Frequency of Comorbid Pathologies and Their Clinical Impact in Multiple System Atrophy.
clinicopathological
comorbid pathology
correlation
multiple system atrophy
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
20 Nov 2023
20 Nov 2023
Historique:
revised:
12
10
2023
received:
22
06
2023
accepted:
08
11
2023
medline:
21
11
2023
pubmed:
21
11
2023
entrez:
21
11
2023
Statut:
aheadofprint
Résumé
Mixed pathology is common at autopsy for a number of age-associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood. We determined the frequency of comorbid pathologic processes in autopsy-confirmed MSA and assessed their clinical correlates. This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank. Clinical information, including age at onset or death, clinical subtype, initial symptoms, antemortem clinical diagnosis, and cognitive dysfunction was collected. We assessed comorbid pathologies including Alzheimer's disease neuropathologic change, Lewy-related pathology, argyrophilic grain disease, age-related τ astrogliopathy, transactive DNA-binding protein 43 pathology, cerebral amyloid angiopathy, and cerebrovascular small vessel disease and examined their clinical impact. The majority of MSA patients (62%) had no significant comorbid pathologies. There was a positive correlation between age at onset or death with the number of comorbid pathologies; however, even in the highest quartile group (average age at death 78 ± 6 years), the average number of comorbid pathologies was <2. Logistic regression analysis revealed that none of the assessed variables, including sex, age at onset, and the presence or absence of each comorbid pathology, were significantly associated with cognitive dysfunction. The majority of MSA patients do not have comorbid pathologies, even in advanced age, indicating that MSA is unique among neurodegenerative disorders in this regard. There was minimal clinical impact of comorbid pathologies in MSA. These findings warrant focusing on α-synuclein for the treatment strategy for MSA. © 2023 International Parkinson and Movement Disorder Society.
Sections du résumé
BACKGROUND
BACKGROUND
Mixed pathology is common at autopsy for a number of age-associated neurodegenerative disorders; however, the frequency of comorbid pathologies in multiple system atrophy (MSA) and their clinical correlations are poorly understood.
OBJECTIVE
OBJECTIVE
We determined the frequency of comorbid pathologic processes in autopsy-confirmed MSA and assessed their clinical correlates.
METHODS
METHODS
This study included 160 neuropathologically established MSA from the Mayo Clinic brain bank. Clinical information, including age at onset or death, clinical subtype, initial symptoms, antemortem clinical diagnosis, and cognitive dysfunction was collected. We assessed comorbid pathologies including Alzheimer's disease neuropathologic change, Lewy-related pathology, argyrophilic grain disease, age-related τ astrogliopathy, transactive DNA-binding protein 43 pathology, cerebral amyloid angiopathy, and cerebrovascular small vessel disease and examined their clinical impact.
RESULTS
RESULTS
The majority of MSA patients (62%) had no significant comorbid pathologies. There was a positive correlation between age at onset or death with the number of comorbid pathologies; however, even in the highest quartile group (average age at death 78 ± 6 years), the average number of comorbid pathologies was <2. Logistic regression analysis revealed that none of the assessed variables, including sex, age at onset, and the presence or absence of each comorbid pathology, were significantly associated with cognitive dysfunction.
CONCLUSIONS
CONCLUSIONS
The majority of MSA patients do not have comorbid pathologies, even in advanced age, indicating that MSA is unique among neurodegenerative disorders in this regard. There was minimal clinical impact of comorbid pathologies in MSA. These findings warrant focusing on α-synuclein for the treatment strategy for MSA. © 2023 International Parkinson and Movement Disorder Society.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : American Parkinson Disease Association
ID : N/A
Organisme : CurePSP
Organisme : Japanese Society of Neurology
Organisme : Mayo Clinic Alzheimer's Disease Research Center
Organisme : Multiple System Atrophy Coalition
Organisme : State of Florida Ed and Ethel Moore Alzheimer's Disease Research Program
Organisme : The Cell Science Research Foundation
Organisme : Uehara Memorial Foundation
Informations de copyright
© 2023 International Parkinson and Movement Disorder Society.
Références
Fanciulli A, Wenning GK. Multiple-system atrophy. N Engl J Med 2015;372(3):249-263.
Wenning GK, Stankovic I, Vignatelli L, et al. The Movement Disorder Society criteria for the diagnosis of multiple system atrophy. Mov Disord 2022;37(6):1131-1148.
Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and shy-Drager syndrome). J Neurol Sci 1989;94(1-3):79-100.
Nishie M, Mori F, Fujiwara H, et al. Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy. Acta Neuropathol 2004;107(4):292-298.
Cykowski MD, Coon EA, Powell SZ, et al. Expanding the spectrum of neuronal pathology in multiple system atrophy. Brain 2015;138(Pt 8):2293-2309.
Sekiya H, Kowa H, Koga H, et al. Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation. Acta Neuropathol 2019;137(3):455-466.
Dickson DW, Lin W, Liu WK, Yen SH. Multiple system atrophy: a sporadic synucleinopathy. Brain Pathol 1999;9(4):721-732.
Koga S, Sekiya H, Kondru N, Ross OA, Dickson DW. Neuropathology and molecular diagnosis of Synucleinopathies. Mol Neurodegener 2021;16(1):83.
Soto C, Pritzkow S. Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases. Nat Neurosci 2018;21(10):1332-1340.
Kovacs GG. Molecular pathology of neurodegenerative diseases: principles and practice. J Clin Pathol 2019;72(11):725-735.
Sweeney MD, Kisler K, Montagne A, Toga AW, Zlokovic BV. The role of brain vasculature in neurodegenerative disorders. Nat Neurosci 2018;21(10):1318-1331.
Irwin DJ, Grossman M, Weintraub D, et al. Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. Lancet Neurol 2017;16(1):55-65.
Spires-Jones TL, Attems J, Thal DR. Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol 2017;134(2):187-205.
Robinson JL, Lee EB, Xie SX, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain 2018;141(7):2181-2193.
DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer's disease. Mol Neurodegener 2019;14(1):32.
Jecmenica Lukic M, Kurz C, Respondek G, et al. Copathology in progressive supranuclear palsy: does it matter? Mov Disord 2020;35(6):984-993.
Takanashi M, Ohta S, Matsuoka S, Mori H, Mizuno Y. Mixed multiple system atrophy and progressive supranuclear palsy: a clinical and pathological report of one case. Acta Neuropathol 2002;103(1):82-87.
Uchikado H, DelleDonne A, Uitti R, Dickson DW. Coexistence of PSP and MSA: a case report and review of the literature. Acta Neuropathol 2006;111(2):186-192.
Silveira-Moriyama L, González AM, O'Sullivan SS, et al. Concomitant progressive supranuclear palsy and multiple system atrophy: more than a simple twist of fate? Neurosci Lett 2009;467(3):208-211.
Dugger BN, Adler CH, Shill HA, et al. Concomitant pathologies among a spectrum of parkinsonian disorders. Parkinsonism Relat Disord 2014;20(5):525-529.
Koga S, Lin WL, Walton RL, Ross OA, Dickson DW. TDP-43 pathology in multiple system atrophy: colocalization of TDP-43 and α-synuclein in glial cytoplasmic inclusions. Neuropathol Appl Neurobiol 2018;44(7):707-721.
Koga S, Li F, Zhao N, et al. Clinicopathologic and genetic features of multiple system atrophy with Lewy body disease. Brain Pathol 2020;30(4):766-778.
Koga S, Dickson DW, Bieniek KF. Chronic traumatic encephalopathy pathology in multiple system atrophy. J Neuropathol Exp Neurol 2016;75(10):963-970.
Sekiya H, Koga S, Otsuka Y, et al. Clinical and pathological characteristics of later onset multiple system atrophy. J Neurol 2022;269(8):4310-4321.
Koga S, Parks A, Uitti RJ, et al. Profile of cognitive impairment and underlying pathology in multiple system atrophy. Mov Disord 2017;32(3):405-413.
Trojanowski JQ, Revesz T. Proposed neuropathological criteria for the post mortem diagnosis of multiple system atrophy. Neuropathol Appl Neurobiol 2007;33(6):615-620.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82(4):239-259.
Thal DR, Rüb U, Orantes M, Braak H. Phases of a beta-deposition in the human brain and its relevance for the development of AD. Neurology 2002;58(12):1791-1800.
Tunold JA, Tan MMX, Koga S, et al. Lysosomal polygenic risk is associated with the severity of neuropathology in Lewy body disease. Brain 2023;146(10):4077-4087.
Montine TJ, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach. Acta Neuropathol 2012;123(1):1-11.
Togo T, Sahara N, Yen SH, et al. Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol 2002;61(6):547-556.
Kovacs GG, Ferrer I, Grinberg LT, et al. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 2016;131(1):87-102.
Kosaka K. Lewy body disease and dementia with Lewy bodies. Proc Jpn Acad Ser B Phys Biol Sci 2014;90(8):301-306.
McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. Neurology 2017;89(1):88-100.
Dickson DW. Parkinson's Disease and Parkinsonism: Neuropathology. Cold Spring Harb Perspect Med 2012;2(8):a009258.
Meneses A, Koga S, O'Leary J, Dickson DW, Bu G, Zhao N. TDP-43 pathology in Alzheimer's disease. Mol Neurodegener 2021;16(1):84.
Team RC. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2022.
Robinson JL, Xie SX, Baer DR, et al. Pathological combinations in neurodegenerative disease are heterogeneous and disease-associated. Brain 2023;146(6):2557-2569.
Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 2003;60(10):1586-1590.
Jellinger KA. Neuropathological findings in multiple system atrophy with cognitive impairment. J Neural Transm (Vienna) 2020;127(7):1031-1039.
Asi YT, Ling H, Ahmed Z, Lees AJ, Revesz T, Holton JL. Neuropathological features of multiple system atrophy with cognitive impairment. Mov Disord 2014;29(7):884-888.
Miki Y, Foti SC, Hansen D, et al. Hippocampal α-synuclein pathology correlates with memory impairment in multiple system atrophy. Brain 2020;143(6):1798-1810.
Bucciantini M, Giannoni E, Chiti F, et al. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature 2002;416(6880):507-511.
Winner B, Jappelli R, Maji SK, et al. In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci U S A 2011;108(10):4194-4199.
Cremades N, Cohen SI, Deas E, et al. Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell 2012;149(5):1048-1059.
Bengoa-Vergniory N, Roberts RF, Wade-Martins R, Alegre-Abarrategui J. Alpha-synuclein oligomers: a new hope. Acta Neuropathol 2017;134(6):819-838.
Sekiya H, Tsuji A, Hashimoto Y, et al. Discrepancy between distribution of alpha-synuclein oligomers and Lewy-related pathology in Parkinson's disease. Acta Neuropathol Commun 2022;10(1):133.
Miki Y, Tanji K, Shinnai K, et al. Pathological substrate of memory impairment in multiple system atrophy. Neuropathol Appl Neurobiol 2022;48(7):e12844.