Intensive Blood Pressure Treatment and Subclinical Brain Infarcts: A Secondary Analysis of SPRINT (Systolic Pressure Intervention Trial).

OBJECTIVE: Subclinical brain infarcts (SBI) increase the risk for stroke and dementia, but whether they should be considered equivalent to symptomatic stroke when determining blood pressure targets remains unclear. We tested whether intensive systolic blood pressure (SBP) treatment reduced the risk of new SBI or stroke and determined the association between SBI and cognitive impairment. METHODS: In this secondary analysis of SPRINT (Systolic Pressure Intervention Trial), participants ≥50 years old, with SBP 130-180mmHg and elevated cardiovascular risk but without known clinical stroke, dementia, or diabetes, were randomized to intensive (<120mmHg) or standard (<140mmHg) SBP treatment. Brain magnetic resonance images collected at baseline and follow-up were read for SBI. The occurrence of mild cognitive impairment (MCI) or probable dementia (PD) was evaluated. RESULTS: For 667 participants at baseline, SBI were identified in 75 (11%). At median 3.9 years follow-up, 12 of 457 had new SBI on magnetic resonance imaging (5 intensive, 7 standard), whereas 8 had clinical stroke (4 per group). Baseline SBI (subhazard ratio [sHR] = 3.90; 95% CI 1.49 to 10.24; p = 0.006), but not treatment group, was associated with new SBI or stroke. For participants with baseline SBI, intensive treatment reduced their risk for recurrent SBI or stroke (sHR = 0.050; 95% CI 0.0031 to 0.79; p = 0.033). Baseline SBI also increased risk for MCI or PD during follow-up (sHR = 2.38; 95% CI 1.23 to 4.61; p = 0.010). INTERPRETATION: New cerebral ischemic events were infrequent, but intensive treatment mitigated the increased risk for participants with baseline SBI, indicating primary prevention SBP goals are still appropriate when SBI are present. ANN NEUROL 2024;95:866-875.

Diffusion tensor free water MRI predicts progression of FLAIR white matter hyperintensities after ischemic stroke.

Background: The progression of FLAIR white matter hyperintensities (WMHs) on MRI heralds vascular-mediated cognitive decline. Even before FLAIR WMH progression, adjacent normal appearing white matter (NAWM) already demonstrates microstructural deterioration on diffusion tensor imaging (DTI). We hypothesized that elevated DTI free water (FW) would precede FLAIR WMH progression, implicating interstitial fluid accumulation as a key pathological step in the progression of cerebral small vessel disease. Methods: Participants at least 3 months after an ischemic stroke or TIA with WMH on MRI underwent serial brain MRIs every 3 months over the subsequent year. For each participant, the WMHs were automatically segmented, serial MRIs were aligned, and a region of WMH penumbra tissue at risk was defined by dilating lesions at any time point and subtracting baseline lesions. Penumbra voxels were classified as either stable or progressing to WMH if they were segmented as new lesions and demonstrated increasing FLAIR intensity over time. Aligned DTI images included FW and FW-corrected fractional anisotropy (FATissue) and mean diffusivity (MDTissue). Logistic regression and area under the receiver-operator characteristic curve (AUC) were used to test whether baseline DTI predicted voxel-wise classification of stable penumbra or progression to WMH while covarying for clinical risk factors. Results: In the included participants (n = 26, mean age 71 ± 9 years, 31% female), we detected a median annual voxel-wise WMH growth of 2.9 ± 2.6 ml. Each baseline DTI metric was associated with lesion progression in the penumbra, but FW had the greatest AUC of 0.732 (0.730 - 0.733) for predicting voxel-wise WMH progression pooled across participants. Discussion: Baseline increased interstitial fluid, estimated as FW on DTI, predicted the progression of NAWM to WMH over the following year. These results implicate the presence of FW in the pathogenesis of cerebral small vessel disease progression.

Intensive systolic blood pressure treatment remodels brain perivascular spaces: A secondary analysis of the Systolic Pressure Intervention Trial (SPRINT).

BACKGROUND: Brain perivascular spaces (PVS) are part of the glymphatic system and facilitate clearance of metabolic byproducts. Since enlarged PVS are associated with vascular health, we tested whether intensive systolic blood pressure (SBP) treatment affects PVS structure. METHODS: This is a secondary analysis of the Systolic PRessure INtervention Trial (SPRINT) MRI Substudy: a randomized trial of intensive SBP treatment to goal < 120 mm Hg vs < 140 mm Hg. Participants had increased cardiovascular risk, pre-treatment SBP 130-180, and no clinical stroke, dementia, or diabetes. Brain MRIs acquired at baseline and follow-up were used to automatically segment PVS in the supratentorial white matter and basal ganglia using a Frangi filtering method. PVS volumes were quantified as a fraction of the total tissue volume. The effects of SBP treatment group and major antihypertensive classes on PVS volume fraction were separately tested using linear mixed-effects models while covarying for MRI site, age, sex, Black race, baseline SBP, history of cardiovascular disease (CVD), chronic kidney disease, and white matter hyperintensities (WMH). RESULTS: For 610 participants with sufficient quality MRI at baseline (mean age 67 ± 8, 40 % female, 32 % Black), greater PVS volume fraction was associated with older age, male sex, non-Black race, concurrent CVD, WMH, and brain atrophy. For 381 participants with MRI at baseline and at follow-up (median ± IQR = 3.9 ± 0.4 years), intensive treatment was associated with decreased PVS volume fraction relative to standard treatment (interaction coefficient: -0.029 [-0.055 to -0.0029] p = 0.029). Reduced PVS volume fraction was also associated with exposure to calcium channel blockers (CCB). CONCLUSIONS: PVS enlargement was partially reversed in the intensive SBP treatment group. The association with CCB use suggests that improved vascular compliance may be partly responsible. Improved vascular health may facilitate glymphatic clearance. Clincaltrials.gov: NCT01206062.

Intensive Systolic Blood Pressure Treatment Remodels Brain Perivascular Spaces: A Secondary Analysis of SPRINT.

Background: Brain perivascular spaces (PVS) are part of the glymphatic system and facilitate clearance of metabolic byproducts. Since enlarged PVS are associated with vascular health, we tested whether intensive systolic blood pressure (SBP) treatment affects PVS structure. Methods: This is a secondary analysis of the Systolic PRessure INTervention (SPRINT) Trial MRI Substudy: a randomized trial of intensive SBP treatment to goal < 120 mm Hg vs. < 140 mm Hg. Participants had increased cardiovascular risk, pre-treatment SBP 130-180, and no clinical stroke, dementia, or diabetes. Brain MRIs acquired at baseline and follow-up were used to automatically segment PVS in the supratentorial white matter and basal ganglia using a Frangi filtering method. PVS volumes were quantified as a fraction of the total tissue volume. The effects of SBP treatment group and major antihypertensive classes on PVS volume fraction were separately tested using linear mixed-effects models while covarying for MRI site, age, sex, black race, baseline SBP, history of cardiovascular disease (CVD), chronic kidney disease, and white matter hyperintensities (WMH). Results: For 610 participants with sufficient quality MRI at baseline (mean age 67±8, 40% female, 32% black), greater PVS volume fraction was associated with older age, male sex, non-Black race, concurrent CVD, WMH, and brain atrophy. For 381 participants with MRI at baseline and at follow-up (median = 3.9 years), intensive treatment was associated with decreased PVS volume fraction relative to standard treatment (interaction coefficient: -0.029 [-0.055 to -0.0029] p=0.029). Reduced PVS volume fraction was also associated with exposure to calcium channel blockers (CCB) and diuretics. Conclusions: Intensive SBP lowering partially reverses PVS enlargement. The effects of CCB use suggests that improved vascular compliance may be partly responsible. Improved vascular health may facilitate glymphatic clearance. Clincaltrials.gov : NCT01206062.

Global changes in diffusion tensor imaging during acute ischemic stroke and post-stroke cognitive performance.

Post-stroke cognitive impairment is related to the effects of the acute stroke and pre-stroke brain health. We tested whether diffusion tensor imaging (DTI) can detect acute, global effects of stroke and predict post-stroke cognitive performance. Patients with stroke or TIA enrolled in a prospective cohort study were included if they had 1) at least one DTI acquisition at acute presentation, 24 hours, 5 days, or 30 days, and 2) follow-up testing with the telephone Montreal Cognitive Assessment (T-MoCA) at 30 and/or 90 days. A whole brain, white-matter skeleton excluding the infarct was used to derive mean global DTI measures for mean diffusivity (MD), fractional anisotropy (FA), free water (FW), FW-corrected MD (MDtissue), and FW-corrected FA (FAtissue). In 74 patients with ischemic stroke or TIA, there was a transient 4.2% increase in mean global FW between acute presentation and 24 hours (p = 0.024) that returned to initial values by 30 days (p = 0.03). Each acute global DTI measure was associated with 30-day T-MoCA score (n = 61, p = 0.0011-0.0076). Acute global FW, MD, FA and FAtissue were also associated with 90-day T-MoCA (n = 56, p = 0.0034-0.049). Transient global FW elevation likely reflects stroke-related interstitial edema, whereas other global DTI measures are more representative of pre-stroke brain health.

Fluid-Attenuated Inversion Recovery Hyperintense Ischemic Stroke Predicts Less Favorable 90-Day Outcome after Intravenous Thrombolysis.

INTRODUCTION: The absence of an ischemic lesion on MRI fluid-attenuated inversion recovery (FLAIR) is helpful in predicting stroke onset within 4.5 h. However, some ischemic strokes become visible on FLAIR within 4.5 h. We hypothesized that the early lesion visibility on FLAIR may predict stroke outcome 90 days after intravenous (IV) thrombolysis, independent of time. MATERIALS AND METHODS: We analyzed data from acute ischemic stroke patients presenting over the last 10 years who were screened with MRI and treated with IV thrombolysis within 4.5 h from onset. Three independent readers assessed whether ischemic lesions seen on diffusion-weighted imaging were also FLAIR positive based on visual inspection. Multivariable regression analyses were used to obtain an adjusted odds ratio of favorable clinical and radiological outcomes based on FLAIR positivity. RESULTS: Of 297 ischemic stroke patients, 25% had lesion visibility on initial FLAIR. The interrater agreement for the FLAIR positivity assessment was 84% (κ = 0.604, 95% CI: 0.557-0.652). Patients with FLAIR-positive lesions had more right hemispheric strokes (57 vs. 41%, p = 0.045), were imaged later (129 vs. 104 min, p = 0.036), and had less frequent favorable 90-day functional outcome (49 vs. 63%, p = 0.028), less frequent early neurologic improvement (30 vs. 58%, p = 0.001), and more frequent contrast extravasation to the cerebrospinal fluid space (44 vs. 26%, p = 0.008). CONCLUSIONS: Early development of stroke lesion on FLAIR within 4.5 h of onset is associated with reduced likelihood of favorable 90-day outcome after IV thrombolysis.

Vessel Wall Imaging of Cerebrovascular Disorders.

PURPOSE OF REVIEW: High-resolution magnetic resonance vessel wall imaging (VWI) permits direct visualization of intracranial arterial wall pathology, providing diagnostic and prognostic information that is complementary to conventional imaging techniques. We highlight the most recent studies that have advanced the clinical application of VWI. RECENT FINDINGS: VWI aids in distinguishing and diagnosing intracranial atherosclerotic disease (ICAD), intracranial dissections, central nervous system vasculitis, reversible cerebral vasoconstriction syndrome, and moyamoya disease. VWI may help predict recurrent stroke in ICAD, treatment effects in vasculitis, and disease progression in moyamoya. VWI also identifies ruptured intracranial aneurysms and may predict stability of unruptured aneurysms. Implementing VWI as an adjunctive imaging technique may permit earlier and noninvasive discrimination of rare vasculopathies. However the prognostic utility of VWI for more common cerebrovascular pathologies requires further validation.

Blood Pressure Control in Aging Predicts Cerebral Atrophy Related to Small-Vessel White Matter Lesions.

Cerebral small-vessel damage manifests as white matter hyperintensities and cerebral atrophy on brain MRI and is associated with aging, cognitive decline and dementia. We sought to examine the interrelationship of these imaging biomarkers and the influence of hypertension in older individuals. We used a multivariate spatial covariance neuroimaging technique to localize the effects of white matter lesion load on regional gray matter volume and assessed the role of blood pressure control, age and education on this relationship. Using a case-control design matching for age, gender, and educational attainment we selected 64 participants with normal blood pressure, controlled hypertension or uncontrolled hypertension from the Northern Manhattan Study cohort. We applied gray matter voxel-based morphometry with the scaled subprofile model to (1) identify regional covariance patterns of gray matter volume differences associated with white matter lesion load, (2) compare this relationship across blood pressure groups, and (3) relate it to cognitive performance. In this group of participants aged 60-86 years, we identified a pattern of reduced gray matter volume associated with white matter lesion load in bilateral temporal-parietal regions with relative preservation of volume in the basal forebrain, thalami and cingulate cortex. This pattern was expressed most in the uncontrolled hypertension group and least in the normotensives, but was also more evident in older and more educated individuals. Expression of this pattern was associated with worse performance in executive function and memory. In summary, white matter lesions from small-vessel disease are associated with a regional pattern of gray matter atrophy that is mitigated by blood pressure control, exacerbated by aging, and associated with cognitive performance.

Thalamic-hippocampal-prefrontal disruption in relapsing-remitting multiple sclerosis.

BACKGROUND: Cortical, thalamic and hippocampal gray matter atrophy in relapsing-remitting MS (RRMS) is associated cognitive deficits. However, the role of interconnecting white matter pathways including the fornix, cingulum, and uncinate fasciculus (UF) is less well studied. OBJECTIVE: To assess MS damage to a hippocampal-thalamic-prefrontal network and the relative contributions of its components to specific cognitive domains. METHODS: We calculated diffusion tensor fractional anisotropy (FA) in the fornix, cingulum and UF as well as thalamic and hippocampal volumes in 27 RRMS patients and 20 healthy controls. A neuropsychological battery was administered and 4 core tests known to be sensitive to MS changes were used to assess cognitive impairment. To determine the relationships between structure and cognition, all tests were grouped into 4 domains: attention/executive function, processing speed, verbal memory, and spatial memory. Univariate correlations with structural measures and depressive symptoms identified potential contributors to cognitive performance and subsequent linear regression determined their relative effects on performance in each domain. For significant predictors, we also explored the effects of laterality and axial versus radial diffusivity. RESULTS: RRMS patients had worse performance on the Symbol Digit Modalities Test, but no significant impairment in the 4 cognitive domains. RRMS had reduced mean FA of all 3 pathways and reduced thalamic and hippocampal volumes compared to controls. In RRMS we found that thalamic volume and BDI predicted attention/executive function, UF FA predicted processing speed, thalamic volume predicted verbal memory, and UF FA and BDI predicted spatial memory. CONCLUSIONS: Hippocampal-thalamic-prefrontal disruption affects cognitive performance in early RRMS with mild to minimal cognitive impairment, confirming both white and gray matter involvement in MS and demonstrating utility in assessing functional networks to monitor cognition.

Detection of altered hippocampal morphology in multiple sclerosis-associated depression using automated surface mesh modeling.

Depression is very common in multiple sclerosis (MS) but the underlying biological mechanisms are poorly understood. The hippocampus plays a key role in mood regulation and is implicated in the pathogenesis of depression. This study utilizes volumetric and shape analyses of the hippocampus to characterize neuroanatomical correlates of depression in MS. A cross-section of 109 female patients with MS was evaluated. Bilateral hippocampi were segmented from MRI scans (volumetric T1 -weighted, 1 mm(3) ) using automated tools. Shape analysis was performed using surface mesh modeling. Depression was assessed using the Center for Epidemiologic Studies-Depression (CES-D) scale. Eighty-three subjects were classified as low depression (CES-D 0-20) versus 26 subjects with high depression (CES-D ≥ 21). Right hippocampal volumes (P = 0.04) were smaller in the high depression versus the low depression groups, but there was no significant difference in left hippocampal volumes. Surface rendering analysis revealed that hippocampal shape changes in depressed patients with MS were clustered in the right hippocampus. Significant associations were found between right hippocampal shape and affective symptoms but not vegetative symptoms of depression. Our results suggested that regionally clustered reductions in hippocampal thickness can be detected by automated surface mesh modeling and may be a biological substrate of MS depression in female patients.

Fornix damage limits verbal memory functional compensation in multiple sclerosis.

Selective atrophy of the hippocampus, in particular the left CA1 subregion, is detectable in relapsing-remitting MS (RRMS) and is correlated with verbal memory performance. We used novel high-resolution imaging techniques to assess the role that functional compensation and/or white matter integrity of mesial temporal lobe (MTL) structures may play in mediating verbal memory performance in RRMS. High-resolution cortical unfolding of structural MRI in conjunction with functional magnetic resonance imaging (fMRI) was used to localize MTL activity in 18 early RRMS patients and 16 healthy controls during an unrelated word-pairs memory task. Diffusion tensor imaging (DTI) and Tract-Based Spatial Statistics (TBSS) were used to assess the integrity of the fornix and the parahippocampal white matter (PHWM), the major efferents and afferents of the hippocampus. RRMS patients showed greater activity in hippocampal and extra-hippocampal areas during unrelated word-pair learning and recall. Increased hippocampal activity, particularly in the right anterior hippocampus and left anterior CA1 was associated with higher verbal memory scores. Furthermore, increased fractional anisotropy (FA) in the fornix was correlated with both greater fMRI activity in this region and better memory performance. Altered hippocampal fMRI activity in RRMS patients during verbal learning may result from both structural damage and compensatory mechanisms. Successful functional compensation for hippocampal involvement in RRMS may be limited in part by white matter damage to the fornix, consistent with the critical role of this pathway in the clinical expression of memory impairment in MS.

Corpus callosal diffusivity predicts motor impairment in relapsing-remitting multiple sclerosis: a TBSS and tractography study.

Motor deficits in relapsing remitting multiple sclerosis (RRMS) patients are monitored using standard measures of disability that assess performance ranging from walking ability to hand function, thus reflecting involvement of a variety of motor pathways. We investigated the relative contributions of diffuse white matter damage and focal lesions using diffusion tensor imaging (DTI), in predicting future worsening of hand function in RRMS. The nine hole peg test (NHPT), a test of fine hand motor control, was used to measure baseline upper limb function in 16 controls and 25 RRMS patients, and then performed at follow-up on 22 of these patients at 6 and 12 months. Tract-based spatial statistics (TBSS) were used across the whole brain as a non-hypothesis driven method for localizing white matter changes associated with motor deficits. Subsequently, we used probabilistic fiber tractography in the corticospinal tracts (CST) and the transcallosal hand motor (TCHM) fibers to assess the predictive power of diffusion metrics and/or functionally relevant visible lesion volumes on the decline of hand motor function over the next 12 months. While fractional anisotropy (FA) and radial diffusivity (RD) of both pathways were strongly associated with NHPT performance at baseline, only RD of the TCHM fibers was predictive of NHPT decline over the next 12 months. Neither total visible lesion load nor pathway specific lesion loads were indicative of NHPT performance or progression. The TCHM fibers may play an important role in modifying the effects of MS pathology on fine motor control, and RD in these fibers may be a sensitive biomarker for future disability.

Smaller cornu ammonis 2-3/dentate gyrus volumes and elevated cortisol in multiple sclerosis patients with depressive symptoms.

BACKGROUND: The hippocampus is likely involved in mood disorders, but in vivo evidence for the role of anatomically distinct hippocampal subregions is lacking. Multiple sclerosis, an inflammatory disease of the central nervous system, is linked to a high prevalence of depression as well as hippocampal damage and may thus provide important insight into the pathologic correlates of medical depression. We examined the role of subregional hippocampal volume for depression in relapsing-remitting multiple sclerosis. METHODS: Anatomically defined hippocampal subregional volumes (cornu ammonis 1-3 [CA1-CA3] and the dentate gyrus [CA23DG], subiculum, entorhinal cortex) were measured using a high-resolution T2-weighted magnetic resonance imaging sequence in 29 relapsing-remitting multiple sclerosis patients and 20 matched healthy control subjects. Diurnal salivary cortisol was assessed at awakening, 4 pm, and 9 pm on 2 consecutive days. Subjects also completed the Beck Depression Inventory. RESULTS: Multiple sclerosis patients showed smaller hippocampal volumes compared with control subjects, particularly in the CA1 and subiculum subregions. In addition, multiple sclerosis patients with depressive symptoms (Beck Depression Inventory score >13) also showed smaller CA23DG volumes and higher cortisol levels. Within the multiple sclerosis group, CA23DG volume was correlated with depressive symptoms and cortisol levels. There were no associations with number of previous steroid treatments, global atrophy, or disease duration. CONCLUSIONS: This report provides in vivo evidence for selective association of smaller CA23DG subregional volumes in the hippocampus with cortisol hypersecretion and depressive symptoms in multiple sclerosis.

Optic disk and white matter abnormalities in a patient with a de novo 18p partial monosomy.

PURPOSE: Neuro-ophthalmologic and neuroimaging features of partial chromosome 18p deletion syndromes have not yet been fully described. METHODS: Careful neuro-ophthalmologic and neuroimaging evaluation of a young woman with a partial 18p deletion, including 3 Tesla MRI and diffusion tensor imaging, cytogenetic analysis on GTG-banded chromosomes, and 244K array CGH analysis. RESULTS: This 17-year-old girl had modest mental retardation, facial dysmorphism, other characteristics typical of 18p deletion syndrome, and anomalous optic disks. MRI showed enlarged third and lateral ventricles, a thin corpus callosum and patchy white matter signal hyperintensities without enhancement, while diffusion tensor imaging (DTI) revealed significant abnormalities of the corpus callosum with relative sparing of the corticospinal tracts. She had a de novo 14.6 Mb deletion on chromosome 18p [del(18)(p11.2>pter)], a region including 143 genes, only 10 of which were likely candidates for phenotypic expression. CONCLUSIONS: This young woman had clinical features similar to those described previously with the 18p deletion syndrome, including moderate mental retardation and dysmorphism without focal neurologic signs. She was myopic, like other 18p deletion patients, supporting the concept that 18p contains a candidate locus for myopia. She also had anomalous optic disks, a feature that may be more common in this syndrome than previously recognized. MRI revealed enlarged ventricles and white matter abnormalities that may be explained in part by haploinsufficiency of ADCYAP1 and LPIN2 in the deleted region of chromosome 18.