Spatially resolved neural slowing predicts impairment and amyloid burden in Alzheimer’s disease

Abstract

Abstract An extensive electrophysiological literature has proposed a pathological “slowing” of neuronal activity in patients on the Alzheimer’s disease (AD) spectrum. Supported by numerous studies reporting increases in low frequency and decreases in high frequency neural oscillations, this pattern has been suggested as a stable biomarker with potential clinical utility. However, no spatially-resolved metric of such slowing exists, stymieing efforts to understand its relation to proteinopathy and clinical outcomes. Further, the assumption that this slowing is occurring in spatially overlapping populations of neurons has not been empirically validated. In the current study, we collected cross-sectional resting state measures of neuronal activity using magnetoencephalography (MEG) from 38 biomarker-confirmed patients on the AD spectrum and 20 cognitively-normal (CN) biomarker-negative older adults. From these data, we compute and validate a new metric of spatially resolved oscillatory deviations from healthy aging for each patient on the AD spectrum. Using this Pathological Oscillatory Slowing Index (POSI), we show that patients on the AD spectrum exhibit robust neuronal slowing across a network of temporal, parietal, cerebellar, and prefrontal cortices. This slowing effect is shown to be directly relevant to clinical outcomes, as oscillatory slowing in temporal and parietal cortices significantly predicted both general (i.e. MoCA scores) and domain-specific (i.e. attention, language, and processing speed) cognitive function. Further, regional amyloid-beta (Aβ) accumulation, as measured by quantitative 18F florbetapir PET, robustly predicted the strength of this pathological neural slowing effect, and the strength of this relationship between Aβ burden and neural slowing also predicted attentional impairments across patients. These findings provide empirical support for a spatially overlapping effect of oscillatory neural slowing in biomarker-confirmed patients on the AD spectrum, and link this effect to both regional proteinopathy and cognitive outcomes in a spatially resolved manner. The POSI also represents a novel metric that is of potentially high utility across a number of clinical neuroimaging applications, as oscillatory slowing has also been extensively documented in other patient populations, most notably Parkinson’s disease, with divergent spectral and spatial features.