Total White Matter Hyperintensities Research Articles

Diastolic dysfunction and cognitive impairment

AbstractBackgroundThe relationship between diastolic dysfunction and cognition is undefined. Diastolic dysfunction is common, disproportionately affects females, and is increasing in the community. While earlier studies suggested that management of diastolic dysfunction did not improve cardiovascular mortality, there is increasing evidence that diastolic dysfunction affects patient outcomes. Our clinical observation is that patients with diastolic dysfunction tend to have increased white matter hyperintensities on imaging. If diastolic dysfunction is found to be associated with cognitive impairment, that would suggest diastolic dysfunction is a novel modifiable risk factor for the development of dementia.MethodEchocardiographic, MRI and neuropsychological data collected by the Framingham Heart Study, Offspring Cohort, at Exam 8 was reviewed. Diastolic measures were related to MRI measures of total cranial brain volume, hippocampal volume and white matter hyperintensities, and to neuropsychological evaluations.ResultData from 1438 participants (Figure 1) showed that increasing E/E’ ratio, indicating increasing diastolic dysfunction, was associated with increased executive function impairment in the Similarities (β±SE:‐0.29±0.09,p<0.002) and FAS Phonemic Fluency (‐1.27±0.33,p<0.001) tasks. Participants with moderate to severe diastolic dysfunction performed more poorly on Logical Memories (‐0.70±0.34,p<0.036) and FAS Phonemic Fluency (‐2.75±1.11,p<0.014), and trended towards increased impairment on Similarities (‐0.59±0.30,p<0.052) (Table 1). Data from 1217 participants (Figure 2) showed that those with mild diastolic dysfunction trended towards increased white matter hyperintensities (0.11±0.07, p<0.105); participants with moderate‐to‐severe diastolic dysfunction had increased white matter hyperintensities (0.30±0.09,p<0.001) (Table 2). Data from 1415 participants showed that increasing E/E’ ratio was associated with increased incident mild cognitive impairment (HR 1.29 [95%CI: 1.01, 1.66], p<0.043; Table 3).ConclusionDiastolic dysfunction was associated increased incident mild cognitive impairment. Increased diastolic dysfunction was associated with impaired executive function and verbal memory on neuropsychological testing, along with increased cerebral small vessel disease as demonstrated by white matter hyperintensities on MR imaging. As cerebral small vessel disease clinically presents with executive function impairment, these results align well. An amnestic impairment was also seen, such as can occur in Alzheimer’s disease. This study suggests that diastolic dysfunction is a novel modifiable risk factor for the development of dementia. Further research examining management of diastolic dysfunction on cognitive outcomes would be of benefit.

Metabolic risk factors, but not vascular lesions and β‐amyloid, are associated with functional connectivity across the Alzheimer’s disease spectrum

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial disease, characterized not only by pathological protein aggregation (Ab and tau), but also by early vascular dysfunctions and functional connectivity alterations (Iturria‐Medina 2016; van der Kant 2019). The study objective was to investigate the association between different markers of vascular health as well as brain β‐amyloid burden and brain network functional connectivity across the AD spectrum.MethodThe sample included 131 participants with normal cognition, subjective cognitive decline, mild cognitive impairment and clinical AD from the IMAP cohort (Caen, France). Vascular risk factors comprised mean arterial pressure, body‐mass‐index (BMI), glycemia and HbA1c levels. White matter hyperintensities (WMH) were segmented from FLAIR‐MRI using the “lesion‐segmentation‐tool” (Schmidt, 2017). Brain β‐amyloid burden was measured by the mean of AV45‐SUVR in an AD‐related neocortex mask (LaJoie 2012). Resting‐state functional connectivity (RSFC) was determined within seven predefined functional networks (Schaefer 2018, Verfaillie 2018). Partial correlation analyses were run to assess associations of vascular risk factors, total WMH load and β‐amyloid burden with RSFC. Additionally, we tested for interaction effects with β‐amyloid status in linear regression analyses. All models were age‐ and sex‐adjusted.ResultParticipant characteristics are presented in Figure 1. Across all participants, higher BMI and higher glycemia were associated with lower RSFC within the default‐mode, salience/ventral‐attention, fronto‐parietal and dorsal‐attention networks (Figure 2 and 3). Results remained significant after correction for diagnostic group status. No associations were found between RSFC and total WMH load or β‐amyloid burden (p≥0.05). There were no significant moderation effects by β‐amyloid positivity (p≥0.05).ConclusionThese findings demonstrate that metabolic‐related vascular risk factors, but not cerebrovascular or β‐amyloid pathologies, are associated with functional connectivity specifically within cognition‐related functional networks. Our study further highlights that connectivity alterations associated with metabolic risk, previously shown in diabetes patients (Musen 2012; Chen 2015), are also present in a non‐diabetic aging and AD cohort. Given that functional connectivity supports reserve capacity, connectivity failure within higher‐order networks may limit resilience against aging and pathological processes.

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

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

Assessment of Leisure Time Physical Activity and Brain Health in a Multiethnic Cohort of Older Adults

Results from longitudinal studies suggest that regular leisure time physical activity (LTPA) is associated with reduced risk of dementia or Alzheimer disease. Data on the association between LTPA and brain magnetic resonance imaging (MRI) measures remain scarce and inconsistent. To examine the association of LTPA and MRI-assessed brain aging measures in a multiethnic elderly population. This cross-sectional study included 1443 older (≥65 years) adults without dementia who were participants of the Washington/Hamilton Heights-Inwood Columbia Aging Project study. LTPA, from self-reported questionnaire, was calculated as metabolic equivalent of energy expenditure. Both moderate to vigorous LTPA, assessed as meeting Physical Activity Guidelines for Americans (≥150 minutes/week) or not, and light-intensity LTPA were also examined. LTPA. Primary outcomes included total brain volume (TBV), cortical thickness, and white matter hyperintensity volume, all derived from MRI scans with established methods and adjusted for intracranial volume when necessary. We examined the association of LTPA with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors. The 1443 participants of the study had a mean (SD) age of 77.2 (6.4) years; 921 (63.8%) were women; 27.0%, 34.4%, and 36.3% were non-Hispanic White, non-Hispanic African American, and Hispanic individuals, respectively; and 27.3% carried the apolipoprotein E (APOE) ɛ4 allele. Compared with the LTPA of nonactive older adults, those with the most LTPA had larger (in cm3) TBV (β [SE], 13.17 [4.42] cm3; P = .003; P for trend = .006) and greater cortical thickness (β [SE], 0.016 [0.008] mm; P = .05; P for trend = .03). The effect size comparing the highest LTPA level with the nonactive group was equivalent to approximately 3 to 4 years of aging (β for 1 year older, -3.06 and -0.005 for TBV and cortical thickness, respectively). A dose-response association was found and even the lowest LTPA level had benefits (eg, TBV: β [SE], 9.03 [4.26] cm3; P = .03) compared with the nonactive group. Meeting Physical Activity Guidelines for Americans (TBV: β [SE], 18.82 [5.14] cm3; P < .001) and light-intensity LTPA (TBV: β [SE], 9.26 [4.29] cm3; P = .03) were also associated with larger brain measures. The association between LTPA and TBV was moderated by race/ethnicity, sex, and APOE status, but generally existed in all subgroups. The results remained similar after excluding participants with mild cognitive impairment. In this study, more physical activity was associated with larger brain volume in older adults. Longitudinal studies are warranted to explore the potential role of physical activity in brain health among older individuals.

Baseline white matter hyperintensities affect the course of cognitive function after small vessel disease-related stroke: a prospective observational study.

Background and purposeCognitive impairment is a common sequel of recent small subcortical infarction (RSSI) and might be negatively affected by preexisting cerebral small vessel disease (SVD). We investigated whether the course of cognitive function in patients with RSSI is influenced by the severity of white matter hyperintensities (WMH), an important imaging feature of SVD.MethodsPatients with magnetic resonance imaging (MRI)‐proven single RSSI were tested neuropsychologically concerning global cognition, processing speed, attention, and set‐shifting. Deep and periventricular WMH severity was assessed using the Fazekas scale, and total WMH lesion volume was calculated from T1‐weighted MRI images. We compared baseline function and course of cognition 15 months after the acute event in patients with absent, mild, and moderate‐to‐severe WMH.ResultsThe study cohort comprised 82 RSSI patients (mean age: 61 ± 10 years, 23% female). At baseline, 40% had cognitive impairment (1.5 standard deviations below standardized mean), and deficits persisted in one‐third of the sample after 15 months. After age correction, there were no significant differences in set‐shifting between WMH groups at baseline. However, although patients without WMH (deep: p < 0.001, periventricular: p = 0.067) or only mild WMH (deep: p = 0.098, periventricular: p = 0.001) improved in set‐shifting after 15 months, there was no improvement in patients with moderate‐to‐severe WMH (deep: p = 0.980, periventricular: p = 0.816). Baseline total WMH volume (p = 0.002) was the only significant predictor for attention 15 months poststroke.ConclusionsThis longitudinal study demonstrates that preexisting moderate‐to‐severe WMH negatively affect the restoration of cognitive function after RSSI, suggesting limited functional reserve in patients with preexisting SVD.

Interaction of Age and Self-reported Physical Sports Activity on White Matter Hyperintensity Volume in Healthy Older Adults.

Cerebral white matter (WM) lesion load, as measured by white matter hyperintensity (WMH) volume with magnetic resonance imaging (MRI), has been associated with increasing age and cardiovascular risk factors, like hypertension. Physical sports activity (PSA) may play an important role in maintaining WM in the context of healthy aging. In 196 healthy older adults, we investigated whether participants reporting high levels of PSA (n = 36) had reduced total and regional WMH volumes compared to those reporting low levels of PSA (n = 160). Age group [young-old (YO) = 50–69 years; old-old (OO) = 70–89 years], PSA group, and age by PSA group interaction effects were tested, with sex, hypertension, and body mass index (BMI) as covariates. We found significant main effects for age group and age by PSA group interactions for total, frontal, temporal, and parietal WMH volumes. There were no main effects of PSA group on WMH volumes. The OO group with low PSA had greater total, frontal, temporal, and parietal WMH volumes than the YO with low PSA and OO with high PSA groups. WMH volumes for the YO and OO groups with high PSA were comparable. These findings indicate an age group difference in those with low PSA, with greater WMH volumes in older adults, which was not observed in those with high PSA. The results suggest that engaging in high levels of PSA may be an important lifestyle factor that can help to diminish WMH lesion load in old age, potentially reducing the impact of brain aging.

CHA2DS2-VASc score, cerebral small vessel disease, and frailty in older patients with atrial fibrillation

The CHA2DS2-VASc score is a validated predictor of ischemic stroke in atrial fibrillation (AF) patients. However, data are limited on whether the CHA2DS2-VASc score is associated with subclinical brain structural changes or physical frailty among older AF patients. We assessed the relationship between CHA2DS2-VASc scores and brain structural changes or physical frailty in AF patients without history of stroke. Overall, 117 patients completed a comprehensive geriatric assessment for physical frailty. In brain magnetic resonance imaging sub-study (n = 49), brain volume and white matter hyperintensity lesion burden were automatically quantified using the LESIONQUANT software program. Patients with high risk of CHA2DS2-VASc scores (≥ 2 in men or ≥ 3 in women) tended to be older and had more comorbidities, higher frailty index, and slower gait speed. Total white matter hyperintensity lesion burden was higher in those with high risk of CHA2DS2-VASc score than in those with intermediate risk (score of 1 in men or 2 in women) of CHA2DS2-VASc score (1.67 [interquartile range: 0.70–3.45] vs. 0.64 [0.19–1.44], p = 0.036). Cognitive function was associated with brain volume, but gait speed was related with white matter hyperintensity lesion burden. In conclusion, we showed a positive relationship between CHA2DS2-VASc scores, white matter hyperintensity lesion burden, and physical frailty in older AF patients. Subclinical brain changes associated with high CHA2DS2-VASc scores may predict physical frailty risk.

Revised Framingham Stroke Risk Profile: Association with Cognitive Status and MRI-Derived Volumetric Measures.

The Framingham Stroke Risk Profile (FSRP) was created in 1991 to estimate 10-year risk of stroke. It was revised in 2017 (rFSRP) to reflect the modern data on vascular risk factors and stroke risk. This study examined the association between the rFSRP and cognitive and brain aging outcomes among participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS). Cross-sectional rFSRP was computed at baseline for 19,309 participants (mean age = 72.84, SD = 8.48) from the NACC-UDS [9,697 (50.2%) normal cognition, 4,705 (24.4%) MCI, 4,907 (25.4%) dementia]. Multivariable linear, logistic, or ordinal regressions examined the association between the rFSRP and diagnostic status, neuropsychological test performance, CDR® Sum of Boxes, as well as total brain volume (TBV), hippocampal volume (HCV), and log-transformed white matter hyperintensities (WMH) for an MRI subset (n = 1,196). Models controlled for age, sex, education, racial identity, APOEɛ4 status, and estimated intracranial volume for MRI models. The mean rFSRP probability was 10.42% (min = 0.50%, max = 95.71%). Higher rFSRP scores corresponded to greater CDR Sum of Boxes (β= 0.02, p = 0.028) and worse performance on: Trail Making Test A (β= 0.05, p < 0.001) and B (β= 0.057, p < 0.001), and Digit Symbol (β= -0.058, p < 0.001). Higher rFSRP scores were associated with increased odds for a greater volume of log-transformed WMH (OR = 1.02 per quartile, p = 0.015). No associations were observed for diagnosis, episodic memory or language test scores, HCV, or TBV. These results support the rFSRP as a useful metric to facilitate clinical research on the associations between cerebrovascular disease and cognitive and brain aging.

Microstructural Connectivity is More Related to Cognition than Conventional MRI in Parkinson's Disease.

The different effects of white matter hyperintensity (WMH) severity and WMH-associated microstructural connectivity on cognition in the early stages of Parkinson's disease (PD) have not been investigated. To investigate the differential effect of WMH severity and WMH-associated microstructural connectivity on cognition in early stages of PD. A total of 136 de novo PD patients were enrolled and divided into groups based on total WMH visual rating scores as follows: mild, moderate, and severe. Microstructural connectivity was measured using graph theoretical analysis according to WMH severity. Additionally, correlation coefficients between WMH-associated microstructural connectivity or WMH scores and cognitive performance were assessed. Patients with severe WMHs demonstrated poorer performance in language function than those with moderate WMHs, and in frontal/executive and visual memory function than those with mild WMHs. Areas of microstructural connectivity were more extensive in patients with severe WMHs compared to those with mild and moderate WMHs, involving frontal and parieto-temporal regions. WMH-associated right fronto-temporo-parietal microstructural disintegration was correlated with cognitive dysfunction in attention, frontal/executive, and memory domains, whereas there was no correlation between WMH scores and any cognitive domains. These data suggest that disruption of microstructural networks by WMHs, rather than WMH burden itself, contributed more to cognitive impairment in PD.

Intracranial vessel wall lesions on 7T MRI and MRI features of cerebral small vessel disease: The SMART-MR study

The etiology of cerebral small vessel disease (CSVD) is the subject of ongoing research. Although intracranial atherosclerosis (ICAS) has been proposed as a possible cause, studies on their relationship remain sparse. We used 7 T vessel wall magnetic resonance imaging (MRI) to study the association between intracranial vessel wall lesions—a neuroimaging marker of ICAS—and MRI features of CSVD. Within the SMART-MR study, cross-sectional analyses were performed in 130 patients (68 ± 9 years; 88% male). ICAS burden—defined as the number of vessel wall lesions—was determined on 7 T vessel wall MRI. CSVD features were determined on 1.5 T and 7 T MRI. Associations between ICAS burden and CSVD features were estimated with linear or modified Poisson regression, adjusted for age, sex, vascular risk factors, and medication use. In 125 patients, ≥1 vessel wall lesions were found (mean 8.5 ± 5.7 lesions). ICAS burden (per + 1 SD) was associated with presence of large subcortical and/or cortical infarcts (RR = 1.65; 95%CI: 1.12–2.43), lacunes (RR = 1.45; 95% CI: 1.14–1.86), cortical microinfarcts (RR = 1.48; 95%CI: 1.13–1.94), and total white matter hyperintensity volume (b = 0.24; 95%CI: 0.02–0.46). Concluding, patients with a higher ICAS burden had more CSVD features, although no evidence of co-location was observed. Further longitudinal studies are required to determine if ICAS precedes development of CSVD.

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.

Association of vascular brain injury, neurodegeneration, amyloid, and cognitive trajectory.

To determine whether vascular and neurodegenerative factors influence cognition before clinically relevant Alzheimer disease pathology, we analyzed MRI measures and amyloid imaging in an ethnoracially diverse cohort of cognitively normal individuals older than 60 years. Participants (n = 154; mean age 74.15 ± 6.94; 50% female; 54% Caucasian, 22.1% Hispanic, 14.9% African American) were recruited from the University of California, Davis Alzheimer's Disease Research Center, who were cognitively normal at baseline, time of PET, and MRI, and received yearly cognitive assessment for 6.23 ± 4.16 years. Mixed model regression with random slope and intercept was calculated for episodic memory and executive function, adjusting for age, sex, education, and ethnicity. Vascular burden score was associated with total white matter hyperintensity (WMH) volume (β, 0.171; 95% confidence interval [CI], 0.024-0.318). WMH volume was associated with low baseline executive function (-0.115; -0.226 to -0.003) and rate of change in memory (-0.029; -0.045 to -0.012). Hippocampal volume was associated with the rate of change in memory (0.040; 0.021-0.059) and executive function (0.024; 0.008-0.039). Continuous measures of amyloid status influenced change in memory (-0.026; -0.044 to -0.008) and executive function (-0.033; -0.046 to -0.021) independently of MRI measures. Vascular brain injury and neurodegeneration are associated with baseline cognitive performance and the rate of longitudinal change independent of amyloid status among community-dwelling, ethnicity diverse cognitively normal individuals, supporting the role of vascular diseases as risk factors for later-life dementia.

Association between red blood cell distribution width and white matter hyperintensities: A large-scale cross-sectional study.

BackgroundRed blood cell distribution width (RDW) is a strong prognostic marker for various medical conditions, such as ischemic strokes. However, the relationships between higher RDW and the subtypes of white matter hyperintensities (WMHs) remain unclear. Hence, this study aimed to thoroughly evaluate the relationships between RDW and the subtypes of WMHs.Patients and methodsThis cross‐sectional study was a retrospective analysis of hospital database (Dongguan Medical System, from April 2015 to February 2017). The presence and subtypes of WMHs were evaluated using Fazekas score with the T2WI‐FLAIR brain images from a 1.5‐T MRI system. The overall sample was randomly split in half. One of the two split‐half samples was used for determining the optimal cutoff value of higher RDW and another for further statistical analyses.ResultsA total of 555 subjects with WMHs and 642 controls were recruited. The optimal cutoff value of higher RDW was 13.25%. Logistic regression revealed that higher RDW (≥13.25%) was positively associated with periventricular WMHs (adjusted OR = 1.81, 95% CI: 1.16–2.82, p = .009). However, higher RDW was not associated with total WMHs (adjusted OR = 1.52, 95% CI: 0.99–2.33, p = .057) and deep WMHs (adjusted OR = 1.21, 95% CI: 0.76–1.94, p = .426).ConclusionOur findings suggested that higher RDW may be independently associated with periventricular WMHs, but not with total WMHs and deep WMHs.

Increased tortuosity of bilateral distal internal carotid artery is associated with white matter hyperintensities.

Although the pathophysiology of white matter hyperintensities remains unclear, we can recently explore the possible relationship with white matter hyperintensities by using quantitative parameter. To demonstrate the relationship between bilateral distal internal carotid arterial tortuosity and total brain white matter hyperintensities volume in elderly individuals. A total of 345 patients (age > 65 years) with brain magnetic resonance (MR) examinations were retrospectively included (44.1% men; mean age = 72.1 ± 6.25 years; 55.9% ≥ 70 years). We measured the Tortuosity Index (TI) of the bilateral distal internal carotid artery and basilar artery on MR angiography imaging, and white matter hyperintensities volume on fluid-attenuated inversion recovery MR sequence. Multiple linear regression was used to assess the association of the TI with quantitatively derived brain white matter hyperintensity volume, after adjusting for demographics (age, sex), vascular risk factors (hypertension, diabetes, heart disease), and vessel diameters, total intracranial volume (TIV). Increased tortuosity of bilateral distal internal carotid artery was associated with greater burden of white matter hyperintensity volume (right: β = 11.223, P = 0.016; left: β = 20.701, P < 0.001). This relationship was independent of age and hypertension, both of which have been considered the strongest risk factors for white matter hyperintensities. Our results suggest that tortuosity of the bilateral distal internal carotid artery is associated with white matter hyperintensities, independent of age and hypertension.

The Impact of Strategic White Matter Hyperintensity Lesion Location on Language

The impact of white matter hyperintensities (WMH) on language possibly depends on lesion location through disturbance of strategic white matter tracts. We examined the impact of WMH location on language in elderly Asians. Cross-sectional. Population-based. Eight-hundred nineteen residents of Singapore, ages (≥65 years). Clinical, cognitive and 3T magnetic resonance imaging assessments were performed on all participants. Language was assessed using the Modified Boston Naming Test (MBNT) and Verbal Fluency (VF). Hypothesis-free region-of-interest-based (ROI) analyses based on major white matter tracts were used to determine the association between WMH location and language. Conditional dependencies between the regional WMH volumes and language were examined using Bayesian-network analysis. ROI-based analyses showed that WMH located within the anterior thalamic radiation (mean difference: -0.12, 95% confidence interval [CI]: -0.22; -0.02, p = 0.019) and uncinate fasciculus (mean difference: -0.09, 95% CI: -0.18; -0.01, p = 0.022) in the left hemisphere were significantly associated with worse VF but did not survive multiple testing. Conversely, WMH volume in the left cingulum of cingulate gyrus was significantly associated with MBNT performance (mean difference: -0.09, 95% CI: -0.17; -0.02, p = 0.016). Bayesian-network analyses confirmed the left cingulum of cingulate gyrus as a direct determinant of MBNT performance. Our findings identify the left cingulum of cingulate gyrus as a strategic white matter tract for MBNT, suggesting that language - is sensitive to subcortical ischemic damage. Future studies on the role of sporadic ischemic lesions and vascular cognitive impairment should not only focus on total WMH volume but should also take WMH lesion location into account when addressing language.

The Longitudinal Assessment of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Alzheimer’s Disease and Their Association With White Matter Hyperintensities in the National Alzheimer’s Coordinating Center’s Uniform Data Set

BackgroundNeuropsychiatric symptoms (NPSs) are common in Alzheimer’s disease (AD). NPSs contribute to patients’ distress, caregiver burden, and institutionalization. White matter hyperintensities (WMHs) appear on magnetic resonance imaging, usually indicative of cerebrovascular disease. WMHs have been associated with certain NPSs. We aimed to assess the relationship between WMH and NPS severity in mild cognitive impairment (MCI) due to AD (MCI-AD) and in AD and to assess the ability of WMHs to predict NPS progression. Data were obtained from the National Alzheimer’s Coordinating Center. MethodsA total of 252 participants (114 with MCI-AD and 138 with AD) were used in this study. Baseline WMHs were quantified using an automated segmentation technique. NPSs were measured using the Neuropsychiatric Inventory. Mixed-effect models and correlations were used to determine the relationship between WMHs and NPSs. ResultsLongitudinal mixed-effect models revealed a significant relationship between increase in Neuropsychiatric Inventory total scores and baseline WMHs (p = .014). There was a significant relationship between baseline WMHs and an increase in delusions (p = .023), hallucinations (p = .040), agitation (p = .093), depression (p = .017), and irritability (p = .002). Correlation plot analysis showed that baseline whole-brain WMHs predicted change in future Neuropsychiatric Inventory total scores (r = .169, p = .008) and predicted change in future agitation severity scores (r = .165, p = .009). WMHs in the temporal lobes (r = .169, p = .008) and frontal lobes (r = .153, p = .016) contributed most to this change. ConclusionsDepression, irritability, and agitation are common NPSs and very distressful to patients and caregivers. Our findings of increased NPS severity over time in MCI-AD and AD with increased WMHs have important implications for treatment, arguing for aggressive treatment of vascular risk factors in patients with MCI-AD or AD.

Periventricular white matter hyperintensity burden and cognitive impairment in early Parkinson's disease.

This study quantified the total brain and periventricular white matter hyperintensity (WMH) burdens in patients with early Parkinson's disease (PD) and explored their associations with cardiovascular risk factors and cognitive performance. A total of 175 non-demented patients with early PD who had undergone baseline brain magnetic resonance imaging were included. Comprehensive neurocognitive testing was conducted to identify PD with mild cognitive impairment (PD-MCI) and to evaluate performances in individual cognitive domains. Cardiovascular risk was expressed as a modified Framingham 10-year cardiovascular risk score (mFRS). A total of 53.7% of this early PD cohort fulfilled the diagnostic criteria for PD-MCI. An increase in mFRS was significantly associated with increases in the total brain WMH (P=0.015) and periventricular WMH (P=0.040) burden, independent of age and gender. The periventricular WMH burden was significantly associated with PD-MCI (P=0.046) in early PD, independent of cardiovascular risk factors. Patients in the 5th quintile of periventricular WMH burden were 8.6 times more likely to have PD-MCI compared with patients in the 1st quintile of periventricular WMH burden (P=0.004). However, total brain WMH burden was not associated with PD-MCI (P=0.158). In individual cognitive domains, heavier periventricular WMH burden was associated with worse executive function and visuospatial function independent of cardiovascular risk factors. Periventricular WMHs are a useful imaging biomarker for cognitive impairment in early PD. Cardiovascular risk factors, although associated with periventricular WMHs, were unable to fully explain the association between periventricular WMHs and cognitive impairment in early PD.

Abstract MP26: Mediterranean Diet And Brain Magnetic Resonance Imaging Measures In Young And Older Adults

Introduction: Accumulative evidence has suggested that higher adherence to a healthy dietary pattern, such as Mediterranean diet (MeDi), is associated with preservation of brain structure and less cerebrovascular events. Little is known for these associations across lifespan. Hypothesis: We hypothesized that MeDi was associated with brain atrophy or small vessel pathology measured using magnetic resonance imaging (MRI) in a cohort of healthy adults aged 20-80. Methods: This cross-sectional study included 375 healthy, non-demented adults recruited from market mailing within a 50-mile radius of Columbia University Medical Center in New York City. The participants age ranged 20-80 years old (mean 55, SD=16); had on average 16 (SD=2.3) years of education; 210 (56%) were females; 67% were Whites, 20% African-Americans, and 13% others. MeDi score (range 0-9) was calculated based on food consumption information collected through food-frequency questionnaire. Total brain volume (TBV) and white matter hyperintensity (WMH) were derived from high-resolution structural MRI scans. We examined the association of MeDi with TBV (milliliter, adjusted for intracranial volume) and WMH (milliliter, log transformed) using regression models adjusted for age, gender, race, education, and total caloric intake. Stratified analyses were performed among young (20-45), mid-age (46-65), and older (65-80) adults. Results: In multivariable-adjusted linear regression models, one unit increase in MeDi score, indicating consumption of one more food meeting the desirable level, was associated with larger TBV (β=2.79, p=0.027) and of less WMH (β= -0.058, p=0.041), corresponding to roughly 1.8 years and 1.3 years of less aging (β=-1.54 for age on TBV and 0.044 for age on WMH), respectively. Furthermore, we found the association between MeDi and TBV was similar across age groups, while the association between MeDi and WMH was only significant in the young adults (b=-0.189, p=0.002). Conclusions: Higher MeDi adherence was associated with healthier brain, indicated by larger brain volumes and less white matter lesion burden. These findings suggest that following a healthy diet may help maintain brain health across life span. To our knowledge, this is the first study to examine the relation of MeDi adherence to brain measures in healthy adults of all ages. The novel findings, especially the finding of MeDi and WMH in young adults, are worth of further confirmation in larger and longitudinal studies.

Abstract WP208: Lower Fractional Anisotropy in White Matter Tracts is Associated With Decreased Manipulative Manual Dexterity Higher Circulating Ceramide Levels in Healthy High-Risk Middle-Aged Individuals

Introduction: We previously reported impaired manipulative manual dexterity measured by grooved peg-board test (GPBT) in healthypeople with increased total brain ischemic white matter hyperintensities. We hypothesized that preclinical white matter tract damage (WMTD), measured as lower regional fractional anisotropy (rFA), is associated with functional decrements measured with GPBT, and with a biomarker of white matter disease, serum ceramides. Methods: Participants were recruited from the GeneSTAR study in families with a history of coronary artery disease. Diffusion tensor imaging was acquired on a Phillips 3T MRI and rFA was calculated using the 181 Eve segmented atlas. 48 susceptible regions for WMTD were analyzed.Liquid chromatography was used to measure ceramides (C). Spearman’s rank correlation (SRC) was used to test statistical associations and Bonferroni method was used to correct for multiple comparisons. Multivariate analysis (GEE) adjusting for age, sex, race and education was performed for associations that were significant in the univariate analyses. Result: Subjects (n=112) were 49±11 years; 49% male and 39% African American. rFA was correlated with decrements on GPBT in the left (L) anterior corona radiata, L genu of the corpus callosum (LGCC), L external capsule, and L &amp; right fornix (RF) (P=0.0009, 0.0008, 0.0002, 0.0003 and 8.2E-07, respectively). Additionally, rFA was negatively correlated with C18:0 in the RF and LGCC (P=1.27E-05 and 2.58E-05, respectively) and C20:0 in RF (P=6.09E-06). C18:0 was correlated with decrements on GPBT (P=0.0025). GEE showed associations between decremental GPBT and rFA in the RF (B = -0.52, 95% CI -1 - 0.03, p= 0.037), between rFA in the RF and Ceramide (C18:0, B= -0.03, 95% CI -0.046--0.0073, p=0.007, C20:0, B=-0.0002, 95%CI -0.0003-0, P= 0.018), as well as rFA in LGCC and Ceramide (C18:0, B=-0.0097, 95% CI -0.019--0.006, P=0.037). GBPT and ceramides were not associated when adjusted for rFA (B = 0.0002 95% CI -0.052 - 0.052 P= 0.99). Conclusion: These analyses support our hypothesis that preclinical WMTD represented by reduced rFA, may undermine neural networks affecting manipulative manual dexterity, with concomitant elevation in serum ceramides in healthy high risk people.

Differential Influence of Location-Specific White-Matter Hyperintensities on Attention Subdomains Measured Using the Attention Network Test.

BackgroundElderly people with white-matter hyperintensities (WMHs) typically show cognitive impairment. Attention, consisting of 3 independent component processes (alerting, orienting, and executive control), is crucial for cognitive functioning. Little is known about how WMHs interfere with these attention subdomains. In the present study, we sought to describe characteristics of attention deficits in patients with age-related WMHs and to assess whether the severity and location of lesions differentially affect specific attention subdomains using the attention network test (ANT), which is a computer-based paradigm tailored to accurately provide behavioral measures of the aforementioned subdomains.Material/MethodsA total of 39 WMH patients and 39 age-, sex-, and education-matched controls underwent comprehensive neuropsychological and ANT evaluation. Brain magnetic resonance imaging (MRI) was performed to visualize severity of total and location-specific WMH lesions. Multiple linear regression analyses adjusted for possible confounders were performed.ResultsCompared with controls, WMH patients showed pronounced deficits in orienting and executive control efficiencies (P<0.050), but not alerting efficiency (P=0.642). As total WMH severity increased, efficiencies in the impaired subdomains significantly declined (P<0.050). In terms of lesion location, fronto-parietal type of periventricular WMH (PWMH) and deep WMH (DWMH) in the parietal lobe affected orienting efficiency, while all PWMH types and DWMH in the frontal, parietal, and temporal lobes affected executive control efficiency (P<0.050). Additional adjustment for other MRI lesions significantly changed the impact on orienting, but not on executive control efficiency.ConclusionsOur results reveal specific attention deficits in patients with age-related WMH and may help clarify how the location of lesions influences their effects on attention subdomains.