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Background: Covert cerebrovascular disease (CCD) includes white matter disease (WMD) and covert brain infarction (CBI). Incidentally discovered CCD is associated with an increased risk of subsequent symptomatic stroke. However, it is unknown whether the severity of WMD or the location of CBI predicts risk. Objectives: The objective of this study was to examine the association of incidentally discovered WMD severity and CBI location with a risk of subsequent symptomatic stroke. Method: This retrospective cohort study includes patients ≥50 years old from the Kaiser Permanente Southern California health system who received neuroimaging for a nonstroke indication between 2009 and 2019. Incidental CBI and WMD were identified via natural language processing of the neuroimage report, and WMD severity was classified into grades. Results: 261,960 patients received neuroimaging, 78,555 (30.0%) were identified to have incidental WMD, and 12,857 were identified (4.9%) to have incidental CBI. Increasing WMD severity is associated with the increased incidence rate of future stroke. However, the stroke incidence rate in CT-identified WMD is higher at each level of severity compared to rates in MRI-identified WMD. Patients with mild WMD via CT have a stroke incidence rate of 24.9 per 1,000 person-years, similar to that of patients with severe WMD via MRI. Among incidentally discovered CBI patients with a determined CBI location, 97.9% have subcortical infarcts rather than cortical infarcts. CBI confers a similar risk of future stroke, whether cortical or subcortical, or whether MRI detected or CT detected. Conclusions: Increasing severity of incidental WMD is associated with an increased risk of future symptomatic stroke, dependent on the imaging modality. Subcortical and cortical CBI conferred similar risks. [ABSTRACT FROM AUTHOR]

Background: Ischemic lesions on diffusion weighted imaging (DWI) are common after acute spontaneous intracerebral hemorrhage (ICH) but are poorly understood for large ICH volumes (> 30 mL). We hypothesized that large blood pressure drops and effect modification by cerebral small vessel disease markers on magnetic resonance imaging (MRI) are associated with DWI lesions. Methods: This was an exploratory analysis of participants in the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial with protocolized brain MRI scans within 7 days from ICH. Multivariable logistic regression analysis was performed to assess biologically relevant factors associated with DWI lesions, and relationships between DWI lesions and favorable ICH outcomes (modified Rankin Scale 0–3). Results: Of 499 enrolled patients, 300 had MRI at median 7.5 days (interquartile range 7–8), and 178 (59%) had DWI lesions. The incidence of DWI lesions was higher in patients with systolic blood pressure (SBP) reduction ≥ 80 mm Hg in first 24 h (76%). In adjusted models, factors associated with DWI lesions were as follows: admission intraventricular hematoma volume (p = 0.03), decrease in SBP ≥ 80 mm Hg from admission to day 1 (p = 0.03), and moderate-to-severe white matter disease (p = 0.01). Patients with DWI lesions had higher odds of severe disability at 1 month (p = 0.04), 6 months (p = 0.036), and 12 months (p < 0.01). No evidence of effect modification by cerebral small vessel disease on blood pressure was found. Conclusions: In patients with large hypertensive ICH, white matter disease, intraventricular hemorrhage volume, and large reductions in SBP over the first 24 h were independently associated with DWI lesions. Further investigation of potential hemodynamic mechanisms of ischemic injury after large ICH is warranted. [ABSTRACT FROM AUTHOR]

RNASET2-deficient leukodystrophy is a rare infantile white matter disorder mimicking a viral infection and resulting in severe psychomotor impairments. Despite its severity, there is little understanding of cellular mechanisms of pathogenesis and no treatments. Recent research using the rnaset2 mutant zebrafish model has suggested that microglia may be the drivers of the neuropathology, due to their failure to digest apoptotic debris during neurodevelopment. Therefore, we developed a strategy for microglial replacement through transplantation of adult whole kidney marrow-derived macrophages into embryonic hosts. Using live imaging, we revealed that transplant-derived macrophages can engraft within host brains and express microglia-specific markers, suggesting the adoption of a microglial phenotype. Tissue-clearing strategies revealed the persistence of transplanted cells in host brains beyond embryonic stages. We demonstrated that transplanted cells clear apoptotic cells within the brain, as well as rescue overactivation of the antiviral response otherwise seen in mutant larvae. RNA sequencing at the point of peak transplant-derived cell engraftment confirms that transplantation can reduce the brain-wide immune response and particularly, the antiviral response, in rnaset2-deficient brains. Crucially, this reduction in neuroinflammation resulted in behavioral rescue--restoring rnaset2 mutant motor activity to wild-type (WT) levels in embryonic and juvenile stages. Together, these findings demonstrate the role of microglia as the cellular drivers of neuropathology in rnaset2 mutants and that macrophage transplantation is a viable strategy for microglial replacement in the zebrafish. Therefore, microglia-targeted interventions may have therapeutic benefits in RNASET2-deficient leukodystrophy. [ABSTRACT FROM AUTHOR]

IntroductionDevelopment of novel diagnostic tools is a top research priority in vascular dementia. A major obstacle is the lack of a simple, non-invasive method to visualize cerebral arteriolar walls in vivo. Retinal arterioles offer a window into the cerebral circulation.MethodsIntensity-based retinal arteriolar visualization in optical coherence tomography (I-bRAVO) was applied to evaluate mean wall thickness (MWT) and wall-to-lumen ratio (WLR) in 250 subjects with sporadic and genetic cerebral small vessel disease (CSVD), non-vascular neurodegenerative diseases (NVND), and healthy controls (HC) in association with imaging and cognitive markers.ResultsMWT and WLR were higher in CSVD, associated with severity of vascular white matter lesions, and correlated with magnetic resonance imaging-based intracranial arteriolosclerosis score. WLR correlated with gray and white matter volume and differentiated asymptomatic sporadic CSVD from HC (area under the curve = 0.82).DiscussionI-bRAVO is a rapid, non-invasive tool. MWT and WLR were associated with imaging markers of CSVD and could contribute to early identification of sporadic CSVD.

Introduction: Poststroke apathy (PSA) is a common neuropsychiatric disorder that may affect up to 30% of stroke patients. Despite the difficulties of investigating this condition (overlapping with depression, heterogeneity of diagnostic criteria, a small number of studies), some recent diffusion tensor imaging studies have suggested that widespread microstructural white matter (WM) disruption plays a key role in the development of PSA. Therefore, we intended to investigate this hypothesis by evaluating the relationship between WM hyperintensities (WMH) and apathy in patients with cerebrovascular disease. Methods: We studied patients with apathy (n = 7), depression (n = 13), comorbid apathy and depression (n = 13), and controls (n = 20), and we investigated the variables associated with the volume of WMH measured by an automated brain MRI segmentation software. Results: The overall prevalence of PSA was 37.7% (pure and comorbid). Patients with apathy presented a higher volume of WMH in comparison to controls. Mini-Mental State Examination (MMSE), NPI-A, and the number of cerebral microbleeds were the only variables associated with WMH. Conversely, NPI-D did not correlate to WMH. Discussion/Conclusion: This is an exploratory study that supports the view of PSA as a distinct syndrome from PSD mediated mainly by diffuse white matter hyperintensities, which suggests that WM disruption is an important pathway to the development of apathy in stroke patients. [ABSTRACT FROM AUTHOR]

Metachromatic Leukodystrophy (MLD) is commonly characterized by the accumulation of sulfatide in various organs, including the central nervous system, leading to neurological and mental symptoms. We reported a case of a two-year-old male patient with psychomotor retardation history, developmental delay, poor overall performance and imaging findings compatible with Leukodystrophy are presented. The goal of this case report is to identify clinical presentation and typical MRI features to diagnose MLD, in the absence of an enzyme assay or a gene mutation investigation.

Objectives: Subjective cognitive decline (SCD) is a preclinical stage of AD. White matter hyperintensities (WMH), an MRI marker of cerebral small vessel disease, associate with AD biomarkers and progression. The impact of WMH on SCD phenotype is unclear. Methods/Design: A retrospective, cross‐sectional analysis was conducted on a diverse cohort with SCD evaluated at the NYU Alzheimer's Disease Research Center between January 2017 and November 2021 (n = 234). The cohort was dichotomized into none‐to‐mild (n = 202) and moderate‐to‐severe (n = 32) WMH. Differences in SCD and neurocognitive assessments were evaluated via Wilcoxon or Fisher exact tests, with p‐values adjusted for demographics using multivariable logistic regression. Results: Moderate‐to‐severe WMH participants reported more difficulty with decision making on the Cognitive Change Index (1.5 SD 0.7 vs. 1.2 SD 0.5, p = 0.0187) and worse short‐term memory (2.2 SD 0.4 vs. 1.9 SD 0.3, p = 0.0049) and higher SCD burden (9.5 SD 1.6 vs. 8.7 SD 1.7, p = 0.0411) on the Brief Cognitive Rating Scale. Moderate‐to‐severe WMH participants scored lower on the Mini‐Mental State Examination (28.0 SD 1.6 vs. 28.5 SD 1.9, p = 0.0491), and on delayed paragraph (7.2 SD 2.0 vs. 8.8 SD 2.9, p = 0.0222) and designs recall (4.5 SD 2.3 vs. 6.1 SD 2.5, p = 0.0373) of the Guild Memory Test. Conclusions: In SCD, WMH impact overall symptom severity, specifically in executive and memory domains, as well as objective performance on global and domain‐specific tests in verbal memory and visual working/associative memory. Key points: White matter hyperintensities impact subjective cognitive decline in executive and memory domainsWhite matter hyperintensities also affect objective measures of cognition in verbal memory and visual working/associative memory [ABSTRACT FROM AUTHOR]

Subcortical white matter ischemic lesions are increasingly recognized to have pathologic overlap in individuals with Alzheimer's disease (AD). The interaction of white matter ischemic lesions with amyloid pathology seen in AD is poorly characterized. We designed a novel mouse model of subcortical white matter ischemic stroke and AD that can inform our understanding of the cellular and molecular mechanisms of mixed vascular and AD dementia. Subcortical white matter ischemic stroke underlying forelimb motor cortex was induced by local stereotactic injection of an irreversible eNOS inhibitor. Subcortical white matter ischemic stroke or sham procedures were performed on human ApoE4-targeted-replacement (TR):5XFAD mice at 8 weeks of age. Behavioral tests were done at 7, 10, 15, and 20 weeks. A subset of animals underwent 18FDG-PET/CT. At 20 weeks of age, brain tissue was examined for amyloid plaque accumulation and cellular changes. Compared with sham E4-TR:5XFAD mice, those with an early subcortical ischemic stroke showed a significant reduction in amyloid plaque burden in the region of cortex overlying the subcortical stroke. Cognitive performance was improved in E4-TR:5XFAD mice with stroke compared with sham E4-TR:5XFAD animals. Iba-1+ microglial cells in the region of cortex overlying the subcortical stroke were increased in number and morphologic complexity compared with sham E4-TR:5XFAD mice, suggesting that amyloid clearance may be promoted by an interaction between activated microglia and cortical neurons in response to subcortical stroke. This novel approach to modeling mixed vascular and AD dementia provides a valuable tool for dissecting the molecular interactions between these two common pathologies.

IntroductionWe investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD).MethodsPlasma was analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults.ResultsPrinciple component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age.DisucssionPlasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.

X-linked adrenoleukodystrophy is an X-linked recessive disease affecting the white matter of the central nervous system along with occasional involvement of the adrenal gland due to mutation of the ABCD1 gene, which leads to accumulation of very-long-chain fatty acid (VLCFA) in the white matter of the brain and adrenal cortex. Diminished vision, speech disturbance, motor weakness, bladder–bowel involvement and adrenal insufficiency can be seen in affected individuals according to phenotype and involved area. In this case, the patient was a 17-year-old male with progressive weakness of all limbs along with the difficulty of speech and vision. Magnetic resonance imaging showed T2 hyperintensity in white matters of temporo-parieto-occipital region, splenium and body of corpus callosum, peritrigonal area, posterior limb of internal capsule and corticospinal tract location of pons and midbrain. His plasma VLCFA was elevated. Along with medical treatment, our rehabilitation team comprising a physiatrist and other supporting members provided rehabilitation management. Although different methods such as dietary modification, bone marrow transplantation and gene therapy have been tried for these types of cases globally, rehabilitation remains the backbone of the management protocol for advanced cases.

White matter changes are seen in a spectrum of disorders in children and adolescents. Understanding their distribution and appearance helps to reach diagnoses in daily radiologic practice. This pictorial essay will outline the magnetic resonance imaging (MRI) appearances of diseases with white matter changes including demyelinating diseases, dysmyelinating disorders/leukodystrophies, infections, autoimmune diseases, vascular causes, mitochondrial disorders and neurocutaneous syndromes, along with a brief overview of clinical aspects of the diseases such as typical age of presentation, etiology, symptoms and signs and treatment options. This article highlights important features in common white matter diseases in children and adolescents. [ABSTRACT FROM AUTHOR]

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aβ) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aβ deposition (18F‐AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aβ and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aβ status. In summary, our study suggests mainly an amyloid‐independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. Highlights: Alzheimer's disease often co‐exists with vascular pathology.We studied a unique cohort enriched for high white matter hyperintensities (WMH).High WMH related to cognitive impairment of semantic fluency and executive function.This relationship was mediated via temporo‐parietal atrophy rather than metabolism.This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy. [ABSTRACT FROM AUTHOR]

Background and purpose: Vascular brain lesions, such as ischemic infarcts, are common among patients with atrial fibrillation (AF) and are associated with impaired cognitive function. The role of physical activity (PA) in the prevalence of brain lesions and cognition in AF has not been investigated. Methods: Patients from the multicenter Swiss‐AF cohort study were included in this cross‐sectional analysis. We assessed regular exercise (RE; at least once weekly) and minutes of weekly PA using a validated questionnaire. We studied associations with ischemic infarcts, white matter hyperintensities, cerebral microbleeds, and brain volume on brain magnetic resonance imaging and with global cognition measured with a cognitive construct (CoCo) score. Results: Among 1490 participants (mean age = 72 ± 9 years), 730 (49%) engaged in RE. In adjusted regression analyses, RE was associated with a lower prevalence of ischemic infarcts (odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.63–0.98, p = 0.03) and of moderate to severe white matter hyperintensities (OR = 0.78, 95% CI = 0.62–0.99, p = 0.04), higher brain volume (β‐coefficient = 10.73, 95% CI = 2.37–19.09, p = 0.01), and higher CoCo score (β‐coefficient = 0.08, 95% CI = 0.03–0.12, p < 0.001). Increasing weekly PA was associated with higher brain volume (β‐coefficient = 1.40, 95% CI = 0.65–2.15, p < 0.001). Conclusions: In AF patients, RE was associated with a lower prevalence of ischemic infarcts and of moderate to severe white matter disease, with larger brain volume, and with better cognitive performance. Prospective studies are needed to investigate whether these associations are causal. Until then, our findings suggest that patients with AF should be encouraged to remain physically active. [ABSTRACT FROM AUTHOR]

Background We aimed to determine whether cerebral white matter hyperintensities ( WMHs ) can distinguish stroke survivors susceptible to rapid kidney function decline from intensive blood pressure ( BP ) lowering. Methods and Results The SPS3 (Secondary Prevention of Small Subcortical Strokes) trial randomized participants with recent lacunar stroke to systolic BP targets of 130 to 149 and

Background We aimed to determine whether cerebral white matter hyperintensities ( WMHs ) can distinguish stroke survivors susceptible to rapid kidney function decline from intensive blood pressure ( BP ) lowering. Methods and Results The SPS3 (Secondary Prevention of Small Subcortical Strokes) trial randomized participants with recent lacunar stroke to systolic BP targets of 130 to 149 and

This review contains up-to-date information on the fundamentals and clinical aspects of white matter disease in chronic progressive cerebrovascular disease with cognitive impairment, the leading risk factors for which are hypertension and cerebral atherosclerosis. Highly informative methods of neuroimaging have contributed significantly to the study of this problem, confirming the important role of white matter changes in the development and progression of cognitive impairment. The full range of the morphological changes in white matter, typical of vascular encephalopathy and cognitive dysfunction, is presented. Chronic hypoperfusion and white matter ischaemia play a leading role in the pathogenesis of white matter changes in vascular dementia development, but alternative hypotheses are also emerging. Further fundamental morphological and clinical studies will help to determine the leading mechanisms of white matter damage in patients with vascular and other age-related forms of dementia. This is necessary for the development of effective methods of treatment and prevention.

Background: Covert cerebrovascular disease (CCD) includes white matter disease (WMD) and covert brain infarction (CBI). Incidentally discovered CCD is associated with increased risk of subsequent symptomatic stroke. However, it is unknown whether the severity of WMD or the location of CBI predicts risk. Objectives: The aim of this study was to examine the association of incidentally discovered WMD severity and CBI location with risk of subsequent symptomatic stroke. Method: This retrospective cohort study includes patients aged ≥50 years old in the Kaiser Permanente Southern California health system who received neuroimaging for a nonstroke indication between 2009 and 2019. Incidental CBI and WMD were identified via natural language processing of the neuroimage report, and WMD severity was classified into grades. Results: A total of 261,960 patients received neuroimaging; 78,555 patients (30.0%) were identified to have incidental WMD and 12,857 patients (4.9%) to have incidental CBI. Increasing WMD severity is associated with an increased incidence rate of future stroke. However, the stroke incidence rate in CT-identified WMD is higher at each level of severity compared to rates in MRI-identified WMD. Patients with mild WMD via CT have a stroke incidence rate of 24.9 per 1,000 person-years, similar to that of patients with severe WMD via MRI. Among incidentally discovered CBI patients with a determined CBI location, 97.9% are subcortical rather than cortical infarcts. CBI confers a similar risk of future stroke, whether cortical or subcortical or whether MRI- or CT-detected. Conclusions: Increasing severity of incidental WMD is associated with an increased risk of future symptomatic stroke, dependent on the imaging modality. Subcortical and cortical CBI conferred similar risks. [ABSTRACT FROM AUTHOR]

Introduction: The primary aim of this paper is to improve the clinical interpretation of white matter hyperintensities (WMHs) and provide an overarching summary of methodological approaches, allowing researchers to design future studies targeting current knowledge gaps. Methods: A meta‐analysis and systematic review was performed investigating associations between baseline WMHs and longitudinal cognitive outcomes in cognitively normal populations, and populations with mild cognitive impairment (MCI), Alzheimer's disease (AD), and stroke. Results: Baseline WMHs increase the risk of cognitive impairment and dementia across diagnostic categories and most consistently in MCI and post‐stroke populations. Apolipoprotein E (APOE) genotype and domain‐specific cognitive changes relating to strategic anatomical locations, such as frontal WMH and executive decline, represent important considerations. Meta‐analysis reliability was assessed using multiple methods of estimation, and results suggest that heterogeneity in study design and reporting remains a significant barrier. Discussion: Recommendations and future directions for study of WMHs are provided to improve cross‐study comparison and translation of research into consistent clinical interpretation. [ABSTRACT FROM AUTHOR]

Abstract Background Older people develop gait and balance dysfunction that is associated with the gradual onset of cerebral white matter disease. White matter disease is easily detected by neuroimaging, whereas small vessels are not; hence, the term small vessel disease is frequently used to describe the parenchyma lesions rather than the underlying small vessel alterations. This study was done to investigate the relationship between the presence and/or absence of white matter disease identified on magnetic resonance imaging with the vestibular findings in elderly patients with dizziness. The current study was conducted on a total number of 30 elderly patients complaining of dizziness and/or instability. The inclusion criteria are patients above 55 years old and a history of vertigo and/or instability. All the study groups were subjected to full neuro-otological history, hearing assessment, video-nystagmography test (VNG), assessment of the risk of fall by functional gait assessment test (FGA), and radiological assessment: magnetic resonance stroke protocol. Results FGA total scores were significantly lower in patients with white matter disease (0.047) specifically PVWM score 3 (0.04) and DWM score 3 (0.19). Abnormal VNG test results were significantly higher in patients with atherosclerotic changes (0.04). The most common VNG finding abnormality was positional nystagmus. Conclusions Normal VNG findings in elderly dizzy patients should be complemented with FGA test to assess the risk of falls. The presence of risk factors for white matter disease (WMD) as hypertension, diabetes mellitus, ischemic heart disease, hyperlipidemia, and migraine is an indication for requesting a further radiological assessment. The most frequent VNG abnormality in elderly patients with white matter disease is positional and positioning nystagmus, and a significant number of patients had positional nystagmus of the non-localizing criteria. FGA test scores are significantly related to the severity of white matter disease. The presence of atherosclerotic changes is significantly related to the presence of VNG test abnormality. It is important to ask the patient about the past history of migraine as it has an effect on VNG, FGA, and radiological findings.

Introduction: Hypertension is associated with white matter hyperintensity (WMH) and cognitive impairment. Further, WMH is associated with cognitive impairment including executive, attention and visuospatial functions. The aim of this study was to investigate the effects of controlled hypertension (cHT) and previously developed concept, ‘WMH age’ on cognitive function and the mediating role of WMH in the effect of cHT on cognitive impairment. Methods: We enrolled 855 Koreans without dementia aged 60 years or older, 326 of whom completed 2-year follow-up assessment. We measured their blood pressure thrice in a sitting position using an automated blood pressure monitoring device. We estimated ‘WMH age’ of every participant using previously developed WMH probability map of healthy older Koreans. We analyzed the mediating effect of WMH age in the association of cHT and cognitive function using the PROCESS Macro model. Results: Old WMH age was associated with a faster decline in the Mini-Mental Status Examination (MMSE; p =.003), Consortium to Establish a Registry for Alzheimer’s Disease total score (CERAD-TS; p =.003), and Frontal Assessment Battery (FAB; p =.007). Old WMH age showed an approximately-six times higher risk of incident mild cognitive impairment (OR = 6.47, 95 % CI = 1.37 – 9.50, p =.024) compared to young or normal WMH age over the 2-year follow-up period in the cHT group. WMH age mediated the effects of cHT on the MMSE, CERAD-TS, and FAB scores at baseline and two-year follow-up period. Conclusions: WMH mediates the adverse effect of hypertension on cognitive function. Elders with cHT who have older WMH age may be at a higher risk of cognitive decline.

Background Covert cerebrovascular disease (CCD) has been shown to be associated with dementia in population‐based studies with magnetic resonance imaging (MRI) screening, but dementia risk associated with incidentally discovered CCD is not known. Methods and Results Individuals aged ≥50 years enrolled in the Kaiser Permanente Southern California health system receiving head computed tomography (CT) or MRI for nonstroke indications from 2009 to 2019, without prior ischemic stroke/transient ischemic attack, dementia/Alzheimer disease, or visit reason/scan indication suggestive of cognitive decline or stroke were included. Natural language processing identified incidentally discovered covert brain infarction (id‐CBI) and white matter disease (id‐WMD) on the neuroimage report; white matter disease was characterized as mild, moderate, severe, or undetermined. We estimated risk of dementia associated with id‐CBI and id‐WMD. Among 241 050 qualified individuals, natural language processing identified 69 931 (29.0%) with id‐WMD and 11 328 (4.7%) with id‐CBI. Dementia incidence rates (per 1000 person‐years) were 23.5 (95% CI, 22.9–24.0) for patients with id‐WMD, 29.4 (95% CI, 27.9–31.0) with id‐CBI, and 6.0 (95% CI, 5.8–6.2) without id‐CCD. The association of id‐WMD with future dementia was stronger in younger (aged

Background: 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., Methods: In a cross-sectional study of 77 people from the DRC, participants underwent neuroimaging to analyze WMH 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 WMH and potential predictors (neurological status, 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 WMH and variables retained in the final model (neurological status, sex, and age)., Results: 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, WMH was significantly associated with dementia (expβ1=1.75, 95% CI=1.14 - 2.71, p-value=0.01) though it had a weak association with age (expβ1=1.03, 95% CI=1.00 - 1.05, p-value=0.05) and sex (male) (expβ1=0.66, 95% CI=0.43 - 1.01, p-value=0.05). In multiple linear regression models, WMH was statistically significantly associated with dementia (expβ1=1.97, 95% CI=1.31 - 2.95, p-value =0.001), male sex (expβ2=0.54, 95% CI=0.36 - 0.80, p-value=0.003), and age (expβ3=1.03, 95% CI=1.00 - 1.06, p-value=0.03). However, WMH was not significantly associated with common cardiovascular risk factors, such as high blood pressure, diabetes, tobacco use, obesity, and high cholesterol levels., Conclusion: WMH is significantly associated with neurological status, 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., Competing Interests: CONFLICT OF INTEREST The authors have no conflict of interest to report.

Acute necrotic hemorrhagic leukoencephalitis (ANHLE) is a subform of acute disseminating leukoencephalitis which is a post viral or vaccination uncommon disease with poor prognosis. Radiological findings include multiple or diffuse lesions involving the white matter and sparing the cortex with or without rim enhancement. In addition to areas of hemorrhages with possible involvement of basal ganglia and thalami. We describe the imaging findings for 2 cases of ANHLE; a 59-years-old male and a 47-years-old female. Both of them were tested positive of SARS-COVID2 with presentation of consciousness loss and respiratory failure. CT and MRI brain show global white matter changes associated with acute hemorrhagic necrosis, although uncommon, are compatible with postviral acute necrotic hemorrhagic leukoencephalitis with end point of death for the first patient and coma for the second patient.

Life expectancy in adults with congenital heart disease (ACHD) has increased. As these patients grow older, they experience aging-related diseases more than their healthy peers. To better characterize this field, we launched the multi-disciplinary BACH (Brain Aging in Congenital Heart disease) San Donato study, that aimed at investigating signs of brain injury in ACHD. Twenty-three adults with repaired tetralogy of Fallot and 23 age- and sex-matched healthy controls were prospectively recruited and underwent brain magnetic resonance imaging. White matter hyperintensities (WMHs) were segmented using a machine-learning approach and automatically split into periventricular and deep. Cerebral microbleeds were manually counted. A subset of 14 patients were also assessed with an extensive neuropsychological battery. Age was 41.78 ± 10.33 years (mean ± standard deviation) for patients and 41.48 ± 10.28 years for controls (p = 0.921). Albeit not significantly, total brain (p = 0.282) and brain tissue volumes (p = 0.539 for cerebrospinal fluid, p = 0.661 for grey matter, p = 0.793 for white matter) were lower in ACHD, while total volume (p = 0.283) and sub-classes of WMHs (p = 0.386 for periventricular WMHs and p = 0.138 for deep WMHs) were higher in ACHD than in controls. Deep WMHs were associated with poorer performance at the frontal assessment battery (r = -0.650, p = 0.012). Also, patients had a much larger number of microbleeds than controls (median and interquartile range 5 [3–11] and 0 [0–0] respectively; p < 0.001). In this study, adults with tetralogy of Fallot showed specific signs of brain injury, with some clinical implications. Eventually, accurate characterization of brain health using neuroimaging and neuropsychological data would aid in the identification of ACHD patients at risk of cognitive deterioration. [ABSTRACT FROM AUTHOR]

The present article reviewed autonomic dysfunction in older individuals. The following estimated incidences are reported among octogenarians (age >80 years): white matter disease (WMD), 80%; Alzheimer's disease (AD), 33%; and dementia with Lewy bodies (DLB), 7%–8%. A combination of AD + WMD is the most common. The estimated incidence in octogenarians of diabetes that produces small fiber neuropathy is 30%. Orthostatic hypotension, overactive bladder, and bowel motility dysfunction also increase with age. The links between all of these disorders are still obscure, but associations have been postulated between orthostatic hypotension with DLB and diabetes, between overactive bladder with WMD and DLB (AD in part), and between bowel motility dysfunction with DLB and diabetes. Management and care of autonomic dysfunction is thus necessary to maximize the quality of life of older individuals and avoid emergency of syncope, urinary retention, or ileus. [ABSTRACT FROM AUTHOR]

Background: It is known that age‐related brain symptoms (namely gait difficulty and/or dementia/delirium) occur in older individuals under hemodialysis (HD). However, it is not known which types of brain disease underlie such symptoms most. Objective: The aim of this study was to correlate brain symptoms with brain diseases in patients undergoing HD. Methods: This was a retrospective study at a multi‐faculty university hospital in Japan over a 12‐month period. All subjects were hospital inpatients undergoing HD (either started during hospitalization or maintenance therapy), with a diagnosis of brain symptoms resulting in referral to the neurogeriatric team (dementia/delirium support team, DST). Results: (1) More than half our HD patients (n = 133) were ≥ 65 years (mean age, 67 years) and male. (2) 37.6% of them showed brain symptoms and were DST‐referred, among whom 62.4% were > 65 years) (P < 0.05). (3) Of the referred patients, 16% had episodes of fall‐related surgery and 30% had aspiration pneumonia (all older). (4) 23.3% of referred patients needed restraint for the safety of HD (mostly older). (5) Most of the neurological disorders were age‐related brain diseases, for example, most commonly a combination of white matter disease (WMD) and Alzheimer's disease (AD) (85%, overlap counted), followed by alcoholism and dementia with Lewy bodies (DLB). Conclusion: In HD patients, age‐related brain symptoms (needed restraint for HD, or with recent fall and/or aspiration) increased with age. The most common underlying brain disease seemed to be a combination of WMD and AD. [ABSTRACT FROM AUTHOR]

Background: It is known that age-related brain symptoms (gait difficulty and dementia) increase the likelihood of fall-related surgery. In contrast, it is not known which types of brain disease underlie such symptoms most. Objective: The aim of this study was to correlate brain diseases with the types of surgeries performed at our hospital for patients who had fallen. Methods: This was a retrospective study at a multifaculty university hospital in Japan, with a 12-month recruiting period, a follow-up period of 3.0 ± 2.5 weeks, and ≥1×/week visits. We assembled a neurogeriatric team to diagnose brain diseases with the use of brain imaging to the extent possible and correlated the diagnoses with types of fall-related surgery. Results: Fall-related surgery was conducted by the orthopedics (OP) and neurosurgery (NS) faculties (total n = 124) at a ratio of about 2 to 1. The underlying brain diseases differed by faculty; for OP, surgery was most commonly performed in patients with a combination of white matter disease (WMD) and Alzheimer's disease (AD) (79%) followed by dementia with Lewy bodies. In contrast, for NS, the most common surgery was for patients with alcoholism (50%) followed by a combination of WMD and AD. Conclusion: Fall-related surgery was performed by the OP and NS faculties at a 2 to 1 ratio. The major underlying brain diseases were a combination of WMD and AD (79%) for OP and alcoholism (50%) for NS. [ABSTRACT FROM AUTHOR]

We postulated that vascular dysfunction mediates the relationship between amyloid load and white matter hyperintensities (WMH) in cerebral amyloid angiopathy (CAA). Thirty-eight cognitively healthy patients with CAA (mean age 70 ± 7.1) were evaluated. WMH was quantified and expressed as percent of total intracranial volume (pWMH) using structural MRI. Mean global cortical Distribution Volume Ratio representing Pittsburgh Compound B (PiB) uptake (PiB-DVR) was calculated from PET scans. Time-to-peak [TTP] of blood oxygen level-dependent response to visual stimulation was used as an fMRI measure of vascular dysfunction. Higher PiB-DVR correlated with prolonged TTP (r = 0.373, p = 0.021) and higher pWMH (r = 0.337, p = 0.039). Prolonged TTP also correlated with higher pWMH (r = 0.485, p = 0.002). In a multivariate linear regression model, TTP remained independently associated with pWMH (p = 0.006) while PiB-DVR did not (p = 0.225). In a bootstrapping model, TTP had a significant indirect effect (ab = 0.97, 95% CI: 0.137–2.461), supporting that the association between PiB-DVR and pWMH is mediated by TTP response. There was no longer a direct effect independent of the hypothesized pathway. Our study suggests that the effect of vascular amyloid load on white matter disease is mediated by vascular dysfunction in CAA. Amyloid lowering strategies might prevent pathophysiological processes leading to vascular dysfunction, therefore limiting ischemic brain injury. [ABSTRACT FROM AUTHOR]

The exposome characterizes all environmental exposures and their impact on a disease. To determine the causally-associated components of the exposome for cerebral small vessel disease (CSVD), we performed mendelian randomization analysis of 5365 exposures on six clinical and subclinical CSVD measures. We found statistically significant evidence (FDR-corrected P < 0.05) that hypertension, high cholesterol, longer television-watching time, lower educational qualifications, younger age of first sexual intercourse, smoking, reduced pulmonary function, higher subjective overall health rating, and frequent tiredness were associated with increased risk of intracerebral hemorrhage or small vessel stroke. Adiposity, diabetes, frequent alcoholic drinks, higher white blood cell count and neutrophil count were significantly associated with higher risk of non-lobar hemorrhage or small vessel stroke, but not lobar hemorrhage. Hypertension, higher arm or leg fat-free mass and higher sitting height were significantly associated with higher white matter hyperintensities. The results were robust to sensitivity analyses and showed no evidence of horizontal pleiotropy. We also identified 41 exposures suggestively associated (uncorrected P < 0.05) with multiple CSVD measures as the "the CSVD exposome". This exposome-wide association study provides insight into CSVD development and prevention. [ABSTRACT FROM AUTHOR]

Abstract 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.

BackgroundThe effects of white matter hyperintensity volume and subclinical brain infarcts on the risk of incident stroke, its ischemic subtypes, and mortality require further study in diverse samples.Methods and resultsStroke-free participants in the Northern Manhattan Study underwent magnetic resonance imaging (N=1287; mean age 71±9 years, 60% women, 15% non-Hispanic white, 17% non-Hispanic black, 68% Hispanic) and were followed for a median of 8 years (interquartile range: 6-9 years). Cox models estimated proportional hazards of incident stroke of all types, ischemic stroke (and its subtypes), and mortality and stratified by race/ethnicity. In total 72 participants (6%) had incident strokes and 244 died (19%). In fully adjusted models, those with larger white matter hyperintensity volume had greater risk of all stroke types (hazard ratio [HR]: 1.4; 95% CI, 1.1-1.9), ischemic stroke (HR: 1.3; 95% CI, 1.0-1.8), and cryptogenic stroke (HR: 2.2; 95% CI, 1.1-4.4). White and black but not Hispanic participants had increased stroke risk (P

Purpose of reviewTo understand the current literature on age-related neural and detrusor changes associated with overactive bladder symptoms.Recent findingsRecent functional magnetic resonance imaging (fMRI) studies have unveiled an age-related decrease in the neural control of continence, represented in the insula, anterior cingulate cortex (ACC) and prefrontal cortex (PFC). Older individuals with overactive bladder symptoms also demonstrate heightened activation of the ACC with low volumes, representing increased bladder sensitivity or sense of urgency. At the level of the bladder, age-related changes in the urothelium, neurotransmitters/receptors (both muscarinic and purinergic), and inflammation [including nerve growth factor (NGF), monocyte chemoattractant protein-1 (MCP-1) and oxidative stress] are also associated with overactive bladder.SummaryOveractive bladder among older adults is a complex condition incorporating physiologic age-related changes from the brain to the bladder and beyond.

Abstract 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.

Reduced cardiac outflow due to left ventricular hypertrophy has been suggested as a potential risk factor for development of cerebral white matter disease. Our study aimed to examine the correlation between left ventricular geometry and white matter disease volume to establish a clearer understanding of their relationship, as it is currently not well-established. Consecutive patients from 2016 to 2021 who were ≥18 years and underwent echocardiography, cardiac MRI, and brain MRI within one year were included. Four categories of left ventricular geometry were defined based on left ventricular mass index and relative wall thickness on echocardiography. White matter disease volume was quantified using an automated algorithm applied to axial T2 FLAIR images and compared across left ventricular geometry categories. We identified 112 patients of which 34.8 % had normal left ventricular geometry, 20.5 % had eccentric hypertrophy, 21.4 % had concentric remodeling, and 23.2 % had concentric hypertrophy. White matter disease volume was highest in patients with concentric hypertrophy and concentric remodeling, compared to eccentric hypertrophy and normal morphology with a trend-P value of 0.028. Patients with higher relative wall thickness had higher white matter disease volume (10.73 ± 10.29 cc vs 5.89 ± 6.46 cc, P = 0.003), compared to those with normal relative wall thickness. Our results showed that abnormal left ventricular geometry is associated with higher white matter disease burden, particularly among those with abnormal relative wall thickness. Future studies are needed to explore causative relationships and potential therapeutic options that may mediate the adverse left ventricular remodeling and its effect in slowing white matter disease progression. [ABSTRACT FROM AUTHOR]

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare genetic form of cerebral white matter disease whose clinicoradiologic correlation has not been completely understood. In this study, we investigated the association between clinical and brain magnetic resonance imaging (MRI) features in 22 Egyptian children (median age 7 years) with MLC. Gross motor function was assessed using the Gross Motor Function Classification System, and evaluation of brain MRI followed a consistent scoring system. Each parameter of extensive cerebral white matter T2 hyperintensity, moderate-to-severe wide ventricle/enlarged subarachnoid space, and greater than 2 temporal subcortical cysts was significantly associated (P <.05) with worse Gross Motor Function Classification System score, language abnormality, and ataxia. Having >2 parietal subcortical cysts was significantly related to a worse Gross Motor Function Classification System score (P =.04). The current study indicates that patients with MLC manifest signification association between certain brain MRI abnormalities and neurologic features, but this should be confirmed in larger studies. [ABSTRACT FROM AUTHOR]

Abstract 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.

White Matter Disease is increasingly being recognized as an important cause of cognitive decline and dementia. Various investigations have linked chronic diet-related conditions to the development of white matter lesions, which appear as white matter hyperintensities on T2-weighted magnetic resonance imaging (MRI) scans of the brain. Thus, it can be postulated that the metabolic, inflammatory, and microvascular changes accompanying a western diet, hyperlipidemia, hypertension, and diabetes mellitus type II (DMII) are potential mediators in the development and progression of white matter disease, which in turn contributes to the development and progression of cognitive decline. This review will examine evidence for potential metabolic, inflammatory, and microvascular determinants of white matter disease and cognitive decline. Specifically, we will focus on the effects of altered insulin signaling in diabetes, obesity-induced oxidative stress, neuroinflammation, arterial stiffness due to hypertension, ischemia secondary to cerebral small vessel disease, and blood brain barrier disturbances.

Aim of study: While Lewy body diseases (LBDs, comprising Parkinson's disease, dementia with Lewy bodies) and white matter diseases (WMD) coexist pathologically, it is uncertain to what extent each disease and the combination of the two manifests clinically, particularly regarding gait disorders. To answer this question, we performed neuroimaging‐assisted analysis. Methods: This was a retrospective cohort study (215 patients with gait, cognitive, or sleep‐autonomic disorders who were referred to our department within a 2‐year period). The inclusion criteria were apparent gait disorder; age >65 years; WMD observed on MRI; and LBD observed on both DAT and MIBG for clarity. Results: We had 39 patients with LBD; 31 with WMD; and 52 with dual diseases. The types of motor disorder in LBD varied (purely akinetic, akineto‐rigid, and tremor forms), whereas in WMD it was purely akinetic with a wide‐based gait. Those with dual diseases showed a clinical combination of the two. Cognitive disorders of LBD‐only and of dual diseases were more severe than WMD only. Sleep disorder and postural hypotension occurred only in LBD‐only and in dual diseases; constipation was common in LBD and dual groups. However, none of the differences reached statistical significance. Conclusion: Among the patients, 23%‐50% of LBD and those of dual diseases had the purely akinetic form, which might be indistinguishable from WMD. In such cases, additional motor (subtle upper‐half akinesia, abnormal posture) and nonmotor (cognitive‐sleep‐autonomic) signatures may help in diagnosing (comorbid) LBD cases that require treatment. [ABSTRACT FROM AUTHOR]

Objective: Age‐related brain symptoms (gait, speech and swallowing difficulties, and dementia) increase the risk of aspiration pneumonia (AP). It is not known which types of brain disease underlie AP most closely. Our neurogeriatric team addressed this issue herein. Patients and Methods: We retrospectively analyzed the cases of in‐patients diagnosed with AP at our multi‐faculty university hospital within a 12‐month recruiting period, with a 3.0 ± 2.5‐week follow‐up and ≥1×/week visits. We determined the patients' organic and neural disorders with neuroimaging to the extent possible. Results: The AP patients (n = 136) were generally old (mean age 75 years, range 3‐98 years) and male‐dominant (81 males, 55 females). All patients showed gait and attention/cognitive problems at admission, suggestive of encephalopathy/delirium. They were treated in 11 hospital wards: neurology (N) or non‐N (ratio ~1:1.3). The ratio of organic disorders (esophageal carcinoma, etc) vs neural disorders was ~1:30. Most of the neural disorders were age‐related brain diseases, eg, a combination of white matter disease (WMD) and Alzheimer's disease (AD), followed by dementia with Lewy bodies (DLB). In total, they were WMD in 111, AD in 102, DLB in 20. Conclusion: A combination of premorbid age‐related brain diseases (a combination of WMD and AD, DLB, etc) with encephalopathy/delirium (and intrinsic brain diseases) might lead to AP. [ABSTRACT FROM AUTHOR]

Periventricular white matter hyperintensities (pvWMH) are neuroimaging abnormalities surrounding the lateral ventricles that are apparent on magnetic resonance imaging (MRI). They are associated with age, neurodegenerative disease, and cerebrovascular risk factors. While pvWMH ultimately represent a loss of white matter structural integrity, the pathological causes are heterogeneous in nature, and currently, cannot be distinguished using neuroimaging alone. pvWMH could occur because of a combination of small vessel disease (SVD), ependymal loss, blood–brain barrier dysfunction, and microgliosis. In this study we aimed to characterize microvascular stenosis, fibrinogen extravasation, and microgliosis within pvWMH with and without imaging evidence of periventricular infarction. Using postmortem neuroimaging of human brains (n = 20), we identified pvWMH with and without periventricular infarcts (PVI). We performed histological analysis of microvessel stenosis, perivascular spaces, microgliosis, and immunohistochemistry against fibrinogen as a measure of serum protein extravasation. Herein, we report distinctions between pvWMH with and without periventricular infarcts based on associations with microvessel stenosis, enlarged perivascular spaces, and fibrinogen IHC. Microvessel stenosis was significantly associated with PVI and with cellular deposition of fibrinogen in the white matter. The presence of fibrinogen was associated with PVI and increased number of microglia. These findings suggest that neuroimaging‐based detection of infarction within pvWMH may help distinguish more severe lesions, associated with underlying microvascular disease and BBB dysfunction, from milder pvWMH that are a highly frequent finding on MRI. [ABSTRACT FROM AUTHOR]

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (r g  = 0.57-0.85), although two were small (r g  = 0.35-0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration., (© 2024 Wiley Periodicals LLC.)

Genetic disorders with predominant central nervous system white matter abnormalities (CNS WMAs), also called leukodystrophies, are heterogeneous entities. We ascertained 117 individuals with CNS WMAs from 104 unrelated families. Targeted genetic testing was carried out in 16 families and 13 of them received a diagnosis. Chromosomal microarray (CMA) was performed for three families and one received a diagnosis. Mendeliome sequencing was used for testing 11 families and all received a diagnosis. Whole exome sequencing (WES) was performed in 80 families and was diagnostic in 52 (65%). Singleton WES was diagnostic for 50/75 (66.67%) families. Overall, genetic diagnoses were obtained in 77 families (74.03%). Twenty‐two of 47 distinct disorders observed in this cohort have not been reported in Indian individuals previously. Notably, disorders of nuclear mitochondrial pathology were most frequent (9 disorders in 20 families). Thirty‐seven of 75 (49.33%) disease‐causing variants are novel. To sum up, the present cohort describes the phenotypic and genotypic spectrum of genetic disorders with CNS WMAs in our population. It demonstrates WES, especially singleton WES, as an efficient tool in the diagnosis of these heterogeneous entities. It also highlights possible founder events and recurrent disease‐causing variants in our population and their implications on the testing strategy. [ABSTRACT FROM AUTHOR]

Background: High blood pressure (BP) is a common risk factor for cerebral small vessel disease including white matter hyperintensity (WMH). Whether increased BP exacerbates WMH by impacting cerebral vascular morphologies remains poorly studied. Purpose: To determine the relationships among high BP, cerebrovascular morphologies, and WMH in elderly individuals. Study Type: Cohort. Subjects: Eight hundred sixty‐three participants (54.2% female) from the Taizhou Imaging Study without clinical evidence of neurologic disorders were included in the analyses. Field Strength/Sequence: 3.0 T; time‐of‐flight magnetic resonance angiography (TOF MRA); T2 fluid‐attenuated inversion recovery (FLAIR); T1 magnetization‐prepared rapid gradient‐echo; gradient echo T2*‐weighted; diffusion tensor imaging; pulsed arterial spin labeling. Assessment: Cerebrovascular morphologic measurements were quantified based on the TOF MRA images, including vessel density, radius, tortuosity, and branch number. WMH lesion volumes (WMHV) and WMH lesion counts (WMHC) were calculated automatically based on the T2 FLAIR images. Statistical Tests: Multivariable linear regression analysis and path analysis with a linear single‐mediator model were employed. A P value <0.05 was considered statistically significant. Results: Higher BP, especially diastolic BP, was significantly correlated with lower cerebrovascular density (β = −104) and lower branch numbers (β = −0.02). Although decreased tortuosity (β = −1.25) and increased radius (β = 93.8) were correlated with BP, no significant relationship of tortuosity (β = −4.6 × 10−4, P = 0.58) or radius (β = 0.03, P = 0.08) with BP in small vessels was found. The proportion of small vessels decreased as BP increased (SBP: β = −6.6 × 10−4; DBP: β = −9.0 × 10−4). Similarly, increased WMHV and WMHC were associated with decreased vessel density (volumes: β = −24, counts: β = −127), decreased tortuosity (volumes: β = −0.08, counts: β = −0.53), and increased radius (volumes: β = 12.6, counts: β = 86.6). Path analyses suggested an association between high BP and WMHs that were mediated by cerebrovascular morphologic changes. Data Conclusion: Structural alterations of cerebral vessels induced by high BP are correlated with WMH. This result suggested that elevated BP might be one of the pathophysiological mechanisms involving in the co‐occurrence of cerebrovascular alteration and small vessel disease. Level of Evidence: 1 Technical Efficacy Stage: 1 [ABSTRACT FROM AUTHOR]

OBJECTIVE: Both structural and functional brain connectivities are closely linked to white matter disease. We discuss several such links of potential interest to neurologists, neurosurgeons, radiologists, and non-clinical neuroscientists. METHODS: Treatment of brains as genuine complex systems suggests major emphasis on the multi-scale nature of brain connectivity and dynamic behavior. Cross-scale interactions of local, regional, and global networks are apparently responsible for much of EEGs oscillatory behaviors. Finite axon propagation speed, often assumed to be infinite in local network models, is central to our conceptual framework. RESULTS: Myelin controls axon speed, and the synchrony of impulse traffic between distant cortical regions appears to be critical for optimal mental performance and learning. Several experiments suggest that axon conduction speed is plastic, thereby altering the regional and global white matter connections that facilitate binding of remote local networks. CONCLUSIONS: Combined EEG and high resolution EEG can provide distinct multi-scale estimates of functional connectivity in both healthy and diseased brains with measures like frequency and phase spectra, covariance, and coherence. SIGNIFICANCE: White matter disease may profoundly disrupt normal EEG coherence patterns, but currently these kinds of studies are rare in scientific labs and essentially missing from clinical environments.

Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross‐sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race. Methods and Results Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion tensor imaging. Participants received florbetapir positron emission tomography imaging to measure brain amyloid. Associations between measures of white matter structure and elevated amyloid status were examined using multivariable logistic regression. Among 322 participants (43% Black), each SD increase in white matter hyperintensity volume was associated with a greater odds of elevated amyloid (odds ratio [OR], 1.37; 95% CI, 1.03–1.83) after adjusting for demographic and cardiovascular risk factors. In race‐stratified analyses, a greater white matter hyperintensity volume was more strongly associated with elevated amyloid among Black participants (OR, 2.00; 95% CI, 1.15–3.50), compared with White participants (OR, 1.29; 95% CI, 0.89–1.89). However, the race interaction was not statistically significant (P interaction=0.09). We found no association between white matter microstructure and elevated amyloid. Conclusions The results suggest a modest positive relationship between white matter hyperintensity and elevated amyloid in older adults without dementia. Although the results indicate that this association is nonsignificantly stronger among Black participants, these findings will need to be confirmed or refuted using larger multiracial cohorts.