Enabling endpoint development for interventional clinical trials in individuals with Angelman syndrome: a prospective, longitudinal, observational clinical study (FREESIAS).

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by the absence of a functional UBE3A gene, which causes developmental, behavioral, and medical challenges. While currently untreatable, comprehensive data could help identify appropriate endpoints assessing meaningful improvements in clinical trials. Herein are reported the results from the FREESIAS study assessing the feasibility and utility of in-clinic and at-home measures of key AS symptoms. METHODS: Fifty-five individuals with AS (aged < 5 years: n = 16, 5-12 years: n = 27, ≥ 18 years: n = 12; deletion genotype: n = 40, nondeletion genotype: n = 15) and 20 typically developing children (aged 1-12 years) were enrolled across six USA sites. Several clinical outcome assessments and digital health technologies were tested, together with overnight 19-lead electroencephalography (EEG) and additional polysomnography (PSG) sensors. Participants were assessed at baseline (Clinic Visit 1), 12 months later (Clinic Visit 2), and during intermittent home visits. RESULTS: The participants achieved high completion rates for the clinical outcome assessments (adherence: 89-100% [Clinic Visit 1]; 76-91% [Clinic Visit 2]) and varied feasibility of and adherence to digital health technologies. The coronavirus disease 2019 (COVID-19) pandemic impacted participants' uptake of and/or adherence to some measures. It also potentially impacted the at-home PSG/EEG recordings, which were otherwise feasible. Participants achieved Bayley-III results comparable to the available natural history data, showing similar scores between individuals aged ≥ 18 and 5-12 years. Also, participants without a deletion generally scored higher on most clinical outcome assessments than participants with a deletion. Furthermore, the observed AS EEG phenotype of excess delta-band power was consistent with prior reports. CONCLUSIONS: Although feasible clinical outcome assessments and digital health technologies are reported herein, further improved assessments of meaningful AS change are needed. Despite the COVID-19 pandemic, remote assessments facilitated high adherence levels and the results suggested that at-home PSG/EEG might be a feasible alternative to the in-clinic EEG assessments. Taken altogether, the combination of in-clinic/at-home clinical outcome assessments, digital health technologies, and PSG/EEG may improve protocol adherence, reduce patient burden, and optimize study outcomes in AS and other rare disease populations.

Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer's disease: a phase 1b, randomized, placebo-controlled trial.

Tau plays a key role in Alzheimer's disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989 .

Neuropsychological performance in young adults with cannabis use disorder.

BACKGROUND AND AIMS: Cannabis is a commonly used recreational drug in young adults. The worldwide prevalence in 18- to 25-year-olds is approximately 35%. Significant differences in cognitive performance have been reported previously for groups of cannabis users. However, the groups are often heterogeneous in terms of cannabis use. Here, we study daily cannabis users with a confirmed diagnosis of cannabis use disorder (CUD) to examine cognitive performance on measures of memory, executive function and risky decision-making. METHODS: Forty young adult daily cannabis users with diagnosed CUD and 20 healthy controls matched for sex and premorbid intelligence quotient (IQ) were included. The neuropsychological battery implemented was designed to measure multiple modes of memory (visual, episodic and working memory), risky decision-making and other domains of executive function using subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: Our results showed that young adult daily cannabis users with CUD perform significantly poorer on tasks of visual and episodic memory compared with healthy controls. In addition, executive functioning was associated with the age of onset. CONCLUSIONS: Further research is required to determine whether worse performance in cognition results in cannabis use or is a consequence of cannabis use. Chronic heavy cannabis use during a critical period of brain development may have a particularly negative impact on cognition. Research into the persistence of cognitive differences and how they relate to functional outcomes such as academic/career performance is required.

Extemporaneous preparation strategy for early phase clinical studies.

Extemporaneous preparations (EPs) of investigational drugs, which are compounded at the clinical study site by a pharmacist, are being increasingly used in early phase clinical studies to accelerate the development of new medicines. The successful application of EP strategies in clinical studies requires 'fit-for-purpose' formulation design and preparation processes, as well as administration procedures that are safe, flexible, cost-effective, and simple to adapt by a compounding pharmacist at the clinical site. DNS-7801 is a weakly basic investigational compound that exhibits a higher aqueous solubility at lower pH with its solubility dropping off precipitously with increase in pH. This phenomenon is known to result in potential risk of variable and decreased exposure in vivo. Combination of citrate buffer at pH 3.0 and hydroxypropylbetadex enabled formulation of DNS-7801 solutions that were stable as formulated and up on manipulation for oral administration. The solutions were compatible with apple juice, used to mask (blind) the potential taste differences between the placebo and DNS-7801 solutions when dosing study subjects. The oral administration of the solutions resulted in dose proportional Cmax, AUC0-24, and AUC0-∞ of DNS-7801 in non-elderly and elderly subjects. A key advantage of the use of an EP approach with DNS-7801 was the flexibility in dose selection that this approach offered because DNS-7801 concentration in the preparation and/or volume could be readily adjusted based on real-time cohort data.

A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults.

There are no FDA-approved pharmacotherapies for cannabis dependence. Cannabis is the most widely used illicit drug in the world, and patients seeking treatment for primary cannabis dependence represent 25% of all substance use admissions. We conducted a phase IIa proof-of-concept pilot study to examine the safety and efficacy of a calcium channel/GABA modulating drug, gabapentin, for the treatment of cannabis dependence. A 12-week, randomized, double-blind, placebo-controlled clinical trial was conducted in 50 unpaid treatment-seeking male and female outpatients, aged 18-65 years, diagnosed with current cannabis dependence. Subjects received either gabapentin (1200 mg/day) or matched placebo. Manual-guided, abstinence-oriented individual counseling was provided weekly to all participants. Cannabis use was measured by weekly urine toxicology and by self-report using the Timeline Followback Interview. Cannabis withdrawal symptoms were assessed using the Marijuana Withdrawal Checklist. Executive function was measured using subtests from the Delis-Kaplan Executive Function System. Relative to placebo, gabapentin significantly reduced cannabis use as measured both by urine toxicology (p=0.001) and by the Timeline Followback Interview (p=0.004), and significantly decreased withdrawal symptoms as measured by the Marijuana Withdrawal Checklist (p<0.001). Gabapentin was also associated with significantly greater improvement in overall performance on tests of executive function (p=0.029). This POC pilot study provides preliminary support for the safety and efficacy of gabapentin for treatment of cannabis dependence that merits further study, and provides an alternative conceptual framework for treatment of addiction aimed at restoring homeostasis in brain stress systems that are dysregulated in drug dependence and withdrawal.

Effects of chronic, heavy cannabis use on executive functions.

This case describes the clinical course of a cannabis-dependent individual entering a 12-week abstinence-based research program. The case illustrates the effects of chronic, heavy cannabis use on executive functions at three time points: 1) 24 hours of abstinence; 2) 4 weeks of abstinence; and 3) 12 weeks of abstinence. It is followed by discussions by two clinical psychologists and a psychiatrist. The findings described here have important clinical implications, as executive functions have a vital role in treatment participation and in sustaining recovery. It should be of particular interest to clinicians who work with people with cannabis use disorders.

An evidence based review of acute and long-term effects of cannabis use on executive cognitive functions.

Cannabis use has been shown to impair cognitive functions on a number of levels-from basic motor coordination to more complex executive function tasks, such as the ability to plan, organize, solve problems, make decisions, remember, and control emotions and behavior. These deficits differ in severity depending on the quantity, recency, age of onset and duration of marijuana use. Understanding how cannabis use impairs executive function is important. Individuals with cannabis-related impairment in executive functions have been found to have trouble learning and applying the skills required for successful recovery, putting them at increased risk for relapse to cannabis use. Here we review the research on the acute, residual, and long-term effects of cannabis use on executive functions, and discuss the implications for treatment.

Chronic alcohol consumption impairs visuo-spatial associative memory in periadolescent rhesus monkeys.

UNLABELLED: Alcohol abuse in the adult is often preceded by high alcohol consumption during adolescence. Profound changes in brain structure and function occur during this developmental period, therefore alcohol may impact essential cognitive skill development during the formal educational years. The objective of this study was to determine if chronic oral alcohol intake slows acquisition and performance of cognitive tasks in male adolescent rhesus monkeys. Treatment groups (Alcohol, N=4; Control, N=3) were evaluated on bimanual dexterity and tests of visuo-spatial memory and learning adapted from the Cambridge Neuropsychological Test Automated Battery. Animals were trained daily in 30 min sessions and had subsequent access to alcohol/Tang® solutions (Alcohol group) or Tang® only (Control group) Monday through Friday for 11 months. Recordings of brainstem auditory evoked potentials (BSAEP) were conducted periodically before and during the chronic drinking. RESULTS: Chronic alcohol drinking (ave of 1.78 g/kg alcohol per session) impaired behavioral performance assessed ∼22 h after the prior drinking session. The Alcohol group required more trials than the Control group to reach criterion on the visuo-spatial memory task and showed increased sensitivity to trial difficulty and retention interval. Alcohol animals also had slowed initial acquisition of the bimanual task. The latency of P4 and P5 BSAEP peaks were also delayed in the Alcohol group. Chronic alcohol consumption impaired the acquisition and performance of a spatial memory task and disrupted brainstem auditory processing, thus these results show that repeated alcohol exposure in adolescence interferes with a range of brain functions including complex visuo-spatial mnemonic processing.

Long-lasting reduction in hippocampal neurogenesis by alcohol consumption in adolescent nonhuman primates.

Binge alcohol consumption in adolescents is increasing, and studies in animal models show that adolescence is a period of high vulnerability to brain insults. The purpose of the present study was to determine the deleterious effects of binge alcohol on hippocampal neurogenesis in adolescent nonhuman primates. Heavy binge alcohol consumption over 11 mo dramatically and persistently decreased hippocampal proliferation and neurogenesis. Combinatorial analysis revealed distinct, actively dividing hippocampal neural progenitor cell types in the subgranular zone of the dentate gyrus that were in transition from stem-like radial glia-like cells (type 1) to immature transiently amplifying neuroblasts (type 2a, type 2b, and type 3), suggesting the evolutionary conservation of milestones of neuronal development in macaque monkeys. Alcohol significantly decreased the number of actively dividing type 1, 2a, and 2b cell types without significantly altering the early neuronal type 3 cells, suggesting that alcohol interferes with the division and migration of hippocampal preneuronal progenitors. Furthermore, the lasting alcohol-induced reduction in hippocampal neurogenesis paralleled an increase in neural degeneration mediated by nonapoptotic pathways. Altogether, these results demonstrate that the hippocampal neurogenic niche during adolescence is highly vulnerable to alcohol and that alcohol decreases neuronal turnover in adolescent nonhuman primate hippocampus by altering the ongoing process of neuronal development. This lasting effect, observed 2 mo after alcohol discontinuation, may underlie the deficits in hippocampus-associated cognitive tasks that are observed in alcoholics.

Acamprosate in the treatment of alcohol dependence: clinical and economic considerations.

Acamprosate has been commercially available in the USA since 2004 to treat alcohol dependence. Its safety and efficacy have been demonstrated in a number of clinical trials worldwide, which overall have shown significant improvements in abstinence compared with placebo. As with all alcoholism pharmacotherapies, acamprosate is used in conjunction with psychosocial interventions. One frequently described mechanism stipulates that acamprosate supports abstinence by normalizing the often protracted dysregulation of NMDA-mediated glutamatergic neurotransmission that follows chronic heavy alcohol use and withdrawal. This article reviews the clinical safety and efficacy of acamprosate, as well as results from recent pharmacoeconomic and human laboratory studies. These data elucidate the economic benefits of acamprosate, as well as its effects on cognition and alcohol-related sleep disturbances.

Robust and stable drinking behavior following long-term oral alcohol intake in rhesus macaques.

Face validity in animal models of alcohol abuse and dependence is often at odds with robust demonstrations of ethanol-seeking. This study determined the relative influence of ethanol and a flavorant in maintaining ethanol intake in a nonhuman primate model of "cocktail" drinking. Four-year-old male monkeys were maintained on a 6% ethanol/6% Tang solution made available in daily (M-F) 1-h sessions. Experiments determined the effect of (1) a second daily access session, (2) concurrent presentation of the Tang vehicle, (3) sequential presentation of the vehicle in the first daily session and the ethanol solution in the second session, (4) altering the Tang concentration, (5) altering the ethanol concentration, and (6) removal of the flavorant. Mean daily intake (2.7+/-0.2 g/kg/day) was stable over 7 months. Simultaneous availability of a large, but not a low-moderate, volume of the vehicle reduced ethanol intake by about 50%. Decreasing the concentration of Tang in the first daily session reduced ethanol intake, whereas intake of the standard solution was increased in the second session. Ethanol consumption was decreased by only 27% when the flavorant was removed. In summary, alterations that reduced intake in the first daily session resulted in compensatory increases in ethanol intake in the second session, suggesting that animals sought a specific level of ethanol intake per day. It is concluded that models with excellent face validity (flavored beverages) can produce reliable ethanol intake in patterns that are highly consistent with ethanol-seeking behavior.

Oral administration of (+/-)3,4-methylenedioxymethamphetamine and (+)methamphetamine alters temperature and activity in rhesus macaques.

RATIONALE: Emergency Department visits and fatalities in which (+/-)3,4-methylenedioxymethamphetamine (MDMA) or (+)methamphetamine (METH) are involved frequently feature unregulated hyperthermia. MDMA and METH significantly elevate body temperature in multiple laboratory species and, most importantly, can also produce unregulated and threatening hyperthermia in nonhuman primates. A majority of prior animal studies have administered drugs by injection whereas human consumption of "Ecstasy" is typically oral, an important difference in route of administration which may complicate the translation of animal data to the human condition. OBJECTIVE: To determine if MDMA and METH produce hyperthermia in monkeys following oral administration as they do when administered intramuscularly. METHODS: Adult male rhesus monkeys were challenged intramuscularly (i.m.) and per os (p.o.) with 1.78 or 5 mg/kg (+/-)MDMA and with 0.1 or 0.32 mg/kg (+)METH. Temperature and activity were monitored with a radiotelemetry system. RESULTS: Oral administration of either MDMA or METH produced significant increases in body temperature. Locomotor activity was suppressed by MDMA and increased by METH following either route of administration. CONCLUSIONS: The data show that the oral route of administration is not likely to qualitatively reduce the temperature increase associated with MDMA or METH although oral administration did slow the rate of temperature increase. It is further established that MDMA reduces activity in monkeys even after relatively high doses and oral administration.

Impact of ambient temperature on hyperthermia induced by (+/-)3,4-methylenedioxymethamphetamine in rhesus macaques.

The ambient temperature (T(A)) under which rodents are exposed to (+/-)3,4-methylenedioxymethamphetamine (MDMA) affects the direction and magnitude of the body temperature response, and the degree of hypo/hyperthermia generated in subjects can modify the severity of lasting brain changes in 'neurotoxicity' models. The thermoregulatory effects of MDMA have not been well described in non-human primates and it is unknown if T(A) has the potential to affect acute hyperthermia and therefore other lasting consequences of MDMA. The objective of this study was to determine if the temperature alteration produced by MDMA in nonhuman primates depends on T(A) as it does in rats and mice. Body temperature and spontaneous home cage activity were monitored continuously in six male rhesus monkeys via radiotelemetry. The subjects were challenged intramuscularly with 0.56-2.4 mg/kg (+/-)MDMA under each of three T(A) conditions (18, 24, and 30 degrees C) in a randomized order. The temperature was significantly elevated following injection with all doses of MDMA under each ambient temperature. The magnitude of mean temperature change was approximately 1 degrees C in most conditions suggesting a closely controlled thermoregulatory response in monkeys across a range of doses and ambient temperatures. Activity levels were generally suppressed by MDMA; however, a 50% increase over vehicle was observed after 0.56 MDMA under the 30 degrees C condition. It is concluded that MDMA produces a similar degree of hyperthermia in rhesus monkeys across a range of T(A) conditions that result in hypothermia or exaggerated hyperthermia in rodents. Monkey temperature responses to MDMA appear to be more similar to humans than to rodents and therefore the monkey may offer an improved model of effects related to MDMA-induced hyperthermia.

Differential contributions of dopaminergic D1- and D2-like receptors to cognitive function in rhesus monkeys.

RATIONALE: Dopaminergic neurotransmission is critically involved in many aspects of complex behavior and cognition beyond reward/reinforcement and motor function. Mental and behavioral disorders associated with major disruptions of dopamine neurotransmission, including schizophrenia, attention deficit/hyperactivity disorder, Parkinson's disease, Huntington's disease, and substance abuse produce constellations of neuropsychological deficits in learning, memory, and attention in addition to other defining symptoms. OBJECTIVE: To delineate the role dopaminergic D1- and D2-like receptor subtypes play in complex brain functions. MATERIALS AND METHODS: Monkeys (N = 6) were trained on cognitive tests adapted from a human neuropsychological assessment battery (CAmbridge Neuropsychological Test Automated Battery). The battery included tests of spatial working memory (self-ordered spatial search task), visuo-spatial associative memory and learning (visuo-spatial paired associates learning task, vsPAL) and motivation (progressive ratio task, PR). Tests of motor function (bimanual motor skill task, BMS; rotating turntable task, RTT) were also included. The effects of the dopamine D2-like antagonist raclopride (10-56 microg/kg, i.m.) and the D1-like antagonist SCH23390 (SCH, 3.2-56 microg/kg, i.m.) on cognitive performance were then determined. RESULTS: Deficits on PR, RTT, and BMS performance were observed after both raclopride and SCH23390. Spatial working memory accuracy was reduced to a greater extent by raclopride than by SCH, which was unexpected, given prior reports on the involvement of D1 signaling for spatial working memory in monkeys. Deficits were observed on vsPAL performance after raclopride, but not after SCH23390. CONCLUSIONS: The intriguing results suggest a greater contribution of D2- over D1-like receptors to both spatial working memory and object-location associative memory.

Hyperthermia induced by 3,4-methylenedioxymethamphetamine in unrestrained rhesus monkeys.

BACKGROUND: Exposure to (+/-)3,4-methylenedioxymethamphetamine ((+/-)MDMA) results in lasting reductions of many markers for serotonin terminals in a range of species. In rodents, the severity of insult depends in large part on the generation of hyperthermia in the subject. (+/-)MDMA can produce either hyperthermia or hypothermia in rodents depending on the ambient temperature and these effects may be limited to the S(+) enantiomer. Limited prior evidence suggests (+/-)MDMA does not produce hyperthermia in chair-restrained monkeys [Bowyer, J.F., Young, J.F., Slikker, W., Itzak, Y., Mayorga, A.J., Newport, G.D., Ali, S.F., Frederick, D.L., Paule, M.G., 2003. Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations. Neurotoxicology 24, 379-390]. This study was therefore conducted to determine if racemic MDMA and its enantiomers induce hyperthermia and increase spontaneous locomotor activity in unrestrained rhesus monkeys. METHODS: Body temperature and spontaneous home cage activity were monitored continuously in four monkeys via radiotelemetric devices. The subjects were challenged with 1.7 mg/kg, i.m., (+/-)MDMA, S(+)MDMA and R(-)MDMA in pseudorandomized order. RESULTS: Maximum and average temperature in the 4h interval post-dosing was elevated 0.7-0.9 degrees C by (+/-)MDMA and each enantiomer. Reductions in locomotor activity following dosing did not reliably differ from vehicle effects. CONCLUSIONS: MDMA produces an acute hyperthermia in unrestrained rhesus monkeys, much as it does with rats, mice, pigs, rabbits and humans. Hyperthermia occurs despite no increase in locomotor activity thus the effect does not depend on motor activation. Each enantiomer appears to be equivalently active thus primates may differ from rodents in thermoregulatory sensitivity to the R(-) enantiomer. Significant differences in outcome between this and a prior study in monkeys indicate a need for additional study of the thermoregulatory impact of MDMA in nonhuman primates.

A retrospective review of the neuropsychological test performance of physicians referred for medical infractions.

Physician-related errors are rising, resulting in an increase in disciplinary actions by licensing medical authorities. It has been previously reported that cognitive impairment may be responsible for 63% of all physician-related medical adverse events. In this paper we examine neuropsychological testing results from 148 physicians referred for assessment by the California Medical Board (CMB) for various infractions. The neuropsychological test performance of the physicians was compared to normative reference samples. Overall, they performed in the average range on most measures; however, they demonstrated relative deficits on tests of sequential processing, attention, logical analysis, eye-hand coordination, verbal and non-verbal learning. These findings reveal that this cohort of physicians is performing lower than expected on tests of intellectual and neuropsychological functioning. Applying a neuropsychological framework to the assessment of physicians may uncover potential cognitive factors that contribute to medical practice errors.