Ross, Owen A.

AbstractIntraneuronal accumulation of misfolded α-synuclein is the pathological hallmark of Parkinson’s disease and dementia with Lewy bodies, often co-occurring with variable degrees of Alzheimer’s disease related neuropathology. Genetic association studies have successfully identified common variants associated with disease risk and phenotypic traits in Lewy body disease, yet little is known about the genetic contribution to neuropathological heterogeneity.Using summary statistics from Parkinson’s disease and Alzheimer’s disease genome-wide association studies, we calculated polygenic risk scores and investigated the relationship with Lewy, amyloid-β and tau pathology. Associations were nominated in neuropathologically defined samples with Lewy body disease from the Netherlands Brain Bank (n = 217) and followed up in an independent sample series from the Mayo Clinic Brain Bank (n = 394). We also generated stratified polygenic risk scores based on single-nucleotide polymorphisms annotated to eight functional pathways or cell types previously implicated in Parkinson’s disease and assessed for association with Lewy pathology in subgroups with and without significant Alzheimer’s disease co-pathology.In an ordinal logistic regression model, the Alzheimer’s disease polygenic risk score was associated with concomitant amyloid-β and tau pathology in both cohorts. Moreover, both cohorts showed a significant association between lysosomal pathway polygenic risk and Lewy pathology, which was more consistent than the association with a general Parkinson’s disease risk score and specific to the subset of samples without significant concomitant Alzheimer’s disease related neuropathology.Our findings provide proof of principle that the specific risk alleles a patient carries for Parkinson’s and Alzheimer’s disease also influence key aspects of the underlying neuropathology in Lewy body disease. The interrelations between genetic architecture and neuropathology are complex, as our results implicate lysosomal risk loci specifically in the subset of samples without Alzheimer’s disease co-pathology. Our findings hold promise that genetic profiling may help predict the vulnerability to specific neuropathologies in Lewy body disease, with potential relevance for the further development of precision medicine in these disorders.

Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic, progressive microangiopathy caused by mutations in the NOTCH3 gene. Patients often present with migraine and progressive subcortical infarcts resulting in vascular cognitive impairment and death. Currently, there are no disease modifying treatments. Limiting future trials is the lack of an objective construct to classify and monitor severity of disease. The purpose of this study was to gain experience with a novel CADASIL severity grading system. Methods: Neurologists at 5 academic centers retrospectively reviewed charts of those with confirmed CADASIL. Demographic and clinical data were recorded. The CADASIL severity grades were then assigned: 0 (asymptomatic), 1 (migraine alone), 2 (stroke or mild cognitive impairment), 3 (gait impairment or early dementia) and 4 (bedbound) based on available data. Standard descriptive statistical analyses were used. Results: We identified 138 patients; overall mean age of 50.9±13.1 years, 42.8% were men. 15 (10.9%) were grade 0, 50 (36.2%) were grade 1, 41 (44.2%) were grade 2, 12 (8.7%) were grade 3, and none were grade 4. Those with less severe disease tended to be younger, more likely men, had a lower rate of hypertension and diabetes mellitus and were less frequently tobacco users, Table 1. Increasing number of vascular risk factors was associated with higher severity grading. Conclusion: Our study highlights the ability of this severity scale to separate those with CADASIL into an ordinal system. As known in the literature, more advanced phenotypes of CADASIL tend to have more vascular risk factors. Future trials may consider utilizing this ordinal construct to monitor disease progression, response to therapy, or as a screening tool.

AbstractBackgroundAs gene‐targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial‐ready cohorts is limited.ObjectiveThe objectives are to (1) establish an international cohort of affected and unaffected individuals with PD‐linked variants; (2) provide harmonized and quality‐controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD.MethodsWe conducted a worldwide, systematic online survey to collect individual‐level data on individuals with PD‐linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ‐1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed.ResultsWe collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ‐1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published.ConclusionsWithin the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD‐linked variants; (2) provide harmonized and quality‐controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene‐targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

AbstractBackgroundWe recently discovered a novel tau binding partner, SERPINA5, to be upregulated in Alzheimer’s disease (AD) and co‐localize with corticolimbic tau distribution. As tau pathology is also observed in primary tauopathies, we hypothesized that SERPINA5 burden would mirror tau burden in these diseases. Thus, we sought to define the relationship between SERPINA5 and tau in primary tauopathies and compare this relationship to AD.MethodImmunohistochemistry was performed on the hippocampus or cingulate in 4 groups (n=6 per disease group): 1) AD, 2) 3R+4R primary age‐related tauopathy, 3) 4R tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grains disease), and 4) 3R tauopathy (Pick’s disease). Burden analyses for SERPINA5 and a phospho‐tau marker (AT8) were performed on digitized whole slide images.ResultVisual interpretation of SERPINA5 immunostaining identified both neuronal and glial inclusions that are commonly AT8‐positive in primary tauopathies. There were exceptions to this pattern such as SERPINA5‐positive Pick bodies being rarely observed. However, some pathologic structures, like ballooned neurons, were preferentially stained by SERPINA5. Quantitative analyses confirmed this observation with AT8 and SERPINA5 burden correlating in both the cingulate (R2=0.47, p<0.0001, Figure 1a) and hippocampus (R2=0.74, p<0.0001, Figure 1d). Nonparametric rank sum tests revealed majority of the primary tauopathies had less AT8 and SERPINA5 burden compared to AD in both the cingulate and hippocampus (Figure1b‐c, e‐f; Table 1).ConclusionSERPINA5 immunostaining patterns in primary tauopathies reflect tau immunostaining patterns. Our data suggests the SERPINA5‐tau interaction may not be specific for AD, which may implicate the role of SERPINA5 more broadly across tauopathies.

AbstractBackgroundA recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline.MethodsIn this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment.ResultsThe APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P &lt; .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014).ConclusionsPatients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

Parkinson’s disease (PD) by its common understanding is a late-onset sporadic movement disorder. However, there is a need to recognize not only the fact that PD pathogenesis expands beyond (or perhaps to) the brain but also that many early-onset patients develop motor signs before the age of 50 years. Indeed, studies have shown that it is likely the protein aggregation observed in the brains of patients with PD precedes the motor symptoms by perhaps a decade. Studies on early-onset forms of PD have shown it to be a heterogeneous disease with multiple genetic and environmental factors determining risk of different forms of disease. Genetic and neuropathological evidence suggests that there are α-synuclein centric forms (e.g., SNCA genomic triplication), and forms that are driven by a breakdown in mitochondrial function and specifically in the process of mitophagy and clearance of damaged mitochondria (e.g., PARKIN and PINK1 recessive loss-of-function mutations). Aligning genetic forms with recognized environmental influences will help better define patients, aid prognosis, and hopefully lead to more accurately targeted clinical trial design. Work is now needed to understand the cross-talk between these two pathomechanisms and determine a sense of independence, it is noted that autopsies studies for both have shown the presence or absence of α-synuclein aggregation. The integration of genetic and environmental data is critical to understand the etiology of early-onset forms of PD and determine how the different pathomechanisms crosstalk.