Total White Matter Lesion Volume Research Articles

Cerebrovascular pulsatility indicates preoperative subcortical cognitive impairment and an increased risk for postoperative delirium in elderly patients undergoing elective spine surgery.

Advances in spine surgery enable safe interventions in elderly patients, but perioperative neurocognitive disorders (pNCD), such as post-operative delirium (POD) and cognitive dysfunction (POCD), remain a serious concern. Pre-operative cognitive impairment is a major risk factor for pNCD. Comprehensive pre-operative cognitive assessments are not feasible in clinical practice, making effective screening methods desirable. This study investigates whether pre-operative cerebrovascular duplex sonography can assess subcortical (vascular) cognitive impairment and the risk for POD. This prospective single-center study recruited patients aged ≥60 years scheduled for elective spine surgery at a German university hospital. Patients underwent pre-operative assessments including cognitive abilities (CERAD test battery), structural MRI, and cerebrovascular duplex sonography. POD screening was conducted three times daily for at least 3 days. The primary hypothesis, that the mean pulsatility index (PI) of both internal carotid arteries (ICA) predicts POD risk, was tested using logistic regression. Secondary analyses examined the association between POD risk and ICA flow (time-averaged peak velocities, TAPV) and correlations with cognitive profiles and MRI characteristics. POD occurred in 22% of patients (n = 22/99) within three postoperative days. Patients with POD were significantly older (75.9 ± 5.4 vs. 70.0 ± 6.9 years, p < 0.01) but did not differ by gender (p = 0.51). ICA PI significantly predicted POD risk (OR = 5.46 [95%CI: 1.81-16.49], p = 0.003), which remained significant after adjustment for age and duration of surgery (ORadj = 6.38 [95% CI: 1.77-23.03], p = 0.005). TAPV did not inform the POD risk (p = 0.68). ICA PI Pre-operative cognitive scores were significantly associated with ICA PI (mean CERAD score: r = -0.32, p < 0.001). ICA PI was also significantly associated with total white matter lesion volume (τ = 0.19, p = 0.012) and periventricular white matter lesion volume (τ = 0.21, p = 0.007). This is the first study to demonstrate that cerebrovascular duplex sonography can assess the risk for POD in elderly spine surgery patients. Increased ICA PI may indicate subcortical impairment, larger white matter lesion load, and lower white matter volume, predisposing factors for POD. Pre-operative cerebrovascular duplex sonography of the ICA is widely available, easy-to-use, and efficient, offering a promising screening method for POD risk. Increased ICA PI could supplement established predictors like age to adjust surgical and peri-operative procedures to individual risk profiles.

Randomized trial of n‐3 PUFA for cerebral white matter hyperintensities, medial temporal lobe atrophy and white matter integrity in older non‐demented adults: Per‐protocol and ApoE stratified results

AbstractBackgroundBlood levels of marine n‐3 PUFA (20:5; 22:6) are inversely associated with cerebral white matter lesion volume (WML), suggesting that n‐3 may offer one approach to reduce this major vascular contributor to cognitive impairment and dementia. This trial determined whether n‐3 slows WML progression and sustains white matter integrity over 3‐years in older non‐demented adults with suboptimum n‐3 status and WML (NCT01953705).MethodsDouble‐blind, placebo‐controlled trial in non‐demented adults age 75 and older with plasma omega‐3 (20:5 + 22:6) &lt; 110 ug/mL and total WML ≥ 5 cm3. Participants were randomized to 1.65 g of n‐3 (975 mg‐20:5, 675 mg‐22:6) or placebo. Primary outcome was the annual WML progression with biomarker‐based ITT, per‐protocol (PP) and APOE4 stratified analysis. Total brain, medial temporal lobe, and diffusion tensor imaging (DTI) of white matter integrity were secondary outcomes. Linear mixed‐effects models were used.Result102 participants randomized (51 per group; mean age 81; 60% female, 28% APOE4+), 78 completed 3‐year visit (39 per group). Under mITT, annual WML change was 1.34 cm3 (95%CI: 0.80‐1.88) vs. 1.19 (0.64‐1.74) (p = 0.303) and annual DTI fractional anisotropy (FA) change was ‐0.002718 vs ‐0.001352 (p = 0.069) in the placebo and active, respectively. PPA comparing participants with study exit plasma omega‐3 ≤ 110 ug/mL vs above this threshold exhibited WML change of 1.71 cm3 vs. 0.99 (p = 0.026) and DTI radial diffusivity change of 5.412e06 mm2/sec vs. 3.143e06 (p = 0.047). No effects on WML were observed by APOE genotype (e4 p = 0.196; non‐carriers p = 0.785), however, e4 carriers on placebo had annual DTI FA change of ‐0.005 vs. ‐0.002 in the active arm (p = 0.037).ConclusionOmega‐3 did not slow total WML progression in all randomized participants; however, those that superseded the plasma n‐3 threshold established in preliminary studies (110 ug/mL) had 50% and 43% reduction in annual WML and annual DTI RD progression, respectively. These results highlight responders and macro‐and microscopic structural features sensitive to omega‐3 that warrant more extensive studies powered to detect cognitive effects and dementia incidence.NIH‐National Institute on Aging R01 AG043398 (GLB).

Association of Intensive vs Standard Blood Pressure Control With Cerebral White Matter Lesions

The effect of intensive blood pressure lowering on brain health remains uncertain. To evaluate the association of intensive blood pressure treatment with cerebral white matter lesion and brain volumes. A substudy of a multicenter randomized clinical trial of hypertensive adults 50 years or older without a history of diabetes or stroke at 27 sites in the United States. Randomization began on November 8, 2010. The overall trial was stopped early because of benefit for its primary outcome (a composite of cardiovascular events) and all-cause mortality on August 20, 2015. Brain magnetic resonance imaging (MRI) was performed on a subset of participants at baseline (n = 670) and at 4 years of follow-up (n = 449); final follow-up date was July 1, 2016. Participants were randomized to a systolic blood pressure (SBP) goal of either less than 120 mm Hg (intensive treatment, n = 355) or less than 140 mm Hg (standard treatment, n = 315). The primary outcome was change in total white matter lesion volume from baseline. Change in total brain volume was a secondary outcome. Among 670 recruited patients who had baseline MRI (mean age, 67.3 [SD, 8.2] years; 40.4% women), 449 (67.0%) completed the follow-up MRI at a median of 3.97 years after randomization, after a median intervention period of 3.40 years. In the intensive treatment group, based on a robust linear mixed model, mean white matter lesion volume increased from 4.57 to 5.49 cm3 (difference, 0.92 cm3 [95% CI, 0.69 to 1.14]) vs an increase from 4.40 to 5.85 cm3 (difference, 1.45 cm3 [95% CI, 1.21 to 1.70]) in the standard treatment group (between-group difference in change, -0.54 cm3 [95% CI, -0.87 to -0.20]). Mean total brain volume decreased from 1134.5 to 1104.0 cm3 (difference, -30.6 cm3 [95% CI, -32.3 to -28.8]) in the intensive treatment group vs a decrease from 1134.0 to 1107.1 cm3 (difference, -26.9 cm3 [95% CI, 24.8 to 28.8]) in the standard treatment group (between-group difference in change, -3.7 cm3 [95% CI, -6.3 to -1.1]). Among hypertensive adults, targeting an SBP of less than 120 mm Hg, compared with less than 140 mm Hg, was significantly associated with a smaller increase in cerebral white matter lesion volume and a greater decrease in total brain volume, although the differences were small. ClinicalTrials.gov Identifier: NCT01206062.

Characterization of gray-matter multiple sclerosis lesions using double inversion recovery, diffusion, contrast-enhanced, and volumetric MRI

PurposeTo investigate gray-matter (GM) lesions in relapsing-remitting multiple sclerosis (MS) using double-inversion recovery (DIR) MRI, determine GM lesions prevalence, spatial distribution and characterize their contrast-enhancement, diffusion characteristics and compare them to white-matter (WM) lesions. This is the first study, to our knowledge, to investigate GM MS lesions using double-inversion recovery MRI, to determine GM lesion prevalence and location, and characterize contrast-enhancement and diffusion characteristics, compared to WM lesion characteristics in the same patients. We also correlated GM lesion counts, volume and apparent diffusion coefficient (ADC) with total brain, WM, and GM volumes, as well as 25-foot walk test as a clinical disability. Materials and MethodsThis retrospective study included 44 relapsing-remitting MS patients (12M/32F, 41 ± 13 years) and 24 age-matched healthy controls (14M/10F, 36 ± 13 years). Lesions were segmented based on DIR and grouped into GM, subcortical WM, and periventricular WM lesions. ADC was tabulated for contrast-enhancing and non-enhancing lesions. Unpaired two sample t-tests were used for comparison between groups. Linear regression was used to evaluate the relationship between number of GM lesions, number of total lesions, total GM lesion volume, and total WM lesion volume with brain volumes and clinical data. ResultsGM MS lesions were present in the majority (86.4%, 38/44) of RRMS patients based on DIR, suggesting GM damage plays an important role in MS pathogenesis. The majority of the GM lesions were located in the frontal lobe. The percentage of lesions in GM that were contrast-enhanced was similar to those in WM, suggesting that blood-brain barrier integrity is likely affected similarly in GM and WM. Contrast-enhanced GM lesions showed higher ADC. GM lesion count and volume were correlated with global and regional brain atrophy, and with more severe disability group. ConclusionThis study characterized GM MS lesions using double-inversion recovery, contrast-enhanced and diffusion MRI. Understanding GM lesion pathophysiology using MRI in vivo, may prove useful for improving targeted therapy and monitoring disease progression.

Brain Volumes and Longitudinal Cognitive Change: A Population-based Study.

To investigate the association of brain volumes, white matter lesion (WML) volumes, and lacunes, with cognitive decline in a population-based cohort of nondemented persons. Within the Rotterdam Study, 3624 participants underwent brain magnetic resonance imaging. Cognition was evaluated at baseline (2005 to 2009) and at the follow-up visit (2011 to 2013). We used a test battery that tapped into domains of executive function, information processing speed, motor speed, and memory. The volumetric measures assessed were total brain volume, lobar (gray matter and white matter) volumes, and hippocampal volumes. We also studied the association of WML volumes and lacunes with cognitive decline using linear regression models. Total brain volume was associated with decline in global cognition, information processing, and motor speed (P<0.001) in analyses controlled for demographic and vascular factors. Specifically, smaller frontal and parietal lobes were associated with decline in information processing and motor speed, and smaller temporal and parietal lobes were associated with decline in general cognition and motor speed (P<0.001 for all tests). Total WML volume was associated with decline in executive function. Lobar WML volume, hippocampal volume, and lacunes were not associated with cognitive decline. Lower brain volume is associated with subsequent cognitive decline. Although lower total brain volume was significantly associated with decline in global cognition, specific lobar volumes were associated with decline in certain cognitive domains.

AEROBIC EXERCISE PROMOTES EXECUTIVE FUNCTIONING AND ASSOCIATED FUNCTIONAL NEUROPLASTICITY

Vascular cognitive ischaemia (VCI) is the second most common type of cognitive dysfunction worldwide and is due to cerebrovascular disease. While targeted aerobic exercise is a promising approach to delay the progression of VCI by reducing cardiometabolic risk factors, few randomized controlled trials to date have specifically assessed the efficacy of aerobic exercise on cognitive and brain outcomes in this high-risk group. Thus, the goal of this secondary analysis study was to examine the effect of moderate-intensity aerobic exercise training on executive functions and functional neural plasticity among older adults with mild subcortical ischaemic vascular cognitive impairment (SIVCI). Seventy-one older adults with mild SIVCI were randomly assigned to: 1) a 6-month, 3x/week aerobic training (AT; n=36) or usual care (CON; n=35). This secondary analysis included 21 (mean age 71.5 years) participants; 10 from AT group and 11 from CON group. All 21 participants completed functional magnetic resonance imaging (fMRI) sessions at baseline and trial-completion. During the fMRI sessions, performance on the Eriksen flanker task and task-evoked neural activity were assessed. At trial completion, after adjusting for baseline MoCA, baseline total white matter lesion volume, and baseline performance, compared with the CON group, the AT group significantly improved flanker task performance. Moreover, compared with the CON, the AT group demonstrated reduced activation in the left lateral occipital cortex and right superior temporal gyrus. Reduced activity in these brain regions was significantly associated with improved (i.e., faster) flanker task performance at trial completion, suggesting aerobic training increased neural efficiency. Thus, aerobic training among older adults with mild SIVCI can improve executive functions and neural efficiency of associated brain areas.

Chronic Use of Aspirin and Total White Matter Lesion Volume: Results from the Women's Health Initiative Memory Study of Magnetic Resonance Imaging Study

To investigate the relationship between aspirin and subclinical cerebrovascular heath, we evaluated the effect of chronic aspirin use on white matter lesions (WML) volume among women. Chronic aspirin use was assessed in 1365 women who participated in the Women's Health Initiative Memory Study of Magnetic Resonance Imaging. Differences in WML volumes between aspirin users and nonusers were assessed with linear mixed models. A number of secondary analyses were performed, including lobe-specific analyses, subgroup analyses based on participants' overall risk of cerebrovascular disease, and a dose-response relationship analysis. The mean age of the women at magnetic resonance imaging examination was 77.6 years. Sixty-one percent of participants were chronic aspirin users. After adjusting for demographic variables and comorbidities, chronic aspirin use was nonsignificantly associated with 4.8% (95% CI: -6.8%, 17.9%) larger WML volumes. These null findings were confirmed in secondary and sensitivity analyses, including an active comparator evaluation where aspirin users were compared to users of nonaspirin nonsteroidal anti-inflammatory drugs or acetaminophen. There was a nonsignificant difference in WML volumes between aspirin users and nonusers. Further, our results suggest that chronic aspirin use may not have a clinically significant effect on WML volumes in women.

Aerobic exercise promotes executive functions and impacts functional neural activity among older adults with vascular cognitive impairment

BackgroundVascular cognitive impairment (VCI) results from cerebrovascular disease, and worldwide, it is the second most common type of cognitive dysfunction. While targeted aerobic training is a promising approach to delay...

Sensorimotor cortex injury effects on recovery of contralesional dexterous movements in Macaca mulatta

The effects of primary somatosensory cortex (S1) injury on recovery of contralateral upper limb reaching and grasping were studied by comparing the consequences of isolated lesions to the arm/hand region of primary motor cortex (M1) and lateral premotor cortex (LPMC) to lesions of these same areas plus anterior parietal cortex (S1 and rostral area PE). We used multiple linear regression to assess the effects of gray and white matter lesion volumes on deficits in reaching and fine motor performance during the first month after the lesion, and during recovery of function over 3, 6 and 12months post-injury in 13 monkeys. Subjects with frontoparietal lesions exhibited larger deficits and poorer recovery as predicted, including one subject with extensive peri-Rolandic injury developing learned nonuse after showing signs of recovery. Regression analyses showed that total white matter lesion volume was strongly associated with initial post-lesion deficits in motor performance and with recovery of skill in reaching and manipulation. Multiple regression analyses using percent damage to caudal M1 (M1c), rostral S1 (S1r), LPMC and area PE as predictor variables showed that S1r lesion volumes were closely related to delayed post-lesion recovery of upper limb function, as well as lower skill level of recovery. In contrast, M1c lesion volume was related primarily to initial post-lesion deficits in hand motor performance. Overall, these findings demonstrate that frontoparietal injury impairs hand motor function more so than frontal motor injury alone, and results in slower and poorer recovery than lesions limited to frontal motor cortex.

Reversibility of White Matter Hyperintensity by Revascularization Surgery in Moyamoya Disease

White matter lesions (WMLs) indicate progressive cerebral small vessel disease and are frequently observed in aging people and stroke patients. The purpose of this study was to evaluate WMLs and the influence of revascularization surgery for WMLs in patients with moyamoya disease. A total of 42 hemispheres in 21 patients with moyamoya disease were included in this analysis. WMLs were detected on fluid-attenuated inversion recovery (FLAIR) imaging in 24 hemispheres. The distribution pattern of WMLs was categorized. WMLs were measured by manually creating a region of interest, and the total WML volume in the hemisphere was estimated and compared with the control group. Clinical features of patients with WMLs and postoperative changes were analyzed. The total WML volume in moyamoya disease was significantly higher than that of controls (P = .014). WMLs were observed in the internal watershed zone, especially in the watershed zone between the anterior cerebral artery and the middle cerebral artery. Patients with WMLs had significantly higher magnetic resonance angiography scores compared with controls (P = .015). A given patient's total WML volume per hemisphere was significantly decreased after surgery (P = .001). WMLs on FLAIR imaging increase in patients with moyamoya disease and are reversible by revascularization surgery. Improvement of cerebral blood flow is partly related to the decrease in WMLs. The present results provide insight into the potential role of revascularization surgery.

The contribution of white matter lesions (WML) to Parkinson's disease cognitive impairment symptoms: A critical review of the literature

We reviewed the impact of white matter lesions (WML) of cerebrovascular origin on cognitive impairment in Parkinson's disease (PD) patients. A search of PUBMED and Googlescholar.com revealed eleven studies that met the inclusion criteria: diagnosis based on the United Kingdom Brain Bank criteria (UK BBC); cognitive assessment; WML assessed on magnetic resonance imaging (MRI) by semiquantitative visual scales or automated method.Eight studies described the negative impact of WML on cognition in PD. Patients with mild cognitive impairment (MCI) and dementia had significantly more WML than the group without MCI and dementia. There was significant relationship between increasing total WML volume and worse performance on executive function, memory and language. Patients with vascular parkinsonism and dopaminergic denervation had more severe frontal lobe dysfunctions than patients with PD. In contrast in three studies there was no negative correlation between WML and cognition. Although the progression of neurodegenerative process in advanced stage of PD has been recognized as being mainly responsible for cognitive impairment in PD, WML may also be a contributing factor. It is possible that by reducing the vascular risk factors that cause WML cognitive impairment could be prevented or slowed down.

Effect of white matter lesions on manual dexterity in healthy middle-aged persons.

We hypothesized that integrated motor-visual functions measured by manipulative manual dexterity are affected by white matter lesion (WML) burden as measured on cranial MRI across relevant brain regions in subjects at risk of preclinical occult vascular disease. A real-time cross-sectional study of healthy subjects aged 29 to 74 years with a family history of early-onset coronary artery disease (n = 714; mean age, 51 ± 11 years; mean education, 14 ± 3 years; 42% male; 38% black) were identified from probands with coronary artery disease diagnosed before age 60 years. WMLs on 3-tesla brain MRI and Grooved Pegboard scores were measured. WMLs were observed at all ages. Mean pegboard scores were 108 ± 18, similar to normal populations. In unadjusted analysis, WMLs and pegboard scores were significantly correlated by region (total WMLs, r = 0.34, p = 0.0001; frontal [r = 0.34, p < 0.0001], insula [r = 0.31, p < 0.0001], parietal [r = 0.31, p < 0.0001], and temporal [r = 0.17, p < 0.0001]). In multivariate analysis predicting (log) pegboard score adjusted for age, sex, race, education, regional or total volumes, and familial non-independence, total WML volume (p = 5.79E - 05) and regional WML volumes (p < 0.01) retained statistical significance in all but the youngest age quartile (29-43 years). Greater WML volumes in different brain regions are associated with higher pegboard scores (worse performance) independent of age, sex, race, education, and total or regional volumes. This suggests that small vessel cerebrovascular disease may be present in healthy individuals in a preclinical state with measurable impact on complex integrative functions in individuals with excess risk of clinical vascular disease.

Structural and functional assessment of the brain in European Americans with mild-to-moderate kidney disease: Diabetes Heart Study-MIND.

Advanced chronic kidney disease (CKD) is associated with altered cerebral structure and function. Relationships between mild-to-moderate CKD and brain morphology and cognitive performance were evaluated in European Americans (EAs). A total of 478 EAs with estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2) and urine albumin:creatinine ratio (UACR) < 300 mg/g, most with type 2 diabetes (T2D), were included. Measures of total intracranial volume (TICV), cerebrospinal fluid volume, total white matter volume (TWMV), total gray matter volume (TGMV), total white matter lesion volume (TWMLV), hippocampal white matter volume (HWMV) and hippocampal gray matter volume (HGMV) were obtained with magnetic resonance imaging. Cognitive testing included memory (Rey Auditory Visual Learning Test), global cognition (Modified Mini-Mental State Examination) and executive function (Stroop Task, Semantic Fluency, Digit Symbol Substitution Test). Associations with CKD were assessed using log-transformed eGFR and UACR, adjusted for age, sex, body mass index, smoking, hemoglobin A1c, blood pressure, diabetes duration, cardiovascular disease and education. Participants were 55.2% female, 78.2% had T2D; mean ± SD age 67.6 ± 9.0 years, T2D duration 16.4 ± 6.5 years, eGFR 92.0 ± 22.3 mL/min/1.73 m(2) and UACR 23.8 ± 39.6 mg/g. In adjusted models, eGFR was negatively associated with TICV only in participants with T2D [parameter estimate (β): -72.2, P = 0.002]. In non-diabetic participants, inverse relationships were observed between eGFR and HGMV (β: -1.0, P = 0.03) and UACR and normalized TWMLV (β: -0.2, P = 0.03). Kidney function and albuminuria did not correlate with cognitive testing. In EAs with mild CKD enriched for T2D, brain structure and cognitive performance were generally not impacted. Longitudinal studies are necessary to determine when cerebral structural changes and cognitive dysfunction develop with progressive CKD in EAs.

Structural MRI correlates of apathy symptoms in older persons without dementia: AGES-Reykjavik Study.

We aimed to investigate the relation between apathy symptoms and structural brain changes on MRI, including white matter lesions (WMLs) and atrophy, in a large cohort of older persons. Cross-sectional analyses are based on 4,354 persons without dementia (aged 76 ± 5 years) participating in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study. Apathy symptoms were assessed with 3 items from the 15-item Geriatric Depression Scale. Brain volumes and total WML volume were estimated on 1.5-tesla MRI using an automated segmentation program; regional WML load was calculated using a semiquantitative scale. Regression analyses were adjusted for age, sex, education, intracranial volume, vascular risk factors, physical activity, brain infarcts, depressive symptoms, antidepressants, and cognitive status. Compared to those with <2 apathy symptoms, participants with ≥ 2 apathy symptoms (49% of the cohort) had significantly smaller gray matter volumes (mean adjusted difference -3.6 mL, 95% confidence interval [CI] -6.2 to -1.0), particularly in the frontal and temporal lobes; smaller white matter volumes (mean adjusted difference -1.9 mL, 95% CI -3.6 to -0.3), mainly in the parietal lobe; and smaller thalamus volumes. They were also more likely to have WMLs in the frontal lobe (adjusted odds ratio = 1.08, 95% CI 0.9-1.3). Excluding participants with a depression diagnosis did not change the associations. In this older population without dementia, apathy symptoms are associated with a more diffuse loss of both gray and white matter volumes, independent of depression.

Abstract 109: Manipulative Dexterity is Associated with Occult White Matter Ischemic Lesions in Healthy Asymptomatic Persons at Increased Risk for Cardiovascular Disease

Introduction: Persons with a family history of early-onset coronary artery disease (CAD) have an excess risk of stroke and CAD. White matter lesions (WML) on MRI represent small vessel ischemic cerebrovascular disease and are associated with incident stroke and neurocognitive decline with age. We hypothesized manipulative manual dexterity, an integration of fine motor, visual spatial, and cognition function, may be affected by increased WML burden in task-relevant brain regions across age ranges in persons at risk for pre-clinical occult vascular disease. We tested this in a large population with a family history of early CAD. Methods: Healthy 29-74 year old subjects (N=714; mean age 51± 11 years; mean education 14 ± 3 years; 42% male, 38% Black) were identified from probands with CAD &lt;60 years. WML location and volumes were measured on 3T FLAIR MRI. Manipulative manual dexterity was measured with standardized timed grooved pegboard test. Left and right pegboard scores were averaged. Results: WML were observed in all age groups; mean overall pegboard scores were 108±18, and were within reference norms. In unadjusted analysis, pegboard scores were highly correlated in the expected direction with total WML volumes, r=0.34, p=&lt;.0001; subcortical volumes r=0.30, &lt;.0001 periventricular volumes r=0.31, &lt;.0001; and with most regional WML volumes; frontal 0.34, &lt;.0001; insula r=0.31, p&lt;.0001, parietal r=0.31, p&lt;.0001, and temporal volumes r=0.17, p &lt;.0001. In separate multivariate regression analyses predicting (log) pegboard score adjusted for age, sex, race, education and nonindependence of families (GEE), total WML volume became more statistically significant ( p=5.79E-05) while other regions retained statistical significance, p&lt; 0.01. Conclusions: Our findings in a large population-based sample with a family history of early CAD confirm that greater WML volumes in multiple brain locations are associated with higher pegboard scores (worse performance) independent of age, sex, race, and education. This suggests that small vessel cerebrovascular disease is present in an early preclinical state and that WML volumes impact manipulative manual dexterity in healthy middle-aged and younger individuals with excess risk for clinical vascular disease.

Association of Multiple Sclerosis Related Cognitive Impairment with an MRI Derived Composite Score

Background: MRI-derived metrics such as atrophy, burden of disease (BOD), and cortical lesions (CL) have independently been reported to be associated with Multiple Sclerosis (MS) related cognitive impairment (CI). Composite scores combining some of these individual metrics have also been shown to improve correlations with MS-related physical disability; however the value of a composite score for MS-related CI has not yet been evaluated. In this study we assessed the relationship between CI and a quantitative composite score constructed from MRIderived metrics to include total white matter lesion volume, CL number, and normalized cerebrospinal fluid (nCSF), a measure of brain atrophy. Methods: Thirty three (n=33) patients underwent neuropsychological testing and were classified into CI groups using a 4-point severity scale (0, 1, 2, 3) where zero indicates non-impaired, “1” represents borderline, “2” represents mild, and “3” represents moderate CI. Images obtained at 3T were segmented into tissue and lesion compartments from which BOD and nCSF were quantitatively measured. CL number was identified visually by consensus. BOD, nCSF, and CL number were then transformed to z-scores: zBOD, znCSF and zCL, and a composite score “Z3”was constructed from these measures. The associations between Z3 and CI and the individual transformed measures (z-scores) and CI were evaluated via ordinal logistic regression. Results: Z3 was significantly associated with CI (OR=1.443, 95% Confidence Interval: 1.048-1.987, p=0.024) with a slightly larger OR than any individual measure. Of the individual measures, only BOD had a significant association with CI (OR=1.064, 95% Confidence Interval: 1.008-1.123, p=0.025). No significant association was found between atrophy or CL and CI. Conclusion: The Z3 score is associated with increased CI severity. This association was mainly driven by BOD. Larger studies are needed to assess the potential advantage of a composite score over measures of white matter lesion burden alone.

Hypoglycaemia‐induced changes in regional brain volume and memory function

Hypoglycaemic events can be a serious complication of insulin therapy in Type 1 diabetes mellitus. Severe hypoglycaemic exposure can lead to episodic memory impairments, including anterograde amnesia. However, relatively little is known regarding the long-term impact of severe hypoglycaemia on brain structure in Type 1 diabetes mellitus. The goals of the present study were to gain a greater understanding of the long-term effects of severe hypoglycaemia exposure on brain structure and the neural correlates of memory impairments in Type 1 diabetes mellitus. Regional grey and white matter volume and total white matter lesion volume were quantified in an individual with long-standing hypoglycaemia-induced anterograde amnesia and compared with age- and gender-matched healthy controls. Our patient has significant reductions in grey matter volume in the hippocampus, thalamus and pallidum, and significant reductions in white matter volume in the splenium, isthmus of the cingulate and cerebellum. He also has a significantly larger total white matter lesion volume than controls. This case study highlights the potential of hypoglycaemia for permanent deleterious effects on brain structure and memory function. Our results suggest that subcortical grey matter, periventricular white matter and posterior white matter may be most susceptible to injury from hypoglycaemia exposure, and that structural damage to the hippocampus and isthmus of the cingulate may play a central role in hypoglycaemia-induced memory impairments.

1H-MR spectroscopy metabolite levels correlate with executive function in vascular cognitive impairment

BackgroundWhite matter hyperintensities (WMHs) are associated with vascular cognitive impairment (VCI) but fail to correlate with neuropsychological measures. As proton MR spectroscopy (1H-MRS) can identify ischaemic tissue, we hypothesised that...

Spatial Distribution of Cerebral White Matter Lesions Predicts Progression to Mild Cognitive Impairment and Dementia

ContextWhite matter lesions (WML) increase the risk of dementia. The relevance of WML location is less clear. We sought to determine whether a particular WML profile, based on the density and location of lesions, could be associated with an increased risk of mild cognitive impairment (MCI) or dementia over the following 7 years.MethodsIn 426 healthy subjects from a cohort of community-dwelling people aged 65 years and over (ESPRIT Project), standardized cognitive and neurological evaluations were repeated after 2, 4 and 7 years. Patterns of WML were computed with a supervised data mining approach (decision trees) using the regional WML volumes (frontal, parietal, temporal, and occipital regions) and the total WML volume estimated at baseline. Cox proportional hazard models were then constructed to study the association between WML patterns and risk of MCI/dementia.ResultsTotal WML volume and percentage of WML in the temporal region proved to be the best predictors of progression to MCI and dementia. Specifically, severe total WML load with a high proportion of lesions in the temporal region was significantly associated with the risk of developing MCI or dementia.ConclusionsAbove a certain threshold of damage, a pattern of WML clustering in the temporal region identifies individuals at increased risk of MCI or dementia. As this WML pattern is observed before the onset of clinical symptoms, it may facilitate the detection of patients at risk of MCI/dementia.

Association of White-Matter Lesions with Brain Atrophy Markers: The Three-City Dijon MRI Study

Background: Brain atrophy and white-matter lesions (WML) are common features at cerebral MRI of both normal and demented elderly people. In a population-based study of 1,792 elderly subjects aged 65–80 years, free of dementia, who had a cerebral MRI at entry, we investigated the relationship between WML volume and brain atrophy markers estimated by hippocampal, gray matter (GM) and cerebrospinal fluid (CSF) volumes. Methods: An automated algorithm of detection and quantification of WML was developed, and voxel-based morphometry methods were used to estimate GM, CSF and hippocampal volumes. To evaluate the relation between those volumes and WML load, we used analysis of covariance and multiple linear regression models adjusting for potential confounders and total intracranial volumes. Results: Age was highly correlated with WML load and all brain atrophy markers. Total WML volume was negatively associated with both GM (β = –0.03, p < 0.0001) and hippocampal volumes (β = –0.75, p = 0.0009) and positively with CSF volumes (β = 0.008, p = 0.02) after controlling for sex, age, education level, hypertension and apolipoprotein E genotype. Evidence for a relationship between brain atrophy markers and WML was stronger for periventricular WML. We found that the relationship between WML and hippocampal volumes was independent of other brain tissue volumes. Conclusion: These results suggest that, in the brain of nondemented elderly subjects, degenerative processes and vascular changes co-occur and are related independently of vascular risk factors.