Temporal White Matter Hyperintensities Research Articles

Impact of age and apolipoprotein E ε4 status on regional white matter hyperintensity volume and cognition in healthy aging.

White matter hyperintensity (WMH) volume is a neuroimaging marker of lesion load related to small vessel disease that has been associated with cognitive aging and Alzheimer's disease (AD) risk. The present study sought to examine whether regional WMH volume mediates the relationship between APOE ε4 status, a strong genetic risk factor for AD, and cognition and if this association is moderated by age group differences within a sample of 187 healthy older adults (APOE ε4 status [carrier/non-carrier] = 56/131). After we controlled for sex, education, and vascular risk factors, ANCOVA analyses revealed significant age group by APOE ε4 status interactions for right parietal and left temporal WMH volumes. Within the young-old group (50-69 years), ε4 carriers had greater right parietal and left temporal WMH volumes than non-carriers. However, in the old-old group (70-89 years), right parietal and left temporal WMH volumes were comparable across APOE ε4 groups. Further, within ε4 non-carriers, old-old adults had greater right parietal and left temporal WMH volumes than young-old adults, but there were no significant differences across age groups in ε4 carriers. Follow-up moderated mediation analyses revealed that, in the young-old, but not the old-old group, there were significant indirect effects of ε4 status on memory and executive functions through left temporal WMH volume. These findings suggest that, among healthy young-old adults, increased left temporal WMH volume, in the context of the ε4 allele, may represent an early marker of cognitive aging with the potential to lead to greater risk for AD.

Regional White Matter Hyperintensities and Alzheimer's Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment.

Alzheimer's disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders. We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD. WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aβ 40, Aβ 42, Aβ 42/Aβ 40 ratio, phosphorylated tau-181 [p-tau181], and total tau [t-tau]) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)). Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181, t-tau, and Aβ 40), particularly among APOE ɛ 4 carriers (independent of Aβ 42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aβ 42/Aβ 40. In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (∼<65 versus 65+ years), independent of Aβ 42/Aβ 40 and p-tau181. These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aβ 42/Aβ 40) in parietal WMHs.

White matter hyperintensity load varies depending on subjective cognitive decline criteria.

Increased age and cognitive impairment is associated with an increase in cerebrovascular pathology often measured as white matter hyperintensities (WMHs) on MRI. Whether WMH burden differs between cognitively unimpaired older adults with subjective cognitive decline (SCD +) and without subjective cognitive decline (SCD -) remains conflicting, and could be related to the methods used to identify SCD. Our goal was to examine if four common SCD classification methods are associated with different WMH accumulation patterns between SCD + and SCD - . A total of 535 cognitively unimpaired older adults with 1353 time points from the Alzheimer's Disease Neuroimaging Initiative were included in this study. SCD was operationalized using four different methods: Cognitive Change Index (CCI), Everyday Cognition Scale (ECog), ECog + Worry, and Worry. Linear mixed-effects models were used to investigate the associations between SCD and overall and regional WMH burden. Overall temporal WMH burden differences were only observed with the Worry questionnaire. Higher WMH burden change over time was observed in SCD + compared to SCD - in the temporal and parietal regions using the CCI (temporal, p = .01; parietal p = .02) and ECog (temporal, p = .02; parietal p = .01). For both the ECog + Worry and Worry questionnaire, change in WMH burden over time was increased in SCD + compared to SCD - for overall, frontal, temporal, and parietal WMH burden (p < .05). These results show that WMH burden differs between SCD + and SCD - depending on the questionnaire and the approach (regional/global) used to measure WMHs. The various methods used to define SCD may reflect different types of underlying pathologies.

APOE4 and Confluent White Matter Hyperintensities Have a Synergistic Effect on Episodic Memory Impairment in Prodromal Dementia.

White matter hyperintensities (WMH) are a known risk factor for cognitive decline. While the ɛ4 allele of apolipoprotein E gene (APOE4) is another risk factor for cognitive decline, it remains unclear how APOE4 affects the relationship between WMH and cognitive decline, specifically in the prodromal stage of dementia. To determine how APOE4 moderates the relationship between WMH and cognition in prodromal dementia. Two-hundred-sixteen participants with prodromal dementia underwent magnetic resonance imaging (MRI), neuropsychological testing (global and domain wise), cardiovascular risk factor assessments, and APOE genotyping. Visual ratings for WMH as well as total and lobar WMH volumes were quantified. Moderation analysis was performed to determine the influence of APOE4 on the relationship between WMH and performance on global and domain-specific cognitive measures. The role of confluent and non-confluent WMH on cognition was additionally studied using logistic regression. APOE4 carriers (n = 49) had poorer memory and higher global WMH (10.01 mL versus 6.23 mL, p = 0.04), temporal WMH (1.17 mL versus 0.58 mL, p = 0.01), and occipital WMH (0.38mL versus 0.22 mL, p = 0.02) compared to APOE4 non-carriers (n = 167). Moderation analysis revealed that APOE4 positivity strengthened the relationship between higher global as well as lobar WMH burden and poorer episodic memory. Furthermore, APOE4 carriers with confluent WMH were 4.81 times more likely to have impaired episodic memory compared to non-confluent WMH and non-APOE carriers. The impact of WMH on memory may be strongest among APOE4 carriers. Clinicians targeting WMH would need to consider the APOE4 allele and WMH severity status to strategize cognitive interventions.

White Matter Hyperintensities and Cognitive Impairment in Healthy and Pathological Aging: A Quantified Brain MRI Study

Background: Brain changes involving the white matter (WM), often an indication of cerebrovascular pathology, are frequently seen in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). Few studies have examined possible cognitive domain- or group-specific cognitive effects of WM pathology in old age, MCI, and AD. Objective: Our purpose was to examine the relationship between WM hyperintensities (WMH), a typical marker for WM pathology, and cognitive functioning in healthy old age and pathological aging using quantified MRI data. Methods: We utilized multidomain neuropsychological data and quantified MRI data from a sample of 42 cognitively healthy older adults and 44 patients with MCI/AD (total n = 86). Results: After controlling for age and education, WMH in the temporal and parieto-occipital lobes was associated with impairments in processing speed and parieto-occipital pathology with verbal memory impairment in the whole sample. Additionally, temporal WMH was associated with impaired processing speed in the patient group specifically. Conclusions: WM pathology is strongly associated with impaired processing speed, and our results indicate that these impairments arise from WMH in the temporal and parieto-occipital regions. In MCI and AD patients with temporal WMH, processing speed impairments are especially prominent. The results of this study increase our knowledge of cognitive repercussions stemming from temporal and/or parieto-occipital WM pathology in healthy and pathological aging.

Nociceptive Primitive Reflexes in Neurologically and Cognitively Healthy Aging Subjects.

To assess the prevalence of three nociceptive primitive reflexes (nPR), i.e., glabellar tap, snout reflex, and palmomental reflex, in neurologically and cognitively healthy (NCH) aging subjects. To investigate whether nPR are cross-sectionally associated with white matter hyperintensities (WMH), lacunes, atrophy of the caudate nuclei, and global brain atrophy. A total of 1246 NCH subjects aged 45-91 years were included in the study and underwent standard brain MRI. Atrophy of the caudate nuclei and global brain atrophy were assessed through the bicaudate ratio (BCr) and lateral ventricles to brain ratio (LVBr), respectively. WMH were assessed through visual rating scales. Lacunes were also rated. Association of nPR with vascular risk factors/diseases and imaging findings was evaluated using logistic regression analysis. nPR were exhibited by 33.1% of subjects and increased with age. Subjects with nPR performed less than subjects without nPR in tests evaluating global cognition, executive functions, attention, and language. Snout reflex was the most common nPR, followed by glabellar tap and palmomental reflex. Glabellar tap was associated with parieto-temporal WMH, BCr, and LVBr; snout reflex was associated with frontal lacunes, temporal WMH, BCr, and LVBr; palmomental reflex was associated with parieto-occipital WMH, basal ganglia lacunes, BCr, and LVBr. This study demonstrates that in NCH aging individuals, nPR are associated with WMH, lacunes, BCr, and LVBr and are probably a warning sign of incipient cognitive decline. Therefore, NCH subjects presenting nPR should manage their vascular risk factors/vascular diseases rigorously in order to prevent or delay progression of small vessel disease, and future neurological and cognitive disabilities.

Modifiable vascular risk factors, white matter disease and cognition in early Parkinson's disease.

Dementia in Parkinson's disease (PD) is common and disabling. Identification of modifiable risk factors for it is essential. Vascular risk factors (VRFs) may be associated with cognitive decline in early PD. Biomarkers that serve as surrogates of the long-term effect of VRFs on PD are needed. To that end, we aimed to quantitate white matter hyperintensities (WMH) in early PD, measure associations with VRFs and examine relationships between WMH and longitudinal cognition. Participants in the Parkinson's Progression Markers Initiative study (141 patients with PD, 63 healthy controls) with adequate baseline structural brain magnetic resonance imaging data were included. Hypertension and diabetes history, and body mass index were combined to create a vascular risk score. WMH were quantitated via automated methods. Cognition was assessed annually with a comprehensive test battery. In the PD group, vascular risk score was associated with WMH for total brain (β=0.210; P=0.021), total white matter (β=0.214; P=0.013), frontal (β=0.220; P=0.002) and temporal (β=0.212; P=0.002) regions. Annual rate of change in global cognition was greater in those with higher vascular risk score (β=-0.040; P=0.007) and greater WMH (β=-0.029; P=0.049). Higher temporal WMH burden was associated with great decline over time in verbal memory (β=-0.034; P=0.031). In early PD, modifiable VRFs are associated with WMH on brain magnetic resonance imaging. Temporal WMH burden predicts decline in verbal memory. WMH may serve as a surrogate marker for the effect of VRFs on cognitive abilities in PD.

Brain-Area Specific White Matter Hyperintensities: Associations to Falls in Parkinson's Disease.

Falls are common among people with idiopathic Parkinson's disease (IPD) and are suggested to be associated with white matter hyperintensities (WMH) of the brain. To investigate the contribution of brain area-specific WMH to the risk of falls in IPD. In fifty participants with IPD, occurrence and severity of WMH in specific brain areas were determined using Scheltens (without lateralization) and Age-related white matter changes (ARWMC) (with lateralization) scores. Falls were evaluated with the fall item of the Unified PD Rating Scale (UPDRS). Correlations between area-specific WMH and falls were tested with stepwise backward regression and multivariate regression analyses. In this cohort of participants with IPD, left temporal WMH were associated with occurrence of falls. Frontal WMH of both hemispheres showed tendencies towards significance for the association with falls. According to our study, WMH in the left temporal area are significantly associated with falls in IPD. Potential reasons for this association could be deficits in memory, navigation, orientation, auditory processing, and fear conditioning, which are all associated with pathologies of the left temporal lobe.

Patients with Increased Non-Ceruloplasmin Copper Appear a Distinct Sub-Group of Alzheimer's Disease: A Neuroimaging Study.

Meta-analyses show that copper non-bound to ceruloplasmin (non-Cp Cu, also known as 'free' copper) in serum is higher in a percentage of Alzheimer's disease (AD) patients. Genetic heterogeneity in AD patients stratified on the basis of non-Cp Cu cut-off sustains the existence of a copper AD metabolic subtype. In order to find evidence of the existence of a detectable metabolic subtype of AD associated to copper abnormalities, we explore the hypothesis of a neuroimaging pattern heterogeneity in an homogenous and well characterized AD population classified in two groups by the stratification of patients on the basis non-Cp Cu cut-off. We assessed levels of copper, ceruloplasmin, non-Cp Cu, cerebrospinal levels of total Tau protein (h-tau), Thr 181 phosphorylated tau protein (P-tau) and β-amyloid 1-42, and APOE4 genotype in 66 AD patients and compared neuroimaging indices of a visual rating scale of cerebral atrophy and neurovascular burden in AD patients stratified in 'Normal' and 'High' non-Cp Cu groups. The stratification for non-Cp Cu originated AD groups which did not differ for medial temporal lobe atrophy, periventricular hyperintensities, deeper hyperintensities (including frontal, parietooccipital and temporal white matter hyperintensities), infratentorial hyperintensities indices, while they differed for global atrophy. More specifically, AD patients within the high non-Cp Cu group had a less severe burden of global atrophy (p=0.042). This neuroimaging heterogeneity between AD groups is suggestive of the existence of a copper metabolic subtype of AD; non-Cp Cu appears a good marker of this copper AD.

REGIONAL WHITE MATTER HYPERINTENSITY CHANGES PREDICT COGNITIVE DECLINE IN MILD COGNITIVE IMPAIRMENT OF SUBCORTICAL VASCULAR TYPE: A THREE-YEAR FOLLOW-UP STUDY

White matter hyperintensities (WMH) is a typical marker of small vessel disease and known to be related to cognitive impairment. A previous cross-sectional study also suggested that WMH were associated with frontal dysfunction, regardless of their locations. However, a previous study from our group suggested that WMH location as well as WMH volume might be important in predicting cognitive impairments, especially in the specific domains. In this study, we investigated the effects of longitudinal WMH changes on cognitive decline in patients with subcortical vascular mild cognitive impairment (svMCI), globally and regionally. We hypothesized that regional changes of WMH, especially in the frontal region, may predict cognitive decline than global or other regional changes of WMH. We prospectively recruited 92 patients from a single referral center. All patients underwent neuropsychological tests, 3T brain magnetic resonance image (MRI), and [11C] Pittsburgh compound B (PiB) PET. Neuropsychological tests and brain MRI were performed annually. Mean follow up length was 3.7 ± 1.5 years. Linear mixed effect regression models were used to evaluate the relationship between WMH change and cognitive change. Time, age, sex, years of education, PiB standardized uptake value ratio, and time varying WMH volume were used as fixed effects and subjects were used as random effects. Total WMH change linked to cognitive decline in attention (beta coefficiency = -0.0001; P value = 0.003) and visuospatial domains (beta coefficiency = -0.0001; P value = 0.033). Periventricular WMH (PWMH) change did not show any significant effect on cognitive decline. However, deep WMH (DWMH) changes predicted the alteration of attention and frontal executive function. WMH change in the frontal, and occipital regions had impact on deterioration of attention, visuospatial and frontal executive functions. The temporal WMH change was associated with decreased score of attention, and frontal executive function. The parietal WMH change related with only attention domain. Our findings suggested that WMH change were associated with decline in the frontal related function, regardless of their location. Furthermore, DWHM changes, but not PWMH changes, were more likely to affect cognitive changes.

Posterior Atrophy and Medial Temporal Atrophy Scores Are Associated with Different Symptoms in Patients with Alzheimer's Disease and Mild Cognitive Impairment.

BackgroundWhether the occurrence of posterior atrophy (PA) and medial temporal lobe atrophy (MTA) was correlated with cognitive and non-cognitive symptoms in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients are unclear.MethodsPatients with probable AD and MCI from a medical center outpatient clinic received attention, memory, language, executive function evaluation and Mini-Mental Status Examination (MMSE). The severity of dementia was rated by the Clinical Dementia Rating (CDR) Sum of Box (CDR-SB). The neuropsychiatric inventory (NPI) subscale of agitation/aggression and mood symptoms was also applied. Magnetic resonance imaging (MRI) was scored visually for the MTA, PA and white matter hyperintensity (WMH) scores.ResultsWe recruited 129 AD and 31 MCI (mean age 78.8 years, 48% female) patients. MMSE scores, memory, language and executive function were all significantly decreased in individuals with AD than those with MCI (p < 0.01). MTA and PA scores reflected significant atrophy in AD compared to MCI; however, the WMH scores did not differ. The MTA scores were significantly correlated with the frontal, parieto-occipital and global WMH scores (p < 0.01) while the PA scores showed a correlation with the parieto-occipital and temporal WMH scores (p < 0.01). After adjusting for age, education, APOE4 gene and diagnostic group covariates, the MTA scores showed a significant association with MMSE and CDR-SB, while the right side PA scores were significantly associated with NPI-agitation/aggression subscales (p < 0.01).ConclusionRegional atrophy is related to different symptoms in patients with AD or MCI. PA score is useful as a complementary measure for non-cognitive symptom.

Effect of BDNF Val66Met polymorphism on regional white matter hyperintensities and cognitive function in elderly males without dementia

White matter lesions, also termed White Matter Hyperintensities (WMH), on T2-weighted MR images, are common in the elderly population. Of note, their presence is often accompanied with cognitive decline and the risk of dementia. Even though previous brain ischemia and WM lesion studies have been conducted and indicated that brain-derived neurotrophic factor (BDNF) might protect against neuronal cell death, the interaction between regional WMH volume and the BDNF Val66Met polymorphism on the cognitive performance of healthy elderly population remains unclear. To investigate the genetic effect of BDNF on cognitive function and regional WMH in the healthy elderly population, 90 elderly men, without dementia, with a mean age of 80.6 ± 5.6 y/o were recruited to undergo cognitive tests, structural magnetic resonance imaging (MRI) scans, and genotyping of BDNF alleles. Compared with Met homozygotes, Val homozygotes showed significantly inferior short-term memory (STM) performance (P = .001). A tendency toward dose-dependent effects of the Val allele on WMH volume was found, and Val homozygotes showed larger WMH volume in the temporal (P = .035), the occipital (P = .006), and the global WMH volume (P = .025) than others. Significant interaction effects of BDNF genotypes with temporal WMH volume on STM performance was observed (F1,89 = 4.306, P = .041). Val homozygotes presented steeper negative correlation compared to Met carriers. Mediation analysis also demonstrated that WMH in temporal, limbic, and subcortical regions might mediate the relationship between BDNF's genetic effect and STM performance. Our findings supported the hypothesis that the BDNF Val66Met polymorphism may affect susceptibility to regional WMH volume and such genotype-by-WMH interaction effect is correlated with cognitive decline in non-demented elderly males, in which the Met allele plays a protective role.

White matter hyperintensities and amyloid are independently associated with entorhinal cortex volume among individuals with mild cognitive impairment

BackgroundCurrent hypothetical models of Alzheimer's disease (AD) pathogenesis emphasize the role of β-amyloid (Aβ), tau deposition, and neurodegenerative changes in the mesial temporal lobe, particularly the entorhinal cortex and hippocampus. However, many individuals with clinical AD who come to autopsy also exhibit cerebrovascular disease. The relationship between AD and vascular pathology is unclear, especially whether they represent additive and independent effects on neuronal injury. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to (1) confirm whether entorhinal cortex and hippocampal volume are associated with memory among individuals with amnestic mild cognitive impairment (MCI) who are at risk for AD; and (2) determine whether regional white matter hyperintensity (WMH) volume, a radiological marker of small-vessel cerebrovascular disease, is associated with entorhinal cortex and hippocampal volume independent of putative AD biomarkers in this group. MethodsCognitive test scores, entorhinal cortex volume, hippocampus volume, intracranial volume, and cerebrospinal fluid-derived phosphorylated tau and Aβ1-42 protein levels were measured in 199 subjects with amnestic MCI (mean age = 74.89 ± 7.47). Lobar WMH volumes were derived from T1-, proton-density-, and T2-weighted magnetic resonance imaging scans. We examined the association between entorhinal cortex volume and cognition. Next, we examined the association of tau and Aβ1-42 with entorhinal cortex volume and between lobar WMH and entorhinal cortex volume. Finally, tau, Aβ1-42, and regional WMH volumes were entered simultaneously to predict entorhinal cortex volume. We repeated the analyses with hippocampal volume instead of entorhinal cortex volume. The analyses were also repeated with the sample restricted to those MCI patients who transitioned to AD on subsequent ADNI follow-up visits (n = 86). ResultsLarger entorhinal cortex volume was associated with better memory but not with performance on a task of executive functioning. Lower levels of Aβ1-42 and higher temporal WMH volumes were associated with smaller entorhinal cortex volume. When entered simultaneously, temporal lobe WMH volume was more reliably associated with entorhinal cortex volume than was Aβ1-42. The findings were similar for hippocampus volume and when the sample was restricted to MCI patients who subsequently transitioned to AD. ConclusionsThe findings confirm the role of entorhinal cortex and hippocampus volume in influencing memory decline in amnestic MCI, and emphasize that even in this nominally AD prodromal condition, WMH may be influencing regional neurodegeneration.

Regional white matter hyperintensities in normal aging, single domain amnestic mild cognitive impairment, and mild Alzheimer’s disease

Few studies have examined white matter hyperintensities (WMH) along the cognitive continuum between single-domain amnestic mild cognitive impairment (sd-aMCI) and Alzheimer’s disease (AD). The aims of our study were to explore relationships between the extent and location of WMH and disease severity along the cognitive continuum and to determine whether differences in the distribution of WMH could be predictive of specific patterns of cognitive impairment. We compared cognitive function, vascular risk factors, and regional (frontal lobe, parieto-occipital [PO] lobe, temporal lobe, periventricular [PV] white matter and deep white matter) WMH volume in 37 patients with mild AD, 23 patients with sd-aMCI, and 24 age-matched and education-matched normal controls. A quantitative volumetric method was applied to measure WMH burden. Total and regional WMH burdens, except for those in the temporal lobe, were significantly correlated with age ( p < 0.01). We found a trend toward increasing WMH volume with disease severity, higher in AD than in sd-aMCI and lowest in the controls. Total WMH volume was associated with the global cognitive test score. In multiple linear regression analysis, PV WMH volume, but not deep WMH volume, strongly predicted performances on the Controlled Oral Word Association test and the Color Word Stroop test after adjusting for important demographic variables. Only PO WMH volume was a significant predictor of a cognitive test score when frontal and temporal WMH volumes were simultaneously entered into the regression model. The extent and distribution of WMH, especially in the PV and PO regions, were associated with disease severity and reduced cognition.

Cognitive Deficits Are Associated with Frontal and Temporal Lobe White Matter Lesions in Middle-Aged Adults Living in the Community

BackgroundThe association between brain white matter lesions and cognitive impairment in old age is well established. However, little is known about this association in midlife. As this information will inform policy for early preventative healthcare initiatives, we investigated non-periventricular frontal, temporal, parietal and occipital lobe white matter hyperintensities (WMH) in relation to cognitive function in 428 (232 women) community-dwelling adults aged 44 to 48 years.ResultsFrontal white matter lesions were significantly associated with greater intraindividual RT variability in women, while temporal WMH were associated with face recognition deficits in men. Parietal and occipital lobe lesions were unrelated to cognitive performance. These findings did not differ when education and a range of health variables, including vascular risk factors, were taken into account.ConclusionGender differences in WMH-cognition associations are discussed, and we conclude that small vessel disease is present in midlife and has functional consequences which are generally not recognized. Preventative strategies should, therefore, begin early in life.

P3-151: White matter hyperintensities within cholinergic pathways in Alzheimer's disease affecting the clock drawing test performance

Cerebral white matter hyperintensities (WMH) are common findings on MRI in elderly people. Two possible mechanisms have been suggested: 1) by disruption of corticocortical association fibers or fronto-subcortical neuronal networks; 2) interference with cholinergic projecting pathway. The purpose of this study is to evaluate how WMH can affect on the Clock Drawing Test in Alzheimer disease (AD). One hundred twenty seven patients with AD were enrolled for this study. Subjects met the National Institute of Neurological Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) research criteria for possible or probable AD. All subjects were taken MRI to measure the severity of WMH based on visual inspection of T2-weighted and proton-density MRI. Subjects underwent standardized neuropsychological testing, including Korean versions of the Mini-Mental State Exam (MMSE) and the modified MMSE (3MS) to assess cognitive domains of interest (attention, memory, executive function) as well as general level of cognition. Clock Drawing Test (CDT) was given to all patients to analyze the level of performance and error-types. Manos scoring protocol was adopted for the evaluation of CDT results. Cognitive measures and the CDT were assessed independently by a neuropsychologist and a neurologist who were not aware of clinical information. The Age-Related White Matter Changes (ARWMC) rating scale of the European Task Force was used as a general measure of WMH severity. WMH involved in cholinergic pathways were measured by the Cholinergic Pathways Hyperintensities Scale (CHIPS). Performance of the CDT as well as overall level of cognition showed significant relation with the WMC severity. Temporal WMH in ARWMC had stronger relationship with the CDT performance than other areas. WMH of the posterior corona radiata in CHIPS showed significant correlation with the CDT performance. Interference in the cholinergic projecting pathway as well as disruption of cortico-subcortical neural networks by WMH may contribute to the impaired CDT performance in AD.

White Matter Hyperintensities Rather Than Lacunar Infarcts Are Associated With Depressive Symptoms in Older People: The LADIS Study

Both white matter hyperintensities (WMH) and lacunar infarcts have been associated with the development of depression in older subjects, although the relative importance of the two and the influence of lesion location and concomitant vascular disease are unclear. This study investigates the relationship between location and burden of WMH and lacunes on depressive features in older people. In a pan-European multicenter study of 626 older subjects, the authors examined the relationship between regional magnetic resonance imaging white matter hyperintensities, number of lacunar infarcts, depressive symptoms as assessed by the 15-item geriatric depression scale (GDS), cognitive status (Mini-Mental Status Examination), hypertension, and self-perceived health quality of life (QoL). The authors found depressive symptoms to be correlated with WMH rating in the frontal (N=626; Spearman's rho=0.161, p <0.001) and temporal (rho=0.14, p <0.001) but not occipitoparietal region (rho=0.07, p=0.07). Basal ganglia lacunes were only weakly correlated with GDS (rho=0.09, p=0.03), and lacunes in other regions showed no association. In a ordinal logistic regression model (controlling for QoL, Mini-Mental Status Examination, age, and with an interaction between WMH and hypertension), temporal WMH in the absence of hypertension independently predicted GDS, whereas neither history of stroke nor number of lacunar infarcts did. The authors compared left- versus right-sided WMH and found no effect of laterality on depressive symptoms. The results suggest that in this population of nondisabled older people, WMH have a greater influence on depressive symptoms than infarcts.

White matter hyperintensities are associated with impairment of memory, attention, and global cognitive performance in older stroke patients.

The importance of white matter hyperintensities (WMH) for cognitive performance in older stroke patients is largely unknown. We hypothesized that processing speed and executive dysfunction will be associated with frontal WMH whereas impaired memory will be associated with temporal WMH. Neuropsychological assessments using the Cambridge Cognitive Examination (CAMCOG) and the Cognitive Drug Research (CDR) were completed for 96 stroke survivors aged older than 75 and 23 age-matched controls. Magnetic resonance imaging whole-brain axial FLAIR images were undertaken to visualize WMH and an automated threshold technique was used to determine their volume. In comparison to controls, the stroke patients had significantly greater volume of WMH in all key areas. Within the stroke group, a consistent pattern of significant association was identified between total and frontal WHM volumes and attention and processing speed tasks (eg, choice reaction time [right: R=0.24 P=0.02; left: R=0.26, P=0.01]), but not with executive function. There were significant associations between memory and temporal WMH volumes (right: R=0.27, P=0.008; left: R=0.20, P=0.047). In older stroke patients, cognitive processing speed and performance on measures of attention are significantly associated with WMH volume, particularly in the frontal lobe regions, whereas memory impairment is associated with the volume of temporal lobe WMH.

Effect of white matter hyperintensities on cortical cerebral blood volume using perfusion MRI

White matter hyperintensities (WMHs) are commonly seen on brain magnetic resonance imaging (MRI) scans of elderly individuals, but their functional significance remains controversial. We used perfusion-weighted MRI to determine the impact of WMHs on cortical regional cerebral blood volume (rCBV). We studied 24 elderly stroke patients and 27 control subjects with conventional MRI which included T2-weighted FLAIR coronal slices through whole brain and gadolinium-DTPA (0.2 mmol/kg)-based perfusion MRI (pMRI) with echo planar imaging. Volumes of WMHs, including deep WMHs and periventricular hyperintensities (PVHs), were computed by an automated method after excluding regions of infarction. Partial correlations between WMH and corresponding cortical rCBV were determined after correction for age and atrophy. The relative rCBV of gray matter was higher in control subjects and there was no significant hemispheric asymmetry. When both stroke and control groups were included, there were significant correlations among frontal cortical rCBV and frontal WMHs, temporal cortical rCBV with temporal WMHs, and cortical rCBV with both total deep WMHs and PVHs. Although the trends of correlation still existed when the two groups were analyzed separately, they were not significant. The correlations between cortical rCBV and WMHs in the same lobe were significant for subjects with more severe hyperintensities irrespective of the group. In conclusion, T2-weighted WMHs are associated with reduced rCBV in the cerebral cortex, particularly in individuals with extensive hyperintensities.

Neuroanatomical correlates of selected executive functions in middle-aged and older adults: a prospective MRI study

Neuroanatomical substrates of age-related differences in working memory and perseverative behavior were examined in a sample of healthy adults (50–81 years old). The participants, who were screened for history of neurological, psychiatric, and medical conditions known to be linked to poor cognitive performance, underwent magnetic resonance imaging (MRI) and were administered tests of working memory and perseveration. Regional brain volumes and the volume of white matter hyperintensities (WMH) were measured on magnetic resonance images. The analyses indicate that the volume of the prefrontal cortex (PFC) and the volume of white matter hyperintensities in the prefrontal region are independently associated with age-related increases in perseverative errors on the Wisconsin Card Sorting Test (WCST). When participants taking antihypertensive medication were excluded from the analysis, both the volume of the prefrontal cortex and the frontal white matter hyperintensities (FWMH) still predicted increases in perseveration. Neither reduced volume of the prefrontal cortex nor the FWMH volume was linked to age-associated declines in working memory. The volumes of the fusiform gyrus (FG) and the temporal white matter hyperintensities (TWMH) were unrelated to cognitive performance.