Association of Left Ventricular Hypertrophy and Atrial Fibrillation with Hemorrhagic Evolution of Small Vessel Disease.

OBJECTIVES: Cerebral small vessel disease (SVD) is often associated with hypertension and may evolve towards intracerebral hemorrhage (ICH) or lacunar ischemic stroke. However, the factors favoring the evolution towards ICH or lacunar stroke are not well understood. MATERIALS AND METHODS: This retrospective study included 326 consecutive patients (71.1±13.2 years, 38% women): 143 with deep ICH and 183 with lacunar lesions (LL) <2 cm, which were visible in a deep location on brain CT scan. Among LL patients, 143 had a small-artery occlusion (SAO) stroke according to the TOAST classification. Clinical characteristics plus laboratory and neuroradiological variables of these patients had been prospectively collected and a subgroup underwent echocardiography. RESULTS: In multivariate analysis, ICH patients (97% hypertensive), compared to SAO patients (89% hypertensive), had greater left ventricular wall thickness (LVWT; OR 4.15, 95%CI 1.64-10.53, for those with LVWT ≥ 1.4 cm, 70% of whom were hemorrhagic) and lower prevalence of white matter lesions (OR 0.30, 95%CI 0.13-0.70), ever smokers (OR 0.39, 95%CI 0.18-0.82) and diabetics (OR 0.29, 95% CI 0.10-0.84). Moreover, ICH patients had a greater prevalence of atrial fibrillation than LL patients (OR 3.14, 95%CI 1.11-8.93), and so they were more often anticoagulated. CONCLUSIONS: Most SVD patients were hypertensive, but those evolving towards ICH were characterized by organ damage at the cardiac level (increase in LVWT and atrial fibrillation), while those evolving towards lacunar stroke were characterized by a higher prevalence of smokers and diabetics, and by organ damage at the cerebral level (white matter lesions).

Cumulative incidence and risk factors for radiation induced leukoencephalopathy in high grade glioma long term survivors.

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18-69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

Genetic testing of leukodystrophies unraveling extensive heterogeneity in a large cohort and report of five common diseases and 38 novel variants.

This study evaluates the genetic spectrum of leukodystrophies and leukoencephalopathies in Iran. 152 children, aged from 1 day to 15 years, were genetically tested for leukodystrophies and leukoencephalopathies based on clinical and neuroradiological findings from 2016 to 2019. Patients with a suggestive specific leukodystrophy, e. g. metachromatic leukodystrophy, Canavan disease, Tay-Sachs disease were tested for mutations in single genes (108; 71%) while patients with less suggestive findings were evaluated by NGS. 108 of 152(71%) had MRI patterns and clinical findings suggestive of a known leukodystrophy. In total, 114(75%) affected individuals had (likely) pathogenic variants which included 38 novel variants. 35 different types of leukodystrophies and genetic leukoencephalopathies were identified. The more common identified disorders included metachromatic leukodystrophy (19 of 152; 13%), Canavan disease (12; 8%), Tay-Sachs disease (11; 7%), megalencephalic leukodystrophy with subcortical cysts (7; 5%), X-linked adrenoleukodystrophy (8; 5%), Pelizaeus-Merzbacher-like disease type 1 (8; 5%), Sandhoff disease (6; 4%), Krabbe disease (5; 3%), and vanishing white matter disease (4; 3%). Whole exome sequencing (WES) revealed 90% leukodystrophies and genetic leukoencephalopathies. The total diagnosis rate was 75%. This unique study presents a national genetic data of leukodystrophies; it may provide clues to the genetic pool of neighboring countries. Patients with clinical and neuroradiological evidence of a genetic leukoencephalopathy should undergo a genetic analysis to reach a definitive diagnosis. This will allow a diagnosis at earlier stages of the disease, reduce the burden of uncertainty and costs, and will provide the basis for genetic counseling and family planning.

Characterization of Leukoencephalopathy and Association With Later Neurocognitive Performance in Pediatric Acute Lymphoblastic Leukemia.

OBJECTIVES: The most common form of pediatric cancer is acute lymphoblastic leukemia (ALL). Magnetic resonance (MR) neuroimaging studies have revealed leukoencephalopathy (LE) in pediatric ALL, but the impact of LE on long-term neurocognitive performance remains unknown. This study aims to objectively characterize the prevalence, extent, and intensity of LE, and their association with later neurocognitive performance. MATERIALS AND METHODS: Pediatric patients (N = 377) treated for ALL without irradiation underwent MR neuroimaging at 4 time points throughout therapy (end of remission induction [MR1], end of consolidation [MR2], and week 31 [MR3] and week 120 [end therapy, MR4] of continuation treatment) and neurocognitive evaluations at the end of therapy and 2 years later. Generalized estimation equation models with logit link were developed to explore the association between LE prevalence and extent with time points throughout therapy, age at diagnosis (≤5 years or >5 years), treatment risk arm (low risk or standard/high risk), and sex. General linear models were also developed to investigate the association between neuroimaging metrics during treatment and neurocognitive performance at 2-year follow-up. RESULTS: The prevalence of LE was greatest (22.8%, 74/324) after consolidation therapy. The prevalence of LE increased at MR2 relative to MR1 regardless of treatment risk arm (both P's < 0.001), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.013). The extent of white matter affected also increased at MR2 relative to MR1 regardless of treatment risk arm (standard/high risk, P < 0.001; low risk, P = 0.004), age group (both P's < 0.001), or sex (male, P < 0.001; female, P = 0.001). Quantitative relaxation rates were significantly longer in LE compared with that in normal-appearing white matter in the same examination (T1, P < 0.001; T2, P < 0.001). The LE prevalence early in therapy was associated with increased parent ratings of conduct problems (P = 0.039) and learning difficulties (P = 0.036) at 2-year follow-up compared with that at the end of therapy. A greater extent of LE early in therapy was associated with decreasing performance on a measure of processing speed (P = 0.003) from the end of therapy to 2-year follow-up. A larger extent of LE at the end of therapy was associated with decreased performance in reading (P = 0.004), spelling (P = 0.003), and mathematics (P = 0.019) at 2-year follow-up and increasing problems with attention (omissions, P = 0.045; ß, P = 0.015) and memory (list A total recall, P = 0.010) at 2-year follow-up compared with that at the end of therapy. CONCLUSIONS: In this large cohort of pediatric patients treated for ALL without irradiation, asymptomatic LE during therapy can be seen in almost a quarter of patients, involves as much as 10% of the white matter volume, and is associated with decreasing neurocognitive performance, increasing parent reports of conduct problems, and learning difficulties in survivors.

Association between cystatin C gene polymorphism and the prevalence of white matter lesion in elderly healthy subjects.

Cystatin C (CST3) is a cysteine protease inhibitor abundant in the central nervous system, and demonstrated to have roles in several pathophysiological processes including vascular remodeling and inflammation. Previously, we showed a relation of CST3 gene polymorphisms with deep and subcortical white matter hyperintensity (DSWMH) in a small case-control study. In this study, we aimed to investigate the relation in a larger cross-sectional study. Participants of a brain health examination program were recruited (n = 1795) in the study, who underwent routine blood tests and cognitive function tests. Cerebral white matter changes were analyzed by MRI. Additionally, 7 single nucleotide polymorphisms (SNPs) (-82G/C, -78T/G, -5G/A, +4A/C, +87C/T, +148G/A and +213G/A) in the promoter and coding regions of CST3 gene were examined. Among them, carriers of the minor allele haplotype -82C/+4C/+148A were significantly associated with decreased CST3 concentration in the plasma. Unadjusted analysis did not show significant relation between carriers of the minor allele haplotype and periventricular hyperintensity (PVH), but DSWMH was marginally (p < 0.054) increased in this group. After adjusting the effects of other variables like age and kidney function, logistic regression analysis revealed that carriers of the minor allele haplotype were at a significantly increased risk of developing both PVH and DSWMH. Thus, our results suggest that carriers of the minor allele haplotype -82C/+4C/+148A of CST3 gene could be at an increased risk to develop cerebral white matter disturbance.

Cornea: A Window to White Matter Changes in Stroke; Corneal Confocal Microscopy a Surrogate Marker for the Presence and Severity of White Matter Hyperintensities in Ischemic Stroke.

PURPOSE: The presence of white matter hyperintensities (WMH) on MRI imaging confers an increased risk of stroke, dementia, and death. Corneal confocal microscopy (CCM) can detect nerve injury non-invasively and may be a useful surrogate marker for WMH. The objective is to determine whether corneal nerve pathology identified using CCM is associated with the presence of WMH in patients with acute ischemic stroke. METHODS: This is a cross-sectional study where 196 consecutive individuals with acute ischemic stroke were enrolled and underwent neurological examination, MRI brain imaging and CCM. Participants underwent blinded quantification of WMH and corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL). RESULTS: The prevalence of hypertension [P = .013] was significantly higher and CNFD [P = .031] was significantly lower in patients with WMH compared to those without WMH. CNFD and CNFL were significantly lower in patients with DM without WMH [P = .008, P = .019] and in patients with DM and WMH [P = .042, P = .024] compared to patients without DM or WMH, respectively. In a multivariate model, a 1-unit decrease in the CNFD increased the risk of WMH by 6%, after adjusting for age, DM, gender, dyslipidemia, metabolic syndrome, smoking, and HbA1c. DM was associated with a decrease in all CCM parameters but was not a significant independent factor associated with WMH. CONCLUSIONS: CCM demonstrates corneal nerve pathology, which is associated with the presence of WMH in participants with acute ischemic stroke. CCM may be a useful surrogate imaging marker for the presence and severity of WMHs.

Cumulative Blood Pressure Exposure During Young Adulthood and Mobility and Cognitive Function in Midlife.

BACKGROUND: High blood pressure (BP) is a known risk factor for mobility and cognitive impairment in older adults. This study tested the association of cumulative BP exposure from young adulthood to midlife with gait and cognitive function in midlife. Furthermore, we tested whether these associations were modified by cerebral white matter hyperintensity (WMH) burden. METHODS: We included 191 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults), a community-based cohort of young individuals followed over 30 years. Cumulative BP was calculated as the area under the curve (mm Hg×years) from baseline up to year 30 examination. Gait and cognition were assessed at the year 30 examination. Cerebral WMH was available at year 30 in a subset of participants (n=144) who underwent magnetic resonance imaging. Multiple linear regression models were used to assess the association of cumulative BP exposure with gait and cognition. To test effect modification by WMH burden, participants were stratified at the median of WMH and tested for interaction. RESULTS: Higher cumulative systolic and diastolic BPs were associated with slower walking speed (both P=0.010), smaller step length (P=0.011 and 0.005, respectively), and higher gait variability (P=0.018 and 0.001, respectively). Higher cumulative systolic BP was associated with lower cognitive performance in the executive (P=0.021), memory (P=0.015), and global domains (P=0.010), and higher cumulative diastolic BP was associated with lower cognitive performance in the memory domain (P=0.012). All associations were independent of socio-demographics and vascular risk factors (body mass index, smoking, diabetes mellitus and total cholesterol). The association between cumulative BP and gait was moderated by WMH burden (interaction P<0.05). However, the relation between cumulative BP and cognitive function was not different based on the WMH burden (interaction P>0.05). CONCLUSIONS: Exposure to higher BP levels from young to midlife is associated with worse gait and cognitive performance in midlife. Furthermore, WMH moderates the association of cumulative BP exposure with gait, but not with cognitive function in midlife. The mechanisms underpinning the impact of BP exposure on brain structure and function must be investigated in longitudinal studies using a life course approach.

Enfermedad carotídea aterosclerosa y enfermedad de sustancia blanca en sujetos sin historia de infarto cerebral o isquemia cerebral transitoria / Atherosclerotic Carotid Disease and White Matter Disease in Subjects Without a History of Cerebral Infarction or Transient Cerebral Ischemia

Resumen Introducción: La enfermedad carotídea aterosclerosa (ECA) es un factor de riesgo importante para enfermedad vascular cerebral. Objetivo: Analizar la asociación entre factores de riesgo vascular mayores con ECA y leucopatía cerebral en pacientes sin historia de ictus isquémico. Método: Se evaluaron factores de riesgo en sujetos con exploración de carótidas mediante ultrasonografía Doppler dúplex. No se incluyeron casos con historia de infarto cerebral o ataque isquémico transitorio. Los sujetos contaron con resonancia magnética cerebral y se excluyeron aquellos con lesiones isquémicas de grandes vasos. Se construyeron modelos multivariable para la predicción de ECA, estenosis carotídea significativa, carga de ateromas y leucopatía cerebral. Resultados: Se estudiaron 145 sujetos (60.7 % mujeres, edad de 73 años). Se documentó ECA en 54.5 %, estenosis carotídea ≥ 50 % en 9 %, carga de placas de ateroma > 6 en 7.6 % y leucopatía periventricular o subcortical en 28.3 % (20.6 % tenían concurrentemente ECA y leucopatía). Los factores asociados independientemente con ECA fueron edad e hipertensión; con estenosis ≥ 50 %, hipertensión; con cargas de ateromas > 6 placas, edad; con leucopatía, edad, diabetes e hipertensión. La obesidad no se asoció con las variables independientes analizadas. Conclusiones: En los sujetos asintomáticos sin historia de ictus isquémico, la edad y la hipertensión fueron los factores de riesgo más importantes para enfermedad macrovascular. La diabetes mellitus se asoció con enfermedad microvascular. La obesidad por sí sola no fue un determinante mayor de ECA o leucopatía cerebral.

Abstract Introduction: Atherosclerotic carotid artery disease (CAD) is a major risk factor for cerebrovascular disease. Objective: To analyze the association of major vascular risk factors with atherosclerotic CAD and white matter disease (WMD) in patients without a history of ischemic stroke. Method: Risk factors were assessed with carotid examination using Doppler duplex ultrasound. Cases with a history cerebral infarction or transient ischemic attack were not included. Subjects had brain magnetic resonance imaging scans available and those with large-artery ischemic lesions were excluded. Multivariate models were constructed for the prediction of atherosclerotic CAD, significant carotid stenosis, atheroma burden and WMD. Results: One-hundred and forty-five subjects were assessed (60.7% were females, mean age was 73 years). Atherosclerotic CAD was documented in 54.5%, carotid stenosis ≥ 50% in 9.0%, > 6 atheroma plaques in 7.6%, and periventricular or subcortical WMD in 28.3% (20.6% had atherosclerotic CAD and WMD concurrently). Risk factors independently associated with atherosclerotic CAD were age and hypertension; hypertension was associated with ≥ 50% carotid stenosis; age was associated with > 6 atheroma plaques; and age, diabetes and hypertension were associated with WMD. Obesity was not associated with any of the analyzed independent variables. Conclusions: In asymptomatic subjects without a history of ischemic stroke, age and hypertension were the most important risk factors for macrovascular disease. Diabetes mellitus was associated with microvascular disease. Obesity alone was not a major determinant of CAD or WMD.

Causes of mortality and severe morbidity requiring euthanasia in captive Tasmanian devils (Sarcophilus harrisii) in Tasmania.

BACKGROUND: Devil facial tumour disease (DFTD) is a contagious cancer causing marked population declines in wild Tasmanian devils. In response to this threat, a captive insurance population has been established. This study investigated causes of death in captive Tasmanian devils. METHODS: Clinical and laboratory records of captive Tasmanian devils held in seven Tasmanian captive facilities were analysed for cause of death or severe morbidity requiring euthanasia. RESULTS: Neoplasia was found to be the most common cause of mortality/severe morbidity, accounting for 27/63 of deaths. Cutaneous lymphoma was the most frequently observed tumour (10/27), at a higher incidence than previously reported. The most common cause of severe morbidity, following neoplasia, was leucoencephalomyelopathy, which caused severe, progressive hindlimb paresis and ataxia. CONCLUSION: Neoplasia, specifically cutaneous lymphoma, and degenerative neurological conditions are the most frequent causes of death in captive Tasmanian devils in Tasmania. Further work to determine the aetiologies of these conditions, as well as effective treatments, would be valuable.

Beyond sepsis: Staphylococcus epidermidis is an underestimated but significant contributor to neonatal morbidity.

Staphylococcus epidermidis accounts for the majority of cases of neonatal sepsis. Moreover, it has been demonstrated to be associated with neonatal morbidities, such as bronchopulmonary dysplasia (BPD), white matter injury (WMI), necrotizing enterocolitis (NEC) and retinopathy of prematurity (ROP), which affect short-term and long-term neonatal outcome. Imbalanced inflammation has been considered to be a major underlying mechanism of each entity. Conventionally regarded as a harmless commensal on human skin, S. epidermidis has received less attention than its more virulent relative Staphylococcus aureus. Particularities of neonatal innate immunity and nosocomial environmental factors, however, may contribute to the emergence of S. epidermidis as a significant nosocomial pathogen. Neonatal host response to S. epidermidis sepsis has not been fully elucidated. Evidence is emerging regarding the implication of S. epidermidis sepsis in the pathogenesis of neonatal inflammatory diseases. This review focuses on the interplay among S. epidermidis, neonatal innate immunity and inflammation-driven organ injury.

Vascular Risk Factor Profiles Differ Between Magnetic Resonance Imaging-Defined Subtypes of Younger-Onset Lacunar Stroke.

BACKGROUND AND PURPOSE: Differing associations of vascular risk factors with lacunar infarct have been reported, which is likely because of diagnostic differences and possible heterogeneity in the pathogenesis underlying lacunar infarction. In a large magnetic resonance imaging-verified cohort of lacunar infarct patients, we investigated the risk factor profile of lacunar infarction and magnetic resonance imaging characteristics. METHODS: One thousand twenty-three patients with lacunar infarction (mean age, 56.7; SD, 8.5) were recruited from 72 stroke centers throughout the United Kingdom as part of the UK Young Lacunar Stroke DNA Study. Risk factor profiles were compared with 1961 stroke-free population controls with similar age. Furthermore, we tested risk factor profiles of lacunar stroke patients for association with the presence of multiple lacunar infarcts, white matter hyperintensities (WMH), and location of the acute lacunar infarct. RESULTS: Hypertension (odds ratio [OR], 2.21; 95% confidence interval [CI], 1.85-2.64), diabetes mellitus (OR, 2.10; 95% CI, 1.61-2.73), hyperlipidemia (OR, 1.74; 95% CI, 1.46-2.07), and smoking (OR, 1.65; 95% CI, 1.39-1.96) were independently associated in lacunar infarct patients compared with healthy controls. Patients with multiple lacunar infarcts were more likely to be men (OR, 2.53; 95% CI, 1.81-3.53) and have hypertension (OR, 1.54; 95% CI, 1.12-2.04) compared with patients with a single lacunar infarct, independent of other vascular risk factors. The presence of moderate-to-severe WMH versus no or mild WMH was independently associated with increased age (OR, 1.54; 95% CI, 1.12-2.04), hypertension (OR, 2.06; 95% CI, 1.44-2.95), and impaired renal function (OR, 0.90; 95% CI, 0.82-0.98). CONCLUSIONS: In this magnetic resonance imaging-verified lacunar stroke population, we identified a distinct risk factor profile in the group as a whole. However, there were differing risk factor profiles according to the presence of multiple lacunar infarcts and confluent WMH. The association of hypertension, smoking, and renal impairment with the presence of multiple lacunar infarcts and confluent WMH might reflect a diffuse small vessel arteriopathy.

Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts.

BACKGROUND: Leukoencephalopathy with brain calcifications and cysts (LCC) is neuroradiologically characterized by leukoencephalopathy, intracranial calcification, and cysts. Coats plus syndrome is also characterized by the same neuroradiological findings together with defects in retinal vascular development. Indeed, LCC and Coats plus were originally considered to be the same clinical entity termed cerebroretinal microangiopathy with calcifications and cysts, but evidence suggests that they are genetically distinct. Mutations in CTS telomere maintenance complex component 1 (CTC1) and small nucleolar RNA, C/D box 118 (SNORD118) genes have been found to cause Coats plus and LCC, respectively. MATERIALS AND METHODS: Eight unrelated families with LCC were recruited. These patients typically showed major neuroradiological findings of LCC with no signs of extra-neurological manifestations such as retinal abnormality, gastrointestinal bleeding, or hematological abnormalities. SNORD118 was examined by Sanger sequencing in these families. RESULTS: Seven out of eight probands carry compound heterozygous mutations, suggesting that SNORD118 mutations are the major cause of LCC. We identified a total of eight mutation, including four that were novel. Some of the variants identified in this study present heterozygously in public databases with an extremely rare frequency (<0.1%). CONCLUSION: Biallelic SNORD118 mutations were exclusively found in most unrelated families with LCC.

Neurocognitive outcomes among children who experienced seizures during treatment for acute lymphoblastic leukemia.

BACKGROUND: Limited information is available regarding neurocognitive outcomes of children who experience seizures during treatment for acute lymphoblastic leukemia (ALL). Accordingly, the main objectives of this study were to determine the incidence and risk factors for treatment-related seizures among children with ALL, and the neurocognitive outcomes associated with treatment-related seizures. PROCEDURE: Prospective neuropsychological assessment and magnetic resonance imaging (MRI) were planned for all 498 patients with newly diagnosed ALL enrolled on the St. Jude Total Therapy XV (TOTXV) protocol at three time points. The study database was reviewed retrospectively to identify those with treatment-related seizure. To assess neurocognitive changes associated with seizure, each patient with treatment-related seizure was matched with two cohort patients without seizure for age at treatment, gender, race, and treatment intensity. RESULTS: Nineteen patients developed seizure, with a 2-year cumulative risk of 3.82 ± 0.86% (SE). No risk factors were identified to be associated with the development of seizure, with a possible exception of intensive chemotherapy used on the standard/high-risk arm as compared to the low-risk arm. Neuropsychological performance of the seizure group, as compared to normative scores and nonseizure control cohort, indicated problems in attention, working memory, and processing speed. Cognitive deficits persisted 2 years after therapy, with additional declines in intellectual function observed. MRI indicated early neurotoxicity among the seizure group, as evidenced by greater leukoencephalopathy on initial examinations. CONCLUSION: Treatment-related seizures were associated with leukoencephalopathy and decreased neuropsychological performance. Prospective studies are needed to detect changes in neurocognitive status associated with long-term functional impairment.

Cholesteatoma and coexisting findings diagnosed incidentally on MRI.

The explosive growth in the use of diffusion-weighted magnetic resonance imaging (MRI) in the pre- and postoperative evaluations of patients with cholesteatoma has led to a concomitant increase in the number of incidental findings in this population. We describe our retrospective examination of MRI studies in cholesteatoma patients to look for the presence of other coexisting abnormalities. We examined the brain MRIs of 103 patients-45 males and 58 females, aged 3 to 81 years (mean: 31.9 ± 21.3)-who had undergone pre- or postoperative imaging during the management of a cholesteatoma. The MRIs revealed the presence of at least one other anomaly in 79 of these patients (76.7%)-36 males and 43 females, aged 3 to 81 years (mean: 43.5 ± 18.2). These 79 MRIs detected a total of 124 lesions that had been coexisting with cholesteatomas; some of these lesions had overlapped with the cholesteatoma. The two most common findings were sinonasal mucoperiosteal thickening and polyposis (n = 66) and white-matter changes (n = 29). Our results establish the need for routine skilled interpretation of brain MRIs by expert neuroradiologists to ensure that findings coexisting with cholesteatoma are detected so that appropriate management can be provided.

White Matter Lesions, Carotid and Coronary Atherosclerosis in Late-Onset Depression and Healthy Controls.

BACKGROUND: Cerebral white matter lesions (WMLs) are more common in individuals with late-onset or late-life depression. It has been proposed that carotid atherosclerosis may predispose to WMLs by inducing cerebral hypoperfusion. This hemodynamic effect of carotid atherosclerosis could be important for the formation of WMLs in depression. METHODS: The case-control study included 29 patients with late-onset major depressive disorder and 27 controls matched for sex, age, and tobacco use. WML volume, carotid intima-media thickness, and coronary plaque volume were assessed using magnetic resonance imaging, ultrasound scan, and coronary computed tomography (CT) angiography, respectively. RESULTS: The mean age for the total sample was 59.7 ± 4.7 years. There was no difference in carotid intima-media thickness between patients and controls (p = 0.164), whereas a higher WML volume in the patients was found (p = 0.051). In both patients and controls, WML volume was associated with carotid but not with coronary atherosclerosis. In adjusted multiple linear regression, a 0.1mm increase in averaged carotid intima-media thickness was associated with a 52% (95% CI: 8.4-112, p = 0.032) increase in WML volume. The association between carotid intima-media thickness and WML volume was, however, similar in patients and controls. CONCLUSIONS: In older persons aged between 50 and 70 years, WMLs do not seem to be a part of generalized atherosclerotic disease, but seem to be dependent on atherosclerosis in the carotid arteries. Carotid atherosclerosis, however, could not explain the higher WML load observed in the depressed patients, and thus, studies are needed to establish the mechanisms linking depression and WMLs.

Characteristics of Cerebral Microbleeds in Patients with Fabry Disease.

BACKGROUND AND PURPOSE: Fabry disease (FD) is an X-linked lysosomal storage disorder frequently associated with the central nervous system manifestations. Although white matter hyperintensity (WMH) on MRI has been previously reported, little is known about cerebral microbleeds (CMBs) in patients with FD. Our aim is to investigate the clinical characteristics of CMBs in patients with FD. METHODS: All patients with FD were diagnosed by enzyme activity and/or gene analysis at Jikei University Hospital. We retrospectively enrolled consecutive patients with FD who underwent MRI study, including fluid-attenuated inversion recovery and susceptibility-weighted imaging, between July 2008 and September 2013. After categorizing the patients into CMB-positive and CMB-negative groups, we compared the clinical characteristics between the 2 groups. RESULTS: We enrolled 54 patients (males, 24; median age 39 years, interquartile range; 29-50 years). The CMB-positive group included 16 (30%) patients. The number of males was significantly higher in the CMB-positive group than in the CMB-negative group (75% versus 32%, P = .003). The prevalence rates of chronic kidney disease (CKD) (estimated glomerular filtration rate < 60 mL/min/1.73 m(2)) and WMH were higher in the CMB-positive group than in the CMB-negative group (CKD: 44% versus 13%, P = .013; WMH: 88% versus 58%, P = .035). No significant differences in the number of vascular risk factors were observed between the 2 groups. CONCLUSIONS: The distinct characteristics of FD patients with CMBs were male sex, presence of CKD, and WMH. These factors may play an important role in the mechanism of hemorrhagic stroke in FD.

Cerebral white matter lesions and silent cerebral infarcts in postmenopausal women with polycystic ovary syndrome.

OBJECTIVES: The association between polycystic ovary syndrome (PCOS) and cardiovascular disease remains unclear. Our objective was to examine the relation of PCOS with cerebrovascular disease measured by brain magnetic resonance imaging (MRI) as white matter lesions (WMLs) and silent cerebral infarcts (SCIs). METHODS: Seventy postmenopausal women with PCOS and 140 controls participated in the case-control, cross-sectional study. Clinical, anthropometric, hormonal and metabolic parameters were measured. WMLs and SCIs were evaluated by brain MRI. RESULTS: Compared with controls, postmenopausal women with PCOS had higher mean body mass index, larger waist hip ratio, higher level of low-density lipoprotein cholesterol, free androgen index and lower sex hormone-binding globulin level. The PCOS group had a significantly higher prevalence of WMLs (40% versus 22%, p = 0.009), and SCIs (17% versus 7%, p = 0.032) compared to the control group. CONCLUSIONS: Postmenopausal women with PCOS are associated with WMLs and SCIs.

Progression of White Matter Disease and Cortical Thinning Are Not Related in Older Community-Dwelling Subjects.

BACKGROUND AND PURPOSE: We assessed cross-sectional and longitudinal relationships between whole brain white matter hyperintensity (WMH) volume and regional cortical thickness. METHODS: We measured WMH volume and regional cortical thickness on magnetic resonance imaging at ≈73 and ≈76 years in 351 community-dwelling subjects from the Lothian Birth Cohort 1936. We used multiple linear regression to calculate cross-sectional and longitudinal associations between regional cortical thickness and WMH volume controlling for age, sex, Mini Mental State Examination, education, intelligence quotient at age 11, and vascular risk factors. RESULTS: We found cross-sectional associations between WMH volume and cortical thickness within and surrounding the Sylvian fissure at 73 and 76 years (rho=-0.276, Q=0.004). However, we found no significant longitudinal associations between (1) baseline WMH volume and change in cortical thickness; (2) baseline cortical thickness and change in WMH volume; or (3) change in WMH volume and change in cortical thickness. CONCLUSIONS: Our results show that WMH volume and cortical thinning both worsen with age and are associated cross-sectionally within and surrounding the Sylvian fissure. However, changes in WMH volume and cortical thinning from 73 to 76 years are not associated longitudinally in these relatively healthy older subjects. The underlying cause(s) of WMH growth and cortical thinning have yet to be fully determined.

Leukoencephalopathy After Stereotactic Radiosurgery for Brain Metastases.

PURPOSE: Although the use of stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases has increased dramatically during the past decade to avoid the neurocognitive dysfunction induced by whole brain radiation therapy (WBRT), the cumulative neurocognitive effect of numerous SRS sessions remains unknown. Because leukoencephalopathy is a sensitive marker for radiation-induced central nervous system damage, we studied the clinical and dosimetric predictors of SRS-induced leukoencephalopathy. METHODS AND MATERIALS: Patients treated at our institution with at least 2 sessions of SRS for brain metastases from 2007 to 2013 were reviewed. The pre- and post-SRS magnetic resonance imaging sequences were reviewed and graded for white matter changes associated with radiation leukoencephalopathy using a previously validated scale. Patient characteristics and SRS dosimetric parameters were reviewed for factors that contributed to leukoencephalopathy using Cox proportional hazards modeling. RESULTS: A total of 103 patients meeting the inclusion criteria were identified. The overall incidence of leukoencephalopathy was 29% at year 1, 38% at year 2, and 53% at year 3. Three factors were associated with radiation-induced leukoencephalopathy: (1) the use of WBRT (P=.019); (2) a higher SRS integral dose to the cranium (P=.036); and (3) the total number of intracranial metastases (P=.003). CONCLUSIONS: Our results have established that WBRT plus SRS produces leukoencephalopathy at a much higher rate than SRS alone. In addition, for patients who did not undergo WBRT before SRS, the integral dose was associated with the development of leukoencephalopathy. As the survival of patients with central nervous system metastases increases and as the neurotoxicity of chemotherapeutic and targeted agents becomes established, these 3 potential risk factors will be important to consider.

Determinants of white matter hyperintensity burden differ at the extremes of ages of ischemic stroke onset.

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 (ß = .02, P = .018), hypertension (ß = .24, P = .049), and history of tobacco use (ß = .38, P = .001) were independently associated with WMHv in patients with early-onset stroke, whereas male sex (ß = -.30, P = .007), hyperlipidemia (ß = -.27, P = .015), and current alcohol use (ß = .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.