Hyperintense White Matter Lesions Research Articles

Augmentation of perivascular space visualization in basal ganglia and white matter hyperintensity lesion is a meaningful finding for subsequent cognitive decline.

Cerebral small vessel disease (CSVD) causes cognitive decline and perivascular space enlargement is one of the image markers for CSVD. To search for clinical significance in the time-course augmentation of perivascular space in basal ganglia (BG-PVS) for cognitive decline. This study population included 179 participants from a community-based cohort, aged 70 years at baseline. They had undergone magnetic resonance imaging (MRI) studies two or three times between 2000 and 2008. Based on the severity of BG-PVS or white matter hyperintensity lesions (WMHL) in 2000, the participants were divided into low-grade or high-grade groups, respectively. In addition, their time-course augmentation was evaluated, and we created a categorical BG-PVS WMHL change score based on their augmentation (1 = neither, 2 = BG-PVS augmentation only, 3 = WMHL augmentation only, 4 = both). Cognitive function was assessed based on the Mini-Mental State Examination (MMSE); the change was defined as the difference between scores in 2000 and 2008. We used simple or multiple regression analysis for MMSE score change according to MRI findings and clinical characteristics that were probably related to cognitive decline. In univariate analysis, MMSE score change was negatively associated with BG-PVS high grade at baseline and BG-PVS WMHL change score 4; this remained significant in multivariate analysis. In the final model based on the Akaike Information Criterion, BG-PVS WMHL change score 4 was associated with a 3.3-point decline in subsequent MMSE score. This study suggested that augmentation in both BG-PVS and WMHL was associated with subsequent cognitive decline.

Abstract TMP58: Neuroimaging Markers of Patient-Reported Outcomes in Acute Ischemic Stroke

Objectives: To determine the relationship between patient-reported outcome measures (PROMs) and volumetric biomarkers assessed on clinical imaging in acute ischemic stroke (AIS). Background: AIS is a leading cause of long-term disability. White matter hyperintensity (V_WMH), brain (V_Brain) and stroke lesion volume (V_Lesion) have been linked as potential determinants of functional outcomes after stroke. Recently, there has been surging attention to PROMs, which allow for direct, patient-centered health assessments of stroke victims. However, the link between neuroimaging biomarkers and PROMs is not well studied. Methods: Patients presenting to the Emergency Department at Massachusetts General Hospital between February 2017 and February 2020 with a confirmed AIS on MRI were eligible and underwent a follow-up telephone interview, including PROM-10 questionnaires. V_WMH and V_Brain were automatically determined from clinical MRI. V_Lesion was manually segmented. Regression analyses were performed to identify associations of brain volumetrics and clinical variables with PROM-10 subscores and global mental and physical summary scores. Results: Utilizing data from 150 patients (mean age: 64.7; 41.9% female), higher V_WMH was associated with worse global mental (β = -0.65), global physical (β = -0.60), social activities (OR = 0.59), physical health (OR = 0.68), fatigue (OR = 0.69) and social satisfaction (OR = 0.66) scores. V_Lesions were associated with poorer global mental (β = -0.79), social (OR = 0.55) and physical (OR = 0.66) activities, mental health (OR = 0.68) and emotional distress (OR = 0.68) scores. Higher V_Brain was linked to better global mental (β = 0.93), global physical (β = 0.79), physical activities (OR = 1.72) and mental health (OR = 1.54) scores. Conclusions: Imaging biomarkers were significantly associated with PROMs. The inclusion of these markers with PROMs in routine post-stroke assessment can enhance our understanding of recovery.

Higher HbA1c Is Associated With Greater 2-Year Progression of White Matter Hyperintensities.

White matter hyperintensity (WMH) lesions on brain MRI images are surrogate markers of cerebral small vessel disease (CSVD). Longitudinal studies examining the association between diabetes and WMH progression have yielded mixed results. Thus, in this study we investigated the association between HbA1c, a biomarker for the presence and severity of hyperglycemia, and longitudinal WMH change after adjusting for known risk factors for WMH progression. We recruited 64 participants from South Korean memory clinics to undergo brain MRI at the baseline and a two-year follow-up. We found: First, higher HbA1c was associated with greater global WMH volume (WMHV) changes after adjusting for known risk factors (B = 7.7E-04, p = 0.025); Second, the association between baseline WMHV and WMHV progression was only significant at diabetic levels of HbA1c (p < 0.05, when HbA1c > 6.51%), and non-APOE ε4 carriers showed a stronger association between HbA1c and WMHV progression (B = -2.59E-03, p = 0.004); Third, associations of WMHV progression with HbA1c were particularly apparent for deep WMHV change (B = 7.17E-04, p < 0.01) compared to periventricular WMHV change, and for frontal (B = 5.00E-04, p < 0.001) and parietal (B = 1.534-04, p < 0.05) WMHV change compared to occipital and temporal WMHV change. In conclusion, higher HbA1c levels were associated with greater two-year WMHV progression, especially in non-APOE ε4 participants or those with diabetic levels of HbA1c. These findings demonstrate that diabetes may potentially exacerbate cerebrovascular and white matter disease.

Strategically Acquired Gradient Echo (STAGE) Imaging, part IV: Constrained Reconstruction of White Noise (CROWN) Processing as a Means to Improve Signal-to-Noise in STAGE Imaging at 3 Tesla

Increasing the signal-to-noise ratio (SNR) has always been of critical importance for magnetic resonance imaging. Although increasing field strength provides a linear increase in SNR, it is more and more costly as field strength increases. Therefore, there is a major effort today to use signal processing methods to improve SNR since it is more efficient and economical. There are a variety of methods to improve SNR such as averaging the data at the expense of imaging time, or collecting the data with a lower resolution, all of these methods, including imaging processing methods, usually come at the expense of loss of image detail or image blurring. Therefore, we developed a new mathematical approach called CROWN (Constrained Reconstruction of White Noise) to enhance SNR without loss of structural detail and without affecting scanning time. In this study, we introduced and tested the concept behind CROWN specifically for STAGE (strategically acquired gradient echo) imaging. The concept itself is presented first, followed by simulations to demonstrate its theoretical effectiveness. Then the SNR improvement on proton spin density (PSD) and R2⁎ maps was investigated using brain STAGE data acquired from 10 healthy controls (HCs) and 10 patients with Parkinson's disease (PD). For the PSD and R2* maps, the SNR and CNR between white matter and gray matter were improved by a factor of 1.87 ± 0.50 and 1.72 ± 0.88, respectively. The white matter hyperintensity lesions in PD patients were more clearly defined after CROWN processing. Using these improved maps, simulated images for any repeat time, echo time or flip angle can be created with improved SNR. The potential applications of this technology are to trade off the increased SNR for higher resolution images and/or faster imaging.

The volume and the distribution of premorbid white matter hyperintensities: Impact on post-stroke aphasia.

White matter hyperintensities (WMH) are a radiological manifestation of progressive white matter integrity loss. The total volume and distribution of WMH within the corpus callosum have been associated with pathological cognitive ageing processes but have not been considered in relation to post-stroke aphasia outcomes. We investigated the contribution of both the total volume of WMH, and the extent of WMH lesion load in the corpus callosum to the recovery of language after first-ever stroke. Behavioural and neuroimaging data from individuals (N = 37) with a left-hemisphere stroke were included at the early subacute stage of recovery. Spoken language comprehension and production abilities were assessed using word and sentence-level tasks. Neuroimaging data was used to derive stroke lesion variables (volume and lesion load to language critical regions) and WMH variables (WMH volume and lesion load to three callosal segments). WMH volume did not predict variance in language measures, when considered together with stroke lesion and demographic variables. However, WMH lesion load in the forceps minor segment of the corpus callosum explained variance in early subacute comprehension abilities (t = -2.59, p = .01) together with corrected stroke lesion volume and socio-demographic variables. Premorbid WMH lesions in the forceps minor were negatively associated with early subacute language comprehension after aphasic stroke. This negative impact of callosal WMH on language is consistent with converging evidence from pathological ageing suggesting that callosal WMH disrupt the neural networks supporting a range of cognitive functions.

Cognitively healthy Indians with higher Framingham Cardiovascular Risk Scores have higher WMH burden with lesser grey matter, white matter and hippocampal volumes

AbstractBackgroundIncreasing evidence indicates the important role of cardiovascular risk factors in dementia risk, particularly in Indians. It is known that cardiovascular risk factors tend to cluster together, and a widely used multivariable risk scoring is the Framingham Cardiovascular Risk Score (FRS). However, very little is known about the association between FRS and structural brain MRI parameters in cognitively healthy Indians.MethodBaseline clinical and brain MRI data of 487 cognitively healthy Indians (Clinical Dementia Rating score of ‘0’), who are part of two ongoing, large, aging cohort studies in India – Srinivaspura Aging, Neuro Senescence and COGnition study (SANSCOG) study (n = 200) and Tata Longitudinal Study of Aging (TLSA, n = 289) were utilized. FRS was calculated using clinical and blood biochemistry data, whereas brain MRI scans were performed on 3T MRI scanners. White matter hyperintensity (WMH) lesion segmentation was performed using Lesion Segmentation Toolbox (LST) and brain volumes (total grey matter, total white matter, 3rd ventricle, right and left hippocampus) were derived using FreeSurfer software and normalized according to total intracranial volumes of the respective subjects. Linear regression analysis was performed with FRS as independent variable and various structural MRI parameters as dependent variables. A p value of &lt;0.05 was considered significant.ResultUrban subjects with higher FRS had significantly higher WMH volume (β = 0.00011, p&lt;0.001, R2 = 0.130), lower grey matter (β = ‐0.00285, p&lt;0.001, R2 = 0.206), white matter (β = ‐0.00180, p&lt;0.001, R2 = 0.106), right hippocampal (β = ‐0.00004, p&lt;0.001, R2 = 0.180), left hippocampal (β = ‐0.00003, p&lt;0.001, R2 = 0.156) volumes and higher 3rd ventricle volumes (β = 0.00003, p&lt;0.001, R2 = 0.150). Rural subjects higher FRS had lower grey matter (β = ‐0.00166, p&lt;0.001, R2 = 0.118, white matter (β = ‐0.0011, p&lt;0.001, R2 = 0.060), right hippocampal (β = ‐0.00002, p&lt;0.001, R2 = 0.087), left hippocampal (β = ‐0.00002, p&lt;0.001, R2 = 0.084) volumes and higher 3rd ventricle volumes (β = 0.00004, p&lt;0.001, R2 = 0.264) but no significant association was seen with WMH volume.ConclusionThese findings indicate that cardiovascular risk is associated with structural brain changes in cognitively healthy Indians. Since cardiovascular risk can be reduced through cost‐effective community level strategies, such as lifestyle‐based interventions, promptly addressing this risk in Indians could be an important part of dementia prevention strategies.

Association of white matter hyperintensities with long-term EGFR-TKI treatment and prediction of progression risk.

The purpose of this study was to test the hypothesis that brain white matter hyperintensities (WMH) are more common in patients receiving epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and identify clinical risk factors associated with WMH. This multiple-center, prospective cohort study was conducted from March 2017 to July 2020. Two groups of patients with non-small cell lung cancer (NSCLC) who received or did not receive EGFR-TKI were included and followed up for more than 24 months. The progression of WMH was defined as an increase of ≥1 point on the Fazekas visual rating scale between the baseline and at the 2-year follow-up. A modified Poisson regression model was performed to evaluate risk factors on increased WMH load. Among 286 patients with NSCLC, 194 (68%) patients with NSCLC who received EGFR-TKI and 92 (32%) patients with NSCLC without EGFR-TKI treatment were analyzed. Modified Poisson regression analysis showed that EGFR-TKI treatment was independently associated with the WMH progression (EGFR-TKI: aRR 2.72, 95% confidence interval [CI] 1.46-5.06, p=.002). Interleukin (IL)-2, IL-4, and IL-10 were associated with increased WMH in the adjusted model (IL-2: aRR 1.55 [95% CI 1.06-2.25], p = .023; IL-4: aRR 1.66 [95% CI 1.13-2.43], p = .010; IL-10: aRR 1.48 [95% CI 1.06-2.06], p = .020). Patients with NSCLC who received EGFR-TKI may be at higher risk of developing WMH or worsening of WMH burden. The impact of increased WMH lesions in these patients is to be further assessed. IL-2, IL-4, and IL-10 may be used as potential biomarkers to monitor the risk of increased WMH burden.

Effects of intensive blood pressure control on cognitive function in patients with cerebral small vessel disease

ObjectiveThis study aimed to investigate the effects of intensive blood pressure control on cognitive function in elderly patients with cerebral small vessel disease (CSVD). MethodsFrom May 2020 to June 2022, 140 outpatients and inpatients with CSVD and hypertension in the Department of Neurology of Beijing Shijingshan Hospital were selected. They were randomly divided into the standard and intensive blood pressure control groups, and the dosage of antihypertensive drugs was adjusted to reduce the blood pressure to the target level. The patients were followed up for 2 years. The medical records or data at “enrollment” and “2-year follow-up” were analyzed and evaluated. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to evaluate cognitive function. Cranial magnetic resonance imaging was performed to evaluate lacunar infarctions (LIs) and white matter hyperintensity (WMH). Multiple linear regression was used to analyze the correlation between MMSE scores and blood pressure, WMH, and LIs. Results(1) The MMSE and MoCA scores in the standard group were significantly lower than those at enrollment. The WMH score in the standard group was significantly higher than that at enrollment. (2) After the 2-year follow-up, the 24-h systolic blood pressure (SBP), 24-h diastolic blood pressure (DBP), daytime mean SBP, daytime mean DBP, and nighttime mean SBP in the two groups significantly decreased, which had significant statistical significance (P < 0.05). (3) The correlation between blood pressure and MMSE score was analyzed using multiple linear regression analysis. The WMH score, LIs, 24-h SBP, and 24-h DBP were independently correlated with MMSE scores. ConclusionIn elderly patients with hypertension, a decrease in SBP to 126 mmHg, compared with 134 mmHg, can delay cognitive impairment as well as reduce LIs and cerebral WMH lesions in patients with CSVD.

Clinical and cognitive correlates tractography analysis in patients with white matter hyperintensity of vascular origin.

White matter hyperintensity lesions (WMHL) in the brain are a consequence of cerebral small vessel disease and microstructural damage. Patients with WMHL have diverse clinical features, and hypertension, advanced age, obesity, and cognitive decline are often observed. However, whether these clinical features are linked to interrupted structural connectivity in the brain requires further investigation. This study therefore explores the white matter pathways associated with WMHL, with the objective of identifying neural correlates for clinical features in patients with WMHL. Diffusion magnetic resonance imaging (MRI) and several clinical features (MoCA scores, hypertension scores, body mass index (BMI), duration of hypertension, total white matter lesion loads, and education.) highly related to WMHL were obtained in 16 patients with WMHL and 20 health controls. We used diffusion MRI connectometry to explore the relationship between clinical features and specific white matter tracts using DSI software. The results showed that the anterior splenium of the corpus callosum, the inferior longitudinal fasciculus, the anterior corpus callosum and the middle cerebellar peduncle were significantly correlated with hypertension scores (false discovery rate (FDR) = 0.044). The anterior splenium of the corpus callosum, the left thalamoparietal tract, the inferior longitudinal fasciculus, and the left cerebellar were significantly correlated with MoCA scores (FDR = 0.016). The anterior splenium of corpus callosum, inferior fronto-occipital fasciculus, cingulum fasciculus, and fornix/fimbria were significantly correlated with body mass index (FDR = 0.001). Our findings show that hypertension score, MoCA score, and BMI are important clinical features in patients with WMHL, hypertension degree and higher BMI are associated with whiter matter local disconnection in patients with WMHL, and may contribute to understanding the cognitive impairments observed in patients with WMHL.

Stroke-like presentation of acute toxic leukoencephalopathy due to capecitabine treatment with extensive intramyelinic edema.

Stroke-like presentation of acute toxic leukoencephalopathy due to capecitabine treatment with extensive intramyelinic edema.

How often does white matter hyperintensity volume regress in cerebral small vessel disease?

It has been suggested that white matter hyperintensity lesions (WMHs), which typically progress over time, can also regress, and that this might be associated with favorable cognitive performance. We determined the prevalence of WMH regression in patients with cerebral small vessel disease (SVD) and examined which demographic, clinical, and radiological markers were associated with this regression. We used semi-automated lesion marking methods to quantify WMH volume at multiple timepoints in three cohorts with symptomatic SVD; two with moderate-to-severe symptomatic SVD (the SCANS observational cohort and the control arm of the PRESERVE interventional trial) and one with mild-to-moderate SVD (the RUN DMC observational cohort). Mixed-effects ordered logistic regression models were used to test which factors predicted participants to show WMH regression. No participants (0/98) in SCANS, 6/42 (14.3%) participants in PRESERVE, and 6/276 (2.2%) in RUN DMC showed WMH regression. On multivariate analysis, only lower WMH volume (OR: 0.36, 95% CI: 0.23-0.56) and better white matter microstructural integrity assessed by fractional anisotropy using diffusion tensor imaging (OR: 1.55, 95% CI: 1.07-2.24) predicted participant classification as regressor versus stable or progressor. Only a small proportion of participants demonstrated WMH regression across the three cohorts, when a blinded standardized assessment method was used. Subjects who showed regression had less severe imaging markers of disease at baseline. Our results show that lesion regression is uncommon in SVD and unlikely to be a major factor affecting the use of WMH quantification as an outcome for clinical trials.

Neural Substrates of Psychomotor Speed Deficits in Cerebral Small Vessel Disease: A Brain Disconnectome Mapping Study.

It remains unknown which factors influence how brain disconnectivity derived from White Matter Hyperintensity (WMH) lesions leads to psychomotor speed dysfunction, one of the earliest and most common cognitive manifestations in the cerebral Small Vessel Disease (cSVD) population. While the burden of WMH has been strongly linked to psychomotor speed performance, the effect that different locations and volumes of WMH may have on cSVD-related cognitive impairment remains unclear. Therefore, we aimed to explore (1) whether global WMH, deep WMH (DWMH), and periventricular (PVWMH) volumes display different psychomotor speed associations; (2) whether tract-specific WMH volume shows stronger cognitive associations compared with global measures of WMH volume; (3) whether specific patterns of WMH location lead to different degrees of disconnectivity. Using the BCBToolkit, we investigated which pattern of distribution and which locations of WMH lesion result in impaired psychomotor speed in a well-characterized sample (n = 195) of cSVD patients without dementia. Two key findings emerge from our study. First, global (and not tract-specific) measures of WMH volume were associated with psychomotor speed performance. Second, disconnection maps revealed the involvement of callosal tracts, association and projection fibers, and frontal and parietal cortical brain areas related to psychomotor speed, while the lesion location influenced such associations. In conclusion, psychomotor deficits are affected differently by WMH burden and topographic distribution through brain disconnection in non-demented cSVD patients.

A Fully Automated Visual Grading System for White Matter Hyperintensities of T2-Fluid Attenuated Inversion Recovery Magnetic Resonance Imaging.

The Fazekas scale is one of the most commonly used visual grading systems for white matter hyperintensity (WMH) for brain disorders like dementia from T2-fluid attenuated inversion recovery magnetic resonance (MR) images (T2-FLAIRs). However, the visual grading of the Fazekas scale suffers from low-intra and inter-rater reliability and high labor-intensive work. Therefore, we developed a fully automated visual grading system using quantifiable measurements. Our approach involves four stages: (1) the deep learning-based segmentation of ventricles and WMH lesions, (2) the categorization into periventricular white matter hyperintensity (PWMH) and deep white matter hyperintensity (DWMH), (3) the WMH diameter measurement, and (4) automated scoring, following the quantifiable method modified for Fazekas grading. We compared the performances of our method and that of the modified Fazekas scale graded by three neuroradiologists for 404 subjects with T2-FLAIR utilized from a clinical site in Korea. The Krippendorff's alpha across our method and raters (A) versus those only between the radiologists (R) were comparable, showing substantial (0.694 vs. 0.732; 0.658 vs. 0.671) and moderate (0.579 vs. 0.586) level of agreements for the modified Fazekas, the DWMH, and the PWMH scales, respectively. Also, the average of areas under the receiver operating characteristic curve between the radiologists (0.80 ± 0.09) and the radiologists against our approach (0.80 ± 0.03) was comparable. Our fully automated visual grading system for WMH demonstrated comparable performance to the radiologists, which we believe has the potential to assist the radiologist in clinical findings with unbiased and consistent scoring.

Young versus older subject diffusion magnetic resonance imaging data for virtual white matter lesion tractography.

White matter hyperintensity (WMH) lesions on T2 fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and changes in adjacent normal-appearing white matter can disrupt computerized tract reconstruction and result in inaccurate measures of structural brain connectivity. The virtual lesion approach provides an alternative strategy for estimating structural connectivity changes due to WMH. To assess the impact of using young versus older subject diffusion MRI data for virtual lesion tractography, we leveraged recently available diffusion MRI data from the Human Connectome Project (HCP) Lifespan database. Neuroimaging data from 50 healthy young (39.2 ± 1.6 years) and 46 healthy older (74.2 ± 2.5 years) subjects were obtained from the publicly available HCP-Aging database. Three WMH masks with low, moderate, and high lesion burdens were extracted from the WMH lesion frequency map of locally acquired FLAIR MRI data. Deterministic tractography was conducted to extract streamlines in 21 WM bundles with and without the WMH masks as regions of avoidance in both young and older cohorts. For intact tractography without virtual lesion masks, 7 out of 21 WM pathways showed a significantly lower number of streamlines in older subjects compared to young subjects. A decrease in streamline count with higher native lesion burden was found in corpus callosum, corticostriatal tract, and fornix pathways. Comparable percentages of affected streamlines were obtained in young and older groups with virtual lesion tractography using the three WMH lesion masks of increasing severity. We conclude that using normative diffusion MRI data from young subjects for virtual lesion tractography of WMH is, in most cases, preferable to using age-matched normative data.

Dots and spots: A retrospective review of T2-hyperintense white matter lesions in pediatric patients with and without headache.

We aimed to determine if T2-weighted hyperintense white matter lesions (WMLs) on brain magnetic resonance imaging (MRI) occur more frequently in pediatric patients with migraine and other primary headache disorders compared to the general pediatric population. Small foci of T2 hyperintensity in the white matter are frequently identified on brain MRI during the workup of pediatric headache. Such lesions have been reported to be more common among adults with migraine versus adults without migraine; however, this association has not been well established in the pediatric population. We performed a retrospective cross-sectional single-center study of electronic medical records and radiologic studies, examining pediatric patients from 3 to 18 years old who underwent brain MRI between 2016 and 2021. Patients with existing intracranial disease or abnormalities were excluded. Patients with reports of headache were categorized. Imaging was reviewed to determine the number and location of WMLs. Headache-associated disability scores (Pediatric Migraine Disability Assessment) were noted, when available. Brain MRI of 248 patients with a diagnosis of headache (144 with migraine, 42 with non-migraine primary headache, and 62 with headache that could not be further classified) and 490 controls were reviewed. WMLs were encountered commonly among all study participants, with a prevalence of 40.5% (17/42) to 54.1% (265/490). There was no statistically significant difference comparing the number of lesions between each of the headache groups and the control group: migraine group versus control group median [interquartile range (IQR)], 0 [0-3] versus 1 [0-4], incidence rate ratio [95% confidence interval (CI)], 0.99 [0.69-1.44], p = 0.989, non-migraine headache group versus control group median [IQR], 0 [0-3] versus 1 [0-4], 0.71 [0.46-1.31], p = 0.156, headache not otherwise specified group versus control group median [IQR], 0 [0-4] versus 1 [0-4], 0.77 [0.45-1.31], p = 0.291. There was no significant correlation between headache-associated disability and the number of WMLs (0.07 [-0.30 to 0.17], rho [95% CI]). T2 hyperintense WMLs are common within the pediatric population and are not encountered more frequently in pediatric patients with migraine or other primary headache disorders. Thus, such lesions are presumably incidental and unlikely related to headache history.

Periventricular White Matter Fractional Anisotropy as a Biomarker of Cerebral Small Vessel Disease (P11-6.007)

<h3>Objective:</h3> To evaluate the utility of Diffusion Tensor Imaging (DTI)-based microstructural metrics in periventricular white matter (PVWM) versus total white matter as a biomarker of cerebral small vessel disease (CSVD). <h3>Background:</h3> PVWM, supplied exclusively by small arteries, has the lowest cerebral blood flow (CBF) in the brain and a high frequency of white matter hyperintensities (WMH) in aging. Accordingly, PVWM tissue may be particularly sensitive to CSVD. We compared DTI parameters in normal-appearing periventricular white matter (NA-PVWM) to normal-appearing white matter (NAWM) as a whole and assessed their correlations with WMH and vascular risk factors in an older cohort. <h3>Design/Methods:</h3> Multimodal MRI data from N=100 cognitively normal older subjects in the Penn Alzheimer’s Disease Research Center were analyzed. An established CBF-based PVWM mask was used to extract mean values for DTI metrics (fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD)). We derived WMH lesion masks from FLAIR MRI to calculate total WMH volume and to exclude WMH voxels from WM and PVWM regions. <h3>Results:</h3> Cohort mean age was 73(6) years with 61% females. All DTI metrics were significantly higher in NA-PVWM compared to NAWM (all P&lt;0.001). Only FA in both NAWM (P=0.010) and NA-PVWM (P=0.007) was significantly associated with hypertension. None of the DTI metrics were associated with diabetes, hypercholesterolemia, or smoking. After adjustment for age and sex, diffusivity values in both NA-PVWM and NAWM correlated similarly with total WMH volume (all P&lt;0.001, except P=0.003 for AD in NA-PVWM), whereas FA was significantly correlated with WMH volume only in NA-PVWM (P&lt;0.001). <h3>Conclusions:</h3> PVWM differs from total WM in microstructural characteristics derived from DTI. FA in NA-PVWM was associated with hypertension and with overall WMH burden, suggesting that FA in PVWM may be a potential biomarker of CSVD. <b>Disclosure:</b> Dr. Shakibajahromi has nothing to disclose. Dr. Dolui has nothing to disclose. The institution of Dr. Brown has received research support from National Institute of Health. Mr. Tackett has nothing to disclose. Mr. Khandelwal has nothing to disclose. Shokufeh Sadaghiani, 1129 has nothing to disclose. Dr. Taghvaei has nothing to disclose. Paul Yushkevich has nothing to disclose. Dr. Wolk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuronix. Dr. Wolk has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Functional Neuromodulation. Dr. Wolk has received personal compensation in the range of $5,000-$9,999 for serving as a CME Speaker with MJH Life Sciences. Dr. Detre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hura Imaging. The institution of Dr. Detre has received research support from NIH. Dr. Detre has received personal compensation in the range of $500-$4,999 for serving as a grant proposal reviewer with NIH, VA, European Science Foundation,Deutsche Forschungsgemeinschaft.

R1ρ dispersion in white matter correlates with quantitative metrics of cognitive impairment

Much previous neuroimaging research in Alzheimer’s disease has focused on the roles of amyloid and tau proteins, but recent studies have implicated microvascular changes in white matter as early indicators of damage related to later dementia. We used MRI to derive novel, non-invasive measurements of R1ρ dispersion using different locking fields to characterize variations of microvascular structure and integrity in brain tissues. We developed a non-invasive 3D R1ρ dispersion imaging technique using different locking fields at 3T. We acquired MR images and cognitive assessments of participants with mild cognitive impairment (MCI) and compared them to age-matched healthy controls in a cross-sectional study. After providing informed consent, 40 adults aged 62 to 82 years (n = 17 MCI) were included in this study. White matter ΔR1ρ-fraction measured by R1ρ dispersion imaging showed a strong correlation with the cognitive status of older adults (βstd = −0.4, p-value < 0.01) independent of age, in contrast to other conventional MRI markers such as T2, R1ρ, and white matter hyperintense lesion volume (WMHs) measured with T2-FLAIR. The correlation of WMHs with cognitive status was no longer significant after adjusting for age and sex in linear regression analysis, and the size of the regression coefficient was substantially decreased (53% lower). This work establishes a new non-invasive method that potentially characterizes impairment of the microvascular structure of white matter in MCI patients compared to healthy controls. The application of this method in longitudinal studies would improve our fundamental understanding of the pathophysiologic changes that accompany abnormal cognitive decline with aging and help identify potential targets for treatment of Alzheimer's disease.

High Mean Platelet Volume Is Associated with Cerebral White Matter Hyperintensities in Non-Stroke Individuals

The mean platelet volume (MPV) is regarded as a marker for thrombosis, atherosclerosis, and inflammation in various vascular diseases. However, it still remains unclear whether plasma MPV is associated with cerebral white matter hyperintensities (WMH) and cerebral microvascular pathology in the elderly population. We examined whether MPV level is associated with the presence of cerebral WMH on brain magnetic resonance imaging from 870 non-stroke outpatient subjects. The subjects were divided into three groups according to the consecutive level of MPV (low T1, middle T2, and high T3 MPV tertile groups). To determine the association of MPV levels with the WMH, logistic regression and receiver operating characteristic curve analyses were conducted. Subjects with higher MPV level were older and more likely to have hypertension, diabetes mellitus, and low renal function. Cerebral WMH were more prevalent in subjects with higher MPV level. After adjusting for confounding factors, moderate to severe cerebral WMH were significantly associated with high MPV tertile level. This association remained significant after adjusting for other cerebral vascular pathologies. T2 [odds ratio (OR): 1.49, 95% confidence interval (CI): 1.03-2.15] and T3 MPV tertile groups (OR: 1.51, 95%CI: 1.04-2.20) had more cerebral WMH lesions compared to T1 MPV tertile group. In addition, the subjects with higher Fazekas scores showed higher MPV level (p=0.020). We found that high MPV level is independently associated with cerebral WMH. This result suggests that platelet activation plays a role in the development of cerebral WMH.

Spatial distributions of white matter hyperintensities on brain MRI: A pooled analysis of individual participant data from 11 memory clinic cohorts

IntroductionThe spatial distribution of white matter hyperintensities (WMH) on MRI is often considered in the diagnostic evaluation of patients with cognitive problems. In some patients, clinicians may classify WMH patterns as “unusual”, but this is largely based on expert opinion, because detailed quantitative information about WMH distribution frequencies in a memory clinic setting is lacking. Here we report voxel wise 3D WMH distribution frequencies in a large multicenter dataset and also aimed to identify individuals with unusual WMH patterns. MethodsIndividual participant data (N = 3525, including 777 participants with subjective cognitive decline, 1389 participants with mild cognitive impairment and 1359 patients with dementia) from eleven memory clinic cohorts, recruited through the Meta VCI Map Consortium, were used. WMH segmentations were provided by participating centers or performed in Utrecht and registered to the Montreal Neurological Institute (MNI)-152 brain template for spatial normalization. To determine WMH distribution frequencies, we calculated WMH probability maps at voxel level. To identify individuals with unusual WMH patterns, region-of-interest (ROI) based WMH probability maps, rule-based scores, and a machine learning method (Local Outlier Factor (LOF)), were implemented. ResultsWMH occurred in 82% of voxels from the white matter template with large variation between subjects. Only a small proportion of the white matter (1.7%), mainly in the periventricular areas, was affected by WMH in at least 20% of participants. A large portion of the total white matter was affected infrequently. Nevertheless, 93.8% of individual participants had lesions in voxels that were affected in less than 2% of the population, mainly located in subcortical areas. Only the machine learning method effectively identified individuals with unusual patterns, in particular subjects with asymmetric WMH distribution or with WMH at relatively rarely affected locations despite common locations not being affected. DiscussionAggregating data from several memory clinic cohorts, we provide a detailed 3D map of WMH lesion distribution frequencies, that informs on common as well as rare localizations. The use of data-driven analysis with LOF can be used to identify unusual patterns, which might serve as an alert that rare causes of WMH should be considered.

A Nested Attention Guided UNet++ Architecture for White Matter Hyperintensity Segmentation

White Matter Hyperintensity (WMH) is a common finding in Magnetic Resonance Imaging (MRI) of patients with cerebral infarction and is associated with poor prognosis. Accurate and rapid segmentation of WMH lesions is critical for clinicians to assess the risk of rebleeding and the long-term prognosis of thrombolytic patients. However, segmentation can be challenging due to the erratic signals of WMH in MRI, leading to imprecise results. Deep learning-based approaches have been proposed, but the dice similarity coefficient remains low. Atlas images are navigation maps that integrate various medical information expressions. In this study, we propose a nested attention-guided UNet++ framework that employs attention mechanisms to capture local and global features of WMH lesions using atlas images for segmentation. The framework consists of two modules, the atlas attention module, and the nested attention-guided nested U-Net module. The atlas attention module generates the atlas attention map, which is used as the input for the nested attention-guided nested U-Net module that generates the segmentation map of the FLAIR image. Experimental results demonstrate that the proposed NAUNet++ framework converges faster than conventional UNet and UNet++ approaches. Moreover, the nested architecture enhances recall and f1 scores of the segmentation results compared to the attention-guided approach.