Occupational Cancer Research Centre

Over the past few years, several fluid biomarker candidates have been proposed for frontotemporal dementia (FTD). We have previously identified CSF proteins that could separate individuals with genetic FTD from controls. However, it is unknown whether alterations in these CSF protein levels are associated with neurodegenerative processes. The aim of this study was to explore how these CSF biomarker candidates correlate with symptom severity as well as cortical and subcortical atrophy. The levels of fourteen proteins were measured in CSF from 202 individuals, 131 mutation carriers with mutations in C9orf72, GRN, or MAPT, and 71 controls, in a cross-sectional subset from the GENFI cohort. The association between the levels of these proteins and CDR plus NACC FTLD-NM sum-of-boxes, cortical thickness, and subcortical volumes were estimated in the mutation carriers. Elevated CSF levels of five out of fourteen proteins were associated with an increased CDR score in the mutation carriers. Additionally, elevated levels of three of these proteins, NEFM, PTPRN2 and SERPINA3, were associated with reduced cortical thickness and/or subcortical volume among all mutation carriers. Some mutation-specific associations were also observed, with SPP1 and CTSS being associated with CDR and atrophy only in MAPT mutation carriers, while NPTX2 was specific for GRN mutation carriers. As indicated by the association to brain atrophy, the proposed fluid biomarker candidates continue to show promise and additional studies will further elucidate their relationship to cortical atrophy in genetic FTD, and their potential as biomarkers for diagnosis, prognosis, and disease staging.

With current evidence of homologous recombination deficiency (HRD) emerging as a predictive and prognostic biomarker in high-grade serous/endometrioid ovarian cancers (HGSOC/HGEOC), the HALO study (NCT04991051) evaluated the prevalence of the HRD in patients with HGSOC/HGEOC, primary peritoneal cancer (PPC), and fallopian tube cancer (FTC) across Asia, Middle East and Africa (MEA), and Russia. The MEA subset of this cross-sectional, non-interventional study enrolled patients with newly diagnosed stage III/IV (International Federation of Gynaecology and Obstetrics [FIGO] classification) HGSOC/HGEOC, PPC, FTC during May 2021-Jan 2022 with formalin-fixed paraffin-embedded tumour block(s) collected within 120 days of enrolment. Primary endpoints included prevalence of HRD, genomic instability (GI) excluding tumour BRCA mutations (tBRCAm), and tBRCAm. Logistic regression model predicted the risk factors associated with HRD positivity and tBRCAm. Of 195 patients (median [range] age, 58.2 [24.0-89.0] years), 88.7% had primary ovarian tumour. The HRD status was analysed in 180 patients; 52.2% (94/180) were HRD positive – 23.9% (43/180) had high GI scores excluding tBRCA1/2m, and 28.3% (51/180) had tBRCAm. More than two-thirds (71.3%) of patients underwent debulking surgery, 45,1% received neoadjuvant and 50.8% received adjuvant therapy. No patients received PARPi therapy. In univariate analysis, nulliparity was associated with lower odds of HRD positivity (odds ratio [OR]: 0.27, p=0.003). Family history (OR: 0.39, p=0.02) and nulliparous women (OR: 0.19, p=0.03) were associated with lower odds of high GI score. Higher odds of tBRCAm were observed in ex-smokers (OR: 6.77, p=0.02), family history (OR: 3.11, p=0.0009), and surgically resected tissue (OR: 2.00, p=0.04); lower odds in patients with FIGO stage IV (OR: 0.26, p=0.004). In multivariate analysis, h/o genetic-related cancer (OR: 3.75, p=0.002), h/o contraceptive use (OR: 5.19, p=0.009) was associated with higher odds of tBRCA1m whereas FIGO stage IV disease (OR: 0.24, p=0.006) had lower odds of tBRCAm. In the Middle East subset of HALO study, a substantial proportion of patients were HRD positive and had tBRCA1/2m, supporting the clinical relevance of these biomarkers for guiding novel targeted therapies. The study provides real-world evidence of HRD and tBRCA prevalence, informing future research and policy development in precision oncology for the region. Number-NCT04991051 (Date of Approval-September 2020).

We are living in increasingly complex and uncertain times that demand both resilience and agility. A reality that is made ever more challenging in healthcare environments that face long-standing pressures to do more with less by a healthcare workforce that often is exposed to great personal and professional strain. Adopting and actioning principles of trauma-informed organizational culture and leadership can provide a pragmatic and responsive framework that can bolster health worker well-being and system agility in the face of adversity.

Abstract Background Brief emotion‐focused family therapy (EFFT) interventions have demonstrated numerous positive outcomes across the domains of child mental health and parent psychosocial well‐being. However, there is limited research examining interpersonal processes at the family‐level of analysis following 2‐day EFFT programs. Methods This study explored family functioning in the year following a virtual, parent‐focused EFFT intervention ( n = 159 caregivers, representing 124 families and 264 children). Caregivers completed the General Functioning subscale of the Family Assessment Device at 6 timepoints from baseline to 12‐month post‐intervention. Multilevel modeling was used to complete growth curve analysis, exploring post‐intervention changes in family functioning over time. This allowed for the exploration of between versus within family differences pre‐ to post‐intervention in the study sample. Results Variance in family functioning was attributable to stable differences between caregivers (level 2; 59%) and change over time (level 1; 41%), including measurement error. Growth curve analysis identified positive changes in family functioning post‐intervention, with a cubic trajectory of improvement. Higher COVID‐19 disruption, caregiver psychological distress, and parenting stress significantly predicted lower baseline family functioning, but did not significantly interact with change over time. Conclusions These results suggest that there is a general pattern of non‐linear change following EFFT workshops, specifically relating to family interpersonal dynamics. Overall, the study findings expand the evidence base for this promising, brief, relational intervention, now available in virtual formats, thereby increasing access for busy families.

BackgroundThe long‐term consequences of repetitive head impacts in contact sports include cognitive deficits, accelerated brain atrophy, and neurodegenerative diseases. Currently, no studies of former athletes have addressed the connection between brain aging and biological aging, which can be assessed using age‐related DNA methylation (DNAm) profiles. The most studied epigenetic clock is DNAm‐age, which is providing consistent results across tissues (e.g., blood and brain). It includes several measures like DNAm‐age acceleration (DNAmAA), the difference between DNAm‐age and chronological age, and DNAmAA‐residual (DNAmAAr), independent of chronological age. In a cohort of retired athletes, we explored the link between measures of brain age and epigenetic age, including the recently developed DNAmFit‐age reported to be younger in physically fit individuals.MethodWe investigated 126 former contact sports athletes (mean age: 54.5±14.4; 96% male; mean concussion number: 6.8±6.7). Longitudinal assessments were available for 21 athletes (2–3 time points over 1–10 years). Bisulfite‐converted blood DNA was analyzed using the Infinium MethylationEPIC chip, and the DNAm data were submitted to the Horvath calculator (https://dnamage.clockfoundation.org/) to obtain DNAmFit‐age, DNAm‐age, and DNAmAAr. T1‐weighted MRIs were processed using the CAT12‐Toolbox. Regional gray matter volume was examined in relation to DNAmAA, DNAmAAr and DNAmFit‐age acceleration (DNAmFitAA).ResultConsistent with previous findings, chronological age was significantly associated with brain volumes and cortical thickness. DNAmAA, DNAmAAr, and DNAmFitAA remained stable over a period of up to 10 years, and none of these measures were associated with brain volumes or cortical thickness. Notably, multivariate linear regression analysis revealed a significant positive association between DNAmFitAA and the number of concussions (p = 0.0027, B=0.46, R2=0.063), indicating that every additional two concussions correspond to a 5‐year increase in DNAmFitAA.ConclusionIn former athletes, we confirmed that chronological age is associated with cerebral atrophy and identified an association between increased DNAmFitAA and a higher number of concussions. This finding requires validation in independent studies, along with an assessment of the relationship between DNAmFitAA and neurodegeneration. Our analysis did not reveal a link of the examined epigenetic clocks with brain volumes and cortical thickness. Exploration of other epigenetic clocks may provide new insights into the mechanisms underlying brain aging.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by 3 core symptom complexes: parkinsonism, cerebellar syndrome, and dysautonomia. Recent Movement Disorder Society (MDS) criteria allow for the clinical diagnosis of MSA based solely on motor symptoms, without requiring dysautonomia. This study aimed to evaluate the frequency and disease trajectory of MSA patients without dysautonomia compared with those with autonomic involvement. A multicenter cohort of autopsy-confirmed patients with MSA was analyzed for demographic characteristics, symptom onset, and progression of parkinsonism, cerebellar syndrome, and dysautonomia. Clinical data were collected through standardized chart reviews across participating centers and categorized using the MDS-MSA criteria. Patients were grouped according to their initial symptom complex and tracked for the evolution of additional symptoms. Analyses included time to development of further symptom complexes, age at symptom onset, disease duration, and phenotype at the last recorded visit. Patients with motor symptoms only were matched to patients with similar demographics but with dysautonomia. Statistical methods included ANOVA, t tests, Welch t tests, and χ2 tests, with significance set at p < 0.05. Among 140 patients (mean age at onset 62.3 ± 8.9 years; 44% female), 81 (58%) initially presented without dysautonomia (57 with parkinsonism only, 17 with cerebellar syndrome only, 7 with both). At final follow-up, 12 patients (9%) had not developed dysautonomia. These patients showed significantly longer disease duration (mean 8.1 ± 2.1 years) than matched patients with dysautonomia (mean 6.3 ± 2.6 years; p = 0.035). Overall, 51% of patients developed all 3 symptom complexes. Patients with cerebellar onset progressed more rapidly to multisystem involvement than those with parkinsonian onset (mean interval to second symptom: 2.0 vs 3.4 years; p < 0.05). The MDS-MSA criteria expand the diagnostic scope by identifying a motor-only subgroup with a distinct and potentially slower disease course. These findings underscore the importance of including motor-only patients in natural history and interventional studies. Limitations include retrospective data collection and potential variability in symptom documentation.

BackgroundThere is substantial heterogeneity in clinical presentation of genetic Frontotemporal Dementia (FTD), even within the same family. This suggests that additional heritability may exist and contribute to this variable presentation. We examined whether gene‐based aggregate burden of genome‐wide rare variants (minor allele frequency [MAF]: ≤1%) contribute to variation in regional cortical and subcortical grey matter volumes, after controlling for effects of causative mutations in GRN, MAPT, and C9orf72.MethodThis study was embedded within the GENetic Frontotemporal dementia Initiative (GENFI), which recruits genetic FTD cases and their asymptomatic at‐risk family members, both carriers and non‐carriers of FTD mutations. We included 518 participants with genotype (Neurochip; imputed against TOPMed), and T1w‐MRI brain volumetric data. Gene‐based burden tests that aggregate the number of rare variants by gene were used to examine the association of rare variants (MAF: ≤1%) with regional cortical and subcortical grey matter volumes (70 regions of interest [ROIs]), controlling for age, sex, total intracranial volume, mutation status, scanner site, population stratification, and family membership (kinship matrix) using RVTests. Annotations for loss of function mutations (LOF): start gain, stop loss, start loss, essential splice site, stop gain, normal splice site, and non‐synonymous. Multiple testing correction accounted for the number of genes and number of independent grey matter volumes as calculated by matSpD (p‐value threshold: 0.05/(17,053x42) = 6.98 x10‐8).ResultAggregate burden of LOF mutations (DNAJB8‐AS1, WDR26, RDM1P5, BSND, CNOT2, DDA1, ASAH2B, PPM1A, HOXD13, ALDH1A1, CENATAC, ANKRD45) was associated with significantly lower volumes within the left temporal lobe (ROIs: left temporal and lateral temporal left), and greater volume in the putamen bilaterally (TSACC). All genes are protein coding, except the DNAJB8‐AS1 (antisense RNA) and RDM1P5 (pseudogene), and are variably expressed in the brain. Molecular functions of significant genes involve regulation of gene expression, transcription, and cell cycle, ion channel function, and chromosomal segregation. WDR26 and CNOT2 genes have been implicated in neurodevelopment and neurological disorders respectively; BSND gene is involved in neurotransmission.ConclusionIdentification of deleterious or protective rare variants contributing to FTD imaging phenotypes may help identify genetic modifiers of familial FTD. Replication in larger cohorts is needed.