas; Tobacco was first discovered by the native people of Meso- and South-America:Experts believe that the tobacco plant began growing in the Americas in 6000 BCE. In 1 BCE, Americans began finding ways to use tobacco through smoking, chewing, and hallucinogenic enemas.The use of tobacco in religious and public ceremonies was nearly universal throughout the Americas among the various tribes of Native Americans.Its use as a medicine was also universal. The European explorers reported back that tobacco, in its various forms was used to cure almost every ailment known to man.By 1 CE, tobacco was reported to be “nearly everywhere” in the Americas. In 1492, Christopher Columbus set foot in the Americas and was greeted by natives who offered fruits, spears, and tobacco as gifts. He described the tobacco as “pungent dried leaves” and discarded them. [5]So in the Americas, tobacco had already been in use, by the time European settlers arrived, to spread the practice in Europe, where it became popular.However, tobacco was not universally accepted by Europeans when it was first brought back by the explorers. Many found the breathing in of smoke to be peculiar at best and possibly dangerous. Others objected to being exposed to smoke created by the tobacco user.King James I of England issued a strongly-worded description of his disdain for tobacco and smokers, the Counterblast to Tobacco published in 1604:It concludes by saying that smoking is "a custome lothsome to the eye, hatefull to the nose, harmefull to the braine, daungerous to the Lungs, and in the blacke stinking fume thereof, nearest resembling the horrible Stigian smoke of the pit that is bottomelesse." (Dunhill, p.3) [6]FACT—US-African slaves initially used to work in tobacco fields— not on cotton plantations.After enslaved Native American laborers began to die due to exposure to disease, European powers began purchasing enslaved Africans, who became their primary labor source.Britain sent their first slave ships to the British West Indies to work on tobacco plantations and then later sugarcane plantations. [7][8]On September 30, 1619, John sent off a letter to the English ambassador to the Netherlands, Sir Dudley Carleton. “All our riches for the present doe consiste in Tobacco,” he wrote. “Our principall wealth (I should have said) consisteth in servants.”The laborers were mostly white then.But by 1719, John would have written, “Our principal wealth consists in African slaves,” planting tobacco on plantations along the James, York, Rappahannock, and Potomac Rivers in Virginia. [9]Incidentally, the first virus to be discovered was the Tobacco mosaic virus:In 1892, Dmitry Ivanovsky used one of these filters to show that sap from a diseased tobacco plant remained infectious to healthy tobacco plants despite having been filtered.Martinus Beijerinck called the filtered, infectious substance a "virus" and this discovery is considered to be the beginning of virology. [10]**And, tentatively: there seems to be evidence (from a french study) that smokers could be better protected than others from the coronavirus, as “nicotine blocks the viruses docking sites” — (The French scientist has ties to the tobacco industry though). However, another study (US), suggests that “nicotine, in fact, stimulates the cell receptors, meaning that viruses have even better opportunities to penetrate the cells. This could explain the particularly severe courses of the disease in smokers..”. [11]All in all, it has been suggested that smokers are 4 times less likely to contract COVID-19, but also 14 times more likely to suffer from severe symptoms.**To the contrary, "there are a number of studies out there that have been published that have found that smoking leads to more severe disease, the development of severe disease, and puts people at higher risk for being put on a ventilator, being in an ICU, and for dying," Van Kerkhove, who serves as the COVID-19 technical lead at the World Health Organization, said during a media briefing May 8. WHO: Smoking cigarettes won't protect you from the coronavirusFewer than five per cent of 441 COVID-19 patients who needed to be admitted to an Italian hospital were (active) smokers.The scientists described it as a 'very low' number, given that a quarter of the general population are known to be hooked on cigarettes. Study finds 'very low' number of coronavirus patients are smokersFood for thought: (1) Do you think most people will stop smoking due to covid 19? (2) What country is going to be affected the longest by coronavirus? (3) COVID-19 and smoking: A systematic review of the evidenceBy 1900, there were 300,000 different cigar brands and approximately 3.5 billion cigarettes and 6 billion cigars were sold annually.The Federal Food and Drugs Act of 1906 prohibited the sale of adulterated drugs and required reporting of their content on package labels. Initially, nicotine was on the list of drugs slated to be regulated by the FDA through this Act. Yet, after extensive lobbying from the tobacco industry, nicotine was removed from the list of regulated substances.A report, by french investigator M. Maurisse, on the Switzerland’s tobacco industry, showed that the tobacco industry has double standards: “cigarettes sold in Africa are more toxic than those smoked in Europe.” [12]Every year, Switzerland exports almost as many cigarettes as it does chocolate.Swiss tobacco laws are among the weakest in the world; Its tax regime makes it a very attractive location for international companies.Governments, farmers, and firms collaborated to promote tobacco through the middle of the twentieth century.Starting in the 1950s the Swiss government ended regulatory protection of tobacco and began to regulate the consumption and marketing of cigs. [13]The world's top two cigarette firms — Philip Morris International and British American Tobacco, have strong presences in Lausanne and elsewhere in Switzerland. [14]PMI Inc. is a Swiss-domiciled multinational cigarette and tobacco manufacturing company, with its headquarter located in New York, United States;— Its products are sold in over 180 countries!!Until a spin-off in March 2008, PMI was an operating company of Altria—with Altria arguing that this way, PMI would have more "freedom" =leeway outside the responsibilities and standards of American corporate ownership in terms of potential litigation and legislative restrictions to "pursue sales growth in emerging markets", while Altria focuses on the American domestic market. [15]Although tobacco consumption is decreasing globally, by 2030 the number of smokers in Africa is anticipated to rise by nearly 40% from 2010 numbers— the largest expected increase in the world. [16]BAT has promoted sales of its cigarettes in some of the most fragile, war-torn and unstable countries of Africa and the Middle East, documents seen by the Guardian show.…They also show that BAT made plans to launch in South Sudan just two days before it gained independence from the north after years of destruction from a civil war that left 4 million people displaced.—British American Tobacco in Africa: A Past and Present of Double Standards—Revealed: how British American Tobacco exploited war zones to sell cigarettesChild Labor in Global Tobacco Production: A Human Rights Approach to an Enduring DilemmaAccording to the WHO, ninety percent of tobacco is grown in low to mid-income countries, where four in five smokers live. More than forty percent of the world’s tobacco is produced in China alone, while Brazil, Argentina, Bangladesh, Malawi and Zimbabwe are among the other top producers.Limitations of infrastructure and industry subsidies (for tobacco, in low-income countries) means it is difficult to encourage farmers to switch to other crops.The WHO suggests that higher taxes and prices on tobacco products remain the single most consistent means to reduce global tobacco use— though this (tax administration) is rather difficult to enforce in low-income countries with limited resources.“Tobacco is an expensive crop to grow, but so too are most high-value alternative crops.Recent trends in the organization of the tobacco leaf production and marketing chain, including use of integrated production systems, has expanded these multinational corporations’ control over price and other factors while making farmers increasingly dependent. ““Building new, and hopefully better, support systems for other crops is a clear challenge for diversification programs.It will take time for these systems to emerge, and any successful transition from tobacco will likely be a gradual process.” [17]Modern Tobacco Consumption—a few factsTobacco can be consumed in the form of manufactured cigarettes, cigars, hand-rolled, hookah, vaping, chewable, snuff and spliffs (mixed with marijuana).Cigarettes are smoked by over 1 billion people, of which 80% are men.The highest recorded level of smoking among men in Great Britain was 82% in 1948, of whom 65% smoked manufactured cigarettes.British data suggests that up to one third of adults in routine and manual occupations smoked compared to 13% in managerial and professional occupations. ***Worryingly, lung cancer is affecting more and more people who have never smoked in their lives – in particular, women. However, smoking still accounts for at least 87% of lung cancer deaths.Moreover, over the last few decades, lung cancer survival has barely improved. In 1971-1972, the chance of surviving for 10 years after diagnosis was just 3%, and by 2010-2011, a mere 5%.Lastly, the fertilisers that farmers use to increase the size of their tobacco crops contain the naturally-occurring radionuclide radium and its decay products. [18]“Tobacco manufacturers have been aware of the alpha-radioactivity presence in tobacco smoke since the sixties.” —Polonium_and_Lung_CancerIn the US, smoking kills more citizens than alcohol, road accidents, HIV, guns, and illegal drugs combined.More than ten times as many U.S. citizens have died prematurely from cigarette smoking than have died in all the wars fought by the US.Heavy smokers cut their lifespan by 13 years on average & Smokers who survive to 70 still lose four years of life ...And now, Philip Morris International, has released a statement on its radical decision to create smoke-free-alternatives for tobacco consumption:“We will be far more than a leading cigarette company. We’re building PMI’s future on smoke-free products that are a much better choice than cigarette smoking.Indeed, our vision — for all of us at PMI — is that these products will one day replace cigarettes.” ——Delivering a smoke-free futurechimney sweeps, black crows or black cats—nicotine and the human brainDo you remember trading cards, shiny marbles, or perhaps, ‘Diddl Blätter’? [19]Cigarettes are the single-most traded item on the planet, with approximately 1 trillion being sold from country to country each year.Map is biased for some of the countries with the highest consumption, such as Andorra, Luxembourg and Belgium. These countries are known to sell cigarettes at lower prices than their neighbours, and as such attract foreign buyers. [20]Excerpt: Tobacco smuggling in Montenegro.. “But it is also known for its smuggling routes through the heart of the Balkans, which, during the breakup of the former Yugoslavia, allowed organized crime to thrive.”Italian authorities noted as much in the DIA report. “Montenegro, for a decade, was the real Tortuga of the Adriatic sea,” they wrote, comparing the Balkan state to a Caribbean island notorious for its pirates. “A heaven for illicit trafficking; impunity granted to mobsters… a place where authorities guaranteed the passage of illicitly traded goods.”… Once in Italy, the untaxed cigarettes were sold by the mafia on the black market.However, trading stuff exists not just to be transformed into ash, air and but’ts ..Nicotine reaches the brain within 8 seconds of inhalation.Its somatic effects include increased heart rate and blood pressure, increased alertness, and reduced appetite.Nicotine was found to reduce the speed smokers ‘became bored with a visual re-inforcer (habituation)’— suggesting that smoking seems to both enhance and prolong the pleasure of other activities. ***Although nicotine is an addictive substance, it is actually the tobacco present in nicotine products that is implicated in deadly cancers.In fact, many researchers are beginning to question whether nicotine is truly more harmful than a daily dose of caffeine…Tobacco smoking may delay habituation of reinforcer effectiveness in humans.Thoughts of a smoker —Does cigarette smoking offer any benefits?:Human Nature is very complex, but when humans were able to create, control and use fire to their advantage, that was a major milestone in mankind's progression.The ability to harness and control fire and smoke, basically the control that one gets from the actions of smoking (cigarettes, pipes, cigars), are feeding a primal natural instinct that is inherent in us, and have been since the dawn of mankind.Nicotine is an alkaloid found in the nightshade family of plants (Solanaceae)— predominantly in tobacco. Other members of the nightshades include:Tomato, potato, eggplant (aubergine), and green pepper, all of which contain nicotine in low quantities.Nicotine alkaloids are also found in the leaves of the cacao plant.—Nicotine in food, psychoactive?10 g of eggplant contains about 1 μg of nicotine, while 19.2 g of pureed tomatoes contain the same level of nicotine. It takes 1000 μg to equal 1 mg, so you would need to eat 10 kg, or about 22 lbs, of eggplant to take in as much nicotine as you'd get from three hours of minimal passive smoke.Plus, several scientists have pointed out that the absorption of nicotine through the lungs is very different from the absorption of nicotine through digestion. —medicalsciences.stackexchange: How much nicotine is in tea and vegetables—From research—on nicotine:(1) The vast majority of biomedical research investigating the neurobiological and neurophysiological bases of smoking cessation focus on nicotine, as nicotine is the salient psychoactive substance in tobacco, mediating the reinforcing effects of cigarette smoking and other forms of tobacco.However, there has been some recent interest into the role of other tobacco constituents and byproducts..Nicotine exerts its effects via stimulation of the nicotinic acetylcholine receptors (nAChR), which are located in the: central nervous system at interganglionic junctions of the autonomic nervous system, and on target organs throughout the body as part of the parasympathetic autonomic nervous system.More than 80% of the nicotine absorbed undergoes metabolism in the liver.The binding of nicotine to nAChR in the brain is involved in the rewarding effects of nicotine and in the adaptations that occur in response to chronic exposure, which give rise to dependence and to withdrawal responses. The positive reinforcing aspects of nicotine addiction primarily results from the release of dopamine.Studies show that individuals with psychiatric co-morbidities, compared to those without, start smoking younger, consume more cigarettes, are more dependent on tobacco, and are less likely to quit smoking:Because these psychiatric disorders are associated with various cognitive impairments, including deficits in attention, working memory, and response inhibition functions, the cognitive enhancing effects of nicotine may be especially important determinants of the initiation and maintenance of smoking in this population. [21]The present study suggests that nicotine increases regional efficiency in limbic and paralimbic areas, thereby promoting information exchange between these areas and the rest of the brain. This effect also may be particularly relevant to disease states. [22]A meta-analysis was performed from 24 studies, testing the performance of chronic tobacco smokers compared with non-smokers, on neuropsychological tests related to eight different neuropsychological domains.The results revealed a cross-sectional association between neuropsychological impairments and chronic tobacco smoking in:cognitive impulsivity,non-planning impulsivity,attention,intelligence,short term memory,long term memory,and cognitive flexibility,with the largest effect size being related to cognitive impulsivity (SDM = 0.881, p <0.005),and the smallest effect size being related to intelligence (SDM = 0.164, p < 0.05), according to Cohen’s benchmark criteria.No association was found between chronic smoking and motor impulsivity (SDM = 0.105, p = 0.248). [23](2) Quitting can be harder for individuals with dark pigmented skin compared to individuals with pale skin since nicotine has an affinity for melanin-containing tissues.Nicotine forms complexes with melanin and the amounts of nicotine bound to melanin increase with rising initial drug concentrations and prolongation of incubation time.Melanin-containing tissues can store nicotine up to 30 days after a single injection, what was observed in mice. [24]Nicotine also causes changes to the skin:Yellow discolouration/staining of teeth, fingernails, and finger etc.Dry, rough skin.Discolouration of skin, including lips.Dull/grey complexion.Vascular, collagen and elastin dysfunction/damage.Premature ageing, wrinkle development (smoker’s lines), fine lines, broken capillaries and veins, dark circles. [25]It is widely recognized that tobacco smoke causes skin pigmentation. No studies, however, have directly evaluated the mechanisms of the changes in smoker's skin pigmentation. In this study, when cultured with water-soluble tobacco smoke extract, the human epidermal melanocytes grew to a large size and produced more melanins. [26]Visual impressions created by skin color, especially facial skin color, are important in interactions within and between human communities. We observed skin color changes after smoking cessation within a short time period. Skin color was measured through simple instrumental evaluation. [27]These data show that “nicotine is a sticky molecule,” observes William Nazaroff… It’s no surprise that tobacco’s nicotine can pass through the skin. Farm workers can get sick if too much nicotine rubs onto them from tobacco leaves. And nicotine patches have been designed to deliver the chemical dermally — through the skin. [28]Something to keep in mind is that smokers may get more sun exposure and also drink more alcohol (and more painkillers…).For more: Smoking and its effects on the skin(3) ———Nicotine and NeurodegenerationDegeneration of central cholinergic neurons impairs memory, and enhancement of cholinergic synapses improves cognitive processes.Cholinergic signaling is also anti-inflammatory, and neuroinflammation is increasingly linked to adverse memory, especially in Alzheimer’s disease.Much of the evidence surrounding cholinergic impacts on the neuroimmune system focuses on the α7 nicotinic acetylcholine (ACh) receptor, as stimulation of this receptor prevents many of the effects of immune activation.…While there is considerable evidence that cholinergic signaling improves memory, fewer studies have linked the “cholinergic anti-inflammatory pathway” to memory processes. The Cholinergic System Modulates Memory and Hippocampal Plasticity via Its Interactions with Non-Neuronal CellsAcetylcholine is essential to normal CNS function, modulating cognitive, emotional and behavioral functions, including learning and memory, reward, wakefulness and attention.Appropriate levels of ACh are required to process relevant sensory information and for encoding environmental cues that drive goal-directed behavior.Disruptions of cholinergic transmission contribute to the pathophysiology of neuropsychiatric disorders, including Alzheimer’s disease, schizophrenia and drug addiction.Illuminating the role of cholinergic signaling in circuits of attention and emotionally salient behaviorsA recent human imaging study suggests that ACh levels are elevated in patients who are actively depressed— as measured by occupancy of nicotinic receptors throughout the brain— and remain high in patients who have a history of depression.In addition, despite the recent failure of a large clinical trial, other clinical and preclinical studies have shown that blockers of cholinergic (both muscarinic and nicotinic) receptors can induce antidepressant-like responses.These observations have renewed interest in the adrenergic-cholinergic balance hypothesis of mania and depression, which states that heightened cholinergic tone and decreased noradrenergic tone could lead to depressive symptoms.Source: Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behaviorChapter: ….Furthermore, due to its high membrane permeability, nicotine penetrates into the cytoplasm to bind nicotinic receptors expressed on mitochondrial membranes to activate, through an ion-flux-independent process, enzymatic cascades preventing cell death. …Overall, these results suggest that nicotine or related drugs might represent a strategy to counteract neurodegeneration. [29]In particular, alterations in reward processing have been reported, evidenced by increases in tobacco abuse after TBI in both addicts and tobacco-naïve individuals. This suggests that mesolimbic-mesocortical dopaminergic reward pathways are affected.Source: Nicotine-Induced Conditional Place Preference Is Affected by Head Injury: Correlation with Dopamine Release in the Nucleus Accumbens ShellNicotine Acts on Cholinergic Signaling Mechanisms to Directly Modulate Choroid Plexus FunctionClinical Trial: Nicotine Patch Shows Benefits in Mild Cognitive Impairment(4) A study, led by Ursula Winzer-Serhan, PhD, an associate professor at the Texas A&M College of Medicine, and her collaborators, found that nicotine’s ability to be neuroprotective may be partly due to its well-known ability to suppress the appetite:..In contrast, the group getting the highest concentration of nicotine ate less, gained less weight and had more receptors, indicating that at higher doses, the drug gets into the brain where it can impact behavior.However, even at high doses, it didn’t seem to have worrying behavioral side effects like making the individuals more anxious, which the researchers were concerned could happen..[30](5) There is an increased risk, around 30–40% higher, that a smoker will develop type 2 diabetes. Type 2 diabetes development involves the loss of the body’s ability to produce or use insulin, leading to excess glucose in the blood and poor use of glucose as cellular fuel.Diabetes can have many serious consequences, including heart and kidney disease, blindness, and poor circulation leading to ulcers and amputation.People with diabetes also have a harder time quitting smoking.A study that investigated nicotine and its neurological effects, established an interesting link between nicotine and insulin:Nicotine activates receptor proteins in neurons.The activation of these proteins, found in a particular brain region (medial habenula, mHb), leads to an aversive responses to nicotine.However, using mice it was found that activation of these receptors also leads to increases in the release of glucagon and insulin hormones from the pancreas, which leads to increased blood sugar levels (— a change associated with an increased risk of diabetes in humans).This increased blood sugar levels in turn seem to inhibit the activity of neurons which express those proteins, establishing a feedback loop, and as a result of this feedback, aversive responses to smoking are no longer triggered, resulting in nicotine dependence. [31]Nicotine is a strong activator of the hypothalamus–pituitary–adrenal axis — a network that promotes the release of stress hormones.The function of the mHb (medial habenula) is altered by stress,and stress hormones induce changes in blood glucose— indicating that the effects are not solely the result of nicotine's’ effect on the mHb, but also an indirect effect through HPA-axis activation. [32]Overview of blood sugar control—insulin, glucagon and glucose.Notably, mHb is the source of one of the major cholinergic pathways in the brain:In rat studies of learned helplessness, a model of human MDD (depression), researchers observed increased metabolic activity in the MHb (medial habenula), LHb, and IPN along with decreased metabolic activity in the VTA, basal ganglia, and amygdala.These effects may be attributed to restricted (localised) brain expression of IL-18, a proinflammatory cytokine, in the superior subnucleus of the MHb.Noradrenergic inputs into the MHb may trigger Interleukin-18.IL-18 is known to promote sleep in rabbits and rats and stimulates stress-induced immune responses that cause brain inflammation; —This stress response could lead to depression and other mood disorders.The inflammatory response caused by IL-18 may also cause degradation of the FR white matter pathway between the MHb and IPN; —These white matter disruptions may play a role in schizophrenia.The MHb may also play an important role in anxiety and fear.Source: The medial habenula: still neglected. Interesting:The Habenula: Darkness, Disappointment, and DepressionThe medial habenula and interpeduncular nucleus circuitry is critical in addiction, anxiety, and mood regulationCigarette smoke destabilizes NLRP3 protein by promoting its ubiquitination (on cigarette caused immune dysfunction)SWS promoting MHb-IPN-MRN circuit opposes the theta promoting circuit, active wake and REM sleepNotes:IL-18 is important for immune response against microbials. The pro-inflammatory cytokine was predominantly studied as a modulator of immune functions, and produced in the adrenal cortex following activation of the hypothalamic-pituitary-adrenal axis.In fact: During psychological stress, activation of HPA axis has been correlated to increased levels of pro-inflammatory cytokines (IL-1, IL-4, IL-6, IL-18, and TNF-α), probably through the action of ACTH (hormone).One of the nicotinic acetylcholine receptors (the alpha-7 nicotinic acetylcholine receptor), abounds on nerve cells in many distinct regions of the brain —defects in its function have been implicated in both Alzheimer’s disease and schizophrenia.Moreover, it has been suggested that schizophrenia could be an autoimmune disease. [33]Nicotine in cigarette smoke has been shown to suppress inflammation:Also, nicotine has been shown to suppress immune activation and proinflammatory responses through direct effects on immune cells and through effects on neurally mediated pathways.This would suggest that nicotine or its metabolites may be useful for treating neurocognitive impairment.However, chronic nicotine exposure can result in desensitization of the receptor in association with an increase in receptor numbers, and, paradoxically, an increase in proinflammatory responses…[34]Nicotine-mimicking drugs could help treat inflammatory diseasesHowever: One more reason to swear off tobacco: The inflammatory trap induced by nicotineNicotinic acetylcholine receptors in neuropathic and inflammatory pain(6) Nicotine may improve cognition in neuroinflammatory disorders:Current evidence shows that nicotine, and some of its derivatives diminish oxidative stress and neuroinflammation in the brain and improve synaptic plasticity and neuronal survival of dopaminergic neurons.In vivo these effects resulted in improvements in mood, motor skills and memory in subjects suffering from Parkinson’s Disease pathology. [35]This study suggests a mechanistic explanation for how tobacco users are protected from Parkinson’s and how the tobacco component nicotine confers neuroprotection; more specifically, nicotine suppresses SIRT6* (reducing abundance of SIRT6 in neuronal culture and brain tissue) which confers resistance to neuron and cell death…We find that reduction of SIRT6 is partly responsible for neuroprotection afforded by nicotine.Additionally, SIRT6 abundance is greater in Parkinson’s patient brains, and decreased in the brains of tobacco users.We also identify SNPs that promote SIRT6 expression and simultaneously associate with an increased risk of Parkinson’s.Our data suggest that SIRT6 plays a pathogenic and pro-inflammatory role in Parkinson's and that nicotine can provide neuroprotection by accelerating its degradation. [36]SIRT6 is a multi-tasking, stress response protein— functioning in multiple molecular pathways related to ageing, including DNA repair, telomere maintenance, glucose & lipid metabolism, inflammation & cancer:SIRT6 improves overall health and extends lifespan when overexpressed and causes early mortality and signs of premature ageing in its absence;SIRT6 deficiency is associated with various diseases including inflammation, heart hypertrophy, liver dysfunction, adipocyte/muscle disorders, and cancer;SIRT6 loss in non-human primates has been linked to developmental retardation;SIRT6 has also a role at the crossroad among energy metabolism, stress control, and circadian rhythm;A SIRT6 inhibitor may serve as a potential therapeutic agent in diabetes, immune-mediated disorders, and cancer (e.g. a synthetic inhibitor of SIRT6 improved glucose tolerance in a type 2 diabetes mouse model). [37]However, a study found that SIRT6 over-expression may prevent progression of diabetes (by suppressing insulin resistance and inflammation—high fat diet/mice).. [38][39]Moreover, following DNA damage, Sirt6 is recruited to double-strand breaks ensuring the proper activation of downstream DDR factors leading to an efficient DNA repair. Studies in diabetic patients showed greater oxidative damage to DNA. This indicates that the role of Sirt6 in DNA damage may as a new therapeutic pathway for cancer and diabetes related disorders.Review: The Role of Sirt6 in Obesity and DiabetesThe importance of SIRT6 in mammals is illustrated by the fact that SIRT6 deficient mice have retarded postnatal development associated with cellular genomic instability, systemic metabolic defects, and exhibited premature senescence and aging, with early death occurring at around 4 weeks after birth.…Over-expression of SIRT6 in the hippocampus CA1 region of rats impaired the formation of long-term contextual fear memory (but not short-term fear memory);…From the discussion above it appears that the neuroprotective effect of SIRT6 may be somewhat context-dependent rather than universal. The basis of this context dependency is not yet clear.More: Is SIRT6 Activity Neuroprotective and How Does It Differ from SIRT1 in This Regard?(7) Nicotine interacts with the choroid plexus, a structure that produces cerebrospinal fluid, which has been implicated in regulating neurogenesis.The lateral ventricle choroid plexus (LVCP), located within the LVs adjacent to the SVZ, produces CSF that carries signals which influence neurogenesis.Rejuvenating subventricular zone neurogenesis in the aging brainThe CSF is produced within brain ventricles by the choroid plexuses, which express many secreted factors found to influence neurogenesis, including growth factors, morphogens, and guidance clues..OTX2 Signals from the Choroid Plexus to Regulate Adult NeurogenesisThe choroid plexus was found to express markers of endogenous cholinergic signaling, including multiple nicotinic acetylcholine receptor subtypes in a region-specific manner, and application of nicotine was found to induce cellular activation, as evidenced by calcium influx in primary tissue.CSF released from the choroid plexus has been shown to regulate neurogenesis throughout the lifespan and to play a role in Alzheimer’s disease pathology...although the full extent of factors released by the choroid plexus with relevance to disease pathology remains to be elucidated. The extensive basolateral infoldings of the choroid plexus afford significant surface area for the release and uptake of signaling factors, whereas tight gap junctions and transporters regulate passage of substances between the blood and CSF .The rate of production of CSF is projected to allow for turnover of approximately four times per day in humans, and thus, the levels of circulating factors can be continuously regulated to influence neural function.Nicotine Acts on Cholinergic Signaling Mechanisms to Directly Modulate Choroid Plexus FunctionNote: Adult neurogenesis is still being debated. [40](8) However, it has been demonstrated that nicotine exerts its biological effects through nicotinic acetylcholine receptors in human lung cancer ..—Nicotine and cancer: Links, research, and how to quit.According to biophysicist, Harold ‘Skip’ Garner, nicotine which is thought to be merely addictive, is mutagenic:“Previous tests measure and classify whether nicotine is a carcinogen or mutagen were conducted with old technology, sponsored by tobacco companies. What we’ve done is, we made a direct measurement of the genome using the latest technology of next gen sequencing and we could directly measure the number of mutations that exposure to nicotine caused.”Garner and his team at the Virginia Bioinformatics Institute at Virginia Tech found nicotine causes thousands of mutations in cells, --- a known precursor to cancer.The conclusion, nicotine alone can cause cancer even without the other chemicals in conventional cigarettes. He says alternative nicotine delivery systems actually make the situation worse.“When you smoke cigarettes the actual dose is fairly low because it has to spread out through your entire body, but when you’re administering nicotine through a patch or you’re chewing it with gum or you’re inhaling it with e-cigarettes, your mouth and your skin get very high doses of nicotine.” [41][42]Nicotine: Carcinogenicity and Effects on Response to Cancer Treatment – A Review(9) Tobacco, Cocaine— from the perfect start to the finish lineTobacco use typically begins in adolescence, with around 90% of adult smokers starting before the age of 18.Smoking during early adolescence is associated with significantly increased risk of future cocaine abuse.While tobacco use has declined in recent decades, teen e-cigarette use has increased at an exponential rate, and the percentage of high-school e-cigarette smokers recently surged to over 30%.Teens that smoke e-cigarettes have a higher propensity to initiate other substance use, including cocaine.Adolescence is the final developmental stage before adulthood, with hallmark changes to dopaminergic circuitry and synaptic pruning.Regions that receive dopaminergic innervation, such as the nucleus accumbens (NAc), basolateral amygdala (BLA), and prefrontal cortex (PFC), are among the last brain circuits to fully mature in both humans and rodents.Within the NAc and PFC, dopamine D2 receptors are functionally immature.The adolescent brain also experiences a pruning of select synapses, with a concurrent strengthening of remaining connections.Nicotine interferes with adolescent brain maturation, and causes persistent changes in neuronal signaling.Microglia are the resident immune cells of the brain and contribute to essential aspects of early brain development. These cells are critical for developmental synaptic refinement, and prune synapses in an activity-dependent manner.Overall, we show that adolescent-nicotine exposure promotes a maladaptive reactive microglial state, which causes an increase in cocaine reinforcement.Source: Microglial activation increases cocaine self-administration following adolescent nicotine exposureThinking of giving up?Nicotine attacks the animal part of the brain that you don’t need to have any conscious awareness of; all your brain knows is that you’re in a situation in which you normally smoke, so light up a cigarette. The job of the conscious part of the brain is to find a way of countering that.For every day you carry on smoking after your mid-thirties, you will lose an average of six hours of life. Smokers are basically living an 18-hour day until they stop. The moment you stop then you start to recover life expectancy at a rate of six hours a day. That means it’s always urgent, but it’s never too late.Don't give up giving up smoking: An expert's guide to quitting“Some people smoke to put nicotine in their veins, others to put a cloud between them and others.” ― André Aciman, Find Me“What is this thing you call substance abuse?All I wanna do is forget and get loose.Drinking and smoking over and overWhat's so great about a life that's sober?There's nothing cool about being youngWhen the monsters of night have stolen the sun.I'm tired of searching for words in the sky.All I wanna do is drink and die.Nothing is real. It's all a big lie.All I wanna do is drink and die.There's nothing cool about being youngWhen the monsters of night have stolen the sun.”― Benjamin Alire Sáenz, Last Night I Sang to the MonsterLooks informative (Book): Industrial-Strength DenialAir Pollution and Cigarette Equivalence - Berkeley EarthDid you know that the word ‘smog’ was invented by a Londoner, by merging ‘smoke’ with ‘fog’? —Great Smog of London | Facts, Pollution, Solution, & HistoryStudy Links Smoking, Reduced Parkinson’s Risk, But Comes with CaveatPhilip Morris hides data in plain sight on dangers of new heat-not-burn productBig Tobacco loses tax battle in California, but Big Marijuana is on the riseDownload: Synergistic carcinogenic effects of tobacco smoke and other constituentsWebsite: Tobacco Underground contains articles such as “Made For Smuggling”, “Blame The Distributor”; China’s Marlboro Country; and Ukraine’s ‘Lost’ Cigarettes Flood Europe.Footnotes[1] https://ec.europa.eu/eurostat/statistics-explained/pdfscache/39738.pdf[2] https://discovery.ucl.ac.uk/id/eprint/1522254/1/Quirmback%20and%20Gerry%20Gender%20education%20and%20Russia's%20tobacco%20epidemic.pdf[3] Youth - Tobacco Atlas[4] German reunification 25 years on: how different are east and west really[5] Tobacco-related carcinogenesis in head and neck cancer[6] The History of Tobacco and Its Growth Throughout the World[7] Lesson summary: Slavery in the British colonies (article) | Khan Academy[8] The Horrible Fate of John Casor, The First Black Man to be Declared Slave for Life in America[9] The Hopefulness and Hopelessness of 1619[10] Viral immunology: reunion of the conjoined twins disciplines[11] Does nicotine help against the new coronavirus? | DW | 27.04.2020[12] The blazing success of Swiss cigarettes in Africa[13] The Evolution of Smoking in Switzerland[14] Top tobacco companies worldwide 2018 | Statista[15] Philip Morris International - Wikipedia[16] https://www.researchgate.net/figure/Estimated-smoking-prevalence-in-2020-and-2030-under-base-case-scenario_tbl2_224846816[17] Why getting farmers to switch from tobacco crops is a struggle[18] Cigarette Smoke Radioactivity and Lung Cancer Risk[19] Diddl - Wikipedia[20] Smoking[21] Cognitive Effects of Nicotine: Recent Progress[22] Nicotine Increases Brain Functional Network Efficiency[23] Chronic tobacco smoking and neuropsychological impairments: A systematic review and meta-analysis[24] Nicotine impact on melanogenesis and antioxidant defense system in HEMn-DP melanocytes[25] 7 ways smoking can impact your skin, according to experts[26] Tobacco smoke-induced skin pigmentation is mediated by the aryl hydrocarbon receptor.[27] Changes in Skin Color after Smoking Cessation[28] Nicotine from smoke enters body through the skin | Science News for Students[29] Nicotine Neuroprotection of Brain Neurons: The Other Side of Nicotine Addiction[30] Could Nicotine Help Protect The Aging Brain? - Neuroscience News[31] Brain-to-pancreas signalling axis links nicotine and diabetes[32] Brain-to-pancreas signalling axis links nicotine and diabetes[33] Autoimmune Diseases and Psychotic Disorders[34] Cigarette Smoke and Nicotine Effects on Brain Proinflammatory Responses and Behavioral and Motor Function in HIV-1 Transgenic Rats[35] Beneficial effects of nicotine, cotinine and its metabolites as potential agents for Parkinson’s disease[36] Nicotine promotes neuron survival and partially protects from Parkinson’s disease by suppressing SIRT6[37] SIRT6 - an overview[38] SIRT6 over-expression may prevent progression of diabetes, study finds[39] Sirtuin 6 Builds a Wall Against Inflammation, Trumping Diabetes[40] No New Neurons? No Problem![41] Nicotine Not As Safe As Once Thought[42] Cellular evidence on how nicotine and e-cigarettes increase cancer risk in humans (and mice)

I apologize for the length of this response, but ... there's so much information to cover, and I'm not sure exactly what lies behind your question. Ergo, this response is broken into four sections:(1) What is traumatic brain injury (TBI)?(2) Are all TBIs caused by contact sports, military injuries, and domestic violence the same?(3) Is TBI a risk factor for Alzheimer's disease (AD) and related neurodegenerative disorders that cause dementia?(4) Is TBI a risk factor for "chronic traumatic encephalopathy (CTE)"?There has been widespread publicity about mild traumatic brain injuries (mTBIs, aka "concussion") experienced at a younger age causing "chronic traumatic encephalopathy (CTE)" and/or being a risk factor for developing neurodegenerative disorders such as Alzheimer's disease (AD) later in life. There has been a lot of research on this subject, which has produced a lot of conflicting conclusions. After having plowed through literally hundreds papers, I can state with confidence: There is no consensus among researchers that there is adequate evidence for mTBIs causing dementia in general, or Alzheimer's or CTE in particular. In fact, many experts question whether there even is such a disorder as CTE.So why the ongoing controversy? The answer is "science by press release". This is a serious problem that causes all sorts of false information becoming widespread on the internet, typified by a recent post on Quora: Sunny Smith's answer to Did Daniel Perl sincerely change his mind about Alzheimer's disease, or did he 'sell out' to the aluminum industry (ALCOA)? Dr Perl -- a very fine scientist with an exemplary reputation among his peers -- continues to experience the all-too-long-term effects of this phenomenon. He had published an excellent paper which presented his findings that signals related to the element aluminum were found in the "nuclear region" of a high percentage of brain neurons containing neurofibrillary tangles (NFTs). NFTs are a hallmark of Alzheimer’s disease. Dr Perl did not speculate on the significance of those findings, either in the paper itself or in response to subsequent inquiries from the press. However, a psychiatry resident who did not know Dr Perl, and who had not ever done any research relevant to the subject, had read the paper and written a brief "letter to the editor" of the journal containing a totally unfounded speculation that human exposure to aluminum pots and pans might cause Alzheimer's ... which, in Perl's words, "really stirred up interest by the lay press and was like pouring gasoline on a smoldering fire." The paper was published in 1980. Perl has been struggling unsuccessfully to put out the fire ever since.In the question of whether brain injuries may cause CTE, the gasoline (an entire tanker full) was a Hollywood movie, "Concussion," starring Will Smith, which has, unfortunately, been taken as the gospel truth by the public. Wild claims about the cause of death of several celebrities have continued to fan the flames, as have the sensationalistic lawsuit filed against the NFL by its football players, plus some of the most incredibly irresponsible and completely misleading blogs, purporting to be news stories, that I've ever seen. Due to the resulting concerns of parents with children playing contact sports, and of veterans who have seen combat, the publicity surrounding CTE is unprecedented. It has resulted in enormous pressure on Congress to fund major programs to study the relationships (if any) of head injuries and dementias. Ergo, many scientists with any pretensions at all of being qualified to study any aspect of the subject are competing for their share of the pot. Many are jumping into an area that is entirely new to them, and don't understand the complicated issues involved. Some researchers have great difficulty in maintaining objectivity, especially in speaking with the press, and are unwilling to kill the golden goose by saying loud and clear that CTE has not been shown to actually exist. And, sadly, a number of purportedly qualified researchers are constantly stirring the pot, to keep the money flowing.Science is constantly evolving. Conclusions are made based on a given study, and the results are also (hopefully) compared/contrasted with other, related studies. Then someone else comes along and asks questions that weren't addressed by any previous studies and produces new information, new hypotheses, new ways of looking at the subject ... and perhaps some, or even all, of the previous conclusions will eventually be discounted. When it comes to a subject as incredibly complex and complicated as the long-term effects of brain injuries in humans, it takes many years of scientists from many different disciplines questioning and critiquing all of the different study designs and the logic used to reach conclusions to develop a consensus opinion. A summary of a recent CTE conference says, "Media attention has far outpaced the available science. In most areas of science, researchers make progress in relative obscurity before the general media develops an interest. Here the opposite has happened."Several warnings should be kept in mind when reading news stories (or research papers, for that matter.) Never believe anything about dementias that is based on studies done in mice. Even genetically engineered mice do not develop Alzheimer's. In fact, age-related neurodegenerative diseases are largely limited to humans and rarely occur spontaneously in any other species, so animal model studies are suspect. (So are in vitro cell and tissue culture studies, since they cannot mimic what happens inside the human body.) Retain a very healthy skepticism about studies on neurodegenerative disorders in humans that rely solely on clinical diagnosis, without any attempt to confirm the diagnoses by neuropathological analyses (i.e., postmortem autopsies), because an estimated 20-30% of cases clinically diagnosed with Alzheimer's have additional pathologies or no Alzheimer's pathology at all. Don't believe conclusions from studies in which Alzheimer's is diagnosed within a few years of exposure to a potential risk factor, since it is now widely accepted that the Alzheimer's pathology cascade is triggered some 20-25 years before clinical symptoms emerge. If the time between TBI and onset of dementia is short, the injury may have resulted from subclinical motor or cognitive dysfunction. Never believe the conclusions from studies involving small numbers of test subjects -- it's too likely the data will be skewed, one way or another. Always remember that correlation does not imply causation. Far too many people (many scientists included) believe it does. Never believe that a "risk factor" is something that is known to cause dementia. If someone says that TBI is a risk factor for Alzheimer's or CTE, that just means that a correlation has been observed, typically in an epidemiological study -- it does not mean that a TBI will cause Alzheimer's. Never never never never never believe news reports about dementias. Just never. And be leery of blogs that report on new studies -- the bloggers don't (often can't) do an objective analysis of the caliber of the new study and/or how its findings relate to other studies on the same general topic, and so they don't put the new study into perspective.The study cited by the blog Jae Starr references is quite interesting, but please notice that its topic is the potential outcome of TBIs incurred by patients ≥55 years old, and is therefore irrelevant to your question. Age at injury is thought to play a big role in what happens later in life. Recent studies have shown that, relative to younger people, older adults who sustain a TBI tend to have particularly poor outcomes and slower recovery, even after milder injuries. These findings suggest that TBI in older adults may represent a clinical condition that is distinct from that observed in younger adults. Unlike younger adults who most commonly incur TBI in accidents that are unlikely to be related to, or reflective of, their overall health status (e.g., motor vehicle crashes), the majority of TBIs among older adults are the result of falls. Several aspects of aging may contribute to fall risk, including imbalance, frailty, joint disorders, chronic medical conditions, and medication interactions. It is therefore possible that falls are actually a symptom of age-related decline. In aging, the brain undergoes widespread atrophy (brain shrinking), neuronal shrinkage, reduced synaptic density, and decreased neural plasticity. The effects of a TBI are then overlaid upon these age-related structural and functional changes, which likely affects the course of recovery after injury. Thus, the aging brain may be more vulnerable to damage, such that significant injury can result from a milder blow, and there is less "reserve" with which to recover. The presence of multiple pre-existing medical comorbidities and the polypharmacy required to manage comorbid conditions may make TBI harder to diagnose and treat in older adults, and may increase the risk for secondary complications. Anticoagulant therapy, in particular, has been associated with poorer outcomes after TBI, including increased incidence of intracranial hemorrhage, longer lengths of hospital stay, and greater in-hospital mortality. The possibility that older adults are more vulnerable to more secondary complications after TBI is consistent with research indicating that younger people are more frequently seen in emergency rooms and discharged, whereas older adults more often require hospital admission for TBIs of similar severity.(1) What is traumatic brain injury (TBI)?TBI is a broad category that encompasses closed head injury, open head injury, and penetrating head injury. I am assuming that the person in question had a closed head injury in which there is no skull fracture and the dura remains intact. The pathology of a closed head TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health.Although mild TBI (mTBI, "concussion") is portrayed in the literature as a definable condition, it encompasses a wide spectrum of potential biomechanical precursors, including nature and type of impact, directionality of acceleration-deceleration phenomena, and individual susceptibilities; and the diagnosis of mTBI may be entirely subjective, as it is often based on self-reported neurological symptoms and/or provided by physicians and other personnel with wide variability in experience in the diagnosis of TBI. mTBI is broadly defined as a head injury that temporarily affects brain functioning. Symptoms may include a brief loss of consciousness (usually ≤30 minutes), post-traumatic amnesia (<24 hours), trouble with thinking, memory or concentration, headaches, nausea, blurry vision, mild diplopia, light sensitivity, seeing bright lights, tinnitus, sleep disturbances or mood changes. Some symptoms may begin immediately, while others may appear days after the injury. Indications that a more serious injury was incurred include worsening of symptoms such as headaches, persistent vomiting, increasing disorientation or a deteriorating level of consciousness, seizures, and unequal pupil size. Most concussions "without complication" cannot be detected with MRI or CT scans. Acute signs and symptoms related to concussion resolve within 10 days of injury in 90% to 95% of adult athletes, but may linger longer in concussed children and adolescents. When symptoms persist longer than 10 days, full recovery usually is made within a matter of weeks.Patients diagnosed with moderate or severe TBIs are often grouped together, as they exhibit gross structural damage on neuroimages. Moderate to severe closed head injuries result in widespread damage to the brain because the brain "ricochets" within the skull. The brain stem, frontal lobe, and temporal lobe are particularly vulnerable because of their location near bony protrusions. Overt abnormalities are typically focal in nature and can include cerebral contusions, extra or subdural hematomas, subarachnoid hemorrhage, intracranial or intraventricular bleeding, and/or skull fractures. Studies on the long-term prognosis of patients with "moderate to severe" TBI typically involved persons who suffered a rapid impact injury to the brain causing a loss of consciousness (>30 minutes to 24 hours, moderate TBI, or >24 hours, severe TBI) and post-traumatic amnesia (>1 to <7 days, moderate, or >7 days, severe), were admitted for emergency medical attention, and had MRI or CT scans that were positive for visible brain injury on the day of injury.(2) Are all TBIs caused by contact sports, military injuries, and domestic violence the same?In an effort to convince the public that the long-term outcome of mTBI is a serious concern of major (one might say epidemic) proportions, research has focused on a variety of high-risk populations, such as contact sport athletes (including American football, boxing, ice hockey, mixed martial arts, and soccer), military personnel, and victims of domestic violence, all of whom are at particularly high risk for suffering mTBI, repetitive mTBI, and repetitive sub-concussive head trauma. However, TBI exposure across many of these high-risk populations has not remained stable over time, a phenomenon known to epidemiologists as a "secular trend." For example, a study of professional boxers in the United Kingdom and Australia found that from 1930 to 2003 the average professional boxer's career duration dropped nearly 75% (from 19 to 5 years) while the average number of career bouts dropped 96% (from 336 to 13). This reduction in exposure over time paralleled increases in medical oversight, and raises the possibility that the quality of chronic neurologic sequelae of boxing may have changed over time as well. Similarly, professional American football has changed dramatically over the past few decades, with increasing medical oversight and changes to protective gear and rules of play aimed specifically at improving player safety. Other secular trends may be associated with heightened exposure to mTBI. For example, among military veterans, mortality following TBI has declined dramatically since the Vietnam war, leaving an increasing number of military veterans living with sequelae of TBI and potentially being at heightened risk of repeat TBI. War tactics have also changed such that blast injuries, which frequently result in mild TBI (or sub-concussive head trauma), are extremely common. A recent survey of deployed troops in Operation Iraqi Freedom and Operation Enduring Freedom found that 17% reported mTBI during deployment, and of these, 59% reported more than one mTBI.In addition to secular trends, the biomechanics and resultant neuronal injury of an mTBI sustained by, say, a football player may differ markedly from those incurred by a boxer. The symptoms produced by brain trauma show evidence of these differences. Approximately 17% of retired professional boxers who participated in the sport in earlier years exhibit a chronic traumatic brain injury (dementia pugilistica) which comprises predominantly motor symptoms, such as ataxia, dysarthria, and parkinsonism. (This syndrome rarely occurs among amateur boxers.) A review of the earlier cases of dementia pugilistica concluded it was likely that at least some cases reflected chronic neurologic deficits due to acute brain contusions or hemorrhages sustained during a boxing bout -- i.e., moderate to severe brain trauma, not mild TBI, and not a progressive neurodegenerative disorder.In contrast, cognitive and neurobehavioral features predominate in football players with histopathologic evidence of CTE; few, if any, exhibited motor features. This stark difference is also reflected in the neuropathology, with studies finding more cerebellar scarring in professional boxers compared with football players. These differences could be attributable to differences in the biomechanics of the injuries, specific to the nature of each sport. For example, some studies found that although boxers may sustain more angular acceleration and torsional injuries, football players may be more likely to sustain transverse and linear acceleration/deceleration injuries.In short, it cannot be concluded that repetitive brain trauma experienced under diverse circumstances causes the same, long-term neurologic sequelae.(3) Is TBI a risk factor for Alzheimer's disease (AD) and related neurodegenerative disorders that cause dementia?It has long been thought that moderate to severe TBI in early life or midlife is a risk factor for late-life Alzheimer's disease (AD). However, the more scientists try to study the relationship (if any), the more they realize that the methods used in earlier studies had too many flaws to produce reliable conclusions. These early studies largely used case-controlled designs, and were subject to limitations including insufficient numbers of dementia cases in study populations, short follow-up periods, recall bias, reverse causation, differing definitions of TBI, potential misclassification of neurodegenerative disease, and and especially a failure to adequately control for potential confounders, such as medical and psychiatric comorbidities, socioeconomic status, alcohol intoxication, physical fitness, blood pressure, and low premorbid cognitive function; and very few have considered death as a competing risk. Studies that take into consideration a greater number of health and lifestyle variables in the models tend to find no relationship or a weak relationship between TBI and all-cause dementia.It is very challenging to design studies with sufficient sample size and follow-up time to minimize the risk of reverse causation and allow for an adequate induction period between a TBI and a diagnosis of dementia. Alzheimer's and the alpha-synucleinopathies have an insidious onset, and there is evidence that the pathological cascade is triggered as much as 20-25 years before clinical symptoms begin to emerge. These progressive neurodegenerative dementias are also difficult to diagnose, and very few studies include post-mortem brain autopsies to confirm the disorders that were actually present. AD diagnosis can be based on different consensus criteria, which vary in the core phenotype and biomarker technologies (cerebrospinal fluid and imaging) used. A recent study concluded that the very consensus criteria used to diagnose AD are themselves a source of potential ascertainment bias and non-equivalent classification. For example, one study used clinical and imaging data for 155 patients meeting NINCDS-ADRDA criteria for possible (n= 55) or probable (n=100) AD. Four other commonly used diagnostic classification systems were re-applied systematically to these cases, and diagnoses were compared against this benchmark and each other. Only 53 subjects (34%) met all five consensus criteria. Although some classification systems overlap better than others, none are entirely equivalent. In the extreme, the percentage agreement was so low as to exclude one half of individuals when cases were re-classified using a second system. In addition, it must be noted that these findings were based on diagnoses made late in the disease course. Not only were patients suspected of having AD at the outset, but they had been assessed at a tertiary referral clinic, where they had been followed for a minimum of one year, and had three follow-ups. More of the clinical syndrome therefore had emerged, making a diagnosis on purely clinical grounds much easier.Accurate diagnosis of Alzheimer's faces particular challenges during early stages of disease when clinical features are sparse, due to AD's highly variable clinical presentation, non-AD pathologies that can mimic the AD syndrome, and the high prevalence of co-morbidities such as cerebrovascular disease that can complicate, or even obscure, the underlying biology. There is significant phenotypic variation in Alzheimer's. This variation is consistent enough to merit the definition of subtypes, it is extreme enough to lead to misdiagnosis, and it is common enough to complicate broadly-defined criteria, as is often the case with consensus guidelines.Furthermore, an injury that might trigger the AD pathology cascade in one individual might not trigger it in dozens of others. There are a mind-boggling number of factors that can affect the susceptibility of a given individual. Most people are only aware of a handful of genetic factors that increase risk, or that can, in a few rare cases, actually cause early-onset familial AD (eFAD). However, it is now thought that development of dementia is a lifelong process that begins decades before the onset of the disease, and is even influenced in the womb. Epigenetics is the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself. Epigenetic factors involved in shaping the brain's physical structure during intrauterine development fall into two main groups, i.e., maternal factors (including diet, smoking, alcoholism, hypertension, malnutrition, trace elements, stress, diabetes, substance abuse, and exposure to environmental toxicants), and fetal factors (including hypoxia/asphyxia, placental insufficiency, prematurity, low birth weight, drugs administered to the mother or to the baby, and all factors causing intrauterine growth restriction.) After birth, epigenetic changes are associated with epidemiological risk factors such as aging and environmental exposures (e.g., heavy metals, including arsenic, nickel, chromium, cadmium, and lead), as well as psychiatric outcomes and neurodegeneration. Dementia risk is also modified by perinatal events, education status, nutritional intake, gastrointestinal tract microbiota, degree of physical activity, and cognitive and social engagement. Several of these factors affect adult-onset vascular disorders including strokes, hypertension, atherosclerotic disease, atrial fibrillation, diabetes mellitus, dyslipidemia, hyperinsulinaemia, hyperglycaemia, hyperhomocysteinemia, and obesity. It is increasingly recognized that factors which increase cardiovascular disease or brain vascular pathology exacerbate the onset or progression of late-onset dementias.As a result, research on later-life risk and the clinical trajectory for dementia following TBI remains in its infancy.Almost all epidemiological studies of the relationship between TBI and AD have at least two major limitations. First, most have used self-report information to determine a history of TBI exposure. While the collection of exposure information before the onset of dementia may be a valid approach, collection of exposure data from people who are already cognitively impaired has obvious drawbacks in the reliability of the data. Second, most studies have relied on billing codes for clinical diagnosis of AD rather than using an array of recently developed biomarkers or neuropathological examination. These limitations were overcome in several recent studies examining the relationship between TBI and AD. For example, a 2016 review of data from three large community-based cohort studies on brain aging and dementia -- the Religious Orders Study (ROS), the Memory and Aging Project (MAP), and the Adult Changes in Thought (ACT) study -- sought to determine whether TBI with more than one hour loss of consciousness (i.e., moderate to severe TBI) is associated with an increased risk for clinical and neuropathological findings of AD, Parkinson disease (PD), and other dementias. A total of 7130 persons participated in these three studies, with a total autopsy sample size of 1682 brains. The studies concluded that TBI with loss of consciousness (LOC) was not associated with the development of mild cognitive impairment, dementia, clinical AD, or Alzheimer pathological changes. In addition, a recent report of Vietnam-era veterans with moderate to severe TBI found no evidence for increased rates of amyloid deposits on florbetapir positron emission tomography scans associated with TBI and no evidence for medial temporal lobe atrophy in those with PTSD and/or TBI relative to the controls. To circumvent the limitation of self-reported TBI in cognitively impaired participants, the studies used self-reported TBI with loss of consciousness collected at a time when participants were known to be cognitively intact, or medical records information to document TBI exposure. Likewise, none of these studies relied solely on clinical diagnosis of dementia and AD, but augmented diagnosis with neuropathology evaluations, or MRI and florbetapir PET scans.These studies excluded patients with young-onset dementia. The risk of developing young-onset dementia after TBI was examined in a landmark study that followed ~800,000 Swedish military recruits for up to three decades, around 45,000 of whom had sustained a TBI. TBI was not associated with risk of Alzheimer's.Another interesting line of evidence comes from studies on microglia. There is compelling evidence to suggest that bipolar/rod-shaped microglia play a pivotal role in central nervous system (CNS) repair, and are involved in the internalization of degenerating neurons following CNS injury. A recent case study involving autopsy of over 160 patients showed that the presence of bipolar/rod-shaped microglia in the hippocampus and cerebral cortex was directly related to an AD cohort with aging and AD-related pathology such as dementia, and the formation of senile plaques and neurofibrillary tangles. However, there was no association between bipolar/rod-shaped microglia and a self-reported history of TBI.Different neurodegenerative disorders may have different risk factors, and there is some preliminary evidence that moderate to severe TBI may be associated with the alpha-synucleinopathies "dementia with Lewy bodies (DLB)" and Parkinson's disease (PD), which can eventually progress to Parkinson's disease dementia (PDD) in some patients. (Multiple system atrophy and pure autonomic failure belong to this same family, but have not been diagnosed in these studies, possibly due to their rarity.) For example, the 2016 review of data from the three large community-based cohort studies on brain aging and dementia (above) found that moderate to severe TBI was associated with with Lewy body accumulation, progression of parkinsonian features, and the risk for incident Parkinson disease, as well as cerebral cortical microinfarcts. The Swedish study reported a risk for other (non-Alzheimer's) young-onset dementia types. However, the absolute risk of illness was very low: only 0.07% of the cohort developed dementia.It should be noted that DLB has often been misdiagnosed as Alzheimer's, especially in the 1990s, which might account for some of the variability in studies on the relationship between TBI and Alzheimer's. Parkinson's disease is not a single disorder and has multiple subtypes; and there is also a high misdiagnosis rate between Parkinson's disease and parkinsonisms. (Parkinsonism is a set of symptoms, and the term does not imply a particular disorder that causes the symptoms.) Post-traumatic parkinsonism may be transient and is hypothesized to be primarily due to traumatic axonal disruption of nigro-striatal-frontal pathways. Among those cases that become chronic or progressive, it is conceivable that neurodegenerative pathology may be a contributing factor. This hypothesis, however, is currently speculative and requires further study.Systematic meta-analysis reviews of the literature on the risk of developing Alzheimer's and related dementias after suffering an mTBI as an adult have failed to establish a link. (Such reviews establish stringent criteria for the publications to be included in their analyses. There have been many studies, some finding a correlation and some not. Most of these are not included in the meta-analyses because of serious problems with their experimental designs and/or data analyses.) For example, the WHO task force on mild TBI published its first review on the prognosis for mTBI in children and adults in 2004 and updated it in 2014. They found no evidence of an increased risk of dementia after mTBI in adults. For children, objective evidence of chronic cognitive impairment exists only when there is intracranial pathology ("complicated" mTBI); otherwise, there was consistent and methodologically sound evidence that "children's prognosis after mild traumatic brain injury is good, with quick resolution of symptoms and little evidence of residual cognitive, behavioural or academic deficits." They noted that the literature on the risk of dementia after mTBI "is of varying quality and causal inferences are often mistakenly drawn from cross-sectional studies."(4) Is TBI a risk factor for "chronic traumatic encephalopathy (CTE)"?Despite all the widespread publicity on athletes involved in contact sports developing "chronic traumatic encephalopathy (CTE)", the claims are wildly misleading, and often untrue.For example, CTE is represented as occurring frequently in retired National Football League (NFL) players. However, several reviews note that a high rate of duplication (i.e., re-reporting cases across multiple publications) exists in the clinical CTE literature, leading to an erroneous, highly inflated impression of the total number of CTE cases reported. The incidence of CTE has been estimated at less than 4% of professional American football players, based on the numbers of cases obtained in a given period versus the number of athletes who died during the same period. If all of these professional athletes at risk were to be used as the exposure, then the incidence rate would be less than 0.01%.Despite claims that CTE is characterized by suicidality, recent studies of NFL retirees report that they have an all-cause mortality rate that is approximately half of the expected rate, and are much less likely to commit suicide. Only 26 of more than 26,000 former NFL athletes evaluated since 1920 died by suicide, 80% of whom had documented risk factors for suicide (e.g., substantial life stressors).Let me reiterate: recent studies have concluded that NFL retirees have an all-cause mortality rate that is about half that of the general population. This raises the issue of the health benefits attributable to engaging in sports such as football, which may far outweigh an increase in the risk of dementia -- if, indeed, there is any. Physical activity reduces the risk for cardiovascular disease, type 2 diabetes, hypertension, obesity, and stroke, and produces beneficial effects on cholesterol levels, antioxidant systems, inflammation, and vascular function. Exercise also enhances psychological health, reduces age-related loss of brain volume, improves cognition, reduces the risk of developing dementia, and impedes neurodegeneration. And yet, discussions on CTE rarely mention these health benefits.Parents worry over whether to let their children engage in contact sports, for fear of risking late-life dementia. However, a large, community-based study published in 2012 concluded that high school students who played American football from 1946 to 1956 did not have an increased risk of later developing dementia, Parkinson's, or ALS compared with non–football-playing high school males, despite poorer equipment and less regard for concussions compared with today and no rules prohibiting head-first tackling (spearing). A similar, even larger study published in 2017 on high school football players and their nonplaying counterparts who graduated in 1957 found that playing high school football is not associated with cognitive impairment later in life and, in fact, may help prevent depression and lead to greater lifetime levels of physical activity. A follow-up to the 2012 study, published in 2017, concluded that varsity high school football players from 1956 to 1970 did not have an increased risk of developing neurodegenerative diseases, including dementia, parkinsonism and ALS, compared with athletes engaged in other varsity sports.Manley et al (2017) note: "A major limitation in the clinical assessment, survey, neuroimaging, cohort and autopsies studies published to date is that most do not consider relevant third variables when examining the association between prior concussions and long-term brain health problems. When evaluating the association between an 'exposure' (i.e., concussion or repetitive head impacts) and 'outcome' (e.g., long-term brain health problems), the possible roles of a relevant third variable are (i) effect modifier (e.g., host susceptibility factors), (ii) intermediary and (iii) confounder. There are many candidate third variables that might be associated with the long-term cognitive and mental health of former athletes, from the psychiatric and neuroscience literature, including genetics, childhood adversity, personality factors, resilience, family history of mental health and neurological problems, steroid use, drug and alcohol use, opiate misuse, chronic pain, depression, anxiety, life stress, marital and family problems, diet and nutrition, exercise, obesity, diabetes, heart disease, other general medical problems, small vessel ischaemic disease and a diverse range of neurological conditions and diseases. In a survey study of former Division I collegiate athletes, for example, socioeconomic (i.e., income) and nutritional factors (i.e., greater fat and cholesterol and overall lower diet quality) were associated with perceived cognitive difficulties in older adults."Iverson et al (2018) point out: "In addition, factors relating to the resistance and resilience of the human brain to damaging effects of repetitive mild neurotrauma are not understood. When one considers, for example, the enormous neurotrauma exposure of boxers in the early part of the 20th century, and the fact that only 17% of those studied developed a diagnosed neurological syndrome, the resilience and plasticity of the human brain is likely remarkable. Therefore, researchers and clinicians are encouraged to be cautious when considering the clinical symptoms and psychosocial problems of former athletes, civilians, and military veterans, and to be mindful of potential iatrogenic effects of diagnosing a progressive neurodegenerative disease in someone with a psychiatric illness due mostly or entirely to other factors."Many reviews published over the past five or six years have repeatedly warned that there is no solid evidence that CTE exists as a separate and distinct neuropathology. There are no epidemiologically sound population-based studies of CTE, and there are no accurate estimates of prevalence or incidence of CTE. The recently proposed neuropsychiatric presentations of CTE broadly overlap those of other known neurodegenerative disorders, as well as other forms of psychopathology. Many of the clinical symptoms that have been attributed to CTE pathology are common in the general population (e.g., depression, anxiety, anger, financial problems, marital problems, headaches, bodily pain, and insomnia). Since there is no unique CTE neuropsychological clinical profile, CTE cannot be diagnosed before death.Let me emphasize: CTE cannot be diagnosed in living individuals. CTE has been associated with mood, behavior, cognitive, and/or motor symptoms that may closely resemble Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and/or vascular dementia (VaD). Among epidemiological studies reporting an association between TBI (or mTBI or repetitive mTBI) and neurodegenerative disorders that lack autopsy-confirmation, the degree to which these clinical diagnoses actually reflect true PD, AD, FTD, ALS, VaD, or any combination thereof, remains unknown.To date, no studies have causally linked clinical symptoms with neuropathology. Thus, the differential diagnosis of CTE based on clinical evidence alone has not yet been validated. Researchers have also questioned the neuropathological diagnosis of CTE on the basis of methodological flaws, including studies primarily based on post-mortem brain samples of convenience (donated by concerned family members), biased retrospective reports, inconsistent neuropathological findings, and lack of prospective, longitudinal, and case-controlled studies. Different stains used in the lab to detect neuropathogical features in tissue samples yield different levels of sensitivity; CTE brain samples that were originally reported to contain no β-amyloid were later re-examined using the much more sensitive immunohistochemical staining and showed extensive, diffuse-type β-amyloid plaques that had not been observed previously. It is also unclear how frequently neuropathologists use the specific stains shown to adequately identify the presence of abnormalities said to be specific to CTE in samples from nonathletes, normal elderly individuals, or in those with other diseases unique to well-studied neurodegenerative disorders (e.g., AD, FTD, and ALS). Moreover, because the pathological lesions are reportedly irregularly distributed, the detection of CTE in autopsy cohorts may require additional sampling compared to routine practices.Most of the gross and microscopic features that have been described as "characteristic" of CTE have not, as yet, been independently verified as specific to CTE, and virtually all are associated with aging, other neurological diseases, or both. Hyperphosphorylated tau pathology and the accumulation of other altered proteins such as β-amyloid, α-synuclein and TDP-43-positive immunoreactivity occur with human aging and diverse neurodegenerative diseases, and can also be found in people who are cognitively normal; thus, it would be incorrect to assume that any such pathology is unique to, or caused by, CTE. Multiple biological, genetic, environmental and lifestyle factors likely contribute to the final disease profile as currently defined.Polypathology and disease comorbidities are common in patients with AD, PD, DLB, cerebrovascular disease, and hippocampal sclerosis. It can be difficult to determine the extent to which each pathological change contributed to the emergence and course of a given person's clinical symptoms without rigorous clinicopathological correlation. Even then, correlation between proteinopathy and clinical signs can be limited. It is now well established that a large percentage of former athletes identified as having "CTE neuropathology" also have neuropathology associated with age related neurodegenerative diseases such as AD, PD, DLB, hippocampal sclerosis, and ALS, to the extent that these athletes meet full neuropathological criteria for an alternative, well-characterized neurodegenerative disease. The progression of clinical symptoms in those cases is expected as a direct result of those primary neurodegenerative diseases. Often, however, whenever the purported pathology of CTE is identified in these samples, regardless of the amount, the case is conceptualized as CTE, when it might well be more appropriate to conceptualize the person as having another neurodegenerative disease with small amounts of CTE neuropathology. In fact, in studies involving traditional brain banks, the majority of people identified as having CTE pathology have only mild forms (e.g., Stage I or Stage II), in association with a separate and primary, relentlessly progressive and fatal neurodegenerative disease.There is no solid evidence that CTE inevitably progresses to dementia. In fact, there is emerging evidence from several research groups that CTE pathology is limited to Stage I or less in many people, even the very elderly. One prominent group of CTE investigators proposed 4 stages of clinical CTE corresponding to the proposed 4 stages of the neuropathologic progression of CTE, and described common clinical features seen at each stage. Initially, stage I symptoms were said to include headaches and decreased attention and concentration. Stage II symptoms were said to progress to depression, explosivity, and memory loss; and then in stage III, to progress to executive dysfunction and cognitive impairment. Individuals in stage IV were said to show word-finding difficulty, aggression, and dementia. However, in their more recent studies, these investigators state that individuals with stage I neuropathology are unlikely to be symptomatic at all and that subjects with stage II pathology may also be asymptomatic. NINDS says this work is "preliminary", given that the neuropathology described by consensus criteria had weak, if any, correlation with clinical phenotypes. First, not all cases that were examined showed all criteria for all stages. Rather, the staging descriptions represent a collection of features seen together across multiple cases, with the essential feature of tau distribution and severity as perhaps the underlying abnormality defining a given stage. This makes the identification of stage-defining criteria complex. Second, these stages arose from multiple case studies and are therefore based on cross-sectional rather than longitudinal data. It is conceivable that each stage could represent distinct disease processes rather than a progressive disease. In the absence of longitudinal data, it is difficult to predict whether the disease would progress in sequential stages as defined. Third, the contribution of other variables to each presentation requires larger, prospective, and longitudinal studies. Age, psychiatric or substance use history, family or genetic risk factors, and/or other comorbid neurodegenerative conditions that may have contributed to each individual's neuropathologic classification within a stage need to be considered. Fourth, it is well established that tau pathology and β-amyloid deposits can be found in adults who are healthy or who have diverse health conditions and therefore are not unique to CTE, although the topography of disease may be different in CTE. However, performing longitudinal histopathologic studies is basically impossible unless sequential brain biopsies were performed, given the lack of specific in vivo p-tau biomarkers. Older studies with boxers did not show any such progression, and a 2014 review noted that "classic CTE" does "not appear to advance in a predictable and sequential series of stages." Therefore, it should be emphasized that the proposed pathologic stages of CTE are descriptive and the implication that one stage mechanistically follows another is a hypothesis requiring further study.Moreover, the "pathognomonic lesion of CTE" (i.e., an abnormal perivascular accumulation of abnormal hyperphosphorylated tau in neurons, astrocytes, and cell processes in an irregular pattern around small blood vessels at the depths of the cortical sulci) is not, in fact, unique to CTE. Tau deposition is the predominant pathology in a number of neurologic diseases that have never been linked to athletics or head trauma. Some of these diseases have genetic causes, some have environmental toxic causes, and others are still of unknown cause. The first "baby step" toward the development of validated neuropathological criteria for CTE, taken in 2016 by the first of a proposed series of consensus panels funded by the NINDS/NIBIB, involved an extremely limited number of brain samples from just a handful of the known tauopathies, i.e., 10 recently acquired cases of suspected CTE, including 7 cases with β-amyloid plaques and 3 cases without β-amyloid plaques; 5 cases of Alzheimer’s (AD); and 2 cases each of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), parkinsonism dementia complex of Guam (GPDC), argyrophilic grain disease, and primary age-related tauopathy (PART). All of these were "of at least moderate disease severity" (the AD cases all being Braak stage V-VI, for example), which may not reflected the neuropathologies of earlier stages.Other tauopathies that have not yet been "officially" evaluated for "CTE lesions" by a consensus panel include FTDP-17, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, epilepsy, Down syndrome, Pick complex disorders, autism, Creutzfeldt-Jakob disease, the Lewy body variant of Alzheimer's disease, hippocampal sclerosis, hippocampal-sparing AD, limbic-predominant AD (LP-AD), the various "aging-related tau astrogliopathy" (ARTAG) types, schizophrenia, and alcohol and/or drug abuse.Some of these are already known to produce so-called "CTE pathology." For example, several recent studies concluded that brain tissue from nonposttraumatic epilepsy cases displayed levels and expression patterns of phosphorylated tau that were virtually indistinguishable from samples obtained from postmortem brains with CTE, and even from a few "control" samples. The researchers also noted that they cannot rule out that CTE patients were epileptic or suffering from occasional seizures during their life span. This is not implausible given that epilepsy may be a long-term complication of TBI. A 2015 study did not find an association between head injury and amyotrophic lateral sclerosis (ALS), and, in fact, the tau pathology of CTE was evident in ALS cases regardless of whether they had suffered a head injury. A 2016 study on the frequency of ARTAG in the basal forebrain supported the concept that CTE and ARTAG may share a common etiological pathway. Studies published in 2017 concluded that several ARTAG types may coexist in the same brain; and that there is considerable overlap of ARTAG with CTE- and primary FTLD-tauopathy-related tau pathologies. A 2016 study of the brains of individuals age 18-60 years, from a routine neuropathology service, concluded that alcohol and/or drug (opiates and steroids) abuse were significant predictors of CTE-like changes, even in the absence of head trauma.In fact, the "pathognomonic lesion of CTE" is even seen in the brains of cognitively normal people.Now, the above depends on the presence of tau, and sometimes on the presence of hyperphosphorylated tau. However, tau is a much more complicated protein than this would imply -- the structure and morphology of tau itself is highly variable, making it a much more complex analyte than β-amyloid and other proteins. To further complicate the matter, tau aggregates are subject to an array of posttranslational modifications including acetylation, glycosylation, glycation, prolyl-isomerization, nitration, and ubiquitination, all of which have the potential to alter the morphology of tau and, thus, affect the ability of specific stains and antibodies to bind to it as an analyte. To date, I have found very little indication that any study on CTE has evaluated the structure, morphology, and posttranslational modifications of the tau proteins in the neurofibrillary aggregates, or the structure and composition of the constituents -- including non-tau constituents -- in the aggregates.In fact, the most intriguing question relevant both to the physiological and pathophysiological function of tau is the biological meaning of the large heterogeneity of isoforms of tau ... meaning that immunostaining may not be nearly specific enough to untangle which isoforms are involved in any of the many different tauopathies.Finally, descriptions of the first consensus meeting on the neuropathology of CTE reveal several other serious flaws that cause the findings to be highly questionable. Seven neuropathologists were given digitised images to review on the 25 cases of a variety of tauopathies. They were made aware in advance this was a study of CTE and given the proposed criteria for CTE but were blinded to the individual cases. They reported an overall Kappa of 0.67 for tauopathies and a Kappa of 0.78 for CTE. [Cohen's kappa coefficient (κ) is a statistic which measures inter-rater agreement for qualitative (categorical) items. In general, a Kappa score of 0.61–0.80 is considered to show substantial agreement among raters.] In the 10 cases of presumptive CTE, the seven neuropathologists (i.e., 70 reviews) were classed as being in agreement if they simply identified CTE. There were seven disagreements where one or more reviewer failed to mention CTE which formed the basis of Kappa statistic. However, in a further 36 of those 70 reviews, additional diagnoses were identified which had not been described a priori by the study leads, usually comorbid Alzheimer's pathology. The Kappa score did not include these 36 non-CTE diagnoses. I.e., there was considerable disagreement among the raters that was not reported in the original publication. Given the average age of the cases was 70, one would have thought that it was essential to be able to distinguish CTE from Alzheimer's, as the null hypothesis must surely be that it is simply an atypical distribution of Alzheimer's pathology, or even simply age-related changes. (The activity of the phosphatases which dephosphorylate phosphorylated tau changes with age and temperature, thus affecting the amount of phosphorylated tau found in brain specimens in an age-dependent manner. NFTs are commonly found in the aging brain and often have no direct correlation with functional deficits.)Maroon et al (2015) systematically reviewed all published cases of CTE and found that multiple duplicate publications cited what turned out to be a total of 153 cases. They concluded that "the neuropathological and clinical findings related to CTE overlap with many common neurodegenerative diseases. Our review reveals significant limitations of the current CTE case reporting and questions the widespread existence of CTE in contact sports."Despite the numerous limitations to the extremely preliminary NINDS/NIBIB study, and conflicting evidence from many other studies, the "pathognomonic lesion of CTE" is now widely represented (I should say "misrepresented") as "proving" the existence of a distinct and separate, progressive neurodegenerative disorder, and is used to confirm the "diagnosis" of CTE.The direct causation of CTE-like p-tau deposits by trauma is not fully established. For example, it is not clear why CTE-like deposits do not develop at sites of cerebral contusion. The absence of CTE-like changes at sites of contusion make hypotheses concerning blood-brain barrier opening, inflammation, and (iron-associated) oxidative changes less appealing as the initiators of the process. There is also concern that these tiny abnormalities might not have any specific clinical significance, at all.Finally, some reviews have noted that studies with negative findings are less likely to be published, and since only published studies are reviewed, there is a potential for publication bias in the reviews' conclusions.For some of the objective reviews on what is, and is not, known about CTE, see, e.g.:-- Harmon KG, Clugston JR, Dec K, et al. American Medical Society for Sports Medicine position statement on concussion in sport. Br J Sports Med 2019;53:213–225.American Medical Society for Sports Medicine position statement on concussion in sport-- Iverson GL, Keene CD, Perry G, Castellani RJ. The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features. Journal of Alzheimer's Disease 2018; 61(1): 17–28.The Need to Separate Chronic Traumatic Encephalopathy Neuropathology from Clinical Features-- Aldag M, Armstrong RC, Bandak F, Bellgowan PS, Bentley T, Biggerstaff S, Caravelli K, Cmarik J, Crowder A, DeGraba TJ, Dittmer TA. The biological basis of chronic traumatic encephalopathy following blast injury: a literature review. Journal of neurotrauma. 2017 Sep 1;34(S1):S-26.The Biological Basis of Chronic Traumatic Encephalopathy following Blast Injury: A Literature Review-- Manley G, Gardner AJ, Schneider KJ, et al. A systematic review of potential long-term effects of sport-related concussion. Br J Sports Med 2017;51:969-977.A systematic review of potential long-term effects of sport-related concussion-- Brix KA, Brody DL, Grimes JB, Yitzhak A. Military Blast Exposure and Chronic Neurodegeneration: Summary of Working Groups and Expert Panel Findings and Recommendations. Journal of Neurotrauma. 2017 Sep 1;34(S1):S-18.Military Blast Exposure and Chronic Neurodegeneration: Summary of Working Groups and Expert Panel Findings and Recommendations-- McAllister T, McCrea M. Long-term cognitive and neuropsychiatric consequences of repetitive concussion and head-impact exposure. Journal of athletic training. 2017 Mar;52(3):309-17.Long-Term Cognitive and Neuropsychiatric Consequences of Repetitive Concussion and Head-Impact Exposure-- Senecal G, Gurchiek E, Slattery E. The brain and beyond in the aftermath of head trauma-a systems view of development for contact sport athletes. Cogent Psychology. 2017 Jan 1;4(1):1330935.https://cogentoa.com/article/10.1080/23311908.2017.1330935-- Carson A. Concussion, dementia and CTE: are we getting it very wrong? J Neurol Neurosurg Psychiatry 2017;88:462-464.https://pdfs.semanticscholar.org/6917/6d01dd5536daebf6de49a46221be138efe9e.pdf-- Ban VS, Madden CJ, Bailes JE, et al. The Science and Questions Surrounding Chronic Traumatic Encephalopathy. Neurosurg Focus. 2016;40(4):e15Medscape Log In-- Asken BM, Sullan MJ, Snyder AR, Houck ZM, Bryant VE, Hizel LP, et al. Factors influencing clinical correlates of chronic traumatic encephalopathy (CTE): a review. Neuropsychol Rev. 2016; 26:340-363.Factors Influencing Clinical Correlates of Chronic Traumatic Encephalopathy (CTE): A Review-- Castellani RJ, Perry G, Iverson GL. Chronic effects of mild neurotrauma: putting the cart before the horse?. Journal of Neuropathology & Experimental Neurology. 2015 Jun 1;74(6):493-9.Chronic Effects of Mild Neurotrauma: Putting the Cart Before the Horse?-- Castellani RJ. Chronic traumatic encephalopathy: A paradigm in search of evidence?. Laboratory Investigation. 2015 Jun;95(6):576.Chronic traumatic encephalopathy: A paradigm in search of evidence?-- Maroon JC, Winkelman R, Bost J, Amos A, Mathyssek C, Miele V. Chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases. PLoS One (2015) 10:e0117338. Chronic Traumatic Encephalopathy in Contact Sports: A Systematic Review of All Reported Pathological Cases-- Randolph C. Is Chronic Traumatic Encephalopathy a Real Disease? Curr Sports Med Rep. 2014; 13(1):33-37.Is Chronic Traumatic Encephalopathy a Real Disease? : Current Sports Medicine Reports-- Karantzoulis S, Randolph C. Modern chronic traumatic encephalopathy in retired athletes: what is the evidence? Neuropsychol Rev. 2013;23(4):350–60.http://mercy.typepad.com/files/brain-damage-in-athletes.pdfThere are many other reviews that agree with those on the above list, and may even contain a few additional concerns about the limitations of the work done to date and the "conclusions" trumpeted by the news media. For example, a 2017 JAMA review discussed at length the fact that few data exist on expected or normal-range functioning in elite athletes. Instead, expected performance is often based on performance of individuals with similar demographic characteristics such as age, sex, race/ethnicity, and years of education. Controlling or adjusting for years of education is complicated for many elite athletes whose quality of education (i.e., educational achievement, typically defined by literacy level or vocabulary skills) may be far below their actual years of education. It has been well established that considering quality of education, rather than quantity, is a far better method for characterizing cognitive performance in individuals with notable discrepancies between educational quality and quantity. Studies show that factoring in these "crystallized" abilities (i.e., those unaffected by disease processes) significantly attenuates racial/ethnic differences in test scores, and is likely superior to quantity of education at estimating memory, attention, semantic fluency, and executive functioning, among other domains. Family socioeconomic background, including income, education, occupation, access to medical care, and early cognitive stimulation, significantly affects adult functioning. Socioeconomic background is associated with childhood disorders such as learning disabilities or ADHD, which in turn affect the functioning of professional athletes and influence later expression of neurodegenerative disorders. Asken et al (above) gives a particularly extensive and compelling discussion of biopsychosocial factors that may contribute to symptoms commonly associated with CTE.Numerous papers claim that CTE was first reported in boxers in 1920, when it was called "punch drunk syndrome", later replaced by the term "dementia pugilistica’ in 1937. Castellani and Perry (2017) produced an objective, detailed, comprehensive review of all studies that have been done on boxers. It emphasizes the extensive neurotrauma incurred by boxers prior to World War II, which vastly exceeded the levels of exposure today; the considerable heterogeneity seen in the clinical symptoms and neuropathology; the fact that even among historical cases with extreme levels of trauma exposure, progressive disease was the exception rather than the rule; and the rarity of "dementia pugilistica" in modern-day boxers. The few dementia pugilistica cases reported in the recent literature either lack the neurological syndrome (dysarthria, ataxia, asymmetric hyperreflexia, etc.) that allowed identification of dementia pugilistica in the first place, or have clinical signs that are attributable to other major diseases. Nowadays, supposed "dementia pugilistica" is diagnosed purely by p-tau immunohistochemistry, either in the absence of neurological signs or in the context of other neurological diseases. This leaves open the question of whether there is any clinical significance of the patchy p-tau immunoreactivity, identified by highly sensitive means, that is now considered to be the "pathognomonic lesion of CTE." Notably, 7 of the 68 best-studied boxers included in the 2013 review by Smith et al did not have hyperphosphorylated tau, which is supposedly "the" hallmark feature of CTE.- - - --- Castellani RJ, Perry G. Dementia Pugilistica Revisited. Journal of Alzheimer's Disease. 2017 Jan 1;60(4):1209-21.Dementia Pugilistica Revisited-- Smith DH, Johnson VE, Stewart W. Chronic neuropathologies of single and repetitive TBI: substrates of dementia? Nat Rev Neurol. 2013;9:211–221.Chronic neuropathologies of single and repetitive TBI: substrates of dementia?A comparison of community-based studies on dementia [Rush Memory and Aging Project (USA), Religious Orders Study (USA), Medical Research Council Cognitive Function and Ageing Study (UK), Cambridge City Over-75's Cohort (UK), Vantaaa 85+ (Finland), Hisayama (Japan), Honolulu–Asia Aging Study (USA, Japanese–American), Adult Changes in Thought (USA), Baltimore Longitudinal Study of Ageing (USA), Oregon Brain Aging Study (USA), 90+ Study (The Leisure World Retirement Community, USA), and Vienna Trans-Danube Aging (VITA) study (Austria)] with recent clinic-based studies showed that more atypical pathologies are found in clinic-based studies and, therefore, generalization of their findings to the general population may be problematic.The constantly changing perspectives on Alzheimer's, despite the disease having been extensively studied in thousands of postmortem brains and tens of thousands of patients, make it painfully clear that no one can possibly claim to be able to diagnose or describe CTE from the miniscule amount of research done to date.For one thing, there can be a great deal of variability in the pathological features of the brain, even within a "single" neurological disorder. Some of this variability may be common and consistent enough to rise to the definition of a "subtype" or "variant." For example, prototypic Alzheimer's is a late-onset AD (LOAD) syndrome with amnestic impairment predominating in association with hippocampal and temporal-parietal atrophy and/or decreased perfusion/metabolism. Clinically, memory decline is accompanied by similar worsening in other cognitive domains. Relatively symmetric and generalized atrophy and hypometabolism/hypoperfusion distinguish typical AD from the more focal topography of variants.Temporal variant AD is a syndrome of isolated episodic memory impairment with notably slow decline; even when memory is significantly impaired, visuospatial and executive function remain borderline to normal. Plaques and neurofibrillary tangles are limited to the limbic regions with little or no spread to the neocortical areas; hypoperfusion is limited to the mesiotemporal lobes, while the temporal-parietal changes seen in prototypic AD are absent. Unique among atypical AD variants, temporal variant AD is a LOAD syndrome, and may present even later than typical AD.In several other variants, non-amnestic presentations predominate. For example, language variant AD is often an early-onset sporadic AD (EOAD) syndrome of gradually worsening non-fluent speech typified by significant agrammatism, phonemic paraphasias, relative preservation of memory, and often atrophy of the left perisylvian region on imaging. These individuals have pathologically confirmed AD with a topographically atypical distribution of neurofibrillary tangles predominantly within the left neocortex, sometimes sparing the hippocampus. The early non-fluent language impairment of this subtype distinguishes it from the aphasic syndrome of prototypic AD, which is generally semantic in nature, with surface dyslexia occurring as a feature of later stage disease.This non-fluency also distinguishes language variant AD from the second AD language syndrome, Logopenic Progressive Aphasia (LPA). In LPA, speech rate is slowed but grammar and articulation are preserved. Rather, impaired repetition typifies LPA. LPA is commonly associated with AD pathology, demonstrates left posterior temporal and inferior parietal hypoperfusion, and has a strong association with β-amyloid deposition on PiB-PET.Frontal variant AD is an extremely rare EOAD subtype, associated with significant frontal cognitive and behavioural symptoms. Pathologically there is a predominance of NFT in the frontal regions (10-fold increase over prototypic AD), with comparable loading in the entorhinal cortex and other regions. Amyloid plaques and the lack of the cell loss, microvacuolarization, and gliosis in layers II and III distinguish frontal variant AD from FTD.An inferior parietal lobule variant of EOAD, which commonly presents with progressive acalculia (difficulty performing simple mathematical tasks, such as adding, subtracting, multiplying and even simply stating which of two numbers is larger), has been reported recently; MRI imaging disclosed biparietal atrophy, disproportionately worse on the left.Several newer criteria now give well-defined schemes under which co-morbidities can be recognized within the context of AD. These employ the term "possible AD," such as "clinically possible, due to etiologically mixed AD". Allowed co-morbidities include (1) "substantial" cerebrovascular disease (i.e. temporally related stroke or presence of multiple/extensive infarcts), (2) core features of DLB (aka the "Lewy body variant of AD", which is associated with more perceptual impairment, though milder than what occurs in "pure" DLB), (3) other active neurologic disease, (4) other active non-neurologic disease, and (5) cognitive-affecting medication use. Considering only dementia-associated pathologies, the frequency of non-classical AD findings (including neocortical Lewy bodies, hippocampal sclerosis, and microinfarcts) ranged in one study from 9.7-43%. The same study found that such co-morbidities independently correlated with cognitive decline, suggesting that quantity of total pathology, rather than specific pathologies, determined disease severity.Even considering only the classical AD pathological processes, there is increasing evidence of variation in topography (i.e., the distribution of AD pathology and associated atrophy) which can define subtypes of AD. For example, hippocampal-sparing AD and limbic-predominant AD account for about 25% of AD. In comparison to prototypic AD, hippocampal-sparing AD has higher NFT densities in cortical areas and lower NFT densities in hippocampus, while limbic-predominant AD has lower NFT densities in cortical areas and higher NFT densities in the hippocampus. Hippocampal-sparing AD has less hippocampal atrophy than prototypic AD and limbic-predominant AD. Clinical presentation, age of onset, disease duration, and rate of decline differ among the AD subtypes.Variation also occurs in non-neuronal Alzheimer's pathology. For example, neuropathological, genetic, and biochemical studies have provided support for the hypothesis that microglia participate in AD pathogenesis. Five microglia morphological phenotypes have been identified, i.e., ramified, hypertrophic, dystrophic, rod-shaped, and amoeboid. Preliminary studies have found variations in microglial characteristics that show some degree of disease specificity, including, (1) increased microglia density and number in hippocampal sclerosis of aging (HS-aging) and mixed AD + HS-aging; (2) low microglia density in Dementia with Lewy bodies; (3) increased number of dystrophic microglia in HS-aging; and (4) increased proportion of dystrophic to all microglia in Dementia with Lewy bodies.The term comorbidities or mixed pathologies is used when brain tissue displays a mixture of protein alterations or other pathologies. There are numerous reports indicating that when "concomitant" pathologies are seen in a patient with certain neurodegenerative diseases, the clinical phenotype might be altered. In addition, there are cases where many alterations are seen in a sparse extent, but jointly they lead to a clinical syndrome. On the other hand, several protein alterations are found in middle-aged and aged brains from cognitively normal subjects, including hyperphosphorylated tau, β-amyloid, α-synuclein, and Tar DNA-binding protein. Thus it is no longer sufficient to confirm a certain pathology to be seen, e.g., AD- or LBD-related; in addition the concomitant aging-related alterations have to be looked for.Mixed pathologies are surprisingly common. Although AD has been regarded as the most common cause of dementia in older people, the prevalence of mixed pathologies is, on average, at least as frequent. Mixed pathologies increase the odds of dementia up to almost 10 times, and up to three times compared with patients with only one pathology. Moreover, the higher the Braak and Braak stage of neurofibrillary degeneration and the amount of NPs, the more probable the presence of further pathological alterations. The rate of neuropathologically confirmed intermediate- and high-likelihood AD plus any other second pathology was reported as up to almost 54% in a subset of the Rush Memory and Aging Project cohort. In the VITA study, where mixed pathologies were defined as any other pathologies, including also less regarded pathologies such as HS and TDP-43 proteinopathy, and non-AD tauopathies, the prevalence of mixed pathologies was over 70%. The Honolulu–Asia Aging Study also concluded that the co-occurrence of combined pathologies contributes to the severity of dementia and that the frequency of these pathologies increases with age. The high prevalence of mixed pathologies confirmed by autopsy supports the theory that a combination of neuropathological alterations often has a cumulating effect, and -- if reaching the individual's threshold for cognitive impairment -- manifests as clinical dementia.There are a number of what were initially thought to be unique disorders that were subsequently discovered to be syndromes found in several neurodegenerative disorders. Understanding the potential mechanisms underlying a disease of the brain requires correlating accurate syndromic diagnosis with pathology, genetics, and imaging. For example, Corticobasal Syndrome (CBS) is a progressive, neurodegenerative condition characterized by asymmetric motor symptoms in the setting of apraxia, cortical sensory impairment, and, in prototypic cases, the alien limb phenomenon. CBS was previously thought to be associated with specific pathological changes termed Corticobasal Degeneration (CBD). However, it was eventually discovered that confirmed CBS due to CBD (CBS-CBD) affects only a subset of patients. It is now recognized that CBS occurs in association with a number of other pathologies including sporadic Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Creutzfeldt-Jakob disease (CJD), and progressive supranuclear palsy (PSP). Genetic causes of clinical CBS also vary, with causative mutations identified in Microtubule-Associated Protein Tau (MAPT), Progranulin (PGRN), and hexanucleotide repeat expansions in C9orf72. Two mutations in the Presenilin-1 gene (PSEN1), which are responsible for the majority of early-onset familial Alzheimer's disease (eFAD) cases, have recently been associated with CBS.