Dataset Information

Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial.

ABSTRACT: Despite limited evidence to support the use of amantadine to enhance cognitive function after traumatic brain injury (TBI), the clinical use for this purpose is highly prevalent and is often based on inferred belief systems. The aim of this study was to assess effect of amantadine on cognition among individuals with a history of TBI and behavioral disturbance using a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100?mg twice-daily versus placebo for 60 days. Included in the study were 119 individuals with two or more neuropsychological measures greater than 1 standard deviation below normative means from a larger study of 168 individuals with chronic TBI (>6 months post-injury) and irritability. Cognitive function was measured at treatment days 0, 28, and 60 with a battery of neuropsychological tests. Composite indices were generated: General Cognitive Index (included all measures), a Learning Memory Index (learning/memory measures), and Attention/Processing Speed Index (attention and executive function measures). Repeated-measures analysis of variance revealed statistically significant between-group differences favoring the placebo group at day 28 for General Cognitive Index (p?=?0.002) and Learning Memory Index (p?=?0.001), but not Attention/Processing Speed Index (p?=?0.25), whereas no statistically significant between-group differences were found at day 60. There were no statistically significant between-group differences on adverse events. Cognitive function in individuals with chronic TBI is not improved by amantadine 100?mg twice-daily. In the first 28 days of use, amantadine may impede cognitive processing. However, the effect size was small and mean scores for both groups were generally within expectations for persons with history of complicated mild-to-severe TBI, suggesting that changes observed across assessments may not have functional significance. The use of amantadine to enhance cognitive function is not supported by these findings.

SUBMITTER: Hammond FM

PROVIDER: S-EPMC6157374 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial.

Hammond Flora M FM Sherer Mark M Malec James F JF Zafonte Ross D RD Dikmen Sureyya S Bogner Jennifer J Bell Kathleen R KR Barber Jason J Temkin Nancy N

Journal of neurotrauma 20180607 19

Despite limited evidence to support the use of amantadine to enhance cognitive function after traumatic brain injury (TBI), the clinical use for this purpose is highly prevalent and is often based on inferred belief systems. The aim of this study was to assess effect of amantadine on cognition among individuals with a history of TBI and behavioral disturbance using a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice-daily versus placebo for 60 days. In ...[more]

PMID: 29742960

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Project description:The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and ?/?-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.

Project description:Warfare has long been associated with traumatic brain injury (TBI) in militarized zones. Common forms of TBI can be caused by a physical insult to the head-brain or by the effects of a high velocity blast shock wave generated by the detonation of an explosive device. While both forms of trauma are distinctly different regarding the mechanism of trauma induction, there are striking similarities in the cognitive and emotional status of survivors. Presently, proven effective therapeutics for the treatment of either form of TBI are unavailable. To be able to develop efficacious therapies, studies involving animal models of physical- and blast-TBI are required to identify possible novel or existing medicines that may be of value in the management of clinical events. We examined indices of cognition and anxiety-like behavior and the hippocampal gene transcriptome of mice subjected to both forms of TBI. We identified common behavioral deficits and gene expression regulations, in addition to unique injury-specific forms of gene regulation. Molecular pathways presented a pattern similar to that seen in gene expression. Interestingly, pathways connected to AlzheimerM-bM-^@M-^Ys disease displayed a markedly different form of regulation depending on the type of TBI. While these data highlight similarities in behavioral outcomes after trauma, the divergence in hippocampal transcriptome observed between models suggests that, at the molecular level, the TBIs are quite different. These models may provide tools to help define therapeutic approaches for the treatment of physical- and blast-TBIs. Based upon observations of increasing numbers of personnel displaying TBI related emotional and behavioral changes in militarized zones, the development of efficacious therapies will become a national if not a global priority. Keywords: Physical-traumatic brain injury; Blast-traumatic brain injury; Cognitive dysfunction; Gene expression; Molecular pathway(s); Neurodegeneration; Stem cells; AlzheimerM-bM-^@M-^Ys disease A mild physical-TBI was induced using a concussive head trauma device described previously (Milman et al., 2005; Zohar et al., 2003). Briefly, mice were lightly anesthetized (Isoflurane) and placed under the weight-drop concussive head trauma instrument. The device consisted of a metal tube (inner diameter 13 mm), placed vertically over the mouse head. A metal weight (30 g) was dropped from the top of the tube (80 cm) and struck the skull at the right side temporal area between the corner of the eye and the ear. A sponge supported the head, allowing some antero-posterior motion without any rotational head movement at the moment of the impact. Experimental conditions used to create a mild low-level blast-TBI and the subsequent model characterization, have been described in detail elsewhere (Rubovitch et al., 2011). In brief, mice were anaesthetized with a combination of ketamine (100 mg/kg) and xylazine (10 mg/kg). Once the animals were fully anaesthetized they were placed at a defined distance from a detonation source, in this case 7 meters. Pressure sensors were used to measure the explosion shock wave pressure (PSI) generated by the detonation (Free-Field ICPM-BM-. Blast Pressure Sensor; PCB Piezoelectronics, Depew, NY, USA, Model 137). At 7 meters from the source of the detonation, the animals were exposed to a maximum of a 2.5 PSI (17.2 kPa) pressure shock wave. Immediately after the induction of the injury, mice were placed back in their cages. Once the animals had recovered from the anesthesia, basic neurological assessments were undertaken to identify any acute neurological dysfunction. Only animals exhibiting no evidence of acute neurological damage post injury were subsequently used in further experiments. Sham treated mouse groups were treated identically; however, they were not exposed to physical- or blast-TBI. Mouse hippocampus tissues were randomly selected from the larger library of samples generated from the behavioral experiments and the numbers utilized in the gene expression study were as follows: sham, n = 5: physical-TBI, n = 4; blast-TBI, n = 7.

Dataset Information

Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial.

Publications

Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial.

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