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Medial Temporal Lobe Disconnection and Hyperexcitability Across Alzheimer's Disease Stages
Lorenzo Pasquini1, Farzaneh Rahmani2, Somayeh Maleki-Balajoo3,4
1Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
Abstract:
The posteromedial cortex (PMC) and medial temporal lobes (MTL) are two brain regions particularly vulnerable in Alzheimer's disease (AD). We have reviewed the spatiotemporal patterns of amyloid-β and tau accumulation, local MTL functional alterations and MTL-PMC network reconfiguration, and propose a model to relate these elements to each other. Functional and structural MTL-PMC disconnection happen concomitant with amyloid-β plaques and neurofibrillary tau accumulation within these same regions. Ongoing disconnection is accompanied by dysfunctional intrinsic local MTL circuit hyperexcitability, which exacerbates across distinct clinical stages of AD. Our overarching model proposes a sequence of events relating the spatiotemporal patterns of amyloid-β and tau accumulation to MTL-PMC disconnection and local MTL hyperexcitability. We hypothesize that cortical PMC amyloid-β pathology induces long-range information processing deficits through functional and structural MTL-PMC dysconnectivity at early disease stages, which in turn drives local MTL circuit hyperexcitability. Intrinsic local MTL circuit hyperexcitability subsequently accelerates local age-related tau deposition, facilitating tau spread from the MTL to the PMC, eventually resulting in extensive structural degeneration of white and grey matter as the disease advances. We hope that the present model may inform future longitudinal studies needed to test the proposed sequence of events.
Insights
Alzheimer's disease (AD) involves brain changes in the posteromedial cortex (PMC) and medial temporal lobes (MTL). Our model links amyloid-β and tau buildup to network disconnection and hyperexcitability, explaining AD progression.
Area of Science:
- Neuroscience
- Neuropathology
- Alzheimer's Disease Research
Background:
- Posteromedial cortex (PMC) and medial temporal lobes (MTL) are vulnerable brain regions in Alzheimer's disease (AD).
- Spatiotemporal patterns of amyloid-β and tau accumulation, functional alterations, and network changes are key pathological features in AD.
Purpose of the Study:
- To propose a model explaining the relationship between amyloid-β and tau pathology, network disconnection, and local hyperexcitability in AD.
- To elucidate the sequence of events linking molecular pathology to network dysfunction and neurodegeneration in AD.
Main Methods:
- Review of spatiotemporal patterns of amyloid-β and tau accumulation.
- Analysis of functional alterations in MTL circuits.
- Examination of MTL-PMC network reconfiguration.
Main Results:
- Functional and structural disconnection between MTL and PMC occurs with amyloid-β and tau accumulation.
- Local MTL circuit hyperexcitability exacerbates with disease progression.
- Amyloid-β pathology in PMC may initiate long-range deficits, driving MTL hyperexcitability and subsequent tau spread.
Conclusions:
- A proposed model links amyloid-β/tau accumulation to MTL-PMC disconnection and hyperexcitability.
- MTL hyperexcitability may accelerate tau deposition and spread, leading to advanced neurodegeneration.
- The model provides a framework for future longitudinal studies to validate the proposed sequence of AD pathology.