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Multiple system atrophy (MSA) is characterized by accumulation of phosphorylated α-synuclein (p-syn) as glial cytoplasmic inclusions in the brain and a specific biomarker for this disorder is urgently needed. We aimed at investigating if p-syn can also be detected in skin Remak non-myelinating Schwann cells (RSCs) as Schwann cell cytoplasmic inclusions (SCCi) and may represent a reliable clinical biomarker for MSA. This cross-sectional diagnostic study evaluated skin p-syn in 96 patients: 46 with probable MSA (29 with parkinsonism type MSA and 17 with cerebellar type MSA), 34 with Parkinson's disease (PD) and 16 with dementia with Lewy bodies (DLB). We also included 50 healthy control subjects. Patients were recruited from five different medical centres. P-syn aggregates in skin sections were stained by immunofluorescence, followed by analyses with confocal microscopy and immuno-electron microscopy. All analyses were performed in a blinded fashion. Overall, p-syn aggregates were found in 78% of MSA patients and 100% of patients with PD/DLB, whereas they could not be detected in controls. As for neuronal aggregates 78% of MSA patients were positive for p-syn in somatic neurons, whereas all PD/DLB patients were positive in autonomic neurons. When analysing the presence of p-syn in RSCs, 74% of MSA patients were positive, whereas no such SCCi could be observed in PD/DLB patients. Analyses by immuno-electron microscopy confirmed that SCCi were only found in cases with MSA and thus absent in those with PD/DLB. In conclusion, our findings demonstrate that (i) fibrillar p-syn in RSCs is a pathological hallmark of MSA and may be used as a specific and sensitive disease biomarker; (ii) in Lewy body synucleinopathies (PD/DLB) only neurons contain p-syn deposits; and (iii) the cell-specific deposition of p-syn in the skin thus mirrors that of the brain in many aspects and suggests that non-myelinated glial cells are also involved in the MSA pathogenesis.

Background Melanopsin retinal ganglion cell (mRGC)-mediated pupillary light reflex (PLR) abnormalities have been documented in several neurodegenerative disorders including Parkinson's disease. Overall, isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents the strongest prodromal risk factor for impending α-synucleinopathies. Objectives To quantitatively compare PLR and mRGC-mediated contribution to PLR in 16 iRBD patients and 16 healthy controls. Methods iRBD and controls underwent extensive neuro-ophthalmological evaluation and chromatic pupillometry. In iRBD, PLR metrics were correlated with clinical variables and with additional biomarkers including REM atonia index (RAI), DaTscan, and presence of phosphorylated-α-synuclein (p-α-syn) deposition in skin biopsy. Results We documented higher baseline pupil diameter and decreased rod-transient PLR amplitude in iRBD patients compared to controls. PLR rod-contribution correlated with RAI. Moreover, only iRBD patients with evidence of p-α-syn deposition at skin biopsy showed reduced PLR amplitude compared to controls. Conclusion The observed PLR abnormalities in iRBD might be considered as potential biomarkers for the risk stratification of phenoconversion of the disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

There are currently no standardized therapies for Parkinson disease (PD). Curcumin shows anti-amyloidogenic properties in vitro and may be a promising treatment for PD. We evaluated the effects of curcumin supplementation on clinical scales and misfolded, phosphorylated α-synuclein (p-syn) accumulation in skin biopsies in 19 PD patients who received curcumin supplementation for 12 months and 14 PD patients to treated with curcumin. The patients underwent autonomic (COMPASS-31), motor (MDS-UPDRS and H&Y) and nonmotor (NMSS) questionnaires and skin biopsies to evaluate clinical involvement and p-syn load in skin nerves at the beginning and the end of study. Curcumin and curcuminoid levels were assayed in plasma and CSF. Supplemented patients showed detectable CSF curcuminoid levels that were lower than those in plasma. They showed a decrease of COMPASS-31 and NMSS scores, and a slight p-syn load decrease versus untreated patients who displayed a worsening of these parameters despite increased levodopa doses. Multiple regression models showed a significant effect of curcumin supplementation in decreasing the worsening of the clinical parameters and p-syn load at after curcumin treatment. These data suggest that curcumin can cross the blood-brain barrier, that it is effective in ameliorating clinical parameters and that it shows a tendency to decrease skin p-syn accumulation in PD patients.

Small fiber neuropathy (SFN) is characterized by the involvement of Aδ and C fibers leading to sensory, mainly pain, and/or autonomic symptoms. Multiple chemical sensitivity syndrome (MCS) is an incompletely defined condition characterized by the onset of various symptoms in patients after exposure to several chemical substances. Pain is a common symptom in these patients. In this study, we report the histological and clinical data of a cohort of 21 patients who had been diagnosed as having MCS and who were referred to us with the suspicion of SFN because of chronic pain. All patients underwent neurological clinical examination, (including scales for pain and autonomic disorders), and a skin biopsy. Age-matched healthy subjects were used as controls for the skin biopsies. Nerve conduction studies and serum screening to exclude possible causes of peripheral neuropathy were also performed. Skin biopsies disclosed a somatic SFN in all patients. Although the majority (18 out of 21) of patients also had autonomic symptoms. we found sparing of autonomic innervation in the biopsies. These observations suggest that chronic pain in MCS could be secondary to the presence of somatic SFN, although more data are needed to confirm these observations.

Fabry disease is a rare X-linked lysosomal storage disorder due to pathogenic variants of the galactosidase alpha (GLA) gene, leading to a deficiency of alpha-galactosidase A. The inadequate enzymatic activity leads to progressive glycosphingolipids accumulation within tissues and subsequent multi-systemic dysfunction, with predominant involvement of heart, kidney, and nervous system. Two subtypes are recognized: the classic type and the late-onset type. We here describe the clinical characteristics of a patient with late-onset Fabry disease carrying a not previously identified GLA gene variant. This 50-year-old man came to hospital because of an acute ischemic stroke. He also complained of acroparesthesia and had angiokeratomas in the nape and the back. Blood alpha-galactosidase A activity was low, plasmatic lyso-Gb3 level was borderline, cardiac MRI showed cardiac fibrosis, brain MRI documented cerebrovascular disease, and skin biopsy revealed small fiber neuropathy without globotriaosylceramide-3 skin deposits. Genetic study by means of targeted next-generation sequencing analysis disclosed a missense substitution c.1139CT (p.Pro380Leu) in the GLA gene. We suggest that this novel variant should be considered as pathogenic and associated with a late-onset variant of Fabry disease with a predominant neurological phenotype.

This work aimed to report the demographic and clinical characteristics of two new cases with non-paraneoplastic anti-Hu-associated gut motility impairment, and perform a thorough revision covering anti-Hu-associated paraneoplastic (PGID) and non-paraneoplastic (nPGID) gastrointestinal dysmotility. Several case series have clearly established a relationship between certain type of cancers, the development of circulating anti-Hu antibodies, and the concomitant usually severe gastrointestinal dysmotility; in contrast, a few studies focused on anti-Hu-associated nPGID. We searched for studies regarding anti-Hu-associated gastrointestinal manifestations and extracted data concerning clinical characteristics of patients, including specific demographic, oncological, neurological, gastrointestinal, histological, and treatment response features. Forty-nine articles with a total of 59 cases of anti-Hu-associated gastrointestinal dysmotility were analyzed. The patients’ age at symptom onset significantly differed between PGID and nPGID (median 61 vs 31 years, p

Background: Evidence suggests that skin represents a suitable matrix for demonstrating α-synuclein oligomers as a diagnostic biomarker for Lewy body disease. Objective: The objective of this study was to evaluate the diagnostic performance of skin α-syn real-time quaking-induced conversion assay in patients with Lewy body disease. Methods: We analyzed skin punches taken in vitam (n=69) or postmortem (n=49) from patients with PD, dementia with Lew bodies (DLB), incidental Lewy body pathology, and neurological controls. Seventy-nine patients underwent both CSF and skin α-synuclein real-time quaking-induced conversion assay. Results: Overall, the skin α-synuclein real-time quaking-induced conversion assay distinguished Lewy body disease patients with 94.1% accuracy (sensitivity, 89.2%; specificity, 96.3%). Assay sensitivity reached 94.1% in the 17 Lewy body disease patients analyzed in the cervical region. In patients with both CSF and skin samples, the 2 real-time quaking-induced conversion assay protocols yielded similar diagnostic accuracy (skin, 97.5%; CSF, 98.7%). Conclusion: Skin punch biopsies might represent a valid and convenient alternative to CSF analysis to demonstrate Lew body-related α-synuclein deposition in patients with Lewy body disease. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective/methods Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017. Results Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients. Conclusions Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.

Background 5–10% of amyotrophic lateral sclerosis (ALS) patients presented a positive family history (fALS). More than 30 genes have been identified in association with ALS/frontotemporal dementia (FTD) spectrum, with four major genes accounting for 60–70% of fALS. In this paper, we aimed to assess the contribution to the pathogenesis of major and rare ALS/FTD genes in ALS patients. Methods We analyzed ALS and ALS/FTD associated genes by direct sequencing or next-generation sequencing multigene panels in ALS patients. Results Genetic abnormalities in ALS major genes included repeated expansions of hexanucleotide in C9orf72 gene (7.3%), mutations in SOD1 (4.9%), FUS (2.1%), and TARDBP (2.4%), whereas variants in rare ALS/FTD genes affected 15.5% of subjects overall, most frequently involving SQSTM1 (3.4%), and CHMP2B (1.9%). We found clustering of variants in ALS major genes in patients with a family history for “pure” ALS, while ALS/FTD related genes mainly occurred in patients with a family history for other neurodegenerative diseases (dementia and/or parkinsonism). Conclusions Our data support the presence of two different genetic components underlying ALS pathogenesis, related to the presence of a family history for ALS or other neurodegenerative diseases. Thus, family history may help in optimizing the genetic screening protocol to be applied.

Stiff person syndrome is a rare condition characterised by prolonged stiffness with superimposed muscle spasms. Immunotherapy relies mainly on intravenous immunoglobulin, steroids and plasma exchange. Azathioprine or rituximab are other possible options. We describe two patients who showed a good clinical response with intravenous immunoglobulin and persistence of the clinical improvement after shifting to equivalent dosage of subcutaneous immunoglobulin. Both patients received a diagnosis of stiff person syndrome based on their clinical symptoms (episodes of stiffness and spasms) and presence of antiglutamic acid decarboxylase. Treatment with intravenous immunoglobulin was started with improvement of symptoms as reported by patients and confirmed also by the spasm frequency scale and modified Ashworth scale. After clinical stabilisation in order to avoid the hospitalisation required for intravenous immunoglobulin treatment a switch to subcutaneous immunoglobulins was made. After one year of follow-up from the switch, the patients show clinical stability. Their scores on the modified Ashworth scale, spasm frequency scale and on the 10 Meter Walking Test were also stable. Subcutaneous formulation of immunoglobulin could be as effective as intravenous immunoglobulin in the maintenance treatment of Stiff person syndrome, although studies involving a larger cohort of patients are needed in order to confirm our anecdotal experience.

ObjectiveTo compare the diagnostic accuracy of ice pack test (IPT) and single-fiber EMG (SF-EMG) in patients with suspected ocular myasthenia (OM) presenting with ptosis.MethodsWe studied consecutive patients referred for the clinical suspicion of OM. Patients underwent IPT and stimulated SF-EMG on the orbicularis oculi muscle. Receiver operating characteristic curve analysis was performed to determine the accuracy of IPT, SF-EMG, and their combination.ResultsWe included 155 patients, 102 with OM and 53 with other diagnosis (OD). The IPT had a sensitivity of 86% (95% confidence interval [CI] 79–93) and a specificity of 79% (95% CI 68–90). SF-EMG showed a sensitivity of 94% (95% CI 89–98) and a specificity of 79% (95% CI 68–90). Overall, IPT and SF-EMG showed discordant results in 30 cases, 16 OM and 14 OD. The combination of IPT and SF-EMG, using the positivity of at least one test for OM diagnosis, increased the sensitivity to 98% (95% CI 95–100), reducing the specificity to 66% (95% CI 53–78), whereas using the positivity of both tests, we obtained a sensitivity of 82% (95% CI 75–90) and a specificity of 92% (95% CI 85–99). The negativity of both tests had a 94% (95% CI 87–100) negative predictive value. Comparison of the areas under the curve showed no differences in the diagnostic accuracy of IPT, SF-EMG, and their combinations.ConclusionsIPT and SF-EMG have similar diagnostic accuracy in patients with OM presenting with ptosis. The negativity of both tests strongly suggests another diagnosis.Classification of evidenceThis study provides Class I evidence that both the IPT and SF-EMG accurately identify patients with OM.

Prion real‐time quaking‐induced conversion (RT‐QuIC) is an ultrasensitive assay detecting pathological aggregates of misfolded prion protein in biospecimens. We studied 71 punch biopsy skin samples of 35 patients with Creutzfeldt–Jakob disease (CJD), including five assessed in vitam. The results confirmed the high value of skin prion RT‐QuIC for CJD diagnosis (89% sensitivity and 100% specificity) and support its use in clinical practice. Preliminary data based on a limited number of cases suggest that prion‐seeding activity in the skin varies according to the prion strain, being higher in sporadic CJD subtypes linked to the V2 strain (VV2 and MV2K) than in typical CJDMM1.

A 27-year-old woman presented with acute onset of double vision, right-sided orbital pain exacerbated by ocular movements, and ipsilateral conjunctival hyperemia. Her personal medical history was negative and she denied any recent illness, journey, or sick contact. Family history was positive for Hashimoto thyroiditis in her mother. Neurologic evaluation revealed complete lateral and partial upward gaze palsy in her right eye, with binocular horizontal diplopia. The remaining clinical examination was unremarkable; in particular, pupillary reflex was preserved and there was no evidence of ptosis, conjunctival chemosis, proptosis, eye discharge, or visual defects.

To date, approximately 20 heterozygous mainly loss-of-function variants inWe describe the clinical history of a patient with SCA and conducted genetic investigations including mitochondrial DNA analysis and exome sequencing.This male patient was reported to have unstable gait with tremors at the lower limbs and dysarthric speech since childhood. A neurologic examination also showed dysarthria, nystagmus, action tremor, dysmetria, and weak deep tendon reflexes. He had marked cerebellar atrophy at brain MRI, more evident at vermis. Molecular analysis, including exome sequencing and an in silico panel analysis of genes associated with SCA, revealed the c.1121TC [p.V374A] mutation inThis report consolidates the pathogenicity of the V374A

Introduction Recurrent Painful Ophthalmoplegic Neuropathy, previously known as Ophthalmoplegic Migraine, is a poorly characterized disorder mainly because there are few cases described. We report a new case of Recurrent Painful Ophthalmoplegic Neuropathy and a review of the literature to contribute to increasing the knowledge of the clinical features of this disorder. Case report and review of literature A 45-year-old woman presented with adult-onset recurrent attacks of abducens and oculomotor palsy associated with diplopia followed by headache. Most notably, pain always presented many days after oculomotor impairment, a feature never described in the literature. A diagnosis of possible Recurrent Painful Ophthalmoplegic Neuropathy was made after excluding other possible mimicking disorders. Symptoms usually resolved gradually with corticosteroid therapy, albeit without a clear-cut benefit. Clinical data collected from 1989 to 2022 showed that adult onset in Recurrent Painful Ophthalmoplegic Neuropathy is not uncommon. While III cranial nerve palsy is typical, VI and IV nerve palsy have also been described. Pathophysiology and diagnosis Several hypotheses have been proposed, including nerve compression, ischemia or inflammation/demyelination, but none has been completely accepted. Diagnosis remains of exclusion; magnetic resonance imaging and blood exams are key in differential diagnosis. Conclusions Our case gives us the possibility to expand the clinical features of Recurrent Painful Ophthalmoplegic Neuropathy, also contributing to updating the pathophysiological hypotheses.

Background: Previous studies reported skin phosphorylated α-synuclein (p-syn) deposits in Parkinson’s disease (PD) patients but not in patients with parkinsonism due to tauopathies, although data on the latter are limited. Objective: We aimed to assess the presence of skin p-syn deposits in patients with clinical diagnosis of parkinsonism usually due to tauopathy and PD. Methods: We consecutively recruited 26 patients, 18 fulfilling clinical diagnostic criteria of progressive supranuclear palsy (PSP) and 8 of corticobasal syndrome (CBS), 26 patients with PD, and 26 healthy controls (HC). All subjects underwent skin biopsy to study p-syn deposits in skin nerves by immunofluorescence. Results: Skin p-syn deposits were present in only two of the PSP/CBS patients and none of the HC. Conversely, all PD patients showed p-syn deposition (p

Raw data pertaining to the article "Cannabis-based products in a neurological setting: a clinical and pharmacokinetic survey" Authors:Susan Mohamed, Giovanna Lopane, Loredana Sabattini, Cinzia Scandellari, Diletta Zardi, Vincenzo Donadio, Giovanni Rizzo, Alessandro Perrone, Alessandra Lugaresi, Manuela Contin Abstract Background and aim: Limited data are available in clinical settings on the pharmacokinetics of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We investigated the use of cannabis-based products in neurological practice, monitoring patients’ steady-state cannabinoids plasma concentrations matched with different preparations. Methods: This was a prospective, single-center, observational study. Patients underwent venous blood withdrawal before the cannabinoids’ morning dose, and then 2.5 hours post dosing. Spasticity or pain were patient self-assessed by the Numeric Rating Scale (NRS) before the morning cannabinoids administration and 2.5 hours post dosing. Results: Thirty-three patients were enrolled. Main indications for cannabinoids were spasticity and chronic pain. Sixteen patients were treated with oromucosal spray formulation and 17 with oil-based solutions. Both cannabinoids’ trough plasma concentrations were ≤ limit of detection (0.1 ng/ml) in 45% of patients. Intrasubject cannabinoids’ plasma levels significantly increased over baseline values in patients treated with Bediol® oil (p Conclusion: This is the first study investigating cannabinoids plasma concentrations of oral and oromucosal preparations in real-world neurological practice. Findings of similar bioavailability for both CBD and THC after galenic oil compared with oromucosal spray dosing may be clinically relevant and deserve additional research in larger cohorts. &nbsp

Purpose: to assess phosphorylated α-synuclein (p-syn) deposits distribution in a patient affected by early stage Parkinson’s disease and orthostatic hypotension, through a longitudinal skin biopsy study. Findings: our study showed a p-syn widespread spatial diffusion fromdeepautonomic dermis nerve bundles to autonomic terminalssuggesting a centrifugal spread of p-syn from ganglia to the innervation target structures. Furthermore, the present case suggests the possibility to discriminate synucleinopaties at an early stage of disease by means of skin biopsy. Conclusions: if confirmed these data supported skin biopsy as useful and promising tool for the diagnosis, longitudinal evaluation and pathological understanding of Parkinson’s disease.

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We describe a novel ATP7A gene mutation associated with distal motor neuropathy, mild connective tissue abnormalities and autonomic disturbances. Next-generation sequencing analysis of a lower-motor neuron diseases gene panel was performed in two sibs presenting with distal motor neuropathy plus an autonomic dysfunction, which main manifestations were retrograde ejaculation, diarrhea and hyperhydrosis. Probands underwent dysmorphological, neurological, electrophysiological as well as biochemical evaluations and somatic and autonomic innervation studies on skin biopsies. A novel missense mutation (p.A991D) was identified in the X-linked ATP7A gene, segregating in both brothers and inherited from their healthy mother. Biochemical studies on patients’ blood samples showed reduced serum copper and ceruloplasmin levels. Clinical and neurophysiological evaluation documented dysautonomic signs. Quantitative evaluation of skin innervation disclosed a small fiber neuropathy with prevalent autonomic involvement. Mutations in the ATP7A gene, encoding for a copper-transporting ATPase, have been associated with the severe infantile neurodegenerative Menkes disease and in its milder variant, the Occipital Horn Syndrome. Only two ATP7A mutations were previously reported as causing, a pure axonal distal motor neuropathy (dHMN-SMAX3). The phenotype we report represents a further example of this rare genotype-phenotype correlation and highlights the possible occurrence in SMAX3 of autonomic disturbances, as described for Menkes disease and Occipital Horn Syndrome.

A 58-year-old man presented to our neurologic clinic with progressive distal weakness in the left hand. Six months prior, he started noticing weakness in the hand. This progressively worsened and led to difficulty in manipulating objects. The patient denied sensory symptoms.

We read with interest the publication entitled “In vivo distribution of α-synuclein in multiple tissues and biofluids in Parkinson disease.”1 In the article, Chahine et al.1 discuss the results of the Systemic Synuclein Sampling Study (S4 study). This was an important step toward the in vivo diagnosis of synucleinopathy. Unfortunately, although the detection of phosphorylated alpha-synuclein was highly specific, sensitivity was quite poor, particularly for skin (with a sensitivity of 24.1%). The authors note that there were several explanations for such findings, including the earlier diagnosis of PD in the S4 study compared with the relatively small studies performed at other centers.

Objective To evaluate the prognostic value of needle electromyography (EMG) genioglossus involvement in patients with amyotrophic lateral sclerosis (ALS) at diagnosis. Methods We separately explored the prognostic value of clinical bulbar lower motor neuron (LMN) signs and EMG genioglossus involvement using Cox proportional hazard models adjusted for age, gender, diagnostic delay, presence of bulbar upper motor neuron (UMN) signs, EMG cervical and lumbosacral region involvement, ALSFRS-R score and C9Orf72 gene status. Then, we compared the prognostic value of EMG masseter and genioglossus abnormalities in a subset of patients in whom both muscles were analysed. Results 103 ALS patients were included in the study. Neurophysiological genioglossus involvement was associated with a shorter survival (p = 0.002), a shorter time to moderate dysphagia (p = 0.0001) and to severe dysarthria (p = 0.012). Its prognostic value was still evident in patients without clinical bulbar LMN signs. Bulbar clinical LMN signs were only associated with an earlier onset of moderate dysphagia (p = 0.0001). EMG masseter abnormalities did not reach statistical significance with regard to all the clinical milestones. Conclusions Genioglossus EMG at diagnosis could provide important information about ALS progression rate. The masseter muscle seems to be less involved in ALS. Significance EMG genioglossus involvement is a prognostic factor in ALS.

Importance Deposition of the pathological α-synuclein (αSynP) in the brain is the hallmark of synucleinopathies, including Parkinson disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). Whether real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) assays can sensitively detect skin biomarkers for PD and non-PD synucleinopathies remains unknown. Objective To develop sensitive and specific skin biomarkers for antemortem diagnosis of PD and other synucleinopathies. Design, Setting, and Participants This retrospective and prospective diagnostic study evaluated autopsy and biopsy skin samples from neuropathologically and clinically diagnosed patients with PD and controls without PD. Autopsy skin samples were obtained at 3 medical centers from August 2016 to September 2019, and biopsy samples were collected from 3 institutions from August 2018 to November 2019. Based on neuropathological and clinical diagnoses, 57 cadavers with synucleinopathies and 73 cadavers with nonsynucleinopathies as well as 20 living patients with PD and 21 living controls without PD were included. Specifically, cadavers and participants had PD, LBD, MSA, Alzheimer disease, progressive supranuclear palsy, or corticobasal degeneration or were nonneurodegenerative controls (NNCs). A total of 8 approached biopsy participants either refused to participate in or were excluded from this study due to uncertain clinical diagnosis. Data were analyzed from September 2019 to April 2020. Main Outcomes and Measures Skin αSynPseeding activity was analyzed by RT-QuIC and PMCA assays. Results A total of 160 autopsied skin specimens from 140 cadavers (85 male cadavers [60.7%]; mean [SD] age at death, 76.8 [10.1] years) and 41 antemortem skin biopsies (27 male participants [66%]; mean [SD] age at time of biopsy, 65.3 [9.2] years) were analyzed. RT-QuIC analysis of αSynPseeding activity in autopsy abdominal skin samples from 47 PD cadavers and 43 NNCs revealed 94% sensitivity (95% CI, 85-99) and 98% specificity (95% CI, 89-100). As groups, RT-QuIC also yielded 93% sensitivity (95% CI, 85-97) and 93% specificity (95% CI, 83-97) among 57 cadavers with synucleinopathies (PD, LBD, and MSA) and 73 cadavers without synucleinopathies (Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration, and NNCs). PMCA showed 82% sensitivity (95% CI, 76-88) and 96% specificity (95% CI, 85-100) with autopsy abdominal skin samples from PD cadavers. From posterior cervical and leg skin biopsy tissues from patients with PD and controls without PD, the sensitivity and specificity were 95% (95% CI, 77-100) and 100% (95% CI, 84-100), respectively, for RT-QuIC and 80% (95% CI, 49-96) and 90% (95% CI, 60-100) for PMCA. Conclusions and Relevance This study provides proof-of-concept that skin αSynPseeding activity may serve as a novel biomarker for antemortem diagnoses of PD and other synucleinopathies.

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ObjectiveTo 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.MethodsWe 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.ResultsImmunofluorescence 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.ConclusionsBoth 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 EvidenceThis study provides Class III evidence that immunofluorescence or RT-QuIC accurately distinguish synucleinopathies from non-synucleinopathies.

Introduction: Cardiac [123I]metaiodobenzylguanidine scintigraphy (123I-MIBG) is considered a useful test in differentiating multiple system atrophy (MSA) and Lewy body disorders (LBD), including idiopathic Parkinson's disease (IPD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF). The detection of skin nerve phosphorylated α-synuclein (p-α-syn) deposits could be an alternative marker in vivo. We sought to compare 123I-MIBG scintigraphy and skin biopsy findings in α-synucleinopathies. Methods: We studied 54 patients (7 DLB, 21 IPD, 13 PAF, 13 MSA) who underwent 123I-MIBG scintigraphy and skin biopsy to evaluate cardiac innervation and skin p-α-syn deposition, respectively. Results: Cardiac denervation was observed in 90.5% IPD, 100% DLB and PAF and in none of the MSA patients (P < 0.0001) whereas p-α-syn deposits were detected in all DLB and PAF, in 95.2% of IPD and 69.2% of MSA patients (P = 0.02). However, the analysis of skin structures disclosed a different distribution of the deposits in somatic subepidermal plexus and autonomic fibers among groups, showing that p-α-syn deposits rarely affected the autonomic fibers in MSA as opposed to LBD. Studying the p-α-syn deposition in autonomic nerves, concordance among I123-MIBG scintigraphy and skin biopsy results was observed in 100% of DLB and PAF, 95.2% IPD and 92.3% MSA patients. I123-MIBG scintigraphy and autonomic p-α-syn deposits analysis both showed a sensitivity of 97.5% and a specificity of 100% and 92.3%, respectively, in distinguishing LBD and MSA. Conclusion: Skin biopsy and 123-MIBG scintigraphy can be considered alternative tests for the differential diagnosis of IPD, PAF and DLB versus MSA.

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.

Objective To verify whether the finding of denervation activity on EMG at the time of diagnosis has a prognostic value in amyotrophic lateral sclerosis (ALS). Methods We retrospectively studied all the patients discharged with a diagnosis of ALS between January 2009 and January 2017. 92 patients met the inclusion criteria. We mainly verified three prognostic targets: (1) Time to non-invasive ventilation (NIV) or tracheostomy. (2) Time to percutaneous endoscopic gastrostomy or parental nutrition. (3) Survival. All EMG examinations were reviewed and a denervation score (DS) was calculated. The association of DS with clinical milestones was analysed, adjusting for disease duration, age , sex, and clinical phenotype. Results We found a significant association between bulbar DS and time to NIV/tracheostomy (HR: 3.34, 95% CI: 1.49 to 7.48, p = 0.002) and with survival (HR 3.633, 95% CI 1.681–7.848, p = 0.001), regardless of the clinical phenotype. Furthermore, we found a significant influence of a general DS on survival (HR: 2.62, 95% CI 1.335–5.160, p = 0.005). Conclusion EMG assessment could be of value not just for ALS diagnosis but also for its intrinsic prognostic value. Significance EMG could provide additional information about the rate of progression of ALS as early as the diagnosis is made.

This study aimed to investigate phosphorylated alpha-synuclein (p-syn) in autonomic skin nerves of Parkinson disease (PD) patients with and without orthostatic hypotension (OH). We studied 28 PD patients with normal corrected Mini-Mental State Examination including 14 patients with neurogenic OH (PD + OH) and 14 matched patients did not complain of OH (PD - OH); 7 of whom were re-evaluated over a follow-up period (4 +/- 2 years). Skin biopsy was performed in proximal and distal sites. PD + OH patients showed a higher p-syn deposition than PD - OH, with widespread autonomic cholinergic and adrenergic skin nerve involvement. Over the follow-up period, PD - OH patients showed an increase in motor dysfunction scores without autonomic symptoms and a slight increase of skin p-syn deposition but still lower than PD + OH, mainly restricted to adrenergic fibers of skin vessels (SV). In summary, PD - OH patients showed a wide involvement of p-syn deposits in autonomic cholinergic and adrenergic skin nerves compared with PD -OH, and PD -OH patients showed a lower load of skin p-syn restricted to adrenergic fibers of SV still persisting over the follow-up period. The data supported a different pathogenesis between PD + OH and PD - OH and may help to identify a specific diagnostic trait for PD + OH.

BACKGROUND AND PURPOSE We aimed to test the clinical utility of the leg:thigh intraepidermal nerve-fiber (IENF) density ratio as a parameter to discriminate between length-dependent small-fiber neuropathy (SFN) and small-fiber sensory ganglionopathy (SFSG) in subjects with signs and symptoms of small-fiber pathology. METHODS We retrospectively evaluated thigh and leg IENF density in 314 subjects with small-fiber pathology (173 with distal symmetrical length-dependent SFN and 141 with non-length-dependent SFSG). A group of 288 healthy subjects was included as a control group. The leg:thigh IENF density ratio was calculated for all subjects. We used receiver operating characteristic curve analyses to assess the ability of this parameter to discriminate between length-dependent SFN and SFSG, and the decision curve analysis to estimate its net clinical benefit. RESULTS In patients with neuropathy, the mean IENF density was 14.8 ± 6.8/mm at the thigh (14.0 ± 6.9/mm in length-dependent SFN and 15.9 ± 6.7/mm in patients with SFSG) and 7.5 ± 4.5/mm at the distal leg (5.4 ± 3.2/mm in patients with length-dependent SFN and 10.1 ± 4.6/mm in patients with SFSG). The leg:thigh IENF density ratio was significantly (P < 0.01) lower in patients with length-dependent SFN (0.44 ± 0.23) compared with patients with SFSG (0.68 ± 0.28). The area under the curve of the receiver operating characteristic analysis to discriminate between patients with length-dependent SFN and SFSG was 0.79. The decision curve analysis demonstrated the clinical utility of this parameter. CONCLUSIONS The leg:thigh IENF ratio represents a valuable tool in the differential diagnosis between SFSG and length-dependent SFN.