Tractography at 3T MRI of Corpus Callosum Tracts Crossing White Matter Hyperintensities

BACKGROUND AND PURPOSE:The impact of white matter hyperintensities on the diffusion characteristics of crossing tracts is unclear. This study used quantitative tractography at 3T MR imaging to compare, in the same individuals, the diffusion characteristics of corpus callosum tracts that crossed white matter hyperintensities with the diffusion characteristics of corpus callosum tracts that did not pass through white matter hyperintensities.MATERIALS AND METHODS:Brain T2 fluid-attenuated inversion recovery–weighted and diffusion tensor 3T MR imaging scans were acquired in 24 individuals with white matter hyperintensities. Tractography data were generated by the Fiber Assignment by Continuous Tracking method. White matter hyperintensities and corpus callosum tracts were manually segmented. In the corpus callosum, the fractional anisotropy, radial diffusivity, and mean diffusivity of tracts crossing white matter hyperintensities were compared with the fractional anisotropy, radial diffusivity, and mean diffusivity of tracts that did not cross white matter hyperintensities. The cingulum, long association fibers, corticospinal/bulbar tracts, and thalamic projection fibers were included for comparison.RESULTS:Within the corpus callosum, tracts that crossed white matter hyperintensities had decreased fractional anisotropy compared with tracts that did not pass through white matter hyperintensities (P = .002). Within the cingulum, tracts that crossed white matter hyperintensities had increased radial diffusivity compared with tracts that did not pass through white matter hyperintensities (P = .001).CONCLUSIONS:In the corpus callosum and cingulum, tracts had worse diffusion characteristics when they crossed white matter hyperintensities. These results support a role for white matter hyperintensities in the disruption of crossing tracts.

The corpus callosum (CC) is the largest commissural tract with >200 million axons connecting the cerebral hemispheres.¹ Atrophy of the CC is a marker of neurodegeneration and has been reported in cerebrovascular disease.^2–8 White matter hyperintensities (WMH) are high-signal lesions on T2-weighted MR imaging that represent cerebral small vessel disease and have been associated with CC atrophy.^7,9–14 The reason for changes in the corpus callosum with WMH is unclear. Earlier studies have suggested that WMH may be an incidental finding and that CC atrophy results from a coexisting disease process.^7,10–17 For example, WMH are seen with Alzheimer disease, in which CC atrophy can occur by cortical atrophy and subsequent Wallerian degeneration of corpus callosum fibers originating from pyramidal neurons.^{7,10,13,15,16} These studies also suggest that WMH may directly cause CC atrophy by disrupting fibers of the corpus callosum as they are passing through the ischemic lesions in the deep white mater.^7,10–17Diffusion tensor imaging can detect early changes in white matter microstructure before atrophy occurs and could clarify the relationship between WMH and the CC.¹⁸ In DTI, pathologic processes that alter the structural integrity of tracts lead to changes in water diffusion and mean diffusivity (MD) and radial diffusivity (RD) as well as changes in the directionality of diffusion and fractional anisotropy (FA).^18,19 In patients with WMH, decreased FA and increased MD were found in the CC.¹³ Another study demonstrated correlations among CC atrophy, the FA/MD of deep white matter, and the FA/MD of the CC.¹⁷ These results confirm an association between WMH and the entire CC but do not distinguish between the effects of WMH on callosum tracts that cross WMH (CC-WMH) and those that do not cross WMH. If CC-WMH tracts had worse diffusion characteristics than CC tracts not crossing WMH, this feature would support an increased role for WMH in changes in the corpus callosum.Tractography is an application of DTI that allows the reconstruction of white matter tracts.¹⁸ In quantitative tractography, the diffusion characteristics (MD, RD, and FA) along the full trajectory of select fiber tracts can be assessed.¹⁸ This study used quantitative tractography to compare the diffusion characteristics of CC-WMH tracts with those of CC tracts not crossing WMH. For comparison, this study also performed a similar analysis in tracts that crossed WMH (WMH tracts) compared with those that did not cross WMH (lesion-free tracts) in the cingulum, long association fibers, corticospinal/bulbar tracts, and thalamic projection fibers. We hypothesized that CC-WMH tracts would have worse diffusion characteristics (increased MD and RD and decreased FA) compared with CC tracts not crossing WMH.     

White Matter Hyperintensity Volume and Cerebral Perfusion in Older Individuals with Hypertension Using Arterial Spin-Labeling

BACKGROUND AND PURPOSE:White matter hyperintensities of presumed vascular origin in elderly patients with hypertension may be part of a general cerebral perfusion deficit, involving not only the white matter hyperintensities but also the surrounding normal-appearing white matter and gray matter. We aimed to study the relation between white matter hyperintensity volume and CBF and assess whether white matter hyperintensities are related to a general perfusion deficit.MATERIALS AND METHODS:In 185 participants of the Prevention of Dementia by Intensive Vascular Care trial between 72 and 80 years of age with systolic hypertension, white matter hyperintensity volume and CBF were derived from 3D FLAIR and arterial spin-labeling MR imaging, respectively. We compared white matter hyperintensity CBF, normal-appearing white matter CBF, and GM CBF across quartiles of white matter hyperintensity volume and assessed the continuous relation between these CBF estimates and white matter hyperintensity volume by using linear regression.RESULTS:Mean white matter hyperintensity CBF was markedly lower in higher quartiles of white matter hyperintensity volume, and white matter hyperintensity volume and white matter hyperintensity CBF were negatively related (standardized β = −0.248, P = .001) in linear regression. We found no difference in normal-appearing white matter or GM CBF across quartiles of white matter hyperintensity volume or any relation between white matter hyperintensity volume and normal-appearing white matter CBF (standardized β = −0.065, P = .643) or GM CBF (standardized β = −0.035, P = .382) in linear regression.CONCLUSIONS:Higher white matter hyperintensity volume in elderly individuals with hypertension was associated with lower perfusion within white matter hyperintensities, but not with lower perfusion in the surrounding normal-appearing white matter or GM. These findings suggest that white matter hyperintensities in elderly individuals with hypertension relate to local microvascular alterations rather than a general cerebral perfusion deficit.

White matter hyperintensities (WMHs) of presumed vascular origin are a common finding on brain MR imaging in elderly individuals. WMH prevalence estimates in asymptomatic older individuals range from 45% to >90%, depending on age and severity.¹ Clinically, WMHs are associated with cognitive decline, neuropsychiatric symptoms, loss of functional independence, and increased mortality.^2,3 Advanced age and hypertension are the strongest risk factors for WMHs, especially for the confluent subtype.^1–4The pathophysiology of WMHs has not yet been fully elucidated. They often appear together with other signs of cerebral small-vessel disease, an umbrella term for neuroradiologic anomalies often found in asymptomatic elderly individuals.^4,5 Histologically, confluent WMHs appear as a continuum of increasing tissue damage resembling chronic low-grade ischemia.^1,5 Therefore, WMHs may be the result of chronic low-grade white matter hypoperfusion.^1,5,6 In agreement, CBF within WMHs is lower compared with normal-appearing WM (NAWM).^7–14Whether WMHs are associated with a lower cerebral perfusion in general, also involving the surrounding NAWM and gray matter, is unclear. Some findings suggest that WMHs may relate to lower whole-brain or GM perfusion,^7,11,15,16 and WMHs have been associated with reduced blood flow velocity in the large intracranial arteries, outside the WM.^17–19 On a broader level, the association between WMHs and chronic cardiac disease also hints at a relation with general perfusion.²⁰ WMHs primarily originate in physiologically poorly perfused areas (ie, the periventricular and deep WM), explaining how even a slight cerebral perfusion deficit could provoke low-grade ischemia in those regions associated with WMHs.^21,22 Low perfusion in NAWM has also been associated with subsequent WMH development.²³ While these findings seem to suggest that WMHs are related to a perfusion deficit extending beyond the WMHs, current evidence remains circumstantial.In this study, we address the hypothesis that WMHs are associated with lower cerebral perfusion, not only within the WMHs but also in the surrounding NAWM and GM. If so, this could be a first step in determining why WMHs form in elderly individuals and toward preventive treatment. Because age and hypertension are the strongest risk factors for asymptomatic WMHs, we tested this hypothesis in a large cohort of community-dwelling elderly with hypertension, by using noninvasive arterial spin-labeling MR imaging. Arterial spin-labeling was chosen because this method of perfusion measurement allows noninvasive (ie, without contrast) MR imaging measurement of CBF within a scanning time of as little as 4 minutes, facilitating large-scale CBF measurement in research settings and eventually enabling clinical application.     

Morphologic,Distributional, Volumetric,and Intensity Characterization of Periventricular Hyperintensities

BACKGROUND AND PURPOSE:White matter hyperintensities are characteristic of old age and identifiable on FLAIR and T2-weighted MR imaging. They are typically separated into periventricular or deep categories. It is unclear whether the innermost segment of periventricular white matter hyperintensities is truly abnormal or is imaging artifacts.MATERIALS AND METHODS:We used FLAIR MR imaging from 665 community-dwelling subjects 72–73 years of age without dementia. Periventricular white matter hyperintensities were visually allocated into 4 categories: 1) thin white line; 2) thick rim; 3) penetrating toward or confluent with deep white matter hyperintensities; and 4) diffuse ill-defined, labeled as “subtle extended periventricular white matter hyperintensities.” We measured the maximum intensity and width of the periventricular white matter hyperintensities, mapped all white matter hyperintensities in 3D, and investigated associations between each category and hypertension, stroke, diabetes, hypercholesterolemia, cardiovascular disease, and total white matter hyperintensity volume.RESULTS:The intensity patterns and morphologic features were different for each periventricular white matter hyperintensity category. Both the widths (r = 0.61, P < .001) and intensities (r = 0.51, P < .001) correlated with total white matter hyperintensity volume and with each other (r = 0.55, P < .001) for all categories with the exception of subtle extended periventricular white matter hyperintensities, largely characterized by evidence of erratic, ill-defined, and fragmented pale white matter hyperintensities (width: r = 0.02, P = .11; intensity: r = 0.02, P = .84). The prevalence of hypertension, hypercholesterolemia, and neuroradiologic evidence of stroke increased from periventricular white matter hyperintensity categories 1 to 3. The mean periventricular white matter hyperintensity width was significantly larger in subjects with hypertension (mean difference = 0.5 mm, P = .029) or evidence of stroke (mean difference = 1 mm, P < .001). 3D mapping revealed that periventricular white matter hyperintensities were discontinuous with deep white matter hyperintensities in all categories, except only in particular regions in brains with category 3.CONCLUSIONS:Periventricular white matter hyperintensity intensity levels, distribution, and association with risk factors and disease suggest that in old age, these are true tissue abnormalities and therefore should not be dismissed as artifacts. Dichotomizing periventricular and deep white matter hyperintensities by continuity from the ventricle edge toward the deep white matter is possible.

The presence of brain white matter hyperintensities is a common neuroradiologic finding in older individuals without disease¹ and in those with neurologic disease. They appear on CT as areas of decreased attenuation. On MR imaging, they appear as areas of increased signal intensity in T2-weighted and FLAIR brain images and as hypointense areas in T1-weighted images. White matter hyperintensities (WMH) are typically separated into periventricular or deep categories.² Periventricular white matter hyperintensities (PVWMH) are regarded as hyperintensities adhering to a “continuity rule,” so that they are confluent with and extend away from the ventricular wall.^2,3 Deep white matter hyperintensities (DWMH), conversely, are said to be separated from the PVWMH by at least 1 voxel⁴ and reside within the deep white matter.It is not clear from previous investigations whether the innermost segment of PVWMH is indeed white matter pathology or is a mere manifestation of artifacts from CSF flow signal. PVWMH that exhibit a regular pattern and are narrower than 2 voxels have been considered true white matter abnormalities by some,^2,3 whereas others classified them as artifacts.⁵ However, no evidence has been provided to support these conventions.The criteria for separating WMH into PVWMH or DWMH have typically relied on rules of continuity of WMH from the lateral ventricles,^6,7 but distance from the ventricular edges has also been proposed. For example, PVWMH have been reported to penetrate as much as 7 and 13 mm into the brain parenchyma,^8,9 and any WMH found within 3 mm from the ventricular wall have been proposed to belong to a distinct subtype, “juxtaperiventricular.”⁶ Some studies^2,10 render these classifications artificial. Others claim that they are arbitrary¹¹ and contrary to pathologic evidence of common vascular mechanisms, or they have suggested that PVWMH and DWMH volumes are highly correlated and have found that their spatial analysis failed to identify distinct subpopulations for PVWMH and DWMH.¹² Thus, a robust analysis of PVWMH morphology, distribution, and clinical correlates is required to determine a more appropriate classification of these hyperintense regions and their associations.The purpose of this study was to characterize PVWMH more clearly by their spatial distribution, signal intensity, and relationship to risk factors. The analyses were designed to test 3 hypotheses concerning the definition and classification of PVWMH: 1) A hyperintense thin white line detected along the rim of the lateral ventricle is not a manifestation of a partial volume effect (artifacts) but is evidence of abnormal tissue; 2) PVWMH and DWMH dichotomization is possible and appropriate by a compound rule of continuity from the ventricular surface, unique distribution patterns, and morphologic characteristics; and 3) both PVWMH and DWMH are associated because they have similar distributional properties and common risk factors and therefore are potentially part of the same disease process.     

Association of White Matter Hyperintensities with Low Serum 25-Hydroxyvitamin D Levels

BACKGROUND AND PURPOSE:Vitamin D deficiency is associated with cognitive impairment in the elderly and with increased white matter T2 hyperintensities in elderly debilitated patients. We investigated the relationship between serum vitamin D and brain MR findings in adult outpatients.MATERIALS AND METHODS:Brain MR studies of 56 patients ages 30–69 years were selected when vitamin D level had been obtained within 90 days of the MRI. White matter T2 hyperintensities were characterized by size and location by two neuroradiologists. Manual volumetric analysis was assessed in patients more than 50 years of age.RESULTS:The entire cohort showed a significant negative relationship between serum 25-hydroxyvitamin D and the number of confluent juxtacortical white matter T2 hyperintensities (P = .047). The cohort ages 50 years and older showed stronger correlation between confluent white matter T2 hyperintensities and serum 25-hydroxyvitamin D in the juxtacortical region; number (P = .015) and size of white matter T2 hyperintensities (P = .048). Atrophy was not significantly related to serum 25-hydroxyvitamin D by radiologist visual analysis or by the bicaudate ratio.CONCLUSIONS:We found a significant relationship between vitamin D and white matter T2 hyperintensities in independent adult outpatients, especially over the age of 50 years.

There is accumulating scientific evidence that vitamin D supplements can be protective against some chronic diseases. ^1–6 The National Institutes of Health supports a large ongoing study to test for such effects.² Investigators have begun to test for brain imaging findings that correlate with serum vitamin D levels.^6–8The January 2010 issue of Neurology contained 3 studies that evaluated hundreds of elderly subjects to test for a relationship between vitamin D status and dementia or cognitive impairment.^4,8,9 The Annweiler and Buell studies evaluated women only and both women and men, respectively; both showed a significant relationship between low vitamin D and dementia or cognitive impairment. The Slinin report only evaluated men and showed a trend for a relationship between vitamin D and cognitive impairment. A later study by Annweiler et al,¹⁰ with male and female subjects, showed lower serum 25-hydroxyvitamin D (Vit D) in patients with mild cognitive impairment compared with cognitively healthy individuals. A prospective study with 6-year follow-up involving more than 800 elderly patients showed significant increased risk of cognitive decline in those with low Vit D compared with sufficient levels.¹¹Studies have begun to examine the relationship between Vit D and brain MR findings in mice and in humans with significant disease. In 2010, Fernandes de Abreu et al⁷ examined the offspring of maternal vitamin D deficient mice by MR. The mice had smaller ventricles at the age of 30 weeks, which normalized by 70 weeks. Hippocampal volume significantly decreased from weeks 30–70. Young mice also showed learning deficits.⁷ The Buell study evaluated 318 dependent, elderly patients with a mean age of 73 years and found a significant negative relationship between Vit D and white matter T2 hyperintensities (WMH) volume.⁸ Weinstock-Guttman et al⁶ published a 2011 study examining the relationship between Vit D and brain MR in 193 patients with multiple sclerosis. Their patients had a mean age of 46 years. They did not find a significant relationship between Vit D and WMH. However, a more recent longitudinal study showed a significant correlation between Vit D and the subsequent development of lesions in patients with multiple sclerosis.¹² The Buell and Weinstock-Guttman studies did not account for dietary vitamin D supplementation.The purpose of this study was to determine if Vit D levels are associated with white matter abnormalities in an outpatient population by MR imaging.     

Vascular Dysfunction in Leukoaraiosis

BACKGROUND AND PURPOSE:The pathogenesis of leukoaraiosis has long been debated. This work addresses a less well-studied mechanism, cerebrovascular reactivity, which could play a leading role in the pathogenesis of this disease. Our aim was to evaluate blood flow dysregulation and its relation to leukoaraiosis.MATERIALS AND METHODS:Cerebrovascular reactivity, the change in the blood oxygen level–dependent 3T MR imaging signal in response to a consistently applied step change in the arterial partial pressure of carbon dioxide, was measured in white matter hyperintensities and their contralateral spatially homologous normal-appearing white matter in 75 older subjects (age range, 50–91 years; 40 men) with leukoaraiosis. Additional quantitative evaluation of regions of leukoaraiosis was performed by using diffusion (n = 75), quantitative T2 (n = 54), and DSC perfusion MRI metrics (n = 25).RESULTS:When we compared white matter hyperintensities with contralateral normal-appearing white matter, cerebrovascular reactivity was lower by a mean of 61.2% ± 22.6%, fractional anisotropy was lower by 44.9 % ± 6.9%, and CBF was lower by 10.9% ± 11.9%. T2 was higher by 61.7% ± 13.5%, mean diffusivity was higher by 59.0% ± 11.7%, time-to-maximum was higher by 44.4% ± 30.4%, and TTP was higher by 6.8% ± 5.8% (all P < .01). Cerebral blood volume was lower in white matter hyperintensities compared with contralateral normal-appearing white matter by 10.2% ± 15.0% (P = .03).CONCLUSIONS:Not only were resting blood flow metrics abnormal in leukoaraiosis but there is also evidence of reduced cerebrovascular reactivity in these areas. Studies have shown that reduced cerebrovascular reactivity is more sensitive than resting blood flow parameters for assessing vascular insufficiency. Future work is needed to examine the sensitivity of resting-versus-dynamic blood flow measures for investigating the pathogenesis of leukoaraiosis.

Age-related changes in the cerebral white matter are apparent on MR imaging. They appear as bright regions on T2-weighted images and are called white matter hyperintensities (WMH) if they are presumed to be of vascular origin. These areas are characterized by myelin pallor, reactive astrogliosis, and loss of oligodendrocytes, axons, and myelin fibers.¹ This rarefaction of white matter tissue is the origin of the term “leukoaraiosis,” derived from the Greek words “leuko-” for white and “araios” for rarefied.² As many as 95% of individuals older than 50 years of age demonstrate these white matter changes, particularly in the periventricular and deep white matter.^3,4 Once thought to represent benign age-related changes, studies during the past 25 years have shown that WMH are associated with morbidity, including cognitive impairment⁵ and disability.^6–8Substantial evidence indicates that age-related vascular changes may lead to WMH, including increased vessel tortuosity,⁹ increased stringed vessels (remnants of capillaries with no endothelial cells), and vessel basement membrane thickening.¹⁰ Histopathologic analysis of abnormal white matter shows venular intramural collagen deposition leading to wall-thickening stenosis.¹¹ The vascular anatomy of the white matter provides an intrinsically higher vascular resistance compared with the cortex.¹² Interestingly, white matter areas with excellent collateral blood supply, such as the subcortical U-fibers, do not usually show age-related WMH.¹³ Collectively, these findings suggest an association between vascular dysfunction and leukoaraiosis.In the present study, we sought to further characterize the vascular pathophysiology of WMH by evaluating cerebrovascular reactivity (CVR). CVR is defined as the change in cerebral blood flow induced by a vasoactive stimulus. Reduced CVR, normally found in the white matter of young healthy individuals,¹⁴ has been shown to spatially correspond with predilection maps of age-related leukoaraiosis development.¹⁵ CVR reductions are associated with cortical thinning,¹⁶ the risk of future ischemic stroke,¹⁷ cognitive decline,¹⁸ and abnormal diffusion tensor imaging metrics.¹⁹ WMH are associated with increased mean diffusivity (MD) and decreased fractional anisotropy, likely representing axonal destruction and glial proliferation.²⁰ Previous studies have found a relationship between impaired CVR and abnormal diffusion metrics in the white matter of patients with Moyamoya disease¹⁹ and steno-occlusive carotid disease,²¹ suggesting that chronic hypoperfusion is associated with pathologic changes to white matter microstructure. Moreover, vascular dysfunction in the form of blood-brain barrier leakage in WMH is also associated with increased MD.²²We evaluated CVR in regions of WMH and normal-appearing white matter (NAWM) by measuring the change in blood oxygen level–dependent (BOLD) MR imaging in response to a standard CO₂ challenge. To characterize the hemodynamic properties and microstructure of WMH, we obtained additional MR images and performed DTI and DSC perfusion MR imaging. We hypothesized that both CVR and these additional MR imaging metrics would differ between leukoaraiosis and NAWM.     

Decreased T1 Contrast between Gray Matter and Normal-Appearing White Matter in CADASIL

BACKGROUND AND PURPOSE:CADASIL is the most frequent hereditary small-vessel disease of the brain. The clinical impact of various MR imaging markers has been repeatedly studied in this disorder, but alterations of contrast between gray matter and normal-appearing white matter remain unknown. The aim of this study was to evaluate the contrast alterations between gray matter and normal-appearing white matter on T1-weighted images in patients with CADASIL compared with healthy subjects.MATERIALS AND METHODS:Contrast between gray matter and normal-appearing white matter was assessed by using histogram analyses of 3D T1 high-resolution MR imaging in 23 patients with CADASIL at the initial stage of the disease (Mini-Mental State Examination score > 24 and modified Rankin scale score ≤ 1; mean age, 53.5 ± 11.1 years) and 30 age- and sex-matched controls.RESULTS:T1 contrast between gray matter and normal-appearing white matter was significantly reduced in patients compared with age- and sex-matched controls (patients: 1.35 ± 0.08 versus controls: 1.43 ± 0.04, P < 10⁻⁵). This reduction was mainly driven by a signal decrease in normal-appearing white matter. Contrast loss was strongly related to the volume of white matter hyperintensities.CONCLUSIONS:Conventional 3D T1 imaging shows significant loss of contrast between gray matter and normal-appearing white matter in CADASIL. This probably reflects tissue changes in normal-appearing white matter outside signal abnormalities on T2 or FLAIR sequences. These contrast alterations should be taken into account for image interpretation and postprocessing.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small-vessel disease of the brain secondary to mutations of the NOTCH3 gene.¹ Conventional MR imaging markers have been repeatedly investigated in this disorder.^2–5 The impact of lacunar lesions detected on T1-weighted sequences seems more important than that of white matter lesions observed on FLAIR sequences.⁶ Recently, various measures of brain and cortical atrophy were shown to be related to clinical worsening.^7,8As reported in the context of Alzheimer disease,⁹ contrast between gray matter and normal-appearing white matter (NAWM) may be altered in CADASIL. This could have important implications for both image interpretation in the clinical setting and postprocessing in research studies. So far however, the alterations of MR imaging T1 contrast between GM and NAWM have not been evaluated in CADASIL. The aim of the present study was to assess potential contrast alterations between GM and NAWM on T1-weighted images in patients with CADASIL at the initial stage of the disease compared with age- and sex-matched individuals.     

Influence of Small Vessel Disease and Microstructural Integrity on Neurocognitive Functioning in Older Individuals: The DANTE Study Leiden

BACKGROUND AND PURPOSE:Small vessel disease is a major cause of neurocognitive dysfunction in the elderly. Small vessel disease may manifest as white matter hyperintensities, lacunar infarcts, cerebral microbleeds, and atrophy, all of which are visible on conventional MR imaging or as microstructural changes determined by diffusion tensor imaging. This study investigated whether microstructural integrity is associated with neurocognitive dysfunction in older individuals, irrespective of the conventional features of small vessel disease.MATERIALS AND METHODS:The study included 195 participants (75 years of age or older) who underwent conventional 3T MR imaging with DTI to assess fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. Cognitive tests were administered to assess cognitive domains, and the Geriatric Depression Scale-15 and Apathy Scale of Starkstein were used to assess symptoms of depression and apathy, respectively. The association between DTI measures and neurocognitive function was analyzed by using linear regression models.RESULTS:In gray matter, a lower fractional anisotropy and higher mean diffusivity, axial diffusivity, and radial diffusivity were associated with worse executive function, psychomotor speed, and overall cognition and, in white matter, also with memory. Findings were independent of white matter hyperintensities, lacunar infarcts, and cerebral microbleeds. However, after additional adjustment for normalized brain volume, only lower fractional anisotropy in white and gray matter and higher gray matter radial diffusivity remained associated with executive functioning. DTI measures were not associated with scores on the Geriatric Depression Scale-15 or the Apathy Scale of Starkstein.CONCLUSIONS:Microstructural integrity was associated with cognitive but not psychological dysfunction. Associations were independent of the conventional features of small vessel disease but attenuated after adjusting for brain volume.

The occurrence of small vessel disease (SVD), seen on conventional MR imaging as white matter hyperintensities (WMHs), lacunar infarcts, cerebral microbleeds, and brain atrophy,¹ increases with advancing age.² SVD is a major cause of cognitive³ and possibly psychological dysfunction.⁴ Nevertheless, the relationship between these overt signs of SVD and cognitive and psychological dysfunction is modest, and interindividual variability is high. It is suggested that these visible lesions represent only the tip of the iceberg and that SVD may also cause more subtle and diffuse microstructural changes in the brain. Microstructural integrity can be determined with diffusion tensor imaging, which measures the diffusion of cerebral water molecules. Diffusion changes have been observed not only in lesions visible on standard MR imaging but also in the surrounding normal-appearing brain tissue.^5–7 The pathologic processes underlying changes in DTI measures include axonal degeneration and ischemic demyelination,^7,8 which may lead to disruption of white matter tracts that connect brain regions involved in cognitive functions.DTI measures of WM microstructural integrity may have additional value in explaining the variance in cognitive function beyond conventional MR imaging features of SVD.⁹ It has also been shown that microstructural integrity is an independent predictor of cognitive function beyond other features of SVD. Cross-sectional studies in older individuals (mean age, 60–70 years) found that diffusion signal abnormality in WMHs, and particularly in normal-appearing white matter, was associated with cognitive dysfunction, irrespective of WMHs, lacunar infarcts, or brain volume.^10–12 A longitudinal study in older individuals (mean age, 74 years) demonstrated that diffusion signal abnormalities in normal-appearing gray or white brain tissue, rather than in WMHs, predicted faster cognitive decline 3 years later, regardless of conventional SVD features.¹³ Furthermore, a cross-sectional study (mean age, 69 years) found that compared with controls, older individuals with psychological dysfunction had diffusion signal abnormalities, even after the exclusion of WMHs from the DTI measurements.¹⁴Currently, no data are available for determining the role of microstructural integrity as an independent predictor of neurocognitive function in the oldest elderly individuals, in whom overt features of SVD and, in particular, atrophy are more prevalent. Therefore, this cross-sectional study investigated whether microstructural integrity is independently associated with cognitive and psychological dysfunction in an older population (mean age, 81 years) beyond other features of SVD.     

Redefining the Pulvinar Sign in Fabry Disease

BACKGROUND AND PURPOSE:The pulvinar sign refers to exclusive T1WI hyperintensity of the lateral pulvinar. Long considered a common sign of Fabry disease, the pulvinar sign has been reported in many pathologic conditions. The exact incidence of the pulvinar sign has never been tested in representative cohorts of patients with Fabry disease. The aim of this study was to assess the prevalence of the pulvinar sign in Fabry disease by analyzing T1WI in a large Fabry disease cohort, determining whether relaxometry changes could be detected in this region independent of the pulvinar sign positivity.MATERIALS AND METHODS:We retrospectively analyzed brain MR imaging of 133 patients with Fabry disease recruited through specialized care clinics. A subgroup of 26 patients underwent a scan including 2 FLASH sequences for relaxometry that were compared with MRI scans of 34 healthy controls.RESULTS:The pulvinar sign was detected in 4 of 133 patients with Fabry disease (3.0%). These 4 subjects were all adult men (4 of 53, 7.5% of the entire male population) with renal failure and under enzyme replacement therapy. When we tested for discrepancies between Fabry disease and healthy controls in quantitative susceptibility mapping and relaxometry maps, no significant difference emerged for any of the tested variables.CONCLUSIONS:The pulvinar sign has a significantly lower incidence in Fabry disease than previously described. This finding, coupled with a lack of significant differences in quantitative MR imaging, allows hypothesizing that selective involvement of the pulvinar is a rare neuroradiologic sign of Fabry disease.

Fabry disease (FD) is a rare X-linked metabolic disorder caused by insufficient/absent lysosomal α-galactosidase A activity. This enzymatic defect leads to pathologic storage of glycosphingolipids, especially globotriaosylceramide, occurring in all tissues and causing multiorgan progressive dysfunction, in the kidney, heart, and central nervous system.^1,2Neurologic involvement is common in FD.³ Most prominent manifestations include cerebrovascular events, such as transient ischemic attacks and strokes, chronic cerebral vasculopathy, and vessel ectasia, especially in the posterior circulation.^4–7 Such clinical manifestations translate, on brain MR imaging, in the presence of white matter hyperintensities³ and increased basilar artery diameter,^8,9 both nonspecific for FD.^10,11The pulvinar sign (PS), defined as the exclusive involvement of the lateral pulvinar with symmetric hyperintensity on unenhanced T1-weighted brain MR imaging, has long been considered a common neuroradiologic sign of FD.^8,12–16 Originally thought to be pathognomonic of FD,^12,13 the PS has actually been reported in other conditions, such as metabolic disorders (eg, Krabbe or Tay-Sachs disease),^17,18 CNS infections,¹⁹ or after chemoradiation therapy¹⁵; therefore, its pathognomonic role has been largely rediscussed.^20,21 In fact, the pulvinar nuclei are sensitive to metabolic disturbances, and their MR imaging appearance can be altered in a variety of conditions, especially in patients in whom an abnormal renal function can be a relevant confounding comorbidity.Moreover, the prevalence of the PS among the FD population has been reconsidered across the years.^14–15,22 To date, the exact incidence of the PS has never been tested in a large and representative cohort of patients with FD, because all studies conducted so far were limited to small samples¹³ or performed only on affected males.¹²In this respect, quantitative MR imaging (qMRI) and, in particular, relaxometry are likely to provide unique insight into the pathogenetic mechanisms of the PS. Indeed, a variety of microstructural conditions leading to a shorter longitudinal relaxation rate (R1) (thus, to T1WI hyperintensity) are associated with a faster free induction decay (ie, increase in R2*) and a rise of the pure transverse relaxation rate (R2). As a result, competitive roles of the longitudinal and transverse relaxation rates in MR signal generation suggest that standard evaluations of signal intensity are not the best choice for studying the incidence of PS-associated changes. A thorough relaxometry study would disentangle the contributions of several physical quantities to signal equation of conventional sequences, therefore providing a more accurate indication of the actual PS incidence.This study has dual aims: 1) to assess the prevalence of PS in a large cohort of subjects with FD by retrospectively analyzing T1WI of 133 patients, and 2) to determine, for the first time, whether relaxometry modifications could be detected in the pulvinar, independent of the PS.     

Subcortical Deep Gray Matter Pathology in Patients with Multiple Sclerosis Is Associated with White Matter Lesion Burden and Atrophy but Not with Cortical Atrophy: A Diffusion Tensor MRI Study

BACKGROUND AND PURPOSE:The association between subcortical deep gray matter, white matter, and cortical pathology is not well understood in MS. The aim of this study was to use DTI to investigate the subcortical deep gray matter alterations and their relationship with lesion burden, white matter, and cortical atrophy in patients with MS and healthy control patients.MATERIALS AND METHODS:A total of 210 patients with relapsing-remitting MS, 75 patients with progressive MS, and 110 healthy control patients were included in the study. DTI metrics in whole brain, normal-appearing white matter, normal-appearing gray matter, and subcortical deep gray matter structures were compared. The association between DTI metrics of the subcortical deep gray matter structures with lesion burden, normalized white matter volume, and normalized cortical volume was investigated.RESULTS:DTI measures were significantly different in whole brain, normal-appearing white matter, and normal-appearing gray matter among the groups (P < .01). Significant differences in DTI diffusivity of total subcortical deep gray matter, caudate, thalamus, and hippocampus (P < .001) were found. DTI diffusivity of total subcortical deep gray matter was significantly associated with normalized white matter volume (P < .001) and normalized cortical volume (P = .033) in healthy control patients. In both relapsing and progressive MS groups, the DTI subcortical deep gray matter measures were associated with the lesion burden and with normalized white matter volume (P < .001), but not with normalized cortical volume.CONCLUSIONS:These findings suggest that subcortical deep gray matter abnormalities are associated with white matter lesion burden and atrophy, whereas cortical atrophy is not associated with microstructural alterations of subcortical deep gray matter structures in patients with MS.

Although in the past MS has been considered an inflammatory demyelinating disease affecting primarily the white matter of the central nervous system, currently, a substantial number of studies have established that gray matter is also involved in different stages of the disease.^1–5 Cortical and subcortical deep gray matter (SDGM) atrophy occurs also in the early stages of MS, and disability progression is significantly influenced by the neuronal loss of the gray matter.^6–8Atrophy of the SDGM structures is associated with disability progression and cognitive dysfunctions and can also predict the conversion to clinically definite MS.^9–12 An increasing body of evidence suggests that the atrophy of cortical and SDGM structures is associated with white matter lesion burden,¹³ but the underlying pathophysiologic processes remain poorly understood. Secondary Wallerian degeneration is certainly implicated in neuronal damage of gray matter structures; however, it seems unlikely to be the sole cause of gray matter pathology.^4,14DTI is an advanced MR imaging technique that has been used in a number of in vivo and ex vivo studies.^15,16 DTI measures are able to identify alterations outside the focal lesions in the so-called normal-appearing white matter and normal-appearing gray matter that remain largely undetected with conventional MR imaging in patients with MS.¹⁷There is a growing interest in studying the DTI alterations of the SDGM in the different stages of the MS disease process. Previous studies suggested that SDGM DTI abnormalities are also present in patients with clinically isolated syndrome^18,19 and are associated with disability progression as well as cognitive dysfunctions in patients with MS.^20–23Although different studies have investigated the associations between white matter lesions, brain atrophy, and DTI alteration in patients with MS,^24–26 the same relationships were not extensively investigated in healthy people whose pathophysiologic alteration of the brain cannot be attributable to the inflammatory process in the central nervous system. Therefore, in the current study, we aimed to investigate volumetric and DTI global, tissue-specific, and regional brain differences in a large cohort of healthy control (HC) patients, patients with relapsing-remitting MS (RRMS), and patients with progressive MS (PMS). We hypothesized that microstructural abnormalities of SDGM structures detected by DTI techniques are associated with lesion burden, and with white matter and gray matter volume alterations in patients with MS. Another aim was to explore the same associations in the HC group.     

Lower Magnetization Transfer Ratio in the Forceps Minor Is Associated with Poorer Gait Velocity in Older Adults

BACKGROUND AND PURPOSE:Gait disturbances in the elderly are disabling and a major public health issue but are poorly understood. In this multimodal MR imaging study, we used 2 voxel-based analysis methods to assess the voxelwise relationship of magnetization transfer ratio and white matter hyperintensity location with gait velocity in older adults.MATERIALS AND METHODS:We assessed 230 community-dwelling participants of the Austrian Stroke Prevention Family Study. Every participant underwent 3T MR imaging, including magnetization transfer imaging. Voxel-based magnetization transfer ratio–symptom mapping correlated the white matter magnetization transfer ratio of each voxel with gait velocity. To assess a possible relationship between white matter hyperintensity location and gait velocity, we applied voxel-based lesion-symptom mapping.RESULTS:We found a significant association between the magnetization transfer ratio within the forceps minor and gait velocity (β = 0.134; 95% CI, 0.011–0.258; P = .033), independent of demographics, general physical performance, vascular risk factors, and brain volume. White matter hyperintensities did not significantly change this association.CONCLUSIONS:Our study provides new evidence for the importance of magnetization transfer ratio changes in gait disturbances at an older age, particularly in the forceps minor. The histopathologic basis of these findings is yet to be determined.

Gait abnormalities in older adults are common.^1,2 They are associated with falls^3,4 and represent a serious public health issue.^1,5 A complex brain network manages supraspinal gait control.⁶ White matter hyperintensities (WMHs) are common and not necessarily related to clinical symptoms. However on a group level, widespread WMHs have been associated with gait dysfunction, probably as the consequence of disruption of the supraspinal gait network,^7–9 and were related to gait performance in several studies,^10–13 but results are conflicting.^9,14,15 One explanation for conflicting results might be that as reported for cognitive decline,^16–18 widespread, invisible, and highly variable microstructural changes in normal-appearing white matter also contribute to gait abnormalities in addition to visible lesions. This hypothesis is supported by 2 DTI studies that reported the higher mean diffusivity and lower fractional anisotropy in the genu of the corpus callosum to be correlated with poorer gait performance independent of visible WMHs.^14,19Complementary information on microstructural brain tissue alterations may come from magnetization transfer imaging (MTI). Other than DTI, which offers information on brain tissue organization,²⁰ MTI offers information on tissue composition.²¹ Magnetization transfer ratio (MTR) is one of the few MR imaging measures that have been validated postmortem to represent a direct marker of myelin content.²²The only study on MTR and gait found that lower MTR was associated with poorer gait performance, independent of WMHs.²³In this large multimodal MR imaging study, we used voxel-based MTR symptom mapping (VMTRSM) and voxel-based lesion symptom mapping (VLSM) to identify those brain areas in which MTR or WMH-related tissue alterations relate to gait velocity. We hypothesized that alterations, if any, would mainly be located within the frontal white matter because intact fontal subcortical pathways have been reported to be crucial for maintenance of gait performance at a higher level.^6,24     

Characterization of Extensive Microstructural Variations Associated with Punctate White Matter Lesions in Preterm Neonates

BACKGROUND AND PURPOSE:Punctate white matter lesions are common in preterm neonates. Neurodevelopmental outcomes of the neonates are related to the degree of extension. This study aimed to characterize the extent of microstructural variations for different punctate white matter lesion grades.MATERIALS AND METHODS:Preterm neonates with punctate white matter lesions were divided into 3 grades (from mild to severe: grades I–III). DTI-derived fractional anisotropy, axial diffusivity, and radial diffusivity between patients with punctate white matter lesions and controls were compared with Tract-Based Spatial Statistics and tract-quantification methods.RESULTS:Thirty-three preterm neonates with punctate white matter lesions and 33 matched controls were enrolled. There were 15, 9, and 9 patients, respectively, in grades I, II, and III. Punctate white matter lesions were mainly located in white matter adjacent to the lateral ventricles, especially regions lateral to the trigone, posterior horns, and centrum semiovale and/or corona radiata. Extensive microstructural changes were observed in neonates with grade III punctate white matter lesions, while no significant changes in DTI metrics were found for grades I and II. A pattern of increased axial diffusivity, increased radial diffusivity, and reduced/unchanged fractional anisotropy was found in regions adjacent to punctate white matter lesion sites seen on T1WI and T2WI. Unchanged axial diffusivity, increased radial diffusivity, and reduced/unchanged fractional anisotropy were observed in regions distant from punctate white matter lesion sites.CONCLUSIONS:White matter microstructural variations were different across punctate white matter lesion grades. Extensive change patterns varied according to the distance to the lesion sites in neonates with severe punctate white matter lesions. These findings may help in determining the outcomes of punctate white matter lesions and selecting treatment strategies.

Punctate white matter lesions (PWMLs) are common in neonates and have been found in >20% of preterm neonates (<37 weeks of gestation).^1–5 These lesions may cause severe neurologic disorders, such as cerebral palsy.^2,4 PWMLs can be identified on conventional MR imaging as hyperintensity on T1WI and hypointensity on T2WI.^1–3,6 PWMLs without cystic lesions can be divided into 3 grades.⁶ The grading scale ascends in severity on the basis of the number, size, and distribution of cerebral white matter lesions. Extensive microstructural alterations in white matter beyond the PWMLs visible on conventional MR imaging have been observed.³ The neurodevelopmental outcome of neonates is related to the degree of extension associated with PWMLs.^7,8 However, little is known about the extent of microstructural variations for different PWML grades. More detail is needed regarding the size ranges, shapes, and locations of neonatal/infantile PWMLs, PWML diffusion characteristics, and the distinction between hemorrhagic and nonhemorrhagic PWMLs.⁹DTI could provide quantitative metrics that reveal microstructural alterations associated with lesions.^10,11 DTI metrics, especially directional diffusivities, are sensitive to underlying histopathologic processes.¹² Several methods for analyzing DTI data have been proposed. Tract-Based Spatial Statistics (TBSS; http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/TBSS) is an automated approach for assessing alterations on major white matter tracts.¹³ The tract quantification method was proposed to characterize the location of alterations in white matter.¹⁴ These automated quantified methods have been used to detect variations due to brain development or injury^3,13–15 and may enable characterization of alterations associated with PWMLs.The goal of this study was to explore white matter microstructural variations associated with PWMLs of different grades in preterm neonates and to characterize the change in microstructural patterns along white matter tracts.     

MTT and Blood-Brain Barrier Disruption within Asymptomatic Vascular WM Lesions

BACKGROUND AND PURPOSE:White matter lesions of presumed ischemic origin are associated with progressive cognitive impairment and impaired BBB function. Studying the longitudinal effects of white matter lesion biomarkers that measure changes in perfusion and BBB patency within white matter lesions is required for long-term studies of lesion progression. We studied perfusion and BBB disruption within white matter lesions in asymptomatic subjects.MATERIALS AND METHODS:Anatomic imaging was followed by consecutive dynamic contrast-enhanced and DSC imaging. White matter lesions in 21 asymptomatic individuals were determined using a Subject-Specific Sparse Dictionary Learning algorithm with manual correction. Perfusion-related parameters including CBF, MTT, the BBB leakage parameter, and volume transfer constant were determined.RESULTS:MTT was significantly prolonged (7.88 [SD, 1.03] seconds) within white matter lesions compared with normal-appearing white (7.29 [SD, 1.14] seconds) and gray matter (6.67 [SD, 1.35] seconds). The volume transfer constant, measured by dynamic contrast-enhanced imaging, was significantly elevated (0.013 [SD, 0.017] minutes⁻¹) in white matter lesions compared with normal-appearing white matter (0.007 [SD, 0.011] minutes⁻¹). BBB disruption within white matter lesions was detected relative to normal white and gray matter using the DSC-BBB leakage parameter method so that increasing BBB disruption correlated with increasing white matter lesion volume (Spearman correlation coefficient = 0.44; P < .046).CONCLUSIONS:A dual-contrast-injection MR imaging protocol combined with a 3D automated segmentation analysis pipeline was used to assess BBB disruption in white matter lesions on the basis of quantitative perfusion measures including the volume transfer constant (dynamic contrast-enhanced imaging), the BBB leakage parameter (DSC), and MTT (DSC). This protocol was able to detect early pathologic changes in otherwise healthy individuals.

Understanding vascular contributions that influence cognitive decline and dementia is a national research priority.^1,2 Cerebrovascular small-vessel disease (cSVD) is associated with stroke and dementia and is potentially modifiable.^3-5 Many aspects of vascular disease of the brain can be detected with MR imaging. Features associated with cSVD include small subcortical (lacunar) infarcts, white matter hyperintensities, dilated perivascular spaces, microbleeds, brain atrophy, and increased BBB permeability.^6,7 White matter lesions (WMLs) seen on T2-weighted MR imaging are the most common feature of cSVD, estimated to represent 40% of cSVD disease burden.⁶ WMLs are accompanied by many pathologic changes, including BBB disruption.^8-17 While other multifactorial pathophysiologic mechanisms are undoubtedly involved, including hypertension, genetic factors, and inflammation,^18-25 changes in CBF and increasing BBB permeability have been implicated as markers of WML progression and may have a causative role.^13,26Quantifying different measures of hemodynamics such as CBF, CBV, and BBB disruption directly within WMLs has been difficult. Previous studies have shown decreased CBF in larger brain regions associated with WMLs but not within WMLs themselves.^6,7,17,26-32 These studies have also identified increased regional nonlesional volume transfer constant (K^trans) using gadolinium (Gd)-based dynamic contrast-enhanced (DCE) MR imaging, but these methods have drawbacks such as decreased signal discrimination within and without WMLs and a dependence on adequate correction for decreased perfusion within WMLs.^7,31,33 Some studies have detected decreased CBF within lesions using arterial spin-labeling,³⁴ while others have detected these changes within regions surrounding WMLs and within ROIs within WMLs.^26,35Presently, new imaging approaches and data-processing pipelines are needed to allow us to segment WMLs and measure subtle intralesion changes in CBF, MTT, and BBB disruption. Measures of BBB permeability incorporate MR imaging surrogates, which detect Gd extravasation outside the microvasculature due to disruption of the BBB related to microvascular injury.^7,31 In the current study, on a voxel-by-voxel basis, we quantify 2 different parameters related to tissue abnormality: K^trans from DCE MR imaging and the BBB leakage parameter (K₂) from DSC MR imaging,^28,29 which can relate changes in BBB transport and/or CBF.³⁶ These values can then be assessed for WMLs to get insight into changes in BBB functioning and tissue perfusion. In addition, we assessed MTT, which reflects tissue perfusion.In the Genetic Study of Atherosclerosis Risk (GeneSTAR) cohort study, we have identified individuals with a family history of early-onset coronary vascular disease with earlier WMLs detected in midlife,³⁷ with a concomitant impact on measures of cognitive-motor function.³⁸ In this relatively young high-risk subgroup (average age, 54.1 [SD, 3.5] years) of 21 participants with repeat MR imaging, we have observed rapid rates of WML progression associated with cognitive decline.³⁹ In this study, we present a data-analysis pipeline that incorporates segmentation of WMLs^40,41 and quantification of perfusion-based measures of MTT, CBF, K₂, and K^trans from both DSC and DCE MR imaging. This work builds on previous work measuring microvascular perfusion and Gd extravasation in different regions of the brain.^31,42 We propose that these Gd-based representations of BBB disruption in WMLs, with knowledge of the CBF, may enable identifying WMLs at risk of progression at a stage at which they may respond to strategies of disease prevention.^3,4,6     

Gestational Age at Birth and Brain White Matter Development in Term-Born Infants and Children

BACKGROUND AND PURPOSE:Studies on infants and children born preterm have shown that adequate gestational length is critical for brain white matter development. Less is known regarding how variations in gestational age at birth in term infants and children affect white matter development, which was evaluated in this study.MATERIALS AND METHODS:Using DTI tract-based spatial statistics methods, we evaluated white matter microstructures in 2 groups of term-born (≥37 weeks of gestation) healthy subjects: 2-week-old infants (n = 44) and 8-year-old children (n = 63). DTI parameters including fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated by voxelwise and ROI methods and were correlated with gestational age at birth, with potential confounding factors such as postnatal age and sex controlled.RESULTS:Fractional anisotropy values, which are markers for white matter microstructural integrity, positively correlated (P < .05, corrected) with gestational age at birth in most major white matter tracts/regions for the term infants. Mean diffusivity values, which are measures of water diffusivities in the brain, and axial and radial diffusivity values, which are markers for axonal growth and myelination, respectively, negatively correlated (P < .05, corrected) with gestational age at birth in all major white matter tracts/regions excluding the body and splenium of the corpus callosum for the term infants. No significant correlations with gestational age were observed for any tracts/regions for the term-born 8-year-old children.CONCLUSIONS:Our results indicate that longer gestation during the normal term period is associated with significantly greater infant white matter development (as reflected by higher fractional anisotropy and lower mean diffusivity, axial diffusivity, and radial diffusivity values); however, similar associations were not observable in later childhood.

It is well known that infants born with low gestational age (preterm, <37 completed weeks of gestation) are relatively more vulnerable to brain white matter injury or abnormal white matter development. White matter damage in extremely or very preterm infants (<32 completed weeks of gestation) is common, and increased risk is associated with lower gestational age¹; white matter microstructural differences in moderate or late preterm infants (32–36 completed weeks of gestation) compared with term infants have also been reported.² The abnormality of white matter development associated with low gestational age in preterm infants may extend well beyond infancy, as indicated by observed differences in adolescents born prematurely compared with term-born controls.^3–5 Furthermore, abnormal white matter development associated with preterm birth is also linked to adverse long-term neurodevelopmental outcomes in children at different ages.^6–8The effects of gestational age on neurologic or neurodevelopment for term-born children (≥37 completed weeks of gestation) have not been investigated until recently. Several new studies (most of them population-based) reported positive associations between longer gestational age (excluding postterm, which is ≥42 weeks of gestation) and better cognitive and/or neurodevelopment in term-born children, such as higher scores on Bayley scales of mental and motor development during the first year of life^9,10; more school readiness and cognitive and educational ability at age 3 years¹¹; higher intelligence quotient scores¹² and less vulnerability to low early developmental index at age 6–7 years¹³; greater reading, math, and achievement scores in the third grade¹⁴; and better test scores in elementary and middle school and higher probability of being gifted.¹⁵Brain structural and functional development is directly related with neurodevelopment and cognitive performance in children. However, very few studies have addressed whether length of gestation at term birth is associated with differences in later brain development in children as measured by neuroimaging, particularly for white matter development (a recent study reported associations between longer gestation and higher brain gray matter density measured by MR imaging in term-born healthy 6–10-year-old children¹⁶). In addition, although white matter maturation before and after term has been investigated via imaging studies,¹⁷ there is insufficient quantitative characterization of white matter maturation during the normal term period beyond the common perception that white matter is developing rapidly during this time. In each week of gestation and/or week of life during the term period, white matter continues to mature in patterns of posterior to anterior and central to peripheral.¹⁸ A few studies have evaluated white matter microstructures in relation to term gestational ages^19,20; nevertheless, studies including white matter imaging data for term-born infants have mostly focused on the comparison to preterm,^20,21 but not on the trajectory of white matter development in term-born infants during the normal term period. Nor is it clear whether gestational lengths at birth of term-born infants impact this trajectory and longer-term development into childhood. In this study, DTI measures were used to examine potential associations between gestational age at birth and brain white matter microstructural development in 2 well-characterized cohorts of healthy term-born subjects (2-week old infants and 8-year-old children).     

Gray Matter Growth Is Accompanied by Increasing Blood Flow and Decreasing Apparent Diffusion Coefficient during Childhood

BACKGROUND AND PURPOSE:Normal values of gray matter volume, cerebral blood flow, and water diffusion have not been established for healthy children. We sought to determine reference values for age-dependent changes of these parameters in healthy children.MATERIALS AND METHODS:We retrospectively reviewed MR imaging data from 100 healthy children. Using an atlas-based approach, age-related normal values for regional CBF, apparent diffusion coefficient, and volume were determined for the cerebral cortex, hippocampus, thalamus, caudate, putamen, globus pallidus, amygdala, and nucleus accumbens.RESULTS:All gray matter structures grew rapidly before the age of 10 years and then plateaued or slightly declined thereafter. The ADC of all structures decreased with age, with the most rapid changes occurring prior to the age of 5 years. With the exception of the globus pallidus, CBF increased rather linearly with age.CONCLUSIONS:Normal brain gray matter is characterized by rapid early volume growth and increasing CBF with concomitantly decreasing ADC. The extracted reference data that combine CBF and ADC parameters during brain growth may provide a useful resource when assessing pathologic changes in children.

At birth, brain volume is approximately one-third that of a healthy adult brain and undergoes rapid growth during the first 3 months.¹ By the age of 1 year, brain volume has already doubled in size.² Initially, most hemispheric growth relates to an increase in gray matter volume,³ thought to reflect synapse formation occurring earliest in the primary motor and sensory cortices and later in the prefrontal cortex,⁴ directing a posterior-to-anterior pattern of hemispheric white matter maturation.⁵ After the first few years, white matter volume increases at a higher rate during the rest of the childhood,⁶ while synaptic pruning occurs concurrently in the gray matter.⁴Compared with macrostructural analysis using image-based volume extraction, diffusion-weighted MR imaging can be used to probe microstructural changes, including myelination patterns^7,8 and white matter connectivity,⁹ and has also shown utility for brain tumor characterization¹⁰ and metabolic diseases.¹¹ Various studies have examined apparent diffusion coefficient changes of white matter in children.^12–14 However, at present, the ADC of the gray matter, notably at the cortical level, is not well-documented.While volumetric and diffusion analysis can be used to probe macro- and microstructural changes, respectively, arterial spin-labeling (ASL) cerebral blood flow is increasingly used clinically to obtain advanced physiologic information.^15–18 ASL may be particularly useful in the pediatric population because it does not require intravenous contrast or ionizing radiation. However, only a few studies have examined ASL CBF changes in children.^19,20These few studies have included ASL CBF of unsedated healthy term and preterm neonates²¹ or infants 3–5 months of age.²² Apart from these 2 studies, normal values have also been assessed as part of studies investigating CBF changes across the whole life span with only limited data from children²⁰ or for feasibility analysis of ASL imaging, also using only a limited number of healthy children.¹⁹At present, no study has examined the CBF of a healthy pediatric cohort across the age spectrum. Therefore, the goal of this study was to extract and establish age-related CBF values in gray matter along with corresponding volume and diffusion metrics.     

Gray Matter Volume Reduction Is Associated with Cognitive Impairment in Neuromyelitis Optica

BACKGROUND AND PURPOSE:Whether gray matter impairment occurs in neuromyelitis optica is a matter of ongoing debate, and the association of gray matter impairment with cognitive deficits remains largely unknown. The purpose of this study was to investigate gray matter volume reductions and their association with cognitive decline in patients with neuromyelitis optica.MATERIALS AND METHODS:This study included 50 patients with neuromyelitis optica and 50 sex-, age-, handedness-, and education-matched healthy subjects who underwent high-resolution structural MR imaging examinations and a battery of cognitive assessments. Gray matter volume and cognitive differences were compared between the 2 groups. The correlations of the regional gray matter volume with cognitive scores and clinical variables were explored in the patients with neuromyelitis optica.RESULTS:Compared with healthy controls (635.9 ± 51.18 mL), patients with neuromyelitis optica (602.8 ± 51.03 mL) had a 5.21% decrease in the mean gray matter volume of the whole brain (P < .001). The significant gray matter volume reduction in neuromyelitis optica affected the frontal and temporal cortices and the right thalamus (false discovery rate correction, P < .05). The regional gray matter volumes in the frontal and temporal cortices were negatively correlated with disease severity in patients with neuromyelitis optica (Alphasim correction, P < .05). Patients with neuromyelitis optica had impairments in memory, information processing speed, and verbal fluency (P < .05), which were correlated with gray matter volume reductions in the medial prefrontal cortex and thalamus (Alphasim correction, P < .05).CONCLUSIONS:Gray matter volume reduction is present in patients with neuromyelitis optica and is associated with cognitive impairment and disease severity in this group.

Neuromyelitis optica (NMO) is an idiopathic, severe, demyelinating disease of the central nervous system that is characterized by optic neuritis and myelitis.^1,2 Although the brain is traditionally considered to be spared in NMO,³ recent studies have identified brain lesions in 60% of patients with this condition.⁴ In 10% of patients with NMO, the site of brain lesions on MR imaging coincides with high concentrations of the water channel aquaporin 4,^5,6 the target of NMO immunoglobulin G (NMO-IgG).Although several investigations have revealed gray matter impairment in NMO by comparing intergroup differences in the regional homogeneity,⁷ amplitude of low-frequency fluctuation,⁸ diffusivity,^9–11 perfusion,¹² and magnetization transfer ratio,¹³ whether GM structural impairment is a feature of NMO is an ongoing debate. Several studies have identified reductions in GM volume (GMV)^14–16 or cortical thickness¹⁷ in patients with NMO; however, 3 additional studies have failed to demonstrate reductions in the GMV^18,19 or cortical thickness in patients.²⁰ These conflicting outcomes may result from the low statistical power of the relatively small sample sizes (15–30 patients with NMO in previous studies). Studies with a large sample of patients with NMO may help clarify this issue.Cognitive impairment has been repeatedly reported in patients with NMO^{10,17,18,21–24} and is characterized by deficits in multiple cognitive domains, including memory, attention, and speed of information processing. The neural correlates of the cognitive impairment in NMO have been attributed to focal reductions in white matter volume and integrity.^10,18 A recent study found no correlation between cognitive impairment and cortical thinning in 23 patients with NMO.¹⁷ However, it remains unknown whether GMV reduction is associated with cognitive impairment in these patients.By recruiting a large sample of patients with NMO (n = 50), we aimed to clarify the GMV changes in NMO and the correlations of GMV changes with cognitive impairment and clinical variables in these patients.     

Test-Retest and Interreader Reproducibility of Semiautomated Atlas-Based Analysis of Diffusion Tensor Imaging Data in Acute Cervical Spine Trauma in Adult Patients

BACKGROUND AND PURPOSE:DTI is a tool for microstructural spinal cord injury evaluation. This study evaluated the reproducibility of a semiautomated segmentation algorithm of spinal cord DTI.MATERIALS AND METHODS:Forty-two consecutive patients undergoing acute trauma cervical spine MR imaging underwent 2 axial DTI scans in addition to their clinical scan. The datasets were put through a semiautomated probabilistic segmentation algorithm that selected white matter, gray matter, and 24 individual white matter tracts. Regional and white matter tract volume, fractional anisotropy, and mean diffusivity values were calculated. Two readers performed the nonautomated steps to evaluate interreader reproducibility. The coefficient of variation and intraclass correlation coefficient were used to assess test-retest and interreader reproducibility.RESULTS:Of 42 patients, 30 had useable data. Test-retest reproducibility of fractional anisotropy was high for white matter as a whole (coefficient of variation, 3.8%; intraclass correlation coefficient, 0.93). Test-retest coefficient-of-variation ranged from 8.0%–18.2% and intraclass correlation coefficients from 0.47–0.80 across individual white matter tracts. Mean diffusivity metrics also had high test-retest reproducibility (white matter: coefficient-of-variation, 5.6%; intraclass correlation coefficient, 0.86) with coefficients of variation from 11.6%–18.3% and intraclass correlation coefficients from 0.57–0.74 across individual tracts, with better agreement for larger tracts. The coefficients of variation of fractional anisotropy and mean diffusivity both had significant negative relationships with white matter volume (26%–27% decrease for each doubling of white matter volume, P < .01).CONCLUSIONS:DTI spinal cord segmentation is reproducible in the setting of acute spine trauma, specifically for larger white matter tracts and total white or gray matter.

DTI is a technique that provides microstructural evaluation not afforded by conventional MR imaging techniques.¹ In various disease states, DTI has been extensively investigated in brain applications and can detect abnormalities in otherwise normal-appearing brain regions^2,3 and is able to predict outcomes.⁴ Early DTI use shows promise in detecting spinal cord abnormalities associated with spinal cord injury,^5,6 demyelinating diseases,⁷ spondylotic myelopathy,⁸ HIV myelopathy,⁹ and various inflammatory and vascular myelopathies.¹⁰ In acute spinal cord trauma, DTI has shown value in assessing microstructural injury, differentiating between hemorrhagic and nonhemorrhagic contusions, and strong correlation with clinical injury scores.⁵Similar to brain DTI, tract-based white matter analysis of the spinal cord may offer additional insight into white matter characteristics in both healthy and diseased states.^11–13 Current methods of evaluating spine DTI data, however, are either purely qualitative assessments or labor-intensive hand-drawn ROIs that may be prone to reader-related variability/imprecision and poor reproducibility. In brain DTI, completely automated methods are available to reliably parcel the brain,¹⁴ with application to clinical care.¹⁵ Recently, a set of tools has been released as part of the “Spinal Cord Toolbox” that can allow for spinal cord registration, segmentation, and parcellation.¹⁶ The Spinal Cord Toolbox (https://www.nitrc.org/projects/sct/) has been applied to flaccid myelitis on T2-weighted imaging,¹⁷ functional imaging of the spine,¹⁸ and T2*, DTI, and inhomogeneous magnetization transfer sequences in healthy patients at a range of ages.¹⁹ To date, evaluation of the reproducibility of spinal cord segmentation and analysis algorithms such as the Spinal Cord Toolbox when using DTI sequences has been lacking. In addition, the reproducibility of DTI in the setting of acute spinal cord trauma has yet to be evaluated. Determination of these characteristics is particularly important in the setting of trauma evaluation, where the presence of factors such as pain or cognitive dysfunction from associated injuries, medication effect, susceptibility artifact from metallic fusion hardware, or the presence of external lines may impact image acquisition and interpretation.In this study, we evaluated the test-retest reproducibility of a semiautomated atlas-based technique for extracting tract-specific and level-specific diffusion metrics in patients with acute cervical spine trauma. Furthermore, we also assessed the influence of reader-induced variability on the parcellation process.     

Enhanced Axonal Metabolism during Early Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis

BACKGROUND AND PURPOSE:The considerable clinical effect of natalizumab in patients with relapsing-remitting multiple sclerosis might be explained by its possible beneficial effect on axonal functioning. In this longitudinal study, the effect of natalizumab on absolute concentrations of total N-acetylaspartate, a marker for neuronal integrity, and other brain metabolites is investigated in patients with relapsing-remitting multiple sclerosis by using MR spectroscopic imaging.MATERIALS AND METHODS:In this explorative observational study, 25 patients with relapsing-remitting multiple sclerosis initiating natalizumab treatment were included and scanned every 6 months for 18 months. Additionally 18 matched patients with relapsing-remitting multiple sclerosis continuing treatment with interferon-β or glatiramer acetate were included along with 12 healthy controls. Imaging included short TE 2D-MR spectroscopic imaging with absolute metabolite quantification of total N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, myo-inositol, and glutamate. Concentrations were determined for lesional white matter, normal-appearing white matter, and gray matter.RESULTS:At baseline in both patient groups, lower concentrations of total N-acetylaspartate and creatine and phosphocreatine were found in lesional white matter compared with normal-appearing white matter and additionally lower glutamate in lesional white matter of patients receiving natalizumab. In those patients, a significant yearly metabolite increase was found for lesional white matter total N-acetylaspartate (7%, P < .001), creatine and phosphocreatine (6%, P = .042), and glutamate (10%, P = .028), while lesion volumes did not change. In patients receiving interferon-β/glatiramer acetate, no significant change was measured in lesional white matter for any metabolite, while whole-brain normalized lesion volumes increased.CONCLUSIONS:Patients treated with natalizumab showed an increase in total N-acetylaspartate, creatine and phosphocreatine, and glutamate in lesional white matter. These increasing metabolite concentrations might be a sign of enhanced axonal metabolism.

Multiple sclerosis is an inflammatory and neurodegenerative disease of the central nervous system. The acute pathology of the disease is characterized by focal lesions in the white matter,¹ while accumulation of gray matter damage is more prominent in the progressive stage of the disease.²Previous spectroscopy studies found that lesional WM (LWM) (ie, only lesions or WM directly surrounding lesions) is characterized by decreased levels of total N-acetylaspartate (tNAA), a marker of neuronal integrity, and decreased total creatine (tCr), a marker of energy metabolism, combined with higher levels of choline-containing compounds, a marker of cell membrane turnover.^3,4 In the WM, an increased Cho/tCr ratio has been detected before the lesions are visible on conventional MR imaging.⁵ In the normal-appearing WM (NAWM), decreased tNAA and increased mIns, a marker of gliosis, have been found^6–8 and have shown correlations with clinical disability scores.^9,10The anti-inflammatory effect of natalizumab,¹¹ second-line therapy for relapsing-remitting MS (RRMS) in most countries, leads to a dramatic reduction in the formation of WM lesions, a decrease in the whole-brain atrophy rate, and improved rates of clinical progression and relapses.^12,13 Previous studies have shown that interferon β-1b (IFNb) and glatiramer acetate (GA) increase tNAA concentrations in MS,^14,15 but the effect of natalizumab remains unclear.We, therefore, performed MR spectroscopic imaging (MRSI) in patients starting natalizumab treatment and repeated measurements every 6 months in LWM, NAWM, and GM. Measurements were compared with those in healthy controls. Additionally, patients with RRMS continuing on IFNb/GA were followed during the same period.     

Basilar Artery Changes in Fabry Disease

BACKGROUND AND PURPOSE:Dolichoectasia of the basilar artery is a characteristic finding of Fabry disease. However, its prevalence, severity, and course have been poorly studied. This study quantitatively evaluated, by MRA, a panel of basilar artery parameters in a large cohort of patients with Fabry disease.MATERIALS AND METHODS:Basilar artery mean diameter, curved length, “origin-to-end” linear distance (linear length), and tortuosity index ([curved length ÷ linear length] − 1) were retrospectively measured on 1.5T MRA studies of 110 patients with Fabry disease (mean age, 39.4 ± 18.6 years; 40 males) and 108 control patients (mean age, 42.0 ± 18.2 years; 40 males).RESULTS:Patients with Fabry disease had increased basilar artery mean diameter (P < .001) and basilar artery linear length (P = .02) compared with control patients. Basilar artery curved length and tortuosity index correlated with age in both groups (P < .001), whereas basilar artery linear length correlated with age only in patients with Fabry disease (P = .002). Patients with Fabry disease showed a basilar artery curved length mean increase of 4.2% (9.7% in male patients with Fabry disease versus male control patients), whereas the basilar artery mean diameter had a mean increase of 12.4% (14.3% in male patients with Fabry disease versus male control patients). Male patients with Fabry disease had increased basilar artery mean diameter, curved length, and tortuosity index compared with female patients with Fabry disease (P = .04, P = .02, and P < .001, respectively) and male control patients (P < .001, P = .01, and P = .006, respectively). Female patients with Fabry disease demonstrated an age-dependent increase of basilar artery mean diameter that became significant (P < .001) compared with female control patients above the age of 45 years.CONCLUSIONS:The basilar artery of patients with FD is subjected to major remodeling that differs according to age and sex, thus providing interesting clues about the pathophysiology of cerebral vessels in Fabry disease.

Fabry disease (OMIM 301500; FD) is a rare X-linked (Xq22.1) disease caused by mutations in the GLA gene causing deficiency of the hydrolase α-galactosidase A (α-GalA, E.C. 3.2.1.22).¹ The enzyme deficiency results in impaired sphingolipid catabolism with lysosomal accumulation of upstream metabolites (mainly globotriaosylceramide [Gb₃] and its deacylated compound globotriaosylsphingosine [lysoGb₃]). All organs are involved, with major damage to the kidneys, heart, and nervous system. The brain might present white matter vascular-like abnormalities, TIAs, and stroke at a young age,² suggesting that micro- and macroangiopathy might have a pivotal role in the pathogenesis of brain lesions. Indeed, both small and large blood vessels have been consistently shown to present functional and morphologic changes in patients with FD.^3–5 Increased vessel tortuosity has been found in the retina⁶ and in the skin,^7,8 and intracranial artery dolichoectatic changes have been repeatedly observed in patients with FD during both pathologic and neuroimaging evaluations.^9–17Hitherto, most of the latter studies either referred to small samples or evaluated single specific aspects of artery dolichoectasia (such as the vessel lumen diameter). In addition, these studies applied different quantification methods or semiquantitative scores for the severity of the intracranial FD-related vessel changes, leading to conflicting results about the role of sex, age, and treatments.Our retrospective, transversal, case-control MRA study quantitatively investigated the morphologic basilar artery lumen changes (Fig 1) by applying a comprehensive panel of measurements encompassing all aspects of vessel dolichoectasia (diameter, length, and tortuosity) on a large cohort of patients with FD, aiming to provide a detailed picture of FD-related basilar artery changes according to age and sex.Open in a separate windowFig 1.MIP of an MRA study in A, a 41-year-old male patient with FD and B, a control patient. Note a mild increase of the tortuosity of the basilar artery and a more evident increase of the lumen diameter (compare the basilar artery with the contiguous ICA) C, Drawing of a tortuous basilar artery showing the real curved length (dashed line) and the linear distance between the basilar artery extremes (dotted line).     

Dilated Perivascular Spaces in the Basal Ganglia Are a Biomarker of Small-Vessel Disease in a Very Elderly Population with Dementia

BACKGROUND AND PURPOSE:Dilated perivascular spaces have been shown to be a specific biomarker of cerebral small-vessel disease in young patients with dementia. Our aim was to examine the discriminative power of dilated cerebral perivascular spaces as biomarkers of small-vessel disease in a very elderly population of patients with dementia.MATERIALS AND METHODS:We studied healthy volunteers (n = 65; mean age, 78 ± 5.6 years) and subjects with vascular dementia (n = 39; mean age, 76.9 ± 7.7 years) and Alzheimer disease (n = 47; mean age, 74.1 ± 8.5 years). We compared white matter hyperintensity and 2 semiquantitative perivascular space scoring systems (perivascular space-1 and perivascular space-2). Intra- and interobserver agreement was assessed by using a weighted Cohen κ statistic. Multinomial regression modeling was used to assess the discriminative power of imaging features to distinguish clinical groups.RESULTS:White matter hyperintensity scores were higher in vascular dementia than in Alzheimer disease (P < .05) or healthy volunteers (P < .01). The perivascular space-1 score was higher in vascular dementia and Alzheimer disease than in healthy volunteers (P < .01). The perivascular space-2 score in the centrum semiovale showed no intergroup differences. However, perivascular space-2 in the basal ganglia was higher in vascular dementia than in Alzheimer disease (P < .05) or healthy volunteers (P < .001) and higher in Alzheimer disease than in healthy volunteers (P < .001). Modeling of dementia versus healthy volunteers, Alzheimer disease versus healthy volunteers, and vascular dementia against Alzheimer disease demonstrated perivascular space-2_{basal ganglia} as the only imaging parameter with independent significant discriminative power (P < .01, P < .01, and P < .05) with areas under the receiver operating characteristic curve of 0.855, 0.774, and 0.71, respectively. Modeling of vascular dementia versus healthy volunteers showed that perivascular space-2_{basal ganglia} (P < .01) and the modified Scheltens score (P < .05) contributed significant, independent discriminatory power, accounting for 34% and 13% of the variance in the model respectively.CONCLUSIONS:Dilated perivascular spaces remain a valuable biomarker of small-vessel disease in an elderly population.

Alzheimer disease (AD) and vascular dementia (VaD) account for approximately 80% of dementias.¹ They can occur separately but are more likely to coexist with increasing age.² Vascular dementia is multifactorial in nature and may result from thrombotic or embolic large-vessel occlusion with consequent cortical infarction or, more commonly, cerebral small-vessel disease (SVD) with ischemic injury to deep brain structures and cerebral white matter.^3,4 While segmental infarction and hemorrhages can be identified on MR imaging, there is a pressing need for reliable biomarkers of SVD.⁵ Potential imaging biomarkers include deep white matter hyperintensities, dilated perivascular spaces (PVS), lacunar stroke, cerebral microbleeds, and cerebral atrophy.⁵Histologically, PVS are a feature of moderate-to-severe SVD.⁶ Imaging studies have shown them to be highly discriminative for diseases associated with SVD, including lacunar stroke,⁷ treatment-resistant late-onset depression,⁸ and vascular dementia.⁶ In each of these cases, PVS provided greater discriminative power than deep white matter hyperintensity scores. A study of 32 healthy elderly subjects also showed that PVS scoring correlated with Framingham stroke risk when deep white matter hyperintensity scores did not.⁹This study builds on previous studies of PVS in young patients with dementia⁶ and older patients with lacunar stroke.⁷ Both SVD and imaging features of vascular disease are increasingly common with advanced age and are commonly found in healthy subjects and in patients with primary neurodegenerative disorders such as AD. These findings are reflected with the scoring systems used by previous authors. Patankar et al,⁶ working in young patients with early-onset dementia, used a scoring system designed to detect early SVD on the basis of the presence of small numbers of PVS in the basal ganglia, with higher scores corresponding to both an increased number and location farther from the brain surface. In elderly individuals, PVS throughout the basal ganglia are increasingly common so that the discriminatory power of this scoring system is likely to be reduced. Consequently, Doubal et al,⁷ comparing PVS in older patients with lacunar and cortical stroke, used a scoring system based on the maximum number of PVS in any single axial section through the basal ganglia and centrum semiovale.In this study, we examined the utility of PVS and deep white matter hyperintensities as biomarkers of SVD in a very elderly population and compared the discriminative power of the previously described PVS scoring systems to discriminate AD from VaD.