Early β-amyloid accumulation and hypoconnectivity in the default mode network are related to its disengagement from global brain activity

Abstract

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSImportanceC_ST_ABSThe specific pattern/trajectory of {beta}-amyloid (A{beta}) pathology spreading in Alzheimers disease (AD), from default mode network (DMN) regions to sensory-motor areas, is well known, but poorly understood. ObjectiveTo determine if resting-state global brain activity is linked to early A{beta} deposition in the DMN. DesignThis is a retrospect analysis of multi-modal and longitudinal data from the Alzheimers disease Neuroimaging Initiative (ADNI) cohort. SettingThe ADNI was a multicenter project involving 63 research centers. ParticipantsThe study included 144 participants (72.6 {+/-} 7.5 years; 73 females) of whom 28 were controls, 21 had significant memory concerns, 72 had cognitive impairment (N=72), and 23 had AD. There were both baseline and 2-year follow-up data for A{beta}-PET for 112 of the subjects. They were classified into following stages based on the CSF A{beta}42 (CSF+: 0.872 SUVR) levels: non-A{beta}-accumulators (CSF-/PET-); early-A{beta}-accumulators (CSF+/PET-); and late-A{beta}-accumulators (CSF+/PET+). ExposureResting-state brain activity was assessed by functional magnetic resonance imaging (rsfMRI), whereas glymphatic function was estimated by the coupling between fMRI blood-oxygen-level-dependent (BOLD) signals and CSF movements. Main Outcomes and MeasuresCortical A{beta} accumulation measured by 18F-AV45 amyloid-positron emission tomography (PET), CSF A{beta}42, and total and phosphorylated tau protein levels in all participants. ResultsGlymphatic function assessed by fMRI was strongly ({rho} > 0.43, P < 0.042) associated with various markers of protein aggregation in early A{beta} accumulators in whom A{beta} just begins to accumulate cortically in the DMN. Among these early accumulators, the preferential A{beta} accumulation in the DMN regions in the subsequent two years was correlated with lower gBOLD signal ({rho} = 0.51, P = 0.027) and lower local glymphatic function ({rho} = 0.48, P = 0.041) in the same regions at baseline. Conclusions and RelevanceResting-state global brain activity and related glymphatic function are linked to A{beta} pathology, particularly its preferential deposition in the DMN at the earliest AD stages. This suggests potential novel early therapeutic directions that might provide disease modification. KO_SCPLOWEYC_SCPLOW PO_SCPLOWOINTSC_SCPLOWO_ST_ABSQuestionC_ST_ABSWhy does the {beta}-amyloid (A{beta}) plaque deposit preferentially in the default mode network (DMN) regions at early preclinical stages of Alzheimers disease? FindingsIn this analytic observational cohort study with 144 subjects, we found that the preferential reduction of global resting-state brain activity in the DMN, as well as its coupling with cerebrospinal fluid movement, was significantly correlated with the preferential A{beta} accumulation in these DMN regions among 19 subjects with early A{beta} accumulation. MeaningResting-state global brain activity plays a role in the early A{beta} accumulation in the DMN, presumably due to its involvement in glymphatic clearance.