White Matter Demyelination Research Articles

Clemastine Induces Oligodendrocyte Progenitor Pool Exhaustion and Senescence in the Context of Chronic Demyelination in a Rabbit Model.

Clemastine has emerged as a promising therapy for the restoration of neurologic function in patients with multiple sclerosis (MS). However, clemastine and other agents with prodifferentiative effects on oligodendrocyte progenitor cells (OPCs) in rodent models have underperformed in clinical trials. We hypothesized that the preclinical studies showed more robust effects because of the abundance of OPCs in rodent models. To better examine the therapeutic potential of clemastine, we examined its effect on demyelinated white matter lesions in rabbits, which exhibit progenitor densities and limited remyelination more closely matching those found in tissues from patients with MS. We used lysolecithin to induce demyelination in white matter of New Zealand rabbits and then administered oral clemastine (10mg/kg/day) for various periods before assessing the OPC and oligodendrocyte (OL) populations in these lesions. Daily administration of clemastine for the full study period (56 days) increased oligodendrogenesis in white matter lesions. However, shorter durations of treatment failed to increase overall OL density despite enhancing OPC-to-OL differentiation. This effect was due to exhaustion of the OPC pool, as the differentiating progenitors were not replaced because of reduced OPC proliferation. Notably, delayed administration of clemastine led to an accumulation of activated OPCs expressing markers of senescence. Although capable of driving OL differentiation, clemastine treatment in rabbits hampered progenitor pool replenishment, induced senescence, and promoted conversion of microglia/macrophages to a proinflammatory phenotype. Whether these effects would also occur in humans or with other prodifferentiative therapies should be studied further, but our data suggest the need to carefully consider progenitor dynamics in the treatment of MS. ANN NEUROL 2024.

Disability independent of cerebral white matter demyelination in progressive multiple sclerosis

The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.

2274: Demyelination in white matter after pediatric brain tumor treatment, assessed with quantitative MRI

2274: Demyelination in white matter after pediatric brain tumor treatment, assessed with quantitative MRI

Nervonic acid protects against oligodendrocytes injury following chronic cerebral hypoperfusion in mice

Chronic cerebral hypoperfusion (CCH) has been acknowledged as a potential contributor to cognitive dysfunction and brain injury, causing progressive demyelination of white matter, oligodendrocytes apoptosis and microglia activation. Nervonic acid (NA), a naturally occurring fatty acid with various pharmacological effects, has been found to alleviate neurodegeneration. Nonetheless, evidence is still lacking on whether NA can protect against neurological dysfunction resulting from CCH. To induce CCH in mice, we employed the right unilateral common carotid artery occlusion (rUCCAO) method, followed by oral administration of NA daily for 28 days after the onset of hypoperfusion. We found that NA ameliorated cognitive function, as evidenced by improved performance of NA-treated mice in both novel object recognition test and Morris water maze test. Moreover, NA mitigated demyelination and loss of oligodendrocytes in the corpus callosum and hippocampus of rUCCAO-treated mice, and prevented oligodendrocyte apoptosis. Furthermore, NA protected primary cultured murine oligodendrocytes against oxygen-glucose deprivation (OGD)-induced cell death in a concentration-dependent manner. These findings indicated that NA promotes oligodendrocyte maturation both in vivo and in vitro. Our findings suggest that NA offers protective effects against cerebral hypoperfusion, highlighting its potential as a promising treatment for CCH and related neurological disorders.

Intrinsic and extrinsic contributors to subregional thalamic volume loss in multiple sclerosis.

To evaluate the intrinsic and extrinsic microstructural factors contributing to atrophy within individual thalamic subregions in multiple sclerosis using in vivo high-gradient diffusion MRI. In this cross-sectional study, 41 people with multiple sclerosis and 34 age and sex-matched healthy controls underwent 3T MRI with up to 300 mT/m gradients using a multi-shell diffusion protocol consisting of eight b-values and diffusion time of 19 ms. Each thalamus was parcellated into 25 subregions for volume determination and diffusion metric estimation. The soma and neurite density imaging model was applied to obtain estimates of intra-neurite, intra-soma, and extra-cellular signal fractions for each subregion and within structurally connected white matter trajectories and cortex. Multiple sclerosis-related volume loss was more pronounced in posterior/medial subregions than anterior/ventral subregions. Intra-soma signal fraction was lower in multiple sclerosis, reflecting reduced cell body density, while the extra-cellular signal fraction was higher, reflecting greater extra-cellular space, both of which were observed more in posterior/medial subregions than anterior/ventral subregions. Lower intra-neurite signal fraction in connected normal-appearing white matter and lower intra-soma signal fraction of structurally connected cortex were associated with reduced subregional thalamic volumes. Intrinsic and extrinsic microstructural measures independently related to subregional volume with heterogeneity across atrophy-prone thalamic nuclei. Extrinsic microstructural alterations predicted left anteroventral, intrinsic microstructural alterations predicted bilateral medial pulvinar, and both intrinsic and extrinsic factors predicted lateral geniculate and medial mediodorsal volumes. Our results might be reflective of the involvement of anterograde and retrograde degeneration from white matter demyelination and cerebrospinal fluid-mediated damage in subregional thalamic volume loss.

Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity.

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.

Localized Changes in Dentate Nucleus Shape and Magnetic Susceptibility in Friedreich Ataxia.

The dentate nuclei of the cerebellum are key sites of neuropathology in Friedreich ataxia (FRDA). Reduced dentate nucleus volume and increased mean magnetic susceptibility, a proxy of iron concentration, have been reported by magnetic resonance imaging studies in people with FRDA. Here, we investigate whether these changes are regionally heterogeneous. Quantitative susceptibility mapping data were acquired from 49 people with FRDA and 46 healthy controls. The dentate nuclei were manually segmented and analyzed using three dimensional vertex-based shape modeling and voxel-based assessments to identify regional changes in morphometry and susceptibility, respectively. Individuals with FRDA, relative to healthy controls, showed significant bilateral surface contraction most strongly at the rostral and caudal boundaries of the dentate nuclei. The magnitude of this surface contraction correlated with disease duration, and to a lesser extent, ataxia severity. Significantly greater susceptibility was also evident in the FRDA cohort relative to controls, but was instead localized to bilateral dorsomedial areas, and also correlated with disease duration and ataxia severity. Changes in the structure of the dentate nuclei in FRDA are not spatially uniform. Atrophy is greatest in areas with high gray matter density, whereas increases in susceptibility-reflecting iron concentration, demyelination, and/or gliosis-predominate in the medial white matter. These findings converge with established histological reports and indicate that regional measures of dentate nucleus substructure are more sensitive measures of disease expression than full-structure averages. Biomarker development and therapeutic strategies that directly target the dentate nuclei, such as gene therapies, may be optimized by targeting these areas of maximal pathology. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuropsychiatric symptoms in Multiple Sclerosis (MS): Case Report of a First Manic Episode in a Patient with Suspected MS

IntroductionMultiple Sclerosis (MS) is an inflammatory disease affecting primarily the central nervous system, characterized by focal lesions of white-matter demyelination. It can present with a variety of neurological symptoms, including monocular vision loss, sensory loss, paresthesias, limb weakness, ataxia and bladder dysfunction, and has a typically chronic and progressive course. Neuropsychiatric manifestations including depressive or manic symptoms, anxiety disorders and psychosis, are also frequently observed, and are of particular importance to mental health practitioners.ObjectivesTo describe a case of a 45-year-old female patient with a history of suspected MS presenting with manic symptoms, and to discuss the possible neuropsychiatric manifestations of Multiple Sclerosis.MethodsClinical case report and literature review.ResultsA 45-year-old woman was brought to the emergency department presenting with severe acute agitation, irritable mood, rapid speech and persecutory delusions. She had no prior history of neuropsychiatric symptoms, but her medical history was notable for a suspected diagnosis of MS, having suffered an episode of optic neuritis 16 years before the present episode. Magnetic Ressonance Imaging performed 3 months before emergency admission documented non-specific white-matter lesions presenting as hyper-intense in long TR sequences, as well as a cervical lesion of atypical characteristics, representing possible spondylotic myelopathy or demyelination. A head CT performed at emergency admission did not reveal relevant acute findings. The patient was hospitalized and initiated risperidone and valproic acid therapy. She responded favorably to medication, with progressive stabilization of mood and remission of delusional ideas over three weeks.ConclusionsNeuropsychiatric symptoms are a common and concerning manifestation of Multiple Sclerosis. The present case illustrates that clinicians should be on alert for signs of mood and psychotic symptoms in patients with suspected or confirmed MS, as these can manifest at any point during the disease course.Disclosure of InterestNone Declared

Deletion of Slc9a1 in Cx3cr1+ cells stimulated microglial subcluster CREB1 signaling and microglia-oligodendrocyte crosstalk

Microglial Na/H exchanger-1 (NHE1) protein, encoded by Slc9a1, plays a role in white matter demyelination of ischemic stroke brains. To explore underlying mechanisms, we conducted single cell RNA-seq transcriptome analysis in conditional Slc9a1 knockout (cKO) and wild-type (WT) mouse white matter tissues at 3 days post-stroke. Compared to WT, Nhe1 cKO brains expanded a microglial subgroup with elevated transcription of white matter myelination genes including Spp1, Lgals3, Gpnmb, and Fabp5. This subgroup also exhibited more acidic pHi and significantly upregulated CREB signaling detected by ingenuity pathway analysis and flow cytometry. Moreover, the Nhe1 cKO white matter tissues showed enrichment of a corresponding oligodendrocyte subgroup, with pro-phagocytosis and lactate shuffling gene expression, where activated CREB signaling is a likely upstream regulator. These findings demonstrate that attenuation of NHE1-mediated H+ extrusion acidifies microglia/macrophage and may underlie the stimulation of CREB1 signaling, giving rise to restorative microglia-oligodendrocyte interactions for remyelination.

Positive effect of microvascular proliferation on functional recovery in experimental cervical spondylotic myelopathy.

Cervical Spondylotic Myelopathy (CSM), the most common cause of spinal cord dysfunction globally, is a degenerative disease that results in non-violent, gradual, and long-lasting compression of the cervical spinal cord. The objective of this study was to investigate whether microvascular proliferation could positively affect neural function recovery in experimental cervical spondylotic myelopathy (CSM). A total of 60 male adult Sprague-Dawley (SD) were randomly divided into four groups: Control (CON), Compression (COM), Angiostasis (AS), and Angiogenesis (A G),with 15 rats in each group. Rats in the AS group received SU5416 to inhibit angiogenesis, while rats in the AG group received Deferoxamine (DFO) to promote angiogenesis. Motor and sensory functions were assessed using the Basso Beattie Bresnahan (BBB) scale and somatosensory evoked potential (SEP) examination. Neuropathological degeneration was evaluated by the number of neurons, Nissl bodies (NB), and the de-myelination of white matter detected by Hematoxylin & Eosin(HE), Toluidine Blue (TB), and Luxol Fast Blue (LFB) staining. Immunohistochemical (IHC) staining was used to observe the Neurovascular Unit (NVU). Rats in the CON group exhibited normal locomotor function with full BBB score, normal SEP latency and amplitude. Among the other three groups, the AG group had the highest BBB score and the shortest SEP latency, while the AS group had the lowest BBB score and the most prolonged SEP latency. The SEP amplitude showed an opposite performance to the latency. Compared to the COM and AS groups, the AG group demonstrated significant neuronal restoration in gray matter and axonal remyelination in white matter. DFO promoted microvascular proliferation, especially in gray matter, and improved the survival of neuroglial cells. In contrast, SU-5416 inhibited the viability of neuroglial cells by reducing micro vessels. The microvascular status was closely related to NVU remodeling an-d functional recovery. Therefore, proliferation of micro vessels contributed to function -al recovery in experimental CSM, which may be associated with NVU remodeling.

Cerebral Perfusion Characteristics and Dynamic Brain Structural Changes in Stroke-Prone Renovascular Hypertensive Rats: A Preclinical Model for Cerebral Small Vessel Disease.

Hypertension is a leading cause of cerebral small vessel disease (CSVD) and vascular dementia in elderly individuals. We aimed to assess cerebral perfusion and dynamic changes in brain structure in stroke-prone renovascular hypertensive rats (RHRSPs) with different durations of hypertension and to investigate whether they have pathophysiological features similar to those of humans with CSVD.The RHRSP model was established using the two-kidney, two-clip (2k2c) method, and the Morris water maze (MWM) test, MRI, immunohistochemistry, and biochemical analysis were performed at multiple time points for up to six months following the 2k2c operation.Systolic blood pressure was significantly greater in the RHRSP group than in the sham-operated group at week 4 post-surgery and continued to increase over time, leading to cognitive decline by week 20. Arterial spin labeling revealed cerebral hypoperfusion in the RHRSP group at 8 weeks, accompanied by vascular remodeling and decreased vessel density. Diffusion tensor imaging and Luxol fast blue staining indicated that white matter disintegration and demyelination gradually progressed in the corpus callosum and that myelin basic protein levels decreased. Eight weeks after surgery, blood-brain barrier (BBB) leakage into the corpus callosum was observed. The albumin leakage area was negatively correlated with the myelin sheath area (r=-0.88, p<0.001). RNA-seq analysis revealed downregulation of most angiogenic genes and upregulation of antiangiogenic genes in the corpus callosum of RHRSPs 24 weeks after surgery.RHRSPs developed cerebral hypoperfusion, BBB disruption, spontaneous white matter damage, and cognitive impairment as the duration of hypertension increased. RHRSPs share behavioral and neuropathological characteristics with CSVD patients, making them suitable animal models for preclinical trials related to CSVD.

LMNB1‐duplication mediated nuclear architecture alteration and demyelination of cerebral white matter in a patient with ADLD

<i>LMNB1</i>‐duplication mediated nuclear architecture alteration and demyelination of cerebral white matter in a patient with ADLD

High Levels of Perivascular Inflammation and Active Demyelinating Lesions at Time of Death Associated with Rapidly Progressive Multiple Sclerosis Disease Course: A Retrospective Postmortem Cohort Study.

Analysis of postmortem multiple sclerosis (MS) tissues combined with in vivo disease milestones suggests that whereas perivascular white matter infiltrates are associated with demyelinating activity in the initial stages, leptomeningeal immune cell infiltration, enriched in B cells, and associated cortical lesions contribute to disease progression. We systematically examine the association of inflammatory features and white matter demyelination at postmortem with clinical milestones. In 269 MS brains, 20 sites were examined using immunohistochemistry for active lesions (ALs) and perivenular inflammation (PVI). In a subset of 22, a detailed count of CD20+ B cells and CD3+ T cells in PVIs was performed. ALs were detected in 22%, whereas high levels of PVI were detected in 52% of cases. ALs were present in 35% of cases with high levels of PVI. Shorter time from onset of progression to death was associated with increased prevalence and higher levels of PVI (both p < 0.0001). Shorter time from onset of progression to wheelchair use was associated with higher prevalence of ALs (odds ratio [OR] = 0.921, 95% confidence interval [CI] = 0.858-0.989, p = 0.0230) and higher level of PVI (OR = 0.932, 95% CI = 0.886-0.981, p = 0.0071). High levels of PVI were associated with meningeal inflammation and increased cortical demyelination and significantly higher levels of B lymphocytes within the PVI. ALs, a feature of early disease stage, persist up to death in a subgroup with high levels of PVI. These features link to a rapid progressive phase and higher levels of meningeal inflammation and B-cell infiltrates, supporting the hypothesis that chronic inflammation drives progression in MS. ANN NEUROL 2024;95:706-719.

Physical Exercise Counteracts Aging-Associated White Matter Demyelination Causing Cognitive Decline.

In the central nervous system, oligodendrocytes wrap around neuronal axons to form myelin, an insulating layer or sheath that allows for the efficient conductance of action potentials. In addition to structural insulation, myelin provides encased axons with nutrient, metabolic and defensive support. Demyelination, or myelin loss, can therefore cause axonal dysfunction, leading to neurological impairment and disease. In Alzheimer's disease (AD), progressive white matter demyelination is acknowledged as one of the earliest pathologies preceding symptom onset. Unfortunately, current pharmacotherapy for slowing demyelination or promoting remyelination in AD is nonexistent. Exercise is recognized for its wide-ranging benefits to human health, including improved mental health and the prevention of lifestyle-related diseases. Mounting evidence suggests the contribution of physical activity in delaying the progression of dementia in elderly populations. Recent mechanistic studies have shown that exercise facilitates myelination in the brain through the vitalization of intrinsic pro-myelination cues, such as increased neurotrophic factors and electrical activity. In this review, we summarize and discuss the potential of physical exercise on counteracting aging-associated white matter demyelination, which causes cognitive decline in AD. We highlight the need of further basic and clinical research investigations on this topic to establish novel approaches for healthy and improved brain aging.

PATHOGENESIS OF DEMYELINATING DISEASES IN TERMS OF ECOPATHOLOGY

The experiment have been researched changes that may occur in the brains of people who worked or lived for a long time in an area of risk of permanent pollution with non-toxic doses of lead, 20-30 years after leaving the area. It was revealed that in the brain of experimental animals the number of neurons is reduced, gliosis, proliferation of microglia, destruction of blood vessels are noted, and processes of demyelination of white matter occur. These changes are more or less pronounced in all areas of the brain, to a greater extent in animals that received lead in more quantities. The identified morphological changes in the brain suggest that lead is one of the causes of the pathogenesis of demyelinating diseases.

Debris generated by laser and/or balloon cause cerebral infarction with different severity.

The purpose of this study is to determine the effects that debris generated by laser and/or balloon on the brain. Debris generated by laser, balloon, and laser combined with balloon were collected and then injected into rats' left common carotid artery. Rats were divided into five groups: sham, saline, laser (L), balloon (B), and laser combined with balloon (LB). The cognition ability of rats was evaluated by Morris water maze. Cerebral blood flow (CBF) was examined by laser speckle. TTC staining and MRI scan were conducted to detect cerebral ischemic infarction. Intracranial arteries in rats were visualized by MRI angiography via contrast medium injected via tail vein. Immunohistologic staining for NeuN and Iba1 and hematoxylin-eosin staining were performed to assess brain infarction. White matter demyelination was assessed by Luxol fast blue staining. Long-term memory and CBF of rats in different groups exhibited no significant difference. No obstruction sign in intracranial artery tree was noticed in each group. Debris generated by different treatments all caused brain infarction. Infarction lesion caused by debris produced by balloon was much more severe than the one caused by debris generated by laser. While the LB group lay in between. The thickness of white matter decreased in the B group, but not in the L and LB groups. Rat brain has a tolerance for debris as cognition ability and cerebral blood flow are not significantly declined. The severity of cerebral infarction varies by debris generated by different treatments.

Huangqi-Guizhi-Wuwu Decoction regulates differentiation of CD4+ T cell and prevents against experimental autoimmune encephalomyelitis progression in mice

BackgroundMultiple sclerosis (MS) is a demyelination disorder caused by an overactive immune response. Its pathological characteristics include CNS inflammation, white matter demyelination, glial cell proliferation, and so on. Huangqi-Guizhi-Wuwu Decoction (HGWD), which is recorded in the Synopsis of the Golden Chamber, is used clinically for the therapy of MS, but its mechanism is still elusive. PurposeThis study was aimed to investigate the impact of HGWD on the classical animal model for MS, experimental autoimmune encephalomyelitis (EAE), and explore the underlying action mechanism. ResultsHGWD ameliorated the pathogenesis of EAE mice, and improved their neurobehavior and pathological tissue damage. Network pharmacology predictions revealed the action mechanism of HGWD in EAE mice might be related to its effect on the immune system of mice. HGWD effectively suppressed the inflammatory infiltration in CNS, while also preventing the elevation of CD4+T cells of mice with EAE. HGWD could increase the ratio of Treg cells, up-regulate the secretion of IL-10 and Foxp3 mRNA expression, inhibit the ratio of Th1 and Th17 cells, down-regulate IFN-γ and IL-17 protein expression, as well as RORγT and T-bet gene expression in EAE mice. In addition, HGWD-containing serum modulated Th1/Th17/Treg cell differentiation in vitro. Moreover, HGWD inhibited the p-JAK1, p-JAK2, p-STAT1, p-STAT3 and p-STAT4 proteins and elevated the p-STAT5 protein in lymphoid tissues of EAE mice. ConclusionHGWD improved the progress of EAE by regulating the proportion of CD4+T cell subtype differentiation, which might be exerted through JAK/STAT signaling pathway, providing a pharmacological basis for the clinical treatment of MS.

Lobe‐specific changes in white matter volume and myelination following 6‐month 40 Hz gamma sensory stimulation in patients on the Alzheimer’s disease spectrum

AbstractBackgroundAlthough morphometric changes in Alzheimer’s Disease (AD) occur both in gray and white matter, gray matter changes had been the primary focus of previous work. Recent studies have highlighted the importance of pathological changes in white matter and myelination in AD patients, including early changes to oligodendrocytes and transcription of myelin protein genes in the white matter prior to symptoms of cognitive decline, even in subjects with AD but without other neurological comorbidities (Ferrer et al., 2020). Since neuronal activities, particularly network oscillations have been shown to promote myelination, the present study examined how 40Hz gamma stimulation affected white matter volume and myelination in different cortical lobes in patients with AD.MethodData were obtained from the Overture trial (NCT03555281) in which treatment participants received daily, at‐home, 40Hz gamma sensory stimulation for six months, while placebo participants received sham stimulation (treatment‐to‐placebo ratio 2:1). Magnetic resonance imaging (MRI) data were collected at 1.5 Tesla at baseline, month 3, and month 6. MRI T1 images and T1w/T2w ratios were used to estimate volume (N = 38) and myelination (N = 36), respectively. Using Bayesian linear mixed effects modeling, we estimated white matter volume and myelination percent changes with respect to baseline. Treatment group results were reported in relation to the placebo group.ResultWith respect to the placebo group: In the left hemisphere, the treatment group exhibited reduced white matter atrophy in the frontal lobe (‐3.27±1.4, p = 0.0225), in the temporal lobe (‐3.9±1.76, p = 0.0306), in the parietal lobe (‐3.32±1.43, p = 0.0236), in the occipital lobe (‐4.1±1.72, p = 0.0195) and reduced demyelination in the frontal lobe (‐5.13±2.12, p = 0.0186), in the temporal lobe (‐5.33±2.42, p = 0.0321), in the parietal lobe (‐5.7±2.07 (p = 0.0079), in the occipital lobe (‐5.65±2.52, p = 0.0296). In the right hemisphere, the treatment group trended towards reduced white matter volume loss and demyelination in all lobes, however, demyelination was significantly reduced in the parietal lobe (‐4.48±2.09, p = 0.037), and in the occipital lobe (‐5.5±2.22, p = 0.0165).ConclusionWhite matter atrophy and demyelination were statistically significantly reduced in all lobes of the left hemisphere and trended towards reduction in the right hemisphere, demonstrating that 40Hz sensory stimulation can reduce the neurodegeneration associated with AD.

Trem2 deficiency attenuates microglial phagocytosis and autophagic-lysosomal activation in white matter hypoperfusion.

Chronic cerebral hypoperfusion leads to sustained demyelination and a unique response of microglia. Triggering receptor expressed on myeloid cells 2 (Trem2), which is expressed exclusively on microglia in the central nervous system (CNS), plays an essential role in microglial response in various CNS disorders. However, the specific role of Trem2 in chronic cerebral hypoperfusion has not been elucidated. In this study, we investigated the specific role of Trem2 in a mouse model of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis (BCAS). Our results showed that chronic hypoperfusion induced white matter demyelination, microglial phagocytosis, and activation of the microglial autophagic-lysosomal pathway, accompanied by an increase in Trem2 expression. After Trem2 knockout, we observed attenuation of white matter lesions and microglial response. Trem2 deficiency also suppressed microglial phagocytosis and relieved activation of the autophagic-lysosomal pathway, leading to microglial polarization towards anti-inflammatory and homeostatic phenotypes. Furthermore, Trem2 knockout inhibited lipid droplet accumulation in microglia invitro. Collectively, these findings suggest that Trem2 deficiency ameliorated microglial phagocytosis and autophagic-lysosomal activation in hypoperfusion-induced white matter injury, and could be a promising target for the treatment of chronic cerebral hypoperfusion.

A - 114 Long Term Cognitive Sequela of Intracranial Radiation Therapy in a Pediatric Cerebellar Medulloblastoma Survivor.

Intracranial radiation therapy (IRT) for pediatric brain tumors is associated with late delayed brain injury due to cerebrovascular abnormality, white matter necrosis, demyelination, and gliosis which are irreversible. As a result, persistent cognitive deficits in adulthood emerge which are aggravated by younger age at diagnosis, higher radiation dose, whole brain radiation (WBR), and concurrent chemotherapy. The case is a childhood brain tumor survivor seen 18years post treatment who displayed cognitive deficits reflecting the cognitive sequela of WBR that overlapped with the anatomical distribution of white matter damage sustained. 23-year-old Black male with a history of childhood cerebellar medulloblastoma diagnosed at age 4, tumor resection, WBR, chemotherapy, more recent seizure disorder and medullary stroke, diabetes, and hypertension was seen for a neuropsychological evaluation due to memory complaints. His neuroimaging showed white matter hyperintensities in bilateral temporal and occipital lobes, bilateral cerebellar hemispheres, bilateral frontal lobes, medial posterior right cerebellar cyst, and 10 x 5mm cyst in the left temporal lobe. Results showed FSIQ = 59 and deficits in language, processing speed, visuospatial abilities, executive functioning, and verbal memory. His auditory working memory and visual memory were preserved. Based on his numerous adaptive limitations, moderate intellectual development disorder diagnosis was given. Deficits across several cognitive domains were consistent with multi-focal white matter lesions seen in patient's neuroimaging which reflect radiographic findings related to long-term sequela of previous intracranial radiation. A unique finding was relatively preserved visual memory as findings related to asymmetrical memory dysfunction in childhood medulloblastoma survivors are scarce.