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Patients suffering from the behavioral variant of Frontotemporal Dementia (FTD-b) often exaggerate their abilities. Are those errors in judgment limited to domains in which patients under-perform, or do FTD-b patients overestimate their abilities in other domains? Is overconfidence in FTD-b patients domain-specific or domain-general? To address this question, we asked patients at early stages of FTD-b to judge their performance in two domains (attention, perception) in which they exhibit relatively spared abilities. In both domains, FTD-b patients overestimated their performance relative to patients with Dementia of Alzheimer Type (DAT) and healthy elderly subjects. Results are consistent with a domain-general deficit in metacognitive judgment. We discuss these findings in relation to “regression to the mean” accounts of overconfidence and the role of emotions in metacognitive judgments.
To evaluate whether cerebrospinal fluid biomarkers, apolipoprotein e4, neuroimaging abnormalities, and neuropsychological data differentially predict progression from mild cognitive impairment (MCI) to dementia for men and women.
Participants who were diagnosed with MCI at baseline (n = 449) were classified as either progressing to Alzheimer’s dementia at follow-up or as not progressing. Men and women were first compared using bivariate analyses. Sex-stratified Cox proportional hazard regressions were performed examining the relationship between baseline data and the likelihood of progressing to dementia. Sex interactions were subsequently examined.
Cox proportional hazard regression controlling for age and education indicated that all variables significantly predicted subsequent progression to dementia for men and women. Sex interactions indicated that only Rey Auditory Verbal Learning Test (RAVLT) delayed recall and Functional Activities Questionnaire (FAQ) were significantly stronger risk factors for women. When all variables were entered into a fully adjusted model, significant risk factors for women were Aβ42, hippocampal volume, RAVLT delayed recall, Boston Naming Test, and FAQ. In contrast, for men, Aβ42, p-tau181, p-tau181/Aβ42, hippocampal volume, category fluency and FAQ were significant risk factors. Interactions with sex were only significant for p-tau181/Aβ42 and RAVLT delayed recall for the fully adjusted model.
Men and women with MCI may to differ for which factors predict subsequent dementia although future analyses with greater power are needed to evaluate sex differences. We hypothesize that brain and cognitive reserve theories may partially explain these findings.
To describe the neuroimaging and other methods for assessing vascular contributions to neurodegeneration in the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) study, a Canadian multi-center, prospective longitudinal cohort study, including reliability and feasibility in the first 200 participants.
COMPASS-ND includes persons with Alzheimer’s disease (AD; n = 150), Parkinson’s disease (PD) and Lewy body dementias (LBDs) (200), mixed dementia (200), mild cognitive impairment (MCI; 400), subcortical ischemic vascular MCI (V-MCI; 200), subjective cognitive impairment (SCI; 300), and cognitively intact elderly controls (660). Magnetic resonance imaging (MRI) was acquired according to the validated Canadian Dementia Imaging Protocol and visually reviewed by either of two experienced readers blinded to clinical characteristics. Other relevant assessments include history of vascular disease and risk factors, blood pressure, height and weight, cholesterol, glucose, and hemoglobin A1c.
Analyzable data were obtained in 197/200 of whom 18 of whom were clinically diagnosed with V-MCI or mixed dementia. The overall prevalence of infarcts was 24.9%, microbleeds was 24.6%, and high white matter hyperintensity (WMH) was 31.0%. MRI evidence of a potential vascular contribution to neurodegeneration was seen in 12.9%–40.0% of participants clinically diagnosed with another condition such as AD. Inter-rater reliability was good to excellent.
COMPASS-ND will be a useful platform to study vascular brain injury and its association with risk factors, biomarkers, and cognitive and functional decline across multiple age-related neurodegenerative diseases. Initial findings show that MRI-defined vascular brain injury is common in all cognitive syndromes and is under-recognized clinically.
Damage to the corticospinal tract (CST) from stroke leads to motor deficits. The damage can be quantified as the amount of overlap between the stroke lesion and CST (CST Injury). Previous literature has shown that the degree of motor deficits post-stroke is related to the amount of CST Injury. These studies delineate the stroke lesion from structural T1-weighted magnetic resonance imaging (MRI) scans, often acquired for research. In Canada, computed tomography (CT) is the most common imaging modality used in routine acute stroke care. In this proof-of-principle study, we determine whether CST Injury, using lesions delineated from CT scans, significantly explains the variability in motor impairment in individuals with stroke.
Thirty-seven participants with stroke were included in this study. These individuals had a CT scan within the acute stage (7 days) of their stroke and underwent motor assessments. Brain images from CT scans were registered to MRI space. We performed a stepwise regression analysis to determine the contribution of CST injury and demographic variables in explaining motor impairment variability.
Using clinically available CT scans, we found modest evidence that CST Injury explains variability in motor impairment (R2adj = 0.12, p = 0.02). None of the participant demographic variables entered the model.
We show for the first time a relationship between CST Injury and motor impairment using CT scans. Further work is required to evaluate the utility of data derived from clinical CT scans as a biomarker of stroke motor recovery.
Large prospective observational studies have cast doubt on the common assumption that endovascular thrombectomy (EVT) is superior to intravenous thrombolysis for patients with acute basilar artery occlusion (BAO). The purpose of this study was to retrospectively review our experience for patients with BAO undergoing EVT with modern endovascular devices.
All consecutive patients undergoing EVT with either a second-generation stent retriever or direct aspiration thrombectomy for BAO at our regional stroke center from January 1, 2013 to March 1, 2019 were included. The primary outcome measure was functional outcome at 1 month using the modified Rankin Scale (mRS) score. Multivariable logistic regression was used to assess the association between patient characteristics and dichotomized mRS.
A total of 43 consecutive patients underwent EVT for BAO. The average age was 67 years with 61% male patients. Overall, 37% (16/43) of patients achieved good functional outcome. Successful reperfusion was achieved in 72% (31/43) of cases. The median (interquartile range) stroke onset to treatment time was 420 (270–639) minutes (7 hours) for all patients. The procedure-related complication rate was 9% (4/43). On multivariate analysis, posterior circulation Alberta stroke program early computed tomography score and Basilar Artery on Computed Tomography Angiography score were associated with improved functional outcome.
EVT appears to be safe and feasible in patients with BAO. Our finding that time to treatment and successful reperfusion were not associated with improved outcome is likely due to including patients with established infarcts. Given the variability of collaterals in the posterior circulation, the paradigm of utilizing a tissue window may assist in patient selection for EVT. Magnetic resonance imaging may be a reasonable option to determine the extent of ischemia in certain situations.
Recent investigations now suggest that cerebrovascular reactivity (CVR) is impaired in Alzheimer’s disease (AD) and may underpin part of the disease’s neurovascular component. However, our understanding of the relationship between the magnitude of CVR, the speed of cerebrovascular response, and the progression of AD is still limited. This is especially true in patients with mild cognitive impairment (MCI), which is recognized as an intermediate stage between normal aging and dementia. The purpose of this study was to investigate AD and MCI patients by mapping repeatable and accurate measures of cerebrovascular function, namely the magnitude and speed of cerebrovascular response (τ) to a vasoactive stimulus in key predilection sites for vascular dysfunction in AD.
Thirty-three subjects (age range: 52–83 years, 20 males) were prospectively recruited. CVR and τ were assessed using blood oxygen level-dependent MRI during a standardized carbon dioxide stimulus. Temporal and parietal cortical regions of interest (ROIs) were generated from anatomical images using the FreeSurfer image analysis suite.
Of 33 subjects recruited, 3 individuals were excluded, leaving 30 subjects for analysis, consisting of 6 individuals with early AD, 11 individuals with MCI, and 13 older healthy controls (HCs). τ was found to be significantly higher in the AD group compared to the HC group in both the temporal (p = 0.03) and parietal cortex (p = 0.01) following a one-way ANCOVA correcting for age and microangiopathy scoring and a Bonferroni post-hoc correction.
The study findings suggest that AD is associated with a slowing of the cerebrovascular response in the temporal and parietal cortices.
Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.
Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.
Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.
This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.
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.
The World Alzheimer Report 2016 estimated that 47 million people are living with dementia worldwide (Alzheimer's Disease International, 2016). In the inaugural World Health Organization Ministerial Conference on Global Action against Dementia, six of the top ten research priorities were focused on prevention, identification, and reduction of dementia risk, and on delivery and quality of care for people with dementia and their carers (Shah et al., 2016). While the Lancet Neurology Commission has suggested that even minor advances to delay progression or ameliorate symptoms might have substantial financial and societal benefits (Winblad et al., 2016), advances have been slow.
New onset of mood and behavioral changes in middle-aged patients are frequently the first manifestations of an unrecognized neurocognitive disorder. Impairment of social cognition, the cognitive ability to process social information coming from others, such as emotions, to attribute mental states to others, and to respond appropriately to them, is often at the origin of behavioral manifestations in neurodegenerative disorders.
This paper reviews the current literature on social cognition impairment in neurocognitive disorders, particularly in prodromal stages of behavioral-variant frontotemporal dementia (bvFTD), Alzheimer's disease (AD), idiopathic Parkinson's disease (IPD), and Lewy body dementia (LBD). The concepts of social cognition will be reviewed, including its impairment and neural basis, its clinical assessment, and the different therapeutic interventions available clinically.
Socially inappropriate behaviors, such as loss of empathy, inappropriateness of affect, and disinhibition are frequently reported in prodromal bvFTD and in prodromal AD. Lack of self-control, reduced perception of social cues, such as recognition of facial emotions and sarcastic speech, and impaired Theory of Mind all contribute to the neuropsychiatric symptoms and are secondary to neurodegeneration in specific brain regions. In contrasts to bvFTD and AD, deficits in social cognition in IPD occur later in the course of the disease and are often multifactorial in origin.
Through various manifestations, social inappropriateness is frequently the first clinical sign of a neurodegenerative process, especially in AD and bvFTD, years before noticeable impairment on classical neuropsychological assessment and brain atrophy on imaging.
Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.
Despite much progress in stroke prevention and acute intervention, recovery and rehabilitation have traditionally received relatively little scientific attention. There is now increasing interest in the development of stroke recovery drugs and innovative rehabilitation techniques to promote functional recovery after completed stroke. Experimental work over the past two decades indicates that pharmacologic intervention to enhance recovery may be possible in the subacute stage, days to weeks poststroke, after irreversible injury has occurred. This paper discusses the concept of “rehabilitation pharmacology” and reviews the growing literature from animal studies and pilot clinical trials on noradrenergic pharmacotherapy, a new experimental strategy in stroke rehabilitation. Amphetamine, a monoamine agonist that increases brain norepinephrine levels, is the most extensively studied drug shown to promote recovery of function in animal models of focal brain injury. Further research is needed to investigate the mechanisms and clinical efficacy of amphetamine and other novel therapeutic interventions on the recovery process.
Dementia is a common neurological condition affecting many older individuals that leads to a loss of independence, diminished quality of life, premature mortality, caregiver burden and high levels of healthcare utilization and cost. This is an updated systematic review and meta-analysis of the worldwide prevalence and incidence of dementia.
The MEDLINE and EMBASE databases were searched for relevant studies published between 2000 (1985 for Canadian papers) and July of 2012. Papers selected for full-text review were included in the systematic review if they provided an original population-based estimate for the incidence and/or prevalence of dementia. The reference lists of included articles were also searched for additional studies. Two individuals independently performed abstract and full-text review, data extraction, and quality assessment of the papers. Random-effects models and/or meta-regression were used to generate pooled estimates by age, sex, setting (i.e., community, institution, both), diagnostic criteria utilized, location (i.e., continent) and year of data collection.
Of 16,066 abstracts screened, 707 articles were selected for full-text review. A total of 160 studies met the inclusion criteria. Among individuals 60 and over residing in the community, the pooled point and annual period prevalence estimates of dementia were 48.62 (CI95%: 41.98-56.32) and 69.07 (CI95%: 52.36-91.11) per 1000 persons, respectively. The respective pooled incidence rate (same age and setting) was 17.18 (CI95%: 13.90-21.23) per 1000 person-years, while the annual incidence proportion was 52.85 (CI95%: 33.08-84.42) per 1,000 persons. Increasing participant age was associated with a higher dementia prevalence and incidence. Annual period prevalence was higher in North America than in South America, Europe and Asia (in order of decreasing period prevalence) and higher in institutional compared to community and combined settings. Sex, diagnostic criteria (except for incidence proportion) and year of data collection were not associated with statistically significant different estimates of prevalence or incidence, though estimates were consistently higher for females than males.
Dementia is a common neurological condition in older individuals. Significant gaps in knowledge about its epidemiology were identified, particularly with regard to the incidence of dementia in low- and middle-income countries. Accurate estimates of prevalence and incidence of dementia are needed to plan for the health and social services that will be required to deal with an aging population.