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A definitive diagnosis of Alzheimer's disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55–90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21—all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis. From counts of all aggregates (N) in a pre-defined field image and measures of the average area (A) of aggregates per image, the number-to-area ratios in a natural logarithmic form Ln(A/N) were determined for all patient samples. AD cell lines formed fewer large aggregates (cells clustered together) than non-AD or AHC cell lines. The cut-off value of Ln(A/N) = 6.98 was determined from the biomarker values of non-demented apparently healthy control (AHC) cases. Unequivocal validation by autopsy, genetics, and/or dementia criteria was possible for all 73 patient samples. The samples were collected from multiple centers—four US centers and one center in Japan. The study found no effect of center-to-center variation in fibroblast isolation, cell growth, or cell aggregation values (Ln(A/N)). The autopsy-confirmed MI Biomarker distinguished AD from non-AD dementia (non-ADD) patients and correctly diagnosed AD even in the presence of other co-morbid pathologies at autopsy (True Positive = 25, False Negative = 0, False Positive = 0, True Negative = 21, and Accuracy = 100%. Sensitivity and specificity were calculated as 100% (95% CI = 84 to 100.00%). From these findings, the MI assay appears to detect AD with great accuracy—even with abundant co-morbidity. [ABSTRACT FROM AUTHOR]

Background: Life expectancy (LE) following Alzheimer's disease (AD) is highly variable. The literature to date is limited by smaller sample sizes and clinical diagnoses.Objective: No study to date has evaluated predictors of AD LE in a retrospective large autopsy-confirmed sample, which was the primary objective of this study.Methods: Participants (≥50 years old) clinically and neuropathologically diagnosed with AD were evaluated using National Alzheimer's Coordinating Center (N = 1,401) data. Analyses focused on 21 demographic, medical, neuropsychiatric, neurological, functional, and global cognitive predictors of LE at AD dementia diagnosis. These 21 predictors were evaluated in univariate analyses. Variables found to be significant were then entered into a forward multiple regression. LE was defined as months between AD diagnosis and death.Results: Fourteen predictors were significant in univariate analyses and entered into the regression. Seven predictors explained 27% of LE variance in 764 total participants. Mini-Mental State Examination (MMSE) score was the strongest predictor of LE, followed by sex, age, race/ethnicity, neuropsychiatric symptoms, abnormal neurological exam results, and functional impairment ratings. Post-hoc analyses revealed correlations of LE were strongest with MMSE ≤12.Conclusion: Global cognitive functioning was the strongest predictor of LE following diagnosis, and AD patients with severe impairment had the shortest LE. AD patients who are older, male, white, and have more motor symptoms, functional impairment, and neuropsychiatric symptoms were also more likely have shorter LE. While this model cannot provide individual prognoses, additional studies may focus on these variables to enhance predictions of LE in patients with AD. [ABSTRACT FROM AUTHOR]

The diagnosis of Parkinson's disease (PD) is challenging at all stages due to variable symptomatology, comorbidities, and mimicking conditions. Postmortem assessment remains the gold standard for a definitive diagnosis. While it is well recognized that PD manifests pathologically in the central nervous system with aggregation of α-synuclein as Lewy bodies and neurites, similar Lewy-type synucleinopathy (LTS) is additionally found in the peripheral nervous system that may be useful as an antemortem biomarker. We have previously found that detection of LTS in submandibular gland (SMG) biopsies is sensitive and specific for advanced PD; however, the sensitivity is suboptimal especially for early-stage disease. Further, visual microscopic assessment of biopsies by a neuropathologist to identify LTS is impractical for large-scale adoption. Here, we trained and validated a convolutional neural network (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total of 8,450 LTS and 35,066 background objects were annotated following an inter-rater reliability study with Fleiss Kappa = 0.72. We used transfer learning to train a CNN model to classify image patches (151 × 151 pixels at 20× magnification) with and without the presence of LTS objects. The trained CNN model showed the following performance on image patches: sensitivity: 0.99, specificity: 0.99, precision: 0.81, accuracy: 0.99, and F-1 score: 0.89. We further tested the trained network on 1230 naïve WSI from the same cohort of research subjects comprising 42 PD patients and 14 controls. Logistic regression models trained on features engineered from the CNN predictions on the WSI resulted in sensitivity: 0.71, specificity: 0.65, precision: 0.86, accuracy: 0.69, and F-1 score: 0.76 in predicting clinical PD status, and 0.64 accuracy in predicting PD stage, outperforming expert neuropathologist LTS density scoring in terms of sensitivity but not specificity. These findings demonstrate the practical utility of a CNN detector in screening for LTS, which can translate into a computational tool to facilitate the antemortem tissue-based diagnosis of PD in clinical settings. [ABSTRACT FROM AUTHOR]

Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s–1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD. [ABSTRACT FROM AUTHOR]

To determine if Alzheimer's disease (AD), its Lewy body (LB) variant (LBV), and diffuse LB disease (DLBD) are distinguishable at initial clinical evaluation, data from autopsy-confirmed AD, LBV, and DLBD were examined. No significant differences were found in age at onset, age at death, total duration of illness, duration of illness before initial visit, duration of illness from initial visit to death, or severity of illness at initial evaluation. Hallucinations and delusions were significantly more frequent for LBV and DLBD, respectively, than for AD, and falls were more frequent for DLBD than for AD. Extrapyramidal symptoms (EPS) were less frequent in neuroleptic-free AD subjects than in LB subjects; the percentage of AD patients with EPS after neuroleptic exposure was less than that among LB patients. Seizures were significantly more common for DLBD than for AD or LBV. LB dementias differed from AD at initial evaluation, with more frequent hallucinations and delusions, EPSs, and seizures, and longitudinally in neuroleptic sensitivity, but the data did not distinguish LBV from DLBD. [ABSTRACT FROM AUTHOR]

Reports on the investigation of a delayed death following injury in an automobile accident. Occurrence of the hemorrhage after the accident; Hospitalization of the patient for skeletal trauma; Absence of symptoms of brain injury; Findings of the autopsy.