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Association of innervation-adjusted alpha-synuclein in arrector pili muscles with cardiac noradrenergic deficiency in autonomic synucleinopathies

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Abstract

Background

Autonomic synucleinopathies feature deposition of the protein alpha-synuclein (AS) in neurons [e.g., Lewy body neurogenic orthostatic hypotension (nOH)] or glial cells (multiple system atrophy, MSA). AS in skin biopsies might provide biomarkers of these diseases; however, this approach would be complicated or invalidated if there were substantial loss of AS-containing nerves. We report AS content in arrector pili muscles in skin biopsies after adjustment for local innervation in patients with Lewy body nOH or MSA. Cardiac sympathetic neuroimaging by myocardial 18F-dopamine positron emission tomography (PET) was done to examine pathophysiological correlates of innervation-adjusted AS.

Methods

Thirty-one patients (19 Lewy body nOH, 12 MSA) underwent thoracic 18F-dopamine PET and skin biopsies. AS signal intensity analyzed by immunofluorescence microscopy was adjusted for innervation by the ratio of AS to protein gene product (PGP) 9.5, a pan-axonal marker (Harvard lab site), or the ratio of AS to tyrosine hydroxylase (TH), an indicator of catecholaminergic neurons (NIH lab site).

Results

The Lewy body nOH group had higher ratios of AS/PGP 9.5 or log AS/TH than did the MSA group (0.89 ± 0.05 vs. 0.66 ± 0.04, −0.13 ± 0.05 vs. −1.60 ± 0.33; p < 0.00001 each). All 19 Lewy body patients had AS/PGP 9.5 > 0.8 or log AS/TH > 1.2 and had myocardial 18F-dopamine-derived radioactivity < 6000 nCi-kg/cc-mCi, the lower limit of normal. Two MSA patients (17%) had increased AS/PGP or log AS/TH, and two (17%) had low 18F-dopamine-derived radioactivity.

Conclusions

Lewy body forms of nOH are associated with increased innervation-adjusted AS in arrector pili muscles and neuroimaging evidence of myocardial noradrenergic deficiency.

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Abbreviations

AS:

Alpha-synuclein

18F-DA:

18F-dopamine

MSA:

Multiple system atrophy

nOH:

Neurogenic orthostatic hypotension

PAF:

Pure autonomic failure

PD:

Parkinson disease

PGP 9.5:

Protein gene product 9.5

SMA:

Smooth muscle actin

TH:

Tyrosine hydroxylase

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Authors and Affiliations

  1. Autonomic Medicine Section (formerly Clinical Neurocardiology Section), Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 9000 Rockville Pike MSC-1620, Building 10 Room 8N260, Bethesda, MD, 20892-1620, USA

    Risa Isonaka & David S. Goldstein

  2. Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Christopher H. Gibbons, Ningshan Wang & Roy Freeman

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  1. Risa Isonaka
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  2. Christopher H. Gibbons
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  5. David S. Goldstein
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Correspondence to David S. Goldstein.

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Isonaka, R., Gibbons, C.H., Wang, N. et al. Association of innervation-adjusted alpha-synuclein in arrector pili muscles with cardiac noradrenergic deficiency in autonomic synucleinopathies. Clin Auton Res 29, 587–593 (2019). https://doi.org/10.1007/s10286-019-00644-6

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