Yusuke Yakushiji

Brain Microbleeds and Global Cognitive Function in Adults Without Neurological Disorder

Background and Purpose— Increasing attention has been paid to associations between cognitive dysfunction and brain microbleeds (MBs). Because all previous studies have investigated patients with neurological disorders, we examined subjects without neurological disorder in order to clarify pathogenic relationships. Methods— A total of 518 consecutive adults without neurological disorder who had undergone health-screening tests of the brain were studied prospectively. Gradient-echo T2*-weighted MRI using a 1.5-T system was used to detect MBs. The Mini-Mental State Examination (MMSE) was administered to determine cognitive functions. MMSE scores <27 or >1.5 SDs below the age-related mean were regarded as subnormal. Results— MBs were found in 35 subjects (6.8%). MMSE score <27 was found in 25 subjects (4.8%), with MMSE score >1.5 SDs below the age-related mean in 34 subjects (6.6%). Univariate analysis showed presence and number of MBs, short duration of education, and severe white matter hyperintensities as significantly associated with subnormal scores. In logistic regression analysis, presence of MBs (odds ratio [OR], 5.44; 95% CI, 1.83 to 16.19) and number of MBs (OR, 1.32; 95% CI, 1.04 to 1.68) still displayed significant associations with MMSE score <27. Logistic regression analysis revealed a significant relationship between presence (OR, 3.93; 95% CI, 1.44 to 10.74) and number (OR, 1.26; 95% CI, 1.01 to 1.59) of MBs and MMSE score >1.5 SDs below the age-related mean. Among MMSE subscores, “attention and calculation” was significantly lower in MB-positive subjects (P=0.017). Conclusions— MBs appear to be primarily associated with global cognitive dysfunction.

Distributional Impact of Brain Microbleeds on Global Cognitive Function in Adults Without Neurological Disorder

Background and Purpose— Brain microbleeds (MBs) are considered to be associated with cognitive decline and can be pathologically and topographically classified as cerebral amyloid angiopathy-related (located in lobar regions) and hypertensive microangiopathy-related (located in deep regions). We examined whether different effects on global cognitive function might be seen with different distributions of MBs. Methods— A total of 1279 adults without neurological disorders were studied prospectively. Subjects were divided into 4 groups: without-MBs group; lobar group; deep group; and with in both areas (diffuse group). The Mini-Mental State Examination was administered to determine global cognitive functions, with scores <27 regarded as subnormal. Results— MBs were detected in 98 subjects (8%): 36 subjects (3%) classified as lobar group, 48 subjects (4%) as deep group, and 14 subjects (1%) as diffuse group. Subnormal scores were found in 76 subjects (5.9%), associated with age, education, hypertension, severe white matter hyperintensities, and distribution and number of MBs. In the final model of logistic regression analysis, the deep group (OR, 2.79; 95% CI, 1.14–6.79) was associated with subnormal scores, whereas the lobar group (OR, 0.77; 95% CI, 0.17–3.44) was not. Trend for the diffuse group did not reach the level of significance (OR, 5.01; 95% CI, 0.88–28.41). These trends were also seen in analysis using another cut-off point for subnormal score. Scores for total Mini-Mental State Examination and attention and calculation were significantly lower in the deep group and the diffuse groups compared with the without-MBs group. Conclusions— This Japanese cross-sectional study demonstrated that MB-related global cognitive dysfunction seems to occur based on hypertensive pathogenesis rather than on cerebral amyloid angiopathy.

Topography and associations of perivascular spaces in healthy adults The Kashima Scan Study

Objective: We investigated whether the topography of MRI-visible perivascular spaces (PVS) is associated with markers of specific underlying small vessel disease, including cerebral microbleed (CMB) distribution, in neurologically healthy adults. Methods: We analyzed baseline data of an ongoing Japanese population-based cohort study. PVS were rated in the basal ganglia (BG-PVS) and centrum semiovale (CSO-PVS) on axial T2-weighted MRI using a validated rating scale (score 0–4). BG-PVS degree was classified as low (score <2) or high (score ≥2). CSO-PVS degree was classified as low (score <3) or high (score ≥3). Independent demographic, clinical, and imaging factors for high degree of BG-PVS and CSO-PVS were investigated. Results: A total of 1,575 neurologically healthy adults were included (mean age 57.1 years, SD 9.7; 47% male). In multivariable analyses, high degree of BG-PVS (n = 212, 14%) was associated with deep or infratentorial CMBs (odds ratio [OR] 2.77, 95% confidence interval [CI] 1.62–4.74), a marker of hypertensive arteriopathy; by contrast, high degree of CSO-PVS (n = 357, 23%) was associated with strictly lobar CMBs (OR 2.49, 95% CI 1.35–4.61), which share risk factors with cerebral amyloid angiopathy. Both high degree of BG-PVS and CSO-PVS were associated with hypertension (OR 2.03, 95% CI 1.46–2.82 and OR 1.39, 95% CI 1.07–1.81, respectively), lacunes (OR 3.35, 95% CI 1.92–5.86; OR 1.83 95% CI 1.08–3.08), and severe white matter hyperintensities (OR 2.17, 95% CI 1.42–3.31; OR 1.35, 95% CI 0.93–1.96), but these associations were stronger for high degree of BG-PVS. Conclusions: In a neurologically healthy cohort, the associations of PVS differ according to their topography. PVS distribution may be useful for the early detection and classification of small vessel disease.

Outcome of intracerebral hemorrhage associated with different oral anticoagulants

Objective: In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non–vitamin K antagonist oral anticoagulation–related ICH (NOAC-ICH) and vitamin K antagonist–associated ICH (VKA-ICH). Methods: We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score ≤2 and investigated in multivariable logistic regression. ICH volume was measured by ABC/2 or a semiautomated planimetric method. HE was defined as an ICH volume increase >33% or >6 mL from baseline within 72 hours. Results: We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6–38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0–27.9) for VKA-ICH (p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52–1.64] [p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18–1.19 [p = 0.11]). Conclusions: In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH.

Clinical Characteristics by Topographical Distribution of Brain Microbleeds, With a Particular Emphasis on Diffuse Microbleeds

From the perspective of the underlying pathogenesis of primary intracerebral hemorrhage (pICH), the topographical distribution of brain microbleeds (MBs) is divided into the lobar area and the deep brain or infratentorial areas. We investigated clinical features, including ambulatory blood pressure (ABP), of patients with MBs distributed in both areas (diffuse MBs). A total of 124 patients with first-ever acute stroke were enrolled prospectively. Gradient-echo T2∗-weighted magnetic resonance imaging (MRI) was performed using a 1.5-T scanner. Patients were classified into 4 groups: MBs-negative group (n=68), those with MBs in lobar areas (lobar group; n=6), those with MBs in deep or infratentorial areas (deep or infratentorial group; n=31), and those with MBs in both areas (diffuse group; n=19). The admission casual BP (CBP) was recorded in all patients, and ABP was measured in the ischemic stroke patients. There were significant differences in the distribution of MBs (P=.004) among the 6 stroke subtypes. All stroke subtypes except transient ischemic attack had diffuse MBs; pICH had the highest prevalence of it (35%). The severity of white matter hyperintensity (WMH) differed among the 4 groups (P < .0001), with the diffuse group having the highest prevalence of early confluent (47%) and confluent types (21%). ABP and CBP were significantly higher in the deep and diffuse groups compared with the MBs-negative group, but did not differ between the lobar group and the MBs-negative group. Our data suggest that diffuse MBs are associated with hypertensive stroke, elevated BP, and severe WMH. The pathogenesis of diffuse MBs may be related to the more severe microangiopathy involved in hypertensive arteriopathy and cerebral amyloid angiopathy.

Marked cerebral atrophy is correlated with kidney dysfunction in nondisabled adults.

The relationship between kidney dysfunction, such as chronic kidney disease (CKD), and brain morphology has attracted increasing attention, but the association between kidney dysfunction and cerebral atrophy has yet to be determined. The purpose of this study was to clarify the relationship between kidney function and a substantial degree of cerebral atrophy. A total of 610 consecutive Japanese adults without neurological disorders who had undergone health screening tests of the brain were studied prospectively. Magnetic resonance imaging was performed using a 1.5-T scanner. Using a computer-assisted processing system, the percentage of cerebrum atrophy (%Cerebrum atrophy) was calculated as an index of cerebral atrophy. Atrophy was defined as >2 s.d.s below the mean %Cerebrum atrophy. The glomerular filtration rate (GFR) was estimated using the revised equations for estimated GFR from serum creatinine in Japan. Kidney function variables included the GFR value and the prevalence of subjects with GFR <60 ml min−1 per 1.73 m2. Cerebral atrophy was found in 25 (4.1%) cases. Univariate analysis showed that age, male sex, hypertension, each kidney function variable, white matter hyperintensities and lacunae were associated with cerebral atrophy. On logistic regression analysis, GFR (odds ratio (OR), 0.64; 95% confidence interval (CI), 0.42–0.98) and GFR <60 ml min−1 per 1.73 m2 (OR, 5.93; 95% CI, 1.82–19.27) were significantly associated with cerebral atrophy. On sub-analysis, GFR <60 ml min−1 per 1.73 m2 was significantly associated with cortical atrophy (OR, 3.23; 95% CI, 1.15–9.11). Decreased GFR was significantly associated with cerebral atrophy, indicating that treatment of CKD may control age-related degenerative processes of the brain.

Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis

Objective: We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity). Methods: This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2–4, 5–10, and >10 CMBs), using random effects models. Results: We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2–12.6 vs 1.1%, 95% CI 0.5–1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1–3 years): OR 3.1 (95% CI 1.4–6.8; p = 0.006), 4.3 (95% CI 1.8–10.3; p = 0.001), and 3.4 (95% CI 1.4–8.3; p = 0.007) for 2–4, 5–10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1–15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts. Conclusions: CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.

Significantly increased antibody response to heterogeneous nuclear ribonucleoproteins in cerebrospinal fluid of multiple sclerosis patients but not in patients with human T-lymphotropic virus type I–associated myelopathy/tropical spastic paraparesis

It has been reported that antibodies (Abs) against heterogeneous nuclear ribonucleoproteins (hnRNPs) are associated with human T-lymphotropic virus type I (HTLV-I)—associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). However, these studies were done under nonmasked conditions. In order to determine whether Abs against hnRNPs associate with HAM/TSP and MS, the authors assayed Abs against two major hnRNPs, hnRNP A1 and A2/B1, in 105 cerebrospinal fluid (CSF) samples under fully masked conditions. Samples included 40 cases of HAM/TSP, 28 of MS, and 37 of other neurological diseases. Anti-hnRNP A1 Abs, and especially anti-hnRNP A2/B1 Abs, were found significantly more often in the CSF of MS patients than in other groups. However, there was no difference in the incidence of anti-hnRNP A1 Abs between HAM/TSP and other disease groups.

Interferon β-responsive inclusion body myositis in a hepatitis C virus carrier

Although an immune-mediated theory has been proposed for the pathogenesis of inclusion body myositis (IBM),1,2⇓ immunosuppressive treatment is not beneficial. We report a case of IBM occurring in a hepatitis C virus (HCV) carrier and showing improvement with the administration of a high dose of interferon-β (IFNβ). A 68-year-old man was admitted because of generalized muscle weakness that progressed for over 8 years. Eight years earlier, he had developed chronic renal failure due to hyperuricemia and was treated with hemodialysis three times a week. At the induction of hemodialysis he was found to be a HCV carrier. Family history was unremarkable. General physical examination revealed no abnormalities other than hepatomegaly. On neurologic examination, symmetric weakness and atrophy of muscles were noted in all extremities. He was unable to stand, remain standing, or walk. Evaluation using manual muscle testing (MMT) scores included scores of 5 (normal) to 0 (complete paralysis). The results were …

Glucose utilization in the inferior cerebellar vermis and ocular myoclonus.

In a patient with symptomatic ocular myoclonus, the authors observed the regional cerebral metabolic rate of glucose use (rCMRGlu) before and after successful treatment with clonazepam. Even after the symptoms resolved, the rCMRGlu in the hypertrophic olive increased persistently, whereas that in the inferior cerebellar vermis contralateral to the hypertrophic olive decreased. The inferior cerebellar vermis, belonging to the vestibulocerebellar system, may be associated with the generation of symptomatic ocular myoclonus.