White Matter Hypointensities Research Articles

Brain morphology, cognition, and β-amyloid in older adults with superior memory performance.

The mechanisms underlying superior cognitive performance in some older adults are poorly understood. We used a multimodal approach to characterize imaging and cognitive features of 26 successful agers (SA; defined by superior episodic memory ability) and 103 typical older adults. Cortical thickness was greater in multiple regions in SA including right anterior cingulate and prefrontal cortex and was related to baseline memory performance. Similarly, hippocampal volume was greater in SA and associated with baseline memory. SA also had lower white matter hypointensity volumes and faster processing speed. While PiB burden did not differ, there was a significant group interaction in the relationship between age and PiB such that older SA individuals were less likely to have high brain β-amyloid. Over time, memory performance in typical older adults declined more rapidly than in SA, although there was limited evidence for different rates of brain atrophy. These findings indicate that superior memory in aging is related to greater cortical and white matter integrity as well as slower decline in memory performance.

Menkes disease: A case report

Menkes' disease is a rare neurodegenerative disorder due to an intracellular defect of a cop- per transport protein. We describe a 7 months male patient who presented with seizures, hypoactivity and absence of visual contact. The investigation disclosed pilli torti and thrycorrexis nodosa in the hair, low serum levels of both copper and ceruloplasmin, brain magnetic resonance study showed atrophy and white matter hypointensities on T1-weighted images, electroencephalogram reveals moderate background activ- ity disorganization and epileptiform activity, and muscle biopsy with type 2 fiber atrophy. The clinical, lab- oratorial, genetic, muscle biopsy and neurophysiological findings in Menkes' disease are discussed.

Beta-amyloid and Cortical Thickness Reveal Racial Disparities in Preclinical Alzheimer's Disease.

African Americans are two to four times more likely to develop dementia as Non-Hispanic Whites. This increased risk among African Americans represents a critical health disparity that affects nearly 43 million Americans. The present study tested the hypothesis that older African Americans with elevated beta-amyloid would show greater neurodegeneration (smaller hippocampal volumes and decreased cortical thickness) than older Non-Hispanic Whites with elevated beta-amyloid. Data from the Harvard Aging Brain Study (HABS) were used to form a group of older African Americans and two matched groups of Non-Hispanic White adults. Amyloid-positive African Americans had decreased cortical thickness in most of the Alzheimer's disease (AD) signature regions compared with amyloid-positive Non-Hispanic Whites. This factor was negatively correlated with age and white matter hypointensities. Using support vector regression, we also found some evidence that African Americans have an older “brain age” than Non-Hispanic Whites. These findings suggest that African Americans might be more susceptible to factors causing neurodegeneration, which then might accelerate the rate of a diagnosis of AD.

Impact of Stent-Assisted Recanalization of Carotid Artery Stenosis on Brain Volume Changes

Objective: The purpose of this study was to investigate the effect of recanalization on stenotic internal carotid artery on brain volume changes in stent applied patients. Materials and Methods: Carotid stenting was performed in 17 patients with severe carotid artery stenosis between June 2013 and April 2014. High resolution 3D T1 weight images were obtained from each patient 24 hours before and 7.2 ± 3.6 months (mean ± standard deviation) after the procedure on a 3T magnetic resonance imaging scanner. Intracranial total cortical grey matter, total cortical white matter, white matter hypointensity, total intraventricular and subcortical grey matter volumes were assessed by FreeSurfer version 4.5.0. Results: A significant reduction was found in total cortical white matter and subcortical grey matter volumes (p<0.05). A significant increase was found in white matter hypointensity and total intraventricular volumes after procedure (p<0.05). However, no statistical significant difference was found in total cortical grey matter volume before and after procedure (p=0.902). Conclusion: The significant reduction in the postoperative intracranial total cortical white matter and subcortical grey matter volumes and the significant increase in the white matter hypointensity volume were considered to be secondary to neuronal damage. J Clin Exp Invest 2016; 7(4): 283-289

Cognitive reserve lessens the burden of white matter lesions on executive functions in bipolar disorder.

The concept of cognitive reserve (CR) hypothesizes that intellectually stimulating activities provide resilience against brain pathology/disease. Whereas brain abnormalities and cognitive impairment are frequently reported in bipolar disorder (BD), it is unknown whether the impact of brain alterations can be lessened by higher CR in BD. We tested if higher CR would reduce the influence of total volumes of deep white matter hypointensities (WMH), ventricular cerebrospinal fluid (CSF), and prefrontal cortex on memory, executive, and attention/speed functions in patients with BD (n = 75). Linear regression models with interaction terms for CR and brain volumes were applied to directly test if CR reduces the influence of brain pathology on cognitive domains. CR reduced the influence of total volumes of deep WMH (β = -0.38, Q = 0.003) and ventricular CSF (β = -41, Q = 006) on executive functions. The interactions between CR and total volumes of deep WMH/ventricular CSF appear to account for executive functioning in BD. The results suggest that the concept of CR is applicable in BD. Higher reserve capacity in BD alters the relationship between brain pathology and clinical presentation.

Neuroanatomical correlates of HPA axis biomarkers among children at elevated risk for schizophrenia

Background: The hypothalamic-pituitary-adrenal (HPA) axis disturbances observed in psychosis might feasibly contribute to some of the structural brain abnormalities associated with the disorder (i.e., via the potentially toxic effects of elevated glucocorticoid levels on the brain). However, the association between brain structure and cortisol has rarely been investigated. The current study examined relationships between salivary cortisol and regional brain volumes among at-risk children aged 11-14 years, who present multiple antecedents of schizophrenia (ASz=30) or a family history of illness (FHx=22), and typically-developing children (TD=32). Methods: Volumes of specific brain regions known to express glucocorticoid receptors were extracted from structural brain images using FreeSurfer. Diurnal cortisol levels and the cortisol awakening response (CAR) were determined from multiple salivary cortisol samples obtained throughout the day. Results: In the FHx group only, higher diurnal cortisol was correlated with smaller right amygdala and white matter hypointensity volumes (r=-0.51 and -0.62, respectively, p<0.05). In post-hoc analyses, a higher CAR was associated with smaller bilateral cerebellum, bilateral hippocampus, right ventral diencephalon, and total subcortical grey matter volumes among FHx children with a first-degree relative with schizophrenia. In FHx children with an affected second-degree relative, increased diurnal cortisol levels were associated with smaller left hippocampal and white matter hypointensity volumes. Conclusions: Our findings are consistent with the few previous studies examining cortisol and brain structure among adults with established psychosis. These associations may not necessarily reflect a direct effect of cortisol on the developing brain; indeed, abnormal neurodevelopment affecting these brain regions may contribute to HPA-axis dysregulation. Funding: This work was supported by a Sir Henry Wellcome Postdoctoral Fellowship (107395/Z/15/Z) and a Waterloo Foundation Child Development Fund grant (164/1719)

Diagnosis and Genetic Analysis of Glutaric Acidaemia Type I: Very rarely seen inborn error of metabolism.

Diagnosis and Genetic Analysis of Glutaric Acidaemia Type I: Very rarely seen inborn error of metabolism.

Periventricular white matter abnormalities and restricted repetitive behavior in autism spectrum disorder.

Malformations of cortical development are found at higher rates in autism spectrum disorder (ASD) than in healthy controls on postmortem neuropathological evaluation but are more variably observed on visual review of in-vivo MRI brain scans. This may be due to the visually elusive nature of many malformations on MRI. Here, we utilize a quantitative approach to determine whether a volumetric measure of heterotopic gray matter in the white matter is elevated in people with ASD, relative to typically developing controls (TDC). Data from a primary sample of 48 children/young adults with ASD and 48 age-, and gender-matched TDCs, selected from the Autism Brain Imaging Data Exchange (ABIDE) open-access database, were analyzed to compare groups on (1) blinded review of high-resolution T1-weighted research sequences; and (2) quantitative measurement of white matter hypointensity (WMH) volume calculated from the same T1-weighted scans. Groupwise WMH volume comparisons were repeated in an independent, multi-site sample (80 ASD/80 TDC), also selected from ABIDE. Visual review resulted in equivalent proportions of imaging abnormalities in the ASD and TDC group. However, quantitative analysis revealed elevated periventricular and deep subcortical WMH volumes in ASD. This finding was replicated in the independent, multi-site sample. Periventricular WMH volume was not associated with age but was associated with greater restricted repetitive behaviors on both parent-reported and clinician-rated assessment inventories. Thus, findings demonstrate that periventricular WMH volume is elevated in ASD and associated with a higher degree of repetitive behaviors and restricted interests. Although the etiology of focal WMH clusters is unknown, the absence of age effects suggests that they may reflect a static anomaly.

Circulating hematopoietic progenitor cell number is associated with prefrontal cortical thickness, white matter integrity and PTSD duration in combat-exposed veterans

Background Circulating hematopoietic progenitor cells (PCs; CD34+ and CD34+/KDR+) facilitate neurogenesis and neovascularization, promoting increased cortical thickness and white matter integrity in animal models. However, it unknown whether low PCs are associated with trauma symptoms or neurovascular health among veterans. Objectives Determine whether lower PCs are associated with: (1) posttraumatic stress disorder (PTSD) diagnosis, duration and symptoms, (2) decreased prefrontal cortical (PFC) thickness, and (3) reduced white matter integrity, indexed by white matter hypointensities (WMH), and tracts relevant to fear processing: the Uncinate Fasciculus (UF) and Inferior Fronto-Occipital Fasciculus (IFOF). Methods 100 male and 8 female combat-exposed veterans reported PTSD symptoms (43 PTSD+) and were studied by 3T MRI, acquiring whole brain T1-weighted images and, for a subsample ( n = 54), diffusion tensor images. PCs were characterized by flow cytometry. Results Higher CD34+/KDR+ counts were related to greater PFC thickness (DM-PFC and DL-PFC), while higher CD34+ counts were related to better IFOF (but not UF) integrity and fewer WMH, controlling for age, gender, smoking, cardiovascular comorbidities and head injury. In PTSD+ subjects, CD34+/KDR+ counts were inversely related to time since the worst trauma, but not PTSD diagnosis or current symptoms. Conclusions PCs are associated with enhanced white matter integrity and PFC thickness, with potential implications for neurovascular plasticity and fear processing. In patients with PTSD, PCs may exhibit accelerated depletion with increasing time post-trauma.

Relationship between Insulin-Resistance Processing Speed and Specific Executive Function Profiles in Neurologically Intact Older Adults.

This study investigated the relationship between insulin-resistance and constituent components of executive function in a sample of neurologically intact older adult subjects using the homeostasis model assessment (HOMA-IR) and latent factors of working memory, cognitive control and processing speed derived from confirmatory factor analysis. Low-density lipoprotein (LDL), mean arterial pressure (MAP), along with body mass index (BMI) and white matter hypointensity (WMH) were used to control for vascular risk factors, adiposity and cerebrovascular injury. The study included 119 elderly subjects recruited from the University of California, San Francisco Memory and Aging Center. Subjects underwent neuropsychological assessment, fasting blood draw and brain magnetic resonance imaging (MRI). Partial correlations and linear regression models were used to examine the HOMA-IR-executive function relationship. Pearson correlation adjusting for age showed a significant relationship between HOMA-IR and working memory (rp = -.18; p = .047), a trend with cognitive control (rp = -.17; p = .068), and no relationship with processing speed (rp = .013; p = .892). Linear regression models adjusting for demographic factors (age, education, and gender), LDL, MAP, BMI, and WMH indicated that HOMA-IR was negatively associated with cognitive control (r = -.256; p = .026) and working memory (r = -.234; p = .054). These results suggest a greater level of peripheral insulin-resistance is associated with decreased cognitive control and working memory. After controlling for demographic factors, vascular risk, adiposity and cerebrovascular injury, HOMA-IR remained significantly associated with cognitive control, with working memory showing a trend. These findings substantiate the insulin-resistance-executive function hypothesis and suggest a complex interaction, demonstrated by the differential impact of insulin-resistance on processing speed and specific aspects of executive function.

Fat may affect magnetic resonance signal intensity and brain tissue volumes

Obesity/overweight is reported to affect MR-measured brain tissue volume and white matter (WM) signal intensity. This study investigated possible effects of fat on these measures, using pig fat on three participants at a 4T magnet. Grey matter volumes in the presence of fat were lower than baseline measures. Total WM volumes in the presence of fat were higher than baseline measures. WM hypo-intensities on T1-weighted images were higher in the presence of fat than baseline measures. Therefore physical effects of head fat of obese/overweight individual may at least, partly contribute to the association of obesity/overweight with MR structural measures.

The Role of Carotid Intima-Media Thickness in Predicting Longitudinal Cognitive Function in an Older Adult Cohort

Background and Purpose: Carotid atherosclerosis is a risk factor for cerebrovascular disease in older adults. Although age-related cognitive decline has been associated with cerebrovascular disease, not much is known about the consequences of carotid atherosclerosis on longitudinal cognitive function. This study examines the longitudinal relationship between atherosclerosis and cognition in a sample of non-demented older subjects using baseline measurements of carotid intima media thickness (CIMT) and annual cognitive measures of executive function (EXEC) and verbal memory (MEM). Methods: Baseline measurements included CIMT derived from B-mode carotid artery ultrasound, structural T1-weighted images of white matter hypointensities (WMH), white matter lesions (WML), and cerebral infarct. Hypertension, low-density lipoprotein (LDL), diabetes, and waist to hip ratios (WHR) were included as covariates in our models to control for cerebrovascular risks and central adiposity. Annual composite scores of EXEC and MEM functions were derived from item response theory. Linear mixed models were used to model longitudinal cognitive change. Results: A significant inverse relationship was found between baseline CIMT and annual EXEC score, but not annual MEM score. Subjects included in the highest 4th quartile of CIMT showed a rate of annual decline in EXEC score that was significant relative to subjects in lower quartile groups (p < 0.01). The relationship between the 4th quartile of CIMT and annual EXEC score remained significant after independently adjusting for imaging measures of white matter injury and cerebral infarct. Conclusions: Older adult subjects with the highest index of CIMT showed an annual decline in EXEC scores that was significant relative to subjects with lower quartile measurements of CIMT, independent of our measures of white matter injury and cerebral infarct. Our findings suggest that elevated measures of CIMT may mark an atherosclerotic state, resulting in a decline in executive function and not memory in non-demented older adults. i 2014 S. Karger AG, Basel

Twelve-year monitoring of a patient with megalencephalic leukoencephalopathy with subcortical cysts

Megalencephalic leukoencephalopathy (MLC) with subcortical cysts is an infantile-onset inherited disease of the brain white matter with a defect in brain ion and water homoeostasis, which leads to an abnormal brain volume regulation. Clinical features of the disease can be variable, but patients typically show early-onset macrocephaly, motor abnormalities, seizures, and almost constant late-onset mild mental deterioration. Brain magnetic resonance imaging (MRI) reveals diffusely abnormal and mildly swollen white matter as well as subcortical cysts in the anterior temporal and frontoparietal regions. We describe here clinical findings and volumetric MRI and (1)H-MR spectroscopic imaging ((1)H-MRSI) data of a 12-year follow-up on a patient with MLC. The patient had only slight clinical worsening during the long follow-up. Volumetric findings showed substantially unchanged cystic volumes and mild brain atrophy rate. In addition, there was no over time increase in the volume of white matter hypointense lesions seen on FLAIR images at baseline, but the degree of hypointensity of these white matter voxels increased over 12 years. Longitudinal (1)H-MRSI examination showed long-term undetectable metabolite signals in the white matter, whereas the metabolic pattern of gray matter voxels remained unchanged over time. Results show that, in MLC, the chronic brain white matter changes resulting from the brain ion, and water homeostasis can be monitored by quantitative MRI modalities. This might be important for assessing treatment effects.

Motor recovery from constraint induced movement therapy is not constrained by extent of tissue damage following stroke.

The purpose of this study was to delineate the relationship between several types of T1-weighted MRI pathology and motor rehabilitation potential following Constraint Induced Movement therapy (CI therapy) in chronic stroke. Stepwise regression was employed (n = 80) to identify predictors of motor recovery (prior to therapy) and of response to Constraint-Induced Movement therapy [measured via the Wolf Motor Function Test (WMFT) and Motor Activity Log (MAL)] from among the following: age, side of motor deficit, chronicity, gender, lesion volume, peri-infarct damage volume, white matter hypointensity volume, ventricular asymmetry, and lesion location. Although extent of total stroke damage weakly correlated with poorer performance on the WMFT prior to therapy, this relationship was mediated by the location of the damage. No metric of tissue damage examined here was associated with real-world arm use at baseline (MAL at pre-treatment) or with CI therapy-induced improvement in either best motor performance upon request (WMFT) or spontaneous arm use for daily activities (MAL). In sum, the extent of brain tissue damage of any type examined here poorly predicted motor function and response to rehabilitation in chronic stroke.

Structural Magnetic Resonance Imaging in an adult cohort following prenatal and early postnatal exposure to tetrachloroethylene (PCE)-contaminated drinking water

This population-based retrospective cohort study examined Structural Magnetic Resonance Imaging (MRI) of the brain in relation to prenatal and early postnatal exposure to tetrachloroethylene (PCE)-contaminated drinking water on Cape Cod, Massachusetts. Subjects were identified through birth records from 1969 through 1983. Exposure was modeled using pipe network information from town water departments, a PCE leaching and transport algorithm, EPANet water flow modeling software, and Geographic Information System (GIS) methodology. Brain imaging was performed on 26 exposed and 16 unexposed subjects. Scans were acquired on a Philips 3T whole body scanner using the ADNI T1-weighted MP-RAGE scan. The scans were processed by FreeSurfer version 4.3.1 software to obtain measurements of specific brain regions. There were no statistically significant differences between exposed and unexposed subjects on the measures of white matter hypointensities (β: 127.5mm3, 95% CI: −259.1, 1514.0), white matter volumes (e.g. total cerebral white matter: β: 21230.0mm3, 95% CI: −4512.6, 46971.7) or gray matter volumes (e.g. total cerebral gray matter: β: 11976.0mm3, 95% CI: −13657.2, 37609.3). The results of this study suggest that exposure to PCE during gestation and early childhood, at the levels observed in this population, is not associated with alterations in the brain structures studied.

2. Visual aid skills and socioeconomic status in children with Batten disease

2. Visual aid skills and socioeconomic status in children with Batten disease

Menkes' disease: case report

Menkes disease is a rare neurodegenerative disorder due to an intracellular defect of a copper transport protein. We describe a 7 months male patient who presented with seizures, hypoactivity and absence of visual contact. The investigation disclosed pilli torti and thrycorrexis nodosa in the hair, low serum levels of both copper and ceruloplasmin, brain magnetic resonance study showed atrophy and white matter hypointensities on T1-weighted images, electroencephalogram reveals moderate background activity disorganization and epileptiform activity, and muscle biopsy with type 2 fiber atrophy. The clinical, laboratorial, genetic, muscle biopsy and neurophysiological findings in Menkes disease are discussed.

Contralateral hemimicrencephaly and clinical–pathological correlations in children with hemimegalencephaly

In paediatric epilepsy surgery patients with hemimegalencephaly (HME; n = 23), this study compared clinical, neuroimaging and pathologic features to discern potential mechanisms for suboptimal post-hemispherectomy developmental outcomes and structural pathogenesis. MRI measured affected and non-affected cerebral hemisphere volumes for HME and non-HME cases, including monozygotic twins where one sibling had HME. Staining against neuronal nuclei (NeuN) determined grey and white matter cell densities and sizes in HME and autopsy cases, including the non-affected side of a HME surgical/autopsy case. By MRI, the affected hemisphere was larger and the non-affected side smaller in HME compared with non-HME children. The affected HME side showed enlarged abnormal deep grey and white matter structures and/or T2-weighted hypointensity in the subcortical white matter in 75% of cases, suggestive of excessive pre-natal neurogenesis and heterotopias. Histopathological examination of the affected HME side revealed immature-appearing neurons in 70%, polymicrogyria (PMG) in 61% and balloon cells in 45% of cases. Compared with autopsy cases, in HME children NeuN cell densities on the affected side were increased in the molecular layer and upper cortex (+244 to +18%), decreased in lower cortical layers (-35%) and increased in the white matter (+139 to +149%). Deep grey matter MRI abnormalities and/or T2-weighted white matter hypointensity correlated with the presence of immature-appearing neurons and PMG on histopathology, decreased NeuN cell densities in lower cortical layers and a positive history of infantile spasms. Post-surgery seizure control was associated with decreased NeuN densities in the molecular layer. In young children with HME and epilepsy, these findings indicate that there are bilateral cerebral hemispheric abnormalities and contralateral hemimicrencephaly is a likely explanation for poorer post-surgery seizure control and cognitive outcomes. In addition, our findings support the hypothesis that HME pathogenesis probably involves somatic mutations that affect each developing cerebral hemisphere differently with more neurons than expected on the HME side.

Distribution of cranial MRI abnormalities in patients with symptomatic and subclinical CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare, inherited cause of early stroke and dementia, with a poor prognosis. This study was performed to clarify lesion appearance and pattern of lesion distribution in CADASIL. 20 members of a single family were tested for the CADASIL gene mutation and studied with cranial MRI. Scans were evaluated for lesion load and pattern of lesion distribution. 19 patients had cranial MRI, of whom 11 had normal MRI scans, were clinically unaffected and tested negative for the CADASIL gene mutation. The remaining eight patients had abnormal cranial MRI scans: seven patients were positive for the CADASIL gene mutation and one (untested) patient was severely clinically affected. Three of the patients who tested positive for the CADASIL gene mutation were clinically unaffected at the time of imaging. All eight patients with abnormal cranial MRI had subcortical white matter abnormalities, mostly in frontal and temporal lobes. Lesions involving the corpus callosum were present on sagittal T2 weighted images in four of five clinically affected and one of three clinically unaffected patients. Lesions involving the deep grey nuclei and the brain stem were common. On T1 weighted images, lesions were either poorly defined (confluent white matter hypointensity) or well defined (cystic infarcts or enlarged perivascular spaces). Atrophy was infrequent. Familiarity with the range of cranial MRI appearances may aid diagnosis of CADASIL. Recognition of cranial imaging features in asymptomatic CADASIL patients could prompt earlier diagnosis.

Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability.

Magnetic resonance imaging (MRI) monitoring of disease progression in multiple sclerosis is limited by the lack of correlation of abnormalities seen on T2-weighted imaging, and disability. We studied the histopathology of multiple sclerosis lesions, as depicted by MRI, in a large postmortem sample, focusing on axonal loss. Tissue samples from 17 patients were selected immediately postmortem for histopathological analysis on the basis of T2-weighted imaging, including normal appearing white matter and T1 hypointense lesions. In each region, we measured magnetization transfer ratios (MTR), T1 contrast ratio, myelin, and axonal density. T2 lesions (109 samples) were heterogeneous with regard to MRI appearance on T1 and MTR, whereas axonal density ranged from 0% (no residual axons) to 100% (normal axonal density). Of 64 T2 lesions, 17 were reactive (mild perivascular inflammation only), 21 active, 15 chronically active, and 11 chronically inactive. MTR and T1 contrast ratio correlated strongly with axonal density. Also in normal appearing white matter (24 samples), MTR correlated with axonal density. In conclusion, postmortem tissue sampling by using MRI revealed a range of pathology, illustrating the high sensitivity and low specificity of T2-weighted imaging. T1 hypointensity and MTR were strongly associated with axonal density, emphasizing their role in monitoring progression in multiple sclerosis.