Donepezil therapy in clinical practice: a randomized crossover study.

OBJECTIVE: To determine the efficacy of donepezil hydrochloride for the treatment of Alzheimer disease in patients drawn from clinical practice. DESIGN: Two-center, randomized, placebo-controlled, double-masked crossover study. SETTING: Memory disorders units at Massachusetts General and Brigham and Women's hospitals, Boston. PATIENTS: Sixty individuals (30 men and 30 women; mean +/- SD age, 75.0+/-9.5 years) with probable Alzheimer disease and scores of 20 or less on the information-memory-concentration subscale of the Blessed Dementia Scale. INTERVENTIONS: Placebo wash-in, followed in randomized sequence by (1) donepezil hydrochloride therapy, 5 mg/d, for 6 weeks, followed by placebo washout for 6 weeks and (2) placebo treatment for 6 weeks. PRIMARY OUTCOME MEASURE: Change in Alzheimer's Disease Assessment Scale cognitive subscale scores from the beginning to the end of the two 6-week treatment periods. RESULTS: Among patients completing treatment and testing for both periods (n = 48), subscale scores improved (mean +/- SEM) 2.17+/-0.98 points (95% confidence interval, 0.20-4.10 points) during donepezil therapy relative to placebo therapy (P = .04). Scores returned toward baseline within 3 weeks of drug washout. There was no associated change in caregiver-rated global impression (donepezil vs placebo: proportion improved, 0.24 vs 0.22; proportion worsened, 0.27 vs 0.35; P = .34) or on specific tests of explicit memory or verbal fluency. Contrary to studies with tacrine, the presence of the apolipoprotein E epsilon4 allele did not predict donepezil treatment failure. Most common adverse events related to donepezil therapy were nausea (5 patients), diarrhea (3 patients), and agitation (3 patients). Serious events possibly related to drug use were seizure, pancreatitis, and syncope (1 patient each). CONCLUSION: This independent confirmation of data from phase 3 trials suggests that donepezil therapy modestly improves cognition in patients with Alzheimer disease who are encountered in clinical practice.

Neuropsychological deficits in Lyme disease patients with and without other evidence of central nervous system pathology.

A small percentage of Lyme patients develop mild to moderate encephalopathic symptoms months to years after diagnosis and treatment. Their symptoms typically include fatigue, memory loss, sleep disturbance, and depression. However, the etiology of this syndrome remains controversial. It is generally thought that Lyme patients with abnormal cerebral spinal fluid (CSF) have a neurological basis to their illness. To further examine this question, we compared Lyme patients with evidence of abnormal CSF, intrathecal antibody to Borrelia burgdorferi, elevated protein, or a positive polymerase chain reaction for B. burgdorferi DNA (n = 14); Lyme patients with normal CSF (n = 18); and healthy controls (n = 15) on a battery of neuropsychological and personality tests. Although both Lyme groups reported memory problems, only the Lyme group with abnormal CSF had measurable memory deficits. Both Lyme groups had higher depression scores than the normal control group, although depression was not correlated with memory scores. It appears that Lyme patients with abnormal CSF may have a neurological basis to their illness, whereas affective symptoms, common to many chronic disorders, may predispose other Lyme patients to the perception of cognitive dysfunction.

Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats.

Basic fibroblast growth factor (bFGF) is a polypeptide that supports the survival of brain cells (including neurons, glia, and endothelia) and protects neurons against a number of toxins and insults in vitro. This factor is also a potent dilator of cerebral pial arterioles in vivo. In previous studies, we found that intraventricularly administered bFGF reduced infarct volume in a model of focal cerebral ischemia in rats. In the current study, bFGF (45 micrograms/kg/h) in vehicle, or vehicle alone, was infused intravenously for 3 h, beginning at 30 min after permanent middle cerebral artery occlusion by intraluminal suture in mature Sprague-Dawley rats. After 24 h, neurological deficit (as assessed by a 0- to 5-point scale, with 5 = most severe) was 2.6 +/- 1.0 in vehicle-treated and 1.5 +/- 1.3 in bFGF-treated rats (mean +/- SD; N = 12 vs. 11; p = 0.009). Infarct volume was 297 +/- 65 mm3 in vehicle- and 143 +/- 135 mm3 in bFGF-treated animals (p = 0.002). During infusion, there was a modest decrease in mean arterial blood pressure but no changes in arterial blood gases or core or brain temperature in bFGF-treated rats. Autoradiography following intravenous administration of 111In-labeled bFGF showed that labeled bFGF crossed the damaged blood-brain barrier to enter the ischemic (but not the nonischemic) hemisphere. Whether the infarct-reducing effects of bFGF depend on intraparenchymal or intravascular mechanisms requires further study.

ERP indices and neuropsychological performance as predictors of functional outcome in dementia.

We compared the relative value of neuropsychological and event-related potentials (ERPs) obtained during both passive and active auditory oddball paradigm measures for determining functional outcome in dementia 4 years following initial assessment. Functional outcome was assessed by structured interview of family members of 29 patients with dementia, and patients' functional status was rated in seven areas: mortality, incontinence, institutionalization, ADL dependence, verbal responsiveness, recognition of family members, and capacity for social interaction. A total functional outcome score (ADLTOTAL) was obtained by summing across these individual outcome measures. Many of the neuropsychological measures correlated strongly with overall functional outcome, whereas P3 amplitude and latency on the active ERP condition were the only ERP indices to predict functional outcome. When ERP and neuropsychological measures were considered simultaneously using stepwise multiple regression analyses, the neuropsychological measures were better predictors of most functional outcomes, although P3 latency was the best predictor of mortality. However, neuropsychological performance and ERPs appear to be sensitive to different functional outcomes. Therefore, evaluation of both ERPs and neuropsychological performance may ultimately have prognostic utility in the assessment of patients with dementia.

An interprofessional model for serving youth at risk for substance abuse: the team case study.

Three models of interprofessional education appropriate for serving youth at risk for substance abuse are described. One of the models, the team case study, was evaluated by school personnel trained in its use. Results indicated that participants were more sensitive to the multiple needs of youth at risk, experienced increased comfort in seeking consultation from other agents working with such youth, and were more confident of their abilities to select and implement appropriate interventions for youth at risk for substance abuse following their training.

Dissociation of autonomic and subjective responses to emotional slides in right hemisphere damaged patients.

Autonomic and subjective responses to emotional and neutral slides were studied in patients with right hemisphere damage (RHD), left hemisphere damage (LHD) and normal controls (CON). Orienting and habituation to a series of pure tones (1000 Hz) were also examined. All subjects showed appropriate slide recognition and there were no group differences in subjective ratings. The CON group showed higher skin conductance responses (SCRs) to the emotional slides relative to the neutral slides, while the RHD group showed lower SCRs to both sets of slides. The LHD group showed higher SCRs independent of slide type. The results support the hypothesis (Heilman and Watson, Handbook of Neurology, Elsevier Science, 1989) that emotional paucity in RHD patients may be related to reduced autonomic arousal. However, there were no significant differences between groups in the orienting response or habituation to loud tones, suggesting that decreased arousal following RHD is not ubiquitous.

Lateralization of memory for the visual attributes of objects: evidence from the posterior cerebral artery amobarbital test.

We used the posterior cerebral artery amobarbital test to examine how each temporal lobe mediates memory for objects. Temporal lobectomy candidates were presented with four objects while one hemisphere was anesthetized. We assessed recall and recognition following recovery from the drug. Verbal recall was significantly better following object presentation to the left hemisphere when the left hemisphere was not the seizure focus. Recognition memory, tested with two identical objects, two objects that shared the same name but had different physical characteristics, and two foils, was superior following object presentation to the right hemisphere. Only the right hemisphere could discriminate identical objects from same-name foils. These data confirm that the left temporal lobe has an advantage in encoding the verbal representation of an object and suggest that the right temporal lobe is critical for memory of specific visual attributes of objects.

Habituation and sensitization of the orienting response following bilateral anterior cingulotomy.

Skin conductance response (SCR) was measured in an orienting response (OR) and habituation paradigm in 10 post-cingulotomy and age-matched control subjects. While both groups habituated, the cingulotomy patients exhibited a slower habituation rate, and greater variability across trials compared to controls. Habituation abnormalities were not associated with increased sensitization, as neither extended habituation training or dishabituation differentiated the groups. An increased frequency of spontaneous SCR activations occurred post-cingulotomy. The results suggest that the cingulate cortex influences the temporal stability of habituation. These findings are consistent with the subtle attentional dysfunction noted following cingulate damage.

Relation of eye color and gender to Type A scores and vocational preference.

Type A behavior scores on the Jenkins Activity Survey, Form T, and ACT Interest Inventory data were collected for 90 male and 90 female university students who equally represented three eye-color groups, black/brown, blue, and other. Chi-squared analyses indicated no statistically significant associations at the .05 level. Observations which may be of interest to researchers are noted.

Memory impairment and depression in patients with Lyme encephalopathy: comparison with fibromyalgia and nonpsychotically depressed patients.

Lyme encephalopathy, primarily manifested by disturbances in memory, mood, and sleep, is a common late neurologic manifestation of Lyme disease. We compared 20 patients with Lyme encephalopathy with 11 fibromyalgia patients and 11 nonpsychotically depressed patients using the California Verbal Learning Test, Wechsler Memory Scale, Rey-Osterrieth Complex Figure Test, Minnesota Multiphasic Personality Inventory (MMPI), and Beck Depression Inventory. Compared with patients with fibromyalgia or depression, the Lyme encephalopathy group showed mild, but statistically significant, memory deficits on two of the three memory tests. In contrast, the patients with fibromyalgia scored significantly higher than both other groups on the MMPI scale most sensitive to somatic concerns (scale 1), while the depressed patients scored higher than the Lyme patients on the scales most sensitive to depression (scale 2) and anxiety (scale 7). Physical complaints and depression were not major factors in memory performance among Lyme patients. These data support the hypothesis that Lyme encephalopathy is caused by CNS dysfunction and cannot be explained as a psychological response to chronic illness.

Relationship of drug use to involvement in school, home, and community activities: results of a large survey of adolescents.

All 7th, 9th, and 11th grade students in 129 school districts responded to a 466-variable survey that primarily assessed drug use but also contained questions about involvement in various activities. Meaningful relationships were obtained between students' involvement in school, family, and church activities and reported use of tobacco, alcohol, and marijuana. Factors reflecting the extent of parental supervision were also related to the reported use of those substances.

Changing attentional demands in left hemispatial neglect.

Seven variations of a letter cancellation test were used to examine how varying attentional demands affect hemispatial neglect in patients with right hemisphere lesions. While the 14 targets always remained in the same location, the number of distractors (zero, nine, 28, or 82) as well as their complexity (one letter or nine different letters) were varied. The percentage of targets canceled in the left hemispace was linearly related to the number of distractors. There were no differences between the complexity conditions. In a second study, the same 14 targets were presented but the distractors (zero, 14, or 41) were all placed on the right. Increasing the number of distractors on the right increased neglect on both sides of the space. Taken together, these results suggest that, while the limited attentional resources of the left hemisphere are biased toward the right hemispace, the absence of contralateral attentional demands allows these resources to be directed ipsilaterally.