Molecular and neuroimaging biomarkers of Alzheimer’s disease at #SfN16
This year’s Society for Neuroscience (SfN) conference was rich with emerging advances in the detection of neuropathological changes that occur during Alzheimer’s disease. The cutting edge of this research was presented at the nanosymposium on Molecular and Neuroimaging Biomarkers of Alzheimer’s Disease Saturday afternoon. From genetics to brain structure to molecular markers, this session highlighted the diversity of tools researchers are employing to better understand the neural effects of both normal and pathological aging.
Alzheimer’s disease pathology is known to originate in the brain’s medial temporal lobe – most notably in the entorhinal cortex and hippocampus – before spreading to more extensive cortical regions. Although prior research has therefore focused largely on structural changes in this region, new evidence shared at SfN this year suggests that aberrant brain structure beyond the medial temporal lobe may serve as an additionally powerful disease biomarker.
Taylor Schmidt from the University of Cambridge presented findings that basal forebrain gray matter atrophy precedes atrophy in the entorhinal cortex, in cognitively impaired and healthy older adults with high amyloid burden, a pathological hallmark of Alzheimer’s disease. Not only did basal forebrain atrophy predict delayed recall performance, but this effect was mediated by amyloid levels. Could subcortical atrophy, perhaps driven by amyloid deposition, precede cortical degeneration to serve as an earlier biomarker of Alzheimer’s pathology?
Arash Sereshki of the University of Alberta expanded upon these findings, encouraging researchers to look beyond the hippocampus for signatures of brain aging. Using high-resolution MRI, his work showed that volume of the amygdala, a region involved in fear and reward learning among other functions, was a strong predictor of age-related neural changes. The basal nucleus of the amygdala showed the most robust atrophy with age, but this association only occurred in men.
Owen Philips from Stanford University explored the effects of Alzheimer’s disease on white matter, delving beyond the thick, deep fibers that characterize the brain’s celebrated connective superhighway. Instead of examining the white matter of the cingulum, corpus callosum or fornix, his group evaluated whether superficial white matter – which myelinates later and is more complex than deep white matter – is affected by Alzheimer’s disease. Using vertex-wise analysis, they found widespread increased diffusivity in the superficial white matter of Alzheimer’s disease patients compared to healthy controls, most prominently in the temporal lobe. This diffusion signal negatively correlated with global cognitive function, indicating that greater superficial white matter diffusion was a good indicator of the severity of cognitive impairment.
Various factors integratively determine the type and extent of neuropathology that one may sustain in older age, and which may ultimately lead to the neurodegenerative changes discussed by Schmidt, Sereshki and Phillips. Although genetics only play one part in this pathological cascade, the APOE and BDNF genes are well-documented contributors to risk for cognitive impairment in older age.
Melanie Sweeney of the University of Southern California examined effects of the APOE4 allele, which increases risk for Alzheimer’s disease, on neurovascular health. Her group reported that breakdown of the blood brain barrier, which selectively filters substances into the brain from the blood, is greater in individuals with APOE4 than those without the risk gene. APOE4 carriers also demonstrated increased permeability of the blood brain barrier, even at preclinical stages (i.e., before any disease symptoms), beginning first in the hippocampus, one of the earliest sites to undergo neurodegeneration in Alzheimer’s disease.
Nikolai Malykhin, also from the University of Alberta, looked more closely as how genetics affect morphometry in subregions of the hippocampus. In cognitively normal adults, volumes of all hippocampal subregions were greater for those carrying the APOE2 variant, which lowers risk for Alzheimer’s disease. Volume of the dentate gyrus – but no other hippocampal subregions – was reduced for BDNF met-carriers, showing that BDNF effects on hippocampal size were more specific than APOE effects.
Although amyloid and tau are the molecular hallmarks of Alzheimer’s disease, they have been remarkably challenging to detect in the living human brain. However, thanks to impressive methodological advances, there has been a recent surge in the development of tools to visualize the most sensitive molecular disease biomarkers.
Xiaotian Fang from Uppsala University presented a novel imaging technique that uses an antibody that, fused with a blood brain barrier-passage molecule, can enter the brain and bind to amyloid protofibrils, suspected to be the toxic component of amyloid plaques. This tracer effectively labeled amyloid protofibrils in a mouse model of Alzheimer’s disease and holds promise as a more sensitive imaging tool than current amyloid plaque tracers.
Finally, Maja Mustapic of the NIA explored the potential of extracellular vesicles in the blood – which can transport molecules such as amyloid or tau to the brain – as Alzheimer’s disease biomarkers. Levels of phosphorylated tau in these vesicles distinguished Alzheimer’s disease patients from normal controls with high accuracy, both at disease onset and before symptoms were manifest. Analysis of other vesicular molecules is underway.
As exemplified by the diverse techniques presented in this session, a multimodal approach may be our best bet for the most accurate early detection of neuropathological events. I’m already eagerly awaiting #SfN17 for updates on the ongoing advances in the development of Alzheimer’s disease biomarkers over the coming year.
Image credit https://www.flickr.com/photos/nihgov/
Any views expressed are those of the author, and do not necessarily reflect those of PLOS.
Emilie Reas received her PhD in Neuroscience from UC San Diego, where she used fMRI to study memory. As a postdoc at UCSD, she currently studies how the brain changes with aging and disease. In addition to her tweets for @PLOSNeuro she is @etreas.