Cortical thinning related to periventricular and deep white matter hyperintensities

Previous studies showed that white matter hyperintensities (WMH) are related to cognitive decline in patients with mild cognitive impairment (MCI) or dementia. Moreover, periventricular WMH (periventricular white matter hyperintensities (PWMH)) and deep WMH (deep white matter hyperintensities (DWMH)) may have different effects on cognition. The purpose of this study is to investigate the contributions of PWMH and DWMH to the topography of cortical thinning and to investigate the relationship among WMH, cortical thinning, and cognitive impairments. Participants included 226 patients with Alzheimer's disease or subcortical vascular dementia, and 135 patients with amnestic MCI or subcortical vascular MCI. Cortical thickness was measured using the surface based method. The topography of cortical thinning related to WMH was distributed in the frontal and perisylvian regions, which was similar to that of PWMH. In contrast, there were only small areas of cortical thinning inversely associated with DWMH, which were distributed in medial frontal and lingual gyrus. PWMH, but not DWMH, were associated with the frontal thinning and executive dysfunction; where both PWMH and frontal thinning were independently associated with executive dysfunction. Our results suggest that PWMH are associated with frontal thinning, which is further associated with frontal executive dysfunction.     

White Matter Integrity Following Traumatic Brain Injury: The Association with Severity of Injury and Cognitive Functioning

Traumatic brain injury (TBI) frequently results in impairments of memory, speed of information processing, and executive functions that may persist over many years. Diffuse axonal injury is one of the key pathologies following TBI, causing cognitive impairments due to the disruption of cortical white matter pathways. The current study examined the association between injury severity, cognition, and fractional anisotropy (FA) following TBI. Two diffusion tensor imaging techniques—region-of-interest tractography and tract-based spatial statistics—were used to assess the FA of white matter tracts. This study examined the comparability of these two approaches as they relate to injury severity and cognitive performance. Sixty-eight participants with mild-to-severe TBI, and 25 healthy controls, underwent diffusion tensor imaging analysis. A subsample of 36 individuals with TBI also completed cognitive assessment. Results showed reduction in FA values for those with moderate and severe TBI, compared to controls and individuals with mild TBI. Although FA tended to be lower for individuals with mild TBI no significant differences were found compared to controls. Information processing speed and executive abilities were most strongly associated with the FA of white matter tracts. The results highlight similarities and differences between region-of-interest tractography and tract-based spatial statistics approaches, and suggest that they may be used together to explore pathology following TBI.     

Testing the white matter retrogenesis hypothesis of cognitive aging

The retrogenesis hypothesis postulates that late-myelinated white matter fibers are most vulnerable to age- and disease-related degeneration, which in turn mediate cognitive decline. While recent evidence supports this hypothesis in the context of Alzheimer's disease, it has not been tested systematically in normal cognitive aging. In the current study, we examined the retrogenesis hypothesis in a group (n = 282) of cognitively normal individuals, ranging in age from 7 to 87 years, from the Brain Resource International Database. Participants were evaluated with a comprehensive neuropsychological battery and were imaged with diffusion tensor imaging. Fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (DA), measures of white matter coherence, were computed in 2 prototypical early-myelinated fiber tracts (posterior limb of the internal capsule, cerebral peduncles) and 2 prototypical late-myelinated fiber tracts (superior longitudinal fasciculus, inferior longitudinal fasciculus) chosen to parallel previous studies; mean summary values were also computed for other early- and late-myelinated fiber tracts. We examined age-associated differences in FA, RD, and DA in the developmental trajectory (ages 7-30 years) and degenerative trajectory (ages 31-87 years), and tested whether the measures of white matter coherence mediated age-related cognitive decline in the older group. FA and DA values were greater for early-myelinated fibers than for late-myelinated fibers, and RD values were lower for early-myelinated than late-myelinated fibers. There were age-associated differences in FA, RD, and DA across early- and late-myelinated fiber tracts in the younger group, but the magnitude of differences did not vary as a function of early or late myelinating status. FA and RD in most fiber tracts showed reliable age-associated differences in the older age group, but the magnitudes were greatest for the late-myelinated tract summary measure, inferior longitudinal fasciculus (late fiber tract), and cerebral peduncles (early fiber tract). Finally, FA in the inferior longitudinal fasciculus and cerebral peduncles and RD in the cerebral peduncles mediated age-associated differences in an executive functioning factor. Taken together, the findings highlight the importance of white matter coherence in cognitive aging and provide some, but not complete, support for the white matter retrogenesis hypothesis in normal cognitive aging.     

Effects of cerebrovascular disease and amyloid beta burden on cognition in subjects with subcortical vascular cognitive impairment

Cerebrovascular disease (CVD) and amyloid burden are the most frequent pathologies in subjects with cognitive impairment. However, the relationship between CVD, amyloid burden, and cognition are largely unknown. We aimed to evaluate whether CVD (lacunes, white matter hyperintensities, and microbleeds) and amyloid burden (Pittsburgh compound B [PiB] retention ratio) contribute to cognitive impairment independently or interactively. We recruited 136 patients with subcortical vascular cognitive impairment who underwent magnetic resonance imaging, PiB–positron emission tomography, and neuropsychological testing. The number of lacunes was associated with memory, frontal dysfunctions, and disease severity. The volume of white matter hyperintensities and the PiB retention ratio were associated only with memory dysfunction. There was no direct correlation between CVD markers and PiB retention ratio except that the number of lacunes was negatively correlated with the PiB retention ratio. In addition, there were no interactive effects of CVD and PiB retention ratio on cognition. Our findings suggest that CVD and amyloid burden contribute independently and not interactively to specific patterns of cognitive dysfunction in patients with subcortical vascular cognitive impairment.     

White matter microstructure of the cingulum and cerebellar peduncle is related to sustained attention and working memory: A diffusion tensor imaging study

The non-invasive imaging technique of diffusion tensor imaging (DTI) has been used to investigate the microstructural properties of white matter (WM). The present study investigated whether individual differences in the WM structure of normal subjects as measured by fractional anisotropy (FA) values correlate with cognitive performance in terms of sustained attention and working memory. Subjects underwent DTI and performed the Continuous Performance Test (CPT) and N-back task. FA values throughout the brain were correlated with behavioral performance on a voxel-by-voxel basis to investigate relationships between WM microstructure and cognitive function. The discriminability index of CPT correlated positively with FA of the right cingulum. Accuracy of the 2-back task correlated positively with FA in bilateral cerebellar peduncles. WM microstructure of the right cingulum and bilateral cerebellar peduncles appears related to cognitive function such as sustained attention and working memory in the human brain.     

White matter microstructure is associated with cognitive control in children

Cognitive control, which involves the ability to pay attention and suppress interference, is important for learning and achievement during childhood. The white matter tracts related to control during childhood are not well known. We examined the relationship between white matter microstructure and cognitive control in 61 children aged 7–9 years using diffusion tensor imaging (DTI). This technique enables an in vivo characterization of microstructural properties of white matter based on properties of diffusion. Such properties include fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, measures thought to reflect specific biological properties of white matter integrity. Our results suggest that children with higher estimates of white matter integrity in the corona radiata, superior longitudinal fasciculus, posterior thalamic radiation, and cerebral peduncle were more accurate during incongruent (> > < > >, < < > < <) and neutral (-->--, --<--) trials of a task of cognitive control. Importantly, less interference during the task (i.e., incongruent and neutral difference scores) was associated with greater white matter microstructure in the posterior thalamic radiation and cerebral peduncle. Fiber tracts in a frontal–parietal–striatal–motor circuit seem to play a role in cognitive control in children.     

Distinctive disruption patterns of white matter tracts in Alzheimer's disease with full diffusion tensor characterization

To characterize the white matter structural changes at the tract level and tract group level, comprehensive analysis with 4 metrics derived from diffusion tensor imaging (DTI), fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD), was conducted. Tract groups, namely limbic, commissural, association, and projection tracts, include white matter tracts of similar functions. Diffusion tensor imaging data were acquired from 61 subjects (26 Alzheimer's disease [AD], 11 subjects with amnestic mild cognitive impairment [aMCI], and 24 age-matched controls). An atlas-based approach was used to survey 30 major cerebral white matter tracts with the measurements of FA, MD, AxD, and RD. Regional cortical atrophy and cognitive functions of AD patients were also measured to correlate with the structural changes of white matter. Synchronized structural changes of cingulum bundle and fornix, both of which are part of limbic tract group, were revealed. Widespread yet distinctive structural changes were found in limbic, commissural, association, and projection tract groups between control and AD subjects. Specifically, FA, MD, and RD of limbic tracts, FA, MD, AxD, and RD of commissural tracts, MD, AxD, and RD of association tracts, and MD and AxD of projection tracts are significantly different between AD patients and control subjects. In contrast, the comparison between aMCI and control subjects shows disruption only in the limbic and commissural tract groups of aMCI subjects. MD values of all tract groups of AD patients are significantly correlated to cognitive functions. Difference between AD and control and that between aMCI and control indicates a progression pattern of white matter disruption from limbic and commissural tract group to other tract groups. High correlation between FA, MD, and RD measurements from limbic tracts and cortical atrophy suggests the disruption of the limbic tract group is caused by the neuronal damage.     

Effect of human immunodeficiency virus on the brain: A review

Thirty million people are infected with human immunodeficiency virus (HIV) worldwide, and HIV-associated neurocognitive disorder (HAND) is one of the most common comorbidities of HIV. However, the effect of HIV on the brain has not been fully investigated. This article aimed to review the changes to the brain due to HIV in terms of atrophy, diffusion changes, and hyperintensities. Studies have observed significant atrophy in subcortical gray matter, as well as in cortical white and gray matter. Moreover, the ventricles enlarge, and the sulci widen. Although HIV causes changes to the white and gray matter of the brain, few diffusion tensor imaging studies have investigated the changes to gray matter integrity. White and gray matter hyperintensities have frequently been observed in HIV-positive individuals, with the subcortical gray matter (caudate nucleus and putamen) and periventricular white matter frequently affected. In conclusion, subcortical gray matter is the first brain region to be affected and is affected most severely. Additionally, this review highlights the gaps in the literature, since the effect of HIV on the brain is not fully known. Future studies should continue to investigate the effect of HIV on the brain in different stages of the disease, and alternate therapies should be developed since highly active antiretroviral therapy is currently ineffective at treating HAND.     

Quantitative fiber tracking of lateral and interhemispheric white matter systems in normal aging: relations to timed performance

The integrity of white matter, as measured in vivo with diffusion tensor imaging (DTI), is disrupted in normal aging. A current consensus is that in adults advancing age affects anterior brain regions disproportionately more than posterior regions; however, the mainstay of studies supporting this anterior-posterior gradient is based primarily on measures of the corpus callosum. Using our quantitative fiber tracking approach, we assessed fiber tract integrity of samples of major white matter cortical, subcortical, interhemispheric, and cerebellar systems (11 bilateral and 2 callosal) on DTI data collected at 1.5T magnet strength. Participants were 55 men (age 20-78 years) and 65 women (age 28-81 years), deemed healthy and cognitively intact following interview and behavioral testing. Fiber integrity was measured as orientational diffusion coherence (fractional anisotropy, FA) and magnitude of diffusion, which was quantified separately for longitudinal diffusivity (lambdaL), an index of axonal length or number, and transverse diffusivity (lambdaT), an index of myelin integrity. Aging effects were more evident in diffusivity than FA measures. Men and women, examined separately, showed similar age-related increases in longitudinal and transverse diffusivity in fibers of the internal and external capsules bilaterally and the fornix. FA was lower and diffusivity higher in anterior than posterior fibers of regional paired comparisons (genu versus splenium and frontal versus occipital forceps). Diffusivity with older age was generally greater or FA lower in the superior than inferior fiber systems (longitudinal fasciculi, cingulate bundles), with little to no evidence for age-related degradation in pontine or cerebellar systems. The most striking sex difference emerged for the corpus callosum, for which men showed significant decline in FA and increase in longitudinal and transverse diffusivity in the genu but not splenium. By contrast, in women the age effect was present in both callosal regions, albeit modestly more so in the genu than splenium. Functional meaningfulness of these age-related differences was supported by significant correlations between DTI signs of white matter degradation and poorer performance on cognitive or motor tests. This survey of multiple fiber systems throughout the brain revealed a differential pattern of age's effect on regional FA and diffusivity and suggests mechanisms of functional degradation, attributed at least in part to compromised fiber microstructure affecting myelin and axonal morphology.     

White matter damage of patients with Alzheimer’s disease correlated with the decreased cognitive function

Increasing evidence demonstrates that there is marked damage and dysfunction in the white matter in Alzheimer’s disease (AD). The present study investigates the nature of white matter damage of patients with Alzheimer’s disease with diffusion tensor magnetic resonance imaging (DTI) and analyses the relationship between the white matter damage and the cognition function. DTI, as well as T1 fluid attenuated inversion recovery (FLAIR) and T2-FLAIR, was performed on probable patients of Alzheimer’s disease, and sex and age matched healthy volunteers to measure the fractional anisotropy (FA) and mean diffusivity (MD) in the genu and splenium of the corpus callosum, anterior and posterior limbs of the internal capsule, and the white matter of frontal, temporal, parietal, and occipital lobes. FA was lower in the splenium of corpus callosum, as well as in the white matter of the frontal, temporal, and parietal lobes from patients with Alzheimer’s disease than in the corresponding region from healthy controls and was strongly positive correlated with MMSE scores, whereas FA appeared no different in the anterior and posterior limbs of internal capsule, occipital lobes white matter, and the genu of corpus callosum between the patients and healthy controls. MD was significantly higher in the splenium of corpus callosum and parietal lobes white matter from patients than in that those from healthy controls and was strongly negative correlated with MMSE scores, whereas MD in the anterior and posterior limbs of internal capsule, as well as in frontal, temporal, occipital lobes white matter and the genu of corpus callosum, was not different between the patients and healthy controls. The most prominent alteration of FA and MD was in the splenium of corpus callosum. Our results suggested that white matter of patients with Alzheimer’s disease was selectively impaired and the extent of damage had a strong correlation with the cognitive function, and that selective impairment reflected the cortico–cortical and cortico–subcortical disconnections in the pathomechanism of Alzheimer’s disease. The values of FA and MD in white matter, especially in the splenium of corpus callosum in AD patients, might be a more appropriate surrogate marker for monitoring the disease progression.     

Cerebral changes on MRI and cognitive function: the CASCADE study

The aging, non-demented brain undergoes several physiological changes, some of which may affect cognitive function. The goal of the present study was to examine the associations between subcortical and periventricular white matter hyperintensities (WMHs), cortical and subcortical atrophy, and cognitive function (episodic memory, word fluency, attention, and perceptual, cognitive, and motor speed). This was done within a European collaborative study, Cardiovascular Determinants of Dementia (CASCADE), in which magnetic resonance imaging (MRI) was performed on community-dwelling individuals. The study includes 1254 persons from eight European study centers, ranging between 64 and 76 years of age (M 69.4+/-3.3; 55% men). When demographics (age, education, and sex), study center, and concurrent brain changes had been adjusted for, periventricular WMHS predicted lower performance in word fluency and the Stroop test (time), and subcortical atrophy predicted lower performance in motor speed and the Stroop test (errors). The findings are consistent with findings from lesion and functional neuroimaging studies.     

White Matter Differences Predict Cognitive Vulnerability to Sleep Deprivation

Objectives:

In other disciplines, white matter (WM) differences have been linked to cognitive impairments. This study sets out to clarify whether similar microstructural differences in WM tracts predict a person''s cognitive vulnerability to the effects of total sleep deprivation (TSD).

Design:

Participants completed a simple visual-motor task both before and after 24 h of TSD. Using a median split on the percent change in accuracy from pre-TSD to post-TSD, participants were separated into susceptibility groups. A diffusion tensor MR imaging (DTI) scan was acquired from each participant, and fractional anisotropy (FA) was calculated, examined across the brain, and compared between susceptibility groups.

Setting:

University of Texas at Austin.

Participants:

Thirty-two West Point cadets (9 females, 23 males) between 19 and 25 years of age.

Results:

Participant susceptibility to TSD was correlated with lower FA values in multiple regions of white matter, including the genu of corpus callosum and ascending and longitudinal white matter pathways. Significantly higher FA values in those less vulnerable to TSD, indicating increased neural connectivity and WM organization, may moderate the cognitive effects of sleep deprivation.

Conclusions:

Differences in distributed WM pathways reflect, and may contribute to, a person''s ability to function effectively when sleep deprived. The widespread nature of this effect supports previous views that TSD has a global effect on brain functioning.

Citation:

Rocklage M; Williams V; Pacheco J; Schnyer DM. TitleTitleTitle. SLEEP 2009;32(8):1100-1103.     

Arterial stiffness,the brain and cognition: A systematic review

BackgroundArterial stiffness is a known predictor of cardiovascular disease, and has also been associated with markers of cerebral small vessel disease as well as poor cognitive function and cognitive decline. The consistency of these associations and their relationship to each other are unclear.MethodWe conducted a systematic review of the evidence associating arterial stiffness with cognitive function and cognitive decline, and with makers of cerebral small vessel disease, specifically lacunar infarcts and white matter hyperintensities.ResultsThirteen cross-sectional studies examining arterial stiffness and white matter hyperintensities or lacunar infarctions reported a positive association between increased arterial stiffness and radiological findings of cerebral small vessel disease. Two longitudinal studies examining the relationship between arterial stiffness and white matter hyperintensities found increased pulse wave velocity to be an independent predictor of white matter hyperintensity volume. Fifteen cross-sectional and seven longitudinal studies examining arterial stiffness and cognition were identified. Fourteen of the fifteen cross-sectional studies associated increased arterial stiffness with lower cognitive function, and six of the seven longitudinal studies found arterial stiffness to be predictive of cognitive decline.ConclusionArterial stiffness is associated with cerebral small vessel disease and decreased cognitive function. However methodological limitations such as differing covariates between studies and an over-reliance on the MMSE to measure cognition are a concern across much of the literature.     

Accelerated white matter aging in schizophrenia: role of white matter blood perfusion

Elevated rate of age-related decline in white matter integrity, indexed by fractional anisotropy (FA) from diffusion tensor imaging, was reported in patients with schizophrenia. Its etiology is unknown. We hypothesized that a decline of blood perfusion to the white matter may underlie the accelerated age-related reduction in FA in schizophrenia. Resting white matter perfusion and FA were collected using pseudo-continuous arterial spin labeling and high-angular-resolution diffusion tensor imaging, respectively, in 50 schizophrenia patients and 70 controls (age = 18–63 years). Main outcome measures were the diagnosis-by-age interaction on whole-brain white matter perfusion, and FA. Significant age-related decline in brain white matter perfusion and FA were present in both groups. Age-by-diagnosis interaction was significant for FA (p < 0.001) but not white matter perfusion. Age-by-diagnosis interaction for FA values remained significant even after accounting for age-related decline in perfusion. Therefore, we replicated the finding of an increased rate of age-related white matter FA decline in schizophrenia and observed a significant age-related decline in white matter blood perfusion, although the latter did not contribute to the accelerated age-related decline in FA. The results suggest that factors other than reduced perfusion account for the accelerated age-related decline in white matter integrity in schizophrenia.     

Diffusion tensor imaging of two unrelated Chinese men with hereditary spastic paraplegia associated with thin corpus callosum

Hereditary spastic paraplegia (HSP) associated with thin corpus callosum is a rare autosomal recessive neurodegenerative disorder characterized by an abnormally thin corpus callosum, normal motor development, slowly progressive spastic paraparesis and cognitive deterioration. To investigate and localize abnormalities in the brains of two Chinese patients with HSP-TCC, with mutations in the spatacsin gene. Diffusion tensor imaging (DTI) was used to determine the mean diffusion (MD) and fractional anisotropy (FA) in the brains of the patients in comparison to 20 healthy subjects. Voxel-based analysis (VBA) of both the diffusion and anisotropy values were performed using statistical parametric mapping (SPM). Significant changes with MD increase and FA reduction were found in the already known lesions including the corpus callosum, cerebellum and thalamus. In addition, changes were also found in regions that appear to be normal in conventional MRI, such as the brain stem, internal capsule, cingulum and subcortical white matter including superior longitudinal fascicle and inferior longitudinal fascicle. Neither increase in FA nor reduction in MD was detected in the brain. Our study provides clear in vivo MR imaging evidence of a more widespread brain involvement of HSP-TCC. MD is more sensitive than FA in detecting lesions in thalamus and subcortical white matter, suggesting that MD may be a better marker of the disease progression.     

Regional white matter hyperintensities: aging,Alzheimer's disease risk,and cognitive function

White matter hyperintensities (WMH) of presumed vascular origin, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging, are known to increase with age and are elevated in Alzheimer's disease (AD). The cognitive implications of these common markers are not well understood. Previous research has primarily focused on global measures of WMH burden and broad localizations that contain multiple white matter tracts. The aims of this study were to determine the pattern of WMH accumulation with age, risk for AD, and the relationship with cognitive function utilizing a voxel-wise analysis capable of identifying specific white matter regions. A total of 349 participants underwent T1-weighted and high-resolution T2-weighted fluid attenuated inversion recovery magnetic resonance imaging and neuropsychological testing. Increasing age and lower cognitive speed and flexibility (a component of executive function), were both significantly associated with regional WMH throughout the brain. When age was controlled, lower cognitive speed and flexibility was independently associated with WMH in the superior corona radiata. Apolipoprotein E ε4 and parental family history of AD were not associated with higher burden of WMH. The results contribute to a larger body of literature suggesting that white matter measures are linked with processing speed, and illustrate the utility of voxel-wise analysis in understanding the effect of lesion location on cognitive function.     

Cognitive dysfunction and white matter abnormalities in antiphospholipid syndrome

Diagnosis of the antiphospholipid syndrome (APS) requires that a patient have both a clinical event (thrombosis or pregnancy loss) and persistently positive antiphospholipid antibodies (aPL). Although stroke and transient ischemic attack are the most common neurologic manifestations of APS, both cognitive dysfunction and magnetic resonance imaging (MRI) white matter hyperintensities can occur in aPL-positive patients (with or without APS). Relatively little is known about the cognitive pattern in aPL-positive patients; MRI white matter hyperintensities may be related to underlying attentional and executive cognitive impairment. Studies with sophisticated neuroimaging techniques aimed to better understand MRI white matter hyperintensities may eventually facilitate our understanding of cognitive dysfunction in aPL-positive patients.     

Longitudinal changes of cortical morphology in CADASIL

In CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy), a genetic model of subcortical ischemic vascular dementia (SIVD), clinical status was previously found related to cortex morphology. In the present report, alterations of cortex morphology and their links to clinical worsening were investigated in 190 CADASIL patients followed during 24.4 months. Linear models were used to test relationships between: (1) clinical worsening and changes of depth of cortical sulci and of cortical thickness; (2) alterations of cortical morphology and changes of volume of white matter hyperintensities (WMH(v)) and of lacunar lesions (LL(v)). Reduction of sulcal depth was independently associated with increased time to complete trail making test A and B (p < 0.0001 and p = 0.004) and that of cortical thickness to increased disability (modified Rankin's scale, p = 0.008), while brain atrophy was only related to global cognitive worsening (Mattis dementia rating scale, p = 0.002). The impact of volume of lacunar lesions on cortical alterations was larger than that of volume of white matter hyperintensities. Cortical alterations, mainly related to lacunar lesions, evolve parallel to clinical worsening. These results further support the eventual role of cortical alterations in subcortical ischemic vascular dementia.     

Diffusion tensor and magnetization transfer MRI measurements of periventricular white matter hyperintensities in old age

Regions of diffuse periventricular white matter hyperintensities (PVWMH) are a common finding on T(2)-weighted MRI scans of older subjects, but their aetiology remains unclear. The aim of this study was to characterize differences in water diffusion and magnetization transfer MRI parameters between macroscopically normal-appearing white matter (NAWM) and PVWMH in a cohort of normal older subjects. Forty-two non-demented 83-year olds underwent structural, diffusion tensor and magnetization transfer MRI. Mean diffusivity (), fractional anisotropy (FA), axial (lambda(ax)) and radial (lambda(rad)) diffusivity, and magnetization transfer ratio (MTR) were measured in both NAWM and PVWMH in frontal and parieto-occipital white matter, and centrum semiovale. For all three regions, PVWMH had greater , lambda(ax) and lambda(rad) than NAWM, while FA and MTR were significantly reduced compared with normal tissue (p<0.01). For PVWMH, MTR was significantly correlated (Spearman's rho in the range -0.93 to 0.70; p<0.01) with , FA, lambda(ax) and lambda(rad) in all three regions. Conversely, for NAWM, the only significant correlation between MTR and a water diffusion parameter was for lambda(rad) in parieto-occipital white matter (rho=-0.40; p<0.05), with all other correlations close to the rho=0 level. These data indicate that in normal white matter, characterized by structurally coherent cell membranes, the degree of water molecule diffusion and myelination are held within relatively tight limits. However, within PVWMH, MTR correlates strongly with water diffusion parameters probably because of the pathologically associated neuronal loss, demyelination and gliosis.