Moderate White Matter Hyperintensities Research Articles

Glymphatic dysfunction mediates the influence of choroid plexus enlargement on information processing speed in patients with white matter hyperintensities.

Glymphatic dysfunction has been correlated with cognitive decline, with a higher choroid plexus volume (CPV) being linked to a slower glymphatic clearance rate. Nevertheless, the interplay between CPV, glymphatic function, and cognitive impairment in white matter hyperintensities (WMHs) has not yet been investigated. In this study, we performed neuropsychological assessment, T1-weighted three-dimensional (3D-T1) images, and diffusion tensor imaging (DTI) in a cohort of 206 WMHs subjects and 43 healthy controls (HCs) to further explore the relationship. The DTI analysis along the perivascular space (DTI-ALPS) index, as a measure of glymphatic function, was calculated based on DTI. Severe WMHs performed significantly worse in information processing speed (IPS) than other three groups, as well as in executive function than HCs and mild WMHs. Additionally, severe WMHs demonstrated lower DTI-ALPS index and higher CPV than HCs and mild WMHs. Moderate WMHs displayed higher CPV than HCs and mild WMHs. Mini-Mental State Examination, IPS, and executive function correlated negatively with CPV but positively with DTI-ALPS index in WMHs patients. Glymphatic function partially mediated the association between CPV and IPS, indicating a potential mechanism for WMHs-related cognitive impairment. CPV may act as a valuable prognostic marker and glymphatic system as a promising therapeutic target for WMHs-related cognitive impairment.

Neuropsychiatric symptoms and white matter hyperintensities in older adults without dementia.

We aimed to examine associations between neuropsychiatric symptoms (NPS) and white matter hyperintensities (WMH) status in older adults without dementia under the hypothesis that WMH increased the odds of having NPS. Longitudinal analysis of data acquired from the National Alzheimer's Coordinating Center Uniform Data Set. Data were derived from 46 National Institute on Aging - funded Alzheimer's Disease Research Centers. NACC participants aged ≥50 years with available data on WMH severity with a diagnosis of mild cognitive impairment (MCI) or who were cognitively unimpaired (CU) were studied. Among 4617 CU participants, 376 had moderate and 54 extensive WMH. Among 3170 participants with MCI, 471 had moderate and 88 had extensive WMH. Using Cardiovascular Health Study (CHS) scores, WMH were coded as no to mild (CHS score: 0-4), moderate (score: 5-6) or extensive (score: 7-8). NPS were quantified on the Neuropsychiatric Inventory Questionnaire. Binary logistic regression models estimated the odds of reporting each of 12 NPS by WMH status separately for individuals with MCI or who were CU. Compared to CU individuals with no to mild WMH, the odds of having elation [9.87, (2.63-37.10)], disinhibition [4.42, (1.28-15.32)], agitation [3.51, (1.29-9.54)] or anxiety [2.74, (1.28-5.88)] were higher for the extensive WMH group, whereas the odds of having disinhibition were higher for the moderate WMH group [1.94, (1.05-3.61)]. In the MCI group, he odds of NPS did not vary by WMH status. Extensive WMH were associated with higher odds of NPS in CU older adults but not in those with MCI.

Correlation between serum ANGPTL4 levels and white matter hyperintensity and cognitive impairment in patients with cerebral small vessel disease.

To investigate the correlation between serum angiopoietin-like protein 4 (ANGPTL4) levels, white matter hyperintensity (WMH), and cognitive impairment (CI) in patients with cerebral small vessel disease (CSVD). This cross-sectional study enrolled 171 patients with CSVD who attended the First Affiliated Hospital of Xinxiang Medical University from December 2021 to July 2022. All subjects underwent a 3.0T head magnetic resonance imaging, neuropsychology assessment, and blood sampling. Serum ANGPTL4 levels were detected by enzyme-linked immunosorbent assay and the severity of WMH was assessed by the Fazekas scale. According to the Montreal Cognitive Assessment (MoCA) scale, subjects were divided into normal cognition group (NC, n=80) and CI group (n=91). According to the total Fazekas scores, subjects were divided into a mild WMH group (n=84), a moderate WMH group (n=70), and a severe WMH group (n=17). Serum ANGPTL4 levels were significantly higher in the CI group than in the NC group (p<.05) and were negatively correlated with mini-mental state examination scores and MoCA scores (r=-0.26, -0.341, p<.05). Serum ANGPTL4 levels increased significantly in the mild to moderate WMH group but tended to decrease in the severe WMH group. Binary logistic regression analysis showed that ANGPTL4 was an independent influencing factor for CSVD-CI (OR=2.062, 95% CI (1.591-2.674), p<.001). The area under curve of ANGPTL4 for CSVD-CI was 0.847 (0.791-0.903). ANGPTL4 may be involved in the process of white matter damage and CI in CSVD patients and shows a diagnostic value for CSVD-CI.

Artificial intelligence reveals brain aging patterns in 27,402 individuals without diagnosed cognitive impairment that are linked to genetics, biomedical measures, and cognitive decline

AbstractBackgroundUnderstanding heterogeneity of structural brain changes in aging may provide insights into susceptibility to neurodegenerative diseases. We characterize the genetics underlying brain structural heterogeneity within cognitively unimpaired (CU) individuals using data‐driven machine learning applied to a diverse dataset of 27,402 individuals from 11 neuroimaging studies from the iSTAGING consortium.MethodStructural brain morphologic patterns of CU individuals were independently examined in four decade‐long intervals spanning ages 45 to 85. Within each interval, Smile‐GAN (Yang et al., 2021) was trained on baseline anatomic and white matter hyperintensity (WMH) volumes. Smile‐GAN probability scores were used as phenotypes in genome‐wide association studies (GWAS). Specifically, we performed multiple linear regressions controlling for confounders (e.g., age) via Plink (Purcell et al., 2007). We observed longitudinal clustering stability across decades, so individuals from adjacent age groups were combined into broader age groups ([45,65), [65,85)) due to the large sample requirement of GWAS. Genomic loci, represented by the top leading single nucleotide polymorphisms (SNPs), were defined considering linkage disequilibrium. We investigated associations of SNPs with clinical traits and mapped them to genes using the GWAS Catalog (Buniello et al., 2019).ResultThree structural brain aging patterns, relative to resilient agers (A0), consistent across decades, emerged: A1, or ‘typical’ aging with low atrophy and WMHs, and two ‘advanced’ aging patterns, one showing elevated WMHs and modest atrophy (A2) and the other displaying severe, widespread atrophy and moderate WMH load (A3) (Figure 1). GWAS discovered eight and six genomic loci in [45,65) and [65,85) age groups, respectively (Table 1, Figure 2). The lead SNPs for A1 and A2 were previously associated with several cardiometabolic risk factors, WMHs, and regional brain volumes. Interestingly, rs4843552, previously associated with white matter microstructure and regional brain volumes, showed opposite effects for A1 (protection) and A2 (risk), consistent with the neuroimaging patterns. WDR41 in A3 group was previously associated with the age of Alzheimer’s disease onset (Herold et al., 2016).ConclusionReproducible neuroimaging patterns defined by regional atrophy and WMH burden were identified across CU individuals and demonstrated unique genetics. Further research is needed to elucidate the neuropathological pathways that mediate these relationships.

The correlation between medial pattern of intracranial arterial calcification and white matter hyperintensities

Background and aimsDespite reported correlations between intracranial arterial calcification (IAC) and white matter hyperintensities (WMH), little is known about the relationship between IAC pattern and WMH. By differentiating intimal and medial IAC, we aimed to investigate the relationship between IAC pattern and WMH. MethodsConsecutive acute stroke patients were included. IAC pattern was categorized as intimal or medial on plain brain CT. The number of cerebral arteries involved by IAC for each patient was recorded. IAC severity was defined as focal or diffuse. On brain MRI, the burden of WMH was visually graded and classified as absent mild, moderate and severe. Multiple logistic regression was performed to examine the relationship between IAC and WMH. ResultsAmong 265 patients, intimal IAC was detected in 54.7% patients and medial IAC in 48.5% patients. Diffuse IAC was present in 27.9% patients, all of which were medial. WMH was found in 75.5% patients, including 39.6% patients with mild WMH, 26.0% with moderate WMH, and 9.8% with severe WMH. The severity of medial IAC was correlated with WMH occurrence (p < 0.001). Chi-square linear trend suggested the number of arteries involved by medial IAC (p < 0.001) and the severity of medial IAC (p < 0.001) were correlated with WMH burden. Multiple ordinal logistic regression demonstrated a positive correlation of WMH burden with the number of arteries involved by medial IAC (p < 0.001) and the severity of medial IAC (p < 0.001). ConclusionsMedial IAC was correlated with WMH. The dose-effect relationship between medial IAC and WMH suggests underlying shared mechanisms of intracranial large artery disease and small vessel disease.

Altered dynamic functional network connectivity and topological organization variance in patients with white matter hyperintensities.

White matter hyperintensities (WMHs) of presumed vascular origin are important imaging biomarkers of cerebral small vessel disease (CSVD). Previous studies have verified abnormal functional brain networks in CSVD. However, most of these studies rely on static functional connectivity, and only a few focus on the varying severity of the WMHs. Hence, our study primarily explored the disrupted dynamic functional network connectivity (dFNC) and topological organization variance in patients with WMHs. This study included 38 patients with moderate WMHs, 47 with severe WMHs, and 68 healthy controls (HCs). Ten independent components were chosen using independent component analysis based on resting-state functional magnetic resonance imaging. The dFNC of each participant was estimated using sliding windows and k-means clustering. We identified three reproducible dFNC states. Among them, patients with WMHs had a significantly higher occurrence in the sparsely connected State 1, but a lower occurrence and shorter duration in the positive and stronger connected State 3. Regarding topological organization variance, patients with WMHs showed higher variance in local efficiency but not global efficiency compared to HCs. Among the WMH subgroups, patients with severe WMHs showed similar but more obvious alterations than those with moderate WMHs. These altered network characteristics indicated an imbalance between the functional segregation and integration of brain networks, which was correlated with global cognition, memory, executive functions, and visuospatial abilities. Our study confirmed aberrant dFNC state metrics and topological organization variance in patients with moderate-to-severe WMHs; thus, it might provide a new pathway for exploring the pathogenesis of cognitive impairment.

A typology of cerebral small vessel disease based on imaging markers

BackgroundLacunes, microbleeds, enlarged perivascular spaces (EPVS), and white matter hyperintensities (WMH) are brain imaging features of cerebral small vessel disease (SVD). Based on these imaging markers, we aimed to identify subtypes of SVD and to evaluate the validity of these markers as part of clinical ratings and as biomarkers for stroke outcome.MethodsIn a cross-sectional study, we examined 1207 first-ever anterior circulation ischemic stroke patients (mean age 69.1 ± 15.4 years; mean NIHSS 5.3 ± 6.8). On acute stroke MRI, we assessed the numbers of lacunes and microbleeds and rated EPVS and deep and periventricular WMH. We used unsupervised learning to cluster patients based on these variables.ResultsWe identified five clusters, of which the last three appeared to represent distinct late stages of SVD. The two largest clusters had no to only mild or moderate WMH and EPVS, respectively, and favorable stroke outcome. The third cluster was characterized by the largest number of lacunes and a likewise favorable outcome. The fourth cluster had the highest age, most pronounced WMH, and poor outcome. Showing the worst outcome, the fifth cluster presented pronounced microbleeds and the most severe SVD burden.ConclusionThe study confirmed the existence of different SVD types with different relationships to stroke outcome. EPVS and WMH were identified as imaging features of presumably early progression. The number of microbleeds and WMH severity appear to be promising biomarkers for distinguishing clinical subgroups. Further understanding of SVD progression might require consideration of refined SVD features, e.g., for EPVS and type of lacunes.

Cognition mediates the relationship between white matter hyperintensity and motor function in patients with cerebral small vessel disease: a cross-sectional study.

White matter hyperintensity (WMH) is a common neuroimaging marker of cerebral small vessel disease (SVD) and a critical independent predictor of motor dysfunction, which increases the risk of disability, morbidity, and mortality. However, the mechanism underlying the relationship between WMH and motor function has not yet been fully clarified. It was hypothesized that cognitive impairment mediates the relationship between WMH and motor dysfunction in patients with SVD, which were considered predictor and outcome variables, respectively. A total of 221 patients with SVD were enrolled in this study, and their magnetic resonance imaging (MRI), neuropsychological, and motor function data were collected. The MRI data were visually assessed to determine the WMH burden using the Fazekas scale. Cognition was evaluated using the Montreal Cognitive Assessment (MoCA). Motor function was assessed using the Tinetti Gait and Balance Scale and the Short Physical Performance Battery (SPPB). Finally, a bootstrap analysis was performed to determine whether cognition mediated the relationship between WMH and motor function. Of all the patients, 30.3% had mild WMH, 37.6% had moderate WMH, and 32.1% had severe WMH. Patients' cognition and motor function decreased as the WMH burden increased (P<0.01). The MoCA scores were associated with the Tinetti scale (r=0.545, P<0.01) and SPPB scores (r=0.365, P<0.01). Finally, multi-categorical mediation models confirmed our research hypothesis; the coefficients for the indirect effects had 95% confidence intervals (CIs) that excluded zero, indicating statistically significant mediation effects. WMH is associated with motor dysfunction, and this association is mediated by cognition in patients with SVD. This finding highlights the importance of early interventions targeting cognitive function to reduce the risk of motor dysfunction.

Different Dynamic Nodal Properties Contribute to Cognitive Impairment in Patients with White Matter Hyperintensities.

White matter hyperintensities (WMHs) are commonly observed in older adults and are associated with cognitive impairment. Although previous studies have found abnormal functional connectivities in patients with WMHs based on static functional magnetic resonance imaging (fMRI), the topological properties in the context of brain dynamics remain relatively unexplored. Herein, we explored disrupted dynamic topological properties of functional network connectivity in patients with WMHs and its relationship with cognitive impairment. We included 36 healthy controls (HC) and 104 patients with mild WMHs (n = 39), moderate WMHs (n = 37), and severe (n = 28) WMHs. The fMRI data of all participants were analyzed using Anatomical Automatic Labeling (AAL) and a sliding-window approach to generate dynamic functional connectivity matrics. Then, graph theory methods were applied to calculate the topological properties. Comprehensive neuropsychological scales were used to assess cognitive functions. Relationships between cognitive functions and abnormal dynamic topological properties were evaluated by Pearson's correlation. We found that the patients with WMHs had higher temporal variability in regional properties, including betweenness centrality, nodal efficiencies, and nodal clustering coefficient. Furthermore, we found that the degree of centrality was related to executive function and memory, and the local coefficient correlated to executive function. Our results indicate that patients with WMHs have higher temporal variabilities in regional properties and are associated with executive and memory function.

Spatiotemporal Dynamics of Cerebral Vascular Permeability in Type 2 Diabetes-Related Cerebral Microangiopathy

AimsDiabetes-related cerebral microangiopathy can manifest as cerebral small vessel disease (CSVD) and exhibit cognitive decline. To find the early change of function in advance, this study examined the spatiotemporal dynamics of cerebral vascular permeability (Ktrans) in the progression of type 2 diabetes mellitus (T2DM).Methods Ktrans was cross-sectionally measured in T2DM and non-diabetes groups with or without CSVD using dynamic contrast-enhanced MRI (DCE-MRI).ResultsIn all patients with T2DM, the Ktrans of white matter (WM) was increased, whereas the Ktrans of gray matter (GM) was increased only in T2DM with CSVD. The involvement of WM was earlier than GM and was before the CSVD features could be visualized on MRI. Among the commonly available four CSVD items of MRI, microbleeds were the most sensitive, indicating the increased permeability in all patients. Increased Ktrans in T2DM was more associated with moderate WM hyperintensity but less with the presence of lacunae or multiple perivascular spaces, in contrast to patients without diabetes. The differential correlation suggested distinct mechanisms underlying diabetes-related CSVD and other CSVDs.ConclusionsThis study highlights the early development of cerebral microangiopathy with increased BBB leakage in T2DM, before the CSVD features can be visualized on MRI. The results may increase the proactivity of clinicians in recognizing the subsequent neurological comorbidities.

Abnormal Degree Centrality in White Matter Hyperintensities: A Resting-State Functional Magnetic Resonance Imaging Study.

Background: White matter hyperintensities (WMHs) are a common occurrence with aging and are associated with cognitive impairment. However, the neurobiological mechanisms of WMHs remain poorly understood. Functional magnetic resonance imaging (fMRI) is a prominent tool that helps in non-invasive examinations and is increasingly used to diagnose neuropsychiatric diseases. Degree centrality (DC) is a common and reliable index in fMRI, which counts the number of direct connections for a given voxel in a network and reflects the functional connectivity within brain networks. We explored the underlying mechanism of cognitive impairment in WMHs from the perspective of DC.Methods: A total of 104 patients with WMHs and 37 matched healthy controls (HCs) were enrolled in the current study. All participants underwent individual and overall cognitive function tests and resting-state fMRI (rs-fMRI). WMHs were divided into three groups (39 mild WMHs, 37 moderate WMHs, and 28 severe WMHs) according to their Fazekas scores, and the abnormal DC values in the WMHs and HCs groups were analyzed.Results: There was a significant difference in the right inferior frontal orbital gyrus and left superior parietal gyrus between the WMHs and HCs groups. The functional connectivity between the right inferior frontal orbital gyrus and left inferior temporal gyrus, left superior parietal gyrus, and left parietal inferior gyrus was also different in the WMHs group.Conclusion: The change in DC value may be one of the underlying mechanisms of cognitive impairment in individuals with WMHs, which provides us with a new approach to delaying cognitive impairment in WMHs.

Microstructural Connectivity is More Related to Cognition than Conventional MRI in Parkinson's Disease.

The different effects of white matter hyperintensity (WMH) severity and WMH-associated microstructural connectivity on cognition in the early stages of Parkinson's disease (PD) have not been investigated. To investigate the differential effect of WMH severity and WMH-associated microstructural connectivity on cognition in early stages of PD. A total of 136 de novo PD patients were enrolled and divided into groups based on total WMH visual rating scores as follows: mild, moderate, and severe. Microstructural connectivity was measured using graph theoretical analysis according to WMH severity. Additionally, correlation coefficients between WMH-associated microstructural connectivity or WMH scores and cognitive performance were assessed. Patients with severe WMHs demonstrated poorer performance in language function than those with moderate WMHs, and in frontal/executive and visual memory function than those with mild WMHs. Areas of microstructural connectivity were more extensive in patients with severe WMHs compared to those with mild and moderate WMHs, involving frontal and parieto-temporal regions. WMH-associated right fronto-temporo-parietal microstructural disintegration was correlated with cognitive dysfunction in attention, frontal/executive, and memory domains, whereas there was no correlation between WMH scores and any cognitive domains. These data suggest that disruption of microstructural networks by WMHs, rather than WMH burden itself, contributed more to cognitive impairment in PD.

The effect of severity of white matter hyperintensities on loss of functional independency in patients with mild cognitive impairment: A CREDOS-LTCI (clinical research center for dementia of South Korea-long term card insurance) study

ObjectiveBy combining data from the Clinical Research Center for Dementia of South Korea(CREDOS) study and long-term care insurance(LTCI), we aimed to assess whether the severity of white matter hyperintensity(WMH) predicted functional decline in cases of amnestic mild cognitive impairment(MCI). MethodsWMH was evaluated in 3,569 patients with amnestic MCI using the visual rating scale developed for the CREDOS study. The participants were classified as having amnestic MCI with minimal WMH change(aMCI), with moderate WMH change(maMCI) and with severe WMH change(saMCI) according to the severity of the WMH measurements. A Kaplan–Meier survival probability estimate was used to compute median time from the diagnosis of MCI to LTCI enrollment for the three MCI groups. The effect of various risk factors of LTCI enrollment was evaluated using Cox’s proportional hazards model, adjusted for covariates. ResultsAs compared with aMCI cases, maMCI and saMCI patients required help with daily activities of living at a younger age. The saMCI and maMCI patients had higher risk of LTCI enrollment as compared with that of the aMCI patients. Younger patients(≤ 65y) with MCI had a 3.201 times higher risk of early LTCI enrollment than older patients(> 65y) did. High clinical dementia rating score and female sex were also risk factors of early LTCI enrollment. ConclusionsWMH predicted the rate of global functional decline and loss of independence in patients with MCI. The findings support the use of neuroimaging of WMH, in conjunction with biomarkers, as a tool in predicting functional decline in patients with MCI.

Clinical Characteristics of Non-Amnestic Mild Cognitive Impairment: A Single-Center Experience

Background To evaluate the clinical characteristics of patients with non-amnestic mild cognitive impairment (naMCI) in a memory disorder clinic at a single center. Methods A retrospective study was conducted involving 312 patients with naMCI from May 2011 to July 2018. Brain magnetic resonance imaging and detailed neuropsychological tests were performed in all patients. We used the proposed criteria for naMCI to classify the patients into single- and multiple-domain groups. We compared the baseline clinical characteristics, neuroimaging findings, and the rate of progression to dementia between these two groups. Results The 312 patients comprised 210 in the single-domain group (67.3%) and 102 in the multiple-domain group (32.7%). The mean age was significantly higher in the multiple-domain group than in the single-domain group. The years of education, mean Mini Mental State Examination score, and mean Clinical Dementia Rating Scale Sum of Boxes score were significantly lower in the multiple-domain group than in the single-domain group. The Z-scores of neuropsychological tests in most cognitive domains were significantly lower in the multiple-domain group than in the single-domain group. Compared to the single-domain group, the multiple-domain group showed more-severe medial temporal atrophy and contained a higher proportion of patients with moderate white-matter hyperintensities. Thirteen (8.4%) patients with naMCI progressed to dementia, most of who were diagnosed with Alzheimer’s disease. Conclusions We present a single-center experience of clinical characteristics in patients with naMCI. Close observation of the clinical profiles of patients with naMCI may help identify individuals at the greatest risk of dementia. Key Words: Cognitive dysfunction, Dementia, Alzheimer disease

Neuropsychological impact of white matter hyperintensities in older adults without dementia

The purpose of this study was to determine (a) if simple clinical judgements of white matter hyperintensities (WMH) on imaging are associated with measurable cognitive impacts in otherwise cognitively normal older adults, (b) if neuropsychological measures can predict those with WMH, and (c) the frequency of low cognitive scores in those with WMH on a battery of measures. Forty-four individuals judged free of other cognitive disorders despite moderate to extensive WMH were compared with 50 individuals matched on age (mean of 83), education (college educated), and gender (predominantly female). Data was obtained from the National Alzheimer’s Coordinating Center database. The group with at least moderate WMH had lower scores on the Trail Making Test A, verbal fluency, and digit span. A component score derived from these measures was a significant predictor of the presence of WMH, though only correctly classified 68% of participants. Even in individuals free from other suspected conditions, clinically judged moderate to extensive WMH was associated with cognitive weaknesses for processing speed, working memory, and executive functioning. This shows that a relatively simple judgment of WMH burden is meaningfully associated with worse cognition. Implications and future directions for are discussed.

BOLD-based cerebrovascular reactivity vascular transfer function isolates amplitude and timing responses to better characterize cerebral small vessel disease.

Cerebrovascular reactivity (CVR) is a dynamic measure of the cerebral blood vessel response to vasoactive stimulus. Conventional CVR measures amplitude changes in the blood-oxygenation-level-dependent (BOLD) signal per unit change in end-tidal CO2 (PET CO2 ), effectively discarding potential timing information. This study proposes a deconvolution procedure to characterize CVR responses based on a vascular transfer function (VTF) that separates amplitude and timing CVR effects. We implemented the CVR-VTF to primarily evaluate normal-appearing white matter (WM) responses in those with a range of small vessel disease. Comparisons between simulations of PET CO2 input models revealed that boxcar and ramp hypercapnia paradigms had the lowest relative deconvolution error. We used a T2 * BOLD-MRI sequence on a 3T MRI scanner, with a boxcar delivery model of CO2 , to test the CVR-VTF approach in 18 healthy adults and three white matter hyperintensity (WMH) groups: 20 adults with moderate WMH, 12 adults with severe WMH, and 10 adults with genetic WMH (CADASIL). A subset of participants performed a second CVR session at a one-year follow-up. Conventional CVR, area under the curve of VTF (VTF-AUC), and VTF time-to-peak (VTF-TTP) were assessed in WM and grey matter (GM) at baseline and one-year follow-up. WMH groups had lower WM VTF-AUC compared with the healthy group (p<0.0001), whereas GM CVR did not differ between groups (p>0.1). WM VTF-TTP of the healthy group was less than that in the moderate WMH group (p=0.016). Baseline VTF-AUC was lower than follow-up VTF-AUC in WM (p=0.013) and GM (p=0.026). The intraclass correlation for VTF-AUC in WM was 0.39 and coefficient of repeatability was 0.08 [%BOLD/mm Hg]. This study assessed CVR timing and amplitude information without applying model assumptions to the CVR response; this approach may be useful in the development of robust clinical biomarkers of CSVD.

The Spatial Associations of Cerebral Blood Flow and Spontaneous Brain Activities with White Matter Hyperintensities-An Exploratory Study Using Multimodal Magnetic Resonance Imaging.

White matter hyperintensities (WMHs) have been reported to be correlated with functional brain changes, but the association of the specific WMHs distribution pattern with regional functional changes remains uncertain. The aim of this study is to explore the possible spatial correlation of WMH with changes in cerebral blood flow (CBF) and spontaneous brain activities in elderly using a novel approach. The WMHs, CBF, and spontaneous brain activities measured by intrinsic connectivity contrast (ICC), were quantified using multimodal magnetic resonance imaging for 69 elderly subjects. Such approach enables us to expand our search for newly identified correlated areas by drawing strengths of different modes and provides a means for triangulation as well as complementary insights. The results showed significant positive correlations between WMH volumes in the right superior corona radiata and CBF in the left supplementary motor area, as well as between WMH volumes in left anterior limb internal capsule and CBF in the right putamen. Significant correlations of regional WMH volumes and ICC were also detected between the right anterior corona radiata and the left cuneus, and the right superior occipital cortex, as well as between the right superior corona radiata and the left superior occipital cortex. These findings may suggest a regional compensatory functional enhancement accounting for the maintenance of cognitively normal status, which can be supported by the widely observed phenomenon that mild to moderate WMH load could have little effect on global cognitive performance.

Mental speed is associated with the shape irregularity of white matter MRI hyperintensity load.

Brain MRI white matter hyperintensities (WMHs) are common in elderly subjects. Their impact on cognition, however, appears highly variable. Complementing conventional scoring of WMH load (volume and location) by quantitative characterization of the shape irregularity of WMHs might improve the understanding of the relationship between WMH load and cognitive performance. Here we propose the "confluency sum score" (COSU) as a marker of the total shape irregularity of WMHs in the brain. The study included two independent patient samples: 87 cognitively impaired geriatric inpatients from a prospective neuroimaging study (iDSS) and 198 subjects from the National Alzheimer's Coordinating Center (NACC) database (132 with, 66 w/o cognitive impairment). After automatic segmentation and clustering of the WMHs on FLAIR (LST toolbox, SPM8), the confluency of the i-th contiguous WMH cluster was computed as confluencyi=[1/(36π)∙surfacei3/volumei2]1/3-1. The COSU was obtained by summing the confluency over all WMH clusters. COSU was tested for correlation with CERAD-plus subscores. Correlation analysis was restricted to subjects with at least moderate WMH load (≥ 13.5ml; iDSS / NACC: n=52 / 80). In the iDSS sample, among the 12 CERAD-plus subtests the trail making test A (TMT-A) was most strongly correlated with the COSU (Spearman rho = -0.345, p=0.027). TMT-A performance was not associated with total WMH volume (rho =0.147, p=0.358). This finding was confirmed in the NACC sample (rho = -0.261, p=0.023 versus rho = -0.040, p=0.732). Cognitive performance in specific domains including mental speed and fluid abilities seems to be more strongly associated with the shape irregularity of white matter MRI hyperintensities than with their volume.

Pathogenesis of cerebral microbleeds: In vivo imaging of amyloid and subcortical ischemic small vessel disease in 226 individuals with cognitive impairment

Cerebral microbleeds (CMBs) are a neuroimaging marker of small vessel disease (SVD) with relevance for understanding disease mechanisms in cerebrovascular disease, cognitive impairment, and normal aging. It is hypothesized that lobar CMBs are due to cerebral amyloid angiopathy (CAA) and deep CMBs are due to subcortical ischemic SVD. We tested this hypothesis using structural magnetic resonance imaging (MRI) markers of subcortical SVD and in vivo imaging of amyloid in patients with cognitive impairment. We included 226 patients: 89 with Alzheimer disease-related cognitive impairment (ADCI) and 137 with subcortical vascular cognitive impairment (SVCI). All subjects underwent amyloid imaging with [(11) C] Pittsburgh compound B (PiB) positron emission tomography, and MRI to detect CMBs and markers of subcortical SVD, including the volume of white matter hyperintensities (WMH) and the number of lacunes. Parietal and occipital lobar CMBs counts were higher in PiB(+) ADCI with moderate WMH than PiB(+) ADCI with minimal WMH, whereas PiB(-) patients with SVCI (ie, "pure" SVCI) showed both lobar and deep CMBs. In multivariate analyses of the whole cohort, WMH volume and lacuna counts were positively associated with both lobar and deep CMBs, whereas amyloid burden (PiB) was only associated with lobar CMBs. There was an interaction between lacuna burden and PiB retention on lobar (but not deep) CMBs (p<0.001). Our findings suggest that although deep CMBs are mainly linked to subcortical SVD, both subcortical SVD and amyloid-related pathologies (eg, CAA) contribute to the pathogenesis of lobar CMBs, at least in subjects with mixed lobar and deep CMBs. Furthermore, subcortical SVD and amyloid-related pathologies interact to increase the risk of lobar CMBs.

Cortical Atrophy and White Matter Hyperintensities in HIV: The Hawaii Aging with HIV Cohort Study

As many human immunodeficiency virus (HIV)-seropositive individuals are now living longer after infection because of highly active antiretroviral therapy, aging-related manifestations of cerebral small-vessel ischemic vascular disease, such as brain white matter hyperintensities (WMHs), are becoming increasingly important in this population. This study was designed to determine the relationship between WMHs and cortical volumes in HIV-seropositive individuals. Voxel-based morphometry was used to compare cortical volumes among 62 HIV-seropositive individuals participating in the Hawaii Aging with HIV Cohort Study, 30 with moderate WMHs and 32 with minimal or no WMHs. Presence of moderate WMHs was associated with decreased cortical volumes in the frontal lobes bilaterally. These findings suggest that age-related WMHs are associated with reduced frontal gray matter volumes in HIV-seropositive individuals, supporting the hypothesis that the frontal lobes may have greater susceptibility to the effects of small-vessel ischemic vascular disease.