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In a randomized trial, solanezumab, a humanized monoclonal antibody against soluble amyloid, did not slow cognitive decline over a period of 80 weeks in patients with mild Alzheimer’s disease and with PET or CSF biomarkers of amyloid-related disease.

PET imaging plays a critical role in the diagnosis and follow-up of Alzheimer's disease (AD). However, current methods face significant limitations for two key measures: (1) Non-displaceable binding potential (BP ) of amyloid-beta (Aβ), which measures Aβ plaque accumulation but requires prolonged >100 min study times; (2) Cerebral blood flow (CBF), an indicator of neurodegeneration which typically requires an additional, separate study. To address these challenges, we developed a novel processing workflow which calculates absolute CBF from standard dynamic Aβ PET scans using our lab's flow-modified 2-tissue compartment model (F2TCM, EJNMMI Res.11:2), and estimates BP from a 20-min dynamic scan post-injection through multiple-fold cross-linear calibration. Data from 10 patients enrolled in the ongoing BioMind clinical trial data at our institution were used. Each dataset included a 45 min dynamic scan after injection of 300 MBq of 18F-florbetaban and a 10 min scan at 110 min post-injection, acquired with a GE Healthcare OMNI Legend PET/CT scanner. Images were reconstructed using the Q. Clear protocol for higher resolution arterial input function measurements, and the smoother VPHD protocol to improve signal-to-noise for CBF estimation. CBF was calculated using the F2TCM, BP using Logan graphical analysis relative to the cerebellum, and centiloid scores and SUVr were obtained with MIMneuro (MIM Software Inc.). Figure 1 shows the similarities/differences of CBF maps derived from 3-, 20- and 45-min dynamic scans for three patients with 18F-florbetaben centiloids (SUVr) of 11.1 (1.03), 68.1 (1.38), and 164.4 (1.98), respectively. Voxel-wise comparisons of CBF of all 10 patients showed mean MSE of 18±11 and 156±110 mL/min/100g for 20 and 3 min relative to 45 min, respectively. Figure 2 shows BP maps for a 45 min scan, followed by uncalibrated and calibrated 20 min scans. Calibration slopes, intercepts, uncalibrated and calibrated MSEs were 0.95±0.03, 0.08±0.01, 0.012±0.0044 and 0.0070±0.0013, respectively, based on five-fold cross calibration. This study highlights the potential of a streamlined 20-minute Aβ PET imaging protocol to measure BP as a surrogate for the centiloid score, while also providing complementary CBF measurements to enhance diagnostic and prognostic utility.

Reductions in cerebral blood flow are associated with Alzheimer's Disease pathological changes and represent a potential therapeutic target. Measuring changes in middle cerebral artery velocity (MCAv) using transcranial Doppler ultrasound measurement of acute changes in MCAv during dynamic maneuvers and uncover relationships with cerebral autoregulation. We tested the hypothesis that changes in cerebral autoregulation are associated with clinical change in patients with mild cognitive impairment. Thirty MCI participants completed a supine-to-stand transition with beat-to-beat MCAv and mean arterial pressure (MAP) collected. Ten patients were cognitively intact and provided control measures. A 30-second supine and standing average were calculated and a standing-induced nadir average of the lowest 3-beats. Dynamic cerebral autoregulation (dCA) was calculated as (MCAv -MCAv /MCAv )/(MAP -MAP /MAP ). K-means clustering was used to split MCI participants into higher-standing-velocity (n = 9) and lower-standing-velocity (n = 21) groups. A one-way analysis of variance was employed to determine group differences for MoCA scores and dCA. A two-way repeated measures ANOVA assessed group by position (supine, nadir, standing) effects for cardiorespiratory and cerebrovascular indices. Significance was set to p <0.05. MoCA scores were significantly higher in controls and the higher-standing-velocity groups compared to the lower-standing-velocity group (Figure 2). dCA was enhanced in the lower-standing-velocity group compared to the higher-standing-velocity group (Figure 2) with an inverse relationship between dCA and standing MCAv at diastole. Interactions were observed for the resistance index, cerebrovascular resistance index, and MCAv at diastole (p = 0.045, 0.008, and, 0.004 respectively). Effects of position were observed for all cardiopulmonary and cerebrovascular metrics other than MCAv at systole. This is the first study investigating a supine-to-standing induced dCA response within a cohort of people with MCI. Contrary to our hypothesis, an enhanced dCA was observed in the higher-standing-velocity group compared to the lower-standing-velocity group despite the higher-standing-velocity group having greater cognitive scores. Interestingly, the higher-standing-velocity group with MCI and controls had similar MoCA scores and dCA. An enhanced dCA may be a compensatory mechanism in the neurodegenerative disease processes. The unexpected results highlight the importance of uncovering hemodynamic pathways in clinical populations and identifying the adaptions made to preserve cognitive function in the face of dementia.

Previous studies have demonstrated altered brain activity in Alzheimer's disease using task based functional MRI (fMRI), network based resting-state fMRI, and glucose metabolism from 18F fluorodeoxyglucose-PET (FDG-PET). Our goal was to define a novel indicator of neuronal activity based on a first-order textural feature of the resting state functional MRI (RS-fMRI) signal. Furthermore, we examined the association between this neuronal activity metric and glucose metabolism from 18F FDG-PET. We studied 15 normal elderly controls (NEC) and 15 probable Alzheimer disease (AD) subjects from the AD Neuroimaging Initiative. An independent component analysis was applied to the RS-fMRI, followed by template matching to identify neuronal components (NC). A regional brain activity measurement was constructed based on the variation of the RS-fMRI signal of these NC. The standardized glucose uptake values of several brain regions relative to the cerebellum (SUVR) were measured from partial volume corrected FDG-PET images. Comparing the AD and NEC groups, the mean brain activity metric was significantly lower in the accumbens, while the glucose SUVR was significantly lower in the amygdala and hippocampus. The RS-fMRI brain activity metric was positively correlated with cognitive measures and amyloid β1-42 cerebral spinal fluid levels; however, these did not remain significant following Bonferroni correction. There was a significant linear correlation between the brain activity metric and the glucose SUVR measurements. This proof of concept study demonstrates that this novel and easy to implement RS-fMRI brain activity metric can differentiate a group of healthy elderly controls from a group of people with AD.

Background There is a projected and growing gap of geriatricians in Canada. Geriatricians play a crucial role in addressing the health needs of older adults. We aimed to understand the factors that influence the choice of first-practice location for new geriatricians in the context of an aging Canadian population. Methods We distributed an online survey to geriatric medicine subspecialty residents and recently licensed geriatricians in Canada. The survey was developed through expert opinions, career planning sessions, and a literature review. There were nine survey sections: general characteristics, location determinants, practice determinants, colleague determinants, support and space, non-clinical opportunities, income models, lifestyle factors, and recruitment determinants. The data were analyzed descriptively. Results A total of 61 respondents (51 English, 10 French) completed the survey. The respondents were new practicing geriatricians (37) and geriatric medicine residents (24). Most planned to practice in Ontario (26.2%) or Quebec (27.9%), and 75.4% were women. Flexibility in work-life balance (95.1%), collegiality (93.4%) and reasonable call schedules (93.4%) were the most important factors influencing first practice location. Income did not rank among the highest priorities for choosing the first practice location relative to other factors but was mentioned in open-ended responses to recruitment questions. Conclusions This is the first survey identifying the determinants of first practice location in geriatric medicine in Canada. Work-life balance and collegial support are a priority for new geriatricians and may be the strongest incentives a program can provide. For recruitment, income incentives may be beneficial to building new specialized geriatric services. Future research will examine determinants of first practice location among Care of the Elderly clinicians.

Évaluation complète d’une étude de cohorte canadienne portant sur la démence et la neuro-dégénérescence. Contexte : L’évaluation globale de la neuro-dégénérescence et de la démence (COMPASS-ND), étude de cohorte du Consortium canadien en neuro-dégénérescence associée au vieillissement (CCNV), représente une initiative nationale visant à promouvoir la recherche portant sur la démence et à soutenir les programmes de recherche des équipes du CCNV. Totalisant 2310 sujets recrutés partout au pays, cette cohorte longitudinale regroupe des individus fortement « phénotypés » qui présentent diverses formes de démence et de pertes de mémoire légères. En plus de sujets âgés dont les fonctions cognitives sont intactes, ces 2310 sujets ont permis de valider les hypothèses formulées par les équipes du CCNV. Méthodes : Nous avons utilisé de nombreux documents pour décrire cette étude : le protocole de la COMPASS-ND ; la demande initiale de subvention ; le cinquième rapport d’étape semi-annuel du CCNV soumis aux Instituts de recherche en santé du Canada (IRSC) en décembre 2017 ; ainsi que d’autres documents produits à la suite de modifications consécutives à la mise en œuvre de ce projet. Résultats : L’étude de cohorte COMPASS-ND du CCNV inclut des participants de partout au Canada dont les divers états cognitifs sont associés à des maladies neurodégénératives ou au risque d’en souffrir. Ils feront l’objet d’un large éventail d’examens expérimentaux, cliniques, génétiques et d’imagerie afin d’aborder de manière spécifique les causes, le diagnostic, le traitement et la prévention de ces états cognitifs chez les personnes âgées. Les données obtenues à la suite d’évaluations cliniques et cognitives, ainsi que celles issues d’échantillons biologiques, d’imagerie cérébrale, de tests génétiques et de dons de cerveaux, seront utilisées pour tester les hypothèses générées par les équipes de recherche du CCNV et d’autres chercheurs canadiens. Cette étude constitue donc à ce jour l’étude canadienne la plus complète et la plus ambitieuse au sujet de la démence. La présentation des données initiales ayant eu lieu en 2018, la cohorte devrait atteindre sa taille maximale d’ici à 2020.Conclusion : La disponibilité des données de l’étude COMPASS-ND stimulera considérablement la recherche sur la démence au Canada au cours des prochaines années.

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/m 2 ), 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.

The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) used wide inclusion criteria recruiting participants across the spectrum from normal cognition to cognitive impairment to all types of clinical dementia, including mixed dementia. 1173 participants comprising 11 diagnostic cohorts, completed screening, clinical, neuropsychology, sensory and motor assessments, magnetic resonance imaging (MRI) and provided biomarker bio-samples. Recruitment was from advertising and specialty clinics for neurocognitive disorders and/or memory impairment. Robust data monitoring and cleaning occurred on the baseline and Time 2 data. Genetic, MRI, Cerebrospinal Fluid (CSF) and the majority of blood biomarkers analyses have been completed. Data releases uploaded to the Longitudinal Online Research and Imaging System (LORIS) include alpha numeric baseline data, neuroimaging analyses, CSF, genetic and blood biomarkers. 40 autopsies have been completed. 119 data access requests have been submitted to the Data Access Subcommittee. All returning participants will repeat Time 3 extensive clinical and neuropsychology assessments, MRI and provide bio-samples. Phase III new recruitment will include 400 diverse participants, with up to Grade 12 education, who are not cognitively impaired, or who have cognitive impairment, but not dementia. The balance of each cohort for sex/gender will be a consideration. COMPASS-ND fills a knowledge gap by recruiting participants representing the full spectrum of neurodegeneration. This distinguishes COMPASS-ND from other large-scale studies. Challenges and strategies for engagement and research site level funding will be discussed. Data are available to registered researchers and trainees in Canada and around the world through data access requests.

Recruiting persons with dementia for clinical trials can be challenging. Building on a guide initially developed to assist primary-care-based memory clinics in their efforts to support research, a key stakeholder working group meeting was held to develop a standardized research recruitment process, with input from patients, care partners, researchers, and clinicians. Discussions in this half-day facilitated meeting focused on the wishes and needs of patients and care partners, policy and procedures for researchers, information provided to patients, and considerations for memory clinics. Patients and care partners valued the opportunity to contribute to science and provided important insights on how to best facilitate recruitment. Discussions regarding proposed processes and procedures for research recruitment highlighted the need for a new, patient-driven approach. Accordingly, a key stakeholder co-designed “Memory Clinic Research Match” program was developed that has the potential to overcome existing barriers and to increase recruitment for dementia-related research. Il peut être difficile de recruter des personnes vivant avec un trouble neurocognitif pour des essais cliniques. Un groupe d’intervenants clés s’est réuni pour mettre au point un processus standardisé de recrutement pour la recherche à partir d’un guide initialement conçu pour soutenir les efforts des cliniques de la mémoire établies en milieu de soins primaires pour promouvoir la recherche. Le processus prévoit la participation des patients, des proches aidants, des chercheurs et des cliniciens. Au cours de cette rencontre d’une demi-journée, les discussions ont porté sur les désirs et les besoins des patients et des proches aidants, les politiques et procédures auxquelles les chercheurs doivent se conformer, l’information fournie aux patients et les implications pour les cliniques de la mémoire. Les patients et les proches aidants ont apprécié cette occasion de contribuer à la science et ont fourni d’importants éclairages sur la meilleure façon de faciliter le recrutement. Les discussions concernant les processus et procédures de recrutement pour la recherche ont fait ressortir la nécessité d’une nouvelle approche axée sur les patients. En conséquence, les intervenants clés ont conçu un programme de recrutement pour la recherche dans les cliniques de la mémoire (« Memory Clinic Research Match ») qui vise à surmonter les obstacles actuels et à accroître le recrutement pour la recherche relative aux troubles neurocognitifs.

This study aims to develop and validate a Bayesian risk prediction model that combines research cohort data with elicited expert knowledge to predict dementia progression in people with mild cognitive impairment (MCI). This is a prognostic risk prediction modeling study based on cohort data (Alzheimer's disease neuroimaging initiative [ADNI]; n = 365) of research participants with MCI and elicited expert data. Bayesian Cox models were used to combine expert knowledge and ADNI data to predict dementia progression in people with MCI. Posterior distributions were obtained based on Gibbs sampler and the predictive performance was evaluated using ten-fold cross-validation via c-index, integrated calibration index (ICI), and integrated brier score (IBS). 365 people with MCI were included, mean age was 73 years (SD = 7.5), and 39% developed dementia within 3 years. When expert knowledge was incorporated, the c-index, ICI, and IBS values were 0.74 (95% CI 0.70-0.79), 0.06 (95% CI 0.05-0.08), and 0.17 (95% CI 0.14-0.19), respectively. These were similar to the model without expert knowledge data. The addition of expert knowledge did not improve model accuracy in this ADNI sample to predict dementia progression in individuals with MCI.