Sunnybrook Dementia Study Research Articles

Relationships between polymorphisms in EPHX2, CYP2J2, CYP2C9, and CYP2C8, white matter hyperintensities, and regional atrophy

AbstractBackgroundWhite matter hyperintensities (WMH) of presumed vascular origin commonly coincide with neurodegeneration. Previous studies reported heterogeneous relationships between WMH and atrophy. Cytochrome P450s CYP2J2, CYP2C8, and CYP2C9 are involved in the vascular ischemic response and soluble epoxide hydrolase (EPHX2) metabolizes its products, which have been implicated in vascular pathology. Here we investigate potential effects of single nucleotide polymorphisms (SNPs) in these genes on WMH and atrophy.MethodPatients with vascular cognitive impairment and/or neurodegenerative diagnoses were drawn from the Sunnybrook Dementia Study (NCT01800214), Vascular Brain Health (VBH) study, and the Brain‐Eye Amyloid Memory (BEAM) study. SNPs were genotyped using the Illumina Neurochip. Patients of European ancestry confirmed via principal components analysis were included. Variants in candidate genes were identified by variant IDs from dbSNP. Linkage‐disequilibrium‐based clumping on minor allele frequency (MAF) was applied via PLINK v1.9 (LD threshold: 0.2) to prioritize SNPs with higher MAF (removing SNPs with MAF<10%). Imaging (T1, T2/PD and FLAIR) was acquired at 3.0T for volumetric analysis using an in‐house segmentation (SABRE/Lesion Explorer). Linear regression models controlling for age, sex, Mini Mental State Exam, and head size were used to assess effects of the SNPs on WMH or atrophy, and effects of SNP×WMH interactions on atrophy in R. Genotypes were coded additively.ResultAmong included participants (n = 508, 71±11 years, 51% female), EPHX2 rs2741351 C/A (MAF = 16%) was associated with frontal (F = 3.54, p = 0.030), temporal (F = 5.86, p = 0.003), and global (F = 6.18, p = 0.002) atrophy. CYP2J2 C/T rs11572214 was associated with frontal (F = 3.99, p = 0.019) and global (F = 4.13, p = 0.017) atrophy. CYP2C8 rs11572174 G/A (MAF = 12%) was associated with deep WMH (F = 3.71, p = 0.025). EPHX2 rs2279591 C/T (MAF = 28%) moderated the association between periventricular WMH and temporal atrophy (F = 5.48, p = 0.004); CYP2C9 rs6583964 G/A (MAF = 47%) moderated the association between periventricular WMH and frontal atrophy (F = 3.74, p = 0.024); and CYP2J2 rs11572214 (MAF = 42%) moderated the association between deep WMH and temporal atrophy (F = 3.58, p = 0.029).ConclusionGenetic variation in the CYP450‐soluble epoxide hydrolase pathway was related to WMH and brain atrophy in people with cognitive impairment. The results suggest that this pathway may contribute to small vessel cerebrovascular disease, and to its impact on neurodegeneration.

Neuropsychiatric symptoms as a sign of small vessel disease progression in cognitive impairment.

Neuropsychiatric symptoms associate cross-sectionally with cerebral small vessel disease but it is not clear whether these symptoms could act as early clinical markers of small vessel disease progression. We investigated whether longitudinal change in Neuropsychiatric Inventory (NPI) scores associated with white matter hyperintensity (WMH) progression in a memory clinic population. We included participants from the prospective Sunnybrook Dementia Study with Alzheimer's disease and vascular subtypes of mild cognitive impairment and dementia with two MRI and ≥ 1 NPI. We conducted linear mixed-effects analyses, adjusting for age, atrophy, vascular risk factors, cognition, function, and interscan interval. At baseline (n=124), greater atrophy, age, vascular risk factors and total NPI score were associated with higher baseline WMH volume, while longitudinally, all but vascular risk factors were associated. Change in total NPI score was associated with change in WMH volume, χ2=7.18, p=0.007, whereby a one-point change in NPI score from baseline to follow-up was associated with a 0.0017 change in normalized WMH volume [expressed as cube root of (WMH volume cm³ as % intracranial volume)], after adjusting for age, atrophy, vascular risk factors and interscan interval. In memory clinic patients, WMH progression over 1-2 years associated with worsening neuropsychiatric symptoms, while WMH volume remained unchanged in those with stable NPI scores in this population with low background WMH burden.

Polymorphisms in EPHX2 and CYP2J2 moderate associations between white matter hyperintensities and temporal lobe atrophy.

White matter hyperintensities (WMH) of presumed vascular origin commonly coincide with neurodegeneration. Previous studies have reported heterogeneous relationships between WMH and atrophy. Cytochrome P450 (CYP) 2J2 (CYP2J2) is involved in the vascular ischemic response and soluble epoxide hydrolase (EPHX2) metabolizes its products, which have been implicated in vascular pathology and WMH. Here we investigate the potential moderation effect of CYP2J2 and EPHX2 single nucleotide polymorphisms (SNPs), individually and interactively, on the association between WMH and atrophy. Patients with vascular cognitive impairment or neurodegenerative diagnoses (n=447) from the Sunnybrook Dementia Study (NCT01800214), Vascular Brain Health (VBH) study, and the Brain-Eye Amyloid Memory (BEAM) study were genotyped for SNPs in EPHX2 and CYP2J2. SNPs were genotyped by the Illumina Neurochip and were selected a priori based on literature. All participants were confirmed to have European ancestry via multi-dimensional scaling using the genotype data. Imaging analysis was performed on 3D T1 and T2/PD weighted images for brain segmentation and volumetric acquisition using SABRE, and WMH volumes were acquired on T2/PD/FLAIR images using Lesion Explorer. Linear regression models controlling for age, sex, Mini Mental State Exam, and head size were used to assess moderation effects of the SNPs (WMH×SNP interactions) on associations between WMH and temporal atrophy using SPSS (v.26). Presence of minor alleles were assessed using a dominant genetic model. The intron variant EPHX2 rs7816586 G/A polymorphism had a trending moderation effect on the association between periventricular WMH and left temporal atrophy where the minor A-allele (frequency=11.52%) was protective (F=3.958, p=0.047) in extensive WMH. The promoter variant CYP2J2 rs10889162 C/T had a significant moderation effect on the association between deep WMH and right temporal atrophy where the minor T-allele (frequency=8.61%) was protective in cases of extensive WMH (F=5.771, p=0.017). No interaction between the EPHX2 and CYP2J2 SNPs was detected. We identified potential moderation effects of genetic variation in EPHX2 and CYP2J2 on the association between WMH and temporal lobe atrophy across neurodegenerative diagnoses. The lack of SNP×SNP interactions suggests that these genes may act independently, consistent with WMH×SNP interaction effects that occurred in association with different anatomical WMH locations.

White matter hyperintensities in autopsy-confirmed frontotemporal lobar degeneration and Alzheimer\u2019s disease

BackgroundWe aimed to systematically describe the burden and distribution of white matter hyperintensities (WMH) and investigate correlations with neuropsychiatric symptoms in pathologically proven Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD).MethodsAutopsy-confirmed cases were identified from the Sunnybrook Dementia Study, including 15 cases of AD and 58 cases of FTLD (22 FTLD-TDP cases; 10 FTLD-Tau [Pick’s] cases; 11 FTLD-Tau Corticobasal Degeneration cases; and 15 FTLD-Tau Progressive Supranuclear Palsy cases). Healthy matched controls (n = 35) were included for comparison purposes. Data analyses included ANCOVA to compare the burden of WMH on antemortem brain MRI between groups, adjusted linear regression models to identify associations between WMH burden and neuropsychiatric symptoms, and image-guided pathology review of selected areas of WMH from each pathologic group.ResultsBurden and regional distribution of WMH differed significantly between neuropathological groups (F5,77 = 2.67, P’ = 0.029), with the FTLD-TDP group having the highest mean volume globally (8032 ± 8889 mm3) and in frontal regions (4897 ± 6163 mm3). The AD group had the highest mean volume in occipital regions (468 ± 420 mm3). Total score on the Neuropsychiatric Inventory correlated with bilateral frontal WMH volume (β = 0.330, P = 0.006), depression correlated with bilateral occipital WMH volume (β = 0.401, P < 0.001), and apathy correlated with bilateral frontal WMH volume (β = 0.311, P = 0.009), all corrected for the false discovery rate. Image-guided neuropathological assessment of selected cases with the highest burden of WMH in each pathologic group revealed presence of severe gliosis, myelin pallor, and axonal loss, but with no distinguishing features indicative of the underlying proteinopathy.ConclusionsThese findings suggest that WMH are associated with neuropsychiatric manifestations in AD and FTLD and that WMH burden and regional distribution in neurodegenerative disorders differ according to the underlying neuropathological processes.

Brain atrophy trajectories predict differential functional performance in Alzheimer's disease: Moderations with apolipoprotein E and sex.

IntroductionWe examine whether distinct brain atrophy patterns (using brain parenchymal fraction [BPF]) differentially predict functional performance and decline in Alzheimer's disease (AD), and are independently moderated by (1) a key AD genetic risk marker (apolipoprotein E [APOE]), (2) sex, and (3) high‐risk group (women APOE ɛ4 carriers).MethodsWe used a 2‐year longitudinal sample of AD patients (baseline N = 170; mean age = 71.3 [9.1] years) from the Sunnybrook Dementia Study. We applied latent class analysis, latent growth modeling, and path analysis. We aimed to replicate our findings (N = 184) in the Alzheimer's Disease Neuroimaging Initiative.ResultsWe observed that high brain atrophy class predicted lower functional performance and steeper decline. This association was moderated by APOE, sex, and high‐risk group. Baseline findings as moderated by APOE and high‐risk group were replicated.DiscussionWomen APOE ɛ4 carriers may selectively be at a greater risk of functional impairment with higher brain atrophy.

White Matter Hyperintensities Relate to Activities of Daily Living More Strongly in Dementia with Lewy Bodies than in Alzheimer’s disease-The Sunnybrook Dementia Study (4351)

White Matter Hyperintensities Relate to Activities of Daily Living More Strongly in Dementia with Lewy Bodies than in Alzheimer’s disease-The Sunnybrook Dementia Study (4351)

Clinical dementia severity associated with ventricular size is differentially moderated by cognitive reserve in men and women

BackgroundInterindividual differences in cognitive reserve (CR) are associated with complex and dynamic clinical phenotypes observed in cognitive impairment and dementia. We tested whether (1) CR early in life (E-CR; measured by education and IQ), (2) CR later in life (L-CR; measured by occupation), and (3) CR panel (CR-P) with the additive effects of E-CR and L-CR, act as moderating factors between baseline ventricular size and clinical dementia severity at baseline and across 2 years. We further examined whether this moderation is differentially represented by sex.MethodsWe examined a longitudinal model using patients (N = 723; mean age = 70.8 ± 9.4 years; age range = 38–90 years; females = 374) from the Sunnybrook Dementia Study. The patients represented Alzheimer’s disease (n = 439), mild cognitive impairment (n = 77), vascular cognitive impairment (n = 52), Lewy body disease (n = 30), and frontotemporal dementia (n = 125). Statistical analyses included (1) latent growth modeling to determine how clinical dementia severity changes over 2 years (measured by performance on the Dementia Rating Scale), (2) confirmatory factor analysis to establish a baseline E-CR factor, and (3) path analysis to predict dementia severity. Baseline age (continuous) and Apolipoprotein E status (ɛ4−/ɛ4+) were included as covariates.ResultsThe association between higher baseline ventricular size and dementia severity was moderated by (1) E-CR and L-CR and (2) CR-P. This association was differentially represented in men and women. Specifically, men in only the low CR-P had higher baseline clinical dementia severity with larger baseline ventricular size. However, women in the low CR-P showed the (1) highest baseline dementia severity and (2) fastest 2-year decline with larger baseline ventricular size.ConclusionsClinical dementia severity associated with ventricular size may be (1) selectively moderated by complex and additive CR networks and (2) differentially represented by sex.Trials registrationClinicalTrials.gov, NCT01800214. Registered on 27 February 2013.

Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts.

BackgroundThere are few data concerning the association between season and cognition and its neurobiological correlates in older persons—effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects.Methods and findingsWe analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07–0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07–0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years’ difference in age (95% CI 2.1–8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10–1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aβ 42 level (amplitude 0.30 SD [95% CI 0.10–0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21–0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27–0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24–0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20–0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere.ConclusionsSeason has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.

The effect of white matter hyperintensities on verbal memory: Mediation by temporal lobe atrophy.

To determine the relationship between white matter hyperintensities (WMH) presumed to indicate disease of the cerebral small vessels, temporal lobe atrophy, and verbal memory deficits in Alzheimer disease (AD) and other dementias. We recruited groups of participants with and without AD, including strata with extensive WMH and minimal WMH, into a cross-sectional proof-of-principle study (n = 118). A consecutive case series from a memory clinic was used as an independent validation sample (n = 702; Sunnybrook Dementia Study; NCT01800214). We assessed WMH volume and left temporal lobe atrophy (measured as the brain parenchymal fraction) using structural MRI and verbal memory using the California Verbal Learning Test. Using path modeling with an inferential bootstrapping procedure, we tested an indirect effect of WMH on verbal recall that depends sequentially on temporal lobe atrophy and verbal learning. In both samples, WMH predicted poorer verbal recall, specifically due to temporal lobe atrophy and poorer verbal learning (proof-of-principle -1.53, 95% bootstrap confidence interval [CI] -2.45 to -0.88; and confirmation -0.66, 95% CI [-0.95 to -0.41] words). This pathway was significant in subgroups with (-0.20, 95% CI [-0.38 to -0.07] words, n = 363) and without (-0.71, 95% CI [-1.12 to -0.37] words, n = 339) AD. Via the identical pathway, WMH contributed to deficits in recognition memory (-1.82%, 95% CI [-2.64% to -1.11%]), a sensitive and specific sign of AD. Across dementia syndromes, WMH contribute indirectly to verbal memory deficits considered pathognomonic of Alzheimer disease, specifically by contributing to temporal lobe atrophy.

THE IMPACT OF SMALL VESSEL DISEASE BURDEN ON EXECUTIVE FUNCTIONING IN INDIVIDUALS WITH OR AT RISK FOR DEMENTIA

Cerebral small vessel disease (SVD) is common in Alzheimer's disease (AD) and worsens cognition, particularly executive functions. Previous work on this topic used composite measures of executive functions despite ample evidence that they are a collection of individual processes, not a unitary construct. We aimed to elucidate specific associations between regional SVD burden and individual executive measures, using white matter hyperintensities (WMH) as a measure of SVD burden. Participants were 470 adults (aged 50–89) from the Sunnybrook Dementia Study (ClinicalTrials.gov NCT01800214). Ninety-nine were cognitively normal (CN), 56 had mild cognitive impairment, no dementia (CIND) and 315 had AD. Participants with stroke, head trauma, substance abuse, or psychiatric/neurological disorders other than AD were not included. All underwent 1.5T MRI and neuropsychological assessment. Executive measures included phonemic/semantic fluency, forward/backward digit span, Rey figure copy, Wisconsin Card-Sorting Task (WCST), Trails A/B, Stroop, and Digit-Symbol Substitution. Raw scores were standardized against the CN group adjusted for age, sex and education. Regional (dorsolateral, superior medial, inferior medial) WMH volumes were quantified using Lesion Explorer segmentation software, corrected for head-size and normalized using log-transformation. These were entered together as predictors in linear regression models with Z scores on each test as the outcome measures, along with age, sex, and education as covariates. Models included all participants so that WMH/cognition relationships could be explored independently from diagnostic category. Right dorsolateral WMH volumes were negatively associated with Rey copy score (β=-2.6, p<.001); left dorsolateral WMH volumes were negatively associated with WCST total correct trials (β=-0.9, p=.036). Post-hoc analyses showed that WMH/Rey associations were driven primarily by AD participants, while WMH/WCST associations were driven by CIND participants. Results indicate that not all executive functions are affected equally by SVD, and regional distribution of WMH may be selectively associated with different tests. Determining specific associations between SVD/executive processes at different stages of AD is the first step in developing targeted process-specific treatments, which may improve other areas of cognition downstream. This study increases understanding of brain-behavior relationships in SVD, a potentially modifiable risk factor for dementia, in the context of cognitive symptoms in persons with or at risk for AD.

Dynamic Progression of White Matter Hyperintensities in Alzheimer's Disease and Normal Aging: Results from the Sunnybrook Dementia Study.

Although white matter hyperintensities (WMH), markers of cerebral small vessel disease (SVD), are believed to generally increase over time, some studies have shown sharp decreases after therapeutic intervention, suggesting that WMH progression may be more dynamic than previously thought. Our primary goal was to examine dynamic progression of WMH in a real-world sample of Alzheimer’s disease (AD) patients and normal elderly (NC), with varying degrees of SVD. WMH volumes from serial magnetic resonance imaging (MRI; mean = 1.8 years) were measured from NC (n = 44) and AD patients (n = 113) with high and low SVD burden. Dynamic progression for each individual was measured using spatial overlap images to assess shrinkage, growth, and stable WMH volumes. Significant group differences were found for shrinkage (p < 0.001), growth (p < 0.001) and stable (p < 0.001) WMH, where the AD high SVD group showed the largest changes relative to low SVD and NC. Our results suggest spatial progression measured at the individual patient level may be more sensitive to the dynamic nature of WMH.

White matter hyperintensity burden in elderly cohort studies: The Sunnybrook Dementia Study, Alzheimer's Disease Neuroimaging Initiative, and Three-City Study

Given the recent acknowledgement of the complex mixed pathologies that contribute to the clinical expression of dementia, various cohort studies have aimed to examine Alzheimer's disease and cerebrovascular disease as comorbid pathologies, with neuroimaging playing a central role in these studies. Using white matter hyperintensities (WMH) as a biomarker of cerebrovascular disease, we compared WMH burden between the Sunnybrook Dementia Study, the Alzheimer's Disease Neuroimaging Initiative (ADNI-1), the Three-City Study, and various other studies around the world. Based on our findings, it was evident that ADNI-1 had minimal WMH burden relative to other large studies that examine aging and dementia. This low WMH burden in ADNI-1 may be considered as both an advantage, representing a relatively “pure” sample with little confounding vasculopathy, and a disadvantage, as it limits generalizability to “real-world” patient populations with mixed pathologies and to nondemented groups with baseline vascular disease. We explore possible reasons for this distinction, including management of vascular risk factors, gaps in diagnostic criteria, and future directions for clinical research.

Cholinergic subcortical hyperintensities in Alzheimer's disease patients from the Sunnybrook Dementia Study: relationships with cognitive dysfunction and hippocampal atrophy.

Subcortical hyperintensities within the cholinergic fiber projections (chSH) on MRI are believed to reflect cerebral small vessel disease (SVD) which may adversely impact cognition. Additionally, hippocampal atrophy represents a commonly used biomarker to support the diagnosis of Alzheimer's disease (AD). To examine potential differences in neuropsychological test performance between AD patients (n = 234) with high and low chSH volumes and whether these differences corresponded to hippocampal atrophy. A modified version of Lesion Explorer was used to volumetrically quantify chSH severity. The Sunnybrook Hippocampal Volumetry Tool was applied to obtain hippocampal volumes. Composite z-scores to assess executive, memory, and visuospatial functioning were generated from standardized neuropsychological test performance scores. Inter-method technique validation demonstrated a high degree of correspondence with the Cholinergic Pathways Hyperintensities Scale (n = 40, ρ = 0.84, p < 0.001). After adjusting for brain atrophy, disease severity, global SH volumes, and demographic variables, multivariate analyses revealed a significant group difference, with the high chSH group demonstrating poorer memory function compared to the low chSH group (p = 0.03). A significant difference was found between low and high chSH groups in total (p < 0.05) and left (p < 0.01) hippocampal volume. These results suggest degradation of the cholinergic projections due to strategic SVD may independently contribute to memory dysfunction and hippocampal atrophy. Future studies examining subcortical vasculopathy in the cholinergic pathways may have implications on the development of therapeutic strategies for dementia and SVD.

Visible Virchow-Robin spaces on magnetic resonance imaging of Alzheimer's disease patients and normal elderly from the Sunnybrook Dementia Study.

Visible Virchow-Robin spaces (VRS) are commonly used markers for small vessel disease in aging and dementia. However, as previous reports were based on subjective visual ratings, the goal of this project was to validate and apply an MRI-based quantitative measure of VRS as a potential neuroimaging biomarker. A modified version of Lesion Explorer was applied to MRIs from Alzheimer's disease patients (AD: n = 203) and normal elderly controls (NC: n = 94). Inter-rater reliability, technique validity, group/gender differences, and correlations with other small vessel disease markers were examined (lacunes and white matter hyperintensities, WMH). Inter-rater reliability and spatial congruence was excellent (ICC = 0.99, SI = 0.96), and VRS volumes were highly correlated with established rating scales (CS: ρ = 0.84, p < 0.001; BG: ρ = 0.75, p < 0.001). Compared to NC, AD had significantly greater volumes of WMH (p < 0.01), lacunes (p < 0.001), and VRS in the white matter (p < 0.01), but not in the basal ganglia (n.s.). Compared to women, demented and non-demented men had greater VRS in the white matter (p < 0.001), but not in the basal ganglia (n.s.). Additionally, VRS were correlated with lacunes and WMH, but only in AD (r = 0.3, p < 0.01). Compared to women, men may be more susceptible to greater volumes of VRS, particularly in the white matter. RESULTS support the hypothesis that VRS in the white matter may be more related to AD-related vascular pathology compared to VRS found in the basal ganglia. Future work using this novel VRS segmentation tool will examine its potential utility as an imaging biomarker of vascular rather than parenchymal amyloid.

Subcortical hyperintensity volumetrics in Alzheimer's disease and normal elderly in the Sunnybrook Dementia Study: correlations with atrophy, executive function, mental processing speed, and verbal memory.

IntroductionSubcortical hyperintensities (SHs) are radiological entities commonly observed on magnetic resonance imaging (MRI) of patients with Alzheimer’s disease (AD) and normal elderly controls. Although the presence of SH is believed to indicate some form of subcortical vasculopathy, pathological heterogeneity, methodological differences, and the contribution of brain atrophy associated with AD pathology have yielded inconsistent results in the literature.MethodsUsing the Lesion Explorer (LE) MRI processing pipeline for SH quantification and brain atrophy, this study examined SH volumes of interest and cognitive function in a sample of patients with AD (n = 265) and normal elderly controls (n = 100) from the Sunnybrook Dementia Study.ResultsCompared with healthy controls, patients with AD were found to have less gray matter, less white matter, and more sulcal and ventricular cerebrospinal fluid (all significant, P <0.0001). Additionally, patients with AD had greater volumes of whole-brain SH (P <0.01), periventricular SH (pvSH) (P <0.01), deep white SH (dwSH) (P <0.05), and lacunar lesions (P <0.0001). In patients with AD, regression analyses revealed a significant association between global atrophy and pvSH (P = 0.02) and ventricular atrophy with whole-brain SH (P <0.0001). Regional volumes of interest revealed significant correlations with medial middle frontal SH volume and executive function (P <0.001) in normal controls but not in patients with AD, global pvSH volume and mental processing speed (P <0.01) in patients with AD, and left temporal SH volume and memory (P <0.01) in patients with AD.ConclusionsThese brain-behavior relationships and correlations with brain atrophy suggest that subtle, yet measurable, signs of small vessel disease may have potential clinical relevance as targets for treatment in Alzheimer’s dementia.

Treatment effects in multiple cognitive domains in Alzheimer's disease: a two-year cohort study.

IntroductionDespite widespread use of second-generation cholinesterase inhibitors for the symptomatic treatment of Alzheimer’s disease (AD), little is known about the long term effects of cholinergic treatment on global cognitive function and potential specific effects in different cognitive domains. The objectives of this study were to determine the association between cholinergic treatment and global cognitive function over one and two years in a cohort of patients with mild or moderate AD and identify potential differences in domain-specific cognitive outcomes within this cohort.MethodsA cohort of patients meeting the revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for mild or moderate AD, including patients both on treatment with a cholinesterase inhibitor and untreated controls (treated = 65, untreated = 65), were recruited from the Cognitive Neurology Clinic at Sunnybrook Health Sciences Centre, as part of the Sunnybrook Dementia Study. Patients were followed for one to two years and underwent standardized neuropsychological assessments to evaluate global and domain-specific cognitive function. Associations between cholinesterase inhibitor use and global and domain-specific cognitive outcome measures at one and two years of follow-up were estimated using mixed model linear regression, adjusting for age, education, and baseline mini mental state examination (MMSE).ResultsAt one year, treated patients showed significantly less decline in global cognitive function, and treatment and time effects across tests of executive and visuospatial function. At two years, there was a significant trend towards less decline in global cognition for treated patients. Moreover, treated patients showed significant treatment and time effects across tests of executive functioning, memory, and visuospatial function.ConclusionsThe present study offers two important contributions to knowledge of the effectiveness of cholinesterase inhibitor treatment in patients with mild-moderate AD: 1) that second-generation cholinesterase inhibitors demonstrate long-term effectiveness for reducing global cognitive decline over one to two years of follow-up, and 2) that decline in function for cognitive domains, including executive function, memory, and visuospatial skill that are primarily mediated by frontal networks and by the cholinergic system, rather than memory, may be slowed by treatment targeting the cholinergic system.

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. Cross-sectional observational study. Tertiary care hospital-based cognitive neurology subspecialty clinic. A convenience sample of 107 individuals with mild Alzheimer's disease (AD, n=75) or mild cognitive impairment (MCI, n=32) from the Sunnybrook Dementia Study. In addition to the MoCA, all participants completed the Mini-Mental State Examination (MMSE), the Mattis Dementia Rating Scale (DRS), and detailed neuropsychological testing. Convergent validity was supported, with MoCA scores correlating well with the MMSE (correlation coefficient (r)=0.66, P<.001) and the DRS (r=0.77, P<.001) and the MoCA better associated with the DRS than did the MMSE. Criterion validity was supported, with MoCA subscores according to cognitive domain correlating well with analogous neuropsychological tests and, in the case of memory (area under the receiver operating characteristic curve (AUC)=0.86), executive (AUC=0.79), and visuospatial function (AUC=0.79), being reasonably sensitive to impairment in those domains. The MoCA is a valid assessment of cognition that shows good agreement with existing screening tools and global measures (convergent validity) and was superior to the MMSE in this regard. The MoCA domain-specific subscores align with performance on more-detailed neuropsychological tests, suggesting not only good criterion validity for the MoCA, but also that it may be useful in guiding further neuropsychological testing.

Complexity of MRI White Matter Hyperintensity Assessments in Relation to Cognition in Aging and Dementia from the Sunnybrook Dementia Study

Quantification methods for white matter hyperintensities (WMH) on Magnetic Resonance Imaging are heterogeneous, deterring their application. This study compared three WMH rating scales, varying in complexity, and a volumetric method, to evaluate trade-offs between complexity and clinical utility in differentiating dementia subgroups and in correlating with cognition. WMH were rated using the Fazekas, Age-Related White Matter Changes (ARWMC) and Scheltens scales, and segmented by computational volumetry in 108 patients with Alzheimer's Disease (AD), 23 with Mild Cognitive Impairment (MCI) and 34 normal controls (NC). Global and hippocampal atrophy, age and education, were accounted for in correlations of WMH with cognitive domains. Intra- and inter-rater reliability were high (intraclass correlation coefficients = 0.88-0.97) across rating scales. WMH scores of all scales were highly correlated with volumes (Spearman r = 0.78-0.90, Ps < 0.001), as well as with each other (Spearman r = 0.86-0.91, Ps < 0.001). The Fazekas scale showed significant separation between AD, MCI and NC using non-parametric analysis, while the ARWMC and Scheltens' scales, and WMH volumes demonstrated significant correlations (standardized β = -0.19 to -0.24, Ps < 0.05) with cognitive domain scores using multivariate regression analysis, controlling for age, education, global and hippocampal atrophy in patients with AD. This study suggests that the degree of complexity of WMH rating scales did not affect validation against WMH volumes, but did vary in validation against cognition. The simplest scale performed best in separating cognitive subgroups, but the more complex scales and quantification correlated better with cognitive measures, especially executive function. Hence the best choice of scale depends on the particular application.

Advances in Vascular Cognitive Impairment

Advances in Vascular Cognitive Impairment

Independent Cognitive Effects of Atrophy and Diffuse Subcortical and Thalamico-Cortical Cerebrovascular Disease in Dementia

Brain atrophy, cortical infarction, and subcortical ischemic vasculopathy have all been associated with cognitive dysfunction. The interrelationships between these pathologies and their independent contributions to cognitive function remain unclear. Despite the high frequency of Alzheimer disease (AD) in those with clinically diagnosed vascular dementia, and the frequent findings of vascular disease in those with clinically diagnosed AD, many studies of brain-behavior relationships in dementia consider these populations separately. The present study sought to identify the correlates of independent domains of cognitive impairment in an unselected sample across a large range of severity and overlap of AD and VaD. Two hundred five individuals from the Sunnybrook Dementia Study recruited from a university Memory clinic had detailed neuropsychological testing and MRI quantification using a multi-step postprocessing algorithm. A factor analysis of the cognitive protocol yielded a 3-factor solution, provisionally labeled: (1) short-term memory and language, (2) attention and working memory, and (3) mental flexibility. A factor analysis of brain measures identified 3 independent factors with measures of (1) brain atrophy, (2) subcortical vascular disease, and (3) strategic infarcts (anterior-medial thalamus and cortical infarcts). After accounting for the effects of age and education, measures of brain atrophy were the strongest correlates of all cognitive domains. Small vessel disease was independently associated with general severity, impaired short-term memory/language, and reduced mental flexibility, but not with poor working memory, presumably through disruption of frontal-subcortical connections. In contrast, strategic infarcts to anterior-medial thalamus and cortical gray matter were associated with poor short-term and working memory, but not with impairments in mental flexibility or global severity measures. These data support the hypothesis that the thalamico-cortical network subserves both short-term and working memory. The findings also suggest that each type of pathology (atrophy, small vessel disease, and strategic infarcts) contribute independently to the pattern of cognitive disabilities associated with dementia. Particular attention to cerebrovascular disease in deep white or gray matter structures of the thalamico-cortical system is certainly warranted.