Baycrest Hospital

Introduction Cerebrospinal fluid (CSF) pulsations are linked to hemodynamics, with autonomic mechanisms, suggested to modulate slow-wave induced pulsations. Method To explore autonomic regulation’s role in neurofluid flow, independent of sleep and neural activity, we hypothesized that modulating basal CO 2 (altering vascular tone, cardiac activity and respiration) would highlight this link. Results Using resting-state BOLD fMRI in neurofluid regions under different CO 2 levels (capnic states), we found: 1) biomechanical modulation does not explain neurofluid dynamic variations across capnias; 2) beyond respiration, heart-rate variability independently drives low-frequency neurofluid flow, indicating autonomic control; 3) altered CO 2 primarily affects neurofluid dynamics through the frequency (and not amplitude) of heart-rate and respiratory-volume variability. Discussion These results suggest that both hyper- and hypocapnia disrupt how CSF responds to autonomic regulation, seen in deviations from normal cardiac and respiratory responses. Our work reveals neurofluid dynamics’ sensitivity to CO 2 ’s frequency response, best explained by autonomic modulation. Modulating basal CO 2 offers a new way to influence human neurofluid dynamics, independent of sleep or neuronal activity.

Enlarged perivascular spaces (PVS) are imaging markers of cerebral small vessel disease (CSVD) that are associated with age, disease phenotypes, and overall health. Quantification of PVS is challenging but necessary to expand an understanding of their role in cerebrovascular pathology. Accurate and automated segmentation of PVS on T1-weighted images would be valuable given the widespread use of T1-weighted imaging protocols in multisite clinical and research datasets. We introduce segcsvdPVS, a convolutional neural network (CNN)-based tool for automated PVS segmentation on T1-weighted images. segcsvdPVS was developed using a novel hierarchical approach that builds on existing tools and incorporates robust training strategies to enhance the accuracy and consistency of PVS segmentation. Performance was evaluated using a comprehensive evaluation strategy that included comparison to existing benchmark methods, ablation-based validation, accuracy validation against manual ground truth annotations, correlation with age-related PVS burden as a biological benchmark, and extensive robustness testing. segcsvdPVS achieved strong object-level performance for basal ganglia PVS (DSC = 0.78), exhibiting both high sensitivity (SNS = 0.80) and precision (PRC = 0.78). Although voxel-level precision was lower (PRC = 0.57), manual correction improved this by only ~3%, indicating that the additional voxels reflected primary boundary- or extent-related differences rather than correctable false positive error. For non-basal ganglia PVS, segcsvdPVS outperformed benchmark methods, exhibiting higher voxel-level performance across several metrics (DSC = 0.60, SNS = 0.67, PRC = 0.57, NSD = 0.77), despite overall lower performance relative to basal ganglia PVS. Additionally, the association between age and segmentation-derived measures of PVS burden was consistently stronger and more reliable for segcsvdPVS compared to benchmark methods across three cohorts (test6, ADNI, CAHHM), providing further evidence of the accuracy and consistency of its segmentation output. segcsvdPVS demonstrates robust performance across diverse imaging conditions and improved sensitivity to biologically meaningful associations, supporting its utility as a T1-based PVS segmentation tool.

Active music engagement, that is, playing a musical instrument or singing, may be protective of motor function decline in aging. Although playing a musical instrument may transfer to benefits in motor function, it is also possible that the genetic architecture of motor behavior and the motor system brain structures may influence active music engagement. This study investigated whether polygenic scores (PGSs) for five behavioral motor traits, 12 structural brain traits, and seven rate-of-change in brain structure traits trained from existing genome-wide association studies predict active music engagement in four independent cohorts: the Canadian Longitudinal Study on Aging (CLSA; N = 22,198), Wisconsin Longitudinal Study (WLS; N = 4605), Vanderbilt's BioVU Repository (BioVU; N = 6150), and Vanderbilt's Online Musicality Study (OM; N = 1559). Results were meta-analyzed for each PGS main effect across outcomes and cohorts, revealing that PGS for a faster walking pace was associated with higher amounts of active music engagement. Within CLSA, a higher PGS for walking pace was associated with greater odds of engaging with music. Our findings suggest a shared genetic architecture between motor function and active music engagement. Future research should consider the genetic underpinnings of motor behavior when evaluating the effects of music engagement on motor function.

Root disease caused by the fungal pathogen, Armillaria solidipes, is commonly managed for in tree plantations of southeastern British Columbia by removing stumps before planting trees. The potential biocontrol, Hypholoma fasciculare, has been applied less commonly. We summarize the effects of mechanical stump removal and Hypholoma treatments on the development of 13 experimental conifer plantations aged 13–43 years consisting primarily of Douglas-fir ( Pseudotsuga menziesii (Mirb.) Franco), lodgepole pine ( Pinus contorta Douglas ex Loudon), and western larch ( Larix occidentalis Nutt.). Generalized additive models were used in the Akaike information criterion model selection with response variables chronologized for each treatment unit: Armillaria incidence, survivorship, basal diameter, diameter at breast height, height, and basal area index. Stump removals reduced Armillaria incidence in the oldest stands from 3.3% to 1.1%, increased survivorship from 30.3% to 69.7%, and produced 1.72 times greater basal area index. Armillaria reduction with stump removals was greater on Douglas-fir and western larch. At year 21, Hypholoma reduced Armillaria occurrence by 2.1 percentage points, whereas stump removals decreased Armillaria by 1.7 percentage points. Treatment decisions need to weigh silvicultural gains with financial and environmental costs, while Hypholoma treatments warrant expanded research.

IntroductionRuminative brooding is a transdiagnostic symptom defined as repetitive dwelling on thoughts and emotions, and is linked to emotion dysregulation, maladaptive metacognitive beliefs, and abnormal interoception. The relative contributions of these factors and their neural mechanisms remain unclear. In this exploratory study, we mapped these processes onto directed cross-frequency coupling (CFC) networks using resting-state electroencephalography.MethodsWe first identified symptoms of interest for CFC analyses by employing regularized symptom networks, revealing two clusters relevant to brooding: one dominated by interoceptive/mindfulness dimensions and another by metacognitive/emotional dysregulation, with brooding belonging to the latter. We then examined links between representative symptoms from each cluster and resting-state cross-frequency phase–amplitude coupling (PAC) using partial least squares correlation (PLS-C).ResultsEmotional dysregulation and brooding dimensions co-varied with delta-beta PAC (representing a “brooding/dysregulation” neural signature), whereas mindfulness symptoms co-varied with beta-gamma and theta-gamma PAC (representing a “mindfulness/interoception” neural signature). More specifically, for the brooding/dysregulation signature, prefrontal and cingulate phase activity modulated amplitudes in regions implicated in emotion regulation and interoception. In contrast, the mindfulness/interoception signature reflected coupling within circuits supporting emotion regulation/interoception.DiscussionOverall, our results indicated that brooding was more tightly linked to maladaptive metacognitive beliefs and emotional dysregulation than to mindfulness/interoception, consistent with resistance toward one’s thoughts and emotions. Neurally, as reflected through multivariate PLS-C covariance patterns, this may be linked to compensatory top-down control from prefrontal and cingulate areas over interoceptive, affective, and self-referential systems, pointing to the potential value of therapies that cultivate self-acceptance and modify maladaptive metacognitive beliefs for reducing rumination.

BackgroundThe Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS‐ND) study is a national Canadian observational study of participants clinically diagnosed with various forms of dementia and cognitive complaints. Here, we utilize plasma biomarkers including amyloid beta (Aβ42/40), phosphorylated tau‐181 (p‐tau‐181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP), to estimate the prevalence of Alzheimer's disease (AD) pathology in COMPASS‐ND. This enables us to assess concordance between clinical presentation and underlying pathogenesis in participants.MethodBiomarkers were analysed in COMPASS‐ND plasma samples (n = 936) using the Quanterix Simoa HD‐X analyzer with Neurology 4‐plex E and p‐tau‐181 assays. A sub‐cohort (n = 150) of participants with cerebrospinal fluid (CSF) Aβ42, p‐tau‐181 and total tau (Roche Elecsys assays) were utilized to determine plasma biomarker cut‐offs. Area under the receiver operating curve (AUROC) analysis was conducted. Cut‐offs, determined at the Youden's index, were then applied to the remaining COMPASS‐ND participants to estimate the percentage of biomarker positive individuals in each clinically determined diagnostic group.ResultOf the COMPASS‐ND participants with CSF, 80% (n = 120) were on the AD continuum. AUROC analysis revealed an area of 0.768 for Aβ42/40, 0.638 for p‐tau‐181, 0.559 for NfL, and 0.689 for GFAP. Cut‐offs for plasma biomarkers to be considered on the AD continuum were Aβ42/40 <0.068 pg/mL, p‐tau‐181 >2.7 pg/mL, NfL >18.6 pg/mL, and GFAP >134.9 pg/mL. A multi‐biomarker cut‐off based on having positive results for 2 out of 3 from Aβ42/40, p‐tau‐181, and GFAP, yielded a sensitivity of 64% and specificity of 83%. In the remaining n = 786 COMPASS‐ND participants, the multi‐marker panel estimated that AD pathology would be present in 30% (n = 28/93) of cognitively normal, 25% (n = 27/106) of subjective cognitive impairment, 52% (n = 167/321) of mild cognitive impairment, 83% (n = 96/116) of AD, 73% (n = 16/22) of Lewy body dementia, 45% (n = 13/29) of frontal temporal dementia, and 34% (n = 34/99) of Parkinson's disease participants.ConclusionThe plasma biomarkers assays tested have high specificity for detecting AD pathology, enabling their use to estimate AD pathology in a larger cohort. Based on the low sensitivity of the plasma biomarkers tested, we assume that these results underestimate the prevalence of AD pathology in the COMPASS‐ND cohort.

Harmonization of neuropsychological assessment for vascular cognitive impairment and dementia (VCID) is important for ensuring the highest standards and consistency of diagnosis. A battery proposed in 2006 by the National Institute for Neurological Disorders and Stroke and the Canadian Stroke Network (NINDS-CSN) has received much international support. Considering significant advances in the field, including the rise of computerized and remote assessment methods, a revision is needed. To develop an updated harmonized battery and associated assessment guidelines for VCID. NINDS-CSN and other relevant published harmonized neuropsychological batteries, aided by literature review of recent developments in VCID, were used as reference points for an online Delphi survey (≥3 rounds, ≥75% threshold for agreement), including questions on a core test battery based on key cognitive domains that should be assessed for VCID, consideration of computerized and remote assessment methods, and assessment of diverse populations. International experts in neuropsychological assessment from diverse international regions were invited to participate in 2023. Data were analyzed from October 11, 2023, to June 20, 2024. A total of 44 experts participated in 3 survey rounds, with 28 to 31 participants each. Consensus was reached on a core assessment battery of neuropsychological tests based on key cognitive domains, and additional guidelines for a more comprehensive test battery, cognitive screening, telehealth and computerized assessment methods, principles for normative standardization, and the assessment of diverse populations. The key cognitive domains were harmonized with the International Society for Vascular Behavioural and Cognitive Disorders version 2 World Stroke Organization (VasCog-2-WSO) diagnostic criteria for VCID. This consensus statement describes the development of a harmonized neuropsychological assessment battery and guidelines for VCID (VasCog-NP) that expands on the NINDS-CSN battery with more comprehensive and flexible assessment of VCID. Harmonized with the VasCog-2-WSO diagnostic criteria, VasCog-NP could be adopted internationally to further help more consistent neuropsychological evaluations related to VCID, facilitating global comparisons for clinicians and researchers.

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.