Body Mass Index and Leptin Are Related to Cognitive Performance Over 10 Years in Women With and Without HIV Infection.

CONTEXT: It is not yet understood whether people living with HIV infection have an increased risk of Alzheimers Disease and Related Dementias due to enhanced survivorship with highly effective antiretroviral therapies and/or increasing adiposity with aging. OBJECTIVE: This work aimed to determine whether body mass index (BMI) and leptin were longitudinally associated over 10 years with neuropsychological performance (NP) among middle-aged women with HIV (WWH) vs without HIV. METHODS: Women's Interagency HIV Study (WIHS) participants (301 WWH, 113 women without HIV from Brooklyn, New York City, and Chicago had baseline and 10-year BMI and fasting plasma leptin levels using commercial enzyme-linked immunosorbent assay (ng/mL); and demographically adjusted NP T scores (attention/working memory, executive function [EF], processing speed, memory, learning, verbal fluency, motor function, global) at 10-year follow-up. Multivariable linear regression analyses, stratified by HIV serostatus, examined associations between BMI, leptin, and NP. RESULTS: Over 10 years, women (baseline age 39.8 ±â€…9.2 years, 73% Black, 73% WWH) transitioned from average overweight (29.1 ±â€…7.9) to obese (30.5 ±â€…7.9) BMI. Leptin increased 11.4 ±â€…26.4 ng/mL (P < .001). Higher baseline BMI and leptin predicted poorer 10-year EF among all women (BMI ß = -6.97, 95% CI (-11.5 to -2.45) P = .003; leptin ß = -1.90, 95% CI (-3.03 to -0.76), P = .001); higher baseline BMI predicted better memory performance (ß = 6.35, 95% CI (1.96-10.7), P = .005). Greater 10-year leptin increase predicted poorer EF (P = .004), speed (P = .03), and verbal (P = .02) and global (P = 0.005) performance among all women, and WWH. Greater 10-year BMI increase predicted slower processing speed (P = .043) among all women; and among WWH, poorer EF (P = .01) and global (P = .04) performance. CONCLUSION: In middle-aged WIHS participants, 10-year increases in BMI and leptin were associated with poorer performance across multiple NP domains among all women and WWH. Trajectories of adiposity measures over time may provide insight into the role of adipose tissue in brain health with aging.

Contemporary Neuroscience Core Curriculum for Medical Schools.

Medical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their clinical experiences in all other medical disciplines also, because the nervous system plays such a critical role in the function of every organ system. Due to the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the pre-clerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are re-assessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the pre-clerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors.

Pubertal Expression of α4ßδ GABAA Receptors Reduces Seizure-Like Discharges in CA1 Hippocampus.

More than half of children with epilepsy outgrow their seizures, yet the underlying mechanism is unknown. GABAergic inhibition increases at puberty in female mice due to expression of extrasynaptic α4ßδ GABAA receptors (GABARs). Therefore, we tested the role of these receptors in regulating seizure-like discharges in CA1 hippocampus using a high K(+) (8.5 mM) seizure model. Spontaneous field potentials were recorded from hippocampus of pre-pubertal (~28-32 PND) and pubertal (~35-44 PND) female wild-type or α4-/- mice. The coastline length, a measure of burst intensity, was assessed. 8.5 mM K(+) induced seizure-like discharges in over 60% of pre-pubertal slices, but only in 7% of pubertal slices, where the coastline length was reduced by 70% (P = 0.04). However, the pubertal decrease in seizure-like discharges was not seen in the α4-/-, implicating α4ßδ GABARs as the cause of the decreased seizure-like activity during puberty. Administration of THIP or DS2, to selectively increase α4ßδ current, reduced activity in 8.5 mM K(+) at puberty, while blockade of α5-GABARs had no effect. GABAergic current was depolarizing but inhibitory in 8.5 mM K(+), suggesting a mechanism for the effects of α4ßδ and α5-GABARs, which exhibit different polarity-dependent desensitization. These data suggest that α4ßδ GABARs are anti-convulsant during adolescence.

A competency-based longitudinal core curriculum in medical neuroscience.

Current medical educational theory encourages the development of competency-based curricula. The Accreditation Council for Graduate Medical Education's 6 core competencies for resident education (medical knowledge, patient care, professionalism, interpersonal and communication skills, practice-based learning, and systems-based practice) have been embraced by medical schools as the building blocks necessary for becoming a competent licensed physician. Many medical schools are therefore changing their educational approach to an integrated model in which students demonstrate incremental acquisition and mastery of all competencies as they progress through medical school. Challenges to medical schools include integration of preclinical and clinical studies as well as development of learning objectives and assessment measures for each competency. The Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN) assembled a group of neuroscience educators to outline a longitudinal competency-based curriculum in medical neuroscience encompassing both preclinical and clinical coursework. In development of this curriculum, the committee reviewed United States Medical Licensing Examination content outlines, Liaison Committee on Medical Education requirements, prior AAN-mandated core curricula for basic neuroscience and clinical neurology, and survey responses from educators in US medical schools. The newly recommended curriculum provides an outline of learning objectives for each of the 6 competencies, listing each learning objective in active terms. Documentation of experiences is emphasized, and assessment measures are suggested to demonstrate adequate achievement in each competency. These guidelines, widely vetted and approved by the UES membership, aspire to be both useful as a stand-alone curriculum and also provide a framework for neuroscience educators who wish to develop a more detailed focus in certain areas of study.

Distinctions between persistent and reversible group I mGluR-induced epileptiform burst prolongation.

We have previously shown that selective activation of group I metabotropic glutamate receptors (mGluRs) results in long-lasting enhancement of synchronized network activity in the hippocampal slice. Data herein suggest that activation of group I mGluRs need not result in this potentially epileptogenic effect. (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (ACPD), a nonselective mGluR agonist, elicits ictaform bursts identical in appearance to those induced by selective agonists, but ACPD-induced bursts do not persist following removal of the agent. Like the bursts induced by selective agonist, the ACPD bursts are blocked with group I mGluR antagonists and are not dependent on activation of either N-methyl-D-aspartate (NMDA) receptors or protein kinase C. However, they differ from the persistent bursts in that they do not require active protein synthesis and they are not suppressed with L-cysteine sulfinic acid, an agonist at a phospholipase D-coupled metabotropic receptor. These novel findings provide evidence that group I mGluR-induced epileptogenesis may be preventable.

Impact of protein kinase C activation on epileptiform activity in the hippocampal slice.

There is evidence suggesting that protein kinase C (PKC) activation can prevent the enhanced network excitability associated with status epilepticus and group I metabotropic glutamate receptor (mGluR)-induced epileptogenesis. However, we observed no suppression of mGluR-induced burst prolongation in the guinea pig hippocampal slice when applied in the presence of the PKC activator phorbol-12,13-dibutyrate (PDBu). Furthermore, PDBu alone converted picrotoxin-induced interictal bursts into ictal-length discharges ranging from 2 to 6s in length. This effect could not be elicited by the inactive analog 4-alpha-PDBu and was suppressed with the PKC inhibitor chelerythrine, indicating PKC dependence. PKC activation can enhance neurotransmitter release, and both glutamate and acetylcholine are capable of eliciting similar prolonged synchronized discharges. However, neither mGluR1 nor NMDA receptor antagonist suppressed PDBu-driven burst prolongation, suggesting that increased glutamate release alone is unlikely to account for the PKC-induced expression of ictaform discharges. Similarly, atropine, a broad-spectrum muscarinic receptor antagonist, had no effect on PKC-induced burst prolongation. By contrast, AMPA/kainate receptor antagonist abolished PKC-induced burst prolongation, and mGluR5 antagonist significantly blunted the maximum burst length induced by PKC. These data suggest that PKC-induced prolongation of epileptiform bursts is dependent on changes specific to mGluR5 and AMPA/kainate receptors and not mediated simply by a generalized increase in transmitter release.

The controversy concerning plasma homocysteine in Parkinson disease patients treated with levodopa alone or with entacapone: effects of vitamin status.

Levodopa treatment of Parkinson disease results in hyperhomocysteinemia (HHcy) as a consequence of levodopa methylation by catechol-O-methyltransferase (COMT). Although inhibition of COMT should theoretically prevent or reduce levodopa-induced HHcy, results from several prospective studies are conflicting. Our review of these studies suggests that the ability of COMT inhibition to reduce or prevent levodopa-induced HHcy in Parkinson disease patients may be attributed to differences in the vitamin status of the study participants. In patients with low or low-normal folate levels, levodopa administration is associated with a greater increase in homocysteine and concomitant entacapone administration is associated with a greater reduction in homocysteine.

Group I mGluR-induced epileptogenesis: distinct and overlapping roles of mGluR1 and mGluR5 and implications for antiepileptic drug design.

The group I metabotropic glutamate receptor subtypes, mGluR1 and mGluR5, have both distinct and overlapping actions in epileptogenesis. Data are reviewed revealing how activation of these receptor subtypes participates in the induction and maintenance of the long-lasting epileptiform discharges elicited in the hippocampal circuit. Differences in the cellular actions and regional distributions of mGluR1 and mGluR5 provide hints regarding the potential usefulness and limitations of subtype-specific antagonists as antiepileptic agents.

Contrasting roles of protein kinase C in induction versus suppression of group I mGluR-mediated epileptogenesis in vitro.

Activation of group I metabotropic glutamate receptors (mGluRs) elicits persistent ictaform discharges in guinea pig hippocampal slices, providing an in vitro model of epileptogenesis. The induction of these persistent ictaform bursts is prevented by l-cysteine sulfinic acid (CSA), an agonist at phospholipase D (PLD)-coupled mGluRs. Studies described herein examined the role of protein kinase C (PKC) in both the group I mGluR-mediated induction and CSA-mediated suppression of this form of epileptogenesis. Intracellular recordings were performed from CA3 stratum pyramidale and synchronized burst length was monitored. In the presence of 50 microM picrotoxin, a gamma-aminobutyric acid type A antagonist, 250- to 500-ms synchronized bursts were elicited. (S)-3,5-Dihydroxyphenylglycine (DHPG, 50 microM), an agonist at group I mGluRs, increased the burst length to 1-3 s in duration, a change that persisted after agonist washout. This persistent change in burst length was elicited in the presence of 10 microM chelerythrine, a PKC inhibitor, indicating that DHPG-induced epileptogenesis is PKC independent. However, although PLD activation with CSA (100 microM) was highly effective at suppressing group I mGluR-mediated induction of burst prolongation, CSA application in the presence of chelerythrine was no longer effective and resulted in the expression of persistent ictaform bursts. These data suggest that CSA-mediated suppression of group I mGluR-induced epileptogenesis is PKC dependent. We propose that CSA mediates its effect by PLD-driven activation of PKC, which may desensitize the phospholipase C-linked group I mGluRs and thereby prevent group I mGluR-induced epileptogenesis.

Contribution of GABA(B) receptor-mediated inhibition to the expression and termination of group I mGluR-induced ictaform bursts.

In guinea pig hippocampal slices, the GABA(B) receptor antagonist CGP 35348 increased the length of picrotoxin-induced interictal bursts by only 22%, yet it increased the length of group I mGluR-induced ictaform bursts by 85%. These data suggest that (1) suppression of GABAergic inhibition is insufficient to account for group I mGluR agonist-induced ictaform bursts, and (2) although GABA(B) plays a minor role in terminating interictal bursts, it is a major contributor to the termination of mGluR-induced ictaform bursts.

Evidence that phospholipase D activation prevents group I mGluR-induced persistent prolongation of epileptiform bursts.

Selective activation of group I metabotropic glutamate receptors (mGluRs) with (S)-3,5-dihydroxyphenylglycine (DHPG) in guinea pig hippocampal slices converts 275- to 475-ms picrotoxin-induced interictal bursts into persistent seizure-length discharges typically over 1 s in duration. Here we report that l-cysteine sulfinic acid (CSA), a sulfur-containing amino acid, prevented the induction of this persistent group I mGluR-mediated epileptiform burst prolongation. However, CSA had no effect on baseline interictal bursting activity and failed to suppress the expression of the group I mGluR-induced persistent prolonged bursts once they were fully induced. (2R,1'S,2'R,3'S)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-13), a selective antagonist at the phospholipase D (PLD)-coupled mGluR, had no effect of its own on DHPG-induced burst prolongation; however, CSA applied in the presence of PCCG-13 could no longer fully block the burst prolongation induced by DHPG, suggesting that CSA's antiepileptogenic effect is mediated by agonist action at this PLD-coupled receptor. These data parallel our previous data revealing that protein synthesis inhibitors prevent induction but not expression of group I mGluR-mediated persistent seizure-length discharges. Hence, PLD activation with CSA may prevent the synthesis of a protein critical for the induction of group I mGluR-mediated epileptogenesis.

Differential roles for mGluR1 and mGluR5 in the persistent prolongation of epileptiform bursts.

Transient activation of group I metabotropic glutamate receptors (mGluRs) with the selective agonist (S)-3,5-dihydroxyphenylglycine (DHPG) produces persistent prolongation of epileptiform bursts in guinea pig hippocampal slices, the maintenance of which can be reversibly suppressed with group I mGluR antagonists. To determine the relative roles of mGluR1 and mGluR5 in these group I mGluR-dependent induction and maintenance processes, subtype-selective antagonists were utilized. In the presence of picrotoxin, DHPG (50 microM, 20-45 min) converted interictal bursts into 1- to 3-s discharges that persisted for hours following washout of the mGluR agonist. 2-methyl-6-(phenylethynyl)-pyridine (MPEP, an mGluR5 antagonist; 25 microM) and (+)-2-methyl-4-carboxyphenylglycine (LY367385, an mGluR1 antagonist; 20-25 microM) each significantly suppressed the ongoing expression of the mGluR-induced prolonged bursts. However, LY367385 was more effective, reducing the burst prolongation by nearly 90%; MPEP only produced a 64% reduction in burst prolongation. Nevertheless, MPEP was more effective at preventing the induction of the burst prolongation; all 10 slices tested failed to express prolonged bursts both during and after co-application of DHPG with MPEP. Co-application of DHPG with LY367385, in contrast, resulted in significant burst prolongation (in 68% of slices tested) that was revealed on washout of the two agents. These results suggest that while both receptor subtypes participate in both the induction and maintenance of mGluR-mediated burst prolongation, mGluR1 activation plays a greater role in sustaining the expression of prolonged bursts, whereas mGluR5 activation may be a more critical contributor to the induction process underlying this type of epileptogenesis.