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The Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams.
The COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here.
The CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020.
Availability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years.
Background Survival estimates are integral to care for patients diagnosed with dementia. Few Canadian studies have carried out long-term follow-up of well-described cohorts, analyzing survival related to multiple risk factors. Methods Survival analysis of an inception cohort enrolled at a British Columbia (BC) tertiary dementia referral clinic between 1997 and 1999 was undertaken. Vital status was completed for 168 patients diagnosed with dementia. An evaluation of the effects of demographics, vascular risk factors, cognitive and functional ratings, apolipoprotein 4-status, and cholinesterase use on survival was performed using a log-rank test and time-dependent Cox regression. Survival of this dementia cohort was compared with the age-matched life expectancy of persons in BC. Results In all, 158/168 (94.0%) subjects died over 16.6 years, with a median survival of 7.08 years. Risk factors associated with shorter survival in dementia groups included age of onset ≥80 (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.05-2.32); greater functional disability (Disability Assessment for Dementia<55% [HR 1.47, 95% CI 1.04-2.08]); and cumulative medical illness severity (Cumulative Illness Rating Scale≥7 [HR 1.51, 95% CI 1.08-2.12)]. Compared with the BC population, years of potential life lost for dementia subjects aged <65 was 15.36 years, and for dementia subjects aged ≥80 it was 1.82 years. Conclusions Survival in dementia subjects is shorter than population life expectancies for each age strata, with greatest impact on younger patients. For people diagnosed with dementia, age ≥80 years, cumulative medical illness severity, and functional disabilities are the most significant survival predictors and can be used to guide prognosis.
The magnitude of the problems faced by an aging Canadian society has been clearly identified. Perhaps the single most important problem is the increasing incidence of dementia. Alzheimer's disease (AD) accounts for 50-60% of the dementias in later life within a spectrum of other contributing dementias. Regulatory approval has been given to Acetylcholinesterase inhibitors for the symptomatic treatment of mild to moderate AD, and conditional approval to memantine for the symptoms of moderate to severe AD. There has been no regulatory approval for the treatment of the degenerative dementias beyond AD. The very rapid progress in the past decade in biotechnology and in the molecular biology of the dementias is supporting a new generation of innovative treatment strategies that will more directly target the underlying disease pathogenic mechanisms. Such treatments will foreseeably include immunotherapies, anti-aggregants that may prevent misfolding and deposition of proteins, and neuroregenerative interventions. These Guidelines follow the 2nd Canadian Conference on the Development of Antidementia Therapies, held in 2004, which covered a range of design, methodological and ethical issues facing clinical researchers and regulatory authorities. They are intended to provide a common point of reference and guidance in Canada for therapeutic development of the dementias.
Prevention in Alzheimer's disease and other dementias (AD/dementia) is defined on the basis of clinical states and their expressed symptoms. Primary prevention refers to delaying the development of the full-blown state of clinically expressed disease in normal individuals. Current primary prevention research is driven by evidence of AD/dementia protective factors that have emerged from epidemiological studies. The first randomized controlled trials (RCTs) of primary AD/dementia prevention have been designed to test the efficacy and safety of NSAIDs, hormonal therapy, antihypertensive drugs and antioxidants. The experience of these trials has indicated safety concerns as a key issue and highlighted significant design challenges in this type of research. These trials have required large sample sizes and unsustainable costs. There should be consideration given in future trials to enriching study samples with risk factors to increase progression rates to AD/dementia. Innovative strategies will also be needed to recruit and retain subjects given the long follow-up periods, modest perceived benefit and the potential for the risk-benefit ratio to change during the trial. It is foreseeable that regulatory authorities will be presented with primary prevention RCTs for approval and labelling, and that criteria to evaluate such evidence still need to be developed.
The status of Mild Cognitive Impairment (MCI) as a valid construct is controversial. The term encompasses people with heterogeneous clinical profiles, and invites sub-classifications that still require validation. Still, much evidence suggests that, properly selected, many people with MCI - especially Amnestic MCI - are at a high risk of dementia. This paper considers the validity of the construct of MCI as a high-risk state for progression and a target for treatment. We conclude that the status of MCI as an entity remains controversial. On the one hand, it can be argued that the careful section of cases at high risk of developing dementia means that it is a valid target, with the goal being the prevention of dementia. Advocates of this view see a linear progression that they are trying to arrest, but studies have yet to show that this can be done. On the other hand, it can be argued that the patients who progressed did not develop dementia: they actually had a very early form of it. By this view, people without the progressive form will be needlessly exposed to antidementia drugs, and the others should be treated anyway. Why some people progress and others do not is not clear, but the variable rates of progression - between clinic-based and population-based samples and between very similar clinical trials with slightly different inclusion criteria - suggests that MCI is a heterogeneous entity. The phenomenon of slowing or non-progression itself should be investigated, and such investigations likely should extend to people now classified as having mild dementia.
There is currently little information on the genetic epidemiology of Alzheimer disease (AD) among North American Aboriginal populations. No cases of familialAD (FAD) in these populations have been published to date.
Here, we describe a large North American Aboriginal kindred with early onset FAD (EOFAD) in which genetic testing was done.
Results and Conclusions:
A novel Presenilin 1 (PS1) gene mutation (L250F) has been identified. In contrast to the three previously reported families with PS1 codon 250 mutations, affected members of this kindred demonstrate neither myoclonus nor seizures. Furthermore, the identification of a PS1 mutation in a North American Aboriginal kindred presents several unique challenges with respect to knowledge transfer and continuity of care in a geographically remote and culturally distinct community.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, functional disability, and neuropsychiatric symptoms. Initial diagnosis is often delayed to a point when there is significant neurodegenerative pathology and secondary downstream pathogenic sequelae. The disease should be diagnosed during its earliest stage, as this would likely represent an ideal therapeutic window for disease-modifying therapies. Despite recent research that has focused on defining the clinically identifiable at-risk phase that precedes AD, reliable criteria for identifying patients in the prodromal to incipient stages of AD remain elusive.
In addressing the prodrome of AD, it has been clearly recognized that there are age-inappropriate cognitive declines that fall short of meeting the criteria for dementia. Most broadly, patients in this category have been classified as cognitively impaired not demented (CIND). In epidemiological studies, it has been estimated that 19% to 37% of patients ≥65 years of age are CIND. Conditions within the taxonomy of CIND include age-associated memory impairment (AAMI), age-associated cognitive decline (AACD), and mild cognitive impairment (MCI) (Slide 1).
AAMI is defined psychometrically by memory test scores that are ≥1 standard deviation below scores of young healthy control patients. AACD is characterized by scores in any cognitive domain that are ≥1 standard deviation below age- and education-adjusted normal measures. MCI is identified by memory function at a level ≥1.5 standard deviations below age- and education-adjusted means. Of these three conditions, MCI has been investigated most thoroughly and is defined by a clinical phenotype.
Mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal dementia. We used a comprehensive neuropsychological battery to investigate whether early cognitive changes could be detected in GRN mutation carriers before dementia onset. Twenty-four at-risk members from six families with known GRN mutations underwent detailed neuropsychological testing. Group differences were investigated by domains of attention, language, visuospatial function, verbal memory, non-verbal memory, working memory and executive function. There was a trend for mutation carriers (n=8) to perform more poorly than non-carriers (n=16) across neuropsychological domains, with significant between group differences for visuospatial function (p<.04; d=0.92) and working memory function (p<.02; d=1.10). Measurable cognitive differences exist before the development of frontotemporal dementia in subjects with GRN mutations. The neuropsychological profile of mutation carriers suggests early asymmetric, right hemisphere brain dysfunction that is consistent with recent functional imaging data from our research group and the broader literature. (JINS, 2014, 20, 1–10)
Heterogeneity is observed in the patterns of cognition in Alzheimer’s disease (AD). Such heterogeneity might suggest the involvement of different etiological pathways or different host responses to pathology. A total of 627 subjects with mild/moderate AD underwent cognitive assessment with the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale-2 (DRS-2). Latent class analysis (LCA) was performed on cognition subscale data to identify and characterize cognitive subgroups. Clinical, demographic, and genetic factors were explored for association with class membership. LCA suggested the existence of four subgroups; one group with mild and another with severe global impairment across the cognitive domains, one group with primary impairments in attention and construction, and another group with primary deficits in memory and orientation. Education, disease duration, age, Apolipoprotein E-ε4 (APOE ε4) status, gender, presence of grasp reflex, white matter changes, and early or prominent visuospatial impairment were all associated with class membership. Our results support the existence of heterogeneity in patterns of cognitive impairment in AD. Our observation of classes characterized by predominant deficits in attention/construction and memory respectively deserves further exploration as does the association between membership in the attention/construction class and APOE ε4 negative status. (JINS, 2010, 16, 233–243.)
The psychometric criterion of mild cognitive impairment (MCI) generally involves having an unusually low score on memory testing (i.e., −1.5 SDs). However, healthy older adults can obtain low scores, particularly when multiple memory measures are administered. In turn, there is a substantial risk of psychometrically misclassifying MCI in healthy older adults. This study examined the base rates of low memory scores in older adults (55–87 years; n = 550) from the Wechsler Memory Scale–Third Edition (WMS-III; Wechsler, 1997b) standardization sample. The WMS-III consists of four co-normed episodic memory tests (i.e., Logical Memory, Faces, Verbal Paired Associates, and Family Pictures) that yield eight age- and demographically-adjusted standard scores (Auditory Recognition and Working Memory tests not included). When the eight age-adjusted scores were examined simultaneously, 26% of older adults had one or more scores at or below the 5th percentile (i.e., −1.5 SDs). On the eight demographically- adjusted scores, 39% had at least one score at or below the 5th percentile. There was an inverse relationship between intellectual abilities and prevalence of low memory scores, particularly with the age-adjusted WMS-III scores. Understanding the base rates of low scores can reduce the overinterpretation of low memory scores and minimize false-positive misclassification.Drs. Brooks, Iverson, and Feldman have no known, perceived, or actual conflict of interest with this research. Dr. Holdnack is the Senior Research Director with The Psychological Corporation. (JINS, 2008, 14, 463–478.)
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