Joy L. Taylor

Donepezil and flight simulator performance: Effects on retention of complex skills

Abstract—We report a randomized, double-blind, parallel group, placebo-controlled study to test the effects of the acetylcholinesterase inhibitor, donepezil (5 mg/d for 30 days), on aircraft pilot performance in 18 licensed pilots with mean age of 52 years. After 30 days of treatment, the donepezil group showed greater ability to retain the capacity to perform a set of complex simulator tasks than the placebo group, p < 0.05. Donepezil appears to have beneficial effects on retention of training on complex aviation tasks in nondemented older adults.

Modeling the prevalence and incidence of Alzheimer's disease and mild cognitive impairment

A number of systems have been proposed for classifying older adults who suffer from cognitive impairment or decline but do not yet meet criteria for Alzheimers disease (AD). The classification, Mild Cognitive Impairment (MCI), has attracted much attention. It uses relatively specific diagnostic criteria and individuals who meet these criteria appear to be at substantial risk for the development of AD. However, little data is available to define the prevalence of MCI in any age group. We propose a simple mathematical model for the progression of patients from Non-Affected (NA) to MCI to AD. This first-order Markov model defines the likely prevalence of MCI at specific ages. Primary assumptions of the model include an AD prevalence of 1% at age 60 increasing to 25% at age 85 and a conversion rate from MCI to AD of 10% constant across all ages considered. We used the best available information for our model and found (1) that the MCI prevalence increased from 1% at age 60 to 42% at age 85 and (2) that the conversion rate from NA to MCI increased from 1% per year at age 60 to 11% at age 85. In conclusion, this model allows estimation of prevalence of MCI and conversion from NA to MCI based upon known prevalences of AD, conversion rates of MCI to AD, and death rates. Due to its substantial prevalence, MCI may be an important target for screening and possible intervention.

Correlates of memory decline : a 4-year longitudinal study of older adults with memory complaints

Change in memory performance and its correspondence to change in speed of performance and self-reported memory functioning were investigated longitudinally in 30 older adults with memory complaints. Subjects were assessed by self-report questionnaires and cognitive tests 3 times, at near 2-year intervals. A significant decline in word-recall scores was found, which was accompanied at the group level by significant self-reported decline in everyday memory functioning and nonsignificant decline in Wechsler Adult Intelligence Scale Digit Symbol scores (alpha = .05). The oldest subjects showed the most substantial declines in memory performance. At the individual level, however, memory change did not significantly correlate with either change in self-reports or change in Digit Symbol scores. Although these results do not support a cognitive slowing model of decline at the intraindividual level, they do have implications for intervention of age-related memory decline.

Validation of a 26-point Telephone version of the Mini-Mental State Examination

The objective of this study was to assess the convergent validity of a 26-point Telephone Mini-Mental State Examination (MMSE) in a longitudinal cohort of 46 Alzheimer’s disease (AD) patients. Paired in-person and telephone MMSE observations were collected within 35 days of each other. The setting was the Stanford/VA Alzheimer’s Center in Palo Alto, California, and patients’ residences. The 30-point Folstein MMSE was administered in-person, and a 26-point telephone version of the MMSE, adapted from the Adult Lifestyles and Function Interview (ALFI)-MMSE. Total scores for the in-person and telephone MMSE versions correlated strongly (Pearson’s r = .88, P < .001). Hearing impairment and education level did not significantly affect telephone-based performance. The Telephone MMSE can be used to validly estimate in-person MMSE scores of patients with AD. Use of this practical measure can enhance reassessment if returning to the clinic is difficult or if a change in the patient’s medical condition merits a check of mental status by telephone.

Psychoactive Drugs and Pilot Performance: A Comparison of Nicotine, Donepezil, and Alcohol Effects

The cholinergic system plays a major role in cognitive abilities that are essential to piloting an aircraft: attention, learning, and memory. In previous studies, drugs that enhance the cholinergic system through different pharmacologic mechanisms have shown beneficial effects on cognition; but dissimilar cognitive measures were used and samples were not comparable. A comparison within the same cognitive tasks, within comparable samples appears desirable. Toward this aim, we compared effect sizes (ES) of performance-enhancing doses of nicotine (a nicotinic receptor agonist) and donepezil (an acetylcholinesterase inhibitor) as found in our prior work on pilot performance. We also compared cholinergic ES to those of performance-impairing doses of alcohol. In three randomized, placebo-controlled trials, we assessed the flight performance of aircraft pilots in a Frasca 141 simulator, testing I: the acute effects of nicotine gum 2 mg; II: the effects of administration of 5 mg donepezil/day for 30 days; and III: the acute and 8 h-carryover effects of alcohol after a target peak BAC of 0.10%. We calculated the ES of nicotine, donepezil, and alcohol on a flight summary score and on four flight component scores. Compared to placebo, nicotine and donepezil significantly improved, while alcohol significantly impaired overall flight performance: ES (nicotine)=0.80; ES (donepezil)=1.02; ES (alcohol acute)=−3.66; ES (alcohol 8 h)=−0.82. Both cholinergic drugs showed the largest effects on flight tasks requiring sustained visual attention. Although the two tested cholinergic drugs have different pharmacologic mechanisms, their effects on flight performance were similar in kind and size. The beneficial effects of the cholinergic drugs on overall flight performance were large and the absolute (ie nondirectional) sizes were about one-fourth of the absolute ES of acute alcohol intoxication and roughly the same as the absolute 8 h-carryover ES of alcohol.

Cognitive and Noncognitive Symptoms in Dementia Patients: Relationship to Cortisol and Dehydroepiandrosterone

We investigated the relationship between basal cortisol and dehydroepiandrosterone (DHEA) levels and impairment in different cognitive and noncognitive measures and the possible interaction of DHEA with hypercortisolemia in dementia in 27 patients diagnosed with Alzheimers disease (AD). There were 17 men and 10 women. Patients were mildly to moderately cognitively impaired at the time of the initial cortisol measures. Patients were administered the Alzheimers Disease Assessment Scale (ADAS) and Folstein Mini-Mental State Examination (MMSE) at approximately 6-month intervals. Cortisol and DHEA were determined using conventional 125I radioimmunoassay procedures. Pearson product-moment correlations among cortisol and DHEA measures and both initial and longitudinal clinical measures were calculated. There was a relationship between baseline 8 a.m. cortisol levels and cognitive function at the initial testing as measured by the ADAS cognitive measure, with higher cortisol levels being associated with a greater level of impairment. We did not document a relationship between cortisol or DHEA levels and noncognitive measures. There was a significant correlation between both the initial MMSE and ADAS cognitive measures and initial DHEA level, with lower DHEA levels unexpectedly being associated with better performance on these measures. The initial DHEA levels did not predict decline in cognitive function over time. These findings bring into question the potential usefulness of DHEA as a therapeutic agent.

Which Alzheimer Patients Are at Risk for Rapid Cognitive Decline

In the current study of 1062 Alzheimers disease (AD) patients, we employed receiver operating characteristic curve analysis to identify characteristics of patients at increased risk for rapid cognitive decline. The patients are participants at one of the nine Alzheimers Disease Research Centers of California. Rapid decline was defined as a 3-point or greater loss on the Mini-Mental State Examination (MMSE) per year, post visit. The independent variables were age at clinic visit, age at symptom onset of AD, MMSE at patient visit, years of education, gender, ethnicity, living arrangement, presence of aphasia, delusions, hallucinations, and extrapyramidal signs. Receiver operating characteristic curve analysis indicated that AD patients presenting with moderate to severe aphasia, age at clinic visit of 75 years or less, and an MMSE greater than 7 were at increased risk for rapid cognitive decline. This information could help clinicians target these patients for pharmacologic interventions, facilitate long-term care planning, and potentially create savings by delaying or stabilizing the course of the disease. (J Geriatr Psychiatry Neurol 2002; 15:000–000).

Rate of cognitive decline in AD is accelerated by the interleukin-1α -889 *1 allele

The reason for differences in rate of cognitive decline in AD is unknown. The interleukin-1 α (IL-1α) −889 *2 allele is associated with increased risk for AD. Surprisingly, in a sample of 114 patients followed for an average of 3.8 years, individuals homozygous for the IL-1α −889 *1 allele declined significantly more rapidly on the Mini-Mental State Examination than did others. There was no difference in rate of decline between patients with and without the APOEε4 allele. These results support the hypothesis that inflammation is important in the clinical course of AD.

A Comparison of Assessment Techniques Measuring the Effects of Methylphenidate, Secobarbital, Diazepam and Diphenhydramine in Abstinent Alcoholics

In two studies, we studied the comparative sensitivity of different subjective and objective measures to methylphenidate (10 and 20 mg) and secobarbital (100 mg) versus placebo, and diphenhydramine (50 mg) and diazepam (10 and 20 mg) versus placebo in abstinent alcoholics. Subjective measures used were the Visual Analog Mood Scale and the Profile of Mood States. Objective measures were the Stroop and two microcomputer-controlled tasks developed in our lab - a dual pursuit tracking/reaction time task (P-Trak) and a reaction time task with regular and irregular preparatory intervals (PI) of varying length (Reactest). In addition, several baseline measures (Eysenck Personality Inventory, Spielberger State-Trait Anxiety Inventory and NIMH Mood Scale Elderly) were evaluated for their correlation to drug response. All three central nervous system depressants impaired performance on Reactest at the longer PIs and showed a main effect with irregular PIs, but only the 20-mg dose of diazepam impaired reaction time at the shortest PI and showed a main effect with regular PIs. On P-Trak, secobarbital and diazepam 20 mg impaired both tracking and reaction time, while methylphenidate 20 mg improved only the reaction time component. Only diazepam 20 mg affected mood. No effects were noted on the Stroop. The implications of these findings are discussed. Both P-Trak and Reactest with long PIs were more sensitive than VAMS, POMS or Stroop to drug effects. As lower doses of central nervous system depressants impaired reaction time only with longer PIs and showed a main effect only with irregular PIs, cognitive effects of these drugs may be missed if only subjective or short, regular PI tasks are examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleep/Wake Disruption in Alzheimer’s Disease: APOE Status and Longitudinal Course

Disturbed sleep is a major clinical problem in Alzheimer’s disease (AD). Apolipoprotein •4 (APOE •4) carrier status may increase risk of AD, yet there are no data on relations between APOE status and progression of sleep disturbance in AD. The objective of this study was to determine if sleep parameters in AD patients change over time as a function of APOE carrier status. Forty-four community-dwelling AD patients with diagnosis of probable AD were followed from early stages of disease. Their sleep/wake parameters were compared according to APOE status. For APOE •4 carriers, only wake after sleep onset (WASO) increased in association with lower cognitive function as indicated by the Mini-Mental State Examination (MMSE); for non-•4 subjects, increases in WASO and declines in total sleep time, sleep efficiency, and the amplitude of the rest/activity circadian rhythm over time were associated with lower performance on the MMSE. In these data, APOE status was associated with the progression of sleep/wake disturbances in AD. Overall, there was greater deterioration on sleep parameters in patients negative for the •4 allele.