Review Of Current Diabetes Guidelines In Older Adults: Fill & Download for Free

Sweet taste without the calories sounds like a perfect example of no pain, all gain but unfortunately cumulative data suggests otherwise. A poster child for unintended consequences, diet soda (Diet drink) typically contains a type of non-caloric artificial sweetener, Sugar substitute called Aspartame, e.g., NutraSweet or Equal (sweetener). Unintended consequences in the form of not just weight gain but also increased risk of Cardiovascular disease, Diabetes mellitus type 2, Hypertension, Metabolic syndrome, all vigorously disputed of course (see some examples in references 1, 2), which brings us to the glaring caveat we need to keep front and center when considering the science about artificial sweeteners. Historically the food and beverage industry has funded nutrition research so substantially, the ensuing entrenched conflict of interest renders the phrase 'nutrition science' an oxymoron (3).North America currently leads in sales and consumption of diet beverages (see below from 4).Artificial sweetener consumption patterns tend to change rapidly in response to widespread perception of harm attendant to one type of artificial sweetener or another. US artificial sweetener consumption for example moved from cyclamate in the 1960s to Saccharin, e.g., Sweet'n Low, to aspartame which reigned supreme for several decades until being upstaged in the 2010s by Sucralose, e.g., Splenda, mainly because it's highly stable in food (5) while Acesulfame potassium (Ace-K), e.g., Sunett, Sweet & Safe, Sweet One, is also increasing in use. Pepsi embodies such rapid change. In 2015 it changed its US Diet Pepsi formulation replacing aspartame with sucralose and Ace-K (6) but for reasons best known to itself announced in 2016 it was bringing aspartame back while also retaining the reformulated products (7). Meantime so-called natural sweeteners like Stevia aka Truvia are also rapidly increasing in prevalence (4).'If you can avoid taking in more food, does diet soda still somehow make you gain weight?'Weight gain without increased food intake is in fact a strikingly consistent observation in many animal model studies on artificial sweeteners (8, 9, 10). How does this happen? Problem with understanding how these artificial sweeteners affect human metabolism and health long-term is each artificial sweetener is different in chemistry, biology and pharmacokinetics (11, 12, 13, 14, see below from 4, 15). Obviously each will induce different metabolic and health effects.For long, uncertainty dogged epidemiological studies on artificial sweeteners. Do they cause cancer or not? Do they increase risk of diabetes and/or obesity or not? Do they play a role in metabolic syndrome or not? And so on. Given the big bucks riding on ensuring people continued to guzzle at least diet soda even as the tide turned against sodas in general (16), unsurprising really that much of this data is conflicting, mostly due to avoidable study design flaws such as assessing artificial sweetener consumption in conditions far removed from how they're consumed in real life, which is as part of a typical unhealthy 'Western' diet replete in highly processed food and as part of a highly sedentary lifestyle. Few studies included children or elderly or minorities or low income, few examined long-term/chronic/habitual artificial sweetener consumption.In other words, vast chasm between such studies and real life artificial sweetener consumption patterns. Most importantly, since different artificial sweeteners are used in different processed foods and drinks and since studies rarely address a single artificial sweetener specifically, we essentially don't understand how each artificial sweetener influences metabolism and health long-term (17).The few studies such as the San Antonio Heart (18) and Longitudinal Study of Aging (19) that examined elderly and minorities long-term (7 to 9 years follow-up) found substantial weight and waist circumference gain with artificial sweetener consumption (in soda, coffee or tea), even without increased food intake, which echoes animal model studies. Increased abdominal fat is of course now a well-known risk factor for cardiovascular disease and type II diabetes.How to make at least minimal sense of the tower of Babel that is artificial sweetener-related data? Same way as other prickly scientific issues, by looking at conclusions of systematic reviews and Meta-analysis. However, given the entrenched practice of the food and beverage industry funding a massive amount of nutrition research, not meta-analyses by just anyone but rather by those not funded by them. Since Publication bias, i.e., overweening dominance of studies with statistically significant results, is widespread, such reviews and analyses will naturally also be hobbled by the same drawback. However, since they use a set of objective criteria to assess a wide variety of individual studies ranging from cross-sectional to interventional to observational to prospective to randomized, placebo-controlled trials, they're still far more robust and objective than individual studies claiming to find in favor of one or other hypothesis.One such review (20) was conducted by federally funded Purdue University researcher Susan E. Swithers. It assessed differences between diet soda non-consumers and consumers among >450000 participants across 14 independent Prospective cohort study, including the San Antonio Heart Study (18), with an average 16-year followup. It concluded that regardless of baseline weight in the two groups, regardless naturally or artificially sweetened, soda consumption increased risk of not just weight gain but also cardiovascular disease, hypertension, metabolic syndrome and type II diabetes (20). Typically, bad news about artificially sweetened stuff is discredited by arguing overweight people tend to choose it in the first place trying to lose weight, i.e., by arguing reverse causality (21). In other words, arguing drinking artificially sweetened stuff doesn't cause weight gain, rather overweight people drink it to try to lose weight. This review (20) found that not to be the case.Swithers concluded (20),‘recent data from humans and rodent models have provided little support for ASB(everages) [artificially sweetened beverages] in promoting weight loss or preventing negative health outcomes such as T2D [type II diabetes], metabolic syndrome and cardiovascular event'‘current findings suggest that caution about the overall sweetening of the diet is warranted, regardless of whether the sweetener provides energy directly or not’No surprise these conclusions were vigorously disputed on the grounds that (22)'Robust scientific evidence demonstrates benefits of artificial sweeteners’In her authoritative rebuttal (23), Swithers points out the American Heart Association (AHA) and American Diabetes Association (ADA) themselves stated in 2012 lack of robust scientific data about artificial sweeteners (24, emphasis mine),‘paucity of data from well-designed human trials exploring the potential role of (non-nutritive sweeteners) in achieving and maintaining a healthy body weight and minimizing cardiometabolic risk factors.’In other words, these products have been unleashed indiscriminately on society, making their way into thousands upon thousands of food and drinks that billions consume and yet we apparently don't know enough to conclude if they're beneficial or not. Sounds like a recipe for a slow motion disaster, which the modern-day global obesity epidemic indeed is, with both sugars and artificial sweeteners obviously playing leading roles.Another systematic review of 18 studies by US NIH researchers found association between consumption of artificial sweetened beverages and weight gain in children and teens (25).Future artificial sweetener research will likely coalesce around at least 3 aspects:1) How artificial sweeteners influence Gut flora composition and metabolism.2) How they drive behavioral & metabolic compensation.3) Biomarkers to identify those at highest risk of sugar/replacer-induced weight gain and/or metabolic disruption.1) Artificial sweetener effect on Gut flora composition and metabolism.Since most artificial sweetener studies focus on their effect on body weight, important aspects about their metabolism remain under-studied. This is because they were for long considered inert, passing through the GI tract, untouched, unused, little perturbed and little perturbing. Turns out that's not the case at all (26).In a mouse model study (27), maximal daily accepted doses of saccharin, sucralose and aspartame in their drinking water for five weeks induced mouse gut microbiota changes and Impaired glucose tolerance. How this happens is still not clear, especially since aspartame is fully digested to its constituent amino acids in the small intestine unlike saccharin and sucralose. Study found similar results in human volunteers as well. Since most of its experiments involved saccharin, this study's major caveat is limited relevance for diet sodas, which mostly contain aspartame. Obviously similar, larger study needs to examine aspartame effect separately.In a rat model study (28), aspartame exposure led to gut microbiota changes and elevated fasting glucose and reduced insulin-stimulated glucose consumption.Caveat common to all fecal microbiota studies, not just this one: Fecal samples mostly represent distal colon microbiota. Different parts of the GI tract obviously harbor different microbial populations (29). This is especially pertinent for diet vis-a-vis weight gain since most nutrient digestion and absorption is in the small intestine, whose microbial composition is still rather a black box.Implications of artificial sweetener-induced gut microbiota change:Are such changed microbiota better at nutrient harvesting? Better at driving adipose tissue energy storage?These would help explain weight gain even without increased food intake.Are they more harmful to gut's long-term health, making it more leaky, Intestinal permeability, triggering systemic inflammation?This would help explain the long-term harmful consequences such as metabolic syndrome and attendant increased risk of cardiovascular disease and type II diabetes.2) Hypothesis: artificial sweeteners drive behavioral & metabolic compensationSince the 1990s, Purdue University researcher Susan E. Swithers has pioneered animal model studies to explore how artificial sweeteners could uncouple sweet tastes from their metabolic consequences and thus distort ability to predict the latter. In other words, artificial sweeteners may alter how the brain processes reward for sweet taste. Her reviews refer to several such experimental studies (30, 31) by hers and other groups.3) Biomarkers to identify those at highest risk of sugar/replacer-induced weight gain and/or metabolic disruptionBiomarker are measurable, often quantifiable biological indicators of some condition.As with anything diet-related, some seem to gain weight no matter what or how much they eat, some don't while most of the rest fall somewhere in between. How to proactively identify those at highest risk of weight gain and/or metabolic disruption from artificial sweeteners? The US Scientific Report of the 2015 Dietary Guidelines Advisory Committee advises (32),'future experimental studies should examine the relationship between ASSD [artificially sweetened soft drinks] and biomarkers of insulin resistance and other diabetes biomarkers'Only when we have data from such studies will we be able to delve into genetic markers, specific gut microbiota composition, etc., that differentiate those most at risk from the harmful effects of artificial sweeteners, something we have no clue of at present.Bibliography1. Stevens, Haley Curtis. "Diabetes and diet beverage study has serious limitations." The American journal of clinical nutrition 98.1 (2013): 248-249. Diabetes and diet beverage study has serious limitations2. La Vecchia, Carlo. "Artificially and sugar-sweetened beverages and incident type 2 diabetes." The American journal of clinical nutrition 98.1 (2013): 249-250. Artificially and sugar-sweetened beverages and incident type 2 diabetes3. Vox, Julia Belluz, August 16, 2016. Why (almost) everything you know about food is wrong4. Popkin, Barry M., and Corinna Hawkes. "Sweetening of the global diet, particularly beverages: patterns, trends, and policy responses." The Lancet Diabetes & Endocrinology 4.2 (2016): 174-186.5. Sylvetsky, Allison C., and Kristina I. Rother. "Trends in the consumption of low-calorie sweeteners." Physiology & behavior (2016).6. The Guardian, Suzi Gage, 28 April, 2015. Diet Pepsi has dropped aspartame in the US, so why not anywhere else?7. Fortune, John Kell, June 27, 2016. Diet Pepsi with aspartame is making a comeback8. Abou-Donia, Mohamed B., et al. "Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats." Journal of Toxicology and Environmental Health, Part A 71.21 (2008): 1415-1429. https://www.researchgate.net/profile/Benyagoub_Mohamed/publication/23263644_Splenda_alters_gut_microflora_and_increases_intestinal_p-glycoprotein_and_cytochrome_p-450_in_male_rats/links/02bfe50db40f9a9ef1000000.pdf9. Polyák, Éva, et al. "Effects of artificial sweeteners on body weight, food and drink intake." Acta Physiologica Hungarica 97.4 (2010): 401-407. https://www.researchgate.net/profile/Eva_Polyak/publication/49665151_Effects_of_artificial_sweeteners_on_body_weight_food_and_drink_intake/links/5710b31d08ae68dc7909a592.pdf10. de Matos Feijó, Fernanda, et al. "Saccharin and aspartame, compared with sucrose, induce greater weight gain in adult Wistar rats, at similar total caloric intake levels." Appetite 60 (2013): 203-207. https://www.researchgate.net/profile/Marcello_Bertoluci2/publication/232609508_Saccharin_and_aspartame_compared_with_sucrose_induce_greater_weight_gain_in_adult_Wistar_rats_at_similar_total_caloric_intake_levels/links/09e41511db00feb3d5000000.pdf11. Byard, J. L., and L. Golberg. "The metabolism of saccharin in laboratory animals." Food and cosmetics toxicology 11.3 (1973): 391-402.12. Ranney, R. E., et al. "Comparative metabolism of aspartame in experimental animals and humans." Journal of Toxicology and Environmental Health, Part A Current Issues 2.2 (1976): 441-451.13. Arnold, D. L., D. Krewski, and I. C. Munro. "Saccharin: a toxicological and historical perspective." Toxicology 27.3 (1983): 179-256.14. Roberts, A., et al. "Sucralose metabolism and pharmacokinetics in man." Food and chemical toxicology 38 (2000): 31-41.15. Logue, C., et al. "The potential application of a biomarker approach for the investigation of low-calorie sweetener exposure." Proceedings of the Nutrition Society 75.02 (2016): 216-225.16. The New York Times, Margot Sanger-Katz, October 2, 2015. The Decline of ‘Big Soda’17. Wiebe, Natasha, et al. "A systematic review on the effect of sweeteners on glycemic response and clinically relevant outcomes." BMC medicine 9.1 (2011): 1. BMC Medicine18. Fowler, Sharon P., et al. "Fueling the obesity epidemic? Artificially sweetened beverage use and long‐term weight gain." Obesity 16.8 (2008): 1894-1900. https://www.researchgate.net/profile/Ken_Williams6/publication/5321117_Fueling_the_Obesity_Epidemic_Artificially_Sweetened_Beverage_Use_and_Long-Term_Weight_Gain./links/0a85e5389cca553bf7000000.pdf19. Fowler, Sharon PG, Ken Williams, and Helen P. Hazuda. "Diet soda intake is associated with long‐term increases in waist circumference in a biethnic cohort of older adults: The San Antonio longitudinal study of aging." Journal of the American Geriatrics Society 63.4 (2015): 708-715. http://www.nutritiondesseniors.fr/wp-content/uploads/2015/03/soda-light-et-obesite-JAGS2015-2.pdf20. Swithers, Susan E. "Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements." Trends in Endocrinology & Metabolism 24.9 (2013): 431-441. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.689.8610&rep=rep1&type=pdf21. Drewnowski, A., and C. D. Rehm. "The use of low-calorie sweeteners is associated with self-reported prior intent to lose weight in a representative sample of US adults." Nutrition & diabetes 6.3 (2016): e202. http://www.nature.com/nutd/journal/v6/n3/pdf/nutd20169a.pdf22. Johnston, C. A., and J. P. Foreyt. "Robust scientific evidence demonstrates benefits of artificial sweeteners." Trends in endocrinology and metabolism: TEM 25.1 (2014): 1.23. Swithers, Susan E. "A paucity of data, not robust scientific evidence: a response to Johnston and Foreyt." Trends in Endocrinology & Metabolism 25.1 (2014): 2-4.24. Gardner, Christopher, et al. "Nonnutritive sweeteners: current use and health perspectives a scientific statement from the American heart association and the American diabetes association." Diabetes care 35.8 (2012): 1798-1808. http://care.diabetesjournals.org/content/diacare/35/8/1798.full.pdf25. Brown, Rebecca J., Mary Ann De Banate, and Kristina I. Rother. "Artificial sweeteners: a systematic review of metabolic effects in youth." International Journal of Pediatric Obesity 5.4 (2010): 305–312. http://seriecientifica.org/sites/default/files/art_swt_ped_brown_2010.pdf26. Nettleton, Jodi E., Raylene A. Reimer, and Jane Shearer. "Reshaping the gut microbiota: Impact of low calorie sweeteners and the link to insulin resistance?." Physiology & behavior (2016).27. Suez, Jotham, et al. "Artificial sweeteners induce glucose intolerance by altering the gut microbiota." Nature 514.7521 (2014): 181-186. https://www.researchgate.net/profile/Ilana_Kolodkin-Gal/publication/265791239_Artificial_sweeteners_induce_glucose_intolerance_by_altering_the_gut_microbiota/links/543266890cf22395f29c08b6.pdf28. Palmnäs, Marie SA, et al. "Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat." PLoS One 9.10 (2014): e109841. http://journals.plos.org/plosone/article/asset?id=10.1371%2Fjournal.pone.0109841.PDF29. Lichtman, Joshua S., et al. "The effect of microbial colonization on the host proteome varies by gastrointestinal location." The ISME journal (2015).30. Swithers, Susan E. "Artificial sweeteners are not the answer to childhood obesity." Appetite 93 (2015): 85-90. http://www1.appstate.edu/~kms/classes/psy5300/Documents/Swithers2015-obesity.pdf31. Swithers, Susan E. "Not-so-healthy sugar substitutes?." Current opinion in behavioral sciences 9 (2016): 106-110. Not-so-healthy sugar substitutes?32. https://health.gov/dietaryguidelines/2015-scientific-report/pdfs/scientific-report-of-the-2015-dietary-guidelines-advisory-committee.pdfThanks for the R2A, Daniel Kaplan.

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.

Office of Dietary Supplements - Vitamin B12I tried to copy/paste everything here but the tables misalign, and if I snap a screen shot, it’s too small. Just click through the link. :) Highest food sources are beef liver and clams. They are significantly higher than everything else, like light years higher. So even if you don’t like them, taking even a little bit will be better than nothing.Recommended IntakesIntake recommendations for vitamin B12 and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Food and Nutrition Board (FNB) at the Institute of Medicine (IOM) of the National Academies (formerly National Academy of Sciences) [5]. DRI is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender [5], include:Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.Table 1 lists the current RDAs for vitamin B12 in micrograms (mcg) [5]. For infants aged 0 to 12 months, the FNB established an AI for vitamin B12 that is equivalent to the mean intake of vitamin B12 in healthy, breastfed infants.Sources of Vitamin B12FoodVitamin B12 is naturally found in animal products, including fish, meat, poultry, eggs, milk, and milk products. Vitamin B12 is generally not present in plant foods, but fortified breakfast cereals are a readily available source of vitamin B12 with high bioavailability for vegetarians [5,13-15]. Some nutritional yeast products also contain vitamin B12. Fortified foods vary in formulation, so it is important to read the Nutrition Facts labels on food products to determine the types and amounts of added nutrients they contain.Several food sources of vitamin B12 are listed in Table 2.*DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed DVs to help consumers compare the nutrient contents of products within the context of a total diet. The DV for vitamin B12 used for the values in Table 2 is 6.0 mcg for adults and children age 4 years and older [16]. This DV, however, is changing to 2.4 mcg as the updated Nutrition and Supplement Facts labels are implemented [17]. The updated labels and DVs must appear on food products and dietary supplements beginning in January 2020, but they can be used now [18]. FDA does not require food labels to list vitamin B12 content unless a food has been fortified with this nutrient. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.The U.S. Department of Agriculture’s (USDA’s) Nutrient DatabaseWeb site [13]) lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin B12 arranged by nutrient content and by food name.Dietary supplementsIn dietary supplements, vitamin B12 is usually present as cyanocobalamin [5], a form that the body readily converts to the active forms methylcobalamin and 5-deoxyadenosylcobalamin. Dietary supplements can also contain methylcobalamin and other forms of vitamin B12.Existing evidence does not suggest any differences among forms with respect to absorption or bioavailability. However the body’s ability to absorb vitamin B12 from dietary supplements is largely limited by the capacity of intrinsic factor. For example, only about 10 mcg of a 500 mcg oral supplement is actually absorbed in healthy people [8].In addition to oral dietary supplements, vitamin B12 is available in sublingual preparations as tablets or lozenges. These preparations are frequently marketed as having superior bioavailability, although evidence suggests no difference in efficacy between oral and sublingual forms [19,20].Prescription medicationsVitamin B12, in the form of cyanocobalamin and occasionally hydroxocobalamin, can be administered parenterally as a prescription medication, usually by intramuscular injection [12]. Parenteral administration is typically used to treat vitamin B12 deficiency caused by pernicious anemia and other conditions that result in vitamin B12 malabsorption and severe vitamin B12 deficiency [12].Vitamin B12 is also available as a prescription medication in a gel formulation applied intranasally, a product marketed as an alternative to vitamin B12 injections that some patients might prefer [21]. This formulation appears to be effective in raising vitamin B12 blood levels [22], although it has not been thoroughly studied in clinical settings.Vitamin B12 Intakes and StatusMost children and adults in the United States consume recommended amounts of vitamin B12, according to analyses of data from the 1988–1994 National Health and Nutrition Examination Survey (NHANES III) [5,23] and the 1994–1996 Continuing Survey of Food Intakes by Individuals [5]. Data from the 1999–2000 NHANES indicate that the median daily intake of vitamin B12 for the U.S. population is 3.4 mcg [24].Some people—particularly older adults, those with pernicious anemia, and those with reduced levels of stomach acidity (hypochlorhydria or achlorhydria) or intestinal disorders—have difficulty absorbing vitamin B12 from food and, in some cases, oral supplements [25,26]. As a result, vitamin B12 deficiency is common, affecting between 1.5% and 15% of the general population [27,28]. In many of these cases, the cause of the vitamin B12 deficiency is unknown [8].Evidence from the Framingham Offspring Study suggests that the prevalence of vitamin B12 deficiency in young adults might be greater than previously assumed [15]. This study found that the percentage of participants in three age groups (26–49 years, 50–64 years, and 65 years and older) with deficient blood levels of vitamin B12 was similar. The study also found that individuals who took a supplement containing vitamin B12 or consumed fortified cereal more than four times per week were much less likely to have a vitamin B12 deficiency.Individuals who have trouble absorbing vitamin B12 from foods, as well as vegetarians who consume no animal foods, might benefit from vitamin B12-fortified foods, oral vitamin B12 supplements, or vitamin B12 injections [29].Vitamin B12 DeficiencyVitamin B12 deficiency is characterized by megaloblastic anemia, fatigue, weakness, constipation, loss of appetite, and weight loss [1,3,30]. Neurological changes, such as numbness and tingling in the hands and feet, can also occur [5,31]. Additional symptoms of vitamin B12 deficiency include difficulty maintaining balance, depression, confusion, dementia, poor memory, and soreness of the mouth or tongue [32]. The neurological symptoms of vitamin B12 deficiency can occur without anemia, so early diagnosis and intervention is important to avoid irreversible damage [6]. During infancy, signs of a vitamin B12 deficiency include failure to thrive, movement disorders, developmental delays, and megaloblastic anemia [33]. Many of these symptoms are general and can result from a variety of medical conditions other than vitamin B12 deficiency.Typically, vitamin B12 deficiency is treated with vitamin B12 injections, since this method bypasses potential barriers to absorption. However, high doses of oral vitamin B12 may also be effective. The authors of a review of randomized controlled trials comparing oral with intramuscular vitamin B12 concluded that 2,000 mcg of oral vitamin B12 daily, followed by a decreased daily dose of 1,000 mcg and then 1,000 mcg weekly and finally, monthly might be as effective as intramuscular administration [27,28]. Overall, an individual patient’s ability to absorb vitamin B12 is the most important factor in determining whether vitamin B12 should be administered orally or via injection [8]. In most countries, the practice of using intramuscular vitamin B12 to treat vitamin B12 deficiency has remained unchanged [27].Folic acid and vitamin B12Large amounts of folic acid can mask the damaging effects of vitamin B12 deficiency by correcting the megaloblastic anemia caused by vitamin B12 deficiency [3,5] without correcting the neurological damage that also occurs [1,34]. Moreover, preliminary evidence suggests that high serum folate levels might not only mask vitamin B12 deficiency, but could also exacerbate the anemia and worsen the cognitive symptoms associated with vitamin B12 deficiency [6,11]. Permanent nerve damage can occur if vitamin B12 deficiency is not treated. For these reasons, folic acid intake from fortified food and supplements should not exceed 1,000 mcg daily in healthy adults [5].Groups at Risk of Vitamin B12 DeficiencyThe main causes of vitamin B12 deficiency include vitamin B12 malabsorption from food, pernicious anemia, postsurgical malabsorption, and dietary deficiency [12]. However, in many cases, the cause of vitamin B12 deficiency is unknown. The following groups are among those most likely to be vitamin B12 deficient.Older adultsAtrophic gastritis, a condition affecting 10%–30% of older adults, decreases secretion of hydrochloric acid in the stomach, resulting in decreased absorption of vitamin B12 [5,11,35-39]. Decreased hydrochloric acid levels might also increase the growth of normal intestinal bacteria that use vitamin B12, further reducing the amount of vitamin B12 available to the body [40].Individuals with atrophic gastritis are unable to absorb the vitamin B12 that is naturally present in food. Most, however, can absorb the synthetic vitamin B12 added to fortified foods and dietary supplements. As a result, the IOM recommends that adults older than 50 years obtain most of their vitamin B12 from vitamin supplements or fortified foods [5]. However, some elderly patients with atrophic gastritis require doses much higher than the RDA to avoid subclinical deficiency [41].Individuals with pernicious anemiaPernicious anemia, a condition that affects 1%–2% of older adults [11], is characterized by a lack of intrinsic factor. Individuals with pernicious anemia cannot properly absorb vitamin B12 in the gastrointestinal tract [3,5,9,10]. Pernicious anemia is usually treated with intramuscular vitamin B12. However, approximately 1% of oral vitamin B12 can be absorbed passively in the absence of intrinsic factor [11], suggesting that high oral doses of vitamin B12 might also be an effective treatment.Individuals with gastrointestinal disordersIndividuals with stomach and small intestine disorders, such as celiac disease and Crohn’s disease, may be unable to absorb enough vitamin B12 from food to maintain healthy body stores [12,26]. Subtly reduced cognitive function resulting from early vitamin B12 deficiency might be the only initial symptom of these intestinal disorders, followed by megaloblastic anemia and dementia.Individuals who have had gastrointestinal surgerySurgical procedures in the gastrointestinal tract, such as weight loss surgery or surgery to remove all or part of the stomach, often result in a loss of cells that secrete hydrochloric acid and intrinsic factor [5,42,43]. This reduces the amount of vitamin B12, particularly food-bound vitamin B12 [44], that the body releases and absorbs. Surgical removal of the distal ileum also can result in the inability to absorb vitamin B12. Individuals undergoing these surgical procedures should be monitored preoperatively and postoperatively for several nutrient deficiencies, including vitamin B12 deficiency [45].VegetariansStrict vegetarians and vegans are at greater risk than lacto-ovo vegetarians and nonvegetarians of developing vitamin B12 deficiency because natural food sources of vitamin B12 are limited to animal foods [5]. Fortified breakfast cereals and fortified nutritional yeasts are some of the only sources of vitamin B12 from plants and can be used as dietary sources of vitamin B12 for strict vegetarians and vegans. Fortified foods vary in formulation, so it is important to read the Nutrition Facts labels on food products to determine the types and amounts of added nutrients they contain.Pregnant and lactating women who follow strict vegetarian diets and their infantsVitamin B12 crosses the placenta during pregnancy and is present in breast milk. Exclusively breastfed infants of women who consume no animal products may have very limited reserves of vitamin B12 and can develop vitamin B12 deficiency within months of birth [5,46]. Undetected and untreated vitamin B12 deficiency in infants can result in severe and permanent neurological damage.The American Dietetic Association recommends supplemental vitamin B12 for vegans and lacto-ovo vegetarians during both pregnancy and lactation to ensure that enough vitamin B12 is transferred to the fetus and infant [47]. Pregnant and lactating women who follow strict vegetarian or vegan diets should consult with a pediatrician regarding vitamin B12 supplements for their infants and children [5].Vitamin B12 and HealthCardiovascular diseaseCardiovascular disease is the most common cause of death in industrialized countries, such as the United States, and is on the rise in developing countries. Risk factors for cardiovascular disease include elevated low-density lipoprotein (LDL) levels, high blood pressure, low high-density lipoprotein (HDL) levels, obesity, and diabetes [48].Elevated homocysteine levels have also been identified as an independent risk factor for cardiovascular disease [49-51]. Homocysteine is a sulfur-containing amino acid derived from methionine that is normally present in blood. Elevated homocysteine levels are thought to promote thrombogenesis, impair endothelial vasomotor function, promote lipid peroxidation, and induce vascular smooth muscle proliferation [49,50,52]. Evidence from retrospective, cross-sectional, and prospective studies links elevated homocysteine levels with coronary heart disease and stroke [49,52-61].Vitamin B12, folate, and vitamin B6 are involved in homocysteine metabolism. In the presence of insufficient vitamin B12, homocysteine levels can rise due to inadequate function of methionine synthase [6]. Results from several randomized controlled trials indicate that combinations of vitamin B12 and folic acid supplements with or without vitamin B6 decrease homocysteine levels in people with vascular disease or diabetes and in young adult women [62-70]. In another study, older men and women who took a multivitamin/multimineral supplement for 8 weeks experienced a significant decrease in homocysteine levels [71].Evidence supports a role for folic acid and vitamin B12 supplements in lowering homocysteine levels, but results from several large prospective studies have not shown that these supplements decrease the risk of cardiovascular disease [51,65-70]. In the Women’s Antioxidant and Folic Acid Cardiovascular Study, women at high risk of cardiovascular disease who took daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid, and 50 mg vitamin B6 for 7.3 years did not have a reduced risk of major cardiovascular events, despite lowered homocysteine levels [68]. The Heart Outcomes Prevention Evaluation (HOPE) 2 trial, which included 5,522 patients older than 54 years with vascular disease or diabetes, found that daily treatment with 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 for an average of 5 years reduced homocysteine levels and the risk of stroke but did not reduce the risk of major cardiovascular events [66]. In the Western Norway B Vitamin Intervention Trial, which included 3,096 patients undergoing coronary angiography, daily supplements of 0.4 mg vitamin B12 and 0.8 mg folic acid with or without 40 mg vitamin B6 for 1 year reduced homocysteine levels by 30% but did not affect total mortality or the risk of major cardiovascular events during 38 months of follow-up [69]. The Norwegian Vitamin (NORVIT) trial [65] and the Vitamin Intervention for Stroke Prevention trial had similar results [70].The American Heart Association has concluded that the available evidence is inadequate to support a role for B vitamins in reducing cardiovascular risk [51].Dementia and cognitive functionResearchers have long been interested in the potential connection between vitamin B12 deficiency and dementia [50,72]. A deficiency in vitamin B12 causes an accumulation of homocysteine in the blood [6] and might decrease levels of substances needed to metabolize neurotransmitters [73]. Observational studies show positive associations between elevated homocysteine levels and the incidence of both Alzheimer’s disease and dementia [6,50,74]. Low vitamin B12 status has also been positively associated with cognitive decline [75].Despite evidence that vitamin B12 lowers homocysteine levels and correlations between low vitamin B12 levels and cognitive decline, research has not shown that vitamin B12 has an independent effect on cognition [76-80]. In one randomized, double-blind, placebo-controlled trial, 195 subjects aged 70 years or older with no or moderate cognitive impairment received 1,000 mcg vitamin B12, 1,000 mcg vitamin B12 plus 400 mcg folic acid, or placebo for 24 weeks [76]. Treatment with vitamin B12 plus folic acid reduced homocysteine concentrations by 36%, but neither vitamin B12 treatment nor vitamin B12 plus folic acid treatment improved cognitive function.Women at high risk of cardiovascular disease who participated in the Women’s Antioxidant and Folic Acid Cardiovascular Study were randomly assigned to receive daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid and 50 mg vitamin B6, or placebo [79]. After a mean of 1.2 years, B-vitamin supplementation did not affect mean cognitive change from baseline compared with placebo. However, in a subset of women with low baseline dietary intake of B vitamins, supplementation significantly slowed the rate of cognitive decline. In a trial conducted by the Alzheimer’s Disease Cooperative Study consortium that included individuals with mild-to-moderate Alzheimer’s disease, daily supplements of 1 mg vitamin B12, 5 mg folic acid, and 25 mg vitamin B6 for 18 months did not slow cognitive decline compared with placebo [80]. Another study found similar results in 142 individuals at risk of dementia who received supplements of 2 mg folic acid and 1 mg vitamin B12 for 12 weeks [78].The authors of two Cochrane reviews and a systematic review of randomized trials of the effects of B vitamins on cognitive function concluded that insufficient evidence is available to show whether vitamin B12 alone or in combination with vitamin B6 or folic acid has an effect on cognitive function or dementia [81-83]. Additional large clinical trials of vitamin B12 supplementation are needed to assess whether vitamin B12 has a direct effect on cognitive function and dementia [6].Energy and enduranceDue to its role in energy metabolism, vitamin B12 is frequently promoted as an energy enhancer and an athletic performance and endurance booster. These claims are based on the fact that correcting the megaloblastic anemia caused by vitamin B12 deficiency should improve the associated symptoms of fatigue and weakness. However, vitamin B12 supplementation appears to have no beneficial effect on performance in the absence of a nutritional deficit [84].Health Risks from Excessive Vitamin B12The IOM did not establish a UL for vitamin B12 because of its low potential for toxicity. In Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, the IOM states that “no adverse effects have been associated with excess vitamin B12 intake from food and supplements in healthy individuals” [5].Findings from intervention trials support these conclusions. In the NORVIT and HOPE 2 trials, vitamin B12 supplementation (in combination with folic acid and vitamin B6) did not cause any serious adverse events when administered at doses of 0.4 mg for 40 months (NORVIT trial) and 1.0 mg for 5 years (HOPE 2 trial) [65,66].Interactions with MedicationsVitamin B12 has the potential to interact with certain medications. In addition, several types of medications might adversely affect vitamin B12 levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their vitamin B12 status with their healthcare providers.ChloramphenicolChloramphenicol (Chloromycetin®) is a bacteriostatic antibiotic. Limited evidence from case reports indicates that chloramphenicol can interfere with the red blood cell response to supplemental vitamin B12 in some patients [85].Proton pump inhibitorsProton pump inhibitors, such as omeprazole (Prilosec®) and lansoprazole (Prevacid®), are used to treat gastroesophageal reflux disease and peptic ulcer disease. These drugs can interfere with vitamin B12 absorption from food by slowing the release of gastric acid into the stomach [86-88]. However, the evidence is conflicting on whether proton pump inhibitor use affects vitamin B12 status [89-92]. As a precaution, healthcare providers should monitor vitamin B12 status in patients taking proton pump inhibitors for prolonged periods [85].H2 receptor antagonistsHistamine H2 receptor antagonists, used to treat peptic ulcer disease, include cimetidine (Tagamet®), famotidine (Pepcid®), and ranitidine (Zantac®). These medications can interfere with the absorption of vitamin B12 from food by slowing the release of hydrochloric acid into the stomach. Although H2 receptor antagonists have the potential to cause vitamin B12 deficiency [93], no evidence indicates that they promote vitamin B12 deficiency, even after long-term use [92]. Clinically significant effects may be more likely in patients with inadequate vitamin B12 stores, especially those using H2 receptor antagonists continuously for more than 2 years [93].MetforminMetformin, a hypoglycemic agent used to treat diabetes, might reduce the absorption of vitamin B12 [94-96], possibly through alterations in intestinal mobility, increased bacterial overgrowth, or alterations in the calcium-dependent uptake by ileal cells of the vitamin B12-intrinsic factor complex [95,96]. Small studies and case reports suggest that 10%–30% of patients who take metformin have reduced vitamin B12 absorption [95,96]. In a randomized, placebo controlled trial in patients with type 2 diabetes, metformin treatment for 4.3 years significantly decreased vitamin B12 levels by 19% and raised the risk of vitamin B12 deficiency by 7.2% compared with placebo [97]. Some studies suggest that supplemental calcium might help improve the vitamin B12 malabsorption caused by metformin [95,96], but not all researchers agree [98].Vitamin B12 and Healthful DietsThe federal government’s 2015-2020 Dietary Guidelines for Americans notes that “Nutritional needs should be met primarily from foods. … Foods in nutrient-dense forms contain essential vitamins and minerals and also dietary fiber and other naturally occurring substances that may have positive health effects. In some cases, fortified foods and dietary supplements may be useful in providing one or more nutrients that otherwise may be consumed in less-than-recommended amounts.”For more information about building a healthy diet, refer to the Dietary Guidelines for Americansand the U.S. Department of Agriculture’s MyPlate.The Dietary Guidelines for Americans describes a healthy eating pattern as one that:Fish and red meat are excellent sources of vitamin B12. Poultry and eggs also contain vitamin B12.Includes a variety of vegetables, fruits, whole grains, fat-free or low-fat milk and milk products, and oils.Milk and milk products are good sources of vitamin B12. Many ready-to-eat breakfast cereals are fortified with vitamin B12.Includes a variety of protein foods, including seafood, lean meats and poultry, eggs, legumes (beans and peas), nuts, seeds, and soy products.Limits saturated and trans fats, added sugars, and sodium.Stays within your daily calorie needs.