Pathophysiology of Small-Fiber Sensory System in Parkinson's Disease

Abstract

Sensory symptoms are frequent nonmotor complaints in patients with Parkinson's disease (PD). However, few investigations integrally explored the physiology and pathology of the thermonociceptive pathway in PD. We aim to investigate the involvement of the thermonociceptive pathway in PD.Twenty-eight PD patients (16 men, with a mean age and standard deviation of 65.6 ± 10.7 years) free of neuropathic symptoms and systemic disorders were recruited for the study and compared to 23 age- and gender-matched control subjects (12 men, with a mean age and standard deviation of 65.1 ± 9.9 years). We performed skin biopsy, contact heat-evoked potential (CHEP), and quantitative sensory tests (QST) to study the involvement of the thermonociceptive pathway in PD.The duration of PD was 7.1 ± 3.2 (range 2–17 years) years and the UPDRS part III score was 25.6 ± 9.7 (range 10–48) during the off period. Compared to control subjects, PD patients had reduced intra-epidermal nerve fiber (IENF) density (2.48 ± 1.65 vs 6.36 ± 3.19 fibers/mm, P < 0.001) and CHEP amplitude (18.02 ± 10.23 vs 33.28 ± 10.48 μV, P < 0.001). Twenty-three patients (82.1%) had abnormal IENF densities and 18 (64.3%) had abnormal CHEP. Nine patients (32.1%) had abnormal thermal thresholds in the feet. In total 27 patients (96.4%) had at least 1 abnormality in IENF, CHEP, or thermal thresholds of the foot, indicating dysfunctions in the small-fiber nerve system. In control subjects, CHEP amplitude linearly correlated with IENF density (P < 0.001). In contrast, this relationship disappeared in PD (P = 0.312) and CHEP amplitude was negatively correlated with motor severity of PD independent of age, gender, and anti-PD medication dose (P = 0.036), suggesting the influences of central components on thermonociceptive systems in addition to peripheral small-fiber nerves in PD.The present study suggested impairment of small-fiber sensory system at both peripheral and central levels is an intrinsic feature of PD, and skin biopsy, CHEP, and QST provided an integral approach for assessing such dysfunctions.

Early prodromal sensory neuropathy in Pink1-SNCA double mutant Parkinson mice

“…Morphologically, we did not detect overt signs of neuronal death or damage in DRGs of Pink1SNCA mice, but it has been shown that the density of sensory fiber terminals in the skin is reduced in PD patients [15,58], which is not a specific observation for PD associated sensory neuropathies but occurs frequently in sensory neuropathies associated with metabolic diseases such as diabetes mellitus [62]. The similarities suggests that metabolic dysfunctions of sensory neurons, which are not…”

“…They develop a progressive loss of thermal sensation far earlier than the earliest occurrence of clinical motor dysfunctions. The sensory phenotype is reminiscent of QST phenotypes of PD patients, which presents with a predominant loss of thermal sensation and preservation of mechanical sensitivity or mechanical hypersensitivity [18,58]. Pink1SNCA mice replicate the thermal versus mechanical dichotomy.…”

Temperature Sensation in Parkinson’s Disease Measured by Quantitative Sensory Testing

“…Some studies found reduced thermal detection thresholds after STN-DBS (Deep Bran Stimulation of the Subthalamic Nucleus) [3,11,14,16,20,21], suggesting that central pathology plays a role in abnormal thermal sensation. Peripheral deafferentation probably also plays a role [15,17], as small ber neuropathy has been con rmed on skin biopsies in PD patients [6,7].…”

“…Only a limited number of studies have investigated thermal abnormalities in PD [11][12][13][14][15][16][17][18][19] and the underlying pathophysiology still remains unclear. Most of the published studies found increased thermal detection thresholds but no responsiveness to levodopa, suggesting that thermal abnormalities do not depend on dopaminergic de cit.…”

Small Fibre Neuropathy in Parkinson’s Disease: Comparison of Skin Biopsies from the More Affected and Less Affected Sides

“…Intraepidermal nerve fibre density (IENFD) is the gold standard measure to quantify loss of skin innervation to diagnose a small fibre neuropathy (SFN) [5]. Several studies have demonstrated a significant reduction in IENFD in patients with PD [6][7][8]. These studies utilised immunostaining with the pan-axonal marker protein gene product 9.5 (PGP9.5).…”