Cortical Lesion Volume Research Articles

Time of the Day of Traumatic Brain Injury has Minimal Effects on Behavioral and Histological Outcomes in Mice of Both Sexes.

Transcription of > 50% of the mammalian coding genes follows circadian rhythm in an organ-specific manner. Recent findings highlighted the influence of time of the day in the progression of various neurological diseases and therapies. In the present study, we evaluated the effect of time of occurrence of traumatic brain injury (TBI) on behavioral and neuropathological outcomes in mice of both sexes. Following a controlled cortical impact injury induced between Zeitgeber time (ZT)1-4 or ZT13-16, behavioral deficits and brain damage were evaluated. There were no significant differences in post-TBI motor function between groups ZT1-4 and ZT13-16 in either male or female mice compared with the sex-matched naïve control. TBI-induced anxiety-like behavior was significantly higher in the female ZT13-16 cohort compared to the naïve cohort; but, no difference was observed between injured groups in both sexes. Similarly, spatial learning and memory were not significantly different between the ZT1-4 and ZT13-16 groups in both sexes. Post-TBI cortical lesion volume was also not significantly different between ZT1-4 and ZT-13-16 groups in both sexes. The present study observed no significant effects of occurrence time on TBI-induced brain damage or behavioral deficits in male and female mice.

Early regional cerebral grey matter damage predicts long-term cognitive impairment phenotypes in multiple sclerosis: a 20-year study.

Despite grey matter atrophy in cortical and subcortical regions has been related to cognitive impairment in multiple sclerosis, only a few studies evaluated its predictive value for alterations in the long-term. We aimed to determine early predictors of cognitive status after 20 years of multiple sclerosis. In this longitudinal retrospective study, participants underwent a 1.5 T MRI scanning at diagnosis (T0) and after two years (T2), which included the evaluation of regional grey matter volume loss patterns. All individuals with multiple sclerosis underwent a comprehensive neuropsychological assessment at the end of the study and were classified considering their global and specific cognitive domains status (memory, attention/information processing speed, executive functioning). Clinical and MRI characteristics were assessed as predictors of long-term cognitive impairment. Analysis of covariance, t-test, unadjusted and adjusted (for age, sex, disease duration, volume of white matter lesions, volume of cortical lesions) logistic regression were conducted. One hundred seventy-five people with multiple sclerosis (118 females; mean ± SD age at the end of study = 47.7 ± 9.4 years) clinically followed for 20 years from onset (mean ± SD = 19.9 ± 5.1) were evaluated. At the end of the study, 81 (47%) were classified as cognitively impaired: 38 as mildly impaired (22%), and 43 as severely impaired (25%). In particular, 46 were impaired in memory (27%), 66 were impaired in attention/information processing speed (38%), and 71 were impaired in executive functioning (41%). Regression models identified precuneus (adjusted odds ratio = 3.37; P < 0.001), insula (adjusted odds ratio = 2.33; P = 0.036), parahippocampal gyrus (adjusted odds ratio = 2.07; P < 0.001) and cingulate (adjusted odds ratio = 1.81; P = 0.009) as the most associated regions with global cognitive impairment and domains-specific cognitive alterations after a mean of 20 years of multiple sclerosis, after adjusting for demographic and clinical variables as well as for focal white matter and grey matter damage. Early grey matter volume loss of specific cortical and deep grey matter regions predicts global and domain cognitive alterations after 20 years from multiple sclerosis diagnosis.

Pre-operative environmental enrichment does not yield a prophylactic effect against traumatic brain injury-induced neurobehavioral deficits

The robustness of environmental enrichment (EE) in ameliorating neurobehavioral and cognitive deficits after experimental traumatic brain injury (TBI) is unequivocal. What is equivocal is whether EE can function as a prophylactic to afford resiliency and neuroprotection against TBI. We hypothesized that pre-operative EE would yield a protective effect against TBI-induced motor, cognitive, and coping deficits, and that further improvements would be conferred when EE is provided before and after TBI. To test the hypotheses, adult male rats received either 4 weeks of EE or standard (STD) housing prior to undergoing a controlled cortical impact of moderate severity (2.8 mm deformation at 4 m/s) or sham injury while under anesthesia. After injury, the rats were randomly assigned to post-operative EE or STD housing. Motor ability, spatial learning, and memory retention were assessed by beam-walk and water maze tests, respectively. Active and passive behavioral coping strategies were evaluated with the shock probe defensive burying (SPDB) test. c-Fos and cortical lesion volume were also quantified. The post-TBI enrichment groups (EE + TBI + EE and STD + TBI + EE) did not differ (p > 0.05) and performed better than the post-TBI STD-housed groups (EE + TBI + STD and STD + TBI + STD) on motor and cognition (p < 0.05). The post-TBI STD groups did not differ, regardless of whether in EE or STD living conditions before injury (p > 0.05). Moreover, both post-TBI enrichment groups performed better in the SPDB test relative to the STD + TBI + STD group (p < 0.05). c-Fos + cells were upregulated in the ipsilateral CA1 in both pre-injury EE groups relative to the pre-injury STD groups (p < 0.05). No statistical differences were observed in cortical lesion volume among the groups. Overall, these data do not support the hypothesis as no neuroprotective effect was observed with 4 weeks of pre-operative EE and no additional benefit was achieved in the TBI group receiving both pre-and-post EE relative to the TBI group receiving only post-EE. However, the data do reinforce the consistency of post-TBI EE in producing robust neurobehavioral benefits, which further supports this paradigm as a relevant preclinical model of neurorehabilitation.

Association of Cortical Lesions With Regional Glutamate, GABA, N-Acetylaspartate, and Myoinositol Levels in Patients With Multiple Sclerosis.

Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.

Evaluating the Efficacy of Chronic Galantamine on Sustained Attention and Cholinergic Neurotransmission in A Pre-Clinical Model of Traumatic Brain Injury.

Cholinergic disruptions underlie attentional deficits following traumatic brain injury (TBI). Yet, drugs specifically targeting acetylcholinesterase (AChE) inhibition have yielded mixed outcomes. Therefore, we hypothesized that galantamine (GAL), a dual-action competitive AChE inhibitor and α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator, provided chronically after injury, will attenuate TBI-induced deficits of sustained attention and enhance ACh efflux in the medial prefrontal cortex (mPFC), as assessed by invivo microdialysis. In Experiment 1, adult male rats (n = 10-15/group) trained in the 3-choice serial reaction time (3-CSRT) test were randomly assigned to controlled cortical impact (CCI) or sham surgery and administered GAL (0.5, 2.0, or 5.0 mg/kg; i.p.) or saline vehicle (VEH; 1 mL/kg; i.p) beginning 24-h post-surgery and once daily thereafter for 27 days. Measures of sustained attention and distractibility were assessed on post-operative days 21-25 in the 3-CSRT, following which cortical lesion volume and basal forebrain cholinergic cells were quantified on day 27. In Experiment 2, adult male rats (n = 3-4/group) received a CCI and 24 h later administered (i.p.) one of the three doses of GAL or VEH for 21 days to quantify the dose-dependent effect of GAL on invivo ACh efflux in the mPFC. Two weeks after the CCI, a guide cannula was implanted in the right mPFC. On post-surgery day 21, baseline and post-injection dialysate samples were collected in a temporally matched manner with the cohort undergoing behavior. ACh levels were analyzed using reverse phase high-performance liquid chromatography (HPLC) coupled to an electrochemical detector. Cortical lesion volume was quantified on day 22. The data were subjected to ANOVA, with repeated measures where appropriate, followed by Newman-Keuls post hoc analyses. All TBI groups displayed impaired sustained attention versus the pooled SHAM controls (p's < 0.05). Moreover, the highest dose of GAL (5.0 mg/kg) exacerbated attentional deficits relative to VEH and the two lower doses of GAL (p's < 0.05). TBI significantly reduced cholinergic cells in the right basal forebrain, regardless of treatment condition, versus SHAM (p < 0.05). In vivo microdialysis revealed no differences in basal ACh in the mPFC; however, GAL (5.0 mg/kg) significantly increased ACh efflux 30 min following injection compared to the VEH and the other GAL (0.5 and 2.0 mg/kg) treated groups (p's < 0.05). In both experiments, there were no differences in cortical lesion volume across treatment groups (p's > 0.05). In summary, albeit the higher dose of GAL increased ACh release, it did not improve measures of sustained attention or histopathological markers, thereby partially supporting the hypothesis and providing the impetus for further investigations into alternative cholinergic pharmacotherapies such as nAChR positive allosteric modulators.

Contribution of new and chronic cortical lesions to disability accrual in multiple sclerosis.

Cortical lesions are common in multiple sclerosis and are associated with disability and progressive disease. We asked whether cortical lesions continue to form in people with stable white matter lesions and whether the association of cortical lesions with worsening disability relates to pre-existing or new cortical lesions. Fifty adults with multiple sclerosis and no new white matter lesions in the year prior to enrolment (33 relapsing-remitting and 17 progressive) and a comparison group of nine adults who had formed at least one new white matter lesion in the year prior to enrolment (active relapsing-remitting) were evaluated annually with 7 tesla (T) brain MRI and 3T brain and spine MRI for 2 years, with clinical assessments for 3 years. Cortical lesions and paramagnetic rim lesions were identified on 7T images. Seven total cortical lesions formed in 3/30 individuals in the stable relapsing-remitting group (median 0, range 0-5), four total cortical lesions formed in 4/17 individuals in the progressive group (median 0, range 0-1), and 16 cortical lesions formed in 5/9 individuals in the active relapsing-remitting group (median 1, range 0-10, stable relapsing-remitting versus progressive versus active relapsing-remitting P = 0.006). New cortical lesions were not associated with greater change in any individual disability measure or in a composite measure of disability worsening (worsening Expanded Disability Status Scale or 9-hole peg test or 25-foot timed walk). Individuals with at least three paramagnetic rim lesions had a greater increase in cortical lesion volume over time (median 16 µl, range -61 to 215 versus median 1 µl, range -24 to 184, P = 0.007), but change in lesion volume was not associated with disability change. Baseline cortical lesion volume was higher in people with worsening disability (median 1010 µl, range 13-9888 versus median 267 µl, range 0-3539, P = 0.001, adjusted for age and sex) and in individuals with relapsing-remitting multiple sclerosis who subsequently transitioned to secondary progressive multiple sclerosis (median 2183 µl, range 270-9888 versus median 321 µl, range 0-6392 in those who remained relapsing-remitting, P = 0.01, adjusted for age and sex). Baseline white matter lesion volume was not associated with worsening disability or transition from relapsing-remitting to secondary progressive multiple sclerosis. Cortical lesion formation is rare in people with stable white matter lesions, even in those with worsening disability. Cortical but not white matter lesion burden predicts disability worsening, suggesting that disability progression is related to long-term effects of cortical lesions that form early in the disease, rather than to ongoing cortical lesion formation.

Working Memory Training Responsiveness in Parkinson's Disease Is Not Determined by Cortical Thickness or White Matter Lesions.

Patients with Parkinson's disease are highly vulnerable for cognitive decline. Thus, early intervention by means of working memory training (WMT) may be effective for the preservation of cognition. However, the influence of structural brain properties, i.e., cortical thickness and volume of white matter lesions on training responsiveness have not been studied. Here, behavioral and neuroimaging data of 46 patients with Parkinson's disease, 21 of whom engaged in home-based, computerized adaptive WMT, was analyzed. While cortical thickness and white matter lesions volume were associated with cognitive performance at baseline, these structural brain properties do not seem to determine WMT responsiveness.

Development of statistical auto-segmentation method for diffusion restriction gray matter lesions in patients with newly diagnosed sporadic Creutzfeldt–Jakob disease

Quantification of diffusion restriction lesions in sporadic Creutzfeldt-Jakob disease (sCJD) may provide information of the disease burden. We aim to develop an automatic segmentation model for sCJD and to evaluate the volume of disease extent as a prognostic marker for overall survival. Fifty-six patients (mean age ± SD, 61.2 ± 9.9 years) were included from February 2000 to July 2020. A threshold-based segmentation was used to obtain abnormal signal intensity masks. Segmented volumes were compared with the visual grade. The Dice similarity coefficient was calculated to measure the similarity between the automatic vs. manual segmentation. Cox proportional hazards regression analysis was performed to evaluate the volume of disease extent as a prognostic marker. The automatic segmentation showed good correlation with the visual grading. The cortical lesion volumes significantly increased as the visual grade aggravated (extensive: 112.9 ± 73.2; moderate: 45.4 ± 30.4; minimal involvement: 29.6 ± 18.1 mm3) (P < 0.001). The deep gray matter lesion volumes were significantly higher for positive than for negative involvement of the deep gray matter (5.6 ± 4.6 mm3 vs. 1.0 ± 1.3 mm3, P < 0.001). The mean Dice similarity coefficients were 0.90 and 0.94 for cortical and deep gray matter lesions, respectively. However, the volume of disease extent was not associated with worse overall survival (cortical extent: P = 0.07; deep gray matter extent: P = 0.12).

Dopamine enhances recovery after traumatic brain injury through ubiquitylation and autophagic degradation of RIPK1

BackgroundAlthough the neurotransmitter dopamine (DA) plays a crucial pathophysiologic role after traumatic brain injury (TBI), its function and specific underlying mechanisms of action remain unclear.MethodsAdult male mice underwent controlled cortical impact (CCI). We administered DA intraperitoneally to mice for 14 consecutive days, starting 8 h before CCI. On day 3 after brain injury, cortical lesion volume and brain water content were measured. On days 7–13, behavioral tests were performed.ResultsHerein we report that DA inhibits neural death after injury, which is mediated via the dopamine D1 receptor (DRD1). Our results also showed that DRD1 signaling promotes RIPK1 ubiquitination via the E3 ubiquitin ligase Chip and then degradation through autophagy. Importantly, in vivo data revealed that DRD1 signaling prevented neural death, suppressed neuroinflammation, and restored many TBI-related functional sequelae.ConclusionsThese data reveal a novel mechanism involving dopamine, and suggest that DRD1 activation positively regulates Chip-mediated ubiquitylation of RIPK1—leading to its autophagic degradation.

STING-Dependent Signaling in Microglia or Peripheral Immune Cells Orchestrates the Early Inflammatory Response and Influences Brain Injury Outcome.

While originally identified as an antiviral pathway, recent work has implicated that cyclic GMP-AMP-synthase-Stimulator of Interferon Genes (cGAS-STING) signaling is playing a critical role in the neuroinflammatory response to traumatic brain injury (TBI). STING activation results in a robust inflammatory response characterized by the production of inflammatory cytokines called interferons, as well as hundreds of interferon stimulated genes (ISGs). Global knock-out (KO) mice inhibiting this pathway display neuroprotection with evidence that this pathway is active days after injury; yet, the early neuroinflammatory events stimulated by STING signaling remain understudied. Furthermore, the source of STING signaling during brain injury is unknown. Using a murine controlled cortical impact (CCI) model of TBI, we investigated the peripheral immune and microglial response to injury utilizing male chimeric and conditional STING KO animals, respectively. We demonstrate that peripheral and microglial STING signaling contribute to negative outcomes in cortical lesion volume, cell death, and functional outcomes postinjury. A reduction in overall peripheral immune cell and neutrophil infiltration at the injury site is STING dependent in these models at 24 h. Transcriptomic analysis at 2 h, when STING is active, reveals that microglia drive an early, distinct transcriptional program to elicit proinflammatory genes including interleukin 1-β (IL-1β), which is lost in conditional knock-out mice. The upregulation of alternative innate immune pathways also occurs after injury in these animals, which supports a complex relationship between brain-resident and peripheral immune cells to coordinate the proinflammatory response and immune cell influx to damaged tissue after injury.

Neuroimaging markers and disability scales in multiple sclerosis: A systematic review and meta-analysis.

Multiple sclerosis (MS) is a central nervous system disorder marked by progressive neurological impairments. Magnetic resonance imaging (MRI) parameters are key paraclinical measures that play a crucial role in the diagnosis, prognosis, and monitoring of MS-related disability. This study aims to analyze and summarize the existing literature on the correlation between MRI parameters and disability in people with MS (pwMS). The PubMed/MEDLINE, Embase, Scopus, and Web of Science databases were searched from inception to July 19, 2024, and a meta-analysis was carried out using R software version 4.4.0 and the random effects model used to determine the pooled correlation coefficient, with its 95% confidence interval (CI), between MRI measurements and disability scales. Among 5741 studies, 383 studies with 39707 pwMS were included. The meta-analysis demonstrated that Expanded Disability Status Scale (EDSS) had significant correlations with cervical cord volume (r = -0.51, 95% CI: -0.62 to -0.38, I2 = 0%, p-heterogeneity = 0.86, p-value<0.01), cortical lesion volume (r = 0.45, 95% CI: 0.36 to 0.53, I2 = 68%, p-heterogeneity<0.01, p-value<0.01), brain volume (r = -0.40, 95% CI: -0.47 to -0.33, I2 = 41%, p-heterogeneity = 0.05, p-value<0.05), and grey matter volume (GMV) (r = -0.36, 95% CI: -0.49 to -0.21, I2 = 0%, p-heterogeneity = 0.53, p-value<0.01), respectively. This study offers evidence suggesting that cortical lesion volume, brain volume, GMV, and MRI measurements of the spinal cord may constitute reliable indicators for assessing disability in pwMS.

Associations between cortical lesions, optic nerve damage, and disability at the onset of multiple sclerosis: insights into neurodegenerative processes.

BackgroundMultiple sclerosis cortical lesions are areas of demyelination and neuroaxonal loss. Retinal layer thickness, measured with optical coherence tomography (OCT), is an emerging biomarker of neuroaxonal loss. Studies have reported correlations between cortical lesions and retinal layer thinning in established multiple sclerosis, suggesting a shared pathophysiological process. Here, we assessed the correlation between cortical lesions and OCT metrics at the onset of multiple sclerosis, examining, for the first time, associations with physical or cognitive disability. ObjectiveTo examine the relationship between cortical lesions, optic nerve and retinal layer thicknesses, and physical and cognitive disability at the first demyelinating event. MethodsThirty-nine patients and 22 controls underwent 3T-MRI, optical coherence tomography, and clinical tests. We identified cortical lesions on phase-sensitive inversion recovery sequences, including occipital cortex lesions. We measured the estimated total intracranial volume and the white matter lesion volume. OCT metrics included peripapillary retinal nerve fibre layer (pRNFL), ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses. ResultsHigher total cortical and leukocortical lesion volumes correlated with thinner pRNFL (B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01; B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01, respectively). Leukocortical lesion number correlated with colour vision deficits (B = 0.58, 95 %CI 0.039 to 1,11, p = 0.036). Thinner GCIPL correlated with a higher Expanded Disability Status Scale (B = -0.06, 95 % CI -1.1 to -0.008, p = 0.026). MS diagnosis (n = 18) correlated with higher cortical and leukocortical lesion numbers (p = 0.004 and p = 0.003), thinner GCIPL (p = 0.029) and INL (p = 0.041). ConclusionThe association between cortical lesions and axonal damage in the optic nerve reinforces the role of neurodegenerative processes in MS pathogenesis at onset.

A bridge to recovery: Acute amantadine prior to environmental enrichment after brain trauma augments cognitive benefit

Environmental enrichment (EE) facilitates motor and cognitive recovery after traumatic brain injury (TBI). Historically, EE has been provided immediately and continuously after TBI, but this paradigm does not model the clinic where rehabilitation is typically not initiated until after critical care. Yet, treating TBI early may facilitate recovery. Hence, we sought to provide amantadine (AMT) as a bridge therapy before commencing EE. It was hypothesized that bridging EE with AMT would augment motor and cognitive benefits. Anesthetized adult male rats received a cortical impact (2.8 mm deformation at 4 m/s) or sham surgery and then were housed in standard (STD) conditions where they received intraperitoneal AMT (10 mg/kg or 20 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 h after surgery and once daily during the 6-day bridge phase or once daily for 19 days for the non-bridge groups (i.e., continuously STD-housed) to compare the effects of acute AMT plus EE vs. chronic AMT alone. Abbreviated EE, which was presented to closer emulate clinical rehabilitation (e.g., 6 h/day), began on day 7 for the AMT bridge and chronic EE groups. Motor (beam-walking) and cognition (acquisition of spatial learning and memory) were assessed on days 7–11 and 14–19, respectively. Cortical lesion volume and hippocampal cell survival were quantified on day 21. EE, whether provided in combination with VEH or AMT, and AMT (20 mg/kg) + STD, benefitted motor and cognition vs. the STD-housed VEH and AMT (10 mg/kg) groups (p < 0.05). The AMT (20 mg/kg) + EE group performed better than the VEH + EE, AMT (10 mg/kg) + EE, and AMT (20 mg/kg) + STD groups in the acquisition of spatial learning (p < 0.05) but did not differ in motor function (p > 0.05). All groups receiving EE exhibited decreased cortical lesion volumes and increased CA3 neuron survival relative to the STD-housed groups (p < 0.05) but did not differ from one another (p > 0.05). The added cognitive benefit achieved by bridging EE with AMT (20 mg/kg) supports the hypothesis that the temporal separation of combinational therapies is more effective after TBI.

Plasma neurofilament light and brain volumetric outcomes among middle‐aged urban adults

AbstractBackgroundElevated plasma neurofilament light chain (NfL) is associated with dementia, but the specific underlying mechanisms are largely unknown. We examined cross‐sectional and longitudinal relationships of plasma NfL with selected brain structural magnetic resonance imaging (sMRI) prognostic markers of dementia, namely global and cortical brain, hippocampal and white matter lesion volumes (WMLV).MethodData were extracted from three prospective visits within the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study, selecting participants with complete v1 (2004‐2009) and v2 (2009‐2013) plasma NfL exposure and ancillary sMRI data at vscan (2011‐2015, n = 179, mean v1 to vscan time: 5.4y). Multivariable‐adjusted linear regression models were conducted, overall, by sex, and by race, correcting for multiple testing with q‐values.ResultNfL(v1) (Loge transformed) had a moderately strong association with larger WMLV at follow‐up vscan visit, after a period of 5‐6 years of follow‐up, overall (β = +2.131±0.660, b = +0.29, p = 0.001, q = 0.0029). Moreover, a 1 unit increase in NfLv2 was linked to a left hippocampal volume that was lower by 125 mm3 (p = 0.004, q = 0.015), using minimally adjusted models and mainly among males. Associations were largely unaltered by further adjustment for downstream health‐related factors.ConclusionIn summary, plasma NfL may be an independent medium‐term (within 5 years) marker for increase in WMLV, and a short term (within 1 year) marker for smaller hippocampal volumes normalized to the intracranial volume, independently of other confounding factors. Therefore, plasma NfL holds promise as a blood‐based marker to predict future subclinical brain pathologies in middle‐aged adults.

Fucoxanthin ameliorates traumatic brain injury by suppressing the blood–brain barrier disruption

Fucoxanthin is the most abundant marine carotenoid extracted from seaweed. Our previous study has shown that fucoxanthin inhibited oxidative stress after traumatic brain injury (TBI). However, the effects of fucoxanthin on TBI-induced blood-brain barrier (BBB) destruction have not been well understood. In the present study, we found that fucoxanthin improved neurological dysfunction, reduced brain edema, attenuated cortical lesion volume, and decreased dendrites loss after TBI invivo. Moreover, fucoxanthin suppressed BBB leakage, preserved tight junction (TJ) and adherens junction (AJ) proteins, and inhibited MMP-9 expression. Furthermore, fucoxanthin alleviated apoptosis and ferroptosis, and activated mitophagy in endothelial cells (ECs) after TBI. However, the protection of fucoxanthin on BBB was attenuated when mitophagy was inhibited. Importantly, fucoxanthin also provided protective effects in bEnd.3 cells after TBI. Taken together, our results suggested that fucoxanthin played a key role in the protection of BBB after TBI through mitophagy.

Efficacy of a music-based intervention in a preclinical model of traumatic brain injury: An initial foray into a novel and non-pharmacological rehabilitative therapy

Traumatic brain injury (TBI) causes neurobehavioral and cognitive impairments that negatively impact life quality for millions of individuals. Because of its pernicious effects, numerous pharmacological interventions have been evaluated to attenuate the TBI-induced deficits or to reinstate function. While many such pharmacotherapies have conferred benefits in the laboratory, successful translation to the clinic has yet to be achieved. Given the individual, medical, and societal burden of TBI, there is an urgent need for alternative approaches to attenuate TBI sequelae and promote recovery. Music based interventions (MBIs) may hold untapped potential for improving neurobehavioral and cognitive recovery after TBI as data in normal, non-TBI, rats show plasticity and augmented cognition. Hence, the aim of this study was to test the hypothesis that providing a MBI to adult rats after TBI would improve cognition, neurobehavior, and histological endpoints. Adult male rats received a moderate-to-severe controlled cortical impact injury (2.8 mm impact at 4 m/s) or sham surgery (n = 10–12 per group) and 24 h later were randomized to classical Music or No Music (i.e., ambient room noise) for 3 h/day from 19:00 to 22:00 h for 30 days (last day of behavior). Motor (beam-walk), cognitive (acquisition of spatial learning and memory), anxiety-like behavior (open field), coping (shock probe defensive burying), as well as histopathology (lesion volume), neuroplasticity (BDNF), and neuroinflammation (Iba1, and CD163) were assessed. The data showed that the MBI improved motor, cognitive, and anxiety-like behavior vs. No Music (p's < 0.05). Music also reduced cortical lesion volume and activated microglia but increased resting microglia and hippocampal BDNF expression. These findings support the hypothesis and provide a compelling impetus for additional preclinical studies utilizing MBIs as a potential efficacious rehabilitative therapy for TBI.

Exercise intensity and sex alter neurometabolic, transcriptional, and functional recovery following traumatic brain injury

Physical exercise represents a potentially inexpensive, accessible, and optimizable rehabilitation approach to traumatic brain injury (TBI) recovery. However, little is known about the impact of post-injury exercise on the neurometabolic, transcriptional, and cognitive outcomes following a TBI. In the current study, we examined TBI outcomes in adolescent male and female mice following a controlled cortical impact (CCI) injury. Mice underwent a 10-day regimen of sedentary, low-, moderate-, or high-intensity treadmill exercise and were assessed for cognitive function, histopathology, mitochondrial function, and oxidative stress. Among male mice, low-moderate exercise improved cognitive recovery, and reduced cortical lesion volume and oxidative stress, whereas high-intensity exercise impaired both cognitive recovery and mitochondrial function. On the other hand, among female mice, exercise had an intermediate effect on cognitive recovery but significantly improved brain mitochondrial function. Moreover, single nuclei RNA sequencing of perilesional brain tissue revealed neuronal plasticity-related differential gene expression that was largely limited to the low-intensity exercise injured males. Taken together, these data build on previous reports of the neuroprotective capacity of exercise in a TBI model, and reveal that this rehabilitation strategy impacts neurometabolic, functional, and transcriptional outcome measures in an intensity- and sex-dependent manner.

Enriching adult male rats prior to traumatic brain injury does not attenuate neurobehavioral or histological deficits.

Environmental enrichment (EE) confers significant increases in neurobehavioral and cognitive recovery and decreases histological damage in various models of traumatic brain injury (TBI). However, despite EE's pervasiveness, little is known regarding its prophylactic potential. Thus, the goal of the current study was to determine whether enriching rats prior to a controlled cortical impact exerts protection as evidenced by attenuated injury-induced neurobehavioral and histological deficits relative to rats without prior EE. The hypothesis was that enrichment prior to TBI would be protective. After two weeks of EE or standard (STD) housing, anesthetized adult male rats received either a controlled cortical impact (2.8mm deformation at 4m/s) or sham injury and then were placed in EE or STD conditions. Motor (beam-walk) and cognitive (spatial learning) performance were assessed on post-operative days 1-5 and 14-18, respectively. Cortical lesion volume was quantified on day 21. The group that was housed in STD conditions before TBI and received post-injury EE performed significantly better in motor, cognitive, and histological outcomes vs. both groups in STD conditions regardless of whether having received pre-injury EE or not (p<0.05). That no differences in any endpoint were revealed between the two STD-housed groups after TBI suggests that enriching rats prior to TBI does not attenuate neurobehavioral or histological deficits and therefore does not support the hypothesis.

Association between retinal layer thickness and cortical lesions at the onset of clinically isolated syndrome (P11-3.012)

<h3>Objective:</h3> The aim of this study was to evaluate the relationship between retinal layer thickness, cortical lesions (CLs) and disability at the onset of the first demyelinating event (a clinically isolated syndrome (CIS), suggestive of multiple sclerosis (MS). <h3>Background:</h3> Neuroaxonal degeneration is considered the primary cause of permanent disability in patients with MS, thus new biomarkers to quantify neurodegeneration are needed. Reduced retinal layer thickness in MS exists irrespective of optic neuritis (ON) and has been correlated with disability and brain atrophy. In CLs, neuroaxonal degeneration is also present. The relationship between retinal atrophy, CLs and disability in CIS is not well established. <h3>Design/Methods:</h3> We performed a cross-sectional evaluation of thirty-nine patients with CIS known to have CLs as identified on 3T brain MRI, who also underwent Optical Coherence Tomography to quantify retinal layer thickness. We excluded affected eyes in ON patients and used the average values of both eyes in patients without ON. We performed linear regression analyses to evaluate the relationships between the retina measures and CLs characteristics as well as clinical outcomes. Significant results with p&lt;0.05 are reported. <h3>Results:</h3> We found that a thinner combined ganglion cell-inner plexiform layer (GCIPL) was associated with higher juxtacortical lesion numbers and volumes. A thinner peripapillary retinal nerve fiber was associated with higher leukocortical, juxtacortical and total cortical lesion volumes. A thinner GCIPL was correlated with greater disability as measured by the expanded disability status scale. A reduced thickness of GCIPL and inner nuclear layer were associated with MS diagnosis at presentation. <h3>Conclusions:</h3> This study provides support for a relationship between increased cortical damage and retinal layers thinning in CIS suggesting a common pathological process behind these alterations. The association between greater retinal damage and disability confirms the role of GCIPL as a possible biomarker of neurodegeneration even at this early stage of the disease. <b>Disclosure:</b> Dr. Varmpompiti has nothing to disclose. Dr. Chow has nothing to disclose. The institution of Dr. Foster has received research support from Medical Research Council. Dr. Kodali has nothing to disclose. Marios Yiannakas has nothing to disclose. Dr. Kanber has nothing to disclose. Ferran Padros, 8186 has nothing to disclose. Dr. Davagnanam has nothing to disclose. Prof. Ciccarelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Prof. Ciccarelli has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Merck. Prof. Ciccarelli has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for NEUROLOGY Journal. The institution of Ahmed Toosy has received research support from Rosetrees Trust. The institution of Sara Collorone has received research support from Rosetreest Trust. The institution of Sara Collorone has received research support from MAGNIMS/ECTRIMS.

Human umbilical cord mesenchymal stem cell-derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin-mediated mitophagy.

Recently, human umbilical cord mesenchymal stem cell (HucMSC)-derived exosome is a new focus of research in neurological diseases. The present study was aimed to investigate the protective effects of HucMSC-derived exosome in both in vivo and in vitro TBI models. We established both mouse and neuron TBI models in our study. After treatment with HucMSC-derived exosome, the neuroprotection of exosome was investigated by the neurologic severity score (NSS), grip test score, neurological score, brain water content, and cortical lesion volume. Moreover, we determined the biochemical and morphological changes associated with apoptosis, pyroptosis, and ferroptosis after TBI. We revealed that treatment of exosome could improve neurological function, decrease cerebral edema, and attenuate brain lesion after TBI. Furthermore, administration of exosome suppressed TBI-induced cell death, apoptosis, pyroptosis, and ferroptosis. In addition, exosome-activated phosphatase and tensin homolog-induced putative kinase protein 1/Parkinson protein 2 E3 ubiquitin-protein ligase (PINK1/Parkin) pathway-mediated mitophagy after TBI. However, the neuroprotection of exosome was attenuated when mitophagy was inhibited, and PINK1 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed apoptosis, pyroptosis, and ferroptosis and activated the PINK1/Parkin pathway-mediated mitophagy after TBI in vitro. Our results provided the first evidence that exosome treatment played a key role in neuroprotection after TBI through the PINK1/Parkin pathway-mediated mitophagy.