Progression Of White Matter Hyperintensities Research Articles

Arterial stiffness and progression of cerebral white matter hyperintensities in patients with type 2 diabetes and matched controls: a 5-year cohort study

BackgroundStroke is a serious complication in patients with type 2 diabetes (T2DM). Arterial stiffness may improve stroke prediction. We investigated the association between carotid-femoral pulse wave velocity [PWV] and the progression of cerebral white matter hyperintensities (WMH), a marker of stroke risk, in patients with T2DM and controls.MethodsIn a 5-year cohort study, data from 45 patients and 59 non-diabetic controls were available for analysis. At baseline, participants had a mean (± SD) age of 59 ± 10 years and patients had a median (range) diabetes duration of 1.8 (0.8–3.2) years. PWV was obtained by tonometry and WMH volume by an automated segmentation algorithm based on cerebral T2-FLAIR and T1 MRI (corrected by intracranial volume, cWMH). High PWV was defined above 8.94 m/s (corresponding to the reference of high PWV above 10 m/s using the standardized path length method).ResultsPatients with T2DM had a higher PWV than controls (8.8 ± 2.2 vs. 7.9 ± 1.4 m/s, p < 0.01). WMH progression were similar in the two groups (p = 0.5). One m/s increase in baseline PWV was associated with a 16% [95% CI 1–32%], p < 0.05) increase in cWMH volume at 5 years follow-up after adjustment for age, sex, diabetes, pulse pressure and smoking. High PWV was associated with cWMH progression in the combined cohort (p < 0.05). We found no interaction between diabetes and PWV on cWMH progression.ConclusionsPWV is associated with cWMH progression in patients with type 2 diabetes and non-diabetic controls. Our results indicate that arterial stiffness may be involved early in the pathophysiology leading to cerebrovascular diseases.

The Effects of Mean of Visit-to-Visit Blood Pressure on Incident Brain Vascular Lesions and Functional-Cognitive Decline.

Cerebrovascular disease (CeVD) is an underlying cause of cognitive impairment and dementia. Hypertension is a known risk factor of CeVD, but the effects of mean of visit-to-visit blood pressure (BP) on incident CeVD and functional-cognitive decline remains unclear. To determine the association between mean of visit-to-visit BP with the incidence and progression of CeVD [white matter hyperintensities (WMH), infarcts (cortical infarcts and lacunes), cerebral microbleeds (CMBs), intracranial stenosis, and hippocampal volume] as well as functional-cognitive decline over 2 years of follow-up. 373 patients from a memory-clinic underwent BP measurements at baseline, year 1, and year 2. The mean of visit-to-visit systolic BP, diastolic BP, pulse pressure, and mean arterial pressure were calculated. Baseline and year 2 MRI scans were graded for WMH, infarcts, CMBs, intracranial stenosis, and hippocampal volume. Functional-cognitive decline was assessed using locally validated protocol. Logistic and linear regression models with odds ratios, mean difference, and 95%confidence interval were constructed to analyze associations of visit-to-visit BP on CeVD incidence and progression as well as functional-cognitive decline. Higher mean of visit-to-visit diastolic BP was associated with WMH progression. Higher tertiles of diastolic BP was associated with WMH progression and incident CMBs. There was no association between mean of visit-to-visit BP measures with incident cerebral infarcts, intracranial stenosis, change in hippocampal volume, and functional-cognitive decline. These findings suggest the possibility of hypertension-related vascular brain damage. Careful monitoring and management of BP in elderly patients is essential to reduce the incidence and progression of CeVD.

Pro-inflammatory Monocyte Phenotype During Acute Progression of Cerebral Small Vessel Disease.

Background: The etiology of cerebral small vessel disease (SVD) remains elusive, though evidence is accumulating that inflammation contributes to its pathophysiology. We recently showed retrospectively that pro-inflammatory monocytes are associated with the long-term progression of white matter hyperintensities (WMHs). In this prospective high-frequency imaging study, we hypothesize that the incidence of SVD progression coincides with a pro-inflammatory monocyte phenotype.Methods: Individuals with SVD underwent monthly magnetic resonance imaging (MRI) for 10 consecutive months to detect SVD progression, defined as acute diffusion-weighted imaging-positive (DWI+) lesions, incident microbleeds, incident lacunes, and WMH progression. Circulating inflammatory markers were measured, cytokine production capacity of monocytes was assessed after ex vivo stimulation, and RNA sequencing was performed on isolated monocytes in a subset of participants.Results: 13 out of 35 individuals developed SVD progression (70 ± 6 years, 54% men) based on incident lesions (n = 7) and/or upper quartile WMH progression (n = 9). Circulating E-selectin concentration (p < 0.05) and the cytokine production capacity of interleukin (IL)-1β and IL-6 (p < 0.01) were higher in individuals with SVD progression. Moreover, RNA sequencing revealed a pro-inflammatory monocyte signature including genes involved in myelination, blood–brain barrier, and endothelial–leukocyte interaction.Conclusions: Circulating monocytes of individuals with progressive SVD have an inflammatory phenotype, characterized by an increased cytokine production capacity and a pro-inflammatory transcriptional signature.

Entorhinal Perfusion Predicts Future Memory Decline, Neurodegeneration, and White Matter Hyperintensity Progression in Older Adults.

Altered cerebral blood flow (CBF) has been linked to increased risk for Alzheimer's disease (AD). However, whether altered CBF contributes to AD risk by accelerating cognitive decline remains unclear. It also remains unclear whether reductions in CBF accelerate neurodegeneration and development of small vessel cerebrovascular disease. To examine associations between CBF and trajectories of memory performance, regional brain atrophy, and global white matter hyperintensity (WMH) volume. 147 Alzheimer's Disease Neuroimaging Initiative participants free of dementia underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure CBF and serial neuropsychological and structural MRI examinations. Linear mixed effects models examined 5-year rate of change in memory and 4-year rate of change in regional brain atrophy and global WMH volumes as a function of baseline regional CBF. Entorhinal and hippocampal CBF were examined in separate models. Adjusting for demographic characteristics, pulse pressure, apolipoprotein E ɛ4 positivity, cerebrospinal fluid p-tau/Aβ ratio, and neuronal metabolism (i.e., fluorodeoxyglucose standardized uptake value ratio), lower baseline entorhinal CBF predicted faster rates of decline in memory as well as faster entorhinal thinning and WMH progression. Hippocampal CBF did not predict cognitive or brain structure trajectories. Findings highlight the importance of early cerebrovascular dysfunction in AD risk and suggest that entorhinal CBF as measured by noninvasive ASL MRI is a useful biomarker predictive of future cognitive decline and of risk of both.

Reshaping the path of vascular cognitive impairment with resistance training: a study protocol for a randomized controlled trial

BackgroundSubcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment in older adults, due to its modifiable risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities (WMHs), research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, the primary aim of this proof-of-concept randomized controlled trial is to investigate the efficacy of a 12-month, twice-weekly progressive resistance training program on cognitive function and WMH progression in adults with SIVCI. We will also assess the efficiency of the intervention.MethodsEighty-eight community-dwelling adults, aged > 55 years, with SIVCI from metropolitan Vancouver will be recruited to participate in this study. SIVCI will be determined by the presence of cognitive impairment (Montreal Cognitive Assessment < 26) and cerebral small vessel disease using computed tomography or magnetic resonance imaging. Participants will be randomly allocated to a twice-weekly exercise program of (1) progressive resistance training or (2) balance and tone training (i.e., active control). The primary outcomes are cognitive function measured by the Alzheimer’s Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-13 with additional cognitive tests) and WMH progression.DiscussionThe burden of SIVCI is immense, and to our knowledge, this will be the first study to quantify the effect of progressive resistance training on cognitive function and WMH progression among adults with SIVCI. Slowing the rate of cognitive decline and WMH progression could preserve functional independence and quality of life. This could lead to reduced health care costs and avoidance of early institutional care.Trial registrationClinicalTrials.gov NCT02669394. Registered on February 1, 2016

Distinct Hippocampal Subfields Atrophy in Older People With Vascular Brain Injuries.

Many neurological or psychiatric diseases affect the hippocampus during aging. The study of hippocampal regional vulnerability may provide important insights into the pathophysiological mechanisms underlying these processes; however, little is known about the specific impact of vascular brain damage on hippocampal subfields atrophy. To analyze the effect of vascular injuries independently of other pathological conditions, we studied a population-based cohort of nondemented older adults, after the exclusion of people who were diagnosed with neurodegenerative diseases during the 14-year clinical follow-up period. Using an automated segmentation pipeline, 1.5T-magnetic resonance imaging at inclusion and 4 years later were assessed to measure both white matter hyperintensities and hippocampal subfields volume. Annualized rates of white matter hyperintensity progression and annualized rates of hippocampal subfields atrophy were then estimated in each participant. We included 249 participants in our analyses (58% women, mean age 71.8, median Mini-Mental State Evaluation 29). The volume of the subiculum at baseline was the only hippocampal subfield volume associated with total, deep/subcortical, and periventricular white matter hyperintensity volumes, independently of demographic variables and vascular risk factors (β=-0.17, P=0.011; β=-0.25, P=0.020 and β=-0.14, P=0.029, respectively). In longitudinal measures, the annualized rate of subiculum atrophy was significantly higher in people with the highest rate of deep/subcortical white matter hyperintensity progression, independently of confounding factors (β=-0.32, P=0.014). These cross-sectional and longitudinal findings highlight the links between vascular brain injuries and a differential vulnerability of the subiculum within the hippocampal loop, unbiased of the effect of neurodegenerative diseases, and particularly when vascular injuries affect deep/subcortical structures.

Abstract P622: Racial Variation in White Matter Hyperintensity Progression in the ACCORDION MIND Study

Introduction: White matter hyperintensities (WMH) are linked to cognitive decline and stroke. We hypothesized that Black race would be associated with greater WMH progression in the ACCORDION MIND trial. Methods: The primary outcome is WMH progression in mL, evaluated by fitting linear regression to WMH volume on the month 80 MRI and including the WMH volume on the baseline MRI. The primary predictor is patient race, with the exclusion of patients defined as “other” race. We also derived predicted probabilities of our outcome for systolic blood pressure (SBP) levels. Results: We included 276 patients who completed the baseline and month 80 MRI, of which 207 were white, 48 Black, and 21 Hispanic. During follow-up, the mean number of SBP, LDL, and A1c measurements per patient was 21, 8, and 15. The mean (SD) WMH progression was 3.3 (5.4) mL for blacks, 2.5 (3.2) mL for Hispanics, and 2.4 (3.3) mL for whites. In the multivariate regression model (Table 1), Black, compared to white, patients had significantly more WMH progression (β Coefficient 1.26, 95% CI 0.45-2.06, p=0.002). Hispanic, compared to white, patients did not have significantly different WMH progression (p=0.392), nor was there a difference when comparing Hispanic to Black patients (p=0.162). The predicted WMH progression was significantly higher for Black compared to white patients across a mean SBP of 117 to 139 mm Hg (Figure 1). Conclusions: Black diabetic patients in ACCORDION MIND have a higher risk of WMH progression than white patients across a normal range of systolic blood pressure.

Abstract MP14: White Matter Hyperintensity Progression, Macroalbuminuria, and Intensive Glycemic Control in Diabetics

Introduction: White matter hyperintensity (WMH) is associated with a higher risk of stroke, dementia, and depression. Prior research has suggested that renal impairment and diabetes may predispose to the development of WMH. Here, we evaluated the association between WMH volume (WMHv), macroalbuminuria, and glycemic control in a cohort of diabetic patients. Methods: This is a secondary analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) dataset. The primary outcome is WMH progression in mL, evaluated by fitting linear regression to WMHv on the month 40 MRI and including the WMHv on the baseline MRI in the model. The primary predictors were incident macroalbuminuria, defined as new onset urinary albumin &gt;300mg/day, and the ACCORD glucose randomization arm. Results: We included 502 patients. The mean (SD) WMHv at baseline was 2.1 (3.9) mL and at month 40 was 3.6 (5.7) mL. Twenty-three patients (4.6%) developed macroalbuminuria during the study period, who had a higher mean WMH progression (2.9 vs. 1.4 mL, p=0.012). In a linear regression model adjusted for mean systolic blood pressure during follow-up, macroalbuminuria was a significant predictor of WMH progression (Beta 1.20, 95% CI 0.17-2.22, p=0.022). In the same model, the interaction term between glucose randomization arm and macroalbuminuria was highly significant (Beta 3.38, 95% CI 1.20-5.57, p=0.003). The predicted follow-up WMHv for the interaction term are in Figure 1, showing that macroalbuminuria with intensive glycated hemoglobin reduction (goal A1c&lt;6%) was associated with the most WMH progression. Conclusion: In diabetic patients, the development of macroalbuminuria was associated with WMH progression over 40 months, although only in patients assigned to intensive glycemic control. This finding is consistent with the adverse events seen in ACCORD with intensive glycemic control.

Association of White Matter Hyperintensity Progression with Cognitive Decline in Patients with Amnestic Mild Cognitive Impairment.

Background:White matter hyperintensities (WMH) on MRI have been reported to increase the risk of conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). However, effects of the progression of WMH on the cognition of patients with MCI remains unclear to date.Objective:To investigate the association between WMH progression and cognitive decline in amnestic MCI patients.Methods:Thirty-eight subjects with amnestic MCI were analyzed prospectively every year for 2 years. Fourteen MCI subjects dropped out on the final visit, and therefore 24 subjects with MCI were analyzed for the entire duration. The volumes of periventricular hyperintensities (PVH) and deep WMH (DWMH) were measured on T2 FLAIR using the 3D-slicer. The associations between PVH/DWMH progression and cognitive decline were investigated.Results:An increase in DWMH volume significantly correlated with changes in Mini-Mental State Examination and category verbal fluency scores, whereas an increase in PVH volume did not correlate with changes in any item.Conclusion:DWMH progression was closely associated with a decline in frontal lobe function and semantic memory, suggesting that WMH progression might affect some AD pathophysiologies in amnestic MCI patients.

Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer\u2019s Disease

BackgroundIntranasally administered insulin has shown promise in both rodent and human studies in Alzheimer’s disease; however, both effects and mechanisms require elucidation.ObjectiveWe assessed the effects of intranasally administered insulin on white matter health and its association with cognition and cerebral spinal fluid biomarker profiles in adults with mild cognitive impairment or Alzheimer’s disease in secondary analyses from a prior phase 2 clinical trial (NCT01767909).DesignA randomized (1:1) double-blind clinical trial.SettingTwelve sites across the United States.ParticipantsAdults with mild cognitive impairment or Alzheimer’s disease.InterventionParticipants received either twice daily placebo or insulin (20 IU Humulin R U-100 b.i.d.) intranasally for 12 months. Seventy-eight participants were screened, of whom 49 (32 men) were enrolled.MeasurementsChanges from baseline in global and regional white matter hyperintensity volume and gray matter volume were analyzed and related to changes in cerebral spinal fluid biomarkers, Alzheimer’s Disease Assessment Scale-Cognition, Clinical Disease Rating-Sum of Boxes, Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale, and a memory composite.ResultsThe insulin-treated group demonstrated significantly reduced changes in white matter hyperintensity volume in deep and frontal regions after 12 months, with a similar trend for global volume. White matter hyperintensity volume progression correlated with worsened Alzheimer’s disease cerebral spinal fluid biomarker profile and cognitive function; however, patterns of correlations differed by treatment group.ConclusionIntranasal insulin treatment for 12 months reduced white matter hyperintensity volume progression and supports insulin’s potential as a therapeutic option for Alzheimer’s disease.

Venous dysfunction plays a critical role in “normal” white matter disease of aging

A ubiquitous finding on MRI in older individuals, age-related cerebral white matter hyperintensities (WMHs) are associated with cognitive decline, dementia, disability, and death. Currently, these findings are thought to represent small infarcts secondary to lipohyalinotic arteriosclerosis. Commonly though, the anatomic distribution of WMHs is often non-arterial, and parallel the deep venous system. Furthermore, there is discrepant evidence for the role of conventional vascular risk factors such as hypertension, carotid atherosclerosis and diabetes for the development and progression of these. Interventions targeting conventional vascular risk factors lack consistency in preventing the progression of WMHs. There is evidence for age-related hemodynamic cervical venous dysfunction resulting in reduced internal jugular vein venous compliance, venous dilatation, and venous reflux. Similarly, venous collagenosis increases with age. Increased blood–brain barrier (BBB) permeability is also noted with aging. Both hemodynamic venous dysfunction, venous sclerosis, and increased BBB permeability are associated with WMHs. We propose that age-related WMHs are a sequalae of venous dysfunction. Venous dysfunction results initially in increased transmission of venous pressures to the brain. Subsequent BBB disruption leads to increased permeability with progression to end-stage findings of age-related WMHs.

Progression of cerebral small vessel disease in healthy middle‐aged adults associated with inherited risk of Alzheimer’s disease: The PREVENT‐Dementia study

AbstractBackgroundSubclinical brain changes in Alzheimer’s disease (AD) are detectable many years before symptom onset. While cerebral small vessel disease (SVD) has been well‐established as a key pathology in AD, whether genetic predisposition to AD influences markers of SVD in midlife remains unclear. In this study, we compare the longitudinal change in SVD burden between cognitively healthy middle‐aged adults with and without genetic predisposition to AD, and their effect on cognitive decline.Method151 cognitively‐normal participants (age 52.0 ± 5.5; PREVENT‐Dementia study) underwent 3T MRI and cognitive assessment at baseline and two‐year follow‐up. Genetic predisposition to AD was assessed by family history of parental dementia (FH) and APOE4 carriership. White matter hyperintensity (WMH) volumes were segmented and manually corrected on FLAIR MRI and cerebral microbleeds (CMB) on susceptibility‐weighted imaging (Figure 1). WMH volume was adjusted for total intracranial volume and inverse‐normal transformed. SVD progression was compared between groups using ANCOVA and linear mixed modelling in R controlling for sex, age, and education.ResultCross‐sectionally, WMH and CMB did not differ by FH or APOE4 status. However, longitudinal data showed greater WMH progression in FH+ subjects (t=3.94, p&lt;.001) and APOE4+ (t=2.09, p=.038) (Figure 2). The effect of FH on WMH progression was stronger for periventricular WMH (t=3.65, p&lt;.001; deep WMH: t=2.13, p=.035), while APOE4+ subjects displayed greater progression of deep (t=3.30, p=.001), but not periventricular WMH (t=1.17, p=.243). CMB progression did not differ by FH or APOE4 status. Significant three‐way interaction indicated that longitudinal decline in processing speed was associated with global and deep WMH progression in FH+ but not FH‐ subjects (global: t=2.05, p=.042; deep: t=2.90, p=.004; periventricular: t=0.87, p=.384) (Figure 3), while no effect was observed regarding APOE4 carriership.ConclusionCognitively‐healthy individuals with a genetic predisposition to AD displayed greater WMH progression in midlife. WMH progression was associated with longitudinal decline in processing speed in those with FH of parental dementia, but not in those without FH. Taken together, findings suggest that WMH progression is evident decades before dementia might occur, and may be of clinical relevance in predicting cognitive decline particularly in individuals at increased inherited risk of AD.

Effects of omega‐3 fatty acids on cerebral white matter hyperintensities and medial temporal lobe atrophy in older non‐demented adults: A 3‐year randomized‐controlled phase 2 trial

AbstractBackgroundThe n‐3 PUFA may modulate risk for age‐related cognitive impairment through vascular mechanisms. MRI derived cerebral white matter hyperintensities (WMH) presumptively reflect small vessel disease and their accumulation increases risk for age‐related cognitive decline and dementia. Blood n‐3 PUFA are consistently associated with reduced WMH and stroke. The primary aim here was to evaluate n‐3 PUFA supplementation on WMH accumulation over 3 years in an older population with evidence of WMH and absence of n‐3 PUFA supplementation.MethodsThe study was a double‐blind, placebo‐controlled trial, with participants randomized to a daily dose of fish oil (1650 mg combined eicosapentaenoic acid‐EPA and docosahexaenoic acid‐DHA) or placebo oil (soybean) for a 3‐year intervention. Main inclusion criteria were: non‐demented (MMSE &gt; 24), age &gt; 74 years, WMH volume &gt; 5.0 cc, and plasma n‐3 PUFA (EPA+DHA) &lt; 110 umol/L (or &lt; 5.5 percent of total fatty acids). The primary endpoint was 3‐year change in total WMH volume. Secondary endpoints include changes in regional brain volumes and white matter integrity. Exploratory endpoints include measures of cerebral blood flow, domain‐specific and global cognitive measures with subgroup analyses by APOE4 genotype. A linear mixed‐effects model was used to assess the outcomes.Results102 subjects were enrolled (mean age 81±4.4, MMSE 27.8±1.7; 60% female, 27.5% APOE4 positive) and a total of 78 participants completed the trial. Supplementation had no beneficial effect on rate of WMH progression, which increased by a mean of 1.07 cc per year in the n‐3 PUFA group vs 1.12 cc per year in the placebo group (p = 0.30 for time*trial arm interaction). Three‐year changes in executive cognitive function z‐scores were not different between treatment groups (p = 0.24). No differences in adverse events between groups were observed .ConclusionN‐3 PUFA compared with placebo, failed to slow 3‐year WMH accumulation and executive function decline in older non‐demented adults presenting with evidence of WMH. N‐3 PUFA at the 1.65‐gram dose appears safe in older adults over 3‐years. Additional MRI and cognitive outcomes with detailed safety profiles are planned for presentation.

Differential Effects of Confluent and Nonconfluent White Matter Hyperintensities on Functional Connectivity in Mild Cognitive Impairment.

Background: White matter hyperintensities (WMHs) indicate active small vessel disease. Emerging evidence suggests that confluent WMH (C-WMH) results in greater cognitive impairment compared with nonconfluent WMH (NC-WMH) visualized as punctate lesions. However, the mechanism linking C-WMH and early cognitive impairment is not clearly understood. Aims: To investigate the effects of C-WMH and NC-WMH on whole-brain functional connectivity (FC) across 138 regions of interest (ROIs) and cognition in 63 subjects with mild cognitive impairment (MCI). Methods: MCI subjects were classified as C-WMH or NC-WMH using the Staals criteria on the Fazekas WMH scale. Group-level ROI-to-ROI FC trends and differences based on WMH subtypes were computed using standard resting-state functional magnetic resonance imaging analysis. Global cognitive performance was measured with mini-mental state examination (MMSE). Results: Subjects with C-WMH exhibited increased inter-regional FC in the fronto-parietal, fronto-occipital, parieto-occipital, and temporo-parietal regions of the salience, dorsal-attention, default-mode, and visual networks compared with NC-WMH. Increased intra-regional FC was also observed within the frontal and parietal lobes in C-WMH. In addition to widespread increased FC in C-WMH, a few regions in the fronto-temporal and intra-frontal areas demonstrated reduced FC in C-WMH compared with NC-WMH. Analyses of cognitive correlates demonstrated increased parieto-occipital FC to be negatively associated with MMSE in the C-WMH. The increased parieto-occipital FC may be related to loss of higher order inhibitory control in the parieto-occipital regions induced by C-WMH or alternatively a compensatory mechanism to FC alterations induced by C-WMH. Conclusion: C-WMH in subjects with MCI is associated with widespread increase in intra- and inter-regional FC. These findings provide novel insights into divergent FC related to confluence of WMH in MCI. Impact statement White matter hyperintensities (WMHs) have been demonstrated to be a major risk factor for progressive cognitive decline. However, the relationship between structural and functional brain changes related to different types of WMH lesions as well as different stages of WMH progression remains unclear. In this study, we demonstrate that confluent WMH is significantly associated with divergent functional connectivity changes in patients with mild cognitive impairment (MCI). This finding may allow identification of MCI subjects who are adversely affected by WMH and thus provides a window of opportunity to introduce pharmacological and nonpharmacological interventional measures.

Inherited risk of dementia and the progression of cerebral small vessel disease and inflammatory markers in cognitively healthy midlife adults: the PREVENT-Dementia study

Cerebral small vessel disease (SVD) and inflammation are increasingly recognized as key contributors to Alzheimer's disease (AD), although the timing, trajectory, and relation between them early in the disease process is unclear. Therefore, to investigate very early-stage changes, we compared 158 healthy midlife adults with and without inherited AD predisposition (APOE4 carriership (38% positive), parental family history (FH) of dementia (54% positive)) on markers of SVD (white matter hyperintensities (WMH), cerebral microbleeds), and inflammation (C-reactive protein (CRP), fibrinogen), cross-sectionally and longitudinally over two years. While WMH severity was comparable between groups at baseline, longitudinal progression of WMH was greater in at-risk groups (APOE4+ and FH+). Topographically, APOE4 was associated exclusively with deep, but not periventricular, WMH progression after adjusting for FH. Conversely, APOE4 carriers displayed lower CRP levels than noncarriers, but not fibrinogen. Furthermore, interaction analysis showed that FH moderated the effect of SVD and inflammation on reaction time, an early feature of SVD, but not episodic memory or executive function. Findings suggest that vascular and inflammatory changes could occur decades before dementia onset, and may be of relevance in predicting incipient clinical progression.

Modeling subcortical ischemic white matter injury in rodents: unmet need for a breakthrough in translational research.

Subcortical ischemic white matter injury (SIWMI), pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging, is a common cause of cognitive decline in elderly. Despite its high prevalence, it remains unknown how various components of the white matter degenerate in response to chronic ischemia. This incomplete knowledge is in part due to a lack of adequate animal model. The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components. The SIWMI animal models are categorized into 1) chemically induced SIWMI models, 2) vascular occlusive SIWMI models, and 3) SIWMI models with comorbid vascular risk factors. Chemically induced models display consistent lesions in predetermined areas of the white matter, but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities. Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified. When combined with comorbid vascular risk factors (specifically hypertension), however, they can produce progressive and definitive white matter lesions including diffuse rarefaction, demyelination, loss of oligodendrocytes, and glial activation, which are by far the closest to those found in human white matter hyperintensities lesions. However, considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models. In the meantime, in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury. Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.

Effect of intensive blood pressure control on the prevention of white matter hyperintensity: Systematic review and meta-analysis of randomized trials.

Hypertension is an important cause of cerebral small vessel disease, especially of white matter hyperintensity (WMH). The ability of intensive blood pressure (BP) control in preventing this pathological progression remains unclear. The authors systematically searched PubMed, EMBASE, SCOPUS, and Cochrane library for publications until July 20, 2020. Studies included were clinical trials with random allocation to an antihypertensive medication against placebo, or different treatment targets. The primary outcome was intergroup differences in the change of WMH volume. A random-effect model was applied for pooling effect measures. Subgroup analysis and meta-regression were conducted to explore heterogeneity. Seven studies with 2693 patients were identified. Compared with the control group, patients in the intensive BP control group had a slower progression of WMH, with a pooled intergroup standard mean difference (SMD) for WMH change of -0.22 (95% CI: -0.35~-0.09, I2=63%). For studies comparing intensive and standard BP target, the pooled SMD is -0.37 (95% CI:-0.50~-0.24, I2=0%), while the pooled SMD of studies comparing active antihypertensive medication and placebo was only -0.08 (95% CI: -0.17~0.01, I2=0%). Meta-regression analysis showed that the reduction in WMH progression is proportional to the magnitude of intensive BP control (β=-0.028, P<.001). In conclusion, intensive BP control prevents WMH progression, and its effect is associated with the magnitude of intensive BP control.

Correlation between White Matter Hyperintensities Related Gray Matter Volume and Cognition in Cerebral Small Vessel Disease

Background and AimThe relationship between severity of cerebral small vessel disease, as defined by white matter hyperintensities classification, and gray matter volume of different brain regions has not been well defined. This study aimed to investigate brain regions with significant differences in gray matter volume associated with different degrees of white matter hyperintensities in patients with cerebral small vessel disease. Meanwhile, we examined whether correlations existed between gray matter volume in different brain regions and cognitive ability. Methods110 cerebral small vessel disease patients underwent 3.0T Magnetic resonance imaging scans and neuropsychological cognitive assessments. White matter hyperintensities of each subject was graded according to Fazekas grade scale and was divided into two groups: (A) White matter hyperintensities score of 1–2 points (n = 64), (B) White matter hyperintensities score of 3–6 points (n = 46). Gray matter volume was analyzed using voxel-based morphometry implemented in Statistical Parametric Mapping 12 software. ResultsBrain regions with significant differences in gray matter volume between groups were diffused throughout the brain. Patients with high white matter hyperintensities scores exhibited decreased gray matter volume in some subregions of the frontal lobes, the temporal lobes, the parahippocampal gyrus, hippocampus and thalamus (p < 0.05). Among them, gray matter volume in the ventrolateral area of right inferior temporal gyrus, together with the right posterior parietal and occipital thalamus were positively correlated with Montreal Cognitive Assessment scores (p < 0.05). Gray matter volume in the extreme ventrolateral area of right inferior temporal gyrus along with the entorhinal cortex of left parahippocampal gyrus were positively correlated with both Montreal Cognitive Assessment and Mini-Mental Status Examination scores (p < 0.05). ConclusionsCerebral small vessel disease is considered as a whole brain disease and local white matter lesions can influence the gray matter in remote areas. Reducing the severity and progression of white matter hyperintensities may help to prevent secondary brain atrophy and cognitive impairment.

Intracranial Pulsatility in Relation to Severity and Progression of Cerebral White Matter Hyperintensities.

Previous studies suggested an association between increased intracranial arterial pulsatility and the severity of microangiopathic white matter hyperintensities (WMH). However, possible confounders such as age and hypertension were seldomly considered and longitudinal data are lacking. We here aimed to explore whether increased middle cerebral artery pulsatility is associated with baseline severity and progression of cerebral small vessel disease-related WMH in elderly individuals. The study population consisted of elderly participants from the community-based ASPS (Austrian Stroke Prevention Study). Baseline and follow-up assessment comprised transcranial Doppler sonography, brain magnetic resonance imaging, and clinical/laboratory examination of vascular risk factors. Pulsatility index on transcranial Doppler sonography was averaged from baseline indices of both middle cerebral arteries and was correlated with baseline WMH severity and WMH progression over a median follow-up period of 5 years in uni- and multivariable analyses. WMH severity was graded according to the Fazekas scale, and WMH load was quantified by semiautomated volumetric assessment. The study cohort comprised 491 participants (mean age: 60.7±6.9 years; female: 48.5%). Pulsatility index was increased in participants with more severe WMH at baseline (P<0.001) but was not associated with WMH progression during follow-up (rs: 0.097, P=0.099). In multivariable analyses, only arterial hypertension remained significantly associated with baseline severity (P=0.04) and progression (P=0.008) of WMH, although transcranial Doppler sonography pulsatility index was not predictive (P>0.1, respectively). This community-based cohort study of elderly individuals does not support the pulsatility index of the middle cerebral artery on transcranial Doppler sonography as an independent marker of microangiopathic WMH severity and progression over time.

The Effects of Longitudinal White Matter Hyperintensity Change on Cognitive Decline and Cortical Thinning over Three Years.

White matter hyperintensity (WMH) has been recognised as a surrogate marker of small vessel disease and is associated with cognitive impairment. We investigated the dynamic change in WMH in patients with severe WMH at baseline, and the effects of longitudinal change of WMH volume on cognitive decline and cortical thinning. Eighty-seven patients with subcortical vascular mild cognitive impairment were prospectively recruited from a single referral centre. All of the patients were followed up with annual neuropsychological tests and 3T brain magnetic resonance imaging. The WMH volume was quantified using an automated method and the cortical thickness was measured using surface-based methods. Participants were classified into WMH progression and WMH regression groups based on the delta WMH volume between the baseline and the last follow-up. To investigate the effects of longitudinal change in WMH volume on cognitive decline and cortical thinning, a linear mixed effects model was used. Seventy patients showed WMH progression and 17 showed WMH regression over a three-year period. The WMH progression group showed more rapid cortical thinning in widespread regions compared with the WMH regression group. However, the rate of cognitive decline in language, visuospatial function, memory and executive function, and general cognitive function was not different between the two groups. The results of this study indicated that WMH volume changes are dynamic and WMH progression is associated with more rapid cortical thinning.