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Background Vanishing white matter disease (VWMD) is one of the most prevalent inherited leukoencephalopathies, which generally presents in childhood as a progressive disorder while less beginning in adulthood. The present report describes the clinical, neuroimaging, and genetic findings of a female patient with adult-onset VWMD. In addition, to provide a clearer delineation of the clinical and genetic characteristics of female adult-onset VWMD patients, 32 genetically confirmed female adult-onset EIF2B-mutated cases are summarized. Case presentation The patient described here suffered from long-term menometrorrhagia prior to manifesting progressive neurological impairments that included tremors, bilateral pyramidal tract injury, cerebellar ataxia, and dementia. To the best of our knowledge, this is the first female patient with adult-onset VWMD suffering from long-term menometrorrhagia attributed to the c.254 T > A and c.496A > G mutations in the EIF2B2 gene; the c.496A > G mutation has not been reported in previous studies. The patient also exhibited metabolic dysfunction. The present findings widen the spectrum of phenotypic heterogeneity observed in VWMD patients. Conclusions The present report summarizes 33 female patients with adult-onset VWMD to provide an overview of the clinical and genetic characteristics of this disorder and ovarioleukodystrophy. The mean age of clinical onset in female patients with adult-onset VWMD was 36.8 years and the neurological symptoms primarily included motor and cognitive dysfunction such as paraparesis, cerebellar ataxia, and executive deficits. In addition, ovarian failure occurred in all of these female patients and usually preceded the neurological symptoms. Furthermore, several patients also suffered from metabolic dysfunction. All 33 patients had mutations on EIF2B1–5, and of these, the c.338 G > A mutation in the EIF2B5 gene (p.Arg113His) was the most common. These findings suggest that clinicians should be aware of adult-onset forms of VWMD as well as its typical magnetic resonance imaging (MRI) and clinical characteristics although this pathology is usually recognized as a pediatric disorder. No curative treatment is presently available, and thus early recognition is important to prevent triggering events and to allow for genetic counseling.

Background: Vanishing white matter disease (VWM), a human autosomal recessive inherited leukoencephalopathy, is due to mutations in eukaryotic initiation factor 2B (eIF2B). eIF2B is responsible for the initiation of protein synthesis by its guanine nucleotide exchange factor (GEF) activity. Mutations of eIF2B impair GEF activity at different degree. Previous studies implied improperly activated unfolded protein response (UPR) and endoplasmic reticulum stress (ERS) participated in the pathogenesis of VWM. Autophagy relieves endoplasmic reticulum load by eliminating the unfolded protein. It is still unknown the effects of genotypes on the pathogenesis. In this work, UPR and autophagy flux were analyzed with different mutational types. Methods: ERS tolerance, reflected by apoptosis and cell viability, was detected in human oligodendrocyte cell line transfected with the wild type, or different mutations of p. Arg113His, p. Arg269FNx01 or p. Ser610-Asp613del in eIF2Bε. A representative UPR-PERK component of activating transcription factor 4 (ATF4) was measured under the basal condition and ERS induction. Autophagy was analyzed the flux in the presence of lysosomal inhibitors. Results: The degree of ERS tolerance varied in different genotypes. The truncated or deletion mutant showed prominent apoptosis cell viability declination after ERS induction. The most seriously damaged GEF activity of p. Arg269FNx01 group underwent spontaneous apoptosis. The truncated or deletion mutant showed elevated ATF4 under basal as well as ERS condition. Decreased expression of LC3-I and LC3-II in the mutants reflected an impaired autophagy flux, which was more obvious in the truncated or deletion mutants after ERS induction. Conclusions: GEF activities in different genotypes could influence the cell ERS tolerance as well as compensatory pathways of UPR and autophagy. Oligodendrocytes with truncated or deletion mutants showed less tolerable to ERS.

Objective To observe the protective function and mechanism of melatonin(MT)against white matter lesions in corpus callosum induced by chronic cerebral hypoperfusion (CCH) in cerebral small vessel disease (cSVD) rats. Methods Forty⁃four adult male Sprague⁃Dawley rats were divided into sham group, bilateral common carotid artery occlusion (BCCAO) group, MT1 group [BCCAO+melatonin 5mg/(kg·d)]andMT2group[BCCAO+melatonin10mg/(kg·d)]. Four weeks after operation,social activity (sniffing time and crossing number) was assessed to reflect apathetic behavior. Myelin basic protein(MBP) in corpus callosum was detected by immunofluorescence. Transmission electron microscope was used to comparetheG-ratio. Western blotting test was used to detect phosphorylation level of mammalian target of rapamycin (mTOR). Results BCCAO group rats showed fewer sniffing time (t=58.000, P=0.000) and crossing number(t=20.000, P=0.000),lower level of MBP expression(t=20.400, P=0.000),higherlevel ofG⁃ratio(t=-9.800, P=0.000),and lower pmTOR/mTOR ratio(t=20.336, P=0.000)than those of sham group; after treatment of melatonin [5 or 10mg/(kg·d)], MT1 group and MT2 group showed more sniffing time(t=-12.600, P=0.001; t=-26.000, P=0.000) and crossing number(t=-8.400, P=0.000; t=-10.200, P=0.000),higher pmTOR/mTOR ratio(t=-6.022, P=0.014; t=-8.800, P=0.001)than those of BCCAO group but still lower than those of sham group(t=45.400, P=0.000; t=32.000, P=0.000; t=11.600, P= 0.000; t=9.800, P=0.000; t=14.314, P=0.000; t=11.536, P=0.000); while showed higher level of MBP expression(t=-16.800, P=0.001; t=-20.600, P=0.000),and lower leve lof G-ratio(t=8.600, P=0.041; t= 9.200, P=0.030) than those of BCCAO group but similar with sham group (P>0.05, for all); MT2 group showed longer sniffing time than MT1 group (t =-13.400, P =0.000). Conclusions Melatonin could ameliorate apathetic behavioral and white matter lesions in corpu callosums in rats withc SVD,which might be related to the up-regulate of phosphorylation level of mTOR.

INTRODUCTION The effects of sex and apolipoprotein E (APOE)—Alzheimer's disease (AD) risk factors—on white matter microstructure are not well characterized. METHODS Diffusion magnetic resonance imaging data from nine well‐established longitudinal cohorts of aging were free water (FW)–corrected and harmonized. This dataset included 4741 participants (age = 73.06 ± 9.75) with 9671 imaging sessions over time. FW and FW‐corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex and APOE ε4 carrier status. RESULTS Sex differences in FAFWcorr in projection tracts and APOE ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION There are prominent differences in white matter microstructure by sex and APOE ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. Highlights Sex and apolipoprotein E (APOE) ε4 carrier status relate to white matter microstructural integrity. Females generally have lower free water–corrected fractional anisotropy compared to males. APOE ε4 carriers tended to have higher free water than non‐carriers.

INTRODUCTION Neuropsychiatric symptoms (NPS) are prevalent in clinically diagnosed Alzheimer's disease (AD), yet their etiology remains unclear. We assessed associations between NPS and neuropathologic features in dementia patients. METHODS Logistic regression analyses estimated associations between neuropathologic lesions and retroactively assigned NPS phenotypes (early and late psychosis [EPS, LPS], early and late affective symptoms [EAS, LAS]). RESULTS EPS was associated with Lewy body (odds ratio [OR] = 2.4, p < 0.0001) and white matter (OR = 1.7, p < 0.0001) pathology. LPS was associated with moderate/severe neurofibrillary tangles (OR = 2.8, p < 0.0001), moderate/frequent neuritic plaques (OR = 2.3, p < 0.0001), Lewy bodies (OR = 1.9, p < 0.0001), and cerebral amyloid angiopathy (OR = 1.6, p < 0.0001). EAS was associated with white matter injury (OR = 3.4, p < 0.0001); EAS and LAS were associated with moderate/severe neurofibrillary tangles (ORs = 1.7, 1.9, p < 0.005). Risk for EPS, LPS, and EAS increased with total neuropathologic burden. DISCUSSION NPS subtypes are differentially associated with AD/non‐AD neuropathologic features, suggesting that efficiency of interventional targets may depend upon timing and type of NPS. Highlights Timing/nature of neuropsychiatric symptoms (NPS) had distinct associations with brain autopsy findings in the National Alzheimer's Coordinating Center. Increased odds for psychosis symptoms was associated with both Alzheimer's disease neuropathologic change (ADNC) and Lewy body dementia (LBD). Late psychosis symptoms (PS) was most strongly associated with ADNC, early PS most strongly with LBD. Early PS and affective symptoms were both associated with white matter disease.

Background: Cognitive dysfunction in cerebral small vessel disease (CSVD) patients is associated with white matter hyperintensity (WMH), which demonstrates frequency-dependent correlations with brain functional activities. However, the neural mechanisms underlying the relationship between these structural and functional abnormalities and cognitive impairment remain unclear. Methods: We recruited 34 CSVD patients (mean age 63.74 ± 4.85 years, 19 males) and 45 age-matched healthy controls (mean age 63.69 ± 6.15 years, 15 males). All participants underwent magnetic resonance imaging (MRI) scanning and comprehensive cognitive assessments, including three behavioral tasks and a cognitive questionnaire battery. Regional brain activity and network topological properties were separately compared between the two groups for each of the three frequency bands (slow-4, slow-5, and typical band) using two-sample t-tests. Simple and multiple mediation analyses were performed to examine the relationships among WMH, functional brain measures, and global cognition. Results: CSVD patients exhibited frequency-specific alterations in regional activity and reduced global functional organization in the slow-4 band. Frequency-dependent functional measures in the slow-4 band significantly mediated the relationship between deep WMH and cognitive performance. Conclusion: Our findings demonstrate the frequency-specific mediating role of abnormal brain functions in the pathophysiological pathway linking WMHs to cognitive impairment. This study provides new insight into the pathological mechanisms underlying WMH-related cognitive dysfunction. Clinical Trial Registration: ChiCTR2100043346, 02 November 2021, https://www.chictr.org.cn/showproj.html?proj=52285.

White matter hyperintensities (WMHs) are strongly linked to cardiovascular risk factors and other health conditions such as Alzheimer's disease. However, there is a dearth of research on this topic in low-income countries and underserved populations, especially in the Democratic Republic of Congo (DRC) where the population is aging rapidly with increasing cardiovascular risk factors and dementia-related diseases. This study evaluates health factors associated with WMH in the elderly Sub-Saharan Africa (SSA), specifically Congolese adults. In a cross-sectional study of 77 people from the DRC, participants underwent neuroimaging to analyze WMHs volume and completed clinical evaluation, laboratory-based blood exams, self-reported questionnaires, and interviews. A simple linear regression model was conducted to test the association between WMHs and potential predictors (dementia, age, sex, hypertension, diabetes, tobacco abuse, stroke, high cholesterol, cardiovascular medication, and alcohol abuse). Stepwise selection and backward elimination analyses were performed to obtain the final model. Finally, a multiple linear regression model was conducted to assess the association between WMHs and variables retained in the final model (dementia, sex, and age). Of the 77 individuals, 47 (61%) had dementia, 40 (52.6%) were males, and the mean age was 73 years (± 8.0 years standard deviation). In simple linear regression models, WMHs was significantly associated with dementia (expβ1 = 1.75, 95% CI = 1.14-2.71, -value = 0.01) though it had a weak association with age (expβ1 = 1.03, 95% CI = 1.00-1.05, -value = 0.05) and sex (male) (expβ1 = 0.66, 95% CI = 0.43-1.01, -value = 0.05). In multiple linear regression models, WMHs was statistically significantly associated with dementia (expβ1 = 1.97, 95% CI = 1.31-2.95, -value =0.001), male sex (expβ2 = 0.54, 95% CI = 0.36-0.80, -value = 0.003), and age (expβ3 = 1.03, 95% CI = 1.00-1.06, -value = 0.03). However, WMHs was not significantly associated with common cardiovascular risk factors, such as high blood pressure, diabetes, tobacco use, obesity, and high cholesterol levels. WMHs is significantly associated with dementia, sex, and age in the Congolese population. Understanding these predictors may improve our ability to diagnose, assess, and develop preventative treatments for white matter disease in SSA/DRC populations, where neuroimaging is difficult to obtain.

eIF2B is a dedicated guanine nucleotide exchange factor for eIF2, the GTPase that is essential to initiate mRNA translation. The integrated stress response (ISR) signaling pathway inhibits eIF2B activity, attenuates global protein synthesis and upregulates a set of stress-response proteins. Partial loss-of-function mutations in eIF2B cause a neurodegenerative disorder called Vanishing White Matter Disease (VWMD). Previously, we showed that the small molecule ISRIB is a specific activator of eIF2B (Sidrauski et al., 2015 ). Here, we report that various VWMD mutations destabilize the decameric eIF2B holoenzyme and impair its enzymatic activity. ISRIB stabilizes VWMD mutant eIF2B in the decameric form and restores the residual catalytic activity to wild-type levels. Moreover, ISRIB blocks activation of the ISR in cells carrying these mutations. As such, ISRIB promises to be an invaluable tool in proof-of-concept studies aiming to ameliorate defects resulting from inappropriate or pathological activation of the ISR.

Over the last decade knowledge of the role of astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive role in response to damage it is clear that astrocytes actively maintain CNS homeostasis by influencing pH, ion and water balance, the plasticity of neurotransmitters and synapses, cerebral blood flow, and are important immune cells. During disease astrocytes become reactive and hypertrophic, a response that was long considered to be pathogenic. However, recent studies reveal that astrocytes also have a strong tissue regenerative role. Whilst most astrocyte research focuses on modulating neuronal function and synaptic transmission little is known about the cross-talk between astrocytes and oligodendrocytes, the myelinating cells of the CNS. This communication occurs via direct cell-cell contact as well as via secreted cytokines, chemokines, exosomes, and signalling molecules. Additionally, this cross-talk is important for glial development, triggering disease onset and progression, as well as stimulating regeneration and repair. Its critical role in homeostasis is most evident when this communication fails. Here, we review emerging evidence of astrocyte-oligodendrocyte communication in health and disease. Understanding the pathways involved in this cross-talk will reveal important insights into the pathogenesis and treatment of CNS diseases.

Introduction This study examines the relationship between white matter lesions (WML) and vascular cognitive impairment in patients with acute ischemic stroke (AIS). Materials and methods We enrolled 120 AIS patients (79 males, 41 females; mean age 65.63 ± 10.12 years) admitted to the Department of Neurology, Mianyang Central Hospital, between February and November 2019. Demographic and clinical data were collected. All patients underwent cranial magnetic resonance imaging (MRI), and WML were graded using the Fazekas scale: mild WML (score 1–3, n  = 67) and severe WML (score 4–6, n  = 53). WML volume was quantified semi-automatically with 3D Slicer. Cognitive function was longitudinally assessed using the Clinical Dementia Rating (CDR) scale at two follow-up time points: 90 days and 1 year post-stroke. Statistical analyses included Chi-square tests, Spearman correlation, and linear regression. Results At 1 year post-stroke, the severe WML group had higher rates of mild cognitive impairment (MCI) (58.49% vs. 52.24%) and dementia (35.85% vs. 25.37%) compared to the mild WML group (all P  < 0.05). Normal cognitive function was more frequent in the mild WML group (22.39% vs. 5.66%, P  < 0.05). Correlation analyses showed that WML volume, total WML score, deep WML score, and age correlated with 1-year CDR scores ( P  < 0.05). Admission National Institutes of Health Stroke Scale (NIHSS) score, total WML score, and age were associated with 90-day CDR scores. Linear regression indicated that admission NIHSS score ( P  = 0.004, β  = 0.26), total WML score ( P  = 0.047, β  = 0.19), and age ( P  = 0.041, β  = 0.19) independently influenced 90-day cognitive outcomes ( R 2  = 0.13). Conclusion Based on the assessment results of the CDR scale, WML severity, age and admission NIHSS score may demonstrate positive associations with cognitive function at 90 days post-stroke. While WML severity correlates with cognitive impairment at one year post-stroke, it does not appear to be the determining factor.