Latent patterns of task-related functional connectivity in relation to regions of hyperactivation in individuals at risk of Alzheimer’s disease

Corriveau‐Lecavalier, Nick; Rajah, M. Natasha; Mellah, Samira; Belleville, Sylvie

doi:10.1016/j.nicl.2021.102643

Cited by 8 publications

(9 citation statements)

References 78 publications

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“…Previous studies have shown hyperconnectivity in AD networks is associated with hyperactivity[9, 12, 22, 73]. To confirm if this is the case in hAPP mice, we compared functional connectivity, or correlated c-Fos + cell densities between brain regions, both within the visual network and across the brain.…”

Section: Resultsmentioning

confidence: 94%

Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease

L’Esperance

McGhee

Davidson

et al. 2023

Preprint

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Hyperactivity is observed in early Alzheimers disease (AD) in multiple brain regions, including the visual cortex. We recently found that the postsynaptic structures favor visual cortex hyperactivity, which disrupts functional connectivity and leads to visual recognition memory deficits in a mouse AD model. It is unclear whether presynaptic structures also favor hyperactivity and whether hyperactivity depends on the target or source of presynaptic terminals. In addition, it is not well understood whether the functional connectivity of brain regions under nonpathological conditions predicts their hyperactivity in amyloid pathology. We used c-Fos immunolabeling under resting state conditions to map brain-wide neural activity and performed network analysis. We also quantified excitatory and inhibitory presynaptic terminals in hyperactive and non-hyperactive brain regions.We found that hyperactivity in the visual network originates in the cortex, and brain regions highly connected to the primary visual cortex in nonpathological conditions tend to be hyperactive in amyloid pathology. Immunolabeling presynaptic terminals from subcortical and cortical neurons show that the source rather than the target brain regions determine the vulnerability of synapses. Furthermore, we observed a reduction in presynaptic structures selectively in the hyperactive region, indicating presynaptic changes are unfavorable to hyperactivity. Brain regions with higher functional connectivity under nonpathological conditions are vulnerable to hyperactivity in amyloid pathology. Furthermore, presynapse loss may serve as an adaptation to maintain neuronal activity homeostasis.

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Section: Resultsmentioning

confidence: 94%

Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease

L’Esperance

McGhee

Davidson

et al. 2023

Preprint

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“…For instance, well-established cognitive models suggest that the capacity of “binding” separate elements into a compound episode (Li et al, 2005), which can also be understood through the lens of context, would be selectively degraded in PAD (Della Sala et al, 2012; Parra et al, 2010). Studies leveraging experimental tasks assessing associative memory learning, which requires associating target items to contextual features, found lower performance in individuals with PAD compared to healthy controls (Berron et al, 2020; Clément & Belleville, 2012; Corriveau-Lecavalier et al, 2020, 2021; Polcher et al, 2017). Interestingly, some of these studies used functional Magnetic Resonance Imaging and observed that low associative memory performance was accompanied by hyperactivation of hippocampal and temporal areas, a well-documented early biomarker of AD (Corriveau-Lecavalier et al, 2020, 2021; Selkoe, 2019; Zott, 2019; Zott et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Studies leveraging experimental tasks assessing associative memory learning, which requires associating target items to contextual features, found lower performance in individuals with PAD compared to healthy controls (Berron et al, 2020; Clément & Belleville, 2012; Corriveau-Lecavalier et al, 2020, 2021; Polcher et al, 2017). Interestingly, some of these studies used functional Magnetic Resonance Imaging and observed that low associative memory performance was accompanied by hyperactivation of hippocampal and temporal areas, a well-documented early biomarker of AD (Corriveau-Lecavalier et al, 2020, 2021; Selkoe, 2019; Zott, 2019; Zott et al, 2018). Thus, although the network architecture presented in this study was not explicitly designed to reproduce biological learning systems, it is nonetheless consistent with knowledge highlighting the importance of context for efficient learning.…”

Section: Discussionmentioning

confidence: 99%

Neural network process simulations support a distributed memory system and aid design of a novel computer adaptive digital memory test for preclinical and prodromal Alzheimer’s disease.

Stricker¹,

Corriveau‐Lecavalier²,

Wiepert³

et al. 2023

Neuropsychology

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Objective: Growing evidence supports the importance of learning as a central deficit in preclinical/prodromal Alzheimer’s disease. The aims of this study were to conduct a series of neural network simulations to develop a functional understanding of a distributed, nonmodular memory system that can learn efficiently without interference. This understanding is applied to the development of a novel digital memory test. Method: Simulations using traditional feed forward neural network architectures to learn simple logic problems are presented. The simulations demonstrate three limitations: (a) inefficiency, (b) an inability to learn problems consistently, and (c) catastrophic interference when given multiple problems. A new mirrored cascaded architecture is introduced to address these limitations, with support provided by a series of simulations. Results: The mirrored cascaded architecture demonstrates efficient and consistent learning relative to feed forward networks but also suffers from catastrophic interference. Addition of context values to add the capability of distinguishing features as part of learning eliminates the problem of interference in the mirrored cascaded, but not the feed forward, architectures. Conclusions: A mirrored cascaded architecture addresses the limitations of traditional feed forward neural networks, provides support for a distributed memory system, and emphasizes the importance of context to avoid interference. These process models contributed to the design of a digital computer-adaptive word list learning test that places maximum stress on the capability to distinguish specific episodes of learning. Process simulations provide a useful method of testing models of brain function and contribute to new approaches to neuropsychological assessment.

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“…It has been reported that during memory tasks, the activity of neurons in the medial temporal lobe or the hippocampus is greater in patients with early-stage mild cognitive impairment (MCI) than in healthy subjects, and that greater activation of neurons is associated with poorer performance ( Dickerson et al, 2004 ; Yassa et al, 2010 ; Corriveau-Lecavalier et al, 2021a ), indicating that such hyperactivation is detrimental to brain function. In fact, the drug levetiracetam ameliorates the lowered memory performance as well as hyperactive state in the hippocampus of MCI patients ( Bakker et al, 2012 , 2015 ).…”

Section: Excessive and Maladaptive Synaptic Plasticity With Agingmentioning

confidence: 99%

“…However, hippocampal hyperactivation during memory task is already detectable in healthy young APOE ε4 carriers who are unlikely to have Aβ deposition ( Filippini et al, 2009 ; Dennis et al, 2010 ). Besides, hyperactivation is task-dependent, implying that it is associated with altered patterns of functional connectivity ( Corriveau-Lecavalier et al, 2021a ). Although remodeling of the neuronal network compensates for loss of brain function which declines with aging, it has also become evident that plastic remodeling is sometimes detrimental.…”

Section: Excessive and Maladaptive Synaptic Plasticity With Agingmentioning

confidence: 99%

Excessive/Aberrant and Maladaptive Synaptic Plasticity: A Hypothesis for the Pathogenesis of Alzheimer’s Disease

Kawabata¹

2022

Front. Aging Neurosci.

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The amyloid hypothesis for the pathogenesis of Alzheimer’s disease (AD) is widely accepted. Last year, the US Food and Drug Administration considered amyloid-β peptide (Aβ) as a surrogate biomarker and approved an anti-Aβ antibody, aducanumab, although its effectiveness in slowing the progression of AD is still uncertain. This approval has caused a great deal of controversy. Opinions are divided about whether there is enough evidence to definitely consider Aβ as a causative substance of AD. To develop this discussion constructively and to discover the most suitable therapeutic interventions in the end, an alternative persuasive hypothesis needs to emerge to better explain the facts. In this paper, I propose a hypothesis that excessive/aberrant and maladaptive synaptic plasticity is the pathophysiological basis for AD.

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Latent patterns of task-related functional connectivity in relation to regions of hyperactivation in individuals at risk of Alzheimer’s disease

Abstract: Highlights Hyperactivation relates to memory-related network dysfunction in SCD + and MCI. Hippocampal hyperactivation and connectivity relate to worst memory performance. In contrast, neocortical hyperactivation and connectivity may reflect compensation.

Cited by 8 publications

References 78 publications

Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease

Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease

Neural network process simulations support a distributed memory system and aid design of a novel computer adaptive digital memory test for preclinical and prodromal Alzheimer’s disease.

Excessive/Aberrant and Maladaptive Synaptic Plasticity: A Hypothesis for the Pathogenesis of Alzheimer’s Disease

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