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This is a surprisingly complicated question that highlights how much we’ve learned about Alzheimer’s disease (AD) & other dementias, while at the same time exposing how much we don’t understand.BACKGROUNDDementia is defined as age-related cognitive impairment. Dementia = cognitive decline, but the pattern & specific functional realms involved (memory, language, executive, motor, or visual-spatial) may differ in each individual.AD is the most common dementia, but other types of dementia include Lewy Body Dementia (LBD), Frontotemporal Dementia (FTD), and Vascular Dementia (VD). The different dementias are distinguished by characteristic clinical presentations, &, more importantly, by specific neuropathological changes found in the brain at autopsy.AD typically presents with short term memory problems, and AD brains are filled with beta-amyloid plaques (Abeta), and hyperphosphorylated tau tangles (hpfTau).DLB is characterized by variability in level of consciousness (confusion), visual hallucinations (sometimes), and motor abnormalities (sometimes). Intra-neuronal Lewy bodies made of aggregated alpha-synuclein, are its neuropathological hallmark. Lewy bodies limited to the substantia nigra - a brainstem nucleus - cause Parkinson’s disease. Lewy bodies in the amygdala & neocortex cause DLB.FTD may present with behavioral & personality changes (Pick’s disease), primary progressive aphasia (PPA - language problems), or motor abnormalities (corticobasal degeneration, CD, & progressive supranuclear palsy, PSP). FTD neuropathology includes either hpfTau tangles (Pick’s, CD, & PSP), although not the same hpfTau as in AD; or intracellular deposits of ubiquitinated TDP43 (transactive-response-DNA-binding protein 43 kDa). TDP43 deposits are also found in many people with amyotrophic lateral sclerosis (ALS - Lou Gehrig’s disease) & there is a complicated & poorly understood connection between FTD & ALS.VD can present with deficits in any behavioral realm but typically progresses in a stair step fashion, as more & more parts of the brain infarct and die (multi-infarct or lacunar dementia). VD, like coronary artery disease, is mostly due to atherosclerotic (AS) changes in small blood vessels (plaques, hardening of the arteries)This is complicated but the take home message is that dementia means the brain is failing. The brain may be filling with CRAP (Cognition Robbing Amyloid Proteins) killing neurons, shrinking gray matter, & destroying minds & souls. There are different kinds of CRAP (Abeta, hpfTau, Lewy bodies, & TDP43). VD differs in that the problem is AS & multiple (small) strokes (infarcts) killing the brain.Most people don’t distinguish between AD, DLB, FTD, and VD; and use Alzheimer’s as an umbrella term for all dementias.Although there are drugs, cholinesterase inhibitors like Aricept, that can temporarily benefit AD & DLB, there are no disease modifying treatments. There are no cures & no ways to revive a disintegrating brain. NIH has committed to finding a disease modifying treatment by 2025 (wish us luck).Decline in cognitive function, particularly processing speed, is a concomitant of aging, as is gradual shrinkage of the brain. My memory is not what it was when I was 40. My hair is graying & my knees ache more and more. The only competitor Usain Bolt will always lose to, is age. Dementia is age-related , but is not considered “normal”. For nonagenarians and centenarians, this distinction may reflect hope more than reality. At the same time, it’s not rare to find people in their 80s & 90s who are sharp as a tack, still working and contributing to society. However, while the contrast with other body systems may be striking, the brain cannot escape time’s ravages.The neuropathologic changes associated with AD, DLB, FTD, and VD all increase with age. These changes take place over decades & have characteristic neuroanatomic patterns, beginning in one brain region, then spreading to other brain regionsAbout 30% of people over age 70 have Abeta plaques in their brains but are cognitively normal. Abeta plaques tend to appear first in the precuneus & parietal lobe.hpfTau deposits (as tangles or in other forms) begin to appear in entorhinal cortex in the medial temporal lobe by age 40, & by age 80, virtually 100% of people have hpfTau deposits in their brains regardless of whether or not they are demented.Some degree of atherosclerosis (AS) is inevitable as we age. People often have silent, lacunar infarcts in their brains, Of course, a large enough infarct in the wrong brain region will produce catastrophic results: a CVA or stroke with resulting paralysis, blindness, loss of language, etc, etcGenerally speaking, the severity of cognitive impairment correlates with the amount of neuropathological burden. As more CRAP or AS accumulates in the brain over time, the more impairment and the more likely someone will be diagnosed with dementia.However, at autopsy, there are any number of individuals with brains full of CRAP &/or AS changes who were never diagnosed with dementia. Maybe they should have been, & maybe normal age related cognitive decline is due to the gradual accumulation of CRAP & AS, but dementia cannot be diagnosed based solely on neuropathological change.ANSWERSA lot happens in the 10 - 20 years before clinical symptoms of AD (or other dementias) manifest. CRAP & AS are building up. Synapses and neurons are dying off. As demented patients decline, neuropathology worsens, shriveling the brain.Until very recently, AD and other dementias couldn’t be diagnosed until someone died, & were autopsied. Their brains would be sliced into thin sections, and special stains used to highlight Abeta plaques, pTau tangles, Lewy bodies, and TDP43.TDP43These abnormal protein deposits - CRAP - could only be identified after someone died. Diagnosing dementia is actually pretty simple: has there been cognitive/behavioral decline on standard neuropsychological tests, and has this led to impairment in day to day function? Is someone no longer able to do something that they once had no problem doing? The pattern of cognitive/behavioral decline could suggest whether dementia was due to AD, DLB, FTD, or VD, but definitive diagnosis was possible only at autopsy.Not being able to identify which dementia someone has while they’re alive, makes treatment development extremely difficult. The different dementias are associated with different genes, different proteins, and different molecular and cellular processes. The end result is the same: neurons die and behavior deteriorates; but the physiological mechanisms causing this likely differ for different dementias. Consider a car engine: changing the head gasket isn’t going to help a dead alternator.But how can you study living, functioning human brains?One way, invented in the 1970’s & 80’s, & improving greatly over the last 20 years uses magnetic resonance imaging (MRI) to look at brain structureThis is a T2 image of someone with multi-infarct, VD.Here is an example of the brain shrinkage associated with AD.Another approach, also developed in the 1970’s & 80’s is imaging of brain glucose metabolism using positron emission tomography (PET) and an 18-F-deoxyglucose (FDG) radiotracer.FTD , as it’s name implies, mostly affects the frontal and temporal lobes; whereas AD usually begins towards the back of the brain.MRI and FDG-PET have, and continue to contribute a tremendous amount to our understanding of dementia. However, their fundamental shortcoming is that, while they can show where the brain is failing and help identify VD, they can’t tell us which abnormal protein is causing the damage. They tell you that CRAP is there, but not the kind of CRAP.One approach to the problem of specificity is to look at cerebrospinal fluid (CSF) from a lumbar puncture. The brain and spinal cord are bathed in CSF, that can be sampled using a needle (carefully) inserted between lumbar vertebrae in the lower back. Highly specific and sensitive enzyme-linked immunosorbent assays (ELISAs) have been developed for Abeta and hpfTau, and in the 2000’s, investigators demonstrated a characteristic pattern of lowered Abeta and elevated hpfTau in CSF from AD patients (including people at the very earliest stages of mild cognitive impairment). ELISAs have been developed for alpha-synuclein (the protein in Lewy Bodies) and TDP43, but clear cut differences in CSF levels of these proteins haven’t been found in DLB or FTD.We’re still a ways from a clinical laboratory test to diagnose AD, but CSF measures of Abeta and hpfTau are being widely used by investigators to select subjects for clinical trials of drugs that act through Abeta or hpfTau. After all, one wouldn’t expect a drug that worked through Abeta to do much in someone whose problem is with alpha-synuclein (DLB) or TDP43 (FTD).The highest impact advance in dementia diagnosis over the past decade was the development and validation of radiotracers that bind to Abeta plaques in the brain which can then show up on a PET scan.This field has moved incredibly quickly, and there are already 3 FDA approved PET radiotracers - florbetapir, florbetaben, and flutemetamol - that can be used clinically. The major limitation on widespread use of Abeta imaging has been the reluctance of CMS (Medicare) to pay for PET scans. This reluctance is understandable (however, while I agree with CMS, most AD investigators and the Alzheimer’s Assn don’t). Diagnosing dementia isn’t particularly complicated, and doesn’t require a $4–5,000 PET scan. Moreover, 1/3 of people in their 80’s will have positive scans but will not be cognitively impaired. Finally, we don’t have a disease modifying treatment. A positive (or negative) scan is informative but not actionable. It is possible, perhaps even likely, if, in years to come, anti-Abeta treatments are shown to slow onset or progression of AD, then everyone over 65 will need to be screened using Abeta PET scans, so that cognitively intact people with Abeta in their brains won’t later progress to dementia.As important as the development of in vivo Abeta PET imaging has been to studying AD, it has a significant shortcoming. The amount of Abeta plaque &/or where it appears in the brain is only weakly related to cognitive decline. This isn’t entirely surprising, given that people can have brains full of Abeta yet appear entirely normal. Indeed, studies have shown that Abeta begins appearing in the brain 15 - 20 years before there is any cognitive decline.However, a truly electrifying advance is the development of a PET radiotracer (T807 or AV1451, and T808) that label the hpfTau tangles that are the other neuropathological signature of AD.On the right of the figure are PET images of brain Abeta. In the middle are PET images of brain hpfTau. Both Abeta & hpfTau are present in AD, & most evidence suggests that Abeta precedes hpfTau. The presence of hpfTau appears to be more tightly correlated with cognitive decline & may even turn out to be a surrogate endpoint that could be followed in clinical trials. The gold standard for disease progression in AD & other dementias is neuropsychological testing. Unfortunately, neuropsych testing is very noisy, influenced by many different factors extraneous to dementia. hpfTau imaging may provide a more exact biomarker. I am skeptical, particularly since hpfTau imaging is less than 5 years old & we’re already learning that, as well as (perhaps) being more informative, it’s definitely more complicated than Abeta imaging.I changed from working on schizophrenia to AD ~8 years ago, & we’ve learned a huge amount about AD & other dementias since then (not thanks to me, but I feel fortunate to be along for the ride). We’re a ways from a cure (that answer would be even more complicated & longer than this one). Most of this work was paid for by the National Institute on Aging (part of NIH) & will, hopefully, continue to be funded.This answer reflects my opinions alone, and not those of NIA, NIH, HHS, or the Federal Govt.

Yes.There are three conditions necessary for a cube to be solvable:The edges must have an even number of them “flipped”The total twist of the corners must be a whole number (where twisting a corner 1/3 clockwise is 1/3 of a twist, and so on).The parity of the permutation of the edges is the same as the parity of the permutation of the corners.To determine the total twist of the corners, pick two opposite faces (like Up and Down), and examine each corner, recording the twist necessary to get all the up and down colors on the up and down faces (it doesn’t matter if twisting a corner would result in a up color on the down face, or vice versa). If the total twist is not a whole number, such as “twist these two corners 1/3 clockwise”, then the cube is not solvable.To determine the total flip state, look at the edge colors on the top and down faces, as well as the edge colors on the front and back faces of the middle slice. Count how many are “right” — a top color on the bottom face, a front color on the top face, a back color on the back face (in those two spots), etc, compared to how many are “wrong” — a left color on the front face (in those two spots), a right color on top, etc. If there are an odd number “wrong” (or “right”), then the cube is not solvable.There are 8 corner pieces. Pick one, and track the cycle it goes in: the one in the up-right-front spot belongs in the down-right-front spot, which should be in the down-left-back spot, which should be in the up-right-front spot. Write down the cycle like (urf,drf,dlb). Do that again for another corner not tracked, until all corners are tracked. You’ll get a cycle pattern like (urf,drf,dlb)(ulf,ulb)(ubf,dlf)(drb). Count the number of cycles of even length (in this case, 2).There are 12 edge pieces. Do the same task with them as you did with the corner pieces: pick one, track its cycle, write it down, repeat for all twelve. You’ll get a cycle pattern like (uf,df,rf)(lf,ul,ur,br,bl)(ub,db)(dl,dr). Count the number of cycles of even length (in this case, 2)If one of those two even-length-cycle counts is even and the other is odd, then the cube is not solvable.None of these actions require making even one turn.Of course, partially solving it can make it easier to do these counts. If you’ve solved two layers, for instance, it’s easy to see if there’s a flip or twist problem, and looking at the permutations is easier. But you don’t have to do so.

The Fake Natty -(someone who claims they do not use performance enhancing drugs when in fact they do, largely found in the fitness industry )Its a sad place to be but I kind of get it, they get on gear get some gains but then self doubt strikes, they feel as though they haven’t obtained a certain look attributed to gear use and so claim natty,It’s worth noting though gear can help overcome plateaus and help you reach a higher echelon of physical strength/aesthetics, it’s not a magic potion it requires hard work and proper nutrition to, a lot of fake nattys likely don’t want their hard work discounted because of minor assistanceThe real Fake Natty issue is the industry professionals peddling supplements/ workout plans etc who claim natty stating they got the results from *insert product/plan here*Natty people training with workout plans for enhanced athletes can in some instances basically overwork themselves to the point they lose muscle massNatty people who believe the pros used XYZ to get massive may develop dysphoria and other mental health issues because they’re following the BS plan to the letter eating all the right supplements and not getting resultsFemale Pro Dana Linn Bailey recently claimed NattyYeah, sorry women don’t that yolked without <assistance>The pitfall in this instance (and why I stopped following DLB) is women who could stand to benefit from weight training won’t start through fear that they might end up like this,Denial is understandable to a certain extent because in most places PED use is illegal and so if an athlete was to say they were on steroids they may feel as though law enforcement might take an interest and they could use their supplement sponsors, The way forward is to just not answer the question rather than deny usage.So overall I thoroughly dislike fake nattys and they can be pretty dangerous in the right (wrong) circumstances