Quantifying cerebral microbleeds using quantitative susceptibility mapping from magnetization-prepared rapid gradient-echo.

T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) is commonly included in brain studies for structural imaging using magnitude images; however, its phase images can provide an opportunity to assess microbleed burden using quantitative susceptibility mapping (QSM). This potential application for MPRAGE-based QSM was evaluated using in vivo and simulated measurements. Possible factors affecting image quality were also explored. Detection sensitivity was evaluated against standard multiecho gradient echo (MEGE) QSM using 3-T in vivo data of 15 subjects with a combined total of 108 confirmed microbleeds. The two methods were compared based on the microbleed size and susceptibility measurements. In addition, simulations explored the detection sensitivity of MPRAGE-QSM at different representative magnetic field strengths and echo times using microbleeds of different size, susceptibility, and location. Results showed that in vivo microbleeds appeared to be smaller (× 0.54) and of higher mean susceptibility (× 1.9) on MPRAGE-QSM than on MEGE-QSM, but total susceptibility estimates were in closer agreement (slope: 0.97, r2: 0.94), and detection sensitivity was comparable. In simulations, QSM at 1.5 T had a low contrast-to-noise ratio that obscured the detection of many microbleeds. Signal-to-noise ratio (SNR) levels at 3 T and above resulted in better contrast and increased detection. The detection rates for microbleeds of minimum one-voxel diameter and 0.4-ppm susceptibility were 0.55, 0.80, and 0.88 at SNR levels of 1.5, 3, and 7 T, respectively. Size and total susceptibility estimates were more consistent than mean susceptibility estimates, which showed size-dependent underestimation. MPRAGE-QSM provides an opportunity to detect and quantify the size and susceptibility of microbleeds of at least one-voxel diameter at B0 of 3 T or higher with no additional time cost, when standard T2*-weighted images are not available or have inadequate spatial resolution. The total susceptibility measure is more robust against sequence variations and might allow combining data from different protocols.

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.

Association of homocysteine with ventricular dilatation and brain atrophy in Parkinson's disease.

Parkinson's disease (PD) patients are treated with levodopa (L-dopa) to help stabilize their impaired motor abilities; however, L-dopa leads to increased homocysteine (Hcy) levels, which may have a deleterious effect on brain structure and function. The purpose of this study was to examine the impact of increased Hcy concentration on global brain atrophy as determined by magnetic resonance imaging in PD patients and controls. The effect of high Hcy level on ventricular dilatation (percentage of intracranial volume [%ICV]) and total tissue volume (%ICV) was examined at baseline and longitudinally at 36 months. Age, sex, education, and L-dopa duration (in PD patients) were included as covariates. Elevated Hcy levels correlated positively with ventricular dilatation (%ICV) in the whole sample (P = 0.004) and in the PD group (P = 0.008). At baseline, adults with a high Hcy level (>14 µmol/L) had higher ventricular volume (%ICV) than adults with a low Hcy level (≤ 14 µmol/L) in the whole sample (P = 0.006) and in the PD group (P = 0.03), which persisted over 36 months in both the whole sample (P = 0.004) and the PD group (P = 0.03). PD patients with high Hcy concentrations had a greater rate of ventricular enlargement (%ICV) over time compared with those with low Hcy concentration (P = 0.02). Elevated Hcy concentration was associated with increased ventricular dilatation (%ICV) in PD patients. A larger sample with a broader age range and longer follow-up is needed to establish the consequences of high Hcy level, including interactions with genetic and environmental risk factors, in PD.

Cognitive Speed in Neurodegenerative Disease: Comparing Mean Rate and Inconsistency Within and Across the Alzheimer's and Lewy Body Spectra in the COMPASS-ND Study.

Background: Alzheimer's disease (AD) and Lewy body disease (LBD) are characterized by early and gradual worsening perturbations in speeded cognitive responses. Objective: Using simple and choice reaction time tasks, we compared two indicators of cognitive speed within and across the AD and LBD spectra: mean rate (average reaction time across trials) and inconsistency (within person variability). Methods: The AD spectrum cohorts included subjective cognitive impairment (SCI, n = 28), mild cognitive impairment (MCI, n = 121), and AD (n = 45) participants. The LBD spectrum included Parkinson's disease (PD, n = 32), mild cognitive impairment in PD (PD-MCI, n = 21), and LBD (n = 18) participants. A cognitively unimpaired (CU, n = 39) cohort served as common benchmark. We conducted multivariate analyses of variance and discrimination analyses. Results: Within the AD spectrum, the AD cohort was slower and more inconsistent than the CU, SCI, and MCI cohorts. The MCI cohort was slower than the CU cohort. Within the LBD spectrum, the LBD cohort was slower and more inconsistent than the CU, PD, and PD-MCI cohorts. The PD-MCI cohort was slower than the CU and PD cohorts. In cross-spectra (corresponding cohort) comparisons, the LBD cohort was slower and more inconsistent than the AD cohort. The PD-MCI cohort was slower than the MCI cohort. Discrimination analyses clarified the group difference patterns. Conclusions: For both speed tasks, mean rate and inconsistency demonstrated similar sensitivity to spectra-related comparisons. Both dementia cohorts were slower and more inconsistent than each of their respective non-dementia cohorts.

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.

Dementia Risk Prediction in a Longitudinal Geriatric Parkinson's Disease Cohort: Evaluation and Application of the Montreal Parkinson Risk of Dementia Scale.

Background: Parkinson's disease (PD) increases risk for dementia and cascading adverse outcomes. The eight-item Montreal Parkinson Risk of Dementia Scale (MoPaRDS) is a rapid, in-office dementia screening tool. We examine predictive validity and other characteristics of the MoPaRDS in a geriatric PD cohort by testing a series of alternative versions and modelling risk score change trajectories. Methods: Participants were 48 initially non-demented PD patients (Mage = 71.6 years, range = 65-84) from a three-year, three-wave prospective Canadian cohort study. A dementia diagnosis at Wave 3 was used to stratify two baseline groups: PD with Incipient Dementia (PDID) and PD with No Dementia (PDND). We aimed to predict dementia three years prior to diagnosis using baseline data for eight indicators that harmonized with the original report, plus education. Results: Three MoPaRDS items (age, orthostatic hypotension, mild cognitive impairment [MCI]) discriminated the groups both independently and as a composite three-item scale (area under the curve [AUC] = 0.88). The eight-item MoPaRDS reliably discriminated PDID from PDND (AUC = 0.81). Education did not improve predictive validity (AUC = 0.77). Performance of the eight-item MoPaRDS varied across sex (AUCfemales = 0.91; AUCmales = 0.74), whereas the three-item configuration did not (AUCfemales = 0.88; AUCmales = 0.91). Risk scores of both configurations increased over time. Conclusions: We report new data on the application of the MoPaRDS as a dementia prediction tool for a geriatric PD cohort. Results support the viability of the full MoPaRDS, and indicate that an empirically determined brief version is a promising complement.

Identifying key multi-modal predictors of incipient dementia in Parkinson's disease: a machine learning analysis and Tree SHAP interpretation.

Background: Persons with Parkinson's disease (PD) differentially progress to cognitive impairment and dementia. With a 3-year longitudinal sample of initially non-demented PD patients measured on multiple dementia risk factors, we demonstrate that machine learning classifier algorithms can be combined with explainable artificial intelligence methods to identify and interpret leading predictors that discriminate those who later converted to dementia from those who did not. Method: Participants were 48 well-characterized PD patients (Mbaseline age = 71.6; SD = 4.8; 44% female). We tested 38 multi-modal predictors from 10 domains (e.g., motor, cognitive) in a computationally competitive context to identify those that best discriminated two unobserved baseline groups, PD No Dementia (PDND), and PD Incipient Dementia (PDID). We used Random Forest (RF) classifier models for the discrimination goal and Tree SHapley Additive exPlanation (Tree SHAP) values for deep interpretation. Results: An excellent RF model discriminated baseline PDID from PDND (AUC = 0.84; normalized Matthews Correlation Coefficient = 0.76). Tree SHAP showed that ten leading predictors of PDID accounted for 62.5% of the model, as well as their relative importance, direction, and magnitude (risk threshold). These predictors represented the motor (e.g., poorer gait), cognitive (e.g., slower Trail A), molecular (up-regulated metabolite panel), demographic (age), imaging (ventricular volume), and lifestyle (activities of daily living) domains. Conclusion: Our data-driven protocol integrated RF classifier models and Tree SHAP applications to selectively identify and interpret early dementia risk factors in a well-characterized sample of initially non-demented persons with PD. Results indicate that leading dementia predictors derive from multiple complementary risk domains.

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.

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.

Subcortical volumes in cerebral amyloid angiopathy compared with Alzheimer's disease and controls.

Background: Previous reports have suggested that patients with cerebral amyloid angiopathy (CAA) may harbor smaller white matter, basal ganglia, and cerebellar volumes compared to age-matched healthy controls (HC) or patients with Alzheimer's disease (AD). We investigated whether CAA is associated with subcortical atrophy. Methods: The study was based on the multi-site Functional Assessment of Vascular Reactivity cohort and included 78 probable CAA (diagnosed according to the Boston criteria v2.0), 33 AD, and 70 HC. Cerebral and cerebellar volumes were extracted from brain 3D T1-weighted MRI using FreeSurfer (v6.0). Subcortical volumes, including total white matter, thalamus, basal ganglia, and cerebellum were reported as proportion (%) of estimated total intracranial volume. White matter integrity was quantified by the peak width of skeletonized mean diffusivity. Results: Participants in the CAA group were older (74.0 ± 7.0, female 44%) than the AD (69.7 ± 7.5, female 42%) and HC (68.8 ± 7.8, female 69%) groups. CAA participants had the highest white matter hyperintensity volume and worse white matter integrity of the three groups. After adjusting for age, sex, and study site, CAA participants had smaller putamen volumes (mean differences, -0.024% of intracranial volume; 95% confidence intervals, -0.041% to -0.006%; p = 0.005) than the HCs but not AD participants (-0.003%; -0.024 to 0.018%; p = 0.94). Other subcortical volumes including subcortical white matter, thalamus, caudate, globus pallidus, cerebellar cortex or cerebellar white matter were comparable between all three groups. Conclusion: In contrast to prior studies, we did not find substantial atrophy of subcortical volumes in CAA compared to AD or HCs, except for the putamen. Differences between studies may reflect heterogeneity in CAA presenting syndromes or severity.

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.

Pedunculopontine Nucleus Dysconnectivity Correlates With Gait Impairment in Parkinson's Disease: An Exploratory Study.

Background: Gait impairment is a debilitating and progressive feature of Parkinson's disease (PD). Increasing evidence suggests that gait control is partly mediated by cholinergic signaling from the pedunculopontine nucleus (PPN). Objective: We investigated whether PPN structural connectivity correlated with quantitative gait measures in PD. Methods: Twenty PD patients and 15 controls underwent diffusion tensor imaging to quantify structural connectivity of the PPN. Whole brain analysis using tract-based spatial statistics and probabilistic tractography were performed using the PPN as a seed region of interest for cortical and subcortical target structures. Gait metrics were recorded in subjects' medication ON and OFF states, and were used to determine if specific features of gait dysfunction in PD were related to PPN structural connectivity. Results: Tract-based spatial statistics revealed reduced structural connectivity involving the corpus callosum and right superior corona radiata, but did not correlate with gait measures. Abnormalities in PPN structural connectivity in PD were lateralized to the right hemisphere, with pathways involving the right caudate nucleus, amygdala, pre-supplementary motor area, and primary somatosensory cortex. Altered connectivity of the right PPN-caudate nucleus was associated with worsened cadence, stride time, and velocity while in the ON state; altered connectivity of the right PPN-amygdala was associated with reduced stride length in the OFF state. Conclusion: Our exploratory analysis detects a potential correlation between gait dysfunction in PD and a characteristic pattern of connectivity deficits in the PPN network involving the right caudate nucleus and amygdala, which may be investigated in future larger studies.

Diffusion tensor tractography of the fornix in cerebral amyloid angiopathy, mild cognitive impairment and Alzheimer's disease.

PURPOSE: Cerebral amyloid angiopathy (CAA) is a common neuropathological finding and clinical entity that occurs independently and with co-existent Alzheimer's disease (AD) and small vessel disease. We compared diffusion tensor imaging (DTI) metrics of the fornix, the primary efferent tract of the hippocampus between CAA, AD and Mild Cognitive Impairment (MCI) and healthy controls. METHODS: Sixty-eight healthy controls, 32 CAA, 21 AD, and 26 MCI patients were recruited at two centers. Diffusion tensor images were acquired at 3 T with high spatial resolution and fluid-attenuated inversion recovery (FLAIR) to suppress cerebrospinal fluid (CSF) and minimize partial volume effects on the fornix. The fornix was delineated with deterministic tractography to yield mean diffusivity (MD), axial diffusivity (AXD), radial diffusivity (RD), fractional anisotropy (FA) and tract volume. Volumetric measurements of the hippocampus, thalamus, and lateral ventricles were obtained using T1-weighted MRI. RESULTS: Diffusivity (MD, AXD, and RD) of the fornix was highest in AD followed by CAA compared to controls; the MCI group was not significantly different from controls. FA was similar between groups. Fornix tract volume was âˆ¼ 30% lower for all three patient groups compared to controls, but not significantly different between the patient groups. Thalamic and hippocampal volumes were preserved in CAA, but lower in AD and MCI compared to controls. Lateral ventricular volumes were increased in CAA, AD and MCI. Global cognition, memory, and executive function all correlated negatively with fornix diffusivity across the combined clinical group. CONCLUSION: There were significant diffusion changes of the fornix in CAA, AD and MCI compared to controls, despite relatively intact thalamic and hippocampal volumes in CAA, suggesting the mechanisms for fornix diffusion abnormalities may differ in CAA compared to AD and MCI.

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.

Ventricular dilatation and brain atrophy in patients with Parkinson's disease with incipient dementia.

Age-related ventricular enlargement is accelerated in Alzheimer's disease, but its relationship to cognitive decline in Parkinson's disease is less clear, even though dementia is common in Parkinson's disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinson's disease patients developing cognitive decline. Older nondemented patients with Parkinson's disease (33) and age- and sex-matched controls (39) were recruited and prospectively assessed for the development of significant cognitive decline over 36 months. Magnetic resonance imaging was obtained every 18 months, and ventricular volume and total brain gray and white matter volumes were measured using reliable segmentation of T1-weighted volumetric scans. Subjects with incidental intracranial abnormalities, an atypical course, and stroke as well as dropouts were excluded from a cohort of 52 patients and 50 controls. Among 33 patients and 39 controls, 10 patients and 3 controls developed significant cognitive impairment or dementia. Ventricular change and Parkinson's disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini-Mental Status Examination in the Parkinson's disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinson's disease with dementia, with similar change over time in both Parkinson's disease and Parkinson's disease with dementia. White matter volumes were not significantly different between Parkinson's disease and Parkinson's disease with dementia; however, the decrease over time might be greater in Parkinson's disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinson's disease, possibly reflecting both cortical gray and white matter loss.

Association of Orthostatic Hypotension With Cerebral Atrophy in Patients With Lewy Body Disorders.

OBJECTIVE: To evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: Supine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales. RESULTS: A total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy (p = 0.004) and regional atrophy involving the anterior-temporal (p = 0.001) and mediotemporal (p = 0.001) regions, greater in severe vs nonsevere OH (p = 0.001). The WMH burden was similar in those with and without OH (p = 0.49). SH was not associated with brain atrophy (p = 0.59) or WMH (p = 0.72). CONCLUSIONS: OH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.

Corpus callosum and cingulum tractography in Parkinson's disease.

BACKGROUND: In Parkinson's disease (PD) cell loss in the substantia nigra is known to result in motor symptoms; however widespread pathological changes occur and may be associated with non-motor symptoms such as cognitive impairment. Diffusion tensor imaging is a quantitative imaging method sensitive to the micro-structure of white matter tracts. OBJECTIVE: To measure fractional anisotropy (FA) and mean diffusivity (MD) values in the corpus callosum and cingulum pathways, defined by diffusion tensor tractography, in patients with PD, PD with dementia (PDD) and controls and to determine if these measures correlate with Mini-Mental Status Examination (MMSE) scores in parkinsonian patients. METHODS: Patients with PD (17 Males [M], 12 Females [F]), mild PDD (5 M, 1 F) and controls (8 M, 7 F) underwent cognitive testing and MRI scans. The corpus callosum was divided into four regions and the cingulum into two regions bilaterally to define tracts using the program DTIstudio (Johns Hopkins University) using the fiber assignment by continuous tracking algorithm. Volumetric MRI scans were used to measure white and gray matter volumes. RESULTS: Groups did not differ in age or education. There were no overall FA or MD differences between groups in either the corpus callosum or cingulum pathways. In PD subjects the MMSE score correlated with MD within the corpus callosum. These findings were independent of age, sex and total white matter volume. CONCLUSIONS: The data suggest that the corpus callosum or its cortical connections are associated with cognitive impairment in PD patients.

Cognitive and motor correlates of grey and white matter pathology in Parkinson's disease.

INTRODUCTION: Previous studies have found associations between grey matter atrophy and white matter hyperintensities (WMH) of vascular origin with cognitive and motor deficits in Parkinson's disease (PD). Here we investigate these relationships in a sample of PD patients and age-matched healthy controls. METHODS: Data included 50 PD patients and 45 age-matched controls with T1-weighted and FLAIR scans at baseline, 18-months, and 36-months follow-up. Deformation-based morphometry was used to measure grey matter atrophy. SNIPE (Scoring by Nonlocal Image Patch Estimator) was used to measure Alzheimer's disease-like textural patterns in the hippocampi. WMHs were segmented using T1-weighted and FLAIR images. The relationship between MRI features and clinical scores was assessed using mixed-effects models. The motor subscore of the Unified Parkinson's Disease Rating Scale (UPDRSIII), number of steps in a walking trial, and Dementia Rating Scale (DRS) were used respectively as measures of motor function, gait, and cognition. RESULTS: Substantia nigra atrophy was significantly associated with motor deficits, with a greater impact in PDs (p < 0.05). Hippocampal SNIPE scores were associated with cognitve decline in both PD and controls (p < 0.01). WMH burden was significantly associated with cognitive decline and increased motor deficits in the PD group, and gait deficits in both PD and controls (p < 0.03). CONCLUSION: While substantia nigra atrophy and WMH burden were significantly associated with additional motor deficits, WMH burden and hippocampal atrophy were associated with cognitive deficits in PD patients. These results suggest an additive contribution of both grey and white matter damage to the motor and cognitive deficits in PD.

Temporal lobe changes in early, untreated Parkinson's disease.

The purpose of this study was to determine if focal cortical abnormalities may occur in early Parkinson's disease (PD). We studied 26 untreated patients with early PD and 14 healthy control subjects, with cognitive screening and magnetic resonance imaging (MRI). Voxel-based morphometry was used to assess for the presence of localized cortical grey matter (GM) and/or subcortical white matter (WM) changes. Patient and control groups showed no differences in age or gender distribution. Females had a greater GM% than males (P = 0.001). Comparison of patients and controls revealed no difference in local GM volumes. In PD, however, there was decreased WM volume in the anterior right fusiform gyrus and superior temporal gyrus. There were no correlations between the California Verbal Learning Test long delay free recall, Judgment of Line Orientation, Trail Making A or B and either the GM or WM localized volumes. These results suggest that right anterior temporal lobe changes occur in untreated patients with PD. The earliest changes may occur in subcortical white matter rather than temporal cortex.