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Background and ObjectivesThe goal of this work was to investigate the neuroimaging correlates of the Stages of Objective Memory Impairment (SOMI) system operationalized with the Free and Cued Selective Reminding Test (FCSRT), a widely used episodic memory measure.MethodsThe FCSRT begins with a study phase in which items (e.g., grapes) are identified in response to unique semantic cues (e.g., fruit) that are used in the test phase to prompt recall of items not retrieved by free recall. There are 3 test trials of the 16 items (maximum 48). Data from 4,484 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were used. All participants had amyloid PET imaging, and a subset of 1,262 β-amyloid (Aβ)–positive had structural MRIs. We compared the Aβ mean cortical standardized uptake value ratio (SUVR) and volumetric measures of hippocampus, parahippocampal gyrus, entorhinal cortex, and inferior temporal cortex between the 5 SOMI stages.ResultsParticipants had a mean age of 71.3 (SD 4.6) years; 40.6% were male; and 34.6% were APOE ε4 positive. Half had no memory impairment; the other half had retrieval deficits, storage limitations, or both. Analysis of covariance in the entire sample while controlling for age, sex, education, and APOE ε4 showed that individuals in higher SOMI stages had higher global amyloid SUVR (p < 0.001). Both SOMI-4 and -3 subgroups had higher amyloid SUVR than SOMI-0 and SOMI-1 subgroups. Individuals in higher SOMI stages had smaller hippocampal volume (p = 0.003), entorhinal cortex (p < 0.05), and inferior temporal lobes (p < 0.05), but there was no difference between parahippocampal gyrus volume of different SOMI stages. Pairwise comparison of SOMI subgroups showed that the SOMI-4, -3, and -2 subgroups had smaller hippocampal volume than the SOMI-0 and -1 subgroup. The SOMI-4 subgroup had significantly smaller entorhinal cortex and smaller inferior temporal lobe compared to all other groups.DiscussionPresence of Alzheimer disease pathology is closely related to memory impairment according to SOMI stages in the cognitively unimpaired sample of A4. Results from structural MRIs suggest that memory storage impairment (SOMI-3 and -4) is present when there is widespread medial temporal lobe atrophy.Trial Registration InformationClinicalTrials.gov identifier: NCT02008357.Classification of EvidenceThis study provides Class I evidence that, in normal older individuals, higher stages of memory impairment assessed with FCSRT were associated with higher amyloid imaging burden and lower volume of hippocampus, entorhinal cortex, and inferior temporal lobes.

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.

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 ≤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.

imaging was conducted followingz 12 mCi of [11 C] PIB and 60 min dynamic PET scan in 3D mode (septa retracted). Mean cortical binding potential (MCBP) was determined as previously described. Results: Pearson correlation revealed the following correlations and trends between MCBP (for amyloid) and hippocampal subvolumes: left CA2-3 r 1⁄4 -0.29 (p 1⁄4 0.05); right CA2-3 r1⁄4 -0.25 (p1⁄4 0.09); left CA1 r1⁄4 -0.20 (p1⁄4 0.18); right CA1 r 1⁄4 -0.27 (p 1⁄4 0.07). No other regional volumes were correlated with MCBP. Conclusions: In this young healthy cognitively normal population there were trends towards the same pattern seen recently in an amnestic MCI population, with significantly smaller subfield volumes in CA 2-3 and subiculum compared with controls. In our study group only 8/46 participants had elevated MCBP (> 0.18 BP). We will extend our sample to a larger and older population, which can be expected to have higher numbers of participants with elevated amyloid.

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.

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.

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.

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.

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.

The authors evaluate current thinking as to when psychiatrists should call for computed tomography (CT). They discuss changes in the CT scan in CNS disorders likely to be seen by psychiatrists. The CT scan can be of considerable aid when the diagnosis is uncertain, especially since studies have shown that organic brain disease is underrecognized in psychiatric patients. Six case histories illuminate how CT provides diagnostic assistance.

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.