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Formation and development of Lewy pathology: a critical update

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Abstract

Filamentous protein inclusions in neurons (Lewy bodies, LB) and dystrophic neurites containing pathologic α-synuclein (αSyn) are the morphologic hallmarks of sporadic Parkinson disease (PD) and dementia with Lewy bodies (DLB), but are also found in aged subjects and in a variety of neurogenerative disorders. They occur in the central, peripheral, and autonomic nervous system as an essential or coincident feature. Their formation runs through several phases from initial dust-like particles cross-linked with αSyn to aggregation of ubiquitinated dense filaments, formation of LBs, finally degradation and death of the afflicted neurons. Pathologic accumulation of αSyn/LBs proposed by Braak et al. (Neurobiol Aging 24:197–211, 2003), following a predictable sequence of lesions in six stages with ascending progression from medullary and olfactory nuclei to the cortex, has been considered to be linked to clinical dysfunctions. The consensus pathologic guidelines of DLB (Neurology 65:1863–1872, 2005), by semiquantitative scoring to αSyn pathology (LB density and distribution) in specific brain regions, distinguish three phenotypes (brainstem, transitional/limbic, and diffuse neocortical), and also consider concomitant Alzheimer-related pathology. αSyn pathology in the amygdala is often associated with Alzheimer disease. Although some retrospective clinico-pathologic studies have largely confirmed the Braak LB staging system, it shows neither correlation to the clinical severity and duration of parkinsonism nor to nigral αSyn burden and cell loss which significantly correlates with resulting striatal loss of dopamine, dopamine transporter and tyrosine hydroxylase, duration and severity of motor dysfunction. Between 6.3 and 43% of clinically manifested PD cases did not follow this pattern, and in 7–8.3% of those with αSyn-positive inclusions in midbrain and cortex the medullary nuclei were spared. On the other hand, 30–55% of elderly subjects with widespread Lewy pathology revealed no neuropsychiatric symptoms or were not classifiable. Therefore, detection and staging of Lewy pathology without assessment of neuronal loss in specific areas may not have clinical impact and its predictive validity is questionable. For demented patients, modified criteria for categorization of Lewy pathology were proposed. If robust correlations between clinical course and Lewy/αSyn pathology are to be confirmed by future studies, the currently used morphologic staging/classification systems should be revised accordingly.

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  1. Institute of Clinical Neurobiology, Kenyongasse 18, 1070, Vienna, Austria

    Kurt A. Jellinger

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Appendix

Appendix

After submission of this manuscript, a new unified staging system for LB disorders, based on examination of a standard set of 10 brain regions in a large number of autopsy cases suggested four stages of LB pathology: (I) olfactory bulb only; (IIa) brainstem predominant; (IIb) limbic predominant; (III) brainstem and limbic; (IV) neocortical. Progression of these stages was correlated with nigrostriatal degeneration, cognitive impairment and motor dysfunction. The proposed staging system was suggested to improve classification of LB disorders [6]. The results of staging/typing of LB-related αSyn pathology of the BrainNet Europe Consortium were published in the same fascicle of ANP [3].

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Jellinger, K.A. Formation and development of Lewy pathology: a critical update. J Neurol 256 (Suppl 3), 270–279 (2009). https://doi.org/10.1007/s00415-009-5243-y

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