Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy

Brumberg, Joachim; Kuzkina, Anastasia; Lapa, Constantin; Mammadova, Sona; Buck, Andreas; Volkmann, Jens; Sommer, Claudia; Isaias, Ioannis U.; Doppler, Kathrin

doi:10.1016/j.nbd.2021.105332

Cited by 20 publications

(14 citation statements)

References 45 publications

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“…However, this may be due to the different characteristics of the selected patients because our cohort included only patients with idiopathic PD in the early stage of the disease, while previous studies have included mainly patients with PD who were older 27 and with associated orthostatic hypotension. 28 In addition, discrepancies with previous reports 29 may arise from differences in the techniques of nerve visualization and analysis.…”

Section: Discussionmentioning

confidence: 94%

Postganglionic Sudomotor Assessment in Early Stage of Multiple System Atrophy and Parkinson Disease

et al. 2022

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Background and Objectives:Sudomotor impairment has been recognized as a key feature in differentiating Parkinson disease (PD) and multiple system atrophy-parkinsonian type (MSA-P) with the latter been characterized by diffuse anhidrosis in prospective study including patients in late stage of disease.We aimed to evaluate morphological and functional postganglionic sudomotor involvement in patients with new diagnosis MSA-P and PD to identify possible biomarkers that might be of help in differentiating the two conditions in early stage.Methods:One hundred patients with parkinsonism within 2 years from onset of motor symptoms were included in the study. At time of recruitment, questionnaires to assess non-motor, autonomic and small fiber symptoms were administered and patients underwent post-ganglionic sudomotor function assessment by the dynamic sweat test and punch skin biopsy from distal leg. Skin samples were processed for indirect immunofluorescence with a panel of antibodies including noradrenergic and cholinergic markers. The density of intraepidermal, sudomotor and pilomotor nerve fibers was measured on confocal images using dedicated software. A follow-up visit twelve months after recruitment was performed to confirm the diagnosis.Results:We recruited 57 patients with PD (M/F=36/21; age 63.5±9.4years) and 43 patients with MSA-P (M/F=27/16; age 62.3±9.0 years). Clinical scales and questionnaires showed a more severe clinical picture in MSA-P compared to PD patients. Sweating output and intraepidermal, pilomotor and sudomotor nerve densities, compared to controls, were lower in both groups but with a greater impairment in MSA-P patients. Pilomotor and sudomotor nerve density correlated with sweating function and with non-motor clinical symptoms. A composite sudomotor parameter defined as the arithmetic product of sweat production multiplied by the density of sudomotor fibers, efficiently separated the two populations, the receiver operating characteristics showing an area under the curve of 0.83.Discussion:Dynamic sweat test and the quantification of cutaneous autonomic nerves provided to be a sensitive morpho-functional approach to assess postganglionic component of the sudomotor pathway, revealing a more severe involvement in MSA-P than in PD early in the disease course. This approach can be applied to early differentiate the two conditions.Classification of Evidence:This study provides Class II evidence that post ganglionic sudomotor morpho-functional assessment accurately distinguish PD from MSA-P patients.

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Section: Discussionmentioning

confidence: 94%

Postganglionic Sudomotor Assessment in Early Stage of Multiple System Atrophy and Parkinson Disease

et al. 2022

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“…The overall higher sensitivity compared to prior IHC studies likely indicates that RT-QuIC can detect IHC undetectable α-syn aggregates 5 , 9 , 19 . A side-to-side comparison with IHC could provide a more reliable comparison of the methods as well as some insight into the type of affected fibers, which is known to differ between synucleinopathy subtypes 20 – 22 and should be addressed in future studies. Moreover, RT-QuIC assay results were highly reproducible in our inter-laboratory comparison compared to IHC, where sensitivity of phosphorylated α-syn detection varied widely between groups 6 , 23 .…”

Section: Discussionmentioning

confidence: 99%

“…Clinical relevance of skin RT-QuIC is further supported by the correlation of the skin RT-QuIC score with NMSs. Dermal α-syn deposition in PD is known to primarily affect the autonomic nervous system 5 , 20 , 22 and was previously shown to be associated with dysautonomia 10 . In a recent study, peripheral α-syn deposition assessed in the gastrointestinal system and skin both correlated with Lewy body stage in the brain 28 .…”

Section: Discussionmentioning

confidence: 99%

“…An important limitation of our study that must be addressed in the future is omission of patients with atypical parkinsonism. Skin RT-QuIC appears particularly interesting for differential diagnosis with multiple system atrophy, where α-syn is known to preferentially deposit in somatosensory fibers in contrast to autonomic fibers in PD 20 – 22 and was recently shown to be biochemically distinct in a CSF study 41 .…”

Section: Discussionmentioning

confidence: 99%

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Diagnostic value of skin RT-QuIC in Parkinson’s disease: a two-laboratory study

Kuzkina

Bargar

Schmitt

et al. 2021

npj Parkinsons Dis.

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Skin α-synuclein deposition is considered a potential biomarker for Parkinson’s disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of α-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of α-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The α-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9% and showed a high degree of inter-rater agreement between the two laboratories (92.2%). Higher α-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The α-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson’s disease. Moreover, α-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.

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“…Cardiovascular symptoms are mainly expressed as myocardial noradrenergic deficiency due to denervation [81] and impairment of catecholamine turnover, which may cause the accumulation of toxic metabolites, leading to cell death [82]. Aggregates of α-syn have been detected in the sympathetic cardiac fibers [83], as also demonstrated by Isonaka and colleagues who studied a colocalization index of α-syn and tyrosine hydroxylase (TH) as an indicator of innervation. The authors found that all LB patients had an index > 1.5, indicating an accumulation of α-syn along with a neuronal denervation [84].…”

Section: Cardiovascular Symptomsmentioning

confidence: 82%

The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease

Magistrelli

Contaldi

Comi

2021

Life

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Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.

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Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy

Cited by 20 publications

References 45 publications

Postganglionic Sudomotor Assessment in Early Stage of Multiple System Atrophy and Parkinson Disease

Postganglionic Sudomotor Assessment in Early Stage of Multiple System Atrophy and Parkinson Disease

Diagnostic value of skin RT-QuIC in Parkinson’s disease: a two-laboratory study

The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease

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