Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis

Abstract

Background: Great heterogeneity exists in survival and the interval between onset of motor symptoms and dementia symptoms across synucleinopathies. We aimed to identify genetic and pathological markers that have the strongest association with these features of clinical heterogeneity in synucleinopathies.

Methods: In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of patients with Lewy body disorders with autopsy-confirmed α synucleinopathy (as of Oct 1, 2015) who were previously included in other studies from five academic institutions in five cities in the USA. We used histopathology techniques and markers to assess the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathological changes in cortical regions. These samples were graded on an ordinal scale and genotyped for variants associated with synucleinopathies. We assessed the interval from onset of motor symptoms to onset of dementia, and overall survival in groups with varying levels of comorbid Alzheimer's disease pathology according to US National Institute on Aging-Alzheimer's Association neuropathological criteria, and used multivariate regression to control for age at death and sex.

Findings: On the basis of data from 213 patients who had been followed up to autopsy and met inclusion criteria of Lewy body disorder with autopsy-confirmed α synucleinopathy, we identified 49 (23%) patients with no Alzheimer's disease neuropathology, 56 (26%) with low-level Alzheimer's disease neuropathology, 45 (21%) with intermediate-level Alzheimer's disease neuropathology, and 63 (30%) with high-level Alzheimer's disease neuropathology. As levels of Alzheimer's disease neuropathology increased, cerebral α-synuclein scores were higher, and the interval between onset of motor and dementia symptoms and disease duration was shorter (p<0·0001 for all comparisons). Multivariate regression showed independent negative associations of cerebral tau neurofibrillary tangles score with the interval between onset of motor and dementia symptoms (β -4·0, 95% CI -5·5 to -2·6; p<0·0001; R² 0·22, p<0·0001) and with survival (-2·0, -3·2 to -0·8; 0·003; 0·15, <0·0001) in models that included age at death, sex, cerebral neuritic plaque scores, cerebral α-synuclein scores, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates.

Interpretation: Alzheimer's disease neuropathology is common in synucleinopathies and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tangles burden, in addition to α-synuclein pathology and amyloid plaque pathology, are the strongest pathological predictors of a shorter interval between onset of motor and dementia symptoms and survival. Diagnostic criteria based on reliable biomarkers for Alzheimer's disease neuropathology in synucleinopathies should help to identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-β or α synuclein, and to stratify them by level of Alzheimer's disease neuropathology.

Funding: US National Institutes of Health (National Institute on Aging and National Institute of Neurological Disorders and Stroke).

Figure 1. Diagnostic accuracy of the “one-year rule” to detect advanced SYN or AD neuropathology

A) Distribution of neuropathological AD groups among PDD and DLB clinical phenotypes in relation to the one year motor-dementia interval (MDI) rule (dashed line). B) ROC curve analysis testing the diagnostic accuracy of the MDI to distinguish neocortical stage of synucleinopathy. AUC (0·67, p=0·05), sensitivity of 80%, and specificity of 42% using the one-year rule (intersection of dashed lines). C) ROC curve analysis testing the diagnostic accuracy of the MDI to distinguish SYN+AD pathology. AUC (0·72, p=0·0004), sensitivity of 76%, and specificity of 55% using the one-year rule (intersection of dashed lines).

Figure 2. Comparison of motor-dementia interval and survival across Lewy body spectrum patients stratified by neuropathological group

Box-plots display the range of motor-dementia interval (MDI) for (A) total AD neuropathological change, (B) stages of senile plaque pathology, and (C) Braak stages of neurofibrillary tau. Dashed lines represent across-groups comparison (one-way ANOVA) and solid lines represent post-hoc individual group comparisons (independent t-tests) ***=p<0·001, **=p<0·01, *=p≤0·05. Kaplan-Meier curves depict the proportion of patients surviving at given time points observed for (D) total AD neuropathological change, (E) stages of senile plaque pathology, and (F) Braak stages of neurofibrillary tau. Symbols above reference line denote: † p≤0·05 compared to int.AD, * p<0·05 compared to low AD/CA/BI-II, ‡ p<0·02 compared to pure SYN/C0/B0 (independent sample t-tests).

Figure 3. Comparison of cerebral average neuropathology scores with motor-dementia interval and survival in Lewy body spectrum disorders

Scatterplot matrices illustrate individual patient data correlations for each variable row/column combination for (A) MDI and (B) survival. All cerebral pathologies scores are correlated with each other: Cerebral NFT: Cerebral NP (rho= 0·6, p<0·0001), Cerebral NFT: Cerebral SYN (rho=0·5, p<0·0001), Cerebral NP: Cerebral SYN (rho=0·4, p<0·0001), inversely correlated with MDI: Cerebral NFT: MDI (rho= −0·4, p<0·0001), Cerebral NP: MDI (rho= −0·3, p<0·0001), Cerebral SYN: MDI (rho= −0·3, p=0·0001) and survival: Cerebral NFT: survival (rho= −0·4, p<0·0001), Cerebral NP (rho= −0·3, p<0·0001) and Cerebral SYN: Survival (rho= −0·3, p=0·0001).