Lanctôt, Krista L.

The Canadian Consortium on Neurodegeneration in Aging (CCNA) was created by the Canadian federal government through its health research funding agency, the Canadian Institutes for Health Research (CIHR), in 2014, as a response to the G7 initiative to fight dementia. Two five-year funding cycles (2014–2019; 2019–2024) have occurred following peer review, and a third cycle (Phase 3) has just begun. A unique construct was mandated, consisting of 20 national teams in Phase I and 19 teams in Phase II (with research topics spanning from basic to clinical science to health resource systems) along with cross-cutting programs to support them. Responding to the needs of researchers within the CCNA teams, a unique sample of 1173 deeply phenotyped patients with various forms of dementia was accrued and studied over eight years (COMPASS-ND). In the second phase of funding (2019–2024), a national dementia prevention program (CAN-THUMBS UP) was set up. In a short time, this prevention program became a member of the World Wide FINGERS prevention consortium. In this article, the challenges, successes, and impacts of CCNA in Canada and internationally are discussed. Short-term deliverables have occurred, along with considerable promise of impacts in the longer term. The creation of synergy, networking, capacity building, engagement of people with lived experience, and economies of scale have contributed to the considerable success of CCNA by all measures. CCNA is evidence that an organized “centrally-organized” approach to dementia research can catalyze important progress nationally and yield significant and measurable results.

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.

Background: Psychotic symptoms are common in Alzheimer’s disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders, 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders.

Background: Exercise prevents recurrent cardiovascular events and it may combat cognitive decline in coronary artery disease (CAD); however, evidence in type 2 diabetes (T2DM) has been mixed. T2DM and memory decline have been associated with differences in the plasma sphingolipidome. Objective: Here, we will investigate whether T2DM-related sphingolipids predict less memory improvement over an exercise intervention for CAD. Methods: Among participants with CAD entering a 6-month exercise intervention, we matched 20 with T2DM to 40 without T2DM for age, sex, and body mass index. We assessed 45 sphingolipid species using high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometry with multiple reaction monitoring. We assessed memory using the California Verbal Learning Test, 2nd Ed, and the revised Brief Visuospatial Learning Test. Results: Partial least squares discriminant analysis identified 8 species that distinguished T2DM from non-T2DM groups with 83% (95% confidence interval [70%, 95%]) accuracy in a receiver operator characteristic curve (validated by internal resampling, 1000 permutations, p = 0.01). At baseline, T2DM-associated sphingolipids (ceramide C22 : 0, monohexylceramide C16 : 1, and lactosylceramide C24 : 0) were associated with poorer memory, attention, and psychomotor processing speed performance. Among 50 completers, an indirect effect of T2DM on less improvement in verbal memory was mediated by monohexylceramide C16 : 1 (0.86 fewer words recalled, 95% bootstrap confidence interval [–2.32, –0.24]), and an indirect effect of T2DM on less visuospatial memory improvement was mediated by ceramide C22 : 0 concentrations (0.42 fewer points, 95% bootstrap confidence interval [–1.17, –0.05]). Conclusions: Ceramide species associated with T2DM predicted poorer cognitive responses to exercise in patients with CAD.

Abstract Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART ) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross‐PIA white paper that provides both a concise “state‐of‐the‐science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

Abstract The long-term benefits conferred by cardiac rehabilitation (CR) in those with coronary artery disease (CAD) are strongly linked with an improvement in cardiopulmonary fitness. This study aimed to determine the association between peripheral sphingolipids and cardiopulmonary fitness in CAD subjects undertaking CR. Patients with CAD (n = 100, mean age = 64 ± 6 years, 85% male, mean years of education = 17 ± 3 years) underwent 6 months of CR with blood collected at baseline, 3 and 6 months. Cardiopulmonary fitness was assessed by measuring peak oxygen uptake (VO2peak) at all time points. High performance liquid chromatography coupled electrospray ionization tandem mass spectrometry was used to quantify plasma sphingolipid concentrations. Cross-sectional and longitudinal associations between sphingolipids and VO2peak were assessed using linear regressions and mixed models, respectively. Higher concentrations of sphingomyelin C18:1 (β = −0.26, p = .01), ceramides C16:0 (β = −0.24, p = .02), C18:0 (β = −0.29, p = .002), C20:0 (β = −0.24, p = .02) and C24:1 (β = −0.24, p = .01) and monohexylceramide C18:0 (β = −0.23, p = .02) were associated with poorer VO2peak at baseline. An improvement in VO2peak was associated with a decrease in sphingomyelin C18:1 (b = −10.09, p = .006), ceramides C16:0 (b = −9.25, p = .0003), C18:0 (b = −5.44, p = .0003) and C24:1 (b = −2.46, p = .006) and monohexylceramide C18:0 (b = −5.37, p = .005). Specific long chain sphingolipids may be useful markers of fitness and response to exercise in CAD.

Background: Biomarkers in cognitively vulnerable populations, like those with coronary artery disease (CAD), may inform earlier intervention in vascular neurodegeneration. Circulating ceramide C18:0 (CerC18:0) is associated with changes in verbal memory in early neurodegeneration and CAD progression. Objective: To investigate whether plasma CerC18:0 accumulation is associated with longitudinal declines in verbal memory performance in CAD. Methods: In addition to total CerC18:0, we assessed its relative abundance to its precursors as ratios: CerC18:0 to monohexosylceramide C18:0 (MHxCer18:0), CerC18:0 to sphingomyelin C18:0 (SM18:0), and CerC18:0 to sphingosine-1-phosphate (S1P). Verbal memory was assessed using the California Verbal Learning Test 2 nd Ed. Using mixed models in 60 CAD participants, we evaluated associations between baseline CerC18:0 ratios and changes in verbal memory performance, adjusting for age, body mass index, and education. Given that cognitive decline is more rapid following onset of deficits, these associations were compared between those with possible mild vascular neurocognitive disorder (MVND). Results: Increased baseline CerC18:0 concentrations correlated with worse verbal memory performance over time (b[SE] = – 0.91[0.30], p = 0.003). Increased baseline CerC18:0/SM18:0 ( b[SE] = – 1.11[`], p = 0.03) were associated with worse verbal memory performance over time. These associations were not mediated by whether or not patients had possible MVND at baseline. Conclusion: These findings support aberrant CerC18:0 metabolism as an early neurobiological change in vascular neurodegeneration. Future studies should measure enzymes responsible for conversion of sphingolipid precursors into CerC18:0 to assess enzymatic activity.

AbstractBackgroundDepression is highly prevalent in individuals with coronary artery disease (CAD) and increases the risk of future cardiac events and mortality. Sphingolipids have been implicated in the pathophysiology of both CAD and depression. This study assessed the association between plasma sphingolipid concentrations and depressive symptoms in CAD subjects.MethodsDepressive symptoms were measured using the depression subscale of the self‐reported Hospital Anxiety and Depression Scale (HADS). Sphingolipid concentrations were measured from fasting plasma samples using high‐performance liquid chromatography‐coupled electrospray ionization tandem mass spectrometry (LC/MS/MS). Linear regression models were used to assess associations between log‐transformed concentrations of plasma sphingolipids and depressive symptoms.ResultsA total of 111 CAD patients (mean (SD) age = 63.6 ± 6.4, 84.7% male) were included. In linear regression analyses, higher plasma concentrations of ceramides C16:0 (β = 0.204, p = .026) and C18:0 (β = 0.209, p = .023) and sphingomyelin SM18:1 (β = 0.210, p = .024) were significantly associated with higher HADS depression subscale score after adjusting for covariates.ConclusionSphingolipids, in particular the ceramide species C16:0 and C18:0 and the sphingomyelin species SM18:1, may be implicated in the pathophysiology of depression in CAD. The association between plasma sphingolipid concentrations and depression should be further examined in CAD patients and in other populations.