Increase In White Matter Hyperintensities Research Articles

Baseline cognitive dispersion is related to increases in white matter hyperintensities in cognitively preserved older individuals

AbstractBackgroundCognitive dispersion (CD), understood as intra‐individual variability in performance, is considered a sensitive marker of prodromal stages of Alzheimer’s Disease (AD; Halliday et al. J. Intell 2018;6(1):12), and it is thought to complement cognitive performance (CP) in predicting age‐related changes (Costa et al. ClinicNeuropsychol 2019;33(2)). Moreover, white matter hyperintensities (WMH) are a common age‐associated finding that especially impacts processing speed (Boutzoukas et al. Front in AgingNeurosci 2021;13) and executive function (Papp et al. NeuropsycholDev 2014;21(2)). Therefore, we aimed to investigate (i) associations between CD, CP, and WMH, and (ii) whether WMH age‐related changes can be better predicted by baseline CD or CP in a cognitively normal aging sample.MethodOne hundred and three healthy elders (age: 68.61±3.01 years; 72 females) underwent a neuropsychological assessment and a magnetic resonance image acquisition and repeated them after 2 years. Based on processing speed and executive function scores, we computed a baseline CD (i.e., CD‐tp1; using the intraindividual standard deviation method, Costa et al. Clinic Neuropsychol 2019;33(2)) and a CP (calculated with principal component analysis) at both time‐points (i.e., CP‐tp1, CP‐tp2). 3D‐FLAIR sequence was used to estimate WMH volumes (i.e., WMH‐tp1, WMH‐tp2) using the SPM12 Lesion Segmentation Toolbox (Schmidt et al. Neuroimage 2012;59(4)). The baseline volumes were subtracted from the follow‐up ones to obtain the difference (i.e., CP‐diff, WMH‐diff). Statistical analyses were linear regressions adjusted by age, sex, years of education, and intracranial volume for WMH analyses. Paired t‐tests were used for the longitudinal approach.ResultThere was a negative cross‐sectional relationship between CD‐tp1 and CP‐tp1 (B = ‐.240, t = ‐3.034, p = .004; Fig1), while those cognitive measures were unrelated to WMH‐tp1 volumes. Longitudinally, we detected a significant increase in WMH (t = 7.244, p<.001), while CP remained stable and there were no significant associations between CP‐diff and WMH‐diff. The main finding was the significant relationship found between WMH volume increases (i.e., WMH‐diff) and CD‐tp1 (B = ‐.320, t = ‐3.060, p = .003; Fig2), but not with CP‐tp1.ConclusionThe results show that in healthy elderly individuals who evidenced cognitive stability in processing speed and executive function, the CD is a sensitive marker to predict significant age‐related increases in WMH, which would be beneficial in the AD‐continuum.

Cognitive resilience at 3 years after stroke depends on pre‐ and post‐stroke factors

AbstractBackgroundThe incidence of dementia in stroke survivors is greater than in stroke‐free people. However, some stroke survivors show cognitive resilience, withstanding the detrimental effects of stroke. In this study, we explored the differences between cognitively‐impaired (CI) and cognitively‐normal (CN) survivors in comparison with healthy controls (HC).MethodParticipants were sampled from the Cognition And Neocortical Volume After Stroke (CANVAS) study. Sociodemographic, clinical, neuropsychological, cognitive, neuroimaging, sleep, and physical activity data were obtained for 93 stroke participants at 3‐months and 3‐years post‐stroke and for 35 HC at equivalent timepoints. Stroke participants were classified as CN (n = 71) or CI (n = 22) at 3‐years based on mood scores, clinical interviews, and z‐scores of performance in five cognitive domains: attention, memory, language, executive and visuospatial functions. Structural brain volumes were estimated from T1‐weighted MRI using longitudinal FreeSurfer segmentation. Linear random‐intercept mixed‐effects modelling was used to compare between groups and timepoints accounting for differences in age, sex, years‐of‐education, and total‐intracranial volume.ResultThe stroke group overall had higher incidence of atrial fibrillation, scored higher on anxiety and depression, and had lower sleep efficiency compared to HC. Stroke survivors had thinner cortex, less cerebellar grey‐matter (GM), and larger choroid plexuses, and greater enlargement of the ventricles, at both timepoints. The CI survivors had more comorbidities, were older, were less active at both timepoints, and had lower years‐of‐education compared to both CN survivors and HC. They had more vascular risk factors and APOE‐ε4 allele carriage status compared to controls.Only the CI group showed deficits in ipsilesional cortical GM, hippocampal and thalamic volumes, and reduced total brain volume at 3‐months compared to controls. The CI survivors had larger stroke lesions compared to CN survivors and showed a greater increase in white matter hyperintensities between timepoints.At 3 months in CN survivors, cognitive performance in assessed domains was significantly lower, except for language. While performance in the CN survivors improved over time especially in language and visuospatial function, cognitive scores remained lower in the CI survivors, with a decline in memory scores.ConclusionPost‐stroke cognitive resilience appears dependent on clinical, sociodemographic, and neuroimaging factors, which assist in post‐stroke prognostication.

Physiological biomarkers of silent brain damage leading to cognitive impairment and Dementia – direct and accessible clinical evidence

AbstractBackgroundCognitive assessment is the best clinical tool to detect cognitive impairments, yet it is evident only at late stages of disease progression. In contrast, silent brain network changes occur at early stages of the disease and it is estimated that a large proportion of dementias may be prevented or at‐least delayed if detected during early pathophysiology stages. Neuroimaging studies have shown that silent brain network findings, including white matter hyperintensities, lacunar infarctions and temporal atrophy are evident before objective cognitive impairment is detected and even more in ‘at risk’ population with risk factors for dementia. We aimed to evaluate direct physiological biomarkers that provide accessible clinical evidence of silent brain network damage that precede clinical cognitive findings and provide early clinical biomarkers that can facilitate early interventions.MethodBrain network performance was evaluated in 168 subjects ‘at risk’ for developing dementia (Table 1). Direct electrophysiological imaging (“Delphi”) was used to measure magnetically induced brain network electrophysiological response. MRI scans included T1, T2, FLAIR, Diffusion Weighted Imaging (DWI) and (SWI). They were analysed according to Fazekas scale for white matter Hyperintensities (WMH), lacunar Infarctions and medial temporal lobe atrophy (MTA). Objective cognitive evaluations were performed by a neuropsychologist interview and a computerized cognitive battery (NeurotraxTM).ResultDirect electrophysiological imaging (“Delphi”) was able to distinguish between severities of different MRI detected silent brain network damage findings. Magnetically induced direct electrophysiological response wave form adherence (WFA) significantly decreased with increase in WMH (Fig.1A; p<0.0001) and increase in MTA levels (Fig.1B; p<0.0001). Furthermore, WFA significantly decreased in subjects with lacunar infarctions (Fig.1C; p<0.0001).ConclusionSilent brain network deficits preceding dementia and cognitive decline are widely under detected due to lack of accessible tools. Data presented in this study demonstrates “Delphi” technology’s ability to detect silent brain network damage findings and severity levels that are identified in MRI scans. “Delphi” is a clinically accessible, direct, and objective technology that can facilitate early detection, prevention, delayed progression and management of mild cognitive impairment and dementia.

APOE-\u03b54 modulates the association among plasma A\u03b242/A\u03b240, vascular diseases, neurodegeneration and cognitive decline in non-demented elderly adults

Including apolipoprotein E-ε4 (APOE-ε4) status and older age into consideration may increase the accuracy of plasma Aβ42/Aβ40 detecting Aβ+ individuals, but the rationale behind this remains to be fully understood. Besides, both Aβ pathology and vascular diseases are related to neurodegeneration and cognitive decline, but it is still not fully understood how APOE-ε4 modulates these relationships. In this study, we examined 241 non-demented Alzheimer’s Disease Neuroimaging Initiative participants to investigate the associations among age, white matter hyperintensities (WMH), hypertension, hyperlipidemia, body mass index (BMI), plasma Aβ42/Aβ40 measured by liquid chromatography tandem mass spectrometry, and 18F-florbetapir Aβ PET as well as their prediction of longitudinal adjusted hippocampal volume (aHCV) and cognition in APOE-ε4 carriers and non-carriers. We found older age predicted faster WMH increase (p = 0.024) and cortical Aβ accumulation (p = 0.043) in APOE-ε4 non-carriers only, whereas lower plasma Aβ42/Aβ40 predicted faster cortical Aβ accumulation (p < 0.018) regardless of APOE-ε4 status. While larger WMH and underweight predicted (p < 0.05) faster decreases in aHCV and cognition in APOE-ε4 non-carriers, lower plasma Aβ42/Aβ40 predicted (p < 0.031) faster decreases in aHCV and cognition in APOE-ε4 carriers. Higher Aβ PET also predicted faster rates of aHCV (p = 0.010) in APOE-ε4 carriers only, but was related to faster rates of cognitive decline (p < 0.022) regardless of APOE-ε4 status. These findings may provide novel insights into understanding different mechanisms underlie neurodegeneration and cognitive decline in non-demented elderly adults with and without APOE-ε4 allele, which may help the design of anti-Alzheimer’s clinical trials.

Association of Indication for Hospitalization With Subsequent Amyloid Positron Emission Tomography and Magnetic Resonance Imaging Biomarkers.

Hospitalization in older age is associated with accelerated cognitive decline, typically preceded by neuropathologic changes. We assess the association between indication for hospitalization and brain neurodegeneration. Included were participants from the Mayo Clinic Study of Aging, a population-based longitudinal study, with ≥1 brain imaging available in those older than 60 years of age between 2004 and 2017. Primary analyses used linear mixed-effects models to assess association of hospitalization with changes in longitudinal trajectory of cortical thinning, amyloid accumulation, and white matter hyperintensities (WMH). Additional analyses were performed with imaging outcomes dichotomized (normal vs abnormal) using Cox proportional hazards regression. Of 2 480 participants, 1 966 had no hospitalization and 514 had ≥1 admission. Hospitalization was associated with accelerated cortical thinning (annual slope change -0.003 mm [95% confidence interval (CI) -0.005 to -0.001], p = .002), but not amyloid accumulation (0.003 [95% CI -0.001 to 0.006], p = .107), or WMH increase (0.011 cm3 [95% CI -0.001 to 0.023], p = .062). Interaction analyses assessing whether trajectory changes are dependent on admission type (medical vs surgical) found interactions for all outcomes. While surgical hospitalizations were not, medical hospitalizations were associated with accelerated cortical thinning (-0.004 mm [95% CI -0.008 to -0.001, p = .014); amyloid accumulation (0.010, [95% CI 0.002 to 0.017, p = .011), and WMH increase (0.035 cm3 [95% CI 0.012 to 0.058, p = .006). Hospitalization was not associated with developing abnormal cortical thinning (p = .407), amyloid accumulation (p = .596), or WMH/infarctions score (p = .565). Medical hospitalizations were associated with accelerated cortical thinning, amyloid accumulation, and WMH increases. These changes were modest and did not translate to increased risk for crossing the abnormality threshold.

White matter lesions and hippocampal atrophy are associated with cognitive and behavioral and psychological symptoms in patients with Alzheimer's disease and hypertension.

An increasing evidence suggests that hypertension (HTN) could be linked to cognitive impairment and incident Alzheimer's disease (AD). The precise mechanisms linking HTN and AD are not well-known. The objective of this study was to assess the putative association between HTN and AD. We studied in a sample of about one hundred patients with AD the relationship between HTN and demographic data, cognitive function, behavioral and psychological symptoms, vascular risk factors, treatments, APOE genotypes, brain white matter hyperintensities (WMH), and hippocampal atrophy (HA). Patients with HTN had significantly worse cognitive and functional status and higher frequency and severity of behavioral and psychological symptoms (p<0.01). Magnetic resonance imaging analyzes showed significant increases in WMH (p<0.05) and in HA (p<0.01) in patients with AD with HTN compared with those without HTN. Neuroimaging burden (HA and higher degree of severity of WMH) among patients with AD and HTN are associated with the impaired cognitive function and behavioral and psychological symptoms.

Transportation physical activity earlier in life and areas of the brain related to dementia later in life

Efforts to preserve brain function may be most effective when administered before there are changes in the brain, which may occur decades before the onset of Alzheimer's disease symptoms. White matter hyperintensities (WMH), a cardiovascular disease biomarker, are areas of hyperintense signals scattered in the white matter of the brain evident on magnetic resonance images. WMH increase with age and are associated with a higher risk of dementia. The purpose of this study was to determine if there was an association between different domains and intensities of physical activity earlier in life and lower risk of dementia later in life as indicated by less WMH. In this cross-sectional study, face-to-face interviews were conducted with the Lifetime Total Physical Activity Questionnaire. The metabolic equivalent of task (MET) hours/week/year of moderate (3.0-5.9 METs) and vigorous-intensity (≥6 METs) occupation, transportation, household and leisure-time physical activity was obtained across school-age (6-11), adolescence (12-18), young (19-39) and middle adulthood (40-64). WMH were calculated as the percent of intracranial volume in cognitively unimpaired middle (age 40-64) and older adults (age 65+). Simultaneous multiple linear regression determined associations between moderate and vigorous-intensity occupation, transportation, household and leisure-time physical activity across school-age, adolescence, young and middle adulthood with WMH. Greater moderate-intensity transportation physical activity during young (b= -.09, p=.008) and middle adulthood (b= -.14, p=.013) was associated with lower WMH in middle and older adulthood, explaining 28% (p=.003) to 29% (p=.002) of the variance in WMH (n=54). Changes to the physical environment that encourage walking, running or biking, such as sidewalks and bike paths, may be strategies to mitigate the age-related increases in WMH, areas of the brain associated with higher risk of dementia.

Cerebral Perfusion and the Burden of Small Vessel Disease in Patients Referred to a Memory Clinic

Background: Cerebral small vessel disease (SVD) lesions on MRI are common in patients with cognitive impairment. It has been suggested that cerebral hypoperfusion is involved in the etiology of these lesions. Objective: The aim of the study was to determine the relationship between cerebral blood flow (CBF) and SVD burden in patients referred to a memory clinic with SVD on MRI. Method: We included 132 memory clinic patients (mean age 73 ± 10, 56% male) with SVD on MRI. We excluded patients with large non-lacunar cortical infarcts. Global CBF (mL/min per 100 mL of brain tissue) was derived from 2-dimensional phase-contrast MRI focused on the internal carotid arteries and the basilar artery. SVD burden was defined as the sum of (each 1 point): white matter hyperintensities (WMHs) Fazekas 1 or more, lacunes, microbleeds (MBs), or enlarged perivascular spaces (PVS) presence, and each SVD feature separately. Linear regression analyses were performed to study the association between CBF and SVD burden, age- and sex-adjusted. Results: Median SVD burden score was 2, 36.4% of patients had MBs, 35.6% lacunar infarcts, 48.4% intermediate to severe enlarged PVS, and 57.6% a WMH Fazekas score 2 or more. Median WMH volume was 21.4 mL (25% quartile: 9.6 mL, 75% quartile: 32.5 mL). Mean CBF ± SD was 44.0 ± 11.9 mL/min per 100 mL brain. There was no relation between CBF and overall SVD burden (CBF difference per burden score point [95% CI]: −0.5 [−2.4; 1.4] mL/min/100 mL brain, p = 0.9). CBF did also not differ according to presence or absence or an high burden of any of the individual SVD features. Moreover, there was no significant relation between WMH volume and CBF (CBF difference per ml increase in WMH [95% CI] −0.6 [−1.5; 0.3] mL/min/100 mL brain p = 0.2). Conclusion: Global CBF was not related to overall SVD burden or with individual SVD features in this memory clinic cohort, indicating that in this setting these lesions were not primarily due to cerebral hypoperfusion.

Confluent White Matter in Progression to Alzheimer Dementia.

Alongside Alzheimer disease pathology, cerebral small vessel disease (CSVD) contributes to the differential progression rates from mild cognitive impairment (MCI) to dementia. Hence, identification of specific type of CSVD lesions that influence progression is needed. The objective of this study was to evaluate the role of silent CSVD in the progression from MCI to dementia and if confluent white matter hyperintensities (WMHs) pose a higher risk for progression in the clinical setting. Patients with MCI with baseline magnetic resonance imaging and longitudinal follow-up were evaluated. WMH were quantified using visual scoring at baseline (all subjects) and at end of study period (subgroup). Influences of baseline total WMH, baseline confluent WMH, and increase of WMH on progression from MCI to dementia were analyzed. A total of 200 patients with a mean age of 67.9 (SD 8.7) years were evaluated. Progression to dementia was significantly higher among patients with MCI with confluent WMH (55.7% vs. 32.3%; P<0.001). The odds ratio of a patient with confluent WMH progressing to dementia was 2.66. The annual decline in Mini Mental State Examination was significantly higher in those with confluent WMH lesions (-1.60 vs. -1.20; P=0.010). In the subgroup with follow-up magnetic resonance imaging (n=70), patients who demonstrated an increase in WMH had greater decline in annual Mini Mental State Examination scores (-1.79 vs. -0.59; P=0.054). Confluent WMH lesions in MCI are associated with higher rates of progression to dementia.

White matter lesions and temporal atrophy are associated with cognitive and neuropsychiatric symptoms in patients with hypertension and Alzheimer's disease.

An increasing evidence suggests hypertension (HTN) could be linked to cognitive impairment and incident Alzheimer's disease (AD). The precise mechanisms linking HTN and AD are not well-known. The aim of this study was to assess the putative association between HTN and AD. We assessed in patients with AD associations between HTN and demographic and clinical data, vascular risk factors, treatments, APOE genotypes, brain white matter hyperintensities (WMH), and medial temporal atrophy (MTA) in multivariate analysis of covariance. We studied 92 patients with AD (mean ± SD age: 72.12 ± 6.91; women: 66.30%). Patients with HTN had significantly worse cognitive and functional status and higher frequency and severity of neuropsychiatric symptoms (P = .010). Magnetic resonance imaging analyzes showed significant increases in WMH (P = .018) and in MTA (P = .012) in patients with AD with HTN compared with those without HTN. Neuroimaging burden (MTA and higher degree of severity of WMH) among patients with AD and HTN are associated with the impaired cognitive function and neuropsychiatric symptoms.

Associations of pituitary-ovarian hormones and white matter hyperintensities in recently menopausal women using hormone therapy.

Little is known about how menopausal hormone treatment (HT) may influence the development of white matter hyperintensities (WMHs) in the brain. This study evaluated the associations of changes in levels of pituitary-ovarian hormones during HT and changes in WMH. Women (n = 78 adherent to treatment) enrolled in the Kronos Early Estrogen Prevention Study underwent brain magnetic resonance imaging, and blood collection before and after 48 months of randomization to 0.45 mg/d oral conjugated equine estrogen (oCEE) daily, 50 μg/d transdermal 17β estradiol (tE2), or placebo pills and patches. Women in the active treatment groups also received oral 200 mg/d micronized progesterone the first 12 days of the month. Estradiol (E2), estrone (E1), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured in serum by high sensitivity liquid chromatography/mass spectrometry at baseline and following 48 months of HT. Longitudinal change in WMH volume was determined from fluid-attenuated inversion recovery magnetic resonance imaging using a semiautomated image segmentation algorithm. Serum levels of FSH, LH, E1, or E2 did not associate with WMH volume at baseline. After 48 months of treatment, smaller increases in WMH associated with decreases in FSH from baseline in the tE2 group and increases in E1 in both tE2 and oCEE groups. Changes in LH did not associate with changes in WMH in any group. Circulating levels of pituitary-ovarian hormones associate with changes in WMH volume in recently menopausal women using HT. Whether these relationships would be influenced by different doses of tE2 or oCEE remains to be determined. : Video Summary:http://links.lww.com/MENO/A590.

The Predictive Value of Salt Sensitivity and Osmotic Fragility in the Development of Cerebral Small Vessel Disease.

Increased salt intake in food probably affects the progression of cerebral small vessel disease (CSVD), which justifies the study of disturbances in sodium homeostasis associated with the development of CSVD. We aimed to clarify the role of salt sensitivity and osmotic fragility in the development of CSVD. Erythrocyte salt sensitivity was measured using the modified salt blood test, and osmotic fragility was measured using the classic osmotic fragility test in 73 patients with CSVD (48 women; 60.1 ± 6.5 years) and 19 healthy volunteers (14 women; 56.9 ± 6.4 years). Salt sensitivity and osmotic fragility exhibited a predictive value in relation to CSVD. These parameters were associated with an increase in white matter hyperintensities (p = 0.019 and 0.004, respectively). Their simultaneous use increased their predictive ability for CSVD (p < 0.000001; AUC (95% CI), 0.824 (0.724–0.923)). The possibility of predicting CSVD using erythrocyte salt sensitivity and osmotic fragility indicates the value of the individual glycocalyx buffer capacity in relation to sodium and the activity of sodium channels in the development of CSVD. Increased salt sensitivity and osmotic fragility seem to be risk factors for CSVD.

Menopausal hormone therapy, blood thrombogenicity, and development of white matter hyperintensities in women of the Kronos Early Estrogen Prevention Study.

Development of white matter hyperintensities (WMH) in the brain is associated with blood thrombogenicity in recently menopausal women. This study examined the influence of menopausal hormone treatments (MHTs) on this association. Measures of blood thrombogenicity were examined in women of the Kronos Early Estrogen Prevention Study (n = 95) who had brain magnetic resonance imaging before and during the 48 months of randomization to transdermal 17β-estradiol (n = 30), oral conjugated equine estrogen (n = 29) both with progesterone for 12 days per month or placebo pills and patch (n = 36). Principal components (PCs) analysis was used to reduce the dimensionality of 14 markers of platelet activation and blood thrombogenicity. The first 5 PCs were assessed for association with treatment and changes in WMH. Within-person slopes were obtained to capture the extent of WMH change for each woman. WMH increased in all groups over the 48 months (P = 0.044). The partial effect of PC1, representing an average of six thrombogenicity variables (microvesicles derived from endothelium, leukocytes, and monocytes, and positive for tissue factor and adhesion molecules) on WMH was significant (P = 0.003). PC3, reflecting a contrast of platelet microaggregates and adenosine triphosphate secretion versus total platelet count, differed across groups (P = 0.006) with higher scores in the oral conjugated equine estrogen group. The global association between PCs and WMH increase, however, did not differ significantly by MHT (P = 0.207 for interaction between MHT and PC's). In recently menopausal women, the type of MHT did not significantly influence the association of markers of blood thrombogenicity with development of WMH in the brain.

Semantic loss marks early Alzheimer's disease-related neurodegeneration in older adults without dementia.

ObjectiveTo assess progression of semantic loss in early stages of cognitive decline using semantic and letter fluency performance, and its relation with Alzheimer's disease (AD)‐specific neurodegeneration using longitudinal multimodal neuroimaging measures.MethodsChange in verbal fluency was analyzed among 2261 non‐demented individuals with a follow‐up diagnosis of no mild cognitive impairment (MCI), amnestic MCI (aMCI), non‐amnestic MCI (naMCI), or incident dementia, using linear mixed models across 4 years of follow‐up, and relations with magnetic resonance imaging (MRI; n = 1536) and 18F‐fluorodeoxyglucose brain positron emission tomography (18F‐FDG‐PET) imaging (n = 756) using linear regression models across 2 years of follow‐up.ResultsSemantic fluency declined—fastest in those at higher risk for AD (apolipoprotein E [APOE] e4 carriers, Clinical Dementia Rating score of .5, aMCI, or incident dementia)—while letter fluency did not except for those with incident dementia. Lower baseline semantic fluency was associated with an increase in white matter hyperintensities and total mean cortical thinning over time, and regionally with less hippocampal volume as well as more cortical thinning and reduced 18F‐FDG‐PET uptake in the inferior parietal lobule, entorhinal cortex, isthmus cingulate, and precuneus–posterior cingulate area. In contrast, baseline letter fluency was not associated with change in total nor regional neurodegeneration. Whole‐brain neurodegeneration over time was associated with faster decline in both fluencies, while AD‐specific regions were associated with a faster rate of decline in semantic but not letter fluency.InterpretationThis study provides strong evidence of distinctive degeneration of semantic abilities early on in relation to both cognitive decline and AD‐specific neurodegeneration.

Cross-sectional and longitudinal associations between total and regional white matter hyperintensity volume and cognitive and motor function in Parkinson's disease.

BackgroundWhite matter hyperintensities (WMH) are frequently observed on T2-weighted brain magnetic resonance imaging studies of healthy older adults and have been linked with impairments in balance, gait, and cognition. Nonetheless, few studies have investigated the longitudinal effects of comorbid WMH on cognition and motor function in Parkinson's disease.MethodsThe Lesion Segmentation Tool for Statistical Parametric Mapping was used to obtain total lesion volume and map regional WMH probabilities in 29 PD and 42 control participants at two study visits 18 months apart. Both cross-sectional and longitudinal comparisons were made between composite scores in the domains of executive function, memory, and language, and Unified Parkinson's Disease Rating Scale (UPDRS) scores.ResultsWe found no difference between disease and control groups in total WMH volume or progression during the study. Greater regional and global WMH at baseline was more strongly associated with lower executive function in PD subjects than in controls. Increased regional WMH was also more strongly associated with impaired memory performance in PD relative to controls. Longitudinally, no associations between cognitive change and total or regional WMH progression were detected in either group. A positive relationship between baseline regional WMH and total UPDRS scores was present in the control group, but not PD. However, greater WMH increase was associated with a greater increase in UPDRS motor sub-scores in PD.ConclusionsThese findings suggest that although PD patients do not experience greater mean WMH load than normal aged adults, comorbid WMH do exacerbate cognitive and motor symptoms in PD.

Association between periodic limb movements during sleep and cerebral small vessel disease

ObjectivePeriodic limb movements (PLMs) can increase the risk of cardiovascular disease and mortality. Small vessel disease (SVD) has been considered a precursor to symptomatic stroke. We aimed to investigate the association between PLMs and cerebral SVD. MethodsWe enrolled participants who visited our clinic for the evaluation of sleep disturbance and underwent overnight polysomnography and brain magnetic resonance imaging. The processing steps included rating and analyzing white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), asymptomatic lacunar infarctions (ALIs), perivascular spaces (PVSs), and calculating the total SVD score. Logistic regression and correlation analyses were used to examine the association between PLMs during sleep (PLMS) and SVD. ResultsA total of 31 (19 men and 12 women) patients with PLMS index ≥ 15/h were enrolled. The mean age was 61.7 years and the median PLMS index was 46.5/h. A total of 29 controls (16 men and 13 women) with PLMS index < 5/h were also included. PLMS index was positively associated with an increase in WMHs, ALIs, and PVSs (odds ratio [OR] = 1.022, 95% confidence interval [CI] = 1.003–1.040, p = 0.008; OR = 1.024, 95% CI = 1.006–1.043, p = 0.010; OR = 1.029, 95% CI = 1.010–1.049, p = 0.003, respectively). Correlation analyses revealed that total SVD score was significantly correlated with PLMS index (r = 0.504, p < 0.001). ConclusionsAn elevated PLMS index was associated with an increase in WMHs, ALIs, PVSs, and total SVD burden. Our study suggests that PLMS is a marker for SVD, which carries a potential risk for progression to overt stroke or cognitive impairment.

Quantitative and qualitative MRI evaluation of cerebral small vessel disease in an elderly population: a longitudinal study.

Background Cerebral white matter hyperintensities (WMHs), lacunes, and microbleeds are seen on magnetic resonance imaging (MRI) in small vessel disease (SVD). Purpose To assess SVD on MRI and its evolution over five years in an elderly population and to investigate whether relative cerebral blood flow (rCBF) at baseline was related to the progression of white matter (WM) lesions. Material and Methods In a population-based study, 406 participants aged 75 years underwent morphological MRI of the brain and 252 of them again at age 80 years. At age 75 years, a perfusion scan was also done. WMHs were evaluated qualitatively (visual scoring) and quantitatively (CASCADE software). Lacunes and microbleeds were counted. Results A significant progression of the WMH score and WMH volume occurred over five years ( P < 0.0001). New lacunes were seen in 10%. Participants with new lacunes at age 80 years showed a more pronounced increase in WMHs (P < 0.0001). Microbleeds were present in 14% at age 75 years. The visual WMH score was significantly associated with the presence of microbleeds ( P < 0.0001). There was no relationship between total WM rCBF and WMH volume at age 75 years, and no significant associations between regional or total rCBF at age 75 years and changes in WMH volume over five years. The total WM and GM volume decreased significantly between the ages of 75 and 80 years ( P < 0.0001). Conclusion MRI manifestations of SVD progressed over five years in an elderly population (age range = 75-80 years). rCBF was not associated with WMH volume or progression of WMH volume.

Peripheral (deep) but not periventricular MRI white matter hyperintensities are increased in clinical vascular dementia compared to Alzheimer's disease.

Background and purposeVascular dementia (VAD) is a complex diagnosis at times difficult to distinguish from Alzheimer's disease (AD). MRI scans often show white matter hyperintensities (WMH) in both conditions. WMH increase with age, and both VAD and AD are associated with aging, thus presenting an attribution conundrum. In this study, we sought to show whether the amount of WMH in deep white matter (dWMH), versus periventricular white matter (PVH), would aid in the distinction between VAD and AD, independent of age.MethodsBlinded semiquantitative ratings of WMH validated by objective quantitation of WMH volume from standardized MRI image acquisitions. PVH and dWMH were rated separately and independently by two different examiners using the Scheltens scale. Receiver operator characteristic (ROC) curves were generated using logistic regression to assess classification of VAD (13 patients) versus AD (129 patients). Clinical diagnoses were made in a specialty memory disorders clinic.ResultsUsing PVH rating alone, overall classification (area under the ROC curve, AUC) was 75%, due only to the difference in age between VAD and AD patients in our study and not PVH. In contrast, dWMH rating produced 86% classification accuracy with no independent contribution from age. A global Longstreth rating that combines dWMH and PVH gave an 88% AUC.ConclusionsIncreased dWMH indicate a higher likelihood of VAD versus AD. Assessment of dWMH on MRI scans using Scheltens and Longstreth scales may aid the clinician in distinguishing the two conditions.

White Matter Hyperintensity Accumulation During Treatment of Late-Life Depression.

White matter hyperintensities (WMHs) have been shown to be associated with the development of late-life depression (LLD) and eventual treatment outcomes. This study sought to investigate longitudinal WMH changes in patients with LLD during a 12-week antidepressant treatment course. Forty-seven depressed elderly patients were included in this analysis. All depressed subjects started pharmacological treatment for depression shortly after a baseline magnetic resonance imaging (MRI) scan. At 12 weeks, patients underwent a follow-up MRI scan, and were categorized as either treatment remitters (n=23) or non-remitters (n=24). Among all patients, there was as a significant increase in WMHs over 12 weeks (t(46)=2.36, P=0.02). When patients were stratified by remission status, non-remitters demonstrated a significant increase in WMHs (t(23)=2.17, P=0.04), but this was not observed in remitters (t(22)=1.09, P=0.29). Other markers of brain integrity were also investigated including whole brain gray matter volume, hippocampal volume, and fractional anisotropy. No significant differences were observed in any of these markers during treatment, including when patients were stratified based on remission status. These results add to existing literature showing the association between WMH accumulation and LLD treatment outcomes. Moreover, this is the first study to demonstrate similar findings over a short interval (ie 12 weeks), which corresponds to the typical length of an antidepressant trial. These findings serve to highlight the acute interplay of cerebrovascular ischemic disease and LLD.

Abstract T MP109: Leptomeningeal Collaterals, Ageing and Metabolic Syndrome in Development of White Matter Hyperintensities

Background: Ageing and metabolic syndrome are associated with poor leptomeningeal collateral status. Animal studies suggest that collateral rarefaction and consequent decrease in vascular efficiency may result in increase in white matter hyperintensities. Using mediational analysis, we test if the known effect of ageing and metabolic syndrome on development of white matter hyperintensities is mediated through collateral status. Methods: Data are from the Keimyung Stroke Registry. Consecutive patients with M1 segment middle cerebral artery (MCA) ± intracranial internal carotid artery (ICA) occlusions on baseline CT-angiography (CTA) and brain MRI done within 90 minutes after admission CT/CTA, from May 2004 to July 2009, were included. Baseline and follow-up imaging was analyzed blinded to all clinical information. Two raters assessed leptomeningeal collaterals on baseline CTA by consensus, using previously validated regional leptomeningeal score (rLMC). FLAIR volume of white matter hyperintensities (ml) was measured in the unaffected hemisphere using Quantomo® software. The template of Baron and Kenney along with two tests (Sobel’s and Aroian’s) was used to test for the presence of mediation. Results: Baseline characteristics (n=120): mean age 67.4±11.4 years, male (53.3%), median baseline NIHSS 14 (IQR 11-20), and median stroke symptom onset to CTA 166 minutes (IQR 96-262). Poor collateral status at baseline (rLMC score 0-10) was seen in 42/120 (35%). Mean periventricular hyperintensity (PVH) volume was 6.5 ml (SD=6.0) while mean white matter hyperintensity (WMH-total) volume was 8.6 ml (SD=8.0). Higher age was associated with increased PVH and WMH-total (p&lt;0.01) while metabolic syndrome was associated with increased PVH only (p=0.03). We did not find statistical evidence of leptomeningeal collaterals mediating the association between ageing and PVH/WMH-total or between metabolic syndrome and PVH (Sobel’s and Aroian’s test p&gt;0.05). Conclusion: The effect of ageing and metabolic syndrome on development of white matter hyperintensities is independent of an effect mediated through the poor collateral status.