Geriatric Psychiatry Research: Herpesviruses, Brain Metals, DBS
New research suggests that viruses and metals in the brain may exacerbate Alzheimer disease and deep brain stimulation shows promise in slowing cognitive decline.
New research suggests that viruses and metals in the brain may exacerbate Alzheimer disease, and on the positive side, deep brain stimulation may slow progression in older patients: herpesviruses may play a role in Alzheimer's disease; metals in the brain may drive Alzheimer’s disease progression; and deep brain stimulation shows promise for older patients with mild Alzheimer’s disease.
Human herpesviruses are more abundant in the brains of patients and may play a role in regulatory genetic networks that are believed to lead to the disease. An analysis of data from three major brain banks led to the construction, mapping, and comparison of regulatory gene networks in areas of the brain known to be affected by AD on multiple levels.
Human herpesvirus DNA and RNA were more abundant in the brains of those diagnosed postmortem with AD; this abundance correlated with clinical dementia scores. Two viruses found to be most strongly associated with AD, HHV-6A and HHV-7, were not as abundant in the brains of those with other neurodegenerative disorders. The viral genes were regulating and being regulated by the human genes, which impacted the genes associated with increased risk of AD.
Clinical implications: “Previous studies of viruses and Alzheimer's has always been very correlative. But we were able to do statistical causal inference testing and more sophisticated analysis, which allowed us to identify how the viruses are directly interacting with or co-regulating or being regulated by Alzheimer's genes. I don't think we can answer whether herpesviruses are a primary cause of Alzheimer's disease. But what's clear is that they're perturbing networks and participating in networks that directly accelerate the brain towards the Alzheimer's topology,” said co-senior author Joel Dudley, who is a member of the ASU-Banner Neurodegenerative Disease Research Center.
Source: Readhead B, et al. Multiscale Analysis of Independent AD Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Neuron 2018.
Iron species associated with the formation of amyloid protein plaques in the human brain have been associated with toxicity that leads to mental deterioration in patients with AD. Amyloid plaque cores from two patients who had died with a formal diagnosis of AD were scanned using synchrotron X-ray spectromicroscopy. The magnetic state of the iron species in the plaques was analyzed to confirm the presence of various iron minerals.
Several chemically reduced iron species, including a proliferation of a magnetic iron oxide called magnetite not commonly found in the human brain, were found in the amyloid protein plaques.
Clinical Implications: “Iron is an essential element in the brain, so it is critical to understand how its management is affected in Alzheimer’s disease. The advanced X-ray techniques that we used in this study have delivered a step-change in the level of information that we can obtain about iron chemistry in the amyloid plaques. We are excited to have these new insights into how amyloid plaque formation influences iron chemistry in the human brain, as our findings coincide with efforts by others to treat Alzheimer’s disease with iron-modifying drugs,” said co-author Dr. Joanna Collingwood, Associate Professor at the School of Engineering at the University of Warwick, UK.
Source: Everett J, et al. Nanoscale synchrotron X-ray speciation of iron and calcium compounds in amyloid plaque cores from AD subjects. Nanoscale. Published online April, 24 2018.
Patients with AD over aged 65 years appear to derive the most benefit from deep brain stimulation (DBS). A randomized, double-blind, multicenter phase II clinical trial included 42 patients with AD. DBS electrodes were implanted in their brains directed at the fornix, a bundle of nerve fibers that carry signals from the hippocampus, and were followed for two years. Those patients aged 65 years or older appeared to experience a slower progression of AD than younger patients, regardless of when their device was turned on.
Clinical Implications: “We are encouraged by these findings as they continue to help us identify who will benefit most from deep brain stimulation to treat Alzheimer's disease and learn more about this illness. With so few treatments available and the incidence of Alzheimer's only expected to increase, we really need to fully explore all treatments that seem to be of benefit to patients,” said Andres Lozano, MD, of the Krembil Neuroscience Centre at Toronto Western.
Source: Posporelis S, et al. Deep Brain Stimulation of the Memory Circuit: Improving Cognition in Alzheimer's Disease.J Alzheimers Dis. 2018;2:337-347.