The human brain is organized into macroscale functional networks that exhibit temporally synchronized spontaneous neural activity, known as functional connectivity (FC). Considering the high energetic cost of synaptic transmission (Tomasi et al. 2013, Aiello et al. 2015), hybrid imaging combining resting-state functional MRI (rsfMRI) with 18 F-Fluorodeoxyglucose positron emission tomography (FDG-PET) offers a unique opportunity to study the relationship between FC and energy demands. Alzheimer's is associated with significant dissociation between regional metabolism and neural activity, particularly within functionally active network hubs (Marchitelli et al. 2018); however, other neurodegenerative disorders remain unexplored. Frontotemporal dementia (FTD) is a rare form of dementia marked by functional breakdown of the salience network (SN), which regulates appropriate responses to stimuli. Like Alzheimer's, we hypothesized that FTD would be characterized by functional/metabolic dissociation; however, network-level breakdown would be most evident in the SN given its role in the disease process. FDG-PET and rsfMRI were simultaneously collected on a Siemens Biograph mMR scanner from 18 controls and 20 behavioral-variant FTD (bvFTD) patients. FDG maps were converted into standardized uptake value ratio (SUVr). Local FC was quantified as Regional Homogeneity (ReHo), an fMRI metric reflecting regional synchronization of neural activity. Voxel-wise Spearman correlations were used to assess the relationship between ReHo and FDG-SUVr. Furthermore, inter-regional FC was measured with seed-based FC analysis. Group comparisons were made using 2-sample t-tests ( p  <0.05) while correcting for multiple comparisons. Reduced correlations between FDG and ReHo were found within the hubs of the SN in bvFTD, particularly bilateral anterior insula (AI) (Table). Analysis of inter-regional FC revealed diminished communication between the AI and other SN hubs (Table). The disconnection between local FC and metabolism in the anterior insula (AI), coupled with disrupted intra-network communication within the SN, supports the hypothesis of insula being a primary target in FTD (Seeley, 2010). These findings indicate a critical role of FC/metabolism coupling in maintaining network integrity and suggests that its disruption may lead to progressive breakdown of the SN, contributing to the functional deficits characteristic of the disease.

Abstract BACKGROUND Genetic frontotemporal dementia (FTD) shows large differences in symptom profiles, brain atrophy patterns, and progression rate, making clinical trials difficult to design and power. There is a need for biomarkers that can model disease progression, identify biologically distinct groups, and support efficient trial enrichment. METHODS We applied contrastive trajectory inference (cTI), a machine-learning method, to structural MRI, white matter hyperintensity, and demographic data from 736 participants in the GENFI cohort, including non-carriers and carriers of C9orf72 , GRN , or MAPT mutations. cTI produced an individual “genetic FTD progression score” (0–1) and grouped mutation carriers into data-driven subtypes. We tested construct validity using correlations between progression score and cognitive/functional measures, examined subtype differences in brain–behavior coupling, plasma neurofilament light (NfL), and longitudinal decline, and compared cTI-based trial enrichment against age, cortical thickness and NfL using analytic and simulation-based power analyses. RESULTS Genetic FTD progression scores correlated strongly with global dementia severity and multiple cognitive domains (all p < 0.001), confirming robust clinical scoring. Two mutation-carrier subtypes emerged: a Progressive Track (Subtype 2) with strong associations between progression score and cognitive/functional impairment, rising NfL, and faster longitudinal decline; and a Dissociated Track (Subtype 3) with comparable levels of structural variation but weak or absent clinical and NfL changes, suggesting relative biological stability. Baseline subtype membership added prognostic value for future decline in processing speed and language beyond baseline severity. Notably, for C9orf72 and GRN , cTI-informed enrichment reduced required recruited sample size per arm by about 61–75% compared with unenriched designs, and outperformed enrichment using age, cortical thickness or NfL in both analytic and simulation-based power analyses. CONCLUSIONS Machine-learning stratification of genetic FTD reveals a progressive and a dissociated disease track and provides individualized progression scores that closely track clinical status. cTI progression scores offer a powerful tool for trial enrichment, enabling smaller, more efficient prevention and early-intervention trials than conventional MRI or NfL markers alone.

White matter hyperintensities (WMHs) are critical markers of cerebrovascular health and neurodegenerative disease. Accurate and reproducible quantification of WMHs is essential for characterizing vascular contributions to aging, cognition, and Alzheimer disease and related dementias. Deep learning pipelines have emerged as powerful tools for WMH segmentation, yet limited research compares their performance using expert evaluation as the benchmark. Here, we assess the performance of five deep learning WMH segmentation pipelines by comparing their outputs through blinded neuroradiologist ratings. We processed FLAIR scans from 100 older adults (aged 80 and older) enrolled in the SuperAging Research Initiative. 3D T 2 ‐weighted FLAIR and T 1 ‐weighted MPRAGE sequences followed the ADNI‐3 protocol, acquired across five sites, using 3T scanners from three vendors (GE, Siemens, Philips). Binary segmentation masks from five deep learning pipelines were utilized: sysu_media, ANTSx, DeepWMH, TrUE‐Net, and HyperMapp3r. A neuroradiologist (C.V.) evaluated the per‐participant level randomized segmentation masks, overlaid on the FLAIR and T 1 ‐weighted image, using a 7‐point Likert‐type scale, where 1 indicated “poor segmentation” and 7 indicated “excellent segmentation". Ratings were based on anatomical plausibility and alignment with WMH voxels visible on FLAIR. To compare scores, a Kruskal‐Wallis test and post‐hoc Mann‐Whitney pairwise comparisons were used. The Kruskal‐Wallis test revealed significant differences in segmentation quality across the five pipelines ( p = 7.73 x 10 ‐43 ). Post‐hoc Mann‐Whitney tests showed ANTSx (mean rating = 5.59 ± 1.17) performed significantly better than all other pipelines (all p < 0.00001), while HyperMapp3r (mean rating = 2.33 ± 1.22) consistently received significantly lower ratings (all p < 0.00001). DeepWMH (mean rating = 4.45 ± 1.34), sysu_media (mean rating = 4.18 ± 1.20), and TrUE‐Net (mean rating = 4.49 ±1.18) had comparable ratings, with no significant differences between the three. This study highlights significant variability in the quality of WMH segmentation across commonly used deep learning pipelines when benchmarked against expert evaluation. Among the evaluated pipelines, ANTSx demonstrated superior performance, producing clinically plausible segmentations with high anatomical fidelity. These findings underscore the importance of expert validation in selecting and refining automated segmentation tools for research and clinical applications in aging and neurodegenerative disease.

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.

BACKGROUND:Apathy is a common neuropsychiatric syndrome in neurodegenerative dementias, though its underlying mechanisms are not well understood. It is characterized, in part, by a reduction in self-initiated action (ie, voluntary actions instigated by internal or external stimuli). The sense of agency (SoA) refers to the feeling of control over one's actions and the outcomes of those actions. Experimentally, SoA can be measured using the intentional binding effect, where the perceptual attraction of a voluntary action to an immediate effect of that action is indicative of increased SoA. OBJECTIVE:The current study aimed to investigate aberrant SoA as a potential mechanism contributing to apathy. METHOD:Thirty-eight participants with mild cognitive impairment or Alzheimer disease, frontotemporal dementia, Lewy body disease or Parkinson disease (LBD/PD), and healthy controls were recruited for this study. We used the total score on the Apathy Evaluation Scale to index apathy severity across participants. RESULTS:Our results did not show an association between apathy and intentional binding. However, there were significant group-based differences. Compared to healthy controls, participants in the LBD/PD group demonstrated significantly more intentional binding driven by a pronounced perceptual attraction of their actions to the subsequent outcomes. CONCLUSION:These findings suggest altered sensorimotor and cognitive control processes that may be associated with the self-initiation deficits seen in individuals with neurodegenerative dementias and apathy.

BACKGROUND AND OBJECTIVES:Plasma biomarkers of Alzheimer disease (AD), neuroinflammation, and neurodegeneration are increasingly being used in clinical trials for diagnosis and monitoring of dementia. However, their association with longitudinal structural brain MRI changes, an important outcome measure across neurodegenerative and cerebrovascular diseases, is less known. We investigated how baseline plasma biomarkers reflect MRI markers of progression over time in patients with neurodegenerative and cerebrovascular diseases. METHODS:This longitudinal cohort study included patients from the Ontario Neurodegenerative Disease Research Initiative diagnosed with AD or mild cognitive impairment (AD/MCI), Parkinson disease (PD), frontotemporal dementia spectrum disorders (FTD), or cerebrovascular disease (CVD), followed annually for 2 years. Recruitment took place at specialized university-based dementia, movement disorders, and/or stroke clinics in the province of ON, Canada. MRI outcomes included markers of cerebral atrophy (ventricular CSF and regional gray matter volumes) and of small vessel disease pathology (white matter hyperintensity [WMH], perivascular spaces, and lacunar volumes). Hemorrhagic markers at baseline were also included. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau181 and tau217 (p-tau181, p-tau217), and β-amyloid (Aβ42/40) were quantified from blood samples collected at baseline using Simoa and used as predictors in linear mixed models adjusted for time (months), age, sex, apolipoprotein E (APOE)-ε4 carrier status, kidney function, vascular risk factors, microtubule-associated protein tau (MAPT) diplotypes, waist-hip circumference ratio, and disease duration. RESULTS:We analyzed 1,240 MRIs from 473 patients (age: 69.2 ± 7.4 [range: 49-87]; 32.8% women). Elevated baseline levels of GFAP, NfL, p-tau181, and p-tau217, and to a lesser extent decreased levels of Aβ42/40, were significantly associated with more cerebral atrophy and WMH burden at baseline (|B| = 0.02 to 1.69, p = 0.044 to <0.001) and with progression over time (|B| = 0.001 to 0.028, p = 0.049 to <0.001) in the pooled disease-agnostic group. Within disease-specific cohorts, GFAP and NfL were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, PD, FTD, or CVD. P-tau181 and p-tau217 were associated with cerebral atrophy and/or small vessel disease copathology in AD/MCI, CVD, PD-MCI, or PD-dementia. DISCUSSION:Selected plasma biomarkers seem useful as prognosis and monitoring tools of longitudinal imaging changes within real-world populations of neurodegenerative and/or cerebrovascular diseases, and provide insight into overlap across diseases in shared pathologic burden.

Background and Objectives Executive dysfunction is a core feature of frontotemporal dementia (FTD). While there has been extensive research into such impairments in sporadic FTD, there has been little research in the familial forms. Methods Seven hundred fifty-two individuals were recruited in total: 214 C9orf72; 205 progranulin (GRN) and 86 microtubule associated protein tau (MAPT) mutation carriers, stratified into asymptomatic, prodromal, and fully symptomatic; and 247 mutation-negative controls. Attention and executive function were measured using the Weschler Memory Scale-Revised (WMS-R) Digit Span Backwards (DSB), Wechsler Adult Intelligence Scale-Revised Digit Symbol task, Trail Making Test Parts A and B, and the Delis-Kaplan Executive Function System Color Word Interference Test. Linear regression models with bootstrapping were used to assess differences between groups. Correlation of task score with disease severity was also performed, as well as an analysis of the neuroanatomical correlates of each task. Results Fully symptomatic C9orf72, GRN, and MAPT mutation carriers were significantly impaired on all tasks compared with controls (all p < 0.001), except on the WMS-R DSB in the MAPT mutation carriers (p = 0.147). While asymptomatic and prodromal C9orf72 individuals also demonstrated differences compared with controls, neither the GRN or MAPT asymptomatic or prodromal mutation carriers showed significant deficits. All tasks were significantly correlated with disease severity in each of the genetic groups (all p < 0.001). Discussion Some individuals with C9orf72 mutations show difficulties with executive function from very early on in the disease and this continues to deteriorate with disease severity. By contrast, similar difficulties occur only in the later stages of the disease in GRN and MAPT mutation carriers. This differential performance across the genetic groups will be important in neuropsychological task selection in upcoming clinical trials.

BACKGROUND:The human brain is organized into macroscale functional networks that exhibit temporally synchronized spontaneous neural activity, known as functional connectivity (FC). Considering the high energetic cost of synaptic transmission (Tomasi et al. 2013, Aiello et al. 2015), hybrid imaging combining resting-state functional MRI (rsfMRI) with 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) offers a unique opportunity to study the relationship between FC and energy demands. Alzheimer's is associated with significant dissociation between regional metabolism and neural activity, particularly within functionally active network hubs (Marchitelli et al. 2018); however, other neurodegenerative disorders remain unexplored. Frontotemporal dementia (FTD) is a rare form of dementia marked by functional breakdown of the salience network (SN), which regulates appropriate responses to stimuli. Like Alzheimer's, we hypothesized that FTD would be characterized by functional/metabolic dissociation; however, network-level breakdown would be most evident in the SN given its role in the disease process. METHOD:FDG-PET and rsfMRI were simultaneously collected on a Siemens Biograph mMR scanner from 18 controls and 20 behavioral-variant FTD (bvFTD) patients. FDG maps were converted into standardized uptake value ratio (SUVr). Local FC was quantified as Regional Homogeneity (ReHo), an fMRI metric reflecting regional synchronization of neural activity. Voxel-wise Spearman correlations were used to assess the relationship between ReHo and FDG-SUVr. Furthermore, inter-regional FC was measured with seed-based FC analysis. Group comparisons were made using 2-sample t-tests (p <0.05) while correcting for multiple comparisons. RESULT:Reduced correlations between FDG and ReHo were found within the hubs of the SN in bvFTD, particularly bilateral anterior insula (AI) (Table). Analysis of inter-regional FC revealed diminished communication between the AI and other SN hubs (Table). CONCLUSION:The disconnection between local FC and metabolism in the anterior insula (AI), coupled with disrupted intra-network communication within the SN, supports the hypothesis of insula being a primary target in FTD (Seeley, 2010). These findings indicate a critical role of FC/metabolism coupling in maintaining network integrity and suggests that its disruption may lead to progressive breakdown of the SN, contributing to the functional deficits characteristic of the disease.

Established in 2021, the SuperAging Research Initiative is a multisite, longitudinal study focused on identifying resilience and resistance factors that promote successful cognitive aging. “SuperAgers” are defined as individuals age 80+ with episodic memory performance that is average or better for individuals 20-30 years younger. The SuperAging Research Initiative aims to advance knowledge of the neurobiology of brain aging, resilience, and resistance against “typical” age-related cognitive decline and pathologic declines seen in Alzheimer's disease and related disorders. The SuperAging Research Initiative is focused on increasing racial-ethnic, geographical, and educational diversity by enrolling 500+ participants across the United States and Canada. The mid-project recruitment and enrollment success, baseline participant characteristics, and initial study findings from the unique cohort are highlighted. Participant enrollment and harmonized data collection is ongoing at five North American sites. The protocol includes behavioral, biological, environmental, genetic, and psychosocial characteristics that may contribute to successful cognitive aging. Two embedded Research Projects provide focused opportunities to extend the depth and breadth of science. Project 1 utilizes state-of-the-art wearable technology to obtain quantitative measurements of daily activity, and Project 2 uses transcriptomic, genetic, and protein profiling to examine immune and inflammatory system parameters. Across sites, >280 participants (ages 80-101 with 6-20 years education) have enrolled in the harmonized protocol using community engaged research (CER) strategies. More than 12 states/provinces are represented. To date, approximately 20% participants identify with a historically underrepresented racial-ethnic group. Sites leveraging existing CER methodology have enrolled a higher percentage of racially diverse participants (30+%). The Project 1 protocol has shown strong feasibility (>90%), yielding high-quality data (>95% data recovery) for a fully remote sensor data collection protocol. Project 2 has begun initial analyses, and estimates to date suggest SuperAgers have similar Alzheimer's disease polygenic risk scores compared to their cognitively-average peers. The prospective, longitudinal study of SuperAgers is feasible and provides a unique opportunity to identify mechanisms conferring cognitive resilience and resistance against “typical” and pathologic age-related cognitive decline. Outcomes may identify novel modifiable factors that promote successful cognitive aging.

BackgroundGenetic frontotemporal dementia (FTD) along with Alzheimer's disease (AD), is one of the most prevalent early-onset dementias. The differential diagnosis of FTD from primary psychiatric disorder (PPD) has been challenging due to significant symptom overlap, particular as FTD often presents with prolonged psychiatric prodromes.ObjectiveThis study aims to evaluate whether blood-based neurofilament light chain (NfL) can differentiate genetic FTD from PPD, and to determine a global clinical cutoff to differentiate genetic FTD carriers from PPD with high specificity and sensitivity.MethodsData (ages 40-81) were obtained from FTD mutation carriers (GENFI; n = 474; n = 120 C9orf72, n = 114 GRN, n = 50 MAPT, n = 190 controls), and PPD (Biobanque Signature; n = 848). Blood-based NfL was measured with SIMOA HD-X (BbS) and SIMOA HD-1 (GENFI).ResultsBlood-based NfL was higher in all symptomatic mutations compared to PPD. Mildly symptomatic (0 < FTLD CDR-SOB-NM < 4) C9orf72 and GRN carriers also had higher NfL. ROC curve revealed an optimal blood-based NfL cutoff of 22.1 pg/mL (J = 0.647) to distinguish symptomatic genetic FTD from PPD (78.5% sensitivity, 86.2% specificity, AUC = 0.908). For mildly symptomatic subjects, a cutoff of 16.2 pg/mL (J = 0.601) differentiated groups with 86.7% sensitivity and 73.5% specificity (AUC = 0.870).ConclusionsNfL holds potential as a blood-based biomarker for symptomatic genetic FTD carriers, with moderate accuracy to distinguish PPD from mild forms including C9orf72.

The SuperAging Research Initiative employs wearable technologies to evaluate whether ‘SuperAgers’ (individuals aged 80+ with episodic memory comparable to those 2-3 decades younger) exhibit preserved biological and physiological complexity compared to Controls. This preliminary analysis examines variability in early group-level data and considers alternate methods for capturing variability and complexity in daily health-related activities. Data collection and analysis are ongoing. Participants wear wrist and ankle inertial measurement units and a trunk sensor (accelerometer with electrocardiography) 24h daily over 14 days, with scheduled wear breaks. To date, 127 participants have completed device wearing. Volumetric measures of physical activity, mobility, and sleep are derived from limb devices using a custom analytics pipeline (NiMBalWear) validated for use with older adults (Beyer et al. 2024). In this analysis, group level data from 61 participants (42% SuperAgers, 60% female, mean age 85±4.8 years) were compared using independent t-tests (α=0.05). Overall, device wear compliance has been high (>90%) and data loss limited. Across all 61 participants, median (SD) sedentary time was 684 (93) min/day, moderate-to-vigorous physical activity (MVPA) time was 24.5 (29.0) min/day, step count was 8,232 (4,021) steps/day, sleep duration was 6.94 (1.05) hr/day, and sleep efficiency was 0.83 (0.09). There were no significant differences in group median or median SD between SuperAger and Control participants (Table 1). Notably, there was a high degree of variability in both groups, consistent with our study of young-older adults with and without neurodegeneration (under review). Day-to-day variability often exceeded between-participant variability. Range of within-participant variability (SD) was 19-170 min/day for sedentary time, 1-58 min/day for MVPA time, 673-5,860 steps/day for step count, 0.3–1.9 hr/day for sleep duration, and 2-16% for sleep efficiency. Objective capture of health-related behaviours in 80+ year olds has been rare but is important, highlighted by the variability observed among study participants. While results should be interpreted cautiously, volumetric measures of behavior do not appear to differentiate SuperAgers from Controls. This underscores the necessity for further investigation into the structure and relationship of behavioural patterns using more advanced measures of variability (e.g. ApEN, LZC, Gini index), which are underway for this unique dataset.

Polyunsaturated fatty acids are metabolized by cytochrome P450 (CYP450) into anti-inflammatory, pro-resolving epoxides, which are rapidly converted to inactive and cytotoxic diols by soluble epoxide hydrolase (sEH). Increased CYP450-sEH metabolites are associated with worse cognition in type 2 diabetes mellitus (T2DM), and greater white matter hyperintensities (WMH) in patients with stroke. We examined whether the relationship between linoleic acid (LA)-derived CYP450-sEH metabolites (oxylipins) and small vessel disease (SVD) markers differ across diabetes status. Cognitively impaired patients with neurodegenerative/ vascular cognitive disorders from the Ontario Neurodegenerative Disease Research Initiative ( https://braininstitute.ca/ondri ) were classified as having normoglycemia, prediabetes, or T2DM based on a self-report of diabetes diagnosis, glycated hemoglobin (HbA1c), and antidiabetic medication use. Unesterified plasma oxylipins were quantified via ultra-high-performance liquid chromatography tandem mass spectrometry, from which diol to epoxide ratios, a proxy of sEH activity, were calculated. SVD markers included WMH, perivascular spaces (PVS), and lacunes (LACN) quantified through T1- and T2-weighted structural MRI. Linear regression models controlling for age, sex, BMI, intracranial volume, hypertension, APOE-ε4 status, HDL, HbA1c, neurodegenerative diagnoses, and antidiabetic medication use, were used. Among 493 participants, 238 normoglycemic (48.4% female, age = 67.6±8.5 years), 161 prediabetes (35.4% female, age = 69.8±6.8 years), and 94 T2DM participants (20.2% female, age = 69.5±7.2 years) were identified. In the whole group, increased 9,10-LA ratio was associated with greater PVS (β = 0.097, p = 0.030), but not WMH or LACN. No association was observed with the 12,13-LA ratio. Significant interaction with HbA1c predicting WMH was observed with the 9,10-LA ratio (β = 0.530, p = 0.020), and similar effect size was seen with the 12,13-LA ratio (β = 0.482, p = 0.069). Subgroup analyses revealed a positive association in T2DM only (9,10-LA: β = 0.313, p = 0.001; 12,13-LA: β = 0.226, p = 0.020). No interaction effects with HbA1c predicting PVS or LACN were observed. In the normoglycemic subgroup, the 12,13-LA ratio was negatively associated with LACN (β = -0.121, p = 0.025), whereas in T2DM, a positive association was observed (β = 0.213, p = 0.039). Similarly with the 9,10-LA ratio, in the normoglycemic subgroup, a non-significant negative association was observed (β = -0.100, p = 0.071), whereas in T2DM, a positive association was observed (β = 0.225, p = 0.032). Diabetes status affects the association between LA-derived oxylipins and SVD markers. sEH may be a potential therapeutic target in T2DM to reduce neurovascular damage and subsequent cognitive decline.

Background Apathy in patients with Alzheimer's disease (AD) is associated with significant morbidity and is often one of the first neuropsychiatric symptoms to present in mild cognitive impairment (MCI). Apathy is associated with accelerated cognitive decline and atrophy in fronto-striatal regions of the brain. Previous work has shown a link between apathy and the APOE gene in the context of AD, as the APOE epsilon 4 allele is already known to be associated with the onset of AD. However, other genetic associations with apathy are largely unexplored. Objective To examine whether interactions between genetic variants related to neurotransmitter systems and regional brain atrophy are associated with apathy in patients with MCI and AD. Methods In a sample of individuals with AD (n = 266), MCI (n = 518), and cognitively normal controls (n = 378), a partial least squares correspondence analysis modeled interactions between single nucleotide polymorphisms, structural whole-brain imaging variables, and apathy. Results An interaction was found between apathy, the possession of an APOE epsilon 4 allele combined with minor homozygosity for the DAT1 (dopamine transporter 1) gene, and regional brain atrophy. This interaction was closely linked to the MCI and AD groups. Conclusions The results point to an association of a dopaminergic genetic marker and apathy in the AD continuum and may inform future design of clinical trials of apathy, as well as new treatment targets.

The multisite SuperAging Research Initiative (SRI) was established in 2021 to identify resilience and resistance factors promoting cognitive healthspan through a harmonized multidisciplinary protocol with prospective data collection. The designation of SuperAger is reserved for individuals age 80+ with episodic memory performance that is at least average for those 2-3 decades younger. Research studies of this relatively uncommon phenotype allow for investigations of fundamental importance to the neurobiology of brain aging, resilience, resistance, and avoidance of cognitive decline related to “average aging” and more severe impairments associated with Alzheimer’s and related dementias (ADRD). The SRI is focused on increasing participant diversity and deep phenotyping through the enrollment of 500+ participants into a multi-component longitudinal protocol. This presentation will summarize the engagement, recruitment, and baseline characteristics as well as the initial scientific findings from the cohort. Enrollment and harmonized data collection occurs across North American sites in the U.S. and Canada. The SRI includes three Cores (Administrative/Biostatistics, Clinical/Imaging, and Biospecimen/Neuropathology) and two Research Projects. The Core infrastructure provides behavioral, health, genetic, environmental, socioeconomic, psychosocial, neuropsychologic, neuroimaging, and neuropathologic measurements. Project 1 uses state-of-the-art wearable technology to obtain quantitative measurements of daily life (e.g., sleep, physical activity, and social engagement) to determine whether SuperAgers have relatively preserved physiologic and behavioral ‘complexity’. Project 2 uses transcriptomic, genetic, and protein profiling to examine central and peripheral immune and inflammatory system parameters. Community-engaged research practices have been implemented, yielding enrollment of >170 participants (ages 80-108) into the multicomponent harmonized protocol. Approximately half of the participants have been co-enrolled into Project 1 and the majority have provided biospecimens for Project 2. Additional engagement and recruitment strategies are being deployed and evaluated for efficacy to promote increased enrollment of diverse participants. The multidisciplinary study of 80+ year-olds with exceptional memory including imaging, blood draw, and unsupervised remote data collection using wearable technologies is feasible. The prospective study of SuperAgers is uncommon but holds promise for identifying mechanisms of resilience and resistance. Outcomes have potential relevance for isolating modifiable factors for promoting healthspan and avoiding ADRD.

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.

Background No treatments exist for apathy in people with frontotemporal dementia. Previously, in a randomised double-blind, placebo-controlled, dose-finding study, intranasal oxytocin administration in people with frontotemporal dementia improved apathy ratings on the Neuropsychiatric Inventory over 1 week and, in a randomised, doubleblind, placebo-controlled, crossover study, a single dose of 72 IU oxytocin increased blood-oxygen-level-dependent signal in limbic brain regions. We aimed to determine whether longer treatment with oxytocin improves apathy in people with frontotemporal dementia. Methods We conducted a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b trial, enrolling participants from 11 expert frontotemporal dementia outpatient clinics across Canada and the USA. People aged 30-80 years with a diagnosis of probable frontotemporal dementia, a Neuropsychiatric Inventory apathy score of 2 or higher, a study partner who interacted with them for at least 3 h per day, and stable cognitive and behavioural medications for 30 days were eligible for inclusion. In stage 1, participants were randomly assigned (1:1:1:1:1:1) to one of three dose schedules (every day, every other day, and every third day) of 72 IU intranasal oxytocin or placebo and to the order they would received the intervention in the crossover; intranasal oxytocin or placebo were administered twice daily for 6 weeks, with a 6-week washout and then crossover to the other intervention. In stage 2, new participants were randomised (1:1) to the dose that had been determined as optimal in stage 1 or to placebo, with crossover as in stage 1. Randomisation used variable block sizes and was stratified by participant sex and Clinical Dementia Rating severity score. All kits of investigational product were identical and produced centrally, and all local teams, study staff, and participants were masked to treatment allocation and order. The primary outcome was difference in the change in Neuropsychiatric Inventory apathy scores for oxytocin versus placebo periods in the per- protocol population after 6 weeks of treatment. Safety was assessed at each visit via electrocardiogram, blood work, and collection of data on adverse events. This trial is registered at ClinicalTrials.gov (NCT03260920). Findings Between Jan 31, 2018, and Dec 11, 2020, 70 patients were screened for stage 1 and 60 (86%) were enrolled. 45 (75%) completed both treatment periods of stage 1. 72 IU oxytocin every third day was the optimal dose schedule from stage 1 based on its Bayesian posterior probability (Pr(Best)=0478). Between June 28, 2021, and Jan 31, 2023, 42 patients were screened for stage 2, and 34 (81%) were enrolled. 28 (82%) completed both treatment periods in stage 2. 38 (40%) of 94 participants were female and 56 (60%) were male (mean age 659 years, SD 82) Treatment with oxytocin every third day resulted in an improved Neuropsychiatric Inventory apathy score, with an estimated -132 points (95% CI -243 to -021) relative to placebo (one sided p=0010). Two adverse events were reported in at least 5% of participants: upper respiratory tract infection (five [6%] of 78 participants on placebo and three [5%] on every third day at all doses of oxytocin) and headache (two [3%] participants on placebo, one [7%] of 15 participants on oxytocin every day, and two [4%] of 55 participants on oxytocin every third day). No adverse events were attributed to oxytocin treatment. Interpretation Intranasal oxytocin given every third day was well tolerated and was associated with a small reduction in apathy in patients with frontotemporal dementia. Future trials might investigate intermittent dosing of more potent formulations than in this study, to establish whether larger effects are possible. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

SuperAgers—individuals aged 80 and older who perform episodic memory tasks at least as well as those 20 to 30 years younger—provide valuable insights into cognitive resilience and resistance to neurodegeneration. The SuperAging Research Initiative (SRI), led by researchers at the University of Chicago, aims to advance research on SuperAgers, particularly emphasizing increasing Black representation in aging studies. In 2022, the SRI established its first Canadian site at Western University in partnership with the University of Waterloo and Sunnybrook Research Institute, capitalizing on the province's historical significance in Black migration to Canada alongside Western's leadership in aging research. This presentation will outline a strategic university-community partnership for recruiting and retaining SRI participants in Canada. In 2023, we commenced recruiting and enrolling a targeted sample of 100 Canadian SuperAgers and controls. Western University is the lead enrollment site. In collaboration with community partners, Western Media/Communications teams, the SRI sites, and SuperAging participants, we developed a multifaceted community-engaged research (CER) strategy and branding campaign tailored to the Canadian consortium. We facilitated 16 media appearances and organized five community events. We trained SRI participant volunteers to serve as ambassadors, engaging with organizations, hosting information sessions, and co-designing marketing materials. Through this campaign, thirteen new strategic partnerships emerged with faith communities, political and community leaders, social clubs, historical societies, medical practices, libraries, and community centers. CER efforts attracted interest from 121 age-eligible individuals, with 55 completing at least one baseline visit, exceeding our 50% enrollment target, with 0% attrition of eligible participants at two-year follow-up. Half of the study enrollments are directly attributed to SRI ambassador activities. Highlighting the persistence required to establish community partnerships, the first Black participant enrolled twenty months after site approvals. These findings underscore the effectiveness of a multifaceted strategy for recruiting healthy octogenarians and nonagenarians. They also emphasize the importance of involving community partners and peer ambassadors in recruitment and retention efforts. Importantly, our experiences highlight the time and significant resources necessary to cultivate and maintain partnerships and community trust for the successful engagement of individuals 80 and older in research, particularly those from diverse communities.