Search

The central nervous system (CNS) is surrounded by three membranes called meninges. Specialised fibroblasts, originating from the mesoderm and neural crest, primarily populate the meninges and serve as a binding agent. Our goal was to compare fibroblasts from meninges and skin obtained from the same human‐aged donors, exploring their molecular and cellular characteristics related to CNS functions. We isolated meningeal fibroblasts (MFs) from brain donors and skin fibroblasts (SFs) from the same subjects. A functional analysis was performed measuring cell appearance, metabolic activity, and cellular orientation. We examined fibronectin, serpin H1, β‐III‐tubulin, and nestin through qPCR and immunofluorescence. A whole transcriptome analysis was also performed to characterise the gene expression of MFs and SFs. MFs appeared more rapidly in the post‐tissue processing, while SFs showed an elevated cellular metabolism and a well‐defined cellular orientation. The four markers were mostly similar between the MFs and SFs, except for nestin, more expressed in MFs. Transcriptome analysis reveals significant differences, particularly in cyclic adenosine monophosphate (cAMP) metabolism and response to forskolin, both of which are upregulated in MFs. This study highlights MFs' unique characteristics, including the timing of appearance, metabolic activity, and gene expression patterns, particularly in cAMP metabolism and response to forskolin. These findings contribute to a deeper understanding of non‐neuronal cells' involvement in CNS activities and potentially open avenues for therapeutic exploration. [ABSTRACT FROM AUTHOR]

Background: SNCA p.V15A was reported in five families. In vitro models showed increased aggregation and seeding activity, mitochondrial damage, and apoptosis. Mutant flies had reduced flying ability and survival. Objectives: To clinically and functionally evaluate SNCA p.V15A in a large Italian family with Parkinson's disease (PD). Methods: Genetic diagnosis was reached through next‐generation sequencing. Pathogenicity was assessed by molecular dynamics simulation and biochemical studies on peripheral blood mononuclear cells (PBMCs). Results: Five siblings carried SNCA p.V15A; three developed bradykinetic‐rigid PD in their 50s with rapid motor progression and variable cognitive impairment. A fourth sibling had isolated mood disturbance, whereas the fifth was still unaffected at age 47. The mutant protein showed decreased stability and an unstable folded structure. Proband's PBMCs showed elevated total and phosphorylated α‐synuclein (α‐syn) levels and significantly reduced glucocerebrosidase activity. Conclusion: This study demonstrates accumulation of α‐synV15A in PBMCs and strengthens the link between α‐syn pathophysiology and glucocerebrosidase dysfunction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

SNCA protein product, α‐synuclein, is widely renowned for its role in synaptogenesis and implication in both aging and Parkinson's disease (PD), but research efforts are still needed to elucidate its physiological functions and mechanisms of regulation. In this work, we aim to characterize SNCA‐AS1, antisense transcript to the SNCA gene, and its implications in cellular processes. The overexpression of SNCA‐AS1 upregulates both SNCA and α‐synuclein and, through RNA‐sequencing analysis, we investigated the transcriptomic changes of which both genes are responsible. We highlight how they impact neurites' extension and synapses' biology, through specific molecular signatures. We report a reduced expression of markers associated with synaptic plasticity, and we specifically focus on GABAergic and dopaminergic synapses, for their relevance in aging processes and PD, respectively. A reduction in SNCA‐AS1 expression leads to the opposite effect. As part of this signature is co‐regulated by the two genes, we discriminate between functions elicited by genes specifically altered by SNCA‐AS1 or SNCA's overexpression, observing a relevant role for SNCA‐AS1 in synaptogenesis through a shared molecular signature with SNCA. We also highlight how numerous deregulated pathways are implicated in aging‐related processes, suggesting that SNCA‐AS1 could be a key player in cellular senescence, with implications for aging‐related diseases. Indeed, the upregulation of SNCA‐AS1 leads to alterations in numerous PD‐specific genes, with an impact highly comparable to that of SNCA's upregulation. Our results show that SNCA‐AS1 elicits its cellular functions through the regulation of SNCA, with a specific modulation of synaptogenesis and senescence, presenting implications in PD. [ABSTRACT FROM AUTHOR]

The actual role of SARS‐CoV‐2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS‐CoV‐2 or by pre‐existing conditions. Findings of 9 Coronavirus disease 2019 (COVID‐19) cases and 6 matched non‐COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS‐CoV‐2, lymphocytes, astrocytes, endothelium, and microglia. A semi‐quantitative scoring was applied to grade microglial activation. Thal‐Braak stages and the presence of small vessel disease were determined in all cases. COVID‐19 cases had a relatively short clinical course (0–32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID‐19 cases showed non‐SARS‐CoV‐2‐specific changes including hypoxic‐agonal alterations, and a variable degree of neurodegeneration and/or pre‐existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS‐CoV‐2 were detected. Microglial activation in the brainstem was significantly greater in COVID‐19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS‐CoV‐2 infection. In COVID‐19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer's pathology and COVID‐19, cortical neuroinflammation is not related to COVID‐19 per se but mostly to pre‐existing neurodegeneration. COVID‐19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number of brain lymphocytes probably related to systemic lymphopenia. Thus, no neuropathological evidence of SARS‐CoV‐2‐specific encephalitis is detectable. The microglial hyperactivation in the brainstem, and in the hippocampus of COVID‐19 patients with delirium, appears as a specific topographical phenomenon, and probably represents the neuropathological basis of the "COVID‐19 encephalopathic syndrome" in the elderly. [ABSTRACT FROM AUTHOR]

Stress granules (SGs) are dynamic condensates associated with protein misfolding diseases. They sequester stalled mRNAs and signaling factors, such as the mTORC1 subunit raptor, suggesting that SGs coordinate cell growth during and after stress. However, the molecular mechanisms linking SG dynamics and signaling remain undefined. We report that the chaperone Hsp90 is required for SG dissolution. Hsp90 binds and stabilizes the dual‐specificity tyrosine‐phosphorylation‐regulated kinase 3 (DYRK3) in the cytosol. Upon Hsp90 inhibition, DYRK3 dissociates from Hsp90 and becomes inactive. Inactive DYRK3 is subjected to two different fates: it either partitions into SGs, where it is protected from irreversible aggregation, or it is degraded. In the presence of Hsp90, DYRK3 is active and promotes SG disassembly, restoring mTORC1 signaling and translation. Thus, Hsp90 links stress adaptation and cell growth by regulating the activity of a key kinase involved in condensate disassembly and translation restoration. SYNOPSIS: Hsp90 promotes the disassembly of stress granules and other condensates in part by binding and stabilizing the dual‐specificity tyrosine‐phosphorylation‐regulated kinase 3 (DYRK3). Inhibition or loss of Hsp90 results in DYRK3 destabilization, stress granule persistence and failure to restore mTORC1 signaling and translation. Hsp90 regulates DYRK3 stability and activity.Partitioning into condensates protects DYRK3 from aggregation.Hsp90 couples SG disassembly and mTORC1‐dependent cell growth in part via DYRK3.ALS fibroblasts and motor neurons show reduced expression of DYRK3. [ABSTRACT FROM AUTHOR]

Background: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD). The impact of different variants on the PD clinical spectrum is still unclear. Objectives: We determined the frequency of GBA‐related PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time. Methods: Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. β‐glucocerebrosidase activity was measured. The Kaplan‐Meier method and Cox proportional hazard regression models were performed. Results: Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA‐PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA‐PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA‐PD had the lowest β‐glucocerebrosidase activity. Conclusions: GBA‐PD is highly prevalent in Italy. Different types of mutations underlie distinct phenotypic profiles. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Frailty is a frequent and potentially reversible age‐related syndrome. Current evidence supports the associations between Frailty, cognitive impairment and dementia. The aim of the study is to estimate the predictive role of Frailty syndrome in incident dementia and cognitive impairment, as well as the modulation of genetic‐psycho‐social factors, such as APOEɛ4 polymorphism and loneliness in a non‐demented Italian cohort of elderly individuals. Method: Data are from a cohort of 1,321 persons aged 70‐74 years old, living in Abbiategrasso (Milan, Itay): the InveCe.Ab study (Guaita et al. 2013; clinical trials.gov NCT01345110). The sample took place in 2009 with follow‐ups in 2012 and 2014. Frailty was measured by Frailty Index (FI). The FI was then separated into Frail (FI>0.25), pre‐Frail (FI = 0.08‐0.25) and non‐Frail (FI < 0.08) groups. Dementia was defined using the DSM‐IV‐TR. Global cognition was assessed by the Mini Mental State Examination (MMSE), Comorbidity by Cumulative Illness Rating Scale (CIRS). Result: Frailty was associated with cumulative incidence of dementia (p<0.001), MMSE score at baseline (p<0.001), difference in MMSE score between 2009 and 2014 (p 0.005), CIRS (p<0.001).After four follow‐up years, 4.6% developed Dementia. In the longitudinal regression models adjusted for age, gender, level of education and loneliness, APOEɛ4 carrier status, Frailty was associated with incident dementia (OR=7.75,95% CI 3.26‐18.41), with higher risk of dementia for frail men compared to women (OR=13.79, 95% CI 4.11–46.21; OR= 4.63, 95% CI 1.32‐16.26, respectively). In linear regression models, adjusted for the same variables, Frailty also showed a significant association with the decrease of MMSE score in follow‐up only in males (male: β ‐0.131,95% CI ‐7.16 – ‐0.15; females: β‐0.085, 95% CI ‐5.60 – 0.19). Other covariates, such as loneliness, were independently associated with the outcomes. However, the interaction term for loneliness and frailty was not significant in predicting incident dementia. Conclusion: in our large population sample, Frailty is associated with cognitive impairment and cognitive decline. These results suggest that Frailty syndrome, especially if accompanied by other genetic‐psycho‐social characteristics such as loneliness, could be considered by clinicians as a red flag for early detection of cognitive disorders. [ABSTRACT FROM AUTHOR]

Abstract: Neurofilament proteins (Nf) are a biomarker of disease progression in amyotrophic lateral sclerosis (ALS). This study investigated whether there are major differences in expression from in vivo measurements of neurofilament isoforms, from the light chain, NfL (68 kDa), compared with larger proteins, the medium chain (NfM, 150 kDa) and the heavy (NfH, 200‐210 kDa) chains in ALS patients and healthy controls. New immunological methods were combined with Nf subunit stoichiometry calculations and Monte Carlo simulations of a coarse‐grained Nf brush model. Based on a physiological Nf subunit stoichiometry of 7 : 3 : 2 (NfL:NfM:NfH), we found an ‘adaptive’ Nf subunit stoichiometry of 24 : 2.4 : 1.6 in ALS. Adaptive Nf stoichiometry preserved NfL gyration radius in the Nf brush model. The energy and time requirements for Nf translation were 56 ± 27k ATP (5.6 h) in control subjects compared to 123 ± 102k (12.3 h) in ALS with ‘adaptive’ (24:2.4:1.6) Nf stoichiometry (not significant) and increased significantly to 355 ± 330k (35.5 h) with ‘luxury’ (7:3:2) Nf subunit stoichiometry (p < 0.0001 for each comparison). Longitudinal disease progression‐related energy consumption was highest with a ‘luxury’ (7:3:2) Nf stoichiometry. Therefore, an energy and time‐saving option for motor neurons is to shift protein expression from larger to smaller (cheaper) subunits, at little or no costs on a protein structural level, to compensate for increased energy demands. [ABSTRACT FROM AUTHOR]

Background: Genetics, transcriptomic and epigenetics play an important interplay in influencing the clinical picture and the final diagnosis of patients affected by neurodegenerative diseases. Clinical diagnosis is often inaccurate compared to the neuropathological one, which remains the gold standard for neurodegenerative disease diagnosis so far. For this reason, it becomes necessary to strengthener molecular efforts to sustain clinical diagnosis. Here, we present the molecular characterization of two kindred cases (mother and son) initially diagnosed as slow and fast dementia and, after post‐mortem neuropathological examination, classified as Alzheimer's Disease (AD) and Dementia with Lewy Body (DLB) respectively. Method: A customized panel of over 6000 genes associated to mendelian disorders and to inherited neurodegenerative diseases was sequenced by NGS (SureSelectQXT Target Enrichment, Agilent Technology) on peripheral blood DNA of the two patients. Total RNA from hippocampus, parietal lobe, substantia nigra and basal ganglia was extracted and RNA‐Seq analysis was run (SENSE Total RNA‐Seq, Lexogen). Differentially Expressed Genes (DEGs) were identified via R package DESeq2. Kegg pathway and Gene Ontology (GO) analyses for biological processes were made using enrichR. AlphaLisa analysis was performed on brain homogenates to investigate the dimethylation status of Histone 3 Lysine 9 (H3‐K9) and Histone 3 Lysine 4 (H3‐K4) and the acetylation status of H3‐K9. Result: Seven variants were found to be shared by patients (Table 1), while six variants were present only in the son and (Table 2). DEGs analysis revealed a dysregulation in the mother's hippocampus and in the son's substantia nigra, with a 10‐fold higher number of DEGs. GO analyses highlighted a deregulation in the epigenetic landscape. In particular, the substantia nigra of the son resulted hypomethylated and hyperacetylated respectively in the H3‐K9 residue, while the mother resulted globally hypermethylated in all the brain areas analysed at the H3‐K9 and H3‐K4 residues. Conclusion: We identified genetic factors that may explain the AD and the DBL phenotypes and DEGs in AD‐ and DBL‐specific brain areas involved in the epigenetic spectrum. Our investigation highlighted either the importance of DNA and RNA sequencing and the relevance to study the epigetic lanscape to support differential diagnoses of complex neurodegenerative pathologies. [ABSTRACT FROM AUTHOR]

Background: Research on brain tissue is essential to understand the biological mechanisms underlying neurodegenerative diseases and brain aging processes.Brain donation for research is influenced by many factors both in clinical and non‐clinical samples. The aim of the present study is to explore the features associated with the decision to join the brain donation program of the Abbiategrasso Brain Bank (ABB) in the context of a population‐based study on brain aging. Method: The longitudinal cohort study InveCe.Ab enrolled participants aged 70‐75 years and residing in Abbiategrasso (MI). During the second follow‐up of the study (2014), the participants fill a questionnaire to investigate attitudes through brain donation for research purpose (N=1010). We compared socio‐cultural aspects and questionnaire responses between participants who adhere to brain donation (N=163; 16,1%) and those who refuse (N=847) using Student's t Test and chi‐squared test when appropriate. Variables showing significant differences in the group comparisons were included in a logistic regression model with brain donation status (yes/no) as the dependent variable. Result: The groups were comparable for age and sex, while ABB donors were significantly more educated (donors: 7,74, non‐donors: 6,70; p=0,000), more frequently prone to organ donation (donors: 93,4%; non‐donors: 64,3%, p=0,000) and to cremation (donors: 76,8%; non‐donors: 44,8%; p=0,000). Among those who were favorable for brain donation in the questionnaire, only 43,6% actually signed up for brain donation (p=0,000). Moreover, brain donation was associated with friends relationship satisfaction (donors: 96,5%; non‐donors: 91,4%; p=0,023) and better self‐reported health (donors: 83,3%; non‐donors: 73,4%; p=0,028), despite no difference between groups was found in the number of chronic disease (p=0,49). Finally, in the multivariable model, being prone to organ donation was the main factor associated with actual registration for brain donation. The availability for cremation remained significant only for males. Conclusion: Despite a positive attitude through brain donation in nearly half of the respondents, only a minority of older adults actually engage in a brain donation program. Being prone to organ donation was the main factor associated with brain donation subscription. The donors were more educated, with a positive attitude through their health and their relationships with friends. [ABSTRACT FROM AUTHOR]

Background: The role of diet as a modifiable factor that may affect the incidence of dementia is currently under investigation. The diet effect could be mediated by blood level of Folic Acid and Cobalamin, whose low levels are recognized as risk factors for dementia. The aim of this work is to evaluate the effects of habitual fruit intake, Cobalamin and Folic Acid on the cumulative incidence of dementia over a period of 4 years in elderly people free of basal dementia. Method: The subjects were 1321 people born between 1935‐39, enrolled in 2010 by the "InveCe.Ab" study (ClinicalTrials.gov ID: NCT01345110). The cohort was re‐evaluated in 2014 and the onset of dementia was ascertained. The association between fruit consumption and metabolic parameters with dementia at baseline was analyzed with t‐test for quantitative variables and with Pearson chi‐square for qualitative variables. The risk/protection effect of habitual fruit consumption and metabolic mediators on the onset of dementia after 4 years was evaluated by multiple logistic regression. Result: 988 subjects were included in the analysis, The new cases of dementia between 2010 and 2014 were 50. The high habitual fruit consumption was inversely associated with dementia incidence (p = 0.007) and also directly associated with higher levels of Folic Acid (p < 0.005). Women had higher levels of Folic Acid and Cobalamin (p < 0.001) and a tendency towards higher fruit consumption (p = 0.06). The logistic model using Folic Acid, Cobalamin, and sex as covariates, shows that the usual consumption of fruit reduces the 4‐year risk of developing dementia, (OR: 0.421; 95% CI: 0.213‐ 0.831) with a significant interaction between fruit consumption and Folate (OR: 0.771; 95% CI. 0.607‐0.980). Furthermore a higher level of Cobalamin results protective versus dementia. Conclusion: Our data show that in a population of 70‐75 years the cumulative incidence of dementia is significantly reduced by habitual fruit consumption independently of the plasma levels of Cobalamin. Folate could be the metabolic mediator of this protection. [ABSTRACT FROM AUTHOR]

Frailty is a geriatric, multi-dimensional syndrome that reflects multisystem physiological change and is a transversal measure of reduced resilience to negative events. It is characterized by weakness, frequent falls, cognitive decline, increased hospitalization and dead and represents a risk factor for the development of Alzheimer's disease (AD). The fact that frailty is recognized as a reversible condition encourages the identification of earlier biomarkers to timely predict and prevent its occurrence. SAMP8 (Senescence-Accelerated Mouse Prone-8) mice represent the most appropriate preclinical model to this aim and were used in this study to carry transcriptional and metabolic analyses in the brain and plasma, respectively, upon a characterization at cognitive, motor, structural, and neuropathological level at 2.5, 6, and 9 months of age. At 2.5 months, SAMP8 mice started displaying memory deficits, muscle weakness, and motor impairment. Functional alterations were associated with a neurodevelopmental deficiency associated with reduced neuronal density and glial cell loss. Through transcriptomics, we identified specific genetic signatures well distinguishing SAMP8 mice at 6 months, whereas plasma metabolomics allowed to segregate SAMP8 mice from SAMR1 already at 2.5 months of age by detecting constitutively lower levels of acylcarnitines and lipids in SAMP8 at all ages investigated correlating with functional deficits and neuropathological signs. Our findings suggest that specific genetic alterations at central level, as well as metabolomic changes in plasma, might allow to early assess a frail condition leading to dementia development, which paves the foundation for future investigation in a clinical setting., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials., (© 2015 Wiley Periodicals, Inc.)