Abstract
The role of α-synuclein (αSyn) in schizophrenia is unknown, whereas in a recent animal model of depression, α- and γ-synuclein have been related to its pathophysiology. Previous biochemical studies in Brodmann area 9 showed significant reduction of αSyn in both chronic schizophrenia and bipolar disorder. Here, prevalence and cerebral distribution of αSyn were examined in 80 autopsy cases of elderly subjects (41 chronic schizophrenia, 12 late live depression/LLD and bipolar disorder/BD, and 27 age-matched controls without neuropsychiatric disorders). Using immunohistochemistry, αSyn-positive lesions (Lewy bodies and neurites) were assessed semiquantitatively. Among 41 chronic schizophrenics, all except one showing low neuritic Braak stages (mean 1.46), three brains (7.3%) revealed only few αSyn-positive inclusions restricted to medullary nuclei. Among 12 LLD and BD patients with mean Braak stage 2.25, αSyn-positive pathology was seen in two cases (16.7%) with clinical LLD, but none in BD. Among 27 controls, showing mean neuritic Braak stage 2.6, seven brains (26%) with higher mean age showed αSyn-positive lesions, either isolated in substantia nigra and nucleus basalis of Meynert (n = 2 each), in medullary nuclei, locus ceruleus and substantia nigra (n = 2), with additional involvement of nucleus basalis (n = 1). This first preliminary study in non-demented psychiatric disorders indicates that αSyn/Lewy pathology in chronic schizophrenia is significantly less frequent than in clinically healthy elderly people (P < 0.01), showing 10–30% of so-called incidental Lewy body disease. Among chronic affective disorders, according to our small cohort, the incidence of Lewy-pathology in LLD appears to be comparable to a healthy elderly population, whereas its occurence in BD is to be elucidated.
Similar content being viewed by others
References
Al-Wandi A, Ninkina N, Millership S, Williamson SJ, Jones PA, Buchman VL (2008) Absence of alpha-synuclein affects dopamine metabolism and synaptic markers in the striatum of aging mice. Neurobiol Aging. Online 19 Dec 2008, doi:10.1016/j.neurobiolaging.2008.1011.1001
American Psychiatric Association (2000) Diagnostic and statistical manual of mental disorders. Text revision, 4th edn. American Psychiatric Association, Washington, DC
Beach TG, Adler CH, Sue LI, Peirce JB, Bachalakuri J, Dalsing-Hernandez JE, Lue LF, Caviness JN, Connor DJ, Sabbagh MN, Walker DG (2008) Reduced striatal tyrosine hydroxylase in incidental Lewy body disease. Acta Neuropathol 115:445–451
Bennett MC (2005) The role of alpha-synuclein in neurodegenerative diseases. Pharmacol Ther 105:311–331
Bernstein HG, Krell D, Baumann B, Danos P, Falkai P, Diekmann S, Henning H, Bogerts B (1998) Morphometric studies of the entorhinal cortex in neuropsychiatric patients and controls: clusters of heterotopically displaced lamina II neurons are not indicative of schizophrenia. Schizophr Res 33:125–132
Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112:389–404
Braak H, Bohl JR, Muller CM, Rub U, de Vos RA, Del Tredici K (2006) Stanley Fahn Lecture 2005: The staging procedure for the inclusion body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord 21:2042–2051
Dao-Castellana MH, Paillere-Martinot ML, Hantraye P, Attar-Levy D, Remy P, Crouzel C, Artiges E, Feline A, Syrota A, Martinot JL (1997) Presynaptic dopaminergic function in the striatum of schizophrenic patients. Schizophr Res 23:167–174
DelleDonne A, Klos KJ, Fujishiro H, Ahmed Z, Parisi JE, Josephs KA, Frigerio R, Burnett M, Wszolek ZK, Uitti RJ, Ahlskog JE, Dickson DW (2008) Incidental Lewy body disease and preclinical Parkinson disease. Arch Neurol 65:1074–1080
Dickson DW, Fujishiro H, DelleDonne A, Menke J, Zeshan A, Klos KJ, Josephs KA, Frigerio R, Burnett M, Parisi JE, Ahlskog JE (2008) Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol 115:437–444
Falkai P, Schneider-Axmann T, Honer WG (2000) Entorhinal cortex pre-alpha cell clusters in schizophrenia: quantitative evidence of a developmental abnormality. Biol Psychiatry 47:937–943
Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114(Pt 5):2283–2301
Galvin JE (2006) Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson’s disease: a case for the selective vulnerability of the substantia nigra. Acta Neuropathol 112:115–126
Gibb WR (1986) Idiopathic Parkinson’s disease and the Lewy body disorders. Neuropathol Appl Neurobiol 12:223–234
Gibb WR, Lees AJ (1988) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 51:745–752
Haroutunian V, Religa D, Laudon H, Stycznska M, Winblad B, Naslund J (2003) Amyloid-beta pathology in Alzheimer’s disease and schizophrenia. Online Abstract Viewer/Itinerary Planner Washington, DC. Society for Neuroscience, Program No. 447.442
Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Bramon-Bosch E, Valmaggia L, Johns L, Broome M, McGuire PK, Grasby PM (2009) Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry 66:13–20
Jakob H, Beckmann H (1986) Prenatal developmental disturbances in the limbic allocortex in schizophrenics. J Neural Transm 65:303–326
Jeannotte AM, McCarthy JG, Redei EE, Sidhu A (2008) Desipramine modulation of alpha-, gamma-synuclein, and the norepinephrine transporter in an animal model of depression. Neuropsychopharmacology. Online 17 Sept 2008, doi:10.1038/npp.2008.1146
Jellinger KA, Gabriel E (1999) No increased incidence of Alzheimer’s disease in elderly schizophrenics. Acta Neuropathol 97:165–169
Jellinger KA (2004) Lewy body-related alpha-synucleinopathy in the aged human brain. J Neural Transm 111:1219–1235
Jellinger KA (2007) Morphological substrates of parkinsonism with and without dementia: a retrospective clinico-pathological study. J Neural Transm Suppl:91–104
Kazantsev AG, Kolchinsky AM (2008) Central role of alpha-synuclein oligomers in neurodegeneration in Parkinson disease. Arch Neurol 65:1577–1581
Klos KJ, Ahlskog JE, Josephs KA, Apaydin H, Parisi JE, Boeve BF, DeLucia MW, Dickson DW (2006) Alpha-synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals. Neurology 66:1100–1102
Koziorowski D, Friedman A, Arosio P, Santambrogio P, Dziewulska D (2007) ELISA reveals a difference in the structure of substantia nigra ferritin in Parkinson’s disease and incidental Lewy body compared to control. Parkinsonism Relat Disord 13:214–218
Lopez OL, Becker JT, Sweet RA, Martin-Sanchez FJ, Hamilton RL (2006) Lewy bodies in the amygdala increase risk for major depression in subjects with Alzheimer disease. Neurology 67:660–665
Mirra SS, Gearing M, McKeel DW Jr, Crain BJ, Hughes JP, van Belle G, Heyman A (1994) Interlaboratory comparison of neuropathology assessments in Alzheimer’s disease: a study of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). J Neuropathol Exp Neurol 53:303–315
Niizato K, Arai T, Kuroki N, Kase K, Iritani S, Ikeda K (1998) Autopsy study of Alzheimer’s disease brain pathology in schizophrenia. Schizophr Res 31:177–184
Nikolaus S, Antke C, Kley K, Poeppel TD, Hautzel H, Schmidt D, Muller HW (2007) Investigating the dopaminergic synapse in vivo. I. Molecular imaging studies in humans. Rev Neurosci 18:439–472
Norris EH, Giasson BI, Lee VM (2004) Alpha-synuclein: normal function and role in neurodegenerative diseases. Curr Top Dev Biol 60:17–54
Obi K, Akiyama H, Kondo H, Shimomura Y, Hasegawa M, Iwatsubo T, Mizuno Y, Mochizuki H (2008) Relationship of phosphorylated alpha-synuclein and tau accumulation to Abeta deposition in the cerebral cortex of dementia with Lewy bodies. Exp Neurol 210:409–420
Purohit DP, Davidson M, Perl DP, Powchik P, Haroutunian VH, Bierer LM, McCrystal J, Losonczy M, Davis KL (1993) Severe cognitive impairment in elderly schizophrenic patients: a clinicopathological study. Biol Psychiatry 33:255–260
Rapp MA, Schnaider-Beeri M, Grossman HT, Sano M, Perl DP, Purohit DP, Gorman JM, Haroutunian V (2006) Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry 63:161–167
Ross GW, Petrovitch H, Abbott RD, Nelson J, Markesbery W, Davis D, Hardman J, Launer L, Masaki K, Tanner CM, White LR (2004) Parkinsonian signs and substantia nigra neuron density in decendents elders without PD. Ann Neurol 56:532–539
Scarr E, Gray L, Keriakous D, Robinson PJ, Dean B (2006) Increased levels of SNAP-25 and synaptophysin in the dorsolateral prefrontal cortex in bipolar I disorder. Bipolar Disord 8:133–143
Siever LJ, Davis KL (2004) The pathophysiology of schizophrenia disorders: perspectives from the spectrum. Am J Psychiatry 161:398–413
Singleton AB (2005) Altered alpha-synuclein homeostasis causing Parkinson’s disease: the potential roles of dardarin. Trends Neurosci 28:416–421
Sweet RA, Hamilton RL, Butters MA, Mulsant BH, Pollock BG, Lewis DA, Lopez OL, DeKosky ST, Reynolds CFIII (2004) Neuropathologic correlates of late-onset major depression. Neuropsychopharmacology 29:2242–2250
World Health Organization (1992) The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. WHO, Geneva
Acknowledgments
The study was supported in part by the Society for the Support of Research in Experimental Neurology, Vienna, Austria. The author thanks Mrs. V. Rappelsberger for excellent laboratory work and Mr. E. Mitter-Ferstl, PhD, for secretarial and computer work.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jellinger, K.A. Lewy body/α-synucleinopathy in schizophrenia and depression: a preliminary neuropathological study. Acta Neuropathol 117, 423–427 (2009). https://doi.org/10.1007/s00401-009-0492-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-009-0492-5