Citations

AbstractBackgroundThe semantic fluency task involves naming as many items as possible in a given category (e.g., animals) in one minute. It is often interpreted as a measure of word retrieval, but also draws on executive function abilities to organize responses and develop task‐specific strategies. Indeed, both language skills and dementia severity ratings have recently been found to correlate with semantic fluency performance in patients with primary progressive aphasia (Riello et al., 2022; Scheffel et al., 2021). Here, we focused instead on how performance on language and executive function measures predicts longitudinal change in semantic fluency performance in patients with progressive agrammatic aphasia and/or apraxia of speech (AOS).MethodPatients with isolated agrammatic aphasia (n = 10), isolated AOS (n = 42), or a combination of the two (n = 59) with 1‐7 visits (mean = 2.19) were included. We used Bayesian hierarchical linear models to investigate whether baseline measures of executive function or language were associated with the rate at which semantic fluency performance changes over time while accounting for baseline diagnosis group, sex, education, age at baseline, and baseline disease duration.ResultSemantic fluency performance declined over time, at a similar rate irrespective of diagnostic group (isolated or combined aphasia or AOS; Figure 1). Across all patients, higher executive function abilities at baseline, as indicated by faster Trails Making Test B completion times, predicted higher baseline semantic fluency performance and also a steeper annual rate of decline (Figure 2). Similarly, higher fluency ratings during the Western Aphasia Battery‐Revised picture description at baseline were associated with higher baseline semantic fluency performance and faster decline. Baseline performance on the Boston Naming Test and Token Test were also associated with baseline semantic fluency, but not with longitudinal change.ConclusionThese results better delineate how language and executive function abilities support performance in the semantic fluency task. Higher abilities in those areas at baseline do not appear to be protective over time. Rather, the differences in semantic fluency that are present at baseline disappear as the disease progresses.

AbstractBackgroundThe ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study is designed to characterize both sporadic and familial FTLD (f‐FTLD) through annual detailed clinical, neuropsychological, biomarker, and neuroimaging assessments to capture disease onset and trajectory in preparation for therapeutic trails in FTLD. Transitions from asymptomatic to mild disease, or from mild to overt, may reveal critical windows for intervention.Method169 f‐FTLD participants carrying mutations in the main FTLD‐associated genes (79 C9orf72; 37 GRN; 53 MAPT) with at least two clinical assessments were included for analysis of phenoconversion from asymptomatic or mild disease. [CDRÒ + NACC FTLD global scores (Miyagawa et al, 2020) were used to define baseline status at first visit: “asymptomatic” = 0 and “mild” = 0.5. Conversion was defined as “partial” (asymptomatic to mild), “definite” (asymptomatic to overt [CDRÒ + NACC FTLD > = 1) and “mild to overt” (0.5 to > = 1).ResultDefinite conversion occurred most often in MAPT mutation carriers, with 5/43 asymptomatic carriers transitioning through mild to overt across multiple visits. Definite conversion was also seen in 2/65 C9orf72 expansion carriers and 1/30 GRN mutation carriers. All definite converters were assessed as mild (CDRÒ + NACC FTLD = 0.5) for at least one intermediate visit; definite conversion was observed from 2‐4 years from initial assessment. Partial conversions also occurred in all three genetic groups (MAPT: 6; C9orf72: 5; GRN: 5). Further conversion is expected to be observed in these participants in additional follow‐up visits. C9orf72 expansion carriers were less likely to progress from a baseline of mild to overt (3/14) than GRN carriers (4/6) or MAPT (7/10).ConclusionLongitudinal assessment through natural history studies can capture early phenoconversion in carriers of FTLD‐associated genetic mutations; corresponding imaging, cognitive, and biomarker profiles captured may provide insights into disease mechanisms and trajectories.

AbstractBackgroundThe ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) research consortium is actively enrolling participants across 23 North American centers to characterize sporadic and familial frontotemporal dementia (FTD) and prepare for disease‐modifying clinical trials. The ability to identify, otherwise unknown, relatives among these participants is critical to rigorously build family structures for downstream clinical and genetic research studies.MethodsGenome‐wide SNP genotyping data from ALLFTD participants was used to perform lineage analyses using PLINK. Briefly, QC was performed to remove individuals with low call rate and filter autosomal SNPs for missingness, allele frequency, and deviation from Hardy‐Weinberg equilibrium, before pruning SNPs for linkage disequilibrium. Identity‐by‐descent (IBD) estimates were then calculated for determining relatedness, followed by family‐network identification and pedigree reconstruction using PRIMUS.ResultsAbout 46% of ALLFTD participants that were genotyped and passed QC (n = 1,453) had reported a family history, while 50% (n = 721) did not and were considered sporadic. We identified a total of 460 participants that had at least one relative who was second degree or closer (PI_HAT>0.1875) based on IBD sharing, resulting in 150 family networks. This included 9 participants who self‐identified as sporadic, demonstrating the utility of direct genetic characterization to determine familiality in FTD. Most of the predicted families were associated with disease causing variants in the 3 major FTD‐causing genes: 66 families with known C9orf72 repeat expansion carriers, 35 with MAPT (including 11 families with the variant historically known as p.P301L) and 30 with GRN pathogenic variant carriers, as well as 2 families with carriers of both a C9orf72 expansion and a GRN pathogenic variant. We also identified 5 families with carriers of pathogenic variants in other familial dementia genes (2 TARDBP, 2 VCP and 1 PSEN1), as well as 12 families with yet unknown genetic etiology.ConclusionsThis dataset sets up a crucial resource to increase statistical accuracy and power in downstream association studies using the clinical, neuropsychological, neuroimaging and biomarker data currently being generated by the ALLFTD consortium. It will also facilitate genetic studies aimed at novel gene discovery, and identification of haplotypes and genetic modifiers associated with the 3 major FTD causal genes.

AbstractBackgroundGene expression changes have been identified in post‐mortem brain tissue of AD cases when compared with controls, implicating various genes and pathways. Such findings provide important insights into molecular dysregulation associated with this disease and nominate therapeutic targets. Here we investigate brain gene and co‐expression network changes in a cohort of AD cases to identify associations with degree of AD neuropathology including Braak stage (Tau), Thal phase (Amyloid beta) and brain tissue levels of five AD‐related proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodGene expression measures were collected from temporal cortex (TCX) tissue of 477 AD cases, available through the Mayo Clinic Brain Bank, using RNA sequencing (Illumina TruSeq mRNA) performed on the HiSeq4000. Following quality control 456 cases remained for analysis. Braak and Thal were provided by an experienced neuropathologist and TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Weighted gene coexpression network analysis (WGCNA) R package was used to build co‐expression networks. Genes and networks were tested for association with neuropathology and AD‐related protein levels, adjusting for relevant covariates.ResultA total of 57,353 genes were profiled, of which 19,044 were reliably expressed above background levels and formed 20 co‐expression modules. 36 genes were associated with Braak stage, 10 with Thal phase and up to 9,000 with the AD‐related protein fractions. Brain levels of pTau had the greatest number of associations, with an overrepresentation of genes involved in synaptic signalling and immune response gene ontology biological processes. 16 of the coexpression modules associated with at least one trait after Bonferroni correction for number of tests.ConclusionWe have identified a number of genes and networks associated with different aspects of AD neuropathology and associated proteins, further lending support to the involvement of synaptic and immune biology in AD. However it is not clear whether observed changes cause disease or are a consequence of the neurodegenerative process. Comparison of these findings across different proteins and fractions is expected to reveal common and distinct vulnerabilities associated with amyloid and tau, and different stages of protein aggregation.

AbstractBackgroundThe p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) has been reported to increase Alzheimer’s disease (AD) risk. This mutation in the extracellular domain of TREM2 localizes at the cleavage site and was shown to enhance shedding and impair phagocytosis in vitro by ectopic expression of TREM2‐H157Y in HEK293 cells. However, the physiological and AD‐related outcomes of TREM2 H157Y mutation in vivo remain unknown.MethodWe generated a novel Trem2 H157Y knock‐in mouse model through CRISPR‐Cas9 technology and investigated how Trem2 H157Y mutation impacts TREM2 proteolytic processing, synaptic function, and AD‐related amyloid pathology by conducting biochemical assays, immunofluorescent staining, hippocampal electrophysiology, and in vivo micro‐dialysis in awake, free‐moving animals.ResultConsistent with previous in vitro findings, TREM2‐H157Y increases the amount of soluble TREM2 (sTREM2) in the cortex and serum of mutant mice compared to the wild type controls. Interestingly, the Trem2 H157Y variant enhances synaptic plasticity without affecting microglial density and morphology. In the presence of amyloid pathology, TREM2‐H157Y surprisingly accelerates Aβ clearance and reduces amyloid burden and microgliosis.ConclusionTaken together, our findings support a beneficial effect of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD, we speculate TREM2‐H157Y might increase AD risk through an amyloid‐independent pathway, as such its effects on tauopathy and neurodegeneration merit further investigation.

Patients undergoing abdominal oncologic surgical procedures require particular surgical and anesthesiologic considerations. Traditional pain management, such as opiate treatment, continuous epidural analgesia, and non-opioid drugs, may have serious side effects in this patient population. We evaluated erector spinae plane (ESP) blocks for postoperative pain management following elective oncologic abdominal surgeries. In this single-center, prospective, and randomized study, we recruited 100 patients who underwent elective oncological abdominal surgery between December 2020 and January 2022 at Soroka University Medical Center in Beer Sheva, Israel. We compared postoperative pain levels in patients who were treated with a preincisional ESP block in addition to traditional pain management with intravenous opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen, compared to patients who were only given traditional pain management (control). Patients who were treated with a preincisional ESP block demonstrated significantly lower Visual Analog Scale scores at 60 minutes and 4, 8, and 12 hours following the surgery, compared to the control group ( p < 0.001 ). Accordingly, patients in the ESP group required less morphine from 60 minutes to 12 hours after surgery, but they required increased non-opioid postoperative analgesia management at 4, 8, and 12 hours after surgery ( p from 0.002 to <0.001) compared to the control group. In this study, we found ESP blocks to be a safe, technically simple, and effective treatment for postoperative pain management after elective oncologic abdominal procedures.

Abstract Study Design: Cross-sectional study. Objectives: To determine etiologic factors related to spinal cord injury (SCI) severity and to assess factors related to benefit from care in individuals seen for SCI in six Eastern and South-eastern Asian countries. Setting: Care centers in Bangladesh, India, Malaysia, Nepal, Sri Lanka, and Thailand. Methods: Data from multiple centers collected between October 2015 and February 2021 were analyzing using descriptive statistics and logistic regression. Results: Among 2,634 individuals, the leading cause of SCIs was falls (n=1410, 54%). Most single-level SCIs occurred in the thoracic spine (n=977, 39%). Greater than half of SCIs (n=1423, 54%) were graded American Spinal Injury Association Impairment Scale (AIS) A. Thoracic SCIs accounted for 53% (n=757) of all single-level AIS A SCIs, and the percentage of thoracic SCIs graded AIS A (78%) was significantly higher than cervical (51%), lumbar (24%), sacral (8%), and multiple level (15%) SCIs (p<0.001). Regression analyses isolated predictive factors both of SCI severity and inpatient improvement. Four factors predicted injury severity: age, spinal region, injury etiology, and country of residence. Four factors also predicted inpatient improvement: age, spinal region, AIS grade on intake, and country of residence. Conclusions: Falls were the leading cause of traumatic SCIs, most of which occurred from ≥1 meter. The thoracic spine was the most commonly injured region, and thoracic SCIs were associated with both increased injury severity and poorer recovery. Age, spinal region, and country were each predictive factors of both SCI severity and inpatient improvement. Sponsorship: Mayo Clinic Global Health Program

Abstract The recycling of membrane proteins from endosomes to the cell surface is vital for cell signaling and survival. Retriever, a trimeric complex of VPS35L, VPS26C and VPS29, together with the CCC complex comprising CCDC22, CCDC93, and COMMD proteins, plays a crucial role in this process. The precise mechanisms underlying Retriever assembly and its interaction with CCC have remained elusive. Here, we present the first high-resolution structure of Retriever determined using cryogenic electron microscopy. The structure reveals a unique assembly mechanism, distinguishing it from its remotely related paralog, Retromer. By combining AlphaFold predictions and biochemical, cellular, and proteomic analyses, we further elucidate the structural organization of the entire Retriever-CCC complex and uncover how cancer-associated mutations disrupt complex formation and impair membrane protein homeostasis. These findings provide a fundamental framework for understanding the biological and pathological implications associated with Retriever-CCC-mediated endosomal recycling.

Background and purpose Cerebral venous thrombosis (CVT) is usually treated with systemic anticoagulation, but mechanical thrombectomy (MT) and local infusion of a thrombolytic agent have been proposed as an alternative therapy. In this study, we analyze National Inpatient Sample (NIS) to determine the trends of MT including discharge other than home (DOTH) and mortality. Material and methods Healthcare Utilization Program-NIS (HCUP-NIS) was queried between 2005 and 2018 for CVT and MT. Cochran–Armitage test was conducted to assess linear trend of proportion of utilization and DOTH of MT. Multivariable logistic regression was conducted to assess odds of undergoing MT among CVT admissions, odds of in-hospital mortality, and DOTH for all admissions involving MT for CVT. Results A total of 1331 (1.56%) admissions involved MT out of 85,370 CVT cases. Utilization of MT had an upward trend of 0.13% ( p < 0.001) per year. Trend in proportion of incidence of DOTH among MT admission remained stationary (trend: 0.70%; p = 0.417). Patients with cerebral edema (odds ratio [OR]: 4.34; p < 0.001) or hematological disorders (OR: 2.28; p < 0.001) were more likely to receive MT for CVT. Additionally, patients with coma (OR: 3.17; p = 0.023) or cerebral edema (OR: 4.40; p = 0.001) had higher odds of mortality. Conclusion There was an increasing trend of utilization of MT. Proportions of DOTH among MT procedures, however, remained stable. Patients with greater risk factors, including hematological disorders and cerebral edema, were more likely to undergo MT. Among patients treated with MT, those with coma or cerebral edema were more likely to die.

Background: Vaccination in patients with multiple sclerosis (MS) treated with immunosuppressive drugs is highly recommended. Regarding COVID-19 vaccination, no specific concern has been raised. Objectives: We aimed to evaluate if COVID-19 vaccination or infection increased the risk of disease activity, either radiological or clinical, with conversion to MS in a cohort of people with a radiologically isolated syndrome (RIS). Methods: This multicentric observational study analyzed patients in the RIS Consortium cohort during the pandemic between January 2020 and December 2022. We compared the occurrence of disease activity in patients according to their vaccination status. The same analysis was conducted by comparing patients’ history of COVID-19 infection. Results: No difference was found concerning clinical conversion to MS in the vaccinated versus unvaccinated group (6.7% vs 8.5%, p > 0.9). The rate of disease activity was not statistically different (13.6% and 7.4%, respectively, p = 0.54). The clinical conversion rate to MS was not significantly different in patients with a documented COVID-19 infection versus non-infected patients. Conclusion: Our study suggests that COVID-19 infection or immunization in RIS individuals does not increase the risk of disease activity. Our results support that COVID-19 vaccination can be safely proposed and repeated for these subjects.