Phosphorylated α-Synuclein Deposits in Cutaneous Nerves of Early Parkinsonism

Abstract

Background: The role of peripheral phosphorylated-α-Synuclein (p-α-syn) deposition on nerve degeneration in synucleinopathies is still unknown. Objective: To assess the cutaneous neural distribution of p-α-Syn deposits and its correlation with clinical data and with morphology and function of cutaneous sensory and autonomic nerves in early Parkinson’s disease (PD) and multiple system atrophy-parkinson type (MSA-p). Methods: We recruited 57 PD (F/M = 21/36; age 63.5±9.4 years) and 43 MSA-p (F/M = 16/27; age 62.3±9.0 years) patients within 2 years from motor symptoms. We applied questionnaires and clinical scales, sensory thresholds, and sudomotor testing to assess severity of motor and non-motor involvement and sensory and autonomic dysfunction. We quantified, in skin biopsy from thigh, leg, and fingertip, epidermal, pilomotor, and sudomotor nerve fibers, Meissner corpuscles and intrapapillary myelinated endings and the neural distribution of p-α-syn deposits. Results: Compared to controls, we found a cutaneous denervation paralleling functional and clinical impairment. Sensory and autonomic denervation was more severe in MSA-p than in PD. Deposits of p-α-syn were found in the majority of patients, with no significant differences among sites in both groups. Higher occurrence of p-α-syn deposits in autonomic nerves differentiated (p < 0.01) PD from MSA-p. p-α-syn deposits correlated positively with sudomotor function, epidermal, pilomotor and sudomotor nerve densities, and inversely with non-motor symptoms and disease progression. Conclusion: Our work demonstrated an early peripheral sensory and autonomic involvement in synucleinopathies, more severe in MSA-p than in PD. Higher p-α-syn deposits in autonomic nerves differentiated PD from MSA-p. p-α-syn deposits were associated with preserved innervation and slower disease progression.

Pain in Multiple System Atrophy a Systematic Review and Meta‐Analysis

“…The mechanisms underlying neuropathic forms of pain in MSA are not fully understood to date. Reduced subjective and objective pain thresholds have been reported in MSA individuals 21,[41][42][43] and both peripheral, that is, large and small fiber neuropathy, 31,[44][45][46][47] as well as central mechanisms likely contribute to such phenomenon. Within the central nervous system, nociception may be facilitated by neurodegenerative changes affecting the spinal cord, 41,42,48,49 or supraspinal pain-processing relays, including serotoninergic and noradrenergic brainstem nuclei, thalamus, and basal ganglia.…”

“…The prevalence of pain in individuals with MSA seems higher compared to other forms of atypical parkinsonism, including corticobasal degeneration and progressive supranuclear palsy (PSP), for which another recent meta‐analysis estimated a pooled pain prevalence of 25% and 52%, respectively. 13 Several factors may account for the higher prevalence of pain in MSA individuals: the different distribution of neuropathological changes, 22 a more pronounced spinal cord , 30 or small fiber involvement in MSA individuals that may contribute to an altered pain perception, 31 or ultimately the presence of multiple potentially painful motor and autonomic features typical of advanced MSA stages. On the other hand, the cognitive impairment developing in individuals with PSP might prevent them from recognizing or communicating painful sensations, introducing an additional barrier to pain recognition in clinical practice.…”

Alpha-Synuclein in Peripheral Tissues as a Possible Marker for Neurological Diseases and Other Medical Conditions

“…The first description of the presence of aSyn in the skin from 3 of 16 PD patients and in 1 of 5 HCs was carried out by Michel et al in 2005 [ 123 ]. Since then, there have been many reports regarding the detection of aSyn and phosphorylated aSyn in skin biopsies as a possible marker for PD and other synucleinopathies, which are summarized in Table 3 [ 123 , 168 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237...…”

“…Since then, there have been many reports regarding the detection of aSyn and phosphorylated aSyn in skin biopsies as a possible marker for PD and other synucleinopathies, which are summarized in Table 3 [ 123 , 168 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 , 220 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 , 236 , 237 ]. Depending on the method used and the site on which the skin biopsy was performed (with higher rates of positivity for cervical skin), the frequency of detection of aSyn in PD patients has shown great variability...…”

“…Depending on the method used and the site on which the skin biopsy was performed (with higher rates of positivity for cervical skin), the frequency of detection of aSyn in PD patients has shown great variability, ranging from positive percentages of lower than 10% [ 196 , 200 ] to 80–100% [ 201 , 203 , 208 , 214 , 216 , 217 , 219 , 220 , 221 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 231 , 232 , 234 , 235 , 236 , 237 ]. The frequency of immunopositivity for aSyn and/or aSyn deposition was evenly and significantly higher for PD patients than for HCs [ 195 , 197 , 198 , 199 , 201 , 202 , 203 , 204 , 206 , 207 , 209 , 210 , 212 , 223 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 234 ...…”