Martin, Nicholas B.

AbstractBackgroundMultiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar syndromes. Although consensus criteria have been widely used to diagnose MSA, accurate clinical diagnosis remains challenging. Other neurodegenerative disorders, such as Lewy body disease, can mimic MSA.ObjectivesWe described clinical and neuropathologic findings of two patients with Creutzfeldt–Jakob disease (CJD) who had antemortem clinical diagnoses of MSA.MethodsThe brain bank for neurodegenerative disorders was queried for cases with a clinical diagnosis of MSA, but neuropathologic findings of CJD.ResultsCase 1 was a 55‐year‐old man with a 6‐month history of orthostatic hypotension, parkinsonism, cerebellar ataxia, bradyphrenia, and memory impairment. Case 2 was a 65‐year‐old man who had a 5‐year history of cerebellar ataxia, parkinsonism, and cognitive impairment, as well as a 7‐year history of dream enactment behavior. Neither case had characteristic α‐synuclein immunoreactive neuronal or glial inclusions typical of MSA. Instead, they had spongiform encephalopathy with neuronal loss and gliosis with prion protein‐immunoreactive kuru‐like plaques. Genetic analyses in case 1 had wild‐type PRNP, whereas case 2 revealed a 4‐octapeptide repeat insertion in PRNP.ConclusionsEven when clinical features suggest MSA, CJD should also be considered if the progression is rapid or the disease course is atypical, such as the absence of autonomic dysfunction for an extended period.

ObjectiveRecent evidence supports a link between increased TDP‐43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP‐43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP‐43 pathology and related neurodegeneration in the absence of typical AD pathologies.MethodsWe overexpressed human TDP‐43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe‐knockout (Apoe‐KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP‐43 overexpression‐related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP‐43 pathology in 160 postmortem brains from autopsy‐confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD‐MND) in the Mayo Clinic Brain Bank.ResultsWe found that TDP‐43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe‐KO mice. In the motor cortex of the ALS and FTLD‐MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP‐43‐positive dystrophic neurites.InterpretationOur data suggest a genotype‐specific effect of APOE on TDP‐43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830–843