Decline In Fractional Anisotropy Research Articles

Protective effects of human urinary kallidinogenase against corticospinal tract damage in acute ischemic stroke patients.

This study aimed to assess the effects of human urinary kallidinogenase (HUK) on motor function outcome and corticospinal tract recovery in patients with acute ischemic stroke (AIS). This study was a randomized, controlled, single-blinded trial. Eighty AIS patients were split into two groups: the HUK and control groups. The HUK group was administered HUK and standard treatment, while the control group received standard treatment only. At admission and discharge, the National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI) and muscle strength were scored. The primary endpoint was the short-term outcomes of AIS patients under different treatments. The secondary endpoint was the degree of corticospinal tract fiber damage under different treatments. There was a significant improvement in the NIHSS Scale, BI and muscle strength scores in the HUK group compared with controls (Mann-Whitney U test; P < 0.05). Diffusion tensor tractography classification and intracranial arterial stenosis were independent predictors of short-term recovery by linear regression analysis. The changes in fractional anisotropy (FA) and apparent diffusion coefficient (ADC) decline rate were significantly smaller in the HUK group than in the control group ( P < 0.05). Vascular endothelial growth factor (VEGF) increased significantly after HUK treatment ( P < 0.05), and the VEGF change was negatively correlated with changes in ADC. HUK is beneficial for the outcome in AIS patients especially in motor function recovery. It may have protective effects on the corticospinal tract which is reflected by the reduction in the FA and ADC decline rates and increased VEGF expression. The study was registered on ClinicalTrials.gov (unique identifier: NCT04102956).

CSF sTREM2 has opposite association with brain structural damage rate at early and late stage of Alzheimer’s disease

AbstractBackgroundThe role of neuroinflammation in the pathogenesis of Alzheimer’s disease (AD) is still controversial. Recent studies proposed that microglial response may have a stage‐dependent effect on disease progression. Considering the CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) has emerged as a promising marker of microglial activation, we aimed to further test this hypothesis by studying the association between baseline sTREM2 with dynamic brain structural changes in different stage of AD.Method22 amyloid‐positive (A+) and tau‐positive (T+) AD patients and 24 A+T+ MCI patients were identified from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. The patients had baseline measurements of CSF A‐beta, P‐Tau, sTREM2, baseline and follow‐up T1‐weighted and diffusion tensor imaging (DTI) scans, and were followed up for at least one year. Voxel‐based morphometry (VBM) analysis was performed to assess grey matter volumetric change, while fractional anisotropy (FA) and mean diffusivity (MD) were derived from DTI scans to evaluate white matter microstructural integrity. Linear mixed effect models were then applied to model the longitudinal change of grey and white matter integrity, and to analyze the influence of baseline sTREM2 on the rate of brain structural changes.ResultIn A+T+ AD patients, baseline CSF sTREM2 was associated with faster FA decline and MD increase in association fibers including corpus callosum, inferior longitudinal fasciculus, cingulum, inferior fronto‐occipital fasciculus, and superior longitudinal fasciculus. In A+T+ MCI patients, baseline CSF sTREM2 was associated slower grey matter volumetric loss in regions including Alzheimer’s signature cortices such as angular gyrus and precuneus, while mixed findings were found regarding white matter integrity, with a protective effect with regard to MD but a potential negative effect against FA values in association fibers.ConclusionThe current study suggests that microglial activation at early AD stage might have a protective effect against neurodegeneration, while at late stage, it might facilitate neurodegenerative process. These observations support the hypotheses that microglial response is an active factor in the process of Alzheimer’s pathogenesis, and that it has stage‐dependent effects on disease progression. Future efforts on modulating microglial activation could be promising, given a carefully selected time window for intervention.

Progressive alterations in white matter microstructure across the timecourse of Huntington's disease.

Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD). We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn-HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24-month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15-month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract-based spatial statistics. An optimized pipeline was employed to generate participant-specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion-carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS). HD expansion-carriers from TrackOn-HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion-carriers. The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution.

Abstract TMP82: Changes In DTI Metrics In The Lateral Ventricle Of Patients With Intraventricular Hemorrhage (IVH)

Objective: To evaluate a non-invasive surrogate imaging marker for blood evacuation in patients with IVH. Clinical Relevance: Extension of intracerebral hemorrhage (ICH) to the ventricles increases the 48 hours mortality by 43%, requiring external ventricular drains (EVD) to mitigate hydrocephalus and monitor intracranial pressures. Blood increases CSF viscosity, altering the diffusion coefficient. We hypothesize change in lateral ventricle (LV) DTI metrics, fractional anisotropy (FA) and mean diffusivity (MD), can be used as a marker for blood removal after IVH. Methods: A sub-cohort of 20 patients in SHRINC trial with ICH and IVH were serially imaged at day 1 (T1=20), 14 (T1=20), 28 (T3=16), and 42 (T4=13) on a 3T MRI system. The serial T1w, segmented LV (JHU WM atlas) volumes, FA, and MD maps were registered. The FA and MD of ipsi and contralesional LV were recorded. Clinical assessment (NIHSS) was associated with the change in FA and MD of LV. A mixed model statistical analysis was performed. Results: We serially imaged 11M/9F with average age 55.4±8.7 years. The baseline hematoma volume and NIHSS were 22.1±18.5 cc and 16.1±8.7 respectively. The patients had basal ganglia (n=12) and thalamic (n=8) ICH extended into LV. The ipsilesional FA was significantly (T1=0.24, T4=0.15, p&lt;0.001) decreased (1.17% /day), and MD was significantly (T1 = 1.49*10 -3 mm 2 /sec, T4 = 2.37 *10 -3 mm 2 /sec, p&lt;0.001) increased (2.4 x 10 -5 mm 2 /sec/day). At T4, there was no relationship (p=0.919) between ipsilesional and contra-MD of LV (Fig-1). Patients with higher baseline NIHSS had a significant temporal decline in FA than those with lower NIHSS (p&lt;0.05). Temporally, ipsilesional MD was negatively associated with the baseline NIHSS (p=0.039). Conclusion: The data suggest that DTI metrics of FA and MD are associated with blood clearance from the ipsilesional ventricle.

Longitudinal corpus callosum microstructural decline in early-stage Parkinson’s disease in association with akinetic-rigid symptom severity

Previous diffusion tensor imaging (DTI) studies of Parkinson’s disease (PD) show reduced microstructural integrity of the corpus callosum (CC) relative to controls, although the characteristics of such callosal degradation remain poorly understood. Here, we utilized a longitudinal approach to identify microstructural decline in the entire volume of the CC and its functional subdivisions over 2 years and related the callosal changes to motor symptoms in early-stage PD. The study sample included 61 PD subjects (N = 61, aged 45–82, 38 M & 23 F, H&Y ≤ 2) from the Parkinson’s Progressive Markers Initiative database (PPMI). Whole-brain voxel-wise results revealed significant fractional anisotropy (FA) and mean diffusivity (MD) changes in the CC, especially in the genu and splenium. Using individually drawn CC regions of interest (ROI), our analysis further revealed that almost all subdivisions of the CC show significant decline in FA to certain extents over the two-year timeframe. Additionally, FA seemed lower in the right hemisphere of the CC at both time-points, and callosal FA decline was associated with FA and MD decline in widespread cortical and subcortical areas. Notably, multiple regression analysis revealed that across-subject akinetic-rigid severity was negatively associated with callosal FA at baseline and 24 months follow-up, and the effect was strongest in the anterior portion of the CC. These results suggest that callosal microstructure alterations in the anterior CC may serve as a viable biomarker for akinetic-rigid symptomology and disease progression, even in early PD.

Longitudinal associations of absolute versus relative moderate-to-vigorous physical activity with brain microstructural decline in aging

Higher moderate-to-vigorous intensity (MVPA) may preserve brain structural integrity, but evidence is mostly cross-sectional and relies on absolute PA measures. We examined longitudinal associations of absolute MVPA using population-level activity count thresholds and relative MVPA using individual heart rate reserve (HRR) via Actiheart with subsequent changes in brain diffusion tensor imaging (DTI) over average of 3.8 years in 248 initially cognitively normal individuals (56−91 years). DTI markers included areas important for memory (temporal areas), executive (prefrontal cortex, superior longitudinal fasciculus), and motor function (precentral gyrus, putamen, caudate, body of corpus callosum). Associations of MVPA with changes in DTI markers were examined using linear mixed-effects models, adjusted for demographics and apolipoprotein e4 carrier status. Each additional 22 min of relative MVPA per day was significantly associated with less decline in fractional anisotropy of uncinate fasciculus and cingulum-hippocampal part and with less increase in mean diffusivity of entorhinal cortex and parahippocampal gyrus. Absolute MVPA was not associated with DTI changes. More time spent in relative MVPA by HRR may prevent brain microstructural decline in selected temporal areas.

Accelerated decline in white matter microstructure in subsequently impaired older adults and its relationship with cognitive decline.

Little is known about a longitudinal decline in white matter microstructure and its associations with cognition in preclinical dementia. Longitudinal diffusion tensor imaging and neuropsychological testing were performed in 50 older adults who subsequently developed mild cognitive impairment or dementia (subsequently impaired) and 200 cognitively normal controls. Rates of white matter microstructural decline were compared between groups using voxel-wise linear mixed-effects models. Associations between change in white matter microstructure and cognition were examined. Subsequently impaired individuals had a faster decline in fractional anisotropy in the right inferior fronto-occipital fasciculus and bilateral splenium of the corpus callosum. A decline in right inferior fronto-occipital fasciculus fractional anisotropy was related to a decline in verbal memory, visuospatial ability, processing speed and mini-mental state examination. A decline in bilateral splenium fractional anisotropy was related to a decline in verbal fluency, processing speed and mini-mental state examination. Accelerated regional white matter microstructural decline is evident during the preclinical phase of mild cognitive impairment/dementia and is related to domain-specific cognitive decline.

Registration quality filtering improves robustness of voxel-wise analyses to the choice of brain template

MotivationMany clinical and scientific conclusions that rely on voxel-wise analyses of neuroimaging depend on the accurate comparison of corresponding anatomical regions. Such comparisons are made possible by registration of the images of subjects of interest onto a common brain template, such as the Johns Hopkins University (JHU) template. However, current image registration algorithms are prone to errors that are distributed in a template-dependent manner. Therefore, the results of voxel-wise analyses can be sensitive to template choice. Despite this problem, the issue of appropriate template choice for voxel-wise analyses is not generally addressed in contemporary neuroimaging studies, which may lead to the reporting of spurious results. ResultsWe present a novel approach to determine the suitability of a brain template for voxel-wise analysis. The approach is based on computing a “distance” between automatically-generated atlases of the subjects of interest and templates that is indicative of the extent of subject-to-template registration errors. This allows for the filtering of subjects and candidate templates based on a quantitative measure of registration quality. We benchmark our approach by evaluating alternative templates for a voxel-wise analysis that reproduces the well-known decline in fractional anisotropy (FA) with age. Our results show that filtering registrations minimizes errors and decreases the sensitivity of voxel-wise analysis to template choice. In addition to carrying important implications for future neuroimaging studies, the developed framework of template induction can be used to evaluate robustness of data analysis methods to template choice.

Simvastatin maintains white matter integrity in healthy middle‐aged adults with increased risk for Alzheimer’s disease: A secondary analysis of a randomized controlled trial

AbstractBackgroundThe brain is the most cholesterol‐rich organ and myelin contains 70% of total brain cholesterol. Statins are potent cholesterol‐lowing medications used by millions of adults for prevention of cerebrovascular disease, yet the effect of statins on cholesterol‐rich brain white matter (WM) is largely unknown. In this study, diffusion tensor imaging (DTI) data collected during an 18‐month randomized controlled trial in healthy middle‐aged adults with a parental family history of Alzheimer’s disease (ClinicalTrial.gov NCT00939822) was used to determine the effect of simvastatin (40mg/daily) on WM integrity.Method73 participants were randomly assigned to drug or placebo (placebo group: N=38, baseline age 55.7±8.0yrs, 76.3% female; simvastatin group: N=35, baseline age 56.7±6.3yrs, 68.6% female) and underwent MRI (T1‐weighted, T2FLAIR, and DTI at baseline, 6m, 12m, and 18m). DTI parameter maps were used for longitudinal WM microstructure and tract‐based spatial statistics analyses. Total gray matter (GM), WM, and WM hyperintensity (WMH) volumes were calculated from T1‐weighted and T2FLAIR imaging. ANCOVA models (covariates: age, sex, APOE4‐genotype) tested the effect of treatment group on percent change in neuroimaging measures at each study visit. Model‐based path analysis tested whether the effects of simvastatin on WM microstructure were mediated by change in serum total cholesterol (TC) levels.ResultThere were no differences in baseline neuroimaging measures between treatment groups. At 18 months, the simvastatin group showed significantly attenuated decline in fractional anisotropy (FA) and attenuated increase in radial diffusivity (RD) in total WM relative to the placebo group (Fig1). At 12 and 18 months, the simvastatin group showed preserved WM volume relative the placebo group, but no differences in GM or WMH volume (Fig2). Approximately 30% of the effect of simvastatin on change in WM microstructure was mediated by change in serum TC (Fig3).Conclusion18 months of simvastatin use in statin‐naïve middle‐aged adults resulted in preserved WM microstructure and volume compared to placebo, suggestive of a potential protective effect of simvastatin on WM. Changes in FA and RD (but not axial diffusivity) suggest simvastatin‐induced alterations in myelin content, and partial mediation by change in serum TC suggests pleotropic effects of simvastatin on WM.

Brain Substrates of Time-Based Prospective Memory Decline in Aging: A Voxel-Based Morphometry and Diffusion Tensor Imaging Study.

Time-based prospective memory (TBPM) allows us to remember to perform intended actions at a specific time in the future. TBPM is sensitive to the effects of age, but the neural substrates of this decline are still poorly understood. The aim of the present study was thus to better characterize the brain substrates of the age-related decline in TBPM, focusing on macrostructural gray matter and microstructural white matter integrity. We administered a TBPM task to 22 healthy young (26 ± 5.2years) and 23 older (63 ± 5.9years) participants, who also underwent volumetric magnetic resonance imaging and diffusion tensor imaging scans. Neuroimaging analyses revealed lower gray matter volumes in several brain areas in older participants, but these did not correlate with TBPM performance. By contrast, an age-related decline in fractional anisotropy in several white-matter tracts connecting frontal and occipital regions did correlate with TBPM performance, whereas there was no significant correlation in healthy young subjects. According to the literature, these tracts are connected to the anterior prefrontal cortex and the thalamus, 2 structures involved in TBPM. These results confirm the view that a disconnection process occurs in aging and contributes to cognitive decline.

A prospective harmonized multicenter DTI study of cerebral white matter degeneration in ALS.

To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS). Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale-Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center. Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe. Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes and, to a lesser degree, in the corticopontine/corticorubral tracts and corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS. NCT02405182.

124 Correlating structure and function to better identify surrogate end points for clinical trial design: a longitudinal clinical and imaging study of primary progressive aphasia

IntroductionMeasuring longitudinal change in white matter tracts offers a highly sensitive way of monitoring the course of a range of neurodegenerative conditions. However, it remains unclear how structural changes correlate with symptom progression. Clinically meaningful outcomes remain a key requirement in therapeutic trial design so imaging biomarkers need to accurately predict these outcomes. Identifying surrogate clinical end points is of particular importance in neurodegenerative conditions where clinical change evolves slowly. To address this the current study aims to identify potential surrogate end points by assessing correlations between clinical and neuroimaging measures.Methods30 patients meeting consensus criteria for a diagnosis of primary progressive aphasia underwent longitudinal imaging and neuropsychological assessments at baseline and one year. A mixed effects model was designed to test for significant interactions over time between changes in neuropsychological performance and Fractional Anisotropy (FA) in key white matter tracts.ResultsDeclining single word comprehension correlated with reducing FA within bilateral inferior longitudinal fasciculus (ILF), bilateral superior longitudinal fasciculus (SLF) and the genu of the corpus callosum; declining naming ability correlated with reducing FA in the left ILF, right uncinate fasciculus and right SLF; declining word repetition correlated with reducing FA within the left ILF.ConclusionsDeclining neuropsychological scores correlated with longitudinal decline in FA in a number of white matter tracts across an anatomically distributed language network. Correlations between function and structure provide evidence that monitoring structural white matter changes in the tracks identified may have value as a surrogate end point for future clinical trials.

In vivo high-resolution diffusion tensor imaging of the developing neonatal rat cortex and its relationship to glial and dendritic maturation

Diffusion tensor imaging (DTI) is increasingly utilized as a sensitive tool for studying brain maturation and injuries during the neonatal period. In this study, we acquired high resolution in vivo DTI data from neonatal rat brains from postnatal day2 (P2) to P10 and correlated temporal changes in DTI derived markers with microstructural organization of glia, axons, and dendrites during this critical period of brain development. Group average images showed dramatic temporal changes in brain morphology, fractional anisotropy (FA) and mean diffusivity (MD). Most cortical regions showed a monotonous decline in FA and an initial increase in MD from P2 to P8 that declined slightly by P10. Qualitative histology revealed rapid maturation of the glial and dendritic networks in the developing cortex. In the cingulate and motor cortex, the decreases in FA over time significantly correlated with structural anisotropy values computed from histological sections stained with glial and dendritic markers. However, in the sensory and visual cortex, other factors probably contributed to the observed decreases in FA. We did not observe any significant correlations between FA and structural anisotropy computed from the axonal histological marker.

Vascular burden and APOE ε4 are associated with white matter microstructural decline in cognitively normal older adults

White matter microstructure can be measured with diffusion tensor imaging (DTI). While increasing age is a predictor of white matter (WM) microstructure changes, roles of other possible modifiers, such as cardiovascular risk factors, APOE ε4 allele status and biological sex have not been clarified.We investigated 665 cognitively normal participants from the Baltimore Longitudinal Study of Aging (age 50–95, 56.7% female) with a total of 1384 DTI scans. WM microstructure was assessed by fractional anisotropy (FA) and mean diffusivity (MD). A vascular burden score was defined as the sum of five risk factors (hypertension, obesity, elevated cholesterol, diabetes and smoking status). Linear mixed effects models assessed the association of baseline vascular burden on baseline and on rates of change of FA and MD over a mean follow-up of 3.6 years, while controlling for age, race, and scanner type. We also compared DTI trajectories in APOE ε4 carriers vs. non-carriers and men vs. women.At baseline, higher vascular burden was associated with lower FA and higher MD in many WM structures including association, commissural, and projection fibers. Higher baseline vascular burden was also associated with greater longitudinal decline in FA in the hippocampal part of the cingulum and the fornix (crus)/stria terminalis and splenium of the corpus callosum, and with greater increases in MD in the splenium of the corpus callosum. APOE ε4 carriers did not differ from non-carriers in baseline DTI metrics but had greater decline in FA in the genu and splenium of the corpus callosum. Men had higher FA and lower MD in multiple WM regions at baseline but showed greater increase in MD in the genu of the corpus callosum. Women showed greater decreases over time in FA in the gyrus part of the cingulum, compared to men.Our findings show that modifiable vascular risk factors (1) have a negative impact on white matter microstructure and (2) are associated with faster microstructural deterioration of temporal WM regions and the splenium of the corpus callosum in cognitively normal adults. Reducing vascular burden in aging could modify the rate of WM deterioration and could decrease age-related cognitive decline and impairment.

Progressive Decline in Gray and White Matter Integrity in de novo Parkinson's Disease: An Analysis of Longitudinal Parkinson Progression Markers Initiative Diffusion Tensor Imaging Data.

Background: Progressive neuronal loss in neurodegenerative diseases such as Parkinson’s disease (PD) is associated with progressive degeneration of associated white matter tracts as measured by diffusion tensor imaging (DTI). These findings may have diagnostic and functional implications but their value in de novo PD remains unknown. Here we analyzed longitudinal DTI data from Parkinson’s Progression Markers Initiative de novo PD patients for changes over time relative to healthy control (HC) participants.Methods: Baseline and 1-year follow-up DTI MRI data from 71 PD patients and 45 HC PPMI participants were included in the analyses. Whole-brain fractional anisotropy (FA) and mean diffusivity (MD) images were compared for baseline group differences and group–by–time interactions. Baseline and 1-year changes in DTI values were correlated with changes in DTI measures and symptom severity, respectively.Results: At baseline, PD patients showed significantly increased FA in brainstem, cerebellar, anterior corpus callosal, inferior frontal and inferior fronto-occipital white matter and increased MD in primary sensorimotor and supplementary motor regions. Over 1 year PD patients showed a significantly stronger decline in FA compared to HC in the optic radiation and corpus callosum and parietal, occipital, posterior temporal, posterior thalamic, and vermis gray matter. Significant increases in MD were observed in white matter of the midbrain, optic radiation and corpus callosum, while gray matter of prefrontal, insular and posterior thalamic regions. Baseline brainstem FA white matter (WM) values predicted 1-year changes in FA white matter and MD gray matter values. White but not gray matter changes in both FA and MD were significantly associated with changes in symptom severity.Conclusion: Significant gray and white matter DTI alterations are observable at the time of PD diagnosis and expand in the first year of de novo PD to other cortical and white matter regions. This pattern of DTI changes is in line with preclinical and neuroanatomical studies suggesting that the increased spatial spread of alpha-synuclein neuropathology is the key mechanism of PD progression. Taken together, these findings suggest that DTI may serve as a sensitive biomarker of disease progression in early-stage PD.

O6.5. LINKING CORTICAL AND CONNECTIONAL PATHOLOGY IN SCHIZOPHRENIA

BackgroundSchizophrenia is associated with cortical thinning and breakdown in white matter microstructure. Whether these pathological processes are related remains unclear. We used multimodal neuroimaging to investigate the relation between regional cortical thinning and breakdown in adjacent infracortical white matter as a function of age and illness duration.MethodsStructural magnetic resonance and diffusion images were acquired in 218 schizophrenia patients and 167 age-matched healthy controls to map cortical thickness (CT) and fractional anisotropy (FA) in regionally adjacent infracortical white matter at various cortical depths.ResultsBetween-group differences in CT and infracortical FA were inversely correlated across cortical regions (r=−0.5, p<0.0001), such that the most anisotropic infracortical white matter was found adjacent to regions with extensive cortical thinning. This pattern was evident in early (20 years: r=−0.3, p=0.005) and middle life (30 years: r=−0.4, p=0.004, 40 years: r=−0.3, p=0.04), but not beyond 50 years (p>0.05). Frontal pathology contributed most to this pattern, with extensive cortical thinning in patients compared to controls at all ages (p<0.05); in contrast to initially increased frontal infracortical FA in patients at 30 years, followed by rapid decline in frontal FA with age (rate of annual decline; patients: 0.0012, controls 0.0006, p<0.001).DiscussionCortical thinning and breakdown in white matter anisotropy are inversely related in young schizophrenia patients, with abnormally elevated white matter myelination found adjacent to frontal regions with extensive cortical thinning. We argue that elevated frontal anisotropy reflects regionally-specific, compensatory responses to cortical thinning, which are eventually overwhelmed with increasing illness duration.

Longitudinal hippocampal and extra-hippocampal microstructural and macrostructural changes following temporal lobe epilepsy surgery

Objectives1) Characterize the evolution of microstructural changes in the contralateral, non-operated hippocampus—using longitudinal diffusion tensor imaging (DTI)—following surgery for temporal lobe epilepsy (TLE). 2) Characterize the downstream extra-hippocampal volumetric changes of the fornix and mammillary bodies after TLE surgery. 3) Examine the relationship between these measures and seizure/cognitive outcome. MethodsSerial structural and DTI brain MRI scans were collected in 25 TLE patients pre- and post-surgery (anterior temporal lobectomy, ATL – 13; selective amygdalohippocampectomy, SelAH – 12) and in 12 healthy controls. Contralateral hippocampal fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) were computed with manual hippocampal tracings as volumes of interest following co-registration to anatomical images. Fornix and mammillary body volumetry was performed by manual segmentation. ResultsAfter surgery, the non-resected hippocampus showed significant postoperative decline in FA (p = 0.0001), with increase of MD (p = 0.01) and RD (p = 0.0001). In contrast to the timing of our previously reported volume changes where atrophy is observed in the first week, diffusion changes occurred late, taking 1–3 years to develop and are not significant at one week after surgery. Diffusion changes are accompanied by delayed limbic circuit volume loss in the mammillary bodies (35%; p < 0.0001) and fornix (24%; p < 0.0001) compared to baseline. There was no correlation between postoperative diffusion or structural changes and memory score nor did the degree of postoperative change in hippocampal DTI parameters, mammillary body volume or fornix volume vary significantly based on seizure outcome. SignificanceDifferences observed in the timing of postoperative volume (first week) and FA/MD (one year) changes would suggest that early contralateral hippocampal atrophy is not secondary to fluid shifts (dehydration) while the late DTI changes suggest ongoing microstructural changes extending beyond the early postoperative period. Postoperative hippocampal diffusion changes are accompanied by delayed mammillary body and fornix volume loss which did not differ when stratified by seizure outcome nor was correlated with degree of hippocampal diffusion change. Finally, we did not identify any significant correlation between postoperative diffusion parameter change and memory performance.

PB 1 In vivo assessment of neurodegeneration in the brain by serial longitudinal diffusion tensor imaging – an application to amyotrophic lateral sclerosis

Introduction The potential of magnetic resonance imaging (MRI) as a technical biomarker for cerebral alterations is under investigation in neurodegenerative diseases. In this study, a framework for the longitudinal analysis of diffusion tensor imaging (DTI)-based mapping with a series of follow-up scans was applied to longitudinal microstructure assessment of predefined white matter tracts in the course of amyotrophic lateral sclerosis (ALS), as an example for a rapidly progressive neurodegenerative disease. Methods Fifty-four longitudinal DTI datasets from 6 patients with ALS and 3 controls were recorded each 3 months (with up to 15 follow-up scans), yielding a total of 54 longitudinal DTI data sets. After individual alignment and stereotaxic normalization, an averaged DTI data set was created for fibertracking. Fractional anisotropy (FA) values of the tract structures were used to calculate progression rates based on DTI metrics. Results Patients with ALS showed an FA decline along the corticospinal tract (CST) which has been identified as the first affected tract structure in ALS and as the tract correlating with Braak‘s neuropathological stage 1 ( Kassubek et al., 2014 ). FA of controls remained stable in longitudinal DTI scans, whereas, FA decrease progression in the CST ranged from 0.5% to 6% per year in ALS-patients, i.e. four patients showed low progression rates between 0.5% and 2% per year and two patients showed fast progression rates between 3% and 6% per year. The ALS-FRS-R decline correlated significantly with FA decline over time. Conclusion On the basis of the longitudinal DTI data assessment with multiple follow-up measures, FA values were shown to be an in vivo marker for ALS-associated disease progression. That way, imaging-based progression rates at the individual patient level can be determined from DTI scans.

White matter microstructure degenerates in patients with postherpetic neuralgia

The central mechanisms underlying postherpetic neuralgia (PHN) pain remains unknown. The primary purpose of this study was to identify microstructural white matter changes closely related to the PHN pain by means of diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS) analysis. DTI data of the brains were obtained from 8 PHN patients and 8 healthy controls (HC) that were matched in age, gender, and educational level. DTI metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were separately compared between the two groups using TBSS analysis to detect subtle microstructural changes. Partial correlation analyses were also conducted to evaluate the association between the altered DTI measures and clinical features. Average diffusion indices of white matter skeletons in the whole-brain showed no significant difference between the two groups. However, compared to the HC group, patients with PHN pain revealed reductions in localized FA and AD values in white matter underlying insula, occipital lobe, cerebellum, precentral gyrus, and many other regions, but without distinct change in regional MD and RD levels. In addition, decline of FA and AD values in patients represented significant negative correlations with PHN pain duration when the effect of VAS scores were excluded. The current study suggest that there exists altered microstructure integrity of white matter in multiple brain regions in patients with PHN, and these changes increase in size as the duration of the pain increases. These findings might provide a new insight into the mechanism of PHN pain in brain.

Changes in brain white matter integrity after systemic treatment for breast cancer: a prospective longitudinal study.

An increasing number of studies suggest chemotherapy for breast cancer may be neurotoxic. Cross-sectional MRI diffusion tensor imaging (DTI) studies suggest a vulnerability of brain white matter to various chemotherapeutic regimens. Up till now, this was confirmed in one prospective DTI study: Deprez et al. (2012) showed a widespread decline in fractional anisotropy (FA) of breast cancer patients after chemotherapy consisting of 5-fluorouracil (5-FU), epirubicin and cyclophosphamide (FEC) +/- taxanes +/- endocrine treatment. Our aim was to evaluate whether similar detrimental effects on white matter integrity would be observed with the currently widely prescribed anthracycline-based chemotherapy for breast cancer (predominantly doxorubicin and cyclophosphamide +/- taxanes +/- endocrine treatment (=BC+SYST; n=26) compared to no systemic treatment (BC; n=23) and no-cancer controls (NC; n=30). Assessment took place before and six months after chemotherapy, and matched intervals for the unexposed groups. DTI data were analyzed using voxel-based tract-based spatial statistics and region of interest (ROI) analysis. Voxel-based analysis did not show an effect of chemotherapy +/- endocrine treatment on white matter integrity. ROI analysis however indicated subtle detrimental effects of chemotherapy +/- endocrine treatment by showing a larger decline in WM integrity in the superior longitudinal fasciculus and corticospinal tract in BC+SYST than BC. Indications for relatively mild neurotoxicity in our study might be explained by patient characteristics and specific aspects of data analysis. The omission of 5-FU in current treatment regimens or the administration of doxorubicin instead of epirubicin is also discussed as an explanation for the observed effects.