Neuropathology underlying clinical variability in patients with synucleinopathies

Glenda M. Halliday, Janice L. Holton, Tamas Revesz, Dennis W Dickson

Research output: Contribution to journalArticle

212 Citations (Scopus)

Abstract

Abnormal aggregates of the synaptic protein, α-synuclein, are the dominant pathology in syndromes known as the synucleinopathies. The cellular aggregation of the protein occurs in three distinct types of inclusions in three main clinical syndromes. α-Synuclein deposits in neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as incidentally in a number of other conditions. In contrast, α-synuclein deposits largely in oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA). Lastly, α-synuclein also deposits in large axonal spheroids in a number of rarer neuroaxonal dystrophies. Disorders are usually defined by their most dominant pathology, but for the synucleinopathies, clinical heterogeneity within the main syndromes is well documented. MSA was originally viewed as three different clinical phenotypes due to different anatomical localization of the lesions. In PD, recent meta-analyses have identified four main clinical phenotypes, and clinicopathological correlations suggest that more severe and more rapid progression of pathology with chronological age, as well as the involvement of additional neuropathologies, differentiates these phenotypes. In DLB, recent large studies show that clinical diagnosis is too insensitive to identify the syndrome itself, although clinicopathological studies suggest variable clinical features occur in the different pathological forms of this syndrome (pure DLB, DLB with Alzheimer's disease (AD), and AD with amygdala predominant Lewy pathology). The recognition of considerable heterogeneity within the synucleinopathy syndromes is important for the identification of factors involved in changing their pathological phenotype.

Original languageEnglish (US)
Pages (from-to)187-204
Number of pages18
JournalActa Neuropathologica
Volume122
Issue number2
DOIs
StatePublished - Aug 2011

Fingerprint

Synucleins
Lewy Body Disease
Multiple System Atrophy
Phenotype
Lewy Bodies
Pathology
Parkinson Disease
Alzheimer Disease
Neuroaxonal Dystrophies
Clinical Pathology
Inclusion Bodies
Neurites
Amygdala
Dementia
Meta-Analysis
Neuropathology
Proteins

Keywords

  • α-Synuclein
  • Alzheimer's disease
  • Dementia with Lewy bodies
  • Multiple system atrophy
  • Parkinson's disease

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Neuropathology underlying clinical variability in patients with synucleinopathies. / Halliday, Glenda M.; Holton, Janice L.; Revesz, Tamas; Dickson, Dennis W.

In: Acta Neuropathologica, Vol. 122, No. 2, 08.2011, p. 187-204.

Research output: Contribution to journalArticle

Halliday, Glenda M. ; Holton, Janice L. ; Revesz, Tamas ; Dickson, Dennis W. / Neuropathology underlying clinical variability in patients with synucleinopathies. In: Acta Neuropathologica. 2011 ; Vol. 122, No. 2. pp. 187-204.
@article{787e12dbcf6844f089c7c7b191e29feb,
title = "Neuropathology underlying clinical variability in patients with synucleinopathies",
abstract = "Abnormal aggregates of the synaptic protein, α-synuclein, are the dominant pathology in syndromes known as the synucleinopathies. The cellular aggregation of the protein occurs in three distinct types of inclusions in three main clinical syndromes. α-Synuclein deposits in neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as incidentally in a number of other conditions. In contrast, α-synuclein deposits largely in oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA). Lastly, α-synuclein also deposits in large axonal spheroids in a number of rarer neuroaxonal dystrophies. Disorders are usually defined by their most dominant pathology, but for the synucleinopathies, clinical heterogeneity within the main syndromes is well documented. MSA was originally viewed as three different clinical phenotypes due to different anatomical localization of the lesions. In PD, recent meta-analyses have identified four main clinical phenotypes, and clinicopathological correlations suggest that more severe and more rapid progression of pathology with chronological age, as well as the involvement of additional neuropathologies, differentiates these phenotypes. In DLB, recent large studies show that clinical diagnosis is too insensitive to identify the syndrome itself, although clinicopathological studies suggest variable clinical features occur in the different pathological forms of this syndrome (pure DLB, DLB with Alzheimer's disease (AD), and AD with amygdala predominant Lewy pathology). The recognition of considerable heterogeneity within the synucleinopathy syndromes is important for the identification of factors involved in changing their pathological phenotype.",
keywords = "α-Synuclein, Alzheimer's disease, Dementia with Lewy bodies, Multiple system atrophy, Parkinson's disease",
author = "Halliday, {Glenda M.} and Holton, {Janice L.} and Tamas Revesz and Dickson, {Dennis W}",
year = "2011",
month = "8",
doi = "10.1007/s00401-011-0852-9",
language = "English (US)",
volume = "122",
pages = "187--204",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "2",

}

TY - JOUR

T1 - Neuropathology underlying clinical variability in patients with synucleinopathies

AU - Halliday, Glenda M.

AU - Holton, Janice L.

AU - Revesz, Tamas

AU - Dickson, Dennis W

PY - 2011/8

Y1 - 2011/8

N2 - Abnormal aggregates of the synaptic protein, α-synuclein, are the dominant pathology in syndromes known as the synucleinopathies. The cellular aggregation of the protein occurs in three distinct types of inclusions in three main clinical syndromes. α-Synuclein deposits in neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as incidentally in a number of other conditions. In contrast, α-synuclein deposits largely in oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA). Lastly, α-synuclein also deposits in large axonal spheroids in a number of rarer neuroaxonal dystrophies. Disorders are usually defined by their most dominant pathology, but for the synucleinopathies, clinical heterogeneity within the main syndromes is well documented. MSA was originally viewed as three different clinical phenotypes due to different anatomical localization of the lesions. In PD, recent meta-analyses have identified four main clinical phenotypes, and clinicopathological correlations suggest that more severe and more rapid progression of pathology with chronological age, as well as the involvement of additional neuropathologies, differentiates these phenotypes. In DLB, recent large studies show that clinical diagnosis is too insensitive to identify the syndrome itself, although clinicopathological studies suggest variable clinical features occur in the different pathological forms of this syndrome (pure DLB, DLB with Alzheimer's disease (AD), and AD with amygdala predominant Lewy pathology). The recognition of considerable heterogeneity within the synucleinopathy syndromes is important for the identification of factors involved in changing their pathological phenotype.

AB - Abnormal aggregates of the synaptic protein, α-synuclein, are the dominant pathology in syndromes known as the synucleinopathies. The cellular aggregation of the protein occurs in three distinct types of inclusions in three main clinical syndromes. α-Synuclein deposits in neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as incidentally in a number of other conditions. In contrast, α-synuclein deposits largely in oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA). Lastly, α-synuclein also deposits in large axonal spheroids in a number of rarer neuroaxonal dystrophies. Disorders are usually defined by their most dominant pathology, but for the synucleinopathies, clinical heterogeneity within the main syndromes is well documented. MSA was originally viewed as three different clinical phenotypes due to different anatomical localization of the lesions. In PD, recent meta-analyses have identified four main clinical phenotypes, and clinicopathological correlations suggest that more severe and more rapid progression of pathology with chronological age, as well as the involvement of additional neuropathologies, differentiates these phenotypes. In DLB, recent large studies show that clinical diagnosis is too insensitive to identify the syndrome itself, although clinicopathological studies suggest variable clinical features occur in the different pathological forms of this syndrome (pure DLB, DLB with Alzheimer's disease (AD), and AD with amygdala predominant Lewy pathology). The recognition of considerable heterogeneity within the synucleinopathy syndromes is important for the identification of factors involved in changing their pathological phenotype.

KW - α-Synuclein

KW - Alzheimer's disease

KW - Dementia with Lewy bodies

KW - Multiple system atrophy

KW - Parkinson's disease

UR - http://www.scopus.com/inward/record.url?scp=79960842310&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960842310&partnerID=8YFLogxK

U2 - 10.1007/s00401-011-0852-9

DO - 10.1007/s00401-011-0852-9

M3 - Article

C2 - 21720849

AN - SCOPUS:79960842310

VL - 122

SP - 187

EP - 204

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 2

ER -