White Matter Structural Changes Research Articles

Brain structural changes in CADASIL patients: A morphometric magnetic resonance imaging study

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a subcortical, inherited, cerebral small vessel disease. Several studies have revealed the involvement of specific cortical regions. However, the structural brain alterations and their clinical correlations remain largely undetermined. MethodsWe evaluated 22 CADASIL patients and 22 age- and sex-matched healthy controls. We used surface- and voxel-based morphometric data derived from 3.0-T magnetic resonance imaging (MRI) to explore structural changes in gray and white matter. We calculated Pearson correlations between such data and clinical and MRI metrics. ResultsCompared with controls, CADASIL patients exhibited significantly decreased cortical thickness in the left supramarginal gyrus, superior temporal gyrus, transverse temporal gyrus, insula, lateral orbitofrontal gyrus, isthmus cingulate gyrus and precentral gyrus. An extensive decrease in the white (but not gray) matter volume was also evident, predominantly in the frontal, parietal, temporal, and occipital lobes. The number of previous strokes or transient ischemic attacks was negatively associated with the cortical thickness of the left pars opercularis and right posterior cingulate gyrus. ConclusionReductions in cortical thickness and white matter volume were evident in CADASIL patients compared with controls, and higher numbers of strokes and transient ischemic attacks were associated with regional cortical thinning.

Change in Right Inferior Longitudinal Fasciculus Integrity Is Associated With Naming Recovery in Subacute Poststroke Aphasia

Background. Despite progress made in understanding functional reorganization patterns underlying recovery in subacute aphasia, the relation between recovery and changes in white matter structure remains unclear. Objective. To investigate changes in dorsal and ventral language white matter tract integrity in relation to naming recovery in subacute poststroke aphasia. Methods. Ten participants with aphasia after left-hemisphere stroke underwent language testing and diffusion tensor imaging twice within 3 months post onset, with a 1-month interval between sessions. Deterministic tractography was used to bilaterally reconstruct the superior longitudinal fasciculus (SLF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), middle longitudinal fasciculus (MdLF), and uncinate fasciculus (UF). Per tract, the mean fractional anisotropy (FA) was extracted as a measure of microstructural integrity. Naming accuracy was assessed with the Boston Naming Test (BNT). Correlational analyses were performed to investigate the relationship between changes in FA values and change in BNT score. Results. A strong positive correlation was found between FA change in the right ILF within the ventral stream and change on the BNT (r = 0.91, P < .001). An increase in FA in the right ILF was associated with considerable improvement of naming accuracy (range BNT change score: 12-14), a reduction with limited improvement or slight deterioration. No significant correlations were found between change in naming accuracy and FA change in any of the other right or left ventral and dorsal language tracts. Conclusions. Naming recovery in subacute aphasia is associated with change in the integrity of the right ILF.

Procedural and declarative memory brain systems in developmental language disorder (DLD)

The aim of the current study was to examine microstructural differences in white matter relevant to procedural and declarative memory between adolescents/young adults with and without Developmental Language Disorder (DLD) using diffusion tensor imaging (DTI). The findings showed atypical age-related changes in white matter structures in the corticostriatal system, in the corticocerebellar system, and in the medial temporal region in individuals with DLD. Results highlight the importance of considering the age factor in research on DLD. Future studies are needed to examine the developmental relationship between long-term memory and individual differences in language development and learning.

Functional Connectivity of the Supplementary Motor Network Is Associated with Fried's Modified Frailty Score in Older Adults.

Frailty is a geriatric syndrome defined by coexistence of unintentional weight loss, low physical reserve, or activity and is associated with adverse health events. Neuroimaging studies reported structural white matter changes in frail patients. In the current study, we hypothesized that clinical frailty is associated also with functional changes in motion-related cortical areas, that is, (pre-)supplementary motor areas (SMA, pre-SMA). We expected that observed functional changes are related to motor-cognitive test performance. We studied a clinical sample of 143 cognitively healthy patients ≥65 years presenting for elective surgery, enrolled in the BioCog prospective multicentric cohort study on postoperative cognitive disorders. Participants underwent preoperative resting-state functional magnetic resonance imaging, motor-cognitive testing, and assessment of Fried's modified frailty criteria. We analyzed functional connectivity associations with frailty and motor-cognitive test performance. Clinically robust patients (N = 60) showed higher connectivity in the SMA network compared to frail (N = 13) and prefrail (N = 70) patients. No changes were found in the pre-SMA network. SMA connectivity correlated with motor speed (Trail-Making-Test A) and manual dexterity (Grooved Pegboard Test). Our results suggest that diminished functional connectivity of the SMA is an early correlate of functional decline in the older adults . The SMA may serve as a potential treatment target in frailty.

DIFFUSION TENSOR MAGNETIC RESONANCE IMAGING IN EARLY DIAGNOSIS OF STRUCTURAL CHANGES IN BRAIN WHITE MATTER IN SMALL VESSEL DISEASE ASSOCIATED WITH ARTERIAL HYPERTENSION AND IONIZING RADIATION.

to determine the early signs of structural changes in brain white matter in small vessel disease associated with arterial hypertension and exposure to ionizing radiation using DTI-MRI. 45 patients (mean age (57.56 ± 6.34) years) with small vessel disease (SVD) associatedwith arterial hypertension (AH) were examined: group I - 20 patients, participants of liquidation of the accident atthe Chornobyl nuclear power plant (Chornobyl clean-up workers); group II - 25 patients not exposed to ionizingradiation. MRI was performed on an Ingenia 3T tomograph («Philips»). The fractional anisotropy (FA) was determined in the main associative and commissural pathways, periventricular prefrontal areas (fasciculus fronto-occipitalis superior / anterior - f. FO ant., corona radiata anterior - CR ant.) and semioval centers (SC). No signs of cerebral cortex or brain white matter (WM) atrophy, intracerebral microhemorrhages, and widespread areas of leukoaraiosis consolidation were observed in the examined patients. In the Chornobyl clean-up workers a larger number of foci of subcortical leukoaraiosis was visualized (80 %) on MRI images including multiple -8 (40 %), > 0.5 cm - 10 (50 %), with signs of consolidation - 5 (25 %). The results of the FA analysis in semiovalcenters showed its significant decrease in the patients of groups I and II (p < 0,007), regardless of the presence orabsence of visual signs of subcortical leukoaraiosis (ScLA) (III gr.: 253-317, p < 0.00001; IV gr.: 287- 375,p < 0.001). FA indicators in f. FO ant. and CR ant. in the patients of groups I and II differed insignificantly but weresubstantially lower than controls (p < 0.05). FA was significantly lower, compared to reference levels, in visuallyunchanged f. FO ant. (0.389-0.425; p = 0.015) and CR ant. (0.335-0.403; p = 0.05). In patients with AH-associated SVD of middle age, regardless of the effects of ionizing radiation, no significant changes in FA in the mainWM associative and commissural pathways were found (p > 0.05). DTI-MRI allows to detect early signs of structural changes in the white matter of the brain - a significant decrease in fractional anisotropy indicators in visually unchanged periventricular and subcortical areas. Themain associative and commissural pathways of the brain remain intact in the absence of widespread consolidatedfoci of leukoaraiosis and lacunar infarctions. The negative impact of ionizing radiation on the course of SVD associated with arterial hypertension is manifested by more active processes of WM disorganization: the prevalence andtendency to the consolidation of periventricular and subcortical leukoaraiosis foci, a significant FA decrease in semioval centers.

Fixel-based analysis reveals fiber-specific alterations during the progression of Parkinson’s disease

Disruption of brain circuits is one of the core mechanisms of Parkinson’s disease (PD). Understanding structural connection alterations in PD is important for effective treatment. However, due to methodological limitations, most studies were unable to account for confounding factors such as crossing fibers and were unable to identify damages to specific fiber tracts. In the present study, we aimed to demonstrate tract-specific white matter structural changes in PD patients and their relationship with clinical symptoms. Ninety-eight PD patients, divided into early (ES) and middle stage (MS) groups, and 76 healthy controls (HCs) underwent brain magnetic resonance imaging scans and clinical assessments. Fixel-based analysis was used to investigate fiber tract alterations in PD patients. Compared to HCs, the PD patients showed decreased fiber density (FD) in the corpus callosum (CC), increased FD in the cortical spinal tract (CST), and increased fiber-bundle cross-section (FC, log-transformed: log-FC) in the superior cerebellar peduncle (SCP). Analysis of variance (ANOVA) revealed significant differences in FD in the CST and log-FC in the SCP among the three groups. Post-hoc analysis revealed that the mean FD values of the CST were higher in ES and MS patient groups compared to HCs, and the mean log-FC values of the SCP were higher in ES and MS patient groups compared to HCs. Additionally, the FD values of the CC in PD patients were negatively correlated with the Unified Parkinson’s Disease Rating Scale part-III (UPDRS-III) scores (r = -0.257, p = 0.032), Hamilton Depression Rating Scale 17 Items (HAMD-17) scores (r = -0.230, p = 0.033), and Hamilton Anxiety Scale (HAMA) scores (r = -0.248, p = 0.032). Moreover, log-FC values of the SCP (r = 0.274, p = 0.028) and FD values of the CST (r = 0.384, p < 0.001) were positively correlated with the UPDRS-III scores. We concluded that PD patients had both decreased and increased white matter integrity within specific fiber bundles. Additionally, these white matter alterations were different across disease stages, suggesting the occurrence of complex pathological and compensatory changes during the development of PD.

Amnestic mild cognitive impairment in Parkinson's disease: White matter structural changes and mechanisms.

Mild cognitive impairment (MCI) is a heterogeneous cognitive disorder that is often comorbid with Parkinson’s diseases (PD). The amnestic subtype of PD-MCI (PD-aMCI) has a higher risk to develop dementia. However, there is a lack of studies on the white matter (WM) structural changes of PD-aMCI. We characterized the WM structural changes of PD-aMCI (n = 17) with cognitively normal PD (PD-CN, n = 19) and normal controls (n = 20), using voxel-based and tract-based spatial statistics (TBSS) analyses on fractional anisotropy (FA) axial diffusivity (AD), and radial diffusivity (RD). By excluding and then including the motor performance as a covariate in the comparison analysis between PD-aMCI and PD-CN, we attempted to discern the influences of two neuropathological mechanisms on the WM structural changes of PD-aMCI. The correlation analyses between memory and voxel-based WM measures in all PD patients were also performed (n = 36). The results showed that PD-aMCI had smaller FA values than PD-CN in the diffuse WM areas, and PD-CN had higher AD and RD values than normal controls in the right caudate. Most FA difference between PD-aMCI and PD-CN could be weakened by the motor adjustment. The FA differences between PD-aMCI and PD-CN were largely spatially overlapped with the memory-correlated FA values. Our findings demonstrated that the WM structural differences between PD-aMCI and PD-CN were mainly memory-related, and the influence of motor adjustment might indicate a common mechanism underlying both motor and memory impairment in PD-aMCI, possibly reflecting a predominant influence of dopaminergic neuropathology.

Structural neuroimaging of the altered brain stemming from pediatric and adolescent hearing loss-Scientific and clinical challenges.

There has been a spurt in structural neuroimaging studies of the effect of hearing loss on the brain. Specifically, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) technologies provide an opportunity to quantify changes in gray and white matter structures at the macroscopic scale. To date, there have been 32 MRI and 23 DTI studies that have analyzed structural differences accruing from pre- or peri-lingual pediatric hearing loss with congenital or early onset etiology and postlingual hearing loss in pre-to-late adolescence. Additionally, there have been 15 prospective clinical structural neuroimaging studies of children and adolescents being evaluated for cochlear implants. The results of the 70 studies are summarized in two figures and three tables. Plastic changes in the brain are seen to be multifocal rather than diffuse, that is, differences are consistent across regions implicated in the hearing, speech and language networks regardless of modes of communication and amplification. Structures in that play an important role in cognition are affected to a lesser extent. A limitation of these studies is the emphasis on volumetric measures and on homogeneous groups of subjects with hearing loss. It is suggested that additional measures of morphometry and connectivity could contribute to a greater understanding of the effect of hearing loss on the brain. Then an interpretation of the observed macroscopic structural differences is given. This is followed by discussion of how structural imaging can be combined with functional imaging to provide biomarkers for longitudinal tracking of amplification. This article is categorized under: Developmental Biology > Developmental Processes in Health and Disease Translational, Genomic, and Systems Medicine > Translational Medicine Laboratory Methods and Technologies > Imaging.

Fiber-Specific White Matter Alterations in Parkinson's Disease

Background: Disruption of brain circuits, including the basal ganglia network, is one of the core mechanisms of Parkinson’s disease(PD). Understanding the structural connection alterations in PD is the key for relevant treatment. Although, due to methodological limitations, most previous studies suffered from the difficulty of locating white matter damages to specific fiber tracts. In the present study, we aimed to demonstrate tract-specific white matter structural changes and its relationship with clinical symptoms. Methods: Nighty-eight PD patients(41 patients were at early stage and 57 were at middle stage) and 76 healthy controls were enrolled and underwent brain magnetic resonance imaging and neuropsychological tests. We implemented the fixel-based analysis method to investigate both micro- and macro-structural changes in the white matter fibers of PD patients, and to investigate their correlation with clinical symptoms. Findings: We found decreased fiber density(FD) of the corpus callosum and increased FD of the cortical spinal tract in PD patients comparing to healthy controls. We also found increased fiber-bundle cross-section(FC) of the superior cerebellar peduncle of PD patients. Further region-of-interest analysis showed that FD values of the corpus callosum in PD patients were negatively correlated with UPDRS-III scores(r=0.001, p=-0.334), HAMD-17 scores(r=0.043, p=-0.205) and HAMA scores(r=0.02, p=-0.234). Also, log transformed FC values of superior cerebellar peduncle were negatively correlated with HAMD-17 scores(r=0.013, p=-0.251) and positively correlated with MMSE scores(r=0.002, p=0.312). Interpretation: PD patients had both decreased and increased white matter integrity within specific fiber bundles. Additionally, these white matter alterations were different across disease stages, suggesting complex pathological and compensatory changes during the development of PD. Funding Statement: This study was supported by the 13th Five-year Plan for National Key Research and Development Program of China (Grant No. 2016YFC1306600), the Health Foundation for Creative Talents in Zhejiang Province (2016). Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: All the subjects had signed written informed consent forms before participating in the study. This research was approved by the Medical Ethics Committee of 2nd Affiliated Hospital, Zhejiang University.

No relationship between fornix and cingulum degradation and within-network decreases in functional connectivity in prodromal Alzheimer's disease.

The earliest changes in the brain due to Alzheimer's disease are associated with the neural networks related to memory function. We investigated changes in functional and structural connectivity among regions that support memory function in prodromal Alzheimer's disease, i.e., during the mild cognitive impairment (MCI) stage. Twenty-three older healthy controls and 25 adults with MCI underwent multimodal MRI scanning. Limbic white matter tracts-the fornix, parahippocampal cingulum, retrosplenial cingulum, subgenual cingulum and uncinate fasciculus-were reconstructed in ExploreDTI using constrained spherical deconvolution-based tractography. Using a network-of-interest approach, resting-state functional connectivity time-series correlations among sub-parcellations of the default mode and limbic networks, the hippocampus and the thalamus were calculated in Conn. Controlling for age, education, and gender between group linear regressions of five diffusion-weighted measures and of resting state connectivity measures were performed per hemisphere. FDR-corrections were performed within each class of measures. Correlations of within-network Fisher Z-transformed correlation coefficients and the mean diffusivity per tract were performed. Whole-brain graph theory measures of cluster coefficient and average path length were inspecting using the resting state data. MCI-related changes in white matter structure were found in the fornix, left parahippocampal cingulum, left retrosplenial cingulum and left subgenual cingulum. Functional connectivity decreases were observed in the MCI group within the DMN-a sub-network, between the hippocampus and sub-areas -a and -c of the DMN, between DMN-c and DMN-a, and, in the right hemisphere only between DMN-c and both the thalamus and limbic-a. No relationships between white matter tract 'integrity' (mean diffusivity) and within sub-network functional connectivity were found. Graph theory revealed that changes in the MCI group was mostly restricted to diminished between-neighbour connections of the hippocampi and of nodes within DMN-a and DMN-b.

Multidimensional Top-Down Proteomics of Brain-Region-Specific Mouse Brain Proteoforms Responsive to Cocaine and Estradiol.

Cocaine addiction afflicts nearly 1 million adults in the United States, and to date, there are no known treatments approved for this psychiatric condition. Women are particularly vulnerable to developing a cocaine use disorder and suffer from more serious cardiac consequences than men when using cocaine. Estrogen is one biological factor contributing to the increased risk for females to develop problematic cocaine use. Animal studies have demonstrated that estrogen (17β-estradiol or E2) enhances the rewarding properties of cocaine. Although E2 affects the dopamine system, the molecular and cellular mechanisms of E2-enhanced cocaine reward have not been characterized. In this study, quantitative top-down proteomics was used to measure intact proteins in specific regions of the female mouse brain after mice were trained for cocaine-conditioned place preference, a behavioral test of cocaine reward. Several proteoform changes occurred in the ventral tegmental area after combined cocaine and E2 treatments, with the most numerous proteoform alterations on myelin basic protein, indicating possible changes in white matter structure. There were also changes in histone H4, protein phosphatase inhibitors, cholecystokinin, and calmodulin proteoforms. These observations provide insight into estrogen signaling in the brain and may guide new approaches to treating women with cocaine use disorder.

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.

Unveiling early cortical and subcortical neuronal degeneration in ALS mice by ultra-high field diffusion MRI

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily characterized by the progressive impairment of motor functions. However, a significant portion of affected patients develops severe cognitive dysfunction, developing a widespread white (WM) and gray matter (GM) microstructural impairment. The objective of this study is to determine if Gaussian and non-Gaussian diffusion models gathered by ultra-high field diffusion MRI (UHFD-MRI) are an appropriate tool to detect early structural changes in brain white and gray matter in a preclinical model of ALS. ALS brains (G93A-SOD1mice) were scanned in a 16.7 T magnet. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) have shown presymptomatic decrease in axonal organization by Fractional Anisotropy (FA) and neurite content by Intracellular Volume Fraction (ICVF) across deep WM (corpus callosum) as well as superficial (cortex) and deep (hippocampus) GM. Additional diffusion kurtosis imaging (DKI) analysis demonstrated broader and earlier GM reductions in mean kurtosis (MK), possibly related to the decrease in neuronal complexity. Histological validation was obtained by an ALS fluorescent mice reporter (YFP, G93A-SOD1 mice). The combination of DTI, NODDI, and DKI models have proved to provide a more complete assessment of the early microstructural changes in the ALS brain, particularly in areas associated with high cognitive functions. This comprehensive approach should be considered as a valuable tool for the early detection of neuroimaging markers.

Topological reorganization after partial auditory deprivation—a structural connectivity study in single-sided deafness

Growing evidence shows that partial auditory deprivation leads to extensive neural functional plasticity, which occurs not only in the auditory cortex but also in other sensory regions and cognitive areas. However, studies in structural topological properties are still limited, especially those investigating the relationship between structural connectome alterations and auditory abilities. To clarify this, we investigated white matter structural connectivity changes and the relationship between connection strength and hearing abilities in individuals with long-term single-sided deafness (SSD), a common form of partial hearing deprivation, using diffusion tensor imaging and network-based analysis. The results showed globally improved connection efficiency, locally weakened visual networks, and strengthened fronto-parietal sub-networks in SSD compared to normal hearing controls. Furthermore, a strong positive correlation between hearing abilities (including speech recognition in noise and sound localization) and connection strength, mainly in the fronto-parietal areas, was found in SSD. Our study reveals alteration of the structural network connections in SSD, especially in cognitive related networks, which showed close correlation with hearing abilities. Our findings provide new insights into topological white matter reorganization of the brain after partial sensory deprivation.

Speech network regional involvement in bulbar ALS: a multimodal structural MRI study

Objective: To examine gray (GM) and white matter (WM) structural changes in regions of the speech network (SpN) in ALS patients with varying degree of bulbar disease. Methods: T1 and DTI images were obtained for 19 ALS participants and 13 neurologically-intact controls. Surface-based, volumetric, and DTI metrics were obtained for 6 regions-of-interest (ROIs) including the primary motor cortex (PMC), pars triangularis (parsT), pars opercularis (ParsO), posterior superior temporal gyrus (pSTG), and transverse temporal (TT). Disease-effects and brain-behavioral correlates between neuroanatomy and clinical measures of bulbar, limb, and overall disability were examined using linear models. Results: Structural changes were observed in the right oral and limb PMC and left ParsT, TT, and pSTG in ALS. Bulbar motor dysfunction was associated with WM abnormalities in the right oral PMC and left pSTG, and GM changes in bilateral TT. In contrast, symptom progression rate predicted GM and WM changes in bilateral pars opercularis (part of Broca’s area). Grip strength and disease duration models were non-significant. Conclusions: The findings suggested that regions of the left-dominant SpN may be implicated in ALS and degeneration of these areas are related to bulbar disease severity. Involvement of regions that overlap across multiple connectomes such as Broca’s area, however, may be dependent on the rate of disease progression. The work contributes to our understanding of bulbar ALS subtype, which is crucial for predicting disease progression, delivering targeted clinical care, and appropriate recruitment into clinical trials.

Diffuse white matter alteration in CLIPPERS: Advanced MRI findings from two cases

Advanced MRI findings in two patients with probable chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) are presented. Diffusion tensor imaging indices (fractional anisotropy and mean diffusivity), evaluated in both patients at baseline MRI examination before treatment and during follow-up, indicated white matter structural changes not only affecting the brainstem, which represents the primary site of inflammatory damage, but also projection (corona radiata) and associative tracts in both patients, while alterations within the corpus callosum were detected in patient 1# at follow-up. Susceptibility weighted imaging (SWI) revealed hypointense lesions in both patients, MRI spectroscopy (MRS) indicated a mildly increased Cho/NAA ratio with no evidence of lipids/lactate peaks, indicating that it may be used as a non-invasive marker to identify CLIPPERS cases suspected for progression to lymphoma.

The development of white matter structural changes during the process of deterioration of the visual field

Emerging evidence suggests that white matter plasticity in the adult brain is preserved after sensory and behavioral modifications. However, little is known about the progression of structural changes during the process of decline in visual input. Here we studied two groups of patients suffering from advanced retinitis pigmentosa with specific deterioration of the visual field: patients who had lost their peripheral visual field, retaining only central (“tunnel”) vision, and blind patients with complete visual field loss. Testing of these homogeneous groups made it possible to assess the extent to which the white matter is affected by loss of partial visual input and whether partially preserved visual input suffices to sustain stability in tracts beyond the primary visual system. Our results showed gradual changes in diffusivity that are indicative of degenerative processes in the primary visual pathway comprising the optic tract and the optic radiation. Interestingly, changes were also found in tracts of the ventral stream and the corticospinal fasciculus, depicting a gradual reorganisation of these tracts consequentially to the gradual loss of visual field coverage (from intact perception to partial vision to complete blindness). This reorganisation may point to microstructural plasticity underlying adaptive behavior and cross-modal integration after partial visual deprivation.

P088 IMMUNE GENE EXPRESSION DURING ACTIVE DISEASE IS ASSOCIATED WITH BRAIN, COGNITIVE AND BEHAVIORAL CHANGES IN PEDIATRIC CROHN’S DISEASE

Structural brain changes in gray and white matter have been found in adults with Crohn’s disease (CD). In adults, increased disease activity has also been associated with decreased cognitive performance. We have shown similar effects for pediatric CD, particularly for gray matter and associated cognitive and emotional functions. Underlying inflammation and steroid therapy have emerged as contributors, however, associations between brain structure and immune pathways have not been studied. We here aim to replicate earlier findings of brain involvement in pediatric CD, including study of white matter structures, and to elucidate the impact of immune response on the central nervous system. Sixty-one children age 10-15 years (20 CDActive, 23 CDRemission, 18 healthy controls) underwent structural and diffusion-weighted magnetic resonance imaging (MRI/DWI), neuropsychological assessment (IQ, memory, mood), disease severity ratings (PCDAI), and phlebotomy for immune gene expression. Gray matter data (cortical thickness, volume) was analyzed via Freesurfer, white matter [i.e. axial diffusivity (AD), isotropic free water (isoF)] with a diffusion compartment model (DIAMOND). Immune gene expression was assayed via multiplex array (NanoString® nCounter). Analyses were adjusted for age, sex, and steroid, and included correlation, regression, group comparison, and KEEG pathway analyses. Compared to healthy and CD controls, CDActive showed reduced cortical thickness in posterior brain regions [inferior, superior parietal, lateral occipital (ps<.05)], subcortical volume [thalamus, hippocampus (ps<.05)], widespread reduced AD (axonal integrity) and increased isoF (neuroinflammation) across white matter fiber tracts [corpus callosum, cingulum (ps<.01-.05)], poorer cognitive performance and mood [ps<.05]. Findings remained after controlling for steroids. We found 337/594 differentially expressed (240 upregulated) immune genes in CDActive compared to controls, with overlap with cytokine-cytokine receptor (IL-1r, IL-18r, TNF), TLR and Jak-STAT signaling, and complement (C1,2, CR1, ITGAM) gene pathways. Upregulated immune genes were associated with reduced gray and white matter structures, increased neuroinflammation, and poorer memory and mood. Both gray and white matter are reduced in children with active CD, with widespread changes in white matter tracts critical for brain connectivity and information processing, as well as in posterior cortical and limbic regions important for cognition, emotional and pain processing. We provide first indication for potential axonal injury and neuroinflammation. Further, the differentially expressed immune genes found in active CD play a role in synaptic pruning, recruitment of microglia, and apoptosis, and have been implicated in brain development and injury. Findings provide further insights in the molecular basis of brain involvement in CD, and warrant longitudinal study.

P088 IMMUNE GENE EXPRESSION DURING ACTIVE DISEASE IS ASSOCIATED WITH BRAIN, COGNITIVE AND BEHAVIORAL CHANGES IN PEDIATRIC CROHN’S DISEASE

Structural brain changes in gray and white matter have been found in adults with Crohn’s disease (CD). In adults, increased disease activity has also been associated with decreased cognitive performance. We have shown similar effects for pediatric CD, particularly for gray matter and associated cognitive and emotional functions. Underlying inflammation and steroid therapy have emerged as contributors, however, associations between brain structure and immune pathways have not been studied. We here aim to replicate earlier findings of brain involvement in pediatric CD, including study of white matter structures, and to elucidate the impact of immune response on the central nervous system. Sixty-one children age 10-15 years (20 CDActive, 23 CDRemission, 18 healthy controls) underwent structural and diffusion-weighted magnetic resonance imaging (MRI/DWI), neuropsychological assessment (IQ, memory, mood), disease severity ratings (PCDAI), and phlebotomy for immune gene expression. Gray matter data (cortical thickness, volume) was analyzed via Freesurfer, white matter [i.e. axial diffusivity (AD), isotropic free water (isoF)] with a diffusion compartment model (DIAMOND). Immune gene expression was assayed via multiplex array (NanoString® nCounter). Analyses were adjusted for age, sex, and steroid, and included correlation, regression, group comparison, and KEEG pathway analyses. Compared to healthy and CD controls, CDActive showed reduced cortical thickness in posterior brain regions [inferior, superior parietal, lateral occipital (ps<.05)], subcortical volume [thalamus, hippocampus (ps<.05)], widespread reduced AD (axonal integrity) and increased isoF (neuroinflammation) across white matter fiber tracts [corpus callosum, cingulum (ps<.01-.05)], poorer cognitive performance and mood [ps<.05]. Findings remained after controlling for steroids. We found 337/594 differentially expressed (240 upregulated) immune genes in CDActive compared to controls, with overlap with cytokine-cytokine receptor (IL-1r, IL-18r, TNF), TLR and Jak-STAT signaling, and complement (C1,2, CR1, ITGAM) gene pathways. Upregulated immune genes were associated with reduced gray and white matter structures, increased neuroinflammation, and poorer memory and mood. Both gray and white matter are reduced in children with active CD, with widespread changes in white matter tracts critical for brain connectivity and information processing, as well as in posterior cortical and limbic regions important for cognition, emotional and pain processing. We provide first indication for potential axonal injury and neuroinflammation. Further, the differentially expressed immune genes found in active CD play a role in synaptic pruning, recruitment of microglia, and apoptosis, and have been implicated in brain development and injury. Findings provide further insights in the molecular basis of brain involvement in CD, and warrant longitudinal study.

Cerebral patterns of neuropsychological disturbances in hepatitis C patients.

Neuropsychiatric symptoms and cognitive impairment have been consistently reported in patients with hepatitis C virus (HCV) infection. Since the mechanisms behind remain to be established, the present study attempted to assess whether neuropsychological impairments in HCV-infected patients are accompanied by structural alterations in the brain. Therefore, 19 anti-HCV-antibody-positive women with mild liver disease and 16 healthy controls underwent extensive neuropsychological testing and cranial magnetic resonance imaging (MRI) examination. Nine of the patients and five controls were followed up after 6-7years. Voxel-based morphometry and magnetization transfer imaging were utilized to study HCV-associated structural gray and white matter changes. The HCV-infected patients had significantly worse fatigue and depression scores and significantly poorer performance on attention and memory tests than controls. The patients displayed gray matter (GM) atrophy in the bilateral insula and thalamus and a profound GM volume increases in the cerebellum. Microstructural GM changes in the insula were also evident by a reduced magnetization transfer ratio. Structural white matter changes were observed along several descending and crossing fiber tracts. Follow-up at 7years revealed increased GM atrophy in the left amygdala and left parahippocampal regions over time. We conclude that our data provide evidence for structural alterations in the brains of patients with chronic HCV infection. Disturbances of cerebellothalamocortical regions and circuits, linking cerebellar projections to the prefrontal cortex through the thalamus, underpin the emotional and cognitive dysfunction characteristically observed in these patients.