Clinical Autonomic Research

, Volume 22, Issue 1, pp 57–61 | Cite as

Sympathetic noradrenergic before striatal dopaminergic denervation: relevance to Braak staging of synucleinopathy

  • David S. Goldstein
  • Courtney Holmes
  • LaToya Sewell
  • Mee Yeong Park
  • Yehonatan Sharabi
Case Report


Braak’s staging concept of Lewy body disease pathogenesis is based on a spatiotemporal sequence of alpha-synuclein deposition, with autonomic nervous system involvement before synucleinopathy in substantia nigra neurons. A patient with primary chronic autonomic failure underwent biennial brain 6-[18F]DOPA and myocardial 6-[18F]dopamine scanning over 4 years. Low myocardial radioactivity indicated cardiac noradrenergic denervation that persisted. Striatal 6-[18F]DOPA-derived radioactivity initially was normal, 2 years later was decreased subtly, and by 4 years was clearly decreased, accompanied by dementia and parkinsonism. In this case, neuroimaging evidence of cardiac noradrenergic denervation and subsequent progressive striatal dopaminergic denervation fit with Braak staging.


Parkinson Synuclein Braak Sympathetic nervous system Norepinephrine 





Putamen:occipital cortex



This research was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke. Ms. Tereza Jenkins (Clinical Neurocardiology Section) coordinated patient travel. Sandra Pechnik, RN (Clinical Neurocardiology Section) assisted with clinical procedures and scheduling.

Conflict of interest



  1. 1.
    Braak H, Braak E (2000) Pathoanatomy of Parkinson’s disease. J Neurol 247(Suppl 2):II3–II10PubMedCrossRefGoogle Scholar
  2. 2.
    Ding YS, Singhal T, Planeta-Wilson B, Gallezot JD, Nabulsi N, Labaree D, Ropchan J, Henry S, Williams W, Carson RE, Neumeister A, Malison RT (2010) PET imaging of the effects of age and cocaine on the norepinephrine transporter in the human brain using (S, S)-[(11)C]O-methylreboxetine and HRRT. Synapse 64:30–38PubMedCrossRefGoogle Scholar
  3. 3.
    Fujishiro H, Frigerio R, Burnett M, Klos KJ, Josephs KA, Delledonne A, Parisi JE, Ahlskog JE, Dickson DW (2008) Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson’s disease. Mov Disord 23:1085–1092PubMedCrossRefGoogle Scholar
  4. 4.
    Garland EM, Raj SR, Peltier AC, Robertson D, Biaggioni I (2011) A cross-sectional study contrasting olfactory function in autonomic disorders. Neurology 76:456–460PubMedCrossRefGoogle Scholar
  5. 5.
    Goldstein DS (2006) Orthostatic hypotension as an early finding in Parkinson disease. Clin Auton Res 16:46–64PubMedCrossRefGoogle Scholar
  6. 6.
    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. Park Rel Dis 14:600–607CrossRefGoogle Scholar
  7. 7.
    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
  8. 8.
    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
  9. 9.
    Goldstein DS, Sewell L (2009) Olfactory dysfunction in pure autonomic failure: implications for the pathogenesis of Lewy body diseases. Park Rel Dis 15:516–520CrossRefGoogle Scholar
  10. 10.
    Goldstein DS, Sewell L, Sharabi Y (2011) Autonomic dysfunction in PD: a window to early detection? J Neurol Sci (in press)Google Scholar
  11. 11.
    Goldstein DS, Sharabi Y, Karp BI, Bentho O, Saleem A, Pacak K, Eisenhofer G (2007) Cardiac sympathetic denervation preceding motor signs in Parkinson disease. Clin Auton Res 17:118–121PubMedCrossRefGoogle Scholar
  12. 12.
    Kaufmann H, Goldstein DS (2010) Pure autonomic failure: a restricted Lewy body synucleinopathy or early Parkinson disease? Neurology 74:536–537PubMedCrossRefGoogle Scholar
  13. 13.
    Kaufmann H, Nahm K, Purohit D, Wolfe D (2004) Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies. Neurology 63:1093–1095PubMedGoogle Scholar
  14. 14.
    McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–1124PubMedGoogle Scholar
  15. 15.
    Minguez-Castellanos A, Chamorro CE, Escamilla-Sevilla F, Ortega-Moreno A, Rebollo AC, Gomez-Rio M, Concha A, Munoz DG (2007) Do alpha-synuclein aggregates in autonomic plexuses predate Lewy body disorders?: a cohort study. Neurology 68:2012–2018PubMedCrossRefGoogle Scholar
  16. 16.
    Orimo S, Uchihara T, Nakamura A, Mori F, Kakita A, Wakabayashi K, Takahashi H (2008) Axonal alpha-synuclein aggregates herald centripetal degeneration of cardiac sympathetic nerve in Parkinson’s disease. Brain 131:642–650PubMedCrossRefGoogle Scholar
  17. 17.
    Tijero B, Gomez-Esteban JC, Llorens V, Lezcano E, Gonzalez-Fernandez MC, de Pancorbo MM, Ruiz-Martinez J, Cembellin JC, Zarranz JJ (2010) Cardiac sympathetic denervation precedes nigrostriatal loss in the E46 K mutation of the alpha-synuclein gene (SNCA). Clin Auton Res 20:267–269PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • David S. Goldstein
    • 1
  • Courtney Holmes
    • 1
  • LaToya Sewell
    • 1
  • Mee Yeong Park
    • 1
  • Yehonatan Sharabi
    • 1
  1. 1.Clinical Neurocardiology SectionNational Institute of Neurological Disorders and Stroke, National Institutes of HealthBethesdaUSA

Personalised recommendations