Gray matter loss relates to dual task gait in Lewy body disorders and aging.

BACKGROUND: Within the spectrum of Lewy body disorders (LBD), both Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by gait and balance disturbances, which become more prominent under dual-task (DT) conditions. The brain substrates underlying DT gait variations, however, remain poorly understood in LBD. OBJECTIVE: To investigate the relationship between gray matter volume loss and DT gait variations in LBD. METHODS: Seventy-nine participants including cognitively unimpaired PD, PD with mild cognitive impairment, PD with dementia (PDD), or DLB and 20 cognitively unimpaired controls were examined across a multi-site study. PDD and DLB were grouped together for analyses. Differences in gait speed between single and DT conditions were quantified by dual task cost (DTC). Cortical, subcortical, ventricle, and cerebellum brain volumes were obtained using FreeSurfer. Linear regression models were used to examine the relationship between gray matter volumes and DTC. RESULTS: Smaller amygdala and total cortical volumes, and larger ventricle volumes were associated with a higher DTC across LBD and cognitively unimpaired controls. No statistically significant interaction between group and brain volumes were found. Adding cognitive and motor covariates or white matter hyperintensity volumes separately to the models did not affect brain volume and DTC associations. CONCLUSION: Gray matter volume loss is associated with worse DT gait performance compared to single task gait, across cognitively unimpaired controls through and the LBD spectrum. Impairment in DT gait performance may be driven by age-related cortical neurodegeneration.

Brain iron content in cerebral amyloid angiopathy using quantitative susceptibility mapping.

Introduction: Cerebral amyloid angiopathy (CAA) is a small vessel disease that causes covert and symptomatic brain hemorrhaging. We hypothesized that persons with CAA would have increased brain iron content detectable by quantitative susceptibility mapping (QSM) on magnetic resonance imaging (MRI), and that higher iron content would be associated with worse cognition. Methods: Participants with CAA (n = 21), mild Alzheimer's disease with dementia (AD-dementia; n = 14), and normal controls (NC; n = 83) underwent 3T MRI. Post-processing QSM techniques were applied to obtain susceptibility values for regions of the frontal and occipital lobe, thalamus, caudate, putamen, pallidum, and hippocampus. Linear regression was used to examine differences between groups, and associations with global cognition, controlling for multiple comparisons using the false discovery rate method. Results: No differences were found between regions of interest in CAA compared to NC. In AD, the calcarine sulcus had greater iron than NC (ß = 0.99 [95% CI: 0.44, 1.53], q < 0.01). However, calcarine sulcus iron content was not associated with global cognition, measured by the Montreal Cognitive Assessment (p > 0.05 for all participants, NC, CAA, and AD). Discussion: After correcting for multiple comparisons, brain iron content, measured via QSM, was not elevated in CAA compared to NC in this exploratory study.

Dual-task gait and white matter hyperintensities in Lewy body diseases: An exploratory analysis.

Background: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are part of a spectrum of Lewy body disorders, who exhibit a range of cognitive and gait impairments. Cognitive-motor interactions can be examined by performing a cognitive task while walking and quantified by a dual task cost (DTC). White matter hyperintensities (WMH) on magnetic resonance imaging have also been associated with both gait and cognition. Our goal was to examine the relationship between DTC and WMH in the Lewy body spectrum, hypothesizing DTC would be associated with increased WMH volume. Methods: Seventy-eight participants with PD, PD with mild cognitive impairment (PD-MCI), PD with dementia or DLB (PDD/DLB), and 20 cognitively unimpaired participants were examined in a multi-site study. Gait was measured on an electronic walkway during usual gait, counting backward, animal fluency, and subtracting sevens. WMH were quantified from magnetic resonance imaging using an automated pipeline and visual rating. A median split based on DTC was performed. Models included age as well as measures of global cognition and cardiovascular risk. Results: Compared to cognitively unimpaired participants, usual gait speed was lower and DTC was higher in PD-MCI and PDD/DLB. Low DTC participants had higher usual gait speed. WMH burden was greater in high counting DTC participants. Frontal WMH burden remained significant after adjusting for age, cardiovascular risk and global cognition. Conclusion: Increased DTC was associated with higher frontal WMH burden in Lewy body disorders after adjusting for age, cardiovascular risk, and global cognition. Higher DTC was associated with age.

Mediators of cognitive impairment in cerebral amyloid angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with cognitive decline. CAA has diverse impacts on brain structure and function; however, the brain lesions that mediate the association of CAA with cognition are not understood well. AIMS: To determine the degree to which CAA neuroimaging biomarkers mediate the association of CAA with cognitive dysfunction. METHODS: We analyzed cross-sectional data of patients with probable CAA and controls without cognitive impairment from the Functional Assessment of Vascular Reactivity study. Neuropsychological tests were grouped into domains of memory, executive function, and processing speed. Candidate CAA neuroimaging biomarkers were pre-specified based on prior literature, consisting of white matter hyperintensity volume, peak width of skeletonized mean diffusivity (PSMD) on diffusion tensor magnetic resonance imaging (MRI), cerebrovascular reactivity (CVR), cortical thickness, and cortical thickness in a meta-region of interest typically affected by Alzheimer's disease (AD). Cognitive scores and neuroimaging markers were standardized and reported in relation to values in controls. Mediation analysis was used to estimate the total effect of CAA on cognition and the proportion of the total effect that was mediated by neuroimaging biomarkers, controlling for age, sex, and education. RESULTS: There were 131 participants (67 CAA and 64 controls). Mean age was 72.1 ± 7.7 years, and 54.2% were women. As expected, compared to controls, CAA was associated with lower cognition. In mediation analyses, CAA had direct unmediated effects of 48%, 46%, and 52% on all three cognitive domains. The association of CAA with memory was partially mediated by CVR and PSMD, accounting for 18% and 36% of the total effect of CAA. The association of CAA with executive function was partially mediated by PSMD and mean cortical thickness in the AD meta-region of interest (ROI), accounting for 33% and 31% of the total effect of CAA. The association of CAA with processing speed was partially mediated by CVR and PSMD, accounting for 8% and 34% of the total effect of CAA. Among CAA participants, the presence of cortical superficial siderosis was associated with lower processing speed. CONCLUSION: Altered white matter diffusivity (i.e. PSMD), CVR, and atrophy, taken together, account for about half the effect of CAA on cognition.

Quantitative Susceptibility Mapping Changes Relate to Gait Issues in Parkinson's Disease.

BACKGROUND: Quantitative susceptibility mapping (QSM) demonstrates elevated iron content in Parkinson's disease (PD) patients within the basal ganglia, though it has infrequently been studied in relation to gait difficulties including freezing of gait (FOG). Our purpose was to relate QSM of basal ganglia and extra-basal ganglia structures with qualitative and quantitative gait measures in PD. METHODS: This case-control study included PD and cognitively unimpaired (CU) participants from the Comprehensive Assessment of Neurodegeneration and Dementia study. Whole brain QSM was acquired at 3T. Region of interests (ROIs) were drawn blinded manually in the caudate nucleus, putamen, globus pallidus, pulvinar nucleus of the thalamus, red nucleus, substantia nigra, and dentate nucleus. Susceptibilities of ROIs were compared between PD and CU. Items from the FOG questionnaire and quantitative gait measures from PD participants were compared to susceptibilities. RESULTS: Twenty-nine participants with PD and 27 CU participants were included. There was no difference in susceptibility values in any ROI when comparing CU versus PD (p > 0.05 for all). PD participants with gait impairment (n = 23) had significantly higher susceptibility in the putamen (p = 0.008), red nucleus (p = 0.01), and caudate nucleus (p = 0.03) compared to those without gait impairment (n = 6). PD participants with FOG (n = 12) had significantly higher susceptibility in the globus pallidus (p = 0.03) compared to those without FOG (n = 17). Among quantitative gait measures, only stride time variability was significantly different between those with and without FOG (p = 0.04). CONCLUSION: Susceptibilities in basal ganglia and extra-basal ganglia structures are related to qualitative measures of gait impairment and FOG in PD.

Gait in Cerebral Amyloid Angiopathy.

Background Gait is a complex task requiring coordinated efforts of multiple brain networks. To date, there is little evidence on whether gait is altered in cerebral amyloid angiopathy (CAA). We aimed to identify impairments in gait performance and associations between gait impairment and neuroimaging markers of CAA, cognition, and falls. Methods and Results Gait was assessed using the Zeno Walkway during preferred pace and dual task walks, and grouped into gait domains (Rhythm, Pace, Postural Control, and Variability). Participants underwent neuropsychological testing and neuroimaging. Falls and fear of falling were assessed through self-report questionnaires. Gait domain scores were standardized and analyzed using linear regression adjusting for age, sex, height, and other covariates. Participants were patients with CAA (n=29), Alzheimer disease with mild dementia (n=16), mild cognitive impairment (n=24), and normal elderly controls (n=47). CAA and Alzheimer disease had similarly impaired Rhythm, Pace, and Variability, and higher dual task cost than normal controls or mild cognitive impairment. Higher Pace score was associated with better global cognition, processing speed, and memory. Gait measures were not correlated with microbleed count or white matter hyperintensity volume. Number of falls was not associated with gait domain scores, but participants with low fear of falling had higher Pace (odds ratio [OR], 2.61 [95% CI, 1.59-4.29]) and lower Variability (OR, 1.64 [95% CI, 1.10-2.44]). Conclusions CAA is associated with slower walking, abnormal rhythm, and greater gait variability than in healthy controls. Future research is needed to identify the mechanisms underlying gait impairments in CAA, and whether they predict future falls.

Cerebrovascular Reactivity Across the Entire Brain in Cerebral Amyloid Angiopathy.

BACKGROUND AND OBJECTIVES: Reduced cerebrovascular reactivity is proposed to be a feature of cerebral amyloid angiopathy (CAA) but has not been measured directly. Employing a global vasodilatory stimulus (hypercapnia), this study assessed the relationships between cerebrovascular reactivity and MRI markers of CAA and cognitive function. METHODS: In a cross-sectional study, individuals with probable CAA, mild cognitive impairment, or dementia due to Alzheimer disease and healthy controls underwent neuropsychological testing and an MRI that included a 5% carbon dioxide challenge. Cerebrovascular reactivity was compared across groups controlling for age, sex, and the presence of hypertension, and its associations with MRI markers of CAA in participants with CAA and with cognition across all participants were determined using multivariable linear regression adjusting for group, age, sex, education, and the presence of hypertension. RESULTS: Cerebrovascular reactivity data (mean ± SD) were available for 26 participants with CAA (9 female; 74.4 ± 7.7 years), 19 participants with mild cognitive impairment (5 female; 72.1 ± 8.5 years), 12 participants with dementia due to Alzheimer disease (4 female; 69.4 ± 6.6 years), and 39 healthy controls (30 female; 68.8 ± 5.4 years). Gray and whiter matter reactivity averaged across the entire brain was lower in participants with CAA and Alzheimer disease dementia compared to healthy controls, with a predominantly posterior distribution of lower reactivity in both groups. Higher white matter hyperintensity volume was associated with lower white matter reactivity (standardized coefficient [ß], 95% CI -0.48, -0.90 to -0.01). Higher gray matter reactivity was associated with better global cognitive function (ß 0.19, 0.03-0.36), memory (ß 0.21, 0.07-0.36), executive function (ß 0.20, 0.02-0.39), and processing speed (ß 0.27, 0.10-0.45) and higher white matter reactivity was associated with higher memory (ß 0.22, 0.08-0.36) and processing speed (ß 0.23, 0.06-0.40). CONCLUSIONS: Reduced cerebrovascular reactivity is a core feature of CAA and its assessment may provide an additional biomarker for disease severity and cognitive impairment.

Hepatitis C virus co-infection increases neurocognitive impairment severity and risk of death in treated HIV/AIDS.

Previous studies have reported that hepatitis C virus (HCV) co-infection worsens neurocognitive status among individuals with human immunodeficiency virus (HIV)-1 infection. We assessed the prevalence of neurologic disorders and the severity of HIV-associated neurocognitive impairment among HIV-infected individuals in two centralized HIV clinics in Alberta, Canada from 1998 to 2010 based on their HCV serostatus. Of 456 HIV-infected persons without concurrent substance abuse, 91 (20.0%) were HCV seropositive. Of 58 neurologic disorders identified in the cohort, HIV/HCV co-infected individuals exhibited a higher prevalence of multiple neurologic disorders compared to HIV-infected individuals (60.4% vs. 46.6%, p<0.05) and a higher frequency of seizures (28.6% vs. 17.8%, p<0.05). Unlike HIV mono-infected persons, the risk of seizures was independent of immune status in HIV/HCV co-infected individuals (p<0.05). Symptomatic HIV-associated neurocognitive disorders (sHAND) were more severe among HIV/HCV co-infected persons (p<0.05). HCV co-infection was associated with an increased mortality rate (24.2% vs. 14.5%, p<0.05) with a mortality hazard ratio of 2.38 after adjusting for demographic and clinical variables. Our results indicate that the presence of HCV co-infection among HIV-infected individuals increased neurologic disease burden and risk of death, underscoring HCV's capacity to affect the nervous system and survival of HIV-infected persons.