Donald T. Stuss’s research while affiliated with University of Toronto and other places

Objective Some features of attention-deficit/hyperactivity disorder (ADHD) may resemble those of mild cognitive impairment (MCI) in older adults, contributing to diagnostic uncertainty in individuals seeking assessment in memory clinics. We systematically compared cognition and brain structure in ADHD and MCI to clarify the extent of overlap and identify potential features unique to each. Method Older adults from a Cognitive Neurology clinic (40 ADHD, 29 MCI, 37 controls) underwent neuropsychological assessment. A subsample (n = 80) underwent structural neuroimaging. Results Memory was impaired in both patient groups, but reflected a storage deficit in MCI (supported by relatively smaller hippocampi) and an encoding deficit in ADHD (supported by frontal lobe thinning). Both groups displayed normal executive functioning. Semantic retrieval was uniquely impaired in MCI. Conclusion Although ADHD has been proposed as a dementia risk factor or prodrome, we propose it is rather a pathophysiologically-unique phenotypic mimic acting via overlap in memory and executive performance.

Introduction: Disability is common across Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). White matter hyperintensities (WMHs) are prevalent in both diagnoses and associated with disability; both diagnoses show neuropsychiatric symptoms (NPS) and impaired cognition. Methods: In AD and DLB, we examined if WMHs, NPS, and cognition associate with basic and/or instrumental activities of daily living (BADLs and/or IADLs) cross-sectionally, and longitudinally over ≈1.4 years. Results: Across both diagnoses, NPS were not only associated with greater disability in performing both BADLs and IADLs, but were also associated with a decline in the ability to perform BADLs in the AD group. In the DLB group only, higher WMH volume was associated with greater disability in performing both BADLs and IADLs, and was associated with a decline in the ability to perform BADL over time. Discussion: Management of NPS and WMHs, particularly in DLB, might help maintain functionality in dementia patients for longer.

Background We 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). Methods Autopsy-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. Results Burden and regional distribution of WMH differed significantly between neuropathological groups ( F 5,77 = 2.67, P’ = 0.029), with the FTLD-TDP group having the highest mean volume globally (8032 ± 8889 mm ³ ) and in frontal regions (4897 ± 6163 mm ³ ). The AD group had the highest mean volume in occipital regions (468 ± 420 mm ³ ). 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. Conclusions These 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.

Background We 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).Methods Autopsy-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). Data analyses included ANCOVA to compare the burden of WMH on antemortem brain MRI between groups and adjusted linear regression models to identify associations between WMH burden and neuropsychiatric symptoms. ResultsBurden and regional distribution of WMH differed significantly between neuropathological groups ( F 5,77 = 2.67, P’ = 0.029), with the FTLD-TDP group having the highest mean volume globally (8,031.50 ± 8,889.15 mm ³ ) and in frontal regions (4,897.45 ± 6,163.22 mm ³ ). The AD group had the highest mean volume in occipital regions (468.25 ± 420.04 mm ³ ). 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. Conclusions These 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.

Background Large‐scale brain networks are disrupted in Alzheimer’s disease (AD). We posit that network disruption may be explained by additive and multifactor knockout of multiple networks (functional and structural) as opposed to a single system or set of subsystems. Here we test this hypothesis using a data‐driven structural covariance network analysis. Methods Demographic, imaging and available biomarker data were downloaded from 77 normal controls (NC) (age= 72±6, M/F=33/44), 106 persons with amnestic mild cognitive impairment (MCI) (age= 73±8, M/F=70/36) and 42 persons with Alzheimer’s dementia (age=75±9, M/F=25/17) that participated in the Alzheimer’s Disease Neuroimaging Initiative 2.0. We used a multivariate covariance technique to isolate large‐scale grey matter networks that relate fiber tract microstructure derived at different stages of injury to vertex‐based cortical thickness maps. Cortical thickness was computed from 3.0 Telsa T1‐weighted MRI and tract‐based white matter microstructural measures were performed using diffusion tensor imaging; these data were submitted to a multivariate data‐driven analysis. Measures of network integrity (NII) were computed for each significant covariance network for all participants. Univariate models assessed the relationship between biomarkers, demographic variables and NIIs for each network. Network knockouts were defined as an NII <1.5 SD below the NC group average for a given network. Knockout combinations were characterized across individuals and average knockout numbers were compared between groups. Results Eight network ensembles related to tract‐based connectivity or recapitulated functional network architecture. Degradation of these systems was additively and differentially linked to increased age, APOE e4 genotype and unique combinations of white matter hyperintensity volume, CSF markers (CSF amyloid and Tau protein levels) and hippocampal volume in MCI. Knockouts exponentially and significantly increased across groups: NC>MCI>AD (P<0.01). There were 64 unique network knockout combinations across all participants. Conclusion Heterogeneous pathological exposures may additively and differentially disrupt large‐scale networks, leading to many possible network knockout sequences that accumulate exponentially from MCI to AD. These findings may partially explain the endophenotypic heterogeneity in AD and should be assessed in other cohort samples.

Objective Stroke lesions in non-auditory areas may affect higher-order central auditory processing. We sought to characterize auditory functions in chronic stroke survivors with unilateral arm/hand impairment using auditory evoked responses (AERs) with lesion and perception metrics. Methods The AERs in 29 stroke survivors and 14 controls were recorded with single tones, active and passive frequency-oddballs, and a dual-oddball with pitch-contour and time-interval deviants. Performance in speech-in-noise, mistuning detection, and moving-sound detection was assessed. Relationships between AERs, behaviour, and lesion overlap with functional networks, were examined. Results Despite their normal hearing, eight patients showed unilateral AER in the contra-lesional hemisphere with reduced amplitude compared to those with bilateral AERs. Both groups showed increasing attenuation of later components. Hemispheric asymmetry of AER sources was reduced in bilateral-AER patients. N1 and P2 were delayed in individuals with lesions in the basal-ganglia and white-matter, while lesions in the attention network reduced the frequency-MMN (mismatch negativity) responses and increased the pitch-contour P3a response. Patients’ impaired speech-in-noise perception was explained by AER measures and frequency-deviant detection performance with multiple regression. Conclusion AERs reflect disruption of auditory functions due to damage outside of temporal lobe, and further explain complexity of neural mechanisms underlying higher-order auditory perception. Significance Stroke survivors without obvious hearing problems may benefit from rehabilitation for central auditory processing.

Cognitive Changes and the Aging Brain - edited by Kenneth M. Heilman December 2019

White matter hyperintensities (WMH) are presumed to indicate subcortical ischemic vascular disease but their underlying pathobiology remains incompletely understood. The soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory and vasoactive cytochrome p450-derived polyunsaturated fatty acid epoxides into their less active corresponding diol species. Under the hypothesis that the activity of sEH might be associated with subcortical ischemic vascular disease and vascular cognitive impairment, this study aimed to compare the relative abundance of sEH substrates and products in peripheral blood between patients with extensive WMH (discovered due to transient ischemic attack; n = 29) and healthy elderly with minimal WMH (n = 25). The concentration of 12,13-DiHOME (a sEH-derived linoleic acid metabolite), and the ratio of 12,13-DiHOME to its sEH substrate, 12,13-EpOME, were elevated in the extensive WMH group (F1,53 = 5.9, p = 0.019), as was the 9,10-DiHOME/9,10-EpOME ratio (F1,53 = 5.4, p = 0.024). The 12,13-DiHOME/12,13-EpOME ratio was associated with poorer performance on a composite score derived from tests of psychomotor processing speed, attention, and executive function (β = − 0.473, p = 0.001, adjusted r² = 0.213), but not with a composite verbal memory score. In a mediation model, periventricular WMH (but not deep WMH), explained 37% of the effect of the 12,13-DiHOME/12,13-EpOME ratio on the speed/attention/executive function composite score (indirect effect = − 0.50, 95% bootstrap confidence interval [− 0.99, − 0.17] Z-score units). Serum oxylipin changes consistent with higher sEH activity were markers of vascular cognitive impairment, and this association was partly explained by injury to the periventricular subcortical white matter. Full text via SharedIt: https://rdcu.be/bbKF9

Objective: To determine if APOE ε4 influences the association between white matter hyperintensities (WMH) and cognitive impairment in Alzheimer disease (AD) and dementia with Lewy bodies (DLB). Methods: A total of 289 patients (AD = 239; DLB = 50) underwent volumetric MRI, neuropsychological testing, and APOE ε4 genotyping. Total WMH volumes were quantified. Neuropsychological test scores were included in a confirmatory factor analysis to identify cognitive domains encompassing attention/executive functions, learning/memory, and language, and factor scores for each domain were calculated per participant. After testing interactions between WMH and APOE ε4 in the full sample, we tested associations of WMH with factor scores using linear regression models in APOE ε4 carriers (n = 167) and noncarriers (n = 122). We hypothesized that greater WMH volume would relate to worse cognition more strongly in APOE ε4 carriers. Findings were replicated in 198 patients with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI-I), and estimates from both samples were meta-analyzed. Results: A significant interaction was observed between WMH and APOE ε4 for language, but not for memory or executive functions. Separate analyses in APOE ε4 carriers and noncarriers showed that greater WMH volume was associated with worse attention/executive functions, learning/memory, and language in APOE ε4 carriers only. In ADNI-I, greater WMH burden was associated with worse attention/executive functions and language in APOE ε4 carriers only. No significant associations were observed in noncarriers. Meta-analyses showed that greater WMH volume was associated with worse performance on all cognitive domains in APOE ε4 carriers only. Conclusion: APOE ε4 may influence the association between WMH and cognitive performance in AD and DLB.

The goal of this study was to identify neurostructural frontal lobe correlates of cognitive and speaking rate changes in amyotrophic lateral sclerosis (ALS). 17 patients diagnosed with ALS and 12 matched controls underwent clinical, bulbar, and neuropsychological assessment and structural neuroimaging. Neuropsychological testing was performed via a novel computerized frontal battery (ALS-CFB), based on a validated theoretical model of frontal lobe functions, and focused on testing energization, executive function, emotion processing, theory of mind, and behavioral inhibition via antisaccades. The measure of speaking rate represented bulbar motor changes. Neuroanatomical assessment was performed using volumetric analyses focused on frontal lobe regions, postcentral gyrus, and occipital lobes as controls. Partial least square regressions (PLS) were used to predict behavioral (cognitive and speech rate) outcomes using volumetric measures. The data supported the overall hypothesis that distinct behavioral changes in cognition and speaking rate in ALS were related to specific regional neurostructural brain changes. These changes did not support a notion of a general dysexecutive syndrome in ALS. The observed specificity of behavior-brain changes can begin to provide a framework for subtyping of ALS. The data also support a more integrative framework for clinical assessment of frontal lobe functioning in ALS, which requires both behavioral testing and neuroimaging.