Hugh Perry

Does the vagus nerve inform the brain about preclinical tumours and modulate them

The inflammatory microenvironment is thought to play a pivotal part in tumorigenesis. But, can the brain be informed about peripheral preclinical cancer cells? Can it modulate tumour development? One of the key routes for information to reach the brain from visceral regions is through the vagus nerve. Yet, patients with ulcers who have had a vagotomy have been shown to die from cancer more frequently than do those who have not had this procedure, and surgical and chemical vagotomy attenuates tumour-induced anorexia and leads to enhanced tumour progression. We therefore postulate that the vagus nerve participates in informing the brain about tumorigenesis by transmiting information to the brain about tumour-associated proinflammatory cytokines. Furthermore, activation of the vagus could slow tumorigenesis by suppression of peripheral proinflammatory cytokines.

Nutrition for the ageing brain: Towards evidence for an optimal diet.

As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline.

Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder

Background Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. Methods We used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline–High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen–Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q = .025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance. Results A total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation > .70 in both studies). Conclusions MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression.

Repeated exposure to systemic inflammation and risk of new depressive symptoms among older adults

Evidence on systemic inflammation as a risk factor for future depression is inconsistent, possibly due to a lack of regard for persistency of exposure. We examined whether being inflamed on multiple occasions increases risk of new depressive symptoms using prospective data from a population-based sample of adults aged 50 years or older (the English Longitudinal Study of Ageing). Participants with less than four of eight depressive symptoms in 2004/05 and 2008/09 based on the Eight-item Centre for Epidemiologic Studies Depression scale were analysed. The number of occasions with C-reactive protein ⩾3 mg l−1 over the same initial assessments (1 vs 0 occasion, and 2 vs 0 occasions) was examined in relation to change in depressive symptoms between 2008/09 and 2012/13 and odds of developing depressive symptomology (having more than or equal to four of eight symptoms) in 2012/13. In multivariable-adjusted regression models (n=2068), participants who were inflamed on 1 vs 0 occasion showed no increase in depressive symptoms nor raised odds of developing depressive symptomology; those inflamed on 2 vs 0 occasions showed a 0.10 (95% confidence intervals (CIs)=−0.07, 0.28) symptom increase and 1.60 (95% CI=1.00, 2.55) times higher odds. In further analyses, 2 vs 0 occasions of inflammation were associated with increased odds of developing depressive symptoms among women (odds ratio (OR)=2.75, 95% CI=1.53, 4.95), but not among men (OR=0.70, 95% CI=0.29, 1.68); P-for-sex interaction=0.035. In this cohort study of older adults, repeated but not transient exposure to systemic inflammation was associated with increased risk of future depressive symptoms among women; this subgroup finding requires confirmation of validity.

Challenging the central hypothesis that misfolded prion protein accumulation, spread and distribution predicts regions of neurodegeneration

Until now, the 3-dimensional structure of infectious mammalian prions and how this differs from non-infectious amyloid fibrils remained unknown. Mammalian prions are hypothesized to be fibrillar or amyloid forms of prion protein (PrP), but structures observed to date have not been definitively correlated with infectivity. One of the major challenges has been the production of highly homogeneous material of demonstrable high specific infectivity to allow direct correlation of particle structure with infectivity. We have recently developed novel methods to obtain exceptionally pure preparations of prions from prion-infected murine brain and have shown that pathogenic PrP in these high-titer preparations is assembled into rod-like assemblies (Wenborn et al. 2015. Sci. Rep. 10062). Our preparations contain very high titres of infectious prions which faithfully transmit prion strain-specific phenotypes when inoculated into mice making them eminently suitable for detailed structural analysis. We are now undertaking structural characterization of prion assemblies and comparing these to the structure of non-infectious PrP fibrils generated from recombinant PrP

Systemic inflammatory responses to stress and its impact on cognition in people with mild cognitive impairment

relation of cerebrovascular perfusion to domains of cognitive performance in non-demented population based samples due in part to feasibility issues and cost of P.E.T. or MRI. Transcranial Doppler (TCD) ultrasound provides an inexpensive, rapid, non-invasive technique for assessing cerebrovascular function. We examined the cross-sectional associations of TCDmeasures of blood flow velocities in arteries of the circle of Willis to cognitive performance in participants in the EAS cohort. Methods: Analyses included 97 non-demented, community residing elderly, age 3 70. TCD was performed by a trained ultrasound technician using a standardized and validated research protocol during the annual clinic visit which included neuropsychological testing and neurological exams. The group was 52% female, mean age 80.9 (65.6) years, mean education 15 years. Cognitive domain evaluation included episodic memory (Free Recall from Free and Cued Selective Reminding Test-FR-FCSRT and WMS-R Logical Memory I subtest -LM), semantic memory (category fluency CF), executive function (WAIS-III digit symbol substitution test-DSST; Trail-Making Test-B TMT-B), and language (phonemic fluency-FAS).We computed the mean of right and left flow velocities (MFV) for each vessel. Spearman’s correlation coefficients were used to examine the relation of MFV in the anterior (ACA_MFV), posterior (PCA_MFV) andmiddle (MCA_MFV) cerebral arteries to cognitive performance. Linear regression analyses were used to determine whether associations persisted after adjustment for age, sex and education. Results: There was a consistent pattern showing a positive correlation between CF, DSST, TMT-B and FAS with ACA_MFVand PCA_MFVwhile memory tests were not correlated with MFV. The MCA-MFV was not correlated with any cognitive measures. The associations of ACA_MFVand PCA_MFV with cognition remained after adjustment for age sex, and education. Conclusions: Cerebral blood flow appears to be more highly correlated with performance on tests of executive function and language than with tests of episodic memory. This is consistent with prior information suggesting a link between vascular processes and frontal executive function. TCD may be useful for distinguishing persons at risk for amnestic versus non-amnestic mild cognitive impairment. Longitudinal data are needed to confirm this hypothesis.