Yoshiki Yagita

Association between cerebral small vessel diseases and mild parkinsonian signs in the elderly with vascular risk factors

INTRODUCTIONnThe aim of this study was to examine the association between mild parkinsonian signs (MPS), cerebral small-vessel disease (SVD), and total SVD burden in patients with vascular risk factors.nnnMETHODSnWe performed a cross-sectional study among 268 patients with vascular risk factors but without parkinsonism or dementia (71.0xa0±xa07.8 years, 63% male). MPS was evaluated via Unified Parkinsons Disease Rating Scale Part III. Brain MRI was used to determine SVD (cerebral microbleeds [CMBs], lacunar infarctions [LIs], and white matter hyperintensities [WMH]). The presence of each SVD feature was indicated by the total SVD score. Logistic regression analyses were performed adjusting for age, sex, history of stroke, hypertension, diabetes mellitus, and dyslipidemia.nnnRESULTSnIn a multivariate analysis, we found that the presence of CMBs, deep CMBs, mixed (in the basal ganglia and thalamus) LIs, periventricular hyperintensities (PVH), and deep WMH (DWMH), and total SVD score were significantly associated with MPS, whereas strictly lobar CMBs and other LIs (in strictly basal ganglia or strictly thalamus) were not. We also found a significant association between mixed LIs, PVH, DWMH and total SVD score and gait/balance function, between PVH and rigidity, and between mixed LIs and bradykinesia. Among elderly participants (≥73years), the association of total SVD score, deep CMBs, mixed LIs, and PVH, with MPS remained significant.nnnCONCLUSIONnOur results provide additional evidence that SVD including CMBs, and especially total SVD burden, might be a surrogate marker for MPS and support the contribution of hypertensive microangiopathy as the underlying etiology.

Neural network remodeling underlying motor map reorganization induced by rehabilitative training after ischemic stroke

Motor map reorganization is believed to be one mechanism underlying rehabilitation-induced functional recovery. Although the ipsilesional secondary motor area has been known to reorganize motor maps and contribute to rehabilitation-induced functional recovery, it is unknown how the secondary motor area is reorganized by rehabilitative training. In the present study, using skilled forelimb reaching tasks, we investigated neural network remodeling in the rat rostral forelimb area (RFA) of the secondary motor area during 4weeks of rehabilitative training. Following photothrombotic stroke in the caudal forelimb area (CFA), rehabilitative training led to task-specific recovery and motor map reorganization in the RFA. A second injury to the RFA resulted in reappearance of motor deficits. Further, when both the CFA and RFA were destroyed simultaneously, rehabilitative training no longer improved task-specific recovery. In neural tracer studies, although rehabilitative training did not alter neural projection to the RFA from other brain areas, rehabilitative training increased neural projection from the RFA to the lower spinal cord, which innervates the muscles in the forelimb. Double retrograde tracer studies revealed that rehabilitative training increased the neurons projecting from the RFA to both the upper cervical cord, which innervates the muscles in the neck, trunk, and part of the proximal forelimb, and the lower cervical cord. These results suggest that neurons projecting to the upper cervical cord provide new connections to the denervated forelimb area of the spinal cord, and these new connections may contribute to rehabilitation-induced task-specific recovery and motor map reorganization in the secondary motor area.

The Role of Endogenous Neurogenesis in Functional Recovery and Motor Map Reorganization Induced by Rehabilitative Therapy after Stroke in Rats

BACKGROUND AND OBJECTIVEnEndogenous neurogenesis is associated with functional recovery after stroke, but the roles it plays in such recovery processes are unknown. This study aims to clarify the roles of endogenous neurogenesis in functional recovery and motor map reorganization induced by rehabilitative therapy after stroke by using a rat model of cerebral ischemia (CI).nnnMETHODSnIschemia was induced via photothrombosis in the caudal forelimb area of the rat cortex. First, we examined the effect of rehabilitative therapy on functional recovery and motor map reorganization, using the skilled forelimb reaching test and intracortical microstimulation. Next, using the same approaches, we examined how motor map reorganization changed when endogenous neurogenesis after stroke was inhibited by cytosine-β-d-arabinofuranoside (Ara-C).nnnRESULTSnRehabilitative therapy for 4 weeks after the induction of stroke significantly improved functional recovery and expanded the rostral forelimb area (RFA). Intraventricular Ara-C administration for 4-10 days after stroke significantly suppressed endogenous neurogenesis compared to vehicle, but did not appear to influence non-neural cells (e.g., microglia, astrocytes, and vascular endothelial cells). Suppressing endogenous neurogenesis via Ara-C administration significantly inhibited (~50% less than vehicle) functional recovery and RFA expansion (~33% of vehicle) induced by rehabilitative therapy after CI.nnnCONCLUSIONSnAfter CI, inhibition of endogenous neurogenesis suppressed both the functional and anatomical markers of rehabilitative therapy. These results suggest that endogenous neurogenesis contributes to functional recovery after CI related to rehabilitative therapy, possibly through its promotion of motor map reorganization, although other additional roles cannot be ruled out.

Deep Cerebral Microbleeds and Renal Dysfunction in Patients with Acute Lacunar Infarcts

BACKGROUNDnCerebral small-vessel disease (SVD) is associated with renal dysfunction such as chronic kidney disease. Although cerebral microbleeds (CMBs) are common in patients with acute lacunar infarcts (ALI), the association between renal dysfunction and CMBs in such patients remains unclear.nnnMETHODSnBetween April 2007 and March 2013, we evaluated consecutive first-ever ALI patients, who were admitted to our hospital within 24 hours of stroke onset. CMBs were defined as focal areas of signal loss in brain parenchyma less than 5 mm on T2(∗)-weighted gradient-echo imaging. Renal dysfunction was defined as an estimated glomerular filtration rate less than 60 mL/minute/1.73 m(2) on admission. Correlations between renal dysfunction and the presence (model 1) and location of CMBs (model 2; any deep or infratentorial CMBs) were determined by multivariable logistic regression analyses.nnnRESULTSnAmong 152 patients (33.6% men; mean age, 67.6 years), 53 had CMBs. Patients with CMBs were older (69.9 versus 66.3 years, P = .03) and had a higher frequency of white matter hyperintensity (WMH; 62.3% versus 25.3%, P < .001), silent lacunar infarcts (SLI; 75.5% versus 43.3%, P < .001), and renal dysfunction (41.5% versus 22.2%, P = .015) than those without CMBs. On multivariable analyses, renal dysfunction (odds ratio, 95% confidence interval; model 1: 2.38, 1.02-5.66; model 2: 2.78, 1.16-6.81), WMH (3.87, 1.76-8.80; 3.72, 1.64-8.71), SLI (3.85, 1.71-9.14; 4.20, 1.77-10.8), and diabetes mellitus (.26, .09-.63; .24, .08-.63) were independently associated with CMBs.nnnCONCLUSIONSnIn patients with ALI, renal dysfunction was positively associated with CMBs independent of cerebral SVD.

A Case of Hypertensive Encephalopathy with Enlarged Optic Nerve Sheath Measured by Transorbital Sonography.

This case report describes our experience in using transorbital sonography to evaluate pathological changes in the central nervous system in hypertensive encephalopathy. A 49-year-old man with nausea, headache, and mild confusion was diagnosed with hypertensive encephalopathy by brain magnetic resonance imaging (MRI), which revealed vasogenic edema in the bilateral thalamus and the brain stem. Lumbar puncture showed no severe intracranial hypertension. Transorbital sonography showed an increase in the optic nerve sheath diameter (ONSD). Repeated examination revealed a return of the ONSD to an almost normal range after a reduction in blood pressure and a resolution of symptoms. An improvement in cerebral vasogenic edema was confirmed by brain MRI. ONSD might be related to the severity of cerebral vasogenic edema. Repeated measurement of ONSD by transorbital sonography may be useful to assess the pathological course and the effect of treatment in hypertensive encephalopathy.

Temporal Trends in Stroke Severity and Prior Antithrombotic Use Among Acute Ischemic Stroke Patients in Japan

BACKGROUNDnFew existing stroke registries allow for evaluation of stroke severity, stroke subtype and antithrombotic usage prior to stroke onset over a given time period. The present study aimed to elucidate temporal trends in initial presenting stroke severity, stroke subtype and prior antithrombotic use over a 12-year period in a Japanese multicenter stroke registry.nnnMETHODSANDRESULTSnWe included 71,017 acute ischemic stroke patients (72±12 years old; 27,445 women) from the Japan Standard Stroke Registry Study (JSSRS) who were admitted to 94 hospitals between 2001 and 2012. The mean age of stroke onset increased gradually over time (P<0.001). Cardioembolic stroke patients (n=19,247) exhibited more severe NIHSS scores when compared with those with non-cardioembolic stroke (n=50,427). The proportion of cardioembolic stroke patients tended to increase over time, rising from 25.9% in 2001-2002 to 30.2% in 2011-2012 (P<0.001). Among the cardioembolic stroke patients, the frequency of prior anticoagulant use significantly increased from 15.6% in 2001-2002 to 24.8% in 2011-2012 (P<0.001). The frequency of prior antiplatelet use increased from 2001-2002 to 2007-2008 but decreased after 2007-2008. Among both cardioembolic and non-cardioembolic stroke patients, initial stroke severity at admission decreased over time, particularly after 2008.nnnCONCLUSIONSnIn this Japanese study, the mean age of ischemic stroke onset increased, while the initial neurological severity at presentation decreased, over a 12-year period. (Circ J 2016; 80: 2033-2036).

Cilostazol May Decrease Plasma Inflammatory Biomarkers in Patients with Recent Small Subcortical Infarcts: A Pilot Study

BACKGROUNDnThe mechanism of progressive neurological deficit in patients with recent small subcortical infarcts has not yet been clarified. Inflammatory biomarkers and the use of cilostazol may be associated with this phenomenon.nnnMETHODSnBetween May 2013 and April 2014, we evaluated consecutive first-ever patients with stroke due to recent small subcortical infarcts within 48 hours of onset. We divided patients into 2 groups according to the use of antiplatelet agents (cilostazol with or without aspirin versus aspirin alone). Plasma biomarkers such as matrix metalloproteinase-9, interleukin-6, high sensitive C-reactive protein, and amyloid β precursor protein (APP770, indicating endothelial dysfunction) were measured twice: (1) within 24 hours; and (2) 1 week after their admission. Multivariable logistic regression analyses were performed to identify the variables independently associated with progressive neurological deficit and poor functional outcome.nnnRESULTSnWe analyzed 41 patients (male: 63.4%, mean age: 70.8 years). Most of the patients (90%) who were treated with cilostazol were concomitantly treated with aspirin. Matrix metalloproteinase-9 and high sensitive C-reactive protein were higher in patients with progressive neurological deficit compared with those without. APP770 were more likely to be decreased in cilostazol group compared with aspirin group. Multivariable analyses show that traditional risk factors such as age and National Institutes of Health Stroke Scale scores were independently associated with both progressive neurological deficit and poor functional outcome.nnnCONCLUSIONSnInflammatory biomarkers may be associated with progressive neurological deficit. Early initiation of cilostazol may decrease the levels of plasma biomarkers.

Screening for Fabry Disease in Japanese Patients with Young-Onset Stroke by Measuring α-Galactosidase A and Globotriaosylsphingosine

BACKGROUNDnFabry disease is an X-linked lysosomal storage disorder caused by mutations in GLA, which encodes the enzyme α-galactosidase A (α-Gal A). Although the prevalence of Fabry disease in patients with stroke has been reported to range from 0% to 4%, few cohort studies have examined Japanese stroke patients. We aimed to clarify the prevalence of Fabry disease and the frequency of GLA mutations among patients with young-onset stroke in Japan.nnnMETHODSnFrom April 2015 to December 2016, we enrolled patients with young-onset (≤60 years old) ischemic stroke or intracerebral hemorrhage. We measured α-Gal A activity and the concentration of globotriaosylsphingosine in plasma. Genetic evaluations were performed in patients with low α-Gal A activity or high concentrations of globotriaosylsphingosine.nnnRESULTSnOverall, 516 patients (median age of onset, 52 years old; 120 women) were consecutively enrolled in this study. Five patients (4 men and 1 woman) had low α-Gal A activity, and no patients were detected with the screen for plasma globotriaosylsphingosine levels. The genetic analysis did not identify a causative mutation responsible for classic Fabry disease in any of the patients, but 2 patients (.4%) carried the p.E66Q in GLA.nnnCONCLUSIONSnNo patient with Fabry disease was detected in our young-onset stroke cohort.

Plaque Characteristics of Patients with Symptomatic Mild Carotid Artery Stenosis

BACKGROUNDnCarotid revascularization may be considered for severe stenosis, but its use for symptomatic mild stenosis (<50%) with vulnerable plaque or ulcer remains uncertain. The characteristics of patients with symptomatic mild stenosis who underwent revascularization are reviewed.nnnMETHODSnThe subjects of this study were 18 patients with symptomatic mild stenosis (<50%) on angiography from among 175 patients who underwent revascularization in our department. The plaques were evaluated by black-blood magnetic resonance imaging (BB-MRI) and ultrasonography (US) and classified into 2 types: type 1 (nu2009=u200915), a lesion with an ulcer or mobile plaque or thrombosis on angiography or US; and type 2 (nu2009=u20093), a lesion without any of the above. Fourteen patients underwent carotid endarterectomy (CEA), and 4 patients underwent carotid artery stenting.nnnRESULTSnThe stenosis on angiography was 27.2%u2009±u200910.7 (5%-41%), and the area carotid artery stenosis rate on US was 69.8u2009±u200914.5% (44.5%-97%). The stenosis rate of these 2 methods was not at all correlated. In type 1 plaque that underwent CEA, 10 of 11 patients had vulnerable plaque by histopathology, and 1 patient had thrombus on the plaque by operative findings. In type 2 plaque that underwent CEA, all patients had vulnerable plaque by histopathology. During the follow-up period, none of the patients had restenosis or stroke.nnnCONCLUSIONSnThe findings of US and BB-MRI in patients with symptomatic mild stenosis (<50%) on angiography are important for determining treatment. If BB-MRI or US shows the findings of vulnerable plaque in mild stenosis, surgical treatment may be considered for these patients.

Impact of D-dimer levels for short-term or long-term outcomes in cryptogenic stroke patients

BackgroundD-dimer levels are used in several clinical settings, such as in predicting venous thrombosis, cardioembolic stroke and cancer status. In the present study, we investigated the associations between plasma D-dimer levels at admission, clinical characteristics and mortality at discharge in cryptogenic stroke patients. We also investigated whether D-dimer levels can predict long-term outcomes in those patients, including those with and without right-to-left shunt (RLS).MethodsAcute cryptogenic stroke patients (nxa0=xa0295, 72xa0±xa013xa0years old) were consecutively enrolled and retrospectively analyzed. We defined the cryptogenic stroke as an undetermined etiology according to the Trial of Org 10172 in Acute Stroke Treatment criteria. Plasma D-dimer levels at admission were evaluated. Assessments for RLS were performed using saline contrast-transcranial Doppler ultrasonography or contrast-transesophageal echography. Survivors (at discharge) underwent follow-up for up to 3xa0years after stroke onset.ResultsOf the total enrolled cohort, 17 patients died at discharge. D-dimer levels correlated with initial National Institutes of Health Stroke Scale (NIHSS) score (rxa0=xa00.391, Pxa0<xa00.001) and were associated with mortality at discharge [odds ratio 1.04; 95% confidence interval (CI) 1.00–1.08, Pxa0=xa00.049] after adjusting for age, sex and initial NIHSS score. Of the 278 survivors at discharge, 266 patients were evaluated to assess RLS during hospitalization, and 62 patients (23.3%) exhibited RLS. According to the median plasma D-dimer levels at admission (0.7xa0µg/ml), the patients were divided into a low D-dimer group (nxa0=xa0136,xa0<xa0median) and a high D-dimer group (nxa0=xa0130,xa0≥xa0median). Patients in the high D-dimer group were older, more frequently female, had a lower BMI, had a higher prevalence of cancer and had greater initial neurological severity compared to the patients in the low D-dimer group. During the follow-up period (median, 1093xa0days), 31 patients developed recurrent stroke and 33 patients died. High D-dimer levels at admission were independently associated with recurrent stroke and all-cause mortality [hazard ratio (HR) 3.76; 95% CI 1.21–14.1, Pxa0=xa00.021) in patients with RLS, but not in those without RLS (HR 1.35; 95% CI 0.74–2.50, Pxa0=xa00.335).ConclusionsIncreased D-dimer levels at admission were associated with mortality at discharge in cryptogenic stroke patients. In addition, high D-dimer levels were also associated with long-term outcomes in cryptogenic stroke patients with RLS.