The Effect of Curcumin on Idiopathic Parkinson Disease: A Clinical and Skin Biopsy Study.

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.

Presence of Skin α-Synuclein Deposits Discriminates Parkinson's Disease from Progressive Supranuclear Palsy and Corticobasal Syndrome.

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 < 0.001, Chi-square). The two p-syn positive patients were diagnosed with PSP and CBS, respectively. Although clinical and MRI findings supported these diagnoses, both patients had some atypical features more typical of synucleinopathies. CONCLUSION: The detection of skin p-syn deposits may help in the differential diagnosis of parkinsonism. Indeed, in this study, all PD patients and only two out of 26 with a clinical diagnosis of PSP/CBS had skin p-syn deposits. Furthermore, these two patients showed clinical features that could suggest an atypical synucleinopathy presentation or a mixed pathology.

Diagnostic and Prognostic Value of Conventional Brain MRI in the Clinical Work-Up of Patients with Amyotrophic Lateral Sclerosis.

Clinical signs of upper motor neuron (UMN) involvement are important in the diagnosis of amyotrophic lateral sclerosis (ALS) though are often difficult to analyze. Many studies using both qualitative and quantitative evaluations have reported abnormal Magnetic Resonance Imaging (MRI) findings at the level of the pyramidal pathway in patients with ALS. Although the most interesting results were obtained by quantitative studies using advanced MR techniques, the qualitative evaluation of MRI images remains the most-used in clinical practice. We evaluated the diagnostic and prognostic contribution of conventional 3T-MRI in the clinical work-up of ALS patients. Two neuroradiologists retrospectively assessed 3T-MRI data of 93 ALS patients and 89 controls. The features of interest were corticospinal tract (CST) T2/FLAIR hyperintensity, motor cortex (MC) T2*/SWI hypointensity, and selective MC atrophy. All MRI features were significantly more prevalent in ALS patients than in controls. The simultaneous presence of CST FLAIR hyperintensity and MC SWI hypointensity was associated with the highest diagnostic accuracy (sensitivity: 70%; specificity: 81%; positive predictive value, PPV: 90%; negative predictive value, NPV: 51%; accuracy: 73%) and a shorter survival (HR: 6.56, p = 0.002). Conventional 3T-MRI can be a feasible tool to detect specific qualitative changes based on UMN involvement and to support clinical diagnosis of ALS. Importantly, CST FLAIR hyperintensity and MC SWI hypointensity are predictors of shorter survival in ALS patients.

A Longitudinal Skin Biopsy Study of Phosphorylated Alpha-Synuclein in a Patient With Parkinson Disease and Orthostatic Hypotension.

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.

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.

The autonomic innervation of hairy skin in humans: an in vivo confocal study.

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.

Skin Nerve Phosphorylated α-Synuclein Deposits in Parkinson Disease With Orthostatic Hypotension.

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.