P2Y12 Reaction Units and Clinical Outcomes in Acute Large Artery Atherosclerotic Stroke: A Multicenter Prospective Study.

AIMS: We aimed to determine the association between acute platelet reactivity and clinical outcome in acute ischemic stroke (AIS) or transient ischemic attack (TIA) with large-artery atherosclerosis (LAA). METHODS: In this prospective, 16-multicenter study, we enrolled AIS/TIA patients with LAA receiving clopidogrel. We assessed the association of P2Y12 reaction units (PRU) 24 hours after initiation of antiplatelets with the CYP2C19 genotype and recurrent ischemic stroke within 90 days, and the difference between acute (≤ 7 days) and subacute (8-90 days) phases. RESULTS: Among the 230 AIS/TIA patients enrolled, 225 with complete outcome data and 194 with genetic results were analyzed. A higher PRU was significantly associated with recurrent ischemic stroke within 90 days (frequency, 16%), and within 7 days (10%). Twenty-nine patients (15%) belonged to a CYP2C19 poor metabolizer group (CYP2C19＊2/＊2, ＊2/＊3, or ＊3/＊3). Multivariable receiver-operating characteristic analysis showed a greater area-under-the-curve (AUC) in predicting recurrence within 7 days, compared to 8-90 days (AUC, 0.79 versus 0.64; p=0.07), with a cut-off PRU of 254. Multivariable analysis showed high PRU (≥ 254), which had a comparable predictive performance for recurrent ischemic stroke within 7 days (odds ratio, 6.82; 95% CI, 2.23-20.9; p＜0.001) to the CYP2C19 poor metabolizer genotype. The net reclassification improvement, calculated by adding high PRU (≥ 254) to a model including the CYP2C19 poor metabolizer genotype in the prediction of recurrence within 7 days, was 0.83 (p＜0.001). CONCLUSIONS: Acute PRU evaluation possesses predictive value for recurrent ischemic stroke, especially within 7 days in AIS/TIA with LAA.

[Progressive multifocal leukoencephalopathy in a patient with rheumatoid arthritis under salazosulfapyridine treatment].

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by JC virus (JCV) activation. We report an 85-years old man who had been diagnosed to have rheumatoid arthritis (RA) 1.5 years prior to diagnosis of PML, and had been treated with salazosulfapyridine (SASP). He developed weakness of the left upper limb, which progressed gradually for two months. A neurological examination on admission revealed severe palsy of the left upper limb without sensory disturbance, cognitive decline or gait disturbance. Brain MRI revealed white matter lesions in the right frontal lobe around the precentral gyrus. Cerebrospinal fluid (CSF) examination and peripheral lymphocyte counts were normal. HIV was ruled out serologically. There were no findings suggestive of malignancy. We suspected PML and stopped SASP. JCV-DNA was detected in CSF. There were enlarged nuclei positive with VP-1 immunostaining in the brain biopsy materials. Thus, the diagnosis of PML was definitive. Paralysis of the left upper limb began to improve one week after discontinuing SASP. Treatment with mefloquine and mirtazapine was initiated, but he developed severe interstitial pneumonia, which might be caused by mefloquine. Therefore, he underwent rehabilitation without medication. JCV-DNA became undetectable and white matter lesions decreased 6 months later. Paralysis improved and he had no problem with activities of daily living a year later. The risk factor for PML has changed over the last decade, and drugs such as biologics became significant risk factors for patients with autoimmune diseases. There are reports suggesting that systemic lupus erythematosus (SLE) and RA themselves might be independent risk factors for PML. Although there is no previous report of SASP inducing PML, SASP might be the culprit in our case. However, there is another possibility that SAPS and RA worked synergistically for the onset of PML.

Intracardiac Thrombus Following Rivaroxaban Treatment in a Patient with Atrial Fibrillation Associated with Rheumatic Heart Disease.

We report a case of atrial fibrillation with rheumatic heart disease (RHD) who had intracardiac thrombus and cardiogenic cerebral embolism with rivaroxaban therapy. Intracardiac thrombus disappeared after switching from rivaroxaban to warfarin. Patients of RHD have the possibility of gradual progression of valvular disease even if they are old, so we need to distinguish nonvalvular atrial fibrillation from RHD before starting direct oral anticoagulants.

A case of recanalization of innominate artery and right middle cerebral artery embolism due to cardiogenic cerebral infarction with anticoagulation therapy.

An 80-year-old woman had an aortic valve replacement 1 month before admission and took warfarin for transient atrial fibrillation. She developed a disturbance of consciousness and left hemiplegia. On admission, the right radial artery was slightly palpable. Head MRI images showed a hyper-intense area in the right middle cerebral artery territory. MRA images showed an occlusion of the right M1 distal site and decreased signal at the right internal carotid artery. Contrast CT images of the ascending aorta showed an embolus in the innominate artery. She was diagnosed with an innominate artery saddle embolus and occlusion of the right cerebral artery due to cardiac embolism. She was treated with a heparin infusion and warfarin. She recovered consciousness and from hemiplegia gradually. Recanalization of the innominate artery and right cerebral artery was confirmed. In cases where the radial artery is slightly palpable, it is necessary to consider an innominate artery saddle embolus in addition to aortic dissection.

Relationship Between Infarct Volume and Prothrombin Time-International Normalized Ratio in Ischemic Stroke Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: In Japan, warfarin treatment at prothrombin time-international normalized ratio (PT-INR) of 1.60-2.60 is recommended for elderly patients with nonvalvular atrial fibrillation (NVAF). But it remains unknown whether PT-INR 1.60-1.99 has a similar effect on stroke severity as a value >2.0. The purpose of this study was to clarify the association between infarct volume and PT-INR levels.Methods and Results:The 180 patients (mean age, 76 years [SD, 10 years], 53% male) selected from 429 consecutive ischemic stroke patients admitted within 48 h of onset between 2004 and 2014 with NVAF were included. We classified them into 4 groups according to their PT-INR values on admission: no warfarin (NW), 129 patients; PT-INR <1.60 (poor control: PC), 29 patients; PT-INR 1.60-1.99 (low-intensity control: LC), 14 patients; and PT-INR ≥2.00 (high-intensity control: HC), 8 patients. Median (interquartile range: IQR) of infarct volume was 55 mL (IQR 14-175) in the NW, 42 mL (IQR 27-170) in the PC, 36 mL (IQR 6-130) in the LC, and 11 mL (IQR 0-39) in the HC groups. The infarct volume of the HC group was significantly smaller than in the other 3 groups, but no difference existed between the LC and PC groups or the LC and NW groups. CONCLUSIONS: Warfarin control at PT-INR of 1.60-1.99 is not effective for reducing the severity of ischemic stroke in NVAF patients.

Prediction of outcomes in MCI with (123)I-IMP-CBF SPECT: a multicenter prospective cohort study.

OBJECTIVE: The multicenter prospective cohort study (Japan Cooperative SPECT Study on Assessment of Mild Impairment of Cognitive Function: J-COSMIC) aimed to examine the value of (123)I-N-isopropyl-4-iodoamphetamine cerebral blood flow (IMP-CBF) SPECT in regards to early diagnosis of Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). METHODS: Three hundred and nineteen patients with amnestic MCI at 41 participating institutions each underwent clinical and neuropsychological examinations and (123)I-IMP-CBF SPECT at baseline. Subjects were followed up periodically for 3 years, and progression to dementia was evaluated. SPECT images were classified as AD/DLB (dementia with Lewy bodies) pattern and non-AD/DLB pattern by central image interpretation and automated region of interest (ROI) analysis, respectively. Logistic regression analyses were used to assess whether baseline (123)I-IMP-CBF SPECT was predictive of longitudinal clinical outcome. RESULTS: Ninety-nine of 216 amnestic MCI patients (excluding 3 cases with epilepsy (n = 2) or hydrocephalus (n = 1) and 100 cases with incomplete follow-up) converted to AD within the observation period. Central image interpretation and automated ROI analysis predicted conversion to AD with 56 and 58 % overall diagnostic accuracy (sensitivity, 76 and 81 %; specificity, 39 and 37 %), respectively. Multivariate logistic regression analysis identified SPECT as a predictor, which distinguished AD converters from non-converters. The odds ratio for a positive SPECT to predict conversion to AD with automated ROI analysis was 2.5 and combining SPECT data with gender and mini-mental state examination (MMSE) further improved classification (joint odds ratio 20.08). CONCLUSIONS: (123)I-IMP-CBF SPECT with both automated ROI analysis and central image interpretation was sensitive but relatively nonspecific for prediction of clinical outcome during the 3-year follow-up in individual amnestic MCI patients. A combination of statistically significant predictors, both SPECT with automated ROI analysis and neuropsychological evaluation, may increase predictive utility.

A multicenter brain perfusion SPECT study evaluating idiopathic normal-pressure hydrocephalus on neurological improvement.

PURPOSE: This study was designed to investigate the specific cerebral blood flow (CBF) pattern in patients with idiopathic normal-pressure hydrocephalus (iNPH) and a predictive value for shunt responsiveness in a multicenter study (Study of Idiopathic Normal-Pressure Hydrocephalus on Neurological Improvement: SINPHONI). METHODS: Eighty-four iNPH patients underwent shunt operations using MRI selection criteria from the SINPHONI and were subjected to CBF single photon emission computed tomography (SPECT). The perfusion patterns on SPECT were classified: anterior-dominant CBF reduction type (A type), posterior-dominant CBF reduction type (P type), and mixed or diffuse CBF reduction type (M type). The predictive value of the CBF pattern for favorable shunt outcome was evaluated. RESULTS: Favorable outcomes were obtained in 76% (64/84) of patients, and shunt responsiveness was achieved in 85% (71/84) of patients. Areas of severely reduced relative CBF were demonstrated around the corpus callosum and in the sylvian fissure area, which included the effects of dilatations of the ventricles and sylvian fissures and relatively increased perfusion in the medial and lateral frontal, parietal, and occipital areas at high convexity. Forty-nine (58%) cases were A type, 25 (30%) cases were M type, and 10 (12%) cases were P type. A, M, and P type cases exhibited 83, 84, and 90% positive predictive values for shunt responsiveness, respectively. Mean modified Rankin scale and Mini-Mental State Examination scores of the A type group were significantly better than those of other groups. CONCLUSION: The iNPH patients showed various patterns of CBF reduction, but there was no significant difference in the predictive value among the three patterns, though CBF reduction patterns may suggest a severe condition of iNPH.

Reversible alcohol-related dementia: a five-year follow-up study using FDG-PET and neuropsychological tests.

OBJECTIVE: As the pathophysiology of alcohol-related dementia (ARD) is unclear, we examined a patient with reversible ARD using neuropsychological tests and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET). DESIGN: A five-year follow-up case study with neuropsychological tests and FDG-PET. SETTING: Kyoto University Hospital. Patients A 42-year-old patient who was unable to perform his office duties because of slowly progressive amnesia with executive dysfunction. RESULTS: The initial evaluation with neuropsychological tests showed severe verbal memory disturbance. The patient did not discuss his excessive alcohol consumption in the initial history-taking session and thiamine deficiency was absent; therefore, early-stage Alzheimer's disease was suspected. Later, the patient revealed prior excessive alcohol intake and his cognitive function improved markedly after a period of abstinence. Retrospective analysis of initial FDG-PET images using a voxel-wise statistical method revealed glucose hypometabolism in the diencephalon and basal forebrain. Follow-up for 5 years after the initial evaluation showed improved cognitive function and recovery of glucose metabolism in the two brain regions. CONCLUSION: Hypofunction in the diencephalon and basal forebrain was associated with cognitive decline in our patient. This case may provide evidence for the etiopathic brain regions in reversible type ARD.

Gait disturbance associated with white matter changes: a gait analysis and blood flow study.

To clarify the mechanisms underlying gait disturbance secondary to age-related white matter changes (ARWMC), cerebral perfusion was investigated during treadmill walking. Twenty subjects with extensive hyperintensities in the periventricular and deep white matter on T(2)-weighted magnetic resonance images (MRI) were recruited. The ARWMC subjects were classified into gait-disturbed (GD) and non-GD groups according to clinical criteria. All the subjects underwent gait analyses and cerebral perfusion measurements during both gait and rest by using single photon emission computed tomography. The GD group showed greater double support time/phase and stride width, and slower walking velocity, than the non-GD group. In an analysis of pooled data from all the subjects, gait-induced increases in cerebral perfusion were observed in the supplementary motor areas (SMA), lateral premotor cortex (PMC), primary motor and somatosensory areas, visual areas, basal ganglia and cerebellum. A between-group comparison of gait-induced perfusion changes showed relative underactivation of the SMA, thalamus and basal ganglia, together with relative overactivation of the PMC, in the GD group compared with the non-GD group. In a separate correlation analysis including all the subjects, as the double support phase was longer (that was, gait disturbance was more severe), the gait-induced perfusion changes were proportionally reduced in the SMA, visual cortex, and thalamus. The present study suggests that abnormalities in the basal ganglia-thalamo-cortical loops partly explain gait disturbance observed in a subset of subjects with ARWMC.

Correlation between cognitive deficits and glucose hypometabolism in mild cognitive impairment.

BACKGROUND: In patients with mild cognitive impairment (MCI), poor performances on delayed recall and executive function are risk factors of progression to dementia. The aim of the present study was to clarify neural correlates of these neuropsychological deficits. METHODS: Thirty patients with amnestic MCI and 15 control subjects underwent neuropsychological tests including three-word delayed recall, visual delayed recall of Rey complex figure (RCF), and two-relational reasoning of Raven's colored progressive matrices (RCPM) with a (18)F-fluorodeoxyglucose (FDG)-position emission tomography (PET) measurement of resting state. We evaluated a relationship between performance of neuropsychological tests and regional cerebral glucose metabolism using voxel-based analysis. RESULTS: Poor performance in three-word delayed recall was related to glucose hypometabolism in the right medial temporal, right prefrontal, and left superior parietal cortices. The deficit in visual delayed recall of RCF correlated positively with hypometabolism in the bilateral posterior cingulate. The impairment in two-relational reasoning was associated with hypometabolism in the right prefrontal cortex. CONCLUSIONS: The present findings suggest that hypometabolism in the right medial temporal cortex, right prefrontal cortex, left superior parietal cortex, and bilateral posterior cingulate reflects impairments in delayed recall while hypometabolism in the right prefrontal cortex mirrors deficits in executive function in MCI.

Impairment of the cortical GABAergic inhibitory system in catatonic stupor: a case report with neuroimaging.

We report the case of a 32-year-old patient who presented with catatonic stupor during the course of acute aseptic encephalitis involving the right frontotemporal area. Flumazenil-PET performed during the stupor indicated decreased benzodiazepine receptor binding in the right frontotemporal area where glucose metabolism was preserved as revealed by FDG-PET. An injection of diazepam immediately ameliorated catatonic symptoms and reduced widespread high amplitude slow EEG activities with right frontotemporal predominance. Compared with a SPECT study performed a week earlier, there was no abnormal right-sided anteriorly predominant cerebral hyperperfusion after injection of diazepam. While neither flumazenil- nor FDG-PET could be repeated, and with the caveat that generalized convulsions occurred initially and epilepsia partialis continua was present for two weeks starting on the 23rd day after illness onset, these findings suggest that in our case the presentation with catatonic stupor may be related to impairment of the cortical GABAergic inhibitory system.

[Case of a 30-year history of PARK6 --findings from functional imaging of the brain].

We have reported a case of autosomal recessive juvenile parkinsonism PARK6 with a 30-year history. She developed tremor of right lower limb at the age of 23. At the age of 28, she received a clinical diagnosis of early-onset Parkinson's disease. She showed clinical improvements by the treatment with trihexyphenidyl, but symptoms showed slow progression over the subsequent years. L-DOPA therapy was introduced at the age of 42, and five years later, L-DOPA-induced dyskinesia developed. Dystonia, diurnal fluctuation and sleep benefit were absent. She carried a homozygous missense mutation in PINK1 gene, and was diagnosed as PARK6. The brain MRI did not show apparent abnormality. 18F-FDG-positron emission topography (PET) displayed normal uptake in the brain, suggesting normal glucose metabolism. PET imaging with a dopamine D2 receptor ligand 11C-raclopride revealed that postsynaptic 11C-raclopride uptake was normal in the bilateral putamen. After the introduction of pramipexisol, she showed clinical improvements. L-DOPA-induced dyskinesia disappeared with the gradual tapering and withdrawal of L-DOPA. In this PARK6 case, postsynaptic D2 receptors of the nigro-striatal dopaminergic neurons were thought to be maintained despite a long disease history.

Motor cortex stimulation for levodopa-resistant akinesia: case report.

We treated a patient with levodopa-resistant akinesia with motor cortex stimulation (MCS), and she showed dramatic improvement more than 1 year. On admission, the patient presented severe akinesia and gait disturbance without tremor and rigidity, and did not respond to levodopa test. The patient was suspected pure akinesia and progressive supranuclear palsy. First, high-frequency rTMS of primary motor cortex was examined, and showed the dramatic improvement. Next, chronic subdural electrodes were implanted over the motor cortex bilaterally. One year after surgery, the Unified Parkinson's Disease Rating Scale had improved remarkably, and she could walk four times faster than before. The H2 15O PET study showed a significant increase of rCBF in the left SMA and right dorsolateral prefrontal cortex after bilateral MCS. MCS may be an alternative treatment for patients with akinesia, including those with PD, and particularly for levodopa-resistant patients, who respond well to rTMS.

The lack of expression of the peripheral benzodiazepine receptor characterises microglial response in anaplastic astrocytomas.

The peripheral benzodiazepine receptor (PBR) is a 18 kDa molecule mainly involved in cholesterol transport through the mitochondrial membrane. In microglia, PBR is expressed from the earliest stages of activation and appears to exert a pro-inflammatory function. This molecule is commonly up-regulated in inflammatory, degenerative, infective and ischaemic lesions of the central nervous system but it has never been reported in glioma-infiltrating microglia. We examined two anaplastic astrocytomas showing minimal contrast-enhancement and therefore little damage of the blood brain barrier to minimise the presence of blood borne macrophages within tumour tissue. The two lesions were studied in vivo using positron emission tomography (PET) with the specific PBR ligand [(11)C](R)-PK11195 and the corresponding tumour tissue was investigated with an anti-PBR antibody. Glioma-infiltrating microglia were characterised for molecules involved in antigen presentation and cytotoxic activity. As comparison, PBR was investigated in three brains with multiple sclerosis (MS) and three with Parkinson's disease (PD). The expression profile of four anaplastic astrocytomas was also exploited and results were compared to the profile of eleven samples of normal temporal lobe and nine cases of PD. PET studies showed that [(11)C](R)-PK11195 binding was markedly lower in tumours than in the contralateral grey matter. Pathological investigation revealed that glioma-infiltrating microglia failed to express PBR and cytotoxic molecules although some cells still expressed antigen presenting molecules. PBR and cytotoxic molecules were highly represented in MS and PD. Evaluation of microarray datasets confirmed these differences. Our results demonstrated PBR suppression in glioma-infiltrating microglia and suggested that PBR may have a relevant role in modulating the anti-tumour inflammatory response in astrocytic tumours.

Decreased cerebral blood flow and prognosis of Alzheimer's disease: a multicenter HMPAO-SPECT study.

PURPOSE: To determine the usefulness of brain perfusion SPECT for evaluating the severity and progression of Alzheimer's disease (AD). METHODS: Eighty-four AD patients were included. At entry, 99mTc-HMPAO-SPECT, the Mini Mental State Examination (MMSE), Mental Function Impairment Scale (MENFIS), and the Raven Colored Progression Matrix (RCPM) were performed for all 84 patients. During the follow-up periods, two individual MMSE evaluations in 34 patients, two MENFIS evaluations in 30 patients, and two RCPM evaluations in 20 patients were performed. Based on the regions of decreased cerebral blood flow demonstrated on 3D-SSP images of SPECT, the cases were classified as type A (no decrease), type B (decreased blood flow in the parietal or temporal lobe), type C (decreased blood flow in the frontal lobe and parietal or temporal lobe), type Pc (decreased blood flow in posterior cingulate gyrus only), and "other types". The types of decreased blood flow, scores on neuropsychological evaluations, and symptom progression were analyzed. RESULTS: The MENFIS, MMSE, and RCPM scores were poorest in type C patients at entry. The degree of decrease of these scores during the follow-up periods was also greatest in type C. The greatest difference between patients with and without rapid progression in SPECT data of the mild AD patients (MMSE score > or = 24) was in the frontal lobe. CONCLUSION: Decreased blood flow in the frontal lobe of AD patients is correlated not only with reduced cognitive function at the time of the evaluation but with rapid progression in the subsequent clinical course.

Quantification of nicotinic acetylcholine receptors in Parkinson's disease with (123)I-5IA SPECT.

We quantified in vivo brain nicotinic acetylcholine receptor (nAChR) distributions in patients with Parkinson's disease (PD) and evaluated correlations between nAChR distributions and clinical variables of the patients, especially dopaminergic medications. Ten patients with PD without dementia underwent 5-(123)I-iodo-3-(2(S)-azetidinylmethoxy)pyridine ((123)I-5IA) single photon emission computed tomography (SPECT) and the data were compared with those of 10 age-matched healthy volunteers. Correlation analyses between (123)I-5IA distribution volumes (DVs) in each brain region and clinical variables of the patients were also performed. The PD group showed a statistically significant decrease (20-25%) in the brainstem and frontal cortex as compared with the control group. Although age, duration of disease, daily dose of levodopa, duration of PD medication use, and scores on the motor section of Unified Parkinson's Disease Rating Scale were not significantly correlated with DV values in any brain regions, high daily doses of dopamine agonist showed a significant negative correlation with DVs in the cerebellum, and temporal, parietal and occipital cortices. These findings suggest that patients with PD without dementia can show reductions especially in the brainstem and frontal cortex. They also suggest that dopamine agonists can have a negative influence on the distribution of nAChRs.

Neural mechanism of residual inhibition of tinnitus in cochlear implant users.

Residual inhibition is a transient suppression of tinnitus after auditory stimulation has stopped. We used positron emission tomography to study brain regions underlying residual inhibition in three tinnitus patients with cochlear implants and six normal hearing controls. Regional cerebral blood flow was measured and compared under two conditions: with tinnitus and during the residual inhibition of tinnitus. The right anterior middle and superior temporal gyri (Brodmann areas 21 and 38) were activated during residual inhibition, while the right cerebellum was activated during tinnitus perception in the tinnitus patients. No significant activation was observed in the normal controls. Our results suggest that tinnitus and residual inhibition are related to cortical networks of auditory higher-order processing, memory and attention.

Frontal nonconvulsive status epilepticus manifesting somatic hallucinations.

Somatic hallucinations are subjective experience of false, strange sensations of things occurring in or to the body. They can be seen in psychotic disorders, but have not been well described as an ictal psychosis in patients with nonconvulsive status epilepticus (NCSE) of frontal origin. We reported a 69-year-old woman who had NCSE of frontal origin manifesting prolonged somatic hallucinations mimicking a psychiatric disorder and initially treated as such. Ictal EEG revealed the frontal focus and ictal single-photon emission computed tomography (SPECT) showed the activation, not only in the frontal area but also in the parietal area as the projected regions, both of which might be associated with the development of her symptoms. She also had two generalized tonic-chronic seizures out of psychosis. Her psychosis and ictal rhythmic discharges on EEG ceased with valproate and she has since remained free from the symptoms. The current case suggests that long-lasting somatic hallucinations could be an ictal psychosis in frontal NCSE and thus an EEG study is needed for an early diagnosis and treatment.