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Background: Tauopathies are a group of age-related neurodegenerative diseases characterized by the accumulation of pathologically hyperphosphorylated tau protein in the brain, leading to prion-like aggregation and propagation. They include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease (PiD). Currently, reliable diagnostic biomarkers that directly reflect the capability of propagation and spreading of misfolded tau aggregates in peripheral tissues and body fluids are lacking., Methods: We utilized the seed-amplification assay (SAA) employing ultrasensitive real-time quaking-induced conversion (RT-QuIC) to assess the prion-like seeding activity of pathological tau in the skin of cadavers with neuropathologically confirmed tauopathies, including AD, PSP, CBD, and PiD, compared to normal controls., Results: We found that the skin tau-SAA demonstrated a significantly higher sensitivity (75-80%) and specificity (95-100%) for detecting tauopathy, depending on the tau substrates used. Moreover, the increased tau-seeding activity was also observed in biopsy skin samples from living AD and PSP patients examined. Analysis of the end products of skin-tau SAA confirmed that the increased seeding activity was accompanied by the formation of tau aggregates with different physicochemical properties related to two different tau substrates used., Conclusions: Overall, our study provides proof-of-concept that the skin tau-SAA can differentiate tauopathies from normal controls, suggesting that the seeding activity of misfolded tau in the skin could serve as a diagnostic biomarker for tauopathies., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures and protocols were monitored and approved by the Institutional Review Boards (IRBs) of University Hospitals Cleveland Medical Center, Banner Sun Health Research Institute, and IRCCS Institute of Neurological Sciences of Bologna. Written informed consent was obtained from all living subjects undergoing skin biopsy or from family members for skin autopsy. For post-mortem sample collection, we obtained the specimens with respect to the wishes of the deceased and their family, following all legal and ethical guidelines. For skin biopsy procedures, all participants provided their informed consent prior to their inclusion in the study. Consent for publication: All participants in this study have provided written informed consent for their data and samples to be used in this research. Participants were also informed that the results of this study may be published and that all data would be fully anonymized to protect confidentiality. Competing interests: Authors declare that they have no competing interests., (© 2024. The Author(s).)

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., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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., (Copyright © 2021. Published by Elsevier Ltd.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The aim of our study was to assess the distribution of phosphorylated α-synuclein (p-syn) deposits in a patient affected by early stage Parkinson disease and orthostatic hypotension through a longitudinal skin biopsy study. We found widespread p-syn spatial diffusion from deep autonomic dermis nerve bundles to autonomic terminals, suggesting a centrifugal spread of p-syn from ganglia to the innervation target structures. Furthermore, the case suggests the possibility of discriminating synucleinopathies at an early stage of disease by means of skin biopsy. If confirmed, these data support skin biopsy as a useful and promising tool for the diagnosis, longitudinal evaluation, and pathological understanding of Parkinson disease., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

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., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

Purpose: The in vivo diagnosis of synucleinopathies is an important research aim since clinical diagnostic criteria show low accuracy. The skin innervation, especially the autonomic subdivision, is a useful region to search for abnormal α-syn aggregates in synucleinopathies since the peripheral sympathetic nerves can be the earliest-affected neural region and autonomic symptoms may precede the classical symptoms of these disorders., Methods: The major advantages of skin biopsy as an in vivo diagnostic tool for synucleinopathies are that it is an inexpensive and easy-to-perform technique requiring only limited facilities, and that it is repeatable in long-term studies as it causes only minor discomfort to the patient., Results: This review analyzes current progress in this area of research that may facilitate the standardization of this method, potentially eliminating differences among laboratories in the implementation of the method., Conclusions: The most suitable and commonly used technique for identifying in vivo α-syn aggregates in skin nerves is indirect immunofluorescence, although several aspects of this approach need to be standardized, particularly when synucleinopathies without autonomic failure present a patchy distribution of abnormal α-syn aggregates in skin nerves. By contrast, synucleinopathies with autonomic failure may present widespread diffusion of abnormal aggregates in autonomic skin nerves.

The autonomic innervation of the skin includes different subsets of adrenergic and cholinergic fibers both in humans and animals. The corresponding chemical code is complex and often difficult to ascertain. Accordingly, a detailed histochemical description of skin autonomic fiber subtypes is lacking in humans. To characterize skin autonomic nerve subtypes may help to better understand the selective damage of specific skin autonomic fibers affecting human diseases such as the adrenergic fibers directed to skin vessels in Parkinson's disease or the cholinergic sudomotor fibers in Ross Syndrome. The present study aimed at characterizing subtypes of autonomic fibers in relation to their target organs by means of an immunofluorescent technique and confocal microscopy. We studied 8 healthy subjects (5 males and 3 females) aged 45 ± 2 (mean ± SE) years without predisposing causes for peripheral neuropathy or autonomic disorders. They underwent skin biopsy from proximal (thigh) and distal (leg) hairy skin. A combination of adrenergic (i.e. tyrosine-hydroxylase- TH and dopamine beta-hydroxylase- DbH) and cholinergic (vesicular acetylcholine transporter- VACHT) autonomic markers and neuropeptidergic (i.e. neuropeptide Y- NPY, calcitonin gene-related peptide- CGRP, substance P- SP, and vasoactive intestinal peptide- VIP) markers were used to characterize skin autonomic fibers. The analysed skin autonomic structures included: 58 sweat glands, 91 skin arterioles and 47 arrector pili muscles. Our results showed that all skin structures presented a sympathetic adrenergic but also cholinergic innervation although in different proportions. Sympathetic adrenergic fibers were particularly abundant around arterioles and arrector pili muscles whereas sympathetic cholinergic fibers were mainly found around sweat glands. Neuropeptides were differently expressed in sympathetic fibers: NPY were found in sympathetic adrenergic fibers around skin arterioles and very seldom sweat glands but not in adrenergic fibers of arrector pili muscles. By contrast CGRP, SP and VIP were expressed in sympathetic cholinergic fibers. Cholinergic fibers expressing CGRP, SP or VIP without TH or DbH staining were found in arterioles and arrector pili muscles and they likely represent parasympathetic fibers. In addition, all skin structures contained a small subset of neuropeptidergic fibers devoid of adrenergic and cholinergic markers with a likely sensory function. No major differences were found between males and females and proximal and distal sites. In summary hairy skin contains sympathetic adrenergic and cholinergic fibers differently distributed around skin structures with a specific distribution of neuropeptides. The autonomic skin innervation also contains a small amount of fibers, likely to be parasympathetic and sensory.

Background and Purpose: Visualization of phosphorylated α-synuclein at serine 129 (p-syn) in skin nerves is a promising test for the in vivo diagnosis of synucleinopathies. Here the aim was to establish the intra- and inter-laboratory reproducibility of measurement of intraneural p-syn immunoreactivity in two laboratories with major expertise (Würzburg and Bologna)., Methods: In total, 43 patients affected by Parkinson's disease (PD 21 patients), dementia with Lewy bodies (DLB 1), rapid eye movement sleep behaviour disorder (RBD 11), multiple system atrophy (MSA-P 4) and small fibre neuropathy (SFN 6) were enrolled. Skin biopsy was performed at the C7 paravertebral spine region and distal skin sites (thigh or leg). The analysis was standardized in both laboratories and carried out blinded on a single skin section double stained with antibodies to p-syn and the pan-axonal marker protein gene product 9.5. Fifty skin sections were randomly selected for the analysis: 25 from C7 and 25 from distal sites. Differently classified sections were re-evaluated to understand the reasons for the discrepancy., Results: The intra-laboratory analysis showed an excellent reproducibility both in Würzburg (concordance of classification 100% of sections; K = 1; P < 0.001) and Bologna (96% of sections; K = 0.92; P < 0.001). Inter-laboratory analysis showed reproducibility in 45 sections (90%; K = 0.8; P < 0.001) and a different classification in five sections, which was mainly due to fragmented skin samples or weak fluorescent signals., Conclusions: Analysis of p-syn showed excellent inter- and intra-laboratory reproducibility supporting the reliability of this technique. The few ascertained discordances were important to further improve the standardization of this technique., (© European Academy of Neurology 2019.)

To search for discriminating biomarkers, 30 patients with idiopathic rapid-eye-movements sleep behavior disorder (iRBD) were compared with 17 patients with RBD within narcolepsy type 1. Both groups underwent extensive examinations, including skin biopsy searching for phosphorylated α-synuclein deposits and whole-night video-polysomnography. Skin biopsy was positive for phosphorylated α-synuclein deposits in 86.7% of iRBD patients and in none of narcoleptic patients. The analysis of video-polysomnographic motor events showed differences in their occurrence throughout the night in the two groups. iRBD and RBD due to narcolepsy do have different clinical and pathological findings, confirming a different pathophysiology., (© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.)

This study aimed to investigate phosphorylated α-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.

We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify the clinical variability. We studied multiple skin nerve α-syn deposits in 44 patients with synucleinopathy: 15 idiopathic Parkinson's disease (IPD), 12 dementia with Lewy Bodies (DLB), 5 pure autonomic failure (PAF) and 12 multiple system atrophy (MSA). Ten healthy subjects were used as controls. Antibodies against native α-syn, C-terminal α-syn epitopes such as phosphorylation at serine 129 (p-syn) and to conformation-specific for α-syn mature amyloid fibrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specificity in disclosing skin α-syn deposits. In MSA abnormal deposits were only found in somatic fibers mainly at distal sites differently from PAF, IPD and DLB displaying α-syn deposits in autonomic fibers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fibers., In Conclusion: 1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load differences of aggregates may help to identify specific diagnostic traits and support a different pathogenesis among synucleinopathies.

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., (© 2018 EAN.)

Objective: To investigate whether (1) phosphorylated α-synuclein (p-syn) deposits in skin nerves could be useful in differentiating dementia with Lewy bodies (DLB) from different forms of dementia and (2) small fiber neuropathy (SFN) is associated with DLB., Methods: We studied 18 well-characterized patients with DLB (11 with autonomic dysfunction), 23 patients with nonsynucleinopathy dementia (NSD; 13 with young-onset Alzheimer disease dementia, 6 frontotemporal dementia, and 4 vascular dementia), and 25 healthy controls. All participants underwent skin biopsies from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of p-syn, considered the pathologic form of α-synuclein., Results: No p-syn was detected in any skin sample in patients with NSD and controls but was found in all patients with DLB. SFN was found in patients with DLB and the autonomic denervation of skin was more severe in patients with autonomic dysfunctions., Conclusions: (1) In autonomic skin nerves, p-syn is a sensitive biomarker for DLB diagnosis, helping to differentiate DLB from other forms of dementia, although this needs to be confirmed in a larger, more representative sample; and (2) skin autonomic neuropathy is part of the DLB pathology and may contribute to autonomic symptoms., Classification of Evidence: This study provides Class III evidence that p-syn in skin nerve fibers on skin biopsy accurately distinguishes DLB from other forms of dementia., (© 2017 American Academy of Neurology.)

Objective: To test if phosphorylated α-synuclein (p-α-syn) deposits can be detected by means of skin biopsy in patients with idiopathic REM sleep behavior disorder (iRBD) as a potential early histopathologic marker of impending synucleinopathy., Methods: Proximal (cervical) and distal (legs) samples of skin biopsy were obtained from 12 patients with polysomnographically confirmed iRBD and 55 sex- and age-matched healthy controls (HC). P-α-syn deposits were assessed with a monoclonal antibody against p-α-syn at serine 129, disclosed by an immunofluorescence method. In addition, patients underwent an extensive workup in order to search for nonmotor symptoms and neuroimaging findings usually associated with impending neurodegeneration and to exclude subtle motor or cognitive signs., Results: P-α-syn deposits were detected in 9 (75%) out of 12 patients with iRBD and none of the HC. In iRBD, the sensitivity of the test was higher at the cervical site (67%) when compared to the leg site (58%)., Conclusions: Our preliminary findings suggest that skin biopsy in patients with iRBD might be a safe and sensitive procedure to be further tested in order to detect p-α-syn deposits in the premotor stage of synucleinopathies., Classification of Evidence: This study provides Class III evidence that p-α-syn skin deposits identify patients with iRBD., (© 2017 American Academy of Neurology.)

Phosphorylated α-synuclein (p-syn) in skin nerves mainly in the proximal sites is a promising neurodegenerative biomarker for idiopathic Parkinson disease (IPD). However, the p-syn spine distribution particularly in patients with unilateral motor dysfunctions remains undefined. This study aimed to investigate in IPD p-syn differences between left and right cervical spine sites in patients with prevalent unilateral motor symptoms, and cervical and thoracic spine sites in patients with bilateral motor symptoms. We enrolled 28 IPD patients fulfilling clinical diagnostic criteria associated with abnormal nigro-striatal DatScan and cardiac MIBG: 15 with prevalently unilateral motor symptoms demonstrated by DatScan; 13 with bilateral motor symptoms and DatScan abnormalities. Patients underwent skin biopsy searching for intraneural p-syn deposits: skin samples were taken from C7 paravertebral left and right sites in unilateral patients and from cervical (C7) and thoracic (Th12) paravertebral spine regions in bilateral patients. Unilateral patients displayed 20% of abnormal p-syn deposits in the affected motor site, 60% in both sites and 20% only in the non-affected site. P-syn was found in all patients in C7 but in only 62% of patients in Th12. Our data showed that cervical p-syn deposits displayed a uniform distribution between both sides not following the motor dysfunction in unilateral patients, and skin nerve p-syn deposits demonstrated a spine gradient with the cervical site expressing the highest positivity., (© 2017 American Association of Neuropathologists, Inc. All rights reserved.)

Skin biopsy and microneurography are autonomic tests directly evaluating adrenergic and cholinergic sympathetic fibers to identify selective deficiency of a specific peripheral sympathetic subdivision. We describe a patient with tomacular neuropathy due to a deletion of the PMP22 gene who complained of chronic orthostatic hypotension due to a dopamine-β-hydroxylase deficiency confirmed by genetic analysis demonstrating two novel mutations in the DβH gene. To further characterize autonomic dysfunctions the proband underwent skin biopsy and microneurography. These tests disclosed a selective peripheral adrenergic dysfunction demonstrating the possibility to ascertain DβH deficiency. In conclusion, skin biopsy and microneurography may help to increase the diagnosis of this peculiar disorder particularly when routine autonomic nervous system tests show uncertain results., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To characterize the expression in skin nerves of native (n-syn) and misfolded phosphorylated (p-syn) α-synucleins in pure autonomic failure (PAF) and idiopathic Parkinson disease (IPD). The specific aims were to (1) define the importance of n-syn and p-syn as disease biomarkers and (2) ascertain differences in abnormal synuclein skin nerve deposits., Methods: We studied 30 patients, including 16 well-characterized IPD patients and 14 patients fulfilling PAF diagnostic criteria, and 15 age-matched controls. Subjects underwent skin biopsy from proximal (ie, cervical) and distal (ie, thigh and leg) sites to study small nerve fiber and intraneural n-syn and p-syn., Results: PAF and IPD showed length-dependent somatic and autonomic small fiber loss, more severely expressed in patients with higher p-syn load. n-syn was similarly expressed in both groups of patients and controls. By contrast, p-syn was not evident in any skin sample of controls but was found in all PAF and IPD patients, although with different skin innervation. In addition, abnormal α-synuclein deposits were found in all analyzed skin samples in PAF but in only 49% of samples with a higher positivity rate at the proximal site in IPD., Interpretation: (1) Intraneural p-syn was a reliable in vivo marker of PAF and IPD; (2) neuritic p-syn inclusions differed in PAF and IPD, suggesting a different underlying pathogenesis; (3) when searching for abnormal p-syn deposits in skin nerves, the site of analysis is irrelevant in PAF but it is critical in IPD., (© 2015 American Neurological Association.)

Background: (123) I-meta-iodobenzylguanidine ((123) I-MIBG) myocardial scintigraphy is considered reliable in differentiating idiopathic Parkinson's disease (IPD) from other parkinsonisms, but it is biased by pharmacological treatments. Skin biopsy is not influenced by therapy and has disclosed skin denervation in IPD. Our aims were to compare (123) I-MIBG scintigraphy and skin biopsy findings in IPD and parkinsonisms to (1) verify whether myocardial and skin denervations are linked; (2) explore the simultaneous extent of the autonomic dysfunction., Methods: We studied 22 IPD and 11 parkinsonism patients by means of (123) I-MIBG scintigraphy and skin biopsies., Results: In the IPD group, both (123) I-MIBG scintigraphy and skin biopsy results were abnormal in 91% of patients, showing concordance in 82% of cases. In parkinsonisms, results of both tests were normal in all patients., Conclusion: (1) Skin biopsy and (123) I-MIBG scintigraphy provide comparable results; (2) in IPD, autonomic dysfunctions are often simultaneously widespread at cardiac and skin branches. © 2015 International Parkinson and Movement Disorder Society., (© 2015 International Parkinson and Movement Disorder Society.)

Introduction: Fibromyalgia (FM) is a chronic syndrome characterized by widespread pain often accompanied by other symptoms suggestive of neuropathic pain. We evaluated patients for small fiber neuropathy (SFN) who were referred for fibromyalgia (FM)., Methods: We studied 20 consecutive subjects with primary FM. Patients underwent neurological examination, nerve conduction studies, and skin biopsies from distal leg and thigh., Results: Electrodiagnostic studies were normal in all patients. SFN was diagnosed in 6 patients by reduced epidermal nerve fiber density. These patients also showed abnormalities of both adrenergic and cholinergic fibers., Conclusions: A subset of FM subjects have SFN, which may contribute to their sensory and autonomic symptoms. Skin biopsy should be considered in the diagnostic work-up of FM., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: To investigate (1) whether phosphorylated α-synuclein deposits in skin nerve fibers might represent a useful biomarker for idiopathic Parkinson disease (IPD), and (2) the underlying pathogenesis of peripheral neuropathy associated with IPD., Methods: Twenty-one well-characterized patients with IPD were studied together with 20 patients with parkinsonisms assumed not to have α-synuclein deposits (PAR; 10 patients fulfilling clinical criteria for vascular parkinsonism, 6 for tauopathies, and 4 with parkin mutations) and 30 controls. Subjects underwent nerve conduction velocities from the leg to evaluate large nerve fibers and skin biopsy from proximal (i.e., cervical) and distal (i.e., thigh and distal leg) sites to study small nerve fibers and deposits of phosphorylated α-synuclein considered the pathologic form of α-synuclein., Results: Patients with IPD showed a small nerve fiber neuropathy prevalent in the leg with preserved large nerve fibers. PAR patients showed normal large and small nerve fibers. Phosphorylated α-synuclein was not found in any skin sample in PAR patients and controls, but it was found in all patients with IPD in the cervical skin site. Abnormal deposits were correlated with leg epidermal denervation., Conclusions: The search for phosphorylated α-synuclein in proximal peripheral nerves is a sensitive biomarker for IPD diagnosis, helping to differentiate IPD from other parkinsonisms. Neuritic inclusions of α-synuclein were correlated with a small-fiber neuropathy, suggesting their direct role in peripheral nerve fiber damage., Classification of Evidence: This study provides Class III evidence that the presence of phosphorylated α-synuclein in skin nerve fibers on skin biopsy accurately distinguishes IPD from other forms of parkinsonism.

Objectives: Ross syndrome (RS) is a rare degenerative disorder characterized by tonic pupil, areflexia and anhydrosis. The underlying lesion affects postganglionic skin sympathetic nerve fibers whereas the postganglionic muscle sympathetic branch is thought to be spared. Microneurography explores both skin and muscle peripheral sympathetic branches and it does not usually detect peripheral sympathetic outflow in either branch in chronic autonomic failure syndromes. The aim of this study was to record sympathetic activity by microneurography for the first time in RS patients to confirm the selective involvement of skin sympathetic nerve activity (SSNA) with spared muscle sympathetic nerve activity (MSNA)., Methods: We studied seven patients (49 ± 14 years, four males) with a typical clinical picture and skin biopsy findings. Patients underwent cardiovascular reflexes and microneurography from the peroneal nerve (anhydrotic skin) to record MSNA, SSNA and the corresponding organ effector responses (skin sympathetic response-SSR and skin vasomotor response-SVR) in the same innervation field. The absence of sympathetic bursts was established after exploring at least three different corresponding nerve fascicles. Twenty age-matched healthy subjects served as controls., Results: RS patients complained of diffuse anhydrosis and they showed tonic pupil and areflexia. Cardiovascular reflexes were normal. All patients displayed absent SSNA, SSR and SVR whereas MSNA was always recorded showing normal characteristics., Conclusion: Microneurographic study of sympathetic activity from affected skin confirmed the selective involvement of skin sympathetic activity with spared muscle sympathetic activity and it may represent the neurophysiological hallmark of the disease., Significance: Microneurography together with clinical and skin biopsy findings may contribute to RS diagnosis. Our data also suggest that autonomic damage in RS does not involve cardiovascular activity., (Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Recent studies suggest that heterozygous female Fabry disease (FD) patients develop peripheral neuropathy. We used skin biopsy to define somatic and autonomic peripheral nerve characteristics in 21 females with FD who were mainly asymptomatic and had normal renal function. Somatic epidermal and dermal autonomic nerve fiber reductions were found, prevalently in the leg, and no differences were found between symptomatic and asymptomatic individuals. Our findings suggest that females with FD, although asymptomatic, may have somatic and autonomic small fiber neuropathy.

Ross syndrome is characterised by tonic pupil, areflexia and anhidrosis, and the underlying lesion affects postganglionic skin sympathetic nerve fibres. We describe a 51-year-old man who had complained of anhidrosis since adolescence, at which time this problem was limited to the lower arms. The thermoregulatory sweating test disclosed generalised anhidrosis (GA) except for two small skin areas that were located in the right palm and left neck. Immunofluorescence analysis disclosed no cholinergic sudomotor fibres around the sweat glands of non-sweating skin areas, which were evident although sparse and deranged in the sweating site. In our patient, GA was induced by degeneration of postganglionic sympathetic skin nerve fibres, as found in Ross syndrome, although his clinical picture was incomplete as it lacked tonic pupil and areflexia. Isolated GA induced by degeneration of postganglionic sympathetic nerve fibers, directly evaluated by skin biopsy, has not previously been described.

Ross syndrome is described as a rare disorder of sweating associated with areflexia and tonic pupil. Since Ross's first description in 1958, approximately 40 cases have been described. We assessed the involvement of cutaneous innervation in 12 subjects with Ross syndrome using quantitative sensory testing, sweating assessment and immunohistochemical study of anhidrotic and hyperhidrotic skin. This evaluation was repeated over time in 4 out of 12 subjects. In addition, we enrolled four subjects with Holmes-Adie syndrome (areflexia and tonic pupil) to investigate similarities between the two conditions. We found in Ross patients a complex and progressive involvement of cutaneous sensory and autonomic innervation underlying the impairment of heat production and heat dissipation through both loss of sweating and loss of cutaneous blood flow regulation. In Holmes-Adie subjects we found a mild impairment of sweating without thermoregulatory problems. The persistence of a sudomotor vasoactive intestinal peptide-immunoreactive (VIP-ir) innervation, although deranged and poor, definitely differentiated Holmes-Adie from Ross patients. Ross syndrome is a progressive and complex disorder of thermoregulation difficult to differentiate from the probably pathogenetically related Holmes-Adie syndrome. Sweating assessment and skin biopsy are suitable tools to define a boundary between them. Owing to the large number of Ross patients observed in only 5 years, and to the long and complex medical history of most of them, doubts arise on the effective rarity of this condition, and we warn family doctors and other specialists, besides neurologists, to become aware of this complex disorder.

Objective: The aim of this study was to characterize sympathetic adrenergic innervation of the skin in healthy subjects using dopamine beta hydroxylase (DbetaH) as a specific marker for noradrenergic fibers., Methods: Sympathetic adrenergic innervation of human skin was studied in 10 healthy subjects by indirect immunofluorescence and confocal microscopy applied to punch skin biopsies. Noradrenergic fibers were identified both in glabrous and hairy skin using DbetaH antibody., Results: DbetaH immunoreactive fibers were mainly localized in arteriovenous anastomoses, arrector pilorum muscles, and arterioles, whereas few adrenergic fibers were found around sweat glands., Interpretation: Our description of sympathetic adrenergic innervation of human skin aims to improve the diagnostic ability of skin biopsy to detect selective autonomic nervous system disorders.

Objective: Sympathetic skin response (SSR) and skin vasomotor response (SVR) habituation was thought to be induced by neural mechanisms. Here, we investigate the hypothesis that non-neural mechanisms could also be involved., Methods: We recorded sympathetic skin nerve activity (SSNA) from median nerve by microneurography and the corresponding SSR and SVR in 16 healthy subjects. Superficial electrical stimulation of the opposite median nerve was used to induce arousal responses., Results: Throughout stimulation, SSNA, SSR and SVR amplitude showed a significant reduction. During the first ten stimuli, SSNA showed a marked decrease highly correlated to SSR and SVR changes. During the subsequent 20 stimuli SSNA did not change whereas SSR and SVR significantly decreased. SVR was significantly influenced by skin temperature changes., Conclusions: Both neural and non-neural mechanisms are involved in SSR and SVR habituation. The neural mechanisms were predominant during the first part of stimulation whereas non-neural mechanisms prevailed during the last part of stimulation., Significance: During repeated arousal stimuli SSR and SVR amplitude changes did not reflect the strength of the corresponding sympathetic nerve traffic and must be interpreted with caution.

Generalised anhidrosis (GA) shows a uniform clinical picture whether the pathogenesis involves intrinsic abnormalities of sweat glands or postganglionic sympathetic cholinergic nerve dysfunction. We describe two patients who presented intolerance to heat and anhidrosis. In the first patient, symptoms started at 33 years of age, and were associated with absent tendon reflexes and a mydriatic right pupil unreactive to light. The other patient had been unable to sweat since birth. GA was diagnosed on the basis of clinical findings and thermoregulatory tests. Microneurography and morphological analysis of the skin and its innervation disclosed a different lesion site underlying GA in the two patients, and distinguished between a postganglionic autonomic nerve fibre lesion and sweat gland dysfunction.