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A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders.
Biochim Biophys Acta. 2009 Jul; 1792(7):730-40.BB

Abstract

The two most frequent synucleinopathies, Parkinson disease (PD) or brainstem predominant type of Lewy body disease, and dementia with Lewy bodies (DLB), are neurodegenerative multisystem disorders with widespread occurrence of alpha-synuclein containing deposits in the central, peripheral, and autonomic systems. For both Lewy body-related disorders staging/classification systems based on semiquantitative assessment of the distribution and progression pattern of alpha-synuclein pathology are used that are considered to be linked to clinical dysfunctions. In PD a six-stage system is suggested to indicate a predictable sequence of lesions with ascending progression from medullary and olfactory nuclei to the cortex, the first two presymptomatic stages related to incidental Lewy body disease, stages 3 and 4 presenting with motor symptoms and the last two (cortical) stages frequently associated with cognitive impairment. DLB, according to consensus pathologic guidelines, by semiquantitative scoring of alpha-synuclein pathology (Lewy body density and distribution) in specific brain regions, is distinguished into three phenotypes (brainstem, transitory/limbic and diffuse cortical), also considering concomitant Alzheimer-related pathology. Recent retrospective clinico-pathologic studies, although largely confirming the staging system, particularly for younger onset PD with long duration, have shown that between 6.3 and 43% of cases did not follow the proposed caudo-rostral progression pattern of alpha-synuclein pathology. In 7 to 8.3% of clinically manifested PD cases with synuclein inclusions in midbrain and cortex corresponding to LB stages 4-5 the medullary nuclei were spared, whereas mild parkinsonian symptoms were already observed in stages 2 and 3. There is considerable clinical and pathologic overlap between PD (with or without dementia) and DLB, corresponding to Braak LB stages 5 and 6, both frequently associated with variable Alzheimer-type pathology. Dementia often does not correlate with progressed stages of Lewy body pathology, but is related to concomitant Alzheimer lesions or mixed pathologies. There is no relationship between Braak LB stages and clinical severity of PD. Therefore, the predictive validity of this concept is doubtful, since in large unselected autopsy series 30 to 55% of elderly subjects with widespread alpha-synuclein pathology (Braak stages 5-6) revealed no definite neuropsychiatric symptoms or were not classifiable, indicating compensatory mechanisms of the brain. The causes and molecular basis of rather frequent deviations from the proposed caudo-rostral progression of alpha-synuclein pathology in PD, its relation to the onset of classical parkinsonian symptoms, the causes for the lack of definite clinical symptoms despite widespread alpha-synuclein pathology in the nervous system, their relations to Alzheimer-type lesions, and the pathophysiologic impact of both pathologies remain to be further elucidated.

Authors+Show Affiliations

Institute of Clinical Neurobiology Kenyongasse 18, Vienna, Austria. kurt.jellinger@univie.ac.at

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

18718530

Citation

Jellinger, Kurt A.. "A Critical Evaluation of Current Staging of Alpha-synuclein Pathology in Lewy Body Disorders." Biochimica Et Biophysica Acta, vol. 1792, no. 7, 2009, pp. 730-40.
Jellinger KA. A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta. 2009;1792(7):730-40.
Jellinger, K. A. (2009). A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochimica Et Biophysica Acta, 1792(7), 730-40. https://doi.org/10.1016/j.bbadis.2008.07.006
Jellinger KA. A Critical Evaluation of Current Staging of Alpha-synuclein Pathology in Lewy Body Disorders. Biochim Biophys Acta. 2009;1792(7):730-40. PubMed PMID: 18718530.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. A1 - Jellinger,Kurt A, Y1 - 2008/08/05/ PY - 2008/05/01/received PY - 2008/07/23/accepted PY - 2008/8/23/pubmed PY - 2009/8/26/medline PY - 2008/8/23/entrez SP - 730 EP - 40 JF - Biochimica et biophysica acta JO - Biochim Biophys Acta VL - 1792 IS - 7 N2 - The two most frequent synucleinopathies, Parkinson disease (PD) or brainstem predominant type of Lewy body disease, and dementia with Lewy bodies (DLB), are neurodegenerative multisystem disorders with widespread occurrence of alpha-synuclein containing deposits in the central, peripheral, and autonomic systems. For both Lewy body-related disorders staging/classification systems based on semiquantitative assessment of the distribution and progression pattern of alpha-synuclein pathology are used that are considered to be linked to clinical dysfunctions. In PD a six-stage system is suggested to indicate a predictable sequence of lesions with ascending progression from medullary and olfactory nuclei to the cortex, the first two presymptomatic stages related to incidental Lewy body disease, stages 3 and 4 presenting with motor symptoms and the last two (cortical) stages frequently associated with cognitive impairment. DLB, according to consensus pathologic guidelines, by semiquantitative scoring of alpha-synuclein pathology (Lewy body density and distribution) in specific brain regions, is distinguished into three phenotypes (brainstem, transitory/limbic and diffuse cortical), also considering concomitant Alzheimer-related pathology. Recent retrospective clinico-pathologic studies, although largely confirming the staging system, particularly for younger onset PD with long duration, have shown that between 6.3 and 43% of cases did not follow the proposed caudo-rostral progression pattern of alpha-synuclein pathology. In 7 to 8.3% of clinically manifested PD cases with synuclein inclusions in midbrain and cortex corresponding to LB stages 4-5 the medullary nuclei were spared, whereas mild parkinsonian symptoms were already observed in stages 2 and 3. There is considerable clinical and pathologic overlap between PD (with or without dementia) and DLB, corresponding to Braak LB stages 5 and 6, both frequently associated with variable Alzheimer-type pathology. Dementia often does not correlate with progressed stages of Lewy body pathology, but is related to concomitant Alzheimer lesions or mixed pathologies. There is no relationship between Braak LB stages and clinical severity of PD. Therefore, the predictive validity of this concept is doubtful, since in large unselected autopsy series 30 to 55% of elderly subjects with widespread alpha-synuclein pathology (Braak stages 5-6) revealed no definite neuropsychiatric symptoms or were not classifiable, indicating compensatory mechanisms of the brain. The causes and molecular basis of rather frequent deviations from the proposed caudo-rostral progression of alpha-synuclein pathology in PD, its relation to the onset of classical parkinsonian symptoms, the causes for the lack of definite clinical symptoms despite widespread alpha-synuclein pathology in the nervous system, their relations to Alzheimer-type lesions, and the pathophysiologic impact of both pathologies remain to be further elucidated. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/18718530/A_critical_evaluation_of_current_staging_of_alpha_synuclein_pathology_in_Lewy_body_disorders_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(08)00139-7 DB - PRIME DP - Unbound Medicine ER -
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