Relationships between Beta-Amyloid and Functional Connectivity in Different Components of the Default Mode Network in Aging

Abstract

Although beta-amyloid (Aβ) deposition is a characteristic feature of Alzheimer's disease (AD), this pathology is commonly found in elderly normal controls (NC). The pattern of Aβ deposition as detected with Pittsburgh compound-B positron emission tomography (PIB-PET) imaging shows substantial spatial overlap with the default mode network (DMN), a group of brain regions that typically deactivates during externally driven cognitive tasks. In this study, we show that DMN functional connectivity (FC) during rest is altered with increasing levels of PIB uptake in NC. Specifically, FC decreases were identified in regions implicated in episodic memory (EM) processing (posteromedial cortex, ventral medial prefrontal cortex, and angular gyrus), whereas connectivity increases were detected in dorsal and anterior medial prefrontal and lateral temporal cortices. This pattern of decreases is consistent with previous studies that suggest heightened vulnerability of EM-related brain regions in AD, whereas the observed increases in FC may reflect a compensatory response.

Impaired default network functional connectivity in autosomal dominant Alzheimer disease

“…In this context, the high penetrance of ADAD mutations allows us to more confidently model changes in connectivity across the entire disease spectrum in a manner that is considerably more difficult in nonlongitudinal studies of LOAD, given the uncertainty surrounding when and if sporadic subjects with MCI will develop AD. The early decreases in DMN fcMRI in ADAD generally accord well with prior fcMRI studies in LOAD, 2,4 in asymptomatic older individuals with biomarker evidence of Ab deposition, 19,20,36 and in asymptomatic APOE e4 carriers. 15,16,18 Additionally, the presence of observable changes in DMN fcMRI before symptom onset fits well with recent evidence that young, asymptomatic ADAD mutation carriers show changes in memory-task fMRI years before their estimated age of symptom onset.…”

“…2,4 Similar changes are also seen in prodromal and preclinical AD, as evidenced by decreased DMN fcMRI in subjects with mild cognitive impairment (MCI) who progress to AD, 11 asymptomatic APOE e4 carriers, [15][16][17] and Ab biomarker-positive older individuals. [18][19][20] Together, these findings have prompted the development of DMN connectivity as a noninvasive biomarker for detection of early synaptic dysfunction in AD and for tracking potential therapeutic response in clinical trials. Despite being well studied in the symptomatic stages of LOAD, 2,4 alterations in DMN fcMRI have been largely unstudied in cases of familial autosomal dominant AD (ADAD).…”

Measuring Cortical Connectivity in Alzheimer’s Disease as a Brain Neural Network Pathology: Toward Clinical Applications

“…(Mormino et al, 2011) rsfMRI, Amyloid-PET With increasing levels of global PIB uptake in healthy controls, functional connectivity decreases were identified in regions implicated in episodic memory processing while connectivity increases were detected in dorsal and anterior medial prefrontal and lateral temporal cortices.…”

Functional connectivity with the retrosplenial cortex predicts cognitive aging in rats

“…The underlying mechanisms of disconnection are unclear but may be linked to amyloid deposition, which preferentially targets DMN hubs in AD patients (17,18). This pattern is not specific to AD, however, as a substantial proportion of cognitively normal older individuals also exhibit reduced FC in the DMN in association with amyloid burden in these same cortical hubs (19)(20)(21)(22). A significant additional challenge is that, because the preclinical course of AD is protracted and likely extends over more than a decade (23), it is unknown what proportion of clinically normal individuals with significant amyloid burden is already on the pathophysiological trajectory of disease.…”