Effects of muscarinic and adrenergic agonism on auditory P300 in the macaque.

Homologs of human endogenous evoked potentials are known in several species of nonhuman primates, but the neurotransmitter substrates of these potentials remain uncertain. In particular, the role of central cholinergic and adrenergic systems is not yet clearly defined. We recorded cognitive evoked potentials from the scalp in four adult bonnet macaque monkeys during a passive version of the auditory oddball paradigm with unique novel stimuli under saline control conditions. In two subjects each, cognitive evoked potentials were also recorded following intramuscular administration of the m1 muscarinic agonist AF102B or of the alpha-2A noradrenergic agonist guanfacine. On saline, large positivities resembling the human P300 were recorded over midline sites in response to rare or novel auditory stimuli in all four monkeys. The amplitude of these positivities was sensitive to the delivery of fruit-juice reward in association with rare stimuli in three monkeys tested. At cognition-enhancing doses, AF102B enlarged the amplitude of P300-like positivities in both monkeys tested; guanfacine enlarged the amplitude of P300-like positivities in one of two monkeys tested. These results add to existing evidence of human-like endogenous late positivities in monkeys that are influenced by the cholinergic and adrenergic systems, and suggest a possible role of m1 muscarinic and alpha-2A noradrenergic receptor subtypes.

Effects of guanfacine on three forms of distraction in the aging macaque.

alpha-2 adrenoceptor agonists, such as clonidine and guanfacine, enhance attention in aged animals. According to one theory, alpha-2 receptor agonists improve attention by decreasing distractibility to task-irrelevant stimuli. In two healthy aging bonnet macaques, we investigated the effects of low-(0.001 mg/kg) and high-dose (0.05 mg/kg) acute intramuscular guanfacine versus saline control on accuracy (number of trials correct) in three tasks requiring attention: delayed matching-to-sample, one-target visual tracking (test of focused attention) and two-target visual tracking (test of divided attention). Each task employed distracting stimuli in a different paradigmatic context. One monkey responded to guanfacine at both doses with significant rises in accuracy on all three tasks. The second monkey showed significant accuracy improvement for high-dose guanfacine only. No sedation was observed. These results suggest that guanfacine improves attention and reduces distractibility in multiple task contexts in healthy aging primates.

Divided attention-enhancing effects of AF102B and THA in aging monkeys.

The effects of cholinergic drugs proposed for treatment of cognitive impairment in normal aging and dementia on divided attention have been little studied in non-human primates. We tested the hypothesis that cholinergic drugs improve spatial divided attention in primates via a computer task requiring simultaneous tracking of two visual targets in three young and two aged healthy bonnet macaques. Task accuracy (number of correct responses) and reaction time (RT) were measured 2 h after administration of either the m1 agonist +/- -cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine (AF102B; 0.1-2.1 mg/kg IM) or the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroamino-acridine (THA; 0.5-2.0 mg/kg orally). Accuracy increased for four of five monkeys at appropriate doses of one or both cholinomimetics, accompanied in two monkeys by a drop in RT. Responses were less uniform to THA than to AF102B. For the five-monkey group at Best dose, accuracy increased 34% (THA) or 43% (AF102B) above baseline (P<0.05 for both drugs), respectively, with no significant change in RT and with minimal untoward effects. Cholinotherapy may improve divided attention in young and aged healthy primates.

Reduction of motoric agitation and restlessness by AF102B and tacrine in the macaque.

The cholinesterase inhibitor tacrine (THA) and the M1 muscarinic agonist AF102B (cevimeline), both reported to enhance cognition in animals and humans, were tested in 5 macaques for reduction of spontaneous, random movements. Monkeys were videotaped 1 hour after administration of normal saline vehicle, after low- and high-dose intramuscular AF102B, and after low- and high-dose oral THA. Two independent blind judges counted numbers of spontaneous movements made by each monkey over 12 consecutive 15-second segments for each drug condition. Both THA and AF102B reduced movement significantly at high doses without overt side effects, warranting further research on the agitation-reducing potential of cognition-enhancing cholinomimetic drugs.

Effects of AF102B and tacrine on delayed match-to-sample in monkeys.

1. Object working memory, a function which declines in aging and dementia, was tested in young and aged pretrained monkeys using a delayed match-to-sample task. 2. During drug treatment, monkeys were given the m 1 muscarinic agonist AF102B (0.1-2.1 mg/kg i.m.), the cholinesterase inhibitor tacrine (0.5-2.0 mg/kg p.o.), or vehicle controls in a repeated measures design to assess putative cognitive enhancement. 3. Both agents improved task performance in both young and aged monkeys, AF102B yielding equivalent or greater, and less variable, improvement than tacrine. 4. AF102B may represent a low-toxicity alternative to tacrine for the treatment of age-related memory disorders.

Alzheimer and vascular dementias and driving. A prospective road and laboratory study.

OBJECTIVE: To characterize on-the-road, behind-the-wheel driving abilities and related laboratory performances of subjects with mild Alzheimer's disease (AD) and vascular dementia. DESIGN: Prospective, experimental study involving two mild dementia and three age and health control groups. Road test reliability and validity were assessed. SETTING: Greater western Los Angeles. Subjects were enrolled from the community by referral and from the Veterans Affairs dementia and diabetes clinics. PARTICIPANTS: Eighty-seven driving subjects were enrolled; 83 completed the study. A sample of eligible dementia clinic subjects consisting of 15 mild AD patients met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association probable AD criteria, while 12 met Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition and Hachinski diagnostic criteria for multi-infarct dementia (vascular dementia). Clinic control subjects consisted of 15 age-matched patients with diabetes and without a history of stroke or dementia. Community controls consisted of 26 healthy, age-matched, older subjects (> 60 years) and 16 young subjects (20 to 35 years). MAIN OUTCOME MEASURES: Drive score from the Sepulveda (Calif) road test and laboratory measures of attention, perception, and memory. RESULTS: The drive scores in the mild AD group (mean, 22.1; SD, 3.8) and in the vascular dementia group (mean, 24.0; SD, 7.8) differed significantly (P < .001 studentized range test) from the drive scores in the diabetic control group (mean, 31.5; SD, 3.9), the older control group (mean, 32.6; SD, 2.8), and the young control group (mean, 33.6; SD, 3.2). Drive score among the three control groups did not vary significantly. Short-term memory (Sternberg), visual tracking, and Folstein Mini-Mental State Examination scores correlated best with drive score, with a cumulative R2 of 0.68. Drive score and number of collisions and moving violations per 1000 miles driven were negatively correlated (r = -0.38; P < .02). CONCLUSIONS: Based on this study, type and degree of cognitive impairment are better predictors of driving skills than age or medical diagnosis per se. Specific testing protocols for drivers with potential cognitive impairment may detect unsafe drivers more effectively than using age or medical diagnosis alone as criteria for license restriction or revocation.

Assessment of capacity to comply with medication regimens in older patients.

OBJECTIVE: To develop an instrument that will facilitate and focus the assessment of a patient's capacity to adhere to a medication regimen before its initiation. DESIGN: This is a crossectional study that compares medical inpatients and outpatients to an age-matched, community-living, independent and relatively healthy group on their ability to adequately understand and implement hypothetical but realistic medication regimens. SETTING: Department of Veterans Affairs Medical Center, Sepulveda, California. PARTICIPANTS: Fifty-five older subjects (65 years or older) were divided into three groups: (1) generally healthy comparisons (standard group) (n = 20); (2) medical outpatients (n = 15); and (3) medical inpatients ready for discharge (n = 20). MEASUREMENTS: Older subjects were first tested on their capacity to comply with a difficult medication regimen presented in scenario form. If scores on the first scenario did not meet a standard group-derived cutoff point, further testing was conducted with a simpler scenario to identify greater levels of impairment. RESULTS: The outpatient group had significantly lower scenario scores than did the healthy comparison group (P < .03). The simpler scenario also showed a trend toward outpatient impairment (P = .06). In the comparison group, only 5% failed Scenario 1, and none failed Scenario 2. The outpatient group had the most difficulty, with 40% failing Scenario 1 and one-third of those failing Scenario 2. This differed significantly from the comparison groups (Fisher's Exact P < .03). In the inpatient group 20% failed Scenario 1 and 75% of those failing Scenario 2. The sensitivity and specificity of the Folstein Mini-Mental State Examination in identifying scenario-impaired subjects were 73% and 80%, respectively. Question types were analyzed to determine which questions were most frequently missed. Memory and judgment questions were found overall to be the most frequently missed. Healthy controls missed some judgment questions; however, the outpatient group was significantly worse in this category (chi 2 = 5.08; P = .01). All three groups improved their scenario performance significantly with question cueing. CONCLUSION: A significant number of medically ill outpatients encountered difficulty in understanding or remembering correctly hypothetical but realistic medication regimens. This suggests that an older medical patient's cognitive and functional capacity to comply with medication regimens of differing complexity can be specifically assessed before the start of the regimen and probably should be assessed in patients whose compliance capacity is in question. The assessment instrument under development in this study may be helpful in detecting those who need assistance with medications, thus identifying the need for intervention before poor compliance can lead to increased morbidity, rehospitalization, and increased medical costs.