The effect of lumbar puncture on the neurodegeneration biomarker neurofilament light in macaque monkeys.

Introduction: Neurofilament light (NFL) in cerebrospinal fluid (CSF) is elevated in neurodegenerative disease patients, and may track disease progression and treatment. Macaque monkeys are emerging as important translational models of neurodegeneration, and NFL may be a useful biomarker.

Methods: To determine the influence of a previous lumbar puncture (LP) on NFL, we collected CSF at multiple time points in macaque monkeys via LP or cisterna magna puncture.

Behavioral shaping of rhesus macaques using the Cambridge neuropsychological automated testing battery.

Background: The Cambridge neuropsychological test automated battery (CANTAB) is a set of computerized visuospatial tests used to probe cognition in humans. The non-human primate (NHP) version of the battery is a valuable translational research tool to quantify cognitive changes in NHP models of disease by allowing direct comparison with performance data from human patient populations. One limitation is the long training times required for NHPs to reach appropriate levels of task performance, which is prohibitive for high throughput experimental designs.

Electrographic and pharmacological characterization of a progressive epilepsy phenotype in female MeCP2-deficient mice.

Rett Syndrome is a neurodevelopmental disorder caused primarily by mutations in the gene encoding Methyl-CpG-binding protein 2 (MECP2). Spontaneous epileptiform activity is a common co-morbidity present in Rett syndrome, and hyper-excitable neural networks are present in MeCP2-deficient mouse models of Rett syndrome. In this study we conducted a longitudinal assessment of spontaneous cortical electrographic discharges in female MeCP2-deficient mice and defined the pharmacological responsiveness of these discharges to anti-convulsant drugs.

22q11.2 deletion syndrome lowers seizure threshold in adult patients without epilepsy.

Objective: Previous studies examining seizures in patients with 22q11.2 deletion syndrome (22q11.2DS) have focused primarily on children and adolescents.

Prediction of antiepileptic drug treatment outcomes using machine learning.

Objective: Antiepileptic drug (AED) treatments produce inconsistent outcomes, often necessitating patients to go through several drug trials until a successful treatment can be found. This study proposes the use of machine learning techniques to predict epilepsy treatment outcomes of commonly used AEDs.

Approach: Machine learning algorithms were trained and evaluated using features obtained from intracranial electroencephalogram (iEEG) recordings of the epileptiform discharges observed in Mecp2-deficient mouse model of the Rett Syndrome.

Support vector machines using EEG features of cross-frequency coupling can predict treatment outcome in Mecp2-deficient mice.

Anti-convulsive drug treatments of epilepsy typically produce varied outcomes from one patient to the next, often necessitating patients to go through several anticonvulsive drug trials until an appropriate treatment is found. The focus of this study is to predict treatment outcome using a priori electroencephalogram (EEG) features for a rare genetic model of epilepsy seen in patients with Rett Syndrome. Previous work on Mecp2-deficient mice, exhibiting the symptoms of Rett syndrome, have revealed EEG-based biomarkers that track the pathology well.

A Role for Diminished GABA Transporter Activity in the Cortical Discharge Phenotype of MeCP2-Deficient Mice.

Cortical network hyper-excitability is a common phenotype in mouse models lacking the transcriptional regulator methyl-CPG-binding protein 2 (MeCP2). Here, we implicate enhanced GABAB receptor activity stemming from diminished cortical expression of the GABA transporter GAT-1 in the genesis of this network hyper-excitability. We found that administering the activity-dependent GABAB receptor allosteric modulator GS-39783 to female Mecp2(+/-) mice at doses producing no effect in wild-type mice strongly potentiated their basal rates of spontaneous cortical discharge activity.

Characterization of HFOs in short and long duration discharges recorded from in-vivo MeCP2-deficient mice.

Mutations in the X-linked gene encoding methyl CpG-binding protein 2 (MeCP2) have been linked to a neurodevelopmental disorder known as Rett syndrome. The disorder is associated with a number of symptoms, of which epileptic seizures are common. In this study we examined the presence of high frequency oscillations (HFOs) and their interactions with low frequency oscillations (LFOs) during epileptiform-like discharges using intracranial electroencephalogram (iEEG) recordings from male and female Mecp2-deficient mice.

Differential expression of sirtuin family members in the developing, adult, and aged rat brain.

The sirtuins are NAD(+)-dependent protein deacetylases and/or ADP-ribosyltransferases that play roles in metabolic homeostasis, stress response and potentially aging. This enzyme family resides in different subcellular compartments, and acts on a number of different targets in the nucleus, cytoplasm and in the mitochondria. Despite their recognized ability to regulate metabolic processes, the roles played by specific sirtuins in the brain-the most energy demanding tissue in the body-remains less well investigated and understood.

A pilot double-blind trial using verapamil as adjuvant therapy for refractory seizures.

Rationale: Given verapamil's property as a glycoprotein inhibitor, this drug could increase the effective concentration of antiepileptic drugs (AEDs) in the epileptic foci, reducing the number of seizures. This pilot study was designed to evaluate the safety and efficacy of verapamil as adjunct therapy in pharmacoresistant patients with focal onset seizures.

Methods: This was a single-centered, randomized, double-blind and placebo-controlled trial evaluating verapamil as an add-on therapy for adult patients with refractory epilepsy.

Low frequency-modulated high frequency oscillations in seizure-like events recorded from in-vivo MeCP2-deficient mice.

Rett syndrome is a neurodevelopmental condition caused by mutations in the gene encoding methyl CpG-binding protein 2 (MeCP2). Seizures are often associated with Rett syndrome and can be observed in intracranial electroencephalogram (iEEG) recordings. To date most studies have focused on the low frequencies oscillations (LFOs), however recent findings in epilepsy studies link high frequency oscillations (HFOs) with epileptogenesis.

Rescue of behavioral and EEG deficits in male and female Mecp2-deficient mice by delayed Mecp2 gene reactivation.

Mutations of the X-linked gene encoding methyl CpG binding protein type 2 (MECP2) are the predominant cause of Rett syndrome, a severe neurodevelopmental condition that affects primarily females. Previous studies have shown that major phenotypic deficits arising from MeCP2-deficiency may be reversible, as the delayed reactivation of the Mecp2 gene in Mecp2-deficient mice improved aspects of their Rett-like phenotype. While encouraging for prospective gene replacement treatments, it remains unclear whether additional Rett syndrome co-morbidities recapitulated in Mecp2-deficient mice will be similarly responsive to the delayed reintroduction of functional Mecp2.

Characterization of seizure-like events recorded in vivo in a mouse model of Rett syndrome.

Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Spontaneous recurrent discharge episodes are displayed in Rett-related seizures as in other types of epilepsies. The aim of this paper is to investigate the seizure-like event (SLE) and inter-SLE states in a female MeCP2-deficient mouse model of Rett syndrome and compare them to those found in other spontaneous recurrent epilepsy models.

Selective preservation of MeCP2 in catecholaminergic cells is sufficient to improve the behavioral phenotype of male and female Mecp2-deficient mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by mutations of the X-linked MECP2 gene. Although the loss of MeCP2 function affects many neural systems, impairments of catecholaminergic function have been hypothesized to underlie several of the cardinal behavioral deficits of RTT patients and Mecp2-deficient mice. Although recent Mecp2 reactivation studies indicate that RTT may be a reversible condition, it remains unclear whether specifically preserving Mecp2 function within a specific system will be sufficient to convey beneficial effects.

Regional MeCP2 expression levels in the female MeCP2-deficient mouse brain correlate with specific behavioral impairments.

Using female MeCP2-deficient mice as a model, we tested whether MeCP2 expression levels would parallel one another in different regions of the brain and spinal cord, and/or whether the levels of MeCP2 protein in these specific neural regions would correlate with the degree of behavioral impairment seen in individual subjects. Our results show that MeCP2 protein levels are not uniform across different regions of the mosaic brain, and that the relative MeCP2 levels in one region did not necessarily predict its expression levels in other regions of the same mouse. Correlational analysis between region-specific MeCP2 expression levels and the degree of impairment exhibited by mice in specific behavioral tests revealed significant associations.

Daily rhythmic behaviors and thermoregulatory patterns are disrupted in adult female MeCP2-deficient mice.

Mutations in the X-linked gene encoding Methyl-CpG-binding protein 2 (MECP2) have been associated with neurodevelopmental and neuropsychiatric disorders including Rett Syndrome, X-linked mental retardation syndrome, severe neonatal encephalopathy, and Angelman syndrome. Although alterations in the performance of MeCP2-deficient mice in specific behavioral tasks have been documented, it remains unclear whether or not MeCP2 dysfunction affects patterns of periodic behavioral and electroencephalographic (EEG) activity. The aim of the current study was therefore to determine whether a deficiency in MeCP2 is sufficient to alter the normal daily rhythmic patterns of core body temperature, gross motor activity and cortical delta power.