Benjamin Lam

Criterion and convergent validity of the Montreal cognitive assessment with screening and standardized neuropsychological testing.

To compare the validity of the Montreal Cognitive Assessment (MoCA) with the criterion standard of standardized neuropsychological testing and to compare the convergent validity of the MoCA with that of existing screening tools and global measures of cognition.

Frequency of domain-specific cognitive impairment in sub-acute and chronic stroke.

BACKGROUNDnFunctional contributions of cognitive impairment may vary by domain and severity.nnnOBJECTIVEn(1) To characterize frequency of cognitive impairment by domain after stroke by severity (mild: -1.5 ≤ z-score < -2; severe: Z ≤ -2) and time (sub-acute: < 90d; chronic: 90d-2yrs); and (2) To assess the association of cognitive impairment with function in chronic stroke.nnnMETHODSnCognitive function was characterized among 215 people with sub-acute or chronic stroke (66.8 years, 43.3% female). Z-scores by cognitive domain were determined from normative data. Function was defined as the number of IADLs minimally independent.nnnRESULTSn76.3% of sub-acute and 67.3% of chronic stroke participants had cognitive impairment in ≥ 1 domain (p-for-difference = 0.09). Severe impairment was most common in psychomotor speed (sub-acute: 53.5%; chronic: 33.7%). Impairment in executive function was common (sub-acute: 39.5%; chronic: 30.7%) but was usually mild. Severe impairment in psychomotor speed, visuospatial function, and language and any impairment in executive function and memory was associated with IADL impairment (p < 0.03).nnnCONCLUSIONSnMild cognitive impairment is common after stroke but is not associated with functional disability. Impairment in psychomotor speed, executive function, and visuospatial function is common and associated with functional impairment so should be a focus of screening and rehabilitation post-stroke.

Cholinesterase inhibitors in Alzheimer's disease and Lewy body spectrum disorders: the emerging pharmacogenetic story

This review provides an update on the current state of pharmacogenetic research in the treatment of Alzheimers disease (AD) and Lewy body disease (LBD) as it pertains to the use of cholinesterase inhibitors (ChEI). AD and LBD are first reviewed from clinical and pathophysiological perspectives. This is followed by a discussion of ChEIs used in the symptomatic treatment of these conditions, focusing on their unique and overlapping pharmacokinetic and pharmacodynamic profiles, which can be used to identify candidate genes for pharmacogenetics studies. The literature published to date is then reviewed and limitations are discussed. This is followed by a discussion of potential endophenotypes which may help to refine future pharmacogenetic studies of response and adverse effects to ChEIs.

Trail Making Test Elucidates Neural Substrates of Specific Poststroke Executive Dysfunctions

Background and Purpose— Poststroke cognitive impairment is typified by prominent deficits in processing speed and executive function. However, the underlying neuroanatomical substrates of executive deficits are not well understood, and further elucidation is needed. There may be utility in fractionating executive functions to delineate neural substrates. Methods— One test amenable to fine delineation is the Trail Making Test (TMT), which emphasizes processing speed (TMT-A) and set shifting (TMT-B-A difference, proportion, quotient scores, and TMT-B set-shifting errors). The TMT was administered to 2 overt ischemic stroke cohorts from a multinational study: (1) a chronic stroke cohort (N=61) and (2) an acute–subacute stroke cohort (N=45). Volumetric quantification of ischemic stroke and white matter hyperintensities was done on magnetic resonance imaging, along with ratings of involvement of cholinergic projections, using the previously published cholinergic hyperintensities projections scale. Damage to the superior longitudinal fasciculus, which colocalizes with some cholinergic projections, was also documented. Results— Multiple linear regression analyses were completed. Although larger infarcts (&bgr;=0.37, P<0.0001) were associated with slower processing speed, cholinergic hyperintensities projections scale severity (&bgr;=0.39, P<0.0001) was associated with all metrics of set shifting. Left superior longitudinal fasciculus damage, however, was only associated with the difference score (&bgr;=0.17, P=0.03). These findings were replicated in both cohorts. Patients with ≥2 TMT-B set-shifting errors also had greater cholinergic hyperintensities projections scale severity. Conclusions— In this multinational stroke cohort study, damage to lateral cholinergic pathways and the superior longitudinal fasciculus emerged as significant neuroanatomical correlates for executive deficits in set shifting.

Blood-brain barrier opening in Alzheimer's disease using MR-guided focused ultrasound.

Magnetic resonance-guided focused ultrasound in combination with intravenously injected microbubbles has been shown to transiently open the blood–brain barrier, and reduce beta-amyloid and tau pathology in animal models of Alzheimer’s disease. Here, we used focused ultrasound to open the blood–brain barrier in five patients with early to moderate Alzheimer’s disease in a phase I safety trial. In all patients, the blood–brain barrier within the target volume was safely, reversibly, and repeatedly opened. Opening the blood–brain barrier did not result in serious clinical or radiographic adverse events, as well as no clinically significant worsening on cognitive scores at three months compared to baseline. Beta-amyloid levels were measured before treatment using [18F]-florbetaben PET to confirm amyloid deposition at the target site. Exploratory analysis suggested no group-wise changes in amyloid post-sonication. The results of this safety and feasibility study support the continued investigation of focused ultrasound as a potential novel treatment and delivery strategy for patients with Alzheimer’s disease.Magnetic resonance-guided focused ultrasound with injected microbubbles has been used to temporarily open the blood–brain barrier (BBB) in animal models of Alzheimers disease (AD). Here, the authors use this technology to non-invasively open the BBB in 5 patients with mild-to-moderate AD in a phase I trial, and show that the procedure is safe.

Characterizing familial corticobasal syndrome due to Alzheimer's disease pathology and PSEN1 mutations

Corticobasal syndrome (CBS) resulting from genetic Alzheimers disease (AD) has been described only once. Whether familial CBS‐AD is a distinct clinical entity with its own imaging signature remains unknown.

Validity of the QUADAS-2 in Assessing Risk of Bias in Alzheimer's Disease Diagnostic Accuracy Studies

Accurate detection of Alzheimers disease (AD) is of considerable clinical importance. The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) is the current research standard for evaluating the quality of studies that validate diagnostic tests; however, its own construct validity has not yet been evaluated empirically. Our aim was to evaluate how well the proposed QUADAS-2 items and its domains converge to indicate the study quality criteria. This study applies confirmatory factor analysis to determine whether a measurement model would be consistent with meta-analytic data. Cochrane meta-analyses assessing the accuracy of AD diagnostic tests were identified. The seven ordinal QUADAS-2 items, intended to inform study quality based on risk of bias and applicability concerns, were extracted for each of the included studies. The QUADAS-2 pre-specified factor structure (i.e., four domains assessed in terms of risk of bias and applicability concerns) was not testable. An alternative model based on two correlated factors (i.e., risk of bias and applicability concerns) returned a poor fit model. Poor factor loadings were obtained, indicating that we cannot provide evidence that the indicators convergent validity markers in the context of AD diagnostic accuracy metanalyses, where normally the sample size is low (around 60 primary included studies). A Monte Carlo simulation suggested that such a model would require at least 90 primary studies to estimate these parameters with 80% power. The reliability of the QUADAS-2 items to inform a measurement model for study quality remains unconfirmed. Considerations for conceptualizing such a tool are discussed.

The Toronto Cognitive Assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment

BackgroundA need exists for easily administered assessment tools to detect mild cognitive changes that are more comprehensive than screening tests but shorter than a neuropsychological battery and that can be administered by physicians, as well as any health care professional or trained assistant in any medical setting. The Toronto Cognitive Assessment (TorCA) was developed to achieve these goals.MethodsWe obtained normative data on the TorCA (nu2009=u2009303), determined test reliability, developed an iPad version, and validated the TorCA against neuropsychological assessment for detecting amnestic mild cognitive impairment (aMCI) (nu2009=u200950/57, aMCI/normal cognition). For the normative study, healthy volunteers were recruited from the Rotman Research Institute registry. For the validation study, the sample was comprised of participants with aMCI or normal cognition based on neuropsychological assessment. Cognitively normal participants were recruited from both healthy volunteers in the normative study sample and the community.ResultsThe TorCA provides a stable assessment of multiple cognitive domains. The total score correctly classified 79% of participants (sensitivity 80%; specificity 79%). In an exploratory logistic regression analysis, indices of Immediate Verbal Recall, Delayed Verbal and Visual Recall, Visuospatial Function, and Working Memory/Attention/Executive Control, a subset of the domains assessed by the TorCA, correctly classified 92% of participants (sensitivityxa092%; specificityxa091%). Paper and iPad version scores were equivalent.ConclusionsThe TorCA can improve resource utilization by identifying patients with aMCI who may not require more resource-intensive neuropsychological assessment. Future studies will focus on cross-validating the TorCA for aMCI, and validation for disorders other than aMCI.

DIAGNOSTIC DISAGREEMENT AMONG MAJOR CONSENSUS CRITERIA FOR ALZHEIMER'S DISEASE WHEN COMPARED TO THE NINCDS-ADRD

on Aging-Alzhiemer’s Association (NIA-AA; McKhann 2011), (2) International Working Group (IWG; Dubois 2007, Dubois 2010, Dubois 2014), (3) International Classification of Diseases (ICD-10; WHO 2010), and (4) Diagnostic and Statistical Manual of Mental Disorders (DSM-5; APA 2013) • The National Institute of Neurological and Communicative Disorders – Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA; McKhann 1984) criterion remains an important comparator standard given its role in AD research prior to the advent of the newer, biomarkerdriven criteria • A preliminary study of participants from the Sunnybrook Dementia Study (SDS; ClinicalTrials.gov NCT01800214) demonstrated notable discordance between criteria, in particular between the subtype and co-pathology permissive NIA-AA, and the prototypic and biomarker-requiring IWG Diagnostic Disagreement Among Major Consensus Criteria For Alzheimers Disease When Compared to the NINCDS-ADRDA

COMPARISON OF FOUR NEW CONSENSUS CRITERIA AGAINST THE 1984 NINCDS-ARDRA CRITERIA FOR ALZHEIMER'S DISEASE

from 50 to 90 years old. This research was performed as part of a nationwide multicenter cohort called the CREDOS study. Twentynine subjects with SMI progressed to MCI or Alzheimer’s disease (AD) and the others (n1⁄4100) did not progress. We compared baseline demographics, blood chemistry and neuropsychological tests results between the two groups and assessed predictors and the hazard ratio (HR) for the progression. Results: Follow up durations were ranged from 0.5 to 4.7 years. Median time to event was 3.64 years. Age, apolipoprotein E4 (APOE4) incidence, baseline Mini-Mental State Examination (MMSE) score, memory scores, geriatric depression scale (GDS) scores, Boston naming test, Rey complex figure copy/ recall and stroop test scores were different between groups. Old age, abnormal recall scores in MMSE, existence of APOE4 allele and lower verbal memory delayed recall scores were the most potent predictors related with the progression and the sum of the 4 predictors explained better for the progression. Conclusions: Subjects with SMI who progressed to MCI/ AD showed different baseline characteristics and neuropsychological tests results. Old age, worse baseline memory scores and APOE4 allele existence were related with the progression of SMI and combining them might be better to predict the progression. How to better coordinate the relative contributions of each predictor deserves further investigation.