A prospective multi-centre study of susceptibility map-weighted MRI for the diagnosis of neurodegenerative parkinsonism.

OBJECTIVES: This study aimed to compare susceptibility map-weighted imaging (SMwI) using various MRI machines (three vendors) with N-3-fluoropropyl-2-ß-carbomethoxy-3-ß-(4-iodophe nyl)nortropane (18F-FP-CIT) PET in the diagnosis of neurodegenerative parkinsonism in a multi-centre setting. METHODS: We prospectively recruited 257 subjects, including 157 patients with neurodegenerative parkinsonism, 54 patients with non-neurodegenerative parkinsonism, and 46 healthy subjects from 10 hospitals between November 2019 and October 2020. All participants underwent both SMwI and 18F-FP-CIT PET. SMwI was interpreted by two independent reviewers for the presence or absence of abnormalities in nigrosome 1, and discrepancies were resolved by consensus. 18F-FP-CIT PET was used as the reference standard. Inter-observer agreement was tested using Cohen's kappa coefficient. McNemar's test was used to test the agreement between the interpretations of SMwI and 18F-FP-CIT PET per participant and substantia nigra (SN). RESULTS: The inter-observer agreement was 0.924 and 0.942 per SN and participant, respectively. The diagnostic sensitivity of SMwI was 97.9% and 99.4% per SN and participant, respectively; its specificity was 95.9% and 95.2%, respectively, and its accuracy was 97.1% and 97.7%, respectively. There was no significant difference between the results of SMwI and 18F-FP-CIT PET (p > 0.05, for both SN and participant). CONCLUSIONS: This study demonstrated that the high diagnostic performance of SMwI was maintained in a multi-centre setting with various MRI scanners, suggesting the generalisability of SMwI for determining nigrostriatal degeneration in patients with parkinsonism. KEY POINTS: • Susceptibility map-weighted imaging helps clinicians to predict nigrostriatal degeneration. • The protocol for susceptibility map-weighted imaging can be standardised across MRI vendors. • Susceptibility map-weighted imaging showed diagnostic performance comparable to that of dopamine transporter PET in a multi-centre setting with various MRI scanners.

Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms.

Intracranial major artery stenosis/occlusion (ICASO) is the major cause of ischemic stroke. Recent studies have suggested that variants of RNF213, a susceptibility gene for moyamoya disease (MMD), are also related to non-MMD ICASO. Regarding the predominant involvement of steno-occlusion on anterior circulation in MMD, we hypothesized that the ICASO distribution pattern (anterior/posterior) in non-MMD may differ according to RNF213 variants. This study analyzed 1024 consecutive Korean subjects without MMD who underwent computed tomography angiography (CTA) or magnetic resonance angiography (MRA). We evaluated four single nucleotide polymorphisms (SNPs) in the exon region of RNF213: 4448G > A (rs148731719), 4810G > A (rs112735431), 4863G > A (rs760732823), and 4950G > A (rs371441113). Associations between RNF213 variants and anterior/posterior ICASO were examined using multivariate logistic regression analysis. Anterior ICASO was present in 23.0% of study subjects, and posterior ICASO was present in 8.2%. The GA genotype of RNF213 4810G > A (adjusted odds ratio (AOR) [95% confidence interval (CI)], 2.39 [1.14-4.87] compared to GG; p = 0.018) and GA genotype of RNF213 4950G > A (AOR [95% CI], 1.71 [1.11-2.63] compared to GG; p = 0.015) were more frequent in subjects with anterior ICASO. The genotype frequency of RNF213 4863G > A differed significantly according to the presence of posterior ICASO. Further investigations of the functional and biological roles of RNF213 will improve our understanding of the pathomechanisms of ICASO and cerebrovascular disease.

Effect of pioglitazone in acute ischemic stroke patients with diabetes mellitus: a nested case-control study.

BACKGROUND: Pioglitazone is an oral antidiabetic drug with multiple pleiotropic actions. Recent clinical trials have demonstrated that treatment with pioglitazone reduces cardiovascular risk in patients who have had an ischemic stroke. We examined the secondary preventive effects of pioglitazone in acute ischemic stroke patients with diabetes mellitus (DM) based on nationwide real-world data. METHODS: A nested case-control study was conducted with data from the National Health Insurance Service-National Sample Cohort in Korea. Study subjects were diabetic patients admitted for acute ischemic stroke (ICD-10 code; I63) between 2002 and 2013. Cases were defined as patients who suffered from composites of recurrent stroke (I60-63), myocardial infarction (I21), or all-cause mortality after ischemic stroke. Controls were selected by incidence density sampling. Three controls were matched to each case for sex, age, treatment with insulin, and oral antidiabetic medications, with the exception of pioglitazone. Medication history after ischemic stroke was obtained by accessing the prescription records. In the matched dataset, conditional logistic regression analysis was performed with adjustments for hypertension, atrial fibrillation, prior myocardial infarction, and treatment with oral antithrombotics and statins. RESULTS: From the patients with acute ischemic stroke and DM, 1150 cases with primary outcomes were matched to 3450 controls. In the matched analysis, treatment with pioglitazone was significantly associated with a lower cardiovascular risk (adjusted OR [95% CI], 0.43 [0.23-0.83]). CONCLUSIONS: In this nested case-control study using real-world data, treatment with pioglitazone exhibited significant cardiovascular preventive effect in diabetic patients with acute ischemic stroke.

Acute brainstem encephalitis associated with Mycoplasma pneumoniae in an adult: a case report.

Brainstem encephalitis (BE) associated with Mycoplasma pneumoniae in adults is rare, and the diagnosis is challenging. We describe an uncommon case of BE in an immunocompetent patient. A 43-year-old, otherwise healthy woman visited our emergency department with high fever and a sore throat, and 3 days later she returned with an altered drowsy mental status. Magnetic resonance imaging displayed diffuse swelling in bilateral cerebral regions involving the bilateral pons. The sera tested positive for the immunoglobulin (Ig) M antibody against M. Pneumoniae as detected by an enzyme immunoassay (EIA), and on hospital day 10, the level of IgM index against M. pneumoniae further increased from 1.5 to 2.1. We changed the antibiotic regimen from vancomycin and ceftriaxone to clarithromycin based on detection of M. pneumoniae, and we added intravenous immunoglobulin. After one month, the patient fully recovered from the neurological deficits. A follow-up brain magnetic resonance imaging was performed, which showed completely resolved lesions. Particle agglutination assay (PA) and EIA are both largely used to diagnose M. pneumoniae. Compared to the PA test, the EIA test could be a reliable tool because it separately measures IgM and IgG antibodies. We diagnosed BE associated with M. pneumoniae through EIA with an increasing level of IgM in the acute and subacute paired sera. Early treatment with macrolide antibiotics resulted in a good outcome.

CD5L as an Extracellular Vesicle-Derived Biomarker for Liquid Biopsy of Lung Cancer.

Cancer screening and diagnosis can be achieved by analyzing specific molecules within serum-derived extracellular vesicles (EVs). This study sought to profile EV-derived proteins to identify potential lung cancer biomarkers. EVs were isolated from 80 serum samples from healthy individuals and cancer patients via polyethylene glycol (PEG)-based precipitation and immunoaffinity separation using antibodies against CD9, CD63, CD81, and EpCAM. Proteomic analysis was performed using 2-D gel electrophoresis and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). The expression of proteins that were differentially upregulated in the EVs or tissue of lung cancer samples was validated by Western blotting. The area under the curve (AUC) was calculated to assess the predictability of each differentially expressed protein (DEP) for lung cancer. A total of 55 upregulated protein spots were selected, seven of which (CD5L, CLEC3B, ITIH4, SERFINF1, SAA4, SERFINC1, and C20ORF3) were found to be expressed at high levels in patient-derived EVs by Western blotting. Meanwhile, only the expression of EV CD5L correlated with that in cancer tissues. CD5L also demonstrated the highest AUC value (0.943) and was found to be the core regulator in a pathway related to cell dysfunction. Cumulatively, these results show that EV-derived CD5L may represent a potential biomarker-detected via a liquid biopsy-for the noninvasive diagnosis of lung cancer.

Triglyceride/HDL-Cholesterol Ratio as an Index of Intracranial Atherosclerosis in Nonstroke Individuals.

Background: Triglyceride (TG)/high-density lipoprotein cholesterol ratio (THR) is a marker of dyslipidemia, and high THR is associated with an increase in cardiovascular events. In the present study, whether THR was associated with various markers of cerebral vascular pathologies, atherosclerosis of major cerebral arteries, including large artery atherosclerosis (LAA) and cerebral small vessel disease (SVD), in neurologically healthy individuals was investigated. Methods: Vascular risk factors, brain magnetic resonance imaging (MRI) scans, and MR angiograms of 851 study subjects were evaluated. Findings of extracranial atherosclerosis (ECAS) and intracranial atherosclerosis (ICAS) were considered indices of LAA based on brain MR angiograms. The presence of silent lacunar infarct (SLI) and white matter hyperintensities (WMHs) were evaluated as indices of SVD based on brain MRIs. Results: Subjects with ICAS (odds ratio, 1.83; 95% confidence interval, 1.06-3.16; P = 0.03) were significantly more likely to have high THR tertile (THR > 2.06) than low THR tertile (THR < 1.37) after adjusting for cardiovascular risk factors. THR was higher in subjects with multiple ICAS lesions than in those with single ECAS or without ICAS lesions. Associations among THR tertiles in ECAS, SLI, and WMHs were not significant. Conclusion: In the present study, a positive association between high THR and the development of ICAS was observed in neurologically healthy participants.

Differential Impact of Plasma Homocysteine Levels on the Periventricular and Subcortical White Matter Hyperintensities on the Brain.

Background: The clinical significance of cerebral white matter hyperintensities (WMH) on brain magnetic resonance imaging (MRI) has recently increased, and recognized now as a risk factor for future stroke and dementia. High levels of plasma homocysteine (Hcyt) are associated with cerebral WMH. Recent studies suggest a different anatomy and physiology in the arteriolar system may be supplied to the periventricular and deep subcortical white matter. We hypothesize that plasma Hcyt levels have differing impacts on periventricular WMH (PVWMH) than on deep subcortical WMH (DSWMH). Methods: We evaluated plasma Hcyt levels from 937 neurologically healthy participants. The severity of PVWMH and DSWMH was evaluated by the use of a manual grading scale. Moderate to severe PVWMH and DSWMH levels were defined when the Fazekas score was two or three, respectively. Predominant PVWMH (pred-PVWMH) and predominant DSWMH (pred-DSWMH) were defined as having a difference of Fazekas score between PVWMH and DSWMH of two or more. Other confounding variables including age, sex, vascular risk factors, and estimated glomerular filtration rate (eGFR) were also analyzed. Results: Logistic regression revealed that, after adjusting for the confounding variables, PVWMH was associated with old age, hypertension, diabetes mellitus, low eGFR, and high plasma Hcyt levels. DSWMH was associated with old age, hypertension, and hypercholesterolemia but not with plasma Hcyt levels. Plasma Hcyt levels were associated with pred-PVWMH but not with pred-DSWMH. Conclusions: High plasma Hcyt levels are strongly associated with the development of PVWMH but not DSWMH. Our results suggest the possibility that different pathogeneses exist for PVWMH and DSWMH and that dysregulated Hcyt metabolism associated with the development of PVWMH.

A facile synthesis of poly(3-octylthiophene)-titanium dioxide nanocomposite particles in supercritical CO2.

Poly(3-octylthiophene) (P3OT)-titanium dioxide (TiO2) nanocomposite powder where TiO2 was embedded with homogeneous dispersion was synthesized by in-situ chemical oxidative polymerization of 3-octylthiophene in the presence of TiO2 nanoparticles in supercritical carbon dioxide (scCO2), using ferric chloride as the oxidant. The synthesized materials could be obtained as dry powder upon venting of CO2 after the polymerization. The composites were subsequently characterized by FT-IR spectroscopy, transmission electron microscopy (TEM), X-ray diffraction studies (XRD), thermogravimetric analysis (TGA) and photoluminescence (PL). The incorporation of TiO2 in the composite was endorsed by FT-IR studies. TGA revealed enhanced thermal stability of P3OT/TiO2 nanocomposite compared to 3-octylthiophene. TEM analysis showed that well dispersed TiO2 nanoparticles in the polymer matrix. Photoluminescence quenching increased with increasing TiO2 concentration in the composite.

Tonic Upward Eyeball Deviation Mimicking Non-Convulsive Occipital Lobe Status Epilepticus That Was Induced by Hydrocephalus.

Several seizure-like symptoms are difficult to differentiate from epileptic convulsion, and then if they were misdiagnosed, they could be led to grave prognosis. A 41-year-old man was referred to the emergency room due to unconsciousness. Brain computed tomography (CT) revealed acute subdural hemorrhage along the left frontal lobe, and intraparenchymal hemorrhage in the left temporo-occipital lobe. After emergent decompressive craniectomy, he recovered an alert mental state but became progressively drowsy. Four days later, virtually continuous tonic upward eyeball deviation was observed. He had been taking antiepileptic drugs following an occipital lobectomy 20 years prior due to intractable epilepsy, and we assumed these upward eyeball deviations were symptoms of non-convulsive occipital lobe status epilepticus. Hence, doses and classes of antiepileptic drugs were modified, but clinical manifestations did not improve. Follow-up brain CT revealed newly developed hydrocephalus and compression of the mesencephalon. His symptoms fully resolved after a ventriculo-peritoneal shunt operation. In this case report, we describe the case of a patient exhibiting tonic upward eyeball deviation induced by hydrocephalus that was not associated with a seizure.

Post lumbar puncture headache: Case report of a serious adverse event in first-in-human study.

A lumbar puncture can be used to measure the concentrations of drugs and/or pharmacodynamic biomarkers during clinical trials of central nervous system drugs. We report a case of a post lumbar puncture headache (PLPH) in a first-in-human study, which was reported as a serious adverse event. A 20-year-old man received 200 mg of the investigational product (IP) for 7 days and underwent a lumbar puncture for cerebrospinal fluid sampling before IP administration (Day 1, pre-dose) and after 7 days and multiple IP administrations (Day 7, 1 hour post-dose). After discharge on Day 8, the subject complained of headache, nausea, vomiting, neck stiffness, and numbness of the extremities. The symptoms occurred when he got up and disappeared after he remained in the supine position for several minutes. Five days later, he visited the neurology clinic of the main hospital. The neurologist recommended hospitalization for further evaluation and symptom management, and the subject was then admitted to the hospital. There were no abnormal findings in vital signs, laboratory results, or brain-computed tomography. His symptoms disappeared during the hospitalization period. It was important to distinguish whether the headache was IP-related or lumbar puncture-related. Therefore, knowledge of clinical characteristics and differential diagnosis of PLPH is paramount. Furthermore, if severe PLPH occurs, a consultation with a neurologist and imaging studies should be considered for a differential diagnosis of PLPH.

Differential impact of serum total bilirubin level on cerebral atherosclerosis and cerebral small vessel disease.

BACKGROUND: A low serum total bilirubin (T-bil) level is associated with an increased risk of atherosclerosis. However, the differential impact of the serum T-bil level on cerebral atherosclerosis and cerebral small vessel disease (SVD) is still unclear. METHODS: We evaluated serum T-bil levels from 1,128 neurologically healthy subjects. Indices of cerebral atherosclerosis (extracranial arterial stenosis [ECAS] and intracranial arterial stenosis [ICAS]), and indices of SVD (silent lacunar infarct [SLI], and moderate-to-severe white matter hyperintensities [msWMH]) were evaluated by the use of brain magnetic resonance imaging (MRI) and MR angiography. RESULTS: In logistic regression analysis after adjusting for confounding variables, subjects within middle T-bil (odds ratio [OR]: 0.63; 95% CI: 0.41-0.97) and high T-bil tertiles (OR: 0.54; 95% CI: 0.33-0.86) showed a lower prevalence of ECAS than those in a low T-bil tertile. Although subjects with a high T-bil tertile had a lower prevalence of ICAS than those with a low T-bil tertile, the statistical significance was marginal after adjusting for confounding variables. There were no significant differences in the proportions of subjects with SLI and msWMH across serum T-bil tertile groups. CONCLUSIONS: The serum T-bil level is negatively associated with cerebral atherosclerosis, especially extracranial atherosclerosis, but not with SVD.