Navitoclax safety, tolerability, and effect on biomarkers of senescence and neurodegeneration in aged nonhuman primates.

Alzheimer's disease (AD) is the most common global dementia and is universally fatal. Most late-stage AD disease-modifying therapies are intravenous and target amyloid beta (Aß), with only modest effects on disease progression: there remains a high unmet need for convenient, safe, and effective therapeutics. Senescent cells (SC) and the senescence-associated secretory phenotype (SASP) drive AD pathology and increase with AD severity. Preclinical senolytic studies have shown improvements in neuroinflammation, tau, Aß, and CNS damage; most were conducted in transgenic rodent models with uncertain human translational relevance. In this study, aged cynomolgus monkeys had significant elevation of biomarkers of senescence, SASP, and neurological damage. Intermittent treatment with the senolytic navitoclax induced modest reversible thrombocytopenia; no serious drug-related toxicity was noted. Navitoclax reduced several senescence and SASP biomarkers, with CSF concentrations sufficient for senolysis. Finally, navitoclax reduced TSPO-PET frontal cortex binding and showed trends of improvement in CSF biomarkers of neuroinflammation, neuronal damage, and synaptic dysfunction. Overall, navitoclax administration was safe and well tolerated in aged monkeys, inducing trends of biomarker changes relevant to human neurodegenerative disease.

Safety and Efficacy of Levomilnacipran Extended Release in Pediatric Patients Aged 7-17 Years with Major Depressive Disorder: Results of Two Phase 3, Randomized, Double-Blind Studies.

Objective: Major depressive disorder (MDD) presents a significant psychosocial burden, and there is an unmet need for additional treatment options in pediatric patients. Here, we report the results of two phase 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group studies evaluating the efficacy and safety of levomilnacipran extended release in children and adolescents with MDD. Methods: In the first study, LVM-MD-11, patients aged 12-17 years received daily doses of levomilnacipran 40 mg (n = 134), levomilnacipran 80 mg (n = 138), fluoxetine 20 mg (n = 134), or placebo (n = 141). In the second study, LVM-MD-14, patients aged 7-17 years received levomilnacipran 40 to 80 mg (n = 166), fluoxetine 20 mg (n = 166), or placebo (n = 160) daily. Primary and secondary efficacy endpoints were changes in Children's Depression Rating Scale-Revised (CDRS-R) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively. Results: In LVM-MD-11, there were no significant differences in change in CDRS-R total score between patients treated daily with placebo (least squares mean [LSM] change in CDRS-R total score -22.9) versus levomilnacipran 40 mg (-23.3; p = 0.8035) or 80 mg (-22.6; p = 0.8681). Similarly, in LVM-MD-14, there were no significant differences in LSM change in CDRS-R total score with placebo (-21.3) versus levomilnacipran 40 to 80 mg daily (-23.0; p = 0.2215). There were also no significant differences between the fluoxetine and placebo groups in either study for changes in CDRS-R total score. Changes in CGI-S score were not significant between placebo and levomilnacipran 40 to 80 mg daily or between placebo and fluoxetine. Levomilnacipran was generally well tolerated. Conclusions: The high placebo response in this study prevented the detection of an effect of levomilnacipran in children and adolescents. Clinical Trial Registration numbers: NCT02431806 and NCT03569475.

Treadmill-based system for postural studies: Design and validation.

Computer-controlled treadmills are common in many gait labs and offer great potential for conducting perturbation-based postural studies. However, the time-course of these disturbances can be too brief to be controlled manually through product software. Here we present a system that combines a Bertec® split-belt treadmill with custom hardware and software to deliver postural disturbances during standing and record data from multiple sources simultaneously. We used this system to administer to 15 healthy participants an 8-session perturbation-based training protocol in which they learned to respond without stepping to progressively larger perturbations. Kinematic, electromyographic, and force data were collected throughout. Motion capture was used to characterize the accuracy and repeatability of the treadmill-delivered perturbations with respect to duration, displacement, and peak velocity. These (observed) data were compared to that expected based on software commands and the known constraints of the treadmill (i.e., 10 Hz operating speed). We found perturbation durations to be as expected. Peak velocities and displacements were slightly higher than expected (average increases were 0.59 cm/s and 1.76 cm, respectively). Because this increase in magnitude was consistent, it did not impede training or affect data analysis. Treadmill behavior was repeatable across 95 % of trials.

A Multicenter Double-Blind, Placebo-Controlled Trial of Escitalopram in Children and Adolescents with Generalized Anxiety Disorder.

Objective: Generalized anxiety disorder (GAD) in children and adolescents is associated with substantial morbidity and increases the risk of future psychopathology. However, relatively few psychopharmacologic studies have examined treatments for GAD in pediatric populations, especially in prepubertal youth. Methods: Children and adolescents aged 7-17 years of age with a primary diagnosis of GAD were treated with flexibly dosed escitalopram (10-20 mg daily, n = 138) or placebo (n = 137) for 8 weeks. Efficacy measures included the Pediatric Anxiety Rating Scale (PARS) for GAD, Clinical Global Impression of Severity (CGI-S) scale, Children's Global Assessment Scale (CGAS); safety measures included the Columbia-Suicide Severity Rating Scale (C-SSRS) as well as adverse events (AEs), vital signs, and electrocardiographic and laboratory monitoring. Results: Escitalopram was superior to placebo in reducing anxiety symptoms of GAD, as seen in the difference in mean change from baseline to week 8 on the PARS severity for GAD score (least squares mean difference = -1.42; p = 0.028). Functional improvement, as reflected by CGAS score, was numerically greater in escitalopram-treated patients compared with those receiving placebo (p = 0.286), and discontinuation owing to AEs did not differ between the two groups. Vital signs, weight, laboratory, and electrocardiographic results were consistent with previous pediatric studies of escitalopram. Conclusions: Escitalopram reduced anxiety symptoms and was well tolerated in pediatric patients with GAD. These findings confirm earlier reports of escitalopram efficacy in adolescents aged 12-17 years and extend the safety and tolerability data to children with GAD aged 7-11 years. ClinicalTrials.gov Identifier: NCT03924323.

Clinical impact of the first pass effect on clinical outcomes in patients with near or complete recanalization during mechanical thrombectomy for large vessel ischemic stroke.

BACKGROUND AND PURPOSE: The first pass effect has been reported as a mechanical thrombectomy (MT) success metric in patients with large vessel occlusive stroke. We aimed to compare the clinical and neuroimagign outcomes of patients who had favorable recanalization (mTICI 2c or mTICI 3) achieved in one pass versus those requiring multiple passes. METHODS: In this "real-world" multicenter study, patients with mTICI 2c or 3 recanalization were identified from three prospectively collected stroke databases from January 2016 to December 2019. Clinical outcomes were a favorable functional outcome at 90 days (modified Rankin Scale score 0-2), and the rate of symptomatic intracranial hemorrhage (ICH) any ICH, and 90-day mortality. RESULTS: Favorable recanalization was achieved in 390/664 (59%) of consecutive patients who underwent MT (age 71.2 ± 13.2 years, 188 [48.2%] women). This was achieved after a single thrombectomy pass (n = 290) or multiple thrombectomy passes (n = 100). The rate of favorable clinical outcome was higher (41% vs. 28 %, p = .02) in the first pass group with a continued trend on multivariate analysis that did not reaching statistical significance (OR 1.68 95% confidence interval [CI] 1.0-2.95, p = .07). Similarly, the odds of any ICH were significantly lower (OR 0.56 CI 0.32-0.97, p = .03). A similar trend of favorable clinical outcomes was noticed on subgroup analysis of patients with M1 occlusion (OR 1.81 CI 1.01-3.61, p = .08). CONCLUSION: The first-pass reperfusion was associated with a trend toward favorable clinical outcome and lower rates of ICH. These data suggest that the first-pass effect should be the mechanical thrombectomy procedure goal.

Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia.

Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT myeloid neoplasia (MN), clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.

Successful Intravascular Treatment of an Intraosseous Arteriovenous Fistula in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a benign bone disease characterized by expansile lesions that typically stabilize with age. Rarely, FD can undergo malignant transformation, presenting with atypical, rapid growth and destruction of adjacent bone. Other potential causes of rapid FD expansion include secondary lesions, such as aneurysmal bone cysts. We describe a case of an aggressive occipital lesion that presented with pain associated with diplopia and tinnitus, raising concern for malignant transformation. A massive intraosseous arteriovenous fistula was identified giving rise to an anomalous vein coursing to the cavernous sinus with compression of the abducens nerve. The vascular anomaly was mapped and after embolization symptoms resolved; a biopsy with extensive genetic analyses excluded malignancy. The differential diagnosis for expanding FD lesions includes aggressive FD, malignant transformation, and secondary vascular anomalies. In cases when traditional radiographic and histologic assessments are nondescript, use of additional radiographic modalities and genetic analyses are required to make an accurate diagnosis and guide treatment. When vascular anomalies are suspected, detailed angiography with embolization is necessary to define and treat the lesion. However, to rule out malignant transformation, genetic screening is recommended.

Symbiotic Origin of Aging.

Normally aging cells are characterized by an unbalanced mitochondrial dynamic skewed toward punctate mitochondria. Genetic and pharmacological manipulation of mitochondrial fission/fusion cycles can contribute to both accelerated and decelerated cellular or organismal aging. In this work, we connect these experimental data with the symbiotic theory of mitochondrial origin to generate new insight into the evolutionary origin of aging. Mitochondria originated from autotrophic α-proteobacteria during an ancient endosymbiotic event early in eukaryote evolution. To expand beyond individual host cells, dividing α-proteobacteria initiated host cell lysis; apoptosis is a product of this original symbiont cell lytic exit program. Over the course of evolution, the host eukaryotic cell attenuated the harmful effect of symbiotic proto-mitochondria, and modern mitochondria are now functionally interdependent with eukaryotic cells; they retain their own circular genomes and independent replication timing. In nondividing differentiated or multipotent eukaryotic cells, intracellular mitochondria undergo repeated fission/fusion cycles, favoring fission as organisms age. The discordance between cellular quiescence and mitochondrial proliferation generates intracellular stress, eventually leading to a gradual decline in host cell performance and age-related pathology. Hence, aging evolved from a conflict between maintenance of a quiescent, nonproliferative state and the evolutionarily conserved propagation program driving the life cycle of former symbiotic organisms: mitochondria.

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma.

Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro. However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility. Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ. WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance. The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM.

A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2.

Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP3Rs), inhibiting pro-apoptotic Ca2+ signals. The current anti-Bcl-2 agents, ABT-263 (Navitoclax) and ABT-199 (Venetoclax), induce apoptosis by displacing pro-apoptotic proteins from the hydrophobic pocket, but do not inhibit Bcl-2-IP3R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP3 Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP3R interaction and thus inducing Ca2+-mediated apoptosis in chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma cells, including cells resistant to ABT-263, ABT-199, or the Bruton's tyrosine kinase inhibitor Ibrutinib. Moreover, combining BIRD-2 with ABT-263 or ABT-199 enhances apoptosis induction compared to single agent treatment. Overall, these findings provide strong rationale for developing novel therapeutic agents that mimic the action of BIRD-2 in targeting the BH4 domain of Bcl-2 and disrupting Bcl-2-IP3R interaction.

Sociodemographic correlates of meeting US Department of Health and Human Services muscle strengthening recommendations in middle-aged and older adults.

INTRODUCTION: A growing body of evidence demonstrates the health benefits of muscular strength training. Physical activity recommendations encourage all adults to participate regularly in muscle strengthening activities. The purpose of this study was to examine the prevalence of meeting the US Department of Health and Human Services (DHHS) muscular strengthening recommendations by middle-aged and older adults and the sociodemographic characteristics associated with meeting these recommendations, using data from the 2011 Behavioral Risk Factor Surveillance System (BRFSS). METHODS: Data from the 2011 BRFSS were used to examine the prevalence of meeting the DHHS muscle strengthening recommendations by adults older than 45. Simple and multiple regression analyses were used to examine the sociodemographic characteristics associated with meeting the recommendations. RESULTS: Of respondents to the muscle strengthening question (N = 333,507), 79,029 (23.7%) reported meeting the muscle strengthening recommendations. Respondents who were female (odds ratio [OR] = 0.80; 95% confidence interval [CI] 0.78-0.83), widowed (OR = 0.69; 95% CI, 0.66-0.72), 85 or older (OR = 0.63; 95% CI, 0.58-0.68), Hispanic (OR = 0.73; 95% CI, 0.67-0.78), with a body mass index of 30.0 kg/m(2) or higher (OR = 0.47; 95% CI, 0.45-0.49), and with less than a high school education (OR = 0.32, 95% CI, 0.30-0.35) were less likely to meet the recommendations than their counterparts. CONCLUSION: Sociodemographic characteristics such as sex, age, education, and race/ethnicity are significantly associated with meeting the muscle strengthening recommendations, suggesting a need to create tailored interventions and messages to promote participation in strength training.

Bcl-2 regulation of the inositol 1,4,5-trisphosphate receptor and calcium signaling in normal and malignant lymphocytes: potential new target for cancer treatment.

The anti-apoptotic protein Bcl-2 is a versatile regulator of cell survival. Its interactions with its own pro-apoptotic family members are widely recognized for their role in promoting the survival of cancer cells. These interactions are thus being targeted for cancer treatment. Less widely recognized is the interaction of Bcl-2 with the inositol 1,4,5-trisphosphate receptor (InsP3R), an InsP3-gated Ca(2+) channel located on the endoplasmic reticulum. The nature of this interaction, the mechanism by which it controls Ca(2+) release from the ER, its role in T-cell development and survival, and the possibility of targeting it as a novel cancer treatment strategy are summarized in this review. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.

Mechanism of acute ischemic stroke in patients with severe middle cerebral artery atherosclerotic disease.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is one of the most common causes of ischemic stroke worldwide. Although the pathogenesis of cerebral infarct in ICAD has been reported from autopsy series, the mechanism of stroke is not well known. This study used baseline perfusion imaging and diffusion-weighted imaging (DWI) or computerized tomography (CT) imaging to help identify the mechanism of stroke in ICAD involving the middle cerebral artery (MCA). METHODS: We retrospectively reviewed baseline CT or magnetic resonance (MR) perfusion studies and diffusion-weighted MR imaging or CT scans in patients with severe symptomatic MCA stenosis. Perfusion scans were classified according to stage of perfusion deficit, and the acute stroke patterns were categorized as borderzone, cortical, or perforating artery infarcts according to DWI or noncontrast CT. RESULTS: Fifteen patients were included in this analysis. All 15 patients had some type of borderzone infarct. Six had borderzone infarct only, 4 had borderzone and cortical infarcts, and 5 had borderzone, cortical, and perforating artery infarcts. Thirteen of the 15 patients had baseline perfusion deficits. CONCLUSIONS: In patients with severe MCA ICAD, the mechanism of stroke is multifactorial, but hemodynamic insufficiency plays a significant role. This finding is important in selecting a subgroup of patients who may benefit from revascularization.

Epigenetic biomarkers in skin cancer.

Epigenetic aberrations have been associated with cutaneous melanoma tumorigenesis and progression including dysregulated DNA gene promoter region methylation, histone modification, and microRNA. Several of these major epigenetic aberrations have been developed into biomarkers. Epigenetic biomarkers can be detected in tissue and in blood as circulating DNA in melanoma patients. There is strong evidence that biomarkers in cutaneous melanoma will have an important role as companions to therapeutics and overall patient management. Important progress has been made in epigenetic melanoma biomarker development and verification of clinical utility, and this review discusses some of the key current developments and existing challenges.

Balloon-assisted coil embolization of intracranial aneurysms is not associated with increased periprocedural complications.

BACKGROUND: The balloon-assisted coil embolization (BACE) technique represents an effective tool for the treatment of complex wide-necked intracranial aneurysms; however, its safety is a matter of debate. This study presents the authors' institutional experience regarding the safety of the BACE technique. METHODS: 428 consecutive patients with 491 intracranial aneurysms (274 acutely ruptured and 217 unruptured) treated with conventional coil embolization (CCE) or with BACE were retrospectively reviewed. All procedure-related adverse events were reported, regardless of clinical outcome. Thromboembolic events, intraprocedural aneurysm ruptures, device-related complications, morbidity and mortality were compared between the CCE and BACE groups. RESULTS: The total rate of procedural and periprocedural adverse events was 9.6% (47/491 embolizations). Thromboembolic events, intraprocedural aneurysmal rupture and device-related complications occurred in 2.4%, 3.9% and 3.3% of procedures, respectively. The risk of thromboembolic events and device-related problems was similar between the CCE and BACE groups. A trend towards a higher risk of intraprocedural aneurysm rupture was observed in the BACE group (not statistically significant). The total cumulative morbidity and mortality for both groups was 2.6% (11/428 patients) and there was no statistically significant difference in the morbidity, mortality and cumulative morbidity and mortality rates between the two groups. CONCLUSION: In this series of patients with acutely ruptured and unruptured aneurysms, the BACE technique allowed treatment of aneurysms with unfavorable anatomic characteristics without increasing the incidence of procedural complications.

Epigenetics of estrogen receptor-negative primary breast cancer.

Increasingly, breast cancer is being recognized as a heterogeneous disease comprised of molecularly and phenotypically distinct intrinsic tumor subtypes with different clinical outcomes. This biological heterogeneity has significant implications, particularly as it relates to expression profiling of estrogen receptor (ER) status, as classifying breast cancers based on hormone receptor expression impacts not only prognosis but also treatment options and long-term outcomes. Epigenetics has emerged as a promising field for the assessment of hormone receptor status. Epigenetic aberrations have been shown to regulate ER and offer reversible targets for development of new therapies. This review covers ER-negative breast tumor epigenetic aberrations and summarizes the major epigenetic mechanisms governing ER expression and how it impacts treatment of ER-negative breast cancer.

Vascular anatomy of the spinal cord.

In this article, a detailed description of the normal arterial supply and venous drainage of the spinal cord is provided, and the role of catheter angiography and MR angiography in depicting the vascular anatomy of the spinal cord is discussed.

Long-term clinical and angiographic results of Neuroform stent-assisted coil embolization in wide-necked intracranial aneurysms.

BACKGROUND: Neuroform stent-assisted coil embolization facilitates the endovascular treatment of wide-necked intracranial aneurysms. However, the safety and efficacy of its long-term use have not been fully elucidated. OBJECTIVE: To retrospectively examine the long-term results of Neuroform stent usage in conjunction with coil embolization in wide-necked intracranial aneurysms. METHODS: Between November 2002 and December 2010, 79 patients harboring wide-necked intracranial aneurysms were treated with use of the Neuroform stent. The stenting procedure failed in 2 patients. Therefore, 77 patients harboring 79 intracranial aneurysms were included for analysis. Patient and aneurysm characteristics, progression of aneurysm occlusion, and occurrence of complications were analyzed. Follow-up imaging included digital subtraction angiography (DSA) or magnetic resonance angiography (MRA). Kaplan-Meier analysis, as well as univariate analysis were performed to determine the progression of aneurysm occlusion and to examine the predictive factors for complete aneurysm occlusion, respectively. RESULTS: Overall, complete aneurysm occlusion was observed in 42.4% of the cases immediately after treatment and progressed to 96.5% at 7-year follow-up. The mean angiographic follow-up time was 25.8 months (range, 0-84 months). Eleven aneurysms (14%) were re-treated. Sixty-eight patients (88.3%) had favorable clinical outcome with a modified Rankin Scale (mRS) ≤ 1, 3 patients (3.9%) had an mRS of 2, and 5 patients (6.5%) did not have a clinical follow-up. The mean clinical follow-up time was 45.4 months (range, 3-92 months). One patient (1.3%) died of a procedure-related hemorrhage. CONCLUSION: Neuroform stent-assisted coil embolization of wide-necked intracranial aneurysms prevents hemorrhage and provides a high rate of aneurysm occlusion at long-term follow-up.

Discovery of histone deacetylase 8 selective inhibitors.

We have developed an efficient method for synthesizing candidate histone deacetylase (HDAC) inhibitors in 96-well plates, which are used directly in high-throughput screening. We selected building blocks having hydrazide, aldehyde and hydroxamic acid functionalities. The hydrazides were coupled with different aldehydes in DMSO. The resulting products have the previously identified 'cap/linker/biasing element' structure known to favor inhibition of HDACs. These compounds were assayed without further purification. HDAC8-selective inhibitors were discovered from this novel collection of compounds.

Using CT perfusion during the early baseline period in aneurysmal subarachnoid hemorrhage to assess for development of vasospasm.

INTRODUCTION: The aim of this study is to evaluate computed tomography perfusion (CTP) during admission baseline period (days 0-3) in aneurysmal subarachnoid hemorrhage (A-SAH) for development of vasospasm. METHODS: Retrospective analysis was performed on A-SAH patients from Dec 2004 to Feb 2007 with CTP on days 0-3. Cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) maps were analyzed for qualitative perfusion deficits. Quantitative analysis was performed using region-of-interest placement to obtain mean CTP values. Development of vasospasm was determined by a multistage hierarchical reference standard incorporating both imaging and clinical criteria. Student's t test and threshold analysis were performed. RESULTS: Seventy-five patients were included, 37% (28/75) were classified as vasospasm. Mean CTP values in vasospasm compared to no vasospasm groups were: CBF 31.90 ml/100 g/min vs. 39.88 ml/100 g/min (P < 0.05), MTT 7.12 s vs. 5.03 s (P < 0.01), and CBV 1.86 ml/100 g vs. 2.02 ml/100 g (P = 0.058). Fifteen patients had qualitative perfusion deficits with 73% (11/15) developed vasospasm. Optimal threshold for CBF is 24-25 mL/100 g/min with 91% specificity and 50% sensitivity, MTT is 5.5 s with 70% specificity and 61% sensitivity and CBV is 1.7 mL/100 g with 89% specificity and 36% sensitivity. CONCLUSION: These initial results support our hypothesis that A-SAH patients who develop vasospasm may demonstrate early alterations in cerebral perfusion, with statistically significant CBF reduction and MTT prolongation. Overall, CTP has high specificity for development of vasospasm. Future clinical implications include using CTP during the baseline period for early identification of A-SAH patients at high risk for vasospasm to prompt robust preventative measures and treatment.