Generating real-world evidence in Alzheimer's disease: Considerations for establishing a core dataset.

Ongoing assessment of patients with Alzheimer's disease (AD) in postapproval studies is important for mapping disease progression and evaluating real-world treatment effectiveness and safety. However, interpreting outcomes in the real world is challenging owing to variation in data collected across centers and specialties and greater heterogeneity of patients compared with trial participants. Here, we share considerations for observational postapproval studies designed to collect harmonized longitudinal data from individuals with mild cognitive impairment or mild dementia stage of disease who receive therapies targeting the underlying pathological processes of AD in routine practice. This paper considers key study design parameters, including proposed aims and objectives, study populations, approaches to data collection, and measures of cognition, functional abilities, neuropsychiatric status, quality of life, health economics, safety, and drug utilization. Postapproval studies that capture these considerations will be important to provide standardized data on AD treatment effectiveness and safety in real-world settings.

Distinct spatial contributions of amyloid pathology and cerebral small vessel disease to hippocampal morphology.

INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aß) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aß, as assessed by 18F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aß were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aß. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aß-vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aß pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.

Protocol for validating an algorithm to identify neurocognitive disorders in Canadian Longitudinal Study on Aging participants: an observational study.

INTRODUCTION: In population-based research, disease ascertainment algorithms can be as accurate as, and less costly than, performing supplementary clinical examinations on selected participants to confirm a diagnosis of a neurocognitive disorder (NCD), but they require cohort-specific validation. To optimise the use of the Canadian Longitudinal Study on Aging (CLSA) to understand the epidemiology and burden of NCDs, the CLSA Memory Study will validate an NCD ascertainment algorithm to identify CLSA participants with these disorders using routinely acquired study data. METHODS AND ANALYSIS: Up to 600 CLSA participants with equal numbers of those likely to have no NCD, mild NCD or major NCD based on prior self-reported physician diagnosis of a memory problem or dementia, medication consumption (ie, cholinesterase inhibitors, memantine) and/or self-reported function will be recruited during the follow-up 3 CLSA evaluations (started August 2021). Participants will undergo an assessment by a study clinician who will also review an informant interview and make a preliminary determination of the presence or absence of an NCD. The clinical assessment and available CLSA data will be reviewed by a Central Review Panel who will make a final categorisation of participants as having (1) no NCD, (2) mild NCD or, (3) major NCD (according to fifth version of the Diagnostic and Statistical Manual of Mental Disorders criteria). These will be used as our gold standard diagnosis to determine if the NCD ascertainment algorithm accurately identifies CLSA participants with an NCD. Weighted Kappa statistics will be the primary measure of agreement. Sensitivity, specificity, the C-statistic and the phi coefficient will also be estimated. ETHICS AND DISSEMINATION: Ethics approval has been received from the institutional research ethics boards for each CLSA Data Collection Site (Université de Sherbrooke, Hamilton Integrated Research Ethics Board, Dalhousie University, Nova Scotia Health Research Ethics Board, University of Manitoba, McGill University, McGill University Health Centre Research Institute, Memorial University of Newfoundland, University of Victoria, Élisabeth Bruyère Research Institute of Ottawa, University of British Columbia, Island Health (Formerly the Vancouver Island Health Authority, Simon Fraser University, Calgary Conjoint Health Research Ethics Board).The results of this work will be disseminated to public health professionals, researchers, health professionals, administrators and policy-makers through journal publications, conference presentations, publicly available reports and presentations to stakeholder groups.

Relationships between neuropsychiatric symptoms and cognitive profiles in Alzheimer's disease and related syndromes.

OBJECTIVES: To investigate the rate of occurrence of neuropsychiatric symptoms (NPS) and their relationship with age, sex and cognitive performance in subjects with Alzheimer's disease and related dementias (Alzheimer's disease and related dementias [ADRD]). METHODS: This is a retrospective matched case-control study. Data from memory clinic patients included demographic information presence of NPS, and cognitive testing of Orientation, Immediate and Delayed Memory, Visuospatial Function, Working Memory, Attention, Executive Control and Language. Participants were Individuals with subjective cognitive impairment (n = 352), mild cognitive impairment (MCI) (n = 369), vascular MCI (n = 80), Alzheimer's disease (n = 147), vascular dementia (n = 41), mixed dementia (n = 33), and healthy controls (n = 305). Logistic regression was used to investigate the relationship between the presence of NPS, age and sex. A generalised additive model was used to investigate the relationship between presence of NPS, age and cognitive impairment. Analysis of variance was used to investigate differences in cognition between younger and older groups with and without NPS. RESULTS: We found an increased likelihood of occurrence of NPS in younger individuals and females across cohorts. Anxiety, depression, agitation, and apathy were associated with higher overall rate of NPS. We also found that individuals under 65 years of age with NPS had worse cognitive scores than their counterpart without NPS. CONCLUSION: The younger group with ADRD and NPS had lower cognitive scores, probably reflecting more aggressive neurodegenerative disease. Further work will be needed to elicit the degree to which imaging or mechanistic abnormalities distinguish this group.

Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease.

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aß-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aß-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aß-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aß-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aß-PET related more closely to higher cortical Aß (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aß-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

Genome screening, reporting, and genetic counseling for healthy populations.

Rapid advancements of genome sequencing (GS) technologies have enhanced our understanding of the relationship between genes and human disease. To incorporate genomic information into the practice of medicine, new processes for the analysis, reporting, and communication of GS data are needed. Blood samples were collected from adults with a PCR-confirmed SARS-CoV-2 (COVID-19) diagnosis (target N = 1500). GS was performed. Data were filtered and analyzed using custom pipelines and gene panels. We developed unique patient-facing materials, including an online intake survey, group counseling presentation, and consultation letters in addition to a comprehensive GS report. The final report includes results generated from GS data: (1) monogenic disease risks; (2) carrier status; (3) pharmacogenomic variants; (4) polygenic risk scores for common conditions; (5) HLA genotype; (6) genetic ancestry; (7) blood group; and, (8) COVID-19 viral lineage. Participants complete pre-test genetic counseling and confirm preferences for secondary findings before receiving results. Counseling and referrals are initiated for clinically significant findings. We developed a genetic counseling, reporting, and return of results framework that integrates GS information across multiple areas of human health, presenting possibilities for the clinical application of comprehensive GS data in healthy individuals.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Engaging People With Lived Experience of Dementia in Research: Perspectives From a Multi-disciplinary Research Network.

Background: Patient and public involvement/engagement in research on dementia is not new, but it is becoming increasingly common. The objective of this study was to describe researchers' knowledge, attitudes, and activities related to engaging people with lived experience of dementia in research, and how these differ by research theme. Methods: Data were from an online, anonymous survey of researchers within the Canadian Consortium on Neurodegeneration in Aging. Results: Of the 84 researchers who completed the survey (response rate: 27%), 89% agreed they understood the meaning of engaging people with lived experience in research, although this was lower among biomedical researchers. Almost all (93%) agreed that people with lived experience could contribute meaningfully to research, and nearly two-thirds were already incorporating engagement in their research. Some engagement practices reported differed by research theme. Irrespective of the type of research they conduct, researchers were most often motivated by improving the relevance and quality of their research. Conclusions: These findings support an optimistic outlook for engaging people with lived experience of dementia in research, but identify differences across research themes. Understanding approaches to incorporate, evaluate, and adapt engagement activities across research disciplines are needed to enable researchers, as well as others involved in research, to develop and target strategies for patient and public involvement/engagement in research on dementia.

Multidomain trials to prevent dementia: addressing methodological challenges.

BACKGROUND: Multidomain trials to prevent dementia by simultaneously targeting multiple risk factors with non-pharmacological lifestyle interventions show promise. Designing trials to evaluate the efficacy of individual interventions and their combinations is methodologically challenging. Determining the efficacy is, nevertheless, important to individuals, payers, and for resource allocations to support intervention implementation. MAIN BODY: The central rationale for seminal trials improving cardiovascular health or reducing falls risk in older adults is that multifactorial conditions may be amenable to improvement by simultaneously targeting multiple modifiable risk factors. Similar reasoning underlies lifestyle interventions to reduce dementia risk using combinations of physical exercise, cognitive training, diet, amelioration of vascular-metabolic risk factors, and improving sleep quality. Randomizing individuals with at least two modifiable risk factors to "standardly tailored" interventions to mitigate their risk factors, versus a comparator arm, will yield an unbiased estimate of the cumulative average effect of modifying more versus fewer risk factors. The between-group difference in the cognitive primary outcome will reflect both the main effects of the mitigated risk factors, as well as their synergistic effects. However, given the positive trial results, there are inherent challenges in quantifying post hoc which components, or combination of components, were responsible for improvements in cognition. Here, we elaborate on these methodological challenges and important considerations in using a standardly tailored design with two arms (one consisting of multidomain interventions tailored to participants' risk profiles and another consisting of active control conditions). We compare this approach to fully factorial designs and highlight the disadvantages and advantages of each. We discuss partial solutions, including analytical strategies such as risk reduction scores that measure reductions in the number or severity of risk factors in each study arm. Positive results can support the causal inference that between-group differences in the primary cognitive outcome were due to risk factor modification. CONCLUSION: Standardly tailored designs are pragmatic and feasible evaluations of multidomain interventions to reduce dementia risk. We propose sensitivity and exploratory analyses of between-group reductions in the severity of risk factors, as a methodology to bolster causal inferences that between-group differences in the primary cognitive outcome are due to the risk factors modified.

Making the Case for Accelerated Withdrawal of Aducanumab.

The controversial approval in June 2021 by the Food and Drug Administration (FDA) of aducanumab (marketed as Aduhelm), Biogen's monoclonal antibody for patients with Alzheimer's disease, raises significant concerns for the dementia field and drug approval process, considering its lack of adequate evidence for clinical efficacy, safety issues, and cost. On 15 December 2021, an international group of clinicians, basic science experts, psychological and social science researchers, lay people with lived experience of dementia, and advocates for public health met to discuss making a recommendation for whether aducanumab's approval should be withdrawn. Attendees considered arguments both in favor of and in opposition to withdrawal and voted unanimously to recommend that the FDA withdraw its approval for aducanumab and to support the Right Care Alliance's filing of a formal Citizen Petition to this effect.

The Oral and Fecal Microbiota in a Canadian Cohort of Alzheimer's Disease.

BACKGROUND: Despite decades of research, our understanding of Alzheimer's disease (AD) etiology remains incomplete. In recent years, appreciation has grown for potential roles for the microbiota in shaping neurological health. OBJECTIVE: This study aimed to examine associations between the microbiota and AD in a human cross-sectional cohort. METHODS: Forty-five AD patients and 54 matched controls were recruited in Vancouver, Canada. Fecal and oral samples underwent 16S microbiota sequencing. A wide array of demographic and clinical data were collected. Differences between participant groups were assessed, and associations between microbes and clinical variables were examined within the AD population. RESULTS: The gut microbiota of AD patients displayed lower diversity relative to controls, although taxonomic differences were sparse. In contrast, the AD oral microbiota displayed higher diversity, with several taxonomic differences relative to controls, including a lower abundance of the families Streptococcaceae and Actinomycetaceae, and a higher abundance of Weeksellaceae, among others. The periodontitis-associated oral microbe Porphyromonas gingivalis was 5 times more prevalent among patients. No significant associations between gut or oral microbes and cognition were detected, but several correlations existed between microbes and mood disorders and BMI among patients, including a strong positive correlation between Alphaproteobacteria and depression score. CONCLUSION: The gut microbiota of AD patients was not overtly different from controls, although it displayed lower diversity, an overall marker of microbiota health. The oral microbiota did display marked differences. Cognition was not associated with a microbial signature, but other relevant AD factors including mood and BMI did demonstrate an association.

Primary Progressive Aphasia Presenting With Neuropsychiatric Symptoms.

We describe a case of primary progressive aphasia (PPA) with an underlying neurodegenerative motor disorder (possible ALS or PSP), presenting with symptoms of irritability and frustration, that were misdiagnosed and treated as a primary psychiatric disorder, i.e. depression. PPA is a rare neurodegenerative disorder characterized by insidious onset and gradual progression of speech and language impairment. We emphasize that PPA can initially masquerade as or be accompanied by neuropsychiatric symptoms potentially leading to misdiagnosis. Most prevalent neuropsychiatric symptoms reported in the PPA literature are agitation, depression, anxiety, apathy, irritability, abnormal appetite and disinhibition. To ensure early diagnosis of PPA, if a patient presents with new psychiatric symptoms accompanied by new onset speech and/or language impairment, referral to a specialist (i.e., neurologist and/or speech-language pathologist) is recommended.

Evaluation of a Telephone Version for the Montreal Cognitive Assessment: Establishing a Cutoff for Normative Data From a Cross-Sectional Study.

OBJECTIVE: Compare a telephone version and full version of the Montreal Cognitive Assessment (MoCA). METHODS: Cross-sectional analysis of a prospective study. A 20-point telephone version of MoCA (Tele-MoCA) was compared to the Full-MoCA and Mini Mental State Examination. RESULTS: Total of 140 participants enrolled. Mean scores for language were significantly lower with Tele-MoCA than with Full-MoCA (P = .003). Mean Tele-MoCA scores were significantly higher for participants with over 12 years of education (P < .001). Cutoff score of 17 for the Tele-MoCA yielded good specificity (82.2%) and negative predictive value (84.4%), while sensitivity was low (18.2%). CONCLUSIONS: Remote screening of cognition with a 20-point Tele-MoCA is as specific for defining normal cognition as the Full-MoCA. This study shows that telephone evaluation is adequate for virtual cognitive screening. Our sample did not allow accurate assessment of sensitivity for Tele-MoCA in detecting MCI or dementia. Further studies with representative populations are needed to establish sensitivity.

Consensus Statement Regarding the Application of Biogen to Health Canada for Approval of Aducanumab.

Alzheimer's disease is a major cause of morbidity and mortality. Currently, there are no disease-modifying pharmacotherapies for this condition. Aducanumab, an amyloid beta-directed monoclonal antibody that targets aggregated forms of amyloid-beta in the brains of people with Alzheimer's disease, has raised hopes that such a therapy has been discovered, but its approval by the US Food and Drug Administration has engendered a good deal of controversy. A similar application for approval has been submitted to Health Canada. In response to this, a group of Canadian clinical dementia experts representing a number of organizations, including the Canadian Geriatrics Society, was convened by the Canadian Consortium on Neurodegeneration in Aging (CCNA) to discuss the evidence currently available on this agent and seek consensus on what advice they would offer Health Canada on the application. There was wide-spread agreement that it would be premature for aducanumab to receive approval for the treatment of Alzheimer's disease. It was also noted that the Canadian health-care system is poorly prepared at this time to deal with a disease-modifying therapeutic with targeting, administration, and monitoring characteristics like aducanumab. In this paper, the consensus reached is presented along with its underlying rationale.

Implementation of serological and molecular tools to inform COVID-19 patient management: protocol for the GENCOV prospective cohort study.

INTRODUCTION: There is considerable variability in symptoms and severity of COVID-19 among patients infected by the SARS-CoV-2 virus. Linking host and virus genome sequence information to antibody response and biological information may identify patient or viral characteristics associated with poor and favourable outcomes. This study aims to (1) identify characteristics of the antibody response that result in maintained immune response and better outcomes, (2) determine the impact of genetic differences on infection severity and immune response, (3) determine the impact of viral lineage on antibody response and patient outcomes and (4) evaluate patient-reported outcomes of receiving host genome, antibody and viral lineage results. METHODS AND ANALYSIS: A prospective, observational cohort study is being conducted among adult patients with COVID-19 in the Greater Toronto Area. Blood samples are collected at baseline (during infection) and 1, 6 and 12 months after diagnosis. Serial antibody titres, isotype, antigen target and viral neutralisation will be assessed. Clinical data will be collected from chart reviews and patient surveys. Host genomes and T-cell and B-cell receptors will be sequenced. Viral genomes will be sequenced to identify viral lineage. Regression models will be used to test associations between antibody response, physiological response, genetic markers and patient outcomes. Pathogenic genomic variants related to disease severity, or negative outcomes will be identified and genome wide association will be conducted. Immune repertoire diversity during infection will be correlated with severity of COVID-19 symptoms and human leucocyte antigen-type associated with SARS-CoV-2 infection. Participants can learn their genome sequencing, antibody and viral sequencing results; patient-reported outcomes of receiving this information will be assessed through surveys and qualitative interviews. ETHICS AND DISSEMINATION: This study was approved by Clinical Trials Ontario Streamlined Ethics Review System (CTO Project ID: 3302) and the research ethics boards at participating hospitals. Study findings will be disseminated through peer-reviewed publications, conference presentations and end-users.

Brain-Derived Neurotrophic Factor Mitigates the Association Between Platelet Dysfunction and Cognitive Impairment.

Background: Platelet hyperactivity is deleterious in coronary artery disease (CAD), requiring lifelong antiplatelet therapy, and is associated with worse cognitive outcomes. Upon activation, platelets release Brain-Derived Neurotrophic Factor (BDNF), a neurotrophin protective against cognitive decline. Given these apparently opposing effects of platelet activation on cognitive health, we investigated whether BDNF levels intercede in the relationship between platelet activation and cognitive function; and whether this relationship is moderated by the presence of CAD. Methods: In this cross-sectional study, 1,280 participants with (n = 673) and without CAD (n = 607) completed the Montreal Cognitive Assessment (MoCA). Plasma BDNF and soluble P-selectin (a marker of platelet activity) levels were assessed using multiplex flow cytometry. Results: In a mediation model, platelet activity was correlated with higher plasma BDNF concentrations (b = 0.53, p < 0.0001). The relationship between sP-selectin and BDNF concentrations was stronger for individuals without CAD (b = 0.71, p < 0.0001) than for CAD participants (b = 0.43, p < 0.0001; p interaction <0.0001). Higher BDNF concentrations were associated with higher MoCA scores (b = 0.26, p = 0.03). The overall effect of platelet activity on cognitive performance was non-significant (total effect: b = -0.12, p = 0.13), and became significant when accounting for BDNF as a mediating factor (direct effect: b = -0.26, p = 0.01). This resulted in a positive indirect effect of platelet activity (via BDNF) on MoCA scores (b = 0.14, CI 95% 0.02-0.30), that was smaller in CAD participants than in non-CAD participants [Δ -0.07 (95% CI -0.14 to -0.01)]. Conclusions: BDNF released from activated platelets could be a mitigating factor in a negative association between platelet activity and cognitive function.

Trajectories of decline on instrumental activities of daily living prior to dementia in persons with mild cognitive impairment.

OBJECTIVES: The main objective was to determine the trajectory of instrumental activities of daily living (iADL) decline in persons with mild cognitive impairment (MCI) who progressed towards dementia relative to persons with MCI who remained stable. METHODS/DESIGN: At study entry, 121 participants met criteria for MCI. Based on the follow-up, 47 participants later converted to dementia and were identified as progressors. Sixteen participants, identified as decliners, presented a significant cognitive decline but did not reach the criteria for dementia within the study timeframe. Stable MCI remained cognitively stable during the 5-year follow-up; n = 58. Participants completed a yearly assessment using clinical tests/questionnaires, neuropsychological measures, and functional autonomy assessment until they met criteria for dementia. The average number of months for the follow-up was 34. RESULTS: Many years of stable performance followed by an accelerated decline just prior to diagnosis, was observed for complex activities for progressors. No change was found for stable MCI and a gradual linear decline characterized decliners. The housekeeping-related activities component showed a linear decline in progressors and did not change in stable and decliner MCI. We found a predictive model that includes significant predictors of dementia conversion with a high diagnostic accuracy the following year (area under the curve = 0.94 [95% confidence level; lower bound: 0.87, upper bound: 1]). CONCLUSIONS: It is critical to assess iADL that reflect complex activities in the evaluation of MCI individuals as their impairment, combined with change on cognitive markers, indicates a higher risk of dementia progression 1 or 2 years later.

CCCDTD5 recommendations on early and timely assessment of neurocognitive disorders using cognitive, behavioral, and functional scales.

INTRODUCTION: Earlier diagnosis of neurocognitive disorders and neurodegenerative disease is needed to implement preventative interventions, minimize harm, and reduce risk of exploitation in the context of undetected disease. Along the spectrum from subjective cognitive decline (SCD) to dementia, evidence continues to emerge with respect to detection, staging, and monitoring. Updates to previous guidelines are required for clinical practice. METHODS: A subcommittee of the 5th Canadian Consensus Conference on Diagnosis and Treatment of Dementia (CCCDTD) reviewed emerging evidence to address the following: (1) Is there a role for screening at-risk patients without clinical concerns? In what context is assessment for dementia appropriate? (2) What tools can be used to evaluate patients in whom cognitive decline is suspected? (3) What important information can be gained from an informant, using which measures? (4) What instruments can be used to get more in-depth information to diagnose mild cognitive impairment (MCI) or dementia? (5) What is the approach to those with cognitive concerns but without objective changes (ie, SCD)? (6) How do we track response to treatment and change over time? The Grading of Recommendations Assessment, Development, and Evaluation system was used to rate quality of the evidence and strength of the recommendations. RESULTS: We recommend instruments to assess and monitor cognition, behavior, and function across the cognitive spectrum, including reports from patient and informant. We recommend against screening asymptomatic older adults but recommend investigation for self- or informant reports of changes in cognition, emergence of behavioral or psychiatric symptoms, or decline in function or self-care. Standardized assessments should be used for cognitive and behavioral change that have sufficient validity for use in clinical practice. DISCUSSION: The CCCDTD5 provides evidence-based recommendations for detection, assessment, and monitoring of neurocognitive disorders. Although these guidelines were developed for use in Canada, they may also be useful in other jurisdictions.

CCCDTD5: research diagnostic criteria for Alzheimer's Disease.

The CCCDTD5 reviewed the research diagnostic criteria for Alzheimer's disease proposed in the NIA-AA Research Framework and supports their use in research but not in clinical practice.