Byeong C. Kim

Magnetic Resonance Imaging Improves Cerebrospinal Fluid Biomarkers in the Early Detection of Alzheimer's Disease

Little is known of combined utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers for prediction of Alzheimers disease (AD) and longitudinal data is scarce. We examined these biomarkers at baseline and longitudinally in incipient AD. Forty-five subjects [21 controls (NL-NL), 16 stable MCI (MCI-MCI), 8 MCI who declined to AD (MCI-AD)] received MRI and lumbar puncture at baseline and after 2 years. CSF measures included total and phosphorylated tau (T-tau, P-tau(231)), amyloid-beta (Abeta(42)/Abeta(40)) and isoprostane. Voxel-based morphometry identified gray matter concentration (GMC) differences best distinguishing study groups and individual GMC values were calculated. Rate of medial temporal lobe (MTL) atrophy was examined using regional boundary shift (rBS) method. At baseline, for MRI, MCI-AD showed reduced GMC-MTL, and for CSF higher CSF T-tau, P-tau(231), IP and lower Abeta(42)/Abeta(40) as compared with MCI-MCI or NL-NL. Longitudinally, rBS-MTL atrophy was higher in MCI-AD than in either MCI-MCI or NL-NL, particularly in the left hemisphere. CSF data showed longitudinally greater increases of isoprostane in MCI-AD as compared with NL-NL. Combining baseline CSF-P-tau(231) and GMC-MTL significantly increased overall prediction of AD from 74% to 84% (p(step)<0.05). These results provide support for including multiple modalities of biomarkers in the identification of memory clinic patients at increased risk for dementia.

Effects of Flavonoid Compounds on β-amyloid-peptide-induced Neuronal Death in Cultured Mouse Cortical Neurons

Excessive accumulation of β-amyloid peptide (Aβ) is one of the major mechanisms responsible for neuronal death in Alzheimers disease. Flavonoids, primarily antioxidants, are a group of polyphenolic compounds synthesized in plant cells. The present study aimed to identify flavonoid compounds that could inhibit Aβ-induced neuronal death by examining the effects of various flavonoids on the neurotoxicity of Aβ fragment 25-35 (Aβ25-35) in mouse cortical cultures. Aβ25-35 induced concentration- and exposure-time-dependent neuronal death. Neuronal death induced by 20 µM Aβ25-35 was significantly inhibited by treatment with either Trolox or ascorbic acid. Among 10 flavonoid compounds tested [apigenin, baicalein, catechin, epicatechin, epigallocatechin gallate (EGCG), kaempferol, luteolin, myricetin, quercetin, and rutin], all except apigenin showed strong 1,1-diphenyl-2-pycrylhydrazyl (DPPH) scavenging activity under cell-free conditions. The flavonoid compounds except apigenin at a concentration of 30 µM also significantly inhibited neuronal death induced by 20 µM Aβ25-35 at the end of 24 hours of exposure. Epicatechin, EGCG, luteolin, and myricetin showed more potent and persistent neuroprotective action than did the other compounds. These results demonstrated that oxidative stress was involved in Aβ-induced neuronal death, and antioxidative flavonoid compounds, especially epicatechin, EGCG, luteolin, and myricetin, could inhibit neuronal death. These findings suggest that these four compounds may be developed as neuroprotective agents against Alzheimers disease.

Endovascular treatment and the outcomes of atherosclerotic intracranial stenosis in patients with hyperacute stroke.

BACKGROUND The importance of underlying atherosclerotic intracranial artery stenosis (ICAS) in hyperacute stroke patients who receive endovascular therapy remains unknown. OBJECTIVE To report and compare the outcomes of multimodal endovascular therapy in patients with hyperacute stroke with and without underlying ICAS. METHODS A total of 172 consecutive patients with acute stroke were treated with multimodal endovascular therapy that was heavily weighted toward stent-based thrombectomy. Patients with ICAS underwent emergent intracranial angioplasty or stenting. Data were compared between patients with and without ICAS. Revascularization was defined as Thrombolysis in Cerebral Infarction grade ≥2b. A favorable outcome was defined as a modified Rankin Scale score ≤2 or equal to the premorbid modified Rankin Scale score at 3 months. RESULTS ICAS was responsible for acute ischemic symptoms in 40 patients (22.9%). Revascularization and favorable outcome occurred more frequently in the ICAS group than in the control group (95% vs 81.8%, P = .04; 65% vs 40.2%, P = .01, respectively). The median baseline National Institutes of Health Stroke Scale score was significantly lower in the ICAS group compared with the control group (10 vs 12; P = .002). There were no significant differences between the 2 groups in the rates of symptomatic hemorrhage and mortality. CONCLUSION Emergent intracranial angioplasty with or without stenting is safe and feasible and yields a high rate of revascularization and favorable outcome in patients with hyperacute stroke and underlying ICAS. Patients with underlying ICAS have less severe infarctions at presentation and higher successful revascularization after multimodal endovascular therapy in the setting of hyperacute stroke compared with those with other stroke subtypes.

Prognostication of Recovery in Patients With Acute Ischemic Stroke Through the Use of Brain SPECT With Technetium-99m—Labeled Metronidazole

Background and Purpose— We hypothesized that technetium-99m-ethylene dicysteine-metronidazole (99mTc-EC-MN) localizes to brain tissue that is hypoxic but viable. This study prospectively evaluated the relationship between neurological outcome and uptake of 99mTc-EC-MN in peri-infarcted regions of the brain. Methods— Eight patients with acute ischemic stroke in the territory of the left middle cerebral artery underwent 99mTc-EC-MN and 99mTc-ethyl cysteinate dimer (ECD) brain SPECTs on the same day during the subacute stage (10.3±2.5 days). The infarct volumes from 99mTc-ECD images (IVECD), infarct volumes from diffusion-weighted MRI images (IVDW), and hypoxic volume (HV) from 99mTc-EC-MN images were calculated. The net infarct volume (NIVECD) was defined as IVECD minus HV. The National Institutes of Health Stroke Scale scores were measured on admission and days 1, 3, 7, and 30. Results— IVECD was greater than IVDW. The lesion-to-normal count-density ratios of 99mTc-EC-MN ranged from 1.80 to 5.96. HV was 60.2±65.2 cm3, and the mean percent HV was 24.5±28.1% of IVECD. NIVECD was 162.6±133.4 cm3 and was significantly smaller than IVECD. NIVECD was significantly correlated with National Institutes of Health Stroke Scale score at 1 month and was a significant predictor of neurological deficit at 1 month. Conclusions— 99mTc-EC-MN brain SPECT can detect hypoxic tissue after acute ischemic stroke and, in combination with 99mTc-ECD brain SPECT, is useful in predicting neurological outcome in ischemic stroke patients.

Regional cerebral blood flow differences in patients with mild cognitive impairment between those who did and did not develop Alzheimer's disease

Mild cognitive impairment (MCI) is a heterogeneous condition associated with increased risk of Alzheimers disease (AD) and other dementias. This study aimed to identify areas of initial hypoperfusion in MCI conversion to AD using technetium (Tc-99m) hexamethylpropyleneamine oxime (TC-99m HMPAO) single photon emission computed tomography (SPECT) to compare baseline cerebral hypoperfusion in converted MCI and non-converted MCI patients and normal controls. Forty-nine MCI patients were recruited for brain magnetic resonance imaging (MRI), detailed neuropsychological testing, Tc-99m HMPAO SPECT, and 1- to 2-year periodic follow-up to monitor progression to dementia status. We processed SPECT images with Statistical Parametric Mapping 8 (SPM8) software and performed voxel-based statistical parametric mapping analysis. Thirty-nine of 49 MCI patients were included in our analysis. Nine patients were diagnosed with conversion to AD, on average 19.0±6.6 months after initial assessment. Compared with normal controls, converted MCI patients demonstrated perfusion deficits in both parahippocampal gyri and right precuneus, and non-converted MCI patients demonstrated hypoperfusion in the left parahippocampal gyrus. Compared with non-converted MCI patients, converted MCI patients demonstrated significant hypoperfusion in both cingulate gyri and right precuneus. Our study suggests that using brain SPECT to identify initial hypoperfusion in patients with MCI may be helpful for predicting MCI patients likely to develop AD.

Meningitis Caused by Streptococcus suis: Case Report and Review of the Literature

Background Human infection with Streptococcus suis (S. suis), a zoonotic pathogen, has been reported mainly in pig-rearing and pork-consuming countries. Meningitis is the most-common clinical manifestation and is often associated with deafness and vestibular dysfunction. Case Report A 57-year-old man was referred to the hospital with headaches, fevers, chills, and hearing impairment. Meningitis was confirmed and S. suis was isolated from the cerebrospinal fluid. Spondylodiscitis occurred after 2 weeks of antibiotic treatment, and was successfully treated with a prolonged course of antibiotics for another 4 weeks. His hearing loss was irreversible despite the improvement of other symptoms. Conclusions We report the first human case of S. suis infection in Korea. In patients presenting with meningitis, S. suis should be considered if the characteristic features of prominent and early hearing loss are present.

Cassia obtusifolia seed ameliorates amyloid β-induced synaptic dysfunction through anti-inflammatory and Akt/GSK-3β pathways.

ETHNOPHARMACOLOGICAL RELEVANCE Tea infused with the seed of Cassia obtusifolia has been traditionally used as an herbal remedy for liver, eye, and acute inflammatory diseases. Recent pharmacological reports have indicated that Cassiae semen has neuroprotective effects, attributable to its anti-inflammatory actions, in ischemic stroke and Parkinsons disease models. AIM OF THE STUDY Previously, the ethanol extract of C. obtusifolia seeds (COE) was reported to have memory enhancing properties. However, the effects of COE in an Alzheimers disease (AD) model are currently unknown. In this study, we investigated the effect(s) of COE on aberrant synaptic plasticity and memory impairment induced by amyloid β (Aβ), a key toxic component found in the AD brain. MATERIALS AND METHODS To determine the effect of COE on Aβ-induced aberrant synaptic plasticity, we used acute mouse hippocampal slices and delivered theta burst stimulation to induce long-term potentiation (LTP). Western blots were used to detect Aβ- and/or COE-induced changes in signaling proteins. The novel object location recognition test was conducted to determine the effect of COE on Aβ-induced recognition memory impairment. RESULTS COE was found to ameliorate Aβ-induced LTP impairment in the acute hippocampal slices. Glycogen synthase kinase-3β (GSK-3β), a key molecule in LTP impairment, was activated by Aβ. However, this process was inhibited by COE via Akt signaling. Moreover, COE was found to attenuate Aβ-induced microglia, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX) activation. In the in vivo studies performed, COE ameliorated the Aβ-induced object recognition memory impairment. CONCLUSION These results suggest that COE exhibits neuroprotective activities against Aβ-induced brain disorders.

Clinical and genetic analysis of MAPT, GRN, and C9orf72 genes in Korean patients with frontotemporal dementia

The hexanucleotide repeat expansion (GGGGCC) in chromosome 9 open-reading frame 72 (C9orf72) and mutations in the microtubule-associated protein tau (MAPT) and progranulin (GRN) genes are known to be associated with the main causes of familial or sporadic amyotrophic lateral sclerosis and frontotemporal dementia (FTD) in Western populations. These genetic abnormalities have rarely been studied in Asian FTD populations. We investigated the frequencies of mutations in MAPT and GRN and the C9orf72 abnormal expansion in 75 Korean FTD patients. Two novel missense variants of unknown significance in the MAPT and GRN were detected in each gene. However, neither abnormal C9orf72 expansion nor pathogenic MAPT or GRN mutation was found. Our findings indicate that MAPT, GRN, and C9orf72 mutations are rare causes of FTD in Korean patients.

Midbrain atrophy in vascular Parkinsonism.

Background: Midbrain atrophy is a well-known feature of progressive supranuclear palsy (PSP). Some clinical features of vascular parkinsonism (VP) such as pseudobulbar phenomena, lower body predominance and early postural instability suggest that the brainstem could be associated with VP. The aim of this study was to determine whether midbrain atrophy was present in patients with VP. Methods: We measured the midbrain (Amd) and pons area (Apn) of 20 patients with VP, 15 patients with probable PSP and 30 patients with idiopathic Parkinson’s disease (IPD). The Amd and Apn were measured on mid-sagittal T1-weighted MRI scans using a computerized image analysis system. Results: For the Amd, the patients with VP (99.86 mm2) and PSP (87.30 mm2) had significantly smaller areas than the patients with IPD (130.52 mm2). For the Apn, there was a significant difference only between the VP (407.23 mm2) and the IPD (445.05 mm2) patients. The Amd/Apn ratios of the patients with VP (0.245) and PSP (0.208) were significantly smaller than in the patients with IPD (0.292). Conclusions: Our study shows that brainstem atrophy often occurs in patients with VP and the midbrain is more vulnerable than the pons to atrophic changes.

Isolated trochlear palsy due to midbrain stroke

Trochlear palsy from intra-axial lesions usually accompanies other neurological deficits, and isolated trochlear palsy due to midbrain stroke is extremely rare. We report two patients with isolated trochlear nerve palsy due to circumscribed dorsal midbrain strokes, one from infarction and the other from hemorrhage, which are located in the region of the trochlear nucleus or adjacent fascicle. Focal brain stem stroke should be considered as a rare cause of trochlear palsy even though there are no associated neurological deficits.