Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer’s disease

Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer’s disease (AD), but little is known about the molecular mechanisms underlying this regional vulnerability. Here we utilize the 10 × Visium platform to define the spatial transcriptomic profile in both AD and control (CT) MTG. We identify unique marker genes for cortical layers and the white matter, and layer-specific differentially expressed genes (DEGs) in human AD compared to CT. Deconvolution of the Visium spots showcases the significant difference in particular cell types among cortical layers and the white matter. Gene co-expression analyses reveal eight gene modules, four of which have significantly altered co-expression patterns in the presence of AD pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell–cell-communications among microglia, oligodendrocytes, astrocytes, and neurons, which may contribute to the cellular and regional vulnerability in early AD. Using single-molecule fluorescent in situ hybridization, we validated the cell-type-specific expression of three novel DEGs (e.g., KIF5A, PAQR6, and SLC1A3) and eleven previously reported DEGs associated with AD pathology (i.e., amyloid beta plaques and intraneuronal neurofibrillary tangles or neuropil threads) at the single cell level. Our results may contribute to the understanding of the complex architecture and neuronal and glial response to AD pathology of this vulnerable brain region

Validation of SATURN, a free, electronic, self‐administered cognitive screening test

BackgroundCognitive screening is limited by clinician time and variability in administration and scoring. We therefore developed Self-Administered Tasks Uncovering Risk of Neurodegeneration (SATURN), a free, public-domain, self-administered, and automatically scored cognitive screening test, and validated it on inexpensive (<$100) computer tablets.MethodsSATURN is a 30-point test including orientation, word recall, and math items adapted from the Saint Louis University Mental Status test, modified versions of the Stroop and Trails tasks, and other assessments of visuospatial function and memory. English-speaking neurology clinic patients and their partners 50 to 89 years of age were given SATURN, the Montreal Cognitive Assessment (MoCA), and a brief survey about test preferences. For patients recruited from dementia clinics (n = 23), clinical status was quantified with the Clinical Dementia Rating (CDR) scale. Care partners (n = 37) were assigned CDR = 0.ResultsSATURN and MoCA scores were highly correlated (P < .00001; r = 0.90). CDR sum-of-boxes scores were well-correlated with both tests (P < .00001) (r = -0.83 and -0.86, respectively). Statistically, neither test was superior. Most participants (83%) reported that SATURN was easy to use, and most either preferred SATURN over the MoCA (47%) or had no preference (32%).DiscussionPerformance on SATURN-a fully self-administered and freely available (https://doi.org/10.5061/dryad.02v6wwpzr) cognitive screening test-is well-correlated with MoCA and CDR scores

Wolframin is a novel regulator of tau pathology and neurodegeneration

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer’s disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD. The role of WFS1 in Tauopathies and its levels in tau pathology-associated neurodegeneration, however, is largely unknown. Here we report that WFS1 deficiency is associated with increased tau pathology and neurodegeneration, whereas overexpression of WFS1 reduces those changes. We also find that WFS1 interacts with tau protein and controls the susceptibility to tau pathology. Furthermore, chronic ER stress and autophagy-lysosome pathway (ALP)-associated genes are enriched in WFS1-high excitatory neurons in human AD at early Braak stages. The protein levels of ER stress and autophagy-lysosome pathway (ALP)-associated proteins are changed in tau transgenic mice with WFS1 deficiency, while overexpression of WFS1 reverses those changes. This work demonstrates a possible role for WFS1 in the regulation of tau pathology and neurodegeneration via chronic ER stress and the downstream ALP. Our findings provide insights into mechanisms that underpin selective neuronal vulnerability, and for developing new therapeutics to protect vulnerable neurons in AD

Bruikbaarheid en validiteit van de Nederlandse versie van de Montreal Cognitive Assessment (MoCA-D) bij het diagnosticeren van Mild Cognitive Impairment,Applicability and validity of the Dutch version of the Montreal Cognitive Assessment (moCA-d) in diagnosing MCI

Contains fulltext : 87418.pdf (publisher's version ) (Closed access)OBJECTIVE: The MoCA is a new screening test to detect Mild Cognitive Impairment (MCI). Purpose of this study is validating the Dutch version (MoCA-D). METHOD: We administered the MoCA-D to healthy control subjects and to elderly with MCI or dementia from a memory disorder outpatient clinic and a geriatric (outpatient) clinic (n = 30, 32, 37 respectively, age > or = 60). Neuropsychological testing was part of the standard procedure for patients to diagnose MCI. Sensitivity, specificity and predictive values (positive: PPV and negative: NPV) of the MoCA-D were assessed. RESULTS: A significant effect of group was found on MoCA-D total score (F (2.95) =67.9; p < 0.01). With a cutoff score of < or = 25, sensitivity and specificity to detect MCI in relation to healthy controls were 72% and 73%, respectively. PPV and NPV were 84% and 56%, respectively. With a cut-off score of < or = 20, sensitivity to detect dementia in relation to MCI was 100% for severe dementia and 75% for mild dementia. Specificity for dementia was 81%, PPV 94% and NPV 55%. CONCLUSION: The MoCA-D distinguishes between healthy elderly, MCI patients and dementia patients. However, in this study, insufficient sensitivity and poor specificity were found. For the present, applying a broader and flexible screening procedure in order to detect MCI seems a more useful method than the interpretation of one test result in particular.10 p