John Wesson Ashford

Neuropsychiatric diagnosis and management of chronic sequelae of war-related mild to moderate traumatic brain injury

Soldiers with a traumatic brain injury (TBI) present with an array of neuropsychiatric symptoms that can be grouped into nosological clusters: (1) cognitive dysfunctions: difficulties in memory, attention, language, visuospatial cognition, sensory-motor integration, affect recognition, and/or executive function typically associated with neocortical damage; (2) neurobehavioral disorders: mood, affect, anxiety, posttraumatic stress, and psychosis, as well as agitation, sleep problems, and libido loss, that may have been caused by damage to the cortex, limbic system, and/or brain stem monoaminergic projection systems; (3) somatosensory disruptions: impaired smell, vision, hearing, equilibrium, taste, and somatosensory perception frequently caused by trauma to the sensory organs or their projections through the brain stem to central processing systems; (4) somatic symptoms: headache and chronic pain; and (5) substance dependence. TBI-related cognitive impairment is common in veterans who have served in recent conflicts in the Middle East and is often related to blasts from improvised explosive devices. Although neurobehavioral disorders such as depression and posttraumatic stress disorder commonly occur after combat, the presentation of such disorders in those with head injury may pass undetected with use of current diagnostic criteria and neuropsychological instruments. With a multidimensional approach (such as the biopsychosocial model) applied to each symptom cluster, psychological, occupational, and social dysfunction can be delineated and managed.

Formoterol, a Long-Acting β2 Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome

BACKGROUND Down syndrome is associated with significant failure in cognitive function. Our previous investigation revealed age-dependent degeneration of locus coeruleus, a major player in contextual learning, in the Ts65Dn mouse model of Down syndrome. We studied whether drugs already available for use in humans can be used to improve cognitive function in these mice. METHODS We studied the status of β adrenergic signaling in the dentate gyrus of the Ts65Dn mouse model of Down syndrome. Furthermore, we used fear conditioning to study learning and memory in these mice. Postmortem analyses included the analysis of synaptic density, dendritic arborization, and neurogenesis. RESULTS We found significant atrophy of dentate gyrus and failure of β adrenergic signaling in the hippocampus of Ts65Dn mice. Our behavioral analyses revealed that formoterol, a long-acting β2 adrenergic receptor agonist, caused significant improvement in the cognitive function in Ts65Dn mice. Postmortem analyses revealed that the use of formoterol was associated with a significant improvement in the synaptic density and increased complexity of newly born dentate granule neurons in the hippocampus of Ts65Dn mice. CONCLUSIONS Our data suggest that targeting β2 adrenergic receptors is an effective strategy for restoring synaptic plasticity and cognitive function in these mice. Considering its widespread use in humans and positive effects on cognition in Ts65Dn mice, formoterol or similar β2 adrenergic receptor agonists with ability to cross the blood brain barrier might be attractive candidates for clinical trials to improve cognitive function in individuals with Down syndrome.

MR Spectroscopy for Assessment of Memantine Treatment in Mild to Moderate Alzheimer Dementia

OBJECTIVES Magnetic Resonance Spectroscopy (MRS) may provide a precise and reliable assessment of the extent and severity of neural tissue loss caused by various diseases. In particular, the N-Acetyl Aspartate (NAA) and Creatine (Cr) ratio has been found to be an indicator of the degree of neuronal loss in Alzheimers disease (AD). Memantine is thought to benefit the AD brain by stabilizing the NMDA receptors on neurons in turn reducing excitotoxicity. Despite its effectiveness in treating moderate to severe AD, memantine has not had similar success in the treatment of mildly demented AD patients. The objective of this study was to test whether memantine would slow or prevent the loss of neurons in mild to moderate AD patients. METHODS A double-blind placebo-controlled study was designed to measure the effect of a year-long course of memantine in patients with a probable AD diagnosis with mild to moderate dementia. The primary outcome measure was stipulated to be change in MRS NAA/Cr ratio in inferior parietal cortex in memantine relative to the placebo treatment condition. The secondary outcome measures were changes in cognitive and function scale scores. RESULTS This pilot study failed to demonstrate a benefit of memantine on the primary outcome measure, the inferior parietal NAA/Cr ratio, or the secondary outcome measures. CONCLUSIONS More studies are needed to determine the effect of memantine on regions of the brain significantly affected by AD pathology.

Donepezil treatment in ethnically diverse patients with Alzheimer disease.

OBJECTIVE To compare the outcome of donepezil treatment in ethnically diverse Alzheimer disease (AD) patients with ethnically diverse AD patients who did not receive donepezil. METHODS Patients meeting NINCDS-ADRA criteria for probable or possible AD from a consortium of California sites were systematically followed for at least 1 year in this prospective, observational study. Their treatment regimens, including prescription of donepezil, were determined by their individual physician according to his or her usual criteria. Patients self-identified their ethnicity. RESULTS The 64 ethnically diverse AD patients who completed the study and received donepezil treatment had an average 1-year decline of 2.30 points (standard deviation: 3.9) on the 30-point Mini-Mental State Exam compared with a 1.70-point (standard deviation: 4.2) decline in the 74 ethnically diverse completers who received no donepezil or other anti-AD drugs during the study period. This difference was not statistically significant. The overall Cohen effect size of this treatment-associated difference was estimated at -0.15. After using propensity analyses and other techniques to assess factors that could bias prescribing decisions, the lack of benefits associated with donepezil treatment remained. The lack of donepezil benefits also remained when more traditional analyses were applied to these data. CONCLUSION Ethnically diverse AD patients in this study apparently did not benefit from 1 year of donepezil treatment. These unpromising results are in contrast to modest benefits of donepezil treatment measured in a directly comparable California study involving white non-Latino AD patients.

Challenges to be overcome using population-based sampling methods to recruit veterans for a study of post-traumatic stress disorder and traumatic brain injury

BackgroundMany investigators are interested in recruiting veterans from recent conflicts in Afghanistan and Iraq with Traumatic Brain Injury (TBI) and/or Post Traumatic Stress Disorder (PTSD). Researchers pursuing such studies may experience problems in recruiting sufficient numbers unless effective strategies are used. Currently, there is very little information on recruitment strategies for individuals with TBI and/or PTSD. It is known that groups of patients with medical conditions may be less likely to volunteer for clinical research. This study investigated the feasibility of recruiting veterans returning from recent military conflicts— Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) - using a population-based sampling method.MethodsIndividuals were sampled from a previous epidemiological study. Three study sites focused on recruiting survey respondents (n = 445) who lived within a 60 mile radius of one of the sites.ResultsOverall, the successful recruitment of veterans using a population-based sampling method was dependent on the ability to contact potential participants following mass mailing. Study enrollment of participants with probable TBI and/or PTSD had a recruitment yield (enrolled/total identified) of 5.4%. We were able to contact 146 individuals, representing a contact rate of 33%. Sixty-six of the individuals contacted were screened. The major reasons for not screening included a stated lack of interest in the study (n = 37), a failure to answer screening calls after initial contact (n = 30), and an unwillingness or inability to travel to a study site (n = 10). Based on the phone screening, 36 veterans were eligible for the study. Twenty-four veterans were enrolled, (recruitment yield = 5.4%) and twelve were not enrolled for a variety of reasons.ConclusionsOur experience with a population-based sampling method for recruitment of recent combat veterans illustrates the challenges encountered, particularly contacting and screening potential participants. The screening and enrollment data will help guide recruitment for future studies using population-based methods.

Active Cigarette Smoking in Cognitively-Normal Elders and Probable Alzheimer’s Disease is Associated with Elevated Cerebrospinal Fluid Oxidative Stress Biomarkers

Neurodegenerative diseases and chronic cigarette smoking are associated with increased cerebral oxidative stress (OxS). Elevated F2-isoprostane levels in biological fluid is a recognized marker of OxS. This study assessed the association of active cigarette smoking with F2-isoprostane in concentrations in cognitively-normal elders (CN), and those with mild cognitive impairment (MCI) and probable Alzheimers disease (AD). Smoking and non-smoking CN (n = 83), MCI (n = 164), and probable AD (n = 101) were compared on cerebrospinal fluid (CSF) iPF2α-III and 8,12, iso-iPF2α-VI F2-isoprostane concentrations. Associations between F2-isoprostane levels and hippocampal volumes were also evaluated. In CN and AD, smokers had higher iPF2α-III concentration; overall, smoking AD showed the highest iPF2α-III concentration across groups. Smoking and non-smoking MCI did not differ on iPF2α-III concentration. No group differences were apparent on 8,12, iso-iPF2α-VI concentration, but across AD, higher 8,12, iso-iPF2α-VI level was related to smaller left and total hippocampal volumes. Results indicate that active cigarette smoking in CN and probable AD is associated with increased central nervous system OxS. Further investigation of factors mediating/moderating the absence of smoking effects on CSF F2-isoprostane levels in MCI is warranted. In AD, increasing magnitude of OxS appeared to be related to smaller hippocampal volume. This study contributes additional novel information to the mounting body of evidence that cigarette smoking is associated with adverse effects on the human central nervous system across the lifespan.

Findings from the national memory screening day program

To report experience with a large, nation‐wide public memory screening program.

Ethics review as a catalyst for progress.

There are several points where ethical decision-making has become paralyzed and inefficient as the field of Alzheimers disease study has advanced. The focus of this review is to highlight these points and several lines of research that can inform ethical decision-making. The goal is to identify barriers and to move toward solutions. Examples of other fields of study that can be particularly useful for innovative ways to study effective ethical decision-making include implementation science and neuroscience of decision-making, as well as therapeutic investigations of other domains such as the human biology and psychology.

Spatial test for agricultural pesticide "blow-in" effect on prevalence of Parkinson's disease.

The current study used Department of Veteran’s Affairs (VA) clinical records, State of California pesticide application records, spatial maps of distribution of Parkinson’s disease patients, and pesticide applications to determine if there was evidence for “blow-in” of pesticides as a factor in explaining the prevalence of Central Valley Parkinson’s disease. The results did not support the hypothesis of increasing prevalence of Parkinsonism attributable to wind drift.