Produce for Change: Can Fruits and Veggies Reduce Risk of AD?

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    In our previous blogs we have touched upon a couple aspects of how diet can impact neurological function and risk for diseases like Alzheimer’s. As interdisciplinary studies are becoming increasingly more common, we are discovering even more ways that diet and exercise impact our overall health, genetics, and cognitive functioning. Today we will be focusing on a recent study suggesting that consumption of dietary flavonols, a class of molecules found in a variety of fruits and vegetables, might reduce risk for Alzheimer’s disease (AD) and improve cognitive functioning. In fact, if you read our blog regularly you may already know about one flavonoid (of which flavonols are a subclass), resveratrol, which is the predicted cause behind the “French Paradox”. If you aren’t familiar with the French Paradox you can read about it (and much more) on our blog at centerforcognitivehealth.com.

    Flavonols (and flavonoids) are a subclass of molecules called polyphenols, given their name for the many phenol rings that make up their chemical structure. Because of this shape, they act as antioxidants and many have powerful anti-inflammatory properties. In animal studies flavonols improve memory and learning and decrease the severity of AD pathology including decreased deposition of beta-amyloid plaques and neurofibrillary tangles with reduced microgliosis. Recent research by the Rush Memory and Aging Project (MAP) has attempted to determine if these effects are generalizable to human models, focusing on four common flavonols: kaempferol, quercetin, myricetin, and isorhamnetin.

    MAP began this study in 1997, taking a community of elderly volunteers with no known history of dementia, and began giving them yearly clinical neurological exams and comprehensive food frequency questionnaires (FFQ). They parsed apart the effect of diet on AD-induced dementia onset over the course of the next several years. As of 2018, 921 out of 1,920 participants were randomized in the study excluding individuals with possible AD diagnoses at screening and those with missing data. At each annual evaluation, the participants were given 19 cognitive tests later reviewed by a blinded neuropsychologist. A diagnostic classification for each individual was determined by a neurologist, geriatrician, and geriatric nurse practitioner. When analyzing these results, they took care to account for APOE genotyping, years of schooling, participation in cognitively stimulating activities, physical activity, depressive symptoms, and hypertension to control for any possible confounding variables causing cognitive dysfunction outside of dementia itself. Lastly, they analyzed the FFQ data based on the USDA’s Database for the Flavonoid Content of Selected Foods to determine each participant’s average flavonoid intake.

    Among the 921 participants who did not have dementia at the beginning of the study, 220 developed AD dementia during the follow-up period (average follow-up period was 6.2 years), with a mean age of 81.2 years at onset. Statistical analysis of all this data determined that dietary intake of flavonols were significantly predictive of a 48% decreased risk for AD. In terms of the specific flavonols, isorhamnetin and myricetin were associated with a 38% decreased risk and kaempferol was associated with a 50% decreased risk. Quercetin showed no significant effect on AD risk. Considering that these flavonols frequently co-occur in fruits and vegetables, they also modeled them all simultaneously to determine if one or more of the statistically significant effects were simply due to presence of another flavonol. As it turned out, only kaempferol had an independent association with AD risk. In essence this means that the protective effects of the other flavonols discussed in this study were only present when they co-occurred with the presence of kaempferol, suggesting that kaempferol was the most (and possibly the only) effective biomodulator.

    Kaempferol is abundant in leafy greens. As a general trend, it is clear that modifying one’s diet to include more fruits and vegetables of all kinds is likely to improve both general and cognitive health. However, with the rise of genomic testing, if you or someone you know becomes aware of an increased likelihood of AD it may be worth emphasizing intake of leafy greens and incorporating things like salad, broccoli, or peas into your culinary repertoire regularly. Additionally, while little research has been done on diet’s effect on symptomatic progression of those already suffering from AD, the antioxidant activity of flavonols like kaempferol may also be able to slow the disease progression. Hopefully, more research will be done on this particular topic in the future, but even if this is not the case, in this study those in the highest quintile of flavonol intake also had reduced risk of diabetes, hypertension, and stroke compared to the lowest quintile providing a serious possibility for increased quality of life overall.

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Sources:
Holland, T. M., Agarwal, P., Wang, Y., Leurgans, S. E., Bennett, D. A., Booth, S. L., & Clare Morris, M. Dietary flavonols and risk of Alzheimer dementia [Internet]. Neurology. 2020. Available from: https://n.neurology.org/content/early/2020/01/29/WNL.0000000000008981
Bakalar, N. Why Fruits and Vegetables May Lower Alzheimer’s Risk [Internet]. New York Times. 2020. Available from: https://www.nytimes.com/2020/02/04/well/mind/why-fruits-and-vegetables-may-lower-alzheimers-risk.html

Neuroprotective Tap Water: Correlations in Lithium Concentration and Dementia

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    Within the last few years, an interesting correlation has been discovered between the concentration of lithium in municipal water sources and the incidents of dementia in areas with varying amounts of lithium. In fact, it seems that lithium might provide some form of neuroprotection such that the higher concentration present in tap water predicts a decreased risk of dementia onset later in life. 

    Lithium has been used therapeutically since the mid-19th century but due to lack of scientific publications on its efficacy at the time, it was forgotten and while still used occasionally, administration of lithium was not a widely accepted medical practice. The first accepted use of lithium was promoted by Alfred Baring Garrod, a London internist, for treatment of gout resulting in an increased prevalence of lithium-containing products. In 1870, a Philadelphia neurologist recommended lithium bromide as an anticonvulsant and a hypnotic, followed a year later by Dr. William Hammond being the first physician to prescribe it for mania with relative effectiveness. After this, there are no significant historical references to the use of lithium in a medical setting for many years. 

    After lithium’s brief break from the medical limelight an Australian doctor by the name of John Cade, having read about lithium’s history as a treatment for gout, hypothesized that some condition involving uric acid (the underlying cause of gout) might also play a role in his manic patients’ “psychotic excitement”. In 1949, Cade decided to use lithium for a case study on its efficacy and gave 10 patients lithium citrate and lithium carbonate. Some responded remarkably well, even becoming “normal” enough to be released from in-patient treatment. Cade’s report of this small case study was noticed by others and soon the University of Melbourne began a trial with over 100 patients, discovering that lithium did indeed have very beneficial effects on mania.

    Lithium’s exact mechanism of action in the nervous system is complex. One widely agreed upon finding, however, is that lithium does not have direct or immediate action in the brain, but rather operates through the “second messenger” cyclic-AMP (cAMP). Lithium requires chronic administration over a long period of time to have significant effects.  Are areas with higher lithium concentrations in the groundwater providing an accidental neuroprotective treatment and if so, would it be possible to intentionally implement this on a wider scale, like with fluoride in drinking water and dental health?

    So far, the answer to this seems promising, particularly when it comes to Alzheimer’s disease (AD). The first study to suggest this found that people who live in areas with higher concentrations of lithium in the water were 17% less likely to develop dementia. This led to a growing library of research into lithium as a preventative measure for dementia. A study in rat models genetically modified to express amyloid plaques, like those in AD, found that low concentrations of lithium improved early learning deficits and reduced the number of amyloid plaques in the hippocampus. Regions with higher concentrations of lithium in the water have also been correlated to lower violent crime rates, fewer arrests associated with drug use/addiction, and lower suicide rates suggesting that this small level of lithium intake is capable of impacting behavior and cognition.

    Dr. Cuello, who oversaw the rat-model studies above, supports future lithium trials in AD patients. Microdosing lithium is an especially practical treatment as small amounts are more prone to pass the blood-brain barrier, while minimizing the amount of lithium in the blood, and therefore decreasing the likelihood of adverse effects. Lithium’s use in AD is just beginning but if you are interested in finding your area’s lithium concentration it is available from the United States Geological Survey (USGS).

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Sources:
Kessing, L. V., Gerds, T. A., & Ersboll, A. K. Association of Lithium in Drinking Water With the Incidence of Dementia [Internet]. JAMA Psychiatry. 2017. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710473/#!po=40.9091
Shorter, E. The history of lithium [Internet]. Bipolar Disorders. 2009. Available from:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712976/
Sandoiu, A. Lithium microdose could stop Alzheimer’s from advancing [Internet]. Medical News Today. 2020. Available from:  https://www.medicalnewstoday.com/articles/can-lithium-halt-progression-of-alzheimers-disease
Brunello, N., & Tascedda, F. Cellular mechanisms and second messengers: relevance to the psychopharmacology of bipolar disorders [Internet]. 2003. Available from: https://academic.oup.com/ijnp/article/6/2/181/719874
Schrauzer, G. N., & Shrestha, K. P. Lithium in drinking water and incidences of crimes, suicides, and arrests related to drug addictions [Internet]. 1990. Available from: https://www.ncbi.nlm.nih.gov/pubmed/1699579

Reflections: How an Interactive Art Exhibit is Building Community

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    Art and music therapy are by no means new ideas, with the term art therapy first being coined in 1942 by British artist Adrian Hill and music therapy being implemented on a large scale around the same time to help soldiers during WWII. The fields of art and music therapy have continued to grow and, while not the most common forms of therapy, are still used today for a variety of conditions, primarily in the case of neurological disorders. One such disorder in which art and music therapies provide benefits is dementia. Combining art and music therapy with community outreach has great potential for therapeutic relief and providing a sense of connection with both art and those you experience it with.

    The Nasher Museum of Art at Duke University is implementing this combination with great benefits for all involved. A recent program, called “Reflections”, allows for a private viewing of the museum by a very special group of 26 people. Half of those present suffer from a dementia-causing illness, primarily Alzheimer’s, and the other half are their caregivers. While being shown around the exhibit each person is encouraged to take part in a discussion about how the art they’re admiring makes them feel. Throughout the experience the tour guide asks progressively deeper questions about what feelings, and even memories, the art triggers. Through this process, those suffering from Alzheimer’s and other dementing illnesses are stimulated in a low stress environment and in a way that, in some cases, allows for access of memories that might not be retrievable otherwise.

    After viewing the art, participants in the “Reflections” program are brought to an exhibit focusing on music. It starts as an activity in which guests are given song lyrics and asked to find a visual art piece which, in their mind, encompasses that lyric. Then they are shown art pieces that use aspects of music, for example, a piece called “Cats and Dogs” that features vinyls such as “Purple Rain” by Prince, “November Rain” by Guns N’ Roses, and “Rain” by the Beatles. When asked if this piece brought about any specific memories one woman reminisced about receiving one of these albums from her sister at age 16, showcasing the power that music can have on memory and cognition. Finally, they are brought to a part of the museum in which music is played, changing from live music performed by Duke’s orchestra to a DJ who plays and remixes songs from the 1950s all the way up to releases within the last decade. After one guest asked for a song to dance to, the DJ played “Good Golly Miss Molly” which was met with tapping feet, air pianos, and general enjoyment. 

    Unlike the art, however, the real benefit of this experience is not even on display in the museum. The impact on the lives of those involved is something much more awe-inspiring, in the form of community. One caregiver mentioned that the program gives him and his wife an outing that they look forward to but also provides a sense of security in that “the more you can be with other people that have the same type of issues that you do, you find you’re not alone”. This is crucial because support groups on their own may provide community, and art or music therapy may provide an outlet for emotions and a sense of relief, but no other program combines both of these to allow for the unique relief that one feels when their everyday problems are shared within a community and are then released through engaging and enjoyable activities.

    This program became possible through private donors, the Duke Dementia Family Support Program, and a grant from the Alzheimer’s Foundation of America. Now, thanks to these generous contributions, the Nasher Museum hosts six to eight group tours through “Reflections” one day a month. For those who have taken part in the “Reflections” program this is not just an event or an outing but a rare instance in which they are not alone and are allowed to experience the world around them however they so choose. This provides a sense of freedom either from the symptoms of dementia or from the stress that caring for a loved one with dementia can bring. As such, if you feel called to make a difference like this and are financially capable, I encourage you do consider donating to the Oregon chapter of the Alzheimer’s Association here: https://act.alz.org/site/Donation2?df_id=32112&32112.donation=form1&_ga=2.28875576.527622574.1582139779-1009136760.1572449350

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Sources:
Bitonte, R. A., & De Santo, M. Art Therapy: An Underutilized, yet Effective Tool [Internet]. Mental Illness. 2014. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253394/
Davis, W., & Hadley, S. A History of Music Therapy [Book]. Music Therapy Handbook. 2015. Available from: https://books.google.com/books?hl=en&lr=&id=mfnhBQAAQBAJ&oi=fnd&pg=PA17&dq=music+therapy+history&ots=0jdkyj5043&sig=2dYYWtE_xJhB4s1r9DffyMPrm1w#v=onepage&q=music%20therapy%20history&f=false
Brown, T. How one NC museum is using art and music to unlock memories in people with dementia [Article]. The News & Observer. 2020. Available from: 
https://www.newsobserver.com/entertainment/arts-culture/article238509913.html?fbclid=IwAR2Kca-3D4e76JQktUMUCeUkfIAncbVurOKHhjADz7whAifykEg_MzRvwh4

The Genetics of Alzheimer’s Disease

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    The human genome is complex, unique to each individual, and is the primary driving force behind every biological function and dysfunction. This week’s blog will discuss the genetic underpinnings creating variable risk factors for Alzheimer’s disease (AD), a well-researched topic but infrequently understood. With growing access to commercial genomic testing through companies like 23andMe, understanding the role that genetics play in AD and other diseases is more important than ever. The ability to understand one’s risk of developing AD may allow for the expansion of preventative medical practices to slow or stop disease progression before symptom onset.

    Initial AD genetic research was motivated by the observation that those suffering from the disease were found to have significant accumulation of amyloid beta (Aβ) plaques in the hippocampus, amygdala, and cerebral cortex. As we now know, the location of these plaques correlate well to the symptoms associated with AD such as impaired memory function, reduced emotional regulation, and dysfunctional executive functioning. 

    So how exactly do genetics drive Aβ production and AD pathology? The first mutation identified in inducing AD symptoms was found at the transcriptional site for β-amyloid precursor protein (βAPP) on chromosome 21. It was discovered because trisomy 21, more commonly known as Down’s Syndrome, is associated with deposition of Aβ plaques in young adulthood and drives development of the AD-associated symptoms. This research led to the discovery of 5 βAPP mutations associated with familial AD, however, these mutations cause only about 1% of familial AD cases in total, and are characterized by early onset. Despite this, these discoveries provided insights into the mechanism of Aβ deposition which are present in all AD cases. Furthermore, it led to the discovery of the Apolipoprotein E (ApoE) gene. Research into this gene suggests that a certain allele, a specific form of the ApoE gene known as E4, increases the likelihood of developing late onset AD in a much larger population. Inheritance of one copy of the E4 allele confers significantly increased risk, earlier onset of AD pathology, and higher density of Aβ aggregation. Two copies of E4 increase this risk even more. The E2 allele, on the other hand, provides resistance to Aβ deposition. It is important to mention that not all E4 carriers develop AD and not all AD patients have an E4 allele meaning that there are other risk factors at play, but genetics are a strong associative risk factor.

    βAPP mutations account for a small percentage of early onset AD cases and ApoE4 accounts for a significant percentage of late onset cases, but not all, indicating the presence of other risk factors. The next discovery in AD genetics came in the form of presenilin genes 1 and 2. There are 25 known missense mutations of presenilin 1 and 2 mutations of presenilin 2, all of which correlate with early onset familial AD. A missense mutation refers to the change of a single nucleotide in DNA which then codes for a different amino acid, which are protein building blocks. Imagine one of these presenilin proteins as a house made of bricks, and the missense mutation as a cinderblock where a brick should be, this single change throws the entire balance of the “house” off and in the case of proteins, changes their function. The specific function of presenilin proteins are only weakly understood but cell and animal models suggest that Aβ peptides consisting of 42 residues (Aβ42) have increased aggregation when present with presenilin mutations. Aβ peptides consisting of 40 residues (Aβ40), however, seem to be unaffected by presenilin mutations. Aβ42 peptides normally have increased aggregative properties in comparison to Aβ40, but this activity can be exacerbated by presenilin mutations possibly inducing AD. As with ApoE genes, these mutations do not account for all cases of AD but are clearly playing a powerful role in amyloid protein aggregation and disease manifestation. 

    The gene which codes for microtubule associated protein tau (MAPT) has also been implicated in AD pathology due to the presence of neurofibrillary tangles (NFTs), or aggregates of tau proteins. Tau proteins under normal conditions can be spliced by cellular mechanisms in different ways resulting in 6 different similar but functionally different forms of the protein. Two of these forms, named 3R and 4R, are present more abundantly in AD brains suggesting that these may be the pathological forms. Overexpression of 3R tau proteins alone tends to cause Pick’s disease (a subset of frontotemporal dementia) and overexpression of primarily 4R isoforms can cause corticobasal degeneration or progressive supranuclear palsy. However, the specific isoform tau takes is not the only factor in inducing AD. It seems that, through a different cellular mechanism, tau proteins can become hyperphosphorylated which increases the likelihood of aggregation and impedes clearance of these aggregates once created. 

    There are clearly numerous factors at play in the pathogenesis of AD, all of which seem to interact with each other to increase or minimize risk of developing the disease. While many of these mutations are well understood, there is clearly more to discover with regards to the underlying mechanisms promoting aggregation of these proteins and specifically, how to reverse these mechanisms to allow for dissociation and clearance of Aβ and NFT aggregates.  If you or someone you know has a family history of AD it might be worth getting genetic testing to identify your risk and start taking preventative measures, whether in the form of better sleep habits, dietary changes, implementation of supplements, exercise, or something else! There are numerous other genes not discussed here which are also hypothesized to play a role in AD pathology, so if you’re inspired to learn more, I encourage you to visit http://www.alzgene.org/ for more information about these lesser known genes. 

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Sources: 
Selkoe, D. J. Amyloid β-Protein and the Genetics of Alzheimer’s Disease [Internet]. The Journal of Biological Chemistry. 1996. Available from: https://www.jbc.org/content/271/31/18295.full.pdf
Tanzi, R. E. The Genetics of Alzheimer Disease [Internet]. Cold Spring Harbor Perspectives in Medicine. 2012. Available from: http://perspectivesinmedicine.cshlp.org/content/2/10/a006296.full

LMTM, Tau, and Alzheimer’s: A New Clinical Approach

Many followers of this blog, and those who have participated in our clinical trials, have heard the terms beta-amyloid (Aβ) plaques and tau neurofibrillary tangles time and time again. Both Aβ and tau are protein biomarkers associated with cognitive decline in Alzheimer’s disease (AD). For a long time, the scientific community has focused primarily on reducing Aβ production and aggregation as a means of preventing further decline and attempting to clear Aβ plaques in the brain to alleviate symptoms. Unfortunately, many of these studies have failed to show strong therapeutic potential across all sub-groups of AD patients resulting in the termination of many trials focusing on this method of disease modification. As such, there has been a slow shift from the “amyloid hypothesis”, suggesting that Aβ plaques are the predominant cause of AD, to an interest in the role that tau plays in the disease. A clinical trial aimed at reducing the production and aggregation of tau neurofibrillary tangles through the use of an oral agent, Leuco-Methylthioninium (LMTM), will be recruiting for participants at our clinic soon so I am using this week’s blog to provide information for anyone who might be interested.

The Aβ plaques and tau tangles associated with AD are misfolded proteins, indicating a change in protein shape, also resulting in functional changes. Tau, short for microtubule-associated protein tau, is vital for stabilization of microtubules (a structure critical for all neurons). However, once a tau protein becomes misfolded, either as product of genetics, transcriptional errors, or even physical trauma as seen in CTE or “punch drunk syndrome”, it becomes prionic. This essentially means that the misfolded tau protein can interact with correctly folded tau proteins and change their shape into that of the pathogenic form. Once this cascade begins, misfolded proteins bind together forming aggregates, or neurofibrillary tangles, which negatively impact neuronal function and induce cell death.

In cell models, LMTM administration reduces aggregation of improperly folded tau and promotes disaggregation of pre-existing neurofibrillary tangles. In transgenic mouse models, genetically modified to present with neurofibrillary tangles, LMTM facilitates clearance of neurofibrillary tangles and improves cognitive and motor learning capabilities. Previous trials in humans show variable efficacy for participants with MCI and early AD. Using cognitive assessments as a measure of AD progression, one LMTM trial showed significant improvement in cognition, MRI atrophy rates, and glucose uptake. In fact, the average brain atrophy rate for participants enrolled was typical of mild AD but after 9 months of treatment with LMTM, the atrophy rate decreased similar to that of normal elderly controls. LMTM and its previous trials show great potential for slowing or halting the progression of AD pathology, both cognitively and functionally.

TauRx, the company behind LMTM, has successfully completed two trials in humans with promising results. In the first trial, researchers found no differences between the treatment and control study groups, however, they did indicate a sub-group with improvement. Namely, those not receiving any other AD treatment and using LMTM as a monotherapy appeared to benefit compared to participants taking currently approved AD drugs with LMTM. This encouraged further research into LMTM as a monotherapy to confirm efficacy. In their second trial, as expected, those receiving LMTM at 100 mg/day as their only AD treatment scored better on cognitive assessments than those not using it as a monotherapy. Even the 4 mg dosage group, originally designed as a control, experienced a noticeable benefit if given as a monotherapy. As such, the next trial which we are participating in will focus on LMTM as a monotherapy and will analyze the efficacy of smaller doses (8-16 mg/day).

The dosing phase of the TauRx trial for LMTM treatment will take place over 52 weeks with approximately 7 in-clinic visits. It is a double-blind trial, meaning that neither participants nor researchers will know who is on active drug or placebo during this period. However, if the trial shows potential after these 7 visits, it will transition to an Open Label Extension trial, in which all participants receive active drug and will involve 3 more visits. Furthermore, because the trial is aiming to test LMTM as a monotherapy, the use of AchEIs (e.g. donepezil, galantamine, and rivastigmine) or memantine will need to be discontinued during the screening phase in all participants. It is important to note that all participants will require a study partner, someone who can provide an external perspective on the participant’s cognition and daily function, at each visit. In order to get enrollment in this trial started, potential participants should contact us to undergo a phone memory screen and answer a few questions regarding medication and medical history to confirm basic eligibility.

We, here at the Center for Cognitive Health, are very excited for the possible therapeutic benefits of LMTM in AD, a disease in which there is no current disease modifying drug, so if you, or a loved one, are suffering from AD or MCI and are interested in receiving potentially beneficial treatment while progressing the scientific understanding of AD, we would love to hear from you! You can reach out to the studies coordinator, Tyler Leecing, at (503)-548-0908 or tyler@centerforcognitivehealth.com. You can also find more information about our currently recruiting trials and clinic on our website, centerforcognitivehealth.com, and more about TauRx at taurx.com.

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Sources: 
Barbier, P., Zejneli, O., Martinho, M., Lasorsa, A., Belle, V., Smet-Nocca, C., Tsvetkov, P. O., et al. Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects [Internet]. Aging Neuroscience. 2019. Available from: https://www.frontiersin.org/articles/10.3389/fnagi.2019.00204/full
Wilcock, G. K., Gauthier, S., Frisoni, G.B., Jia, J., Hardlund, J. K., Moebius, H. J., Bentham, P., et al. Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial [Internet]. Journal of Alzheimer’s Disease. 2018. Available from:  https://content.iospress.com/articles/journal-of-alzheimers-disease/jad170560
Elaine Goodman. LMTM [Internet]. Article from Alzheimer’s News Today. Available from: https://alzheimersnewstoday.com/lmtm/

Photobiomodulation: Lighting Up the Brain

     There are, to date, few methods of non-invasive brain stimulation (NIBS) that show therapeutic potential for neurological dysfunction. The most commonly used forms of NIBS are transcranial magnetic stimulation (TMS), which uses a magnet to generate electrical currents thereby increasing activity in the targeted system of the brain, and transcranial direct current stimulation (tDCS), which uses electrodes to directly translate external electrical currents into the brain. Both of these NIBS techniques require multiple sessions of stimulation administered by a technician which make them, in the long run, relatively costly. However, a significantly cheaper and novel method of NIBS, termed transcranial photobiomodulation (tPBM), is currently undergoing research to determine efficacy. The device itself, branded as Vielight, is commercially available, user friendly, and safe. In this blog we will delve into the potential implications of this technology while analyzing the currently available research on Vielight.

     So what exactly is photobiomodulation? 

     It involves administration of pulsing, low-level red and near-infrared (NIR) light on specific locations in the brain to stimulate neural tissue. The Vielight Neuro Gamma model uses LED lights to deliver 40 Hz pulses of NIR transcranially and intranasally to neural structures associated with the default mode network (DMN), a system associated with introspection when the mind is not actively engaging in actions requiring attention. Activation of the DMN is associated with the brain being in an alpha state meaning that one is in a state of “resting wakefulness”. Previous research suggests that increasing alpha wave activity in the brain aids in inhibition of irrelevant cortical areas and integration of activity in relevant areas, essentially streamlining cognition and creating greater functional connectivity between these areas. This has implications for pathological presentations that involve the DMN such as those associated with Alzheimer’s disease (AD), dementia, schizophrenia, autism, anxiety, and depression. Unfortunately, research has not yet delved into its use for any specific disorders but rather, was used on healthy participants to determine the safety and efficacy for impacting cognition.

     In the study, twenty adults were recruited and attended two study visits each. During one visit they received active tPBM stimulation from the Vielight Neuro Gamma model and during the other they received sham stimulation (placebo), double-blinded to avoid researcher bias and to ensure that any detected changes were not a placebo effect. Participants also received pre- and post-stimulation EEGs to measure neural activity. Interestingly, after both active and sham stimulation sessions, the EEG showed an increase in power for all frequency bands (corresponding to different frequencies of neural firing) in comparison to baseline, but differential increases in the higher frequency bands. Specifically, in the active stimulation condition, participants experienced significant power increases of higher frequency bands (alpha, beta, and gamma) and smaller power increases of lower frequency bands (delta and theta).

     Conditions such as AD present with decreased power of high frequency activity and increased power of low frequency bands. If these abnormal ranges of activity are the cause of cognitive decline, then using tPBM to generate more high frequency activity should, in theory, alleviate some of the symptoms. To confirm this, however, will require pre-clinical and clinical trials on participants with dysfunction of the DMN

     We now know what tPBM is and what it does, but how exactly does it work? The specifics behind the neurophysiology are much less well understood than those associated with tDCS or TMS, but there are certain cellular mechanisms that appear to be impacted by NIR light stimulation. The most well studied are mitochondria, after PBM, ATP production increases as well as transcription of genes for protein synthesis, cell proliferation, anti-inflammatory, and antioxidant responses. In layman’s terms, PBM has the potential to maintain the function of neurons while also promoting growth of new neurites such as dendritic spines for enhanced neuronal communication and, as was seen in a rat model study, even the growth of entirely new neurons after ischemic stroke. This study does mention that there is little evidence that tPBM directly impacts neural activity but through the mechanisms mentioned above it may promote maintenance of functional connectivity through neurite growth as well as maintenance of the activity of individual neurons through transcriptional modulation and ATP production.

     In summation, the therapeutic potential of tPBM through Vielight’s relatively cheap, easily accessible, and portable technology is exciting in terms of possibly enhancing cognition for those with AD or dementia, as well as other disorders of the DMN, in the comfort of your own home. However, it is important to address the fact that this is an extremely new method of NIBS that, as of yet, has not been well studied for disease models in human participants. As such, if purchasing a tPBM system is a financial stretch, it is likely worth waiting for further research to confirm its purported therapeutic effects. On the bright side, for this pilot study none of the participants experienced any adverse effects or even abnormal sensations meaning that further research should be easily approved and, hopefully, within the next year or two we will have concrete proof of any effectiveness of tPBM.

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Sources: 
Zomorrodi, R., Loheswaran, G., Pushparaj, A., & Lim, L. Pulsed Near Infrared Transcranial and Intranasal Photobiomodulation Significantly Modulates Neural Oscillations: a pilot exploratory study [Internet]. Nature. 2018. Available from: https://www.nature.com/articles/s41598-019-42693-x
Quiroga, R. Q., & Kreiman, G. Measuring sparseness in the brain: Comment on Bowers (2009) [Internet]. Psychological Review. 2010. Available from:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154835/

Sex Differences in Alzheimer’s Risk and Pathology

    Many facets of our lives are profoundly impacted by our underlying genetic makeup from birth. One particularly impactful genetic difference involves the X and Y chromosomes which, aside from assigning one’s biological sex, also play a crucial role in regulation and expression of other genes. The interaction between sex chromosomes and the apolipoprotein E (APOE) gene, which is commonly correlated to one’s risk of developing Alzheimer’s disease (AD), is well studied both in terms of relative risk as well as particular pathological presentations between males and females. This is especially important because certain sub-groups of AD patients often respond differently to various treatments. In the future, these mild differences in clinical manifestations may provide insights into specific treatments or preventative measures that are more effective in sex-based sub-groups. This week we will be delving into this research.

    One study determined that females were roughly twice as likely as men to develop AD, but that men had shorter lifespans after onset of the disease. These two data points alone outline the significant differences in both risk and expression of the disease amongst males and females. Specifically, in a group of 2611 participants followed for 20 years, it was determined that a 65 year old man without a current AD diagnosis had a 6.3% chance of developing AD later in life. This same study found that a 65 year old woman without a current AD diagnosis had a 12% chance of developing the disease. Once a diagnosis is suspected, several epidemiological studies have suggested that females experience neurodegeneration and onset of symptoms more quickly but also have longer lifespans with the disorder. One possible explanation for this is that, due to the faster onset/progression, women tend to be diagnosed earlier making their post-diagnosis lifespan appear longer, while men who may already be suffering from AD but are mostly asymptomatic are diagnosed later, shortening their post-diagnosis lifespan. However, one review study focusing on mortality associated with all dementing disorders found that men had shorter lifespans regardless of age at diagnosis. All of these acute differences raise the question, what is the difference between males and females when it comes to AD?

    Part of the differences, as we discussed earlier, come down to genetics. One study found that while women are generally more likely to develop AD, men with the APOE ɛ4 allele (a specific variant of the APOE gene) have higher relative risk than women with the APOE ɛ4 allele. Furthermore, they determined that the APOE ɛ2 allele, which is uncommon in the general population but has been hypothesized to confer some resistance to development of AD, only provided this reduced risk in women. However, the study involved very few males with the ɛ2 allele, which may have confounded protection in that population. Men have higher incidence rates of vascular disease and women more commonly take anti-hypertensive drugs. Vascular disorders have been hypothesized to advance the progression of dementia, while regular administration of anti-hypertensive drugs seem to reduce the risk associated with the APOE ɛ4 allele. This may be another confounding variable in the relative risks associated with sex, but even so it suggests that lifestyle differences, such as doctor visits and taking one’s medication may also play a role in the development of AD. You can change your lifestyle but you cannot change your genetics.

   Yet another possible differential between the sexes involves hormone secretion. Mouse models lacking estrogen receptors result in up-regulated estrogen levels, possibly playing a powerful role in neuroprotection. Estradiol, the predominant estrogen produced during reproductive years in females, administered to females prior to a prolonged period of reduced hormone secretion like menopause provided neuroprotective effects. However, if administered after a prolonged reduction in hormone secretion (hypogonadism), estradiol was incapable of producing the same effects, leading us to the “healthy cell hypothesis”. It proposes that normal hormonal secretion promotes healthy cell aging while a period of reduced secretion diminishes the neuroprotective effects of hormones. In animal models, estrogens like estradiol promote turnover of thin spines in neurons which are synaptic structures associated with higher cognitive functioning, particularly of the prefrontal cortex which plays a critical role in executive function. Maintenance of normal hormone levels is crucial because during periods of hypogonadism the cells become “less healthy” and may no longer benefit from the normal protective effects. Among women who develop AD, those that had more lifetime exposure to estrogens developed AD at a later age. This has created interest in the possibility of hormone therapy during the onset of menopause as a possible preventative treatment for AD. 

   Unfortunately, one clinical trial testing the effects of estradiol and estrogen/ medroxyprogesterone supplementation on cerebrovascular events in aging women found hormone replacement to increase risk for breast cancer, stroke, and coronary heart disease, meaning that, as of now, this may not be a safe option for prevention of dementia. Males, on the other hand, experience much less marked decreases in hormone production in the late stages of life which might explain the decreased general risk of AD amongst men if androgens play a similar neuroprotective role in men as estradiol does in women.

        Overall, it is clear that genetic sex interacts with age and general genetics to create extreme variability in risk for AD. Sub-group analyses based on gender, and preclinical and clinical trials focusing on the particular risks associated with each group, may prove to be more effective than a generalized treatment for AD.

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Barnes, L. L., Wilson, R. S., & Bienias, J. L. Sex Differences in the Clinical Manifestations of Alzheimer Disease Pathology [Internet]. Archives of General Psychiatry. 2005. Available from:
https://jamanetwork.com/journals/jamapsychiatry/article-abstract/208641
Qiu, C., Kivipelto, M., Aguero-Torres, H., Winblad, B., & Fratiglioni, L. Risk and protective effects of the APOE gene towards Alzheimer’s disease in the Kungsholmen project: variation by age and sex [Internet]. Journal of Neurology, Neurosurgery, and Psychiatry. 2003. Available from: https://jnnp.bmj.com/content/jnnp/75/6/828.full.pdf
Podcasy, J. L., & Epperson, C. N. Considering sex and gender in Alzheimer disease and other dementias [Internet]. Dialogues in Clinical Neurosciene. 2016. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286729/
Todd, S., Barr, S., Roberts, M., & Passmore, A. P. Survival in dementia and predictors of mortality: a review [Internet]. International Journal of Geriatric Psychiatry. 2013. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/gps.3946
Bailey, M., Wang, A. C.J., & Morrison, J. H. Interactive Effects of Age and Estrogen on Cortical Neurons: Implications for Cognitive Aging [Internet]. Neuroscience. 2011. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166405/?report=reader
Kim, N., Gross, C., & Krumholz, H. M. The Impact of Clinical Trials on the Use of Hormone Replacement Therapy [Internet]. Journal of General Internal Medicine. 2005. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1490267/

The Protective Effects of Sleep for Neurodegeneration

        As we all know, sleep plays a critical role in brain functioning. One such function is memory, with sleep enhancing memory encoding and consolidation. Unsurprisingly, study participants deprived of sleep for 36 hours had significantly worse memory retention and poorer insight into their performance than participants who slept regularly, and administration of caffeine to overcome the decreased alertness was incapable of improving memory function in a sleep deprived sub-group. Another study, utilizing fMRI imaging, showed that sleep deprived participants had decreased activation of the medial temporal lobe in a verbal learning task, but increased prefrontal and parietal lobe activity (presumably to compensate for decreased temporal function) and a corresponding 40% decrease in memory formation of the target words. These results showcase the important role that sleep plays in memory formation, but studies within the last decade have suggested there may be an even more powerful impact on cognition.

        Insomnia is a common complaint amongst patients with neurodegenerative diseases, and was long thought to be a symptom of these disorders. More recently, however, there has been interest in how insomnia might actually be a risk factor for neurodegeneration in a bidirectional relationship. In a study following participants with and without insomnia for 6 years, those in the 90th percentile of sleep fragmentation were 1.5 times more likely to develop Alzheimer’s disease (AD) compared to those in the 10th percentile of sleep fragmentation (representing longer and deeper sleep). Another study, performed over 40 years, showed that patients with complaints of insomnia had a 33% increase in risk for dementia and a 51% increase in risk for AD. Furthermore, a PET imaging study showed that a single night of sleep deprivation significantly increased amyloid-beta deposition (Aβ), even in healthy controls. Results like these promoted further research into the link between insomnia and neurodegeneration providing insight into the neurophysiological effects of sleep.

        This raises the question; How exactly does sleep prevent Aβ buildup and reduce risk for AD and dementia? 

        As you may already know, the brain is contained within a closed cavity, and because of this, any change in volume (such as an influx of blood) will create either a change in pressure or a change in volume of something else (such as cerebrospinal fluid or CSF). Recent studies have been testing these fluid dynamics and how they might play a role in the clearance of toxic by-products such as Aβ. One such study, utilizing blood oxygen level-dependent (BOLD) fMRI imaging and EEG measurement of neural activity found a distinct pattern of fluid flow during slow-wave sleep (SWS) also known as non-rapid eye movement (NREM) sleep. Specifically, it seems that during SWS, a decrease in neural activity also creates a decrease in cranial blood flow. Slow pulses of blood during this phase of sleep are inversely correlated to CSF flow, meaning that as blood flows into the cranial cavity, CSF flows out, and vice versa, in a pulsatile fashion. Because of these pulses of blood flow, waves of CSF are first moved around the brain, mixing with interstitial fluid and taking up toxic by-products, and are then pushed out, effectively clearing toxins from the cranial cavity. In this way, SWS is crucial for neuronal health as this is the only time that hemodynamic flow is coupled with the “bathing” action of CSF. Another related function is proteostasis, the maintenance of healthy proteins and clearance of misfolded proteins. In mice, sleep deprivation impairs proteostasis and causes brain cell death.

        These studies show that lack of sleep contributes to neurodegeneration, but neurodegenerative disorders also contribute to impaired sleep. This bidirectional pathway of toxic protein accumulation causes neurodegeneration that in turn furthers sleep impairment in a repetitive cycle. Thus treatment of sleep disorders is just as important as treatment of cognitive decline in AD patients; sweet dreams!

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Harrison, Y., & Horne, J. A. Sleep loss and temporal memory [Internet]. The Quarterly Journal of Experimental Psychology. 2000. Available from: https://journals.sagepub.com/doi/abs/10.1080/713755870
Drummond, S. P., Brown, G. G., Gillin, J. C., Stricker, J. L., & Wong, E. C. Altered brain response to verbal learning following sleep deprivation [Internet]. Nature. 2000. Available from: https://www.nature.com/articles/35001068
Fultz, N. E., Bonmassar, G., Setsompop, K., Stickgold, R. A., Rosen, R. R., Polimeni, J. R., & Lewis, D. L. Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep [Internet]. Science. 2019. Available from: https://science.sciencemag.org/content/366/6465/628
Grubb, S., & Lauritzen, M. Deep sleep drives brain fluid oscillations [Internet]. Science. 2019. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31672882
Minakawa, E. N., Wada, K., & Nagai, Y. Sleep Disturbance as a Potential Modifiable Risk Factor for Alzheimer’s Disease [Internet]. International Journal of Molecular Sciences. 2019. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412395/
Shokri-Kojori, E., Wang, G., Wiers, C. E., Demiral, S. B., Guo, M., Won Kim, S., Lindgren, E., et. al. β-Amyloid accumulation in the human brain after one night of sleep deprivation [Internet]. Proceedings of the National Academy of Sciences of the United States of America. 2018. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924922/
Shamim, S. A., Warriachm, Z. I., Tariq, M. A., Rana, K. F., & Malik, B. H. Insomnia: Risk Factor for Neurodegenerative Diseases [Internet]. Cureus. 2019. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876903/

Memory Disorders: A Review

        As we look back upon the events of the last decade, it seems fitting to also review the
various types of memory, disorders that affect them, and what we have learned about them over
the years. We will address the neuroanatomy, symptomatology, and treatments of disorders
affecting episodic, working, procedural, and semantic memory functions. Before we do that,
however, let’s outline the basic process of “making” a memory and how this ties into these
individual memory types. In general, a memory undergoes three distinct phases of formation,
known as encoding, consolidation, and retrieval. Dysfunction at any of these stages will result in
memory impairment, manifesting differently depending on the stage affected.

        Episodic memory, refers to encoding and recalling personal experiences as though they
were an “episode” of your life. Neuroanatomically, the Papez circuit subserves encoding of
episodic memory, while the frontal lobes are crucial for its retrieval. This is evidenced by the
famous case of H.M., who underwent bilateral medial temporal lobe removal to treat severe
epilepsy, and wound up with severe anterograde amnesia (the inability to form new memories).
Damage to the hippocampal formation or other structures in the Papez circuit impairs episodic
memory encoding. Episodic memory is also lateralized with visual memory being stored
primarily in the right and verbal memory in the left hippocampus/medial temporal lobe.
Psychometric tests that measure memory dysfunction utilize figure and word-list free recall and
recognition cues. When a patient’s recall errors are improved with recognition cues we then
know that the brain dysfunction is not in Papez circuit (responsible for encoding) but in the
frontal lobes (responsible for retrieval). Normal age-related memory decline is the leading cause
of a retrieval deficit; that is why we keep lists as we get older, to serve as cues for our senior
moments. When that list no longer jogs your memory that is always the sign of a disease and
that is when it’s time to see us.

        Possible causes of damage to Papez circuit include traumatic brain injury (TBI), localized
strokes, Wernicke-Korsakoff syndrome, or transient global amnesia induced by seizure. More
commonly occurring episodic memory disorders include Alzheimer’s disease (AD) and
hippocampal sclerosis (HS). Other neurodegenerative disorders like Lewy body dementia,
Parkinson’s dementia, and frontotemporal lobar degeneration (FTLD) also tend to cause deficits
in episodic memory but present much later in their progression.

        Working memory, often referred to as short-term memory, is the ability to maintain
information in one’s mind in a malleable state so that it might be manipulated in order to
complete goal-oriented behaviors. This type of “memory” is actually more of an executive
function, with the frontal lobes playing the primary role in its maintenance. Because of this,
disorders which impact working memory tend to impact executive functioning. For example,
working memory deficits are well-established in Autism Spectrum Disorder, Attention Deficit
Hyperactivity Disorder, Schizophrenia, and Fetal Alcohol Syndrome. Working memory
dysfunction is also possible in the later phases of neurodegenerative disorders such as AD,
Frontotemporal dementia, Parkinsons, and Lewy body dementia, or after a TBI. Treatment for
executive functioning depends upon the cause of the dysfunction.

        For instance, AD working memory deficits sometimes respond to cholinesterase inhibitors, while Parkinson’s dementia responds better to dopamine replacement therapy. Even normal age-related working memory deficits can be alleviated somewhat by “training” oneself to multitask. In one study, a basic video game called NeuroRacer that involved responding to signs and keeping a car centered on a winding road, was used and after training, participants between 60-85 years old were able to enhance their working memory and multitasking abilities. The most common test of working memory involves retention/recitation of a digit span, either as it was originally given or in reverse. Interestingly, the average digit span that can be retained in working memory is 7
numbers, plus or minus 2, which is why phone numbers consist of 7 digits!

        Procedural memory is nondeclarative, meaning that they can be accessed and operated
automatically. These types of memories, like the name suggests, involve acquisition and
retention of a procedure for cognitive or behavioral skills. An example of a procedural memory
would be how to play a musical instrument or driving a manual car. The anatomical structures
involved in formation and execution of procedural memories include the basal ganglia, the
cerebellum, and the supplementary motor cortex. Impairment of procedural memory is most
common with Parkinson’s disease, but is also found in cases of Huntington’s disease or
cerebellar degeneration syndromes. Treatment and clinical testing of procedural memory deficits
are uncommon, however, treating the motor symptoms of these disorders, such as through
dopamine replacement, has been shown to allow for relearning of previously acquired skills.

        Semantic memory refers to knowledge about words and their meaning, and knowledge
about things in the environment, their relationships, and their uses. Because of the broad amount
semantically cetegorized information, their storage in the brain is distributed throughout.
Considering a given concept might engage structures associated with motion, taste, olfaction,
color, or emotion. For example, neuroimaging shows that comprehension of an action-related
concept triggers activation of motor cortices. Furthermore, diseases that affect the motor system,
like Parkinson’s disease, tend to be accompanied by deficits in action verb comprehension. In
cases with widespread semantic knowledge loss, the anterior and inferolateral temporal lobes
tend to be dysfunctional, implicating these areas as the location of amodal (not associated with
one particular sense or action) semantic knowledge. Semantic information also seems to be
lateralized, with verbal semantic knowledge being stored in the left temporal lobe, and
structural/functional information on the right. The most common test for semantic memory is the
Boston Naming Task, involving naming basic drawings of various objects or naming objects
within a category.

        The most notable cause of severe semantic memory dysfunction is the semantic variant of
primary progressive aphasia (svPPA), a subtype of FTLD, with atrophy centralized in the
anterior left temporal pole. Neuropathology of svPPA frequently includes accumulation of TAR
DNA-binding protein 43, although further research has revealed numerous genetic risk factors
and associated protein biomarkers. AD is another common cause of semantic memory deficits
but symptoms tend to be less distinct than the episodic memory deficits. Treatment of AD-
induced semantic symptoms is the same as treatment of episodic memory symptoms for AD
patients. In the case of svPPA, however, there is interest in using transcranial direct current
stimulation (tDCS) to temporarily boost semantic processing. Post-stroke aphasia, another
potential cause of semantic memory loss, also responds to tDCS. Unfortunately, the results are
inconsistent and require further study.

        Before we conclude, it is worth mentioning that there is still much to learn about these
complex memory systems. These discrete systems are more interconnected than we may think.
Neuroimaging has shown that participants learning to predict the weather with undivided
attention engaged the medial temporal lobe and had a more flexible knowledge of the task.
Participants learning with divided attention engaged the basal ganglia, and had less flexible
knowledge of the task. The basal ganglia might “pick up the slack” when the preferred medial
temporal memory system is otherwise engaged. This same effect has also been observed in
lesion studies, drawing attention to the synergy and competition that might play a role in normal
memory function. Understanding these systems in a less rigid and more holistic way may be the
next frontier of memory research using stimulation of healthy networks to subserve the lost
function of damaged networks. Watch for an upcoming blog on how pulsed light waves
(photobiomodulation) might activate networks in neurodegenerative diseases.

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The French Paradox: Red Wine for a Healthy Mind?

Known since 1992, the French diet is high in saturated fats, a risk for coronary heart disease (CHD), yet they have less than half the CHD-related deaths compared to the US, Sweden, and the UK. High intake of wine, thought to be 57% of alcohol consumption in France, may contribute to this disproportionately low frequency of CHD representing the French paradox. However, heavy alcohol consumption is associated with increased risk of heart attack, arrhythmia, hypertension, and sudden death. This raises the question; How does wine consumption improve cardiovascular health?

Wine, particularly red wine, contains high levels of phenols. One phenol, resveratrol, may contain cardiovascular protectant properties. It inhibits oxidative stress caused by free radicals, preventing cell damage or death. Resveratrol appears to increase lifespan and promote healthy aging. Fruit flies, fish, and nematodes given resveratrol increase their lifespan significantly! In humans low to moderate amounts of wine consumption are associated with decreased cardiovascular- and cerebrovascular disease-related deaths.

Moderate consumption of wine is also associated with lower instances of Alzheimer’s disease (AD). Normally, proteasomes are responsible for degradation of damaged and aggregated proteins such as Aβ, but their activity is impaired in AD. Oxidative stress inactivates proteasomes, which can be prevented with resveratrol administration in disease-model cell cultures. Administration of resveratrol in vitro correlates to increased intracellular degradation of Aβ by proteasomes, suggesting that moderate wine consumption may decrease one’s likelihood of developing AD. Synthetic resveratrol supplements are new to the field and require further research.

One year of resveratrol supplementation (500-2000 mg per day) slowed decline in cognition and function compared to placebo. Yet other studies found no difference with supplementation over 52 weeks. Larger studies over a longer duration are needed. Pterostilbene, a synthetic resveratrol analog, has much higher oral bioavailability and blood-brain barrier permeability warranting further research. Resveratrol administration correlates with decreased central nervous system (CNS) deposition of Aβ, and increased brain shrinkage in AD patients as a product of reduced neuroinflammation.

Resveratrol benefits a variety of other physiological functions, too. It delays or prevents cell death in a variety of cell types, decreases atherosclerotic lesion formation, reduces risk for hypercholesterolemia, maintains glucose homeostasis in diabetes, and promotes tumor suppressor gene expression. In rat models of Lewis lung carcinoma, resveratrol decreases tumor size, weight, and metastasis, indicating a diverse range of effects on chemoprevention. It has powerful effects on energy metabolism. In mice, administration increased aerobic capacity as evidenced by increased running time and oxygen consumption in muscle fibers. Its effects on energy metabolism might also minimize damage from secondary spinal cord injuries. Further research in human models is needed to validate it as a therapeutic.

While resveratrol’s impacts on cognition and AD are inconclusive, it has potential to benefit health in a variety of other ways, which may justify a glass of red wine every so often. If you can’t drink wine, resveratrol is also present in a number of foods, including grapes, peanuts, soybeans, apples, and pomegranates. Red wines contain concentrations between 0.361-1.972 mg/L, meaning that one would have to drink many bottles of wine to achieve the hypothesized therapeutic dose (TD) of 1 gram per day. Even including resveratrol containing foods such as peanuts (0.03-0.14 μg/g) and apples (400 μg/kg) does not reach the TD.  However, these measurements only account for unbound resveratrol. Food and drinks containing pure resveratrol also contain molecular constituents and resveratrol glucosides which occur in higher concentrations and, in some cell culture and animal studies, show higher potency than resveratrol itself. These molecules may actually be the driving force behind the French Paradox, but focused research and clinical trials will be required to confirm this hypothesis.

There are also supplemental tablets derived from Japanese knotweed containing a therapeutic dose of concentrated resveratrol. Unfortunately, research has shown that these supplements are a less effective source of resveratrol as it’s bioavailability and absorption is enhanced by the food matrix present in its naturally occurring forms. Regardless, with so many beneficial impacts in the body and no serious adverse effects we could all stand to increase our resveratrol intake – whether it comes from a glass of red wine, a handful of peanuts, or a supplement. This week, go out and live like the French!

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