Epigenetic predictors of lifestyle traits applied to the blood and brain.

Modifiable lifestyle factors influence the risk of developing many neurological diseases. These factors have been extensively linked with blood-based genome-wide DNA methylation, but it is unclear if the signatures from blood translate to the target tissue of interest-the brain. To investigate this, we apply blood-derived epigenetic predictors of four lifestyle traits to genome-wide DNA methylation from five post-mortem brain regions and the last blood sample prior to death in 14 individuals in the Lothian Birth Cohort 1936. Using these matched samples, we found that correlations between blood and brain DNA methylation scores for smoking, high-density lipoprotein cholesterol, alcohol and body mass index were highly variable across brain regions. Smoking scores in the dorsolateral prefrontal cortex had the strongest correlations with smoking scores in blood (r = 0.5, n = 14, P = 0.07) and smoking behaviour (r = 0.56, n = 9, P = 0.12). This was also the brain region which exhibited the largest correlations for DNA methylation at site cg05575921 - the single strongest correlate of smoking in blood-in relation to blood (r = 0.61, n = 14, P = 0.02) and smoking behaviour (r = -0.65, n = 9, P = 0.06). This suggested a particular vulnerability to smoking-related differential methylation in this region. Our work contributes to understanding how lifestyle factors affect the brain and suggest that lifestyle-related DNA methylation is likely to be both brain region dependent and in many cases poorly proxied for by blood. Though these pilot data provide a rarely-available opportunity for the comparison of methylation patterns across multiple brain regions and the blood, due to the limited sample size available our results must be considered as preliminary and should therefore be used as a basis for further investigation.

Tissue-Specific Immunopathology in Fatal COVID-19.

Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown.Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury.Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence.Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues.Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.

Brain donation procedures in the Sudden Death Brain Bank in Edinburgh.

Brain banks typically receive donations through premortem consent procedures, often through disease-specific patient cohorts, such as dementia. While some control cases can be obtained through this route, access to age-matched control tissues, and some chronic neurologic conditions, particularly psychiatric disorders, can be challenging. The Edinburgh Sudden Death Brain Bank was established to try and increase access to control cases across all ages, and also access to psychiatric disorders through suicides. This chapter outlines the processes for establishing donations through medicolegal postmortems, which, although often with a prolonged postmortem interval, can provide high-quality well-characterized postmortem brain tissue to the neuroscience research community.

Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers.

Cognitive impairment is a recognized effect of drug misuse, including the use of opiates. The pathological basis for this is unknown but the temporal and frontal cortices have been implicated. We have shown previously that deposits of hyperphosphorylated tau in drug user brains exceed those seen in age-matched controls. The present quantitative study of hyperphosphorylated tau and beta amyloid in drug user brains allows comparison with the related pathology in Alzheimer's disease. Brains were obtained from the Edinburgh Medical Research Council Brain Banks, comprising 39 human immunodeficiency virus negative drug users, five subjects with Alzheimer's disease and 37 age-matched, cognitively normal controls, all legally and ethically approved for research. Hyperphosphorylated tau positive (AT8, AT100) neuropil threads were significantly increased in the frontal and temporal cortex, and in the locus coeruleus, of drug users aged > 30 years (all P = 0.04). Under the age of 30 years, drug users showed a similar increase in neuropil threads compared with controls, but this reached significance only in the frontal cortex (P = 0.03). Immunopositivity for both three- and four-repeat tau was present in drug user brains. There was a direct relationship between the numbers of neuropil threads and of neurofibrillary tangles: neurofibrillary tangles were sparse in brains that had neuropil thread counts below 200 cm(2). Hyperphosphorylated tau positive neuropil threads increased at a faster rate in drug users than in controls and the levels of the phosphorylating enzyme, GSK-3, was raised in drug user brains. Beta amyloid (AB4, AB42 and 4G8) was raised in drug user brains (mainly as shadow plaques) but not significantly different from controls and there was no correlation between high beta amyloid and hyperphosphorylated tau in individual cases. Hyperphosphorylated tau levels correlated significantly (P = 0.038) with microglial activation in drug users but not in controls. The levels of hyperphosphorylated tau in drug users fell far short of those seen in Alzheimer's disease but overlapped with those in elderly controls. We conclude that drug users show early Alzheimer's disease-related brain pathology that may be the basis for cognitive impairment and that neuroinflammation is an early accompanying feature. This provides an opportunity to study the pathogenesis of tau pathology in the human brain.

Postmortem tissue donation for research: a positive opportunity?

Previous research using human brain tissue has increased the understanding of many brain disorders, such as Alzheimer's disease and Creutzfeldt Jakob disease. However, there are other conditions, such as multiple sclerosis, which remain poorly understood and which require further investigation. The ongoing decline in the consented postmortem rate poses a threat to tissue collections and, consequently, future research. In the setting of the new Human Tissue legislation the authors set out to ascertain whether families recently and suddenly bereaved were willing to grant authorization for tissue samples and/or organs to be retained for research purposes at the time of medico-legal postmortem examination in adequate numbers to support the establishment of a brain and tissue bank. During the 2-year pilot phase of the project, 96% of families authorized retention of tissue samples for research and 17% agreed to whole brain donation. Respondents to a short questionnaire indicated that they were not further distressed by the approach and the majority were of the opinion that research donation should be offered to all bereaved families. This research concludes that the overwhelming majority of families who are recently and suddenly bereaved are willing to authorize research use of tissue taken at the time of postmortem examination.