Progression Of White Matter Lesions Research Articles

Erythrocyte Sedimentation Rate (ESR) as a Predictor of White Matter Lesion (WML) Progression (P2-5.031)

Erythrocyte Sedimentation Rate (ESR) as a Predictor of White Matter Lesion (WML) Progression (P2-5.031)

Can exercise benefit cerebral white matter myelin? Findings from a 12‐month randomized controlled trial in older adults with vascular cognitive impairment

AbstractBackgroundCerebral small vessel disease is a major underlying cause of subcortical ischemic vascular cognitive impairment (SIVCI). Myelin loss is a feature of cerebral small vessel disease, which may underly cognitive and functional decline in older adults living with SIVCI. Resistance training (RT) is a form of exercise associated with slower progression of white matter lesions, a cerebral small vessel disease marker. However, it remains to be determined whether RT can counteract myelin loss in individuals living with SIVCI. Thus, we examined the impact of a 12‐month, twice‐weekly progressive RT program on myelin content in those with SIVCI.MethodThis was a sub‐study of a 12‐month single‐blinded, randomized controlled trial. Participants (n = 91) were randomized to RT or an active control group (balance and tone exercises [BAT]). Study eligibility included: 1) age 55 years and older; 2) magnetic resonance imaging (MRI) evidence of cerebral small vessel disease; 3) mild cognitive impairment; and 4) the absence of dementia. Myelin was measured using a multi‐echo gradient and spin echo T2 relaxation MRI sequence, indexed as myelin water fraction (MWF). Differences between groups at 12 months were assessed via analysis of covariance adjusting for baseline MWF and estimated intracranial volume. MWF data from fifteen white matter tracts were analyzed. Post‐hoc regressions were conducted to determine if changes in MWF were associated with changes in mobility measured with the Short Physical Performance Battery (SPPB).ResultSeventy‐three participants (RT = 36) aged 74.1 (SD = 5.7), 64% females with high‐quality MRI data were included in the analyses. At 12 months, RT showed lower MWF levels compared with BAT in the genu of the corpus callosum (estimated mean difference [RT – BAT]: ‐0.610, 95% CI: ‐1.041 to ‐0.178, p = 0.006), fornix (‐0.883, 95% CI: ‐1.570 to ‐0.197, p = 0.012), and combined white matter tracts (‐0.326, 95% CI: ‐0.643 to ‐0.009, p = 0.044). Changes in MWF in the combined white matter tracs were positively associated with changes in SPPB (Unstandardized B = 0.124, SE = 0.061, p = 0.047).ConclusionContrary to our expectations, 12 months of balance and tone exercises, but not RT, showed positive changes in myelin. These improvements may result in better mobility in older adults with SIVCI.

Microbial lipopolysaccharide-induced inflammation contributes to cognitive impairment and white matter lesion progression in diet-induced obese mice with chronic cerebral hypoperfusion.

White matter lesions (WMLs) are involved in the pathological processes leading to cognitive decline and dementia. We examined the mechanisms underlying the exacerbation of ischemia-induced cognitive impairment and WMLs by diet-induced obesity, including lipopolysaccharide (LPS)-triggered neuroinflammation via toll-like receptor (TLR) 4. Wild-type (WT) and TLR4-knockout (KO) C57BL/6 mice were fed a high-fat diet (HFD) or low-fat diet (LFD), and subjected to bilateral carotid artery stenosis (BCAS). Diet groups were compared for changes in gut microbiota, intestinal permeability, systemic inflammation, neuroinflammation, WML severity, and cognitive dysfunction. In WT mice, HFD induced obesity and increased cognitive impairment and WML severity compared with LFD-fed mice following BCAS. HFD caused gut dysbiosis and increased intestinal permeability, and plasma LPS and pro-inflammatory cytokine concentrations. Furthermore, HFD-fed mice had higher LPS levels and higher neuroinflammatory status, including increased TLR4 expression, in WMLs. In TLR4-KO mice, HFD also caused obesity and gut dysbiosis but did not increase cognitive impairment or WML severity after BCAS. No difference was found between HFD- and LFD-fed KO mice for LPS levels or inflammatory status in either plasma or WMLs. Inflammation triggered by LPS-TLR4 signaling may mediate obesity-associated exacerbation of cognitive impairment and WMLs from brain ischemia.

Progressive multifocal leukoencephalopathy (PML) treated with pembrolizumab in a patient with mosaic STAT3 gain-of-function mutation

Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal disease of the central nervous system caused by JC virus. It occurs exclusively in immunocompromised hosts and is strongly associated with HIV infection and iatrogenic immunosuppression. Monogenic defects underlying the pathogenesis and reactivation of JC virus are not well understood, although some reports of primary immunodeficiencies (including four cases of STAT1 gain-of-function) have been previously described.A 77 year old male with history of prostate cancer (in remission; treated with radiation and hormonal therapy >10 years ago) presented with dysarthria, ataxia, left-sided weakness, diagnosed with CSF and biopsy-confirmed PML. He underwent an extensive workup upon which no other chronic infectious or oncologic processes were identified. He has never received any form of immunomodulation (including chemotherapy) in the past. Workup revealed low CD4 (347/mm3) and CD8 (282/mm3) T cell counts with normal proportions of naive vs. memory populations. Mitogen stimulation demonstrated poor CD8T cell proliferation. Targeted sequencing revealed a heterozygous mosaic mutation in the DNA-binding domain of STAT3 (c.1229 A > G p.H410R, 14% in 96 reads). This variant had been previously identified in two individuals with large granular lymphocyte (LGL) leukemia and validated as a gain-of-function via downstream signaling assays.Our patient demonstrated a favorable response to PD-1 blockade with pembrolizumab (2 mg/kg) and was discharged to a rehabilitation facility. His MRI brain showed no further progression of cerebellar white matter lesions following three doses of pembrolizumab.To our knowledge, this is the first case to implicate that STAT3 gain-of-function may confer a predisposition to JC virus reactivation and/or control in the pathogenesis of PML. Furthermore, we propose that this patient’s response to pembrolizumab may be partially attributed to STAT3-mediated regulation of the PD-1/PD-L1 axis. Further studies are currently underway to characterize this patient’s mosaic variant in flow cytometry-sorted subsets (including CD8T cells). Additional studies may include measurement of PD-1/PD-L1 expression and basal vs. induced STAT3 phosphorylation in sorted cell populations.

Longitudinal Dopamine D2 Receptor Changes and Cerebrovascular Health in Aging.

Background and ObjectivesCross-sectional studies suggest marked dopamine (DA) decline in aging, but longitudinal evidence is lacking. The aim of this study was to estimate within-person decline rates for DA D2-like receptors (DRD2) in aging and examine factors that may contribute to individual differences in DRD2 decline rates.MethodsWe investigated 5-year within-person changes in DRD2 availability in a sample of older adults. At both occasions, PET with 11C-raclopride and MRI were used to measure DRD2 availability in conjunction with structural and vascular brain integrity.ResultsLongitudinal analyses of the sample (baseline: n = 181, ages: 64–68 years, 100 men and 81 women; 5-year follow-up: n = 129, 69 men and 60 women) revealed aging-related striatal and extrastriatal DRD2 decline, along with marked individual differences in rates of change. Notably, the magnitude of striatal DRD2 decline was ∼50% of past cross-sectional estimates, suggesting that the DRD2 decline rate has been overestimated in past cross-sectional studies. Significant DRD2 reductions were also observed in select extrastriatal regions, including hippocampus, orbitofrontal cortex (OFC), and anterior cingulate cortex (ACC). Distinct profiles of correlated DRD2 changes were found across several associative regions (ACC, dorsal striatum, and hippocampus) and in the reward circuit (nucleus accumbens and OFC). DRD2 losses in associative regions were associated with white matter lesion progression, whereas DRD2 losses in limbic regions were related to reduced cortical perfusion.DiscussionThese findings provide the first longitudinal evidence for individual and region-specific differences of DRD2 decline in older age and support the hypothesis that cerebrovascular factors are linked to age-related dopaminergic decline.

Plasma Biomarkers of Angiogenesis Related to Small Vessel Brain Disease in SPRINT

Meta-analyses incorporating the Systolic Blood Pressure Intervention Trial (SPRINT) have shown a reduced incidence of dementia with blood pressure lowering. However, mechanistic explanations for this effect are lacking, apart from slowed progression of cerebral white matter lesions (WML). Here we examine possible biomarkers of angiogenesis related to small vessel brain disease including bFGF, FLT1, PLGF, TIE-2, VEGF, VEGF-C, and VEGF-D. The biomarkers were assayed in plasma at baseline and during follow-up (median follow-up = 3.8 years) in a subgroup of participants 60 to 89 years old from SPRINT (N=517). We modeled changes in each biomarker using robust linear mixed models accounting for treatment group, time since randomization, and kidney function. Participants were 69.8 ± 7.1 (standard deviation) years of age, 42.1% female, with a mean systolic blood pressure (SBP) of 138.2 ± 17.0 mm Hg. At baseline, none of the biomarkers were associated with WML lesion volume or total brain volumes adjusting for age (all p>0.05), while FLT1, PLGF, and TIE-2 were negatively associated with frontal gray matter cerebral blood flow (partial correlations of -0.11, -0.10, and -0.12 respectively, all p<0.05). For both intensive (target SBP<120 mm Hg) and standard (target SBP<140 m Hg) blood pressure control, mean levels for the majority of biomarkers increased during follow-up, with the exceptions of TIE-2 (decreased over follow-up) and VEGF-D (no change). We did not observe significant between-group differences for the change in these plasma biomarkers of angiogenesis comparing intensive to standard blood pressure treatment.

Cerebral Small Vessel Disease Associated With Atrial Fibrillation Among Older Adults: A Population-Based Study.

Cerebral small vessel disease, as a potential mechanism underlying the association between atrial fibrillation (AF) and dementia, remains poorly investigated. In this cohort study, we sought to examine the association between AF and cerebral small vessel disease markers among older adults. Data on 336 participants (age ≥60 years, mean 70.2 years; 60.2% women) free of dementia, disability, and cerebral infarcts were derived from the population-based Swedish National Study on Aging and Care in Kungsholmen. Structural brain magnetic resonance imaging examinations were performed at baseline (2001–2004) and follow-ups (2004–2007 and 2007–2010). Magnetic resonance imaging markers of cerebral small vessel disease included perivascular spaces, lacunes, and volumes of white matter hyperintensities, lateral ventricles, and total brain tissue. AF was assessed at baseline and follow-ups through clinical examinations, electrocardiogram, and medical records. Data were analyzed using linear mixed-effects models. At baseline, 18 persons (5.4%) were identified to have prevalent AF and 17 (5.6%) developed incident AF over the 6-year follow-up. After multivariable adjustment, AF was significantly associated with a faster annual increase in white matter hyperintensities volume (β coefficient=0.45 [95% CI, 0.04–0.86]) and lateral ventricular volume (0.58 [0.13–1.02]). There was no significant association of AF with annual changes in perivascular spaces number (β coefficient=0.53 [95% CI, −0.27 to 1.34]) or lacune number (−0.01 [−0.07 to 0.05]). Independent of cerebral infarcts, AF is associated with accelerated progression of white matter lesions and ventricular enlargement among older adults.

Fluid biomarkers of Alzheimer’s disease in the Systolic Blood Pressure Intervention Trial

AbstractBackgroundThe Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive treatment (systolic blood pressure (SBP) target &lt;120 mm Hg) reduces the risk for mild cognitive impairment and slows the progression of white matter lesions detected via magnetic resonance imaging (MRI) as compared to standard treatment (SBP&lt;140 mm Hg). However, it is unclear what pathway(s) mediate this effect.MethodWe measured plasma beta‐amyloid 40 (Aβ40), beta‐amyloid 42 (Aβ42), total tau, and neurofilament light (NfL) at baseline and during follow‐up (median follow‐up = 3.8 years) in a subgroup of participants 60 years or older that also participated in SPRINT’s MRI imaging substudy (N=542). We modeled changes in each AD biomarker using robust linear mixed models.ResultThe average baseline age of this subgroup of SPRINT participants was 69.8 ± 7.1 (standard deviation) years; with a mean SBP of 138.2 ± 17.0 mm Hg; and 42.1% were female. At baseline, the strongest plasma biomarker correlations were with age (Spearman’s rho = 0.27 for Aβ40 and 0.43 for NfL, both P&lt;0.001) and estimated Glomerular Filtration Rate (eGFR; rho ranged from –0.21 for Aβ42 to ‐0.42 for NfL, all P&lt;0.001). We observed larger increases in each AD biomarker for participants that experienced ≥30% decline in eGFR during follow‐up, which occurs more frequently with intensive treatment. There were no significant between‐group differences for Aβ40, Aβ42, or total tau, however intensive treatment was associated with larger increases in NfL during follow‐up (mean change per year (MCPY) = 2.6 pg/ml, 95% CI: 1.8‐3.3), as compared to standard treatment (MCPY = 1.6 pg/ml; 95% CI: 1.3‐1.8). This difference was explained by changes in eGFR (between‐group difference in MCPY adjusting for eGFR = 0.04 pg/ml; 95% CI: ‐0.76 ‐ 0.84).ConclusionIn this pilot study of SPRINT participants, after accounting for kidney function, intensive treatment was not associated with significant changes in fluid biomarkers of AD. Our results highlight the need for future studies of blood‐based AD biomarkers to account for renal function, especially within the context of hypertension and vascular disease.

Effect of intensive versus standard blood pressure control on cerebral blood flow in SPRINT

AbstractBackgroundHypertension is a major risk factor for cardiovascular and cerebrovascular disease including stroke, small vessel disease, and dementia. The Systolic blood PRessure INTervention (SPRINT) randomized trial prospectively evaluated the effects of intensive systolic blood pressure (SBP) control (target SBP&lt;120mmHg) versus standard control (SBP&lt;140mmHg) on cardiovascular outcomes in individuals without baseline diabetes or stroke, and included cerebral blood flow (CBF) measurements. Previous studies with much smaller sample sizes and shorter duration suggested stable CBF in response to intensive treatment (SBP&lt;125mmHg) [1], but long term effects are unknown. We evaluated the long‐term effects of intensive blood pressure treatment on CBF.MethodWhole brain CBF was measured at 3T using pseudocontinuous arterial spin labeled (ASL) perfusion MRI at baseline and after 3.9±0.3 years. Total white matter lesion (WML) load was measured from Fluid Attenuated Inversion Recovery T2 MRI. Data from 324 subjects with adequate ASL scan quality acquired from 6 sites were included.ResultDemographics and scanner specific CBF values are provided in Table 1. The intensive treatment group was older (p=0.01), but was otherwise similar to the standard group at baseline. There was a significant effect on the longitudinal CBF change (p=0.006) of the intensive treatment (5.7% increase) compared to the standard treatment (4.0% decrease, Fig 1). Secondary analysis showed a significant increase in age‐adjusted fractional CBF for the intensive treatment group (p&lt;0.001) with no change (p=0.24) in the standard treatment group. Change in CBF was not associated with change in WML.ConclusionSustained intensive antihypertensive treatment does not reduce whole brain CBF, in fact it showed an increase in whole brain CBF relative to standard therapy. While improved CBF might contribute to the reduced WML progression observed in the intensive‐therapy group versus standard therapy in SPRINT[2], we did not observe a direct correlation between CBF changes and WML changes.

Age and Diastolic Blood Pressure Play an Important Role in the Progression of White Matter Lesions: A Meta-Analysis

Introduction: White matter lesions (WMLs) are currently considered as a cerebral microvascular disease, and hypertension is considered as its most important risk factor. This study analysis systematically evaluated the effects of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on the progression of WMLs. Methods: We searched the MeSH terms: “white matter,” “blood pressure,” “hypertension,” “Leukoencephalopathy,” and “leukoaraiosis” on PubMed and Cochrane from January 2000 to August 2019. A total of 12 closely related literature were included for research. Results: The results of the meta-analysis showed that the increase of both SBP and DBP can promote the progression of WMLs (respectively, odds ratio [OR] = 2.90, 95% confidence interval [CI] 2.86–2.94; OR = 3.13, 95% CI 3.03–3.23). Subgroup analysis found that patients with hypertension aged younger than 70 years are at a greater risk of WML progression when their DBP increased (OR = 4.69, 95% CI 3.31–6.65). Conclusion: The relationship between DBP and WMLs is closer than that of SBP. Also, the risk of WML progression in patients aged under 70 years was higher than that in patients aged over 70 years. Furthermore, when DBP is elevated in patients younger than 70 years of age, the risk of WML progression may be higher. Therefore, it is expected that more researchers will attach importance to the change in DBP and identify the range of blood pressure and strategies that control DBP, thus contributing to delay the progression of WMLs.

A Systematic Review of WNT Signaling in Endothelial Cell Oligodendrocyte Interactions: Potential Relevance to Cerebral Small Vessel Disease.

Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is of major importance to maintain a proper BBB. ECs interact with several cell types to provide structural and functional support to the brain. Oligodendrocytes (OLs) myelinate axons in the central nervous system and are crucial in sustaining the integrity of white matter. The interplay between ECs and OLs and their precursor cells (OPCs) has received limited attention yet seems of relevance for the study of BBB dysfunction and white matter injury in cSVD. Emerging evidence shows a crosstalk between ECs and OPCs/OLs, mediated by signaling through the Wingless and Int-1 (WNT)/β-catenin pathway. As the latter is involved in EC function (e.g., angiogenesis) and oligodendrogenesis, we reviewed the role of WNT/β-catenin signaling for both cell types and performed a systematic search to identify studies describing a WNT-mediated interplay between ECs and OPCs/OLs. Dysregulation of this interaction may limit remyelination of WMLs and render the BBB leaky, thereby initiating a vicious neuroinflammatory cycle. A better understanding of the role of this signaling pathway in EC–OL crosstalk is essential in understanding cSVD development.

Determinants of cerebral radiological progression in Fabry disease

Background and aimIt is unclear which patients with Fabry disease (FD) are at risk for progression of white matter lesions (WMLs) and brain infarctions and whether enzyme replacement therapy (ERT)...

Utility of a diffusion-weighted arterial spin labeling (DW-ASL) technique for evaluating the progression of brain white matter lesions

PurposeTo investigate the utility of diffusion-weighted arterial spin labeling (DW-ASL) for detecting the progression of brain white matter lesions. Materials and methodsA total of 492 regions of interest (ROIs) in 41 patients were prospectively analyzed. DW-ASL was performed using the diffusion gradient prepulse of five b-values (0, 25, 60, 102, and 189) before the ASL readout. We calculated the water exchange rate (Kw) with post-processing using the ASL signal information for each b-value. The cerebral blood flow (CBF) was also calculated using b0 images. Using the signal information in FLAIR (fluid-attenuated inversion recovery) images, we classified the severity of white matter lesions into three grades: non-lesion, moderate, and severe. In addition, the normal Kw level was measured from DW-ASL data of 60 ROIs in five control subjects. The degree of variance of the Kw values (Kw-var) was calculated by squaring the value of the difference between each Kw value and the normal Kw level. All patient's ROIs were divided into non-progressive and progressive white matter lesions by comparing the present FLAIR images with those obtained 2 years before this acquisition. ResultsCompared to the non-progressive group, the progressive group had significantly lower CBF, significantly higher severity grades in FLAIR, and significantly greater Kw-var values. In a receiver operator characteristic curve analysis, a high area under the curve (AUC) of 0.89 was obtained with the use of Kw-var. In contrast, the AUCs of 0.59 for CBF and 0.72 for severity grades in FLAIR were obtained. ConclusionsThe DW-ASL technique can be useful to detect the progression of brain white matter lesions. This technique will become a clinical tool for patients with various degrees of white matter lesions.

Evolution of acute lacunar lesions in terms of size and shape: a PICASSO sub-study.

The imaging definition of lacunar infarcts is variable, particularly regarding their size and the presence of cavitation. We investigated the changes of diameter and evolution pattern of acute lacunar infarcts, and the factors associated with the evolution pattern. Patients with acute single subcortical hemispheric or brainstem ischemic lesions of penetrating arterial territories were included. Maximal diameters on initial diffusion-weighted image (DWI) and follow-up fluid-attenuated inversion recovery image (FLAIR), which performed > 12 months after initial DWI, were semi-automatically measured. Clinical characteristics were compared according to evolution patterns on follow-up FLAIR, classified as cavitated, focal lesion without cavitation, and disappeared. Five hundred nine patients were included. Mean time to follow-up was 31.3 ± 13.7 months. Mean diameter of acute lacunar lesions decreased from 12.9 ± 4.4 to 8.5 ± 4.8mm during follow-up. Lesions of 58.2% patients remained as cavitated, 18.3% as focal lesion without cavitation, and 23.6% disappeared. Initial NIHSS score (p = 0.005), diameter of initial lesion (p < 0.001), number of slices showing acute lesion on DWI (p < 0.001), progression of white matter lesion (p < 0.001), number of acute lesions involving gray matter (p = 0.008) and lesion location (p < 0.001) were different among three groups. After adjustment for covariates, diameter of the acute lesion, initial number of old lacunes, and anterior lesion location were associated with the appearance of cavitation. Initial lesion diameter and posterior lesion location were associated with the disappearance. We observed reduction of the acute lacunar lesion diameter in 86%. There were predictive factors of disappearance and cavitation of acute lacunar infarction.

Do All Patients with Multiple Sclerosis Benefit from the Use of Contrast on Serial Follow-Up MR Imaging? A Retrospective Analysis

Patients with multiple sclerosis routinely have MR imaging with contrast every 6-12 months to assess response to medication. Multiple recent studies provide evidence of tissue deposition of MR imaging contrast agents, questioning the long-term safety of these agents. The goal of this retrospective image-analysis study was to determine whether contrast could be reserved for only those patients who show new MS lesions on follow-up examinations. We retrospectively reviewed brain MRIs of 138 patients. To increase our sensitivity, we used a previously described computerized image-comparison software to evaluate the stability or progression of multiple sclerosis white matter lesions in noncontrast FLAIR sequences. We correlated these findings with evidence of contrast-enhancing lesions on the enhanced T1 sequence from the same scan. Thirty-three scans showed an increase in white matter lesion burden. Among those 33 patients, 14 examinations also demonstrated enhancing new lesions. While we found a single example of enhancement of a pre-existing white matter lesion that appeared unchanged in size, that same examination showed an overall increase in lesion burden with enhancement of other, new lesions. Thus, we found that all patients with enhancing lesions had evidence of progression on their noncontrast imaging. Because all enhancing lesions were associated with new lesions on unenhanced imaging and progression was only evident in 24% of patients, in patients with relapsing-remitting MS, it is reasonable to consider reserving contrast for only those patients with evidence of progression on noncontrast MR images.

IL-6, PF-4, sCD40 L, and homocysteine are associated with the radiological progression of cerebral small-vessel disease: a 2-year follow-up study.

BackgroundEndothelial dysfunction (ED) is involved in the pathogenesis of cerebral small vessel disease (SVD), however, it is not clear if specific biomarkers related to ED are associated with radiological progression of SVD.MethodsA single-center, prospective cohort study was conducted among consecutive, adult patients with SVD. Logistic regression was used to analyze the association of each baseline biomarker (highest vs lowest tertile) and the MRI radiological outcome after 2 years. The mean Z-score for vascular inflammation (VI) combined soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble platelet selectin (sP-selectin), CD40 ligand (sCD40 L), platelet factor-4 (PF-4) and homocysteine; Z-score for systemic inflammation (SI) combined high-sensitivity C-reactive protein (hsCRP), interleukin-1α and -6 (IL-1α and IL-6, respectively) and tumor necrosis factor-α (TNF-α).ResultsThe study group comprised 123 patients (age, mean±SD: 72.2±8 years, 49% females), with lacunar stroke (n=49), vascular dementia (n=48), and vascular parkinsonism (n=26). Moreover, 34.9% patients experienced radiological progression, 43% had progression of isolated white matter lesions (WMLs), 23.2% had new lacunes, and 34.8% had both WMLs progression and new lacunes. After adjustment for confounders (age, sex, blood pressure, MRI lesions load), the PF-4 (OR; 95% CI 5.5; 1.5–21), sCD40L (4.6; 1.1–18.6), IL-6 (7.4; 1.48–37), Z-score for VI (4.5; 1.1–18.6), and, marginally, homocysteine (4.1; 0.99–17) were associated with the risk of any radiological progression; further, homocysteine (2.4; 1.4–14), Z-score for SI (2.1; 1.2–14) and, marginally, IL-6 (6.0; 0.95 -38) were related to the development of new lacunes; PF-4 (7.9; 1.6–38) and, marginally, the Z-score for VI (4.2; 0.9–19.5) were correlated with the risk of WMLs progression. Additional adjustment for clinical SVD manifestations did not significantly alter the results.ConclusionThe data supports the concept that ED modulates the radiological progression of SVD and WMLs and lacunes are associated with different inflammatory markers.

Therapeutic Effects of Pretreatment with Tocovid on Oxidative Stress in Postischemic Mice Brain

Dietary supplement is an attempt to reduce the risk of ischemic stroke in high-risk population. A new mixed vitamin E-Tocovid that mainly contains tocotrienols other than tocopherol, attenuated the progression of white matter lesions by oral in humans. However, the effect of Tocovid on ischemic stroke has not been examined. In the present study, we assessed the therapeutic effects of Tocovid pretreatment on transient middle cerebral artery occlusion (tMCAO) in mice. After pretreatment with Tocovid (200 mg/kg/d) or vehicle for 1 month, 60-minute tMCAO was performed, and these mice were examined at 1 day, 3 days, and 7 days after reperfusion. We histologically assessed the effects of Tocovid pretreatment on the expressive changes of oxidative stress markers, cleaved caspase-3, and LC3-II after tMCAO in mice. We observed that Tocovid pretreatment significantly improved the rotarod time, reduced infarct volume, decreased the number of 4-HNE, nitrotyrosine, and 8-OhdG positive cells, inhibited advanced glycation end products biomarkers RAGE, CMA, and CML expressions, and increased Nrf2 and MRP1 levels with GSSG/GSH ratio decrease. Furthermore, Tocovid pretreatment greatly decreased cleaved caspase-3 and LC3-II expressions after tMCAO. The present study obviously demonstrated that Tocovid pretreatment showed neuroprotective effects against oxidative stress and at least in part by antiapoptotic/autophagic cell death in ischemic mice brain.

Abstract TMP91: White Matter Lesion Progression and Cognitive Function Over 5-Years in a Young Susceptible Population

Introduction: Cerebrovascular disease (CVD) and vascular risk factors cluster in families of patients with early-onset coronary artery disease (CAD). In a prior cross-sectional study of 714 healthy middle-aged relatives, we found a high prevalence of early white matter hyperintensity lesions (WMHL) and associated lower cognitive function. Prior WMHL studies have included elderly or demented subjects. Rate of WMHL progression and cognitive decline in quiescent preclinical healthy middle-aged persons remains unknown. Methods: We studied WMHL and cognitive function over 5 years in 20 healthy relatives, age 50-59, of patients with CAD &lt;60 years of age (one subject per family). Persons with any physical or neurological abnormality were excluded. At baseline and follow-up, subjects underwent 3-Tesla brain magnetic resonance imaging. WMHL volumes were determined using automated segmented volumes measured from FLAIR and MPRAGE using a previously described automated pipeline. Cognitive function was measured with the: Delayed Recall, Digit Symbol Substitution, Verbal Fluency, Digit Span, and Grooved Pegboard tests. Results: Our 20 participants were: 50% male, 45% African American (AA), average age was 54.1 (SD 1.57) years, 45% with HTN, 15% smokers, and 50% obese. WMHL prevalence was 92%. The average change in WMHL volume was 819 mm 3 (P&lt;0.0008); this was significant for men (p=0.006), women (p= 0.062), AAs (p= 0.019), and European Americans (EA) (p= 0.018). Decline occurred in all cognitive function tests (average P across all tests was &lt;0.001) in all races and sexes. Vascular risk factors did not change from baseline to follow-up. Conclusion: These striking findings are among the first to demonstrate significant quantitative WMHL volume progression and cognitive decline in a healthy middle-aged population over just 5 years, in AA and EA and both sexes. This small pilot study suggests that early quiescent brain white matter lesion progression and early multidimensional cognitive decline can be detected in healthy susceptible populations using state-of-the-art quantitative volumetric imaging techniques.

Relationships Between Lower Olfaction and Brain White Matter Lesions in Elderly Subjects with Mild Cognitive Impairment.

Olfactory impairment is reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD) and is associated with hippocampal atrophy. In elderly people, dementia with AD neuropathology and white matter lesions (WML) is common. In this context, olfactory impairment could also depend on the presence of WML. To assess the cross-sectional relationship between olfaction and WML in elderly subjects with MCI. Consecutive subjects, >65 years old, diagnosed as MCI after a comprehensive neuropsychological assessment in an expert memory center, with a brain MRI performed within a year and without major depressive state, were included. Olfaction was assessed by the Brief Smell Identification Test (BSIT). Two trained neuroradiologists, blind to cognitive and olfaction status, visually assessed hippocampal atrophy according to Scheltens' scale and WML according to Fazekas criteria. Seventy-five MCI subjects (mean age (SD) = 77.1 (6.2) years, 74.7% of women) were included. After adjustment for age and sex, factors associated with low BSIT scores were older age (p = 0.007), lower BMI (p = 0.08), lower MMSE score (p = 0.05), lower FCRST (p = 0.008), hippocampal atrophy (p = 0.04), periventricular WML (p = 0.007), and deep WML burden (p = 0.005). In multivariate analysis, severe deep WML (OR (95% CI) = 6.29 (1.4-35.13), p = 0.02) remained associated with low BSIT score independently from hippocampal atrophy. In elderly MCI subjects, low olfactory performances are associated with WML, whose progression may be slowed by vascular treatments. A longitudinal study to evaluate whether the progression of WML, hippocampal atrophy and low olfactory function, can predict accurately conversion from MCI to dementia is ongoing.

Low carotid wall shear stress independently accelerates the progression of cognitive impairment and white matter lesions in the elderly.

The association of hemodynamics with cognitive impairment and white matter lesions (WMLs) has come to the foreground in recent years. Six hundred eighty-nine elderly participants aged ≥60 years were eligible enrolled. After an average of 5.4 years follow-up, there was a significant decline in Mini-Mental State Examination (MMSE) scores and increases in total white matter hyperintensities (WMH), periventricular (P)WMH, and deep (D)WMH (P < 0.001). The participants were grouped by the tertiles of carotid mean wall shear stress (WSS). The decline in MMSE scores and the increases in total WMH, PWMH, and DWMH decreased from the lowest group to the highest group. There were significant differences between each group comparison (all P <0.05). Mean WSS was an independent and significant factor for the changes in MMSE scores, total WMH, PWMH, and DWMH after adjustment for confounders (P <0.001). The risk of developing cognitive impairment was higher in the lowest (hazard ratio: 2.753; 95% CI: 1.945 to 3.895; P < 0.001) and intermediate (hazard ratio: 1.531; 95% CI: 1.084 to 2.162; P = 0.015) groups than in the highest group after adjustment for confounders. Similar associations were yielded between peak WSS and the changes in MMSE scores, total WMH, PWMH, and DWMH. Our results indicated that carotid WSS is an independent factor for the progression of cognitive impairment and WMLs in the elderly. Low WSS significantly deteriorates the progression of cognitive impairment and WMLs.