田中 亮太

脳梗塞後の軸索再生は、損傷後の組織再構築において重要な役割を担い、機能回復とも関連する。筆者は、ラット中大脳動脈閉塞モデルのperi-infarct areaにおいて、7日後の急性期に脱落した軸索や樹状突起は56日後の慢性期では再生していることを確認した。In vitroでは、虚血後軸索の再生にはphosphatase tensin homolog deleted on chromosome 10/Akt/Glycogen synthase kinase 3βシグナルが関わることを報告した。ラット慢性脳低灌流モデルでは、L-carnitine経口投与により脳白質において軸索再生とoligodendrocyteの再生によるミエリンの増強が生じ、慢性脳虚血ラットの認知機能障害が改善した。脳梗塞後の軸索再生、機能回復のメカニズムは多岐にわたり、今後軸索再生を目的とした脳梗塞新規治療薬の開発、実用化が期待される。(著者抄録)

BACKGROUND: Circadian blood pressure alterations are frequently observed in Parkinson's disease, but the association between these changes and dementia in the condition remains unclear. Here, we assess the relationship between abnormal nocturnal blood pressure profiles and dementia in Parkinson's disease. METHODS: We enrolled 137 patients with Parkinson's disease, who underwent 24 h ambulatory blood pressure monitoring, following cognitive and clinical assessment. RESULTS: Twenty-seven patients (19.7%) were diagnosed with dementia in this cohort. We observed significant associations of dementia with age, male gender, Hoehn-Yahr (H-Y) stage, diabetes mellitus, history of stroke, presence of cerebrovascular lesions on MRI, and orthostatic hypotension. Univariate logistic regression analysis showed that among the patterns of nocturnal blood pressure profiles, the riser pattern was significantly associated with dementia (OR 11.6, 95%CI: 2.14-215.0, P < 0.01), and this trend was observed after adjusting for all confounding factors except orthostatic hypotension (OR 19.2, 95%CI: 1.12-1960.3, P = 0.04). However, coexistence of a riser pattern and orthostatic hypotension was related to a higher prevalence of dementia (45.2%) than was a riser pattern alone (9.5%). Furthermore, coexistence of a riser pattern and orthostatic hypotension was significantly more associated with dementia than was a riser pattern alone, even after adjusting for confounders (OR 1625.1, 95%CI: 21.9-1343909.5, P < 0.01). CONCLUSIONS: Our results suggest a relationship between a riser pattern coexisting with orthostatic hypotension and dementia in Parkinson's disease. Further prospective studies are warranted to investigate whether abnormal nocturnal blood pressure profiles predict dementia in Parkinson's disease.

A 75-year-old woman presented with consciousness disturbance accompanied by hematemesis. Brain imaging revealed ischemia in the bilateral caudate nuclei and right cerebral watershed area due to stenosis of the right anterior cerebral artery (ACA) and bilateral internal carotid arteries (ICA), and hypoperfusion in the right caudate nucleus. The patient's only symptom was abulia, which gradually resolved. Further brain scans showed that the ICA stenosis had improved, although the right ACA stenosis persisted. This was a rare case of bilateral caudate nucleus infarctions with a hemodynamic etiology.

Conjugate eye deviation (CED) is defined as a sustained shift in horizontal gaze toward 1 side, together with gaze failure to the other side, caused by lesions in the brainstem, basal ganglia, or cortical frontal eye fields. To date, very few reports have described CED in patients with medullary infarction. A 76-year-old woman presented with sudden onset of vertigo and right hemiparesis, accompanied by CED to the right with gaze palsy to the left. Her brain magnetic resonance imaging showed left upper medial medullary infarction involving the left nucleus prepositus hypoglossi (NPH) and adjacent to the left inferior olivary nucleus (ION). After treatments with 200 mg of aspirin and 60 mg of edaravone daily, symptoms gradually improved. The NPH and ION constitute NPH-ION-floccus-vestibular nucleus loop and contribute to the inhibitory mechanisms for horizontal eye movements. In addition, NPH projects excitatory neurons to the contralateral vestibular nucleus. In our case, disorders of the NPH and ION might have dysregulated inhibitory and excitatory projections, and thereby cause CED to the right with gaze palsy to the left. This represents a rare case showing CED to the contralesional side in upper medial medullary infarction.

Background: Early neurological worsening is associated with increased mortality and long-term functional disability. We developed the WORSEN score for predicting whether patients with stroke will deteriorate during the week after stroke onset and investigated its usefulness. Patients and Methods: We retrospectively investigated the cases of 478 patients who were admitted to Juntendo University Hospital between April 2007 and March 2009. Neurological deterioration was defined as a worsening of 4 points or higher on the National Institute of Health Stroke Scale score within 1 week of admission. Based on a previous study, we developed the WORSEN score, which was derived from the following factors: wrong (poor) blood sugar control (W), old myocardial infarction (O), radiological findings (R), infarct size (S), elevated low-density lipoprotein cholesterol (E), and neurological findings (N). Next, we investigated the utility of this scoring system in 456 other patients who were admitted to Juntendo University Hospital and Juntendo Urayasu Hospital between October 2013 and December 2014. Results: First, we checked the utility of the WORSEN score for detecting worsening in cases of stroke. In the first patient group, deterioration was noted in 32.5% of the patients with scores higher than 3 points (sensitivity:.704 and specificity:.744). For checking reproductivity on using the second group, deterioration was detected in 36.1% of the patients with WORSEN scores higher than 3 points (sensitivity:.740 and specificity:.835). Conclusions: Careful attention should be paid to patients with acute stroke with high WORSEN scores. The WORSEN score might become a valuable tool for detecting the neurological deterioration of ischemic stroke.

Background: Peptides with cytoprotective functions, including antioxidants and anti-infectives, could be useful therapeutics. Carnosine, beta-alanine-histidine, is a dipeptide with anti-oxidant properties. Tripeptides of Ala-His-Lys, Pro-His-His, or Tyr-His-Tyr are also of interest in this respect. Results: We synthesized several histidine-containing peptides including glycine or alanine, and tested their cytoprotective effects on hydrogen peroxide toxicity for PC12 cells. Of all these peptides (Gly-His-His, Ala-His-His, Ala-His-Ala, Ala-Ala-His, Ala-Gly-His, Gly-Ala-His (GAH), Ala-His-Gly, His-Ala-Gly, His-His-His, Gly-His-Ala, and Gly- Gly- His), GAH was found to have the strongest cytoprotective activity. GAH decreased lactate dehydrogenase (LDH) leakage, apoptosis, morphological changes, and nuclear membrane permeability changes against hydrogen peroxide toxicity in PC12 cells. The cytoprotective activity of GAH was superior to that of carnosine against hydrogen peroxide toxicity in PC12 cells. GAH also protected PC12 cells against damage caused by actinomycin D and staurosporine. Additionally, it was found that GAH also protected SH-SY5Y and Jurkat cells from damage caused by hydrogen peroxide, as assessed by LDH leakage. Conclusion: Thus, a novel tripeptide, GAH, has been identified as having broad cytoprotective effects against hydrogen peroxide-induced cell damage.

We report a case of limb-shaking transient ischemic attack (TIA) caused by a dissection of the middle cerebral artery (MCA) following lung surgery under general anesthesia. An 81-year-old male patient who underwent lobectomy for lung cancer suddenly developed transient shaking movements of the neck and the left upper distal limb on postoperative day 1. On the basis of the double-barrel appearance of the right M1 segment of the MCA, a diagnosis of MCA dissection was made. Physicians should be aware that limb-shaking TIA is sometimes caused by MCA dissection and could be precipitated by any condition, including lung surgery under general anesthesia.

Aim: Fibromyalgia syndrome (FMS) is defined as chronic widespread pain that cannot be accounted for by any other medical disorder. Our aim was to explore the prevalence of thyroid autoimmunity in patients with FMS. Methods: For determining thyroid function in 207 FMS patients, we tested for the titers of free tri-iodothyronine, free thyroxine, thyroid-stimulating hormone (TSH), anti-thyroid peroxidase antibody (TPOAb), anti-thyroglobulin antibody (TgAb) and anti-TSH receptor antibody (TRAb). Results: Twenty-five patients who had either subclinical hyper-or hypothyroidism, or overt hypothyroidism were excluded. Sixty-nine FMS patients with autoimmune thyroid diseases (AITD) (37.9%, 69/182) were identified. The prevalence of positivity for TRAb, TgAb and TPOAb was 20.3% (n = 37), 16.5% (n = 30) and 13.2% (n = 24), respectively. Compared to control populations in previous studies, the prevalence of TRAb positivity was high, and titers of TRAb were low (1.0-1.5 IU/L). The prevalence of TPOAb and TgAb positivity was not significantly higher than that reported in FMS patients in previous studies. Clinical symptom profiles were identical for FMS patients with and without AITD. Conclusion: We found a high prevalence of AITD among 207 patients with clinically defined FMS, with TRAb being especially prominent among these patients. Further study is needed to evaluate changes in thyroid function among FMS patients with AITD.

We report a case of bilateral hearing loss caused by decreased vascular flow in the anterior inferior cerebellar artery (AICA) territory. A 74-year-old man who experienced right hearing loss 5 months ago presented with bilateral deafness and right cerebellar ataxia; however, no ischemic lesion was detected in the bilateral AICA area. After stroke treatment, hearing loss was improved. One month later, we obtained blood flow improvement in the left AICA territory on single-photon-emission computed tomography and vertebral artery stenosis on magnetic resonance angiography. Therefore, clinicians should recognize that bilateral hearing loss may be related to stroke in the vertebrobasilar artery area.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by cerebral infarction related to mutations in the notch homolog protein 3 (NOTCH3). We enrolled 10 patients whose brain magnetic resonance imaging (MRI) fluid-attenuated inversion recovery images showed hyperintensities (HIs) in the deep white matter and the external capsule. We then investigated the mutations in NOTCH3 using direct sequencing within the region of intron-exon boundaries in exons 2-24 of NOTCH3. Eight patients harboring NOTCH3 mutations (8 of 10) were identified, including a novel mutation, p.C162Y, and 3 cases with a sporadic form. Seven patients with cysteine replacement showed HI in the anterior part of the temporal lobes (ATLs), whereas these changes were not detected in 1 patient without cysteine replacement, p.R75P. Reviewing previous reports, we conclude that the patients can clearly be divided in 2 groups: those with cysteine replacement who showed HI in the ATL and those without cysteine replacement who showed no HI in the ATL. Our findings expand the understanding of genotypeephenotype correlations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. (C) 2016 Elsevier Inc. All rights reserved.

The role of metabolic diseases in ischemic stroke has become a primary concern in both research and clinical practice. Increasing evidence suggests that dysbiosis is associated with metabolic diseases. The aim of this study was to investigate whether the gut microbiota, as well as concentrations of organic acids, the major products of dietary fiber fermentation by the gut microbiota, are altered in patients with ischemic stroke, and to examine the association between these changes and host metabolism and inflammation. We analyzed the composition of the fecal gut microbiota and the concentrations of fecal organic acids in 41 ischemic stroke patients and 40 control subjects via 16S and 23S rRNA-targeted quantitative reverse transcription (qRT)-PCR and high-performance liquid chromatography analyses, respectively. Multivariable linear regression analysis was subsequently performed to evaluate the relationships between ischemic stroke and bacterial counts and organic acid concentrations. Correlations between bioclinical markers and bacterial counts and organic acids concentrations were also evaluated. Although only the bacterial counts of Lactobacillus ruminis were significantly higher in stroke patients compared to controls, multivariable analysis showed that ischemic stroke was independently associated with increased bacterial counts of Atopobium cluster and Lactobacillus ruminis, and decreased numbers of Lactobacillus sakei subgroup, independent of age, hypertension, and type 2 diabetes. Changes in the prevalence of Lactobacillus ruminis were positively correlated with serum interleukin-6 levels. In addition, ischemic stroke was associated with decreased and increased concentrations of acetic acid and valeric acid, respectively. Meanwhile, changes in acetic acid concentrations were negatively correlated with the levels of glycated hemoglobin and low density lipoprotein cholesterol, whereas changes in valeric acid concentrations were positively correlated with the level of high sensitivity C-reactive protein and with white blood cell counts. Together, our findings suggest that gut dysbiosis in patients with ischemic stroke is associated with host metabolism and inflammation.

Renal cell carcinoma (RCC) patients who develop a paraneoplastic syndrome may present with neuromuscular disorders. We herein report the case of a 50-year-old man who suffered from progressive gait disturbance and muscle weakness. The results of a nerve conduction study fulfilled the criteria of chronic inflammatory demyelinating polyneuropathy. An abdominal CT scan detected RCC, the pathological diagnosis of which was clear cell type. After tumor resection and a single course of intravenous immunoglobulin therapy, the patient's symptoms drastically improved over the course of one year. The patient's neurological symptoms preceded the detection of cancer. A proper diagnosis and the initiation of suitable therapies resulted in a favorable outcome.

We herein report the case of a 47-year-old female with the colony-stimulating factor 1 receptor (CSF1R) mutation p. G589R, which is related to hereditary leukoencephalopathy with axonal spheroid (HDLS). The patient presented with an early-onset cognitive decline and progressive aphasia. Brain magnetic resonance imaging revealed HDLS-related alterations. In addition, brain computed tomography revealed interspersed spotty calcifications in the frontal and parietal subcortical white matter, while a characteristic "stepping stone" appearance was observed in the frontal pericallosal regions. Our findings emphasize the importance of calcification appearances in establishing an HDLS diagnosis and in screening for CSF1R mutations.

The anti-paraneoplastic (Ma2/Ta) antibody is related to testicular, lung and ovarian cancers, and might cause paraneoplastic neurological disorders. We present a 25-year-old woman presenting various neurological symptoms of myokymia, chronic widespread pain, tremor, excessive daytime sleepiness, impaired eye of movements, and seizures and autonomic symptoms related to anti-Ma2/Ta antibodies. Needle electromyography showed spontaneous multiplet and myokymic discharges in the left vestus lateralis. Thus, we diagnosed her as Morvan syndrome. After initiation of steroids, plasma exchange and dantrolene, her symptoms partially improved with decreasing intensity of the antigen of anti-Ma2/Ta antibodies, from moderate strong to borderline. The present case expands the clinical spectrum of anti-Ma2/Ta antibodies-related disorders to include the existence of neuroimmune activation and Morvan syndrome.

Background: Midbrain infarction shows diverse patterns of ophthalmoplegia; however, the association of ophthalmoplegia with a precise microanatomy has not been fully studied. Here, we report a patient with characteristic ophthalmoplegia and explore the associated pathologic fiber tracts using diffusion-tensor imaging (DTI). Methods: A 21-year-old woman with an 11-year history of mixed connective tissue disease (MCTD) abruptly developed bilateral internuclear ophthalmoplegia (INO) with upward gaze and convergence palsies. Plasma levels of U1-ribonucleoprotein, double-stranded-DNA antibodies, and cerebrospinal fluid interleukin-6 were all increased. Diffusion-weighted imaging showed an acute ischemic lesion in the periaqueductal gray matter. Results: DTI exhibited a reduction of fractional anisotropy and an increase of apparent diffusion coefficient values in the tract involving the left medial longitudinal fasciculus (MLF) in the midbrain to the posterior commissure (PC) when compared to the right-sided tract in the midbrain and to the bilateral MLF in the upper pontine levels. Antiplatelet and immunosuppressant therapies dramatically improved her symptoms. Conclusions: We believe this is the first case of a patient with juvenile MCTD presenting with bilateral INO with an upward gaze and convergence palsies caused by midbrain infarction associated with vasculitis. It is suggested that DTI might identify the pathologic fiber tract connecting the left MLF in the midbrain to the PC.

Background and Purpose Underlying embolic causes diagnosed by transesophageal echocardiography could be implicated in mechanisms of embolic stroke of undetermined source. We aimed to explore factors, including underlying embolic causes, related to recurrent vascular events in embolic stroke of undetermined source. Methods Patients who fulfilled the diagnostic criteria for embolic stroke of undetermined source and whose potential embolic sources were examined by transesophageal echocardiography were included. Recurrent vascular events, including ischemic stroke, cardiovascular and peripheral artery diseases, and vascular death, were retrospectively analyzed. Cox proportional hazards regression analysis was used to explore factors, including clinical characteristics, embolic causes on transesophageal echocardiography, and the Calcification in the Aortic Arch, Age, Multiple Infarction score (CAM), based on the degree of aortic arch calcification on chest radiograph (0-3 points), age (70 years; 1 point), and multiple infarctions on magnetic resonance imaging (multiple infarcts in 1, 2, or 3 territories of large intracranial arteries, 1, 2, or 3 points) associated with recurrent vascular events. Results A total of 177 patients (age, 64.114.2 years; 127 men) were enrolled. Thirty-one patients had recurrent vascular events (follow-up, 3.5 +/- 2.7 years; annualized rate, 5.0% per person-year). Among embolic causes on transesophageal echocardiography, incidence of recurrent vascular events was high in patients with large aortic arch plaques (7.5% per person-year). Diabetes mellitus (hazard ratio, 2.56; 95% confidence interval, 1.23-5.32; P=0.012) and CAM score grade (hazard ratio, 2.29; 95% confidence interval, 1.11-4.72; P=0.026) predicted recurrent vascular events. Conclusions History of diabetes mellitus and the CAM score could be novel risk factors for recurrent vascular events in embolic stroke of undetermined source.

Background and Purpose Admission hyperglycemia is an independent risk factor for poor outcome of ischemic stroke. Amelioration of hyperglycemia by insulin has not been shown to improve the poststroke outcome. Glucagon-like peptide 1 receptor agonists, which modulate glucose levels by stimulating insulin secretion, have been shown to exert cytoprotective effects by inhibiting inflammation and oxidative stress. This study aimed to evaluate whether the glucagon-like peptide 1 receptor agonist exendin-4 could reduce glucose levels and exert protective effects after acute focal ischemia in hyperglycemic mice. Methods Hyperglycemia was induced by intraperitoneal injection of dextrose 15 minutes before transient middle cerebral artery occlusion was performed for 60 minutes using an intraluminal thread. We assessed 4 groups: (1) normal glucose (vehicle control), (2) induced hyperglycemia, (3) induced hyperglycemia with insulin treatment, and (4) induced hyperglycemia with exendin-4 treatment. Neurovascular injuries in brains from each group were evaluated 24 hours and 7 days post ischemia. Results Hyperglycemia significantly increased infarct volume (36.31.20 versus 26.9 +/- 1.28; P&lt;0.001), brain edema (P&lt;0.05), and hemorrhagic transformation compared with control (P&lt;0.001). This increase in infarct volume was associated with increased blood-brain barrier disruption and matrix metalloproteinase-9 activation. Exendin-4, but not insulin, attenuated matrix metalloproteinase-9 activation, proinflammatory cytokine (tumor necrosis factor-) release, and biomarkers of oxidative stress and showed significant inhibition of infarct growth at 24 hours (23.6 +/- 0.97 versus 36.3 +/- 1.20; P&lt;0.001) and at 7 days after ischemia (21.0 +/- 0.92 versus 29.3 +/- 1.41; P&lt;0.001). Conclusions Treatment with exendin-4 could be a potentially useful therapeutic option for treatment of acute ischemic stroke with transient hyperglycemia.

We report a 19-year-old female presenting with fever, drooling, anarthria, and voluntary facial movement disruption, characteristic of anterior opercular syndrome (AOS). Serological examination revealed Epstein-Barr virus (EBV) infection following acute encephalitis with severe ataxia. A single-photon emission computerized tomography (SPECT) examination indicated hypoperfusion in the left perisylvian region, bilateral thalamus, occipital lobe, and cerebellum. This is the first report of AOS related to EBV encephalitis. SPECT was a useful method for detecting the damaged region of the operculum. In addition, AOS is a clinically distinct entity that may help us understand the mechanisms of language circuits within the operculum.

AimFibromyalgia syndrome (FMS) is an extremely rare complication of neurocognitive disorders (NCDs). We experienced seven such cases, and we discuss their clinical manifestation and pathomechanisms. MethodsSeven patients with FMS as a complication of NCD were enrolled. We used the patients' medical records to identify clinical manifestations and obtain experimental data, such as pain questionnaire scores, cognitive tests, genetics and radiological imaging of the brain. ResultsThe seven patients were clinically diagnosed with frontotemporal NCD (n=3) or Alzheimer's disease (n=4). No patient presented with any organic disorder that would explain their chronic pain. Through their courses, they experienced refractory widespread pain continuously despite analgesics. Brain magnetic resonanceimaging revealed moderate or severe atrophic changes in the temporal lobes and hippocampus. Three-dimensional stereotactic surface projection (3D-SSP) analysis of brain single photon emission computed tomography (SPECT), indicated severe hypoperfusion on the right side of the medial temporal lobe, both sides of the anterior corpus callosum, anterior cingulate gyrus, and primary sensory area. Genetic analysis uncovered no pathogenic mutations. ConclusionsNeurodegenerative disorders are rarely complicated by FMS, which is associated with relatively severe pain. Central sensitization may be a possible risk factor of widespread pain in elderly patients with NCD.

Background: Clinical characteristics are important for determining the etiologies of embolic stroke, including patent foramen ovale and complex aortic plagues demonstrated on transesophageal echocardiography (TEE). This study sought to analyze the clinical signs of cryptogenic stroke (CS) without such embolic etiologies and to examine the association between CS and brain natriuretic peptide (BNP), which is currently unknown. Methods: Patients with CS after routine examinations who underwent TEE were included in this single-center observational study. Patients were classified into the potential embolic sources (PES) group (patients having PES on TEE) and the no potential embolic source (NPES) group. Patients were also categorized according to the tertile of BNP. Results: A total of 158 patients (age, 64.0 +/- 13.9 years; 119 males) with CS were enrolled. The PES group had 108 (68%) patients, and the NPES group had 50 (32%). Hypertension was more common, and glucose, D-dimer, and BNP were higher in the NPES than in the PES group (p &lt; 0.05). NPES was independently associated with high-BNP tertile (OR: 5.61; 95% CI: 1.91 to 16.44; p = 0.002). Conclusions: BNP, an indicator of cardioembolism, was closely associated with NPES. Cardiogenic mechanisms may be implicated in the etiology of CS without potential embolic etiologies on TEE. (C) 2015 Elsevier B.V. All rights reserved.

Introduction: Cerebral microbleeds (CMBs) are frequently observed in patients with cerebrovascular disease and Alzheimer's disease. CMBs that are located in the deep or infratentorial regions and those that are present strictly in the lobar regions reflect hypertensive vasculopathy and cerebral amyloid angiopathy, respectively. The development of CMBs can be accelerated by clinical factors. Orthostatic hypotension (OH) has been reported to be associated with cerebral small vessel disease, such as white matter lesions in Parkinson's disease (PD). We investigated the prevalence, location and risk factors, including OH, for CMBs in patients with PD. Methods: We conducted a retrospective chart review of consecutive patients with PD who were admitted to the Department of Neurology, Juntendo University School of Medicine between January 2010 and July 2014. One hundred and sixty-seven patients with PD who underwent gradient echo T2*-weighted magnetic resonance imaging of the brain were included in the present study. A multivariate logistic regression analysis was performed to investigate the associations between risk factors and the presence of CMBs. Results: CMBs were detected in 29 (17.4%) patients. Among the patients with CMBs, 19 (65.5%) had deep or infratentorial CMBs and 10(34.5%) had strictly lobar CMBs. Hypertension, OH and a history of ischemic stroke were independently associated with deep or infratentorial CMBs, whereas antiplatelet use was independently associated with strictly lobar CMBs. Conclusions: In patients with PD, deep or infratentorial CMBs were more frequent than strictly lobar CMBs, and were associated with hypertension, OH and a history of ischemic stroke. (C) 2015 Elsevier Ltd. All rights reserved.

Background: Early recurrence of an embolism is rarely observed in patients with stroke treated with intravenous thrombolysis. Pre-existing cardiac thrombus is thought as a risk factor for recurrent embolism, although the relationship remains unclear. Methods: The present patient was a 30-year-old man with acute ischemic stroke. Transthoracic echocardiography performed before thrombolysis demonstrated an intraventricular mobile thrombus, and the patient was treated with intravenous thrombolysis 183 minutes after the onset of stroke. During thrombolysis, he suffered from a peripheral artery embolism, without further signs of neurologic deterioration. Repeated transthoracic echocardiography showed the disappearance of the intraventricular thrombus. However, follow-up magnetic resonance imaging disclosed new ischemic lesions at the splenium of the corpus callosum, and body computed tomography showed infarction of the spleen and kidney. The peripheral artery embolism improved spontaneously without further evidence of recurrent embolism. Results: This is the first report to provide findings of an intracardiac mobile thrombus before thrombolysis and to demonstrate the acceleration of detachment of the thrombus during thrombolysis. Conclusions: Because there are currently no guidelines for the use of intravenous thrombolysis for acute ischemic stroke associated with a pre-existing intracardiac thrombus with respect to the efficacy and safety, physicians should pay special attention to similar cases.

Objective: Large atheromatous aortic plaques (AAPs) have been associated with ischemic stroke. There is little evidence to guide the therapeutic strategy for ischemic stroke associated with large AAPs. This study sought to analyze the temporal profile of AAPs after rosuvastatin therapy in Japanese patients with acute ischemic stroke. Methods: The Efficacy of Post-stroke Intensive Rosuvastatin Treatment for aortogenic Embolic stroke (EPISTEME) trial was a prospective, randomized, open-label study. Acute ischemic stroke patients with dyslipidemia and AAPs &gt;= 4-mm-thick on transesophageal echocardiography (TEE) were enrolled and randomly allocated to either the group treated with 5 mg/day rosuvastatin or the control group. The primary endpoint was the changes in volume and composition of AAPs on repeat TEE after 6 months. High-echoic plaque area was analyzed using binary images. Results: A total of 24 Japanese patients (rosuvastatin 12; control 12) were included in the primary analysis. Rosuvastatin substantially reduced low-density lipoprotein cholesterol (LDL-C) compared to control (-42.1% vs. 1.4%, P &lt; 0.001). Percent changes of high-echoic plaque areas were significantly increased in the rosuvastatin group, while they were decreased in the control group (65.8% vs - 14.7%, P &lt; 0.001). There was a significant linear correlation between percent increase in high-echoic plaque area and LDL-C decrease (r = 0.434, P = 0.002). Conclusion: Treatment with 5-mg rosuvastatin for 6 months might induce atheromatous aortic plaque stabilization together with marked LDL-C reduction in Japanese patients with ischemic stroke, which could provide evidence on which to base the therapeutic strategy for aortogenic brain embolism. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Diabetes mellitus (DM) is a major risk factor for stroke and it exacerbates tissue damage after ischemic insult. Diabetes is one of the important causes of the progression of white matter lesion, however, the pathological mechanisms remain unclear. The present study evaluated the influences of type 2 DM on ischemic subcortical white matter injury and the recruitment of oligodendrocyte progenitor cells (OPCs) under chronic cerebral hypoperfusion using type 2 diabetic (db/. db) mice. After bilateral common carotid artery stenosis (BCAS), the rarefaction in the white matter was more severe in db/. db mice than in db/+ mice, and the number of glutathione S-transferase-pi (GST-pi)-positive mature oligodendrocytes (OLG) was lower in db/. db mice than in db/+ mice at 4 and 8 weeks after ischemia. There were no significant differences in the number of single-stranded DNA (ssDNA)-positive apoptotic cells in the deep white matter between the db/. db and db/+ mice. We found a transient increase in the platelet-derived growth factor receptor-α (PDGFRα)-positive OPCs in white matter lesions after ischemia. However, significantly fewer PDGFRα-positive OPCs were detected in db/. db than db/+ mice from 4. weeks after BCAS. The number of Ki67-positive proliferating cells in the deep white matter was significantly lower in db/. db mice than in db/+ mice from 4 to 8. weeks after BCAS. Most of the Ki67-positive cells were PDGFRα-positive OPCs. Finally, we assessed the survival of 5-bromo-2'-deoxyuridine (BrdU)-positive proliferating cells in ischemic white matter, and found significantly poorer survival of BrdU/PDGFRα-positive OPCs or BrdU/GST-pi-positive OLGs in the db/. db mice compared to the db/+ mice in the white matter after BCAS. Our findings suggest that the type 2 DM mice exhibited more severe white matter injury 8 weeks after chronic ischemia. Decreased proliferation and survival of OPCs may play an important role in the progression of white matter lesions after ischemia in diabetics.

Chronic cerebral hypoperfusion causes white-matter lesions (WMLs) with oxidative stress and cognitive impairment. However, the biologic mechanisms that regulate axonal plasticity under chronic cerebral hypoperfusion have not been fully investigated. Here, we investigated whether L-carnitine, an antioxidant agent, enhances axonal plasticity and oligodendrocyte expression, and explored the signaling pathways that mediate axonal plasticity in a rat chronic hypoperfusion model. Adult male Wistar rats subjected to ligation of the bilateral common carotid arteries (LBCCA) were treated with or without L-carnitine. L-carnitine-treated rats exhibited significantly reduced escape latency in the Morris water maze task at 28 days after chronic hypoperfusion. Western blot analysis indicated that L-carnitine increased levels of phosphorylated high-molecular weight neurofilament (pNFH), concurrent with a reduction in phosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN), and increased phosphorylated Akt and mammalian target of rapamycin (mTOR) at 28 days after chronic hypoperfusion. L-carnitine reduced lipid peroxidation and oxidative DNA damage, and enhanced oligodendrocyte marker expression and myelin sheath thickness after chronic hypoperfusion. L-carnitine regulates the PTEN/Akt/mTOR signaling pathway, and enhances axonal plasticity while concurrently ameliorating oxidative stress and increasing oligodendrocyte myelination of axons, thereby improving WMLs and cognitive impairment in a rat chronic hypoperfusion model.

Chronic cerebral hypoperfusion causes white-matter lesions (WMLs) with oxidative stress and cognitive impairment. However, the biologic mechanisms that regulate axonal plasticity under chronic cerebral hypoperfusion have not been fully investigated. Here, we investigated whether L-carnitine, an antioxidant agent, enhances axonal plasticity and oligodendrocyte expression, and explored the signaling pathways that mediate axonal plasticity in a rat chronic hypoperfusion model. Adult male Wistar rats subjected to ligation of the bilateral common carotid arteries (LBCCA) were treated with or without L-carnitine. L-carnitine-treated rats exhibited significantly reduced escape latency in the Morris water maze task at 28 days after chronic hypoperfusion. Western blot analysis indicated that L-carnitine increased levels of phosphorylated high-molecular weight neurofilament (pNFH), concurrent With a reduction in phosphorylated phosphatase tensin homolog deleted on chromosome 10 (PTEN), and increased phosphorylated Akt and mammalian target of rapannycin (mTOR) at 28 days after chronic hypoperfusion. L-carnitine reduced lipid peroxidation and oxidative DNA damage, and enhanced oligodendrocyte marker expression and myelin sheath thickness after chronic hypoperfusion. L-carnitine regulates the PTEN/Akt/mTOR signaling pathway, and enhances axonal plasticity while concurrently ameliorating oxidative stress and increasing oligodendrocyte myelination of axons, thereby improving WMLs and cognitive impairment in a rat chronic hypoperfusion model.

Kimura disease (KD) is an uncommon chronic inflammatory disease presenting as subcutaneous lymphadenopathy with eosinophilia. To date, only a single case of brain embolism caused by fibroblastic endocarditis associated with KD has been reported. Watershed infarction was seen in patients with episodes of severe hypotension or cardiac surgery. We here report a young case of KD who developed ischemic stroke and showed multiple small infarcts in the border zones between the territories of major cerebral arteries, mimicking watershed infarction. Transesophageal echocardiography revealed patent foramen ovale and atrial septal aneurysm. Concurrently, deep venous thrombus in the femoral vein was found on duplex ultrasonography. Our case supports the notion that paradoxical brain embolism associated with KD can cause multiple small embolisms and mimic watershed infarction. (C) 2015 by National Stroke Association

A 64-year-old woman with an aortic mass experienced repeated recurrences of stroke (figure 1) and died 8 months later. The postmortem examination showed the tumor to almost completely obstruct the aortic lumen, while extending to the intracranial arteries without parenchymal invasion (figure 2). The pathologic diagnosis was undifferentiated aortic intimal sarcoma. Primary aortic sarcoma is a rare and aggressive tumor, with clinical symptoms including acute arterial embolism and disseminated metastasis.(1) Although arch atheroma is sometimes identified as a cause of cerebral emboli,(2) this case shows that primary aortic sarcoma should be included in the differential diagnosis of aortic arch diseases.

Aim: Prediabetes is an independent risk factor for future stroke. However, no effective treatment has yet been established for the recurrence of stroke in patients with prediabetes. Here we investigated the effects of pioglitazone, a potent peroxisome proliferator-activated receptor-gamma agonist, for the reduction of recurrent stroke in patients with prediabetes. Methods: Participants were patients who had a symptomatic ischemic stroke or transient ischemic attack (TIA) without a history of type 2 diabetes mellitus and who were diagnosed to have IGT or newly diagnosed diabetes by a 75-g oral glucose tolerance test. These patients were randomized to either receive or not receive pioglitazone. The primary endpoint was a recurrence of ischemic stroke. Results: A total of 120 patients were enrolled in the study. Sixty-three patients received pioglitazone and 57 were enrolled in the control group that did not receive pioglitazone. The majority of patients (68.3%) were prescribed 15 mg of pioglitazone, while the remaining patients (31.7%) were treated with 30 mg of pioglitazone. Over a median follow-up period of 2.8 years, treatment with pioglitazone was found to be associated with a lower rate of the primary endpoint (recurrence of stroke) than that observed in the control group [event rate = 4.8% pioglitazone vs 10.5% control, hazard ratio = 0.62, 95% confidence interval 0.13-2.35, p = 0.49]. However, differences were not statistically significant. Conclusions: While this study was too underpowered to determine the effect of pioglitazone, the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes.

Patients with advanced-stage Parkinson's disease (PD) occasionally experience refractory depression or catatonic stupor. Electroconvulsive therapy (ECT) has been reported as a successful procedure for both severe psychosis and motor symptoms in patients with PD. Four patients with PD who were receiving ECT were quantitatively evaluated using the Unified PD Rating scale part III, Hoehn and Yahr scale, Barthel index, Neuropsychiatric Inventory, mini-mental state examination, Revised Hasegawa's Dementia scale, Beck's Depression Inventory, and Hamilton Rating Scale for Depression-17. We adopted the "half-age" method, which is an age-based stimulus-dosing method. The patients showed improvement in symptoms of psychosis and motor symptoms without any adverse effects. The interval of improvement after ECT varied among patients. Of note, a decrease in psychiatric symptoms successfully alleviated the burden of caregivers. ECT may be useful to treat parkinsonism with refractory psychosis, major depression, or catatonic stupor, within the limitations of the patients enrolled.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal cystic disease, and it is associated with various extrarenal manifestations, including vascular complications, such as intracranial aneurysms, and aortic root dilatation and aneurysms. However, intracranial arterial dissection has rarely been reported. We herein report the cases of 2 patients with ADPKD who developed a vertebral artery (VA) dissection. Dissection was also observed on the other side of the VA and in the internal carotid artery in the first and second patient, respectively. Both patients also had a history of hypertension, which is frequently accompanied by ADPKD, and their serum creatinine levels were normal. Our report supports the importance of considering ADPKD as one of the possible pathogenic factors in arterial dissection.

Heat shock protein 27 (HSP27) exerts cytoprotection against many cellular insults including cerebral ischemia. We previously indicated that intravenous injection of HSP27 purified from human lymphocytes (hHSP27) significantly reduced infarct volume following cerebral ischemia-reperfusion injury, while recombinant HSP27 (rHSP27) was less effective. Phosphorylation is important for HSP27 function, and hHSP27 was more highly phosphorylated than rHSP27. We hypothesized that MAPKAP kinase 2 in vitro-phosphorylated rHSP27 (prHSP27) might increase its brain protection. Mice underwent transient 1-h middle cerebral artery occlusion (MCAO), and then received tail-vein injections of one of the following 1h after reperfusion: hHSP27 as positive control, rHSP27, prHSP27, or bovine serum albumin (BSA) as control. We measured infarct volume, neurological deficits, neurological severity, physiological parameters, cell-death, oxidative stress, and inflammatory response. Compared with BSA controls (30.7±3.1mm3, n=5), infarct volume was reduced by 67% in the hHSP27 positive-control group (10.1±4.6mm3, P&lt 0.001, n=5), 17% following rHSP27 (25.4±3.6mm3, P&lt 0.05, n=5), and 46% following prHSP27 (16.5±4.0mm3, P&lt 0.001, n=9). Compared to the rHSP27 and BSA-treated groups, prHSP27 also reduced functional deficits, and significantly suppressed apoptosis, oxidative stress, and inflammatory responses. Here, we showed the superior neuroprotective effects of phosphorylated HSP27 by administering prHSP27. prHSP27 may be a useful therapeutic agent to protect against acute cerebral ischemic stroke.

We report a case of cerebral venous thrombosis (CVT) associated with a giant adenomyosis. At admission, the patient demonstrated generalized seizures and consciousness disturbance. Brain fluid-attenuated inversion recovery magnetic resonance imaging revealed a localized, high-intensity region in the left frontal lobe. Subsequent brain angiography showed that right internal carotid angiograms display abrupt termination of the anterior half of the superior sagittal sinus and a filling defect in the lateral part of the left transverse sinus. The patient complicated with iron deficiency anemia (IDA) and adenomyosis with higher levels of serum carbohydrate antigen 125 (CA125) and D-dimer. After 1 year from onset, intermittent severe menalgia and headache persisted, and blood examination revealed abnormal values; the patient was receiving oral medications. Finally, adenomyosis resection was performed with a favorable outcome, and no recurrence was observed during the 2-year follow-up period. We conclude that IDA and increased CA125 levels may have promoted hypercoagulability and CVT. This report emphasizes the possible relationship between CVT and adenomyosis.

Background and purpose: Obesity is associated with the risk of coronary artery disease and stroke. Visceral fat plays a significant role in the atherogenic effects of obesity. Whether visceral fat accumulation, as measured by computed tomography (CT), is an independent risk factor for the presence of cerebral small vessel disease (SVD) was investigated. Methods: This study comprised 506 Japanese subjects 35-74 years of age (mean 55.3 years) without a history of symptomatic cerebrovascular disease who underwent health screening tests, including brain magnetic resonance imaging, carotid echography and measurements of the visceral fat area (VFA) and subcutaneous fat area (SFA) on abdominal CT. Visceral fat accumulation was defined as VFA ≥ 100 cm2. Logistic regression analysis was performed to examine the associations between visceral fat accumulation and cerebral SVD such as white matter lesions (WMLs) and silent lacunar infarction (SLI). Results: The prevalence of WMLs and SLI but not carotid plaque were significantly higher in subjects with VFA ≥ 100 cm2 than those with VFA &lt 100 cm2. A VFA ≥ 100 cm2 was associated with WMLs and SLI independent of age, cardiovascular risk factors and other measurements of obesity, such as waist circumference and body mass index. A large waist circumference was independently associated with SLI. SFA, the combination of VFA and SFA, and body mass index were not associated with WMLs or SLI. Conclusions: Visceral fat accumulation was independently associated with the presence of cerebral SVD in subjects without a history of symptomatic cerebrovascular disease. © 2014 EFNS.

We report a rare case of transient "dropped head syndrome'' (DHS) after acute ischemic stroke. A 64-year-old man noticed a sudden onset of mild weakness in his left hand and also difficulty in preventing his head from dropping onto his chest without weakness of the neck extensor muscles. Magnetic resonance images showed acute ischemic changes at the right putamen and caudate nucleus. Surface electromyography (EMG) performed 3 days after the stroke showed that both trapeziuses were hypertonic at rest, whereas the activity of the sternocleidomastoids was gradually increased on passive head lifting, indicating dystonia of the neck muscles. His dropped head fully improved by 9 days after the stroke. Re-examination by surface EMG 30 days after the stroke showed no hypertonic activity in the neck muscles. DHS is characterized by an abnormal ante-fixed posture of the neck, usually observed in patients with neurodegenerative disorders such as multiple system atrophy and Parkinson disease. This is the first case of reversible DHS after acute ischemic stroke, and the accumulation of similar cases will be important to elucidate the mechanisms underlying the development of DHS and stroke-associated movement disorders.

The association of the presence of cerebral microbleeds with antiplatelet use remains controversial. Long durations of antiplatelet use and vascular risk factors may have a greater impact on the development of cerebral microbleeds than short durations. The aim of this study was to determine whether the durations of antiplatelet use and vascular risk factors were associated with the presence of cerebral microbleeds in patients with ischemic cerebrovascular disease, who are frequently treated with antiplatelet agents. Two hundred twenty outpatients with ischemic cerebrovascular lesions (eg, cerebral infarcts and/or white matter lesions) detected by magnetic resonance imaging were examined. Patients with a history of cerebral hemorrhage were excluded. Cerebral microbleeds were observed in 71 (32.3%) patients. Deep or infratentorial microbleeds and strictly lobar microbleeds were observed in 53 (24.1%) patients and 18 (8.2%) patients, respectively. Aspirin use (odds ratio, 2.14; 95% confidence interval [CI], 1.02-4.73; P = .04) and a long duration (&gt;= 10 years) of aspirin use (odds ratio, 3.75; 95% CI, 1.31-10.86; P = .01) were significantly associated with deep or infratentorial microbleeds in the crude analysis, but this became nonsignificant after adjustment for hypertension and other confounding factors. The prevalence of antiplatelet use was significantly higher in the patients with hypertension than in those without hypertension (72.5% versus 49.1%, P = .002). Hypertension (odds ratio, 2.50; 95% CI, 1.11-6.41; P = .04) was significantly associated with the development of deep or infratentorial microbleeds even after adjustment for confounding factors and the association increased with the duration of hypertension. In conclusion, we found a significant association between aspirin use and deep or infratentorial microbleeds, but this association may reflect the presence of hypertension as a confounding factor.

Our objective is to report a rare coexistence of Parry-Romberg disease and ischemic stroke. Here, we report the case of a 34-year-old woman with Parry-Romberg syndrome who developed cerebral infarction. This patient developed sudden left-sided weakness and was admitted to our hospital. Magnetic resonance imaging revealed acute cerebral infarction in the posterior limb of the right internal capsule. The patient had been diagnosed with Parry-Romberg syndrome at the age of 12, and she had a history of migraine without aura. Transesophageal echocardiography revealed a patent foramen ovale, but no atrial septal aneurysm or deep vein thrombosis was observed in the lower extremities. She was treated with 200 mg of aspirin and 10 mg of atorvastatin. Her symptoms gradually improved, and she was discharged 10 days after admission. Parry-Romberg syndrome is a rare disease of progressive hemifacial atrophy with unknown etiology. The potential risk factors for ischemic stroke in Parry-Romberg syndrome include ipsilateral cerebrovascular abnormality or migraine. In addition, patent foramen ovale was identified as a concomitant risk factor in our case.

Background Large atheromatous aortic plaques (AAPs) are associated with stroke recurrence. Rosuvastatin is a potent lipid-lowering agent and suppresses carotid and coronary artery atherosclerosis. It is unclear whether rosuvastatin has anti-atherogenic effects against AAPs in stroke patients. We designed a clinical trial in stroke patients to analyze changes in AAPs after rosuvastatin treatment using repeated transesophageal echocardiography (TEE). This trial is a prospective randomized open label study. Inclusion criteria were patients were ischemic stroke with hypercholesterolemia and AAPs a parts per thousand yen4 mm in thickness. The patients are randomly assigned to either a group treated with 5 mg/day rosuvastatin or a control group. Primary endpoint is the changes in volume and composition of AAPs after 6 months using transesophageal echocardiography (TEE). Biochemical findings are analyzed. By using repeated TEE and binary image analysis, we will be able to compare the dynamic changes in plaque composition of AAPs before and after therapy in the two groups. The EPISTEME trial will provide information on the changes in plaque volume and composition achieved by improvement of lipid profiles with rosuvastatin therapy in stroke patients with aortic atherosclerosis. The results of the study may provide evidence for a therapeutic strategy for aortogenic brain embolism. This study is registered with UMIN-CTR (UMIN000010548).

A 61-year-old man who experienced a sudden onset of unstable gait followed by nuchal pain was admitted to our department. The neurologic examination revealed right-sided limb ataxia, right partial ptosis, and decreased sensation to 50% of the normal side to pinprick and temperature stimuli on the left side below the level of the T-6 dermatome. A lateral medullary infarction caused by spontaneous vertebral artery dissection was diagnosed by magnetic resonance imaging and computed tomography angiography. In conclusion, lateral medullary infarction is an important entity to consider in the differential diagnosis of dermatomal sensory manifestations.

Aim: Aortic arch calcification (AoAC) on chest X-rays represents systemic atherosclerosis and it is associated with ischemic cardiovascular diseases. However, the relationship between ischemic stroke and AoAC has yet to be fully elucidated. Methods: Patients with acute ischemic stroke who were undergoing chest X-ray, blood, and brain magnetic resonance imaging (MRI) examinations were prospectively studied. The extent of AoAC on chest X-ray was divided into four grades (0-3). Clinical characteristics, biochemical findings, white matter lesions on MRI, and AoAC extent were assessed in each stroke subtype, and the factors associated with AoAC were investigated. Results: A total of 175 patients (age, 70 +/- 13 years; 115 men) were enrolled in the study. According to the Trial of Org 10172 in Acute Stroke Treatment classification with minor modification, 33 patients (19%) had small artery occlusion (SAO), 42 (24%) had large artery atherosclerosis, 49 (28%) had cardioembolism, 24 (14%) had stroke with other determined etiologies, and 27 (17%) had stroke with undetermined etiologies. Compared to other stroke subtypes, the extent of AoAC was independently correlated with SAO (all p&lt;0.05). Age (odds ratio [OR]: 1.14, 95% confidence interval [CI]: 1.08 to 1.19, p&lt;0.001), hypertension, (OR: 3.44, 95% CI: 1.23 to 9.66, p=0.019), diabetes mellitus (OR: 2.19, 95% CI: 0.99 to 4.85, p=0.054), white matter lesions (OR: 1.54, 95% CI: 1.00 to 2.36, p=0.048), and SAO (OR: 1.38, 95% CI: 1.02 to 1.89, p=0.040) were significantly associated with AoAC. Conclusions: Age, hypertension, cerebral small artery disease, and possibly diabetes mellitus appear to be closely associated with AoAC in patients with acute ischemic stroke.

Adrenomedullin was originally isolated from pheochromocytoma cells and reduces insulin resistance by decreasing oxidative stress. White matter lesions induced by aging and hyperglycemia play a crucial role in cognitive impairment in poststroke patients. Here, we examine whether adrenomedullin deficiency and aging exacerbate ischemic white matter injury after prolonged cerebral hypoperfusion. Adrenomedullin heterozygous, wild-type young/aged mice were subjected to prolonged hypoperfusion. Prolonged cerebral hypoperfusion followed by immunohistochemical analysis was used to evaluate white matter injury. After prolonged hypoperfusion, white matter damage progressed in a time-dependent manner in AM(+/-) group compared with the wild-type group. The number of oligodendrocyte progenitor cells gradually increased after prolonged hypoperfusion, whereas oligodendrocytes decreased following a transient increase, but the ratio of increase was mild in the AM(+/-) group (p &lt; 0.05). Oxidative stress was detected in oligodendrocytes, with a larger increase in theAM(+/-) group (p &lt; 0.05). Aged mice showed the same tendency, butwhite matter damage was worse, especially in the aged AM(+/-) group. Our results demonstrated that white matter injury was increased in adrenomedullin deficiency, which induced oxidative stress. White matter injury was more exacerbated because of hyperglycemia in aged AM(+/-) group. Adrenomedullin may be an important target in the control of ischemic white matter injury.