Vascular disruption—not amyloid accumulation—is Alzheimer’s first observable brain change

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 - Dementia2

A new analysis of big data largely based on thousands of MR and PET images has shown that changes in blood flow to and within the brain precede amyloid build-up in Alzheimer’s patients.

The observation of vascular dysregulation as Alzheimer’s first giveaway of its presence, the authors of the analysis write, may mark a turning point in unpacking the “cascade of events” that often leads the disease to progress from no symptoms to mild cognitive impairment to debilitating dementia.

Publishing their findings in Nature Communications, lead author Yasser Iturria Medina, PhD, of McGill University’s Montreal Neurological Institute in Quebec and colleagues describe their work analyzing more than 7,700 brain images in a database of the Alzheimer’s Disease Neuroimaging Initiative.

Along with altered cerebral blood flow and abnormally folded amyloid beta proteins, the team looked at glucose metabolism, functional activity and structural tissue brain patterns in 78 brain regions. They mapped these biological factors in vivo using florbetapir PET for amyloid beta deposition, fluorodeoxyglucose PET for glucose metabolism, arterial spin labeling for cerebral blood flow, resting fMRI for neuronal activity at rest and structural MRI for structural tissue properties.

There were 1,171 patients in the cohort under review, and each was previously diagnosed at each visit as healthy control, early mild cognitive impairment, late mild cognitive impairment or probable Alzheimer’s disease patient.

One of the more telling data graphics in the report visually depicts how, in the initial stages of Alzheimer’s, the vascular component separates from the other components. Amyloid beta, metabolism and functional dysregulation stay close, and there is significant overlap among their confidence intervals until the more advanced disease stages.

“Our results suggest that vascular dysregulation is an early pathological event during disease development, followed in biomarker changing levels by amyloid beta deposition, metabolic dysfunction, functional impairment and structural atrophy,” the authors write in their discussion. “Although our multifactorial data-driven analysis does not reveal causal pathologic interactions, concordant evidence suggests that in late-onset Alzheimer’s disease amyloid-beta deposition is mainly caused by a deficiency in the amyloid beta clearance system rather than by an amyloid beta overproduction, whereas amyloid beta clearance is associated with the vascular system’s integrity.”

The authors note that, along with producing a key Alzheimer’s finding, their study develops understanding around the use of big data to integrate multi-modal data sets. In this case, for example, the researchers bridged the neuroimaging and molecular medicine fields to consequential effect.

Given its cross-field advances, the study is likely to have a ripple effect on research into aging and neurodegenerative disorders.

McGill University has published a news article on the research, and Nature Communications has posted the study in its entirety.