Physostigmine: improvement of long-term memory processes in normal humans.

Nineteen normal male subjects received 1.0 milligram of physostigmine or 1.0 milligram of saline by a slow intravenous infusion on two nonconsecutive days. Physostigmine significantly enhanced storage of information into long-term memory. Retrieval of information from long-term memory was also improved. Short-term memory processes were not significantly altered by physostigmine.

Plasma homovanillic acid concentration and the severity of schizophrenic illness.

Concentrations of plasma homovanillic acid before treatment were highly correlated with global severity of illness in schizophrenic patients, both before and after treatment. In contrast, a fixed dose of haloperidol did not affect those concentrations. Thus, in patients with a diagnosis of schizophrenia, plasma homovanillic acid may reflect the severity of illness, but not be influenced by short-term pharmacological perturbations by neuroleptics.

The clinical syndrome of Alzheimer's disease: aspects particularly relevant to clinical trials.

This paper describes the natural history of the clinical syndrome of Alzheimer's disease (AD) including the cognitive deficit, the neuropsychiatric symptoms, impact on daily functioning, risk factors, medical complications and impact on the use of health-care resources. The clinical presentation of the disease varies greatly from the prodrome through end stage; instruments used to quantify the severity of each aspect of the disease have been developed and are described along with their use in clinical drug trials. Drug treatments for AD are usually developed by first showing a positive effect on the cognitive deficit, with later studies investigating drug effects on other clinical aspects of the disease.

Alzheimer's disease. Morbid risk among first-degree relatives approximates 50% by 90 years of age.

The morbid risk of Alzheimer's disease was studied in first-degree relatives of 50 patients who met contemporary clinical research diagnostic criteria and 45 matched controls. Relatives of patients showed a 46% cumulative incidence of probable Alzheimer's disease by 86 years of age. The risk, which was four times the control value, is consistent with other recent reports using similar, modern methods. Although not conclusive, the data suggest the operation of a relatively common, dominant autosomal gene for Alzheimer's disease, the expression of which is delayed until late old age but is largely complete by 90 years of age.

Patterns of risk in first-degree relatives of patients with Alzheimer's disease.

BACKGROUND: Although an increased cumulative risk for primary progressive dementia (PPD) has been repeatedly demonstrated in relatives of probands with Alzheimer's disease (AD), an examination of their rates of illness at different ages has not been previously undertaken. Such an examination might reveal possible age-related characteristics associated with a more familial variety of AD. METHODS: Using family history interviews and survival analysis, the cumulative risk for and 5-year age-specific hazard rates of PPD were assessed in the first-degree relatives of 200 probands with AD and two nondemented control groups--179 elderly ascertained through the Alzheimer's Disease Research Center (ADRC-derived controls) and 427 elderly ascertained from community senior centers (community controls). RESULTS: The PPD risk curve for the relatives of probands with AD rose to about 30% and was significantly higher than the curves for the relatives of the ADRC-derived and community controls, where comparable rates were observed (approximately 12%). The age-specific hazard rates of PPD were calculated in three groups of relatives for each 5-year interval from ages 45 to 49 years through ages 85 to 89 years. The age-specific relative risk (RRi) for PPD in the relatives of probands with AD began to steadily diminish from the 75- to 79-year age interval (RRi = 13.49) through the 85- to 89-year age interval (RRi = 0.96) compared with the relatives of ADRC-derived controls and from the 60- to 64-year age interval (RRi = 16.15) through the 85- to 89-year age interval (RRi = 2.03) compared with the relatives of the community controls. CONCLUSIONS: These data indicate that, for relatives of probands with AD, while the lifetime risk for PPD is greater than in relatives of controls, the familial contribution to the risk for PPD decreases with increasing age. The higher risk for PPD in relatives of probands with AD may be substantially diminished or even eliminated by the latter half of the ninth decade.

Apomorphine and schizophrenia. Treatment, CSF, and neuroendocrine responses.

Previous studies have variably reported the efficacy of apomorphine in treatment of schizophrenia and tardive dyskinesia. Stimulation of dopamine neuron autoreceptors is the presumed mode of action. Low-dose apomorphine (0.75 mg subcutaneously) and placebo were administered to 25 male schizophrenics to evaluate the drug's effect on psychotic and tardive dyskinetic symptoms. No significant improvement or deterioration was seen. Concomitant measurements of plasma prolactin and growth hormone levels and CSF homovanillic acid level indicated that the dose used was centrally active. These results indicate that an active though nonsedating dose of apomorphine does not ameliorate symptoms of schizophrenia or tardive dyskinesia.

Neuropeptide abnormalities in patients with early Alzheimer disease.

BACKGROUND: Deficits in somatostatin-like immunoreactivity (SLI) and corticotropin-releasing factor immunoreactivity (CRF-IR) are well recognized as prominent neurochemical deficits in Alzheimer disease (AD). The question of whether these profound neuropeptidergic deficits found in patients with end-stage disease extend into those with much earlier disease is relatively unanswered. To determine the relation between level of SLI and CRF-IR in different cerebrocortical regions to the earliest signs of cognitive deterioration in AD. METHODS: We examined SLI and CRF-IR levels in 9 neocortical brain regions of 66 elderly patients in a postmortem study of nursing home residents who had either no significant neuropathologic lesions or lesions associated only with AD. Patients were assessed by the Clinical Dementia Rating scale (CDR) to have no dementia or questionable, mild, or moderate dementia, and were compared with 15 patients with severe dementia. RESULTS: Both CRF-IR and SLI were significantly reduced in the cortices of patients with the most severe dementia, but only the levels of CRF-IR were reduced in those with mild (CDR = 1.0) and moderate dementia (CDR = 2.0). Levels of CRF-IR and SLI correlated significantly with CDR, but this correlation was more robust for CRF-IR and persisted even when severely cognitively impaired patients were eliminated from analysis. CONCLUSIONS: Although SLI and CRF-IR levels are significantly reduced in patients with severe dementia, only CRF-IR is reduced significantly in the cortices of those with mild dementia. Thus, CRF-IR can serve as a potential neurochemical marker of early dementia and possibly early AD.

Increased morbid risk for schizophrenia-related disorders in relatives of schizotypal personality disordered patients.

To evaluate whether probands from a clinical sample diagnosed as having DSM-III schizotypal and/or paranoid personality disorder have a familial relationship to the schizophrenia-related disorders, the morbid risk for schizophrenia-related disorders and other psychiatric disorders were evaluated in the first-degree relatives of patients with schizotypal and/or paranoid personality disorder and compared with the corresponding risk for these disorders in the first-degree relatives of patients with other non-schizophrenia-related personality disorders. The morbid risk for all schizophrenia-related disorders, and specifically for schizophrenia-related personality disorders, was significantly greater among the relatives of the probands with schizotypal and/or paranoid personality disorder than among the relatives of probands with other personality disorder. The morbid risk for other psychiatric disorders did not differ significantly between the first-degree relatives of the schizotypal/paranoid personality disorder and the other personality disorder control proband samples. These results suggest a specific familial association between schizophrenia-related disorders, particularly schizophrenia-related personality disorders, and clinically diagnosed schizotypal patients.

Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior.

Dysfunction of the central serotonergic system has been variously associated with depression and with suicidal and/or impulsive aggressive behavior. To evaluate central serotonergic function in relation to these variables, prolactin responses to a single-dose challenge with fenfluramine hydrochloride (60 mg orally), a serotonin releasing/uptake-inhibiting agent, were examined in 45 male patients with clearly defined major affective (n = 25) and/or personality disorder (n = 20) and in 18 normal male control patients. Prolactin responses to fenfluramine among all patients were reduced compared with responses of controls. Reduced prolactin responses to fenfluramine were correlated with history of suicide attempt in all patients but with clinician and self-reported ratings of impulsive aggression in patients with personality disorder only; there was no correlation with depression. These results suggest that reduced central serotonergic function is present in a subgroup of patients with major affective and/or personality disorder and is associated with history of suicide attempt in patients with either disorder, but with impulsive aggression in patients with personality disorder only.

Evaluating prolactin response to dopamine agonists in schizophrenia. Methodological problems.

Serum prolactin (PRL) level was assessed after challenges with apomorphine hydrochloride, saline, dopamine hydrochloride, or levodopa-carbidopa (Sinemet) in 19 control and 38 chronic schizophrenic subjects. Baseline PRL level varied inversely with age. High correlations existed between baseline PRL level and any subsequent absolute measure of PRL after administration of a dopamine agonist or placebo. Percent decrease was not a function of baseline concentrations and was therefore the only independent measure of drug response. Baseline PRL level was generally lower during exacerbation than remission in patients studied during two states of illness. Percent PRL level decrease after apomorphine administration was significantly greater in normal subjects than in schizophrenics. Correction of apomorphine responses for corresponding placebo (saline) values abolished differences between groups. Prolactin responses after dopamine or levodopa-carbidopa did not differ; however, placebo correction was not possible.

Eye tracking, attention, and schizotypal symptoms in nonpsychotic relatives of patients with schizophrenia.

BACKGROUND: Biological relatives of patients with schizophrenia demonstrate an increased prevalence of schizotypal personality disorder symptoms, eye tracking deficits, and attentional disturbances. We investigated whether these hypothesized components of a schizophrenia-related phenotype are associated with one another or are independent in nonpsychotic relatives of patients with schizophrenia. METHODS: Eighty-three nonpsychotic first-degree relatives of 38 patients with schizophrenia and 45 control subjects without a psychiatric diagnosis underwent clinical evaluation, eye tracking evaluation, and the Continuous Performance Test (CPT) of visual attention. RESULTS: Eye tracking qualitative rating was more powerful than quantitative eye tracking measures or CPT measures in discriminating relatives of patients with schizophrenia from control subjects. Correlations between neurocognitive variables and DSM-III-R schizotypal personality disorder symptom clusters suggested that CPT errors of omission are associated with positive schizotypal symptoms. Eye tracking measures were not significantly correlated with schizotypal symptoms or CPT errors in relatives of patients with schizophrenia. CONCLUSIONS: Eye tracking deficits in the relatives of patients with schizophrenia are unrelated to CPT deficits and schizotypal symptoms. Eye tracking deficits and disturbances in visual attention may be separate components of a schizophrenia-related phenotype and should be considered as independent factors in genetic studies of schizophrenia.

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group.

BACKGROUND: Donepezil hydrochloride (Aricept) is a selective acetylcholinesterase inhibitor developed for the treatment of Alzheimer disease. This phase 3 study was 1 of 2 pivotal trials undertaken to establish the efficacy and safety of using donepezil in patients with mild to moderately severe Alzheimer disease. OBJECTIVES: To further examine the efficacy and safety of using donepezil in the treatment of patients with mild to moderately severe Alzheimer disease. To examine the relationships between plasma donepezil concentrations, inhibition of red blood cell acetylcholinesterase activity, and clinical response. METHODS: This was a 12-week, double-blind, placebo-controlled, parallel-group trial with a 3-week single-blind washout. Outpatients at 23 centers in the United States were randomized to receive placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride (5 mg/d during week 1 then 10 mg/d thereafter) administered once daily at bedtime. Primary efficacy was measured using the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change including caregiver information (CIBIC plus). RESULTS: A total of 468 patients entered the study, more than 97% of whom were included in the intention-to-treat (end point) analyses. The use of donepezil produced statistically significant improvements in ADAS-cog, CIBIC plus, and Mini-Mental State Examination scores, relative to placebo. The mean drug-placebo differences, at end point, for the groups receiving 5 mg/d and 10 mg/d of donepezil hydrochloride were, respectively, 2.5 and 3.1 units for ADAS-cog (P<.001); 0.3 and 0.4 units for CIBIC plus (P< or =.008); and 1.0 and 1.3 units for Mini-Mental State Examination (P< or =.004). On the CIBIC plus scale, 32% and 38% of patients, respectively, treated with 5 mg/d and 10 mg/d of donepezil hydrochloride demonstrated clinical improvement (a score of 1, 2, or 3) compared with placebo (18%). The mean (+/-SEM) donepezil plasma concentrations at study end point were 25.9 +/- 0.7 ng/mL and 50.6 +/- 1.9 ng/mL in the groups receiving dosages of 5 mg/d and 10 mg/d, respectively. Corresponding mean (+/-SEM) percentages of inhibition of red blood cell acetylcholinesterase activity were 63.9% +/- 0.9% and 74.7% +/- 1.2% for these 2 dosages, respectively. There was a statistically significant positive correlation between plasma concentrations of donepezil and acetylcholinesterase inhibition; the EC50 (50% effect) was obtained at a concentration of 15.6 ng/mL. A plateau of inhibition (80%-90%) was reached at plasma donepezil concentrations higher than 50 ng/mL. The correlations between plasma drug concentrations and both ADAS-cog (P<.001) and CIBIC plus (P = .006) were also statistically significant, as were the correlations between red blood cell acetylcholinesterase inhibition and change in ADAS-cog (P<.001) and CIBIC plus (P = .005). The incidence of treatment-emergent adverse events with both dosages of donepezil (68%-78%) was comparable with that observed with placebo (69%). The use of 10 mg/d of donepezil hydrochloride was associated with transient mild nausea, insomnia, and diarrhea. There were no treatment-emergent clinically significant changes in vital signs or clinical laboratory test results. More important, the use of donepezil was not associated with the hepatotoxic effects observed with acridine-based cholinesterase inhibitors. CONCLUSION: Donepezil hydrochloride (5 and 10 mg) administered once daily is a well-tolerated and efficacious agent for treating the symptoms of mild to moderately severe Alzheimer disease.

Red blood cell choline. I: Choline in Alzheimer's disease.

Seventeen drug-free patients with Alzheimer's disease (AD) and 15 normal elderly controls, of which 13 age- and sex-matched pairs were included, participated in a study of red blood cell (RBC) and plasma choline. Mean values for RBC choline, plasma choline, and the ratio of RBC/plasma choline did not differ between the AD and control groups. Degree of dementia did not correlate with any blood choline measure. A correlation was found between age and RBC choline (r = 0.57; p less than or equal to 0.01) and the RBC/plasma choline ratio (r = 0.56; p less than or equal to 0.03) in normals, but not in AD patients. RBC choline correlated with plasma choline in AD patients only (r = 0.46, p less than or equal to 0.03). These results do not support the use of RBC and plasma choline concentrations as either a diagnostic tool to identify AD patients or an antemortem index of the cholinergic deficit in brains of patients with Alzheimer's disease.

Red blood cell choline. II: Kinetics in Alzheimer's disease.

The kinetic parameters of choline uptake into red blood cells from patients with Alzheimer's disease and normal elderly controls were compared. The Kd and Vmax values for choline uptake into red cells were determined based on a kinetic analysis of choline uptake at six different concentrations of labeled extracellular choline. The theoretical choline uptake, representing the initial rate of choline influx into choline-depleted red cells given the plasma choline concentration and the kinetic parameters of choline uptake, was also calculated. Alzheimer's disease patients and normal controls did not differ in any kinetic parameter of choline uptake. Kd and Vmax values for red cell choline uptake were strongly correlated among normal controls, but not among patients with Alzheimer's disease. In addition, among the patients with Alzheimer's disease, the theoretical choline uptake was strongly correlated with the severity of dementia. The possible significance of these findings in relation to altered choline metabolism in Alzheimer's disease is discussed.

Memory impairment in schizophrenic patients with tardive dyskinesia.

Memory functioning was contrasted in 40 schizophrenic patients with and without tardive dyskinesia (TD). Visual and verbal memory tests were used to investigate specific types of impairments. The presence of TD was ascertained using the Abnormal Involuntary Movement Scale (AIMS). TD patients scored significantly lower than non-TD patients on two measures of visual learning, though no differences were found for verbal learning or immediate recall. These results are consistent with previous reports that schizophrenic patients with TD demonstrate impaired cognitive functioning. They also raise the possibility that the neurochemical and structural changes underlying TD may produce specific deficits in memory for visual materials. In addition, a significant relationship was found between total score on the Brief Psychiatric Rating Scale (BPRS) and performance on all of the test measures included in the cognitive test battery. This demonstrates the importance of attending to the overall level of schizophrenic symptomatology when evaluating results from experimental learning tasks.

RS 86 in the treatment of Alzheimer's disease: cognitive and biological effects.

Twelve patients who met Research Diagnostic Criteria for Alzheimer's disease (AD) completed a double-blind crossover study comparing oral RS 86, a long-acting and specific muscarinic agonist, with placebo. Cognitive and noncognitive effects were assessed with the Alzheimer's Disease Assessment Scale (ADAS). RS 86 was found to improve ADAS test scores consistently (both cognitive and noncognitive subscales) in seven patients, with a clinically obvious improvement in only two patients. RS 86 produced a significant increase in peak nocturnal cortisol levels, and this increase correlated with improvement on ADAS testing. Similarly, there was a 38% increase in amplitude of the P300 evoked potential with RS 86. The biological findings suggest that RS 86 was effective only to the extent that it enhanced central cholinergic activity.

Plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) and clinical symptoms in Alzheimer's disease.

Postmortem findings point to significant abnormalities in central noradrenergic function in Alzheimer's disease (AD) which may be associated with changes in peripheral markers. In this study, the relationship between the peripheral noradrenergic marker, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), and clinical symptoms was examined in 23 patients with probable AD. Basal MHPG levels correlated significantly with increased cognitive impairment (r = .58, p = .005), controlling for age, age at onset, gender, and time interval between plasma MHPG determination and cognitive testing. These results suggest that plasma MHPG increases as cognitive function in AD deteriorates, further supporting preliminary evidence for increases in noradrenergic indices in association with disease severity in AD.

4-Aminopyridine in the treatment of Alzheimer's disease.

The cognitive and behavioral effect of 4-aminopyridine (4-AP) was examined in Alzheimer's disease (AD) using a dose finding/replication study design. Fourteen inpatients, aged 54-89 years (mean 66.1 +/- 10.6 SD), meeting NINCDS criteria for probable AD, were studied. Three doses of 4-AP--2.5 mg b.i.d., 5 mg b.i.d., and 10 mg b.i.d.--or placebo were administered for 4 consecutive days in random order. Symptomatic assessment was performed on the fourth day of each condition using the Alzheimer Disease Assessment Scale (ADAS). Thereafter, the dose on which the best performance occurred was readministered, as was placebo. Of the 13 patients who completed the dose-finding phase, 7 patients had at least one dose of 4-AP that was associated with less severe symptoms than was placebo, and those patients were included in the replication phase. Results indicated no significant difference in total ADAS scores (p greater than 0.05). Examination of the ADAS subscales revealed no significant 4-AP effect on any particular symptom. Possible explanations of the lack of a drug effect in this study include the unselective release of neurotransmitters by 4-AP, poor penetration into the central nervous system (CNS), and the presenile onset of the disease in these patients.

Empirical evaluation of the factorial structure of clinical symptoms in schizophrenia: effects of typical neuroleptics on the brief psychiatric rating scale.

There has been little investigation of the effect of neuroleptic medication on the structure of symptoms in schizophrenia. In this study, 135 male schizophrenic patients were rated with the Brief Psychiatric Rating Scale (BPRS) after 4 weeks of treatment with typical neuroleptic medication and after 2 weeks free of neuroleptics, with the order of assessment varying across patients. Confirmatory factor analyses (CFA) found that there were no differences in symptom structure across medication status and no differences in the structure of symptoms in treatment responders and nonresponders. The typical 5-factor BPRS model fit the data poorly and the fit improved considerably through deletion of items measuring symptoms not associated with schizophrenia, suggesting that some of the symptoms that contribute to a total BPRS score may be adding primarily error variance. Although the sample size in this study is limited, the results suggest that using total BPRS scores to measure severity of schizophrenic symptoms should be reconsidered.