MRI White Matter Hyperintensities Research Articles

Increased CAIDE dementia risk, cognition, CSF biomarkers, and vascular burden in healthy adults.

To investigate the cognitive profile of healthy individuals with increased Cardiovascular Risk Factors, Aging and Dementia (CAIDE) dementia risk score and to explore whether this association is related to vascular burden and CSF biomarkers of amyloidosis and neurodegeneration. Cognitively normal participants (mean age 57.6 years) from the Gipuzkoa Alzheimer Project study were classified as having high risk (HR; n = 82) or low risk (LR; n = 293) for dementia according to a CAIDE score cutoff of 9. Cognitive composites were compared between groups. We explored using generalized linear models the role of APOE genotype, MRI white matter hyperintensities (WMH), and CSF (n = 218) levels of β-amyloid1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) in the association between CAIDE score and cognition. HR participants obtained lower scores on executive function (EF) (p = 0.001) and visual perception and construction (VPC) (p < 0.001) composites. EF composite was associated with CAIDE score × p-tau (p = 0.001), CAIDE score × t-tau (p = 0.001), and WMH (p = 0.003). VPC composite was associated with APOE (p = 0.001), Aβ1-42 (p = 0.004), the interaction APOE × Aβ1-42 (p = 0.003), and WMH (p = 0.004). Performance on global memory was associated with Aβ1-42 (p = 0.006), APOE (p = 0.008), and their interaction (p = 0.006). Analyses were adjusted for age, education, sex, premorbid intelligence, and stress. Healthy participants at increased dementia risk based on CAIDE scores show lower performance in EF and VPC. This difference is related to APOE, WMH, and Alzheimer biomarkers.

Serum neurofilament light is sensitive to active cerebral small vessel disease.

To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner. In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls. Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1-11 days, rs = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)-related lesions at follow-up. Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.

Relationship Between Indices of CSF HPA AXIS Activity and AD Biomarkers in Late Life Depression

Depression is associated with increased risk for Alzheimer's disease (AD), but the mechanisms for this association remain unclear. In preclinical experiments and human studies in Mild Cognitive Impairment (MCI) and AD, increased Hypothalamic-pituitary-adrenal (HPA) axis activity and elevations in CRF or cortisol levels have been strongly associated with increased brain amyloid β (Aβ) and tau pathology burden. Thus, It has been suggested that increased HPA axis activity associated with depression may provide a potential mechanism for its link to AD. However, increased HPA activity in depression is inconsistent and many elderly depressives actually have decreased rather than increased HPA activity; therefore, it is unclear if HPA activity plays a role in the modulation of AD biomarkers and AD risk in this population. To evaluate this hypothesis, we examined the relationship between CSF indices of HPA axis activity (CRF, cortisol), and biomarkers of AD or brain amyloid burden (Aβ42, Aβ40), neurodegeneration (total-tau), tauopathy (p-tau) in cognitively intact individuals with late-life Major Depression (LLMD) and controls. CSF was obtained from 47 older, 28 with LLMD and 19 healthy controls. All were 60 or older with an MMSE score of at least 28 and without significant MRI white matter hyperintensities. CSF AD biomarkers were determined at baseline. Spearman's correlations were calculated to examine associations between CSF indices of HPA axis activity and CSF AD biomarkers. Neither CSF cortisol nor CRF levels were significantly different across groups. In controls, neither cortisol nor CRF significantly correlated with any of the AD biomarkers examined. In contrast, when participants with LLMD were examined, cortisol was found to be positively associated with t- and p-tau levels (rho=0.477 and rho=0.417, respectively). CRF did not significantly correlate with any variable in this sample. Our results suggest that in depressed elderly, increased basal concentration of morning CSF cortisol levels, which may reflect heightened HPA axis activation, is linked to increased total and phosphorylated tau. In contrast, CSF Aβ levels, which are typically thought to contribute to the link between depression and AD, did not correlate with indices of HPA-axis activation.

Improved Automatic Segmentation of White Matter Hyperintensities in MRI Based on Multilevel Lesion Features.

Brain white matter hyperintensities (WMHs) are linked to increased risk of cerebrovascular and neurodegenerative diseases among the elderly. Consequently, detection and characterization of WMHs are of significant clinical importance. We propose a novel approach for WMH segmentation from multi-contrast MRI where both voxel-based and lesion-based information are used to improve overall performance in both volume-oriented and object-oriented metrics. Our segmentation method (AMOS-2D) consists of four stages following a "generate-and-test" approach: pre-processing, Gaussian white matter (WM) modelling, hierarchical multi-threshold WMH segmentation and object-based WMH filtering using support vector machines. Data from 28 subjects was used in this study covering a wide range of lesion loads. Volumetric T1-weighted images and 2D fluid attenuated inversion recovery (FLAIR) images were used as basis for the WM model and lesion masks defined manually in each subject by experts were used for training and evaluating the proposed method. The method obtained an average agreement (in terms of the Dice similarity coefficient, DSC) with experts equivalent to inter-expert agreement both in terms of WMH number (DSC=0.637 vs. 0.651) and volume (DSC=0.743 vs. 0.781). It allowed higher accuracy in detecting WMH compared to alternative methods tested and was further found to be insensitive to WMH lesion burden. Good agreement with expert annotations combined with stable performance largely independent of lesion burden suggests that AMOS-2D will be a valuable tool for fully automated WMH segmentation in patients with cerebrovascular and neurodegenerative pathologies.

Ischemic lesions, blood pressure dysregulation, and poor outcomes in intracerebral hemorrhage.

To evaluate the associations among diffusion-weighted imaging (DWI) lesions, blood pressure (BP) dysregulation, MRI markers of small vessel disease, and poor outcome in a large, prospective study of primary intracerebral hemorrhage (ICH). The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a multicenter, observational study of ICH among white, black, and Hispanic patients. Of 600 patients, mean (±SD) age was 60.8 ± 13.6 years, median (interquartile range) ICH volume was 9.1 mL (3.5-20.8), and 79.6% had hypertension. Overall, 26.5% of cases had DWI lesions, and this frequency differed by race/ethnicity (black 33.8%, Hispanic 24.9%, white 20.2%, overall p = 0.006). A logistic regression model of variables associated with DWI lesions included lower age (odds ratio [OR] 0.721, p = 0.002), higher first recorded systolic BP (10-unit OR 1.12, p = 0.002), greater change in mean arterial pressure (MAP) prior to the MRI (10-unit OR 1.10, p = 0.037), microbleeds (OR 1.99, p = 0.008), and higher white matter hyperintensity (WMH) score (1-unit OR 1.16, p = 0.002) after controlling for race/ethnicity, leukocyte count, and acute in-hospital antihypertensive treatment. A second model of variables associated with poor 90-day functional outcome (modified Rankin Scale scores 4-6) included DWI lesion count (OR 1.085, p = 0.034) as well as age, ICH volume, intraventricular hemorrhage, Glasgow Coma Scale score, WMH score, race/ethnicity, acute in-hospital antihypertensive treatment, and ICH location. These results support the hypotheses that acute BP dysregulation is associated with the development of DWI lesions in primary ICH and that DWI lesions are, in turn, associated with poor outcomes.

Mental speed is associated with the shape irregularity of white matter MRI hyperintensity load.

Brain MRI white matter hyperintensities (WMHs) are common in elderly subjects. Their impact on cognition, however, appears highly variable. Complementing conventional scoring of WMH load (volume and location) by quantitative characterization of the shape irregularity of WMHs might improve the understanding of the relationship between WMH load and cognitive performance. Here we propose the "confluency sum score" (COSU) as a marker of the total shape irregularity of WMHs in the brain. The study included two independent patient samples: 87 cognitively impaired geriatric inpatients from a prospective neuroimaging study (iDSS) and 198 subjects from the National Alzheimer's Coordinating Center (NACC) database (132 with, 66 w/o cognitive impairment). After automatic segmentation and clustering of the WMHs on FLAIR (LST toolbox, SPM8), the confluency of the i-th contiguous WMH cluster was computed as confluencyi=[1/(36π)∙surfacei3/volumei2]1/3-1. The COSU was obtained by summing the confluency over all WMH clusters. COSU was tested for correlation with CERAD-plus subscores. Correlation analysis was restricted to subjects with at least moderate WMH load (≥ 13.5ml; iDSS / NACC: n=52 / 80). In the iDSS sample, among the 12 CERAD-plus subtests the trail making test A (TMT-A) was most strongly correlated with the COSU (Spearman rho = -0.345, p=0.027). TMT-A performance was not associated with total WMH volume (rho =0.147, p=0.358). This finding was confirmed in the NACC sample (rho = -0.261, p=0.023 versus rho = -0.040, p=0.732). Cognitive performance in specific domains including mental speed and fluid abilities seems to be more strongly associated with the shape irregularity of white matter MRI hyperintensities than with their volume.

Brain mri white matter hyperintensities meeting revised 2010 mcdonald and barkhof criteria for dissemination in space among headache patients

Brain mri white matter hyperintensities meeting revised 2010 mcdonald and barkhof criteria for dissemination in space among headache patients

Abstract T P408: Suboptimal Quality of Reporting of Neuroimaging Methods for Studies of Cerebral Small Vessel Disease

Introduction: The quality of reporting of neuroimaging methods for studies of cerebral small vessel disease is unknown. We systematically reviewed studies of MRI white matter hyperintensities (WMH) of vascular origin to determine the frequency of reporting of key aspects of neuroimaging methods, and whether reporting varied by sample size, study design or journal impact factor. Methods: Three raters independently reviewed 100 consecutive papers reporting WMH severity, either as a primary outcome or covariate, to abstract 50 study characteristics based on the published STRIVE standards (Wardlaw et al Lancet Neurol 2013). Final determinations were made by consensus. An aggregate quality score (range 0-11) was created by adding one point for reporting of each of 11 key characteristics (Table). Spearman correlation or chi-square test, as appropriate, were used to test associations with quality score. Results: Papers were published between 2009 and 2013 with journal impact factors ranging from 0.56 to 15.3, with cohort (79%) and case control (21%) studies represented. Quantitative computational methods were used in 28 studies. MR field strength, MRI sequence types, type of WMH measurement method, blinding and number of raters were reported frequently, but reporting of other characteristics was inconsistent (Table). Study quality score was not correlated with journal impact factor, sample size or cohort study design. Conclusions: There is inconsistent reporting of neuroimaging methods in the small vessel disease imaging literature. Increased adherence to published reporting standards, such as the STRIVE criteria, may facilitate more objective peer review of submitted manuscripts and increase the reproducibility of published results. More work is needed to facilitate adoption of standards and checklists by authors, reviewers and editors.

O3.02 * RADIATION-INDUCED LEUKOENCEPHALOPATHY IS A DEFINITE TYPE OF SMALL VESSEL DISEASE - NEUROPSYCHOLOGICAL AND MRI DESCRIPTION IN 40 PATIENTS

BACKGROUND: Currently, the most common and serious delayed complication of cerebral RT is radiation-induced leukoencephalopathy (RIL), roughly defined, in absence of strictly consensual criteria, by cognitive dysfunctions associated with diffuse FLAIR MRI white matter hyperintensity (HI). The objective of our study is to clearly define the RIL criteria. METHODS: Patients, addressed to our center between June 2010 and June 2012, with medical history of focal or whole brain RT who developed a persistent cognitive complain at least six months after the end of the brain RT, and presenting brain MRI FLAIR abnormalities were eligible. There was a clinical evaluation by a neurologist and a neuropsychological assessment (Edinburgh scale for lateralization, educational level, Mattis dementia rating scale (DRS) and Folsteins'MMSE, Grober and Buschke memory evaluation, forward and backward digit span, phonemic and semantic verbal fluencies, DO80). All patients were scanned by a standardized MRI protocol. White matter FLAIR lesions were evaluated with a 1 to 14 points score according to a modified Scheltens rating scale. Brain atrophy was visually assessed. Consensually defined signs of small vessels diseases (CSVD) were assessed for each patient. RESULT: Fourty patients were enrolled in our study (mostly stage 3 gliomas (27.5%)). The mean fraction dose was 2 Gy (range 1,5-3) and a mean total dose of 49 Gy (range 30-60). Most patient had gait difficulties, urinary trouble and cognitive complain. Memory difficulties were reported by 77% of patients. Neuropsychological assessment showed global and severe cognitive decline. Mattis DRS was abnormal in 75% of the patients. Forward and backward digit span were pathological in 80% patients. On brain MRI, an extensive FLAIR HI with anterior predominance was shown in 68,5% patients. Brain atrophy was present in 87% cases. T2*-weighted- MRI showed hypointensities like “black dots” probably corresponding to microbleeds or radiation induced cavernomas in 52,6% patients. We found no recent small cortical infarct. We found no correlation between FLAIR HI extension, brain atrophy, microbleeds numbers or location, perivascular spaces number, lacunes of presumed vascular origin and the cognitive compound score. We found no correlation between the delay from RT and one of the MRI lesions described above. The patients displayed a loss of executive functions responsible of severe cognitive disability and dementia as previously described in patients with CSVD. Our study give strong clinical and MRI arguments to consider that the RIL is a delayed progressive CSVD, with characteristic evolution and distribution pattern namely implicating distal brain superficial perforating arterioles that serve dorsolateral loops of white matter in the corona radiata and sparing basal ganglia perforating arterioles that spring from the cerebral medial artery.

Comparing Semi-quantitative and Volumetric Measurements of MRI White Matter Hyperintensities: The Northern Manhattan Study (S62.007)

Comparing Semi-quantitative and Volumetric Measurements of MRI White Matter Hyperintensities: The Northern Manhattan Study (S62.007)

Ultrasound measurements of brain tissue pulsatility correlate with MRI white matter hyperintensity

Ultrasound measurements of brain tissue pulsatility correlate with MRI white matter hyperintensity

White matter hyperintensities are associated with visual search behavior independent of generalized slowing in aging

A fundamental controversy is whether cognitive decline with advancing age can be entirely explained by decreased processing speed, or whether specific neural changes can elicit cognitive decline, independent of slowing. These hypotheses are anchored by studies of healthy older individuals where age is presumed the sole influence. Unfortunately, advancing age is also associated with asymptomatic brain white matter injury. We hypothesized that differences in white matter injury extent, manifest by MRI white matter hyperintensities (WMH), mediate differences in visual attentional control in healthy aging, beyond processing speed differences. We tested young and cognitively healthy older adults on search tasks indexing speed and attentional control. Increasing age was associated with generally slowed performance. WMH were also associated with slowed search times independent of processing speed differences. Consistent with evidence attributing reduced network connectivity to WMH, these results conclusively demonstrate that clinically silent white matter injury contributes to slower search performance indicative of compromised cognitive control, independent of generalized slowing of processing speed.

Associations of MRI white matter hyperintensities with cognitive functions, depression and quality of life

Associations of MRI white matter hyperintensities with cognitive functions, depression and quality of life

Cerebrospinal fluid amyloid-β and phenotypic heterogeneity in de novo Parkinson's disease

BackgroundIn Parkinson's disease (PD), the motor presentation characterised by postural instability/gait difficulties (PIGD) heralds accelerated motor, functional and cognitive decline, as compared with the more benign tremor-dominant (TD) variant. This...

Vascular burden and Alzheimer disease pathologic progression

To investigate the vascular contribution to longitudinal changes in Alzheimer disease (AD) biomarkers. The Alzheimer's Disease Neuroimaging Initiative is a clinic based, longitudinal study with CSF, PET, and MRI biomarkers repeatedly measured in participants with normal cognition (NC), mild cognitive impairment (MCI), and mild AD. Participants with severe cerebrovascular risks were excluded. Cardiovascular risk scores and MRI white matter hyperintensities (WMHs) were treated as surrogate markers for vascular burden. Generalized estimating equations were applied, and both vascular burden and its interaction with time (vascular burden × time) or time-varying WMHs were entered into regression models to assess whether biomarker rates of change were modified by vascular burden. Cardiovascular risk profiles were not predictive of progression in CSF β₄₂-amyloid, [¹⁸F]fluorodeoxyglucose (FDG) PET uptake, and MRI hippocampal atrophy. Greater baseline cardiovascular risks or WMHs were generally associated with cognitive impairment, particularly poor executive function. WMHs increased over time with a faster rate in MCI and AD than in NC. Increased time-varying WMH was associated with faster decline in executive function and lower FDG uptake in NC. Otherwise, WMH was not associated with CSF and MRI biomarkers in the 3 groups. These findings remained unchanged after accounting for APOE4. Increased WMHs are associated with aging, decreased glucose metabolism, and decline in executive function but do not affect AD-specific pathologic progression, suggesting that the vascular contribution to dementia is probably additive although not necessarily independent of the amyloid pathway.

The Impact of MRI White Matter Hyperintensities on Dementia in Parkinson's Disease in Relation to the Homocysteine Level and Other Vascular Risk Factors

Background: The role of white matter hyperintensities (WMH) and homocysteine (Hcy) and other vascular risk factors in the pathogenesis of Parkinson's disease (PD) dementia (PDD) remains unclear. Objective: The aim of the study was to assess the impact of WMH, Hcy and other biochemical and vascular risk factors on PDD. Methods: A total of 192 patients with PD and 184 age- and sex-matched healthy controls were included. A semistructured interview was used to assess demographic and clinical variables with respect to vascular risk factors (arterial hypertension, diabetes mellitus, atrial fibrillation, ischemic heart disease, obliterative atherosclerosis, hypercholesterolemia, smoking, alcohol intake). Unified Parkinson's Disease Rating Scale score, Hoehn-Yahr staging and the Schwab-England activities of daily living scale were used to assess motor abilities and activities of daily living. A complex neuropsychological examination with a battery of tests was used to classify patients into a group with dementia (PDD) and a group without dementia (PD). Neuroradiological examination of MRI scans included visual rating scales for WMH (according to the Wahlund and Erkinjunntti rating scales) and the Scheltens scale for hippocampal atrophy. Blood samples for Hcy, folate, vitamin B12, fibrinogen, lipids, glucose, creatinine, transaminases and thyroid stimulating hormone (TSH) were examined. Results: Among all patients, 57 (29.7%) fulfilled the diagnostic criteria for dementia. Significantly higher Hcy plasma levels were noted in PD and PDD groups compared to controls (p < 0.05) and in PDD when compared to PD (p < 0.05). According to multivariate regression analysis, WMH (Erkinjuntti scale), high Hcy, low vitamin B12 and folate plasma levels were independent risk factors for PDD. Vascular risk factors did not play any role in the pathogenesis of PDD and WMH. Conclusions: WMH along with Hcy, folate and vitamin B12 may impact cognition in PD. Therapy with vitamin B12, folate and catechol-O-methyltransferase inhibitors may play a potential protective role against PDD.

The Impact of MRI White Matter Hyperintensities on the Dementia in Parkinson's Disease in Relation to the Homocysteine Level and Other Vascular Risk Factors (P07.126)

The Impact of MRI White Matter Hyperintensities on the Dementia in Parkinson's Disease in Relation to the Homocysteine Level and Other Vascular Risk Factors (P07.126)

Complexity of MRI White Matter Hyperintensity Assessments in Relation to Cognition in Aging and Dementia from the Sunnybrook Dementia Study

Quantification methods for white matter hyperintensities (WMH) on Magnetic Resonance Imaging are heterogeneous, deterring their application. This study compared three WMH rating scales, varying in complexity, and a volumetric method, to evaluate trade-offs between complexity and clinical utility in differentiating dementia subgroups and in correlating with cognition. WMH were rated using the Fazekas, Age-Related White Matter Changes (ARWMC) and Scheltens scales, and segmented by computational volumetry in 108 patients with Alzheimer's Disease (AD), 23 with Mild Cognitive Impairment (MCI) and 34 normal controls (NC). Global and hippocampal atrophy, age and education, were accounted for in correlations of WMH with cognitive domains. Intra- and inter-rater reliability were high (intraclass correlation coefficients = 0.88-0.97) across rating scales. WMH scores of all scales were highly correlated with volumes (Spearman r = 0.78-0.90, Ps < 0.001), as well as with each other (Spearman r = 0.86-0.91, Ps < 0.001). The Fazekas scale showed significant separation between AD, MCI and NC using non-parametric analysis, while the ARWMC and Scheltens' scales, and WMH volumes demonstrated significant correlations (standardized β = -0.19 to -0.24, Ps < 0.05) with cognitive domain scores using multivariate regression analysis, controlling for age, education, global and hippocampal atrophy in patients with AD. This study suggests that the degree of complexity of WMH rating scales did not affect validation against WMH volumes, but did vary in validation against cognition. The simplest scale performed best in separating cognitive subgroups, but the more complex scales and quantification correlated better with cognitive measures, especially executive function. Hence the best choice of scale depends on the particular application.

Correlations between MRI white matter lesion location and executive function and episodic memory

MRI white matter hyperintensity (WMH) volume is associated with cognitive impairment. We hypothesized that specific loci of WMH would correlate with cognition even after accounting for total WMH volume. Subjects were identified from a prospective community-based study: 40 had normal cognition, 94 had mild impairment (defined here as a Clinical Dementia Rating [CDR] score of 0.5 without dementia), and 11 had mild Alzheimer's dementia. Factor analysis of a 22-item neuropsychological battery yielded 4 factors (episodic memory, executive function, spatial skills, and general knowledge). MRI WMH segmentation and analysis was performed using FreeSurfer software. Higher WMH volume was independently associated with lower executive function and episodic memory factor scores. Voxel-based general linear models showed loci where WMH was strongly inversely associated with specific cognitive factor scores (p < 0.001), controlling for age, education, sex, APOE genotype, and total WMH volume. For episodic memory, clusters were observed in bilateral temporal-occipital and right parietal periventricular white matter, and the left anterior limb of the internal capsule. For executive function, clusters were observed in bilateral inferior frontal white matter, bilateral temporal-occipital and right parietal periventricular white matter, and the anterior limb of the internal capsule bilaterally. Specific WMH loci are closely associated with executive function and episodic memory, independent of total WMH volume. The anatomic locations suggest that WMH may cause cognitive impairment by affecting connections between cortex and subcortical structures, including the thalamus and striatum, or connections between the occipital lobe and frontal or parietal lobes.

Cardiovascular Prevention of Cognitive Decline

Midlife cardiovascular risk factors, including diabetes, hypertension, dyslipemia, and an unhealthy lifestyle, have been linked to subsequent incidence, delay of onset, and progression rate of Alzheimer disease and vascular dementia. Conversely, optimal treatment of cardiovascular risk factors prevents and slows down age-related cognitive disorders. The impact of antihypertensive therapy on cognitive outcome in patients with hypertension was assessed in large trials which demonstrated a reduction in progression of MRI white matter hyperintensities, in cognitive decline and in incidence of dementia. Large-scale database correlated statin use and reduction in the incidence of dementia, mainly in patients with documented atherosclerosis, but clinical trials failed to reach similar conclusions. Whether a multitargeted intervention would substantially improve protection, quality of life, and reduce medical cost expenditures in patients with lower risk profile has not been ascertained. This would require appropriately designed trials targeting large populations and focusing on cognitive decline as a primary outcome endpoint.