Microstructural Brain Damage Research Articles

Diffusion Kurtosis Imaging and Radiomics in Diffuse Axonal Injury

This study aimed to assess the feasibility of radiomic features derived from diffusion kurtosis imaging (DK MRI) in identifying microstructural brain damage in diffuse axonal injury (DAI) and predicting its outcome. We hypothesized that radiomic features, computed from parametric DK MRI maps, may differ between healthy individuals and those with trauma, and may be related to DAI outcomes. The study included 31 DAI patients and 12 healthy volunteers. A total of 342,300 radiomic features were calculated (2282 features for each combination of 10 parametric DK maps with 15 regions of interest). Our findings suggest that the set of radiomic features effectively distinguishes between healthy and damaged brain tissues, and can predict DAI outcome. A broad spectrum of radiomic parameters based on DK MRI data showed high diagnostic and prognostic potential in DAI, presenting advantages beyond the traditionally used average values for the regions of interest on parametric DK MRI maps.

Natalizumab Treatment for Relapsing Multiple Sclerosis Stabilises Normal-Appearing White Matter Microstructure: A One-Year Prospective Ultra-High-Field Quantitative Imaging Study.

(1) Background: Natalizumab dramatically reduces relapses and MRI inflammatory activity (new lesions and enhancing lesions) in multiple sclerosis (MS). Chemical exchange saturation transfer (CEST) MRI can explore brain tissue in vivo with high resolution and sensitivity. We investigated if natalizumab can prevent microstructural tissue damage progression measured with MRI at ultra-high field (7 Tesla) over the first year of treatment. (2) Methods: In this one-year prospective longitudinal study, patients with active relapsing-remitting MS were assessed clinically and scanned at ultra-high-field MRI at the time of their first natalizumab infusion, at 6 and 12 months, with quantitative imaging aimed to detect microstructural changes in the normal-appearing white matter (NAWM), including sequences sensitive to magnetisation transfer (MT) effects from amide proton transfer (MTRAPT) and the nuclear Overhauser effect (MTRNOE). (3) Results: 12 patients were recruited, and 10 patients completed the study. The difference in the T1 relaxation times at month 6 and month 12 of natalizumab treatment was not significant, suggesting the lack of accumulation of tissue damage, while improvements were seen in MTR (MTRAPT and MTRNOE measures) at month 12, suggesting a tissue repair effect. This paralleled the expected lack of clinical and radiological worsening of conventional MRI measures of disease activity (new lesions or gadolinium-enhancing lesions). (4) Conclusion: Natalizumab prevents microstructural brain damage and has effects suggesting an improved white matter microstructure measured at ultra-high field during the first year of treatment.

NfL and GFAP in serum are associated with microstructural brain damage in progressive multiple sclerosis.

The potential of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) as biomarkers of disease activity and severity in progressive forms of multiple sclerosis (MS) is unclear. To investigate the relationship between serum concentrations of NfL, GFAP, and magnetic resonance imaging (MRI) in progressive MS. Serum concentrations of NfL and GFAP were measured in 32 healthy controls and 32 patients with progressive MS from whom clinical and MRI data including diffusion tensor imaging (DTI) were obtained during three years of follow-up. Serum concentrations of NfL and GFAP at follow-up were higher in progressive MS patients than in healthy controls and serum NfL correlated with the EDSS score. Decreasing fractional anisotropy (FA) in normal-appearing white matter (NAWM) correlated with worsening EDSS scores and higher serum NfL. Higher serum NfL and increasing T2 lesion volume correlated with worsening paced autitory serial addition test scores. In multivariable regression analyses with serum GFAP and NfL as independent factors and DTI measures of NAWM as dependent factors, we showed that high serum NfL at follow-up was independently associated with decreasing FA and increasing MD in NAWM. Moreover, we found that high serum GFAP was independently associated with decreasing MD in NAWM and with decreasing MD and increasing FA in cortical gray matter. Serum concentrations of NfL and GFAP are increased in progressive MS and are associated with distinct microstructural changes in NAWM and CGM.

Association between periodontal disease and microstructural brain alterations in the Hamburg City Health Study.

The aim of the PAROBRAIN study was to examine the association of periodontal health with microstructural white matter integrity and cerebral small vessel disease (CSVD) in the Hamburg City Health Study, a large population-based cohort with dental examination and brain magnetic resonance imaging (MRI). Periodontal health was determined by measuring clinical attachment loss (CAL) and plaque index. Additionally, the decayed/missing/filled teeth (DMFT) index was quantified. 3D-FLAIR and 3D-T1-weighted images were used for white matter hyperintensity (WMH) segmentation. Diffusion-weighted MRI was used to quantify peak width of skeletonized mean diffusivity (PSMD). Data from 2030 participants were included in the analysis. Median age was 65 years, with 43% female participants. After adjusting for age and sex, an increase in WMH load was significantly associated with more CAL, higher plaque index and higher DMFT index. PSMD was significantly associated with the plaque index and DMFT. Additional adjustment for education and cardiovascular risk factors revealed a significant association of PSMD with plaque index (p < .001) and DMFT (p < .01), whereas effects of WMH load were attenuated (p > .05). These findings suggest an adverse effect of periodontal health on CSVD and white matter integrity. Further research is necessary to examine whether early treatment of periodontal disease can prevent microstructural brain damage.

Experimental cerebral palsy causes microstructural brain damage in areas associated to motor deficits but no spatial memory impairments in the developing rat

IntroductionCerebral palsy (CP) is the major cause of motor and cognitive impairments during childhood. CP can result from direct or indirect structural injury to the developing brain. In this study, we aimed to describe brain damage and behavioural alterations during early adult life in a CP model using the combination of maternal inflammation, perinatal anoxia and postnatal sensorimotor restriction. MethodsPregnant Wistar rats were injected intraperitoneally with 200 µg/kg LPS at embryonic days E18 and E19. Between 3 and 6 h after birth (postnatal day 0 - PND0), pups of both sexes were exposed to anoxia for 20 min. From postnatal day 2 to 21, hindlimbs of animals were immobilized for 16 h daily during their active phase. From PND40, locomotor and cognitive tests were performed using Rota-Rod, Ladder Walking and Morris water Maze. Ex-vivo MRI Diffusion Tensor Imaging (DTI) and Neurite Orientation Dispersion and Density Imaging (NODDI) were used to assess macro and microstructural damage and brain volume alterations induced by the model. Myelination and expression of neuronal, astroglial and microglial markers, as well as apoptotic cell death were evaluated by immunofluorescence. ResultsCP animals showed decreased body weight, deficits in gross (rota-rod) and fine (ladder walking) motor tasks compared to Controls. No cognitive impairments were observed. Ex-vivo MRI showed decreased brain volumes and impaired microstructure in the cingulate gyrus and sensory cortex in CP brains. Histological analysis showed increased cell death, astrocytic reactivity and decreased thickness of the corpus callosum and altered myelination in CP animals. Hindlimb primary motor cortex analysis showed increased apoptosis in CP animals. Despite the increase in NeuN and GFAP, no differences between groups were observed as well as no co-localization with the apoptotic marker. However, an increase in Iba-1+ microglia with co-localization to cleaved caspase 3 was observed. ConclusionOur results suggest that experimental CP induces long-term brain microstructural alterations in myelinated structures, cell death in the hindlimb primary motor cortex and locomotor impairments. Such new evidence of brain damage could help to better understand CP pathophysiological mechanisms and guide further research for neuroprotective and neurorehabilitative strategies for CP patients.

The effect of early cognitive therapy in improving cognitive functions using neuropsychology and diffusion tensor imaging measurements following mild traumatic brain injury: A pilot study

To quantify clinical and structural white matter tract changes over six months, in patients with mild traumatic brain injury (mTBI) following early structured cognitive therapy. This was a non-randomized quasi-experimental study design. All patients with mTBI received written information and education on symptom(s) management before being assigned to structured cognitive therapy or conventional cognitive therapy at two weeks post injury. Structured therapy was one hour per week session by using computer-based and metacognitive training for the first three months followed by one hour per month session for the remaining three months. Conventional therapy was patient focused symptom(s) management and coping strategies. Neuropsychological assessment and Diffusion Tensor Imaging (DTI) were performed at baseline and six months post injury. Each group consisted of four male participants ( n = 8). Mean cognitive therapy duration was 7 hours (SD ± 1.8). There was no demographic, Glasgow Coma Scale, Post Traumatic Amnesia and loss of consciousness duration statistical difference between groups. Although all cognitive domains tested were not statistically significant, the scores for Attention, Memory, Language, and Executive Function domains were higher than conventional group at six months. We analysed nine white matter tracts. Almost all Fractional Anisotropy mean values were lower (Corpus Callosum genu: P = 0.03; splenium: P = 0.05) whereas Mean Diffusivity and Radial Diffusivity mean values were higher at six months. We quantified deficits in various cognitive domains as early as two weeks following mTBI, with higher normal scores in the structured therapy group as compared to conventional group at six months. Abnormal values of DTI parameters may suggest chronic axonal damage of various white matter locations and bundles. We did not yield statistical significance in our analysis due to small sample size caused by high drop-out rate. However, we concluded that early structured cognitive therapy may improve cognitive deficits beyond spontaneous recovery, despite persistent microstructural brain damage.

Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysis.

Objective The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results Fifty-one patients with SLE (mean age 48.8 ± 14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls ( p < 0.0001). Fatigue in SLE was higher than a normal reference range ( p < 0.0001) and associated with lower MD ( ß = -0.61, p = 0.02), depression ( ß = 0.17, p = 0.001), anxiety ( ß = 0.13, p = 0.006) and higher body mass index ( ß = 0.10, p = 0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration ( p = 0.003) and higher MD ( p = 0.03) and, in adjusted analysis, higher levels of IL-6 ( ß = -0.15, p = 0.02) but not with MD. Meta-analysis (10 studies, n = 261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.

Dentate nucleus connectivity in adult patients with multiple sclerosis: functional changes at rest and correlation with clinical features

Background and objective: The dentate nucleus, which is the largest of the cerebellar nuclei, plays a critical role in movement and cognition. The aim of our study was to assess any changes in dentate functional connectivity (FC) in adult relapsing remitting multiple sclerosis (RR-MS) patients and to investigate possible clinical correlates. Materials and methods: In all, 54 patients and 24 healthy subjects (HS) underwent multimodal magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), three-dimensional-T1-weighted and resting state (RS) functional images; they also underwent a cognitive evaluation, that is, attention and information processing speed, by means of the Paced Auditory Serial Addition Test (PASAT). Patients were also scored according to Expanded Disability Status Scale (EDSS). RS-MRI data were analysed using FMRIB Software Library (FSL) tools, with the seed-based method to identify dentate FC. Results: When compared with HS, patients exhibited brain atrophy and widespread DTI abnormalities, as well as greater FC between the dentate nucleus and cortical areas, particularly in the frontal and parietal lobes. Within these areas, FC in patients correlated inversely with clinical impairment. Finally, FC correlated inversely with lesion load and microstructural brain damage. Conclusion: Our findings indicate that dentate FC at rest is altered in MS patients. Whether these functional changes are induced by the disease and play a compensatory role remains to be established.

Deficits in tongue motor control are linked to microstructural brain damage in multiple sclerosis: a pilot study.

BackgroundDeterioration of fine motor control of the tongue is common in Multiple Sclerosis (MS) and has a major impact on quality of life. However, the underlying neuronal substrate is largely unknown. Here, we aimed to explore the association of tongue motor dysfunction in MS patients with overall clinical disability and structural brain damage.MethodsWe employed a force transducer based quantitative-motor system (Q-Motor) to objectively assess tongue function in 33 patients with MS. The variability of tongue force output (TFV) and the mean applied tongue force (TF) were measured during an isometric tongue protrusion task. Twenty-three age and gender matched healthy volunteers served as controls. Correlation analyses of motor performance in MS patients with individual disease burden as expressed by the Expanded Disability Status Scale (EDSS) and with microstructural brain damage as measured by the fractional anisotropy (FA) on Diffusion Tensor Imaging were performed.ResultsMS patients showed significantly increased TFV and decreased TF compared to controls (p < 0.02). TFV but not TF was correlated with the EDSS (p < 0.04). TFV was inversely correlated with FA in the bilateral posterior limb of the internal capsule expanding to the brain stem (p < 0.001), a region critical to tongue function. TF showed a weaker, positive and unilateral correlation with FA in the same region (p < 0.001).ConclusionsChanges in TFV were more robust and correlated better with disease phenotype and FA changes than TF. TFV might serve as an objective and non-invasive outcome measure to augment the quantitative assessment of motor dysfunction in MS.

Functional connectivity changes and their relationship with clinical disability and white matter integrity in patients with relapsing–remitting multiple sclerosis

Background and objective: To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural brain damage, as assessed by diffusion tensor imaging, and clinical impairments. Methods: Thirty relapsing–remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with General-Linear-Model and corrected for multiple comparisons. Results: Patients showed decreased functional connectivity in 5 of 11 resting-state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity. Conclusions: Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities.

A novel method for evaluating brain function and microstructural changes in Parkinson's disease.

In this study, microstructural brain damage in Parkinson's disease patients was examined using diffusion tensor imaging and tract-based spatial statistics. The analyses revealed the presence of neuronal damage in the substantia nigra and putamen in the Parkinson's disease patients. Moreover, disease symptoms worsened with increasing damage to the substantia nigra, confirming that the substantia nigra and basal ganglia are the main structures affected in Parkinson's disease. We also found that microstructural damage to the putamen, caudate nucleus and frontal lobe positively correlated with depression. Based on the tract-based spatial statistics, various white matter tracts appeared to have microstructural damage, and this correlated with cognitive disorder and depression. Taken together, our results suggest that diffusion tensor imaging and tract-based spatial statistics can be used to effectively study brain function and microstructural changes in patients with Parkinson's disease. Our novel findings should contribute to our understanding of the histopathological basis of cognitive dysfunction and depression in Parkinson's disease.

A multi-contrast MRI study of microstructural brain damage in patients with mild cognitive impairment.

ObjectivesThe aim of this study was to investigate pathological mechanisms underlying brain tissue alterations in mild cognitive impairment (MCI) using multi-contrast 3 T magnetic resonance imaging (MRI).MethodsForty-two MCI patients and 77 healthy controls (HC) underwent T1/T2* relaxometry as well as Magnetization Transfer (MT) MRI. Between-groups comparisons in MRI metrics were performed using permutation-based tests. Using MRI data, a generalized linear model (GLM) was computed to predict clinical performance and a support-vector machine (SVM) classification was used to classify MCI and HC subjects.ResultsMulti-parametric MRI data showed microstructural brain alterations in MCI patients vs HC that might be interpreted as: (i) a broad loss of myelin/cellular proteins and tissue microstructure in the hippocampus (p ≤ 0.01) and global white matter (p < 0.05); and (ii) iron accumulation in the pallidus nucleus (p ≤ 0.05). MRI metrics accurately predicted memory and executive performances in patients (p ≤ 0.005). SVM classification reached an accuracy of 75% to separate MCI and HC, and performed best using both volumes and T1/T2*/MT metrics.ConclusionMulti-contrast MRI appears to be a promising approach to infer pathophysiological mechanisms leading to brain tissue alterations in MCI. Likewise, parametric MRI data provide powerful correlates of cognitive deficits and improve automatic disease classification based on morphometric features.

Early Detection of Widespread Progressive Brain Injury after Cardiac Arrest: A Single Case DTI and Post-Mortem Histology Study

ObjectiveWe tested the hypothesis in sense of a proof of principle that white matter (WM) degeneration after cardiopulmonary arrest (CPA) can be assessed much earlier by diffusion tensor imaging (DTI) than by conventional MRI.MethodsWe performed DTI and T2-weighted FLAIR imaging over four serial acquisitions of a 76-year-old man with unresponsive wakefulness syndrome at day 41, 75, 173 and 284 after CPA. DTI was also performed in ten healthy control subjects. Fractional anisotropy (FA) derived from DTI was assessed in eleven regions of interest within the cerebral white matter (WM) and compared with post-mortem neuropathological findings.ResultsIn contrast to conventional FLAIR images that revealed only circumscribed WM damage, the first DTI demonstrated significant reduction of FA across the whole WM. The following FLAIR images (MRI 2-4) revealed increasing atrophy and leukoaraiosis paralleled by clinical deterioration with reduction of wakefulness and intractable seizures. Neuropathological findings confirmed the widespread and marked brain injury following CPA.ConclusionDTI may help to evaluate microstructural brain damage following CPA and may have predictive value for further evolution of cerebral degeneration in the chronic phase after CPA.

In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy, perfusion-weighted and diffusion-tensor imaging

Twenty-two neuropsychiatric (NPSLE) and 13 systemic lupus erythematosus (SLE) patients with a normal appearing brain on plain magnetic resonance (MR) as well as 20 age-matched healthy controls underwent MR spectroscopy (MRS), perfusion-weighted (PWI) and diffusion-tensor imaging (DTI). In MRS NAA/Cr, Cho/Cr and mI/Cr ratios were calculated from the posterior cingulate cortex and left parietal white matter. In PWI, values of cerebral blood volume (CBV) were assessed from 14 regions, including gray and white matter. In DTI fractional anisotropy (FA) values were obtained from 14 white matter tracts including projection, commissural and association fibers. All MR measurements were correlated with clinical data. SLE and NPSLE patients showed significantly (p < 0.05) lower NAA/Cr ratios within both evaluated regions and FA values within the cingulum, as well as a tendency to cortical hypoperfusion. Compared to SLE, NPSLE subjects revealed lower FA values within a wide range of association fibers and corpus callosum. Advanced MR techniques are capable of invivo detection of complex microstructural brain damage in SLE and NPSLE subjects regarding neuronal loss, mild hypoperfusion and white matter disintegrity. MRS and DTI seem to show the highest usefulness in depicting early changes in normal appearing gray and white matter in SLE patients.

Diffusion Measures Indicate Fight Exposure-Related Damage to Cerebral White Matter in Boxers and Mixed Martial Arts Fighters

Traumatic brain injury is common in fighting athletes such as boxers, given the frequency of blows to the head. Because DTI is sensitive to microstructural changes in white matter, this technique is often used to investigate white matter integrity in patients with traumatic brain injury. We hypothesized that previous fight exposure would predict DTI abnormalities in fighting athletes after controlling for individual variation. A total of 74 boxers and 81 mixed martial arts fighters were included in the analysis and scanned by use of DTI. Individual information and data on fight exposures, including number of fights and knockouts, were collected. A multiple hierarchical linear regression model was used in region-of-interest analysis to test the hypothesis that fight-related exposure could predict DTI values separately in boxers and mixed martial arts fighters. Age, weight, and years of education were controlled to ensure that these factors would not account for the hypothesized effects. We found that the number of knockouts among boxers predicted increased longitudinal diffusivity and transversal diffusivity in white matter and subcortical gray matter regions, including corpus callosum, isthmus cingulate, pericalcarine, precuneus, and amygdala, leading to increased mean diffusivity and decreased fractional anisotropy in the corresponding regions. The mixed martial arts fighters had increased transversal diffusivity in the posterior cingulate. The number of fights did not predict any DTI measures in either group. These findings suggest that the history of fight exposure in a fighter population can be used to predict microstructural brain damage.

Structural and Functional Neuroimaging in Migraine: Insights From 3 Decades of Research

Modern imaging methods provide unprecedented insights into brain structure, perfusion, metabolism, and neurochemistry, both during and between migraine attacks. Neuroimaging investigations conducted in recent decades bring us closer to uncovering migraine as a multifaceted, primarily central nervous system disorder. Three main categories of structural and functional brain changes are described in this review, corresponding to the migrainous aura, ictal headache, and interictal states. These changes greatly advance our understanding of multiple pathophysiologic underpinnings of migraine, from central "migraine generating" loci, to cortical spreading depression, intimate mechanisms underlying activation of neuronal pain pathways in vulnerable patients, central sensitization, and chronification. Structural imaging begins to explain the complex connections between migraine and cerebral vascular events, white matter lesions, grey matter density alterations, iron deposition, and microstructural brain damage. Selected structural and functional alterations of brain structures, as identified with imaging methods, may represent the foundation of new diagnostic strategies and serve as markers of therapeutic efficacy.

Antiphospholipid syndrome and the brain in pediatric and adult patients

The most common neurological manifestations of antiphospholipid syndrome (APS) in all age-groups include stroke and transient ischemic attacks due to arterial thromboses and cerebral ischemia. Antiphospholipid antibodies may cause additional non-criteria neurological impairments through vascular, neuroinflammatory and direct neuronal effects. Anti-aggregant or anticoagulant therapies are indicated for APS-related ischemic strokes. Treatment regimens for asymptomatic antibody-positive patients and those with refractory or recurrent disease remain controversial. There is scant literature on the epidemiology and therapy of neurological APS manifestations in pediatric patients. Assessments of modifiable cardiovascular and inherited thrombophilia risk factors are essential in patients with APS. There may be a role for novel neuroimaging modalities in quantifying APS-related microstructural brain damage. The clinical utility of statins, antimalarials, angiotensin-converting enzyme inhibitors, and thrombin inhibitors warrant further research.

Neuroimaging in Migraine—Recent Advances and Perspectives for the Future

Migraine is a very common disorder that imposes substantial individual and societal costs. A better understanding of migraine mechanisms may lead to the development of new therapies and thus improve the management of migraine patients. Magnetic resonance imaging (MRI) techniques and positron emission tomography (PET) have revolutionized our understanding of migraine pathophysiology as a primary central nervous system (CNS) disorder, advanced the search for a central migraine generator, clarified the role of cortical spreading depression (CSD) and central sensitization in the pathogenesis of migraine, and revealed some potential sites of action of migraine medications. Structural imaging has shed light on relationships between migraine and stroke, white matter lesions, iron deposition, microstructural brain damage, and other gray and white matter aberrations. Emerging neuroimaging techniques, such as arterial spin labeling (ASL) and functional connectivity MRI (fcMRI), are beginning to provide further evidence of functional brain alterations in migraine patients. Ultimately, it is hoped that advanced neuroimaging will benefit the individual migraine patient by enhancing our diagnostic abilities, allowing for development of better treatments and serving as an important tool in medical decision-making.