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Background: Longitudinal reports on the clinical features of patients with Alzheimer’s disease (AD) and concomitant cerebrovascular disease are scarce. Methods: We elaborated a working definition of AD with vascular component (ADVC), and this definition was retrospectively investigated in a cohort of patients with cognitive deterioration who were prescribed a cholinesterase inhibitor during usual practice. Results: A total of 137 patients with probable AD and 66 patients with ADVC were studied during a mean follow-up period of 2.8 years. Univariate analyses demonstrated worse functional evolution and anticipation of psychotic symptoms and agitation in the ADVC group. Conclusions: The present results are consistent with an additive model of predominantly frontal-subcortical vascular damage in AD.

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 ( 18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F 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., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

White matter disease in preterm infants comes along with focal destructions or with diffuse myelination disturbance. Recent experimental work with transgenic mice paves the way for a unifying molecular model for both types of brain injury, placing oxygen sensing by oligodendrocyte precursor cells at the center stage. Mice genetically altered to mimic high local oxygen tension in oligodendroglia lineage cells (via deletion of hypoxia-inducible factor, HIF) develop white matter disease resembling cystic periventricular leukomalacia (cPVL) within the first 7 days of life. Mice in which local hypoxia is mimicked in oligodendroglial cells (via genetic inhibition of HIF decay) display arrested oligodendrocyte precursor cell maturation and subsequent hypomyelination, reminiscent of the diffuse white matter disease (dWMD) observed in preterm infants and infants with congenital heart disease. These recent experimental findings on oxygen sensing and myelination are awaiting integration into a clinical framework. Gene regulation in response to hyperoxia or hypoxia, rather than oxidative stress, may be an important mechanism underlying neonatal white matter disease.

Multiple sclerosis (MS) results in inflammatory damage to white matter microstructure. Prior research using bloodoxygen- level dependent (BOLD) imaging indicates MS-related alterations to brain function. What is currently unknown is the extent to which white matter microstructural damage influences BOLD signal in MS. Here we assessed changes in parameters of the BOLD hemodynamic response function (HRF) in patients with relapsing-remitting MS compared to healthy controls. We also used diffusion tensor imaging to assess whether MS-related changes to the BOLD-HRF were affected by changes in white matter microstructural integrity. Our results showed MS-related reductions in BOLD-HRF peak amplitude. These MS-related amplitude decreases were influenced by individual differences in white matter microstructural integrity. Other MS-related factors including altered reaction time, limited spatial extent of BOLD activity, elevated lesion burden, or lesion proximity to regions of interest were not mediators of group differences in BOLD-HRF amplitude. Results are discussed in terms of functional hyperemic mechanisms and implications for analysis of BOLD signal differences [ABSTRACT FROM AUTHOR]

Background: Congenital cytomegalovirus (cCMV) can cause brain inflammation/destruction and teratogenic effects. The only validated neuroimaging prognostic categorization for symptomatic cCMV available is based on destructive lesions seen on computed tomography (CT). Objective: The aim of this study was to establish the predictive ability of a comprehensive neonatal neuroimaging scale in symptomatic cCMV. Methods: Twenty-six infants were studied by neonatal cranial ultrasound scans (US; n = 25), CT (n = 11) and magnetic resonance imaging (MRI; n = 9). A previously validated neuroimaging scale comprising calcifications, ventriculomegaly and atrophy was compared to a newly proposed system adding cerebral dysgenesis and white matter disease. The findings were graded from 0 to 3. Neurodevelopmental assessment included motor and cognitive functions, epilepsy, vision, hearing and behavioral disorders. Results: Both scales showed a significant association with outcome (p < 0.005). Our scale was more accurate in predicting death or moderate- severe disability (area under the curve for scores ≽ 2, 0.88 ± 0.06 vs. 0.80 ± 0.08). All 5 infants with normal neuroimaging survived with intact neurological function. While our scale was highly associated with outcome in patients studied by MRI, it was unable to predict unfavorable outcomes in 2 patients with mildly abnormal US and/or CT. Conclusions: A comprehensive scale based on US and MRI predicts neurodevelopment in symptomatic cCMV. Significant destructive lesions are associated with a poor prognosis. While a strictly normal cranial US predicts a favorable outcome, in case of subtle US abnormalities, MRI is crucial for prognostication. [ABSTRACT FROM AUTHOR]

Background& Purpose: Abnormalities in apparent diffusion coefficient (ADC), fractional anisotropy (FA), and mean diffusivity (MD) values can be used to assess microstructural damage to white matter tracts and could represent a quantitative marker of chronic ischemia and thereby potentially serve as a stroke risk factor or a measure of existing subclinical ischemic disease burden. We performed a systematic review and 3 separate meta-analyses to evaluate the association between unilateral carotid steno-occlusion and ipsilateral ADC, FA, or MD abnormality.Materials& Methods: A comprehensive literature search evaluating the association of carotid disease and quantitative white matter diffusion imaging was performed. The included studies examined patients for ADC, FA, and MD values ipsilateral and contralateral to the site of carotid artery disease. Three meta-analyses using standardized mean differences with assessment of study heterogeneity were performed.Results: Of the 2,920 manuscripts screened, 6 met eligibility for meta-analysis. Of the included manuscripts, 2 studied ADC values, 6 studied FA values, and 2 studied MD values. Our 3 meta-analyses showed standardized mean difference for ADC, FA, and MD values between cerebral hemispheres ipsilateral and contralateral to carotid artery disease site as 1.13 (95% CI: .79-1.47, P < .001), -.42 (95% CI: -.62 to -.21, P < .001), and .23 (95% CI: -.32 to -.77, P = .41), respectively. Measures of heterogeneity showed mild heterogeneity in the 3 meta-analyses.Conclusion: Carotid artery disease is associated with significant ADC and FA value changes, suggesting that carotid disease is associated with quantifiable white matter microstructural damage. [ABSTRACT FROM AUTHOR]

Background: Fluid attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) is a novel radiographic marker detected in acute ischemic stroke (AIS) patients, which is linked to slow blood flow and potentially salvageable brain tissue. Poor leptomeningeal collateral status in AIS patients with proximal artery occlusion (PAO) is associated with larger final infarct and worse clinical outcomes, which are also affected by severity of white matter hyperintensity (WMH). We sought to evaluate FVH utility as a marker of acute collateral vessel status and its association with WMH burden in AIS patients. Methods: Consecutive AIS patients with PAO on baseline CT angiography (CTA) were retrospectively selected from a prospectively derived database. FVH was graded by its location, degree, and score on admission MRI obtained immediately after intravenous tissue plasminogen activator administration. Leptomeningeal collateral flow grade was ranked on admission CTA. WMH volume (WMHV) was assessed using a validated volumetric protocol. Relationship between FVH, collateral flow grade, and WMHV were analyzed. Results: Among 39 patients (mean age 70.5 ± 12.7 years; 56% women, mean National Institutes of Health Stroke Scale score 17.2 (± 4.4)), median WMHV was 6.0 cm(3). FVH score and collateral flow grade were significantly correlated (Spearman's ρ = .41, P = .009). In a univariate regression model, FVH degree was inversely associated with WMHV (β = -.33, P = .04). Conclusions: FVH score detected on acute MRI can be used as a surrogate of collateral flow grade in AIS patients. FVH degree is inversely associated with WMHV, possibly signifying diffuse disease of cerebral vasculature in patients with severe leukoaraiosis. [ABSTRACT FROM AUTHOR]

Introduction Presence of white matter hyperintensity ( WMH) on MRI is a marker of cerebral small vessel disease and is associated with increased small vessel stroke and increased risk of hemorrhagic transformation ( HT) after thrombolysis. Aim We sought to determine whether white matter hypoperfusion ( WMHP) on perfusion CT ( CTP) was related to WMH, and if WMHP predisposed to acute lacunar stroke subtype and HT after thrombolysis. Methods Acute ischemic stroke patients within 12 h of symptom onset at 2 centers were prospectively recruited between 2011 and 2013 for the International Stroke Perfusion Imaging Registry. Participants routinely underwent baseline CT imaging, including CTP, and follow-up imaging with MRI at 24 h. Results Of 229 ischemic stroke patients, 108 were Caucasians and 121 Chinese. In the contralateral white matter, patients with acute lacunar stroke had lower cerebral blood flow ( CBF) and cerebral blood volume ( CBV), compared to those with other stroke subtypes ( P = 0.041). There were 46 patients with HT, and WMHP was associated with increased risk of HT ( R2 = 0.417, P = 0.002). Compared to previously reported predictors of HT, WMHP performed better than infarct core volume ( R2 = 0.341, P = 0.034), very low CBV volume ( R2 = 0.249, P = 0.026), and severely delayed perfusion (Tmax>14 second R2 = 0.372, P = 0.011). Patients with WMHP also had larger acute infarcts and increased infarct growth compared to those without WMHP (mean 28 mL vs. 13 mL P < 0.001). Conclusion White matter hypoperfusion remote to the acutely ischemic region on CTP is a marker of small vessel disease and was associated with increased HT, larger acute infarct cores, and greater infarct growth. [ABSTRACT FROM AUTHOR]

This study aimed to verify whether brain abnormalities, previously described in patients with myotonic dystrophy type 1 (DM1) by magnetic resonance imaging (MRI), progressed over time and, if so, to characterize their progression. Thirteen DM1 patients, who had at least two MRI examinations, were retrospectively evaluated and included in the study. The mean duration (± standard deviation) of follow-up was 13.4 (±3.8) years, over a range of 7–20 years. White matter lesions (WMLs) were rated by semi-quantitative method, the signal intensity of white matter poster-superior to trigones (WMPST) by reference to standard images and brain atrophy by ventricular/brain ratio (VBR). At the end of MRI follow-up, the scores relative to lobar, temporal and periventricular WMLs, to WMPST signal intensity and to VBR were significantly increased compared to baseline, and MRI changes were more evident in some families than in others. No correlation was found between the MRI changes and age, onset, disease duration, muscular involvement, CTG repetition and follow-up duration. These results demonstrated that white matter involvement and brain atrophy were progressive in DM1 and suggested that progression rate varied from patient to patient, regardless of age, disease duration and genetic defect. [ABSTRACT FROM AUTHOR]

Small subcortical infarcts account for 25% of all ischemic strokes. Although once considered to be a small vessel disease with a favorable outcome, recent studies have reported relatively poor long-term prognoses following small subcortical infarcts. Limited pre-clinical modeling has hampered understanding of the etiology and development of treatments for this disease. Therefore, we attempted to develop a new experimental model of small subcortical infarcts in mice to investigate pathophysiological changes in the corticospinal tract and assess long-term behavioral performance. The vasoconstrictor peptide, endothlin-1 (ET-1), in combination with the nitric oxide synthase inhibitor, N(G)-nitro- l -arginine methyl ester ( l -NAME), were injected into the internal capsule of mice. Histological and behavioral tests were performed 0–8 weeks after the injection. The ET-1/ l -NAME injection resulted in severe neurological deficits that continued for up to 8 weeks. The loss of axons and myelin surrounded by reactive gliosis was identified in the region of the injection, in which the vasoconstriction of microvessels was also observed. Moreover, a tract-tracing study revealed an interruption in axonal flow at the internal capsule. The present model of small subcortical infarcts is unique and novel due to the reproduction of neurological deficits that continue for a long period, up to 8 weeks, as well as the use of mice as experimental animals. The reproducibility, simplicity, and easy adoptability make the present model highly appealing for use in further pre-clinical studies on small subcortical infarcts. [ABSTRACT FROM AUTHOR]

Background: To identify quantitative MRI parameters associated with diffusion tensor imaging (DTI) and fast bound-pool fraction imaging (FBFI) that may detect alterations in gray matter and/or white matter in adults with Fabry disease, a lysosomal storage disorder.Materials and Methods: Twelve healthy controls (mean age ± standard deviation: 48.0 ± 12.4 years) and 10 participants with Fabry disease (46.7 ± 12.9 years) were imaged at 3.0 Tesla. Whole-brain parametric maps of diffusion tensor metrics (apparent diffusion coefficient [ADC] and fractional anisotropy [FA]) and the bound-pool fraction (f) were acquired. Mean voxel values of parametric maps from regions-of-interest within gray and white matter structures were compared between cases and controls using the independent t-test. Spearman's rho was used to identify associations between parametric maps and age.Results: Compared with controls, the left thalamus of Fabry participants had an increase in FA (0.29 ± 0.02 versus 0.33 ± 0.05, respectively; P = 0.030) and a trend toward an increase in ADC (0.73 ± 00.02 versus 0.76 ± 0.03 μm(2) /s, respectively; P = 0.082). The left posterior white matter demonstrated a reduction in f (10.45 ± 0.37 versus 9.00 ± 1.84%, respectively; P = 0.035), an increase in ADC (0.78 ± 0.04 versus 0.94 ± 0.19 μm(2) /s, respectively; P = 0.024), and a trend toward a reduction in FA (0.42 ± 0.07 versus 0.36 ± 0.08, respectively; P = 0.052). Among all parameters, only f measured in the left posterior white matter was significantly associated with age in Fabry participants (rho = -0.71; P = 0.022).Conclusion: Parameters derived from DTI and FBFI detect Fabry-related changes in the adult human brain, particularly in the posterior white matter where reductions in myelin density as measured by FBFI appear age related. [ABSTRACT FROM AUTHOR]

Brain MRI was originally considered to appear normal in neuromyelitis optica spectrum disorders (NMO-SD). Typical brain lesions are now well described and have been integrated in the latest revision of NMO-SD criteria, but the NMO-SD MRI pattern remains not yet comprehensive. We report here extensive white matter lesions (EWML) mimicking leukodystrophy in a 50-year-old woman with long-lasting anti-AQP4+ NMO-SD. We suggest that EWML could be a possible brain MRI presentation of NMO-SD patients. [ABSTRACT FROM AUTHOR]

Epilepsy represents an essential component of Parry Romberg syndrome (PRS). This study aimed to identify clinical factors that influence the development of epilepsy and drug-resistant epilepsy (DRE) in PRS. We retrospectively reviewed the medical records of eighty patients with PRS. Data including the age of onset for PRS, history of seizures, use and timing of immunotherapy, antiseizure medication use, and EEG and brain imaging findings were reviewed. For comparison with the patients with epilepsy (PRSe+) group, we selected 18 age and sex-matched controls from the patient without epilepsy (PRSe-) cohort using propensity score matching. Eighteen (22.5%) had epilepsy: 12 were female, and the median age was 14.5 years (range = 6–48 years). Eleven patients developed DRE. The median latency between the onset of cutaneous manifestations and diagnosis and timing and use of immunotherapy was similar between the PRSe + and PRSe- groups. Intracranial abnormalities were commonly seen in the PRSe + group (16 vs. 2, p < 0.01). White matter disease and ipsilateral atrophy were common among the PRSe + group. Timing and use of immunotherapy, epileptiform discharges, and brain imaging abnormalities did not differ between those with DRE and without. The presence and degree of severity of ipsilateral brain abnormalities are risk factors for the development of epilepsy in PRS but not factors in predicting drug resistance. The timing of immunotherapy did not influence the development of PRSe + or DRE. Prospective studies are needed to identify biomarkers for epilepsy and assess the role of immunotherapy on seizure outcomes in PRSe +. • Ipsilateral intracranial manifestations are common in patients with Parry-Romberg syndrome associated epilepsy (PRSe+) • The severity of ipsilateral brain abnormalities is a risk factor for developing PRSe+ but not drug resistance epilepsy. • The timing of immunotherapy did not influence the development of PRSe + or drug resistance epilepsy. • Intracranial findings on brain MRI could serve as a biomarker for epilepsy in Parry-Romberg syndrome. [ABSTRACT FROM AUTHOR]

Objectives: Growing evidence suggests breast cancer susceptibility gene (BRCA) mutations may augment cerebrovascular risk factors. With this influence in mind, we aimed to identify if BRCA mutations increased the prevalence of cerebral small vessel disease (CSVD).Methods and Materials: We performed a retrospective cross-sectional analysis of adults undergoing malignancy evaluation with confirmed BRCA mutations compared to BRCA wildtype individuals. A standard-of-care brain MRI was reviewed. Chi-squared or Fisher's, Wilcoxon rank-sum and the Student's t-test analyses were used when appropriate. Adjusted logistic regression models were fit to calculate odds ratio. Multicollinearity was tested by variance inflation factor calculation and for goodness-of-fit via the Hosmer-Lemeshow test.Results: Of 116 individuals, 44.8% (52/116) carried a BRCA mutation. Demographic and cerebrovascular risk factors did not differ. Cerebral microbleeds were more common in those with BRCA mutation: [32.7% (17/52) vs. 17.2% (11/64), p = 0.05] with an adjusted odds ratio of 2.8 (95%CI 1.08-6.89, p = 0.03). Other markers of CSVD were similar amongst the cohort.Conclusions: We identified a nearly 3-fold increase in identified cerebral microbleed in those with BRCA mutations compared with BRCA wildtype individuals suggestive of an interaction between the BRCA gene and cerebral microbleed formation. Further studies are needed to confirm our findings and to understand clinical implications. [ABSTRACT FROM AUTHOR]

Background: To investigate the clinical and neuroimaging characteristics of leukoencephalopathy among children with acute lymphoblastic leukemia (ALL), especially after chemotherapy., Methods: Clinical data for 17 pediatric patients with leukoencephalopathy and 17 matched controls were retrospectively analyzed. All participants were children with ALL admitted to the Children's Hospital of Soochow University from May 2011 to April 2021. The data mainly consisted of general information, laboratory studies, and imaging diagnostic results., Results: Overall, 94.12% of the patients experienced neurological symptoms. The most common symptoms were seizure (7/17, 41.18%), nausea (5/17, 29.41%), vomiting (5/17, 29.41%), paralysis (5/17, 29.41%), and numbness (4/17, 23.53%). On neuroimaging, multiple and irregular lesions were observed, distributed mainly in the periventricular area (9/17, 52.94%), parietal lobe (6/17, 35.29%), and basal ganglia (5/17, 29.41%). Moreover, there were significant differences in serum sodium (P=0.0001), C-reactive protein (P=0.0124) and blood pressure (P=0.0271) between patients with and without leukoencephalopathy. After aggressive treatment, the clinical symptoms (12/17, 70.59%) and imaging lesions (11/13, 84.62%) gradually improved in most patients., Conclusions: Chemotherapy is an important risk factor related to leukoencephalopathy. Although the clinical symptoms of leukoencephalopathy vary widely, there is a high degree of consistency in its radiological features. Abnormal laboratory results may also help the identification of leukoencephalopathy. Early detection and treatment can improve brain development in the long term., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-22-2180/coif). The authors have no conflicts of interest to declare., (2023 Translational Cancer Research. All rights reserved.)

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 <70 years) versus older (aged ≥70 years) patients and for CT- versus MRI-discovered lesions. For patients with versus without id-WMD on CT, the adjusted HR was 2.87 (95% CI, 2.58-3.19) for older and 1.87 (95% CI, 1.79-1.95) for younger patients. For patients with versus without id-WMD on MRI, the adjusted HR for dementia risk was 2.28 (95% CI, 1.99-2.62) for older and 1.48 (95% CI, 1.32-1.66) for younger patients. The adjusted HR for id-CBI was 2.02 (95% CI, 1.70-2.41) for older and 1.22 (95% CI, 1.15-1.30) for younger patients for either modality. Dementia risk was strongly correlated with id-WMD severity; adjusted HRs compared with patients who were negative for id-WMD by MRI ranged from 1.41 (95% CI, 1.25-1.60) for those with mild disease on MRI to 4.11 (95% CI, 3.58-4.72) for those with severe disease on CT. Conclusions Incidentally discovered CCD is common and associated with a high risk of dementia, representing an opportunity for prevention. The association is strengthened when discovered at younger age, by increasing id-WMD severity, and when id-WMD is detected by CT scan rather than MRI.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2022 the Alzheimer's Association.)

A 55-year-old female presented with a 6-year history of paresthesias, incontinence, spasticity, and gait abnormalities. Neuroimaging revealed white matter abnormalities associated with subependymal nodules. Biochemical evaluation noted increased serum C5-DC glutarylcarnitines and urine glutaric and 3-hydroxyglutaric acids. Evaluation of the glutaryl-CoA dehydrogenase ( GCDH) gene revealed compound heterozygosity consisting of a novel variant (c.1219C>G; p.Leu407Val) and pathogenic mutation (c.848delT; p.L283fs). Together, these results were consistent with a diagnosis of adult-onset type I glutaric aciduria. [ABSTRACT FROM AUTHOR]

White matter lesions ( WML) are common in brain aging and are associated with dementia. We aimed to investigate whether oxidative DNA damage and occur in WML and in apparently normal white matter in cases with lesions. Tissue from WML and control white matter from brains with lesions (controls lesional) and without lesions (controls non-lesional) were obtained, using post-mortem magnetic resonance imaging-guided sampling, from the Medical Research Council Cognitive Function and Ageing Study. Oxidative damage was assessed by immunohistochemistry to 8-hydroxy-2′-deoxoguanosine (8- OHdG) and Western blotting for malondialdehyde. DNA response was assessed by phosphorylated histone H2AX ( γH2AX), p53, senescence markers and by quantitative Reverse transcription polymerase chain reaction ( RT-PCR) panel for candidate DNA damage-associated genes. 8- OHdG was expressed in glia and endothelium, with increased expression in both WML and controls lesional compared with controls non-lesional ( P < 0.001). γH2Ax showed a similar, although attenuated difference among groups ( P = 0.03). Expression of senescence-associated β-galactosidase and p16 suggested induction of senescence mechanisms in glia. Oxidative DNA damage and a DNA damage response are features of WML pathogenesis and suggest candidate mechanisms for glial dysfunction. Their expression in apparently normal white matter in cases with WML suggests that white matter dysfunction is not restricted to lesions. The role of this field-effect lesion pathogenesis and cognitive impairment are areas to be defined. [ABSTRACT FROM AUTHOR]

The article looks at the relationship between coronary artery disease (CAD) and cognitive decline in older people, discussing the authors' research on microstructural characteristics of white matter (WM) in older CAD patients in relation to their cognitive ability.

Deep white matter hyperintensity (DWMH) and periventricular (PV) white matter lesion volumes are associated with age and subsequent stroke. We studied age differences in these volumes accounting for collinearity and risk factors. Subjects were 563 healthy family members of early-onset coronary artery disease patients. Using 3T magnetic resonance imaging, lesions were classified as DWMH or PV. Age association with lesion classification was analyzed using random effects Tobit regression, adjusting for intracranial volume (ICV) and risk factors. Subjects were 60% women, 36% African-American, mean age 51 ± 11 years. In multivariable analysis adjusted for PV and ICV, DWMH was associated with age ( p < 0.001) and female sex ( p = 0.003). PV, adjusted for DWMH and ICV, was age associated ( p < 0.001). For each age decade, DWMH showed 0.07 log units/decade greater volume (95% CI = 0.04–0.11); PV was 0.18 log units/decade greater (95% CI = 0.14–0.23); slope differences ( p < 0.001). In people with a family history of coronary artery disease, PV and DWMH are independently and differentially associated with age controlling for traditional risk factors. [ABSTRACT FROM AUTHOR]

Background: Age is a well-known risk factor for both stroke and increased burden of white matter hyperintensity (WMH), as detected on magnetic resonance imaging (MRI) scans. However, in patients diagnosed with ischemic stroke (IS), WMH volume (WMHv) varies significantly across age groups. We sought to examine the determinants of WMH burden across the ages of stroke onset with the goal to uncover potential age-specific stroke prevention targets. Methods: Adult subjects from an ongoing hospital-based cohort study of IS patients with admission brain MRI were categorized as having early (<55 years), late (>75 years), or average (55-75 years) age of stroke onset. WMHv was measured using a previously validated, MRI-based semi-automated method and normalized for linear regression analyses. Results: Of 1008 IS subjects, 249 had early-onset stroke (24.7%), and 311 had late-onset stroke (30.9%). In multivariable analysis of WMHv using backward stepwise selection, only age (β = .02, P = .018), hypertension (β = .24, P = .049), and history of tobacco use (β = .38, P = .001) were independently associated with WMHv in patients with early-onset stroke, whereas male sex (β = -.30, P = .007), hyperlipidemia (β = -.27, P = .015), and current alcohol use (β = .23, P = .034) were independently associated with WMHv in patients with late-onset stroke. Conclusions: History of tobacco use is a strong independent predictor of WMH burden in patients with early-onset stroke, whereas age is no longer associated with WMHv in IS patients older than 75 years of age. These findings suggest that the major risk factors to target for stroke prevention differ across age groups and may be modifiable. [ABSTRACT FROM AUTHOR]

The currently widespread use of neuroimaging has led neurologists to often face the problem of the differential diagnosis of white matter diseases. There are various forms of leukoencephalopathies (vascular, inflammatory and immunomediated, infectious, metabolic, neoplastic) and sometimes white matter lesions are expression of a genetic disease. While many inherited leukoencephalopathies fall in the child neurologist’s interest, others may have a delayed or even a typical onset in the middle or old age. This field is rapidly growing and, in the last few years, many new inherited white matter diseases have been described and genetically defined. A non-delayed recognition of middle and old age inherited leukoencephalopathies appears important to avoid unnecessary tests and therapies in the patient and to possibly anticipate the diagnosis in relatives. The aim of this review is to provide a guide to direct the diagnostic process when facing a patient with a suspicion of an inherited form of leukoencephalopathy and with clinical onset in middle or old age. Based on a MEDLINE search from 1990 to 2013, we identified 24 middle and old age onset inherited leukoencephalopathies and reviewed in this relation the most recent findings focusing on their differential diagnosis. We provide summary tables to use as a check list of clinical and neuroimaging findings that are most commonly associated with these forms of leukoencephalopathies. When present, we reported specific characteristics of single diseases. Several genetic diseases may be suspected in patients with middle or old age and white matter abnormalities. In only few instances, pathognomonic clinical or associated neuroimaging features help identifying a specific disease. Therefore, a comprehensive knowledge of the characteristics of these inherited white matter diseases appears important to improve the diagnostic work-up, optimize the choice of genetic tests, increase the number of diagnosed patients, and stimulate the research interest in this field. [ABSTRACT FROM AUTHOR]

Background and Purpose: Although the presence of cavitating lacunes on brain imaging may have prognostic implications, the modifiable risk factors underlying these frequently observed lesions are not completely understood. We sought to determine if fasting and post-challenge triglycerides associate with cavitating lacunes.Methods: All first ischemic stroke patients who completed a novel combined oral triglyceride and glucose tolerance test and MRI between January 2009 and June 2012 were included. Fluid-attenuated inversion recovery or T2 MRI sequences were used to visualize cavitating lacunes and white matter hyperintensities, which were graded using the Wahlund visual scale. Results: 190 patients were included (median age 66, IQR 52-73; 33% female; median National Institute of Health Stroke Scale 2, IQR 1-4). A forward stepwise binary logistical regression analysis applying the Hosmer-Lameshow goodness of fit test adjusted for parameters significant in univariate analyses (at the p10: adjusted odds ratio 9.6; 95% CI, 1.55-59.35; P=0.015) and the highest quartile of post-challenge triglycerides (>295 mg/dL; adjusted odds ratio, 7.36; 95% confidence interval 1.24-43.70; P=0.028) independently associated with the presence of cavitating lacunes. Conclusion: Post-challenge serum triglycerides are independently associated with the presence of cavitating lacunes. Clinical Trial Registration Information: The Berlin Cream&Sugar study is registered with EudraCT (2009-010356-97) and clinicaltrials.gov (NCT 01378468).

Background White matter hyperintensities increase the risk of multiple falls in older people, but the effect of sub-cortical infarcts is unknown. Aims By pooling data from two Australian population-based studies, we aimed to investigate the association between subcortical infarcts and multiple falls and whether this relationship, and that of white matter hyperintensities, is mediated or modified by cognitive or sensorimotor factors. Methods Participants underwent structural magnetic resonance imaging and cognitive and sensorimotor assessments. Falls were prospectively measured over 12 months. Subcortical infarcts were detected visually. Total white matter hyperintensity volume was quantified using automated segmentation methods. Generalized linear models were used to examine if sub-cortical infarcts and white matter hyperintensities predicted falls. Results The mean age of the sample (n = 655) was 74·5 (standard deviation 6·7) years, 336 (51·3%) males. Overall, 114 (17·4%) had multiple falls. The majority had no sub-cortical infarcts (n = 491, 75·0%), while 90 had one (13·7%), 41 had two (6·3%), and 33 had more than or equal to three sub-cortical infarcts (5·0%). The risk of multiple falls was elevated in people with more than or equal to three sub-cortical infarcts (adjusted relative risk 1·89, 95% confidence interval 1·03, 3·46) and in the highest quarter of white matter hyperintensity volume (adjusted relative risk 1·46, 95% confidence interval 1·00, 2·13). The effect of sub-cortical infarcts on falls was amplified by poorer vision (P = 0·03). The effect of white matter hyperintensities was amplified by poorer vision (P = 0·008), proprioception (P = 0·03), and muscle strength (P = 0·008). There was no modifying effect of cognitive function. Conclusions Increasing burdens of sub-cortical infarcts and white matter hyperintensities are associated with a risk of falling. Interventions targeting sensorimotor factors along with strategies to prevent sub-cortical infarcts and white matter hyperintensities may reduce the risk of falls. [ABSTRACT FROM AUTHOR]

Background: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors. Methods: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus <55, sex, current smoking, obesity, hypertension, diabetes and low-density lipoprotein >160 mg/dl. Results: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26). Conclusions: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]