The c-Abl inhibitor IkT-148009 suppresses neurodegeneration in mouse models of heritable and sporadic Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease of the central nervous system, with an estimated 5,000,000 cases worldwide. PD pathology is characterized by the accumulation of misfolded α-synuclein, which is thought to play a critical role in the pathogenesis of the disease. Animal models of PD suggest that activation of Abelson tyrosine kinase (c-Abl) plays an essential role in the initiation and progression of α-synuclein pathology and initiates processes leading to degeneration of dopaminergic and nondopaminergic neurons. Given the potential role of c-Abl in PD, a c-Abl inhibitor library was developed to identify orally bioavailable c-Abl inhibitors capable of crossing the blood-brain barrier based on predefined characteristics, leading to the discovery of IkT-148009. IkT-148009, a brain-penetrant c-Abl inhibitor with a favorable toxicology profile, was analyzed for therapeutic potential in animal models of slowly progressive, α-synuclein-dependent PD. In mouse models of both inherited and sporadic PD, IkT-148009 suppressed c-Abl activation to baseline and substantially protected dopaminergic neurons from degeneration when administered therapeutically by once daily oral gavage beginning 4 weeks after disease initiation. Recovery of motor function in PD mice occurred within 8 weeks of initiating treatment concomitantly with a reduction in α-synuclein pathology in the mouse brain. These findings suggest that IkT-148009 may have potential as a disease-modifying therapy in PD.

External ventricular drain use is associated with functional outcome in aneurysmal subarachnoid hemorrhage.

PURPOSE: External ventricular drains (EVD) are commonly used in aneurysmal subarachnoid hemorrhage (aSAH) patients and can be life-saving by diverting cerebrospinal fluid. However, the overall relationship between EVD use and outcome is poorly understood. METHODS: In an exploratory analysis of an aSAH patient cohort, we examined EVD use in relation to modified Rankin Scale (mRS) at hospital discharge and at 6 months (unfavorable outcome = mRS > 2) using univariable and multivariable analyses. RESULTS: EVDs were placed in 31 of 56 (55.4%) patients and more often in women than men (66.7% vs 35.0%, p = 0.022) despite similar rates of hydrocephalus. Women had greater ICU [18 (13.5-25) vs 11.5 (6.5-18.5) days, p = 0.014] and hospital lengths of stay (LOS) [20.5 (16.5-34) vs 13.5 (10.5-27) days, p = 0.015] than men and greater mRS at discharge [4 (3-5) vs 3 (2-3.5), p = 0.011] although mRS at 6 months was similar. Patients with EVDs had longer ICU and hospital LOS and greater mRS at discharge [5 (3-6) vs 2 (2-3), p < 0.001] and at 6 months [4 (2-6) vs 1 (0-2), p = 0.001] than those without an EVD. In multivariable models, EVD use was associated with unfavorable 6-month outcome accounting for age, sex, and admission modified Fisher scale, but not in models adjusting for Hunt and Hess scale and World Federation of Neurological Surgeons scale. CONCLUSION: In an aSAH cohort, the use of EVDs was associated with female sex and longer LOS, and may be linked to functional outcomes at discharge and at 6 months, although these associations warrant further investigation.

Prognostic Value of a Structural Brain MRI Score in the Acute Phase of Aneurysmal Subarachnoid Hemorrhage: A Pilot Study.

BACKGROUND/OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality despite advances in management. We evaluated the prognostic significance of a qualitative score using brain magnetic resonance imaging (MRI) features obtained early after aSAH. METHODS: Patients with aSAH were enrolled in a prospective observational cohort and underwent brain MRI during their acute hospitalization. MRIs were rated using a scoring system that considers the anatomical location of signal intensity changes on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences. The relationship between MRI scores and functional outcome defined by modified Rankin scale (mRS) at 6 months was evaluated in uni- and multivariable models. RESULTS: The cohort included 45 aSAH patients (median World Federation of Neurologic Surgeons (IQR) 2 (1-4)) who underwent brain MRI a mean (SD) of 9.0 ± 8.0 days after aSAH. At 6 months after aSAH, 26 patients had achieved a favorable outcome (mRS ≤ 2) while 15 had an unfavorable outcome (mRS > 2). Deep gray nuclei (DGN) score (p = 0.016), cortex + DGN score (p = 0.015), FLAIR score (p = 0.016), DWI score (p = 0.0045), and overall score (p = 0.0081) were significantly lower in patients with favorable outcome compared to those with unfavorable outcome. However, MRI scores were not independent predictors of outcome in multivariable models adjusting for admission Hunt and Hess, Glasgow Coma Scale, or World Federation of Neurologic Surgeons scales. CONCLUSIONS: In this pilot study, a qualitative scoring system using anatomically defined MRI FLAIR and DWI signal abnormalities identified in the acute phase of aSAH was linked to 6-month functional outcome. However, these scores did not add prognostic value to established indices of neurological severity.