High prevalence of white matter hyperintensities in normal aging: relation to blood pressure and cognition

The occurrence of cerebral white matter hyperintensities (WMHs), and their associations with blood pressure, episodic memory, and other cognitive tasks, were examined in a population-based sample of 123 individuals between 64 and 74 years old. Magnetic Resonance Imaging (MRI) detected subcortical and periventricular hyperintensities in 90% and 67% of the cases, respectively. Subcortical WMHs were related to elevated diastolic blood pressure measured ten years earlier, and periventricular WMHs were related to elevated diastolic blood pressure measured five and ten years earlier. Subcortical hyperintensities were weakly associated with impaired motor speed, but this association was not significant. Periventricular WMHs had a negative effect on episodic memory, although the relation was not linear. Collectively, the notion that white matter hyperintensities impair cognitive function got weak support in this Swedish sample.     

White matter network damage mediates association between cerebrovascular disease and cognition

To determine whether white matter network disruption mediates the association between MRI markers of cerebrovascular disease (CeVD) and cognitive impairment. Participants (n = 253, aged ≥60 years) from the Epidemiology of Dementia in Singapore study underwent neuropsychological assessments and MRI. CeVD markers were defined as lacunes, white matter hyperintensities (WMH), microbleeds, cortical microinfarcts, cortical infarcts and intracranial stenosis (ICS). White matter microstructure damage was measured as fractional anisotropy and mean diffusivity by tract based spatial statistics from diffusion tensor imaging. Cognitive function was summarized as domain-specific Z-scores.Lacunar counts, WMH volume and ICS were associated with worse performance in executive function, attention, language, verbal and visual memory. These three CeVD markers were also associated with white matter microstructural damage in the projection, commissural, association, and limbic fibers. Path analyses showed that lacunar counts, higher WMH volume and ICS were associated with executive and verbal memory impairment via white matter disruption in commissural fibers whereas impairment in the attention, visual memory and language were mediated through projection fibers.Our study shows that the abnormalities in white matter connectivity may underlie the relationship between CeVD and cognition. Further longitudinal studies are needed to understand the cause-effect relationship between CeVD, white matter damage and cognition.     

White matter hyperintensities induce distal deficits in the connected fibers

White matter hyperintensities (WMH) are common in elderly individuals and cause brain network deficits. However, it is still unclear how the global brain network is affected by the focal WMH. We aimed to investigate the diffusion of WMH‐related deficits along the connecting white matters (WM). Brain magnetic resonance imaging data and neuropsychological evaluations of 174 participants (aged 74 ± 5 years) were collected and analyzed. For each participant, WMH lesions were segmented using a deep learning method, and 18 major WM tracts were reconstructed using automated quantitative tractography. The diffusion characteristics of distal WM tracts (with the WMH penumbra excluded) were calculated. Multivariable linear regression analysis was performed. We found that a high burden of tract‐specific WMH was related to worse diffusion characteristics of distal WM tracts in a wide range of WM tracts, including the forceps major (FMA), forceps minor (FMI), anterior thalamic radiation (ATR), cingulum cingulate gyrus (CCG), corticospinal tract (CST), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus‐parietal (SLFP), superior longitudinal fasciculus‐temporal (SLFT), and uncinate fasciculus (UNC). Furthermore, a higher mean diffusivity (MD) of distal tracts was linked to worse attention and executive function in the FMI, right CCG, left ILF, SLFP, SLFT, and UNC. The effect of WMH on the microstructural integrity of WM tracts may propagate along tracts to distal regions beyond the penumbra and might eventually affect attention and executive function.     

White matter structure in autism: preliminary evidence from diffusion tensor imaging.

BACKGROUND: Individuals with autism have severe difficulties in social communication and relationships. Prior studies have suggested that abnormal connections between brain regions important for social cognition may contribute to the social deficits seen in autism. METHODS: In this study, we used diffusion tensor imaging to investigate white matter structure in seven male children and adolescents with autism and nine age-, gender-, and IQ-matched control subjects. RESULTS: Reduced fractional anisotropy (FA) values were observed in white matter adjacent to the ventromedial prefrontal cortices and in the anterior cingulate gyri as well as in the temporoparietal junctions. Additional clusters of reduced FA values were seen adjacent to the superior temporal sulcus bilaterally, in the temporal lobes approaching the amygdala bilaterally, in occipitotemporal tracts, and in the corpus callosum. CONCLUSIONS: Disruption of white matter tracts between regions implicated in social functioning may contribute to impaired social cognition in autism.     

White matter abnormalities in Parkinson's disease patients with glucocerebrosidase gene mutations

Glucocerebrosidase gene mutations represent a genetic risk factor for the development of Parkinson's disease. This study investigated brain alterations in Parkinson's disease patients carrying heterozygous glucocerebrosidase gene mutations using structural and diffusion tensor magnetic resonance imaging. Among 360 Parkinson's disease patients screened for glucocerebrosidase gene mutations, 19 heterozygous mutation carriers (5.3%) were identified. Of these, 15 patients underwent a neuropsychological evaluation and a magnetic resonance imaging scan. Sixteen age‐ and sex‐matched healthy controls and 14 idiopathic Parkinson's disease patients without glucocerebrosidase gene mutations were also studied. Tract‐based spatial statistics was used to perform a white matter voxel‐wise analysis of diffusion tensor magnetic resonance imaging metrics. Mean fractional anisotropy values were obtained from white matter tracts of interest. Voxel‐based morphometry was used to assess gray‐matter atrophy. Cognitive deficits were found in 9 mutation carrier patients (60%). Compared with controls, Parkinson's disease patients carrying glucocerebrosidase gene mutations showed decreased fractional anisotropy in the olfactory tracts, corpus callosum, and anterior limb of the internal capsule bilaterally, as well as in the right anterior external capsule, and left cingulum, parahippocampal tract, parietal portion of the superior longitudinal fasciculus, and occipital white matter. Mutation carrier patients also had decreased fractional anisotropy of the majority of white matter tracts compared with Parkinson's disease patients with no mutations. No white matter abnormalities were found in Parkinson's disease patients without glucocerebrosidase gene mutations. No gray matter difference was found between patients and controls. In Parkinson's disease patients, verbal fluency scores correlated with white matter abnormalities. Parkinson's disease patients carrying glucocerebrosidase gene mutations experience a distributed pattern of white matter abnormalities involving the interhemispheric, frontal corticocortical, and parahippocampal tracts. White matter pathology in these patients may have an impact on the clinical manifestations of the disease, including cognitive impairment. © 2013 Movement Disorder Society     

White matter hyperintensity in neurologically asymptomatic subjects

Recent advances in magnetic resonance imaging (MRI) technology have had a great impact on the delectability of minute, asymptomatic lesions of the central nervous system. The clinical significance and treatment modes of these lesions, such as white matter hyperintensity (WMH) lesions detected by T2 MRI, remain controversial. To address these problems, we retrospectively evaluated WMH lesions in relation to clinical parameters for 240 neurologically asymptomatic persons who had visited a hospital for a medical check-up of the brain. Proton and T2–weighted MRI were obtained using a 0.5 T superconducting MR imager using the spin echo technique with a repetition time (TR) of 2800 msec. An echo delay times (TE) of 40 msec was used for the proton MRI, and a TE of 100 msec was used for the T2-weighted MRI. The images were visually analyzed according to a four-point grading system. The MRI findings were correlated with clinical parameters including age, gender, presenting symptoms, and hypertension. The overall frequency of WMH increased with age. Grades 2 and 3 of WMH were more frequent in aged persons, whereas the occurrence of grade 1 WMH remained relatively constant across age groups. Based on multiple regression analysis, age was the most significant variable influencing the frequency of WMH, followed by hypertension. These results imply that WMH lesions may simply be a phenomenon of aging, or may be an indicator of prepathologic state in an ischemic brain.     

White matter development and early cognition in babies and toddlers

The normal myelination of neuronal axons is essential to neurodevelopment, allowing fast inter‐neuronal communication. The most dynamic period of myelination occurs in the first few years of life, in concert with a dramatic increase in cognitive abilities. How these processes relate, however, is still unclear. Here we aimed to use a data‐driven technique to parcellate developing white matter into regions with consistent white matter growth trajectories and investigate how these regions related to cognitive development. In a large sample of 183 children aged 3 months to 4 years, we calculated whole brain myelin volume fraction (VF_M) maps using quantitative multicomponent relaxometry. We used spatial independent component analysis (ICA) to blindly segment these quantitative VF_M images into anatomically meaningful parcels with distinct developmental trajectories. We further investigated the relationship of these trajectories with standardized cognitive scores in the same children. The resulting components represented a mix of unilateral and bilateral white matter regions (e.g., cortico‐spinal tract, genu and splenium of the corpus callosum, white matter underlying the inferior frontal gyrus) as well as structured noise (misregistration, image artifact). The trajectories of these regions were associated with individual differences in cognitive abilities. Specifically, components in white matter underlying frontal and temporal cortices showed significant relationships to expressive and receptive language abilities. Many of these relationships had a significant interaction with age, with VF_M becoming more strongly associated with language skills with age. These data provide evidence for a changing coupling between developing myelin and cognitive development. Hum Brain Mapp 35:4475–4487, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.     

Fibre orientation atlas guided rapid segmentation of white matter tracts

Fibre tract delineation from diffusion magnetic resonance imaging (MRI) is a valuable clinical tool for neurosurgical planning and navigation, as well as in research neuroimaging pipelines. Several popular methods are used for this task, each with different strengths and weaknesses making them more or less suited to different contexts. For neurosurgical imaging, priorities include ease of use, computational efficiency, robustness to pathology and ability to generalise to new tracts of interest. Many existing methods use streamline tractography, which may require expert neuroimaging operators for setting parameters and delineating anatomical regions of interest, or suffer from as a lack of generalisability to clinical scans involving deforming tumours and other pathologies. More recently, data-driven approaches including deep-learning segmentation models and streamline clustering methods have improved reproducibility and automation, although they can require large amounts of training data and/or computationally intensive image processing at the point of application. We describe an atlas-based direct tract mapping technique called ‘tractfinder’, utilising tract-specific location and orientation priors. Our aim was to develop a clinically practical method avoiding streamline tractography at the point of application while utilising prior anatomical knowledge derived from only 10–20 training samples. Requiring few training samples allows emphasis to be placed on producing high quality, neuro-anatomically accurate training data, and enables rapid adaptation to new tracts of interest. Avoiding streamline tractography at the point of application reduces computational time, false positives and vulnerabilities to pathology such as tumour deformations or oedema. Carefully filtered training streamlines and track orientation distribution mapping are used to construct tract specific orientation and spatial probability atlases in standard space. Atlases are then transformed to target subject space using affine registration and compared with the subject's voxel-wise fibre orientation distribution data using a mathematical measure of distribution overlap, resulting in a map of the tract's likely spatial distribution. This work includes extensive performance evaluation and comparison with benchmark techniques, including streamline tractography and the deep-learning method TractSeg, in two publicly available healthy diffusion MRI datasets (from TractoInferno and the Human Connectome Project) in addition to a clinical dataset comprising paediatric and adult brain tumour scans. Tract segmentation results display high agreement with established techniques while requiring less than 3 min on average when applied to a new subject. Results also display higher robustness than compared methods when faced with clinical scans featuring brain tumours and resections. As well as describing and evaluating a novel proposed tract delineation technique, this work continues the discussion on the challenges surrounding the white matter segmentation task, including issues of anatomical definitions and the use of quantitative segmentation comparison metrics.     

White matter tractography using diffusion tensor deflection

Diffusion tensor MRI provides unique directional diffusion information that can be used to estimate the patterns of white matter connectivity in the human brain. In this study, the behavior of an algorithm for white matter tractography is examined. The algorithm, called TEND, uses the entire diffusion tensor to deflect the estimated fiber trajectory. Simulations and imaging experiments on in vivo human brains were performed to investigate the behavior of the tractography algorithm. The simulations show that the deflection term is less sensitive than the major eigenvector to image noise. In the human brain imaging experiments, estimated tracts were generated in corpus callosum, corticospinal tract, internal capsule, corona radiata, superior longitudinal fasciculus, inferior longitudinal fasciculus, fronto-occipital fasciculus, and uncinate fasciculus. This approach is promising for mapping the organizational patterns of white matter in the human brain as well as mapping the relationship between major fiber trajectories and the location and extent of brain lesions.     

Increase in periventricular white matter hyperintensities parallels decline in mental processing speed in a non-demented elderly population

OBJECTIVE: To investigate the influence of deep white matter hyperintensities (DWMH) and periventricular white matter hyperintensities (PVWMH) on progression of cognitive decline in non-demented elderly people. METHODS: All data come from the nested MRI sub-study of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We performed a 3 year follow up study on 554 subjects of the PROSPER study using both repeated magnetic resonance imaging and cognitive testing. Cognitive decline and its dependency on WMH severity was assessed using linear regression models adjusted for sex, age, education, treatment group, and test version when applicable. RESULTS: We found that the volume of PVWMH at baseline was longitudinally associated with reduced mental processing speed (p = 0.0075). In addition, we found that the progression in PVWMH volume paralleled the decline in mental processing speed (p = 0.024). In contrast, neither presence nor progression of DWMH was associated with change in performance on any of the cognitive tests. CONCLUSION: PVWMH should not be considered benign but probably underlie impairment in cognitive processing speed.     

Altered Hippocampal White Matter Connectivity in Type 2 Diabetes Mellitus and Memory Decrements

Type 2 diabetes mellitus is associated with cognitive decrements. Specifically affected cognitive domains are learning and memory, for which the hippocampus plays an essential role. The pathophysiological mechanism remains to be revealed. The present study examined whether local hippocampal microstructure and white matter connectivity are related to type 2 diabetes and memory performance. Forty participants with type 2 diabetes and 38 participants without type 2 diabetes underwent detailed cognitive assessment and 3‐Tesla diffusion magnetic resonance imaging (MRI). Diffusion MRI was performed to assess microstructure (fractional anisotropy and mean diffusivity) and white matter connectivity (tract volume) of the hippocampus, which were compared between participants with and without type 2 diabetes. No differences in hippocampal microstructure were observed. Participants with type 2 diabetes had fewer white matter connections between the hippocampus and frontal lobe (P = 0.017). Participants who scored lower on memory function, regardless of type 2 diabetes, had fewer white matter connections between the hippocampus and temporal lobe (P = 0.017). Taken together, type 2 diabetes and memory decrements appear to be associated with altered hippocampal white matter connectivity.     

White matter hyperintensities mediate gray matter volume and processing speed relationship in cognitively unimpaired participants

White matter hyperintensities (WMH) have been extensively associated with cognitive impairment and reductions in gray matter volume (GMv) independently. This study explored whether WMH lesion volume mediates the relationship between cerebral patterns of GMv and cognition in 521 (mean age 57.7 years) cognitively unimpaired middle‐aged individuals. Episodic memory (EM) was measured with the Memory Binding Test and executive functions (EF) using five WAIS‐IV subtests. WMH were automatically determined from T2 and FLAIR sequences and characterized using diffusion‐weighted imaging (DWI) parameters. WMH volume was entered as a mediator in a voxel‐wise mediation analysis relating GMv and cognitive performance (with both EM and EF composites and the individual tests independently). The mediation model was corrected by age, sex, education, number of Apolipoprotein E (APOE)‐ε4 alleles and total intracranial volume. We found that even at very low levels of WMH burden in the cohort (median volume of 3.2 mL), higher WMH lesion volume was significantly associated with a widespread pattern of lower GMv in temporal, frontal, and cerebellar areas. WMH mediated the relationship between GMv and EF, mainly driven by processing speed, but not EM. DWI parameters in these lesions were compatible with incipient demyelination and axonal loss. These findings lead to the reflection on the relevance of the control of cardiovascular risk factors in middle‐aged individuals as a valuable preventive strategy to reduce or delay cognitive decline.     

White matter maturation in visual and motor areas predicts the latency of visual activation in children

In humans, white matter maturation is important for the improvement of cognitive function and performance with age. Across studies the variables of white matter maturity and age are highly correlated; however, the unique contributions of white matter to information processing speed remain relatively unknown. We investigated the relations between the speed of the visually-evoked P100m response and the biophysical properties of white matter in 11 healthy children performing a simple, visually-cued finger movement. We found that: (1) the latency of the early, visually-evoked response was related to the integrity of white matter in both visual and motor association areas and (2) white matter maturation in these areas accounted for the variations in visual processing speed, independent of age. Our study is a novel investigation of spatial-temporal dynamics in the developing brain and provides evidence that white matter maturation accounts for age-related decreases in the speed of visual response. Developmental models of cortical specialization should incorporate the unique role of white matter maturation in mediating changes in performance during tasks involving visual processing.     

White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging

Objectives:  Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders.
Methods:  DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis.
Results:  Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication.
Conclusions:  Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.     

Structural white matter abnormalities in patients with idiopathic dystonia

We investigated whether structural white matter abnormalities, in the form of disruption of axonal coherence and integrity as measured with diffusion tensor imaging (DTI), constitute an underlying pathological mechanism of idiopathic dystonia (ID), independent of genotype status. We studied seven subjects with ID: all had cervical dystonia as their main symptom (one patient also had spasmodic dysphonia and two patients had concurrent generalized dystonia, both DYT1‐negative). We compared DTI MR images of patients with 10 controls, evaluating differences in mean diffusivity (MD) and fractional anisotropy (FA). ID was associated with increased FA values in the thalamus and adjacent white matter, and in the white matter underlying the middle frontal gyrus. ID was also associated with increase in MD in adjacent white matter to the pallidum and putamen bilaterally, left caudate, and in subcortical hemispheric regions, including the postcentral gyrus. Abnormal FA and MD in patients with ID indicate that abnormal axonal coherence and integrity contribute to the pathophysiology of dystonia. These findings suggest that ID is not only a functional disorder, but also associated with structural brain changes. Impaired connectivity and disrupted flow of information may contribute to the impairment of motor planning and regulation in dystonia. © 2006 Movement Disorder Society     

White matter reduced streamline coherence in young men with autism and mental retardation

Background and purpose:  It has been proposed that white matter alterations might play a role in autistic disorders; however, published data are mainly limited to high-functioning autism. The goal of this study was to apply diffusion tensor imaging (DTI) and fiber tractography (FT) to study white matter in low-functioning autism and the relationship between white matter and cognitive impairment.
Methods:  Ten low-functioning males with autism (mean age: 19.7 ± 2.83 years) and 10 age-matched healthy males (mean age: 19.9 ± 2.64 years) underwent DTI-MRI scanning. fractional anisotropy (FA) maps were analyzed with whole brain voxel-wise and tract-of-interest statistics. Using FT algorithms, white matter tracts connecting the orbitofrontal cortex (OFC) with other brain regions were identified and compared between the two groups. FA mean values of the autistic group were correlated with intelligence quotient (IQ) scores.
Results:  Low-functioning autistic subjects showed a reduced tract volume and lower mean FA values in the left OFC network compared with controls. In the autistic group, lower FA values were associated with lower IQ scores.
Conclusions:  We showed evidence of OFC white matter network abnormalities in low-functioning autistic individuals. Our results point to a relationship between the severity of the intellectual impairment and the extent of white matter alterations.     

White matter abnormalities observed in bipolar disorder: a diffusion tensor imaging study

OBJECTIVES: An increased incidence in white matter abnormalities is among the most frequently reported brain change in patients with bipolar disorder. The objective of the present study was to examine white matter tract integrity, using diffusion tensor imaging (DTI), in bipolar patients and healthy comparison subjects. METHODS: Eleven DSM-IV bipolar I patients and 10 healthy age- and sex-matched controls were studied. DTI data were acquired on a 1.5 Tesla scanner. Fractional anisotropy (FA) and diffusivity (trace) were determined from axial images using region of interest (ROI) analyses. The ROIs were manually placed in the midline and forward projecting arms of the genu (anterior) and the midline of the splenium (posterior) of the corpus callosum. RESULTS: Bipolar patients had significantly higher FA in the midline of the genu compared with healthy controls. Regional white matter differences were also observed, with significantly lower FA in the genu than forward projecting regions in both groups and lower FA in the genu than the splenium in controls. CONCLUSIONS: Diffusion tensor imaging revealed significant microstructural differences in the genu, as measured by elevated FA in bipolar patients compared with healthy controls. These preliminary findings further support the hypothesis that anomalous frontal brain mechanisms may be associated with bipolar disorder.     

Associations between T1 white matter lesion volume and regional white matter microstructure in aging

White matter lesions, typically manifesting as regions of signal intensity abnormality (WMSA) on MRI, increase in frequency with age. However, the role of this damage in cognitive decline and disease is still not clear, as lesion volume has only loosely been associated with clinical status. Diffusion tensor imaging (DTI) has been used to examine the quantitative microstructural integrity of white matter, and has applications in the examination of subtle changes to tissue that appear visually normal on conventional imaging. The primary goal of this study was to determine whether major macrostructural white matter damage, (total WMSA volume), is associated with microstructural integrity of normal appearing white matter, and if these macrostructural changes fully account for microstructural changes. Imaging was performed in 126 nondemented individuals, ages 43–85 years, with no history of cerebrovascular disease. Controlling for age, greater WMSA volume was associated with decreased fractional anisotropy (FA) in widespread brain regions. Patterns were similar for FA and radial diffusivity but in contrast, WMSA was associated with axial diffusivity in fewer areas. Age was associated with FA in several regions, and many of these effects remained even when controlling for WMSA volume, suggesting the etiology of WMSAs does not fully account for all age‐associated white matter deterioration. These results provide evidence that WMSA volume is associated with the integrity of normal‐appearing white matter. In addition, our results suggest that overt lesions may not account for the association of increasing age with decreased white matter tissue integrity. Hum Brain Mapp 35:1085–1100, 2014. © 2013 Wiley Periodicals, Inc.     

White matter disorders with autosomal dominant heredity: a review with personal clinical case studies and their MRI findings

Sundal C, Ekholm S, Andersen O. White matter disorders with autosomal dominant heredity: a review with personal clinical case studies and their MRI findings.
Acta Neurol Scand: 2010: 121: 328–337.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Background – Leukoencephalopathies are a heterogeneous group of severe encephalopathy syndromes with myelin, axonal or vascular pathology, typically with extensive white matter lesions on MRI T2‐FSE and/or ‐FLAIR sequences. Objectives – This review is restricted to leukoencephalopathies with onset in adult age and a dominant inheritance. These diseases are generally severe and often lethal and present with an exacerbating or insidiously progressive course. Material and methods – The focus is on four syndromes with pure leukoencephalopathies, however, leukoencephalopathies with associated clinical features are included. Results – T2 weighted MR imaging often show features common for leukoencephalopathies, yet shows distinguishing features in transthyretin amyloidosis. Conclusion – The diagnosis within the group of leukoencephalopathies thus characterized by MRI relies mainly upon clinical and genetic analysis. The differential diagnosis against treatable leukoencephalopathies is increasingly relevant.