Advertisement

Clinical Autonomic Research

, Volume 29, Issue 6, pp 587–593 | Cite as

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

  • Risa Isonaka
  • Christopher H. Gibbons
  • Ningshan Wang
  • Roy Freeman
  • David S. GoldsteinEmail author
Research Article

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.

Keywords

Lewy bodies Multiple system atrophy Orthostatic hypotension Synuclein Tyrosine hydroxylase 

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

References

  1. 1.
    Amino T, Orimo S, Takahashi A, Uchihara T, Mizusawa H (2005) Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Path. 15:29–34Google Scholar
  2. 2.
    Antelmi E, Donadio V, Incensi A, Plazzi G, Liguori R (2017) Skin nerve phosphorylated α-synuclein deposits in idiopathic REM sleep behavior disorder. Neurology 88:2128–2131PubMedPubMedCentralGoogle Scholar
  3. 3.
    Constantinescu R, Richard I, Kurlan R (2007) Levodopa responsiveness in disorders with parkinsonism: a review of the literature. Mov Disord 22:2141–2148 (quiz 2295) PubMedGoogle Scholar
  4. 4.
    Cook GA, Sullivan P, Holmes C, Goldstein DS (2014) Cardiac sympathetic denervation without Lewy bodies in a case of multiple system atrophy. Parkinsonism Relat Disord 20:926–928PubMedPubMedCentralGoogle Scholar
  5. 5.
    Delic V, Chandra S, Abdelmotilib H, Maltbie T, Wang S, Kem D, Scott HJ, Underwood RN, Liu Z, Volpicelli-Daley LA, West AB (2018) Sensitivity and specificity of phospho-Ser129 α-synuclein monoclonal antibodies. J Comp Neurol 526:1978–1990PubMedPubMedCentralGoogle Scholar
  6. 6.
    Donadio V, Cortelli P, Elam M, Di Stasi V, Montagna P, Holmberg B, Giannoccaro MP, Bugiardini E, Avoni P, Baruzzi A, Liguori R (2010) Autonomic innervation in multiple system atrophy and pure autonomic failure. J Neurol Neurosurg Psychiatry 81:1327–1335PubMedGoogle Scholar
  7. 7.
    Donadio V, Incensi A, El-Agnaf O, Rizzo G, Vaikath N, Del Sorbo F, Scaglione C, Capellari S, Elia A, Stanzani Maserati M, Pantieri R, Liguori R (2018) Skin α-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study. Sci Rep 8:14246PubMedPubMedCentralGoogle Scholar
  8. 8.
    Donadio V, Incensi A, Piccinini C, Cortelli P, Giannoccaro MP, Baruzzi A, Liguori R (2016) Skin nerve misfolded α-synuclein in pure autonomic failure and Parkinson disease. Ann Neurol 79:306–316PubMedGoogle Scholar
  9. 9.
    Doppler K, Weis J, Karl K, Ebert S, Ebentheuer J, Trenkwalder C, Klebe S, Volkmann J, Sommer C (2015) Distinctive distribution of phospho-alpha-synuclein in dermal nerves in multiple system atrophy. Mov Disord 30:1688–1692PubMedGoogle Scholar
  10. 10.
    Gibbons CH, Garcia J, Wang N, Shih LC, Freeman R (2016) The diagnostic discrimination of cutaneous α-synuclein deposition in Parkinson disease. Neurology 87:505–512PubMedPubMedCentralGoogle Scholar
  11. 11.
    Gilman S, Low P, Quinn N, Albanese A, Ben-Shlomo Y, Fowler C, Kaufmann H, Kockgether T, Lang A, Lantos P, Litvan I, Mathias C, Oliver E, Robertson D, Schatz I, Wenning G (1998) Consensus statement on the diagnosis of multiple system atrophy. Clin Auton Res 8:359–362PubMedGoogle Scholar
  12. 12.
    Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Durr A, Fowler CJ, Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T, Robertson D, Sandroni P, Seppi K, Vidailhet M (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676PubMedPubMedCentralGoogle Scholar
  13. 13.
    Goldstein DS, Cheshire WP (2018) Roles of catechol neurochemistry in autonomic function testing. Clin Auton Res 28:273–288PubMedGoogle Scholar
  14. 14.
    Goldstein DS, Cheshire WP Jr (2017) Beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver. Clin Auton Res 27:361–367PubMedGoogle Scholar
  15. 15.
    Goldstein DS, Holmes C, Bentho O, Sato T, Moak J, Sharabi Y, Imrich R, Conant S, Eldadah BA (2008) Biomarkers to detect central dopamine deficiency and distinguish Parkinson disease from multiple system atrophy. Parkinsonism Relat Disord 14:600–607PubMedPubMedCentralGoogle Scholar
  16. 16.
    Goldstein DS, Holmes C, Cannon RO 3rd, Eisenhofer G, Kopin IJ (1997) Sympathetic cardioneuropathy in dysautonomias. N Engl J Med 336:696–702PubMedGoogle Scholar
  17. 17.
    Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO 3rd (2000) Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 133:338–347PubMedGoogle Scholar
  18. 18.
    Goldstein DS, Holmes C, Lopez GJ, Wu T, Sharabi Y (2018) Cardiac sympathetic denervation predicts PD in at-risk individuals. Parkinsonism Relat Disord 52:90–93PubMedGoogle Scholar
  19. 19.
    Goldstein DS, Holmes C, Sharabi Y, Brentzel S, Eisenhofer G (2003) Plasma levels of catechols and metanephrines in neurogenic orthostatic hypotension. Neurology 60:1327–1332PubMedGoogle Scholar
  20. 20.
    Goldstein DS, Holmes C, Sharabi Y, Wu T (2015) Survival in synucleinopathies: a prospective cohort study. Neurology 85:1554–1561PubMedPubMedCentralGoogle Scholar
  21. 21.
    Goldstein DS, Holmes C, Sullivan P, Donadio V, Isonaka R, Zhong E, Pourier B, Vernino S, Kopin IJ, Sharabi Y (2017) Autoimmunity-associated autonomic failure with sympathetic denervation. Clin Auton Res 27:57–62PubMedGoogle Scholar
  22. 22.
    Goldstein DS, Polinsky RJ, Garty M, Robertson D, Brown RT, Biaggioni I, Stull R, Kopin IJ (1989) Patterns of plasma levels of catechols in neurogenic orthostatic hypotension. Ann Neurol 26:558–563PubMedGoogle Scholar
  23. 23.
    Goldstein DS, Sewell L (2009) Olfactory dysfunction in pure autonomic failure: implications for the pathogenesis of Lewy body diseases. Parkinsonism Relat Disord 15:516–520PubMedPubMedCentralGoogle Scholar
  24. 24.
    Goldstein DS, Sharabi Y (2009) Neurogenic orthostatic hypotension: a pathophysiological approach. Circulation 119:139–146PubMedPubMedCentralGoogle Scholar
  25. 25.
    Goldstein DS, Sharabi Y (2019) The heart of PD: Lewy body diseases as neurocardiologic disorders. Brain Res 1702:74–84PubMedGoogle Scholar
  26. 26.
    Haga R, Sugimoto K, Nishijima H, Miki Y, Suzuki C, Wakabayashi K, Baba M, Yagihashi S, Tomiyama M (2015) Clinical utility of skin biopsy in differentiating between Parkinson’s disease and multiple system atrophy. Parkinsons Dis 2015:167038PubMedPubMedCentralGoogle Scholar
  27. 27.
    Hague K, Lento P, Morgello S, Caro S, Kaufmann H (1997) The distribution of Lewy bodies in pure autonomic failure: autopsy findings and review of the literature. Acta Neuropathol 94:192–196PubMedGoogle Scholar
  28. 28.
    Ikemura M, Saito Y, Sengoku R, Sakiyama Y, Hatsuta H, Kanemaru K, Sawabe M, Arai T, Ito G, Iwatsubo T, Fukayama M, Murayama S (2008) Lewy body pathology involves cutaneous nerves. J Neuropathol Exp Neurol 67:945–953PubMedGoogle Scholar
  29. 29.
    Isonaka R, Holmes C, Cook GA, Sullivan P, Sharabi Y, Goldstein DS (2017) Pure autonomic failure without synucleinopathy. Clin Auton Res 27:97–101PubMedGoogle Scholar
  30. 30.
    Isonaka R, Rosenberg AZ, Sullivan P, Corrales A, Holmes C, Sharabi Y, Goldstein DS (2019) Alpha-synuclein deposition within sympathetic noradrenergic neurons is associated with myocardial noradrenergic deficiency in neurogenic orthostatic hypotension. Hypertension 73:910–918PubMedGoogle Scholar
  31. 31.
    Isonaka R, Sullivan P, Jinsmaa Y, Corrales A, Goldstein DS (2018) Spectrum of abnormalities of sympathetic tyrosine hydroxylase and alpha-synuclein in chronic autonomic failure. Clin Auton Res 28:223–230PubMedGoogle Scholar
  32. 32.
    Kaufmann H, Norcliffe-Kaufmann L, Palma JA, Biaggioni I, Low PA, Singer W, Goldstein DS, Peltier AC, Shibao CA, Gibbons CH, Freeman R, Robertson D (2017) Natural history of pure autonomic failure: a United States prospective cohort. Ann Neurol 81:287–297PubMedPubMedCentralGoogle Scholar
  33. 33.
    McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, Aarsland D, Galvin J, Attems J, Ballard CG, Bayston A, Beach TG, Blanc F, Bohnen N, Bonanni L, Bras J, Brundin P, Burn D, Chen-Plotkin A, Duda JE, El-Agnaf O, Feldman H, Ferman TJ, Ffytche D, Fujishiro H, Galasko D, Goldman JG, Gomperts SN, Graff-Radford NR, Honig LS, Iranzo A, Kantarci K, Kaufer D, Kukull W, Lee VMY, Leverenz JB, Lewis S, Lippa C, Lunde A, Masellis M, Masliah E, McLean P, Mollenhauer B, Montine TJ, Moreno E, Mori E, Murray M, O’Brien JT, Orimo S, Postuma RB, Ramaswamy S, Ross OA, Salmon DP, Singleton A, Taylor A, Thomas A, Tiraboschi P, Toledo JB, Trojanowski JQ, Tsuang D, Walker Z, Yamada M, Kosaka K (2017) Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology 89:88–100PubMedPubMedCentralGoogle Scholar
  34. 34.
    McShane RH, Nagy Z, Esiri MM, King E, Joachim C, Sullivan N, Smith AD (2001) Anosmia in dementia is associated with Lewy bodies rather than Alzheimer’s pathology. J Neurol Neurosurg Psychiatry 70:739–743PubMedPubMedCentralGoogle Scholar
  35. 35.
    Melli G, Vacchi E, Biemmi V, Galati S, Staedler C, Ambrosini R, Kaelin-Lang A (2018) Cervical skin denervation associates with alpha-synuclein aggregates in Parkinson disease. Ann Clin Transl Neurol 5:1394–1407PubMedPubMedCentralGoogle Scholar
  36. 36.
    Orimo S, Amino T, Takahashi A, Kojo T, Uchihara T, Mori F, Wakabayashi K, Takahashi H (2006) Cardiac sympathetic denervation in Lewy body disease. Parkinsonism Relat Disord 12(Suppl 2):S99–S105Google Scholar
  37. 37.
    Orimo S, Kanazawa T, Nakamura A, Uchihara T, Mori F, Kakita A, Wakabayashi K, Takahashi H (2007) Degeneration of cardiac sympathetic nerve can occur in multiple system atrophy. Acta Neuropathol 113:81–86PubMedGoogle Scholar
  38. 38.
    Orimo S, Ozawa E, Oka T, Nakade S, Tsuchiya K, Yoshimoto M, Wakabayashi K, Takahashi H (2001) Different histopathology accounting for a decrease in myocardial MIBG uptake in PD and MSA. Neurology 57:1140–1141PubMedGoogle Scholar
  39. 39.
    Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100PubMedGoogle Scholar
  40. 40.
    Raffel DM, Koeppe RA, Little R, Wang CN, Liu S, Junck L, Heumann M, Gilman S (2006) PET measurement of cardiac and nigrostriatal denervation in parkinsonian syndromes. J Nucl Med 47:1769–1777PubMedGoogle Scholar
  41. 41.
    Shishido T, Ikemura M, Obi T, Yamazaki K, Terada T, Sugiura A, Saito Y, Murayama S, Mizoguchi K (2010) alpha-synuclein accumulation in skin nerve fibers revealed by skin biopsy in pure autonomic failure. Neurology 74:608–610PubMedGoogle Scholar
  42. 42.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedGoogle Scholar
  43. 43.
    Stankovic I, Quinn N, Vignatelli L, Antonini A, Berg D, Coon E, Cortelli P, Fanciulli A, Ferreira JJ, Freeman R, Halliday G, Hoglinger GU, Iodice V, Kaufmann H, Klockgether T, Kostic V, Krismer F, Lang A, Levin J, Low P, Mathias C, Meissner WG, Kaufmann LN, Palma JA, Panicker JN, Pellecchia MT, Sakakibara R, Schmahmann J, Scholz SW, Singer W, Stamelou M, Tolosa E, Tsuji S, Seppi K, Poewe W, Wenning GK (2019) A critique of the second consensus criteria for multiple system atrophy. Mov DisordGoogle Scholar
  44. 44.
    Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182PubMedGoogle Scholar
  45. 45.
    Wang N, Gibbons CH, Freeman R (2011) Novel immunohistochemical techniques using discrete signal amplification systems for human cutaneous peripheral nerve fiber imaging. J Histochem Cytochem 59:382–390PubMedPubMedCentralGoogle Scholar
  46. 46.
    Wang N, Gibbons CH, Lafo J, Freeman R (2013) α-Synuclein in cutaneous autonomic nerves. Neurology 81:1604–1610PubMedPubMedCentralGoogle Scholar
  47. 47.
    Zange L, Noack C, Hahn K, Stenzel W, Lipp A (2015) Phosphorylated α-synuclein in skin nerve fibres differentiates Parkinson’s disease from multiple system atrophy. Brain 138:2310–2321Google Scholar
  48. 48.
    Ziegler MG, Lake CR, Kopin IJ (1977) The sympathetic-nervous-system defect in primary orthostatic hypotension. N Engl J Med 296:293–297PubMedGoogle Scholar

Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2019

Authors and Affiliations

  1. 1.Autonomic Medicine Section (formerly Clinical Neurocardiology Section), Clinical Neurosciences Program, Division of Intramural ResearchNational Institute of Neurological Disorders and Stroke, National Institutes of HealthBethesdaUSA
  2. 2.Department of NeurologyBeth Israel Deaconess Medical CenterBostonUSA

Personalised recommendations