Summary 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).
Summary Background TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin ...inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene ( TARDBP ) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 ( SOD1 ). Methods TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families. Findings We identified two variants in TARDBP , which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available. Interpretation The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein–protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U. Funding National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació ‘la Caixa’.
Summary To date, there have been few systematic attempts to provide a standard operating procedure for the neuropathological diagnosis of Parkinson's disease (PD). Pathological examination cannot ...classify the clinical syndrome with certainty; therefore, the neuropathological diagnosis is, at best, a probability statement. The neuropathological diagnosis of parkinsonism has become increasingly based on fundamental molecular underpinnings, with recognition that the genetics of parkinsonism is heterogeneous and includes disorders that are associated with and without Lewy bodies. The advent of α-synuclein immunohistochemistry has substantially improved the ability to identify Lewy pathology, particularly cortical Lewy bodies and smaller aggregates within processes and the neuropil. In this Review we discuss the diagnostic criteria for the neuropathological assessment of PD. These criteria are provisional and need to be validated through an iterative process that could help with their refinement. Additionally, we suggest future directions for neuropathology research on PD.
ABSTRACT Cognitive impairment is a common and disabling problem in Parkinson’s disease (PD). Identification of genetic variants that influence the presence or severity of cognitive deficits in PD ...might provide a clearer understanding of the pathophysiology underlying this important nonmotor feature. We genotyped 1,105 PD patients from the PD Cognitive Genetics Consortium for 249,336 variants using the NeuroX array. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test–Revised HVLT-R), working memory/executive function (Letter-Number Sequencing and Trail Making Test TMT A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation JoLO), and global cognitive function (Montreal Cognitive Assessment). For common variants we used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates. Rare variants were analyzed using the optimal unified sequence kernel association test. The significance threshold was defined as a false discovery rate corrected P -value ( PFDR ) of 0.05. Eighteen common variants in 13 genomic regions exceeded the significance threshold for one of the cognitive tests. These included GBA rs2230288 (E326K; PFDR = 2.7 x 10-4 ) for JoLO, PARP4 rs9318600 ( PFDR = 0.006) and rs9581094 ( PFDR = 0.006) for HVLT-R total recall, and MTCL1 rs34877994 ( PFDR = 0.01) for TMT B-A. Analysis of rare variants did not yield any significant gene regions. We have conducted the first large-scale PD cognitive genetics analysis and nominated several new putative susceptibility genes for cognitive impairment in PD. These results will require replication in independent PD cohorts.
Objectives: To assess the reliability and interobserver agreement of stroke identification on neuroimaging in patients presenting with dementia.
Design: Comparison study between neurologists, ...radiology reports, and autopsy.
Setting: Dementia registry within a health maintenance organization.
Participants: Dementia patients with computed tomography (CT) scans obtained near the time of diagnosis and postmortem neuropathological examinations (N=99).
Measurements: Three neurologists independently read CT scans for the presence and locations of strokes. Radiology reports from these scans were reviewed. The results from neurologists, radiologists, and autopsies were compared.
Results: The positive predictive value for CT‐observed strokes compared with their presence on autopsy was 0.44 to 0.49, regardless of the specialty of the observer. Strokes were present at autopsy in 46 of 99 cases. Agreement between neurologists on the presence of strokes was fair to moderate (kappa=0.27–0.56). Less agreement was found between neurologists and radiologists (kappa=0.00–0.11). Results improved slightly when each case was evaluated as any stroke present versus no stroke on imaging (kappa=0.34–0.75) or for the presence of multiple strokes (kappa=0.17–0.69).
Conclusion: There is only fair to moderate agreement between observers regarding the identification of strokes on CT scans in patients presenting with dementia. Furthermore, strokes identified on imaging were present on pathology only half the time.
To examine the intracellular and extracellular expression of myocilin in the human and primate trabecular meshwork (TM) in the presence and absence of glucocorticoids.
Myocilin expression was ...examined in cultured human TM cells by Northern blot analysis and myocilin antibody-mediated immunoprecipitation. Myocilin expression was quantified using high-resolution two-dimensional polyacrylamide gel electrophoresis of radiolabeled proteins from human TM cells, TM tissue explants, and perfused human anterior segments cultured with and without dexamethasone (DEX) for 14 to 21 days, as well as TM tissue from pigtailed monkeys treated orally for 1 year with cortisone acetate. Immunofluorescence with anti-myocilin antibodies was used to localize cellular and extracellular expression of myocilin in cultured human TM cells.
Glucocorticoid treatment caused a significant induction of myocilin mRNA, a tetrad of cell-associated proteins, and 8 to 20 secreted proteins (molecular mass M(r) 56 and 59 kDa and isoelectric point pI 5.2 and 5.3) in some, but not all the cultured human TM cells and explanted tissues. Western immunoblot analysis using anti-myocilin peptide antibodies identified these proteins as encoded by the MYOC gene. There was significant induction of the myocilin proteins in three perfusion-cultured human eyes, in which DEX-induced elevated intraocular pressure developed. Monkeys treated 1 year with cortisol acetate showed steroid glaucoma-like morphologic changes in the TM that correlated with the induction of myocilin in the TM. Immunofluorescence analysis of cultured TM cells localized myocilin intracellularly in discrete perinuclear and cytoplasmic vesicular deposits as well as extracellularly on the cell surface associated with the extracellular matrix. In several DEX-treated TM cell lines, there were significant levels of myocilin secreted into the media. Enzymatic deglycosylation of proteins in the TM media converted the higher molecular weight isoforms of myocilin (approximately 57 kDa) to the lower molecular weight isoforms ( approximately 55 kDa).
Although the function of myocilin is unknown, induction of these TM proteins was found in eyes in which glucocorticoid-induced ocular hypertension developed. Therefore, myocilin may play an important pathogenic role in ocular hypertension in addition to its role in certain forms of POAG.
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