Frontal White Matter Research Articles

Novel Psychiatric Disorder 6 Months After Traumatic Brain Injury in Children and Adolescents.

To investigate the factors predictive of novel psychiatric disorders in the interval 0-6 months following traumatic brain injury (TBI). Children ages 5-14 years consecutively hospitalized for mild to severe TBI at five hospitals were recruited. Participants were evaluated at baseline (soon after injury) for pre-injury characteristics including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, family function, family psychiatric history, and adaptive function. In addition to the psychosocial variables, injury severity and lesion location detected with acquisition of a research MRI were measured to develop a biopsychosocial predictive model for development of novel psychiatric disorders. Psychiatric outcome, including occurrence of a novel psychiatric disorder, was assessed 6 months after the injury. The recruited sample numbered 177 children, and 141 children (80%) returned for the six-month assessment. Of the 141 children, 58 (41%) developed a novel psychiatric disorder. In univariable analyses, novel psychiatric disorder was significantly associated with lower SES, higher psychosocial adversity, and lesions in frontal lobe locations, such as frontal white matter, superior frontal gyrus, inferior frontal gyrus, and orbital gyrus. Multivariable analyses found that novel psychiatric disorder was independently and significantly associated with frontal-lobe white matter, superior frontal gyrus, and orbital gyrus lesions. The results demonstrate that occurrence of novel psychiatric disorders following pediatric TBI requiring hospitalization is common and has identifiable psychosocial and specific biological predictors. However, only the lesion predictors were independently related to this adverse psychiatric outcome.

White matter hyperintensities in former American football players.

The presentation, risk factors, and etiologies of white matter hyperintensities (WMH) in people exposed to repetitive head impacts are unknown. We examined the burden and distribution of WMH, and their association with years of play, age of first exposure, and clinical function in former American football players. A total of 149 former football players and 53 asymptomatic unexposed participants (all men, 45-74 years) completed fluid-attenuated inversion recovery magnetic resonance imaging, neuropsychological testing, and self-report neuropsychiatric measures. Lesion Segmentation Toolbox estimated WMH. Analyses were performed in the total sample and stratified by age 60. In older but not younger participants, former football players had greater total, frontal, temporal, and parietal log-WMH compared to asymptomatic unexposed men. In older but not younger former football players, greater log-WMH was associated with younger age of first exposure to football and worse executive function. In older former football players, WMH may have unique presentations, risk factors, and etiologies. Older but not younger former football players had greater total, frontal, temporal, and parietal lobe white matter hyperintensities (WMH) compared to same-age asymptomatic unexposed men. Younger age of first exposure to football was associated with greater WMH in older but not younger former American football players. In former football players, greater WMH was associated with worse executive function and verbal memory.

Spectrum of qualitative and quantitative imaging of pilomyxoid, intermediate pilomyxoid and pilocytic astrocytomas in relation to their genetic alterations.

Pilomyxoid astrocytomas (PMA) are pediatric brain tumors predominantly located in the suprasellar region, third ventricle and posterior fossa, which are considered to be more clinically aggressive than pilocytic astrocytomas (PA). Another entity, intermediate pilomyxoid tumors (IPT), exists within the spectrum of pilocytic/pilomyxoid astrocytomas. The 2021 WHO CNS classification refrained from assigning grade 1 or 2 status to PMA, thereby reflecting the need to further elucidate their clinical and imaging characteristics. We included a total of 15 patients with PMA, IPT and suprasellar PA. We retrospectively evaluated immunohistochemistry, imaging findings and diffusion characteristics within these tumors as well as whole exome sequencing for three of the cases. 87% of the tumors were supratentorial with 11 cases suprasellar in location, 1 case located in the frontal white matter and 1 in the hippocampus. 6 cases demonstrated intraventricular extension. ADC values were higher in PMA and IPT than PA. 3 cases demonstrated KIAA1549-BRAF-fusion, 2 had BRAF[Formula: see text]-mutation and 6 were BRAF-wildtype. All cases had recurrence/progression on follow-up. PMA and IPT do not demonstrate aggressive imaging characteristics in respect to their diffusion imaging with ADC values being higher than PA. Lack of BRAF-alteration in PMA corresponded to atypical location of tumors with atypical driver mutations and mechanisms.

Preservation of frontal white matter tracts in ventricular surgery: favoring an anterior interhemispheric transcallosal approach vs a transcortical transfrontal transventricular approach.

Secondary to the creation of a surgical corridor and retraction, white matter tracts degenerate, causing long-term scarring with potential neurological consequences. Third and lateral ventricle tumors require surgery that may lead to cognitive impairment. Our objective is to compare the long-term consequences of a transcortical transfrontal approach and an interhemispheric transcallosal approach on corpus callosum and frontal white matter tracts degeneration. Surgical patients with ventricular tumor accessible through both approaches were included and clinico-radiological data were retrospectively analyzed. The primary endpoint was the callosotomy length at 3-month post-operative T1 MRI, corrected by the extension of the tumor and the use of neuronavigation. Secondary outcomes included perioperative criteria such as bleeding, use of retractors and duration, FLAIR hypersignal on 3-month MRI, and re-do surgeries. To assess white matter tract interruption, 3-month FLAIR hypersignal was superposed to a tractography atlas. Seventy patients were included, 57 (81%) in the transfrontal group and 13 (19%) in the interhemispheric group. There was no difference in the mean callosotomy length on 3-month MRI (12.3mm ± 5.60 transfrontal vs 11.7mm ± 3.92 interhemispheric, p = 0.79) on univariate and multivariate analyses. The callosotomy length was inferior by - 3.13mm for tumors located exclusively in the third ventricle (p = 0.016), independent of the approach. Retractors were used more often in transfrontal approaches (60% vs 33%, p < 0.001). The extent of frontal FLAIR hypersignal was higher after transfrontal approach (14.1mm vs 0.525mm, p < 0.001), correlated to the use of retractors (p < 0.05). After the interhemispheric approach, no tract other than corpus callosum was interrupted, whereas, after the transfrontal approach, frontal arcuate fibers and projections from the thalamus were interrupted in all patients, the cingulum in 19 (33%), the superior fronto-occipital fasciculus in 15 (26%), and the superior longitudinal fasciculus in 2 (3%). Transfrontal and interhemispheric approaches to the third and lateral ventricles both lead to the same long-term damage to the corpus callosum, but the transfrontal approach interrupts several white matter tracts essential to cognitive tasks such as attention and planning, even in the non-dominant hemisphere. These results encourage all neurosurgeons to be familiar with both approaches and favor the interhemispheric approach when both can give access to the tumor with a comparable risk. Neuropsychological studies are necessary to correlate these anatomical findings to cognitive outcomes.

Pattern of Altered Magnetization Transfer Rate in Alzheimer's Disease.

Biomarkers for Alzheimer's disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. This study aims to quantify the forward magnetization transfer rate (kfor) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal kfor in AD and AD progression. From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC. Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression.

The Metabolic Syndrome Is Associated With Lower Cognitive Performance and Reduced White Matter Integrity in Midlife: The CARDIA Study.

BackgroundCardiovascular disease risk factors play a critical role in brain aging. The metabolic syndrome (MetS), a constellation of cardiovascular risk factors, has been associated with poorer cognition in old age; however, it is unclear if it is connected to brain health earlier in life.MethodsWe investigated the association of MetS (n = 534, 18.5%) vs. no MetS (n = 2,346, 81.5%) with cognition in midlife within the prospective study, Coronary Artery Risk Development in Young Adults (CARDIA). At midlife (mean age 50), MetS was defined using National Cholesterol Education Program guidelines. At the 5-year follow-up, a cognitive battery was administered including tests of processing speed (Digit Symbol Substitution Test, DSST), executive function (the Stroop Test), verbal memory (Rey Auditory Verbal Learning Test, RAVLT), verbal fluency (category and letter fluency), and global cognitive function (Montreal Cognitive Assessment, MoCA). A sub-sample (n = 453) underwent brain MRI.ResultsParticipants with MetS had worse performance on tests of verbal fluency, processing speed, executive function, and verbal memory (p < 0.05), but not on global cognition. MetS was also associated with lower frontal, parietal, temporal, and total white matter integrity (p < 0.05), as assessed with fractional anisotropy.ConclusionsMetS is associated with lower cognition and microstructural brain alterations already at midlife, suggesting that MetS should be targeted earlier in life in order to prevent adverse brain and cognitive outcomes.

Symptomatic care of late-onset Alexander disease presenting with area postrema-like syndrome with prednisolone; a case report

BackgroundAlexander disease (AxD) is classified into AxD type I (infantile) and AxD type II (juvenile and adult form). We aimed to determine the potential genetic cause(s) contributing to the AxD type II manifestations in a 9-year-old male who presented area postrema-like syndrome and his vomiting and weight loss improved after taking prednisolone.Case presentationA normal cognitive 9-year-old boy with persistent nausea, vomiting, and a significant weight loss at the age of 6 years was noticed. He also experienced an episode of status epilepticus with generalized atonic seizures. He showed non-febrile infrequent multifocal motor seizures at the age of 40 days which were treated with phenobarbital. He exhibited normal physical growth and neurologic developmental milestones by the age of six. Occasionally vomiting unrelated to feeding was reported. Upon examination at 9 years, a weak gag reflex, prominent drooling, exaggerated knee-deep tendon reflexes (3+), and nasal tone speech was detected. All gastroenterological, biochemical, and metabolic assessments were normal. Brain magnetic resonance imaging (MRI) revealed bifrontal confluent deep and periventricular white matter signal changes, fine symmetric frontal white matter and bilateral caudate nucleus involvements with garland changes, and a hyperintense tumefactive-like lesion in the brain stem around the floor of the fourth ventricle and area postrema with contrast uptake in post-contrast T1-W images. Latter MRI at the age of 8 years showed enlarged area postrema lesion and bilateral middle cerebellar peduncles and dentate nuclei involvements. Due to clinical and genetic heterogeneities, whole-exome sequencing was performed and the candidate variant was confirmed by Sanger sequencing. A de novo heterozygous mutation, NM_001242376.1:c.262 C > T;R88C in exon 1 of the GFAP (OMIM: 137,780) was verified. Because of persistent vomiting and weight loss of 6.0 kg, prednisolone was prescribed which brought about ceasing vomiting and led to weight gaining of 3.0 kg over the next 3 months after treatment. Occasional attempts to discontinue prednisolone had been resulting in the reappearance of vomiting.ConclusionsThis study broadens the spectrum of symptomatic treatment in leukodystrophies and also shows that R88C mutation may lead to a broad range of phenotypes in AxD type II patients.

Effects of Hippocampal Sparing Radiotherapy on Brain Microstructure-A Diffusion Tensor Imaging Analysis.

Hippocampal-sparing radiotherapy (HSR) is a promising approach to alleviate cognitive side effects following cranial radiotherapy. Microstructural brain changes after irradiation have been demonstrated using Diffusion Tensor Imaging (DTI). However, evidence is conflicting for certain parameters and anatomic structures. This study examines the effects of radiation on white matter and hippocampal microstructure using DTI and evaluates whether these may be mitigated using HSR. A total of 35 tumor patients undergoing a prospective randomized controlled trial receiving either conventional or HSR underwent DTI before as well as 6, 12, 18, 24, and 30 (±3) months after radiotherapy. Fractional Anisotropy (FA), Mean Diffusivity (MD), Axial Diffusivity (AD), and Radial Diffusivity (RD) were measured in the hippocampus (CA), temporal, and frontal lobe white matter (TL, FL), and corpus callosum (CC). Longitudinal analysis was performed using linear mixed models. Analysis of the entire patient collective demonstrated an overall FACC decrease and RDCC increase compared to baseline in all follow-ups; ADCC decreased after 6 months, and MDCC increased after 12 months (p ≤ 0.001, 0.001, 0.007, 0.018). ADTL decreased after 24 and 30 months (p ≤ 0.004, 0.009). Hippocampal FA increased after 6 and 12 months, driven by a distinct increase in ADCA and MDCA, with RDCA not increasing until 30 months after radiotherapy (p ≤ 0.011, 0.039, 0.005, 0.040, 0.019). Mean radiation dose correlated positively with hippocampal FA (p < 0.001). These findings may indicate complex pathophysiological changes in cerebral microstructures after radiation, insufficiently explained by conventional DTI models. Hippocampal microstructure differed between patients undergoing HSR and conventional cranial radiotherapy after 6 months with a higher ADCA in the HSR subgroup (p ≤ 0.034).

Differential perivascular microglial activation in the deep white matter in vascular dementia developed post-stroke.

With the hypothesis that perivascular microglia are involved as neuroinflammatory components of the gliovascular unit contributing to white matter hyperintensities on MRI and pathophysiology, we assessed their status in stroke survivors who develop dementia. Immunohistochemical and immunofluorescent methods were used to assess the distribution and quantification of total and perivascular microglial cell densities in 68 brains focusing on the frontal lobe WM and overlying neocortex in post-stroke dementia (PSD), post-stroke non-dementia (PSND) and similar age control subjects. We primarily used CD68 as a marker of phagocytic microglia, as well as other markers of microglia including Iba-1 and TMEM119, and the myeloid cell marker TREM2 to assess dementia-specific changes. We first noted greater total densities of CD68+ and TREM2+ cells per mm2 in the frontal WM compared to the overlying cortex across the stroke cases and controls (p=0.001). PSD subjects showed increased percentage of activated perivascular CD68+ cells distinct from ramified or primed microglia in the WM (p < 0.05). However, there was no apparent change in perivascular TREM2+ cells. Total densities of TREM2+ cells were only ~10% of CD68+ cells but there was high degree of overlap (>70%) between them in both the WM and the cortex. CD68 and Iba-1 or CD68 and TMEM119 markers were colocalised by ~55%. Within the deep WM, ~30% of CD68+ cells were co-localised with fragments of degraded myelin basic protein. Among fragmented CD68+ cells in adjacent WM of PSD subjects, >80% of the cells expressed cleaved caspase-3. Our observations suggest although the overall repertoire of perivascular microglial cells is not changed in the parenchyma, PSD subjects accrue more perivascular-activated CD68+ microglia rather than TREM2+ cells. This implies there is a subset of CD68+ cells, which are responsible for the differential response in perivascular inflammation within the gliovascular unit of the deep WM.

Evaluation of depressive disorder in end-stage renal disease patients by proton diffusion tensor imaging

This study aimed to evaluate the depressive disorder in the end-stage renal disease (ESRD) patients by proton diffusion tensor imaging (DTI). Fifty-four ESRD patients and 30 healthy subjects were enrolled and received brain DTI. ESRD patients were further divided into non-depression group (nD-ESRD, n=28) and depression group (D-ESRD, n=26). The DTI parameters were collected, and the changes in the white matter fibers microstructure were compared among groups. The correlations of fractional anisotropy (FA) value and laboratory findings with Hamilton Depression Scale (HAMD) 17 score were further evaluated in the D-ESRD group. Results showed that there were significant differences in the course of disease and HAMD17 score (P < 0.05) among three groups. There were significant differences in the serum Ca2+ (t = 3.976, P = 0.032), creatinine (t = 2.024, P = 0.049) and urea nitrogen (t = 2.930, P = 0.037) among three groups. Marked differences were noted in the DTI values of multiple brain regions among three groups. In the D-ESRD group, the FA values of left frontal white matter (r = −0.672, P = 0.003) and left anterior limb of internal capsule (r = −0.476, P = 0.023) were related to the HAMD17 score, and the serum Ca2+ (r = 0.581, P = 0.031) and urea nitrogen (r = 0.796, P = 0.003) were associated with the HAMD17 score. Thus, DTI parameters (especially the change in FA value) are expected to be an auxiliary diagnostic tool to objectively evaluate depression in ESRD patients, which is helpful for the early treatment of depression.

The Wernicke conundrum revisited: evidence from connectome-based lesion-symptom mapping.

Wernicke's area has been assumed since the 1800s to be the primary region supporting word and sentence comprehension. However, in 2015 and 2019, Mesulam and colleagues raised what they termed the 'Wernicke conundrum', noting widespread variability in the anatomical definition of this area and presenting data from primary progressive aphasia that challenged this classical assumption. To resolve the conundrum, they posited a 'double disconnection' hypothesis: that word and sentence comprehension deficits in stroke-based aphasia result from disconnection of anterior temporal and inferior frontal regions from other parts of the brain due to white matter damage, rather than dysfunction of Wernicke's area itself. To test this hypothesis, we performed lesion-deficit correlations, including connectome-based lesion-symptom mapping, in four large, partially overlapping groups of English-speaking chronic left hemisphere stroke survivors. After removing variance due to object recognition and associative semantic processing, the same middle and posterior temporal lobe regions were implicated in both word comprehension deficits and complex non-canonical sentence comprehension deficits. Connectome lesion-symptom mapping revealed similar temporal-occipital white matter disconnections for impaired word and non-canonical sentence comprehension, including the temporal pole. We found an additional significant temporal-parietal disconnection for non-canonical sentence comprehension deficits, which may indicate a role for phonological working memory in processing complex syntax, but no significant frontal disconnections. Moreover, damage to these middle-posterior temporal lobe regions was associated with both word and non-canonical sentence comprehension deficits even when accounting for variance due to the strongest anterior temporal and inferior frontal white matter disconnections, respectively. Our results largely agree with the classical notion that Wernicke's area, defined here as middle superior temporal gyrus and middle-posterior superior temporal sulcus, supports both word and sentence comprehension, suggest a supporting role for temporal pole in both word and sentence comprehension, and speak against the hypothesis that comprehension deficits in Wernicke's aphasia result from double disconnection.

Frontal white matter association with sleep quality and the role of stress.

An important measure of brain health is the integrity of white matter connectivity structures that link brain regions. Studies have found an association between poorer sleep quality and decreased white matter integrity. Stress is among the strongest predictors of sleep quality. This study aimed to evaluate the association between sleep quality and white matter and to test if the relationship persisted after accounting for stress. White matter microstructures were measured by diffusion tensor imaging in a population of Old Order Amish/Mennonite (N=240). Sleep quality was determined by the Pittsburgh Sleep Quality Index. Current stress levels were measured by the perceived stress scale. Exposure to lifetime stress was measured by the lifetime stressor inventory. Microstructures of four white matter tracts: left and right anterior limbs of internal capsule, left anterior corona radiata, and genu of corpus callosum were significantly correlated with sleep quality (all p ≤ 0.001). The current stress level was a significant predictor of sleep quality (p ≤ 0.001) while lifetime stress was not. PSQI remained significantly associated with white matter integrity in these frontal tracts (all p < 0.01) after accounting for current stress and lifetime stress, while current and lifetime stress were not significant predictors of white matter in any of the four models. Sleep quality did not have any substantial mediation role between stress and white matter integrity. Sleep quality was significantly associated with several frontal white matter tracts that connect brain structures important for sleep regulation regardless of current or past stress levels.

Tract-Based Spatial Statistics Analysis of Diffusion Tensor Imaging in Older Adults After the PICMOR Intervention Program: A Pilot Study.

Diffusion tensor imaging (DTI) enables the investigation of white matter properties in vivo by applying a tensor model to the diffusion of water molecules in the brain. Using DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), an attempt has been made to detect age-related alterations in the white matter microstructure in aging research. However, the use of comprehensive DTI measures to examine the effects of cognitive intervention/training on white matter fiber health in older adults remains limited. Recently, we developed a cognitive intervention program called Photo-Integrated Conversation Moderated by Robots (PICMOR), which utilizes one of the most intellectual activities of daily life, conversations. To examine the effects of PICMOR on cognitive function in older adults, we conducted a randomized controlled trial and found that verbal fluency task scores were improved by this intervention. Based on these behavioral findings, we collected in this pilot study diffusion-weighted images from the participants to identify candidate structures for white matter microstructural changes induced by this intervention. The results from tract-based spatial statistics analyses showed that the intervention group, who participated in PICMOR-based conversations, had significantly higher FA values or lower MD, AD, or RD values across various fiber tracts, including the left anterior corona radiata, external capsule, and anterior limb of the internal capsule, compared to the control group, who participated in unstructured free conversations. Furthermore, a larger improvement in verbal fluency task scores throughout the intervention was associated with smaller AD values in clusters, including the left side of these frontal regions. The present findings suggest that left frontal white matter structures are candidates for the neural underpinnings responsible for the enhancement of verbal fluency. Although our findings are limited by the lack of comparable data at baseline, we successfully confirmed the hypothesized pattern of group differences in DTI indices after the intervention, which fits well with the results of other cognitive intervention studies. To confirm whether this pattern reflects intervention-induced white matter alterations, longitudinal data acquisition is needed in future research.

Neuroimaging Correlates of Post-Traumatic Stress Disorder in Traumatic Brain Injury: A Systematic Review of the Literature

IntroductionNeuroimaging has been a highly utilized technique for studying traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) independently of one another, however, neuroimaging has increasingly been identified as a useful tool in better understanding TBI-related psychiatric conditions, such as PTSD.ObjectivesTo complete a systematic review of the literature examining neuroimaging findings in TBI-related PTSD and to highlight the current literature’s limitations in order to strengthen future research.MethodsA PRISMA compliant literature search was conducted in PubMed (MEDLINE), PsychINFO, EMBASE, and Scopus databases prior to May of 2019. The initial database query yielded 4388 unique articles, which were narrowed down based on specified inclusion criteria (e.g., clear TBI definition, clinician-diagnosed PTSD, statistically analyzed relationship between neuroimaging and PTSD, quantified time interval between TBI and neuroimaging).ResultsA final cohort of 10 articles met inclusion criteria, comprising the findings of 482 participants with TBI. Key neuroanatomical findings among the included articles suggest that PTSD is associated with significant changes in whole-brain networks of resting state connectivity and disruptions in bilateral frontal and temporal white matter tracts, fronto-limbic pathways, the internal capsule, and the uncinate fasciculus (Figure 1). Figure 1a:Neuroimaging Findings in TBI-related PTSD.Figure 1b.Replicated Neuroimaging Findings in TBI-related PTSD in the Right Uncinate Fasciculus.ConclusionsAdditional inquiry with attention to specified imaging timing post-injury, consistent TBI definitions, clinician-diagnosed TBI and PTSD, and control groups is crucial to extrapolating discrepancies between primary and TBI-related PTSD. Prospective studies could further differentiate predisposing factors from sequelae of TBI-related PTSD.DisclosureNo significant relationships.

B.1 Can quantitative susceptibility mapping help diagnose and predict recovery of concussion in children?

Background: Quantitative susceptibility mapping (QSM) is an MR sequence that has potential as a biomarker in concussion. We compared QSM in pediatric concussion patients versus a comparison group of children with orthopedic injuries (OI) and assessed QSM’s performance relative to the current clinical benchmark (5P risk score) for predicting persistent postconcussion symptoms (PPCS). Methods: Children (N=967) aged 8-16.99 years with either concussion or OI were prospectively recruited from 5 Canadian centers. Participants completed QSM at a post-acute assessment 2-33 days post-injury. QSM z-score metrics for 9 regions of interest (ROI) were derived from 371 children (concussion=255, OI=116). PPCS at 1-month post-injury was defined using reliable change methods. Results: The concussion and OI groups did not differ significantly in QSM across ROI. Increased frontal white matter (WM) susceptibility predicted reliable increases in parent-rated cognitive symptoms (p=0.001). Together, frontal WM susceptibility and the 5P risk score were better at predicting persistent cognitive symptoms than the 5P risk score alone (p=0.0021). AUC were 0.71 (95%CI: 0.62-0.80) for frontal WM susceptibility, 0.67 (95%CI: 0.56-0.78) for the 5P risk score, and 0.73 (95%CI: 0.64-0.82) for both. Conclusions: This is the first study to demonstrate a potential imaging biomarker that predicts persistent symptoms in children with concussion compared to the current clinical benchmark.

Transcriptomic Profiling Reveals Discrete Poststroke Dementia Neuronal and Gliovascular Signatures

Poststroke dementia (PSD) is associated with pathology in frontal brain regions, in particular dorsolateral prefrontal cortex (DLPFC) neurons and white matter, remote from the infarct. We hypothesised that PSD results from progressive DLPFC neuronal damage, associated with frontal white matter gliovascular unit (GVU) alterations. We investigated the transcriptomic profile of the neurons and white matter GVU cells previously implicated in pathology. Laser-capture microdissected neurons, astrocytes and endothelial cells were obtained from the Cognitive Function After Stroke cohort of control, PSD and poststroke non-dementia (PSND) human subjects. Gene expression was assessed using microarrays and pathway analysis to compare changes in PSD with controls and PSND. Neuronal findings were validated using NanoString technology and compared with those in the bilateral common carotid artery stenosis (BCAS) mouse model. Comparing changes in PSD compared to controls with changes in PSND compared to controls identified transcriptomic changes associated specifically with dementia. DLPFC neurons showed defects in energy production (tricarboxylic acid (TCA) cycle, adenosine triphosphate (ATP) binding and mitochondria), signalling and communication (MAPK signalling, Toll-like receptor signalling, endocytosis). Similar changes were identified in neurons isolated from BCAS mice. Neuronal findings accompanied by altered astrocyte communication and endothelium immune changes in the frontal white matter, suggesting GVU dysfunction. We propose a pathogenic model in PSD whereby neuronal changes are associated with frontal white matter GVU dysfunction leading to astrocyte failure in supporting neuronal circuits resulting in delayed cognitive decline associated with PSD. Therefore, targeting these processes could potentially ameliorate the dementia seen in PSD.

Whole-brain metabolic pattern analysis in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis.

Faciobrachial dystonic seizures (FBDS) and hyponatremia are the distinct clinical features of autoimmune encephalitis (AE) caused by antibodies against leucine-rich glioma-inactivated 1 (LGI1). The present study aims to explore the pathophysiological patterns and neural mechanisms underlying these symptoms. We included 30 patients with anti-LGI1 AE and 30 controls from a retrospective observational cohort. Whole-brain metabolic pattern analysis was performed to assess the pathological network of anti-LGI1 AE, as well as the symptom networks associated with FBDS. Logistic regression was applied to explore independent predictors of FBDS. Finally, we used a multiple regression model to investigate the hyponatremia-associated brain network and its effect on serum sodium levels. The pathological network of anti-LGI1 AE involved hypermetabolism in the cerebellum, subcortical structures and Rolandic area, as well as hypometabolism in the medial prefrontal cortex. The symptom network of FBDS included hypometabolism in the cerebellum and Rolandic area (pFDR <0.05). Hypometabolism in the cerebellum was an independent predictor of FBDS (p < 0.001). Hyponatremia-associated network highlighted a negative effect on the caudate nucleus, frontal and temporal white matter. The metabolism of the hypothalamus was negatively associated with (Pearson's R = -0.180, p = 0.342),whilenottheindependentpredictorforserumsodiumlevel (path c' = -7.238, 95% confidence interval = -30.947 to 16.472). Our results provide insights into the whole-brain metabolic patterns of patients with anti-LGI1 AE, including the symptom network associated with FBDS and the hyponatremia-associated brain network. The findings help us to understand the neural mechanisms underlying anti-LGI1 AE and to evaluate the progress of this disease.

Effects of ibudilast on central and peripheral markers of inflammation in alcohol use disorder: A randomized clinical trial.

Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro-inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non-treatment-seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2weeks of medication. At study mid-point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline-compounds (Cho), myo-inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast-treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast-treated participants had nominally lower C-reactive protein levels at visit 2 and nominally lower TNF-α/IL-10 ratios, relative to placebo. C-reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro-longitudinal ibudilast treatment may induce peripheral and putative central anti-inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti-inflammatory component to the therapeutic action of ibudilast.

Evaluation of toxic effects of chemotherapy in lung malignancies on cerebral white matter using diffusion tensor imaging.

BackgroundNon-small cell lung cancer (NSCLC) is a leading cause of morbidity and mortality. Carboplatin and cisplatin based regimens are used in the treatment of NSCLC. The aim of the study was to find out whether there is a difference in white matter (WM) changes between two platinum-based chemotherapy agents using diffusion tensor imaging (DTI).Patients and methods25 patients who received chemotherapy for NSCLC and 27 age-matched healthy controls were enrolled in the study. Fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD) and radial diffusivity (RD) values of the study population were measured from 11 regions of interest in pre-chemotherapy and post-chemotherapy MRI data.ResultsCisplatin group showed a significant decrease in the FA of the inferior longitudinal fasciculus (P = 0.028). Carboplatin group showed a significant FA decrease and RD increase in the forceps minor (P = 0.022 and P = 0.011, respectively), and a significant reduction in AD and increase in MD in frontal white matter (WM) (P = 0.008 and P = 0.029, respectively). In comparison of post chemotherapy DTI values of the two groups, carboplatin group showed lower FA, and higher MD and RD values than cisplatin group in parieto-occipital WM (P = 0.034, P = 0.034, P = 0.029, respectively).ConclusionsThe findings of the study suggest that subtle effects of chemotherapy detectable with DTI may emerge after the treatment. In addition, carboplatin regimen may have more impact on WM than cisplatin regimen.

Brain metabolite alterations related to alcohol use: a meta-analysis of proton magnetic resonance spectroscopy studies.

Alcohol misuse and alcohol use disorder (AlUD) have neurobiological consequences. This meta-analysis of proton magnetic resonance spectroscopy (MRS) studies aimed to assess the differences in brain metabolite levels in alcohol misuse and AUD relative to controls (PROSPERO registration: CRD42020209890). Hedge's g with random-effects modeling was used. Sub-group and meta-regression techniques explored potential sources of demographic and MRS parameter heterogeneity. A comprehensive literature review identified 43 studies, resulting in 69 models across gray and white matter (GM, WM). Lower N-acetylaspartate levels were found in frontal, anterior cingulate cortex (ACC), hippocampal, and cerebellar GM, and frontal and parietal WM, suggesting decreased neuronal and axonal viability. Lower choline-containing metabolite levels (all metabolites contributing to choline peak) were found in frontal, temporal, thalamic, and cerebellar GM, and frontal and parietal WM, suggesting membrane alterations related to alcohol misuse. Lower creatine-containing metabolite levels (Cr; all metabolites contributing to Cr peak) were found in temporal and occipital cortical GM, while higher levels were noted in midbrain/brainstem GM; this finding may have implications for using Cr as an internal reference. The lack of significant group differences in glutamate-related levels is possibly related to biological and methodological complexities. The few studies reporting on GABA found lower levels restricted to the ACC. Confounding variables were age, abstinence duration, treatment status, and MRS parameters (echo time, quantification type, data quality). This first meta-analysis of proton MRS studies consolidates the numerous individual studies to identify neurometabolite alterations within alcohol misuse and AUD. Future studies can leverage this new formalized information to investigate treatments that might effectively target the observed disturbances.