Yung-Yang Lin

Olfactory bulb (OB) microglia activation and inflammation can lead to olfactory dysfunction, which often occurs after an ischemic stroke. Inhibition of soluble epoxide hydrolase (sEH) attenuates neuroinflammation in brain injuries by reducing the degradation of anti-inflammatory epoxyeicosatrienoic acids. However, whether sEH inhibitors can ameliorate olfactory dysfunction after an ischemic stroke remains unknown. Ischemic brain injury and olfactory dysfunction were induced by middle cerebral artery occlusion (MCAO) in Wistar Kyoto rats. The rats were administered 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a selective sEH inhibitor. Olfactory function, cerebral infarct volume, and the degree of degeneration, microglial polarization and neuroinflammation in OB were evaluated. Following treatment with AUDA, rats subjected to MCAO displayed mild cerebral infarction and OB degeneration, as well as better olfactory performance. In OB, AUDA triggered a modulation of microglial polarization toward the M2 anti-inflammatory type, reduction in proinflammatory mediators, and enhancement of the antioxidant process. The effectiveness of AUDA in terms of anti-inflammatory, neuroprotection and anti-oxidative properties suggests that it may have clinical therapeutic implication for ischemic stroke related olfactory dysfunction. Graphical Abstract

Introduction: Dementia is associated with many comorbidities while being related to Apolipoprotein E (ApoE) polymorphism. However, it is unclear how these clinical illnesses and genetic factors modify the dementia risk.Methods: We enrolled 600 dementia cases and 6000 matched non-dementia controls, with identified ApoE genotype (ε4/ε4, ε4/ε3, and ε3/ε3). Eight comorbidities were selected by medical records, and counted if occurring within 3 years of enrollment.Results: The dementia group had a higher ratio of carrying ε4 allele and prevalence of comorbidities than the non-dementia group. Homozygous ε4 carriers presented the broken line of dementia risk with the peak age at 65–75 years and odds ratio (OR) up to 6.6. The risk only emerged after 65 years of age in ε3/ε4 subjects with OR around 1.6–2.4 when aged > 75 years. Cerebrovascular accident (CVA) is the commonest comorbidity (14.6%). CVA, sleep disorder, and functional gastrointestinal disorders remained as significant risk comorbidities for dementia throughout all age groups (OR = 1.7–5.0). When functional gastrointestinal disorder and ε4 allele both occurred, the dementia risk exceeded the summation of individual risks (OR = 3.7 and 1.9 individually, OR = 6.0 for the combination). Comorbidities could also be predictors of dementia.Conclusion: Combining the genetic and clinical information, we detected cognitive decline and optimize interventions early when the patients present a specific illness in a particular age and carry a specific ApoE allele. Of comorbidities, functional gastrointestinal disorder is the strongest predicting factor for dementia in ε4 allele carriers.

Musical transposing is highly demanding of working memory, as it involves mentally converting notes from one musical key (i.e., pitch scale) to another key for singing or instrumental performance. Because musical transposing involves mental adjustment of notes up or down by a specific amount, it may share cognitive elements with arithmetical operations of addition and subtraction. We compared brain activity during high and low working memory load conditions of musical transposing versus math calculations in classically trained musicians. Magnetoencephalography (MEG) was sensitive to differences of task and working memory load. Frontal-occipital connections were highly active during transposing, but not during math calculations. Right motor and premotor regions were highly active in the more difficult condition of the transposing task. Multiple frontal lobe regions were highly active across tasks, including the left medial frontal area during both transposing and calculation tasks but the right medial frontal area only during calculations. In the more difficult calculation condition, right temporal regions were highly active. In coherence analyses and neural synchrony analyses, several similarities were seen across calculation tasks; however, latency analyses were sensitive to differences in task complexity across the calculation tasks due to the high temporal resolution of MEG. MEG can be used to examine musical cognition and the neural consequences of music training. Further systematic study of brain activity during high versus low memory load conditions of music and other cognitive tasks is needed to illuminate the neural bases of enhanced working memory ability in musicians as compared to non-musicians.

Background: Clinical-diffusion mismatch between stroke severity and diffusion-weighted imaging lesion volume seems to identify stroke patients with penumbra. However, urgent magnetic resonance imaging is sometimes inaccessible or contraindicated. Thus, we hypothesized that using brain computed tomography (CT) to determine a baseline “clinical-CT mismatch” may also predict the responses to thrombolytic therapy. Methods: Brain CT lesions were measured using the Alberta Stroke Program Early CT Score (ASPECTS). A total of 104 patients were included: 79 patients with a baseline National Institutes of Health Stroke Scale (NIHSS) score ≥ 8 and a CT-ASPECTS ≥ 9 who were defined as clinical-CT mismatch-positive (P group) and 25 patients with an NIHSS score ≥ 8 and a CT-ASPECTS < 9 who were defined as clinical-CT mismatch-negative (the N group). We compared their clinical outcomes, including early neurological improvement (ENI), early neurological deterioration (END), delta NIHSS score (admission NIHSS—baseline NIHSS score), symptomatic intracranial hemorrhage (sICH), mortality, and favorable outcome at 3 months. Results: Patients in the P group had a greater proportion of favorable outcome at 3 months (p = 0.032) and more frequent ENI (p = 0.038) and a greater delta NIHSS score (p = 0.001), as well as a lower proportion of END (p = 0.004) than those in the N group patients. There were no significant differences in the incidence rates of sICH and mortality between the two groups. Conclusions: Clinical-CT mismatch may be able to predict which patients would benefit from intravenous thrombolysis.

Background: We proposed an algorithm to automate the components within the identification of components within the nidus of cerebral arteriovenous malformations (AVMs) which may be used to analyze the relationship between its diffuseness and treatment outcomes following stereotactic radiosurgery (SRS). Objectives: to determine the impact of the diffuseness of the AVM nidus on SRS outcomes. Methods: This study conducted regular follow-ups of 209 patients with unruptured AVMs who underwent SRS. The diffuseness of the AVM nidus was estimated by quantifying the proportions of vascular nidal component, brain parenchyma, and cerebrospinal fluid in T2-weighted MRIs. We used Cox regression analysis to characterize the association between nidal diffuseness and treatment outcomes in terms of obliteration rate and radiation-induced change (RICs) rate following SRS. Results: The median AVM volume was 20.7 cm³. The median duration of imaging follow-up was 51 months after SRS. The overall AVM obliteration rate was 68.4%. RICs were identified in 156 of the 209 patients (74.6%). The median proportions of the nidus of AVM and brain parenchyma components within the prescription isodose range were 30.2 and 52.2%, respectively. Cox regression multivariate analysis revealed that the only factor associated with AVM obliteration rate after SRS was AVM volume. However, a larger AVM volume (>20 mL) and a larger proportion of brain parenchyma (>50%) within the prescription isodose range were both correlated with a higher RIC rate following SRS. Conclusions: The diffuseness of the nidus indeed appears to affect the RIC rate following SRS in patients with unruptured AVMs.

Background: Ischemic stroke triggers inflammatory responses and oxidative stress in the brain, and microglia polarization affects the degree of neuroinflammation. It has been reported that the inhibition of soluble epoxide hydrolase (sEH) activity protects brain tissue. However, the anti-inflammatory and antioxidative effects of sEH inhibition in the ischemic brain are not fully understood. This study aimed to investigate the effects of a selective sEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), after ischemic stroke. Methods: Adult male rats with middle cerebral artery occlusion (MCAO) were administered with AUDA or a vehicle. Behavioral outcome, infarct volume, microglia polarization, and gene expression were assessed. Results: Rats treated with AUDA showed better behavioral outcomes and smaller infarct volumes after MCAO. After AUDA treatment, a reduction of M1 microglia and an increase of M2 microglia occurred at the ischemic cortex of rats. Additionally, there was an increase in the mRNA expressions of antioxidant enzymes and anti-inflammatory interleukin-10, and pro-inflammatory mediators were decreased after AUDA administration. Heme oxygenase-1 was mainly expressed by neurons, and AUDA was found to improve the survival of neurons. Conclusion: The results of this study provided novel and significant insights into how AUDA can improve outcomes and modulate inflammation and oxidative stress after ischemic stroke.

Status epilepticus (SE), a pro-epileptogenic brain insult in rodent models of temporal lobe epilepsy, is successfully induced by pilocarpine in some, but not all, rats. This study aimed to identify characteristic alterations within the hippocampal neural network prior to the onset of SE. Sixteen microwire electrodes were implanted into the left hippocampus of male Sprague-Dawley rats. After a 7-day recovery period, animal behavior, hippocampal neuronal ensemble activities, and local field potentials (LFP) were recorded before and after an intra-peritoneal injection of pilocarpine (350 mg/kg). The single-neuron firing, population neuronal correlation, and coincident firing between neurons were compared between SE (n = 9) and nonSE rats (n = 12). A significant decrease in the strength of functional connectivity prior to the onset of SE, as measured by changes in coincident spike timing between pairs of hippocampal neurons, was exclusively found in SE rats. However, single-neuron firing and LFP profiles did not show a significant difference between SE and nonSE rats. These results suggest that desynchronization in the functional circuitry of the hippocampus, likely associated with a change in synaptic strength, may serve as an electrophysiological marker prior to SE in pilocarpine-treated rats.