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BACKGROUND: Epidemiological studies on multisystem atrophy (MSA) are scarce. Our aim has been to analyse 10-year incidence, point prevalence, survival, and the time to diagnosis of MSA in Navarre, a northern Spanish region. METHODS: This is a population-based observational retrospective study, from 2012 to 2021, which covered the population of Navarre (followed until 31 December 2021). Data from various sources of health information were reviewed in order to identify all potential diagnoses of MSA, that were validated from medical records. Patients were included if they fulfilled the new Movement Disorder Society criteria. RESULTS: We observed a crude average annual incidence rate (IR) of 0.49/100,000 person-years, with the highest occurring in the age group of 60-69 years. No significant IR differences by sex or subtype were observed. Point prevalence in December 2021 was 2.43/100,000 inhabitants. Joinpoint analysis for global incidence and prevalence experienced stable annual rates during the whole period, showing an upward trend for prevalence without a statistically significant slop. The median age at symptom onset was 65 years (range 47-76). The median time to diagnosis was 36 months, without statistically significant differences between sex, age at diagnosis or subtypes. Median time of survival from clinical onset was 7 years. Age of onset above 70 years and autonomic onset were associated with reduced survival. CONCLUSIONS: This is the first population-based epidemiological study on MSA in Spain. It provides detailed incidence and prevalence data for MSA that may be useful for appropriate management of health resources.

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Multiple system atrophy (MSA) is a severe, orphan disease characterized by a steady increase in symptoms of parkinsonism, cerebellar disorders, and autonomic failure. In addition to autonomic failure, which is considered the defining symptom of this type of atypical parkinsonism, there are a range of other non-motor clinical manifestations, such as sleep disorders, pain syndrome, anxiety-depressive disorders, cognitive impairment (CI). CI, especially severe CI, has long been considered as a distinctive feature of MCA. Recently, there have been many clinical studies with pathomorphological or neuroimaging confirmation, indicating a high prevalence of cognitive disorders in MCA. In this article, we discuss the pathogenetic mechanisms of the development of MCA and CI in MCA, as well as the range of clinical manifestations of cognitive dysfunction.

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BACKGROUND: International clinical criteria are the reference for the diagnosis of degenerative parkinsonism in clinical research, but they may lack sensitivity and specificity in the early stages. OBJECTIVES: To determine whether magnetic resonance imaging (MRI) analysis, through visual reading or machine-learning approaches, improves diagnostic accuracy compared with clinical diagnosis at an early stage in patients referred for suspected degenerative parkinsonism. MATERIALS: Patients with initial diagnostic uncertainty between Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multisystem atrophy (MSA), with brain MRI performed at the initial visit (V1) and available 2-year follow-up (V2), were included. We evaluated the accuracy of the diagnosis established based on: (1) the international clinical diagnostic criteria for PD, PSP, and MSA at V1 ("Clin1"); (2) MRI visual reading blinded to the clinical diagnosis ("MRI"); (3) both MRI visual reading and clinical criteria at V1 ("MRI and Clin1"), and (4) a machine-learning algorithm ("Algorithm"). The gold standard diagnosis was established by expert consensus after a 2-year follow-up. RESULTS: We recruited 113 patients (53 with PD, 31 with PSP, and 29 with MSA). Considering the whole population, compared with clinical criteria at the initial visit ("Clin1": balanced accuracy, 66.2%), MRI visual reading showed a diagnostic gain of 14.3% ("MRI": 80.5%; P = 0.01), increasing to 19.2% when combined with the clinical diagnosis at the initial visit ("MRI and Clin1": 85.4%; P < 0.0001). The algorithm achieved a diagnostic gain of 9.9% ("Algorithm": 76.1%; P = 0.08). CONCLUSION: Our study shows the use of MRI analysis, whether by visual reading or machine-learning methods, for early differentiation of parkinsonism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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BACKGROUND: Health-related quality of life (Hr-QoL) scales provide crucial information on neurodegenerative disease progression, help improve patient care and constitute a meaningful endpoint for therapeutic research. However, Hr-QoL progression is usually poorly documented, as for multiple system atrophy (MSA), a rare and rapidly progressing alpha-synucleinopathy. This work aimed to describe Hr-QoL progression during the natural course of MSA, explore disparities between patients and identify informative items using a four-step statistical strategy. METHODS: We leveraged the data of the French MSA cohort comprising annual assessments with the MSA-QoL questionnaire for more than 500 patients over up to 11 years. A four-step strategy (1) determined the subdimensions of Hr-QoL, (2) modelled the subdimension trajectories over time, (3) mapped item impairments with disease stages and (4) identified most informative items. RESULTS: Four dimensions were identified. In addition to the original motor, non-motor and emotional domains, an oropharyngeal component was highlighted. While the motor and oropharyngeal domains deteriorated rapidly, the non-motor and emotional aspects were already impaired at cohort entry and deteriorated slowly over the disease course. Impairments were associated with sex, diagnosis subtype and delay since symptom onset. Except for the emotional domain, each dimension was driven by key identified items. CONCLUSION: The multidimensional Hr-QoL deteriorates progressively over the course of MSA and brings essential knowledge for improving patient care. As exemplified with MSA, the thorough description of Hr-QoL over time using the four-step strategy can provide perspectives on neurodegenerative diseases' management to ultimately deliver better support focused on the patient's perspective.

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Introduction: Atypical parkinsonian syndromes (APS) are rare neurodegenerative syndromes for which parkinsonism is one significant feature. APS includes progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS). The diagnosis of APS remains reliant on clinical features with no available diagnostic or prognostic biomarker. Clinical scales remain the gold standard assessment measures in clinical trials and research. The lack of standardised approach for research cohorts has contributed to shortcomings in disease understanding and limits collaboration between researchers. The primary objectives of this study are to (1) establish an assessment protocol for parkinsonian syndromes and (2) to implement it at a single site to establish the viability and utility of populating a clinical and biological databank of patients with APS. Methods: The Monash Alfred Protocol for Assessment of APS was devised by expert consensus within a broad multidisciplinary team. Eligible patients are diagnosed as possible or probable PSP, MSA or CBS by a consultant neurologist with expertise in movement disorders. Participants will be assessed at recruitment and then annually for up to 3 years; individuals within 5 years of index symptom onset will also undergo a once-off 6-month assessment. Ethics and dissemination: Each participant or their legally authorised representative will provide informed written consent prior to commencement of the study. Data will be stored on a locally hosted Research Electronic Data Capture database. Trial registration number: Australian New Zealand Clinical Trials Registry (ANZCTN 12622000923763).

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Objective:To summarize and compare the characteristics of orthostatic hypotension (OH)　in　patients　with　Parkinson′s disease and multiple system atrophy (MSA).Methods:The active standing test data of 210 Parkinson′s disease patients (Parkinson′s disease group) and 85 MSA patients (MSA group) admitted to the Department of Neurology, Xuanwu Hospital, Capital Medical University from January 2021 to March 2022 were retrospectively analyzed. Demographic information, clinical data, Hoehn-Yahr staging, and Unified Parkinson′s Disease Rating Scale (UPDRS), Non-Motor Symptoms Questionnaire (NMSQ), Montreal Cognitive Assessment Scale and Mini-Mental State Examination scores were collected. The comparative analysis of OH was conducted according to the changes of heart rate and blood pressure during the active standing test.Results:Among the 85 patients with MSA, 52 were found with MSA parkinsonism variant (MSA-P) and 33 with MSA cerebellar variant (MSA-C). The 210 Parkinson′s disease patients were aged (61.5±11.0) years, with 116 males (55.2%). The 85　MSA　patients　were aged (60.1±6.8) years, with 44 males (51.8%). Compared with the Parkinson′s disease group, the Hoehn-Yahr staging [2.0(2.0, 3.0) vs 3.0(2.0, 3.0), Z=-5.278, P<0.001], NMSQ[ 25.0(11.0,46.5) vs 45.0(24.0,70.0), Z=-3.632, P<0.001] and UPDRS scores [50.0(32.0,68.0) vs 65.5(44.5,78.5), Z=-3.073, P=0.003] in the MSA group were higher. The incidence of OH in the MSA group was higher than that in the Parkinson′s disease group [63.5% (54/85) vs 25.7%(54/210), χ 2= 37.284, P<0.001], but there was no statistically significant difference between the MSA-P and MSA-C groups . Compared with the Parkinson′s disease group, the MSA group had a higher incidence of classical OH [54.1%(46/85) vs 12.9%(27/210), χ 2=55.316, P<0.001] and neurogenic OH [36.5%(31/85) vs 9.0%(19/210), χ 2=32.326, P<0.001],but there was no statistically significant difference in the incidence of initial OH and delayed OH between the two groups. The incidence of severe OH in the MSA group was also higher than that in the Parkinson′s disease group [57.6%(49/85) vs 16.7%(35/210), χ 2=49.894, P<0.001], but there was no statistically significant difference in the incidence of pre-clinical OH and mild OH between the two groups. Conclusions:The incidence, time change, severity and pathophysiological basis of OH in Parkinson′s disease and MSA patients are different. Different types of OH may help to distinguish MSA from Parkinson′s disease.

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Clinical and cognitive progression in alpha-synucleinopathies is highly heterogeneous. While some patients remain stable over long periods of time, other suffer early dementia or fast motor deterioration. Sleep disturbances and nocturnal blood pressure abnormalities have been identified as independent risk factors for clinical progression but a mechanistic explanation linking both aspects is lacking. We hypothesize that impaired glymphatic system might play a key role on clinical progression. Glymphatic system clears brain waste during specific sleep stages, being blood pressure the motive force that propels the interstitial fluid through brain tissue to remove protein waste. Thus, the combination of severe sleep alterations, such as REM sleep behavioral disorder, and lack of the physiological nocturnal decrease of blood pressure due to severe dysautonomia may constitute the perfect storm for glymphatic failure, causing increased abnormal protein aggregation and spreading. In Lewy body disorders (Parkinson's disease and dementia with Lewy bodies) the increment of intraneuronal alpha-synuclein and extracellular amyloid-ß would lead to cognitive deterioration, while in multisystemic atrophy, increased pathology in oligodendroglia would relate to the faster and malignant motor progression. We present a research model that may help in developing studies aiming to elucidate the role of glymphatic function and associated factors mainly in alpha-synucleinopathies, but that could be relevant also for other protein accumulation-related neurodegenerative diseases. If the model is proven to be useful could open new lines for treatments targeting glymphatic function (for example through control of nocturnal blood pressure) with the objective to ameliorate cognitive and motor progression in alpha-synucleinopathies.

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This is a practical guide to diagnosing and managing multiple system atrophy (MSA). We explain the newly published Movement Disorders Society Consensus Diagnostic Criteria, which include new 'Clinically Established MSA' and 'Possible Prodromal MSA' categories, hopefully reducing time to diagnosis. We then highlight the key clinical features of MSA to aid diagnosis. We include a list of MSA mimics with suggested methods of differentiation from MSA. Lastly, we discuss practical symptom management in people living with MSA, including balancing side effects, with the ultimate aim of improving quality of life.

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INTRODUCTION: Quantitative biomarkers for clinical differentiation of parkinsonian syndromes are still lacking. Our aim was to evaluate the value of combining clinically feasible manual measurements of R2* relaxation rates and mean diffusivity (MD) in subcortical regions and brainstem morphometric measurements to improve the discrimination of parkinsonian syndromes. METHODS: Twenty-two healthy controls (HC), 25 patients with Parkinson's disease (PD), 19 with progressive supranuclear palsy (PSP) and 27 with multiple system atrophy (MSA, 21 with the parkinsonian variant -MSAp, 6 with the cerebellar variant -MSAc) were recruited. R2*, MD measurements and morphometric biomarkers including the midbrain to pons area ratio and the Magnetic Resonance Parkinsonism Index (MRPI) were compared between groups and their diagnostic performances were assessed. RESULTS: Morphometric biomarkers discriminated better patients with PSP (ratio: AUC 0.89, MRPI: AUC 0.89) and MSAc (ratio: AUC 0.82, MRPI: AUC 0.75) from other groups. R2* and MD measurements in the posterior putamen performed better in separating patients with MSAp from PD (R2*: AUC 0.89; MD: AUC 0.89). For the three-class classification "MSA vs PD vs PSP", the combination of MD and R2* measurements in the posterior putamen with morphometric biomarkers (AUC: 0.841) outperformed each marker separately. At the individual-level, there were seven discordances between imaging-based prediction and clinical diagnosis involving MSA. Using the new Movement Disorder Society criteria for the diagnosis of MSA, three of these seven patients were clinically reclassified as predicted by quantitative imaging. CONCLUSION: Combining R2* and MD measurements in the posterior putamen with morphometric biomarkers improves the discrimination of parkinsonism.

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BACKGROUND: Previous studies suggest a link between CAG repeat number in the HTT gene and non-Huntington neurodegenerative diseases. OBJECTIVE: The aim is to analyze whether expanded HTT CAG alleles and/or their size are associated with the risk for developing α-synucleinopathies or their behavior as modulators of the phenotype. METHODS: We genotyped the HTT gene CAG repeat number and APOE-Ɛ isoforms in a case-control series including patients with either clinical or neuropathological diagnosis of α-synucleinopathy. RESULTS: We identified three Parkinson's disease (PD) patients (0.30%) and two healthy controls (0.19%) carrying low-penetrance HTT repeat expansions whereas none of the dementia with Lewy bodies (DLB) or multisystem atrophy (MSA) patients carried pathogenic HTT expansions. In addition, a clear increase in the number of HTT CAG repeats was found among DLB and PD groups influenced by the male gender and also by the APOE4 allele among DLB patients. HTT intermediate alleles' (IAs) distribution frequency increased in the MSA group compared with controls (8.8% vs. 3.9%, respectively). These differences were indeed statistically significant in the MSA group with neuropathological confirmation. Two MSA HTT CAG IAs carriers with 32 HTT CAG repeats showed isolated polyQ inclusions in pons and basal nuclei, which are two critical structures in the neurodegeneration of MSA. CONCLUSIONS: Our results point to a link between HTT CAG number, HTT IAs, and expanded HTT CAG repeats with other non-HD brain pathology and support the hypothesis that they can share common neurodegenerative pathways. © 2022 International Parkinson and Movement Disorder Society.

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AIM: To elucidate the patterns of characteristic hypometabolism on 18F- fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in multisystem atrophy (MSA) and their correlation with the patterns of uptake on dopamine transporter imaging with 99mTc TRODAT-1 SPECT. MATERIAL AND METHODS: A retrospective analysis of 67 patients with clinically diagnosed MSA was performed. All the subjects underwent 99mTc TRODAT-1 SPECT and 18F-FDG PET/CT scanning on two separate days. The 99mTc-TRODAT-1 scans were analyzed visually for asymmetry and rostro-caudal gradient. The FDG uptake patterns were recorded, and areas of hypometabolism that were two standard deviations from the mean were considered abnormal. RESULTS: All the subjects had an abnormal pattern of FDG uptake on PET scan, both on a visual inspection and semiquantitative analysis. In MSA-P subjects (n = 29), diffuse predominant hypometabolism of the globus pallidus-putamen complex was noted, with relative sparing of the caudate nuclei. In MSA-C subjects (n = 25), characteristic hypometabolism was noted in the cerebellum and brainstem. In mixed subtypes (n = 13), variable involvement of the basal ganglia, cerebellum, and brainstem was noted with frontoparietal hypometabolism. A statistically significant difference between MSA-P and MSA-C for gradient reduction and asymmetry with gradient reduction was observed. CONCLUSION: Dopamine transporter imaging with 99mTc TRODAT-1 SPECT not only helps in confirmation of parkinsonian disorders but also demonstrates varying patterns of distribution in different subtypes of MSA. Characteristic patterns of hypometabolism in 18F-FDG PET may help in the differentiation of the subtypes of MSA in the presence of clinically overlapping symptoms.

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Parkinson's disease and related disorders (PDRD) are the second most common neurodegenerative disease and a leading cause of death. However, patients with PDRD receive less end-of-life palliative care (hospice) than other illnesses, including other neurologic illnesses. Identification of predictors of PDRD mortality may aid in increasing appropriate and timely referrals. To systematically review the literature for causes of death and predictors of mortality in PDRD to provide guidance regarding hospice/end-of-life palliative care referrals. We searched MEDLINE, PubMed, EMBASE and CINAHL databases (1970-2020) of original quantitative research using patient-level, provider-level or caregiver-level data from medical records, administrative data or survey responses associated with mortality, prognosis or cause of death in PDRD. Findings were reviewed by an International Working Group on PD and Palliative Care supported by the Parkinson's Foundation. Of 1183 research articles, 42 studies met our inclusion criteria. We found four main domains of factors associated with mortality in PDRD: (1) demographic and clinical markers (age, sex, body mass index and comorbid illnesses), (2) motor dysfunction and global disability, (3) falls and infections and (4) non-motor symptoms. We provide suggestions for consideration of timing of hospice/end-of-life palliative care referrals. Several clinical features of advancing disease may be useful in triggering end-of-life palliative/hospice referral. Prognostic studies focused on identifying when people with PDRD are nearing their final months of life are limited. There is further need for research in this area as well as policies that support need-based palliative care for the duration of PDRD.

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OBJECTIVES: The aim of this study was to evaluate the sensitivity and specificity of various outcomes of acute levodopa challenge test (ALCT) namely improvement of motor function, development of dyskinesia and intolerance; to predict the diagnosis of idiopathic Parkinson's disease (IPD) or Parkinson-plus syndrome; to predict levodopa responsiveness and levodopa-induced dyskinesia (LID) during long-term therapy. METHODS: ALCT was performed on 89 patients with parkinsonism of <2 years and were followed up for 18 months. Improvement of UPDRSm by ≥30% was considered positive. RESULTS: The test was positive in 37 (43.5%) and negative in 48 (56.5%) of 85 patients completing it. Of the 75 patients completing 18 months' follow-up 34 (45.3%) were diagnosed as IPD. A positive ALCT predicted a clinical diagnosis of IPD with sensitivity and specificity of 97.4% and 70.7% respectively. The predictive value of ALCT for long-term levodopa responsiveness was less than predicting a diagnosis of IPD. While appearance of dyskinesia during ALCT had a low predictive value for future LID (sensitivity 14.3%), it had high predictive value for a diagnosis of multisystem atrophy (MSA) (91% specificity and 37.5% sensitivity). The appearance of symptoms of levodopa intolerance (SLI) during ALCT could predict a clinical diagnosis of MSA with high specificity (95.5%) and moderate sensitivity (50%). CONCLUSION: Levodopa responsiveness during ALCT was useful in predicting a diagnosis of IPD but not long-term response to levodopa. The development of dyskinesia during ALCT could not correctly predict LID, but could predict a diagnosis of MSA. The appearance of SLI during ALCT could also predict MSA correctly.

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