Tensor-valued diffusion magnetic resonance imaging in a radiotherapy setting.

Background and purpose: Diagnostic information about cell density variations and microscopic tissue anisotropy can be gained from tensor-valued diffusion magnetic resonance imaging (MRI). These properties of tissue microstructure have the potential to become novel imaging biomarkers for radiotherapy response. However, tensor-valued diffusion encoding is more demanding than conventional encoding, and its compatibility with MR scanners that are dedicated to radiotherapy has not been established. Thus, our aim was to investigate the feasibility of tensor-valued diffusion MRI with radiotherapy dedicated MR equipment. Material and methods: A tensor-valued diffusion protocol was implemented, and five healthy volunteers were scanned with different resolutions using conventional head coil and radiotherapy coil setup with fixation masks. Signal-to-noise-ratio (SNR) was evaluated to assess the risk of signal bias due to rectified noise floor. We also evaluated the repeatability and reproducibility of the microstructure parameters. One patient with brain metastasis was scanned to investigate the image quality and the transferability of the setup to diseased tissue. Results: A resolution of 3 × 3 × 3 mm3 provided images with SNR > 3 for 93 % of the voxels using radiotherapy coil setup. The parameter maps and repeatability characteristics were comparable to those observed with a conventional head coil. The patient evaluation demonstrated successful parameter analysis also in tumor tissue, with SNR > 3 for 93 % of the voxels. Conclusion: We demonstrate that tensor-valued diffusion MRI is compatible with radiotherapy fixation masks and coil setup for investigations of microstructure parameters. The reported reproducibility may be used to plan future investigations of imaging biomarkers in brain cancer radiotherapy.

Cerebral Micro-Structural Changes in COVID-19 Patients - An MRI-based 3-month Follow-up Study.

BACKGROUND: Increasing evidence supported the possible neuro-invasion potential of SARS-CoV-2. However, no studies were conducted to explore the existence of the micro-structural changes in the central nervous system after infection. We aimed to identify the existence of potential brain micro-structural changes related to SARS-CoV-2. METHODS: In this prospective study, diffusion tensor imaging (DTI) and 3D high-resolution T1WI sequences were acquired in 60 recovered COVID-19 patients (56.67% male; age: 44.10 ± 16.00) and 39 age- and sex-matched non-COVID-19 controls (56.41% male; age: 45.88 ± 13.90). Registered fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were quantified for DTI, and an index score system was introduced. Regional volumes derived from Voxel-based Morphometry (VBM) and DTI metrics were compared using analysis of covariance (ANCOVA). Two sample t-test and Spearman correlation were conducted to assess the relationships among imaging indices, index scores and clinical information. FINDINGS: In this follow-up stage, neurological symptoms were presented in 55% COVID-19 patients. COVID-19 patients had statistically significantly higher bilateral gray matter volumes (GMV) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus and right cingulate gyrus and a general decline of MD, AD, RD accompanied with an increase of FA in white matter, especially AD in the right CR, EC and SFF, and MD in SFF compared with non-COVID-19 volunteers (corrected p value <0.05). Global GMV, GMVs in left Rolandic operculum, right cingulate, bilateral hippocampi, left Heschl's gyrus, and Global MD of WM were found to correlate with memory loss (p value <0.05). GMVs in the right cingulate gyrus and left hippocampus were related to smell loss (p value <0.05). MD-GM score, global GMV, and GMV in right cingulate gyrus were correlated with LDH level (p value <0.05). INTERPRETATION: Study findings revealed possible disruption to micro-structural and functional brain integrity in the recovery stages of COVID-19, suggesting the long-term consequences of SARS-CoV-2. FUNDING: Shanghai Natural Science Foundation, Youth Program of National Natural Science Foundation of China, Shanghai Sailing Program, Shanghai Science and Technology Development, Shanghai Municipal Science and Technology Major Project and ZJ Lab.

Brain Edema in Chronic Hepatic Encephalopathy.

Brain edema is a common feature associated with hepatic encephalopathy (HE). In patients with acute HE, brain edema has been shown to play a crucial role in the associated neurological deterioration. In chronic HE, advanced magnetic resonance imaging (MRI) techniques have demonstrated that low-grade brain edema appears also to be an important pathological feature. This review explores the different methods used to measure brain edema ex vivo and in vivo in animal models and in humans with chronic HE. In addition, an in-depth description of the main studies performed to date is provided. The role of brain edema in the neurological alterations linked to HE and whether HE and brain edema are the manifestations of the same pathophysiological mechanism or two different cerebral manifestations of brain dysfunction in liver disease are still under debate. In vivo MRI/magnetic resonance spectroscopy studies have allowed insight into the development of brain edema in chronic HE. However, additional in vivo longitudinal and multiparametric/multimodal studies are required (in humans and animal models) to elucidate the relationship between liver function, brain metabolic changes, cellular changes, cell swelling, and neurological manifestations in chronic HE.

Isolated focal dystonia phenotypes are associated with distinct patterns of altered microstructure.

Objective: Isolated adult-onset focal dystonia is considered a network disorder with disturbances to the motor basal ganglia and cerebellar circuits playing a pathophysiological role, but why specific body regions become affected remains unknown. We aimed to use diffusion tensor imaging to determine if the two most common phenotypes of focal dystonia are associated with distinguishing microstructural changes affecting the motor network. Methods: Fifteen blepharospasm patients, 20 cervical dystonia patients, and 30 age- and sex-matched healthy controls were recruited. Maps of fractional anisotropy and mean diffusivity were analyzed using a voxel-based approach and an automated region-of-interest technique to evaluate deep gray matter nuclei. Correlations between diffusion measures and dystonia severity were tested, and post hoc discriminant analyses were conducted. Results: Voxel-based analyses revealed significantly reduced fractional anisotropy in the right cerebellum and increased mean diffusivity in the left caudate of cervical dystonia patients compared to controls, as well as lower fractional anisotropy in the right cerebellum in cervical dystonia patients relative to blepharospasm patients. In addition to reduced fractional anisotropy in the bilateral caudate nucleus of cervical dystonia patients relative to controls and blepharospasm patients, region-of-interest analyses revealed significantly reduced fractional anisotropy in the right globus pallidus internus and left red nucleus of blepharospasm patients compared to both controls and cervical dystonia patients. Diffusivity measures in the red nucleus of blepharospasm patients correlated with disease severity. In a three-group discriminant analysis, participants were correctly classified with only modest reliability (67-75%), but in a two-group discriminant analysis, patients could be distinguished from each other with high reliability (83-100%). Conclusions: Different focal dystonia phenotypes are associated with distinct patterns of altered microstructure within constituent regions of basal ganglia and cerebellar circuits.

Mean diffusivity in cortical gray matter in Alzheimer's disease: The importance of partial volume correction.

Mean diffusivity (MD) measured by diffusion tensor imaging can reflect microstructural alterations of the brain's gray matter (GM). Therefore, GM MD may be a sensitive marker of neurodegeneration related to Alzheimer's Disease (AD). However, due to partial volume effects (PVE), differences in MD may be overestimated because of a higher degree of brain atrophy in AD patients and in cases with mild cognitive impairment (MCI). Here, we evaluated GM MD changes in AD and MCI compared with healthy controls, and the effect of partial volume correction (PVC) on diagnostic utility of MD. We determined region of interest (ROI) and voxel-wise group differences and diagnostic accuracy of MD and volume measures between matched samples of 39 AD, 39 MCI and 39 healthy subjects before and after PVC. Additionally, we assessed whether effects of GM MD values on diagnosis were mediated by volume. ROI and voxel-wise group differences were reduced after PVC. When using these ROIs for predicting group separation in logistic models, both PVE corrected and uncorrected GM MD values yielded a poorer diagnostic accuracy in single predictor models than regional volume. For the discrimination of AD patients and healthy controls, the effect of GM MD on diagnosis was significantly mediated by volume of hippocampus and posterior cingulate ROIs. Our results suggest that GM MD measurements are strongly confounded by PVE in the presence of brain atrophy, underlining the necessity of PVC when using these measurements as specific metrics of microstructural tissue degeneration. Independently of PVC, regional MD was not superior to regional volume in separating prodromal and clinical stages of AD from healthy controls.

Microstructure of the superior temporal gyrus and hallucination proneness - a multi-compartment diffusion imaging study.

Previous studies reported that the volume of the left superior temporal gyrus (STG) is reduced in patients with schizophrenia and negatively correlated with hallucination severity. Moreover, diffusion-tensor imaging studies suggested a relationship between the brain microstructure in the STG of patients and auditory hallucinations. Hallucinations are also experienced in non-patient groups. This study investigated the relationship between hallucination proneness and the brain structure of the STG. Hallucination proneness was assessed by the Launey Slade Hallucination Scale (LSHS) in 25 healthy individuals who varied in their propensity to hear voices. Brain volume and microstructure of the STG was assessed by magnetic resonance imaging (MRI). Microstructure was examined by conventional diffusion-tensor imaging as well as by neurite orientation dispersion and density imaging (NODDI). The latter decomposes diffusion-based MRI into multiple compartments that characterize the brain microstructure by its neurite complexity known as orientation dispersion (ODI) and by its neurite density (NDI). Hallucination proneness was negatively correlated with the volume and microstructure (fractional anisotropy, neurite complexity) of the left but not the right STG. The strongest relationship (r = -0.563) was observed for neurite complexity (ODI). No correlation was observed for neurite density (NDI). These findings suggest that there is a relationship between the volume and the microstructure of the left STG and hallucination proneness. Dendritic complexity (but not neurite density) is inversely related to hallucination proneness. Metrics based on multi-compartment diffusion models seem to be more sensitive for hallucination-related neural processes than conventional MRI-based metrics.

Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers.

Introduction: Mutations in the progranulin (GRN) gene are a major source of inherited frontotemporal degeneration (FTD) spectrum disorders associated with TDP-43 proteinopathy. We use structural MRI to identify regions of baseline differences and longitudinal changes in gray matter (GM) and white matter (WM) in presymptomatic GRN mutation carriers (pGRN+) compared to young controls (yCTL). Methods: Cognitively intact first-degree relatives of symptomatic GRN+ FTD patients with identified GRN mutations (pGRN+; N = 11, mean age = 41.4) and matched yCTL (N = 11, mean age = 53.6) were identified. They completed a MRI session with T1-weighted imaging to assess GM density (GMD) and diffusion-weighted imaging (DWI) to assess fractional anisotropy (FA). Participants completed a follow-up session with T1 and DWI imaging (pGRN+ mean interval 2.20 years; yCTL mean interval 3.27 years). Annualized changes of GMD and FA were also compared. Results: Relative to yCTL, pGRN+ individuals displayed reduced GMD at baseline in bilateral orbitofrontal, insular, and anterior temporal cortices. pGRN+ also showed greater annualized GMD changes than yCTL at follow-up in right orbitofrontal and left occipital cortices. We also observed reduced FA at baseline in bilateral superior longitudinal fasciculus, left corticospinal tract, and frontal corpus callosum in pGRN+ relative to yCTL, and pGRN+ displayed greater annualized longitudinal FA change in right superior longitudinal fasciculus and frontal corpus callosum. Conclusions: Longitudinal MRI provides evidence of progressive GM and WM changes in pGRN+ participants relative to yCTL. Structural MRI illustrates the natural history of presymptomatic GRN carriers, and may provide an endpoint during disease-modifying treatment trials for pGRN+ individuals at risk for FTD.

Sex differences in white matter alterations following repetitive subconcussive head impacts in collegiate ice hockey players.

OBJECTIVE: Repetitive subconcussive head impacts (RSHI) may lead to structural, functional, and metabolic alterations of the brain. While differences between males and females have already been suggested following a concussion, whether there are sex differences following exposure to RSHI remains unknown. The aim of this study was to identify and to characterize sex differences following exposure to RSHI. METHODS: Twenty-five collegiate ice hockey players (14 males and 11 females, 20.6 ± 2.0 years), all part of the Hockey Concussion Education Project (HCEP), underwent diffusion-weighted magnetic resonance imaging (dMRI) before and after the Canadian Interuniversity Sports (CIS) ice hockey season 2011-2012 and did not experience a concussion during the season. Whole-brain tract-based spatial statistics (TBSS) were used to compare pre- and postseason imaging in both sexes for fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Pre- and postseason neurocognitive performance were assessed by the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). RESULTS: Significant differences between the sexes were primarily located within the superior longitudinal fasciculus (SLF), the internal capsule (IC), and the corona radiata (CR) of the right hemisphere (RH). In significant voxel clusters (p < 0.05), decreases in FA (absolute difference pre- vs. postseason: 0.0268) and increases in MD (0.0002), AD (0.00008), and RD (0.00005) were observed in females whereas males showed no significant changes. There was no significant correlation between the change in diffusion scalar measures over the course of the season and neurocognitive performance as evidenced from postseason ImPACT scores. CONCLUSIONS: The results of this study suggest sex differences in structural alterations following exposure to RSHI. Future studies need to investigate further the underlying mechanisms and association with exposure and clinical outcomes.

White matter alterations and their associations with motor function in young adults born preterm with very low birth weight.

Very low birth weight (VLBW: ≤ 1500 g) individuals have an increased risk of white matter alterations and neurodevelopmental problems, including fine and gross motor problems. In this hospital-based follow-up study, the main aim was to examine white matter microstructure and its relationship to fine and gross motor function in 31 VLBW young adults without cerebral palsy compared with 31 term-born controls, at mean age 22.6 ± 0.7 years. The participants were examined with tests of fine and gross motor function (Trail Making Test-5: TMT-5, Grooved Pegboard, Triangle from Movement Assessment Battery for Children-2: MABC-2 and High-level Mobility Assessment Tool: HiMAT) and diffusion tensor imaging (DTI). Probabilistic tractography of motor pathways of the corticospinal tract (CST) and corpus callosum (CC) was performed. Fractional anisotropy (FA) was calculated in non-crossing (capsula interna in CST, body of CC) and crossing (centrum semiovale) fibre regions along the tracts and examined for group differences. Associations between motor test scores and FA in the CST and CC were investigated with linear regression. Tract-based spatial statistics (TBSS) was used to examine group differences in DTI metrics in all major white matter tracts. The VLBW group had lower scores on all motor tests compared with controls, however, only statistically significant for TMT-5. Based on tractography, FA in the VLBW group was lower in non-crossing fibre regions and higher in crossing fibre regions of the CST compared with controls. Within the VLBW group, poorer fine motor function was associated with higher FA in crossing fibre regions of the CST, and poorer bimanual coordination was additionally associated with lower FA in crossing fibre regions of the CC. Poorer gross motor function was associated with lower FA in crossing fibre regions of the CST and CC. There were no associations between motor function and FA in non-crossing fibre regions of the CST and CC within the VLBW group. In the TBSS analysis, the VLBW group had lower FA and higher mean diffusivity compared with controls in all major white matter tracts. The findings in this study may indicate that the associations between motor function and FA are caused by other tracts crossing the CST and CC, and/or by alterations in the periventricular white matter in the centrum semiovale. Some of the associations were in the opposite direction than hypothesized, thus higher FA does not always indicate better function. Furthermore, widespread white matter alterations in VLBW individuals persist into young adulthood.

SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage.

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration.

Single-subject classification of presymptomatic frontotemporal dementia mutation carriers using multimodal MRI.

Background: Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. Methods: Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). Results: The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUC = 0.570, p = 0.11). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.646 (p = 0.021). The best multimodal model combined radial diffusivity and white matter density features (AUC = 0.680, p = 0.005). Conclusions: FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter.

Comparison of probabilistic tractography and tract-based spatial statistics for assessing optic radiation damage in patients with autoimmune inflammatory disorders of the central nervous system.

Background: Diffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract-based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage. Objective: To evaluate the capacity of TBSS-based atlas region-of-interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL-TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs). Methods: Twenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3 T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs. Results: Absolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from p < 0.0001 to 0.0043). ROC-analysis and effect size estimation revealed higher AUCs and R2 for CSD-PROB (AUC = 0.812; R2 = 0.282) and JHU-TBSS (AUC = 0.756; R2 = 0.262), compared to CON-PROB (AUC = 0.742; R2 = 0.179) and JUEL-TBSS (AUC = 0.719; R2 = 0.161). Differences between CIS/RRMS-NON and HC were only observable in CSD-PROB (AUC = 0.796; R2 = 0.094). No significant differences between CIS/RRMS-ON and HC were detected by any of the methods. Conclusions: All DTI post-processing techniques facilitated the detection of OR damage in patient groups with severe microstructural OR degradation. The comparison of distinct disease groups by use of different methods may lead to different - either false-positive or false-negative - results. Since different DTI post-processing approaches seem to provide complementary information on OR damage, application of distinct methods may depend on the relevant research question.

In utero diffusion tensor imaging of the fetal brain: A reproducibility study.

Our purpose was to evaluate the within-subject reproducibility of in utero diffusion tensor imaging (DTI) metrics and the visibility of major white matter structures. Images for 30 fetuses (20-33. postmenstrual weeks, normal neurodevelopment: 6 cases, cerebral pathology: 24 cases) were acquired on 1.5 T or 3.0 T MRI. DTI with 15 diffusion-weighting directions was repeated three times for each case, TR/TE: 2200/63 ms, voxel size: 1 ∗ 1 mm, slice thickness: 3-5 mm, b-factor: 700 s/mm2. Reproducibility was evaluated from structure detectability, variability of DTI measures using the coefficient of variation (CV), image correlation and structural similarity across repeated scans for six selected structures. The effect of age, scanner type, presence of pathology was determined using Wilcoxon rank sum test. White matter structures were detectable in the following percentage of fetuses in at least two of the three repeated scans: corpus callosum genu 76%, splenium 64%, internal capsule, posterior limb 60%, brainstem fibers 40% and temporooccipital association pathways 60%. The mean CV of DTI metrics ranged between 3% and 14.6% and we measured higher reproducibility in fetuses with normal brain development. Head motion was negatively correlated with reproducibility, this effect was partially ameliorated by motion-correction algorithm using image registration. Structures on 3.0 T had higher variability both with- and without motion correction. Fetal DTI is reproducible for projection and commissural bundles during mid-gestation, however, in 16-30% of the cases, data were corrupted by artifacts, resulting in impaired detection of white matter structures. To achieve robust results for the quantitative analysis of diffusivity and anisotropy values, fetal-specific image processing is recommended and repeated DTI is needed to ensure the detectability of fiber pathways.

White-matter tract abnormalities and antisocial behavior: A systematic review of diffusion tensor imaging studies across development.

Antisocial behavior (AB), including aggression, violence, and theft, is thought be underpinned by abnormal functioning in networks of the brain critical to emotion processing, behavioral control, and reward-related learning. To better understand the abnormal functioning of these networks, research has begun to investigate the structural connections between brain regions implicated in AB using diffusion tensor imaging (DTI), which assesses white-matter tract microstructure. This systematic review integrates findings from 22 studies that examined the relationship between white-matter microstructure and AB across development. In contrast to a prior hypothesis that AB is associated with greater diffusivity specifically in the uncinate fasciculus, findings suggest that adult AB is associated with greater diffusivity across a range of white-matter tracts, including the uncinate fasciculus, inferior fronto-occipital fasciculus, cingulum, corticospinal tract, thalamic radiations, and corpus callosum. The pattern of findings among youth studies was inconclusive with both higher and lower diffusivity found across association, commissural, and projection and thalamic tracts.

Diffusion imaging of reversible and irreversible microstructural changes within the corticospinal tract in idiopathic normal pressure hydrocephalus.

The symptoms of idiopathic normal pressure hydrocephalus (iNPH) can be improved by shunt surgery, but prediction of treatment outcome is not established. We investigated changes of the corticospinal tract (CST) in iNPH before and after shunt surgery by using diffusion microstructural imaging, which infers more specific tissue properties than conventional diffusion tensor imaging. Two biophysical models were used: neurite orientation dispersion and density imaging (NODDI) and white matter tract integrity (WMTI). In both methods, the orientational coherence within the CSTs was higher in patients than in controls, and some normalization occurred after the surgery in patients, indicating axon stretching and recovery. The estimated axon density was lower in patients than in controls but remained unchanged after the surgery, suggesting its potential as a marker for irreversible neuronal damage. In a Monte-Carlo simulation that represented model axons as undulating cylinders, both NODDI and WMTI separated the effects of axon density and undulation. Thus, diffusion MRI may distinguish between reversible and irreversible microstructural changes in iNPH. Our findings constitute a step towards a quantitative image biomarker that reflects pathological process and treatment outcomes of iNPH.

Longitudinal changes in microstructural white matter metrics in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Current avenues of AD research focus on pre-symptomatic biomarkers that will assist with early diagnosis of AD. The majority of magnetic resonance imaging (MRI) based biomarker research to date has focused on neuronal loss in grey matter and there is a paucity of research on white matter. METHODS: Longitudinal DTI data from the Alzheimer's Disease Neuroimaging Initiative 2 database were used to examine 1) the within-group microstructural white matter changes in individuals with AD and healthy controls at baseline and year one; and 2) the between-group microstructural differences in individuals with AD and healthy controls at both time points. RESULTS: 1) Within-group: longitudinal Tract-Based Spatial Statistics revealed that individuals with AD and healthy controls both had widespread reduced fractional anisotropy (FA) and increased mean diffusivity (MD) with changes in the hippocampal cingulum exclusive to the AD group. 2) Between-group: relative to healthy controls, individuals with AD had lower FA and higher MD in the hippocampal cingulum, as well as the corpus callosum, internal and external capsule; corona radiata; posterior thalamic radiation; superior and inferior longitudinal fasciculus; fronto-occipital fasciculus; cingulate gyri; fornix; uncinate fasciculus; and tapetum. CONCLUSION: The current results indicate that sensitivity to white matter microstructure is a promising avenue for AD biomarker research. Additional longitudinal studies on both white and grey matter are warranted to further evaluate potential clinical utility.

High angular resolution diffusion-weighted imaging in mild traumatic brain injury.

We sought to investigate white matter abnormalities in mild traumatic brain injury (mTBI) using diffusion-weighted magnetic resonance imaging (DW-MRI). We applied a global approach based on tract-based spatial statistics skeleton as well as constrained spherical deconvolution tractography. DW-MRI was performed on 102 patients with mTBI within two months post-injury and 30 control subjects. A robust global approach considering only the voxels with a single-fiber configuration was used in addition to global analysis of the tract skeleton and probabilistic whole-brain tractography. In addition, we assessed whether the microstructural parameters correlated with age, time from injury, patient's outcome and white matter MRI hyperintensities. We found that whole-brain global approach restricted to single-fiber voxels showed significantly decreased fractional anisotropy (FA) (p = 0.002) and increased radial diffusivity (p = 0.011) in patients with mTBI compared with controls. The results restricted to single-fiber voxels were more significant and reproducible than those with the complete tract skeleton or the whole-brain tractography. FA correlated with patient outcomes, white matter hyperintensities and age. No correlation was observed between FA and time of scan post-injury. In conclusion, the global approach could be a promising imaging biomarker to detect white matter abnormalities following traumatic brain injury.

Pathology of callosal damage in ALS: An ex-vivo, 7 T diffusion tensor MRI study.

OBJECTIVES: The goal of this study was to better understand the changes in tissue microstructure that underlie white matter diffusion changes in ALS patients. METHODS: Diffusion tensor imaging was carried out in postmortem brains of 4 ALS patients and two subjects without neurological disease on a 7 T MRI scanner using steady-state free precession sequences. Fractional anisotropy (FA) was measured in the genu, body, and splenium of the corpus callosum in formalin-fixed hemispheres. FA of the body and genu was expressed as ratio to FA of the splenium, a region unaffected in ALS. After imaging, tissue sections of the same segments of the callosum were stained for markers of different tissue components. Coded image fields were rated for pathological changes by blinded raters. RESULTS: The FA body/FA splenium ratio was reduced in ALS patients compared to controls. Patchy areas of myelin pallor and cells immunostained for CD68, a microglial-macrophage marker, were only observed in the body of the callosum of ALS patients. Blinded ratings showed increased CD68 + microglial cells in the body of the corpus callosum in ALS patients, especially those with C9orf72 mutations, and increased reactive astrocytes throughout the callosum. CONCLUSION: Reduced FA of the corpus callosum in ALS results from complex changes in tissue microstructure. Callosal segments with reduced FA had large numbers of microglia-macrophages in addition to loss of myelinated axons and astrogliosis. Microglial inflammation contributed to reduced FA in ALS, and may contribute to a pro-inflammatory state, but further work is needed to determine their role.

Brain Microstructural Correlates of Cognitive Dysfunction in Clinically and Biochemically Normal Hepatitis C Virus Infection.

BACKGROUND/AIMS: This study examined correlates of the brain's neurocognitive performance among clinically and biochemically normal adult patient with hepatitis C virus (HCV). We hypothesized that anti-HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using diffusion tensor tractrography (DTT) metrics. METHODS: Anti-HCV positive patient (n = 40), and healthy controls (n = 31), fulfilling inclusion criteria (incidentally detected anti-HCV positive) and able to provide informed consent were screened and recruited for the study. All these subjects and controls underwent subjective assessment of their quality of life related symptoms, neuropsychometric tests (NPT) and magnetic resonance imaging. RESULTS: The patients were subjected to neuroimaging as well as psychological testing. There was no significant difference in basic laboratory parameters in these two groups. Independent t-test reveals significantly lower neuropsychological functioning as compared to healthy control. A significantly decreased FA values and myoinsitol were observed in HCV subjects on sensory, inferior longitudinal fascicules, and STR fiber bundles as compared to healthy control. Bivariate correlation analysis reveals that neuropsychological scores are significantly positive. CONCLUSION: Our result show that HCV positive individuals would demonstrate structural brain abnormalities and neurocognitive dysfunction as well as the changes in cell component and extracellular space in the white matter regions of brain in asymptomatic HCV infection by using DTT metrics.

Predicting pain relief: Use of pre-surgical trigeminal nerve diffusion metrics in trigeminal neuralgia.

Trigeminal neuralgia (TN) is a chronic neuropathic facial pain disorder that commonly responds to surgery. A proportion of patients, however, do not benefit and suffer ongoing pain. There are currently no imaging tools that permit the prediction of treatment response. To address this paucity, we used diffusion tensor imaging (DTI) to determine whether pre-surgical trigeminal nerve microstructural diffusivities can prognosticate response to TN treatment. In 31 TN patients and 16 healthy controls, multi-tensor tractography was used to extract DTI-derived metrics-axial (AD), radial (RD), mean diffusivity (MD), and fractional anisotropy (FA)-from the cisternal segment, root entry zone and pontine segment of trigeminal nerves for false discovery rate-corrected Student's t-tests. Ipsilateral diffusivities were bootstrap resampled to visualize group-level diffusivity thresholds of long-term response. To obtain an individual-level statistical classifier of surgical response, we conducted discriminant function analysis (DFA) with the type of surgery chosen alongside ipsilateral measurements and ipsilateral/contralateral ratios of AD and RD from all regions of interest as prediction variables. Abnormal diffusivity in the trigeminal pontine fibers, demonstrated by increased AD, highlighted non-responders (n = 14) compared to controls. Bootstrap resampling revealed three ipsilateral diffusivity thresholds of response-pontine AD, MD, cisternal FA-separating 85% of non-responders from responders. DFA produced an 83.9% (71.0% using leave-one-out-cross-validation) accurate prognosticator of response that successfully identified 12/14 non-responders. Our study demonstrates that pre-surgical DTI metrics can serve as a highly predictive, individualized tool to prognosticate surgical response. We further highlight abnormal pontine segment diffusivities as key features of treatment non-response and confirm the axiom that central pain does not commonly benefit from peripheral treatments.