Ethnic-Associated Phenotype Variations in Moyamoya Cerebrovascular Outcomes.

INTRODUCTION: Moyamoya has been extensively described in East Asian populations, and despite its accepted clinical presentation and course, it is fundamental to describe major cerebrovascular complications in other ethnically diverse samples. Hence, we sought to determine if distinct ethnic groups are at higher risk of developing stroke using the National Inpatient Sample (NIS) database. METHODS: We included all moyamoya patients admitted from January 2013 until December 2018 in the NIS database. Multivariate regression analysis was used to determine the risk of developing stroke and poor outcomes in different races compared to white patients. RESULTS: Out of the 6093 admissions with diagnosis of moyamoya disease that were captured, 2,520 were white (41.6%), 2,078 were African American (AA) (34.1%), 721 were Hispanic (11.8%), and 496 were Asian (8.14%). For arterial ischemic stroke (AIS), we found that AA race had a significantly reduced risk of AIS compared to white patients (odds ratio = 0.8, 95% confidence interval: 0.7-0.9, p = 0.031). While being Hispanic or Asian significantly increased 1.5 and 2-fold the risk of hemorrhagic stroke. CONCLUSION: This study highlights the unique features and phenotypes of moyamoya cases among different ethnicities. While possibly AA are protected from developing AIS due to underlying causes of moyamoya such as sickle cell disease, Asians seems to be more susceptible to hemorrhagic stroke.

Peripheral Leukocytosis Predicts Cognitive Decline but Not Behavioral Disturbances: A Nationwide Study of Alzheimer's and Parkinson's Disease Patients.

INTRODUCTION: Peripheral and central nervous system inflammation have been linked to the classic symptoms of Parkinson's disease (PD) and Alzheimer's disease (AD). However, it remains unclear whether the analysis of routine systemic inflammatory markers could represent a useful prediction tool to identify clinical subtypes in patients with Parkinson's and Alzheimer's at higher risk of dementia-associated symptoms, such as behavioral and psychological symptoms of dementia (BPSD). METHODS: We performed a multivariate logistic regression using the 2016 and 2017 National Inpatient Sample with International Classification of Diseases 10th edition codes to assess if pro-inflammatory white blood cells (WBCs) anomalies correlate with dementia and BPSD in patients with these disorders. RESULTS: We found that leukocytosis was the most common WBC inflammatory marker identified in 3.9% of Alzheimer's and 3.3% Parkinson's patients. Leukocytosis was also found to be an independent risk factor for Parkinson's dementia. Multivariate analysis of both cohorts showed that leukocytosis is significantly decreased in patients with BPSD compared to patients without BPSD. CONCLUSIONS: These results suggest a link between leukocytosis and the pathophysiology of cognitive dysfunction in both PD and AD. A better understanding of the role of systemic neuroinflammation on these devastating neurodegenerative disorders may facilitate the development of cost-effective blood biomarkers for patient's early diagnosis and more accurate prognosis.

Moyamoya Disease and Syndrome: A National Inpatient Study of Ischemic Stroke Predictors.

OBJECTIVES: Ischemic stroke and hemorrhagic stroke are the most common sequelae of the Moyamoya variants [Moyamoya disease (MMD) and syndrome (MMS)]. We sought to determine the rates of stroke subtypes and the predictive factors of arterial ischemic stroke (AIS) utilizing a large data sample of MMD and MMS patients in the US. MATERIALS AND METHODS: We queried the 2016 and 2017 National Inpatient Sample database for Moyamoya diagnosis plus any of the following associated conditions; sickle cell disease, neurofibromatosis type 1, cranial radiation therapy or Down Syndrome. Multivariate regression determined the risk factors for AIS onset in MMD and MMS. RESULTS: 2323 patients with a diagnosis of Moyamoya were included; 668 (28.8%) patients were classified as MMS and 1655 (71.2%) as MMD. AIS was the most common presentation in both cohorts; however, MMD patients had higher rates of AIS (20.4 vs 6%, p < 0.001), hemorrhagic stroke (7.4vs 2.5%, p < 0.001), and TIA (3.3vs 0.9%, p = 0.001) compared to MMS patients. Multivariate analysis showed that increasing age [OR = 1.017 95%CI: 1.008-1.03, p < 0.001], lipidemia [OR = 1.32 95%CI: 1.02-1.74, p = 0.049], and current smoking status [OR = 1.43 95%CI: 1.04-1.97, p = 0.026] were independent risk factors for AIS in MMD patients, whereas hypertension [OR = 2.61 95%CI: 1.29-5.25, p = 0.007] and African-American race [OR = 0.274, 95%CI: .117-.64, p = 0.003] were independent predictors in the MMS cohort. CONCLUSION: AIS is the most common presentation in both, MMD and MMS. However, MMD patients had higher rates of stroke events compared to MMS. Risk factors for AIS in MMD included increasing age, lipidemia and smoking status, whereas in MMS hypertension was the only independent risk factor.

Phosphoglycerate kinase is a central leverage point in Parkinson's Disease driven neuronal metabolic deficits.

Phosphoglycerate kinase 1 (PGK1), the first ATP producing glycolytic enzyme, has emerged as a therapeutic target for Parkinson's Disease (PD), since a potential enhancer of its activity was reported to significantly lower PD risk. We carried out a suppressor screen of hypometabolic synaptic deficits and demonstrated that PGK1 is a rate limiting enzyme in nerve terminal ATP production. Increasing PGK1 expression in mid-brain dopamine neurons protected against hydroxy-dopamine driven striatal dopamine nerve terminal dysfunction in-vivo and modest changes in PGK1 activity dramatically suppressed hypometabolic synapse dysfunction in vitro. Furthermore, PGK1 is cross-regulated by PARK7 (DJ-1), a PD associated molecular chaperone, and synaptic deficits driven by PARK20 (Synaptojanin-1) can be reversed by increasing local synaptic PGK1 activity. These data indicate that nerve terminal bioenergetic deficits may underly a spectrum of PD susceptibilities and the identification of PGK1 as the limiting enzyme in axonal glycolysis provides a mechanistic underpinning for therapeutic protection.

Bidirectional Regulation of Motor Circuits Using Magnetogenetic Gene Therapy.

Regulating the activity of discrete neuronal populations in living mammals after delivery of modified ion channels can be used to map functional circuits and potentially treat neurological diseases. Here we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity in motor circuits when exposed to magnetic fields. AAV-mediated delivery of a cre-dependent nanobody-TRPV1 calcium channel into the striatum of adenosine 2a (A2a) receptor-cre driver mice led to restricted expression within D2 neurons, resulting in motor freezing when placed in a 3T MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed focal activation of the target region in response to the magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing cre into the globus pallidus led to similar circuit specificity and motor responses. Finally, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in subthalamic nucleus (STN) projection neurons in PitX2-cre parkinsonian mice resulted in reduced local c-fos expression and a corresponding improvement in motor rotational behavior during magnetic field exposure. These data demonstrate that AAV delivery of magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits non-invasively in vivo using clinically available devices for both preclinical analysis of circuit effects on behavior and potential human clinical translation.

Arterial Ischemic Stroke in Moyamoya Patients Who Underwent Vaginal Delivery and Cesarean Section.

BACKGROUND: Moyamoya disease (MMD) is characterized by stenosis, occlusion, and formation of aberrant collaterals of brain vessels. This derangement in the brain vessels in conditions associated with changes in intracranial pressure can lead to arterial ischemic stroke (AIS). A major challenge for stroke physicians is to recommend the safest method of delivery for pregnant patients with MMD. Using a large national database, our objective in this study was to analyze the risk of AIS in patients with MMD who underwent vaginal delivery (VD) and cesarean section (C-section). METHODS: We used the National Inpatient Sample database for the years 2013-2018 to identify patients with a diagnosis of MMD who underwent VD or C-section. Multiple logistic regression was performed to assess the risk of AIS in VD versus C-section. RESULTS: Of 2166 female patients with MMD, 97 underwent VD or C-section: 49 (50.51%) underwent VD, and 48 (49.48%) underwent C-section. The analysis of outcomes between VD and C-section showed a higher prevalence of AIS after VD compared with C-section (8.2% vs 6.3%, P = 0.716). The multivariate analysis for AIS showed that VD is not an independent risk factor compared with C-section (odds ratio = 2.1, 95% CI = 0.3-13.3, P = 0.417). CONCLUSIONS: Our data did not find evidence that VD and C-section are risk factors for AIS in pregnant patients with MMD.

Sterile Leukocytosis Predicts Hemorrhagic Transformation in Arterial Ischemic Stroke: A National Inpatient Sample Study.

OBJECTIVE: Hemorrhage transformation (HT) is a known complication of arterial ischemic stroke (AIS). In addition, it is known that the increase of proinflammatory immune cells in the brain tissue after AIS predict worse outcomes. However, it is not clear whether inflammation due to preceding or post-stroke infections affect outcomes and moreover, if systemic inflammatory markers could be useful as a clinical prediction tool for HT post-stroke. Therefore, our objective was to assess the association between systemic pro-inflammatory profile in AIS patients with HT and in-hospital mortality that did not course with acute infections during hospitalization. METHODS: This study was conducted using the 2016 and 2017 National Inpatient Sample (NIS) with International Classification of Diseases (ICD-10) codes. Multivariate logistic regression was used to examine the association between HT and in-hospital mortality with pro-inflammatory anomalies of white blood cells (WBCs) in AIS patients. Exclusion criteria comprised patients with under 18 years old, and with a diagnosis of gastrointestinal, urogenital, respiratory infection, bacteremia, viral infection, sepsis, or fever. RESULTS: A total of 212,356 patients with AIS were included in the analysis. 422 (0.2%) patients had a HT and 10,230 (4.8%) patients died during hospitalization. The most common WBC pro-inflammatory marker was leukocytosis with 6.9% (n=29/422) of HT and 5.5% (n=560/10,230) of patients that died during hospitalization. After adjusting for socio-demographic, comorbidities and treatment factors, leukocytosis was found to be an independent risk factor for both outcomes, HT [OR = 1.5, 95% CI: 1-2.3, p=0.024] and, in-hospital mortality [OR = 1.5, 95% CI: 1.3-1.6, p < 0.001]. CONCLUSION: Sterile leukocytosis is a potential clinical prediction tool to determine which patients are at higher risk of developing HT and die during hospitalization.

Younger age at intracranial aneurysms rupture among patients with opioid use disorders.

BACKGROUND: Association between opioid abuse and intracranial aneurysms rupture has been suggested in recent studies. However, these observations are limited to single center studies and could be benefited from validation in larger cohorts. Hence, we aimed to study the association between age at aneurysmal subarachnoid hemorrhage (aSAH) and opioid use disorders (OUD) using a large, national database. METHODS: This study was conducted using the 2016 and 2017 National Inpatient Sample (NIS) with ICD-10 codes. Cohorts were categorized as "Non-users", "OUD", and "Multi-drug users". Linear regression models were used to examine the association between OUD and multi-drug users with age at aneurysm rupture, and multiple logistic regression models were used for the association between in-hospital mortality and drug abuse. RESULTS: A total of 17,391 patients with aSAH were captured in the 2016 and 2017 NIS database. Out of these patients, 235 (1.4%) were included in the OUD group and 59 (0.3%) in the multi-drug users' group. Adjusted linear regression showed an unstandardized coefficient (UC) = -12.3 [95%CI = -14.4/-10.1, p < 0.001] for OUD patients and an UC = -16.8 [95%CI = -21.1/-12.5, p < 0.001] for multi-drug users, compared to non-users. The risk of in-hospital mortality was significantly increased in drug user, OR = 1.47 [95%CI: 1.1-2.01, p = 0.017] for OUD patients, and OR = 2.35 [95%CI: 1.35-4.11, p = 0.003] for multi-drug users. CONCLUSIONS: This is the first national study to examine the association between age at intracranial aneurysms rupture and opioid abuse. aSAH patients with history of OUD were 12 years younger compared to non-users, when OUD was combined with other drugs, the age at aneurysms rupture was 17 years younger. Further elucidation regarding the mechanisms by which opioids triggers aneurysms rupture and predispose to worsen outcomes following aSAH is required, as well as appropriate prevention, and management strategies for aSAH patients with OUD.