Acta Neuropathologica

, Volume 115, Issue 4, pp 445–451 | Cite as

Reduced striatal tyrosine hydroxylase in incidental Lewy body disease

  • Thomas Gerald BeachEmail author
  • Charles H. Adler
  • Lucia I. Sue
  • Jeffrey B. Peirce
  • Jyothi Bachalakuri
  • Jessica E. Dalsing-Hernandez
  • Lih Fen Lue
  • John N. Caviness
  • Donald J. Connor
  • Marwan N. Sabbagh
  • Douglas G. Walker
Original Paper


Incidental Lewy body disease (ILBD) is the term used when Lewy bodies are found in the nervous system of subjects without clinically documented parkinsonism or dementia. The prevalence of ILBD in the elderly population has been estimated at between 3.8 and 30%, depending on subject age and anatomical site of sampling. It has been speculated that ILBD represents the preclinical stage of Parkinson’s disease (PD) and/or dementia with Lewy bodies (DLB). Studies of ILBD could potentially identify early diagnostic signs of these disorders. At present, however, it is impossible to know whether ILBD is a precursor to PD or DLB or is just a benign finding of normal aging. We hypothesized that, if ILBD represents an early stage of PD or DLB, it should be associated with depletion of striatal dopaminergic markers. Eleven subjects with ILBD and 27 control subjects were studied. The ILBD subjects ranged in age from 74 to 96 years (mean 86.5) while the control subjects’ age ranged from 75 to 102 years (mean 86.7). Controls and subjects did not differ in terms of age, postmortem interval, gender distribution, medical history conditions, brain weight, neuritic plaque density or Braak neurofibrillary stage. Quantitative ELISA measurement of striatal tyrosine hydroxylase (TH), the principal enzyme for dopamine synthesis, showed a 49.8% (P = 0.01) reduction in ILBD cases, as compared with control cases. The finding suggests that ILBD is not a benign condition but is likely a precursor to PD and/or DLB.


Striatum Dopamine Parkinson’s disease Lewy bodies Pathogenesis Aging 



This research is supported by grants to the Sun Health Research Institute Brain Donation Program and the Arizona Parkinson’s Disease Consortium by the Michael J. Fox Foundation for Parkinson’s Research (The Prescott Family Initiative), the Arizona Biomedical Research Commission (contracts 4001, 0011 and 05-901) and the National Institute on Aging (P30 AG19610). We thank Dr. Haru Akiyama of the Tokyo Institute of Psychiatry for donating the phospho-serine 129 antibody.


  1. 1.
    Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease (1997) The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2Google Scholar
  2. 2.
    Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, Grandinetti A, Blanchette PL, Popper JS, Ross GW (2001) Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology 57:456–462PubMedGoogle Scholar
  3. 3.
    Adler CH (2005) Nonmotor complications in Parkinson’s disease. Mov Disord 20(Suppl 11):S23–S29PubMedCrossRefGoogle Scholar
  4. 4.
    Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H (2005) Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol 15:29–34PubMedCrossRefGoogle Scholar
  5. 5.
    Beach TG, Tago H, Nagai T, Kimura H, McGeer PL, McGeer EG (1987) Perfusion-fixation of the human brain for immunohistochemistry: comparison with immersion-fixation. J Neurosci Methods 19:183–192PubMedCrossRefGoogle Scholar
  6. 6.
    Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 20: 415–455PubMedCrossRefGoogle Scholar
  7. 7.
    Bezard E, Dovero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, Crossman AR, Bioulac B, Brotchie JM, Gross CE (2001) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Neurosci 21:6853–6861PubMedGoogle Scholar
  8. 8.
    Bloch A, Probst A, Bissig H, Adams H, Tolnay M (2006) Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol 32:284–295PubMedCrossRefGoogle Scholar
  9. 9.
    Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 82:239–259CrossRefGoogle Scholar
  10. 10.
    Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U (2002) Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol 249(Suppl 3):III/1–III/5Google Scholar
  11. 11.
    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  12. 12.
    Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134PubMedCrossRefGoogle Scholar
  13. 13.
    Carlsson A, Winblad B (1976) Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. J Neural Transm 38:271–276PubMedCrossRefGoogle Scholar
  14. 14.
    Daniel SE, Hawkes CH (1992) Preliminary diagnosis of Parkinson’s disease by olfactory bulb pathology. Lancet 340:186PubMedCrossRefGoogle Scholar
  15. 15.
    den Hartog Jager WA, Bethlem J (1960) The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 23:283–290CrossRefGoogle Scholar
  16. 16.
    Dexter DT, Sian J, Rose S, Hindmarsh JG, Mann VM, Cooper JM, Wells FR, Daniel SE, Lees AJ, Schapira AH (1994) Indices of oxidative stress and mitochondrial function in individuals with incidental Lewy body disease. Ann Neurol 35:38–44PubMedCrossRefGoogle Scholar
  17. 17.
    Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114:2283–2301PubMedCrossRefGoogle Scholar
  18. 18.
    Forno LS, Norville RL (1976) Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol (Berl) 34:183–197CrossRefGoogle Scholar
  19. 19.
    Fujiwara H, Hasegawa M, Dohmae N, Kawashima A, Masliah E, Goldberg MS, Shen J, Takio K, Iwatsubo T (2002) Alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164PubMedCrossRefGoogle Scholar
  20. 20.
    Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752PubMedGoogle Scholar
  21. 21.
    Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO III (2000) Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 133:338–347PubMedGoogle Scholar
  22. 22.
    Hawkes C (2006) Olfaction in neurodegenerative disorder. Adv Otorhinolaryngol 63:133–151PubMedGoogle Scholar
  23. 23.
    Hornykiewicz O (1993) Parkinson’s disease and the adaptive capacity of the nigrostriatal dopamine system: possible neurochemical mechanisms. Adv Neurol 60:140–147PubMedGoogle Scholar
  24. 24.
    Ishihara L, Brayne C (2006) A systematic review of depression and mental illness preceding Parkinson’s disease. Acta Neurol Scand 113:211–220PubMedCrossRefGoogle Scholar
  25. 25.
    Iwanaga K, Wakabayashi K, Yoshimoto M, Tomita I, Satoh H, Takashima H, Satoh A, Seto M, Tsujihata M, Takahashi H (1999) Lewy body-type degeneration in cardiac plexus in Parkinson’s and incidental Lewy body diseases. Neurology 52:1269–1271PubMedGoogle Scholar
  26. 26.
    Jellinger KA (2004) Lewy body-related alpha-synucleinopathy in the aged human brain. J Neural Transm 111:1219–1235PubMedCrossRefGoogle Scholar
  27. 27.
    Jellinger KA, Attems J (2006) Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies? Acta Neuropathol (Berl) 112:253–260CrossRefGoogle Scholar
  28. 28.
    Johnston BT, Li Q, Castell JA, Castell DO (1995) Swallowing and esophageal function in Parkinson’s disease. Am J Gastroenterol 90:1741–1746PubMedGoogle Scholar
  29. 29.
    Katzenschlager R, Lees AJ (2004) Olfaction and Parkinson’s syndromes: its role in differential diagnosis. Curr Opin Neurol 17:417–423PubMedCrossRefGoogle Scholar
  30. 30.
    Kovari E, Burkhardt K, Lobrinus JA, Bouras C (2007) Lewy body dysphagia. Acta Neuropathol (Berl) 114:295–298CrossRefGoogle Scholar
  31. 31.
    Lemke MR, Fuchs G, Gemende I, Herting B, Oehlwein C, Reichmann H, Rieke J, Volkmann J (2004) Depression and Parkinson’s disease. J Neurol 251(Suppl 6):VI/24–VI/27Google Scholar
  32. 32.
    Li ST, Dendi R, Holmes C, Goldstein DS (2002) Progressive loss of cardiac sympathetic innervation in Parkinson’s disease. Ann Neurol 52:220–223PubMedCrossRefGoogle Scholar
  33. 33.
    McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872PubMedCrossRefGoogle Scholar
  34. 34.
    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
  35. 35.
    Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, van Belle G, Berg L (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486PubMedGoogle Scholar
  36. 36.
    Nakajima R, Takahashi K, Nakamura H, Otomo E, Kameyama M (1981) A quantitative study on the intermediolateral cells of the thoracic cord in degenerative diseases of the nervous system (author’s transl). Rinsho Shinkeigaku 21:581–586PubMedGoogle Scholar
  37. 37.
    Oyanagi K, Wakabayashi K, Ohama E, Takeda S, Horikawa Y, Morita T, Ikuta F (1990) Lewy bodies in the lower sacral parasympathetic neurons of a patient with Parkinson’s disease. Acta Neuropathol (Berl) 80:558–559CrossRefGoogle Scholar
  38. 38.
    Paganini-Hill A (2001) Risk factors for Parkinson’s disease: the leisure world cohort study. Neuroepidemiology 20:118–124PubMedCrossRefGoogle Scholar
  39. 39.
    Pearce RK, Hawkes CH, Daniel SE (1995) The anterior olfactory nucleus in Parkinson’s disease. Mov Disord 10:283–287PubMedCrossRefGoogle Scholar
  40. 40.
    Potulska A, Friedman A, Krolicki L, Spychala A (2003) Swallowing disorders in Parkinson’s disease. Parkinsonism Relat Disord 9:349–353PubMedCrossRefGoogle Scholar
  41. 41.
    Ross GW, Abbott RD, Petrovitch H, Tanner CM, Davis DG, Nelson J, Markesbery WR, Hardman J, Masaki K, Launer L, White LR (2006) Association of olfactory dysfunction with incidental Lewy bodies. Mov Disord 21:2062–2067PubMedCrossRefGoogle Scholar
  42. 42.
    Saito Y, Ruberu NN, Sawabe M, Arai T, Kazama H, Hosoi T, Yamanouchi H, Murayama S (2004) Lewy body-related alpha-synucleinopathy in aging. J Neuropathol Exp Neurol 63:742–749PubMedGoogle Scholar
  43. 43.
    Satoh A, Serita T, Seto M, Tomita I, Satoh H, Iwanaga K, Takashima H, Tsujihata M (1999) Loss of 123I-MIBG uptake by the heart in Parkinson’s disease: assessment of cardiac sympathetic denervation and diagnostic value. J Nucl Med 40:371–375PubMedGoogle Scholar
  44. 44.
    Scigliano G, Musicco M, Soliveri P, Piccolo I, Ronchetti G, Girotti F (2006) Reduced risk factors for vascular disorders in Parkinson disease patients: a case-control study. Stroke 37:1184–1188PubMedCrossRefGoogle Scholar
  45. 45.
    Sharabi Y, Li ST, Dendi R, Holmes C, Goldstein DS (2003) Neurotransmitter specificity of sympathetic denervation in Parkinson’s disease. Neurology 60:1036–1039PubMedGoogle Scholar
  46. 46.
    Takeda S, Yamazaki K, Miyakawa T, Arai H (1993) Parkinson’s disease with involvement of the parasympathetic ganglia. Acta Neuropathol (Berl) 86:397–398CrossRefGoogle Scholar
  47. 47.
    Taki J, Yoshita M, Yamada M, Tonami N (2004) Significance of 123I-MIBG scintigraphy as a pathophysiological indicator in the assessment of Parkinson’s disease and related disorders: it can be a specific marker for Lewy body disease. Ann Nucl Med 18: 453–461PubMedGoogle Scholar
  48. 48.
    Tsuboi Y, Wszolek ZK, Graff-Radford NR, Cookson N, Dickson DW (2003) Tau pathology in the olfactory bulb correlates with Braak stage, Lewy body pathology and apolipoprotein epsilon4. Neuropathol Appl Neurobiol 29: 503–510PubMedCrossRefGoogle Scholar
  49. 49.
    Wakabayashi K, Takahashi H, Takeda S, Ohama E, Ikuta F (1988) Parkinson’s disease: the presence of Lewy bodies in Auerbach’s and Meissner’s plexuses. Acta Neuropathol (Berl) 76:217–221CrossRefGoogle Scholar
  50. 50.
    Wenning GK, Ebersbach G, Verny M, Chaudhuri KR, Jellinger K, McKee A, Poewe W, Litvan I (1999) Progression of falls in postmortem-confirmed parkinsonian disorders. Mov Disord 14:947–950PubMedCrossRefGoogle Scholar
  51. 51.
    Wood BH, Bilclough JA, Bowron A, Walker RW (2002) Incidence and prediction of falls in Parkinson’s disease: a prospective multidisciplinary study. J Neurol Neurosurg Psychiatry 72:721–725PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Thomas Gerald Beach
    • 1
    Email author
  • Charles H. Adler
    • 2
  • Lucia I. Sue
    • 1
  • Jeffrey B. Peirce
    • 1
  • Jyothi Bachalakuri
    • 1
  • Jessica E. Dalsing-Hernandez
    • 1
  • Lih Fen Lue
    • 1
  • John N. Caviness
    • 2
  • Donald J. Connor
    • 1
  • Marwan N. Sabbagh
    • 1
  • Douglas G. Walker
    • 1
  1. 1.Sun Health Research InstituteSun CityUSA
  2. 2.Department of NeurologyMayo ClinicScottsdaleUSA

Personalised recommendations