NEUROLEX - Evidence-based Brain Superfood Building BDNF-induced Brain Plasticity to Restore Learning and Memory Function with ageing

MAINTAINING BRAIN HEALTH BY CONTROLLING INFLAMMATORY PROCESSES - A Mechanism to Promote Successful Ageing

Maintaining brain health promotes successful ageing. The main determinants of brain health are the preservation of cognitive function and remaining free from structural and metabolic abnormalities, including loss of neuronal synapses (brain plasticity), atrophy (loss of brain volume, particularly cortical and hippocampal grey matter), small vessel disease, silent brain infarcts, and focal beta-amyloid protein deposits visible by neuroimaging.

Promising studies indicate that these determinants are to some extent modifiable, even among adults seventy years and older.

Converging animal and human evidence further suggests that systemic, low-grade, chronic inflammation, beginning about mid-life, is a mechanism shared by all these risk factors, and all contributing to both cognitive decline and abnormalities in brain structure and metabolism.

Thus inflammation may provide a prime target for intervention. And it’s very important to note also that chronic inflammation is a key underlying component, providing the “fertile soil” in development and progression of most other chronic, age-related disease including cancer, atherosclerosis, stroke, diabetes, neurocognitive degeneration and dementia.

Specifically, circulating serum inflammatory biomarkers, in particular interleukin-6 (IL-6) and C-Reactive Protein (CRP), have been associated in numerous published university studies with declines in cognitive function, and worsening of brain structural and metabolic characteristics.

SUPER AGERS – GREY MATTER, CORTEX, HIPPOCAMPAL VOLUME

A “normal” characteristic of the ageing process, developing from about our mid-forties, is a gradual decline in memory function and brain mass. However, there are anecdotal reports of individuals, Super Agers, who seem immune to this age-related memory and learning impairment.

A community-dwelling group of these super agers has been the focus of a recent study by researchers at Northwestern University, School of Medicine, Illinois, Chicago, in order to obtain a better understanding of the underlying factors promoting this unusual trajectory of successful ageing. The hope in this has been the prospect that this might provide insight for preventing age-related cognitive impairments including the more severe changes associated with development of Alzheimer’s disease (“Superior Memory and Higher Cortical Volumes in Unusually Successful Cognitive Aging” Journal of the International Neuropsychological Society 2012; vol 18: 1-5).

MRI scans showed that the cortex of the Super Agers was thicker than a comparison group of people 20 or 30 years younger. The cortex is the outer layer of the brain involved in memory, attention and other reasoning and thinking abilities. A thinning cortex suggests a loss of brain cells, or grey matter, explained senior study author Emily Rogalski, assistant research professor at Northwestern University.

RESEARCH FOCUS – SEARCHING FOR ANSWERS

Finding answers to the factors causing this cortical thinning with ageing has been a major focus of the research at the Neurolex company during most of this last decade.

Two key underlying factors soon became obvious in our studies, chronic oxidative stress and low-grade systemic inflammation Both of these strongly-interrelated conditions begin their progress from about our mid-forties. Very importantly, these two conditions are involved in initiation and development of almost all the leading causes of age-related mortality and morbidity including heart disease (atherosclerosis), most cancers and dementia. Furthermore, these diseases are usually characterised by a long etiology or development period, often not becoming clinically evident until a decade or two after their initiation during mid-life.

BRINGING THE NEUROSCIENCE DEVELOPMENTS TOGETHER

The first major breakthrough came with research led by Dr Li-Huei and her team at MIT when they discovered that a protein called histone deacetylase 2 (HDAC2) accumulates early in the brain in the course of Alzheimer’s disease. HDAC2 is known to tighten up spools of DNA, effectively locking down the genes within and reducing their activity or expression. One of these key genes affected in this way is known as brain-derived neurotrophic factor (BDNF), the key gene in regulating the brain’s plasticity.

A hallmark of Alzheimer’s disease is the accumulation of a neurotoxic protein fragment called beta-amyloid (AB). Dr Tsai and her team reasoned that beta-amyloid triggers a cascade of damaging reactions, one of which is to activate HDAC2 which in turn blocks the expression of genes needed for brain plasticity. Once this blockade is in place, it can have a more systemic chronic effect on the brain such as cortical and hippocampal thinning and with it learning and memory function.

Another important development in this work came with a group of neurologists who used Pet imaging and high-resolution structural MR imaging with 119 individuals. Both beta-amyloid (AB) deposition and brain atrophy are invariably associated with Alzheimer’s disease and this process likely begins many years before symptoms appear. The study found that hippocampal volume reduction was related to AB deposition, and concluded that, “AB deposition is associated with a pattern of cortical thickness reduction consistent with Alzheimer’s disease prior to the development of cognitive impairment” (“Amyloid-B Associated Cortical Thinning in Clinically Normal Elderly” Annals of Neurology 2011; vol 69(6): 1032-1042).

The process of neurodegeneration, beginning much earlier than previously thought, was becoming clearer, but further research by a group of researchers from the Departments of Psychiatry and Psychology at the University of Pittsburgh provided the answers we were searching for.

CHRONIC BRAIN AND SYSTEMIC INFLAMMATION AND COGNITIVE CHANGE

Working with the knowledge that converging animal studies suggest that higher peripheral (systemic) levels of chronic inflammation are associated with activation of central inflammatory mechanisms that result in hippocampal neurodegeneration and related impairment of memory function. They had then in human studies, found an inverse relation between peripheral levels of interleukin-6 (IL-6), a relatively stable biomarker of systemic inflammation, and memory function in mid-life adults.

Using a computational structural neuroimaging method, to evaluate the relationship between plasma IL-6 levels and hippocampal grey matter volume in a sample of 76 relatively healthy volunteers aged 30-54 years, they found that peripheral levels of IL-6 co-varied inversely with hippocampal grey matter volume, and this relationship persisted after accounting for several possible confounders, including age, sex, race, years of education, percent body fat, blood pressure, smoking, physical activity, hours of sleep, alcohol use, and total grey matter volume.

The researchers concluded. “To our knowledge, this is the first report of a relationship between a peripheral marker of IL-6 and hippocampal grey matter volume, raising the possibility that low grade systemic inflammation could plausibly presage sub-clinical cognitive decline in part via structural neural pathways.” (“Interleukin-6 Covaries Inversely with Hippocampal Grey Matter Volume in Middle-Aged Adults” Biol Psychiatry 2008; vol 64(6): 484-490).

These results were further confirmed in a study by a group of researchers from the University of Pittsburgh School of Medicine, and The Department of Psychiatry, Mount Sinai School of Medicine, New York. This study examined the relationship between serum levels of 500 relatively healthy community volunteers aged 30 to 54 and a battery of neuropsychological tests evaluating memory and executive function. After controlling for a number of confounding factors, the study revealed an inverse relationship between circulating levels of IL-6 and performance on clusters of tests assessing auditory recognition memory, attention/working memory and executive function.

The study conclusion stated “These findings contribute to a growing body of evidence linking chronic inflammation to poorer cognitive functioning and extend these findings to a midlife community sample, raising the possibility that IL-6 may represent a biomarker for risk of future cognitive decline”. (“Interleukin-6 Covaries Inversely With Cognitive Performance Among Middle-Aged Community Volunteers” Psychosomatic Medicine 2006; vol 68: 895-903).

INFLAMMATION – AGE-RELATED COGNITIVE DECLINE

Finally, a further study by researchers at the University of Pittsburgh confirmed that maintaining brain health promotes successful ageing, and proposed that monitoring and maintaining lower levels of systemic and central inflammation even among older adults could help preserve brain health and support successful aging. (“Maintaining Brain Health by Monitoring Inflammatory Processes: a Mechanism to Promote Successful Aging” Aging and Disease 2011; vol 3(1): 16-33).

The involvement of chronic inflammation in development of mild cognitive impairment and its progression to Alzheimer’s disease is now supported by a robust body of published science as demonstrated in a study by researchers at the Rush University Medical Center, and Rush Alzheimer’s Disease Center, Chicago. In high resolution MRI methodology with a cohort of community dwelling subjects, characterised as having high or low levels of systemic inflammation determined by circulating levels of the pro-inflammatory cytokines C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-a), typical markers of chronic inflammation, it was found that the high inflammation group had significant cortical thinning, compared to the low inflammation group. But it became important in our research to determine if this cortical thinning was a progression in development of memory and cognitive loss, raising the possibility that at some stage suitable measures can be found to halt its progress.

Support for this goal came with a recent study which is the first to report evidence of cortical thinning in the pre-clinical stages of Alzheimer’s disease (AD), Lady Davis Institute and McConnell Brain Imaging Centre, Montreal Neurological Institute, Canada, using MRI procedures to evaluate cortical thickness in a cohort of 34 healthy, 62 mild cognitive impairment (MCI) and 42 Alzheimer’s disease (AD) subjects, found that the thickness of the cortex decreased significantly when the healthy elderly brains were compared to those with MCI. With the further progression of the disease from MCI to Alzheimer’s disease, a general thinning of the entire cortex was found (“Spatial patterns of cortical thinning in mild cognitive impairment and Alzheimer’s disease” Brain 2006; vol 129: 2885-2893).

THE THIRD CULPRIT IN NEUROCOGNITIVE DEGENERATION; EPIGENETIC CHROMATION DYSFUNCTION (GENE SILENCING)

But there still remained a further challenge for us to address. Brain-derived neurotrophic factor (BDNF) is critical for the function and survival of neurons that degenerate in the progression of MCI to Alzheimer’s disease. BDNF has been found to reduce by 34 and 64% in MCI and AD subjects, respectively.

BDNF levels have been shown to positively correlate with cognitive measures such as the Mini Mental State Examination score and demonstrate that reduction of BDNF occurs early in the course of AD and correlates with memory loss and loss of cognitive function.

Synaptic density is decreased in the cortex thinning. BDNF has important roles in neuronal growth and synaptic function in the cortex (brain plasticity), and its decline with ageing is believed to severely compromise cognitive function in development of AD. This is confirmed in post-mortem studies of people with no cognitive impairment (NCI mild cognitive impairment (MCI) or mild to moderate AD. The brain BDNF levels were found to be significantly decreased in MCI and AD compared with NCI samples.

These results demonstrate that epigenetic transcriptional gene-silencing , with its decrease in BDNF is an early event in AD and reduced levels of BDNF appear to be sufficient to compromise cognitive function (“Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease” Journal of Neurochemistry 2005; vol 93: 1412-1421).

This confirmed our earlier major discovery that, in almost every major age-related chronic disease, including not only neurocognitive degeneration, progressive memory and learning functions and Alzheimer’s dementia, CVD and most cancers, although individually extremely complex and multifactorial, there exists a critical development pathway, which we have called the “fertile ground of chronic disease” can be summarised as:-

Redox imbalance, commonly increasing from about our fourth decade, and leading to oxidative stress;
Chronic sub-clinical, low-grade systemic inflammation, in a lethal combination with 1 above; and
Epigenetic remodelling (e.g. DNA hyper/hypomethylation, histone de-acetylation) leading to post-translational gene dysfunction.

BDNF – KEY REGULATOR OF NEURONAL HEALTH AND BRAIN PLASTICITY

Having isolated these factors involved in loss of cognitive function beginning at mid-life, we then turned to the search for evidence-based preventive and therapeutic strategies, and so we began with the large body of published epidemiological studies which indicate that diets which were very high in certain fibre, and fruit and vegetables have a significantly reduced risk for neurodegeneration. Here we were able to discover some incredible facts. One very important factor is that regular consumption of certain dietary fibres allow the bacteria living in our large intestine to produce short chain fatty acids, in particular, butyrate which the body then converts to sodium butyrate. Sodium butyrate is one of the most incredible chemical compounds and it is produced naturally in our colon. Incredible in that it functions in several key ways to prevent and treat chronic disease.

Butyrate has not only anti-inflammatory functions but it also has a very important epigenetic function because it is a recognised histone deacetylase inhibitor, inducing neuroprotective metabolic changes, not the least of which is in actually increasing our level of the neurotrophic memory function, protective BDNF.

THE MEMORIES ARE STILL THERE BUT ACCESS IS BLOCKED – AN HDAC2 INHIBITOR RESTORES RECALL

Epigenetic regulation of gene expression in the mammalian brain is known to play a key role in cognitive function and its dysregulation has been linked to the pathogenesis of neurodegenerative diseases. Enhancing histone acetylation by inhibiting HDACs is becoming recognised as a potential therapeutic strategy to treat memory decline during Alzheimer’s disease.

Scientists at the Massachusetts Institute of Technology (MIT) have evidence from mice bred to develop a human form of Alzheimer’s Disease (AD) that memories of things learned may still be stored in the brain but the overproduction of the specific, inflammation-induced enzyme histone deacetylase 2 (HDAC2) blocks access to these memories. The MIT team led by Dr Li-Huei Tsai were able to block abnormal increase in this enzyme in AD mice and restore access to the memory archive.

Dr. Li-Huei Tsai, Director of the MIT Picower Institute for Learning and Memory and her colleagues blocked the characteristic amyloid beta induced build up of HDAC2 in the A1 area of the hippocampus as well as the entorhinal cortex in the mouse model of AD and it restored structural and synaptic brain plasticity. They also conducted behavioural studies that showed the animals could learn and recall information even after the neurodegenerative process had reached a well-advanced stage.

A further study by researchers at the Laboratory of Aging and Cognitive Diseases, European Neuroscience Institute, University Medicine Goettingen, Germany led by Dr Andre Fischer used AD mice which exhibit very aggressive AD pathology in the form of AB plaques as early as 2 months of age. This is accompanied by dystrophic synaptic boutons, inflammatory responses and robust impairment of cognitive function and synaptic plasticity at 8 months of age.

They were able to show that these 15-month old mice exhibit severe amyloid pathology, memory impairment and decreased hippocampal and cortical histone acetylation and thus comprise a suitable model to test the effect of HDAC inhibitors at an advanced stage of AD progression. They found that a 6-week administration of the HDAC inhibitor sodium butyrate enhanced histone acetylation and significantly facilitated memory function.

The effect correlated with the elevated expression of genes associated with learning and memory processes and the researchers concluded, “These data provide further evidence that targeting histone acetylation using HDAC inhibitors (sodium butyrate) could be a suitable therapeutic strategy to treat memory impairment associated with AD pathogenesis”. (“Sodium Butyrate Improves Memory Function in an Alzheimer’s Disease Mouse Model When Administered at an Advanced Stage of Disease Progression”, Journal of Alzheimer’s Disease; vol 26: 187-197).

NEUROLEX

In summary, our research, supported by robust published studies, clearly shows a progression in most age-related chronic disease, including Alzheimer’s disease, beginning with development of systemic oxidative stress, triggering a cascade of low-grade systemic inflammation and finally leading to epigenetic (chromatin) dysfunction with gene silencing. This progression, usually beginning about mid-life, takes many years, perhaps decades, to develop clinically. It is apparent that any preventive or therapeutic approach to chronic disease must address each of these stages to be successful and NEUROLEX is the first and only product to achieve this goal. Furthermore the product is derived entirely from natural, safe, vegetable fibre approved by ANZFA as a food ingredient.

Further details of this product are available from Dr Maxwell Strong who can be contacted at any time (M: 0418 413657 or 61 2 95318585). Email: maxwellstrongresearch@gmail.com

This leaflet is for information of medical specialists and general medical practitioners. All others with health concerns should always discuss these with your medical practitioner.

www.neurolex.com.au

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