Impact Of White Matter Lesions Research Articles

Differential spatial distribution of white matter lesions in Parkinson's and Alzheimer's diseases and cognitive sequelae.

White Matter Lesions (WML) are a radiological finding common in aged subjects. We explored the impact of WML on underlying neurodegenerative processes. We focused on the impact of WML on two neurodegenerative diseases with different pathology. In this cross-sectional study of 137 subjects (78 female, 59 men, mean age 67.2; 43-87years), we compared WML in healthy controls (HC; n = 55), patients with Alzheimer's disease and amnestic Mild Cognitive Impairment (aMCI), and Parkinson's disease patients with normal cognition and with MCI. Subjects with AD and aMCI were treated as one group (n = 40), subjects with PD and PDMCI were another group (n = 42). MRI T2_FLAIR sequences were analyzed. WML were divided into periventricular (pWML) or subcortical (sWML) depending on their distance from the ventricles. Subjects from the AD + aMCI group, had a significantly greater volume of WML than both HC and the PD + PDMCI group. The volume of WML was greater in the PD + PDMCI than in HC but the difference was not significant. In AD + aMCI subjects, sWML and not pWML were related to a decrease in global cognitive functioning despite greater volume of pWML. In PD + PDMCI, pWML correlate with decline in executive functions and working memory. In HC, pWML correlated with the multidomain decrease corresponding with the aging. This points to a difference between normal aging and pathological aging due to AD and PD brain pathology. The WML location together with underlying disease related neurodegeneration may play a role in determining the effect of WML on cognition. Our results suggest that the impact of WML is not uniform in all patients; rather, their volume, location and cognitive effect may be disease-specific.

Functional connectivity in cognitive control networks mitigates the impact of white matter lesions in the elderly

BackgroundCerebrovascular pathology, quantified by white matter lesions (WML), is known to affect cognition in aging, and is associated with an increased risk of dementia. The present study aimed to investigate whether higher functional connectivity in cognitive control networks mitigates the detrimental effect of WML on cognition.MethodsNondemented older participants (≥ 50 years; n = 230) underwent cognitive evaluation, fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and resting state functional magnetic resonance imaging (fMRI). Total WML volumes were quantified algorithmically. Functional connectivity was assessed in preselected higher-order resting state networks, namely the fronto-parietal, the salience, and the default mode network, using global and local measures. Latent moderated structural equations modeling examined direct and interactive relationships between WML volumes, functional connectivity, and cognition.ResultsLarger WML volumes were associated with worse cognition, having a greater impact on executive functions (β = −0.37, p < 0.01) than on memory (β = −0.22, p < 0.01). Higher global functional connectivity in the fronto-parietal network and higher local connectivity between the salience network and medial frontal cortex significantly mitigated the impact of WML on executive functions, (unstandardized coefficients: b = 2.39, p = 0.01; b = 3.92, p = 0.01) but not on memory (b = -5.01, p = 0.51, b = 2.01, p = 0.07, respectively). No such effects were detected for the default mode network.ConclusionHigher functional connectivity in fronto-parietal and salience networks may protect against detrimental effects of WML on executive functions, the cognitive domain that was predominantly affected by cerebrovascular pathology. These results highlight the crucial role of cognitive control networks as a neural substrate of cognitive reserve in older individuals.

Impact of white matter lesions for depression associated with amnestic MCI and Alzheimer disease

Background: Depression is one of the behavioral and psychological symptoms of dementia commonly seen in patients with Alzheimer disease (AD). Previous study have reported that white matter lesions (WMLs) on MRI is associated with higher depression scores in AD.

The impact of white matter lesions on the cognitive outcome of subthalamic nucleus deep brain stimulation in Parkinson’s disease

ObjectivesWhite Matter lesions (WML) are a risk factor for cognitive impairment in Parkinson’s disease. There is no clear evidence of reduced general cognitive function after DBS. However, a subgroup of patients develops dementia rapidly after DBS despite careful patient selection processes. The aim of this study was to evaluate the load of WML as a possible risk factor for cognitive decline following STN DBS. Patients and methods40 PD-patients receiving bilateral STN-DBS were followed at least three years after surgery to detect dementia. All patients underwent comprehensive neuropsychological assessment and MRI before surgery. The extent of WML was assessed using an automated approach. WML volume was correlated to the onset of dementia and the decline of a cognitive composite score retrospectively. ResultsPatients with a rapid onset of dementia within one, respective three following DBS showed significant higher WML volumes compared to cognitive normal and MCI patients (55.8cm3±18.836 vs. 9.3cm3±12.2; p=0.002). The same significant association was found in a multivariable model, including the covariables age, gender and PD disease duration (p=0.01). WML volume was associated to the rate of decline in cognitive composite score within three years after DBS surgery (p=0.006; R2=0.40) after correction for age. ConclusionsDamaged white matter may lead to a reduced compensation of disconnections in cognitive circuits caused by the implantation of the DBS electrodes or by chronic stimulation.The role of WML as a prognostic factor for the cognitive outcome after DBS may be underestimated. The WML burden should be taken seriously in preoperative risk stratification.

The contribution of white matter lesions to Parkinson's disease motor and gait symptoms: a critical review of the literature.

White matter lesions (WML) associated with cerebrovascular disease (CVD) may be observed on magnetic resonance imaging in Parkinson's disease (PD) patients. WML are an important factor contributing to postural, gait, and cognitive impairment in the elderly without PD and worsening the course of Alzheimer's disease (AD). Numerous articles are available on this topic. Whether WML modify and negatively influence the clinical symptoms, and course of PD is a subject of debate. The aim of this review is to examine the available literature on the contribution of WML to PD motor symptoms in relation to clinical characteristics and methods of assessing WML on MRI. After reviewing the database, we identified 19 studies reporting the relationship between WML and PD; ten studies focusing on the impact of WML on the cognitive status in PD were excluded. We analysed altogether nine studies reporting the relationship between WML and motor signs of PD. The review found association between WML severity and freezing of gait, less significant to responsiveness to dopaminergic treatment and postural instability; no negative impact on tremor and falls was observed. The impact of WML on bradykinesia and rigidity was inconsistent. Comorbid WML is associated with worsening axial motor performance, probably independently from the degree of nigrostriatal dopaminergic denervation in PD. Reducing the vascular risk factors that cause WML may be helpful in preventing the development of axial symptoms and ultimately in improving the quality of life of patients with PD. Given the lack of systematic studies, additional research in this field is needed.

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

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

Strategic lesions in the anterior thalamic radiation and apathy in early Alzheimer's disease.

BackgroundBehavioural disorders and psychological symptoms of Dementia (BPSD) are commonly observed in Alzheimer’s disease (AD), and strongly contribute to increasing patients' disability. Using voxel-lesion-symptom mapping (VLSM), we investigated the impact of white matter lesions (WMLs) on the severity of BPSD in patients with amnestic mild cognitive impairment (a-MCI).MethodsThirty-one a-MCI patients (with a conversion rate to AD of 32% at 2 year follow-up) and 26 healthy controls underwent magnetic resonance imaging (MRI) examination at 3T, including T2-weighted and fluid-attenuated-inversion-recovery images, and T1-weighted volumes. In the patient group, BPSD was assessed using the Neuropsychiatric Inventory-12. After quantitative definition of WMLs, their distribution was investigated, without an a priori anatomical hypothesis, against patients’ behavioural symptoms. Unbiased regional grey matter volumetrics was also used to assess the contribution of grey matter atrophy to BPSD.ResultsApathy, irritability, depression/dysphoria, anxiety and agitation were shown to be the most common symptoms in the patient sample. Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD.ConclusionsThis study indicates that damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI. Disconnection between the prefrontal cortex and the mediodorsal and anterior thalamic nuclei might represent the pathophysiological substrate for apathy, which is one of the most common psychopathological symptoms observed in dementia.

Impact of White Matter Lesions on Depression in the Patients with Alzheimer's Disease.

ObjectiveComorbid depression is common in patients with Alzheimer's disease (AD). An increase in white matter lesions (WMLs) has been associated with depression in both elderly individuals with normal cognition and patients with Alzheimer's disease. We investigated whether the severity and location of WMLs influence the association between WMLs and comorbid depression in AD.MethodsWe enrolled 93 AD patients from Seoul National University Bundang Hospital. We administered both the Mini International Neuropsychiatric Inventory (MINI) and the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD-K) clinical and neuropsychological battery. Subjects also underwent brain magnetic resonance imaging (MRI). We diagnosed AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. We diagnosed depressive disorders according to the DSM-IV diagnostic criteria, and evaluated the severity of depressive symptoms using the Korean version of the Geriatric Depression Scale (GDS-K). We quantified the WML volumes from the brain MRI using a fully automated segmentation algorithm.ResultsThe log of the WML volume in the frontal lobe was significantly associated with depressive disorders (odds ratio=1.905, 95% CI=1.027-3.533, p=0.041), but not with the severity of depressive symptoms as measured by the GDS-K.ConclusionThe WML volume in the frontal lobe conferred a risk of comorbid depressive disorders in AD, which implies that comorbid depression in AD may be attributed to vascular causes.

Modeling the relationship among gray matter atrophy, abnormalities in connecting white matter, and cognitive performance in early multiple sclerosis.

Quantitative assessment of clinical and pathologic consequences of white matter abnormalities in multiple sclerosis is critical in understanding the pathways of disease. This study aimed to test whether gray matter atrophy was related to abnormalities in connecting white matter and to identify patterns of imaging biomarker abnormalities that were related to patient processing speed. Image data and Symbol Digit Modalities Test scores were collected from a cohort of patients with early multiple sclerosis. The Network Modification Tool was used to estimate connectivity irregularities by projecting white matter abnormalities onto connecting gray matter regions. Partial least-squares regression quantified the relationship between imaging biomarkers and processing speed as measured by the Symbol Digit Modalities Test. Atrophy in deep gray matter structures of the thalami and putamen had moderate and significant correlations with abnormalities in connecting white matter (r = 0.39-0.41, P < .05 corrected). The 2 models of processing speed, 1 for each of the WM imaging biomarkers, had goodness-of-fit (R(2)) values of 0.42 and 0.30. A measure of the impact of white matter lesions on the connectivity of occipital and parietal areas had significant nonzero regression coefficients. We concluded that deep gray matter regions may be susceptible to inflammation and/or demyelination in white matter, possibly having a higher sensitivity to remote degeneration, and that lesions affecting visual processing pathways were related to processing speed. The Network Modification Tool may be used to quantify the impact of early white matter abnormalities on both connecting gray matter structures and processing speed.

EPA-0529 - Impact of white matter lesions on the validity of iron deposit measurement in early alzheimer's disease

Mild cognitive impairment (MCI) confers a particularly high annual risk of 10-15% of conversion to Alzheimer's disease (AD). Recent findings suggest that regional brain iron concentration measured by quantitative MR relaxation rate R2' may be useful as a biomarker to evaluate the progression of AD. In this study, we examined the impact of white matter lesion (WML) pathology measured by visual ratings on the validity of iron concentration in converting and stable MCI patients. Retrospective magnetic resonance imaging data were collected for 65 MCI patients. All patients underwent 1.5 Tesla MRI: WML were visually rated on T2 images using the Fazekas and the Scheltens scales, iron concentrations of subcortical regions of interest (ROI) were measured on T2 * maps by calculating the transverse relaxation rate R2'. Further, volumes of gray matter (GM), withe matter (WM) and cerebrospinal fluid (CSF) were calculated. Of 65 subjects, 25 converted to AD during a follow-up of 19.2±7.4 months and 40 remained stable. Converters had significantly more WML in periventricular regions and the temporal lobe as well as lower volume of WM and a higher volume of CSF. In contrast, ROI analysis of iron deposits showed higher iron concentration in the globus pallidus, the insula, the hippocampus and the substantia nigra in non-converters compared to converters. Our results suggest that the validity of the measurement of iron deposits as a biomarker for the imminent conversion from MCI to AD may be limited by the presents of WML pathology.

Education Modulates the Impact of White Matter Lesions on the Risk of Mild Cognitive Impairment and Dementia

Conflicting results have been reported regarding the association between white matter lesions (WML) and cognitive impairment. We hypothesized that education, a marker of cognitive reserve (CR), could modulate the effects of WML on the risk of mild cognitive impairment (MCI) or dementia. We followed 500 healthy subjects from a cohort of community-dwelling persons aged 65 years and over (ESPRIT Project). At baseline, WML volume was measured using a semi-automatic method on T2-weighted MRI. Standardized cognitive and neurological evaluations were repeated after 2, 4, and 7 years. The sample was dichotomized according to education level into low (≤8 years) and high (>8 years) education groups. Cox proportional hazard models were constructed to study the association between WML and risk of MCI/dementia. The interaction between education level and WML volume reached significance (p= 0.017). After adjustment for potential confounders, the association between severe WML and increased MCI/dementia risk was significant in the low education group (≤8 years) (p= 0.02, hazard ratio [HR]: 3.77 [1.29-10.99]), but not in the high education group (>8 years) (p= 0.82, HR: 1.07 [0.61-1.87]). Severe WML significantly increases the risk of developing MCI/dementia over a 7-year period in low educated participants. Subjects with higher education levels were seen to be more likely to be resilient to the deleterious effects of severe WML. The CR hypothesis suggests several avenues for dementia prevention.

Impact of White Matter Lesions and Cognitive Deficits on Conversion from Mild Cognitive Impairment to Alzheimer's Disease

Mild cognitive impairment (MCI) may represent a prodromal stage of dementia and confers a particularly high annual risk of 10-15% for conversion to Alzheimer's disease (AD). Recent findings suggest that white matter lesion pathology (WML) can negatively influence conversion from MCI to AD. In this study, we examined the predictive value of neuropsychological test results and WML pathology on conversion of MCI to AD. Retrospective neuropsychological and magnetic resonance imaging data were collected for MCI patients seen at the University Clinic of Innsbruck between 2005 and 2011. WML were visually rated using the Fazekas and Scheltens scales. Of the 60 subjects, 31 converted to AD during a follow-up of 18.3 ± 7.4 months and 29 remained stable. Orientation, MMSE score, word list learning and recall, visual memory, and naming scores were significantly lower in MCI patients converting to AD than in non-converters. Converters had significantly higher Fazekas scores and more WML in periventricular regions. Periventricular WML were negatively associated with psychomotor speed, and subcortical WML were negatively correlated with visual memory at baseline in all MCI patients. Low scores in orientation and verbal delayed recall were predictors of progression from MCI to AD. Periventricular WML correlate with lower cognitive function in patients with MCI. However, deficits in orientation and verbal memory, but not vascular changes, turned out as predictive for conversion from MCI to AD. Consequently, a higher WML burden may represent a serious risk factor but not an early symptom for the imminent conversion to AD.

Impact of White Matter Lesions on Cognition in Stroke Patients Free from Pre-Stroke Cognitive Impairment: A One-Year Follow-Up Study

Background/Aim: Post-stroke cognitive impairment and dementia may be caused by pure vascular, pure degenerative or mixed disease. The relation between post-stroke cognitive impairment and the combination of vascular pathology and degenerative changes is less evaluated. We aimed to evaluate the associations between white matter lesions (WMLs) and patient performance 1 year after stroke on tests of executive functioning, memory and visuospatial function, adjusted for the effects of lifestyle and disease-related factors, including medial temporal lobe atrophy (MTLA). Methods: Patients with a first-ever stroke or transient ischemic attack were invited to participate in the study. The associations between the cognitive test performances and WMLs were studied using linear regression [Trail Making Test B (TMT B) and 10-word test] and logistic regression (Clock Drawing Test). Results: In total, 199 patients completed the follow-up. The TMT B (p = 0.029) and the 10-word test (p = 0.014) were significantly associated with WMLs; however, the Clock Drawing Test (p = 0.19) was not. The TMT B (p = 0.018) and the 10-word test (p ≤ 0.001) were both significantly associated with MTLA. Conclusion: Impaired executive functioning and memory are significantly associated with WMLs and MTLA. The mechanisms explaining post-stroke cognitive impairment are multifactorial, including different types of vascular pathology and coexisting vascular and degenerative changes.

Evaluating and reducing the impact of white matter lesions on brain volume measurements

MR-based measurements of brain volumes may be affected by the presence of white matter (WM) lesions. Here, we assessed how and to what extent this may happen for WM lesions of various sizes and intensities. After inserting WM lesions of different sizes and intensities into T1-W brain images of healthy subjects, we assessed the effect on two widely used automatic methods for brain volume measurement such as SIENAX (segmentation-based) and SIENA (registration-based). To explore the relevance of partial volume (PV) estimation, we performed the experiments with two different PV models, implemented by the same segmentation algorithm (FAST) of SIENAX and SIENA. Finally, we tested potential solutions to this issue. The presence of WM lesions did not bias measurements for registration-based method such as SIENA. By contrast, the presence of WM lesions affected segmentation-based brain volume measurements such as SIENAx. The misclassification of both gray matter (GM) and WM volumes varied considerably with lesion size and intensity, especially when the lesion intensity was similar to that of the GM/WM interface. The extent to which the presence of WM lesions could affect tissue-class measures was clearly driven by the PV modeling used, with the mixel-type PV model giving a lower error in the presence of WM lesions. The tissue misclassification due to WM lesions was still present when they were masked out. By contrast, refilling the lesions with intensities matching the surrounding normal-appearing WM ensured accurate tissue-class measurements and thus represents a promising approach for accurate tissue classification and brain volume measurements.

Impact of White Matter Lesions on Physical Functioning and Fall Risk in Older People

White matter lesions (WMLs) are common findings on neuroimaging in older people. This review systematically evaluates the published literature on the associations between WMLs and balance, gait, mobility, and falls in older people. Studies were identified with searches of the MEDLINE databases. Articles reporting associations between WMLs and balance, gait, mobility, and falls in older people in cross-sectional and longitudinal studies were included. Thirty-one articles reporting data from 19 studies met the inclusion criteria. There were consistent findings from both cross-sectional and longitudinal studies indicating greater WML volumes are associated with impaired balance, slower gait, and reduced mobility. Most studies addressing regional WML distributions have reported that WMHs in the frontal lobe and periventricular regions show the strongest relationships with balance, gait, and mobility impairments. In relation to falls, a threshold effect was apparent in that only those with severe WML volumes were found to be at increased risk of falling. The findings of this systematic review indicate that WMLs are common and are significantly associated with impaired balance, gait, mobility, and falls in older people. In many studies, however, impaired mobility and increased fall risk are only evident in people who have the most severe degree of WMLs.

White matter lesions in Parkinson disease

Pure vascular parkinsonism without evidence of nigral Lewy body pathology may occur as a distinct clinicopathological entity, but a much more frequent occurrence is the comorbid presence of age-associated white matter lesions (WMLs) in idiopathic Parkinson disease (PD). WMLs are associated with motor and cognitive symptoms in otherwise normal elderly individuals. Comorbid WMLs are, therefore, expected to contribute to clinical symptoms in PD. Studies of WMLs in PD differ with regard to methods of assessment of WML burden and the patient populations selected for analysis, but converging evidence suggests that postural stability and gait motor functions are predominantly affected. WMLs are described to contribute to dementia in Alzheimer disease, and emerging but inconclusive evidence indicates similar effects in PD. In this article, we review the literature addressing the occurrence and impact of WMLs in PD, and suggest that WMLs may exacerbate or contribute to some motor and cognitive deficits associated with PD. We review existing and emerging methods for studying white matter pathology in vivo, and propose future research directions.

Reducing the impact of white matter lesions on automated measures of brain gray and white matter volumes

To develop an automated lesion-filling technique (LEAP; LEsion Automated Preprocessing) that would reduce lesion-associated brain tissue segmentation bias (which is known to affect automated brain gray [GM] and white matter [WM] tissue segmentations in people who have multiple sclerosis), and a WM lesion simulation tool with which to test it. Simulated lesions with differing volumes and signal intensities were added to volumetric brain images from three healthy subjects and then automatically filled with values approximating normal WM. We tested the effects of simulated lesions and lesion-filling correction with LEAP on SPM-derived tissue volume estimates. GM and WM tissue volume estimates were affected by the presence of WM lesions. With simulated lesion volumes of 15 mL at 70% of normal WM intensity, the effect was to increase GM fractional (relative to intracranial) volumes by approximately 2.3%, and reduce WM fractions by approximately 3.6%. Lesion filling reduced these errors to approximately 0.1%. The effect of WM lesions on automated GM and WM volume measures may be considerable and thereby obscure real disease-mediated volume changes. Lesion filling with values approximating normal WM enables more accurate GM and WM volume measures and should be applicable to structural scans independently of the software used for the segmentation.

White matter lesions and lacunar infarcts are differentially associated with brain atrophy: The smart-MR study

Background and aims: Cerebral small-vessel disease (CSVD) may be involved in the pathogenesis of brain atrophy. However, the independent impact of white matter lesions (WML) and lacunar infarcts (LI) on brain atrophy is unknown. We investigated the independent association of WML and LI with brain atrophy.

Lacunar lesions are independently associated with disability and cognitive impairment in CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy caused by mutations of the Notch3 gene. The disease is characterized by T2-hyperintense lesions (subcortical white matter lesions), T1-hypointense lesions (lacunar lesions), and T2*-weighted gradient-echo (GE) lesions (cerebral microhemorrhages [CMs]) visualized on clinical MRI sequences and is considered as a model of "pure" subcortical ischemic vascular dementia. Although numerous studies have investigated the impact of white matter lesions in patients with CADASIL, the clinical importance of lacunar lesions remains unknown. Our purpose was to examine the influence of the visible MRI markers in the disease, including the load of lacunar lesions on cognitive impairment and disability in CADASIL. We collected clinical data from 147 consecutive patients enrolled in an ongoing two-center prospective cohort study. Degree of disability was assessed by modified Rankin scale and Barthel index. Degree of cognitive impairment was assessed by Mattis Dementia Rating Scale and Mini-Mental Status Examination. T1-weighted, fluid-attenuated inversion recovery, and GE images were obtained on a 1.5-T MRI. Volume and location of lacunar lesions, white matter hyperintensities (WMHs), and CMs were assessed. There was a significant independent association between age, volume of lacunar lesions, and global cognitive function scales when analyzed in a multivariable model. In contrast, WMHs and CMs had no independent influence on cognitive function. Disability in this cohort was associated with volume of lacunar lesions, CMs, systolic blood pressure, and age but not with WMHs. Among the lesions observed on conventional MRI in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the overall lacunar lesion burden seems to have the most important impact on cognitive function and disability. These findings suggest that preventive strategies to decrease the risk of lacunar lesions as observed on MRI may reduce disease-related impairment in CADASIL. These results suggest that lacunar lesions may also play a key role in disability and cognitive impairment in more common forms of small-vessel disease.