👤 Livia Parodi

Evidence linking modifiable risk factors to age-related brain diseases, such as dementia, stroke, and depression (DSD), is robust, yet limited regarding long-term change in modifiable risk factors in association with these conditions, particularly in real-world settings. This study aimed to assess whether longitudinal changes in modifiable brain health risk factors were associated with reduced risk of DSD. We analyzed UK Biobank data (2006-2019) from 155,469 participants with general practitioner-linked data. The Brain Care Score (BCS) assesses 12 modifiable risk factors across lifestyle, physical, and social-emotional domains. Longitudinal BCS measurements were derived from repeated general practitioner (GP)-recorded measurements. Changes in the BCS were modeled using linear mixed-effects models, and associations with DSD were evaluated using multivariable Cox models, adjusting for baseline BCS and genetic risk (polygenic risk scores for stroke and depression, and APOE genotype for dementia). Among 155,469 participants (median age = 51 years, 54.3% women), the median annual BCS change was 0.14 (Q1-Q3 = 0.008-0.30) points over a median follow-up of 12.3 years (Q1-Q3 = 11.5-13.1 years). Over time, 82.1% improved their BCS, 12.9% remained stable, and 5.0% worsened over time. Each 1-point annual increase in the BCS was associated with 4% lower risk of incident age-related brain diseases (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.95-0.97). In this large real-world cohort, improvements in modifiable risk factor profiles were associated with lower incidence of DSD, regardless of genetic risk or baseline BCS. Our results provide important information for communicating with patients about the brain health benefits of improving risk factor profiles. ANN NEUROL 2026;99:1113-1123. Show less

Although the optimal approach is debated, systematic genetic screening for hypertrophic cardiomyopathy (HCM) is recommended. The performance of this approach was tested in GEREMY, a HCM prospective observational French register. Screening was based on a 12-gene panel, including the Fabry disease (GLA) and the transthyretin (TTR) genes. In case of a negative result and according to the clinical profile, 17-80 gene panels of were used. A 748 adult cohort was examined: 68.9 % male, 54.6 ± 18.1 years, 27.5 % with a HCM family history, maximal wall thickness 19.1 ± 4.8 mm. Pathogenic or likely pathogenic variants were identified in 296 (39.6 %) patients, localized 1) in sarcomeric genes in 233, most frequently MYBPC3 (150) and MYH7 (42), with 24 identified only by large panels, with multiple variants in 8 patients and 2) in non-sarcomeric genes in 63, identified only with large panels in 26, predominantly TTR (26) and GLA(9), representing 8.8 % and 3.0 % of positive studies, respectively. Performance was 57.1 % before 40 years and 68.6 % in case of FH (vs otherwise 28.7 % and 26.1 % respectively, p < 0.001). In patients with a negative study, 148 had variants of unknown significance and 95 had senile or AL amyloidosis. Systematic genetic screening with a limited panel showed good performance, with diagnosis of Fabry disease (∼1 %) and hereditary TTR amyloidosis (∼3.5 %). Larger targeted panels were conclusive in 35.3 % of patients, of which 12 % had a negative initial approach. Show less

Hypertrophic cardiomyopathy (HCM) is mainly associated with myosin, heavy chain 7 (MYH7) and myosin binding protein C, cardiac (MYBPC3) mutations. In order to better explain the clinical and genetic heterogeneity in HCM patients, in this study, we implemented a target-next generation sequencing (NGS) assay. An Ion AmpliSeq™ Custom Panel for the enrichment of 19 genes, of which 9 of these did not encode thick/intermediate and thin myofilament (TTm) proteins and, among them, 3 responsible of HCM phenocopy, was created. Ninety-two DNA samples were analyzed by the Ion Personal Genome Machine: 73 DNA samples (training set), previously genotyped in some of the genes by Sanger sequencing, were used to optimize the NGS strategy, whereas 19 DNA samples (discovery set) allowed the evaluation of NGS performance. In the training set, we identified 72 out of 73 expected mutations and 15 additional mutations: the molecular diagnosis was achieved in one patient with a previously wild-type status and the pre-excitation syndrome was explained in another. In the discovery set, we identified 20 mutations, 5 of which were in genes encoding non-TTm proteins, increasing the diagnostic yield by approximately 20%: a single mutation in genes encoding non-TTm proteins was identified in 2 out of 3 borderline HCM patients, whereas co-occuring mutations in genes encoding TTm and galactosidase alpha (GLA) altered proteins were characterized in a male with HCM and multiorgan dysfunction. Our combined targeted NGS-Sanger sequencing-based strategy allowed the molecular diagnosis of HCM with greater efficiency than using the conventional (Sanger) sequencing alone. Mutant alleles encoding non-TTm proteins may aid in the complete understanding of the genetic and phenotypic heterogeneity of HCM: co-occuring mutations of genes encoding TTm and non-TTm proteins could explain the wide variability of the HCM phenotype, whereas mutations in genes encoding only the non-TTm proteins are identifiable in patients with a milder HCM status. Show less

End-stage hypertrophic cardiomyopathy (ES-HC) has an ominous prognosis. Whether genotype can influence ES-HC occurrence is unresolved. We assessed the spectrum and clinical correlates of HC-associated mutations in a large multicenter cohort with end-stage ES-HC. Sequencing analysis of 8 sarcomere genes (MYH7, MYBPC3, TNNI3, TNNT2, TPM1, MYL2, MYL3, and ACTC1) and 2 metabolic genes (PRKAG2 and LAMP2) was performed in 156 ES-HC patients with left ventricular (LV) ejection fraction (EF) <50%. A comparison among mutated and negative ES-HC patients and a reference cohort of 181 HC patients with preserved LVEF was performed. Overall, 131 mutations (36 novel) were identified in 104 ES-HC patients (67%) predominantly affecting MYH7 and MYBPC3 (80%). Complex genotypes with double or triple mutations were present in 13% compared with 5% of the reference cohort (p = 0.013). The distribution of mutations was otherwise indistinguishable in the 2 groups. Among ES-HC patients, those presenting at first evaluation before the age of 20 had a 30% prevalence of complex genotypes compared with 19% and 21% in the subgroups aged 20 to 59 and ≥60 years (p = 0.003). MYBPC3 mutation carriers with ES-HC were older than patients with MYH7, other single mutations, or multiple mutations (median 41 vs 16, 26, and 28 years, p ≤0.001). Outcome of ES-HC patients was severe irrespective of genotype. In conclusion, the ES phase of HC is associated with a variable genetic substrate, not distinguishable from that of patients with HC and preserved EF, except for a higher frequency of complex genotypes with double or triple mutations of sarcomere genes. Show less

The objective of this study was to compare the expression of Col1a1, Col1a2, and procollagen I in the seminiferous tubules of immature and adult mice and to characterize the cellular expression pattern of procollagen I in germ cells during spermatogenesis in order to provide necessary groundwork for further functional studies in the process of spermatogenesis. Microarray analysis demonstrated that Col1a1 and Col1a2 were abundantly expressed in the seminiferous tubules of 6-day-old mice compared with 60-day-old mice, and the expression levels of Col1a1 and Col1a2 mRNA were validated using a semi-quantitative RT-PCR assay. Western blot analysis further confirmed that procollagen I was expressed at a higher level in the seminiferous tubules of 6-day-old mice compared with 60-day-old mice. Immunohistochemical analysis revealed that type A spermatogonia were positive for procollagen I in the testis of 6-day-old mice, whereas Sertoli cells were negative for this protein. The in vivo procollagen I staining in type A spermatogonia was corroborated in spermatogonia exhibiting a high potential for proliferation and the ability to form germ cell colonies in in vitro culture. Moreover, procollagen I was also detected in type A spermatogonia, intermediate spermatogonia, type B spermatogonia, and preleptotene spermatocytes in the adult mouse testes, but positive staining disappeared in more differentiated germ cell lineages detaching from the basement membrane, including leptotene spermatocytes, pachytene spermatocytes, round spermatids and elongated spermatids. These data suggest that Col1a1, Col1a2 and procollagen I are associated with type A spermatogonia and play a potential role in mediating the detachment and migration of germ cells during spermatogenesis. Show less