Background There exists great heterogeneity in patient survival and the time interval between motor symptom and dementia onset (MDI) across Lewy body spectrum disorders (LBSD). The goal of this study is to identify genetic and pathological findings that have the strongest association with these features of clinical heterogeneity in LBSD. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of LBSD patients with autopsy-confirmed α-synucleinopathy (as of Oct 1, 2015) recruited from 5 clinical research centres in 5 cities in the USA. Using histopathology techniques and markers, we assessed the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathologic changes in cortical regions using averaged ordinal scores and genotyped cases for variants associated with LBSD. We evaluated the time interval from onset of motor symptoms to dementia (MDI) and overall survival in groups with varying levels of co-morbid Alzheimer’s disease pathology (AD) according to current National Institute on Aging–Alzheimer’s Association neuropathological criteria and used multivariate regression to control for age at death and gender. Findings This study included 213 patients who had been followed to autopsy and met inclusion criteria of clinical LBSD with autopsy-confirmed α-synculeinopathy. Patient groups were characterized by no (n=49,23%), low-level (n=56,26%), intermediate-level (n=45,21%) or high-level (n=63,30%) AD neuropathology. Across groups of increasing levels of AD neuropathology, there were higher cerebral α-synuclein scores, shorter MDI, and shorter disease duration (p<0·0001 all). Multivariate regression found independent negative associations of cerebral tau score with MDI (β= −4·0, 95% CI −5·5 to −2·6; p<0·0001) (R2=0·22, p<0·0001) and with survival (β=−2·0, 95% CI −3·2 to −0·8; p<0·0001) (R2=0·15, p<0·0001) in models including age at death, gender, cerebral neuritic plaque scores, cerebral α-synuclein, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation AD neuropathology is common in LBSD and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tau tangle burden, α-synuclein pathology, and amyloid plaque pathology are the strongest pathological predictors of a shorter MDI and survival in LBSD. In the future, clinical diagnostic criteria which use reliable biomarkers for AD neuropathology in LBSD should help identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-beta or α-synuclein, and stratify them by level of AD neuropathology. Funding NIH (NIA/NINDS).

Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism–dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.

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