Important new molecule in the biology of dementia

Anthony L. Komaroff, NEJM Journal Watch, April 8, 2014

Two molecules — β-amyloid and tau — are important in the biology of Alzheimer disease. Yet, high concentrations of them, either alone or together, do not seem to be sufficient to cause the disease.

In a study in the March 27 issue of Nature (http://dx.doi.org/10.1038/nature13163), researchers evaluated the molecules produced in the brains of older people with preserved cognitive function or with dementia and identified a candidate molecule called REST, which is important in embryonic brain development. The production of REST is silenced after embryonic development is completed, but is turned back on in aging brains. The researchers discovered that production continues in healthy older people with preserved cognition — but switches off in people with mild cognitive impairment, Alzheimer disease, or one of several other dementing diseases. REST deficiency was most striking in areas that are most affected in Alzheimer disease. Experiments showed that REST protects neurons from the toxic effects of β-amyloid and oxidative stress and protects against apoptosis (which is programmed cell death). Deleting the gene for REST in mice led to age-related neurodegeneration.

The REST molecule might protect the brain against age-related degenerative diseases, including Alzheimer disease. This molecule now becomes an important focus in understanding the underlying biology of dementia, as well as a target for therapeutics. Not all new and exciting putative disease-related molecules stand the test of time, but many experts are betting that this one will.

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REST and stress resistance in ageing and Alzheimer’s disease

Tao Lu, Liviu Aron, Joseph Zullo, Ying Pan, Haeyoung Kim, Yiwen Chen, Tun-Hsiang Yang, Hyun-Min Kim, Derek Drake, X. Shirley Liu, David A. Bennett, Monica P. Colaiácovo & Bruce A. Yankner

Nature 507, 448–454 (27 March 2014) doi:10.1038/nature13163

Abstract

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer’s disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer’s disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer’s disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

Sleep clears brain of toxic metabolites

Anthony Komaroff writes in New England Journal of Medicine Journal Watch:

We all know that without enough sleep, mood and cognition are impaired. Certain central nervous system conditions, including migraines and seizures, become more frequent and severe with a lack of sleep. When animals are kept from sleeping, they ultimately die.

Clearly, we need to sleep. But why? In a study in the October 18, 2013, issue of Science (http://dx.doi.org/10.1126/science.1241224), researchers report on a technique they developed for measuring the interstitial space in the brains of living mice. That space is bathed by cerebrospinal fluid that is produced by the choroid plexus and pumped back into the blood in the meninges. The researchers found that, during sleep and anesthesia, the interstitial space increased by 60%. The functional result of this expansion is that many metabolites of neurons and glial cells that spill into the interstitial space are cleared from the space much more rapidly, enter the blood, and are detoxified by the liver. These molecules include β‐amyloid and tau, which build up in the brains of patients with Alzheimer disease. When sleeping animals are aroused, the clearance of toxic metabolites slows markedly.

The researchers speculate that, at least in mice, the buildup of toxic metabolites in the interstitial space in the brain is a trigger for sleep, and that a key purpose of sleep is to clear these metabolites. Maybe the reason we feel restored after a good night’s sleep is because the brain has freed itself of toxins. This hypothesis is arresting in its simplicity and could prove to be profoundly important in human biology (http://dx.doi.org/10.1126/science.1245798).

Emily Underwood comments:

Scientists have long speculated that one of the functions of sleep is to restore and repair the brain, but whether this is a “core” purpose of sleep remains controversial. Now, a paper published in Science this week on page 373 provides direct experimental evidence that the mouse brain cleans itself during sleep, by expanding channels between neurons that allow an influx of cerebrospinal fluid. The fluid flushes out detritus such as amyloid proteins, which accumulate as plaques in Alzheimer's disease, twice as fast when mice are sleeping as when they are awake.

Suzana Herculano-Houzel comments:

We know from personal experience that sleep is not just another brain state but a basic requirement for normal brain function while we are awake. Mental fatigue, poor decision-making, impaired learning, and a heightened risk of migraine and epileptic attacks ensue when we are sleep deprived — and chronic and complete insomnia ultimately lead to death in humans, rats, and flies alike. Why does normal brain function deteriorate with prolonged waking and require sleep to be restored? On page 373 in this issue, Xie et al. report that during sleep, waste products of brain metabolism are removed from the interstitial space among brain cells where they accumulate. Sleep, therefore, might be required for potentially toxic metabolites — the very results of a working brain — to be cleared from the tissue.

human rights

Two-thirds of dementia cases have unknown causes

“Much of late life cognitive decline is not due to common neurodegenerative pathologies”. Patricia A. Boyle, PhD, Robert S. Wilson, PhD, Lei Yu, PhD, Alasdair M. Barr, PhD, William G. Honer, MD, Julie A. Schneider, MD, and David A. Bennett MD. Annals of Neurology. Volume 74, Issue 3, pages 478–489, September 2013. DOI: 10.1002/ana.23964

Objective. The pathologic indices of Alzheimer disease, cerebrovascular disease, and Lewy body disease accumulate in the brains of older persons with and without dementia, but the extent to which they account for late life cognitive decline remains unknown. We tested the hypothesis that these pathologic indices account for the majority of late life cognitive decline.

Methods. A total of 856 deceased participants from 2 longitudinal clinical–pathologic studies, Rush Memory and Aging Project and Religious Orders Study, completed a mean of 7.5 annual evaluations, including 17 cognitive tests. Neuropathologic examinations provided quantitative measures of global Alzheimer pathology, amyloid load, tangle density, macroscopic infarcts, microinfarcts, and neocortical Lewy bodies. Random coefficient models were used to examine the linear relation of pathologic indices with global cognitive decline. In subsequent analyses, random change point models were used to examine the relation of the pathologic indices with the onset of terminal decline and rates of preterminal and terminal decline (ie, nonlinear decline).

Results. Cognition declined a mean of about 0.11U per year (estimate = −0.109, standard error [SE] = 0.004, p < 0.001), with significant individual differences in rates of decline; the variance estimate for the individual slopes was 0.013 (SE = 0.112, p < 0.001). In separate analyses, global Alzheimer pathology, amyloid, tangles, macroscopic infarcts, and neocortical Lewy bodies were associated with faster rates of decline and explained 22%, 6%, 34%, 2%, and 8% of the variation in decline, respectively. When analyzed simultaneously, the pathologic indices accounted for a total of 41% of the variation in decline, and the majority remained unexplained. Furthermore, in random change point models examining the influence of the pathologic indices on the onset of terminal decline and the preterminal and terminal components of the cognitive trajectory, the common pathologic indices accounted for less than a third of the variation in the onset of terminal decline and rates of preterminal and terminal decline.

Interpretation. The pathologic indices of the common causes of dementia are important determinants of cognitive decline in old age and account for a large proportion of the variation in late life cognitive decline. Surprisingly, however, much of the variation in cognitive decline remains unexplained, suggesting that other important determinants of cognitive decline remain to be identified. Identification of the mechanisms that contribute to the large unexplained proportion of cognitive decline is urgently needed to prevent late life cognitive decline.

Vascular Contributions to Cognitive Impairment and Dementia

A Statement for Healthcare Professionals from the American Heart Association/American Stroke Association, by the American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia

Stroke. Published on line July 21, 2011. doi:10.1161/STR.0b013e3182299496

Abstract

Background and Purpose — This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment.

Methods — Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee.

Results — The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury—not solely stroke—ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people.

Conclusions — Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.

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[The Alzheimer's Association: Some autopsy studies show that as many as 80% of individuals with Alzheimer disease also have cardiovascular disease. Autopsies of dementia patients diagnosed with Alzheimer disease showed that 54% had coexisting pathology. The most common coexisting abnormality was previously undetected blood clots or other evidence of vascular disease.]

Alzheimer disease — a neurospirochetosis

Analysis of the evidence following Koch's and Hill's criteria, by Judith Miklossy

Journal of Neuroinflammation 2011, 8:90. doi:10.1186/1742-2094-8-90

Abstract. It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10⁻¹⁷; odds ratio = 20; 95% confidence interval = 8–60; N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific polymerase chain reaction and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.

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[Spirochetes are a kind of bacteria. Treponema pallidum causes syphilis. Borrelia burgdorferi causes Lyme disease. Late-stage syphilis involves dementia, brain atrophy, and amyloid deposition similar to what is seen in Alzheimer disease (AD). Therefore, it has been hypothesized that other spirochetes could cause AD. This review of published data found a strong association between the presence of spirochetes in the blood and AD: AD patients were 20 times more likely to have spirochete infection than non-AD patients. Spirochetes were found in the brains of >90% of AD patients. Borrelia burgdorferi (Lyme disease) in particular was found in the brains of 25% of AD patients and was 13 times more likely to be found in AD brains than in non-AD brains.]