Bisecting N-Acetylglucosamine Correlates with Phospho-Tau181 in Subjective Cognitive Decline but not in Control Cases.

Background: The N-glycan structure bisecting N-acetylglucosamine (bisecting GlcNAc) is present on several N-glycans that are elevated in Alzheimer's disease (AD), and previous studies have shown that bisecting GlcNAc levels correlate with total tau and phospho-tau181 in cerebrospinal fluid at early stages of AD. A recent population-based study showed that bisecting GlcNAc correlates with total tau also in blood and that this correlation could predict conversion to dementia. Objective: In this study, we have further investigated how bisecting GlcNAc relates to total tau and phospho-tau 181 in cerebrospinal fluid samples from controls and cases with early cognitive deficits, stratified by amyloid/tau status and gender. Methods: Relative levels of bisecting GlcNAc in cerebrospinal fluid were measured by an enzyme-linked lectin assay in individuals with subjective cognitive decline, mild cognitive impairment and controls from the Norwegian Dementia Disease Initiation cohort. Results: As in our previous study, the correlation between bisecting GlcNAc and total tau or phospho-tau181 was particularly strong in the subjective cognitive decline group. The correlation was observed in amyloid negative and tau negative as well as amyloid positive and tau positive individuals, both in females and in males. Interestingly, among the amyloid negative and tau negative individuals, the correlation was observed in individuals with subjective cognitive decline but not in the controls. Conclusions: Thus, bisecting GlcNAc could be a biomarker for early cognitive decline.

Human pallial MGE-type GABAergic interneuron cell therapy for chronic focal epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy. One-third of patients have drug-refractory seizures and are left with suboptimal therapeutic options such as brain tissue-destructive surgery. Here, we report the development and characterization of a cell therapy alternative for drug-resistant MTLE, which is derived from a human embryonic stem cell line and comprises cryopreserved, post-mitotic, medial ganglionic eminence (MGE) pallial-type GABAergic interneurons. Single-dose intrahippocampal delivery of the interneurons in a mouse model of chronic MTLE resulted in consistent mesiotemporal seizure suppression, with most animals becoming seizure-free and surviving longer. The grafted interneurons dispersed locally, functionally integrated, persisted long term, and significantly reduced dentate granule cell dispersion, a pathological hallmark of MTLE. These disease-modifying effects were dose-dependent, with a broad therapeutic range. No adverse effects were observed. These findings support an ongoing phase 1/2 clinical trial (NCT05135091) for drug-resistant MTLE.

A glycan epitope correlates with tau in serum and predicts progression to Alzheimer's disease in combination with APOE4 allele status.

INTRODUCTION: There is an urgent need for novel blood biomarkers for the detection of Alzheimer's disease (AD). We previously showed that levels of the bisecting N-acetylglucosamine glycan epitope was elevated in cerebrospinal fluid in AD. However, its diagnostic value in blood is unknown. METHODS: We analyzed blood levels of bisecting N-acetylglucosamine and total tau in a retrospective cohort of 233 individuals. Progression to AD was compared between the groups using Cox regression. The predictive value of the biomarkers was determined by logistic regression. RESULTS: Bisecting N-acetylglucosamine correlated with tau levels (p < 0.0001). Individuals with an intermediate tau/bisecting N-acetylglucosamine ratio had elevated AD risk (hazard ratio = 2.06, 95% confidence interval [CI]: 1.18-3.6). Moreover, a combined model including tau/bisecting N-acetylglucosamine ratio, apolipoprotein E (APOE) ε4 status, and Mini-Mental State Examination score predicted future AD (area under the curve = 0.81, 95% CI: 0.68-0.93). DISCUSSION: Bisecting N-acetylglucosamine in combination with tau is a valuable blood biomarker for predicting AD.

The impact of the COVID-19 pandemic on mortality in people with dementia without COVID-19: a systematic review and meta-analysis.

INTRODUCTION: Significant mortality amongst vulnerable populations, such as people living with dementia, might go undetected during pandemic conditions due to refocus of care efforts. There is an urgent need to fully evaluate the pandemic impact on mortality amongst people living with dementia in order to facilitate future healthcare reforms and prevent deaths. The purpose of this study was to determine whether there was any significant difference in mortality amongst people with dementia without COVID-19 during the COVID-19 pandemic compared to previous years. METHODS: A literature search was conducted in 5 databases. The relative risk ratio and confidence interval was used to estimate the change in mortality rates amongst people with dementia during the COVID-19 pandemic. The I2 value was used to assess heterogeneity, publication bias, and sensitivity analyses were performed. RESULTS: Pooled analysis of 11 studies showed that mortality amongst people living with dementia was significantly increased during the COVID-19 pandemic for people with dementia without COVID-19. Mortality risk increased by 25% during the time period studied. Subgroup analysis was not performed due the low number of included studies. CONCLUSIONS: The results of this study suggest that people with dementia had a significant increased mortality during the pandemic even if they did not have COVID-19. People with dementia should participate in efforts that reduce general social spread and pandemic impact on healthcare system such as vaccinations, mask mandates, and testing. These results have clinical implications as preventing direct COVID-19 infection is not enough to adequately protect people living with dementia from increased mortality. Measures to limit social spread of infections and help support patients should also be a focus for clinicians. Further research should focus on the identification of mechanisms and other explanations for increased mortality as well as contributing factors such as living in care homes and differences between countries with various pandemic strategies.