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Neurodegeneration

Polyphenol-rich diets and neurodegeneration (glycemic control) featured article

Our brains shrink as we grow older, but that doesn't mean you can wait until old age to worry about it—neurodegeneration starts 15–20 years before the onset of symptoms of mild cognitive impairment, dementia, or Alzheimer's disease.

Certain brain structures, like the hippocampus, are particularly vulnerable, accumulating neurofibrillary tangles, undergoing a reduction in synapses, and losing neurons.

The good news is that we can intervene in the process, and one of the most important ways to do this is to keep blood glucose levels in check.

Glucose levels that fall within the high-normal range are associated with an atrophying of the hippocampus. It gets even worse for people with metabolic dysfunction or diabetes, who have higher levels of brain atrophy—hence why Alzheimer's disease is sometimes referred to as "type 3 diabetes." Glucose control is a modifiable risk factor for cognitive decline.

How can one bolster metabolic health in an attempt to stave off brain...

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Episodes

ketogenic diet

Neurological disorders and migraines | Dominic D'Agostino

Posted on May 21st 2022 (about 3 years)

In this clip, Dr. Dominic D'Agostino describes how nutritional ketosis may support the treatment of neurodegenerative and other brain disorders.

parkinson's

Importance of intensity of exercise and dopamine in treating Parkinson's | Giselle Petzinger

Posted on October 28th 2020 (over 4 years)

In this clip, Dr. Giselle Petzinger discusses how intense exercise can impact motor scores in people with Parkinson's disease.

parkinson's

Exercise improves sensitivity to dopamine | Giselle Petzinger

Posted on October 28th 2020 (over 4 years)

In this clip, Dr. Giselle Petzinger explains that strenuous exercise affects dopamine sensitivity in the brains of people with Parkinson's disease.

Topic Pages

  • Creatine

    Mechanistically, creatine buffers neuronal ATP via the phosphocreatine shuttle, mitigating neurodegeneration-induced mitochondrial energy failure.

  • Nicotinamide mononucleotide

    Nicotinamide mononucleotide replenishes NAD+, activating sirtuins and PARP-mediated repair pathways, mitigating mitochondrial dysfunction implicated in neurodegeneration.

  • Senescence

    Senescent glial cells secrete SASP cytokines, ROS and proteases, triggering neuroinflammation, synaptic dysfunction and progressive neurodegeneration.

News & Publications

  • Sleep enhances the brain's waste removal through synchronized fluctuations in norepinephrine and blood volume, a process disrupted by the common sleep aid, zolpidem. https://www.cell.com/cell/abstract/S0092-8674\(24\)01343-6
    Brain Sleep Norepinephrine Neurodegeneration

    The brain doesn’t just rest during sleep—it actively clears out waste that can damage brain cells. This crucial process, known as glymphatic clearance, relies on the movement of cerebrospinal fluid to wash away harmful proteins linked to neurodegenerative diseases. A recent study found that synchronized fluctuations in norepinephrine, blood volume, and cerebrospinal fluid are key drivers of glymphatic clearance during deep sleep, but some popular sleeping pills disrupt this process.

    The researchers tracked blood and cerebrospinal fluid dynamics while mice slept naturally. Then, they examined how zolpidem, commonly known as Ambien, affected these dynamics during sleep.

    They found that norepinephrine fluctuations triggered by the brain’s locus coeruleus drove rhythmic changes in blood vessel size. This facilitated the movement of cerebrospinal fluid into the brain and the removal of waste products. However, zolpidem disrupted norepinephrine activity, reducing cerebrospinal fluid flow and hindering this waste removal process.

    These findings suggest that the brain’s waste removal system relies on a delicate balance of norepinephrine and blood vessel activity. Sleep aids like zolpidem disrupt this process, potentially contributing to neurodegenerative diseases like Alzheimer’s. Learn more about the effects of sleep aids like Ambien in this episode featuring Dr. Matthew Walker.

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  • Lower levels of active B12 linked to slower visual processing and cognitive decline, suggesting current guidelines may not adequately ensure brain health. onlinelibrary.wiley.com
    Brain Micronutrients Vitamin B12 Neurodegeneration

    Scientists have long known that severe B12 deficiency can cause neurological problems, but the exact threshold for deficiency-related damage remains unclear. A recent study found that older adults with B12 levels in the lower end of the normal range showed signs of neurological dysfunction.

    Researchers measured B12 levels and conducted brain scans on 231 healthy older adults. Participants underwent tests to evaluate brain function, including visual processing speed and cognitive performance. The researchers also assessed blood biomarkers associated with nerve damage and brain health.

    They found that lower B12 levels, particularly the active form of the vitamin, were associated with slower visual processing, cognitive decline, and increased signs of white matter damage in the brain. Surprisingly, high levels of the inactive form of B12 correlated with increased tau protein, a marker of neurodegeneration.

    These findings suggest that current B12 guidelines don’t fully capture what the brain needs to function correctly and that even “normal” B12 levels could contribute to neurological changes. They also highlight the role of adequate nutrition throughout the lifespan and support the “micronutrient triage theory"—the idea that the body prioritizes micronutrient utilization for survival over those used for long-term health. Learn more about micronutrient triage theory in this episode featuring Dr. Bruce Ames.

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  • Microplastics in the bloodstream may obstruct tiny blood vessels in the brain, impairing blood flow and causing neurological disorders, according to a recent study in mice. www.science.org
    Brain Pollution Neurodegeneration

    Microplastics are everywhere in the environment—from the water we drink to the air we breathe. Scientists have found these tiny plastic particles in human blood, organs, and even the brain, raising concerns about their potential health effects. A recent study in mice found that microplastics in the bloodstream can obstruct tiny blood vessels in the brain, impairing blood flow and driving neurological disorders.

    Researchers injected fluorescently labeled microplastics into mice and observed how the particles traveled through brain capillaries. In particular, they focused on how immune cells interacted with microplastics and whether they contributed to vascular blockages.

    They found that immune cells engulfed microplastics, driving unintended consequences. These microplastic-laden cells clogged capillaries in the brain, reducing blood flow and triggering neurological impairments in the mice. The blockages resembled tiny blood clots, highlighting a previously unknown way microplastics could harm brain function.

    These findings suggest that microplastics contribute to brain dysfunction by indirectly disrupting blood flow rather than directly penetrating brain tissue. Learn more about microplastics and brain health in this episode featuring Dr. Rhonda Patrick.

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  • Mechanical stresses and myokines produced by muscles during exercise synergistically promote nerve growth and connectivity. onlinelibrary.wiley.com
    Exercise Muscle Neurodegeneration

    Muscle contraction, the hallmark of exercise, releases signaling molecules called myokines that influence cell function throughout the body. However, the mechanical forces it generates may also play a role. A recent lab study found that biochemical and mechanical signals from contracting muscle work synergistically to promote nerve growth and maturation.

    Researchers grew muscle cells on a specialized gel that mimicked the movements of contracting muscles. Then, by adding tiny magnetic particles, they stretched the cells to simulate exercise. They assessed how these forces and the myokines released by the muscle cells influenced the growth of nerve cells.

    They found that nerve cells grew and migrated more readily when exposed to myokines from contracting muscle cells, with more robust effects at higher levels of muscle activity. Stretching the nerve cells mechanically produced similar growth, but further analysis demonstrated that chemical signals were more effective in activating genes related to nerve growth and forming connections.

    These findings suggest that exercise influences nerve health through biochemical and mechanical pathways, providing new insights into how muscle activity supports the nervous system. Myokines also exert anti-cancer effects. Learn more in this episode featuring Dr. Rhonda Patrick.

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  • Excess body fat in the arms and belly increases the risk of neurodegenerative disease. www.neurology.org
    Brain Alzheimer's Aging Fat Dementia Neurodegeneration

    Although many factors influence whether a person develops neurodegenerative diseases like Alzheimer’s and other forms of dementia, excess body fat stands out as a notable risk factor. Some research suggests that where that body fat is located modulates that risk, with a new study finding that higher body fat in the arms and belly increases the likelihood of neurodegenerative disease.

    The study involved more than 412,000 people enrolled in the UK Biobank study. Researchers measured the participants' body composition and tracked their health for about nine years.

    They found that participants with greater muscle strength, bone density, and body fat in their legs were 6% to 25% less likely to develop neurodegenerative diseases. However, those with more body fat in their arms and bellies were 13% to 18% more likely to develop neurodegenerative diseases. Between 10% and 35% of the link between these body composition patterns and neurodegenerative diseases was attributable to the influence of cardiovascular diseases—particularly cerebrovascular diseases.

    Cerebrovascular disease is an umbrella term for conditions that affect the blood vessels that supply the brain, such as strokes and aneurysms. Exercise helps maintain the health of these blood vessels, reducing the risk of neurodegenerative diseases. Learn more in this episode featuring Dr. Axel Montagne.

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  • Men with low testosterone are five to six times more likely to develop dementia. alz-journals.onlinelibrary.wiley.com
    Brain Hormones Testosterone Dementia Neurodegeneration

    Testosterone is the primary male sex hormone, crucial for maintaining fertility and maintaining male sexual characteristics. Some evidence suggests testosterone is neuroprotective. A recent study found that lower testosterone levels are linked with a higher risk for dementia.

    The study involved 581 cognitively healthy older men living in China. Researchers assessed the men’s cognitive function and measured their levels of testosterone and neurofilament light chain, a structural protein that maintains neuronal health and connectivity. Neurofilament light chain is a biomarker for neuronal damage and degenerative diseases, including Alzheimer’s.

    They found that men with lower testosterone levels were roughly five times more likely to experience cognitive decline than those with high levels. Those with low testosterone and high neurofilament light chain levels were approximately six times more likely to experience cognitive decline.

    These findings suggest that lower testosterone and neurodegeneration synergistically contribute to cognitive decline in men. Learn more about low testosterone in this clip featuring Dr. Peter Attia.

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  • Drinking caffeinated coffee reduces the risk of Parkinson's disease by 37 percent. www.neurology.org
    Parkinson's Coffee Caffeine Neurodegeneration

    Coffee is perhaps best known for its stimulant properties, primarily from its caffeine content. Recent research found that caffeine and its metabolites reduce the risk of Parkinson’s disease, a progressive neurodegenerative disorder affecting more than 10 million people worldwide.

    The research was part of the EPIC study, a large, prospective cohort that spans six European countries. Researchers looked at how much coffee participants reported drinking and then tracked who developed Parkinson’s. They used statistical models to estimate the risk of developing the disease and analyzed caffeine metabolites in blood samples taken several years before any Parkinson’s diagnosis.

    They found that participants who drank the most coffee had a 37 percent lower risk of developing Parkinson’s than non-coffee drinkers. In addition, higher levels of caffeine and its principal metabolites (paraxanthine and theophylline) were associated with a lower risk of Parkinson’s, even after considering other risk factors, such as smoking and alcohol use.

    These findings suggest that drinking caffeinated coffee protects against Parkinson’s disease. However, coffee is also rich in other bioactive compounds, including polyphenols, alkaloids, and others – many of which exert potent neuroprotective effects.

    While some forms of Parkinson’s disease are genetic, most cases involve a complex interaction between genetic and environmental risk factors. Learn more in this clip featuring Dr. Giselle Petzinger.

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  • Polyphenols in tea may reduce symptoms and progression of Parkinson's disease. pubmed.ncbi.nlm.nih.gov
    Parkinson's Green Tea Neurodegeneration Polyphenol

    Parkinson’s disease is a progressive neurodegenerative disorder characterized by loss of dopamine-producing neurons, motor impairments, and the accumulation of alpha-synuclein, a neuronal protein that regulates synaptic vesicle movements and neurotransmitter release. However, a growing body of evidence suggests that dietary components protect against the development and progression of the condition. A 2015 study found that polyphenols in tea mitigated neuronal loss, motor impairments, and alpha-synuclein accumulation in a primate model of Parkinson’s disease.

    Researchers treated a group of monkeys with Parkinson’s disease with a mixture of tea polyphenols, including epicatechin, epicatechin gallate, epigallocatechin, and epigallocatechin gallate (commonly known as EGCG), daily for 80 days. Another group of monkeys received no treatment. The researchers assessed the animals' motor function every two weeks and examined their brains.

    They found that treatment with tea polyphenols alleviated motor impairments and neuronal loss in the monkeys and reduced alpha-synuclein accumulation. Monkeys that didn’t receive polyphenols showed marked disease progression.

    These findings suggest that tea polyphenols exert neuroprotective properties in a primate model of Parkinson’s disease. Polyphenols are one of the most common classes of bioactive compounds found in plants. Evidence suggests they exert potent anti-inflammatory, antioxidant, and cardioprotective properties. Learn more about polyphenols in our overview article.

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  • High particulate matter exposure increases the risk of Parkinson's disease by nearly 20 percent. www.neurology.org
    Parkinson's Pollution Environment Neurodegeneration

    People who live in large cities or near industrial areas are often exposed to high levels of particulate matter – a mixture of solid particles and liquid droplets in air pollution that forms fine inhalable particles with diameters typically 2.5 micrograms (PM2.5) or less. A recent study found that high exposure to PM2.5 increases the risk of developing Parkinson’s disease by nearly 20 percent.

    Researchers conducted a population-based study of more than 21 million older adults living in the US. They assessed their exposure to particulate matter based on their geographical location and ascertained whether they had Parkinson’s disease based on Medicare records.

    They found that people exposed to the median PM2.5 level were 56 percent more likely to develop Parkinson’s than those with the lowest PM2.5 exposures. For every additional microgram per cubic meter of PM2.5 exposure, risk increased by 4.2 percent. In the Mississippi-Ohio River Valley, where particulate matter levels are high, the risk of developing Parkinson’s disease was 19 percent greater than in the rest of the country.

    These findings suggest that exposure to particulate matter markedly increases a person’s risk of developing Parkinson’s disease, aligning with other evidence pointing to the disease’s environmental origins. Parkinson’s disease is a neurodegenerative disorder that affects the central nervous system. Caused by the destruction of nerve cells in the part of the brain called the substantia nigra, it typically manifests later in life and is characterized by tremors and a shuffling gait. Learn more about Parkinson’s disease and therapies in this episode featuring Dr. Giselle Petzinger.

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  • Every 1 percent drop in body weight slows brain aging by nearly nine months, highlighting the substantial, and often overlooked, neuroprotective benef elifesciences.org
    Brain Obesity Aging Dementia Sulforaphane Weight Loss Neurodegeneration

    Excess body fat harms multiple organ systems, including the central nervous system, potentially accelerating brain aging. A new study shows that a 1 percent weight loss delays brain aging by nearly nine months.

    Researchers conducted a study involving 102 participants enrolled in the DIRECT-PLUS study who underwent an 18-month lifestyle intervention to promote weight loss. Using magnetic resonance imaging, the researchers assessed the resting-state functional connectivity in the participants' brains and predicted their brain ages. They also evaluated how various health factors, such as body measurements, blood markers, and fat deposits, affect brain aging.

    They found that the brain age prediction model accurately predicted the participants' chronological ages. They also found that brain aging slowed by 8.9 months for every 1 percent of body weight loss, an effect linked with improved liver health and reduced liver, visceral, and subcutaneous fat. Their analysis revealed that lower consumption of processed foods, sweets, and beverages delayed brain aging.

    These findings suggest that weight loss may benefit the brain’s aging process, potentially slowing its aging trajectory. They also underscore the importance of maintaining a healthy weight throughout the lifespan to support overall brain health. Sulforaphane, a bioactive compound derived from broccoli, benefits brain health and may influence its aging, too. Learn more in this episode featuring Dr. Rhonda Patrick.

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  • High blood pressure in early adulthood is linked to late-life neurodegeneration and loss of white matter integrity. www.news-medical.net
    Brain Aging Dementia Blood Pressure Neurodegeneration

    A new study shows that having high blood pressure in early adulthood harms brain health later in life, especially in men. Men who had high blood pressure as young adults had poorer brain health than those with normal blood pressure.

    Researchers performed brain scans on 427 older adults to assess their brain volume and white matter integrity. Then they compared the scans of those who had high blood pressure in early adulthood (between the ages of 30 and 40 years) with those who had normal blood pressure.

    They found that those who had high blood pressure had lower brain volumes and poorer white matter integrity – an indication of impaired cognitive plasticity. The link between high blood pressure and lower brain volume was stronger in men, especially in the frontal cortex and cerebral gray matter.

    These findings suggest that prolonged exposure to high blood pressure has marked effects on brain health later in life, increasing one’s risk of dementia. Exercise can have profound blood pressure-reducing effects, however. Learn more about the brain-protective effects of exercise in this clip featuring Dr. Axel Montagne.

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  • Lactate produced from high-intensity exercise may play crucial memory role and correlates closely with plasma BDNF. www.mdpi.com
    Exercise Brain Aerobic BDNF Neurodegeneration Lactate

    From the article:

    Current research has shown that (i) increased peripheral lactate levels (following high intensity exercise) are associated with increased peripheral BDNF levels, (ii) lactate infusion at rest can increase peripheral and central BDNF levels and (iii) lactate plays a very complex role in the brain’s metabolism. In this review, we summarize the role and relationship of lactate and BDNF in exercise induced neuroplasticity.

    […]

    Several trials have used blood lactate for the monitoring of exercise intensity. These studies indicate that higher lactate concentrations are associated with increased BDNF plasma and/or serum levels. Furthermore, current evidence indicates that high intensity interval training evokes larger BDNF levels compared to moderate and/or intensive continuous exercise […] Current research indicates that lactate transport from astrocytes to neurons plays a crucial role for memory formation and could be a link between exercise and neuroplasticity. Pharmacological inhibition of MCT 2 irreversibly impairs long-term memory. Van de Hall et al. have shown that lactate uptake in the brain increases from 8% at rest up to 20% during exercise.

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  • Testosterone therapy reduced brain atrophy rate by 67% and improved cognition in men with multiple sclerosis. (2007) www.sciencedaily.com
    Hormones Multiple Sclerosis Testosterone Neurodegeneration

    From the article:

    Nancy L. Sicotte, M.D., of the David Geffen School of Medicine at UCLA, Los Angeles, and colleagues conducted a study of testosterone treatment in 10 men with relapsing-remitting MS, characterized by periods of neurologic symptoms (such as numbness or difficulty walking) followed by periods of remission. The men, who had an average age of 46, were enrolled in the study and then entered a six-month pre-treatment phase, during which symptoms were monitored but no therapies were administered. Then, each man applied 10 grams of a gel containing 100 milligrams of testosterone to his upper arms once daily for 12 months.

    “One year of treatment with testosterone gel was associated with improvement in cognitive performance and a slowing of brain atrophy [deterioration],” the authors write. During the first nine months of the study – the period of time before the men began taking testosterone, plus the first three months of treatment, before it had time to take effect – brain volume decreased an average of -0.81 percent per year.

    In the second nine months, this decline slowed by 67 percent to an annual rate of -0.25 percent. “Because the protective effect of testosterone treatment on brain atrophy was observed in the absence of an appreciable anti-inflammatory effect, this protection may not be limited to MS, but may be applicable to those with non-inflammatory neurodegenerative diseases,” including amyotrophic lateral sclerosis or Lou Gehrig’s disease, the authors write.

    In addition, lean body mass (muscle mass) increased an average of 1.7 kilograms (about 3.74 pounds) during the treatment phase. Participants did not report any adverse effects, there were no abnormalities in blood tests taken during the trial and the men’s prostate examination results remained stable.

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  • Elevated testosterone induces apoptosis in neuronal cells, cell study suggests. (2006) www.sciencedaily.com
    Brain Alzheimer's Hormones Testosterone Apoptosis Neurons Neurodegeneration

    From the article:

    The researchers showed that high levels of testosterone triggered programmed cell death in nerve cells in culture. Cell death, or apoptosis, is critical in many life processes, including development and disease. It is characterized by membrane instability, activation of caspases, which are the executioner proteins in apoptosis, change in membrane potential, and DNA fragmentation.

    “In the present study we have demonstrated for the first time that the treatment of neuroblastoma cells with elevated concentrations of testosterone for relatively short periods, six to 12 hours, induces a decrease in cell viability by activation of a cell death program,” Ehrlich said. “Low concentrations of testosterone had no effects on cell viability, whereas at high concentrations the cell viability decreased with incremental increases in hormone concentration.”

    The testosterone-induced apoptosis described in this study occurs through overactivation of intracellular Ca2+ signaling pathways. Overstimulation of the apoptotic program in neurons has been associated with several neurological illnesses, such as Alzheimer disease and Huntington disease.

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  • Exercise protected mice from toxin-induced hippocampal damage by stimulating the production of interleukin-6 in the brain. (2011) www.sciencedaily.com
    Brain Memory Neurodegeneration IL-6

    From the article:

    Previous research has already demonstrated that exercise after brain injury can help the repair mechanisms. This new study shows that exercise before the onset of damage modifies the brain environment in such a way that the neurons are protected from severe insults. The study used an experimental model of brain damage, in which mice are exposed to a chemical that destroys the hippocampus, an area of the brain which controls learning and memory. Mice that were exercised regularly prior to exposure produced an immune messenger called interleukin-6 in the brain, which dampens the harmful inflammatory response to this damage, and prevents the loss of function that is usually observed.

    Pharmacological therapies to downregulate inflammation and address cognitive decline in older adults, and those with Alzheimer’s disease, have been less successful. This research helps understand how exercise could be used to affect the path of many human conditions, such as neurodevelopmental disorders and neurodegenerative diseases. In addition, as a chemical model of neuronal damage was used, it also raises the possibility that exercise could offer protection against the potentially harmful effects of environmental toxins.

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  • Air pollution may attenuate the beneficial association vigorous physical activity with low white-matter hyperintensity volume n.neurology.org
    Exercise Brain Aging Pollution Aerobic Neurodegeneration Small Vessel Disease

    Air pollution negates some of the beneficial effects of vigorous-intensity exercise.

    Components present in air pollution – a mixture of toxic chemicals, gases, and particulate matter – can cross biological barriers, including the blood-brain barrier. Exposure to air pollutants is associated with poor health outcomes and an increased risk for both acute and chronic diseases. A recent study suggests that air pollution negates some, but not all, of the beneficial effects of vigorous-intensity aerobic exercise.

    Robust evidence demonstrates that vigorous-intensity aerobic exercise (defined as activity that achieves a heart rate that is 70 to 80 percent of one’s maximum) benefits brain health. For example, vigorous-intensity aerobic exercise appears to activate the endocannabinoid system to promote motor sequence memory and learning. Other evidence suggests it improves mood.

    The study involved 8,600 adult participants enrolled in the UK Biobank study. Participants wore wrist accelerometers to track their physical activity. They also underwent magnetic resonance imaging (MRI) to assess their structural brain volumes and identify the presence of white matter hyperintensities – areas of the brain that show up as distinct white areas on MRIs and indicate cerebral small blood vessel disease. The investigators estimated the participants' exposure to air pollution based on where the participants lived.

    The investigators found that the more physically active participants were, the less their brains showed evidence of shrinkage, and the fewer white matter hyperintensities they exhibited – an effect roughly equivalent to being three years younger. Participants who were exposed to more air pollution exhibited greater brain shrinkage than those with less exposure – about the amount observed in one year of normal aging. However, participants who exercised the most and had the most exposure to air pollution demonstrated no evidence of more brain shrinkage, but they exhibited more white matter hyperintensities, especially if they engaged in vigorous-intensity aerobic exercise.

    These findings support earlier studies that demonstrate the beneficial health effects of vigorous-intensity exercise on the brain but suggest that exercising in areas where air pollution is high negates some of these benefits. The authors recommended that because most air pollution comes from vehicle exhaust, people should exercise in areas far from heavily trafficked roads.

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  • Peripheral amyloid-beta produced in the liver in type 2 diabetes may be a crucial link to Alzheimer’s disease www.sciencedaily.com
    Brain Alzheimer's Diabetes Neurodegeneration

    Amyloid-beta produced in peripheral tissues provides a link between diabetes and Alzheimer’s disease risk.

    Type 2 diabetes, a metabolic disorder characterized by glucose intolerance and insulin resistance, poses a significant public health concern, affecting roughly 470 million people worldwide. Having type 2 diabetes greatly increases a person’s risk of developing Alzheimer’s disease, but scientists don’t fully understand the mechanisms that drive the increased risk. Findings from a recent study suggest that amyloid-beta produced in tissues outside the brain provides the link between type 2 diabetes and Alzheimer’s disease.

    Amyloid-beta, a toxic peptide produced in the brain, clumps together and forms plaques with age. Its accumulation is a pathological hallmark of Alzheimer’s disease. However, amyloid-beta is produced in peripheral tissues, as well, including those that are sensitive to glucose or insulin, such as the pancreas, adipose tissues, skeletal muscles, and liver. Scientists don’t fully understand the roles peripheral amyloid-beta plays in human health.

    The investigators conducted a three-part experiment in mice, live mouse tissues, and cell cultures. First, they injected mice with glucose after they had fasted for 16 hours to examine the effects of glucose and insulin on blood amyloid-beta levels. They found that the mice experienced a transient increase in blood levels of glucose, insulin, and amyloid-beta. Then they injected amyloid-beta and glucose into mice that can’t produce the protein and found that amyloid-beta suppressed the animals’ insulin response.

    Next, they applied glucose and insulin to live tissues from the pancreas, adipose tissue, skeletal muscle, liver, and kidneys of mice. They found that glucose stimulated the release of amyloid-beta from the pancreas, whereas insulin stimulated its release from adipose tissue, skeletal muscle, and liver tissue. However, when the scientists added glucose along with amyloid-beta to the pancreatic tissue, insulin release was suppressed.

    Finally, they used antibodies that target the amyloid-beta protein to determine where the protein was produced. They found that amyloid-beta was produced and stored in the beta cells of the pancreas and released into circulation when stimulated with glucose.

    These findings suggest that amyloid-beta protein produced in peripheral tissues modulates insulin secretion. They may further provide a mechanism linking type 2 diabetes to Alzheimer’s disease. The investigators posited that high blood glucose and insulin levels that occur in the setting of diabetes increase peripheral amyloid-beta production, altering the balance between brain and peripheral amyloid-beta levels and suppressing the protein’s efflux from the brain. Furthermore, high insulin levels in the brain may impair normal degradation of brain amyloid-beta, increasing the protein’s levels in the brain and driving its accumulation. Learn more about the role of amyloid-beta in Alzheimer’s disease in this clip featuring Dr. Dale Bredesen.

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  • Hsp70 shown to preserve locomotor function and reduce cell death through a stable binding to toxic amyloid-beta42, blocking ability to attack neurons www.sciencedaily.com
    Brain Alzheimer's Heat Stress Sauna Neurodegeneration

    Heat shock proteins suppress amyloid-beta toxicity in the brain.

    Amyloid-beta is a toxic peptide that aggregates and forms plaques in the brain with age. These plaques are widely considered a hallmark of Alzheimer’s disease, a progressive neurodegenerative disease that occurs with age and is the most common cause of dementia. Findings from a 2016 study suggest that heat shock proteins suppress amyloid-beta toxicity in the brain.

    Heat-shock proteins comprise a large, highly conserved family of proteins that are present in all cells, across many species. They play prominent roles in many cellular processes and facilitate several aspects of the protein synthesis machinery, including assembly and folding. Increased expression of heat shock proteins prevents protein disorder and aggregation by repairing proteins that have been damaged or misfolded and may offer protection against neurodegenerative diseases and inhibit the aggregation of amyloid-beta, reducing plaque formation.

    The study involved fruit flies, which serve as useful models for studying amyloid-beta anomalies. The investigators engineered a form of heat shock protein 70, called Hsp70, that could pass into the extracellular space and interact with amyloid-beta and studied its effects on the flies' neurological health.

    They found that Hsp70 suppressed the toxicity of amyloid-beta in cells of the flies' eyes, reduced cell death in brain neurons, and helped maintain the neurons' architecture and function. The investigators posited that these neuroprotective effects were directly related to Hsp70’s capacity to bind to amyloid-beta rather than via refolding mechanisms.

    These findings indicate that heat shock protein 70 may suppress amyloid-beta toxicity, thereby reducing amyloid-beta plaque formation in the brain and serving as a potential therapeutic strategy for Alzheimer’s disease. Heat stress, such as that experienced during sauna use, robustly induces expression of heat shock proteins. Learn more about heat shock proteins and sauna use in our overview article.

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  • Routine tests ignore breakdown of blood-brain barrier and altered cerebral blood flow that precede Alzheimer's diagnosis www.sciencedaily.com
    Brain Alzheimer's Neurodegeneration Blood-Brain Barrier

    From the article:

    “Cognitive impairment, and accumulation in the brain of the abnormal proteins amyloid and tau, are what we currently rely upon to diagnose Alzheimer’s disease, but blood-brain barrier breakdown and cerebral blood flow changes can be seen much earlier,” said Berislav Zlokovic, the Mary Hayley and Selim Zilkha Chair in Alzheimer’s Disease Research at the Keck School of Medicine of USC. “This shows why healthy blood vessels are so important for normal brain functioning.”

    […]

    BBB leaks can be detected with an intravenously administered contrast substance in concert with magnetic resonance imaging. Brain microbleeds, another sign of leakage, also can be picked up with MRI. A slowdown in the brain’s uptake of glucose, visible via PET scan, can be a another result of BBB breakdown. Zlokovic notes that these aren’t tests routinely offered at a doctor’s office.

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  • Model of blood-brain barrier malfunctions when stem cells are derived from cells of patients with Huntington's disease www.sciencedaily.com
    Brain Neurodegeneration Blood-Brain Barrier

    From the article:

    For their study, a team led by Cedars-Sinai investigators generated stem cells known as induced pluripotent stem cells, which can produce any type of cell, using an individual adult’s blood samples. They used these special cells to make neurons, blood-vessel linings and support cells that together make up the blood-brain barrier. The team then placed the various types of cells inside Organ-Chips, which recreated the body’s microenvironment with the natural physiology and mechanical forces that cells experience within the human body.

    The living cells soon formed a functioning unit of a blood-brain barrier that functions as it does in the body, including blocking entry of certain drugs. Significantly, when this blood-brain barrier was derived from cells of patients with Huntington’s disease or Allan-Herndon-Dudley syndrome, a rare congenital neurological disorder, the barrier malfunctioned in the same way that it does in patients with these diseases.

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  • Sulforaphane from broccoli sprouts increase glutathione in the brain by an average of 30% with a 100 micromole per day dose www.sciencedaily.com
    Brain Alzheimer's Parkinson's Schizophrenia Glutathione Antioxidant Neurodegeneration

    Increases of glutathione reverse pattern of brain cell activity associated with schizophrenia:

    They used the chemical sulforaphane found in broccoli sprouts, which is known to turn on a gene that makes more of the enzyme that sticks glutamate with another molecule to make glutathione. When they treated rat brain cells with glutathione, it slowed the speed at which the nerve cells fired, meaning they were sending fewer messages. The researchers say this pushed the brain cells to behave less like the pattern found in brains with schizophrenia.

    However, the impact of sulforaphane may be broader due to the broader effect of increasing glutathione, including in the hippocampus (region impacted by Alzheimer’s disease):

    For their study, published in April 2018 in Molecular Neuropsychiatry, the researchers recruited nine healthy volunteers (four women, five men) to take two capsules with 100 micromoles [17.729mg] daily of sulforaphane in the form of broccoli sprout extract for seven days.

    […]

    The researchers used MRS again to monitor three brain regions for glutathione levels in the healthy volunteers before and after taking sulforaphane. They found that after seven days, there was about a 30% increase in average glutathione levels in the subjects' brains. For example, in the hippocampus, glutathione levels rose an average of 0.27 millimolar from a baseline of 1.1 millimolar after seven days of taking sulforaphane.

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  • Repurposed chemo drug acting on the blood-brain barrier shows dose-dependent increase of dopamine in Parkinson's disease patients www.sciencedaily.com
    Brain Parkinson's Cancer Aging Neurodegeneration Blood-Brain Barrier

    Repurposed chemo drug inactivates protein that destroy’s the blood-brain barrier in Parkinson’s disease:

    The current part of the study just published, examined the cerebrospinal fluid of patients via epigenomics, which is a systematic analysis of the global state of gene expression, in correlation with continuing clinical outcomes. The new analysis helps explain the clinical findings.

    Nilotinib inactivated a protein (DDR1) that was destroying the ability of the blood brain barrier to function properly. When DDR1 was inhibited, normal transport of molecules in and out of the brain filter resumed, and inflammation declined to the point that dopamine, the neurotransmitter depleted by the disease process, was being produced again.

    After 27 months, nilotinib was found to be safe, and patients who received nilotinib showed a dose-dependent increase of dopamine, the chemical lost as a result of neuronal destruction.

    First study to show blood-brain barrier as therapeutic target for Parkinson’s disease:

    “Not only does nilotinib flip on the brain’s garbage disposal system to eliminate bad toxic proteins, but it appears to also repair the blood brain barrier to allow this toxic waste to leave the brain and to allow nutrients in,” Moussa explains. “Parkinson’s disease is generally believed to involve mitochondrial or energy deficits that can be caused by environmental toxins or by toxic protein accumulation; it has never been identified as a vascular disease.”

    “To our knowledge, this is the first study to show that the body’s blood brain barrier potentially offers a target for the treatment for Parkinson’s disease,” Moussa says.

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  • Environmental toxins inhaled through nose may induce inflammation which culminates in the deposit of Lewy bodies in the brain, promoting Parkinson's www.sciencedaily.com
    Brain Parkinson's Aging Dementia Neurodegeneration Lipopolysaccharide

    Lewy bodies found in olfactory areas suggest not only is lost smell a sign of neural damage, but rather a direct link to the mechanism creating the disorder:

    The loss of a sense of smell is known to be one of the earliest signs of Parkinson’s disease (PD) and can even appear years before the characteristic tremors and loss of motor function are seen. Some scientists believe that olfactory dysfunction may not just be a sign of broader neural damage, but rather may have a more direct linkage to the generation of the disorder itself. In support of this idea, deposits of a protein called alpha-synuclein that form Lewy bodies can be found in olfactory areas, as well as in dying dopamine neurons whose loss triggers PD, and mutations in the gene encoding alpha-synuclein produce PD.

    Inflammation triggered in the areas where the olfactory neurons project (recapitulated by lipopolysaccharide) culminate in alpha-synuclein that can cross the blood-brain barrier:

    Results of the study, published in the journal Brain Pathology, showed that application of an irritating component of a bacterium’s cell wall induces inflammation in the areas exactly where the olfactory neurons project, called the olfactory bulb. Moreover, these areas show the hallmark signs of PD, depositions of alpha-synuclein, the core components of Lewy bodies. PD is characterized by progressive motor and non-motor symptoms linked to alpha-synuclein pathology and the loss of dopaminergic neurons in the nigrostriatal system. Toxic aggregates of alpha-synuclein can arise from either overexpression of the protein, changes in protein modifications, and from hereditary mutations.

    […]

    “Data from our study show that the bacterial trigger does not move across the blood-brain barrier,” said Quan. “Rather, a sequential inflammatory activation of the olfactory mucosa triggers a subsequent expression of inflammatory molecules within the brain, propagating the inflammation.”

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  • Processes contributing to cancer may reduce risk of Alzheimer's disease, according to post-mortem analysis www.the-scientist.com
    Alzheimer's Cancer Aging Neurodegeneration

    From the article:

    Thanks to those data, which showed participants with cancer had fewer hallmarks of Alzheimer’s disease in their brains as well as a reduced likelihood of neurodegenerative symptoms during their lifetimes, lead study author Erin Abner, a University of Kentucky epidemiologist and aging researcher and her team were able to offer the clearest picture yet of a molecular mechanism that seems to link the two diseases.

    “The connection is becoming more and more apparent,” New York University cancer researcher Eva Hernando-Monge, who didn’t work on the study, tells The Scientist.

    They investigated cancer deaths for traces of Alzheimer’s:

    As cohort members passed away, the team autopsied their brains to look for biomarkers associated with Alzheimer’s disease, including structures such as neurofibrillary tangles and neuritic plaques. They also noted when someone carried the APOE ε4 allele, a known genetic risk factor for the neurodegenerative condition.

    […]

    The analysis revealed “less Alzheimer’s pathology in the people who had cancer, both amyloid and tau,” Abner says. “We also saw evidence [that] another amyloid pathology—cerebral amyloid angiopathy, which is amyloid aggregation in blood vessel walls—was lower.

    Mechanisms of the cancer-Alzheimer’s anti-relationship:

    Processes related to cell growth and survival, as well as the production of specific molecules including the antistress response protein vimentin and the enzyme carbonic anhydrase, are all upregulated in cancer, he finds. Alzheimer’s occurs when these processes and proteins are downregulated.

    Another review, published in Molecular Psychiatry in 2021, identifies the proteins p53 and PIN1 as implicated in both cancer and Alzheimer’s. PIN1 overexpression is associated with myriad cancers, but its absence is linked to the formation of the Alzheimer’s biomarkers tracked in the Brain study. Meanwhile, p53 has a well-established anticancer role, but can also contribute to neurodegenerative disease.

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  • How precision nutrition may lower the risk of Alzheimer's disease in people with an APOE4 allele www.mdpi.com
    Nutrition Brain Alzheimer's Neurodegeneration Ketogenic Diet

    Abstract

    “The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction.”

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  • Medium chain triglycerides (MCTs) improved cognition in patients with Alzheimer's disease. www.ncbi.nlm.nih.gov
    Brain Alzheimer's Neurodegeneration

    Medium-chain triglycerides improve cognitive function in Alzheimer’s disease.

    The brain relies heavily on glucose as its primary fuel, burning as much as 130 grams of glucose per day. However, glucose metabolism in the brain is impaired in Alzheimer’s disease, contributing to many of the disease’s symptoms. Findings from a recent study demonstrate that ketones derived from medium chain triglyceride metabolism may provide an alternative fuel source for the brain in the setting of Alzheimer’s disease.

    Ketones are molecules produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (such as during fasting), carbohydrate-restrictive diets, starvation, or prolonged intense exercise. Humans produce three types of ketones: acetoacetate, beta-hydroxybutyrate, and acetone. Ketones are readily used as energy by a diverse array of cell types, including neurons, and some evidence suggests that ketones improve cognitive function.

    Medium-chain triglycerides (MCTs) are a class of saturated fats. They are composed of medium-length fatty acid chains (six to 12 carbons long) bound by a glycerol backbone. Medium-chain triglycerides occur naturally in coconut oil, palm oil, and butter, but they can also be synthesized in a laboratory or food processing setting and provided as dietary supplements.

    The randomized, placebo-controlled trial involved 20 adults between the ages of 53 and 84 years who had been diagnosed with Alzheimer’s disease. The investigators used a crossover design, which allows all participants to receive the same treatment, at different times. In this trial, half of the participants received an average of two tablespoons of MCTs daily for three months, while the other half received a comparable amount of olive oil for the same duration. Then the participants switched to the opposite treatment. Participants underwent cognitive testing before, during, and after the intervention. After completing both forms of the intervention, all the participants received MCTs for six months. The investigators collected the participants' demographic and health data, which included measures of blood lipids, fasting insulin, body mass index, and body fat composition.

    They found that 80 percent of the participants demonstrated improved or stable cognitive function while taking the MCTs. The greatest improvements were seen among participants who received MCTs last (providing them nine months of uninterrupted treatment) and among those who were older than 73 years.

    These findings suggest that long-term MCT intake stabilizes cognitive function in adults with Alzheimer’s disease, especially in mild to moderate disease. This was a small study, however, so larger studies are needed to confirm these findings.

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  • Discovery highlights why women are more susceptible to Alzheimer's disease: follicle-stimulating hormone (FSH) may be a major pathogenic factor www.eurekalert.org
    Brain Alzheimer's Aging Neurodegeneration

    From the article:

    “During menopause, the serum concentration of FSH strongly increases, binding to the cognate FSH receptor on neurons and activating the C/EBPβ/AEP pathway. This results in Aβ and Tau pathologies, leading to the development of AD,” said Dr. Zaidi Mone, co-corresponding author of the study and a tenured professor at the Mount Sinai School of Medicine in New York.

    The researchers employed different methods to demonstrate this finding. Using ovariectomized mice, they used anti-FSH antibody treatment to block FSH and inactivate the C/EBPβ/AEP pathway. They also deleted FSH receptor (FSHR) expression in neurons to abolish the binding of FSH to FSHR in the hippocampus. Both of these methods alleviated pathology and cognitive dysfunction. In addition, knockdown of C/EBPβ in the AD mice model decreased AD pathologies.

    Besides working with female mice, the researchers also injected FSH into male mice and discovered that FSH promoted AD pathologies.

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  • D-beta-hydroxybutyrate supplementation restored impaired brain function and protected against neurodegeneration in mouse model of Parkinson's disease www.sciencedaily.com
    Nutrition Brain Parkinson's Aging Ketosis Neurodegeneration

    From the article:

    Infusion of D-beta-hydroxybutyrate (D-beta-HB) to mice suffering from Parkinson disease restored impaired brain function and protected against neurodegeneration and motor skill abnormalities.

    […]

    Przedborski and colleagues administered the neurotoxin MPTP to mice, which caused dopaminergic neurodegeneration and deficits in the mitochondrial electron transport chain reminiscent of Parkinson disease. Using this model of disease, the authors showed that the infusion of the ketone body D-beta-HB restored mitochondrial respiration and protected against MPTP-induced neurodegeneration and motor deficits. The study supports a critical role for mitochondrial defect in Parkinson disease.

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  • Rebalancing gut microbiome with butyrate lengthens survival in mouse model of ALS by repairing intestinal permeability www.sciencedaily.com
    Brain Aging Microbiome Neurodegeneration Butyrate Intestinal Permeability

    From the article:

    In a mouse model of ALS, the compound butyrate helped correct a gut microbiome imbalance and reduced gut leakiness – both symptoms of ALS. The treated mice lived also longer compared to mice that weren’t given butyrate.

    […]

    When the researchers fed the ALS-prone mice butyrate in their water, starting when the mice were 35 to 42 days old, the mice showed a restored gut microbiome profile and improved gut integrity. Butyrate-treated mice also showed improved neuromuscular function and delayed onset of ALS symptoms. Treated mice showed symptoms at 150 days old compared to control mice at about 110 days. Treated mice also lived an average 38 days longer than mice not given butyrate.

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  • Particulate matter in wildfires harms the brain. www.eurekalert.org
    Pollution Neurodegeneration

    Global climate change is driving an increase in wildfire activity characterized by larger fires and longer fire seasons. Wildfire smoke, which can spread over immense geographical areas, often contains a variety of pollutants and exerts a wide range of adverse effects on human health. Evidence from a new rodent study suggests that particulate matter in wildfires drives neuroinflammation, increasing the risk for neurodegenerative diseases.

    Particulate matter in air pollution is a mixture of solid particles and liquid droplets. It is present in fine inhalable particles, with diameters that are generally 2.5 micrograms (PM2.5) or less. Ultrafine particles less than 1 microgram in diameter, referred to as nanoparticles, are often enriched in highly reactive metals such as iron, aluminum, titanium, and others. Exposure to particulate matter in air pollution promotes oxidative stress, increases the risk of developing many chronic diseases, and accelerates aging.

    The investigators studied the effects of wildfire smoke on mice that were housed in a mobile lab located roughly 186 miles (300 kilometers) away from naturally occurring wildfires in the western United States. They exposed the mice to the smoke for four hours every day for 20 days and assessed the animals' immune and inflammatory responses.

    They found that the animals were exposed to high levels of PM2.5. This exposure switched on the activity of brain microglia (immune cells); promoted the infiltration of pro-inflammatory immune cells and molecules into the brain tissues; and increased accumulation of amyloid-beta 42, a toxic protein associated with Alzheimer’s disease and neurodegeneration. Particulate matter exposure also decreased the production of compounds that protect the brain against aging, such as nicotinamide adenine dinucleotide (commonly known as NAD+) and taurine.

    These findings suggest that exposure to PM2.5 in wildfire smoke elicits harmful effects on the brain via activation of immune and inflammatory responses. The investigators noted that the mobile lab used in this study was located a considerable distance from the smoke sources, likely diluting the animals' exposure and reflecting PM2.5 exposures far lower than those experienced by humans living closer to the fires.

    Robust evidence demonstrates that HEPA filter air purifiers reduce indoor PM2.5 concentrations and improve health outcomes, and many government agencies and public health authorities recommend the use of indoor HEPA filters to reduce wildfire smoke exposure and its negative health effects. In addition, well-fitting N95 masks and equivalent respirators can reduce PM2.5 exposure. Interestingly, dietary consumption of omega-3 fatty acids may help protect the brain from damage associated with PM2.5 exposure. Learn more about the health effects of omega-3 fatty acids in this episode featuring Dr. Bill Harris.

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  • Influenza infection may increase a person's risk for Parkinson's disease. www.the-scientist.com
    Parkinson's Virus Neurodegeneration

    Parkinson’s disease, a neurodegenerative disorder that affects the central nervous system, is caused by destruction of nerve cells in the part of the brain called the substantia nigra. Symptoms of Parkinson’s disease typically manifest later in life and are characterized by tremors and a shuffling gait. Findings from a new study indicate that influenza infection may increase a person’s risk for Parkinson’s disease.

    Bacterial and viral infections typically resolve quickly, but in some cases, they elicit long-term adverse effects on human health. For example, streptococcus bacterial infection, which causes strep throat, increases a person’s risk for rheumatic fever, causing fatigue, joint pain, and a dangerous buildup of fluid around the heart. Similarly, human papilloma virus infection, a generally mild sexually transmitted disease, can increase a person’s risk for certain types of cancer. And a growing body of evidence indicates that infection with SARS-CoV-2, the virus that causes COVID-19, is associated with long-term complications that last several weeks or months, a phenomenon previously referred to as “long COVID” and now known as “Post-Acute Sequelae after SARS-CoV-2 infection.”

    The authors of the current study drew on data from the Danish National Patient Registry, a longitudinal registration of detailed administrative and clinical data used exclusively for research. They analyzed more than 61,000 patient records spanning nearly 40 years (1977 to 2016) to identify people who had been diagnosed with influenza and/or Parkinson’s disease.

    They found that more than 10,000 people had been diagnosed with Parkinson’s disease during the study period. Those who were diagnosed with influenza (but not other viral infections) were 73 percent more likely to be diagnosed with Parkinson’s more than ten years later, compared to people who had never had an influenza diagnosis. When the researchers restricted the time frame of when the people were diagnosed with influenza to the peak influenza season (when it was less likely to be a false-positive diagnosis), the association with Parkinson’s disease was even stronger.

    These findings suggest that influenza infection increases the risk of developing Parkinson’s disease. The authors of the study posited that the mechanisms that drive this association may be related to inflammatory responses during a viral infection that could promote subsequent neurodegeneration, but they caution that their findings were observational and therefore not causal.

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  • Omega-3 fatty acids slow memory loss in people with Alzheimer's disease. apple.news
    Nutrition Alzheimer's Omega-3 Neurodegeneration

    Omega-3 fatty acids are essential for human health. They participate in pathways involved in the biosynthesis of hormones that regulate blood clotting, contraction and relaxation of artery walls, and inflammation. They have been shown to help prevent heart disease and stroke; may help control lupus, eczema, and rheumatoid arthritis; and may play protective roles in cancer and other conditions. Findings from a new study suggest that omega-3 fatty acids slow cognitive decline in Alzheimer’s disease.

    Alzheimer’s disease is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. The primary risk factor for Alzheimer’s disease is aging, with risk roughly doubling every five years after the age of 65 years. Nutritional status also plays key roles in Alzheimer’s disease risk and pathology. The intervention study involved 33 people who had been diagnosed with Alzheimer’s disease. Approximately half of the participants took a supplement providing 2.3 grams of omega-3 fatty acids daily for six months; the other half took a placebo. All participants took the Mini Mental State Examination (MMSE), a widely accepted measure of memory and cognitive function, before and after the intervention. The study investigators collected cerebrospinal fluid samples before and after the intervention to measure several biomarkers associated with neurodegenerative diseases and inflammation, including amyloid beta proteins, tau, interleukin 6, chitinase-3-like protein 1 (YKL-40), and neurofilament light (NfL). YKL-40 is associated with neuroinflammation, and NfL is associated with damage to the axons of nerves in brain white matter.

    The MMSE scores of the participants who took the omega-3 fatty acid supplements remained stable over the six-month intervention, decreasing by only 0.06 points, but the scores of those who took the placebo decreased by two points. The two groups' biomarkers were similar at the beginning of the intervention, but YKL-40 and NfL increased slightly in the group that received the omega-3 fatty acid supplement, indicating a possible increase in neurodegeneration and inflammatory responses. However, the increase in the two biomarkers did not correlate with the participants' MMSE scores.

    These findings suggest that omega-3 fatty acids help maintain memory and cognitive function in older adults with Alzheimer’s disease. This was a very small study, however, and further research is needed to confirm any protective effects of omega-3 fatty acid intake in Alzheimer’s disease.

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  • Whole-body hyperthermia activates muscle hormone irisin and increases neuroprotective factors. www.sciencedirect.com
    Exercise Brain Muscle Sauna BDNF Neurodegeneration

    Exposure to high heat while sauna bathing causes mild hyperthermia – an increase in the body’s core temperature – that induces a thermoregulatory response to restore homeostasis and condition the body for future heat stressors. These adaptations to high temperatures involve increased production of brain derived neurotrophic factor (BDNF), a promoter of neuroplasticity, and irisin, a biomarker of exercise. Findings of a new report demonstrate that whole-body hyperthermia increases BDNF and irisin in healthy young adults.

    Whole-body hyperthermia is a therapeutic strategy used to treat various diseases, including cancer and depression. Previous research has shown that use of a hyperthermia chamber increases BDNF to a greater extent than light intensity exercise. Some research has suggested that BDNF production is stimulated by irisin, a hormone secreted from muscle in response to exercise. Irisin may mediate some of the beneficial effects of exercise and sauna use in humans, but additional research is needed.

    The authors recruited 20 male participants (average age, 22 years) and assessed their baseline heat tolerance using a hyperthermia protocol. Participants reclined in a hyperthermia chamber while the researchers increased the temperature of the chamber by 50 degrees F every ten minutes until the participant reached their personal heat threshold. Next, participants completed ten hyperthermia sessions tailored to their baseline conditioning, during which the hyperthermia chamber was set to a temperature of 150 to 175 degrees F. Following a three-week wash-out period, they completed ten sham treatments over two weeks, during which the hyperthermia chamber was set to a temperature of 75 to 77 degrees F.

    Participants had an average core body temperature of 102 degrees F at the end of each whole-body hyperthermia treatment. Following ten whole-body hyperthermia treatments, participants had a significant increase in circulating irisin levels (6.3 micrograms per milliliter) compared to their baseline levels (5.0 micrograms per milliliter) and compared to their irisin levels following the sham treatment (5.4 micrograms per milliliter). Whole-body hyperthermia treatment also significantly increased BDNF levels (28.3 picograms per liter) compared to baseline (25.9 picograms per liter).

    In healthy young adults, ten whole-body hyperthermia significantly increased irisin and BDNF levels. The authors noted that future studies should explore the effects of whole-body hyperthermia on adipose tissue, which also produces irisin.

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  • Irisin, a muscle hormone, mediates the neuroprotective effects of exercise. www.massgeneral.org
    Exercise Brain Alzheimer's Aging Hormones Neurodegeneration

    Aging causes brain changes that impair cognitive function, even in people who do not have Alzheimer’s disease or dementia. However, lifestyle factors like diet and exercise have significant influence over the rate of cognitive decline. Previous research has shown that exercise improves brain health and cognitive function during aging. A new report details the role of the muscle hormone irisin in the neuroprotective effects of exercise

    Irisin, a type of myokine, is a hormone secreted from muscle in response to exercise. Previous research has shown that irisin may mediate some of the beneficial effects of exercise on the brain by stimulating the production of brain-derived neurotrophic factor (BDNF), a growth factor that increases neuroplasticity. Irisin is a fragment of the prohormone FNDC5, which is attached to the membranes of muscle cells. During exercise, irisin is cleaved from FNDC5 and circulates throughout the body to induce adaptations to exercise.

    The authors used mice of varying ages who lack the genes necessary to produce FNDC5, called knock-outs, and genetically-normal mice, called wild-type. Both groups of mice completed exercise testing to measure balance, grip strength, endurance, and motor coordination; a water maze test to measure spatial learning ability and memory; and an open field test to measure locomotor activity levels, anxiety, and willingness to explore. In order to study the effects of irisin supplementation, the investigators conducted a second experiment in which they administered exogenous (i.e., made outside the body) irisin to a strain of mice who develop an Alzherimer’s-like dementia at an early age due to loss of FNDC5 function. The investigators measured structural and psychological changes in the brain throughout both experiments.

    Both knock-out and wild-type mice exercised the same amount during testing. However, unlike the wild-type mice, knock-out mice did not show exercise-induced improvements in spatial learning and memory. Aged knock-out mice had more cognitive decline than wild-type mice and were less likely to prefer novel objects, a behavior associated with loss of function in the hippocampus, the brain region most associated with memory loss in dementia. Indeed, aged knock-out mice showed abnormal neuronal activation patterns in the dentate gyrus, a structure within the hippocampus that contributes to memory formation.

    In contrast to knock-out mice and sedentary wild-type mice, wild-type mice who exercised had increased dendritic complexity and length in the dentate gyrus. This demonstrates the ability of exercise to improve neuronal structure and function in brain areas associated with memory through mechanisms involving irisin. Regular injections with exogenous irisin significantly improved performance on spatial learning and memory tasks in mice with Alzheimer’s-like dementia compared to untreated mice. These improvements may have been caused by dampening of overactive glial activity, leading to reduced inflammation.

    Taken together, these data suggest that irisin is essential for mediating the beneficial effects of exercise on cognitive function. The authors concluded that these data also demonstrate the efficacy of exogenous irisin administration in regulating cognitive function in mice with Alzheimer’s-like dementia, providing support for future use of irisin therapies in humans with dementia.

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  • Folate reduces risk for Alzheimer’s disease. www.frontiersin.org
    Brain Alzheimer's Micronutrients Folate Neurodegeneration

    Alzheimer’s disease, the most common type of neurodegenerative disease in older adults, causes a progressive deterioration of cognitive function. Recent research indicates that folate (vitamin B9) deficiency may play a role in Alzheimer’s pathology along with other micronutrients, such as vitamin A. A recent systematic review and meta-analysis reports that folate deficiency increases the risk for Alzheimer’s disease.

    Folate is an essential nutrient used by the body to create new DNA and RNA and to metabolize amino acids, all of which are necessary for cell division. Good sources of folate include legumes, such as peanuts and chickpeas, and green vegetables such as spinach and asparagus. Previous research has shown that folate supplementation improves cognitive function in older adults through mechanisms that are not well-understood, but likely involve reduced inflammation. Because dose, population characteristics, and testing methods often vary among clinical trials, coming to a consensus about the efficacy of an investigational treatment presents challenges; however, review articles can be a valuable way to combine and report existing data in a new and helpful way. This study is a systematic review and meta-analysis, meaning that the authors searched existing literature for studies related to folate and Alzherimer’s disease, collected studies based on a set of criteria meant to select for high-quality design, and then combined the data and reanalyzed it.

    The authors selected 59 studies that met their criteria for high-quality design. In a sample of more than 2,000 participants from a collection of case-control studies, participants with folate deficiency (less than 13.5 nanomoles per liter) were more than twice as likely to develop Alzheimer’s disease compared to participants with normal folate status (greater than 13.5 nanomoles per liter). Likewise, data from a collection of five cohort studies revealed that participants with folate deficiency were 88 percent more likely to develop Alzheimer’s disease compared to individuals with sufficient folate status. Finally, in a sample of 11 cohort studies, participants who consumed less than the recommended dietary allowance (400 micrograms) were 70 percent more likely to develop Alzheimer’s disease than those who consumed 400 micrograms of folate per day or more.

    This review of the evidence supports a relationship between folate intake and serum folate concentration in reducing risk for developing Alzheimer’s disease. Future studies should utilize an interventional design to investigate the mechanisms of folate in Alzheimer’s pathology.

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  • COVID-19 may increase a person's risk for neurodegenerative disease. www.sciencedirect.com
    COVID-19 Neurodegeneration

    COVID-19 is an acute illness caused by infection with the SARS-CoV-2 virus. Although most people recover from COVID-19 within a few weeks of presenting with symptoms, some experience long-term complications that affect multiple organs, including the heart, lung, kidney, skin, and brain. Findings from a recent study suggest that SARS-CoV-2 infection may promote neurodegenerative disease.

    Neurodegenerative diseases are chronic disorders of the central nervous system that are characterized by chronic progressive loss of neuronal structure and function. They often emerge in mid-to-late adult life and are increasingly common, affecting roughly 37 million people worldwide – a number expected to increase as human lifespan increases. Although scientists don’t fully understand the underlying causes of most neurodegenerative diseases, protein aggregation in the brain is a widely accepted contributing factor. Previous research has shown that the SARS-CoV-2 spike protein binds to heparin (a protein involved in blood clotting) and heparin binding proteins, accelerating the aggregation of proteins involved in neurodegeneration.

    Since many of the biological functions of a protein depend upon its affinity to bind with other proteins, the authors of the study used a web-based algorithm called HDOCK to gauge the binding affinity between the receptor binding domain of the SARS-CoV-2 spike protein between heparin and several aggregation-prone heparin-binding proteins implicated in neurodegenerative diseases, including amyloid-beta, alpha-synuclein, tau, and TAR DNA binding protein.

    They found that SARS-CoV-2 spike protein exhibited differing binding affinities for the various proteins. Heparin showed the highest affinity, with the others exhibiting affinity in decreasing order: prion, amyloid-beta, tau, TAR DNA binding protein, and alpha-synuclein.

    These findings suggest that the heparin-binding site on the spike protein facilitates the subsequent binding to amyloid proteins, potentially leading to neurodegeneration in the brain. Learn more about risk factors that drive Alzheimer’s disease, a type of neurodegenerative disease, in this episode featuring Dr. Dale Bredesen.

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  • 20-minute transcranial direct current stimulation sessions shown to enhance maze performance, memory, brain plasticity in rodent model of Alzheimer's www.sciencedaily.com
    Brain Alzheimer's BDNF Neurodegeneration

    From the article:

    After exposing the mice to single 20-minute tDCS sessions, the researchers saw signs of improved memory and brain plasticity (the ability to form new connections between neurons when learning new information), which lasted at least a week. This intellectual boost was demonstrated by the enhanced performance of the mice during tests requiring them to navigate a water maze and distinguish between known and unknown objects.

    This effect depended on increased production of BDNF:

    More important, the researchers identified the actual molecular trigger behind the bolstered memory and plasticity–increased production of BDNF, a protein essential to brain growth. BDNF, which stands for “brain-derived neurotrophic factor,” is synthesized naturally by neurons and is crucial to neuronal development and specialization.

    “While the technique and behavioral effects of tDCS are not new,” said ONR Global Associate Director Dr. Monique Beaudoin, “Dr. Grassi’s work is the first to describe BDNF as a mechanism for the behavioral changes that occur after tDCS treatment. This is an exciting and growing research area of great interest to ONR.”

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  • Carriers of a common BDNF genetic variant demonstrate more rapid decline from Alzheimer's disease. www.sciencedaily.com
    Brain Alzheimer's Genetics BDNF Neurodegeneration

    BDNF plays critical roles in many aspects of cognitive function, including learning and memory formation. A single-nucleotide polymorphism (SNP) in the gene that encodes BDNF causes a substitution of the amino acid valine (Val) by methionine (Met) in a specific region of the DNA where the gene is located. Evidence suggests that carrying the Met allele (Met/Met or Val/Met genotype) is associated with lower BDNF expression.. A 2017 study found that amyloid-beta burden impaired BDNF-related learning and memory.

    Amyloid-beta is a toxic 42-amino acid peptide that aggregates and forms plaques in the brain with age. Amyloid-beta is associated with Alzheimer’s disease, a progressive neurodegenerative disease that can occur in middle or old age and is the most common cause of dementia.

    The study involved more than 1,000 adults (approximately 55 years at the beginning of the study) who were enrolled in a larger study of Alzheimer’s disease. Nearly 65 percent of the participants were at high risk for developing Alzheimer’s disease, having at least one parent diagnosed with the condition. Each of the participants underwent cognitive assessment and BDNF genotyping five times over a period of four to 11 years. In addition, a small cohort of participants underwent imaging studies to assess amyloid-beta burden.

    The genotyping revealed that approximately one-third of the participants were carriers of the Met-66 allele. Compared to Val/Val carriers, Met-66 carriers showed steeper declines in cognitive function. In addition, Met-66 carriers with greater amyloid-beta burden showed an even greater cognitive decline, likely due to lower BDNF expression. These findings suggest that a SNP in the gene for BDNF influences cognitive health and could serve as a therapeutic target against Alzheimer’s disease.

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  • Restoration of BDNF-mediated signaling as a potential therapeutic strategy against Huntington's disease. www.sciencedaily.com
    Brain BDNF Neurodegeneration

    Huntington’s disease is a progressive neurodegenerative disorder characterized by uncontrolled movements, speech problems, personality changes, and dementia. The disease is caused by a single genetic mutation, called a CAG repeat, that drives abnormal protein folding and aggregation of the huntingtin protein and subsequent death of striatal neurons. Findings from a 2010 study demonstrate that modulating pathways involved in BDNF-mediated signaling shows promise as a therapeutic against Huntington’s disease.

    Evidence suggests that normal huntingtin promotes the expression of BDNF, but mutated huntingtin impairs it. Striatal neurons need BDNF for their normal function and survival. A critical component in BDNF’s actions on striatal cells is a receptor called TrkB, to which BDNF binds. Levels of TrkB are diminished in Huntington’s disease.

    The authors of the in vitro cell study investigated the effects of BDNF administration on mutant huntingtin. They found that altered cell-signaling in the Ras/MAPK/ERK1/2 pathway in cells expressing mutant huntingtin drove the loss of TrkB receptors, increased striatal cells' sensitivity to oxidative damage, and promoted cell death. These findings suggest that identifying ways to modulate the Ras/MAPK/ERK1/2 pathway and restore BDNF-related signaling shows promise as a therapeutic strategy against Huntington’s disease.

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  • Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus www.cell.com
    Alzheimer's Virus Genome Neurodegeneration

    Summary Investigators have long suspected that pathogenic microbes might contribute to the onset and progression of Alzheimer’s disease (AD) although definitive evidence has not been presented. Whether such findings represent a causal contribution, or reflect opportunistic passengers of neurodegeneration, is also difficult to resolve. We constructed multiscale networks of the late-onset AD-associated virome, integrating genomic, transcriptomic, proteomic, and histopathological data across four brain regions from human post-mortem tissue. We observed increased human herpesvirus 6A (HHV-6A) and human herpesvirus 7 (HHV-7) from subjects with AD compared with controls. These results were replicated in two additional, independent and geographically dispersed cohorts. We observed regulatory relationships linking viral abundance and modulators of APP metabolism, including induction of APBB2, APPBP2, BIN1, BACE1, CLU, PICALM, and PSEN1 by HHV-6A. This study elucidates networks linking molecular, clinical, and neuropathological features with viral activity and is consistent with viral activity constituting a general feature of AD.

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  • Traumatic brain injury disrupts the brain's waste removal system, allowing toxic proteins to accumulate in the brain. www.sciencedaily.com
    Brain Alzheimer's Parkinson's Performance Concussion Protein Neurodegeneration Blood-Brain Barrier

    From the article:

    The new research focuses on the impact that traumatic brain injury has on the glymphatic system. It has been long observed that the protein tau plays an important role in the long-term damage sustained by the brain after a trauma. Tau helps stabilize the fibers, or axons, that nerve cells send out to communicate with their neighbors.

    However, during trauma, large numbers of these proteins are shaken free from the axons to drift in the space between the brain’s cells. Once unmoored from nerve cells, these sticky proteins are attracted to each other and, over time, form increasingly larger “tangles” that can become toxic to brain function.

    Under normal circumstances, the glymphatic system is able to clear stray tau from the brain. However, when the researchers studied the brains of mice with traumatic brain injury, they found that the trauma damaged the glymphatic system, specifically the ability of astrocytes – a support cell found in the brain – to regulate the cleaning process.

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