Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial.

BACKGROUND: Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials. OBJECTIVE: To evaluate the association between amyloid (Aß) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS). DESIGN: Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis. SETTING: The EARLY study was conducted at 143 centers across 14 countries. PARTICIPANTS: 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with Aß status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aß levels (Aß-, n=2,824) and those with pathological Aß levels (Aß+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aß1-42. MEASUREMENTS: Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aß groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aß status. RESULTS: Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. Aß+ participants performed worse versus Aß- participants on all cognitive composites though the magnitude of the Aß effect was generally small. The Aß+/- effect size for the PACC (Cohen's d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest Aß+/- effect sizes. CONCLUSIONS: Cross-sectional relationships between Aß and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aß+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aß status cross-sectionally cannot be generalized to sensitivity to change over time.

Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefit.

Cholinesterase (ChE) inhibition represents the most efficacious treatment approach for Alzheimer's disease (AD) to date. This multiple-dose study has examined the relationship between inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities in the cerebrospinal fluid (CSF) and cognitive change (measured by the Computerised Neuropsychological Test Battery [CNTB]) following administration of the ChE inhibitor, rivastigmine (Exelon). In 18 patients with mild to moderate AD, CNTB scores, activities of AChE and BuChE in the CSF, and plasma BuChE activity were determined prior to treatment with rivastigmine. Doses of rivastigmine were then titrated (1 mg b.i.d./week) to final doses of 1, 2, 3, 4, 5 or 6 mg b.i.d. (n = 3 per dose). Following treatment with the target dose of rivastigmine for at least 3 days, CNTB scores were re-determined. CSF samples were continuously collected together with plasma samples prior to and for 12 hours after the final dose of rivastigmine, and AChE and BuChE activities determined.AChE in CSF and BuChE in plasma were dose-dependently inhibited by rivastigmine treatment. The inhibition of BuChE in CSF was not clearly dose-dependent. A statistically significant correlation was observed between the change in CNTB summary score and inhibition of AChE activity (r = -0.56, p < 0.05) and BuChE activity (r = -0.65, p < 0.01) in CSF. Improvement in speed-, attention- and memory-related subtests of the CNTB correlated significantly with inhibition of BuChE but not AChE activity in CSF. Weak or absent correlation with change in cognitive performance was noted for inhibition of plasma BuChE. These results indicate that cognitive improvement with rivastigmine in AD is associated with central inhibition of ChEs and support a role for central BuChE in addition to AChE inhibition in modulating cholinergic function in AD.

The status of ongoing trials for mild cognitive impairment.

Mild cognitive impairment (MCI) is a term used to describe memory decline or other specific cognitive impairment in individuals who do not have dementia or significant impairment of other cognitive functions beyond that expected for their age or education. It has been suggested that as much as 38% of the elderly population would meet criteria for MCI and although the associated memory deficits are mild, the fact that up to 15% of MCI patients, particularly those with a particular type of memory impairment, convert to Alzheimer's disease (AD) annually has prompted serious attention. Despite the high conversion rate, MCI cannot be used synonymously with early or mild AD, as patients with AD are impaired not only in memory performance but in other cognitive domains as well; they meet diagnostic criteria for dementia. However, since there is a high conversion rate from MCI to AD, it is likely many with MCI have the underlying neuropathology of AD, though they do not yet meet clinical diagnostic criteria. Therefore, treatment strategies developed for AD, specifically acetylcholinesterase inhibitors and Cox-2 inhibitors, have been among the first employed to treat MCI. It is hoped that by impeding the progression of MCI in this manner, fewer patients will convert to AD. This article will give a brief overview of the condition of mild cognitive impairment and an account of trial methodology and current treatment strategies being employed for MCI.

Mild cognitive impairment: emerging therapeutics.

OBJECTIVE: To present a general overview of the etiology, definition, and prevalence of mild cognitive impairment (MCI), as well as outline possible treatment strategies. DATA SOURCES: A MEDLINE search was conducted for relevant references generated from 1990 to 2000 concerning MCI, mild to moderate Alzheimer disease (AD), and therapeutic strategies. Several books were also used in the compilation of data for this review, as well as the authors' experience in designing and conducting MCI trials. DATA EXTRACTION: All of the references listed were assessed, and all relevant information was included in this review. DATA SYNTHESIS: Forgetful individuals most likely to develop AD have a condition known as MCI previous to their development of dementia. This condition is hallmarked by memory impairment that is abnormal for the individual's age and educational level. While not all individuals with MCI develop AD, it is apparent that the condition can serve as a potential marker for early onset of AD. CONCLUSIONS: As many clinicians can attest, occasional forgetfulness is a common aspect of the aging process. Eventually, however, a large portion of forgetful individuals, especially those with MCI, will be diagnosed with AD or some other form of dementia. Indeed, many researchers have suggested that MCI should be regarded as incipient AD and that these individuals would benefit from drug therapy. Thus, MCI screening may be beneficial in terms of both early AD intervention and perhaps even AD prevention.

Efficacy of xanomeline in Alzheimer disease: cognitive improvement measured using the Computerized Neuropsychological Test Battery (CNTB).

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 (p < or = 0.05) dose-response trend and a significant (p < or = 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 (p < or = 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-cog < 21) than in moderately impaired patients (ADAS-cog > or = 21), whereas the CNTB was sensitive in the entire study population (mean ADAS-cog = 22.5+/-9.6). Significant (p < or = 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; p < or = 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.

Efficacy and safety of BMY 21,502 in Alzheimer disease.

OBJECTIVE: To assess the efficacy and safety of BMY 21,502, a nootropic agent, in patients with mild-to-moderate Alzheimer disease. DESIGN AND PARTICIPANTS: Sixty-nine patients with Alzheimer disease (28 men, 41 women, mean age 72 y, range 54-92, mean Mini-Mental State Examination (MMSE) score 23.5) were randomized to receive either BMY 21,502 (n = 34) or placebo (n = 35) for 12 weeks of double-blind treatment followed by a 4-week placebo washout period. SETTING: Outpatient research facility. MEASUREMENTS: Primary efficacy assessments were the Alzheimer's Disease Assessment Scale (ADAS) and the Clinical Global Impressions Scale. The Computerized Neurological Test Battery and MMSE were performed as secondary efficacy measurements. RESULTS: Although overall effects were not statistically significant (p > 0.05), patients taking BMY 21,502 showed a mean change in the ADAS cognitive score of -1.5 points at week 12, compared with -0.5 in patients who received placebo. Patients with moderate dementia (MMSE < or = 20) showed a greater change at week 12 with BMY 21,502 (-2.7 points) compared with placebo (+0.3 points), but the difference was not statistically significant. Although BMY 21,502 was well tolerated in general, patients treated with BMY 21,502 experienced higher rates of abnormal liver enzyme concentrations and nausea than did those in the placebo group. There was also a higher rate of discontinuations in the BMY 21,502 group, with 12 of 34 (35%) patients in the BMY 21,502 group discontinuing, compared with 3 of 35 (9%) in the placebo group (p < 0.05). CONCLUSIONS: In this pilot study, BMY 21,502 was not found to be significantly superior to placebo during the treatment period. The compound was generally well tolerated, although 8 of 34 (24%) patients discontinued active drug treatment. Further evaluation of BMY 21,502 in a larger study population may be warranted.

Assessing the neuropsychological profile of stable schizophrenic outpatients.

In an administration of the Computerized Neuropsychological Test Battery (CNTB), stable schizophrenic outpatients (n = 26) showed significant impairment (P < 0.05) relative to normal control subjects (n = 28) in overall function and measures of verbal learning. Except on tests of motor speed, the performance profile of schizophrenic patients was similar to that of elderly normal control subjects (n = 33). This profile of deficits is consistent with findings of other investigators in similar patient populations. In addition to displaying sensitivity to the mild impairments found in outpatients, the CNTB showed high test-retest reliability (r = 0.76, P < 0.0001). It should be useful for evaluating cognitive impairment in clinical trials of prospective treatments.

Effects of the cholinomimetic SDZ ENS-163 on scopolamine-induced cognitive impairment in humans.

Scopolamine-induced cognitive impairment was used in healthy men to evaluate the central nervous system activity of the new cholinomimetic SDZ ENS-163. Eighteen subjects were treated in a crossover design with oral placebo/intravenous saline, 50 mg of oral SDZ ENS-163/intravenous saline, oral placebo/0.4 mg of intravenous scopolamine, and 50 mg of oral SDZ ENS-163/0.4 mg of intravenous scopolamine. The administration of placebo with scopolamine caused significant cognitive impairment, as assessed by the Computerized Neuropsychological Test Battery (CNTB), and also decreased salivation and heart rate. In contrast, SDZ ENS-163 with saline had no effect on CNTB scores, increased salivation, and increased heart rate. Despite the observed cholinomimetic effects of SDZ ENS-163 when administered with saline, the changes in CNTB scores, heart rate, and salivation were indistinguishable between placebo/scopolamine and SDZ ENS-163/scopolamine. Thus, 50 mg of oral SDZ ENS-163 has cholinomimetic activity in normal men, but this dose is insufficient to reverse the muscarinic effects of 0.4 mg of intravenous scopolamine.

The use of the Computerized Neuropsychological Test Battery (CNTB) in an efficacy and safety trial of BMY 21,502 in Alzheimer's disease.

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.

Psychomotor and memory effects of two adinazolam formulations assessed by a computerized neuropsychological test battery.

The memory effects of adinazolam were assessed using the computerized neuropsychological test battery (CNTB). In a single-blind crossover study, 12 volunteers received 2 x 20 mg adinazolam mesylate immediate-release (CT) tablets, 2 x 30 mg sustained-release (SR) tablets, and placebo. Plasma adinazolam and N-desmethyladinozolam (NDMAD) were determined by high-pressure liquid chromatography. Choice reaction time and word-list-learning/delayed-recall CNTB modules were administered at 0, 1, 3 and 6 hours after dosing. Adinazolam and NDMAD maximum peak plasma concentration were lower after SR tablets. Immediate-release tablets significantly prolonged reaction time compared with placebo and SR tablets; reaction time after SR tablets did not differ from placebo. Differences between SR and CT tablets in memory were significant only at 1 hour, but memory scores tended to be higher after SR tablet administration than after the CT tablet. At all times, memory scores were significantly lower than placebo for active treatments. Results suggest that memory is more impaired at lower NDMAD concentrations than is psychomotor function.

A pilot clinical trial of the angiotensin-converting enzyme inhibitor ceranapril in Alzheimer disease.

This pilot clinical trial was a 15-week, double-blind, controlled, three-way crossover study evaluating cognitive effects of ceranapril in subjects with dementia of the Alzheimer type (age range 50-75 years). Computerized (CNTB) and noncomputerized cognitive test batteries revealed no significant results (p > 0.05). On further analysis of the data, however, a study of longer duration and/or higher dosages may be warranted.

A new assessment tool for neuropsychopharmacologic research: the Computerized Neuropsychological Test Battery.

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.

Clinical correlates of lateral ventricular enlargement in bipolar affective disorder.

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.

CT scan and neuropsychological correlates of Alzheimer's disease and Huntington's disease.

"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.