The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) is an observational study of more than 1100 participants across the dementia spectrum. This research note describes the development and features of the neuropsychological research battery, which is available in English and French. The training of staff and procedures for quality assurance are described. The battery assesses learning and memory, processing speed, attention, executive function, visuoperceptual processing, and language, and the available test scores are described. We outline our goals for future work including: (1) increasing the sociodemographic diversity of the participant cohorts, (2) determining the psychometric properties of the battery, (3) establishing robust normative data from control participants followed longitudinally, and (4) examining longitudinal data on individuals at risk of dementia and across the dementia spectrum. The COMPASS-ND neuropsychology data will provide a unique open-access database of deeply phenotyped participants with or at risk of dementia for Canadian and international researchers.

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible condition characterized by gait, cognitive, and urinary impairment and treated with cerebrospinal fluid shunting, yet post-shunt outcomes vary. Coexisting Alzheimer's disease (AD) pathology may contribute to this variability. This systematic review and meta-analysis investigated whether pre-shunt AD co-pathology influences post-shunt outcomes across distinct clinical domains and follow-up durations. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, PubMed, Embase, Scopus, and Web of Science were searched for studies assessing the impact of pre-shunt AD co-pathology on post-shunt outcomes in iNPH. Studies were included in the meta-analysis if they stratified patients by pre-shunt AD status (iNPH-AD vs. iNPH-nAD) and reported at least one post-shunt outcome compared between groups. Random-effects meta-analyses pooled standardized mean differences across short- (<12 months) and long-term (≥12 months) follow-up. Sixteen studies (n = 1825 patients) were included in the systematic review, with nine (n = 428) eligible for meta-analysis. Pre-shunt AD co-pathology prevalence ranged from 23.9% to 67.6%, and post-shunt follow-up duration ranged from 3 to 60 months. No short-term group differences were observed for cognitive outcomes; however, a significant long-term group effect indicated poorer cognitive recovery in the iNPH-AD group. Gait measures showed short-term group differences favoring the iNPH-nAD group, with no group effects at long-term follow-up, whereas urinary outcomes showed no group differences at any follow-up. AD pathology is not a contraindication to shunting; rather, AD biomarker assessment should be incorporated into the pre-shunt workup, as it can enhance outcome prediction and support tailored postoperative management. © 2026 International Parkinson and Movement Disorder Society.

Oxylipin species are generated from omega-3 and omega-6 fatty acids during inflammation, including fatty acid epoxides by cytochrome P450s (CYP450) and their diol metabolites by soluble epoxide hydrolase (sEH). The CYP450-sEH pathway has been implicated in Alzheimer’s disease (AD) but it remains unclear how plasma oxylipins relate to AD biomarkers and neurodegeneration. Fasting plasma CYP450-sEH total (free + esterified) oxylipins were assayed by ultra-high pressure liquid chromatography-tandem mass spectrometry in participants (NCT04104373) clinically diagnosed with AD or mild cognitive impairment (MCI). Plasma AD biomarkers were assayed by SiMoA. At baseline, 1 and 2 years, regional grey matter and white matter hyperintensity (WMH) volumes were quantified using 3.0 T MRI, and cognitive assessments were performed. At baseline (n = 125), participants with AD vs. MCI had higher CYP450-sEH pathway metabolites, apolipoprotein E (APOE) ε4 carriers vs. non-carriers had higher diol levels, and females vs. males had higher omega-6 vs. omega-3 oxylipins. An oxylipin profile of higher diols and lower epoxides was associated with higher pTau181, temporal lobe and hippocampal atrophy, and declines in cognitive performance in multiple domains over 2 years. Higher CYP450-sEH pathway metabolites were associated with the progression of WMH. Larger oxylipin relationships with atrophy and cognitive decline were seen at the MCI stage, in APOE ε4 carriers, and in females. Elevated sEH metabolites were related to biomarkers of AD pathogenesis, and they predicted atrophy, white matter changes, and cognitive decline over 2 years.

Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.

White matter microstructural changes play a crucial role in cognitive decline in aging and neurodegenerative disorders including Alzheimer’s disease (AD). However, the processes underlying white matter microstructural changes and the molecular pathways leading to these changes in AD remain largely unknown. AD involves cortical and juxtacortical microstructural changes, with free water fraction (FWF) as a potential imaging marker. We measured FWF using diffusion magnetic resonance imaging in 68 juxtacortical regions of 153 cognitively normal controls and 194 patients with AD as evidenced by elevated amyloid PET. We estimated the expression of 15,633 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. The biological processes and cell types associated with the linked genes were evaluated. Mediation analysis was used to examine whether FWF mediates the association between APOE ε4 status and cognitive performance. Gene ontological analyses revealed that these genes were enriched for biological processes relating to lipid metabolic process, ensheathment of neurons, and synaptic signaling and were predominantly expressed in oligodendrocytes, GABAergic neurons, and pyramidal neurons from the hippocampus CA region. These ontological enrichment results were replicated in two additional datasets. Furthermore, mediation analyses revealed a domain-specific role of FWF in the association between APOE ε4 status and cognitive performance. Our findings provide mechanistic insights into regional juxtacortical microstructural changes in AD, particularly the processes involving lipid metabolism, offering potential therapeutic targets.

INTRODUCTION:We tested the hypothesis that increased middle cerebral artery velocity (MCA velocity) during complex motor (overground walking) and cognitive tasks (e.g., dual task) is associated with cognitive performance in older adults with varying levels of cognitive ability. METHODS:Fifty-six participants (19 females, 75 ± 7 years old) completed a seated single task that assessed working memory performance; a walking single task, assessing overground walking gait speed; and a dual task, combining both. Continuous MCA velocity was collected, and participants completed a Montreal Cognitive Assessment (MoCA). RESULTS:Higher MCA velocity was associated with faster gait speed, better working memory performance, and greater MoCA scores (all p < 0.05). Participants with lower MoCA scores had lower MCA velocity (p = 0.052), slower gait speed (p = 0.035), and lower working memory performance (p = 0.016) than people with higher MoCA scores. The hyperemic response of MCA velocity from single task walking to the dual task with increased cognitive load significantly contributed to MoCA scores (p = 0.017). DISCUSSION:The functional response of cerebral blood flow with these tests suggests vascular properties may be considered a biomarker indicative of subclinical cognitive function during walking tasks. Highlights:Mobile devices simultaneously assessed neurovascular coupling and dual-task cost.Middle cerebral artery velocity (MCA velocity) is negatively associated with dual-task cost.MCA velocity is associated with gait speed, working memory, and Montreal Cognitive Assessment scores.MCA velocity decreased from controls to mild cognitive impairment to dementia.Novel methodological approach to utilize MCA velocity during overground walking, single-tasks, and dual-tasks.

Mild Behavioral Impairment (MBI) is a condition characterized by neuropsychiatric symptoms (NPS) in older adults without dementia, serving as a precursor to various forms of dementia. This study explores the association between NPS and functional connectivity (FC) within the default mode network (DMN), executive control network (ECN), and salience network (SN) across three high-risk cohorts: mild cognitive impairment (due to Alzheimer’s) (MCI, n = 79), cerebrovascular disease (CVD, n = 144), and Parkinson’s disease (PD, n = 132). A total of 367 participants were recruited from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). The assessment of NPS utilized the Neuropsychiatric Inventory Questionnaire (NPI-Q), with symptom severity rated on a scale from 1 to 3 (mild, moderate, severe). Resting-state FC was analyzed for the DMN, ECN, and SN, using dual regression analysis to generate subject-specific whole-brain FC maps for each network. The association between FC maps and NPS scores was examined using FSL’s randomise with 5,000 permutations, while controlling for age, sex, and education. Results are presented following cluster False Discovery Rate (FDR) correction. The study revealed significant associations between NPS and FC specific to each cohort. In the MCI group, disturbed appetite and nighttime behaviors were correlated with increased FC of the dorsal DMN (p<0.05, R = 0.47, and p = 0.01, R = 0.47). The CVD group exhibited correlations between higher levels of anxiety and decreased FC of the dorsal DMN (p<0.05, R = -0.4), ventral DMN (p<0.05, R = -0.33), and bilateral ECN (p<0.05, R = -0.35 and R = -0.33). The PD group showed disturbed nighttime behavior associated with increased FC in ventral DMN (p<0.05, R = 0.35) and bilateral ECN (p<0.05, R = 0.43 and R = 0.37). This research underscores disorder-specific correlations between specific NPS domains and FC in MCI, CVD, and PD, emphasizing the unique neural underpinnings of symptomatology in each group. Furthermore, it is essential to note the inherent heterogeneity in all groups. Overall, the pathological substrates of neurodegenerative disorders likely play a pivotal role in shaping the neural correlates of MBI within each disorder. These findings provide valuable insights into targeted interventions and avenues for future research in neurodegenerative disorders.

Lecanemab and donanemab are monoclonal antibody therapies that remove amyloid-beta from the brain. They are the first therapies that alter a fundamental mechanism, amyloid-beta deposition, in Alzheimer disease (AD). To inform Canadian decisions on approval and use of these drugs, the Canadian Consortium on Neurodegeneration in Aging commissioned Work Groups to review evidence on the efficacy and safety of these new therapies, as well as their projected impacts on Canadian dementia systems of care. We included persons with lived experience with Alzheimer disease in the discussion about the benefits and harms. Our review of the trial publications found high quality evidence of statistically significant group differences, but also recognized that there are mixed views on the clinical relevance of the observed differences and the value of therapy for individual patients. The drugs are intended for persons with early AD, at a stage of mild cognitive impairment or mild dementia. If patients are treated, then confirmation of AD by positron emission tomography or cerebrospinal fluid analysis and monitoring for risk of amyloid-related imaging abnormalities was recommended, as done in the clinical trials, although it would strain Canadian resource capacity. More data are needed to determine the size of the potentially eligible treatment population in Canada.

INTRODUCTION:Controversial hypotheses suggest that "suboptimal" thyroid function - defined as higher-normal thyroid-stimulating hormone (TSH) (2.0 to 4.5 μIU/mL) or low-normal free thyroxine (FT4) - may increase risk of cognitive decline and dementia in older patients. METHODS:We examined this claim using data from the Canadian Comprehensive Assessment of Neurodegeneration and Dementia cohort (ages 50 to 91; cognitive statuses from unimpaired to dementia, rarer subtypes of dementia excluded). Thyroid function was categorized as "optimal" (TSH < 2.0 μIU/mL or FT4 ≥ 16.74 pmol/L) or "suboptimal." Six hundred eighty-eight participants had TSH data, and 476 participants had FT4 data. RESULTS:Chi-squared analyses showed no significant association between "suboptimal" thyroid function and cognitive impairment (TSH: χ2 = 0.178, p = 0.67; FT4: χ2 = 0.0027, p = 0.96). True hypothyroidism was rare; 98.6% of those with elevated TSH had normal FT4. DISCUSSION:These findings do not support claims that higher-normal TSH or low-normal FT4 contribute to cognitive impairment. Caution is warranted against advocating unproven thyroid supplementation for cognitive health. HIGHLIGHTS:No link was found between "suboptimal" thyroid function and cognitive impairment. Higher-normal TSH levels do not indicate dementia risk or hypothyroidism. Among participants with elevated TSH, 98.6% had normal FT4 levels. Redefining TSH cutoffs to 2.0 μIU/mL lacks clinical justification. Findings question the functional medicine approach of thyroid supplementation for cognitive health.

A growing body of research has focused on inflammation as both a potential biomarker and a risk factor for Alzheimer’s disease (AD). The cytokine Interleukin-6 (IL-6) is involved in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. AD has been associated with increased IL-6 expression in brain, however, increased levels of IL-6 have also been linked to conditions such as diabetes and hypertension. We examined groups of individuals with AD and related disorders (ADRD) as well as healthy controls to check if elevated levels of IL-6 (above 1.9 ng/L) were related to the presence of comorbidities. We investigated individuals with AD (n = 58); mild cognitive impairment (MCI; n = 139); subjective cognitive impairment (SCI; n = 28); and cognitively unimpaired age matched controls (CU; n = 53). We considered four possible subgroups: Group 0 (defined as individuals with normal IL-6 levels and without comorbidities that could be linked to elevated IL-6); Group 1 (individuals with normal levels of IL-6, despite having comorbidities); Group 2 (individuals with elevated IL-6 without comorbidities), and Group 3 (individuals with elevated IL-6 and comorbidities). The comorbidities investigated were hypertension, diabetes, peripheral vascular disease, history of cerebrovascular accident, and rheumatoid arthritis. Logistic regression was used to investigate the relationship between the occurrence of elevated IL-6, age, sex, history of smoking, body mass index (BMI), Montreal Cognitive Assessment scores (MoCA), nutrition and sleep. We found individuals with and without elevated IL-6, and with and without comorbidities in all cohorts (Table 1). We found a significant relationship between elevated IL-6 and aging in all cohorts (Figure 1a). A significant relationship was also found between elevated IL-6 and greater BMI (MCI group only; Figure 1b), lower nutrition scores (SCI group only, Figure 1c), history of smoking (AD group only; Figure 2a) and sex, whereby males had more elevated IL-6 (MCI group; Figure 2b). We found variation in patterns of peripheral inflammation and other common conditions in aging and ADRD. These variations may reflect different mechanistic groups which might help the understanding of variation in clinical features of ADRD, disease progression and response to different therapeutic interventions.

Background "Inflammaging" describes chronic low-grade inflammation observed in aging individuals. It may play a major role in neurodegeneration. Objective To assess blood inflammatory markers in older adults. We hypothesized that elevated inflammation would be found in some cognitively normal older adults but would be more prevalent in individuals with cognitive impairment. Methods Interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in 514 Canadian individuals in COMPASS-ND, a detailed study of cognitive impairment in the elderly. Cumulative link model (CLM) was used to investigate the relationship between inflammation status (low, medium, or high tertiles) and demographic and lifestyle factors along with cognitive function and cognitive diagnoses. Results We found that 12% of cognitively normal older adults had IL-6 levels in the highest tertile, but this increased in cognitively impaired cohorts-36% in Alzheimer's disease, 55% mixed dementia, 30% mild cognitive impairment, and 39% vascular mild cognitive impairment. We found that 36% of cognitively unimpaired older individuals display "elevated" IL-6 (middle and high tertile values), while approximately 70% of those with cognitive impairment also do so. Inflammation markers increased most robustly in association with age, higher body mass index, and higher Fazekas (MRI white matter hyperintensity) score. There were also weaker associations with female sex, nutrition, number of comorbidities, and poor sleep. Conclusions Peripheral low-grade inflammation was common, particularly in individuals with cognitive impairment; and obesity and age were the main drivers. It remains unclear whether treatment targeting such inflammation might have a therapeutic role in dementia prevention.

Monitoring middle cerebral artery blood velocity (MCAv) during maneuvers known to alter cerebral perfusion, such as supine-to-standing transitions or walking, may provide a more comprehensive assessment used to flag individuals susceptible to cerebral hypoperfusion in a way that cannot be achieved at rest. Furthermore, dual-tasks challenge the brain to match MCAv to meet increases in local demands of oxygen and energy in two different functional networks (motor and cognitive), potentially causing cerebral hypoperfusion when competing for shared and/or limited brain resources. We developed a dual-task paradigm comprising of five levels of task complexity, including single-tasks and dual-tasks. The main objective of the study was to evaluate changes in MCAv as task complexity increased, which was demonstrated through cognitive, motor, and combined cognitive-motor tasks in older adults with different cognitive function levels. A secondary objective was to assess the success rate (as a percentage) of obtaining MCAv signals during the dual-task protocol to determine the feasibility of measuring such metrics in older adults with varying levels of cognitive ability. Of the 88 participants (37 females, 75 ± 7 years, 27 ± 4 kg/m2), a MCAv signal was ascertained in 56 participants throughout both single-tasks and both dual-tasks. MCAv increased when transitioning from a simple single-task to a more complex dual-task, while also highlighting a decline in motor and cognitive performance. A full multi-modal signal acquisition (MCAv, blood pressure, and cerebral oxygenation) was acquired for 48 participants. Lower MCAv signal acquisition was observed in females and people with cognitive impairment. We have demonstrated how MCAv changes with increased task complexity, while also uncovering declines in gait and cognitive performance. By establishing the feasibility of obtaining MCAv signals during cognitive stress tests and dynamic movements in older adults with varying cognitive abilities, we can begin to assess cerebral hypoperfusion using a potentially more sensitive indicator linked to neural damage.

INTRODUCTION:Recent research has suggested that neuroinflammation may be important in the pathogenesis of neurodegenerative diseases. Free-water diffusion (FWD) has been proposed as a non-invasive neuroimaging-based biomarker for neuroinflammation. METHODS:Free-water maps were generated using diffusion MRI data in 367 patients from the Ontario Neurodegenerative Disease Research Initiative (108 Alzheimer's Disease/Mild Cognitive Impairment, 42 Frontotemporal Dementia, 37 Amyotrophic Lateral Sclerosis, 123 Parkinson's Disease, and 58 vascular disease-related Cognitive Impairment). The ability of FWD to predict neuroinflammation and neurodegeneration from biofluids was estimated using plasma glial fibrillary-associated protein (GFAP) and neurofilament light chain (NfL), respectively. RESULTS:Recursive Feature Elimination (RFE) performed the strongest out of all feature selection algorithms used and revealed regional specificity for areas that are the most important features for predicting GFAP over NfL concentration. Deep learning models using selected features and demographic information revealed better prediction of GFAP over NfL. DISCUSSION:Based on feature selection and deep learning methods, FWD was found to be more strongly related to GFAP concentration (measure of astrogliosis) over NfL (measure of neuro-axonal damage), across neurodegenerative disease groups, in terms of predictive performance. Non-invasive markers of neurodegeneration such as MRI structural imaging that can reveal neurodegeneration already exist, while non-invasive markers of neuroinflammation are not available. Our results support the use of FWD as a non-invasive neuroimaging-based biomarker for neuroinflammation.

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer’s disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage.

INTRODUCTION:Mild Behavioral Impairment (MBI) is characterized by later-life emergent and persistent neuropsychiatric symptoms (NPS) in older adults without dementia, serving as a potential precursor to various forms of dementia. This study explores the association between NPS and functional connectivity (FC) of the default mode network (DMN), executive control network (ECN), and salience network (SN) across three cohorts: mild cognitive impairment due to AD (MCI), cerebrovascular disease (CVD), and Parkinson's disease (PD). Additionally, the effect of CNS medication on NPS-FC associations was explored. METHODS:Participants were recruited from the Ontario Neurodegenerative Disease Research Initiative (ONDRI). NPS were evaluated using the Neuropsychiatric Inventory Questionnaire (NPI-Q). We used dual regression to generate subject-specific whole-brain FC maps of the DMN, ECN, and SN. Using permutation testing we examined the association between NPS scores and FC maps at baseline (n = 349) and over a 2-year period (n = 225), controlling for age, sex, and years of education. A post-hoc linear model was used to assess the effect of CNS medication on each significant NPI-FC association within each group. RESULTS:In the MCI group (n = 73), baseline disturbed nighttime behavior was positively correlated with functional connectivity (FC) between the anterior sensorimotor network. Longitudinally (n = 46), appetite changes were positively associated with FC between the anterior SN and fusiform gyrus. Disinhibition and apathy correlated with FC between the posterior SN and DMN. In the CVD group (n = 144), baseline anxiety was negatively associated with FC within the DMN and between the right ECN and DMN in the left hippocampus. Longitudinally (n = 99), agitation/aggression changes were negatively associated with FC between the right ECN and left anterior cerebellum. Irritability, the most common symptom in both MCI and CVD, did not have identifiable neural correlates, possibly due to its complexity or analysis limitations. In the PD group (n = 132), baseline disturbed nighttime behavior was positively associated with FC between the right ECN and DMN in the precuneus and left ECN and fusiform gyrus. Longitudinally (n = 80), changes in nighttime behavior correlated with FC between the left ECN and DMN in the precuneus. CNS medications had no effect on NPI-FC associations in the MCI group. In the CVD group, the absence of CNS medications was linked to decreased right ECN FC. In the PD group, Parkinson's medications changed the direction of the NPI night-time score-FC correlation at both baseline and the 2-year assessment, with higher scores associated with reduced left ECN FC in medicated individuals. CONCLUSIONS:In conclusion, our study highlights the critical role of the DMN, ECN, and SN in processing neuropsychiatric symptoms (NPS) across MCI, CVD, and PD populations. We found significant associations between NPS and functional connectivity (FC) within and between these networks. MCI and PD showed positive associations with FC, particularly for disturbed nighttime behavior, while CVD exhibited negative associations, notably with anxiety and agitation. Although irritability was common in both MCI and CVD groups, its neural correlates remain unclear, emphasizing the need for further investigation. These findings support existing literature and pave the way for targeted therapeutic approaches, such as brain stimulation, to alleviate NPS. Additionally, the complex role of CNS medications in modulating NPS and FC warrants further investigation.

Social cognition is impacted early in the disease progression of many neurodegenerative diseases (ND). The Salience network (SN) is an intrinsically connected brain network responsible for social cognitive function. Keys hubs of this brain network, the anterior insula (AI) and anterior cingulate cortex (ACC), are reported to incorporate ‘bottom-up’ signals from subcortical regions such as the amygdala and periaqueductal gray (PAG), but this mechanism and the subcortical contribution to SN connectivity is poorly understood. Our aim was to investigate the contribution of cortical and subcortical structures to SN functional connectivity and to social cognition across NDs. 76 participants (21 Alzheimer’s disease, 13 behavioural variant frontotemporal dementia, and 42 Parkinson’s disease) from the Ontario Neurodegenerative Research Initiative (ONDRI) baseline or one-year follow up visits with resting state fMRI, Montreal Cognitive Assessment (MoCA) total scores, and informant-reported socioemotional sensitivity scores using the Revised Self-Monitoring Scale (RSMS) were included (higher score, indicating higher function). All groups were age- and sex-matched. Fisher-transformed correlation coefficients of functional connectivity from an ROI-to-ROI analysis between cortical and subcortical SN ROIs were used to create a mean cortical SN value and mean subcortical SN value to use in linear regression modelling with behavioural scores. Mean cortical and subcortical SN connectivity were significantly associated with RSMS total score (b = 2.94, p = 0.041; (b = 3.60, p = 0.014, respectively), independent of cognitive function, with higher connectivity predicting higher score. The interaction between cortical and subcortical connectivity was not significantly associated with RSMS total score. Mean cortical and subcortical connectivity was significantly associated with RSMS-EX (expressive behaviour of others) and RSMS-SP (self-presentation) subscores (b = 1.36, p = 0.049; b = 1.44, p = 0.040; b coef = 1.58, p-value = 0.033; b coef = 2.15, p-value = 0.005, respectively). Our results indicate a stronger contribution of subcortical structures to social cognition-related functional connectivity across various neurodegenerative diseases. Despite previous associations with cortical regions, our evidence suggests that alterations in subcortical structures mediate changes in social cognition. Further exploration in larger cohorts is necessary, as impaired social cognition in patients with ND is associated with increased caregiver distress.

Altered cerebrovascular hemodynamics and low cerebral perfusion contribute to the development and progression of dementia. Dynamic cerebral autoregulation (dCA), a measure of the cerebral vasculature’s ability to buffer abrupt changes in mean arterial pressure and prevent hypoperfusion, such as during a supine-to-standing transition, have mixed results in people clinically diagnosed with mild cognitive impairment (MCI, people with objective cognitive impairment but maintained functional independence). Therefore, in 30 people with MCI, we tested the hypothesis that participants with a higher standing middle cerebral artery velocity (MCAv) at diastole (higher-velocity group) would have lower dCA values, to confer better cerebrovascular outcomes and enhanced cognitive function compared to participants with a lower MCAv at diastole (lower-velocity group). This study separated people with MCI into different diastolic MCAv groups. dCA was calculated as (MCAv nadir -MCAv supine /MCAv supine )/(MAP MCAnadir -MAP MCAsupine /MAP MCAsupine ). This work led to the identification of a dysregulated dCA in the higher-velocity group (p = 0.009) compared to the lower-velocity group despite having greater cognitive scores (p = 0.008). Elevated levels of cerebral oxygen tissue saturation (p = 0.039) and lower end-tidal carbon dioxide (p = 0.042) suggest that a favourable dCA value may be a compensatory mechanism in the neurodegenerative disease processes. The unexpected results highlight the importance of uncovering hemodynamic pathways in clinical populations.

Introduction The pathophysiology of dementia is multifactorial and reduced cerebral blood flow (CBF) is a predictor of cognitive impairment. The majority of research on CBF and dementia has been completed in the supine position, however during upright-posture the vascular system must counter gravitational forces and the redistribution of blood volume to the working muscles to maintain CBF. Aim Determine if diastolic middle cerebral artery velocity (MCAdv) during standing is associated with lower performance on a working memory task (WMT, 1-back or 2-back) in older adults. Methods Fifty-three participants (73±6yrs, 17-females: 14 cognitively intact, 30 mild cognitive impairment, 9 dementia) were analyzed. MCAdv profiles the lowest level of flow within a cardiac cycle. Beat-by-beat MCAdv (transcranial Doppler ultrasound) and mean arterial pressure (MAP, plethysmography) were averaged for 30-sec during supine-rest and standing (figure 1). K-means algorithms identified three homogeneous groups (increased-MCAdv, maintained-MCAdv, and reduced-MCAdv) from standing MCAdv (figure 2). Participants completed a 90-second WMT and a performance-based signal detection variable was calculated [sensitivity-A’=0.5+((hit rate−false alarm rate) × (1+hit rate−false alarm rate))/(4 × hit rate × (1−false alarm rate))], and a speed versus accuracy exchange was calculated [sensitivity-A’ score=100xsensitivity-A’/target reaction time(ms)x100]. ANCOVA (covariate: age), and post-hoc analyses were completed on standing MCAdv and WMT. Multiple linear regressions were completed for WMT with age and either MAP or MCAdv (supine and standing), and simple linear regressions were also completed. Significance was set to p≤0.05. Results The reduced-MCAdv group had lower WMT scores (p<0.02) compared to the increased- or maintained-MCAdv groups (figure 2). There was a linear correlation between standing-MCAdv and WMT which was not observed while supine (figure 3). Similarly, regression modelling predicted WMT [F(3,49)=2.533, p=0.068, R2=0.134] with standing-MCAdv, supine-MCAdv, and age, and only standing-MCAdv was a significant predictor variable (p=0.013). This relationship was unique to MCAdv and was not observed with MAP. Discussion Decreased MCAdv when standing, demonstrates a linear relationship with reduced working memory in older adults. This was not observed in the supine position and was not present with measures of peripheral arterial flow (MAP), indicating a unique relationship between dynamic measures of MCAdv and memory tasks, which was not observed at supine rest or in MAP.