White Matter Loss Research Articles

T0901317, a liver X receptor agonist, ameliorates perinatal white matter injury induced by ischemia and hypoxia in neonatal rats

Perinatal white matter injury (PWMI) can lead to permanent neurological damage in preterm infants and bring a huge economic burden to their families and society. Liver X receptors (LXRs) are transcription factors that have been confirmed to mediate the myelination process under physiological conditions and are involved in regulating neurogenesis in adult animal models of acute and chronic cerebral ischemia. However, the role of LXRs in PWMI induced by both ischemic and hypoxic stimulation in the immature brain has not been reported. Herein, we investigated the role of LXRs in a neonatal rat model of white matter loss after hypoxia-ischemia (HI) injury through intraperitoneal injection of the LXR agonist T0901317 (T09) 1 day before and 15 min postinjury. The in vivo data showed that T09 treatment significantly facilitated myelination and ameliorated neurological behavior after PWMI. Moreover, T09 enhanced the proliferation of oligodendrocyte lineage cells and reduced microgliosis and astrogliosis in the microenvironment for oligodendrocytes (OLs), maintaining a healthy microenvironment for myelinating OLs. In vitro data suggested that the expression of the myelin-related genes Plp and Cnpase was increased in OLN-93 cells after T09 intervention compared with OLN-93 cells injured by oxygen and glucose deprivation (OGD). In primary mixed astrocytes/microglia cells, T09 also reduced the expression of Il6, Cox2, Tnfa and Il10 that was induced by OGD. Mechanistically, the mRNA expression level and the protein level of ATP binding cassette subfamily A member 1 (Abca1) decreased after HI injury, and the protective effect of T09 might be related to the activation of the LXRβ-ABCA1 signaling pathway. Our study revealed the protective role of LXRs in myelination and white matter homeostasis, providing a potential therapeutic option for PWMI.

Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion

Intramuscular injection of an Adeno-associated viral vector serotype 1 (AAV1) encoding Neurotrophin-3 (NT3) into hindlimb muscles 24 h after a severe T9 spinal level contusion in rats has been shown to induce lumbar spinal neuroplasticity, partially restore locomotive function and reduce spasms during swimming. Here we investigate whether a targeted delivery of NT3 to lumbar and thoracic motor neurons 48 h following a severe contusive injury aids locomotive recovery in rats. AAV1-NT3 was injected bilaterally into the tibialis anterior, gastrocnemius and rectus abdominus muscles 48-h following trauma, persistently elevating serum levels of the neurotrophin. NT3 modestly improved trunk stability, accuracy of stepping during skilled locomotion, and alternation of the hindlimbs during swimming, but it had no effect on gross locomotor function in the open field. The number of vGlut1+ boutons, likely arising from proprioceptive afferents, on gastrocnemius α-motor neurons was increased after injury but normalised following NT3 treatment, suggestive of a mechanism in which functional benefits may be mediated through proprioceptive feedback. Ex vivo MRI revealed substantial loss of grey and white matter at the lesion epicentre but no effect of delayed NT3 treatment to induce neuroprotection. Lower body spasms and hyperreflexia of an intrinsic paw muscle were not reliably induced in this severe injury model suggesting a more complex anatomical or physiological cause to their induction. We have shown that delayed intramuscular AAV-NT3 treatment can promote recovery in skilled stepping and coordinated swimming, supporting a role for NT3 as a therapeutic strategy for spinal injuries potentially through modulation of somatosensory feedback.

Percentage brain volume change in multiple sclerosis mainly reflects white matter and cortical volume.

Brain atrophy in multiple sclerosis (MS), as measured by percentage brain volume change (PBVC) from brain magnetic resonance imaging (MRI), has been established as an outcome parameter in clinical trials. It is unknown to what extent volume changes within different brain tissue compartments contribute to PBVC. We analyzed pairs of MRI scans (at least 6 months apart) in 600 patients with relapsing-remitting MS. Multiple regression revealed that PBVC mainly reflects volume loss of white and cortical gray matter, while deep gray matter and white matter lesions were less represented. Our findings aid the interpretation of PBVC changes in MS.

Allan-Herndon-Dudley syndrome: Report of a novel pathogenic variant in MCT8 gene

X-linked MCT8 mutations cause Allan-Herndon-Dudley syndrome (AHDS) characterized by severe developmental delay and specific thyroid function abnormality. The report describes a 1 year-old boy with severe developmental delay, truncal hypotonia, quadriparesis (spastic), dystonia, and thyroid function abnormality (high free T3, low reverse T3, low free T4, and normal TSH) suggesting a form of impaired thyroid hormone sensitivity, namely, AHDS. WES analysis yielded novel hemizygous single-base pair duplication in exon 1 of MCT8 gene, validated by Sanger sequencing. MRI revealed generalized demyelination with poor gray and white matter differentiation and loss of brain volume. Indirect markers revealed thyrotoxicosis in some peripheral tissues. Having high index of suspicion for this rare disorder and plausible benefit of inclusion of free T3 assay in initial evaluation of infants and children with idiopathic developmental delay are emphasized. Amelioration of thyrotoxic features with tri-iodothyroacetic acid likely benefits patients at all ages. Neurodevelopmental improvement has been observed in those who received tri-iodoacetic acid early, which is being currently investigated.

4-hydroxyisoleucine mediated IGF-1/GLP-1 signalling activation prevents propionic acid-induced autism-like behavioural phenotypes and neurochemical defects in experimental rats

Autism is a neuropsychiatric disorder characterized by a neurotransmitter imbalance that impairs neurodevelopment processes. Autism development is marked by communication difficulties, poor socio-emotional health, and cognitive impairment. Insulin-like growth factor-1 (IGF-1) and glucagon-like growth factor-1 (GLP-1) are responsible for regular neuronal growth and homeostasis. Autism progression has been linked to dysregulation of IGF-1/GLP-1 signalling. 4-hydroxyisoleucine (HI), a pharmacologically active amino acid produced from Trigonella foenum graecum, works as an insulin mimic and has neuroprotective properties. The GLP-1 analogue liraglutide (LRG) was employed in our investigation to compare the efficacy of 4-HI in autism prevention. The current study explores the protective effects of 4-HI 50 and 100 mg/kg orally on IGF-1/GLP-1 signalling activation in a PPA-induced experimental model of autism. Propionic acid (PPA) injections to rats by intracerebroventricular (ICV) route for the first 11 days of the experiment resulted in autism-like neurobehavioral, neurochemical, gross morphological, and histopathological abnormalities. In addition, we investigated the dose-dependent neuroprotective effects of 4-HI on the levels of several neurotransmitters and neuroinflammatory cytokines in rat brain homogenate and blood plasma. Neuronal apoptotic and anti-oxidant cellular markers were also studied in blood plasma and brain homogenate samples. Furthermore, the luxol fast blue (LFB) staining results demonstrated significant demyelination in the brains of PPA-induced rats reversed by 4-HI treatment. Rats were assessed for spontaneous locomotor impairments, neuromuscular coordination, stress-like behaviour, learning, and memory to assess neurobehavioral abnormalities. The administration of 4-HI and LRG significantly reversed the behavioural, gross and histological abnormalities in the PPA-treated rat brains. After treatment with 4-HI and LRG, LFB-stained photomicrographs of PPA-treated rats' brains demonstrated the recovery of white matter loss. Our findings indicate that 4-HI protects neurons in rats with autism by enhancing the IGF-1 and GLP-1 protein levels.

AP4B1-associated hereditary spastic paraplegia: Expansion of clinico-genetic phenotype and geographic range

BackgroundHereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases that present with weakness and stiffness in the lower limb muscles and lead to progressive neurological decline. Bi-allelic loss-of-function variants in genes that encode subunits of the adaptor protein complex 4 (AP-4) lead to complex HSP. This study aimed to identify causative genetic variants in consanguineous families with HSP from Azerbaijan and Pakistan. MethodsWe performed a thorough clinical and neuroradiological characterization followed by exome sequencing in 7 patients from 3 unrelated families. Segregation analysis was subsequently performed by Sanger sequencing. ResultsWe describe 7 patients (4 males, 2–31 years of age) with developmental delay and spasticity.Similar to the previously reported cases with AP4B1-associated HSP, cases in the present report besides spasticity in the lower limbs had additional features including microcephaly, facial dysmorphism, infantile hypotonia, and epilepsy. The imaging findings included thin corpus callosum, white matter loss, and ventriculomegaly. ConclusionIn this study, we report 7 novel cases of HSP caused by bi-allelic variants in AP4B1 in Azerbaijani and Pakistani families. Our observations will help clinicians observe and compare common and unique clinical features of AP4B1-associated HSP patients, further improving our current understanding of HSP.

Brain Neurons during Physiological Aging: Morphological Features, Autophagic and Mitochondrial Contribution.

Accumulating data suggest that the brain undergoes various changes during aging. Among them are loss of both white and gray matter, neurons and synapses degeneration, as well as oxidative, inflammatory, and biochemical changes. The above-mentioned age-related features are closely related to autophagy and mitochondria. Therefore, we aimed to reveal the most peculiar morphological features of brain nervous tissue and to characterize the expression of autophagy and mitochondrial immunohistochemical biomarkers in neurons of different human brain zones during aging. Counting the number of neurons as well as Microtubule-associated proteins 1A/1B light chain 3B (LC3B), Heat shock protein 70 (HSP70), Lysosome-associated membrane protein type 2A (LAMP2A), Alpha subunit of ATP synthase (ATP5A), and Parkinson disease protein 7 (DJ1) immunohistochemical staining were performed on FFPE samples of human prefrontal cortex, corpus striatum, and hippocampus obtained from autopsy. Statistical analysis revealed a loss of neurons in the studied elderly group in comparison to the young group. When the expression of macroautophagy (LC3B), chaperon-mediated autophagy (HSP70, LAMP2A), and mitochondrial respiratory chain complex V (ATP5A) markers for the young and elderly groups were compared, the latter was found to have a significantly higher rate of optical density, whilst there was no significance in DJ1 expression. These findings, while preliminary, suggest that both autophagy and mitochondria are involved in neuronal maintenance during aging and could indicate their potential role in adaptive mechanisms that occur in aging.

Confounder-adjusted MRI-based predictors of multiple sclerosis disability.

Both aging and multiple sclerosis (MS) cause central nervous system (CNS) atrophy. Excess brain atrophy in MS has been interpreted as "accelerated aging." Current paper tests an alternative hypothesis: MS causes CNS atrophy by mechanism(s) different from physiological aging. Thus, subtracting effects of physiological confounders on CNS structures would isolate MS-specific effects. Standardized brain MRI and neurological examination were acquired prospectively in 646 participants enrolled in ClinicalTrials.gov Identifier: NCT00794352 protocol. CNS volumes were measured retrospectively, by automated Lesion-TOADS algorithm and by Spinal Cord Toolbox, in a blinded fashion. Physiological confounders identified in 80 healthy volunteers were regressed out by stepwise multiple linear regression. MS specificity of confounder-adjusted MRI features was assessed in non-MS cohort (n = 158). MS patients were randomly split into training (n = 277) and validation (n = 131) cohorts. Gradient boosting machine (GBM) models were generated in MS training cohort from unadjusted and confounder-adjusted CNS volumes against four disability scales. Confounder adjustment highlighted MS-specific progressive loss of CNS white matter. GBM model performance decreased substantially from training to cross-validation, to independent validation cohorts, but all models predicted cognitive and physical disability with low p-values and effect sizes that outperform published literature based on recent meta-analysis. Models built from confounder-adjusted MRI predictors outperformed models from unadjusted predictors in the validation cohort. GBM models from confounder-adjusted volumetric MRI features reflect MS-specific CNS injury, and due to stronger correlation with clinical outcomes compared to brain atrophy these models should be explored in future MS clinical trials.

Bioinformatics analysis identified apolipoprotein E as a hub gene regulating neuroinflammation in macrophages and microglia following spinal cord injury.

Macrophages and microglia play important roles in chronic neuroinflammation following spinal cord injury (SCI). Although macrophages and microglia have similar functions, their phagocytic and homeostatic abilities differ. It is difficult to distinguish between these two populations in vivo, but single-cell analysis can improve our understanding of their identity and heterogeneity. We conducted bioinformatics analysis of the single-cell RNA sequencing dataset GSE159638, identifying apolipoprotein E (APOE) as a hub gene in both macrophages and microglia in the subacute and chronic phases of SCI. We then validated these transcriptomic changes in a mouse model of cervical spinal cord hemi-contusion and observed myelin uptake, lipid droplets, and lysosome accumulation in macrophages and microglia following SCI. Finally, we observed that knocking out APOE aggravated neurological dysfunction, increased neuroinflammation, and exacerbated the loss of white matter. Targeting APOE and the related cholesterol efflux represents a promising strategy for reducing neuroinflammation and promoting recovery following SCI.

Aging compromises oligodendrocyte precursor cell maturation and efficient remyelination in the monkey brain.

Age-associated cognitive decline is common among otherwise healthy elderly people, even in the absence of Alzheimer's disease and neuron loss. Instead, white matter loss and myelin damage are strongly associated with cognitive decline. Myelin is subject to lifelong oxidative stress that damages the myelin sheath, which is repaired by cells of the oligodendrocyte lineage. This process is mediated by oligodendrocyte precursor cells (OPCs) that sense the damage and respond by proliferating locally and migrating to the region, where they differentiate into mature myelinating oligodendrocytes. In aging, extensive myelin damage, in combination with inefficient remyelination, leads to chronically damaged myelin and loss ofefficient neuronal conduction. This study used the rhesus monkey model of normal aging to examine how myelin regeneration capacity is affected by age. Results show that older subjects have reduced numbers of new BCAS1 + myelinating oligodendrocytes, which are newly formed cells, and that this reduction is associated with poorer cognitive performance. Interestingly, this does not result from limited proliferation of progenitor OPCs. Instead, the transcription factor NKX2.2, which regulates OPCs differentiation, is significantly decreased in aged OPCs. This suggests that these OPCs have a diminished potential for differentiation into mature oligodendrocytes. In addition, mature oligodendrocytes have reduced RNA expression of two essential myelin protein markers, MBP and PLP. These data collectively suggest that in thenormal aging brain, there is a reduction in regenerative OPCs as well as myelin production that impairs the capacity for remyelination.

Non-Modifiable Factors as Moderators of the Relationship Between Physical Activity and Brain Volume: A Cross-Sectional UK Biobank Study.

Previous research suggests physical activity attenuates grey and white matter loss; however, there appears to be individual variability in this effect. Understanding factors that can influence the relationship between physical activity and brain volume may enable prediction of individual response. The current study examined the relationship between objectively-measured physical activity and brain volume; and whether this relationship is moderated by age, sex, or a priori candidate genetic factors, brain-derived neurotrophic factor (BDNF) Val66Met, or apolipoprotein (APOE) ɛ4 allele carriage. Data from 10,083 men and women (50 years and over) of the UK Biobank were used to examine the study objectives. All participants underwent a magnetic resonance imaging scan to quantify grey and white matter volumes, physical activity monitoring via actigraphy, and genotyping. Physical activity was associated with total grey matter volume, total white matter volume, and right hippocampal volume. Only males had an association between higher physical activity levels and greater cortical grey matter volume, total grey matter volume, and right hippocampal volume. Age moderated the relationship between physical activity and white matter volume. Our results indicate that in males, but not females, an association exists between objectively-measured physical activity and grey matter volume. Age may also play a role in impacting the relationship between physical activity and brain volume. Future research should evaluate longitudinal brain volumetrics to better understand the nature of age and sex-effects on the physical activity and brain volume relationship.

Delineating the epilepsy phenotype of NRROS-related microgliopathy: A case report and literature review

BackgroundNegative regulator of reactive oxygen species (NRROS) related microgliopathy, a rare and recently recognized neurodegenerative condition, is caused by pathogenic variants in the NRROS gene, which plays a major role in the regulation of transforming growth factor-beta 1. MethodsWe report a child presenting with infantile spasms syndrome (ISS) with subsequent progressive neurodegeneration who was identified to harbour a novel likely pathogenic NRROS variant (c.1359del; p.Ser454Alafs*11). The previously published reports of patients with this disorder were also reviewed systematically. ResultsIncluding our index patient, 11 children (6 girls) were identified in total. Early development was normal in seven of these eleven children. All had a history of drug-resistant epilepsy, with 3 having epileptic spasms. The median age at seizure onset and developmental regression was 12 months, and the median age at death was 36 months. Intracranial calcifications were described in eight of eleven children. Neuroimaging revealed progressive cerebral atrophy and white matter loss in all children. The most common reported genetic variation was c.1981delC; (p.Leu661Serfs*97) observed in two families (likely due to a founder effect). ConclusionsPathogenic variants in NRROS should be suspected in children with neuro-regression and drug-resistant epilepsy including ISS with onset in the first two years of life. Punctate or serpiginous calcifications at the grey-white matter junction and acquired microcephaly are further clues towards the diagnosis.

Post-acute blood biomarkers and disease progression in traumatic brain injury.

There is substantial interest in the potential for traumatic brain injury to result in progressive neurological deterioration. While blood biomarkers such as glial fibrillary acid protein (GFAP) and neurofilament light have been widely explored in characterizing acute traumatic brain injury (TBI), their use in the chronic phase is limited. Given increasing evidence that these proteins may be markers of ongoing neurodegeneration in a range of diseases, we examined their relationship to imaging changes and functional outcome in the months to years following TBI.Two-hundred and three patients were recruited in two separate cohorts; 6 months post-injury (n = 165); and >5 years post-injury (n = 38; 12 of whom also provided data ∼8 months post-TBI). Subjects underwent blood biomarker sampling (n = 199) and MRI (n = 172; including diffusion tensor imaging). Data from patient cohorts were compared to 59 healthy volunteers and 21 non-brain injury trauma controls. Mean diffusivity and fractional anisotropy were calculated in cortical grey matter, deep grey matter and whole brain white matter. Accelerated brain ageing was calculated at a whole brain level as the predicted age difference defined using T1-weighted images, and at a voxel-based level as the annualized Jacobian determinants in white matter and grey matter, referenced to a population of 652 healthy control subjects.Serum neurofilament light concentrations were elevated in the early chronic phase. While GFAP values were within the normal range at ∼8 months, many patients showed a secondary and temporally distinct elevations up to >5 years after injury. Biomarker elevation at 6 months was significantly related to metrics of microstructural injury on diffusion tensor imaging. Biomarker levels at ∼8 months predicted white matter volume loss at >5 years, and annualized brain volume loss between ∼8 months and 5 years. Patients who worsened functionally between ∼8 months and >5 years showed higher than predicted brain age and elevated neurofilament light levels.GFAP and neurofilament light levels can remain elevated months to years after TBI, and show distinct temporal profiles. These elevations correlate closely with microstructural injury in both grey and white matter on contemporaneous quantitative diffusion tensor imaging. Neurofilament light elevations at ∼8 months may predict ongoing white matter and brain volume loss over >5 years of follow-up. If confirmed, these findings suggest that blood biomarker levels at late time points could be used to identify TBI survivors who are at high risk of progressive neurological damage.

High replication stress and limited Rad51-mediated DNA repair capacity, but not oxidative stress, underlie oligodendrocyte precursor cell radiosensitivity.

Cranial irradiation is part of the standard of care for treating pediatric brain tumors. However, ionizing radiation can trigger serious long-term neurologic sequelae, including oligodendrocyte and brain white matter loss enabling neurocognitive decline in children surviving brain cancer. Oxidative stress-mediated oligodendrocyte precursor cell (OPC) radiosensitivity has been proposed as a possible explanation for this. Here, however, we demonstrate that antioxidants fail to improve OPC viability after irradiation, despite suppressing oxidative stress, suggesting an alternative etiology for OPC radiosensitivity. Using systematic approaches, we find that OPCs have higher irradiation-induced and endogenous γH2AX foci compared to neural stem cells, neurons, astrocytes and mature oligodendrocytes, and these correlate with replication-associated DNA double strand breakage. Furthermore, OPCs are reliant upon ATR kinase and Mre11 nuclease-dependent processes for viability, are more sensitive to drugs increasing replication fork collapse, and display synthetic lethality with PARP inhibitors after irradiation. This suggests an insufficiency for homology-mediated DNA repair in OPCs—a model that is supported by evidence of normal RPA but reduced RAD51 filament formation at resected lesions in irradiated OPCs. We therefore propose a DNA repair-centric mechanism of OPC radiosensitivity, involving chronically-elevated replication stress combined with ‘bottlenecks’ in RAD51-dependent DNA repair that together reduce radiation resilience.

Relation of sensorimotor and cognitive cerebellum functional connectivity with brain structural damage in patients with multiple sclerosis and no disability.

Background and purposeTo investigate the relationship between the functional connectivity (FC) of the sensorimotor and cognitive cerebellum and measures of structural damage in patients with multiple sclerosis (MS) and no physical disability.MethodsWe selected 144 relapsing–remitting MS patients with an Expanded Disability Status Scale score of ≤1.5 and 98 healthy controls from the Italian Neuroimaging Network Initiative database. From multimodal 3T magnetic resonance imaging (MRI), including functional MRI at rest, we calculated lesion load, cortical thickness, and white matter, cortical gray matter, and caudate, putamen, thalamic, and cerebellar volumes. Voxel‐wise FC of the sensorimotor and cognitive cerebellum was assessed with seed‐based analysis, and multiple regression analysis was used to evaluate the relationship between FC and structural damage.ResultsWhole brain, white matter, caudate, putamen, and thalamic volumes were reduced in patients compared to controls, whereas cortical gray matter was not significantly different in patients versus controls. Both the sensorimotor and cognitive cerebellum showed a widespread pattern of increased and decreased FC that were negatively associated with structural measures, indicating that the lower the FC, the greater the tissue loss. Lastly, among multiple structural measures, cortical gray matter and white matter volumes were the best predictors of cerebellar FC alterations.ConclusionsIncreased and decreased cerebellar FC with several brain areas coexist in MS patients with no disability. Our data suggest that white matter loss hampers FC, whereas, in the absence of atrophy, cortical volume represents the framework for FC to increase.

Evaluation of spectrum of brain changes in alcohol dependence syndrome patients by magnetic resonance imaging

Background: Alcohol is socially and legally accepted substance of abuse ethanol intoxication may lead to loss of subcortical white matter, cerebral atrophy, Wernicke’ sencephalopathy, Marchiafava-Bignami disease etc. [1]Thus the main purpose of the study is to diagnose the alcohol-induced brain changes in Alcohol dependence syndrome patients and thus help in the planning of early treatment of the diagnosed condition, thereby preventing the further neurological decline.Aims1.To describe the various magnetic resonance imaging findings in alcohol dependence syndrome patients.2.To correlate the cortical changes to the number of years of drinking in alcohol dependence syndrome patients.Materials and Methods: The Study group consisted of 55 patients, who fulfilled the alcohol dependence syndrome criteria according to the International Classification of Disease criteria (ICD-10). Alcohol use disorder identification test scale was applied and individual with alcohol dependence score of >15 (for men) were considered for study. MRI brain protocol was used and MRI sequences were meticulously evaluated.Global cortical atrophy scale was used to qualitatively assess the cortical atrophy on FLAIR images. Scoring is given to each lobe separately after assessing the sulci and gyri appearance in each lobe.Results: Most common MRI brain finding was cerebral atrophy (40%) followed by cerebellar atrophy (21.8%), non specific T2 hyperintensities (14.5%) hepatic encephalopathy (5.4%), least common being central pontine myelinosis (1.8%) and marchiafava bignami disease (1.8%).Most common lobe to show changes of atrophy was frontal lobe, followed by parietal, temporal and least occipital lobe.Conclusions: MRI is the most sensitive imaging modality to identify various neuroimaging findings in alcohol dependence syndrome patients. Cortical atrophy findings were seen more in patients who were chronic drinkers with long duration history of alcohol intake alcohol intake of more than 20 years There was a significant association noted between duration of drinking and atrophic changes and the results were statistically significant (p

6 powodów, dla których warto stosować ozanimod w leczeniu rzutowo-remisyjnej postaci stwardnienia rozsianego

Multiple sclerosis is a chronic disease of the central nervous system with white matter damage and loss of oligodendrocytes and neurons. The sphingosine-1-phosphate receptor modulators are available therapies modifying the course of the disease. Ozanimod, with its selective mechanism of action, ensures high effectiveness and safety of treatment of a relapsing and remitting form of this disease.

Relations of Metabolic Health and Obesity to Brain Aging in Young to Middle-Aged Adults.

BackgroundWe aimed to evaluate the association between metabolic health and obesity and brain health measured via magnetic resonance imaging and neurocognitive testing in community dwelling adults.Methods and ResultsFramingham Heart Study Third Generation Cohort members (n=2170, 46±9 years of age, 54% women) without prevalent diabetes, stroke, dementia, or other neurologic conditions were grouped by metabolic unhealthiness (≥2 criteria for metabolic syndrome) and obesity (body mass index ≥30 kg/m2): metabolically healthy (MH) nonobese, MH obese, metabolically unhealthy (MU) nonobese, and MU obese. We evaluated the relationships of these groups with brain structure (magnetic resonance imaging) and function (neurocognitive tests). In multivariable‐adjusted analyses, metabolically unhealthy individuals (MU nonobese and MU obese) had lower total cerebral brain volume compared with the MH nonobese referent group (both P<0.05). Additionally, the MU obese group had greater white matter hyperintensity volume (P=0.004), whereas no association was noted between white matter hyperintensity volume and either groups of metabolic health or obesity alone. Obese individuals had less favorable cognitive scores: MH obese had lower scores on global cognition, Logical Memory‐Delayed Recall and Similarities tests, and MU obese had lower scores on Similarities and Visual Reproductions‐Delayed tests (all P≤0.04). MU and obese groups had higher free water content and lower fractional anisotropy in several brain regions, consistent with loss of white matter integrity.ConclusionsIn this cross‐sectional cohort study of younger to middle‐aged adults, poor metabolic health and obesity were associated with structural and functional evidence of brain aging. Improvement in metabolic health and obesity may present opportunities to improve long‐term brain health.

810 Aberrant Immune Activation Drives Chronic White Matter Loss After Experimental Traumatic Brain Injury

INTRODUCTION: Epidemiological studies suggest a single traumatic brain injury (TBI) initiates progressive neurodegeneration, including extensive white matter (WM) injury; yet, the majority of demyelination and WM atrophy occurs in the years following TBI in both rodents and humans. Chronic immune activation correlates with neurological dysfunction after TBI, but the underlying mechanisms remain undefined. METHODS: To define the molecular changes associated with focal TBI, unbiased Nanostring arrays were utilized after controlled cortical impact, a pre-clinical model of focal TBI, in adult mice. Immune activation was monitored using flow cytometry and neurodegeneration was assessed at 8 weeks post-TBI, by histology, electron microscopy, and magnetic resonance imaging. RESULTS: Genomic profiling revealed acute upregulation of gene classes associated with leukocyte activation, phagocytosis, antigen presentation, lymphocyte activation, and metabolism whereas genes associated with axon/dendrite structure and neural connectivity were downregulated. Infiltrating macrophages, which phagocytosed myelin debris, represented the predominant antigen presenting cells (APCs) within the CNS after TBI. Similarly, a time dependent increase in the number of myelin containing macrophages was observed within cerebrospinal fluid of severe TBI patients. Functionally, APCs stimulated with myelin ex vivo or isolated after TBI increased T-helper (TH) cell proliferation and enhanced pro-inflammatory TH1/TH17 polarization. Myeloid-selective activation of the key metabolic regulator, 5’-adenosine monophosphate-activated protein kinase (AMPK), suppressed myelin reactive T-cells, and reduced neurodegeneration after TBI. CONCLUSIONS: The infiltrating myeloid cells after TBI undergo metabolic dysfunction following phagocytosis of myelin debris and orchestrate the generation of myelin autoreactive T-cells resulting in progressive neurodegeneration.

Timing of selective basal ganglia white matter loss in premanifest Huntington’s disease

ObjectivesTo investigate the timeframe prior to symptom onset when cortico-basal ganglia white matter (white matter) loss begins in premanifest Huntington’s disease (preHD), and which striatal and thalamic sub-region white matter tracts are most vulnerable. MethodsWe performed fixel-based analysis, which allows resolution of crossing white matter fibres at the voxel level, on diffusion tractography derived white matter tracts of striatal and thalamic sub-regions in two independent cohorts; TrackON-HD, which included 72 preHD (approx. 11 years before disease onset) and 85 controls imaged at three time points over two years; and the HD young adult study (HD-YAS), which included 54 preHD (approx. 25 years before disease onset) and 53 controls, imaged at one time point. Group differences in fibre density and cross section (FDC) were investigated. ResultsWe found no significant group differences in cortico-basal ganglia sub-region FDC in preHD gene carriers 25 years before onset. In gene carriers 11 years before onset, there were reductions in striatal (limbic and caudal motor) and thalamic (premotor, motor and sensory) FDC at baseline, with no significant change over 2 years. Caudal motor-striatal, pre-motor-thalamic, and primary motor-thalamic FDC at baseline, showed significant correlations with the Unified Huntington’s disease rating scale (UHDRS) total motor score (TMS). Limbic cortico-striatal FDC and apathy were also significantly correlated. ConclusionsOur findings suggest that limbic and motor white matter tracts to the striatum and thalamus are most susceptible to early degeneration in HD but that approximately 25 years from onset, these tracts appear preserved. These findings may have importance in determining the optimum time to initiate future disease modifying therapies in HD.