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Earliest accumulation of ?-amyloid occurs within the default-mode network and concurrently affects brain connectivity.

ABSTRACT: It is not known exactly where amyloid-? (A?) fibrils begin to accumulate in individuals with Alzheimer's disease (AD). Recently, we showed that abnormal levels of A?42 in cerebrospinal fluid (CSF) can be detected before abnormal amyloid can be detected using PET in individuals with preclinical AD. Using these approaches, here we identify the earliest preclinical AD stage in subjects from the ADNI and BioFINDER cohorts. We show that A? accumulation preferentially starts in the precuneus, medial orbitofrontal, and posterior cingulate cortices, i.e., several of the core regions of the default mode network (DMN). This early pattern of A? accumulation is already evident in individuals with normal A?42 in the CSF and normal amyloid PET who subsequently convert to having abnormal CSF A?42. The earliest A? accumulation is further associated with hypoconnectivity within the DMN and between the DMN and the frontoparietal network, but not with brain atrophy or glucose hypometabolism. Our results suggest that A? fibrils start to accumulate predominantly within certain parts of the DMN in preclinical AD and already then affect brain connectivity.

SUBMITTER: Palmqvist S

PROVIDER: S-EPMC5663717 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity.

Palmqvist Sebastian S Schöll Michael M Strandberg Olof O Mattsson Niklas N Stomrud Erik E Zetterberg Henrik H Blennow Kaj K Landau Susan S Jagust William W Hansson Oskar O

Nature communications 20171031 1

It is not known exactly where amyloid-β (Aβ) fibrils begin to accumulate in individuals with Alzheimer's disease (AD). Recently, we showed that abnormal levels of Aβ42 in cerebrospinal fluid (CSF) can be detected before abnormal amyloid can be detected using PET in individuals with preclinical AD. Using these approaches, here we identify the earliest preclinical AD stage in subjects from the ADNI and BioFINDER cohorts. We show that Aβ accumulation preferentially starts in the precuneus, medial o ...[more]

PMID: 29089479

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Project description:Women are more likely to have Alzheimer's disease (AD) and decline more rapidly once diagnosed despite greater verbal memory early in the disease compared to men-an advantage that has been termed "memory reserve." Resting state functional MRI (fMRI) investigations demonstrate interactions between sex and AD risk factors in default mode network (DMN) connectivity, a network of brain regions showing progressive dysfunction in AD. Separate work suggests connectivity of left prefrontal cortex (PFC) may correlate with more general cognitive reserve in healthy aging. It is unknown whether left prefrontal functional connectivity with anterior and posterior default mode network (aDMN, pDMN) might differ by sex in AD. This study employed group independent component analysis (ICA) to analyze resting state fMRI data from 158 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with baseline diagnoses of normal cognition or early mild cognitive impairment (eMCI). pDMN and aDMN were defined on a subject-specific basis; prefrontal areas were selected from the Brodmann atlas (BA 6, 44, 8, and 9). Moderation regression analyses examined whether sex and amyloid PET positivity (A+/-) moderated effects of apolipoprotein ε4 (APOE ε4) on connectivity between left PFC, aDMN, and pDMN; and between aDMN and pDMN. Significant analyses were followed up with partial correlations assessing relationship of connectivity to verbal memory on the Rey Auditory Verbal Learning Test (RAVLT), and with preliminary analyses within NC and eMCI groups separately. Results showed no sex moderation of effects of A+ and APOE ε4 on left prefrontal/DMN connectivity in the full sample. However, sex significantly moderated impact of A+ and APOE ε4 on connectivity between aDMN and pDMN (p < 0.01). Women with an APOE allele (ε4+) and A+ showed greater aDMN/pDMN connectivity than their ε4- counterparts. No significant results were observed in men. Subgroup analyses suggested the aDMN/pDMN finding was true for those with NC, not eMCI. Partial correlations controlling for age and education showed increased aDMN/pDMN connectivity related to better verbal learning in women (p < 0.01) and not men (p = 0.18). In women at risk for AD or in early symptomatic stages who also have evidence of amyloid burden, stronger aDMN/pDMN connectivity may support verbal learning.

Project description:IntroductionAspects of the built environment relate to health factors and equity in living conditions, and may contribute to racial, ethnic, or economic health disparities. For example, urbanicity is linked with negative factors including exposure to gray space (e.g., impervious surfaces such as concrete, streets, or rooftops). While there is existing research on access to green space and urbanicity on some mental health and cognitive outcomes, there is limited research on the presence of gray space linked with cognitive functioning in youth. The goal of this study was to investigate the link between gray space and amygdala-default mode network (DMN) connectivity.MethodsThis study used data from the ABCD Study. Participants (n = 10,144; age M = 119.11 months, female = 47.62%) underwent resting-state fMRI acquisition at baseline. Impervious surfaces (gray space) were measured via the Child Opportunity Index (COI). To examine the relationship between presence of gray space and -amygdala-DMN (left/right) connectivity, we employed linear mixed effects models. Correlations were run between amygdala-DMN connectivity and internalizing and externalizing symptoms. Finally, post hoc sensitivity analyses were run to assess the impact of race.ResultsMore gray space, adjusting for age, sex, and neighborhood-level variables, was significantly associated with increased left amygdala-DMN connectivity (p = 0.0001). This association remained significant after sensitivity analyses for race were completed (p = 0.01). No significant correlations were observed between amygdala-DMN and internalizing or externalizing symptoms.DiscussionFindings suggest gray space was linked with increased left amygdala-DMN connectivity, circuits that have been implicated in affective processing, emotion regulation, and psychopathology. Thus gray space may be related to alterations in connectivity that may enhance risk for emotion dysregulation. Future investigation of these relationships is needed, as neuroimaging findings may represent early dysregulation not yet observed in the behavioral analyses at this age (i.e., the present study did not find significant relationships with parent-reported behavioral outcomes). These findings can help to inform future public policy on improving lived and built environments.

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Earliest accumulation of ?-amyloid occurs within the default-mode network and concurrently affects brain connectivity.

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Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity.

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