It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra

Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a co...

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Autores principales:	Noritaka Wakasugi, Takashi Hanakawa
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Alzheimer’s disease Parkinson’s disease MRI functional connectivity fluid biomarkers PET Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/8bb76ca5d47640e3b2e0666fb81e2548
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spelling	oai:doaj.org-article:8bb76ca5d47640e3b2e0666fb81e25482021-11-18T07:22:40ZIt Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra1662-513710.3389/fnsys.2021.777706https://doaj.org/article/8bb76ca5d47640e3b2e0666fb81e25482021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnsys.2021.777706/fullhttps://doaj.org/toc/1662-5137Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a continuous spectrum with Parkinson’s disease, collectively termed Lewy body disease (LBD). LBD is characterized by intracellular Lewy bodies containing α-synuclein (α-syn). The core clinical features of AD and LBD spectra are distinct, but the two spectra share common cognitive and behavioral symptoms. The accumulation of pathological proteins, which acquire pathogenicity through conformational changes, has long been investigated on a protein-by-protein basis. However, recent evidence suggests that interactions among these molecules may be critical to pathogenesis. For example, Aβ/tau promotes α-syn pathology, and α-syn modulates p-tau pathology. Furthermore, clinical evidence suggests that these interactions may explain the overlapping pathology between AD and LBD in molecular imaging and post-mortem studies. Additionally, a recent hypothesis points to a common mechanism of prion-like progression of these pathological proteins, via neural circuits, in both AD and LBD. This suggests a need for understanding connectomics and their alterations in AD and LBD from both pathological and functional perspectives. In AD, reduced connectivity in the default mode network is considered a hallmark of the disease. In LBD, previous studies have emphasized abnormalities in the basal ganglia and sensorimotor networks; however, these account for movement disorders only. Knowledge about network abnormalities common to AD and LBD is scarce because few previous neuroimaging studies investigated AD and LBD as a comprehensive cohort. In this paper, we review research on the distribution and interactions of pathological proteins in the brain in AD and LBD, after briefly summarizing their clinical and neuropsychological manifestations. We also describe the brain functional and connectivity changes following abnormal protein accumulation in AD and LBD. Finally, we argue for the necessity of neuroimaging studies that examine AD and LBD cases as a continuous spectrum especially from the proteinopathy and neurocircuitopathy viewpoints. The findings from such a unified AD and Parkinson’s disease (PD) cohort study should provide a new comprehensive perspective and key data for guiding disease modification therapies targeting the pathological proteins in AD and LBD.Noritaka WakasugiTakashi HanakawaTakashi HanakawaFrontiers Media S.A.articleAlzheimer’s diseaseParkinson’s diseaseMRIfunctional connectivityfluid biomarkersPETNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Systems Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alzheimer’s disease Parkinson’s disease MRI functional connectivity fluid biomarkers PET Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Alzheimer’s disease Parkinson’s disease MRI functional connectivity fluid biomarkers PET Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Noritaka Wakasugi Takashi Hanakawa Takashi Hanakawa It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra
description	Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a continuous spectrum with Parkinson’s disease, collectively termed Lewy body disease (LBD). LBD is characterized by intracellular Lewy bodies containing α-synuclein (α-syn). The core clinical features of AD and LBD spectra are distinct, but the two spectra share common cognitive and behavioral symptoms. The accumulation of pathological proteins, which acquire pathogenicity through conformational changes, has long been investigated on a protein-by-protein basis. However, recent evidence suggests that interactions among these molecules may be critical to pathogenesis. For example, Aβ/tau promotes α-syn pathology, and α-syn modulates p-tau pathology. Furthermore, clinical evidence suggests that these interactions may explain the overlapping pathology between AD and LBD in molecular imaging and post-mortem studies. Additionally, a recent hypothesis points to a common mechanism of prion-like progression of these pathological proteins, via neural circuits, in both AD and LBD. This suggests a need for understanding connectomics and their alterations in AD and LBD from both pathological and functional perspectives. In AD, reduced connectivity in the default mode network is considered a hallmark of the disease. In LBD, previous studies have emphasized abnormalities in the basal ganglia and sensorimotor networks; however, these account for movement disorders only. Knowledge about network abnormalities common to AD and LBD is scarce because few previous neuroimaging studies investigated AD and LBD as a comprehensive cohort. In this paper, we review research on the distribution and interactions of pathological proteins in the brain in AD and LBD, after briefly summarizing their clinical and neuropsychological manifestations. We also describe the brain functional and connectivity changes following abnormal protein accumulation in AD and LBD. Finally, we argue for the necessity of neuroimaging studies that examine AD and LBD cases as a continuous spectrum especially from the proteinopathy and neurocircuitopathy viewpoints. The findings from such a unified AD and Parkinson’s disease (PD) cohort study should provide a new comprehensive perspective and key data for guiding disease modification therapies targeting the pathological proteins in AD and LBD.
format	article
author	Noritaka Wakasugi Takashi Hanakawa Takashi Hanakawa
author_facet	Noritaka Wakasugi Takashi Hanakawa Takashi Hanakawa
author_sort	Noritaka Wakasugi
title	It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra
title_short	It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra
title_full	It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra
title_fullStr	It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra
title_full_unstemmed	It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra
title_sort	it is time to study overlapping molecular and circuit pathophysiologies in alzheimer’s and lewy body disease spectra
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/8bb76ca5d47640e3b2e0666fb81e2548
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It Is Time to Study Overlapping Molecular and Circuit Pathophysiologies in Alzheimer’s and Lewy Body Disease Spectra

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