Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.

Importance: Finding a reliable diagnostic biomarker for the disorders collectively known as synucleinopathies (Parkinson disease [PD], dementia with Lewy bodies [DLB], multiple system atrophy [MSA], and pure autonomic failure [PAF]) is an urgent unmet need. Immunohistochemical detection of cutaneous phosphorylated α-synuclein may be a sensitive and specific clinical test for the diagnosis of synucleinopathies. Objective: To evaluate the positivity rate of cutaneous α-synuclein deposition in patients with PD, DLB, MSA, and PAF. Design, Setting, and Participants: This blinded, 30-site, cross-sectional study of academic and community-based neurology practices conducted from February 2021 through March 2023 included patients aged 40 to 99 years with a clinical diagnosis of PD, DLB, MSA, or PAF based on clinical consensus criteria and confirmed by an expert review panel and control participants aged 40 to 99 years with no history of examination findings or symptoms suggestive of a synucleinopathy or neurodegenerative disease. All participants completed detailed neurologic examinations and disease-specific questionnaires and underwent skin biopsy for detection of phosphorylated α-synuclein. An expert review panel blinded to pathologic data determined the final participant diagnosis. Exposure: Skin biopsy for detection of phosphorylated α-synuclein. Main Outcomes: Rates of detection of cutaneous α-synuclein in patients with PD, MSA, DLB, and PAF and controls without synucleinopathy. Results: Of 428 enrolled participants, 343 were included in the primary analysis (mean [SD] age, 69.5 [9.1] years; 175 [51.0%] male); 223 met the consensus criteria for a synucleinopathy and 120 met criteria as controls after expert panel review. The proportions of individuals with cutaneous phosphorylated α-synuclein detected by skin biopsy were 92.7% (89 of 96) with PD, 98.2% (54 of 55) with MSA, 96.0% (48 of 50) with DLB, and 100% (22 of 22) with PAF; 3.3% (4 of 120) of controls had cutaneous phosphorylated α-synuclein detected. Conclusions and Relevance: In this cross-sectional study, a high proportion of individuals meeting clinical consensus criteria for PD, DLB, MSA, and PAF had phosphorylated α-synuclein detected by skin biopsy. Further research is needed in unselected clinical populations to externally validate the findings and fully characterize the potential role of skin biopsy detection of phosphorylated α-synuclein in clinical care.

The association between plasma GPNMB and Parkinson's disease and multiple system atrophy.

AIMS: Parkinson's disease (PD), as the second most common neurodegenerative disorder, often presents diagnostic challenges in differentiation from other forms of Parkinsonism. Recent studies have reported an association between plasma glycoprotein nonmetastatic melanoma protein B (pGPNMB) and PD. METHODS: A retrospective study was conducted, comprising 401 PD patients, 111 multiple system atrophy (MSA) patients, 13 progressive supranuclear palsy (PSP) patients and 461 healthy controls from the Chinese Han population, with an assessment of pGPNMB levels. RESULTS: The study revealed that pGPNMB concentrations were significantly lower in PD and MSA patients compared to controls (area under the receiver operating characteristics curve (AUC) 0.62 and 0.74, respectively, P < 0.0001 for both), but no difference was found in PSP patients compared to controls (P > 0.05). Interestingly, the level of pGPNMB was significantly higher in PD patients than in MSA patients (AUC = 0.63, P < 0.0001). Furthermore, the study explored the association between pGPNMB levels and disease severity in PD and MSA patients, revealing a positive correlation in PD patients but not in MSA patients with both disease severity and cognitive impairment. CONCLUSION: This study successfully replicated prior findings, demonstrating an association between pGPNMB levels and disease severity, and also identified a correlation with cognitive impairment in PD patients of the Chinese Han population. Additionally, this study is the first to identify a significant difference in pGPNMB levels between MSA, PD, and normal controls. The data provide new evidence supporting the potential role of pGPNMB in the diagnosis and differential diagnosis of Parkinsonism.

A retrospective study of autoimmune cerebellar ataxia over a 20-year period in a single institution.

BACKGROUND: It is important to differentiate autoimmune cerebellar ataxia (ACA) from neurodegenerative CA, but this is sometimes difficult. We performed a retrospective study in a single institution in Japan over a 20-year period to reveal the clinical features of ACA. METHODS: Patients with CA as the primary neurological symptom were enrolled from those admitted to the Department of Neurology, Hokkaido University Hospital between April 2002 and March 2022. ACA was diagnosed retrospectively according to the following criteria: (1) CA being the predominant symptom; (2) identification of cancer within 2 years of onset; (3) improvement in cerebellar symptoms following immunotherapy; and (4) ruling out alternative causes of CA. Patients fulfilling criteria (1), (2), and (4) were classified as paraneoplastic cerebellar degeneration (PCD), while those fulfilling (1), (3), and (4) were classified as non-PCD and enrolled as patients with ACA. Neurodegenerative diseases, e.g., multiple system atrophy (MSA), were confirmed retrospectively based on generally used diagnostic criteria and enrolled. Furthermore, the ACA diagnostic criteria proposed by Dalmau and Graus were applied retrospectively to the ACA patients to examine the validity of the diagnoses. RESULTS: Among the 243 patients with CA, 13 were enrolled as ACA; five were PCD and eight were non-PCD. Eight of these cases met the proposed diagnostic criteria by Dalmau and Graus. MSA was the most prevalent disease among CA patients, with 93 cases. The incidence of cerebellar atrophy was significantly lower in ACA (3/13) than in MSA (92/92). Cerebrospinal fluid (CSF) pleocytosis was significantly more frequent in ACA than in MSA (4/13 vs. 2/55, respectively). However, there was no significant difference in the presence of oligoclonal bands, increased protein in CSF, and laterality differences in ataxia. CONCLUSION: ACA was present in ~ 5% of Japanese CA patients. The absence of cerebellar atrophy, despite the presence of CA, strongly supports ACA over MSA. While CSF pleocytosis was observed more often in ACA, the positivity rate was only ~ 30%. Since ACA is treatable, further studies are needed to identify additional clinical features and accurate diagnostic biomarkers.

Non-pharmacological and drug treatment of autonomic dysfunction in multiple system atrophy: current status and future directions.

Multiple system atrophy (MSA) is a sporadic, fatal, and rapidly progressive neurodegenerative disease of unknown etiology that is clinically characterized by autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. Early onset and extensive autonomic dysfunction, including cardiovascular dysfunction characterized by orthostatic hypotension (OH) and supine hypertension, urinary dysfunction characterized by overactive bladder and incomplete bladder emptying, sexual dysfunction characterized by sexual desire deficiency and erectile dysfunction, and gastrointestinal dysfunction characterized by delayed gastric emptying and constipation, are the main features of MSA. Autonomic dysfunction greatly reduces quality of life and increases mortality. Therefore, early diagnosis and intervention are urgently needed to benefit MSA patients. In this review, we aim to discuss the systematic treatment of autonomic dysfunction in MSA, and focus on the current methods, starting from non-pharmacological methods, such as patient education, psychotherapy, diet change, surgery, and neuromodulation, to various drug treatments targeting autonomic nerve and its projection fibers. In addition, we also draw attention to the interactions among various treatments, and introduce novel methods proposed in recent years, such as gene therapy, stem cell therapy, and neural prosthesis implantation. Furthermore, we elaborate on the specific targets and mechanisms of action of various drugs. We would like to call for large-scale research to determine the efficacy of these methods in the future. Finally, we point out that studies on the pathogenesis of MSA and pathophysiological mechanisms of various autonomic dysfunction would also contribute to the development of new promising treatments and concepts.

Clinical milestones as triggers for palliative care intervention in progressive Supranuclear palsy and multiple system atrophy.

not required for reviews.

Cutaneous α-Synuclein Signatures in Patients With Multiple System Atrophy and Parkinson Disease.

BACKGROUND AND OBJECTIVES: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder caused by the abnormal accumulation of α-synuclein in the nervous system. Clinical features include autonomic and motor dysfunction, which overlap with those of Parkinson disease (PD), particularly at early disease stages. There is an unmet need for accurate diagnostic and prognostic biomarkers for MSA and, specifically, a critical need to distinguish MSA from other synucleinopathies, particularly PD. The purpose of the study was to develop a unique cutaneous pathologic signature of phosphorylated α-synuclein that could distinguish patients with MSA from patients with PD and healthy controls. METHODS: We studied 31 patients with MSA and 54 patients with PD diagnosed according to current clinical consensus criteria. We also included 24 matched controls. All participants underwent neurologic examinations, autonomic testing, and skin biopsies at 3 locations. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured. The deposition of phosphorylated α-synuclein was quantified. Results were compared with clinical rating assessments and autonomic function test results. RESULTS: Patients with PD had reduced nerve fiber densities compared with patients with MSA (p < 0.05, all fiber types). All patients with MSA and 51/54 with PD had evidence of phosphorylated α-synuclein in at least one skin biopsy. No phosphorylated α-synuclein was detected in controls. Patients with MSA had greater phosphorylated α-synuclein deposition (p < 0.0001) and more widespread peripheral distribution (p < 0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the 2 disorders. DISCUSSION: α-synuclein is present in the peripheral autonomic nerves of patients with MSA and when combined with synuclein distribution accurately distinguishes MSA from PD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that measurement of phosphorylated α-synuclein in skin biopsies can differentiate patients with MSA from those with PD.

The Effects of Deep Brain Stimulation in Patients with Multiple System Atrophy.

The course of patients with multiple system atrophy (MSA) who undergo deep brain stimulation (DBS) is unclear. In a retrospective review of 1,496 patients with MSA evaluated at our institutions from 1998-2021, 12 patients underwent DBS; 9 had a diagnosis of Parkinson's disease at the time of surgery. Nine patients reported initial improvement in at least one symptom and 7 experienced overall worsening following DBS. All patients had at least one red flag sign or symptom suggesting atypical parkinsonism prior to surgery. Considering overall poor outcomes of DBS in MSA, we recommend careful consideration of red flags in patient selection.

Pharyngolaryngeal semiology and prognostic factors in multiple system atrophy.

INTRODUCTION: Multiple system atrophy (MSA) is a rare degenerative neurological disorder in adults. It induces parkinsonian and/or cerebellar syndrome associated with dysautonomia. Pharyngolaryngeal symptoms are common. Our aim is to describe the Pharyngolaryngeal semiology on one hand, and to ascertain whether the presence of these symptoms represents a prognostic factor for MSA on the other. METHODS: Thus, we carried out a retrospective, single-centre study, on a cohort receiving care at the centre of reference for MSA. The patients were referred for otorhinolaryngology assessment. The data was collected over the year 2020 with the help of computer software from the university hospital centre (UHC). Firstly, we described the Pharyngolaryngeal semiology specific to MSA by questioning patients, and by the results of nasofibroscopic examinations and swallowing tests. We then used multivariate analysis of variance to describe the prognostic factors of MSA progression (in UMSARS I and II points per month of progression) and survival (number of years between the first symptoms and death). RESULTS: This study included a hundred and one patients and made it possible to define a Pharyngolaryngeal semiology profile of MSA, which is: a reduction in laryngeal mobility (primarily vocal cord abduction defects), abnormal movements (particularly at rest or when initiating a movement) and a defect in the protection mechanisms of the upper airways. The swallowing difficulties are moderate and the main mechanisms are delayed pharyngeal swallow and/or an oro-pharyngeal transport defect. In the multivariate analyses, the contributing factors are laryngeal anomalies, modification of solid food to fluid food and nutritional complication. CONCLUSION: ENT specialists should pay close attention to problems in the Pharyngolaryngeal dynamic and then consider a neurological cause. They can also itemize the clinical factors that could have a negative effect on the prognosis of the patient with MSA. Indeed, early detection makes it possible to provide care for respiratory and nutritional complications.

Synuclein-One study: skin biopsy detection of phosphorylated α-synuclein for diagnosis of synucleinopathies.

Finding an easily accessible and reliable tool to diagnose the diseases collectively defined as 'synucleinopathies' is an urgent, unmet priority. The synucleinopathies include Parkinson's disease, multiple system atrophy, pure autonomic failure and dementia with Lewy bodies. There are millions of people who have a diagnosis of a synucleinopathy, with more diagnosed every year. With accessibility, ease of implementation, consistently high sensitivity (>80%) and specificity approaching 100%, skin biopsy has great potential as the clinical test of choice for the diagnosis of synucleinopathies. The large, multi-center Synuclein-One study will determine the sensitivity, specificity, accuracy and precision of α-synuclein detection within punch skin biopsies in patients with clinically established synucleinopathies using standardized, robust methods suitable for large-scale analysis. Clinical Trial Registration: NCT04700722 (ClinicalTrials.gov).

Neuroleptic malignant-like syndrome associated multiple system atrophy: report on three cases.

BACKGROUND: Multiple system atrophy (MSA) associated with neuroleptic malignant-like syndrome (NMLS) is rare and few cases have been described in the literature. CASE PRESENTATION: In the present study, three patients with MSA associated with NMLS were analyzed from January 2012 to January 2020 to characterize their clinical presentations. Data collected from the patients for analysis included general patient history, the fluctuation and severity of disease symptoms, the indicated therapies and disease progression at follow-up. All patients had histories of sudden withdrawal or reduction of levodopa prior to the onset of symptoms. Clinical presentations were characterized by hyperthermia, autonomic dysfunction, worsening of extrapyramidal symptoms, and elevated serum creatine kinase (CK) levels. During hospitalization, one patient rapidly progressed and died, while the other two patients were successfully treated. CONCLUSIONS: Early diagnosis and treatment are very important for patient outcomes in NMLS. Notably, the correct dose and time of administration of dopaminergic medication may be key in treating NMLS.

Postganglionic Sudomotor Assessment in Early Stage of Multiple System Atrophy and Parkinson Disease: A Morpho-functional Study.

BACKGROUND AND OBJECTIVES: Sudomotor impairment has been recognized as a key feature in differentiating Parkinson disease (PD) and multiple system atrophy-parkinsonian type (MSA-P), with the latter characterized by diffuse anhidrosis in prospective study, including patients in late stage of disease. We aimed to evaluate morphologic and functional postganglionic sudomotor involvement in patients with newly diagnosed MSA-P and PD to identify possible biomarkers that might be of help in differentiating the 2 conditions in the early stage. METHODS: One hundred patients with parkinsonism within 2 years from onset of motor symptoms were included in the study. At the time of recruitment, questionnaires to assess nonmotor, autonomic, and small fiber symptoms were administered, and patients underwent postganglionic sudomotor function assessment by the dynamic sweat test and punch skin biopsy from the distal leg. Skin samples were processed for indirect immunofluorescence with a panel of antibodies, including noradrenergic and cholinergic markers. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured on confocal images with dedicated software. A follow-up visit 12 months after recruitment was performed to confirm the diagnosis. RESULTS: We recruited 57 patients with PD (M/F 36/21, age 63.5 ± 9.4 years) and 43 patients with MSA-P (M/F 27/16, age 62.3 ± 9.0 years). Clinical scales and questionnaires showed a more severe clinical picture in patients with MSA-P compared to those with PD. Sweating output and intraepidermal, pilomotor, and sudomotor nerve densities, compared to controls, were lower in both groups but with a greater impairment in patients with MSA-P. Pilomotor and sudomotor nerve density correlated with sweating function and with nonmotor clinical symptoms. A composite sudomotor parameter defined as the arithmetic product of sweat production multiplied by the density of sudomotor fibers efficiently separated the 2 populations; the receiver operating characteristics curve showed an area under the curve of 0.83. DISCUSSION: Dynamic sweat test and the quantification of cutaneous autonomic nerves proved to be a sensitive morpho-functional approach to assess the postganglionic component of the sudomotor pathway, revealing a more severe involvement in MSA-P than in PD early in the disease course. This approach can be applied to differentiate the 2 conditions early. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that postganglionic sudomotor morpho-functional assessment accurately distinguish patients with PD from patients with MSA-P.

Application of bulbocavernosus reflex combined with anal sphincter electromyography in the diagnosis of MSA and PD.

BACKGROUND: Multiple system atrophy (MSA) and Parkinson's disease (PD) are characterized by abnormal changes in the extrapyramidal system and autonomic nervous system. The two diseases are consistent in some clinical manifestations and few objective indicators for preclinical prediction. METHOD: The value of anal sphincter electromyography (EAS-EMG) in the diagnosis of MSA has been recognized by researchers, while the bulbocavernosus reflex (BCR) has been found to be of great significance in the diagnosis of PD and MSA. In this study, the diagnostic value of BCR combined with EAS-EMG in patients with MSA and PD was further discussed. RESULTS: Forty-three patients with MSA, 120 patients with PD and 40 normal controls were recruited, and the BCR and EAS-EMG were evaluated. The average duration, average amplitude, percentage of polyphasic waves, satellite potential, phase pattern and amplitude of strong contraction were observed. The results showed that the abnormal rate of BCR in the control group was 0%, and the abnormal rate of EAS-EMG was 2.5%; these differences were statistically significant compared with the MSA group (BCR 90.9%, EAS-EMG 93.9%). For patients with PD, there were some significant differences in BCR and EAS-EMG between the control group and the PD group. CONCLUSION: Our study revealed that BCR combined with EAS-EMG detection can provide an objective electrophysiological basis for the diagnosis of MSA and PD, which is beneficial for the early treatment of disease.

Video Representation of Dopamine-Responsive Multiple System Atrophy Cerebellar Type.

BACKGROUND Multiple system atrophy cerebellar type (MSA-C) is a subtype of MSA that presents with predominant ataxia along with lesser signs of parkinsonism and autonomic dysfunction. Previous studies have shown benefits from carbidopa/levodopa therapy for the MSA parkinsonian subtype but few studies have focused on the MSA-C subtype. We present a video case of MSA-C that demonstrated significant improvement with carbidopa/levodopa therapy. CASE REPORT A right-handed 61-year-old man with a past medical history of chronic microvascular ischemia, mild lower extremity neuropathy, and lumbar and cervical stenosis status after decompression presented with progressive worsening gait changes over several months with acute deterioration before admission. The initial neurological workup demonstrated bilateral cogwheel rigidity; difficulty with movement initiation. including standing up from a seated position; slow saccadic eye movements; masked facies (hypomimia); right ankle clonus; bilateral upper and left lower limb ataxia; and hyperreflexia. A follow-up workup was negative for metabolic, infectious, and paraneoplastic causes, but magnetic resonance imaging demonstrated cerebellar atrophy along with a "hot cross bun sign" suggestive of probable MSA-C according to consensus criteria, and the patient was started on carbidopa-levodopa. He subsequently demonstrated improvement in key motor domains, including his cogwheel rigidity and gait testing, and was discharged shortly thereafter. CONCLUSIONS Through this case report, we highlight a significant response to L-dopa therapy beyond what is normally expected according to diagnostic criteria for MSA. MSA treatment responsiveness can vary significantly across patients, which warrants additional studies into appropriate treatment choices for patients with Parkinson's disease and MSA.

Parkinsonism and dysautonomia with anti-CV2/CRMP5 associated paraneoplastic neurological syndromes mimicking multiple system atrophy: a case report.

BACKGROUND: Paraneoplastic neurological syndromes (PNSs) are broad-spectrum disorders that can affect any part of the nervous system varying in core symptoms. Onconeural antibodies, including Hu, Yo, Ri, anti-CV2, amphiphysin, Ma2, and Tr are well-characterized and commonly used for the diagnosis of definite PNS. Generally, anti-CV2 antibodies have usually been associated with cerebellar ataxia, chorea, peripheral and autonomic neuropathies, myelopathy, optic neuritis, and retinitis. However, Parkinsonism has not been reported as the core symptom in patients with anti-CV2 antibodies. CASE PRESENTATION: We report a patient with anti-CV2 antibody manifested as Parkinsonism and autonomic dysfunction, which may lead to the diagnosis of multiple system atrophy with predominant Parkinsonism (MSA-P). A lumbar puncture examination was undergone to find a positive anti-CV2 antibody in cerebrospinal fluid. PET-CT showed no tumor. Immunotherapy was adopted and the symptoms were relieved for 5 months. However, with no evidence of tumor, he died after 8 months. CONCLUSIONS: Our findings indicate that PNS with anti-CV2 antibody can be shown as MSA-P mimic. Considering that MSA is a neurodegenerative disease with a poor prognosis, screening for other treatable or controllable factors like PNS presented in this case is necessary when encountering a rapid progressive MSA-mimic patient.

Phosphorylated α-synuclein and phosphorylated tau-protein in sural nerves may contribute to differentiate Parkinson's disease from multiple system atrophy and progressive supranuclear paralysis.

Differential diagnosis of Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear paralysis (PSP) is challenging. This study aimed to investigate the expression of phosphorylated α-synuclein (p-α-syn) and phosphorylated tau-protein (p-tau) in sural nerves from patients with PD, MSA and PSP to find biomarkers for differential diagnosis. Clinical evaluations and sural nerve biopsies were performed on 8 PD patients, 8 MSA patients, 6 PSP patients and 8 controls (CTRs). Toluidine blue staining was used to observe morphological changes in sural nerves. The deposition of p-α-syn and p-tau was detected by immunohistochemistry with semiquantitative evaluation. Locations of p-α-syn and p-tau were identified by double immunofluorescent staining. In case groups, the density of nerve fibres decreased with swollen or fragmented Schwann cells (SCs). All cases (22/22) but no CTRs (0/8) presented p-α-syn immunoreactivity with gradually decreasing semiquantitative levels among the PD (6.00 ± 2.07), MSA (5.00 ± 2.33) and PSP (3.50 ± 1.52) groups. p-tau aggregates were found in 7/8 MSA (1.88 ± 1.46) and 6/6 PSP (1.67 ± 0.52) patients but not in PD patients or CTRs. There were different expression patterns of p-α-syn and p-tau in PD, MSA and PSP patients. These findings suggest that peripheral sensory nerve injury exists in PD, MSA and PSP patients. With a different expression pattern and level, p-α-syn and p-tau in sural nerves may serve as novel biomarkers for differential diagnosis of PD, MSA and PSP.

In Vivo Diagnosis of Synucleinopathies: A Comparative Study of Skin Biopsy and RT-QuIC.

OBJECTIVE: To determine whether (1) immunofluorescence is a reproducible technique in detecting misfolded α-synuclein in skin nerves and subsequently whether (2) immunofluorescence and real-time quaking-induced conversion (RT-QuIC) (both in skin and CSF) show a comparable in vivo diagnostic accuracy in distinguishing synucleinopathies from non-synucleinopathies in a large cohort of patients. METHODS: We prospectively recruited 90 patients fulfilling clinical and instrumental diagnostic criteria for all synucleinopathies variants and non-synucleinopathies (mainly including Alzheimer disease, tauopathies, and vascular parkinsonism or dementia). Twenty-four patients with mainly peripheral neuropathies were used as controls. Patients underwent skin biopsy for immunofluorescence and RT-QuIC; CSF was examined in patients who underwent lumbar puncture for diagnostic purposes. Immunofluorescence and RT-QuIC analysis were made blinded to the clinical diagnosis. RESULTS: Immunofluorescence showed reproducible results between 2 pairs of neighboring skin samples. Both immunofluorescence and RT-QuIC showed high sensitivity and specificity in discriminating synucleinopathies from non-synucleinopathies and controls but immunofluorescence presented higher diagnostic accuracy. Immunofluorescence presented a good level of agreement with RT-QuIC in both skin and CSF in synucleinopathies. CONCLUSIONS: Both immunofluorescence and RT-QuIC showed high diagnostic accuracy, although immunofluorescence displayed the better value as well as optimal reproducibility; they presented a good level of agreement in synucleinopathies, supporting the use of less invasive tests such as skin immunofluorescence or RT-QuIC instead of CSF RT-QuIC as a diagnostic tool for synucleinopathies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that immunofluorescence or RT-QuIC accurately distinguish synucleinopathies from non-synucleinopathies.

Detection of Dermal Alpha-Synuclein Deposits as a Biomarker for Parkinson's Disease.

Alpha-synuclein deposits are detectable in skin biopsies of patients with Parkinson's disease and other synucleinopathies like multiple system atrophy by immunohistochemical staining. As they are easily to obtain, they appear a promising tool for the pre-mortem histopathological confirmation of the disease and as a potential outcome measure in studies targeting alpha-synuclein aggregates. Good sensitivity, specificity, and practicability are the most important requirements of a biomarker. The review gives an overview on all three aspects, addresses methodological problems and the lack of standardized procedures as a major problem and gives an outlook on the future of skin biopsy as a potential diagnostic tool in synucleinopathies.

A Life-threatening Complication of Multiple System Atrophy.

CASE PRESENTATION: A 50-year-old woman was initially seen in 2016 for sleep disorders consultation, referred by Neurology because of progressive cerebellar ataxia syndrome with possible autonomic involvement and sleep-disordered breathing described as having stridorous sounds during her sleep. She had initially presented to Neurology because of issues with balance, and she had frequent falls at home. In 2016, her speech was clear, and she was able to ambulate steadily with a cane. She underwent a diagnostic polysomnogram that did not demonstrate clinically significant sleep apnea. However, the study demonstrated rapid eye movement (REM) sleep without atonia in 62% of REM epochs (normal, up to 27%) and a soft inspiratory stridor during non-REM and REM sleep. The patient was lost to follow-up until she presented to us for reevaluation 3 years later. In the interim, she had been diagnosed with multiple system atrophy-cerebellar type (MSA-C) at another health-care institution.

Differential value of external anal- and urethral-sphincter electromyography in multiple system atrophy cerebellar type and spinocerebellar ataxias.

OBJECTIVE: Clinically differentiating multiple system atrophy cerebellar type (MSA-C) and spinocerebellar ataxias (SCAs) is challenging, especially at early disease stages, because of their similarities in clinical manifestation and imaging results. The purpose of this study was to explore the value of external anal-sphincter electromyography (EAS-EMG) and urethral-sphincter electromyography (US-EMG) for distinguishing between MSA-C and SCAs. METHODS: A total of 51 subjects, including 33 MSA-C and 18 SCAs, were recruited. Average duration and amplitude of motor unit potentials (MUPs), percentage of polyphasic MUPs, amplitude during strong contraction and recruitment pattern during maximal voluntary contraction were recorded and analyzed to identify differential diagnostic results of EAS-EMG and US-EMG for MSA-C and SCAs. RESULTS: Significant differences in average MUP duration, percentage of polyphasic MUPs, and ratio of simple phase and simple-mix phase using EAS-EMG were noted between patients with MSA-C and SCAs. These same parameters also differed significantly between MSA-C and SCAs male patients using US-EMG. CONCLUSIONS: EAS-EMG may serve as a potential method for early differential diagnosis between patients with MSA-C and SCAs. Furthermore, US-EMG could be a supplementary method for males when EAS-EMG is not available.

Skin Biopsy May Help to Distinguish Multiple System Atrophy-Parkinsonism from Parkinson's Disease With Orthostatic Hypotension.

BACKGROUND: The differential diagnosis between multiple system atrophy parkinsonism type (MSA-P) and Parkinson's disease with orthostatic hypotension (PD+OH) is difficult because the 2 diseases have a similar clinical picture. The aim of this study is to distinguish MSA-P from PD+OH by immunostaining for abnormal phosphorylated α-synuclein at serine 129 (p-syn) in cutaneous nerves. METHOD: We recruited 50 patients with parkinsonism and chronic orthostatic hypotension: 25 patients fulfilled the diagnostic criteria for MSA-P and 25 patients for PD+OH. The patients underwent a skin biopsy from the cervical area, thigh, and leg to analyze somatic and autonomic skin innervation and p-syn in skin nerves. RESULTS: Intraneural p-syn positivity was found in 72% of patients with MSA-P, mainly in distal skin sites. More important, p-syn deposits in MSA-P differed from PD+OH because they were mainly found in somatic fibers of subepidermal plexi, whereas scant autonomic fiber involvement was found in only 3 patients. All patients with PD+OH displayed widely distributed p-syn deposits in the autonomic skin fibers of proximal and distal skin sites, whereas somatic fibers were affected only slightly in 4 patients with PD+OH. Skin innervation mirrored p-syn deposits because somatic innervation was mainly reduced in MSA-P. Sympathetic innervation was damaged in PD+OH but fairly preserved in MSA-P. CONCLUSIONS: The p-syn in cutaneous nerves allows the differentiation of MSA-P from PD+OH; MSA-P mainly shows somatic fiber involvement with relatively preserved autonomic innervation; and by contrast, PD+OH displays prevalent abnormal p-syn deposits and denervation in autonomic postganglionic nerves. © 2020 International Parkinson and Movement Disorder Society.