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The cognitive efficacy of the M1-selective muscarinic agonist xanomeline in mild-to-moderate Alzheimer disease (AD) was measured using the Computerized Neuropsychological Test Battery (CNTB) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) in this 17-center, double-blind, placebo-controlled study. Three hundred forty-three patients were randomly assigned to receive 25, 50, or 75 mg xanomeline tartrate or placebo three times daily (t.i.d.) for 24 weeks, followed by placebo for 4 weeks in a single-blind washout phase. Cognitive function was assessed at randomization and after 4, 8, 12, 24, and 28 weeks. Three hundred nineteen patients were included in an intent-to-treat (ITT) analysis; 209 completers had evaluable data at week 24. ITT analysis showed a significant (por = 0.05) dose-response trend and a significant (por = 0.05) between-group comparison favoring 75 mg t.i.d. over placebo for the CNTB summary score but not for the ADAS-cog. In the completer analysis, however, the ADAS-cog showed a significant (por = 0.05) dose-response trend and between-group comparison, whereas the CNTB Summary Score did not. The ADAS-cog was less sensitive to treatment effects in mildly impaired patients (ADAS-cog21) than in moderately impaired patients (ADAS-cogor = 21), whereas the CNTB was sensitive in the entire study population (mean ADAS-cog = 22.5+/-9.6). Significant (por = 0.05) beneficial treatment effects were seen in measures of simple reaction time and delayed verbal recall, which are included in the CNTB but not in the ADAS-cog. During the single-blind placebo washout period, the ADAS-cog score of the placebo group worsened dramatically (change of 2.63 points; por = 0.001), whereas the CNTB score remained stable (change of 1.04 points; p=0.694). Thus, the CNTB appears to be more objective than the ADAS-cog.

BMY 21,502 is a nootropic which protects memory and enhances long-term potentiation according to preclinical findings. Alzheimer's disease (AD) patients who were diagnosed by DSM-III-R and NINCDS-ADRDA criteria were enrolled in a 12-week double-blind investigation of BMY 21,502 vs. placebo at 300 mg tid. The study design included a 1-week placebo lead-in and a 4-week placebo washout in addition to the 12-week double-blind treatment period. Efficacy was assessed with the Alzheimer's Disease Assessment Scale (ADAS) and the Computerized Neuropsychological Test Battery (CNTB) at weeks 4, 8, 12, and 16. Clinical Global Impression (CGI) assessments were also performed biweekly. Sixty-nine patients (28M, 41F; mean age 72 years, range 54 to 92 years) were enrolled in the study. Baseline Mini-Mental Status Examination (MMSE) scores ranged from 16 to 26 (mean 23.5) in patients on active drug (n = 34), and from 15 to 26 (mean 22.5) in placebo patients (n = 35). Baseline efficacy scores were comparable for drug and placebo patients (p > 0.05). Twelve (35%) patients who received BMY 21,502 withdrew from the study, 8 (24%) due to adverse events. Three (9%) patients who received placebo withdrew from the study, all due to adverse events. Patients on active drug who were valid for analysis of efficacy (n = 22) showed a mean decrease in ADAS of -1.5 at week 12, vs. a mean change of -0.5 in patients who received placebo (n = 32), although there was no significant difference between the two (p > 0.05). Correlations between the CNTB summary scores and ADAS cognitive subscores were, nevertheless, highly significant at baseline (r = -0.83, p = 0.0001) and week 12 (r = -0.83, p = 0.0001). Correlations between the word list learning, spatial, and naming subtests of the ADAS and CNTB were also highly significant (p = 0.0001). Although modest, the findings for active drug vs. placebo response in this study suggest that BMY 21,502 should be further investigated, with a larger study population, in order to fully determine the compound's potential efficacy.

The Computerized Neuropsychological Test Battery (CNTB), a new assessment tool for neuropsychopharmacologic research, is based on a neuropsychological approach. While it is based on tests previously shown to be sensitive to subtle changes in neuropsychological functioning, it differs from currently available tools for measuring central nervous system effects of new compounds. It has sensitivity to a broader range of cognitive functioning and is more comprehensive than other measurements in its sampling of neuropsychological functions, providing wider application to diverse clinical populations. The CNTB is valid, reliable, and has two alternative forms. Use of the computer as an expert system maximizes standardization and ease of CNTB administration and data analysis. Using this assessment tool, three groups of subjects were compared: young and elderly neurologically normal subjects and elderly subjects with the dementia syndrome of Alzheimer's disease (AD). The AD subjects' summary score on the CNTB correlated significantly with the Blessed Information Memory Concentration Test score. The CNTB summary score was significantly higher in young subjects than in neurologically normal elderly subjects, demonstrating sensitivity to the effects of aging. The CNTB summary score also was significantly higher in neurologically normal elderly subjects than in elderly subjects with AD dementia. ( J Geriatr Psychiatry Neurol 1991;4:211-217).

“Cortical” and “subcortical” dementia syndromes differ in areas of primary neuropathology and clinical characteristics. Conventional CT scan interpretation, visual inspection of pictures, has not been useful in studying dementia. Recent studies of the digitally stored CT attenuation values have found systematic variations with normal aging and aphasia subtypes. In this study of numerical CT scan information in four Alzheimer's Disease and two Huntington's Disease patients, a double dissociation of frontal and temporal lobe density values was found, and a significant correlation was found between left temporal lobe density and verbal ability measures in the Alzheimer's Disease patients.

The presence of lateral ventricular enlargement in some manic-depressive subjects, as assessed by ventricular-brain ratios (VBRs), has been reported. A study of 27 bipolar patients and 27 individually matched normal controls confirmed that finding. Bipolar patients had significantly larger VBRs than did controls. Clinical measures associated with the presence of ventricular enlargement in the bipolar patients included more frequent hospitalizations and histories of persistent unemployment. Other measures of illness severity or social deterioration were not significantly associated with large VBR.

A qualitative difference of processing type by the two cerebral hemispheres was demonstrated in a picture arrangement task which involved a concept of temporal sequence. Half the sequences were designed to rely on analytic categorical processes and half on configurational processes. The subjects were patients with unilateral hemispheric damage of vascular etiology. Using two measures of performance, latency and errors, patients with right hemisphere damage were seen to be relatively impaired on those sequences designed to employ hypothesized right hemisphere (configurational) processing and patients with left hemisphere damage were seen to be relatively impaired on those sequences designed to employ hypothesized left hemisphere (categorical) processing.

Luria's clinical neuropsychological approach and analysis of frontal lobe syndromes are applied to the study of aging. Brain damage produces both functional deficits and positive signs. The functional deficits seen in association with the aging process resemble those of patients with frontal system pathology. In the present study, performance of normal aging subjects is examined qualitatively for the positive signs associated with damage to frontal structures, namely perseveration and segmentation. Significant positive correlation is found between increasing prevalence of these frontal features and increasing age. Significant sex differences are also found, with males exhibiting more of these frontal features than females.