SNCA Triplication Parkinson's Patient's iPSC-derived DA Neurons Accumulate α-Synuclein and Are Susceptible to Oxidative Stress

Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the α-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of α-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain

Macrovascular Lesions Underlying Spontaneous Intracerebral Hemorrhage

Spontaneous intracerebral hemorrhage (ICH) is a morbid disease with a high case fatality rate. Prognosis, rehemorrhage rates, and acute, clinical decision making are greatly affected by the underlying etiology of hemorrhage. This review focuses on the evaluation, diagnosis, and management of structural, macrovascular lesions presenting with ICH, including ruptured aneurysms, brain arteriovenous malformations, cranial dural arteriovenous fistulas, and cerebral cavernous malformations

Deviation From Personalized Blood Pressure Targets Is Associated With Worse Outcome After Subarachnoid Hemorrhage.

Background and Purpose- Optimal blood pressure (BP) management during the early stages of aneurysmal subarachnoid hemorrhage remains uncertain. Observational studies have found worse outcomes in patients with increased hemodynamic variability, suggesting BP optimization as a potential neuroprotective strategy. In this study, we calculated personalized BP targets at which cerebral autoregulation was best preserved. We analyzed how deviation from these limits correlates with functional outcome. Methods- We prospectively enrolled 31 patients with aneurysmal subarachnoid hemorrhage. Autoregulatory function was continuously measured by interrogating changes in near-infrared spectroscopy (NIRS)-derived tissue oxygenation-a surrogate for cerebral blood flow-as well as intracranial pressure (ICP) in response to changes in mean arterial pressure using time-correlation analysis. The resulting autoregulatory indices were used to identify the upper and lower limit of autoregulation. Percent time that mean arterial pressure exceeded limits of autoregulation was calculated for each patient. Functional outcome was assessed using the modified Rankin Scale at discharge and 90 days. Associations with outcome were analyzed using ordinal multivariate logistic regression. Results- Personalized limits of autoregulation were computed in all patients (age 57.5±13.4, 23F, mean World Federation of Neurological Surgeons 2±1, monitoring time 67.8±50.8 hours). Optimal BP and limits of autoregulation were calculated on average for 89.5±6.7% of the total monitoring period. ICP- and NIRS-derived optimal pressures strongly correlated with one another (P<0.0001). Percent time that mean arterial pressure deviated from limits of autoregulation significantly associated with worse functional outcome at discharge (NIRS, P=0.001; ICP, P=0.004) and 90 days (NIRS, P=0.002; ICP, P=0.003), adjusting separately for age, World Federation of Neurological Surgeons, vasospasm, and delayed cerebral ischemia. Conclusions- Both invasive (ICP) and noninvasive (NIRS) determination of personalized BP targets after aneurysmal subarachnoid hemorrhage is feasible, and these 2 approaches revealed significant collinearity. Furthermore, exceeding individualized limits of autoregulation was associated with poor functional outcomes

Thirty- and 90-Day Readmissions After Treatment of Traumatic Subdural Hematoma: National Trend Analysis.

ObjectiveSubdural hematoma (SDH), a form of traumatic brain injury, is a common disease that requires extensive patient management and resource utilization; however, there remains a paucity of national studies examining the likelihood of readmission in this patient population. The aim of this study is to investigate differences in 30- and 90-day readmissions for treatment of traumatic SDH using a nationwide readmission database.MethodsThe Nationwide Readmission Database years 2013-2015 were queried. Patients with a diagnosis of traumatic SDH and a primary procedure code for incision of cerebral meninges for drainage were identified using the International Classification of Diseases, Ninth Revision, Clinical Modification coding system. Patients were grouped by no readmission (Non-R), readmission within 30 days (30-R), and readmission within 31-90 days (90-R).ResultsWe identified a total of 14,355 patients, with 3106 (21.6%) patients encountering a readmission (30-R: n = 2193 [15.3%]; 90-R: n = 913 [6.3%]; Non-R: n = 11,249). The most prevalent 30- and 90-day diagnoses seen among the readmitted cohorts were postoperative infection (30-R: 10.5%, 90-R: 13.0%) and epilepsy (30-R: 3.7%, 90-R: 1.1%). On multivariate logistic regression analysis, Medicare, Medicaid, hypertension, diabetes, renal failure, congestive heart failure, and coagulopathy were independently associated with 30-day readmission; Medicare and rheumatoid arthritis/collagen vascular disease were independently associated with 90-day readmission.ConclusionsIn this study, we determine the relationship between readmission rates and complications associated with surgical intervention for traumatic subdural hematoma

Fixed Compared With Autoregulation-Oriented Blood Pressure Thresholds After Mechanical Thrombectomy for Ischemic Stroke.

Background and Purpose- Loss of cerebral autoregulation in the acute phase of ischemic stroke leaves patients vulnerable to blood pressure (BP) changes. Effective BP management after endovascular thrombectomy may protect the brain from hypoperfusion or hyperperfusion. In this observational study, we compared personalized, autoregulation-based BP targets to static systolic BP thresholds. Methods- We prospectively enrolled 90 patients undergoing endovascular thrombectomy for stroke. Autoregulatory function was continuously measured by interrogating changes in near-infrared spectroscopy-derived tissue oxygenation (a cerebral blood flow surrogate) in response to changes in mean arterial pressure. The resulting autoregulatory index was used to trend the BP range at which autoregulation was most preserved. Percent time that mean arterial pressure exceeded the upper limit of autoregulation or decreased below the lower limit of autoregulation was calculated for each patient. Time above fixed systolic BP thresholds was computed in a similar fashion. Functional outcome was measured with the modified Rankin Scale at 90 days. Results- Personalized limits of autoregulation were successfully computed in all 90 patients (age 71.6±16.2, 47% female, mean National Institutes of Health Stroke Scale 13.9±5.7, monitoring time 28.0±18.4 hours). Percent time with mean arterial pressure above the upper limit of autoregulation associated with worse 90-day outcomes (odds ratio per 10% 1.84 [95% CI, 1.3-2.7] P=0.002), and patients with hemorrhagic transformation spent more time above the upper limit of autoregulation (10.9% versus 16.0%, P=0.042). Although there appeared to be a nonsignificant trend towards worse outcome with increasing time above systolic BP thresholds of 140 mm Hg and 160 mm Hg, the effect sizes were smaller compared with the personalized approach. Conclusions- Noninvasive determination of personalized BP thresholds for stroke patients is feasible. Deviation from these limits may increase risk of further brain injury and poor functional outcome. This approach may present a better strategy compared with the classical approach of maintaining systolic BP below a predetermined value, though a randomized trial is needed to determine the optimal approach for hemodynamic management

Direct carotid puncture for mechanical thrombectomy in acute ischemic stroke patients with prohibitive vascular access

OBJECTIVE: While the benefit of mechanical thrombectomy (MT) for anterior circulation acute ischemic stroke patients with large vessel occlusion (AIS-LVO) has been clearly established, difficult vascular access may make the intervention impossible or unduly prolonged. In this study, we evaluated safety as well as radiographic and functional outcomes in stroke patients treated with MT via direct carotid puncture (DCP) for prohibitive vascular access. METHODS: We retrospectively studied patients from our prospective AIS-LVO database who underwent attempted MT between 2015–2018. Patients with prohibitive vascular access were divided into two groups: (1) aborted MT (abMT) after failed transfemoral access and (2) attempted MT via DCP. Functional outcome was assessed using the modified Rankin Scale (mRS) at 3 months. Associations with outcome were analyzed using ordinal logistic regression. RESULTS: Of 352 consecutive patients with anterior circulation AIS-LVO who underwent attempted MT, 37 patients (10.5%) were deemed to have prohibitive vascular access (mean age 82±11, 75% female, mean NIHSS 17±5). These included 20 patients in the DCP group and 17 in the abMT group. The two groups were well matched for known predictors of clinical outcome: age, sex, and admission NIHSS. Direct carotid access was successfully obtained in 19 of 20 patients. Successful reperfusion (TICI 2b-3) was achieved in 16 of 19 (84%) patients in the DCP group. Carotid access complications included: an inability to catheterize the carotid artery in 1 patient; small neck hematomas in 4 patients; non-flow limiting CCA dissections in 2 patients; and a delayed, fatal carotid blow-out in 1 patient. The small neck hematomas and non-flow limiting CCA dissections did not require any subsequent interventions and remained clinically silent. Compared to the abMT group, patients in the DCP group had smaller infarct volumes (11 versus 48 ml, P=0.04), a greater reduction in NIHSS (−4 versus +2.9, P=0.03), and better functional outcome (shift analysis for 3-month mRS OR 5.2, 95% CI 1.02–24.5, P=0.048). CONCLUSIONS: DCP for emergent MT in patients with anterior circulation AIS-LVO and prohibitive vascular access is safe and effective, and associated with higher recanalization rates, smaller infarct volumes, and improved functional outcome compared to patients with aborted MT after failed transfemoral access. DCP should be considered in this patient population