Age-related White Matter Changes Research Articles

Lipocalin-type prostaglandin D synthase: a glymphopathy marker in idiopathic hydrocephalus.

Idiopathic normal pressure hydrocephalus in elderly people is considered a form of glymphopathy caused by malfunction of the waste clearance pathway, called the glymphatic system. Tau is a representative waste material similar to amyloid-β. During neurodegeneration, lipocalin-type prostaglandin D synthase (L-PGDS), a major cerebrospinal fluid (CSF) protein, is reported to act as a chaperone that prevents the neurotoxic aggregation of amyloid-β. L-PGDS is also a CSF biomarker in idiopathic normal pressure hydrocephalus and significantly correlates with tau concentration, age, and age-related brain white matter changes detected by magnetic resonance imaging. To investigate this glymphopathy, we aimed to analyze white matter changes and contributing factors in vivo and their interactions ex vivo. Cerebrospinal tap tests were performed in 60 patients referred for symptomatic ventriculomegaly. Patients were evaluated using an idiopathic normal pressure hydrocephalus grading scale, mini-mental state examination, frontal assessment battery, and timed up-and-go test. The typical morphological features of high convexity tightness and ventriculomegaly were measured using the callosal angle and Evans index, and parenchymal white matter properties were evaluated with diffusion tensor imaging followed by tract-based spatial statistics. Levels of CSF biomarkers, including tau, amyloid-β, and L-PGDS, were determined by ELISA, and their interaction, and localization were determined using immunoprecipitation and immunohistochemical analyses. Tract-based spatial statistics for fractional anisotropy revealed clusters that positively correlated with mini-mental state examination, frontal assessment battery, and callosal angle, and clusters that negatively correlated with age, disease duration, idiopathic normal pressure hydrocephalus grading scale, Evans index, and L-PGDS. Other parameters also indicated clusters that correlated with symptoms, microstructural white matter changes, and L-PGDS. Tau co-precipitated with L-PGDS, and colocalization was confirmed in postmortem specimens of neurodegenerative disease obtained from the human Brain Bank. Our study supports the diagnostic value of L-PGDS as a surrogate marker for white matter integrity in idiopathic normal pressure hydrocephalus. These results increase our understanding of the molecular players in the glymphatic system. Moreover, this study indicates the potential utility of enhancing endogenous protective factors to maintain brain homeostasis.

Poststroke Executive Function in Relation to White Matter Damage on Clinically Acquired CT Brain Imaging.

Executive function (EF) impairments are prevalent post stroke and are associated with white matter (WM) damage on MRI. However, less is known about the relationship between poststroke EF and WM damage on CT imaging. To investigate the relationship between poststroke EF and WM damage associated with stroke lesions and WM hypointensities (WMHs) on clinically acquired CT imaging. This study analyzed data from the Oxford Cognitive Screening Program, which recruited individuals aged ≥18 years with a confirmed stroke from an acute stroke unit. The individuals completed a follow-up assessment 6 months post stroke. We included individuals with a CT scan showing a visible stroke who completed follow-up EF assessment using the Oxford Cognitive Screen-Plus rule-finding task. We manually delineated stroke lesions and quantified then dichotomized WM damage caused by the stroke using the HCP-842 atlas. We visually rated then dichotomized WMHs using the Age-Related White Matter Changes Scale. Among 87 stroke survivors (M age = 73.60 ± 11.75; 41 female; 61 ischemic stroke), multivariable linear regression showed that stroke damage to the medial lemniscus ( B = -8.86, P < 0.001) and the presence of WMHs ( B = -5.42, P = 0.005) were associated with poorer EF 6 months post stroke after adjusting for covariates including age and education. Poorer EF was associated with WM damage caused by stroke lesions and WMHs on CT. These results confirm the importance of WM integrity for EF post stroke and demonstrate the prognostic utility of CT-derived imaging markers for poststroke cognitive outcomes.

Evaluation of brain white matter changes on MRI in patients newly diagnosed with obstructive sleep apnea compared with the control group

BackgroundObstructive sleep apnea (OSA) is nowadays introduced as a risk factor for white matter brain changes. Research on OSA and white matter changes provides contradictory evidence for the contextual link between the two conditions. This study aimed to determine the prevalence and severity of OSA and changes in the brain's white matter and the relationship between severity levels of both diseases.MethodsThis was a cross-sectional study in which 40 patients with OSA and 40 patients without OSA underwent polysomnography to determine the severity of OSA and MRI for detecting white matter changes. The severity of white matter changes was classified according to the age-related white matter change (ARWMC) score, and the severity of OSA based on the apnea–hypopnea index (AHI). To evaluate the independent effect of OSA on white matter changes, a multivariate regression model, including the severity of OSA and risk factors, was used.Results76.5% of affected people did not show any changes, and from 13 (32.5%) patients with OSA who experienced white matter changes, 10% were mild, and 22.5% were moderate to severe changes. The white matter changes score increased with increasing OSA severity. The univariate analysis also showed a significant positive correlation between OSA severity and ARWMC score.ConclusionOur major finding was that moderate to severe OSA was independently associated with the prevalence of white matter changes. We also observed a higher prevalence of moderate to severe OSA associated with increasing white matter changes, suggesting that the severity of the disease affects brain structural modification.

Infection, delirium, and risk of dementia in patients with and without white matter disease on previous brain imaging: a population-based study

The increased risk of dementia after delirium and infection might be influenced by cerebral white matter disease (WMD). In patients with transient ischaemic attack (TIA) and minor stroke, we assessed associations between hospital admissions with delirium and 5-year dementia risk and between admissions with infection and dementia risk, stratified by WMD severity (moderate or severe vs absent or mild) on baseline brain imaging. We included patients with TIA and minor stroke (National Institutes of Health Stroke Score <3) from the Oxford Vascular Study (OXVASC), a longitudinal population-based study of the incidence and outcomes of acute vascular events in a population of 94 567 individuals, with no age restrictions, attending eight general practices in Oxfordshire, UK. Hospitalisation data were obtained through linkage to the Oxford Cognitive Comorbidity, Frailty, and Ageing Research Database-Electronic Patient Records (ORCHARD-EPR). Brain imaging was done using CT and MRI, and WMD was prospectively graded according to the age-related white matter changes (ARWMC) scale and categorised into absent, mild, moderate, or severe WMD. Delirium and infection were defined by ICD-10 coding supplemented by hand-searching of hospital records. Dementia was diagnosed using clinical or cognitive assessment, medical records, and death certificates. Associations between hospitalisation with delirium and hospitalisation with infection, and post-event dementia were assessed using time-varying Cox analysis with multivariable adjustment, and all models were stratified by WMD severity. From April 1, 2002, to March 31, 2012, 1369 individuals were prospectively recruited into the study. Of 1369 patients (655 with TIA and 714 with minor stroke, mean age 72 [SD 13] years, 674 female and 695 male, and 364 with moderate or severe WMD), 209 (15%) developed dementia. Hospitalisation during follow-up occurred in 891 (65%) patients of whom 103 (12%) had at least one delirium episode and 236 (26%) had at least one infection episode. Hospitalisation without delirium or infection did not predict subsequent dementia (HR 1·01, 95% CI 0·86-1·20). In contrast, hospitalisation with delirium predicted subsequent dementia independently of infection in patients with and without WMD (2·64, 1·47-4·74; p=0·0013 vs 3·41, 1·91-6·09; p<0·0001) especially in those with unimpaired baseline cognition (cognitive test score above cutoff; 4·01, 2·23-7·19 vs 3·94, 1·95-7·93; both p≤0·0001). However, hospitalisation with infection only predicted dementia in those with moderate or severe WMD (1·75, 1·04-2·94 vs 0·68, 0·39-1·20; pdiff=0·023). The increased risk of dementia after delirium is unrelated to the presence of WMD, whereas infection increases risk only in patients with WMD, suggesting differences in underlying mechanisms and in potential preventive strategies. National Institute for Health and Care Research and Wellcome Trust.

Age-Related Decline in Brain Myelination: Quantitative Macromolecular Proton Fraction Mapping, T2-FLAIR Hyperintensity Volume, and Anti-Myelin Antibodies Seven Years Apart.

Age-related myelination decrease is considered one of the likely mechanisms of cognitive decline. The present preliminary study is based on the longitudinal assessment of global and regional myelination of the normal adult human brain using fast macromolecular fraction (MPF) mapping. Additional markers were age-related changes in white matter (WM) hyperintensities on FLAIR-MRI and the levels of anti-myelin autoantibodies in serum. Eleven healthy subjects (33-60 years in the first study) were scanned twice, seven years apart. An age-related decrease in MPF was found in global WM, grey matter (GM), and mixed WM-GM, as well as in 48 out of 82 examined WM and GM regions. The greatest decrease in MPF was observed for the frontal WM (2-5%), genu of the corpus callosum (CC) (4.0%), and caudate nucleus (5.9%). The age-related decrease in MPF significantly correlated with an increase in the level of antibodies against myelin basic protein (MBP) in serum (r = 0.69 and r = 0.63 for global WM and mixed WM-GM, correspondingly). The volume of FLAIR hyperintensities increased with age but did not correlate with MPF changes and the levels of anti-myelin antibodies. MPF mapping showed high sensitivity to age-related changes in brain myelination, providing the feasibility of this method in clinics.

Distribution of cerebral age-related white matter changes in relation to risk factors in stroke patients

IntroductionThe distribution of cerebral age-related white matter changes (ARWMC) may be indicative of the underlying etiology and could suggest optimal interventions. We aimed to determine if left ventricular hypertrophy (LVH), a marker of uncontrolled hypertension, along with additional risk factors are associated with the distribution of cerebral ARWMC. MethodsWe analyzed data of 172 patients from a hospital stroke registry who had acute stroke and brain MRI. We classified lesion location as superficial (frontal, parieto-occipital, or temporal) or deep (basal nuclei) using the ARWMC scale. We defined a superficial ARWMC index as the superficial minus the deep score. We excluded infratentorial lesions and patients with bilateral strokes. Regression analysis analyzed LVH and other relevant clinical factors for independent association with the superficial ARWMC index. ResultsThe superficial ARWMC scores ranged from 0 to 6, the deep scores from 0 to 3, and the superficial ARWMC index from −2 to 6. We categorized the superficial ARWMC index as −2 to 1 (n = 65), 2 (n = 50), and 3 – 6 (n = 57). In bivariate analysis, ARWMC distribution was significantly associated with older age, lower household income (HI), and lower serum triglyceride (TG) levels. In multiple logistic regression analysis, higher superficial ARWMC index was significantly associated with lower HI (OR 10.72, 95 % CI 2.30–49.85), lower serum low density cholesterol (LDL) (OR 0.86, 95 % CI 0.75–0.98, per 10 mg/dL), and lower serum TG levels (OR 0.91, 95 % CI 0.85–0.99, per 10 mg/dL). The area under the curve in receiver operating characteristic analysis (95 % CI) for HI was 0.63 (0.49–0.76), LDL level 0.64 (0.51–0.77), and TG level 0.77 (0.65–0.88). ConclusionIn this study, LVH was not associated with the distribution of cerebral ARWMC. Using an alternate classification of ARWMC distribution and analyzing additional risk factors in larger studies may yield further discoveries.

The Correlation between Retinal and Choroidal Thickness with Age-Related White Matter Hyperintensities in Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease. Recently, several retinal layers in PSP compared to healthy controls. were found to be thinner. However, no studies evaluating the correlation between retinal layers and cerebral white matter changes, nor eventual choroidal changes in PSP, have been conducted so far. The goals of the present study were to explore potential differences in choroidal structure between PSP and healthy controls, and to describe the relationship between retinal layers' thickness and volume, using spectral-domain optical coherence tomography (SD-OCT) and age-related white matter change scores (ARWMC) using magnetic resonance imaging (MRI) of the brain. Choroidal structures of 26 PSP patients and 26 healthy controls using standard SD-OCT with an enhanced depth imaging (EDI) approach were analyzed; then, retinal the structures of 16 of these PSP patients using standard SD-OCT were examined; finally, the same patients underwent brain MRI, and their cerebral white matter changes were calculated. Non-statistically significant differences between PSP patients' and healthy controls' choroidal structure were found. On the contrary, PSP patients' inner retinal layers (INR), retinal pigmented epithelium (RPE) and all retinal layers' thicknesses in the macular region were found to be significantly correlated with ARWMC, independently from age and axial length (AL). PSP patients' neurological alterations go hand in hand with retinal ones, independently from age and axial length. Our results suggest a mutual relationship between cerebral and retinal structure pathological alterations. On the other hand, no significant differences in the choroidal evaluation compared to healthy controls have been found.

Exploring the relationship between frailty and executive dysfunction: the role of frontal white matter hyperintensities.

Frailty is a geriatric syndrome frequently associated with executive dysfunction and white matter hyperintensities (WMH). But the relation between executive dysfunction and brain changes is poorly understood in frail subjects. Our hypothesis is that frontal-WMH mediates the association between frailty and executive dysfunction. A convenience sample of 113 subjects older than 65 years without dementia was studied with neuropsychological test, a structured clinical interview, physical examination and brain MRI. They were classified as robust or pre-frail and frail using the frailty phenotype score (0-5). The frontal WMH (F-WMH) were manually graduated (0-6) using the "Age-Related White Matter Changes score" from FLAIR sequences at a 3 Tesla brain MRI. A mediation analysis was done for testing whether F-WMH could act as a link factor between frailty phenotype score and executive dysfunction. The group's mean age was 74 ± 6 years, subjects with higher frailty score had more depressive symptoms and worse performance in executive function tests. A regression analysis that explained 52% of the variability in executive functions, revealed a significant direct effect of frailty score (Standardized βcoeff [95% CI] -0.201, [-0.319, -0.049], and F-WMH (-0.152[-0.269, -0.009]) on executive functions, while the F-WMH showed a small partial mediation effect between frailty and executive functions (-0.0395, [-0.09, -0.004]). Frontal matter hyperintensities had a small mediation effect on the association between frailty and executive dysfunction, suggesting that other neuropathological and neurofunctional changes might also be associated with executive dysfunction in frail subjects.

Probing Evidence of Cerebral White Matter Microstructural Disruptions in Ischemic Heart Disease Before and Following Cardiac Rehabilitation: A Diffusion Tensor MR Imaging Study.

Ischemic heart disease (IHD) is linked to brain white matter (WM) breakdown but how age or disease effects WM integrity, and whether it is reversible using cardiac rehabilitation (CR), remains unclear. To assess the effects of brain aging, cardiovascular disease, and CR on WM microstructure in brains of IHD patients following a cardiac event. Retrospective. Thirty-five IHD patients (9 females; mean age = 59 ± 8 years), 21 age-matched healthy controls (10 females; mean age = 59 ± 8 years), and 25 younger controls (14 females; mean age = 26 ± 4 years). 3 T diffusion-weighted imaging with single-shot echo planar imaging acquired at 3 months and 9 months post-cardiac event. Tract-based spatial statistics (TBSS) and tractometry were used to compare fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) in cerebral WM between: 1) older and younger controls to distinguish age-related from disease-related WM changes; 2) IHD patients at baseline (pre-CR) and age-matched controls to investigate if cardiovascular disease exacerbates age-related WM changes; and 3) IHD patients pre-CR and post-CR to investigate the neuroplastic effect of CR on WM microstructure. Two-sample unpaired t-test (age: older vs. younger controls; IHD: IHD pre-CR vs. age-matched controls). One-sample paired t-test (CR: IHD pre- vs. post-CR). Statistical threshold: P < 0.05 (FWE-corrected). TBSS and tractometry revealed widespread WM changes in older controls compared to younger controls while WM clusters of decreased FA in the fornix and increased MD in body of corpus callosum were observed in IHD patients pre-CR compared to age-matched controls. Robust WM improvements (increased FA, increased AD) were observed in IHD patients post-CR. In IHD, both brain aging and cardiovascular disease may contribute to WM disruptions. IHD-related WM disruptions may be favorably modified by CR. 3 TECHNICAL EFFICACY: Stage 2.

Cortical atrophy on baseline computed tomography imaging predicts clinical outcome in patients undergoing endovascular treatment for acute ischemic stroke

ObjectiveMultiple variables beyond the extent of recanalization can impact the clinical outcome after acute ischemic stroke due to large vessel occlusions. Here, we assessed the influence of small vessel disease and cortical atrophy on clinical outcome using native cranial computed tomography (NCCT) in a large single-center cohort.MethodsA total of 1103 consecutive patients who underwent endovascular treatment (EVT) due to occlusion of the middle cerebral artery territory were included. NCCT data were visually assessed for established markers of age-related white matter changes (ARWMC) and brain atrophy. All images were evaluated separately by two readers to assess the inter-observer variability. Regression and machine learning models were built to determine the predictive relevance of ARWMC and atrophy in the presence of important baseline clinical and imaging metrics.ResultsPatients with favorable outcome presented lower values for all measured metrics of pre-existing brain deterioration (p < 0.001). Both ARWMC (p < 0.05) and cortical atrophy (p < 0.001) were independent predictors of clinical outcome at 90 days when controlled for confounders in both regression analyses and led to a minor improvement of prediction accuracy in machine learning models (p < 0.001), with atrophy among the top-5 predictors.ConclusionNCCT-based cortical atrophy and ARWMC scores on NCCT were strong and independent predictors of clinical outcome after EVT.Clinical relevance statementVisual assessment of cortical atrophy and age-related white matter changes on CT could improve the prediction of clinical outcome after thrombectomy in machine learning models which may be integrated into existing clinical routines and facilitate patient selection.Key Points• Cortical atrophy and age-related white matter changes were quantified using CT-based visual scores.• Atrophy and age-related white matter change scores independently predicted clinical outcome after mechanical thrombectomy and improved machine learning–based prediction models.• Both scores could easily be integrated into existing clinical routines and prediction models.

Assessment of cheese sign and its association with vascular risk factors: Data from PUMCH dementia cohort.

In the clinic, practitioners encounter many patients with an abnormal pattern of dense punctate magnetic resonance imaging (MRI) signal in the basal ganglia, a phenomenon known as "cheese sign". This sign is reported as common in cerebrovascular diseases, dementia, and old age. Recently, cheese sign has been speculated to consist of dense perivascular space (PVS). This study aimed to assess the lesion types of cheese sign and analyze the correlation between this sign and vascular disease risk factors. A total of 812 patients from Peking Union Medical College Hospital (PUMCH) dementia cohort were enrolled. We analyzed the relationship between cheese sign and vascular risk. For assessing cheese sign and defining its degree, the abnormal punctate signals were classified into basal ganglia hyperintensity (BGH), PVS, lacunae/infarctions and microbleeds, and counted separately. Each type of lesion was rated on a four-level scale, and then the sum was calculated; this total was defined as the cheese sign score. Fazekas and Age-Related White Matter Changes (ARWMC) scores were used to evaluate the paraventricular, deep, and subcortical gray/white matter hyperintensities. A total of 118 patients (14.5%) in this dementia cohort were found to have cheese sign. Age (odds ratio [OR]: 1.090, 95% confidence interval [CI]: 1.064-1.120, P <0.001), hypertension (OR: 1.828, 95% CI: 1.123-2.983, P = 0.014), and stroke (OR: 1.901, 95% CI: 1.092-3.259, P = 0.025) were risk factors for cheese sign. There was no significant relationship between diabetes, hyperlipidemia, and cheese sign. The main components of cheese sign were BGH, PVS, and lacunae/infarction. The proportion of PVS increased with cheese sign severity. The risk factors for cheese sign were hypertension, age, and stroke. Cheese sign consists of BGH, PVS, and lacunae/infarction.

Brain MRI correlations with disease burden and biomarkers in Fabry disease

ObjectiveTo quantitatively evaluate cerebral small vessel disease (CSVD) in brain magnetic resonance imaging (MRI) and its correlation with disease burden and markers in Fabry disease, a rare X-linked lysosomal storage disease.MethodsWe collected brain MRI data from seventy-one Chinese patients with Fabry disease. CSVD was evaluated using an age-related white matter change rating scale, Fazekas scale, enlarged perivascular spaces grading scale, lacunar infarction scale, Microbleed Anatomical Rating Scale, global cortical atrophy scale, and small-vessel disease score. Factors associated with MRI lesions, including sex, clinical subtype, disease severity, disease burden, genotype, and biomarkers, were also analyzed.ResultsOf 71 patients, 16 (22.5%) experienced ischemic stroke. The incidences of lacunar infarctions, white matter hyperintensities, and cerebral microbleeds were 55%, 62%, and 33%, respectively. The abnormal MRI group had later disease onset, longer disease duration, and a higher Mainz Severity Score Index (p < 0.05) than the normal MRI group. Patients with more severe clinical phenotypes also had higher CVSD-related scores. Sex and GLA mutational type were not closely associated with brain MRI lesions. Of the disease markers, the Mainz Severity Score Index and plasma globotriaosylsphingosine (Lyso-Gb3) were closely correlated with the majority of the MRI scores, whereas α-galactosidase A activity was not.ConclusionBrain MRI revealed progressive lacunar infarctions, white matter hyperintensities, and decreased brain volume in patients with Fabry disease. Brain MRI lesions were closely related to onset-age; disease duration, severity, burden; and plasma Lyso-Gb3. However, they were not associated with sex, α-galactosidase A activity, or GLA mutation type.

Spatial and Temporal Gait Characteristics in Patients Admitted to a Neuro-Rehabilitation Department with Age-Related White Matter Changes: A Gait Analysis and Clinical Study.

Patients with age-related white matter changes (ARWMC) frequently present a gait disorder, depression and cognitive impairment. Our aims are to define which alterations in the gait parameters are associated with motor or neuro-psychological impairment and to assess the role of motor, mood or cognitive dysfunction in explaining the variance of the gait parameters. Patients with gait disorders admitted to a Neuro-rehabilitation Department, affected by vascular leukoencephalopathy who had ARWMC confirmed by a brain MRI, were consecutively enrolled, classified by a neuroradiological scale (Fazekas 1987) and compared to healthy controls. We excluded subjects unable to walk independently, subjects with hydrocephalus or severe aphasia, with orthopaedic and other neurological pathologies conditioning the walking pattern. Patients and controls were assessed by clinical and functional scales (Mini Mental State Examination, Geriatric Depression Scale, Nevitt Motor Performance Scale, Berg Balance Scale, Functional Independence Measure), and computerised gait analysis was performed to assess the spatial and temporal gait parameters in a cross-sectional study. We recruited 76 patients (48 males, aged 78.3 ± 6.2 years) and 14 controls (6 males, aged 75.8 ± 5 years). In the multiple regression analysis, the gait parameter with overall best model summary values, associated with the ARWMC severity, was the stride length even after correction for age, sex, weight and height (R2 = 0.327). The motor performances justified at least in part of the gait disorder (R2 change = 0.220), but the mood state accounted independently for gait alterations (R2 change = 0.039). The increase in ARWMC severity, the reduction of motor performance and a depressed mood state were associated with a reduction of stride length (R = 0.766, R2 = 0.587), reduction of gait speed (R2 = 0.573) and an increase in double support time (R2 = 0.421). The gait disorders in patients with ARWMC are related to motor impairment, but the presence of depression is an independent factor for determining gait alterations and functional status. These data pave the way for longitudinal studies, including gait parameters, to quantitatively assess gait changes after treatment or to monitor the natural progression of the gait disorders.

Brain volumes and white matter diffusion across the adult lifespan in temporal lobe epilepsy.

Typical aging is associated with gradual cognitive decline and changes in brain structure. The observation that cognitive performance in mesial temporal lobe epilepsy (TLE) patients diverges from controls early in life with subsequent decline running in parallel would suggest an initial insult but does not support accelerated decline secondary to seizures. Whether TLE patients demonstrate similar trajectories of age-related gray (GM) and white matter (WM) changes as compared to healthy controls remains uncertain. 3D T1-weighted and diffusion tensor images were acquired at a single site in 170 TLE patients (aged 23-74 years) with MRI signs of unilateral hippocampal sclerosis (HS, 77 right) and 111 healthy controls (aged 26-80 years). Global brain (GM, WM, total brain, and cerebrospinal fluid) and regional volumes (ipsi- and contralateral hippocampi), and fractional anisotropy (FA) of 10 tracts (three portions of corpus callosum, inferior longitudinal, inferior fronto-occipital and uncinate fasciculi, body of fornix, dorsal and parahippocampal-cingulum, and corticospinal tract) were compared between groups as a function of age. There were significant reductions of global brain and hippocampi volumes (greatest ipsilateral to HS), and FA of all 10 tracts in TLE versus controls. For TLE patients, regression lines run in parallel to those from controls for brain volumes and FA (for all tracts except the parahippocampal-cingulum and corticospinal tract) versus age across the adult lifespan. These results imply a developmental hindrance occurring earlier in life (likely in childhood/neurodevelopmental stages) rather than accelerated atrophy/degeneration of most brain structures herein analyzed in patients with TLE.

RNAseq transcriptome profiling reveals activation of immune responses and disrupted circadian patterns in the cerebral white matter of aged mice (P4-6.003)

<h3>Objective:</h3> We aim to map transcriptome profiles of mouse corpus callosum using young (5-month-old) and aged (24-month-old) mice. <h3>Background:</h3> Aging is a risk factor for several neurological diseases. Although the approach of transcriptome profiling by RNAseq has been used to examine age-related changes in RNA expression levels in the brain, how aging affects the transcriptome of cerebral white matter is still mostly unknown. <h3>Design/Methods:</h3> All experimental procedures followed NIH guidelines and were approved by the MGH Institutional Animal Care and Use Committee. Male C57BL6J mice (N=12 for the young; N=12 for the aged) were used. Mice were sacrificed at either ZT1, ZT7, ZT13, or ZT19 to obtain corpus callosum samples (N=3/group). Then, RNA samples were prepared and used for bulk RNAseq. <h3>Results:</h3> Regardless of the time zones for sample preparation, inflammatory responses were activated in aged mice. Especially, genes that are related to complement classical pathways were significantly upregulated in the aged corpus callosum compared to the young group. On the other hand, there were several upregulated genes in the young group. The most upregulated gene in the young corpus callosum was tenascin C, which is a major extracellular matrix glycoprotein, and the pathway analysis showed that the pathways of glial cell development (GO:0021782) and regulation of nervous system development (GO:0051960) were highly enriched in the list of differentially expressed genes (DEGs). Interestingly, the circadian patterns of some genes were disrupted in the aged corpus callosum. In addition, the number of DEGs between young and aged mice was more significant in ZT1 (inactive phase for mice) compared to ZT13 (active phase), suggesting that age-related differences in gene expression patterns may depend on circadian time points. <h3>Conclusions:</h3> Our current study provides a novel dataset for white-matter-specific transcriptome profiles in mice. Our data would help us understand the mechanism of age-related transcriptome changes in cerebral white matter. <b>Disclosure:</b> Dr. Ishikawa has nothing to disclose. Dr. Hamanaka has nothing to disclose. Dr. Mandeville has nothing to disclose. Mrs. Guo has nothing to disclose. Dr. Li has nothing to disclose. Akihiro Shindo has nothing to disclose. Eng Lo has nothing to disclose. Ken Arai has nothing to disclose.

Cerebral small-vessel disease at high altitude: A comparison of patients from plateau and plain.

Cerebral small-vessel disease (CSVD) is prevalent worldwide and one of the major causes of stroke and dementia. For patients with CSVD at high altitude, a special environmental status, limited information is known about their clinical phenotype and specific neuroimaging change. We investigated the clinical and neuroimaging features of patients residing at high altitude by comparing with those in the plain, trying to explore the impact of high altitude environment on CSVD. Two cohorts of CSVD patients from the Tibet Autonomous Region and Beijing were recruited retrospectively. In addition to the collection of clinical diagnoses, demographic information and traditional vascular risk factors, the presence, location, and severity of lacunes and white matter hyperintensities were assessed by manual counting and using age-related white matter changes (ARWMC) rating scale. Differences between the two groups and influence of long-term residing in the plateau were analyzed. A total of 169 patients in Tibet (high altitude) and 310 patients in Beijing (low altitude) were enrolled. Fewer patients in high altitude group were found with acute cerebrovascular events and concomitant traditional vascular risk factors. The median (quartiles) ARWMC score was 10 (4, 15) in high altitude group and 6 (3, 12) in low altitude group. Less lacunes were detected in high altitude group [0 (0, 4)] than in low altitude group [2 (0, 5)]. In both groups, most lesions located in the subcortical (especially frontal) and basal ganglia regions. Logistic regressions showed that age, hypertension, family history of stroke, and plateau resident were independently associated with severe white matter hyperintensities, while plateau resident was negatively correlated with lacunes. Patients of CSVD residing at high altitude showed more severe WMH but less acute cerebrovascular events and lacunes in neuroimaging, comparing to patients residing at low altitude. Our findings suggest potential biphasic effect of high altitude on the occurrence and progression of CSVD.

Diffusion tensor imaging (DTI) studies of cerebral white matter integrity in normal to moderate cardiovascular risk patients

Background &amp; Objectives: The cerebral small vessel disease (CSVD) manifest as white matter lesion (WML) in magnetic resonance imaging (MRI). The diffusion tensor imaging (DTI) study shows a lower white matter integrity in white matter lesion (WML) and its penumbra region, suggesting cerebral white matter damage. The aim of this study is to establish correlation between the DTI values of white matter with the age related white matter changes (ARWMC) visual rating score and identify predictors of ARWMC score. Methods: 63 brain MRI images of subjects were selected. Relevant clinical information of the subjects which satisfied QRISK2 risk factors were retrieved from the patients’ folder. DTI parameters were obtained via postprocessing at OsiriX DTImap workstation. Results: FA frontal (r = -0.36; p = 0.003) and AD frontal (r = -0.26; p = 0.040) had a substantial and negative correlation with the ARWMC score. There was a significant positive correlation shown between the ARWMC score and RD frontal (r = 0.30; p = 0.018). There were positive significant association between the ARWMC score and age (b(95%CI): 0.106 (0.061, 0.151); p&lt;0.001) and QRISK2 score (b(95%CI): 0.235 (0.036, 0.433)). Conclusion: DTI is a good method to study the cerebral white matter integrity. It was found that frontal lobe is the first region affected in relation to ageing, in particular the myelin integrity. Increasing age and higher QRISK2 cardiovascular risk factors were shown to increase the ARWMC score.

Association of Chronic Covert Cerebral Infarctions and White Matter Hyperintensities With Atrial Fibrillation Detection on Post-Stroke Cardiac Rhythm Monitoring: A Cohort Study.

Background This study was conducted to explore the association of different phenotypes, count, and location of chronic covert brain infarctions (CBIs) with detection of atrial fibrillation (AF) on prolonged post-stroke cardiac rhythm monitoring (PCM). Methods and Results We conducted a cohort single-center study of consecutive first-ever ischemic stroke or transient ischemic attack patients undergoing PCM between January 2015 and December 2017. We blindly rated CBI phenotypes according to established definitions and white matter hyperintensities (WMHs) according to the age-related white matter changes rating scale. We used (multiple) regression models to assess the association of the imaging biomarkers and incident AF on PCM. A total of 795 patients (median [interquartile range]) aged 69 (57-78) years, 41% women, median National Institutes of Health Stroke Scale score 2 (0-5), median PCM duration 14 (7-14) days, and AF detection in 61 patients (7.7%) were included. On univariate analysis, WMHs (per point odds ratio, 1.35 [95% CI, 1.03-1.78]) but not CBIs (odds ratio, 0.90 [95% CI, 0.52-1.56]) were associated with AF detection. Neither CBI phenotype, count, nor location were associated with AF detection. After adjustment for age, hypertension, and stroke severity, neither increasing WMHs (per point adjusted odds ratio, 0.85 [95% CI, 0.60-1.20]) nor CBIs (adjusted odds ratio, 0.60 [95% CI, 0.33-1.09]) were independently associated with AF detection. Conclusions Although WMHs and CBIs represent surrogate biomarkers of vascular risk factors, neither WMHs nor CBIs, including their phenotypes, count, and location, were independently associated with AF detection on PCM. In patients with manifest ischemic stroke or transient ischemic attack, the presence of imaging biomarkers of chronic ischemic injury does not seem promising to further refine prediction tools for AF detection on PCM.

White matter hyperintensities are an independent predictor of cognitive decline 3 years following first-ever stroke—results from the PROSCIS-B study

BackgroundWhite matter hyperintensities (WMH) are the result of cerebral small vessel disease and may increase the risk of cognitive impairment (CI), recurrent stroke, and depression. We aimed to explore the association between selected cerebrovascular risk factors (CVRF) and WMH load as well as the effect of increased WMH burden on recurrent vascular events, CI, and depression in first-ever ischemic stroke patients.Methods431 from the PROSpective Cohort with Incident Stroke (PROSCIS) were included; Age-Related White Matter Changes (ARWMC) score was used to assess WMH burden on FLAIR. The presence of CVRF (defined via blood pressure, body-mass-index, and serological markers of kidney dysfunction, diabetes mellitus, and hyperlipoproteinemia) was categorized into normal, borderline, and pathological profiles based on commonly used clinical definitions. The primary outcomes included recurrent vascular events (combined endpoint of recurrent stroke, myocardial infarction and/or death), CI 3 years post-stroke, and depression 1-year post-stroke.ResultsThere was no clear association between CVRF profiles and WMH burden. High WMH lesion load (ARWMC score ≥ 10) was found to be associated with CI (adjusted OR 1.05 [95% CI 1.00–1.11]; p < 0.02) in a mixed-model analysis. Kaplan–Meier survival analysis showed a visible increase in the risk of recurrent vascular events following stroke; however, after adjustment, the risk was non-significant (HR 1.5 [95% CI 0.76–3]; p = 0.18). WMH burden was not associated with depression 1-year post stroke (adjusted OR 0.72 [95% CI 0.31–1.64]; p = 0.44).ConclusionHigher WMH burden was associated with a significant decline in cognition 3 years post-stroke in this cohort of first-ever stroke patients.

How relevant are cerebral white matter lesions in the D313Y variant of the α-galactosidase A gene? Neurological, cardiological, laboratory, and MRI data of 21 patients within a follow-up of 3years.

Fabry disease is an inherited metabolic disorder with various symptoms. Neurological manifestations are small fiber neuropathy, cerebral white matter lesions (WML), megadolicho basilar artery, and stroke. The relevance of the D313Y variant in the galactosidase alpha gene is controversially discussed. We aimed at elucidating the implications of this differential diagnosis of multiple sclerosis (MS), focussing on the analysis of WML over time and correlations with other markers. We reviewed retrospectively the clinical, laboratory, and magnetic resonance imaging data of 21 carriers of the D313Y variant at a single German outpatient clinic for MS between 2004 and 2021. In our cohort (15 females, 6 males), mean age at diagnosis was 44.1 ± 16.3years, and mean follow-up duration was 3.1 ± 3.9years. WML were rated on both, the Fazekas scale and the age-related white matter changes rating scale, and were of variable interindividual extent. Follow-up imaging showed virtually no progress. WML did not correlate with the severity of clinical findings or lysoGb3 levels. Symptomatic carriers of the variant are characterized by an almost complete lack of internal organ manifestations and laboratory findings, usually associated with Fabry disease. WML in carriers of the D313Y variant do not seem to be suitable for assessing or predicting the (para-) clinical status. Concerning MS patients, the variant and its clinical signs can be a differential diagnosis, but also a co-factor. Imaging and cerebrospinal fluid findings facilitate the distinction between both entities.