Robert H. Lipsky

Epigenetic mechanisms regulating learning and long-term memory

A balance between rapid, short lived, neuronal responses and prolonged ones fulfill the biochemical and cellular requirements for creating a molecular memory. I provide an overview of epigenetic mechanisms in the brain and discuss their impact on synaptic plasticity, cognitive functions, and discuss a recent example of how they can contribute to neurodegeneration and the cognitive decline associated with Alzheimers disease.

Association of nosocomial infections with delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage

OBJECTIVE Delayed cerebral ischemia (DCI) is a recognized complication of aneurysmal subarachnoid hemorrhage (aSAH) that contributes to poor outcome. This study seeks to determine the effect of nosocomial infection on the incidence of DCI and patient outcome. METHODS An exploratory analysis was performed on 156 patients with aSAH enrolled in the Cerebral Aneurysm Renin Angiotensin System study. Clinical and radiographic data were analyzed with univariate analysis to detect risk factors for the development of DCI and poor outcome. Multivariate logistic regression was performed to identify independent predictors of DCI. RESULTS One hundred fifty-three patients with aSAH were included. DCI was identified in 32 patients (20.9%). Nosocomial infection (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.09-11.2, p = 0.04), ventriculitis (OR 25.3, 95% CI 1.39-458.7, p = 0.03), aneurysm re-rupture (OR 7.55, 95% CI 1.02-55.7, p = 0.05), and clinical vasospasm (OR 43.4, 95% CI 13.1-143.4, p < 0.01) were independently associated with the development of DCI. Diagnosis of nosocomial infection preceded the diagnosis of DCI in 15 (71.4%) of 21 patients. Patients diagnosed with nosocomial infection experienced significantly worse outcomes as measured by the modified Rankin Scale score at discharge and 1 year (p < 0.01 and p = 0.03, respectively). CONCLUSIONS Nosocomial infection is independently associated with DCI. This association is hypothesized to be partly causative through the exacerbation of systemic inflammation leading to thrombosis and subsequent ischemia.

Repeated ketamine administration alters N-methyl-d-aspartic acid receptor subunit gene expression: Implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans

For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis.

Epigenetics of depression.

Major depressive disorder (MDD) is a leading cause of disability worldwide and is associated with poor psychological, medical, and socioeconomic outcomes. Although much has been learned about the etiology and treatment options of MDD over the past decade, there remain unanswered questions that pose challenges to improving acute and chronic outcomes for those with MDD. MDD is a clinically heterogeneous disorder. Genetic studies to date have indicated a number of genes, including transporters, neurotransmitters, neurotrophins, and their associated signaling networks that may predispose individuals to MDD and may also predict treatment outcomes. However, twin studies indicate that genes account for only a small degree of the variation in MDD. Thus, other mechanisms, through epigenetic marks, may act to form a molecular memory of previous gene-to-environment interactions and to establish vulnerabilities (or, conversely, resistance) to MDD. Current evidence supports a role for pre-, peri-, and early postnatal adversities and stressful life events into adulthood affecting epigenetic patterns, providing a mechanistic foundation to develop epigenetic marks as biomarkers for MDD. This review presents the evidence supporting a role for epigenetic effects in MDD and in treatment response. We also discuss the controversy behind modulating epigenetic mechanisms in long-term antidepressant pharmacotherapy.

Association of renin-angiotensin system genetic polymorphisms and aneurysmal subarachnoid hemorrhage.

OBJECTIVE Renin-angiotensin system (RAS) genetic polymorphisms are thought to play a role in cerebral aneurysm formation and rupture. The Cerebral Aneurysm Renin-Angiotensin System (CARAS) study prospectively evaluated common RAS polymorphisms and their relation to aneurysmal subarachnoid hemorrhage (aSAH). METHODS The CARAS study prospectively enrolled aSAH patients and controls at 2 academic centers in the United States. A blood sample was obtained from all patients for genetic evaluation and measurement of plasma angiotensin-converting enzyme (ACE) concentration. Common RAS polymorphisms were detected using 5 exonuclease (TaqMan) genotyping assays and restriction fragment length polymorphism analysis. RESULTS Two hundred forty-eight patients were screened, and 149 aSAH patients and 50 controls were available for analysis. There was a recessive effect of the C allele of the angiotensinogen ( AGT) C/T single-nucleotide polymorphism (SNP) (OR 1.94, 95% CI 0.912-4.12, p = 0.0853) and a dominant effect of the G allele of the angiotensin II receptor Type 2 ( AT2) G/A SNP (OR 2.11, 95% CI 0.972-4.57, p = 0.0590) on aSAH that did not reach statistical significance after adjustment for potential confounders. The ACE level was significantly lower in aSAH patients with the II genotype (17.6 ± 8.0 U/L) as compared with the ID (22.5 ± 12.1 U/L) and DD genotypes (26.6 ± 14.2 U/L) (p = 0.0195). CONCLUSIONS The AGT C/T and AT2 G/A polymorphisms were not significantly associated with aSAH after controlling for potential confounders. However, a strong trend was identified for a dominant effect of the G allele of the AT2 G/A SNP. Downregulation of the local RAS may contribute to the formation of cerebral aneurysms and subsequent presentation with aSAH. Further studies are required to elucidate the relevant pathophysiology and its potential implication in treatment of patients with aSAH.

Genetic predictors of outcome following traumatic brain injury

The nature of traumatic brain injury (TBI) has acute and chronic outcomes for those who survive. Over time, the chronic process of injury impacts multiple organ systems that may lead to disease. We discuss possible mechanisms and methodological issues in the context of candidate gene association studies using TBI patient populations. Because study population sizes have been generally limited, we discussed results on genes that have been the focus of independent studies. We also present a justification for testing more speculative candidate genes in recovery from TBI, such as those involved in circadian rhythm, to outline the importance of prioritizing functional variants in genes that may modulate recovery or provide neuroprotection from TBI. Finally, we provide a perspective on how future research will integrate population level genetic findings with the biological basis of disease in order to create a resource of predictive outcome measures for individual patients.

Predictors of Shunt Insertion in Aneurysmal Subarachnoid Hemorrhage

OBJECTIVEnHydrocephalus is a common complication of aneurysmal subarachnoid hemorrhage (aSAH), requiring permanent cerebrospinal fluid (CSF) diversion in up to two thirds of patients. Factors that predict permanent CSF diversion are not well established.nnnMETHODSnAn exploratory analysis of 149 patients enrolled in the CARAS (Cerebral Aneurysm Renin Angiotensin System) study was performed in an effort to identify factors predictive of permanent CSF diversion after aSAH; only the 135 patients surviving the initial hospitalization were included in the present study. CARAS was a prospective, multicenter study investigating the impact of genetic polymorphisms in patients with aSAH and enrolled patients from September 2012 to Januaryxa02015.nnnRESULTSnOne hundred and forty-nine patients with aSAH were enrolled in CARAS, with 135 (90.6%) patients surviving the initial hospitalization. Sixty-four of these patients (47.4%) required permanent CSF diversion. Multivariable analysis identified the following as independent risk factors: sympathomimetic illicit drug use, external ventricular drain (EVD) insertion, and hyponatremia. A scoring system based on EVD insertion (2 points), Hunt and Hess grade (1 point if grade ≥4) and modified Fisher computed tomography grade (1 point if grade 4) produced an area under the curve of 0.8 (P < 0.001).nnnCONCLUSIONSnSympathomimetic illicit drug use, EVD insertion, and hyponatremia are the strongest predictors of shunt insertion in patients with aSAH. Moreover, a scoring system based on EVD insertion, Hunt and Hess grade, and modified Fisher computed tomography grade can reliably predict the need for shunt placement in patients with aSAH.

Association of cystathionine beta-synthase polymorphisms and aneurysmal subarachnoid hemorrhage

OBJECTIVE Cystathionine β-synthase (CBS) is involved in homocysteine and hydrogen sulfide (H2S) metabolism. Both products have been implicated in the pathophysiology of cerebrovascular diseases. The impact of CBS polymorphisms on aneurysmal subarachnoid hemorrhage (aSAH) and its clinical sequelae is poorly understood. METHODS Blood samples from all patients enrolled in the CARAS (Cerebral Aneurysm Renin Angiotensin System) study were used for genetic evaluation. The CARAS study prospectively enrolled aSAH patients at 2 academic institutions in the United States from 2012 to 2015. Common CBS polymorphisms were detected using 5exonuclease genotyping assays. Analysis of associations between CBS polymorphisms and aSAH was performed. RESULTS Samples from 149 aSAH patients and 50 controls were available for analysis. In multivariate logistic regression analysis, the insertion allele of the 844ins68 CBS insertion polymorphism showed a dominant effect on aSAH. The GG genotype of the CBS G/A single nucleotide polymorphism (rs234706) was independently associated with unfavorable functional outcome (modified Rankin Scale Score 3-6) at discharge and last follow-up, but not clinical vasospasm or delayed cerebral ischemia (DCI). CONCLUSIONS The insertion allele of the 844ins68 CBS insertion polymorphism was independently associated with aSAH while the GG genotype of rs234706 was associated with an unfavorable outcome both at discharge and last follow-up. Increased CBS activity may exert its neuroprotective effects through alteration of H2S levels, and independent of clinical vasospasm and DCI.

Stress-Related Mental Health Symptoms in Coast Guard: Incidence, Vulnerability, and Neurocognitive Performance

U.S. Coast Guard (CG) personnel face occupational stressors (e.g., search and rescue) which compound daily life stressors encountered by civilians. However, the degree CG personnel express stress-related mental health symptoms of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) is understudied as a military branch, and little is known concerning the interplay of vulnerabilities and neurocognitive outcomes in CG personnel. The current study addressed this knowledge gap, recruiting 241 active duty CG personnel (22% female) to assess mental health, personality, and neurocognitive function. Participants completed a battery of scales: PTSD Checklist with military and non-military prompts to screen for PTSD, Psychological Health Questionnaire 8 for MDD, and scales for behaviorally inhibited (BI) temperament, and distressed (Type D) personality. Neurocognitive performance was assessed with the Defense Automated Neurobehavioral Assessment (DANA) battery. Cluster scoring yielded an overall rate of PTSD of 15% (95% CI: 11–20%) and 8% (95% CI: 3–9%) for MDD. Non-military trauma was endorsed twice that of military trauma in those meeting criteria for PTSD. Individual vulnerabilities were predictive of stress-related mental health symptoms in active duty military personnel; specifically, BI temperament predicted PTSD whereas gender and Type D personality predicted MDD. Stress-related mental health symptoms were also associated with poorer reaction time and response inhibition. These results suggest rates of PTSD and MDD are comparable among CG personnel serving Boat Stations to those of larger military services after combat deployment. Further, vulnerabilities distinguished between PTSD and MDD, which have a high degree of co-occurrence in military samples. To what degree stress-related mental healthy symptoms and attendant neurocognitive deficits affect operational effectiveness remains unknown and warrant future study.

Associations between endothelin polymorphisms and aneurysmal subarachnoid hemorrhage, clinical vasospasm, delayed cerebral ischemia, and functional outcome

OBJECTIVE Endothelin-1, a potent vasoconstrictor, and its receptors may be involved in the pathogenesis of aneurysmal subarachnoid hemorrhage (aSAH), clinical vasospasm, delayed cerebral ischemia (DCI), and functional outcome following aSAH. In the present study, common endothelin single nucleotide polymorphisms (SNPs) and their relation to aSAH were evaluated. METHODS Blood samples from all patients enrolled in the Cerebral Aneurysm Renin Angiotensin System (CARAS) study were used for genetic evaluation. The CARAS study prospectively enrolled patients with aSAH at 2 academic institutions in the US from 2012 to 2015. Common endothelin SNPs were detected using 5 exonnuclease (TaqMan) genotyping assays. Analysis of associations between endothelin SNPs and aSAH and its clinical sequelae was performed. RESULTS Samples from 149 patients with aSAH and 50 controls were available for analysis. In multivariate logistic regression analysis, the TG (odds ratio [OR] 2.102, 95% confidence interval [CI] 1.048-4.218, p = 0.036) and TT genotypes (OR 7.884, 95% CI 1.003-61.995, p = 0.05) of the endothelin-1 T/G SNP (rs1800541) were significantly associated with aSAH. There was a dominant effect of the G allele (CG/GG genotypes; OR 4.617, 95% CI 1.311-16.262, p = 0.017) of the endothelin receptor A G/C SNP (rs5335) on clinical vasospasm. Endothelin SNPs were not associated with DCI or functional outcome. CONCLUSIONS Common endothelin SNPs were found to be associated with presentation with aSAH and clinical vasospasm. Further studies are required to elucidate the relevant pathophysiology and its potential implications in the treatment of patients with aSAH.