Family history of FXTAS is associated with age-related cognitive-linguistic decline among mothers with the FMR1 premutation

Background Women who carry a premutation allele of the FMR1 gene are at increased vulnerability to an array of age-related symptoms and disorders, including age-related decline in select cognitive skills. However, the risk factors for age-related decline are poorly understood, including the potential role of family history and genetic factors. In other forms of pathological aging, early decline in syntactic complexity is observed and predicts the later onset of neurodegenerative disease. To shed light on the earliest signs of degeneration, the present study characterized longitudinal changes in the syntactic complexity of women with the FMR1 premutation across midlife, and associations with family history of fragile X-associated tremor/ataxia syndrome (FXTAS) and CGG repeat length. Methods Forty-five women with the FMR1 premutation aged 35–64 years at study entry participated in 1–5 longitudinal assessments spaced approximately a year apart (130 observations total). All participants were mothers of children with confirmed fragile X syndrome. Language samples were analyzed for syntactic complexity and participants provided information on family history of FXTAS. CGG repeat length was determined via molecular genetic testing. Results Hierarchical linear models indicated that women who reported a family history of FXTAS exhibited faster age-related decline in syntactic complexity than those without a family history, with that difference emerging as the women reached their mid-50 s. CGG repeat length was not a significant predictor of age-related change. Conclusions Results suggest that women with the FMR1 premutation who have a family history of FXTAS may be at increased risk for neurodegenerative disease, as indicated by age-related loss of syntactic complexity. Thus, family history of FXTAS may represent a personalized risk factor for age-related disease. Follow-up study is needed to determine whether syntactic decline is an early indicator of FXTAS specifically, as opposed to being a more general age-related cognitive decline associated with the FMR1 premutation.

Gluten, Inflammation, and Neurodegeneration

Growing evidence supports a potential link between dietary gluten intake and neurodegenerative disease in susceptible populations. Observational data supporting this link are described along with interventional study data evaluating the effects of restricting gluten from the diet in patients with neurologic disorders. Suggested underlying mechanisms between gluten intake and neurodegeneration are discussed.

Identifying healthy individuals with Alzheimer neuroimaging phenotypes in the UK Biobank

Identifying prediagnostic neurodegenerative disease is a critical issue in neurodegenerative disease research, and Alzheimer's disease (AD) in particular, to identify populations suitable for preventive and early disease modifying trials. Evidence from genetic studies suggest the neurodegeneration of Alzheimer's disease measured by brain atrophy starts many years before diagnosis, but it is unclear whether these changes can be detected in sporadic disease. To address this challenge we train a Bayesian machine learning neural network model to generate a neuroimaging phenotype and AD-score representing the probability of AD using structural MRI data in the Alzheimer's Disease Neuroimaging Cohort (cut-off 0.5, AUC 0.92, PPV 0.90, NPV 0.93). We go on to validate the model in an independent real world dataset of the National Alzheimer's Coordinating Centre (AUC 0.74, PPV 0.65, NPV 0.80), and demonstrate correlation of the AD-score with cognitive scores in those with an AD-score above 0.5. We then apply the model to a healthy population in the UK Biobank study to identify a cohort at risk for Alzheimer's disease. This cohort have a cognitive profile in keeping with Alzheimer's disease, with strong evidence for poorer fluid intelligence, and with some evidence of poorer performance on tests of numeric memory, reaction time, working memory and prospective memory. We found some evidence in the AD-score positive cohort for modifiable risk factors of hypertension and smoking. This approach demonstrates the feasibility of using AI methods to identify a potentially prediagnostic population at high risk for developing sporadic Alzheimer's disease.

Extracellular Vesicle Delivery of Neferine for the Attenuation of Neurodegenerative Disease Proteins and Motor Deficit in an Alzheimer’s Disease Mouse Model

Exosomes are nano-extracellular vesicles with diameters ranging from 30 to 150 nm, which are secreted by the cell. With their role in drug cargo loading, exosomes have been applied to carry compounds across the blood–brain barrier in order to target the central nervous system (CNS). In this study, high-purity exosomes isolated by the ultra-high-speed separation method were applied as the natural compound carrier, with the loading efficiency confirmed by UHPLC-MS analysis. Through the optimization of various cargo loading methods using exosomes, this study compared the efficiency of different ways for the separation of exosomes and the exosome encapsulation of natural compounds with increasing molecular weights via extensive in vitro and in vivo efficacy studies. In a pharmacokinetic study, our data suggested that the efficiency of compound’s loading into exosomes is positively correlated to its molecular weight. However, with a molecular weight of greater than 1109 Da, the exosome-encapsulated natural compounds were not able to pass through the blood–brain barrier (BBB). In vitro cellular models confirmed that three of the selected exosome-encapsulated natural compounds—baicalin, hederagenin and neferine—could reduce the level of neurodegenerative disease mutant proteins—including huntingtin 74 (HTT74), P301L tau and A53T α-synuclein (A53T α-syn)—more effectively than the compounds alone. With the traditional pharmacological role of the herbal plant Nelumbo nucifera in mitigating anxiety, exosome-encapsulated-neferine was, for the first time, reported to improve the motor deficits of APP/PS1 (amyloid precursor protein/ presenilin1) double transgenic mice, and to reduce the level of β-amyloid (Aβ) in the brain when compared with the same concentration of neferine alone. With the current trend in advocating medicine–food homology and green healthcare, this study has provided a rationale from in vitro to in vivo for the encapsulation of natural compounds using exosomes for the targeting of BBB permeability and neurodegenerative diseases in the future.

COVID-19 related outcomes among individuals with neurodegenerative diseases: a cohort analysis in the UK biobank

Background An increased susceptibility to COVID-19 has been suggested for individuals with neurodegenerative diseases, but data are scarce from longitudinal studies. Methods In this community-based cohort study, we included 96,275 participants of the UK Biobank who had available SARS-CoV-2 test results in Public Health England. Of these, 2617 had a clinical diagnosis of neurodegenerative diseases in the UK Biobank inpatient hospital data before the outbreak of COVID-19 (defined as January 31st, 2020), while the remaining participants constituted the reference group. We then followed both groups from January 31st, 2020 to June 14th, 2021 for ascertainment of COVID-19 outcomes, including any COVID-19, inpatient care for COVID-19, and COVID-19 related death. Logistic regression was applied to estimate the association between neurogenerative disease and risks of COVID-19 outcomes, adjusted for multiple confounders and somatic comorbidities. Results We observed an elevated risk of COVID-19 outcomes among individuals with a neurodegenerative disease compared with the reference group, corresponding to a fully adjusted odds ratio of 2.47 (95%CI 2.25–2.71) for any COVID-19, 2.18 (95%CI 1.94–2.45) for inpatient COVID-19, and 3.67 (95%CI 3.11–4.34) for COVID-19 related death. Among individuals with a positive test result for SARS-CoV-2, individuals with neurodegenerative diseases had also a higher risk of COVID-19 related death than others (fully adjusted odds ratio 2.08; 95%CI 1.71–2.53). Conclusion Among UK Biobank participants who received at least one test for SARS-CoV-2, a pre-existing diagnosis of neurodegenerative disease was associated with a subsequently increased risk of COVID-19, especially COVID-19 related death.

Analysis of the Biomarkers for Neurodegenerative Diseases in Aged Progranulin Deficient Mice

Neurodegenerative diseases are debilitating impairments that affect millions of people worldwide and are characterized by progressive degeneration of structure and function of the central or peripheral nervous system. Effective biomarkers for neurodegenerative diseases can be used to improve the diagnostic workup in the clinic as well as facilitate the development of effective disease-modifying therapies. Progranulin (PGRN) has been reported to be involved in various neurodegenerative disorders. Hence, in the current study we systematically compared the inflammation and accumulation of typical neurodegenerative disease markers in the brain tissue between PGRN knockout (PGRN KO) and wildtype (WT) mice. We found that PGRN deficiency led to significant neuron loss as well as activation of microglia and astrocytes in aged mice. Several characteristic neurodegenerative markers, including α-synuclein, TAR DNA-binding protein 43 (TDP-43), Tau, and β-amyloid, were all accumulated in the brain of PGRN-deficient mice as compared to WT mice. Moreover, higher aggregation of lipofuscin was observed in the brain tissue of PGRN-deficient mice compared with WT mice. In addition, the autophagy was also defective in the brain of PGRN-deficient mice, indicated by the abnormal expression level of autophagy marker LC3-II. Collectively, comprehensive assays support the idea that PGRN plays an important role during the development of neurodegenerative disease, indicating that PGRN might be a useful biomarker for neurodegenerative diseases in clinical settings.

Systemic Inflammation Accelerates Changes in Microglial and Synaptic Markers in an Experimental Model of Chronic Neurodegeneration

Bacterial infections are a common cause of morbidity and mortality in the elderly, and particularly in individuals with a neurodegenerative disease. Experimental models of neurodegeneration have shown that LPS-induced systemic inflammation increases neuronal damage, a process thought to be mediated by activation of “primed” microglia. The effects of a real systemic bacterial infection on the innate immune cells in the brain and neuronal networks are less well described, and therefore, in this study we use the ME7 prion model to investigate the alterations in microglia activation and phenotype and synaptic markers in response to a low grade, live bacterial infection. Mice with or without a pre-existing ME7 prion-induced neurodegenerative disease were given a single systemic injection of live Salmonella typhimurium at early or mid-stage of disease progression. Immune activation markers CD11b and MHCII and pro-inflammatory cytokines were analyzed 4 weeks post-infection. Systemic infection with S. typhimurium resulted in an exaggerated inflammatory response when compared to ME7 prion mice treated with saline. These changes to inflammatory markers were most pronounced at mid-stage disease. Analysis of synaptic markers in ME7 prion mice revealed a significant reduction of genes that are associated with early response in synaptic plasticity, extracellular matrix structure and post-synaptic density, but no further reduction following systemic infection. In contrast, analysis of activity-related neuronal receptors involved in development of learning and memory, such as Grm1 and Grin2a, showed a significant decrease in response to systemic bacterial challenge. These changes were observed early in the disease progression and associated with reduced burrowing activity. The exaggerated innate immune activation and altered expression of genes linked to synaptic plasticity may contribute to the onset and/or progression of neurodegeneration.

Integrated Proteomic and Metabolomic Analyses of the Mitochondrial Neurodegenerative Disease MELAS

MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes) is a progressive neurodegenerative disease caused by pathogenic mitochondrial DNA variants. The pathogenic mechanism of MELAS remains enigmatic due to the exceptional clinical...