In Vivo Tau, Amyloid, and Gray Matter Profiles in the Aging Brain

Sepulcre, Jorge; Schultz, Aaron P.; Sabuncu, Mert R.; Gómez-Isla, Teresa; Chhatwal, Jasmeer P.; Becker, Alex; Sperling, Reisa A.; Johnson, Keith A.

doi:10.1523/jneurosci.0639-16.2016

“…This was in contrast to the pattern observed for NFQ, which had a relatively greater association with tau in the precuneus compared to the medial and lateral temporal regions in a pattern recapitulating IC-4 (Figure 7C). These results are in line with a recent regional analysis of tau, amyloid, and gray matter (Sepulcre et al, 2016). …”

Section: Resultssupporting

confidence: 92%

Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum

Jones

¹

,

Graff‐Radford

²

,

Lowe

³

et al. 2017

Cortex

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Functionally related brain regions are selectively vulnerable to Alzheimer’s disease pathophysiology. However, molecular markers of this pathophysiology (i.e., beta-amyloid and tau aggregates) have discrepant spatial and temporal patterns of progression within these selectively vulnerable brain regions. Existing reductionist pathophysiologic models cannot account for these large-scale spatiotemporal inconsistencies. Within the framework of the recently proposed cascading network failure model of Alzheimer’s disease, however, these large-scale patterns are to be expected. This model postulates the following: 1) a tau-associated, circumscribed network disruption occurs in brain regions specific to a given phenotype in clinically normal individuals; 2) this disruption can trigger phenotype independent, stereotypic, and amyloid-associated compensatory brain network changes indexed by changes in the default mode network; 3) amyloid deposition marks a saturation of functional compensation and portends an acceleration of the inciting phenotype specific, and tau-associated, network failure. With the advent of in vivo molecular imaging of tau pathology, combined with amyloid and functional network imaging, it is now possible to investigate the relationship between functional brain networks, tau, and amyloid across the disease spectrum within these selectively vulnerable brain regions. In a large cohort (n = 218) spanning the Alzheimer’s disease spectrum from young, amyloid negative, cognitively normal subjects to Alzheimer’s disease dementia, we found several distinct spatial patterns of tau deposition, including ‘Braak-like’ and ‘non-Braak-like’, across functionally related brain regions. Rather than arising focally and spreading sequentially, elevated tau signal seems to occur system-wide based on inferences made from multiple cross-sectional analyses we conducted looking at regional patterns of tau signal. Younger age-of-disease-onset was associated with ‘non-Braak-like’ patterns of tau, suggesting an association with atypical clinical phenotypes. As predicted by the cascading network failure model of Alzheimer’s disease, we found that amyloid is a partial mediator of the relationship between functional network failure and tau deposition in functionally connected brain regions. This study implicates large-scale brain networks in the pathophysiology of tau deposition and offers support to models incorporating large-scale network physiology into disease models linking tau and amyloid, such as the cascading network failure model of Alzheimer’s disease.

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“…Supporting this theoretical finding is the recent observation that tau and amyloid-b, despite their independent patterns of spatial deposition, overlap with brain tissue loss in hub regions of multimodal networks [58]. These multimodal networks are also metabolically expensive and display higher rates of cerebral blood flow, aerobic glycolysis, and oxidative A), the ratio of counts (or hits) across the subnetworks.…”

Section: Selective Vulnerability Of Multimodal Network In Admentioning

confidence: 85%

IC‐P‐033: Resting‐State Network Dysfunction in Alzheimer’s Disease: A Systematic Review and Meta‐Analysis

Badhwar

¹

,

Tam

²

,

Dansereau

³

et al. 2016

Alzheimer's & Dementia

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Introduction: We performed a systematic review and meta-analysis of the Alzheimer's disease (AD) literature to examine consistency of functional connectivity alterations in AD dementia and mild cognitive impairment, using resting-state functional magnetic resonance imaging. Methods: Studies were screened using a standardized procedure. Multiresolution statistics were performed to assess the spatial consistency of findings across studies. Results: Thirty-four studies were included (1363 participants, average 40 per study). Consistent alterations in connectivity were found in the default mode, salience, and limbic networks in patients with AD dementia, mild cognitive impairment, or in both groups. We also identified a strong tendency in the literature toward specific examination of the default mode network. Discussion: Convergent evidence across the literature supports the use of resting-state connectivity as a biomarker of AD. The locations of consistent alterations suggest that highly connected hub regions in the brain might be an early target of AD.

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“…Supporting this theoretical finding is the recent observation that tau and amyloid-b, despite their independent patterns of spatial deposition, overlap with brain tissue loss in hub regions of multimodal networks [58]. These multimodal networks are also metabolically expensive and display higher rates of cerebral blood flow, aerobic glycolysis, and oxidative glucose metabolism [59].…”

Section: Selective Vulnerability Of Multimodal Network In Admentioning

confidence: 92%

O3‐08‐02: Resting‐State Network Dysfunction in Alzheimer's Disease: A Systematic Review And Meta‐Analysis

Badhwar

¹

,

Tam

²

,

Dansereau

³

et al. 2016

Alzheimer's & Dementia

View full text Add to dashboard Cite

Introduction: We performed a systematic review and meta-analysis of the Alzheimer's disease (AD) literature to examine consistency of functional connectivity alterations in AD dementia and mild cognitive impairment, using resting-state functional magnetic resonance imaging. Methods: Studies were screened using a standardized procedure. Multiresolution statistics were performed to assess the spatial consistency of findings across studies. Results: Thirty-four studies were included (1363 participants, average 40 per study). Consistent alterations in connectivity were found in the default mode, salience, and limbic networks in patients with AD dementia, mild cognitive impairment, or in both groups. We also identified a strong tendency in the literature toward specific examination of the default mode network. Discussion: Convergent evidence across the literature supports the use of resting-state connectivity as a biomarker of AD. The locations of consistent alterations suggest that highly connected hub regions in the brain might be an early target of AD.

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In Vivo Tau, Amyloid, and Gray Matter Profiles in the Aging Brain

Cited by 165 publications

References 63 publications

Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum

Tau, amyloid, and cascading network failure across the Alzheimer's disease spectrum

IC‐P‐033: Resting‐State Network Dysfunction in Alzheimer’s Disease: A Systematic Review and Meta‐Analysis

O3‐08‐02: Resting‐State Network Dysfunction in Alzheimer's Disease: A Systematic Review And Meta‐Analysis

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