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Dual pathology of Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) commonly are found together at autopsy, but mixed dementia (MX) is difficult to diagnose during life. Biological criteria to diagnose AD have been defined, but are not available for vascular disease. We used the biological criteria for AD and white matter injury based on MRI to diagnose MX. Then we measured multiple biomarkers in CSF and blood with multiplex biomarker kits for proteases, angiogenic factors, and cytokines to explore pathophysiology in each group. Finally, we used machine learning with the Random forest algorithm to select the biomarkers of maximal importance; that analysis identified three proteases, matrix metalloproteinase-10 (MMP-10), MMP-3 and MMP-1; three angiogenic factors, VEGF-C, Tie-2 and PLGF, and three cytokines interleukin-2 (IL-2), IL-6, IL-13. To confirm the clinical importance of the variables, we showed that they correlated with results of neuropsychological testing.

Background: The dual inhibitors of receptor interacting protein kinase-1 and -3 (RIP1 and RIP3) play an important role in cell death processes and inflammatory responses. White matter injury (WMI), a leading cause of neurodevelopmental disabilities in preterm infants, which is characterized by extensive myelination disturbances and demyelination. Neuroinflammation, leads to the loss and differentiation-inhibition of oligodendrocyte precursor cells (OPCs), represents a major barrier to myelin repair. Whether the novel RIP1/RIP3 dual inhibitor ZJU-37 can promote transplanted OPCs derived from human neural stem cells (hOPCs) survival, differentiation and myelination remains unclear. In this study, we investigated the effect of ZJU-37 on myelination and neurobehavioral function in a neonatal rat WMI model induced by hypoxia and ischemia. Methods: In vivo, P3 rat pups were subjected to right common carotid artery ligation and hypoxia, and then treated with ZJU-37 or/and hOPCs, then OPCs apoptosis, myelination, glial cell and NLRP3 inflammasome activation together with cognitive outcome were evaluated at 12 weeks after transplantation. In vitro, the effect of ZJU-37 on NLRP3 inflammasome activation in astrocytes induced by oxygen–glucose deprivation (OGD) were examined by western blot and immunofluorescence. The effect of ZJU-37 on OPCs apoptosis induced by the conditioned medium from OGD-injured astrocytes (OGD-astrocyte-CM) was analyzed by flow cytometry and immunofluorescence. Results: ZJU-37 combined with hOPCs more effectively decreased OPC apoptosis, promoted myelination in the corpus callosum and improved behavioral function compared to ZJU-37 or hOPCs treatment. In addition, the activation of glial cells and NLRP3 inflammasome was reduced by ZJU-37 or/and hOPCs treatment in the neonatal rat WMI model. In vitro, it was also confirmed that ZJU-37 can suppress NLRP3 inflammasome activation in astrocytes induced by OGD. Not only that, the OGD-astrocyte-CM treated with ZJU-37 obviously attenuated OPC apoptosis and dysdifferentiation caused by the OGD-astrocyte-CM. Conclusions: The novel RIP1/RIP3 dual inhibitor ZJU-37 may promote OPC survival, differentiation and myelination by inhibiting NLRP3 inflammasome activation in a neonatal rat model of WMI with hOPC graft. [ABSTRACT FROM AUTHOR]

Dual pathology of Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) commonly are found together at autopsy, but mixed dementia (MX) is difficult to diagnose during life. Biological criteria to diagnose AD have been defined, but are not available for vascular disease. We used the biological criteria for AD and white matter injury based on MRI to diagnose MX. Then we measured multiple biomarkers in CSF and blood with multiplex biomarker kits for proteases, angiogenic factors, and cytokines to explore pathophysiology in each group. Finally, we used machine learning with the Random forest algorithm to select the biomarkers of maximal importance; that analysis identified three proteases, matrix metalloproteinase-10 (MMP-10), MMP-3 and MMP-1; three angiogenic factors, VEGF-C, Tie-2 and PLGF, and three cytokines interleukin-2 (IL-2), IL-6, IL-13. To confirm the clinical importance of the variables, we showed that they correlated with results of neuropsychological testing. [ABSTRACT FROM AUTHOR]

The pace of understanding cognitive decline and dementia has rapidly accelerated over the past decade, with constantly evolving insights into the vascular contributions to cognitive impairment and dementia (VCID). Notably, more overlap has been discovered in the pathophysiology between what was previously understood to be Alzheimer's disease and VCID, leading to a heightened emphasis on disease prevention through early and aggressive control of vascular risk factors. One particularly vulnerable population may be those with cardiac disease, as they are at risk for cerebrovascular disease, which itself can lead to dementia, and increasing evidence supports cognitive impairment in disease processes such as heart failure and atrial fibrillation, independent of ischemic stroke, suggesting other potential mechanisms. In this article, we review the evidence supporting the relationship between cardiac disease, cerebrovascular disease, and cognitive decline and discuss the ongoing and future research efforts aimed at defining the important relationship between these entities. [ABSTRACT FROM AUTHOR]

Objective: Older individuals often have multiple etiologies for their lower urinary tract symptoms (LUTS); i.e., both urologic (U) and neurologic (N) etiologies. Few studies have investigated 'triple disease' (typically one U and two N components) in the LUTS of older adults. Herein, we had specialists from both urology and neurology address triple- and quadruple-etiology disease. Patients and methods: This was a retrospective study with a 12-month recruiting period. We ascertained LUTS by standard questionnaires and bladder diaries. Urodynamics, sphincter EMG, prostate echography, and a neurologic examination were conducted for each patient as well as neuroimaging and neurophysiology examinations when appropriate. The diagnoses of the etiologies were based on published criteria. Results: We analyzed the cases of 141 older (age > 65 years) adults with LUTS referred from both urology (27%) and neurology departments (73%). The final etiologies were U (n = 69, 49%), N (n = 136, 96%), and a combination (U and N) (n = 77, 55%, overlap counted). The majority of U diagnoses were benign prostatic hyperplasia. The majority of N diagnoses were dementia with Lewy bodies, white matter disease (brain); lumbar spondylosis, and diabetes (peripheral disease). We noted triple-disease etiology in 25% (n = 35), increasing with each decade of age (18.2% of sexagenarians, 23.5% of septuagenarians, 39.1% of octogenarians). However, the differences were not significant. Conclusion: Our results demonstrate that triple disease for LUTS is the most common in octogenarians, and clinicians thus need to untangle LUTS etiologies to provide appropriate care and management of older adults. [ABSTRACT FROM AUTHOR]

We sought to examine the frequency of depression after small vessel-type stroke (SVS) and associated risk factors. We conducted a retrospective analysis of a prospective cohort of patients enrolled in the American Stroke Association-Bugher SVS Study, which included 200 participants within 2-years of SVS and 79 controls without a history of stroke from 2007 to 2012 at four sites. The primary outcome was PHQ-8, with scores ≥10 consistent with post-stroke depression (PSD). A logistic regression adjusted for age, race, sex, history of diabetes and Short-Form Montreal Cognitive Assessment score (SF-MoCA) was used to compare the risk of having depression after SVS compared to controls. Another logistic regression, adjusted for age, sex, race, level of education, SF-MoCA, white matter disease (WMD) burden, stroke severity (NIHSS), time between stroke and depression screen, history of diabetes, and history of hypertension was used to identify factors independently associated with depression in participants with SVS. The cohort included 161 participants with SVS (39 excluded due to missing data) and 79 controls. The mean interval between stroke and depression screening was 74 days. Among participants with SVS, 31.7% (n = 51) had PSD compared to 6.3% (n = 5) of controls (RR = 5.44, 95% CI = 2.21-13.38, p = 0.0002). The only two variables independently associated with PSD in participants with SVS were female sex (RR = 1.84, 95% CI = 1.09-3.09, p = 0.020) and diabetes (RR 1.69, 95% CI 1.03-2.79). After adjusting for several demographic and clinical variables, having a SVS was associated with an approximate 5-fold increased risk of depression and was more frequent in women and in those with diabetes. The extent of WMD was not independently associated with PSD, suggesting that small vessel disease in the setting of an overt SVS may not account for the increased prevalence of depression. [ABSTRACT FROM AUTHOR]

Background: There are numerous barriers to identifying patients with silent brain infarcts (SBIs) and white matter disease (WMD) in routine clinical care. A natural language processing (NLP) algorithm may identify patients from neuroimaging reports, but it is unclear if these reports contain reliable information on these findings.Methods: Four radiology residents reviewed 1000 neuroimaging reports (RI) of patients age > 50 years without clinical histories of stroke, TIA, or dementia for the presence, acuity, and location of SBIs, and the presence and severity of WMD. Four neuroradiologists directly reviewed a subsample of 182 images (DR). An NLP algorithm was developed to identify findings in reports. We assessed interrater reliability for DR and RI, and agreement between these two and with NLP.Results: For DR, interrater reliability was moderate for the presence of SBIs (k = 0.58, 95 % CI 0.46-0.69) and WMD (k = 0.49, 95 % CI 0.35-0.63), and moderate to substantial for characteristics of SBI and WMD. Agreement between DR and RI was substantial for the presence of SBIs and WMD, and fair to substantial for characteristics of SBIs and WMD. Agreement between NLP and DR was substantial for the presence of SBIs (k = 0.64, 95 % CI 0.53-0.76) and moderate (k = 0.52, 95 % CI 0.39-0.65) for the presence of WMD.Conclusions: Neuroimaging reports in routine care capture the presence of SBIs and WMD. An NLP can identify these findings (comparable to direct imaging review) and can likely be used for cohort identification. [ABSTRACT FROM AUTHOR]

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer's disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aβ1-42 pathology (Aβ+/−) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aβ+ compared with Aβ− controls. In MCI-Aβ+ compared with Aβ− controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aβ+ and MCI-Aβ+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology. [ABSTRACT FROM AUTHOR]

Objectives: Aim of this study was to evaluate the association between cerebral microbleeds (CMBs) and white matter disease (WMD) with intracerebral hemorrhage (ICH) after intravenous thrombolysis (IVT) with rt-PA. We also evaluated whether CMBs characteristics and WMD burden correlate with symptomatic ICH and outcome. Methods: We included acute ischemic stroke (AIS) patients treated with IVT. The number and location of CMBs as well as severity of WMD were rated analyzing pre- or post-treatment MRI. Multivariable regression analysis was used to determine the impact of CMB and WMD on ICH subgroups and outcome measures. Results: 434 patients were included. CMBs were detected in 23.3% of them. ICH occurred in 34.7% of patients with CMBs. Independent predictors of parenchymal hemorrhage were the presence of CMBs (OR 2.724, 95% CI 1.360–5.464, p = 0.005) as well as cortical-subcortical stroke (OR 3.629, 95% CI 1.841–7.151, p < 0.001) and atherothrombotic stroke subtype (OR 3.381, 95% CI 1.335–8.566, p = 0.010). Either the presence, or number, and location of CMBs, as well as WMD, was not independently associated with the development of SICH. No independent association between the presence, number, or location of CMBs or WMD and outcome measures was observed. Conclusions: The results of our study suggest that the exclusion of eligible candidates to administration of IV rt-PA only on the basis of CMBs presence is not justified. The clinical decision should be weighed with a case-by-case approach. Additional data are needed to evaluate the benefit-risk profile of rt-PA in patients carrying numerous microbleeds. [ABSTRACT FROM AUTHOR]

Peroxisomes play an essential role in lipid metabolism via interaction with other intracellular organelles. The information about the role of the Acyl‐CoA‐binding domain containing‐protein 5 (ACBD5) in these interactions in human cells is emerging. Moreover, a few patients with retinal dystrophy and leukodystrophy caused by pathogenic variants in ACBD5 have been recently introduced. Here, we present a 36‐year‐old female with retinal dystrophy, leukodystrophy, and psychomotor regression due to a novel homozygous variant in ACBD5. Our study adds to the growing knowledge of this peroxisomal disorder by providing phenotypic details of the first adult patient. [ABSTRACT FROM AUTHOR]

PDK1 (3-Phosphoinositide dependent protein kinase-1) is a member in the PI3K (phosphatidylinositol 3 kinase) pathway and is implicated in neurodevelopmental disease with microcephaly. Although the role of PDK1 in neurogenesis has been broadly studied, it remains unknown how PDK1 may regulate oligogenesis in the central nervous system (CNS). To address this question, we generated oligodendrocyte (OL) lineage cells specific PDK1 conditional knockout (cKO) mice. We find that PDK1 cKOs display abnormal white matter (WM), massive loss of mature OLs and severe defect in myelination in the CNS. In contrast, these mutants exhibit normal neuronal development and unchanged apoptosis in the CNS. We demonstrate that deletion of PDK1 severely impairs OL differentiation. We show that genetic or pharmacological inhibition of PDK1 causes deficit in the mammalian target of rapamycin (mTor) signaling and down-regulation of Sox10. Together, these results highlight a critical role of PDK1 in OL differentiation during postnatal CNS development.

Background: Oligovascular niche mediates interactions between cerebral endothelial cells and oligodendrocyte precursor cells (OPCs). Disruption of OPC-endothelium trophic coupling may aggravate the progress of cerebral white matter injury (WMI) because endothelial cells could not provide sufficient support under diseased conditions. Endothelial progenitor cells (EPCs) have been reported to ameliorate WMI in the adult brain by boosting oligovascular remodeling. It is necessary to clarify the role of the conditioned medium from hypoxic endothelial cells preconditioned EPCs (EC-pEPCs) in WMI since EPCs usually were recruited and play important roles under blood-brain barrier disruption. Here, we investigated the effects of EC-pEPCs on oligovascular remodeling in a neonatal rat model of WMI. Methods: In vitro, OPC apoptosis induced by the conditioned medium from oxygen-glucose deprivation-injured brain microvascular endothelial cells (OGD-EC-CM) was analyzed by TUNEL and FACS. The effects of EPCs on EC damage and the expression of cytomokine C-X-C motif ligand 12 (CXCL12) were examined by western blot and FACS. The effect of the CM from EC-pEPCs against OPC apoptosis was also verified by western blot and silencing RNA. In vivo, P3 rat pups were subjected to right common carotid artery ligation and hypoxia and treated with EPCs or EC-pEPCs at P7, and then angiogenesis and myelination together with cognitive outcome were evaluated at the 6th week. Results: In vitro, EPCs enhanced endothelial function and decreased OPC apoptosis. Meanwhile, it was confirmed that OGD-EC-CM induced an increase of CXCL12 in EPCs, and CXCL12-CXCR4 axis is a key signaling since CXCR4 knockdown alleviated the anti-apoptosis effect of EPCs on OPCs. In vivo, the number of EPCs and CXCL12 protein level markedly increased in the WMI rats. Compared to the EPCs, EC-pEPCs significantly decreased OPC apoptosis, increased vascular density and myelination in the corpus callosum, and improved learning and memory deficits in the neonatal rat WMI model. Conclusions: EC-pEPCs more effectively promote oligovascular remodeling and myelination via CXCL12-CXCR4 axis in the neonatal rat WMI model. [ABSTRACT FROM AUTHOR]

In recent years, it has become apparent that the gut microbiome can influence the functioning and pathological states of organs and systems throughout the body. In this study, we tested the hypothesis that the gut microbiome has a major role in the disruption of the blood‐brain barrier (BBB) in the spontaneously hypertensive stroke prone rats (SHRSP), an animal model for hypertensive cerebral small vessel disease (CSVD). Loss of BBB is thought to be an early and initiating component to the full expression of CSVD in animal models and humans. To test this hypothesis, newly born SHRSP pups were placed with foster dams of the SHRSP strain or dams of the WKY strain, the control strain that does not demonstrate BBB dysfunction or develop hypertensive CSVD. Similarly, WKY pups were placed with foster dams of the same or opposite strain. The rationale for cross fostering is that the gut microbiomes are shaped by environmental bacteria of the foster dam and the nesting surroundings. Analysis of the bacterial genera in feces, using 16S rRNA analysis, demonstrated that the gut microbiome in the rat pups was influenced by the foster dam. SHRSP offspring fostered on WKY dams had systolic blood pressures (SBPs) that were significantly decreased by 26 mmHg (P < .001) from 16‐20 weeks, compared to SHRSP offspring fostered on SHRSP dams. Similarly WKY offspring fostered on SHRSP dams had significantly increased SBP compared to WKY offspring fostered on WKY dams, although the magnitude of SBP change was not as robust. At ~20 weeks of age, rats fostered on SHRSP dams showed enhanced inflammation in distal ileum regardless of the strain of the offspring. Disruption of BBB integrity, an early marker of CSVD onset, was improved in SHRSPs that were fostered on WKY dams when compared to the SHRSP rats fostered on SHRSP dams. Although SHRSP is a genetic model for CSVD, environmental factors such as the gut microbiota of the foster dam have a major influence in the loss of BBB integrity. [ABSTRACT FROM AUTHOR]

Objective: Delirium/dementia (collectively called cognitive spectrum disorder [CSD]) is a major issue in hospital wards. However, few reports are available on the incidence of CSD on multi‐faculty wards or on the factors contributing to it. The aim of this study was to address these issues by a neurogeriatric team (neurologists, psychiatrists, specialist nurses, and link nurses from all wards). Patients and Methods: This was a retrospective study with a 12‐month recruiting period, a prospective follow‐up period of 3.0 ± 2.5 weeks, and ≥1×/week visits. We diagnosed acute‐onset delirium by the Confusion Assessment Method and analyzed underlying conditions. We also diagnosed premorbid dementia by neurocognitive examination and neuroimaging following published criteria. Results: Our subjects were 723 CSD from 15 faculties, accounting for 6.5% of admissions, 393 men and 330 women, mean age 81 years. CSD was prevalent in cardiology/cardiac surgery (CAR), orthopedic surgery (OP), and neurology/neurosurgery (N), with dementia alone in ophthalmology and a combination of delirium/dementia in the other faculties. Premorbid dementia were diagnosed with Alzheimer's disease (AD), white matter disease, dementia with Lewy bodies (DLB), or some combination of these. Delirium was accompanied by worsening of gait difficulty. The ratio of brain (N) versus extra‐brain was 105 (14.5%):618 (85.5%). Severe CSD was common in DLB than AD but without statistical significance. Conclusion: Total 6.5% of hospital admissions showed CSD, with CAR, OP, and N being prevalent. The ratio of brain versus extra‐brain was 14.5%:85.5%. Severe CSD was more prevalent in DLB patients than in AD patients, but without statistical significance. [ABSTRACT FROM AUTHOR]

We used plasma neuronal extracellular vesicles to examine how neuronal insulin signaling proteins relate cross-sectionally to brain structure in nondemented older adults with varying levels of cortical amyloid. Extracellular vesicles enriched for neuronal origin by anti-L1CAM immunoabsorption were isolated from plasma of Atherosclerosis Risk in Communities–Positron Emission Tomography study participants (n = 88; mean age: 77 years [standard deviation: 6]). Neuronal extracellular vesicle levels of phosphorylated insulin signaling cascade proteins were quantified. Brain volume and white matter hyperintensity (WMH) volume were assessed using 3T magnetic resonance imaging. After adjusting for demographic variables and extracellular vesicle marker Alix, higher levels of a neuronal insulin signaling composite measure were associated with lower WMH and greater temporal lobe volume. Secondary analyses found the levels of downstream protein kinases involved in cell survival (p70S6K) and tau phosphorylation/neuroinflammation (GSK-3β) to be most strongly associated with WMH and temporal lobe volume, respectively. Associations between neuronal insulin signaling and lower WMH volume were attenuated in participants with elevated cortical amyloid. These results suggest that enhanced neuronal proximal insulin signaling is associated with preserved brain structure in nondemented older adults. • Extracellular vesicles derived from neurons were isolated in plasma of older adults. • Neuronal extracellular vesicle insulin signaling cascade proteins were quantified. • Neuronal insulin signaling was associated with preserved regional brain volume. • In absence of amyloid, neuronal insulin was associated with preserved white matter. • Downstream protein kinases p70S6K and GSK-3β showed the most robust associations. [ABSTRACT FROM AUTHOR]

White matter hyperintensities of presumed vascular origin (WMH) are a prevalent form of cerebral small-vessel disease and an important risk factor for post-stroke cognitive dysfunction. Despite this prevalence, it is not well understood how WMH contributes to post-stroke cognitive dysfunction. Preliminary findings suggest that increasing WMH volume is associated with total hippocampal volume in chronic stroke patients. The hippocampus, however, is a complex structure with distinct subfields that have varying roles in the function of the hippocampal circuitry and unique anatomical projections to different brain regions. For these reasons, an investigation into the relationship between WMH and hippocampal subfield volume may further delineate how WMH predispose to post-stroke cognitive dysfunction. In a prospective study of acute ischemic stroke patients with moderate/severe WMH burden, we assessed the relationship between quantitative WMH burden and hippocampal subfield volumes. Patients underwent a 3T MRI brain within 2–5 days of stroke onset. Total WMH volume was calculated in a semi-automated manner. Mean cortical thickness and hippocampal volumes were measured in the contralesional hemisphere. Total and subfield hippocampal volumes were measured using an automated, high-resolution, ex vivo computational atlas. Linear regression analyses were performed for predictors of total and subfield hippocampal volumes. Forty patients with acute ischemic stroke and moderate/severe white matter hyperintensity burden were included in this analysis. Median WMH volume was 9.0 cm3. Adjusting for intracranial volume and stroke laterality, age (β = −3.7, P < 0.001), hypertension (β = −44.7, P = 0.04), WMH volume (β = −0.89, P = 0.049), and mean cortical thickness (β = 286.2, P = 0.006) were associated with total hippocampal volume. In multivariable analysis, age (β = −3.3, P < 0.001) and cortical thickness (β = 205.2, P = 0.028) remained independently associated with total hippocampal volume. In linear regression for predictors of hippocampal subfield volume, increasing WMH volume was associated with decreased hippocampal-amygdala transition area volume (β = −0.04, P = 0.001). These finding suggest that in ischemic stroke patients, increased WMH burden is associated with selective hippocampal subfield degeneration in the hippocampal-amygdala transition area.

Background Research links blood pressure variability (BPV) with stroke; however, the association with cerebral small‐vessel disease (CSVD) remains unclear. As BPV and mean blood pressure are interrelated, it remains uncertain whether BPV adds additional information to understanding cerebrovascular morphological characteristics. Methods and Results A systematic review was performed from inception until March 3, 2019. Eligibility criteria included population, adults without stroke (

• Late onset unexplained epilepsy LOUE is pharmacosensitive with 8% drug resistant. • In patients with discharges, LOUE is mostly temporal, with left predominance. • As compared to controls, patients with LOUE have more vascular risk factors. To investigate neurophysiologic and neuroimaging characteristics of patients with late onset unexplained epilepsy (LOUE). We performed a retrospective chart review of elderly patients with ICD9 diagnosis codes consistent with epilepsy/seizures. Inclusion criteria included unprovoked seizures, and absence of cortical lesions on magnetic resonance imaging (MRI). Electroencephalograms (EEGs) findings were also analyzed. MRI images were scored for degree of white matter hyperintensities (Fazekas Scale) and mesial temporal atrophy (MTA). Vascular risk factors, and Framingham Heart Study general cardiovascular disease (FHS-CVD) risk scores were compared to controls from the Harvard Aging Brain study (HABS). We identified 224 LOUE patients and 8% were drug resistant. Epileptiform abnormalities were captured on EEG in 35%. The location was temporal with left sided predominance in 49%. Fazekas scale consisted of 25% beginning of confluent lesions, and 10% large confluent lesions. MTA scores consisted of 21% moderate-severe hippocampal atrophy. LOUE patients had on average a 2.3% (adjusted), 7.4% (unadjusted) increased FHS-CVD score. Our findings highlight LOUE as pharmacosensitive and left temporal predominant. Given the higher prevalence of vascular risk factors, investigations are needed to study their role in pathophysiology. Physicians caring for patients with LOUE should evaluate for vascular risk factors and investigate the presence of hippocampal atrophy. [ABSTRACT FROM AUTHOR]

White matter hyperintensities of presumed vascular origin (WMH) are a prevalent form of cerebral small-vessel disease and an important risk factor for post-stroke cognitive dysfunction. Despite this prevalence, it is not well understood how WMH contributes to post-stroke cognitive dysfunction. Preliminary findings suggest that increasing WMH volume is associated with total hippocampal volume in chronic stroke patients. The hippocampus, however, is a complex structure with distinct subfields that have varying roles in the function of the hippocampal circuitry and unique anatomical projections to different brain regions. For these reasons, an investigation into the relationship between WMH and hippocampal subfield volume may further delineate how WMH predispose to post-stroke cognitive dysfunction. In a prospective study of acute ischemic stroke patients with moderate/severe WMH burden, we assessed the relationship between quantitative WMH burden and hippocampal subfield volumes. Patients underwent a 3T MRI brain within 2–5 days of stroke onset. Total WMH volume was calculated in a semi-automated manner. Mean cortical thickness and hippocampal volumes were measured in the contralesional hemisphere. Total and subfield hippocampal volumes were measured using an automated, high-resolution, ex vivo computational atlas. Linear regression analyses were performed for predictors of total and subfield hippocampal volumes. Forty patients with acute ischemic stroke and moderate/severe white matter hyperintensity burden were included in this analysis. Median WMH volume was 9.0 cm3. Adjusting for intracranial volume and stroke laterality, age (β = −3.7, P < 0.001), hypertension (β = −44.7, P = 0.04), WMH volume (β = −0.89, P = 0.049), and mean cortical thickness (β = 286.2, P = 0.006) were associated with total hippocampal volume. In multivariable analysis, age (β = −3.3, P < 0.001) and cortical thickness (β = 205.2, P = 0.028) remained independently associated with total hippocampal volume. In linear regression for predictors of hippocampal subfield volume, increasing WMH volume was associated with decreased hippocampal-amygdala transition area volume (β = −0.04, P = 0.001). These finding suggest that in ischemic stroke patients, increased WMH burden is associated with selective hippocampal subfield degeneration in the hippocampal-amygdala transition area. [ABSTRACT FROM AUTHOR]

Introduction: Orthostatic Hypotension (OH) is an abnormal drop in blood pressure (BP) that occurs following orthostatic challenge. OH is associated with increased risk of falls, cognitive impairment and death. White Matter Hyperintensities (WMH) on MR Brain are associated with vascular risk factors such as hypertension, diabetes and age. We examined whether extent White matter intensities were associated with presence of OH detected in a community dwelling population of older people. Methods: Individuals from the MR sub-study of the Irish Longitudinal Study of Ageing underwent a 3 Tesla MR Brain scan to assess WMH severity (Schelten's Score). The scans were performed during the Wave 3 TILDA health assessment phase when the subjects also underwent assessment for OH with an active stand protocol. Data was analysed for association between WMH and vascular risks and orthostatic change in BP 10 second intervals during the OH evaluation. Results: 440 subjects were investigated; median age 72 years (65–92 years) and 228 (51.5%) female. Range of Scheltens' Scores was 0–32. Mean score was 9.72 (SD 5.87). OH was detected in 68.4% (301). On linear regression, positive associations were found between Scheltens' Score and age, hypertension, prior history of stroke and TIA, and with OH at 30, 70, 90 and 100 seconds following standing (p < 0.05, O.R. 1.9–2.5). Conclusion: WMD is associated with OH detected at multiple time points using active stand in community dwelling older subjects. Further research is necessary to evaluate the direction of this association. [ABSTRACT FROM AUTHOR]

Objective: Alzheimer's disease (AD), Lewy body disease (LBD), and white matter disease (WMD) are common in the elderly. Although these diseases are observed together pathologically, the extent to which these diseases occur together clinically is uncertain. To address this question, we analyzed the clinical neuroimaging data of Japanese patients. Patients and Methods: This was a prospective study with a 3.0‐year recruiting period, a prospective follow‐up period of 2.0 ± 1.5 years, and ≥1×/year visits. We recruited 770 referred subjects who had undergone three neuroimaging markers: brain magnetic resonance imaging (MRI), dopamine transporter (DAT) scanning, and metaiodobenzylguanidine (MIBG) myocardial scintigraphy. Results: Among the 770 patients, 731 fulfilled the criteria of some of or all of the three diseases as follows: WMD (n = 46), WMD + AD (n = 110), WMD + LBD (n = 89), WMD + AD +LBD (n = 86), AD (n = 118), LBD (n = 239), and AD + LBD (n = 43). In total, there were patients with WMD (n = 331), AD (n = 357), and LBD (n = 414) (with overlap); dual diseases (n = 242; 33%) and triple diseases (n = 86; 12%). Clinically, pure WMD showed overactive bladder but mild gait/cognitive disorder. Pure AD showed cognitive disorder alone. Pure LBD showed cognitive, gait, and sleep/autonomic disorders. Triple/dual diseases showed combined clinical features, depending on the underlying diseases. However, these differences did not reach statistical significance. Conclusion: Forty‐five percent of the patients who visited dementia/movement disorder/sleep‐autonomic disorder clinics showed either triple or dual diseases. It is important to follow such patients from the viewpoint of disease progression and necessary care. [ABSTRACT FROM AUTHOR]

Hypomyelinating Leukodystrophies (HLDs) are a genetically heterogeneous, clinically overlapping group of disorders with the unifying MR imaging appearance of myelin deficit in the brain. In fact, it is the MRI phenotype that typically raises the diagnostic suspicion in this single largest group of undiagnosed leukodystrophies and guides gene testing for confirmation. This article reviews the neurobiology of myelination, focussing on the complex interplay of molecular genetic pathways and presents a practical clinico-radiological diagnostic algorithm based on the neuroimaging patterns of the common hypomyelinating disorders. The authors also address the current controversies about the definition and use of the term 'hypomyelination'. • Hypomyelination is a commonly encountered MR imaging phenotype in Paediatric Neurology practice. • Many clinically and genetically diverse group of disorders share the hypomyelination phenotype on imaging. It is imperative to differentiate primary delayed myelination and demyelination from this entity. • Clinical clues, pattern recognition and recognition of other associated imaging findings can help narrow these differential diagnoses and guide the diagnostic process. • Our understanding of normal myelination and disorders affecting it is still evolving. This leads to semantic confusions and diagnostic conundrums around hypomyelinating disorders. Accurate description of imaging features and reverse phenotyping after genetic diagnosis are possible practical solutions. [ABSTRACT FROM AUTHOR]

Introduction: Neurological assessment of patients with burn injuries may be complicated by a variety of factors including artificial ventilation and sedation, cerebral hypoxia and intoxication. Medically unstable intubated patients present logistical challenges for radiological imaging. The role of neuroimaging as an adjunct to clinical assessment of burn injured patients has not yet been determined.Aim: This study aims to investigate the indications, findings and outcomes of neuroimaging studies performed for burn injured patients.Methods: A retrospective case series study of adult burn patients admitted over an 8 year period was completed in the National Burns Centre at St James's Hospital, Dublin. Neuroimaging studies carried out for patients admitted during the study period were reviewed by a Consultant Radiologist and Consultant Stroke Physician. Outcomes included neuroimaging findings, prevalence of white matter disease (Fazekas scale), length of stay, discharge destination, predicted and observed mortality.Results: 1328 consecutive patients with burn injuries were admitted during the study period. 56 patients underwent neuroimaging studies with computerised tomography, magnetic resonance imaging or both. 46 out of 56 neuroimaged patients (82.1%) had significant radiological findings, including 14 patients (25%) with acute findings. There was a high prevalence of white matter disease (mean total Fazekas score: 3.59) and acute cerebral infarction (7 patients). Patients with radiological findings required additional in-patient rehabilitation and had increased length of stay (Median 47.0 days vs. 27.5 days, p < 0.027). Patients with resuscitation burns or associated inhalation injury were significantly more likely to undergo neuroimaging (p < 0.0001) and to have positive radiological findings. Predicted mortality was higher in patients with positive neuroimaging findings compared to patients with normal neuroimaging studies, although there was no significant difference in observed mortality between these two groups.Conclusion: Neuroimaging is used appropriately in patients admitted with burns and provides valuable applicable clinical information when indicated. [ABSTRACT FROM AUTHOR]

Background: The rate of decline in language in primary progressive aphasia (PPA) is highly variable and difficult to predict at baseline. The severity of diffuse white matter disease (leukoaraiosis), a marker of overall brain health, may substantially influence the rate of decline. Aims: To test the hypothesis that leukoaraiosis is associated with a steeper decline in naming in PPA. Methods and procedures: In this longitudinal, observational study, 29 individuals with PPA (all variants) were administered the Boston Naming Test (BNT) at baseline and 1 year later. Two raters evaluated leukoaraiosis on baseline MRI, using the Cardiovascular Health Study scale. We evaluated the effects of leukoaraiosis severity, age, education, and baseline BNT on decline measured by change in BNT accuracy with multivariable linear regression. We also evaluated the effects of these variables on the dichotomized outcome of faster decline in BNT (worst 50%) versus slower decline (best 50%) using logistic regression. Outcomes and results: Taken together, leukoaraiosis, age, education, and baseline BNT score predicted change in BNT score (F(3, 25) = 8.12; p = 0.0006). Change in BNT score was predicted by severity of leukoaraiosis (t = −3.81; p = 0.001) and education (t = −2.45; p = 0.022), independently of the other variables. When we dichotomized outcome into upper 50th percentile versus lower 50th percentile (faster decline), faster decline was predicted by all variables together (chi-squared = 13.91; p = 0.008). However, only leukoaraiosis independently predicted outcome (OR = 2.80; 95%CI: 1.11 to 7.03). For every 1 point increase on the CHS rating scale, there was 2.8 times higher chance of showing faster decline in naming. Conclusion: Severity of leukoaraiosis is associated with steeper decline in naming in PPA. This imaging marker can aide in prognosis and planning by caregivers and stratification of participants in clinical trials. [ABSTRACT FROM AUTHOR]

Background: We developed an image patch classification-based method to detect early ischemic stroke. The accuracy of this method was >75%. We aimed to analyze patients' image data to identify interference factors that would affect its accuracy. Methods: We conducted a retrospective analysis of 162 patients who were hospitalized with acute ischemic stroke. Factors related to the noncontrast computed tomography (ncCT) determination results were analyzed according to the patient's sex, age, clinical symptoms, cerebral infarction volume, cerebral infarction location, and whether or not the white matter high (WMH) signal was combined. Results: The volume of cerebral infarction was positively correlated with the predicted results. The correct percentages of patients with volumes >1 and <1 mL were 59.18 and 83.19%, respectively, and the difference was statistically significant (p = 0.001). The correct percentage of the internal capsule region (47.1%) was significantly lower than that of the other groups (p = 0.011). The correct percentage of lateral ventricular paraventricular infarction was significantly lower than that of non-lateral ventricle patients (70.8 vs. 85.7%). In patients with lateral ventricular paraventricular infarction, if the WMH was combined, the correct percentage will decreased further as the Fazekas level increased. The correct percentage of lateral ventricle infarction combined with Fazekas 3 was 40.0%, which was statistically significant compared with the patient having Fazekas 0 with lateral ventricular infarction (p = 0.01). Conclusions: WMH had a similar computed tomography appearance to cerebral infarction and could interfere with the prediction of the cerebral infarction region by ncCT. This result provides a reference for clinicians to choose imaging methods for identifying acute cerebral infarction areas. [ABSTRACT FROM AUTHOR]

Aim: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an inherited rare disease affecting young adults. We present the clinical, imaging, and neuropathological results of our case series, emphasizing biopsy histology combined with clinical information will increase the accuracy of early diagnosis.Methods: In total, 4 females and 2 male ALSP patients with onset at ages 24-45 years were enrolled. Clinical manifestations, neuroimaging, and histopathology as well as gene mutation were analyzed and compared with literature.Results: Clinical manifestations include cognitive decline with/without psycho-behavior problems and movement disorders including paralysis, hemiplegia, parkinsonism, and pyramidal tract injury, as well as dysarthria, dysphagia, and sensory disturbances. MRI showed multiple periventricular and subcortical white matter lesions, involving the corpus callosum, with no enhancement, but with persistent hyperintensity on diffuse-weighted imaging. Histology showed widespread white matter damage and pale stain, especially destroyed axons with spheroids and funicular axons which were stained with neurofilament and ubiquitin. Foamy and pigmented macrophages were another typical change. CSF1R mutation was found in 4 of them. All of the patients were misdiagnosed and treated for a long time for multiple sclerosis, cerebral infarction, normal pressure hydrocephalus, etc. CONCLUSION: ALSP will cause rapidly progressing dementia with/without movement disorders in young adults. The definite diagnosis should be based on a comprehensive analysis of clinical manifestations, and neuroimaging, histology, and genetic results. Early biopsy will add to the accuracy of the diagnosis. [ABSTRACT FROM AUTHOR]

Leukoaraiosis refers to lesions with high signal intensity on magnetic resonance imaging (MRI) in periventricular and subcortical white matter that results from chronic microvascular ischemic brain damage. Increasing evidence suggests that serum CA 19–9 is associated with non-malignant conditions including type 2 diabetes, dyslipidemia, and metabolic syndrome, which are closely related to microangiopathy. Thus, we hypothesized that serum CA 19-9 levels would be associated with cerebrovascular microangiopathy measured by leukoaraiosis among middle-aged and older adults. This cross-sectional study included 1833 Korean adults aged ≥45 years who participated in a health examination program between 2010 and 2011. Serum CA 19-9 levels were quantified by chemiluminescence immunoassay and categorized as quartiles: Q1: ≤4.5, Q2: 4.6–7.5, Q2: 7.6–12.2, and Q4: ≥12.3 ng/mL. Odds ratios (ORs) and 95% confidence intervals (CIs) for leukoaraiosis based on brain MRI scans were calculated across serum CA19-9 quartiles using multiple logistic regression analysis. The overall prevalence of leukoaraiosis was 4.6% and increased with serum CA 19-9 quartiles. Compared to the lowest quartile, the OR (95% CI) of the highest CA 19–9 quartile for leukoaraiosis was 2.20 (1.10–4.42) after adjusting for age, sex, BMI, regular exercise, hypertension, type 2 diabetes, dyslipidemia, smoking status, and alcohol drinking. Serum CA 19-9 levels were positively and independently associated with leukoaraiosis. Our findings indicate that serum CA 19-9 level might be a useful additional measure for assessing cerebrovascular microangiopathy in clinical settings. Image 1 • Leukoaraiosis results from chronic microvascular ischemic brain damage. • Serum CA 19-9 is associated with diseases closely related to microangiopathy. • Leukoaraiosis prevalence increased with serum CA 19–9 quartiles. • Serum CA 19-9 level might be useful to assess cerebrovascular microangiopathy. [ABSTRACT FROM AUTHOR]

The standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. We identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. All six IOPD patients (4 males/2 females) had been treated with ERT for 12–15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9–15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. Among a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline. [ABSTRACT FROM AUTHOR]

Brucellosis is a multisystem zoonotic disease. We report an unusual case of neurobrucellosis with seizures in an immunocompromised patient in Saudi Arabia who underwent renal transplantation. Magnetic resonance imaging of the brain showed diffuse white matter lesions. Serum and cerebrospinal fluid were positive for Brucella sp. Granuloma was detected in a brain biopsy specimen.

In diseases such as multiple sclerosis (MS), inflammation can injure the myelin sheath that surrounds axons, a process known as demyelination. The spontaneous regeneration of myelin, called remyelination, is associated with restoration of function and prevention of axonal degeneration. Boosting remyelination with therapeutic intervention is a promising new approach that is currently being tested in several clinical trials. The endogenous regulation of remyelination is highly dependent on the immune response. In this review article, we highlight the cell biology of remyelination and its regulation by innate immune cells. For the purpose of this review, we discuss the roles of microglia, and also astrocytes and oligodendrocyte progenitor cells (OPCs) as they are being increasingly recognized to have immune cell functions.

The solute carrier family 16 member 1 (SLC16A1) gene encodes for monocarboxylate transporter 1 (MCT1) that mediates the movement of monocarboxylates, such as lactate and pyruvate across cell membranes. Inactivating recessive homozygous or heterozygous mutations in the SLC16A1 gene were described in patients with recurrent ketoacidosis and hypoglycemia, a potentially lethal condition. In the brain where MCT1 is highly localized around axons and oligodendrocytes, glucose is the most crucial energy substrate while lactate is an alternative substrate. MCT1 mutation or reduced expression leads to neuronal loss due to axonal degeneration in an animal model. Herein, we describe a 28 months old female patient who presented with the first hypoglycemic attack associated with ketoacidosis starting at the age of 3 days old. Whole exome sequencing (WES) performed at 6 months of age revealed a c.218delG mutation in exon 3 in the SLC16A1 gene. The variant is expected to result in loss of normal MCT1 function. Our patient is amongst the youngest presenting with MCT1 deficiency. A detailed neuroimaging assessment performed at 18 months of age revealed a complex white and gray matter disease, with heterotopia. The threshold of blood glucose to circumvent neurological sequelae cannot be set because it is patient-specific, nevertheless, neurodevelopmental follow up is recommended in this patient. Further functional studies will be required to understand the role of the MCT1 in key tissues such as the central nervous system (CNS), liver, muscle and ketone body metabolism. Our case suggests possible neurological sequelae that could be associated with MCT1 deficiency, an observation that could facilitate the initiation of appropriate neurodevelopmental follow up in such patients.

Background: Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a heterogeneous metabolic disorder inherited in an autosomal recessive manner. Pathogenic mutations in MTHFR gene have been associated with severe MTHFR deficiency. The clinical presentation of MTHFR deficiency is highly variable and associated with several neurological anomalies.Methods: Direct whole-exome sequencing (WES) was performed in all the five available individuals from the family, including the affected individual (III-7) using standard procedures.Results: We observed a proband (III-7) with an abnormality in the cerebral white matter, apnoea, and microcephaly. WES analysis identified a novel homozygous non-sense mutation (c.154C>T; p.Arg52*) in MTHFR gene that segregated with the disease phenotype within the family.Conclusion: We identified a novel non-sense mutation in MTHFR gene in a single Egyptian family with severe MTHFR deficiency. The present investigation is clinically important, as it adds to the growing list of MTHFR mutations, which might help in genetic counseling of families of affected children and proper genotype-phenotype correlation.

The elderly often suffer from "mild" dementia due to white matter disease, which is another name for repeated brain infarctions. The degeneration of white matter, which links various parts of the brain to the spinal cord, is the root cause of this disorder, which develops with age. Dementia, imbalance, and movement problems are symptoms of this degenerative disease that worsen with age. This research's goal is to study current therapy options and identify methods for early diagnosis of white matter illness. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement for meta-analyses and systematic reviews served as the basis for our literature review. Results from the search in ScienceDirect and Medline/Pubmed led to the finalization of 33 studies. The complex relationship between white matter hyperintensities (WMHs) and neurological disorders is the subject of this comprehensive review, which sheds light on the varied terrain of WMH studies by highlighting their consequences and developing evaluation techniques., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Malani et al.)

Background Associations between subtle changes in cardiac and cerebral structure and function are not well understood, with some studies suggesting that subclinical cardiac changes may be associated with markers of vascular brain insult. Methods and Results Data from the ARIC (Atherosclerosis Risk in Communities) Study (5th ARIC visit; 2011‐2013; N=1974) were used to explore relationships between abnormalities of cardiac structure/function and subclinical brain disease and to test specific associations between those cardiac and vascular brain changes that share a common mechanism. In adjusted models white matter hyperintensities were 0.66 cm3 greater (95% confidence interval [CI] 0.08‐1.25) for every 1‐mm increase in left ventricular LV wall thickness and 0.64 cm3 greater (95% CI 0.19‐1.08) for every 10 g/m2 increase in LV mass index, both markers of LV structure. Odds of brain infarction also increased with greater LV wall thickness (odds ratio 1.11, 95% CI 1.01‐1.23 per 1 mm) and larger LV mass (odds ratio 1.08, 95% CI 1.00‐1.17 per 10 g/m2). Higher ejection fraction (per 5%), a marker of systolic function, was significantly associated with decreased odds of overall infarct (odds ratio 0.85, 95% CI0.77‐0.95), but not with cortical infarction (odds ratio 0.92, 95% CI0.78‐1.08). Conclusions Among elderly participants in a large cohort study, subclinical markers of LV structure and LV systolic dysfunction were associated with increased odds of brain infarction and more white matter hyperintensities, independent of other vascular risk factors. This suggests end‐organ dysfunction occurs in the heart and brain in parallel, with further studies needed to determine causality.

Objective: To determine if the presence of cerebral white matter disease (WMD) affects the response to anti-cholinergic medications. Materials and Methods: This was a retrospective cohort of age-matched patients treated for OAB with anti-cholinergic medications between January 2010 and December 2017. Inclusion criteria were a chief complaint of OAB, never evaluated by a urogynecologist for OAB, treated with a maximum dose for a minimum of 4 weeks, and underwent head computed tomography (CT) within 12 months of starting therapy. Patients with WMD were matched 1:1 by age and number of prior failed antimuscarinics to controls with normal head CTs. Exclusion criteria included incomplete documentation of therapeutic response, non-WMD CT abnormalities, and non-idiopathic OAB. The primary outcome was anti-cholinergic treatment failure. Pairwise analysis between groups was performed using Wilcoxon rank-sum and Fisher's exact test where appropriate. Univariate logistic regression was performed, and any variable that was associated with treatment failure and a p value ≤ 0.2 was included in the multivariable regression analysis. Results: Sixty-eight cases were matched with 68 controls. Patients with WMD were more likely to have undergone hysterectomy (57.4% vs. 41.2%, p = 0.04) and to use diuretics (31.1% vs. 19.1%, p = 0.04). Patients with WMD were more likely to fail treatment compared with controls (60.7% vs. 29.4%, p = 0.004). After adjusting for confounders, WMD was strongly associated with an increased probability of failure (aOR = 7.31, 95% CI: 1.49–12.20). Additional significant risk factors for treatment failure were the previous number of failed medications (aOR = 3.65 per medication, 95% CI: 1.48–9.01) and a rising HbA1c (aOR: 1.39 per 1.0% increase, 95% CI: 1.0–1.91). Conclusion: WMD is independently associated with anti-muscarinic treatment failure in women with overactive bladder symptoms. [ABSTRACT FROM AUTHOR]

In diseases such as multiple sclerosis (MS), inflammation can injure the myelin sheath that surrounds axons, a process known as demyelination. The spontaneous regeneration of myelin, called remyelination, is associated with restoration of function and prevention of axonal degeneration. Boosting remyelination with therapeutic intervention is a promising new approach that is currently being tested in several clinical trials. The endogenous regulation of remyelination is highly dependent on the immune response. In this review article, we highlight the cell biology of remyelination and its regulation by innate immune cells. For the purpose of this review, we discuss the roles of microglia, and also astrocytes and oligodendrocyte progenitor cells (OPCs) as they are being increasingly recognized to have immune cell functions. [ABSTRACT FROM AUTHOR]

Ambulatory blood pressure (ABP) reflects the end-organ vascular stress in daily life; however, its influence on brain neuronal fiber integrity and cerebral blood flow (CBF) remains unclear. The objective of this study was to determine the associations among ABP, white matter (WM) neuronal fiber integrity, and CBF in older adults. We tested 144 participants via ABP monitoring and diffusion tensor imaging. The total level and pulsatile indices of CBF were measured by phase-contrast MRI and transcranial Doppler, respectively. Neuropsychological assessment was conducted in 72 participants. Among ambulatory and office BP measures, elevated 24-h pulse pressure (PP) was associated with the greatest number of WM skeleton voxels with decreased fractional anisotropy (FA) and increased mean diffusivity (MD). Furthermore, these associations remained significant after adjusting for age, antihypertensive use, aortic stiffness, WM lesion volume, and office PP. Radial diffusivity (RD) was elevated in the regions with decreased FA, while axial diffusivity was unaltered. The reduction in diastolic index explained a significant proportion of the individual variability in FA, MD, and RD. Executive function performance was correlated with WM fiber integrity. These findings suggest that elevated ambulatory PP may deteriorate brain neuronal fiber integrity via reduction in diastolic index. [ABSTRACT FROM AUTHOR]

Background: Severe 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency is a heterogeneous metabolic disorder inherited in an autosomal recessive manner. Pathogenic mutations in MTHFR gene have been associated with severe MTHFR deficiency. The clinical presentation of MTHFR deficiency is highly variable and associated with several neurological anomalies. Methods: Direct whole-exome sequencing (WES) was performed in all the five available individuals from the family, including the affected individual (III-7) using standard procedures. Results: We observed a proband (III-7) with an abnormality in the cerebral white matter, apnoea, and microcephaly. WES analysis identified a novel homozygous non-sense mutation (c.154C>T; p.Arg52*) in MTHFR gene that segregated with the disease phenotype within the family. Conclusion: We identified a novel non-sense mutation in MTHFR gene in a single Egyptian family with severe MTHFR deficiency. The present investigation is clinically important, as it adds to the growing list of MTHFR mutations, which might help in genetic counseling of families of affected children and proper genotype-phenotype correlation. [ABSTRACT FROM AUTHOR]

Human amylin is a 37 amino-acid pancreatic peptide that forms neuro-toxic aggregates that deposit in the endothelium of brain capillaries of patients with diabetes, potentially contributing to cerebral small vessel ischemic injury. Pathogenic amylin also deposits in the capillary endothelium in other organs, including the skin. The aim of this study was to test the hypothesis that skin capillary amylin deposition correlates with cerebral small vessel amylin deposition, potentially providing a clinically useful marker of cerebral amylin deposition. Immunohistochemistry (IHC) was performed for human amylin and collagen IV in brain and skin sections of rats (age 15–16 months) with pancreatic overexpression of amyloidogenic human amylin polypeptide (HIP rats), and control rats (Wild type; WT; rats that express non-amyloidogenic rat amylin) using antibodies binding amylin (n = 5 male and 5 female rats for each group) and antibodies binding Hypoxia inducing factor (HIF)-1α and HIF-2α (n = 3 for each group). The reactive amylin-aldehyde 4-hydroxynonenal (4-HNE) adduct was measured in skin homogenates. (n = 4 for each group) Brain capillaries isolated from HIP rats had higher amylin content compared to WT rats using Western blot with anti-amylin antibody (p = 0.0010). The HIF-1α and HIF-2α immunoreactivity signals in skin from HIP and WT rats were similar (p = 0.2 for HIF-1 α, and p = 0.75 for HIF-2α). Amylin-4HNE adduct formation was higher in HIP rats compared to WT rats (p = 0.0014). There was phenotypic similarity between brain and skin capillary amylin based on co-staining for human amylin and collagen IV in both HIP and WT rats. Skin and brain capillary amylin deposition are similar providing evidence that a skin biopsy might be providing a potential biomarker for diabetes-associated intracranial vasculopathy. [ABSTRACT FROM AUTHOR]

Background and objectives: Little is known about the effect of osteoporosis on cognitive function in the acute and recovery phases of stroke. Early bone mineral density assessments during acute stroke may be a useful marker of cognitive function. We evaluated the effect of osteoporosis on cognitive function at the early and recovery phase of ischemic stroke in patients aged >50 years. Materials and Methods: We retrospectively examined consecutive patients with acute stroke hospitalized between 2016 and 2018. Osteoporosis was defined as a T-score Results: Of the 260 included subjects (107 men and 153 women), 70 (26.9%) had osteoporosis. Cognitive impairment was more severe in the osteoporosis group than in the non-osteoporosis group (30.5% versus 47.1%, p = 0.001). After the recovery phase of stroke, the proportion of patients with cognitive impairment remained higher in the osteoporosis group. The multivariate analysis revealed a correlation between a low femoral neck bone mineral density and severe cognitive impairment in the acute and recovery phases of stroke (adjusted odds ratio (OR) 4.09, 95% confidence interval (CI) 1.11–15.14 in the acute phase, and adjusted OR 11.17, 95% CI 1.12–110.98 in the recovery phase). Conclusions: Low bone mineral density is associated with poor cognitive function in the acute and recovery phases of stroke.

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.