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Spinal Lewy body pathology in older adults without an antemortem diagnosis of Parkinson's disease.

ABSTRACT: To test the hypothesis that Lewy body pathology (LBs) is present in the spinal cord of older community-dwelling adults without a clinical diagnosis of Parkinson's disease (PD). We studied 162 prospective autopsies from older adults with PD (N = 6) and without PD (N = 156). We documented the presence of LBs in cerebrum and brainstem structures from each of the six regions used for Braak PD staging and four spinal cord levels (C5/6, T7, L4/5 and S4/5). Parkinsonism proximate to death was based on a previously validated measure present if two or more of the four signs of parkinsonism were present based on a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS). Fifty-three of 156 individuals without PD (34%) had LBs in a least one site within the CNS. About half of cases with LBs in the cerebrum or brainstem, (25/53, 47%) also had spinal LBs. Almost 90% (22/25, 88%) of cases with spinal LBs had LBs in the cerebrum (Braak stages 4-6) and about 10% (3/25, 12%) had only brainstem LBs (Braak stages 1-3). Four of six cases with PD showed LBs in cerebrum, brainstem and spinal cord. Individuals with LBs in the spinal cord were more likely to have clinical parkinsonism proximate to death compared to individuals with LBs in brainstem and cerebrum alone (52% vs. 32%; Chi-Square x² = 5.368, d.f. = 1, P = 0.0.021) and more severe nigral neuronal loss (48% vs. 11%; Chi-Square x² = 9.049, d.f. = 1, P = 0.003). These findings were unchanged when we included cases with a history of PD. Older community-dwelling adults without a clinical diagnosis of PD have evidence of LBs throughout the CNS including the spinal cord which is associated with parkinsonism and more severe nigral neuronal loss.

SUBMITTER: Buchman AS

PROVIDER: S-EPMC5874164 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The diagnosis of Parkinson's disease (PD) is challenging at all stages due to variable symptomatology, comorbidities, and mimicking conditions. Postmortem assessment remains the gold standard for a definitive diagnosis. While it is well recognized that PD manifests pathologically in the central nervous system with aggregation of α-synuclein as Lewy bodies and neurites, similar Lewy-type synucleinopathy (LTS) is additionally found in the peripheral nervous system that may be useful as an antemortem biomarker. We have previously found that detection of LTS in submandibular gland (SMG) biopsies is sensitive and specific for advanced PD; however, the sensitivity is suboptimal especially for early-stage disease. Further, visual microscopic assessment of biopsies by a neuropathologist to identify LTS is impractical for large-scale adoption. Here, we trained and validated a convolutional neural network (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total of 8,450 LTS and 35,066 background objects were annotated following an inter-rater reliability study with Fleiss Kappa = 0.72. We used transfer learning to train a CNN model to classify image patches (151 × 151 pixels at 20× magnification) with and without the presence of LTS objects. The trained CNN model showed the following performance on image patches: sensitivity: 0.99, specificity: 0.99, precision: 0.81, accuracy: 0.99, and F-1 score: 0.89. We further tested the trained network on 1230 naïve WSI from the same cohort of research subjects comprising 42 PD patients and 14 controls. Logistic regression models trained on features engineered from the CNN predictions on the WSI resulted in sensitivity: 0.71, specificity: 0.65, precision: 0.86, accuracy: 0.69, and F-1 score: 0.76 in predicting clinical PD status, and 0.64 accuracy in predicting PD stage, outperforming expert neuropathologist LTS density scoring in terms of sensitivity but not specificity. These findings demonstrate the practical utility of a CNN detector in screening for LTS, which can translate into a computational tool to facilitate the antemortem tissue-based diagnosis of PD in clinical settings.

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Spinal Lewy body pathology in older adults without an antemortem diagnosis of Parkinson's disease.

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