White Matter Microstructural Alterations Research Articles

The association between White matter microstructure alterations detected by Diffusional kurtosis imaging in Neural circuit and post-stroke depression

ABSTRACT Aim In order to study the mechanism of post-stroke depression (PSD), we used diffusion kurtosis imaging (DKI) to describe the changes in white matter (WM) microstructure in PSD patients, to investigate the association between WM damage in limbic-cortical-striatal-pallidal-thalamic (LCSPT) circuit and PSD, and the utility of DKI in the diagnosis of PSD. Methods Fifty-eight participants were divided into different groups: control group (n=20), stroke patients without depression (Non-PSD, n=21) and PSD group (n=17). All were taken DKI scans. The WM of bilateral superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, temporal lobe, parietal lobe, occipital lobe, the anterior and posterior limb of internal capsule, the genu and splenium of corpus callosum were selected as the regions of interest (ROI) and selected mean kurtosis (MK), radial kurtosis (RK), axial kurtosis (AK) as the DKI parameters. Results Compared with control and Non-PSD, MK of PSD group in bilateral superior frontal gyrus, middle frontal gyrus, temporal lobe and the genu of corpus callosum were decreased significantly, as well as the RK in left superior frontal gyrus, bilateral middle frontal gyrus and temporal lobe. But there was no significant difference in AK. Besides, the decrease in MK and RK in frontal and temporal lobe was negatively associated with the severity of PSD. Conclusion Our research indicated that the damage to WM microstructure in the frontal lobe, temporal lobe and the genu of corpus callosum may be related toPSD. DKI explores the microstructural changes of WM in PSD patients and may be an auxiliary diagnostic method for PSD.

Neuroimaging Findings in Adolescents and Young Adults with Anorexia Nervosa: A Systematic Review.

Background: Anorexia nervosa (AN) is a serious, multifactorial mental disorder affecting predominantly young females. This systematic review examines neuroimaging findings in adolescents and young adults up to 24 years old, in order to explore alterations associated with disease pathophysiology. Methods: Eligible studies on structural and functional brain neuroimaging were sought systematically in PubMed, CENTRAL and EMBASE databases up to 5 October 2020. Results: Thirty-three studies were included, investigating a total of 587 patients with a current diagnosis of AN and 663 healthy controls (HC). Global and regional grey matter (GM) volume reduction as well as white matter (WM) microstructure alterations were detected. The mainly affected regions were the prefrontal, parietal and temporal cortex, hippocampus, amygdala, insula, thalamus and cerebellum as well as various WM tracts such as corona radiata and superior longitudinal fasciculus (SLF). Regarding functional imaging, alterations were pointed out in large-scale brain networks, such as default mode network (DMN), executive control network (ECN) and salience network (SN). Most findings appear to reverse after weight restoration. Specific limitations of neuroimaging studies in still developing individuals are also discussed. Conclusions: Structural and functional alterations are present in the early course of the disease, most of them being partially or totally reversible. Nonetheless, neuroimaging findings have been open to many biological interpretations. Thus, more studies are needed to clarify their clinical significance.

A randomized controlled trial investigating the impact of maternal dietary supplementation with pomegranate juice on brain injury in infants with IUGR

Animal studies have demonstrated the therapeutic potential of polyphenol-rich pomegranate juice. We recently reported altered white matter microstructure and functional connectivity in the infant brain following in utero pomegranate juice exposure in pregnancies with intrauterine growth restriction (IUGR). This double-blind exploratory randomized controlled trial further investigates the impact of maternal pomegranate juice intake on brain structure and injury in a second cohort of IUGR pregnancies diagnosed at 24–34 weeks’ gestation. Ninety-nine mothers and their eligible fetuses (n = 103) were recruited from Brigham and Women’s Hospital and randomly assigned to 8 oz pomegranate (n = 56) or placebo (n = 47) juice to be consumed daily from enrollment to delivery. A subset of participants underwent fetal echocardiogram after 2 weeks on juice with no evidence of ductal constriction. 57 infants (n = 26 pomegranate, n = 31 placebo) underwent term-equivalent MRI for assessment of brain injury, volumes and white matter diffusion. No significant group differences were found in brain volumes or white matter microstructure; however, infants whose mothers consumed pomegranate juice demonstrated lower risk for brain injury, including any white or cortical grey matter injury compared to placebo. These preliminary findings suggest pomegranate juice may be a safe in utero neuroprotectant in pregnancies with known IUGR warranting continued investigation.Clinical trial registration: NCT04394910, https://clinicaltrials.gov/ct2/show/NCT04394910, Registered May 20, 2020, initial participant enrollment January 16, 2016.

Associations between different white matter properties and reward-based performance modulation.

Humans can be motivated by the prospect of gaining a reward. However, the extent to which we are affected by reward information differs from person to person. A possible mechanism underlying these inter-individual differences may be alterations in white matter (WM) microstructure; however, the relationship between WM properties and reward-based behaviour in healthy participants has not yet been explored. Here, we used a fixel-based approach to investigate potential associations between WM tracts and performance in a reward-cuing task. We found that WM properties in the corpus callosum, right uncinate fasciculus, left ventral cingulum, and accumbofrontal tracts were inversely related to reward-triggered performance benefits (indexed by faster reaction times). Moreover, smaller WM property values in the corpus callosum, uncinate fasciculus, and accumbofrontal tracts were associated with higher scores on the Behavioral Inhibition System scale, reflecting greater sensitivity to potential punishment. Finally, we also observed associations between functional hemodynamic activity in the ventral striatum and WM microstructure. The finding that reward-based behavioural benefits are related to lower measures of WM tracts is in contrast to studies linking higher WM metrics to superior cognitive performance. We interpret the current pattern in terms of higher susceptibility to motivationally relevant stimuli, which is in line with the current and previous studies reporting inverse relationships between WM properties and motivational traits. Taking a broader perspective, such propensities may only be beneficial up to a certain point, at which thesemay become detrimental to performance and even manifest as impulsive and addictive behaviour.

Sex differences in microstructural white matter alterations of mathematics anxiety based on diffusion MRI connectometry.

Mathematics Anxiety (MA) is a feeling of stress, tension, and fear in situations engaging with math-related tasks. Herein, we utilized Diffusion Magnetic Resonance Imaging (DMRI) connectometry approach to tracking white matter (WM) fibers with a significant correlation with the severity of MA. A total of 77 healthy adult participants (50 males, mean age ± SD = 26.00 ± 3.54) were included from the Leipzig Study for Mind-Body-Emotion Interactions (LEMON) database. Abbreviated Math Anxiety Scale (AMAS) questionnaire was used for assessing the participant's feelings when facing a math-related activity. DMRI data were prepared and analyzed with the connectometry approach. Multiple regression models were then carried out to examine the correlation of WM microstructural connectivity with AMAS score. DMRI connectometry showed a significant association between AMAS score and increased microstructural connectivity in left arcuate fasciculus (AF), the body of corpus callosum (CC), right cingulum, and left inferior longitudinal fasciculus (ILF) in male participants with moderate effect size false discovery rate (FDR = 0.040). Furthermore, DMRI connectometry in females identified a positive correlation between AMAS score and microstructural connectivity in the genu of CC, right ILF, and bilateral fornices with small-to-moderate effect size (FDR = 0.012) and a negative correlation between AMAS score and microstructural connectivity in the bilateral cingulum with small-to-moderate effect size (FDR = 0.032) Conclusion: Our findings support that structures with functional relation to language processing areas (e.g., AF) or limbic system (cingulum, CC, fornix, and ILF) play a significant role in MA. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Association of White Matter Integrity With Executive Function and Antidepressant Treatment Outcome in Patients With Late-Life Depression

ObjectiveWhile patients with late-life depression (LLD) often exhibit microstructural white matter alterations that can be identified with diffusion tensor imaging (DTI), there is a dearth of information concerning the links between DTI findings and specific cognitive performance, as well as between DTI measures and antidepressant treatment outcomes. DesignNeuroimaging and cognitive tests were conducted at baseline in 71 older adults participating in a larger, 8-week duration antidepressant randomized controlled trial. Correlations between DTI measures of white matter integrity evaluated with tract-based spatial statistics, baseline neurocognitive performance, and prospective antidepressant treatment outcome were evaluated. ResultsFractional anisotropy (FA), an index of white matter integrity, was significantly positively associated with better cognitive function as measured by the Initiation/Perseveration subscale of the Dementia Rating Scale in the bilateral superior longitudinal fasciculus (SLF), bilateral SLF-temporal, and right corticospinal tract (CST). An exploratory analysis limited to these tracts revealed that increased FA in the right CST, right SLF, and right SLF-temporal tracts was correlated with a greater decrease in depressive symptoms. Increased FA in the right CST predicted a greater chance of remission, while increased FA in the right CST and the right SLF predicted a greater chance of treatment response. ConclusionIn late-life depression LLD subjects, white matter integrity was positively associated with executive function in white matter tracts which act as key connecting structures underlying the cognitive control network. These tracts may play a role as a positive prognostic factor in antidepressant treatment outcome.

In vivo tensor-valued diffusion MRI of focal demyelination in white and deep grey matter of rodents

BackgroundMultiple sclerosis (MS) is a chronic inflammatory demyelinating disease leading to damage of white matter (WM) and grey matter (GM). Magnetic resonance imaging (MRI) is the modality of choice to assess brain damage in MS, but there is an unmet need in MRI for achieving higher sensitivity and specificity to MS-related microstructural alterations in WM and GM. ObjectiveTo explore whether tensor-valued diffusion MRI (dMRI) can yield sensitive microstructural read-outs for focal demyelination in cerebral WM and deep GM (DGM). MethodsEight rats underwent L-α-Lysophosphatidylcholine (LPC) injections in the WM and striatum to introduce focal demyelination. Multimodal MRI was performed at 7 Tesla after 7 days. Tensor-valued dMRI was complemented by diffusion tensor imaging, quantitative MRI and proton magnetic resonance spectroscopy (MRS). ResultsQuantitative MRI and MRS confirmed that LPC injections caused inflammatory demyelinating lesions in WM and DGM. Tensor-valued dMRI illustrated a significant decline of microscopic fractional anisotropy (µFA) in both LPC-treated WM and DGM (P < 0.005) along with a marked increase of isotropic kurtosis (MKI) in DGM (P < 0.0001). ConclusionTensor-valued dMRI bears considerable potential for microstructural imaging in MS, suggesting a regional µFA decrease may be a sensitive indicator of MS lesions, while a regional MKI increase may be particularly sensitive in detecting DGM lesions of MS.

White matter microstructure disruption in early stage amyloid pathology.

IntroductionAmyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer's disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cognitively unimpaired cohort.MethodsWe included 179 individuals from the European Medical Information Framework for AD (EMIF‐AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract‐level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomography (PET) imaging to assess amyloid burden.ResultsRegression analyses showed a non‐linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingulate cortex strongly related to AxD and RD measures in the genu CC.DiscussionEarly amyloid deposition is associated with changes in WM microstructure. The non‐linear relationship might reflect multiple stages of axonal damage.

Diffusion MRI Captures White Matter Microstructure Alterations in PRKN Disease.

Background:Although pathological studies usually indicate pure dopaminergic neuronal degeneration in patients with parkin (PRKN) mutations, there is no evidence to date regarding white matter (WM) pathology. A previous diffusion MRI study has revealed WM microstructural alterations caused by systemic oxidative stress in idiopathic Parkinson’s disease (PD), and we found that PRKN patients have systemic oxidative stress in serum biomarker studies. Thus, we hypothesized that PRKN mutations might lead to WM abnormalities.Objective:To investigate whether there are WM microstructural abnormalities in early-onset PD patients with PRKN mutations using diffusion tensor imaging (DTI).Methods:Nine PRKN patients and 15 age- and sex-matched healthy controls were recruited. DTI measures were acquired on a 3T MR scanner using a b value of 1,000 s/mm2 along 32 isotropic diffusion gradients. The DTI measures were compared between groups using tract-based spatial statistics (TBSS) analysis. Correlation analysis was also performed between the DTI parameters and several serum oxidative stress markers obtained in a previously conducted metabolomic analysis.Results:Although the WM volumes were not significantly different, the TBSS analysis revealed a corresponding decrease in fractional anisotropy and an increase in mean diffusivity and radial diffusivity in WM areas, such as the anterior and superior corona radiata and uncinate fasciculus, in PRKN patients compared with controls. Furthermore, 9-hydroxystearate, an oxidative stress marker, and disease duration were positively correlated with several parameters in PRKN patients.Conclusion:This pilot study suggests that WM microstructural impairments occur in PRKN patients and are associated with disease duration and oxidative stress.

Altered white matter microstructure is related to cognition in adults with congenital heart disease.

Adults with congenital heart disease are at risk for persisting executive function deficits, which are known to affect academic achievement and quality of life. Alterations in white -matter microstructure are associated with cognitive impairments in adolescents with congenital heart disease. This study aimed to identify microstructural alterations potentially associated with executive function deficits in adults with congenital heart disease. Diffusion tensor imaging and tract-based spatial statistics were conducted in 45 patients (18 females) and 54 healthy controls (26 females) aged 18–32 years. Fractional anisotropy of white matter diffusion was compared between groups and correlated with an executive function score, derived from an extensive neuropsychological test battery. Patients showed widespread bilateral reduction in fractional anisotropy (P < 0.05, multiple comparison corrected) compared to controls. Lower fractional anisotropy was driven by patients with moderate and severe defect complexity (compared to controls: P < 0.001). Executive function scores were lower in patients (P < 0.05) and associated with lower fractional anisotropy in the left superior corona radiata and the corticospinal tract (corrected P < 0.05). Our findings confirm alterations of white matter microstructure in adults with congenital heart disease, mainly in those patients of moderate to severe complexity. These alterations are associated with impairments in executive functioning. A better understanding of the neurocognitive deficits may help counselling and care of patients with congenital heart disease across their lifespan and have the potential to improve their outcome and quality of life.

The cingulum in very preterm infants relates to language and social-emotional impairment at 2 years of term-equivalent age

BackgroundRelative to full-term infants, very preterm infants exhibit disrupted white matter (WM) maturation and problems related to development, including motor, cognitive, social-emotional, and receptive and expressive language processing. ObjectiveThe present study aimed to determine whether regional abnormalities in the WM microstructure of very preterm infants, as defined relative to those of full-term infants at a near-term age, are associated with neurodevelopmental outcomes at the age of 18–22 months. MethodsWe prospectively enrolled 89 very preterm infants (birth weight < 1500 g) and 43 normal full-term control infants born between 2016 and 2018. All infants underwent a structural brain magnetic resonance imaging scan at near-term age. The diffusion tensor imaging (DTI) metrics of the whole-brain WM tracts were extracted based on the neonatal probabilistic WM pathway. The elastic net logistic regression model was used to identify altered WM tracts in the preterm brain. We evaluated the associations between the altered WM microstructure at near-term age and motor, cognitive, social-emotional, and receptive and expressive language developments at 18–22 months of age, as measured using the Bayley Scales of Infant Development, Third Edition. ResultsWe found that the elastic net logistic regression model could classify preterm and full-term neonates with an accuracy of 87.9% (corrected p < 0.008) using the DTI metrics in the pathway of interest with a 10% threshold level. The fractional anisotropy (FA) values of the body and splenium of the corpus callosum, middle cerebellar peduncle, left and right uncinate fasciculi, and right portion of the pathway between the premotor and primary motor cortices (premotor-PMC), as well as the mean axial diffusivity (AD) values of the left cingulum, were identified as contributive features for classification. Increased adjusted AD values in the left cingulum pathway were significantly correlated with language scores after false discovery rate (FDR) correction (r = 0.217, p = 0.043). The expressive language and social-emotional composite scores showed a significant positive correlation with the AD values in the left cingulum pathway (r = 0.226 [p = 0.036] and r = 0.31 [p = 0.003], respectively) after FDR correction. ConclusionOur approach suggests that the cingulum pathways of very preterm infants differ from those of full-term infants and significantly contribute to the prediction of the subsequent development of the language and social-emotional domains. This finding could improve our understanding of how specific neural substrates influence neurodevelopment at later ages, and individual risk prediction, thus helping to inform early intervention strategies that address developmental delay.

Regional microstructural alteration of the corpus callosum in preclinical Alzheimer’s disease

AbstractBackgroundWhile previous studies consistently reported regional microstructural changes of the cerebral white matter (WM) in Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI), little information is available for such changes in the preclinical stage of AD. We first aimed to investigate regional microstructural alteration of the WM in cognitively normal (CN) older adults with amyloid‐beta (Aβ) deposition. We also tried to develop a prediction model for Aβ positivity in CN using information on WM microstructural alteration and clinical variables that can be easily obtained in memory clinics.MethodSeventy‐five CN older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease (KBASE) cohort were included in the analyses. All Participants underwent comprehensive clinical and neuropsychological assessment, T1 MRI, diffusion tensor imaging (DTI), and [11C]PiB‐PET. All CN subjects were divided into Aβ positive (CN+) and negative (CN‐) based on the level of cerebral Aβ retention on [11C]PiB‐PET. Multivariate stepwise logistic regression analyses were conducted to develop Aβ positivity prediction models.ResultWhen compared to CN‐, CN+ showed high mean diffusivity (MD) value of the genu of the corpus callosum (CC_genu) (F(1,73) = 6.357, p = 0.014, Figure 1). The area under the curve (AUC) of the receiver operating characteristics curve for the Aβ positivity prediction model only using MD of the CC_genu was 0.653 [confidence interval (CI) = 0.511‐0.794]. Model with MD of the CC_genu, age, and word list recall and constructional recall test scores were finally selected. The AUC of the final model was 0.851 [CI = 0.765‐0.937] (Figure 2).ConclusionThe findings indicate that microstructural alteration of the CC_genu occurs even in the stage of preclinical AD. When taken together with episodic memory scores commonly available in clinical practice, information about such regional WM microstructural alteration can be used to screen preclinical AD.

Cognitive status, brain amyloid pathology, and neurodegeneration are associated with altered white matter microstructure

AbstractBackgroundBrain amyloid (AB) and neurodegeneration (assessed using PET and MRI) are key AD pathology biomarkers, particularly during transitions from cognitively unimpaired (CU) to cognitively impaired (CI) states. Importantly, the role of brain white matter microstructural measures in these changes, such as those derived from neurite orientation dispersion and density imaging (NODDI), are poorly understood. We explored roles of cognitive status, brain amyloid pathology, and neurodegeneration on NODDI Free Water (FW), a potential neuroinflammation biomarker.MethodParticipants enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort (N=74, Table 1) underwent neuropsychological assessment, T1/NODDI MRI, and PiB PET. Participants were adjudicated as cognitively impaired (MCI or AD) or unimpaired using NIA‐AA criteria. T1 MRI were processed (FreeSurfer v5.3) to generate regions of interest (ROIs). An “AD‐signature” cortical thickness value was calculated, and thresholded to classify participants as neurodegeneration‐positive (N+) or ‐negative (N‐). A set of AD‐sensitive cortical ROIs was used to extract mean PET signal, which was thresholded to adjudicate AB positivity (AB‐/AB+). NODDI was processed to yield parameter maps using AMICO; mean isotropic volume fraction (FW) was calculated over a set of white matter tract ROIs. A two‐way ANOVA/ANCOVA (covariates: age, sex, education) assessed effects of neurodegeneration and AB on FW (N+/N‐ x AB+/AB‐), and a two‐way ANOVA/ANCOVA assessed effects of cognitive impairment and AB on FW (CU/CI x AB+/AB‐).ResultWe first examined effects of neurodegeneration and AB on NODDI FW. We found a significant main effect of neurodegeneration (p=.042), such that N+ had higher FW; this was marginal after adjustment (p=.07). We also observed a significant main effect of AB (p&lt;.001; adjusted p=.012), with AB+ having higher FW. There was no significant interaction. We next explored how cognitive status and AB interacted on FW. We found a significant main effect of cognitive impairment, with CI having higher FW (p=.018; adjusted p=.013). We also found an interaction between diagnosis and AB (p=.037; adjusted p=.044) such that among AB+ individuals, presence of CI related to increased FW (Figure 1).ConclusionNODDI FW increases were significantly affected by the presence of neurodegeneration, AB positivity, and cognitive impairment.

Microstructural alterations of regional white matter tracts predict tau deposition in the Alzheimer’s disease signature regions

AbstractBackgroundWe first aimed to investigate the association between regional white matter (WM) microstructural alterations with tau deposition in Alzheimer’s disease (AD) signature cortical regions. We also tried to develop models to predict pathological tau deposition positivity with regional WM microstructural alterations.MethodOne‐hundred nine older adults with normal cognition or mild cognitive impairment recruited from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease (KBASE) cohort were included in the analyses. All Participants underwent structural MRI (T1), diffusion tensor imaging, PiB‐PET and Tau‐PET (AV‐1451) scans. AD signature cortical regions for tau deposition included the angular gyrus, posterior cingulate, and inferior temporal cortical regions (Jack et al. 2017). Pathological tau positivity was determined by the presence of significantly high deposition in the Braak regions III‐VI according to the ADNI cutoff (Baker et al. 2017).ResultMean diffusivity (MD) of the posterior corona radiata, fornix, and posterior thalamic radiation were significantly associated with tau deposition in AD signature regions (F(1,107) = 13.48, p &lt; 0.005; F(1,107) = 17.38, p &lt; 0.001; F(1,107) = 15.92, p &lt; 0.001, respectively) (Fig 1). Fractional anisotropy (FA) of the bilateral posterior thalamic radiation was also significantly associated with tau deposition in AD signature regions (F(1,107) = 17.14, p &lt; 0.005) (Fig 1). Pathological tau positivity prediction model based on FA value of the posterior thalamic radiation, MD values of the posterior corona radiata and fornix had area under the curve (AUC) of receiver operating characteristics curve of 0.73 [0.62‐0.84] (Fig. 2a). With additional information on amyloid beta positivity, the AUC increased to 0.86 [0.78‐0.95] (Fig. 2b).ConclusionThe findings indicate that microstructural alterations of the specific regional WM tracts closely linked to AD‐signature cortical regions are strongly correlated with tau deposition in the same cortical regions. Moreover, the findings also support propagation of tauopathy through WM tracts. The information on regional WM alteration may be used for the prediction of pathological tau deposition.

Long longitudinal tract lesion contributes to progression of Alzheimer’s disease

AbstractBackgroundThe pattern of degenerative changes in white matter (WM) microstructure and its relationship with cognitive function have not been clarified yet in the course of Alzheimer’s disease (AD). The present research aimed to explore the alterations of WM microstructure and its relationship with clinical features in amnestic mild cognitive(aMCI) and AD patients.MethodNeuropsychological data and diffusion tensor imaging (DTI) images were collected from 28 AD subjects, 31 aMCI subjects, and 27 normal controls (NC). Tract‐based spatial statistics (TBSS) were used to investigate fractional anisotropy (FA) and mean diffusivity (MD) among groups. Relationship between diffusion metrics and cognitive functions was examined. A support vector machine (SVM) classification was performed to determine the discriminative ability of DTI metrics in separating aMCI and AD patients from controls.ResultThe values of diffusion metrics in aMCI group presented intermediately between NC and AD groups. As compared to controls or aMCI patients, AD patients displayed widespread WM lesions, including the inferior longitudinal fasciculus, inferior fronto‐occipital fasciculi, superior longitudinal fasciculus and so on. However, no significant FA/MD differences were detected between NC and aMCI groups. Significant relationships between FA/MD metrics of long longitudinal tract and AVLT‐DR scores were found in aMCI and AD groups, respectively. The accuracy of DTI metrics in differentiating controls and AD patients were highly reached 89% and 85% according to SVM.ConclusionWM microstructure is extensively disrupted in AD. Long longitudinal tract integrity is closely related to memory and would hold potential value for monitoring the course of Alzheimer's disease.

Multi-shell Diffusion MRI Models for White Matter Characterization in Cerebral Small Vessel Disease.

To test the hypothesis that multi-shell diffusion models improve the characterization of microstructural alterations in cerebral small vessel disease (SVD), we assessed associations with processing speed performance, longitudinal change, and reproducibility of diffusion metrics. We included 50 patients with sporadic and 59 patients with genetically defined SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) with cognitive testing and standardized 3T MRI, including multi-shell diffusion imaging. We applied the simple diffusion tensor imaging (DTI) model and 2 advanced models: diffusion kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI). Linear regression and multivariable random forest regression (including conventional SVD markers) were used to determine associations between diffusion metrics and processing speed performance. The detection of short-term disease progression was assessed by linear mixed models in 49 patients with sporadic SVD with longitudinal high-frequency imaging (in total 459 MRIs). Intersite reproducibility was determined in 10 patients with CADASIL scanned back-to-back on 2 different 3T MRI scanners. Metrics from DKI showed the strongest associations with processing speed performance (R 2 up to 21%) and the largest added benefit on top of conventional SVD imaging markers in patients with sporadic SVD and patients with CADASIL with lower SVD burden. Several metrics from DTI and DKI performed similarly in detecting disease progression. Reproducibility was excellent (intraclass correlation coefficient >0.93) for DTI and DKI metrics. NODDI metrics were less reproducible. Multi-shell diffusion imaging and DKI improve the detection and characterization of cognitively relevant microstructural white matter alterations in SVD. Excellent reproducibility of diffusion metrics endorses their use as SVD markers in research and clinical care. Our publicly available intersite dataset facilitates future studies. This study provides Class I evidence that in patients with SVD, diffusion MRI metrics are associated with processing speed performance.

Tau-related white-matter alterations along spatially selective pathways

Progressive accumulation of tau neurofibrillary tangles in the brain is a defining pathologic feature of Alzheimer's disease (AD). Tau pathology exhibits a predictable spatiotemporal spreading pattern, but the underlying mechanisms of this spread are poorly understood. Although AD is conventionally considered a disease of the gray matter, it is also associated with pronounced and progressive deterioration of the white matter (WM). A link between abnormal tau and WM degeneration is suggested by findings from both animal and postmortem studies, but few studies demonstrated their interplay in vivo. Recent advances in diffusion magnetic resonance imaging and the availability of tau positron emission tomography (PET) have made it possible to evaluate the association of tau and WM degeneration (tau-WM) in vivo. In this study, we explored the spatial pattern of tau-WM associations across the whole brain to evaluate the hypothesis that tau deposition is associated with WM microstructural alterations not only in isolated tracts, but in continuous structural connections in a stereotypic pattern. Sixty-two participants, including 22 cognitively normal subjects, 22 individuals with subjective cognitive decline, and 18 with mild cognitive impairment were included in the study. WM characteristics were inferred by classic diffusion tensor imaging (DTI) and a complementary diffusion compartment model – neurite orientation dispersion and density imaging (NODDI) that provides a proxy for axonal density. A data-driven iterative searching (DDIS) approach, coupled with whole-brain graph theory analyses, was developed to continuously track tau-WM association patterns. Without applying prior knowledge of the tau spread, we observed a distinct spatial pattern that resembled the typical propagation of tau pathology in AD. Such association pattern was not observed between diffusion and amyloid-β PET signal. Tau-related WM degeneration is characterized by an increase in the mean diffusivity (with a dominant change in the radial direction) and a decrease in the intra-axonal volume fraction. These findings suggest that cortical tau deposition (as measured in tau PET) is associated with a lower axonal packing density and greater diffusion freedom. In conclusion, our in vivo findings using a data-driven method on cross-sectional data underline the important role of WM alterations in the AD pathological cascade with an association pattern similar to the postmortem Braak staging of AD. Future studies will focus on longitudinal analyses to provide in vivo evidence of tau pathology spreads along neuroanatomically connected brain areas.

Concurrent alterations of white matter microstructure and functional activities in medication-free major depressive disorder.

Although numerous studies have revealed the structural and functional alterations in major depressive disorder (MDD) using unimodal diffusion magnetic resonance imaging (MRI) or functional MRI, however, the potential associations between changed microstructure and corresponding functional activities in the MDD has been largely uninvestigated. Herein, 27 medication-free MDD patients and 54 gender-, age-, and educational level-matched healthy controls (HC) were used to investigate the concurrent alterations of white matter microstructure and functional activities using tract-based spatial statistics (TBSS) analyses, fractional amplitude of low-frequency fluctuation (fALFF), and degree centrality (DC). The TBSS analyses revealed significantly decreased fractional anisotropy (FA) in the superior longitudinal fasciculus (SLF I) in the MDD patients compared to HC. Correlation analyses showed that decreased FA in the SLF I was significantly correlated with fALFF in left pre/postcentral gyrus and binary, weighted DC in right posterior cerebellum. Moreover, the fALFF in left pre/postcentral gyrus significantly reduced in MDD patients while binary and weighted DC in right posterior cerebellum significantly increased in MDD patients. Our results revealed concurrent structural and functional changes in MDD patients suggesting that the underlying structural disruptions are an important indicator of functional abnormalities.

Brain Development in Infants of Mothers With Gestational Diabetes Mellitus: A Diffusion Tensor Imaging Study.

The objective of this study was to investigate clinical neurocognitive performance and microstructural white matter (WM) alterations in infants of mothers with gestational diabetes mellitus (GDM) using diffusion tensor imaging. Infants (corrected gestational age, 33.42-36.00 weeks) of mothers with GDM (n = 31) and gestational age- and sex-matched unexposed controls (n = 31) accomplished 3-T diffusion tensor imaging scans and neurocognitive tests. Diffusion tensor imaging measures, mainly referring to fractional anisotropy (FA) values, were compared between 2 groups, and within-group analysis of correlation between FA values and neurocognitive testing outcomes in GDM-exposed infants was conducted subsequently. Fractional anisotropy was significantly decreased in the splenium of corpus callosum, posterior limb of internal capsule, thalamus in infants of mothers with GDM when compared with controls (P < 0.05), reflecting microstructural WM abnormalities in the GDM group. Decreased FA was associated with worse neurocognitive performance in the exposed group (P < 0.05). Individuals of mothers with GDM showed microstructural WM abnormalities in different brain regions, which were significantly related to worse neurocognitive performance. This might reveal that GDM directly insults the brain development of the offspring.

Reduced fractional anisotropy in projection, association, and commissural fiber networks in neonates with prenatal methamphetamine exposure.

Prenatal exposure to methamphetamine is associated with neurostructural changes, including alterations in white matter microstructure. This study investigated the effects of methamphetamine exposure on microstructure of global white matter networks in neonates. Pregnant women were interviewed beginning in mid-pregnancy regarding their methamphetamine use. Diffusion weighted imaging sets were acquired for 23 non-sedated neonates. White matter bundles associated with pairs of target regions within five networks (commissural fibers, left and right projection fibers, and left and right association fibers) were estimated using probabilistic tractography, and fractional anisotropy (FA) and diffusion measures determined within each connection. Multiple regression analyses showed that increasing methamphetamine exposure was significantly associated with reduced FA in all five networks, after control for potential confounders. Increased exposure was associated with lower axial diffusivity in the right association fiber network and with increased radial diffusivity in the right projection and left and right association fiber networks. Within the projection and association networks a subset of individual connections showed a negative correlation between FA and methamphetamine exposure. These findings are consistent with previous reports in older children and demonstrate that microstructural changes associated with methamphetamine exposure are already detectable in neonates.