Multiple system atrophy with amyloid-ß-predominant Alzheimer's disease neuropathologic change.

Multiple system atrophy is a neurodegenerative disease with α-synuclein pathology predominating in the striatonigral and olivopontocerebellar systems. Mixed pathologies are considered to be of low frequency and mostly comprise primary age-related tauopathy or low levels of Alzheimer's disease-related neuropathologic change. Therefore, the concomitant presence of different misfolded proteins in the same brain region is less likely in multiple system atrophy. During the neuropathological evaluation of 21 consecutive multiple system atrophy cases, we identified four cases exhibiting an unusual discrepancy between high Thal amyloid-ß phase and low transentorhinal Braak neurofibrillary tangle stage. We mapped α-synuclein pathology, measured the size and number of glial cytoplasmic inclusions and compared the amyloid-ß peptides between multiple system atrophy and Alzheimer's disease. In addition, we performed α-synuclein seeding assay from the affected putamen samples. We performed genetic testing for APOE, MAPT, PSEN1, PSEN2 and APP. We refer to the four multiple system atrophy cases with discrepancy between amyloid-ß and tau pathology as 'amyloid-ß-predominant Alzheimer's disease neuropathologic change-multiple system atrophy' to distinguish these from multiple system atrophy with primary age-related tauopathy or multiple system atrophy with typical Alzheimer's disease neuropathologic change. As most multiple system atrophy cases with mixed pathologies reported in the literature, these cases did not show a peculiar clinical or MRI profile. Three amyloid-ß-predominant Alzheimer's disease neuropathologic change-multiple system atrophy cases were available for genetic testing, and all carried the APOE ɛ4 allele. The extent and severity of neuronal loss and α-synuclein pathology were not different compared with typical multiple system atrophy cases. Analysis of amyloid-ß peptides revealed more premature amyloid-ß plaques in amyloid-ß-predominant Alzheimer's disease neuropathologic change-multiple system atrophy compared with Alzheimer's disease. α-Synuclein seeding amplification assay showed differences in the kinetics in two cases. This study highlights a rare mixed pathology variant of multiple system atrophy in which there is an anatomical meeting point of amyloid-ß and α-synuclein, i.e. the striatum or cerebellum. Since biomarkers are entering clinical practice, these cases will be recognized, and the clinicians have to be informed that the prognosis is not necessarily different than in pure multiple system atrophy cases but that the effect of potential α-synuclein-based therapies might be influenced by the co-presence of amyloid-ß in regions where α-synuclein also aggregates. We propose that mixed pathologies should be interpreted not only based on differences in the clinical phenotype but also on whether protein depositions regionally overlap, potentially leading to a different response to α-synuclein-targeted therapies.

Survey of Canadian Physician Use of Botulinum Toxin A (BoNT-A) for Paratonia: Real World Insights.

Paratonia is a form of hypertonia characterized by an inability to relax muscles in the setting of cognitive impairment. Paratonia results in pain, refusal of care, and caregiver burden. We sent surveys to 67 Canadian physiatrists and neurologists regarding their experience treating paratonia with botulinum toxin A (BoNT-A). Twenty-seven survey respondents were included in the analysis. Thirteen percent of survey respondents treating paratonia with BoNT-A reported a significant clinically relevant improvement; 74% endorsed a moderately clinically relevant improvement; 13% endorsed a slight clinically relevant improvement. Ninety percent of survey respondents endorsed significant barriers in treating paratonia with BoNT-A.

Case of a Man with Hemichorea and Behavioral Changes: "A Red Herring".

Background: Progressive supranuclear palsy (PSP)-pallido-nigro-luysian atrophy (PNLA) is a neuropathological entity thought to be a variant of classic PSP. Clinical features and pathologic hallmarks are the same in both conditions; however, age and order of symptom onset, disease duration and prognosis, and distribution and density of pathology differentiate the 2 entities. Objectives: This study presents a PSP-PNLA case confirmed pathologically with a clinical presentation of hemichorea/ballism, spasticity, progressive hemiparesis, and a frontal behavioral syndrome with relative cognitive sparing early in the disease course. Methods: We describe the clinical progression in this unique case supplemented with video and imaging findings in the form of magnetic resonance imaging and brain single photon emission computed tomography. Final diagnosis is via pathological analysis at autopsy. Results: We present an elderly gentleman who manifested a clinical syndrome consisting of subacute onset of chorea that at presentation was distinctly unilateral and a frontal behavioral syndrome in the setting of mild thrombocytopenia and elevated anticardiolipin antibodies. Positive antiphospholipid antibodies resulted in an initial antemortem diagnosis of primary antiphospholipid syndrome as a cause of his chorea. Longitudinal follow-up over 5 years demonstrated a progression of clinical features with hemi-motor impersistence/chorea, disinhibition and impulsivity, and eventually corticospinal distribution weakness on the initially affected side. He required nursing home care and falls necessitated wheelchair use. Postmortem neuropathological study revealed a diagnosis of frontotemporal lobar degeneration-tau, PSP-PNLA. Conclusions: This case broadens the phenotype of PSP-PNLA and to our knowledge is the only case presenting with unilateral chorea.

Non-Motor Fluctuations in Parkinson's Disease: Validation of the Non-Motor Fluctuation Assessment Questionnaire.

BACKGROUND: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms. OBJECTIVES: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA). METHODS: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire. RESULTS: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy. CONCLUSIONS: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society.

Paratonia in Dementia: A Systematic Review.

BACKGROUND: Paratonia is a dementia-induced motor abnormality. Although paratonia affects virtually all people with dementia, it is not well known among clinicians and researchers. OBJECTIVE: The aim of this study was to perform a systematic review of the literature on the definition, pathogenesis, diagnosis, and intervention of paratonia as well as to propose a research agenda for paratonia. METHODS: In this systematic review, the Embase, PubMed, CINAHL, and Cochrane CENTRAL databases were searched for articles published prior to December 2019. Two independent reviewers performed data extraction and assessed the risk of bias of the studies. The following data were extracted: first author, year of publication, study design, study population, diagnosis, assessment, pathogenesis, therapy and interventions. RESULTS: Thirty-five studies met the inclusion criteria and were included. Most studies included in the review mention clinical criteria for paratonia. Additionally, pathogenesis, method of assessment, diagnosis, and paratonia severity as are interventions to address paratonia are also discussed. CONCLUSION: This systematic review outlines what is currently known about paratonia, as well as discusses the preliminary research on the underlying mechanisms of paratonia. Although paratonia has obvious devastating impacts on health and quality of life, the amount of research to date has been limited. In the last decade, there appears to have been increased research on paratonia, which hopefully will increase the momentum to further advance the field.

Educational Needs and Considerations for a Visual Educational Tool to Discuss Parkinson's Disease.

BACKGROUND: In our clinical experience, people with Parkinson's disease (PwP) and their caregivers have difficulty understanding the complexities of the disease, which has a multitude of symptoms and involved therapies. We undertook a needs assessment to understand the need for, and to guide the development of, an educational tool. METHODS: We invited PwP, caregivers and health care providers (HCP) from across Canada to participate in an online survey to determine the need and desired content for such a tool. RESULTS: Respondents included 450 PwP, 335 caregivers, and 96 HCP from across Canada. 86.5% of HCP reported that it was "very important" for patients to understand issues in PD and 84.4% would use a visual aid to explain these issues. Results showed that 81.9-95.7% of caregivers and PwP were not "very satisfied" with the explanations of all domains in PD. Non-motor symptoms and cognitive issues were highly ranked by all groups as difficult to understand or explain. Older PwP (those with PD for less than 5 years and those who reported that their HCP spent less than 15 minutes counselling in each clinic visit) were less likely to fully understand and be satisfied with the explanations of most issues in PD. INTERPRETATION: There is a need for better patient education when discussing PD issues in the clinical setting. Older PwP that have been recently diagnosed have the greatest educational needs. Potential users indicate that a visual aid would help and non-motor symptoms, particularly cognitive issues, need to be a focus of such a tool.