Cognitive impairment in multiple system atrophy: Changing concepts

Abstract Multiple system atrophy (MSA) is characterized by a variable combination of cerebellar ataxia, parkinsonism and pyramidal signs associated with autonomic failure. Classically, cognitive impairment was not considered a clinical feature of MSA and dementia was pointed out as an exclusion diagnostic criteria. Based on comprehensive neuropsychological assessment, cognitive impairment was found to be a frequent feature in MSA, and clinically-defined dementia is now reported in 14-16% of cases. This article reviews the current data on cognitive impairment in MSA along with its neuropsychological profile and pathophysiology.

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Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy

International Journal of Molecular Sciences ◽

10.3390/ijms21082775 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2775 ◽

Cited By ~ 2

Author(s):

Lisa Mészáros ◽

Alana Hoffmann ◽

Jeanette Wihan ◽

Jürgen Winkler

Keyword(s):

Multiple System Atrophy ◽

Cerebellar Ataxia ◽

Autonomic Failure ◽

Neuronal Loss ◽

Symptomatic Treatment ◽

Alpha Synuclein ◽

Rapid Progression ◽

Cytoplasmic Inclusions ◽

Atypical Parkinsonian Syndrome ◽

Disease Modifying

Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6–9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available. Consequently, distinct pharmacological targets have been explored and investigated in clinical studies based on MSA-related symptoms and pathomechanisms. Parkinsonism, cerebellar ataxia, and autonomic failure are the most important symptoms targeted by symptomatic treatments in current clinical trials. The most prominent pathological hallmark is oligodendroglial cytoplasmic inclusions containing alpha-synuclein, thus classifying MSA as synucleinopathy. Additionally, myelin and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting α-syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy.

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Mild cognitive impairment: cognitive screening or neuropsychological assessment?

Brazilian Journal of Psychiatry ◽

10.1590/s1516-44462008000400003 ◽

2008 ◽

Vol 30 (4) ◽

pp. 316-321 ◽

Cited By ~ 36

Author(s):

Breno Satler Diniz ◽

Paula Villela Nunes ◽

Monica S Yassuda ◽

Fernanda S Pereira ◽

Mariana K Flaks ◽

...

Keyword(s):

Cognitive Impairment ◽

Clinical Practice ◽

Mild Cognitive Impairment ◽

Neuropsychological Assessment ◽

Mental State ◽

Mini Mental State Examination ◽

Screening Tests ◽

Neuropsychological Profile ◽

State Examination ◽

Multiple Domain

OBJECTIVE: To describe the neuropsychological profile of mild cognitive impairment subtypes (amnestic, non-amnestic and multiple-domain) of a clinical sample. We further address the diagnostic properties of the Mini-Mental State Examination and the Cambridge Cognitive Examination for the identification of the different mild cognitive impairment subtypes in clinical practice. METHOD: Cross-sectional clinical and neuropsychological evaluation of 249 elderly patients attending a memory clinic at a university hospital in Sao Paulo, Brazil. RESULTS: The performance of patients with mild cognitive impairment was heterogeneous across the different subtests of the neuropsychological battery, with a trend towards an overall worse performance for amnestic (particularly multiple domain) mild cognitive impairment as compared to non-amnestic subtypes. Screening tests for dementia (Mini-Mental State Examination and Cambridge Cognitive Examination) adequately discriminated cases of mild Alzheimer's disease from controls, but they were not accurate to discriminate patients with mild cognitive impairment (all subtypes) from control subjects. CONCLUSIONS: The discrimination of mild cognitive impairment subtypes was possible only with the aid of a comprehensive neuropsychological assessment. It is necessary to develop new strategies for mild cognitive impairment screening in clinical practice.

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Progression of Nigrostriatal Denervation in Cerebellar Multiple System Atrophy: A Prospective Study

Neurology ◽

10.1212/wnl.0000000000013172 ◽

2021 ◽

pp. 10.1212/WNL.0000000000013172

Author(s):

Thomas Wirth ◽

Izzie Jacques NAMER ◽

Ben Monga ◽

Caroline BUND ◽

Andra Valentina Iosif ◽

...

Keyword(s):

Multiple System Atrophy ◽

Prospective Study ◽

Diagnostic Criteria ◽

Cerebellar Ataxia ◽

Late Onset ◽

Final Diagnosis ◽

Binding Ratio ◽

A Prospective Study ◽

Principal Criterion

Background and Objectives:Nigro-striatal dopaminergic denervation (NSDD) remains poorly characterized in cerebellar multiple system atrophy (MSA-C). We aimed to study NSDD progression in MSA-C and evaluate the capacity for [123I]-FP-CIT-SPECT and parkinsonism to differentiate MSA-C from idiopathic late-onset cerebellar ataxia (ILOCA).Material and methods:We included 85 patients successively referred for sporadic late-onset cerebellar ataxia (SLOCA). Every six months, SARA, UPDRS-III and SDFS scores were measured, and MSA-C diagnostic criteria were searched for. Striatal/occipital dopaminergic binding ratio was evaluated every year with [123I]-FP-CIT-scintigraphy.Results:After a mean follow-up of 33.8 months, 33 patients had probable MSA-C, 8 possible MSA-C and 44 ILOCA. SARA and UPDRS-III scores worsened faster in the probable MSA-C group (p<0.01) compared to the ILOCA group. Baseline striatal/occipital ratio was lower (2.3 vs 2.97; p<0.01) and more decreasing among probable MSA-C patients (p<0.01). Weighting dysautonomia and parkinsonism and/or NSDD as additional and principal criterion, respectively, in the possible MSA-C diagnostic criteria slightly improved their specificity (81.6% vs 76.9%) and sensitivity (77.8% vs 72.2%) to predict a final diagnosis of probable MSA-C.Conclusions:Rapid symptoms worsening and NSDD existence and progression predict MSA-C among SLOCA patients. Parkinsonism, NSDD and dysautonomia should be considered equivalent for possible MSA-C diagnosis.

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Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-315813 ◽

2017 ◽

Vol 89 (2) ◽

pp. 175-184 ◽

Cited By ~ 32

Author(s):

Shunsuke Koga ◽

Dennis W Dickson

Keyword(s):

Multiple System Atrophy ◽

Cerebellar Ataxia ◽

Neurodegenerative Disorder ◽

Cytoplasmic Inclusion ◽

Olivopontocerebellar Atrophy ◽

Cytoplasmic Inclusions ◽

Cellular Origin ◽

Recent Advances ◽

Neuronal Cytoplasmic Inclusions ◽

Variable Combination

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterised by a variable combination of autonomic failure, levodopa-unresponsive parkinsonism, cerebellar ataxia and pyramidal symptoms. The pathological hallmark is the oligodendrocytic glial cytoplasmic inclusion (GCI) consisting of α-synuclein; therefore, MSA is included in the category of α-synucleinopathies. MSA has been divided into two clinicopathological subtypes: MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia, which generally correlate with striatonigral degeneration and olivopontocerebellar atrophy, respectively. It is increasingly recognised, however, that clinical and pathological features of MSA are broader than previously considered.In this review, we aim to describe recent advances in neuropathology of MSA from a review of the literature and from information derived from review of nearly 200 definite MSA cases in the Mayo Clinic Brain Bank. In light of these new neuropathological findings, GCIs and neuronal cytoplasmic inclusions play an important role in clinicopathological correlates of MSA. We also focus on clinical diagnostic accuracy and differential diagnosis of MSA as well as candidate biomarkers. We also review some controversial topics in MSA. Cognitive impairment, which has been a non-supporting feature of MSA, is considered from both clinical and pathological perspectives. The cellular origin of α-synuclein in GCI and a ‘prion hypothesis’ are discussed. Finally, completed and ongoing clinical trials targeting disease modification, including immunotherapy, are summarised.

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A Case of Multiple System Atrophy (MSA) – First Presentation in a Psychiatry Service

Medicina Moderna - Modern Medicine ◽

10.31689/rmm.2021.28.4.461 ◽

2021 ◽

Vol 28 (4) ◽

pp. 461-463

Author(s):

Elena Alina ROSCA ◽

◽

Andra Livia BRONESCU ◽

Ovidiu Iulian TUDOR ◽

◽

...

Keyword(s):

Multiple System Atrophy ◽

Cerebellar Ataxia ◽

Autonomic Failure ◽

Somatic Symptoms ◽

Depression And Anxiety

A 67 years old female developed cognitive defficits, depression and anxiety as first symptoms of multiple system atrophy (MSA). In the course of an year autonomic failure, parkinsonism and cerebellar ataxia also developed. The case is particular because of the somatic symptoms that were initially categorised as psychogenic, the presence of confusional and vertigo episodes that were recurring but not permanent.

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Mild Cognitive Impairment: Advantages of a Comprehensive Neuropsychological Assessment

Current Alzheimer Research ◽

10.2174/15672050113109990014 ◽

2013 ◽

Vol 10 (10) ◽

pp. 1098-1106 ◽

Cited By ~ 4

Author(s):

E.I. Drexler ◽

B. Voss ◽

K. Amunts ◽

F. Schneider ◽

U. Habel

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Neuropsychological Assessment

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The Prevalence of Mild Cognitive Impairment among Chinese People: A Meta-Analysis

Neuroepidemiology ◽

10.1159/000512597 ◽

2021 ◽

Vol 55 (2) ◽

pp. 79-91

Author(s):

Yan Deng ◽

Siqi Zhao ◽

Guangwen Cheng ◽

Jiajia Yang ◽

Benchao Li ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Diagnostic Criteria ◽

Meta Analysis ◽

Random Effect ◽

Random Effect Model ◽

Internal Validity ◽

Screening Tools ◽

Chinese Elderly ◽

Pooled Prevalence

Background: Mild cognitive impairment (MCI) induced the majority number of dementia patients. The prevalence of MCI in China varied across studies with different screening tools and diagnostic criteria. Objective: A systematic review and meta-analysis was conducted to estimate the pooled MCI prevalence among the population aged 55 years and older in China. Methods: PubMed, EMBASE, CNKI, Wanfang, CQVIP, and CBMdisc were searched for studies on prevalence of MCI among Chinese elderly between January 1, 1980, and February 10, 2020. The quality assessment was conducted via external validity, internal validity, and informativity, the pooled prevalence was calculated through the random-effect model, and the homogeneity was evaluated by Cochran’s Q test and I2. Results: Fifty-three studies with 123,766 subjects were included. The pooled prevalence of MCI among Chinese elderly was 15.4% (95% CI: 13.5–17.4%). Subgroup analyses indicated that the prevalence calculated with different screening tools was 20.2% (95% CI: 15.1–25.9%) for Montreal Cognitive Assessment (MoCA) and 13.0% (95% CI: 10.7–15.5%) for Mini-Mental State Examination (MMSE). According to different diagnostic criteria, the prevalence was 14.8% (95% CI: 12.2–17.6%) for Petersen criteria, 15.0% (95% CI: 12.7–17.5%) for DSM-IV, and 21.2% (95% CI: 17.5–25.2%) for Chinese Expert Consensus on Cognitive Impairment (CECCI). Besides, women, older adults, illiterate people, rural residents, and those who lived with unhealthy lifestyles and morbidity showed higher prevalence. Conclusions: The prevalence of MCI in China was 15.4%, which varied by demographics, lifestyles, morbidity, screening tools, and diagnostic criteria. In further studies, screening tools and diagnosis criteria should be considered when estimating MCI prevalence.

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Clinical features and disease severity in patients with mosaic neurofibromatosis type 1: a single-center study and literature review

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01796-3 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

C. Ejerskov ◽

M. Raundahl ◽

P. A. Gregersen ◽

M. M. Handrup

Keyword(s):

Cognitive Impairment ◽

Learning Disability ◽

Diagnostic Criteria ◽

Clinical Features ◽

Neurofibromatosis Type 1 ◽

Plexiform Neurofibroma ◽

Neurofibromatosis Type ◽

Language Delay

Abstract Background The mosaic form of neurofibromatosis type 1 (NF1) is called mosaic NF1 (MNF1). No specific MNF1 follow-up guidelines exist. It is debatable if patients with MNF1 should be clinically examined and undergo follow-up in accordance with the standard NF1 guidelines, as MNF1 patients more often may develop more benign phenotypes and thereby less disease-associated complications including cognitive impairment. We discussed the need for a specific MNF1 follow-up guideline with focus on frequency of plexiform neurofibromas and NF1-associated complications. Method A systematic retrospective data collection in a MNF1 cohort from one of two Danish national centers of NF1 Expertise was completed. Data collected included demographics, clinical features including NF1 diagnostic criteria and NF1-associated complications. Recent literature in the field was reviewed. Results We identified 17 patients with MNF1 with a median age of 37 years [4; 66]. Eleven (65%) were females. Five patients (30%) had a plexiform neurofibroma. The median age at detection of plexiform neurofibroma was 30 years [14; 60]. Nine (53%) had at least one NF1-related complication; scoliosis, hypertension, ADHD, learning disability, language delay, autism and delay in gross and fine motor function development. We reviewed nine articles. In total, 126 cases were described within three case-series. Nineteen (15%) had a plexiform neurofibroma and in total, 23 NF1-associated complications were reported including language delay, learning disability and skeletal abnormalities. Furthermore, from the literature it was evident that the diagnosing of MNF1 varies among physicians and across countries. Conclusion Patients with MNF1 present with plexiform neurofibromas and other NF1-related complications with a frequency requiring that follow-up of MNF1 patients should be in accordance with the standard NF1 guideline in both childhood and adulthood. Physicians should be aware of cognitive impairment as a complication to MNF1. To develop a specific MNF1 follow-up guideline, there is a need for an international consensus on the diagnostic criteria for MNF1 and a follow-up study conducted in a larger MNF1 cohort.

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