Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Family history of Alzheimer's disease alters cognition and is modified by medical and genetic factors

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer’s disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18–85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.publishedVersionCopyright Talboom et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credite

Intravenous allogeneic mesenchymal stromal cell therapy in 13 Pugs with presumptive early necrotizing meningoencephalitis.

ObjectiveTo describe the tolerability and activity of IV allogeneic mesenchymal stromal cell (MSC) therapy in 13 Pugs with presumptive early necrotizing meningoencephalitis (NME).Methods255 Pugs were screened from 2021 to 2024 for neurological examination (NE) abnormalities suggestive of early NME. All dogs received a minimum of 2 NEs spaced 2 to 4 weeks apart. An NE score (NES) was assigned at each visit. Magnetic resonance imaging, CSF analysis, and infectious disease testing was obtained in all affected Pugs. Pugs with consistent or progressive NES and MRI or CSF findings supportive of early NME were eligible for MSC therapy.ResultsNE abnormalities prior to MSC therapy included spinal hyperesthesia (11 of 13 [85%]), paw placement deficit (11 of 13 [85%]), menace deficit (9 of 13 [69%]), obtundation (9 of 13 [69%]), seizures (7 of 13 [54%]), and ataxia (4 of 13 [31%]). The NES improved in all dogs within 24 hours of the first dose of MSC (mean improvement, 86%). Mild adverse events were noted after 3 of 30 MSC doses (10%). All 13 dogs are currently in remission (follow-up time, 5 to 43 months); 7 of 13 Pugs (54%) remained in remission after MSC therapy alone, and 6 of 13 (46%) required the addition of immunosuppressive therapy.ConclusionsIV allogeneic MSC administration was well tolerated and resulted in immediate clinical benefit in this small cohort of Pugs with presumptive early NME. Strategies to maintain the long-term benefits of MSC therapy require further study.Clinical relevanceImmunomodulatory MSC therapy may be a potential treatment for neuroinflammatory disease in dogs. Further studies are needed to optimize long-term benefits

Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies

Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies

THE IMPACT OF AGING ON THE TRANSCRIPTIONAL PROFILE OF HUMAN SKELETAL MUSCLE

J.J. Dickinson1, L.J. D’Acquisto1, M. Naymik2, A.C. D’Lugos3, J.M. Dickinson1, FACSM 1Central Washington University, Ellensburg, WA 2Translational Genomics Research Institute, Phoenix, AZ 3University of Florida, Gainesville, FL It is well known that advancing age is associated with deleterious changes in the size and function of skeletal muscle that contribute to reduced ability to perform daily activities and increased risk for injury. However, the precise molecular factors that contribute to declines in skeletal muscle size and function with advancing age are not completely understood. PURPOSE: To identify age-related differences in the transcriptional profile of human skeletal muscle. METHODS: Skeletal muscle biopsy samples (vastus lateralis) were analyzed from otherwise healthy younger (27±3yr; 8M, 1F; BMI: 24.5±2.0 kg•m-2; VO2max: 37.1±4.0 ml•kg-1•min-1) and older adults (68±5yr; 6M, 3F; BMI: 25.9±4.7 kg•m-2; VO2max: 33.6±9.6 ml•kg-1•min-1). All muscle biopsies were obtained after an overnight fast under resting conditions controlling for previous physical activity and caffeine and alcohol consumption. Total RNA was isolated and whole transcriptome next-generation sequencing (HISeq2500, Illumina) was performed on cDNA. Sequencing data were analyzed using HTSeq and differential gene expression between young and old was identified using DESeq2 (with young as reference). Genes with an adjusted p-value of \u3c0.1 were considered differentially expressed. RESULTS: Of the 20,810 genes that were identified, 1,515 genes were considered to be differentially expressed in older adults compared to young. Among these genes, 729 were up-regulated while 786 were down-regulated in older adults compared to young. Many of the differentially expressed genes up-regulated in older adults were associated with energy metabolism, while many of the differentially expressed genes down-regulated in older adults were associated with cell membrane formation. CONCLUSION: These data highlight differences in the transcriptional profile of aging human skeletal muscle that may be related to age-related changes in skeletal muscle. Further research is needed to identify to what extent these unique transcriptional profiles may provide insight on therapeutic targets for aging skeletal muscle