APOE4 carriership status influences [11C]PiB white matter retention in cognitively healthy older adults.

Background: Alterations to microstructural integrity in white matter hyperintensities (WMH) in patients with severe leukoaraiosis are poorly understood. Neurite density and orientation dispersion imaging (NODDI) produce better estimates of myelin density than diffusion tensor MRI (DTI) and therefore may provide additional in vivo insight into WMH pathophysiology. Methods: NODDI was acquired in a prospective study of acute ischemic stroke patients with advanced white matter disease (N=36). Neurite density (ND), and orientation dispersion (OD) were calculated along with model-free diffusion parameters: mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and fractional anisotropy (FA). Median values were measured in in the hemisphere contralateral to the incident stroke in regions of WMH and in normal appearing white matter (NAWM) and compared (paired Wilcoxon-exact test). Linear regression was performed to evaluate univariate predictors of log-transformed WMH volumes (log WMHv). Results: Patient characteristics were: mean±SD age 69±10 y, time-to-MRI 2.8±1.2 days, median [IQ] normalized WMHv 4.7 [2.3-9.3] and 61% men. MD, AD and RD were greater, while FA, MK, AK, RK, OD and ND were lower in WMH compared to NAWM (P<0.001, see Figure). Increased MD (P=0.004), AD (P<0.0001) and AK (P=0.01) in NAWM and decreased OD in NAWM (P=0.01) were significant predictors of increased log WMHv. Discussion: Diffusivity, kurtosis and ND and OD in acute stroke patients with moderate to severe leuokoaraiosis differed significantly between NAWM and WMH in the contralateral hemisphere. Reduced neurite density is suggestive of microstructural injury. Reduced OD is typically associated with greater organization, but might also reflect restricted extracellular space diffusivity. The association of MD, AD, AK and OD in NAWM with WMH burden suggests there is ongoing risk for developing future WMH.

Cerebral small vessel disease (SVD) is a major health problem for its contribution to ≈45% of dementias, and about a fifth of all strokes worldwide, representing one of the most important causes of disabilities.1 The term SVD refers to a group of pathological processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. The most common forms are age- and hypertension-related SVD and cerebral amyloid angiopathy (CAA).2 Vessel wall changes may lead to both ischemic and hemorrhagic consequences: (1) a state of chronic hypoperfusion or vascular dysfunction responsible for incomplete infarction,3,4 (2) acute focal necrosis (lacunar infarct), or (3) vessel rupture manifesting as hemorrhagic SVD. The clinical consequences of SVD are various and mainly consist of cognitive, mood, and motor dysfunctions leading to functional disability in the late stages of the disease. Magnetic resonance imaging (MRI) has become crucial in the diagnosis of SVD enabling the evaluation of the disease progression both in the clinical and research settings. However, correlations between clinical features of SVD and conventional MRI measures have been partially discordant. Some authors suggested that the cumulative effect of SVD lesions, rather than the individual lesions themselves determines the clinical impact,5 whereas others suggested that the presence and severity of alterations nonvisible on conventional MRI might also be an explanation.6 In the past decade, diffusion tensor imaging (DTI) has been increasingly used for the evaluation of SVD patients because it is sensitive to tissue damage and can show abnormalities in both areas of white matter hyperintensities (WMH) and in normal appearing WM (NAWM). Despite the high sensitivity in detecting cerebral damage, DTI has a low specificity in detecting the underlying cause. In fact, we can only infer that DTI changes reflect a loss of WM …

Introduction: White matter hyperintensities (WMH), a common neuroradiological feature seen with aging, increases the risk of stroke, dementia, disability and mortality. The underlying pathophysiology leading to WMH is incompletely understood. Here, we examined the role of regional cerebral blood flow (CBF) and oxygen extraction fraction (OEF) in WMH. Methods: Subjects with WMH (n=9) and age-matched controls (n=9) were imaged in a 3T MRI Scanner. OEF was obtained using an asymmetric spin echo sequence while CBF was obtained with pseudo-continuous arterial spin labeling. WMH were graded according to Fazekas et al. For tissue-type quantification, CBF and OEF images were segmented to classify whole brain (WB), gray matter (GM), white matter (WM), white matter hyperintensities (WMH), and normal appearing white matter (NAWM). Results: CBF and OEF in WB, GM and WM did not differ between cohorts. However, differences emerged when comparing the WMH and NAWM segmented tissues. Specifically, CBF in WMH was less than half that seen in NAWM in the WMH group, and similarly lower than normal WM in controls. Moreover, OEF in WMH was higher compared to NAWM and WM in controls, but this did not reach statistical significance (Table). Conclusions: CBF and OEF did not differ between subjects with or without WMH. However, within the WMH group, regions of WMH had significantly lower but not absent CBF and trends towards higher OEF compared to NAWM and normal WM in controls. These data suggest that regions of WMH do not represent irreversibly infarcted tissue, but rather, may be viable tissue under chronic metabolic stress. Increased OEF in WMH may be a marker of salvageable brain tissue; However, additional work is needed to confirm these results.

Aging is associated with microstructural white matter (WM) changes. WM microstructural characteristics, measured with diffusion tensor imaging (DTI), are different in normal appearing white matter (NAWM) and WM hyperintensities (WMH). It is largely unknown how the microstructural properties of WMH are associated with cognition and if there are regional effects for specific cognitive domains. We therefore examined within 200 healthy older participants (a) differences in microstructural characteristics of NAWM and WMH per cerebral lobe; and (b) the association of macrostructural (WMH volume) and microstructural characteristics (within NAWM and WMH separately) of each lobe with measures of executive function and processing speed. Multi-modal imaging (i.e., T1, DTI, and FLAIR) was used to assess WM properties. The Stroop and the Trail Making Test were used to measure inhibition, task-switching (both components of executive function), and processing speed. We observed that age was associated with deterioration of white matter microstructure of the NAWM, most notably in the frontal lobe. Older participants had larger WMH volumes and lowest fractional anisotropy values within WMH were found in the frontal lobe. Task-switching was associated with cerebral NAWM volume and NAWM volume of all lobes. Processing speed was associated with total NAWM volume, and microstructural properties of parietal NAWM, the parietal WMH, and the temporal NAWM. Task-switching was related to microstructural properties of WMH of the frontal lobe and WMH volume of the parietal lobe. Our results confirm that executive functioning and processing speed are uniquely associated with macro- and microstructural properties of NAWM and WMH. We further demonstrate for the first time that these relationships differ by lobar region. This warrants the consideration of these distinct WM indices when investigating cognitive function.

<h3>Objective:</h3> To evaluate the utility of Diffusion Tensor Imaging (DTI)-based microstructural metrics in periventricular white matter (PVWM) versus total white matter as a biomarker of cerebral small vessel disease (CSVD). <h3>Background:</h3> PVWM, supplied exclusively by small arteries, has the lowest cerebral blood flow (CBF) in the brain and a high frequency of white matter hyperintensities (WMH) in aging. Accordingly, PVWM tissue may be particularly sensitive to CSVD. We compared DTI parameters in normal-appearing periventricular white matter (NA-PVWM) to normal-appearing white matter (NAWM) as a whole and assessed their correlations with WMH and vascular risk factors in an older cohort. <h3>Design/Methods:</h3> Multimodal MRI data from N=100 cognitively normal older subjects in the Penn Alzheimer’s Disease Research Center were analyzed. An established CBF-based PVWM mask was used to extract mean values for DTI metrics (fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD)). We derived WMH lesion masks from FLAIR MRI to calculate total WMH volume and to exclude WMH voxels from WM and PVWM regions. <h3>Results:</h3> Cohort mean age was 73(6) years with 61% females. All DTI metrics were significantly higher in NA-PVWM compared to NAWM (all P&lt;0.001). Only FA in both NAWM (P=0.010) and NA-PVWM (P=0.007) was significantly associated with hypertension. None of the DTI metrics were associated with diabetes, hypercholesterolemia, or smoking. After adjustment for age and sex, diffusivity values in both NA-PVWM and NAWM correlated similarly with total WMH volume (all P&lt;0.001, except P=0.003 for AD in NA-PVWM), whereas FA was significantly correlated with WMH volume only in NA-PVWM (P&lt;0.001). <h3>Conclusions:</h3> PVWM differs from total WM in microstructural characteristics derived from DTI. FA in NA-PVWM was associated with hypertension and with overall WMH burden, suggesting that FA in PVWM may be a potential biomarker of CSVD. <b>Disclosure:</b> Dr. Shakibajahromi has nothing to disclose. Dr. Dolui has nothing to disclose. The institution of Dr. Brown has received research support from National Institute of Health. Mr. Tackett has nothing to disclose. Mr. Khandelwal has nothing to disclose. Shokufeh Sadaghiani, 1129 has nothing to disclose. Dr. Taghvaei has nothing to disclose. Paul Yushkevich has nothing to disclose. Dr. Wolk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuronix. Dr. Wolk has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Functional Neuromodulation. Dr. Wolk has received personal compensation in the range of $5,000-$9,999 for serving as a CME Speaker with MJH Life Sciences. Dr. Detre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hura Imaging. The institution of Dr. Detre has received research support from NIH. Dr. Detre has received personal compensation in the range of $500-$4,999 for serving as a grant proposal reviewer with NIH, VA, European Science Foundation,Deutsche Forschungsgemeinschaft.

ObjectiveTo investigate the associations of Pittsburgh compound‐B (PiB) uptake in white matter hyperintensities (WMH) and normal appearing white matter (NAWM) with white matter (WM) integrity measured with DTI and cognitive function in cognitively unimpaired older adults.MethodsCognitively unimpaired older adults from the population‐based Mayo Clinic Study of Aging (n = 537, age 65–95) who underwent both PiB PET and DTI were included. The associations of WM PiB standard uptake value ratio (SUVr) with fractional anisotropy (FA) and mean diffusivity (MD) in the WMH and NAWM were tested after adjusting for age. The associations of PiB SUVr with cognitive function z‐scores were tested after adjusting for age and global cortical PiB SUVr.ResultsThe WMH PiB SUVr was lower than NAWM PiB SUVr (P < 0.001). In the WMH, lower PiB SUVr correlated with lower FA (r = 0.21, P < 0.001), and higher MD (r = −0.31, P < 0.001). In the NAWM, lower PiB SUVr only correlated with higher MD (r = −0.10, P = 0.02). Both in the WMH and NAWM, lower PiB SUVr was associated with lower memory, language, and global cognitive function z‐scores after adjusting for age and global cortical PiB SUVr.InterpretationReduced PiB uptake in the WMH is associated with a loss of WM integrity and cognitive function after accounting for the global cortical PiB uptake, suggesting that WM PiB uptake may be an early biomarker of WM integrity that precedes cognitive impairment in older adults. When using WM as a reference region in cross‐sectional analysis of PiB SUVr, individual variability in WMH volume as well as age should be considered.

Reduced binding of Pittsburgh Compound-B in areas of white matter hyperintensities

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood–brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3–90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities (P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age (P < 0.001), all biomarkers varied with white matter hyperintensities burden (P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension (P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood–brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood–brain barrier leakage mediates small vessel disease-related brain damage.

White matter hyperintensities (WMH) of presumed vascular origin are a common finding in brain magnetic resonance imaging of older individuals and contribute to cognitive and functional decline. It is unknown how WMH form, although white matter degeneration is characterized pathologically by demyelination, axonal loss, and rarefaction, often attributed to ischemia. Changes within normal-appearing white matter (NAWM) in subjects with WMH have also been reported but have not yet been fully characterized. Here, we describe the in vivo imaging signatures of both NAWM and WMH in a large group of community-dwelling older people of similar age using biomarkers derived from magnetic resonance imaging that collectively reflect white matter integrity, myelination, and brain water content. Fractional anisotropy (FA) and magnetization transfer ratio (MTR) were significantly lower, whereas mean diffusivity (MD) and longitudinal relaxation time (T1) were significantly higher, in WMH than NAWM (p < 0.0001), with MD providing the largest difference between NAWM and WMH. Receiver operating characteristic analysis on each biomarker showed that MD differentiated best between NAWM and WMH, identifying 94.6% of the lesions using a threshold of 0.747 × 10−9 m2s−1 (area under curve, 0.982; 95% CI, 0.975–0.989). Furthermore, the level of deterioration of NAWM was strongly associated with the severity of WMH, with MD and T1 increasing and FA and MTR decreasing in NAWM with increasing WMH score, a relationship that was sustained regardless of distance from the WMH. These multimodal imaging data indicate that WMH have reduced structural integrity compared with surrounding NAWM, and MD provides the best discriminator between the 2 tissue classes even within the mild range of WMH severity, whereas FA, MTR, and T1 only start reflecting significant changes in tissue microstructure as WMH become more severe.

Background: In acute ischemic stroke (AIS), cerebral tissue damage and clinical outcomes are linked to pre-existing microvascular dysfunction, manifesting as white matter hyperintensity (WMH). Elevated blood-brain barrier permeability (BBB-P) has been implicated in advanced WMH. We tested the microstructural integrity of BBB as measured by dynamic susceptibility contrast (DSC) MRI K 2 coefficient values in AIS patients with advanced WMH. Methods: Twenty patients enrolled in a prospective acute MRI study underwent diffusion tensor (DTI) and DSC MRI on admission for AIS. BBB-P estimates were derived from DSC MRI using the K 2 coefficients. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) maps were calculated. Mean K 2 , MD, AD, RD and FA values were measured in regions of WMH and normally appearing white matter (NAWM) in the hemisphere contralateral to AIS and compared (two-tailed Student t-Test). WMH volume (WMHv) was assessed on acute FLAIR using a validated semi-automated volumetric protocol. Linear regression was performed to evaluate significant predictors of K 2 , MD, AD, RD, and FA. Correlation analysis was performed (Pearson product-moment). Results: Mean age of subjects was 66 (±10) years, 30% were women, median WMHv 3.5cm 3 [IQR 1.6-7.4]. K 2 values differed significantly between WMH and NAWM (0.32 x10 -3 vs. 1.1 x10 -3 , p&lt;0.03), as did the diffusivity metrics for WMH and NAWM (FA: 0.25 vs 0.38; MD: 1.3 x10 -3 vs 0.84 x10 -3 ; AD: 1.6 x10 -3 vs 1.2 x10 -3 ; RD: 1.14 x10 -3 vs 0.66 x10 -3 ; all p&lt;0.0001). K 2 and RD values were correlated within WMH (R=-0.45, P=0.046) but not in NAWM (R=0.06, P=0.81). Multivariate analysis found systolic BP (SBP) and lnWMHv to be significant predictors of MD (P=0.0009), AD (P=0.002), and RD (P=0.002) in NAWM. Discussion: BBB-P and diffusivity values in patients with AIS and advanced leukoaraiosis differed significantly between WMH and NAWM in the hemisphere contralateral to acute infarct. Association between the RD and K 2 coefficients in WMH suggests the role of BBB-P in pathophysiology of WMH and the loss of microstructural white matter integrity associated with it. Further, the influence of SBP and lnWMHv on NAWM diffusivity values suggests ongoing risk for developing future WMH.

White matter hyperintensities (WMH) are the most prevalent markers of cerebral small vessel disease (SVD), which is the major vascular risk factor for dementia. Microvascular pathology and neuroinflammation are suggested to drive the transition from normal-appearing white matter (NAWM) to WMH, particularly in individuals with hypertension. However, current imaging techniques cannot capture ongoing NAWM changes. The transition from NAWM into WMH is a continuous process, yet white matter lesions are often examined dichotomously, which may explain their underlying heterogeneity. Therefore, we examined microvascular and neurovascular inflammation pathology in NAWM and severe WMH three-dimensionally, along with gradual magnetic resonance imaging (MRI) fluid-attenuated inversion recovery (FLAIR) signal (sub-)segmentation. In WMH, the vascular network exhibited reduced length and complexity compared to NAWM. Neuroinflammation was more severe in WMH. Vascular inflammation was more pronounced in NAWM, suggesting its potential significance in converting NAWM into WMH. Moreover, the (sub-)segmentation of FLAIR signal displayed varying degrees of vascular pathology, particularly within WMH regions. These findings highlight the intricate interplay between microvascular pathology and neuroinflammation in the transition from NAWM to WMH. Further examination of neurovascular inflammation across MRI-visible alterations could aid deepening our understanding on WMH conversion, and therewith how to improve the prognosis of SVD.

White matter hyperintensities negatively impact white matter structure and relate to cognitive decline in aging. Diffusion tensor imaging detects changes to white matter microstructure, both within the white matter hyperintensity and extending into surrounding (perilesional) normal-appearing white matter. However, diffusion tensor imaging markers are not specific to tissue components, complicating the interpretation of previous microstructural findings. Myelin water imaging is a novel imaging technique that provides specific markers of myelin content (myelin water fraction) and interstitial fluid (geometric mean T2). Here we combined diffusion tensor imaging and myelin water imaging to examine tissue characteristics in white matter hyperintensities and perilesional white matter in 80 individuals (47 older adults and 33 individuals with chronic stroke). To measure perilesional normal-appearing white matter, white matter hyperintensity masks were dilated in 2 mm segments up to 10 mm in distance from the white matter hyperintensity. Fractional anisotropy, mean diffusivity, myelin water fraction, and geometric mean T2 were extracted from white matter hyperintensities and perilesional white matter. We observed a spatial gradient of higher mean diffusivity and geometric mean T2, and lower fractional anisotropy, in the white matter hyperintensity and perilesional white matter. In the chronic stroke group, myelin water fraction was reduced in the white matter hyperintensity but did not show a spatial gradient in perilesional white matter. Across the entire sample, white matter metrics within the white matter hyperintensity related to whole-brain white matter hyperintensity volume; with increasing white matter hyperintensity volume there was increased mean diffusivity and geometric mean T2, and decreased myelin water fraction in the white matter hyperintensity. Normal-appearing white matter adjacent to white matter hyperintensities exhibits characteristics of a transitional stage between healthy white matter and white matter hyperintensities. This effect was observed in markers sensitive to interstitial fluid, but not in myelin water fraction, the specific marker of myelin concentration. Within the white matter hyperintensity, interstitial fluid was higher and myelin concentration was lower in individuals with more severe cerebrovascular disease. Our data suggests white matter hyperintensities have penumbra-like effects in perilesional white matter that specifically reflect increased interstitial fluid, with no changes to myelin concentration. In contrast, within the white matter hyperintensity there are varying levels of demyelination, which vary based on the severity of cerebrovascular disease. Diffusion tensor imaging and myelin imaging may be useful clinical markers to predict white matter hyperintensity formation, and to stage neuronal damage within white matter hyperintensities.

Background: White Matter Hyperintensities (WMH) are thought to represent end-stage white matter injury. Increasing WMH burden is associated with greater risk of stroke, infarct growth, and poor outcomes after stroke. Understanding the microstructural changes of normal appearing white matter (NAWM) that predate WMH development is therefore clinically relevant as it could identify targets for therapeutic intervention to reduce stroke risk and improve post-stroke outcomes. Diffusion tensor imaging-based axial (AD) and radial diffusivity (RD) can assess white matter axonal integrity and myelin status, respectively. In a cohort of patients with acute ischemic stroke (AIS), we measured NAWM and WMH AD and RD to elucidate the white matter microstructural changes associated with WMH burden. Methods: Brain MRI with diffusion tensor imaging sequences was acquired within 48 hours of admission on consecutive AIS patients. WMH volume (WMHv) was measured in a semi-automated manner. Median fractional anisotropy, mean diffusivity, RD, and AD values were calculated within NAWM and WMH in the hemisphere contralateral to the acute lesion. Linear regression analysis was performed to evaluate predictors of WMH. Level of significance was set at P &lt; 0.05 for all analyses. Results: In 319 AIS patients, mean age was 67 +/- 15.9 years. Median WMHv was 6.19 cm3 (IQR 3.0-12.6 cm 3 ). Mean AD was significantly increased in WMH compared to NAWM (WMH: 1.29 vs. NAWM: 1.16 x 10 -3 , mm 2 /s; P &lt; 0.0001). In multivariable linear regression, age (β = 0.18, P = 0.017) and NAWM AD (β = 42.3, P = 0.012) were independent predictors of WMHv. Diffusivity anisotropy metrics of WMH were not associated with WMHv. Conclusions: In patients with AIS, NAWM AD is an independent predictor of WMHv. Our findings suggest that loss of NAWM axonal integrity contributes to WMH development.

White matter hyperintensities (WMH) are frequently seen on neuroimaging of elderly and are associated with cognitive decline and the development of dementia. Yet, the temporal dynamics of conversion of normal-appearing white matter (NAWM) into WMH remains unknown. We examined whether and when progression of WMH was preceded by changes in fluid-attenuated inversion recovery and diffusion tensor imaging values, thereby taking into account differences between participants with mild versus severe baseline WMH. From 266 participants of the RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort), we semiautomatically segmented WMH at 3 time points for 9 years. Images were registered to standard space through a subject template. We analyzed differences in baseline fluid-attenuated inversion recovery, fractional anisotropy, and mean diffusivity (MD) values and changes in MD values over time between 4 regions: (1) remaining NAWM, (2) NAWM converting into WMH in the second follow-up period, (3) NAWM converting into WMH in the first follow-up period, and (4) WMH. NAWM converting into WMH in the first or second time interval showed higher fluid-attenuated inversion recovery and MD values than remaining NAWM. MD values in NAWM converting into WMH in the first time interval were similar to MD values in WMH. When stratified by baseline WMH severity, participants with severe WMH had higher fluid-attenuated inversion recovery and MD and lower fractional anisotropy values than participants with mild WMH, in all areas including the NAWM. MD values in WMH and in NAWM that converted into WMH continuously increased over time. Impaired microstructural integrity preceded conversion into WMH and continuously declined over time, suggesting a continuous disease process of white matter integrity loss that can be detected using diffusion tensor imaging even years before WMH become visible on conventional neuroimaging. Differences in microstructural integrity between participants with mild versus severe WMH suggest heterogeneity of both NAWM and WMH, which might explain the clinical variability observed in patients with similar small vessel disease severity.

Changes in microvessel density in normal-appearing white matter in relation to cerebral small vessel disease: A cohort study.