Abstract
Pathological aggregates of alpha-synuclein in peripheral dermal nerve fibers can be detected in patients with idiopathic Parkinson's disease and multiple system atrophy. This study combines skin biopsy staining for p-alpha-synuclein depositions and radionuclide imaging of the heart with [123I]-metaiodobenzylguanidine to explore peripheral denervation in both diseases. To this purpose, 42 patients with a clinical diagnosis of Parkinson's disease or multiple system atrophy were enrolled. All patients underwent a standardized clinical work-up including neurological evaluation, neurography, and blood samples. Skin biopsies were obtained from the distal and proximal leg, back, and neck for immunofluorescence double labeling with anti-p-alpha-synuclein and anti-PGP9.5. All patients underwent myocardial [123I]-metaiodobenzylguanidine scintigraphy. Dermal p-alpha-synuclein was observed in 47.6% of Parkinson's disease patients and was mainly found in autonomic structures. 81.0% of multiple system atrophy patients had deposits with most of cases in somatosensory fibers. The [123I]-metaiodobenzylguanidine heart-to-mediastinum ratio was lower in Parkinson's disease than in multiple system atrophy patients (1.94 ± 0.63 vs. 2.91 ± 0.96; p < 0.0001). Irrespective of the diagnosis, uptake was lower in patients with than without p-alpha-synuclein in autonomic structures (1.42 ± 0.51 vs. 2.74 ± 0.83; p < 0.0001). Rare cases of Parkinson's disease with p-alpha-synuclein in somatosensory fibers and multiple system atrophy patients with deposits in autonomic structures or both fiber types presented with clinically overlapping features. In conclusion, this study suggests that alpha-synuclein contributes to peripheral neurodegeneration and mediates the impairment of cardiac sympathetic neurons in patients with synucleinopathies. Furthermore, it indicates that Parkinson's disease and multiple system atrophy share pathophysiologic mechanisms of peripheral nervous system dysfunction with a clinical overlap.
Highlights
Deposition of alpha-synuclein aggregates in neurons and glia can be found in idiopathic Parkinson’s disease (PD) and multiple system atro phy (MSA) (Dickson et al, 1999; Dickson et al, 2009)
Patients with MSA show p-alpha-syn-positive dermal nerve fibers but affected fiber types differ from PD: in MSA, depositions have mainly been observed in somatosensory fibers of the subepidermal plexus, while they predominantly occur in autonomic dermal nerve fibers in PD (Donadio et al, 2018b; Doppler et al, 2015)
The remaining 42 pa tients had a diagnosis of PD or MSA (21 patients in each group)
Summary
Deposition of alpha-synuclein aggregates in neurons and glia can be found in idiopathic Parkinson’s disease (PD) and multiple system atro phy (MSA) (Dickson et al, 1999; Dickson et al, 2009). In PD, alpha-synuclein aggregates are typically found in neurons forming socalled Lewy bodies, whereas in MSA oligodendrocytes are predomi nantly affected by glial cytoplasmic inclusions (Dickson et al, 1999; Dickson et al, 2009; Spillantini, 1999). Patients with MSA show p-alpha-syn-positive dermal nerve fibers but affected fiber types differ from PD: in MSA, depositions have mainly been observed in somatosensory fibers of the subepidermal plexus, while they predominantly occur in autonomic dermal nerve fibers in PD (Donadio et al, 2018b; Doppler et al, 2015). MIBG uptake is typically clearly reduced in PD, but not or only slightly reduced in patients with MSA (Orimo et al, 2012; Treglia et al, 2012)
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