Cognitive and neuroimaging predictors of instrumental activities of daily living.

Impaired ability to conduct daily activities is a diagnostic criterion for dementia and a determinant of healthcare services utilization and caregiver burden. What predicts decline in instrumental activities of daily living (IADLs) is not well understood. This study examined measures of episodic memory, executive function, and MRI brain volumes in relation to baseline IADLs and as predictors of rate of IADL change. Participants were 124 elderly persons with cognitive function between normal and moderate dementia both with and without significant small vessel cerebrovascular disease. Random effects modeling showed that baseline memory and executive function (EXEC) were associated with baseline IADL scores, but only EXEC was independently associated with rate of change in IADLs. Whereas hippocampal and cortical gray matter volumes were significantly associated with baseline IADL scores, only hippocampal volume was associated with IADL change. In a model including cognitive and neuroimaging predictors, only EXEC independently predicted rate of decline in IADL scores. These findings indicate that greater executive dysfunction at initial assessment is associated with more rapid decline in IADLs. Perhaps executive function is particularly important with respect to maintaining IADLs. Alternatively, executive dysfunction may be a sentinel event indicating widespread cortical involvement and poor prognosis.     

The Personality Research Form as a therapy outcome measure of social behavior

Reported two studies that examined the efficacy of the Personality Research Form (PRF) as an outcome measure for interventions designed to increase social competence. In the first study (N = 83), the degree to which PRF scales can predict criteria frequently used in social skills training outcome research was examined, and the PRF was shown to be sensitive to such criteria. The second study (N = 24) assessed the relative degree to which the PRF scales and more frequently used outcome measures, including the above criteria, are affected by factors non-specific to social skills training interventions (suggestion for improvement). While three PRF scales were affected significantly, demand effects were much more pervasive on the other measures, which suggests that those measures can be used to obtain valid estimates of treatment effects only when experimental control of non-specific effects is possible. Two PRF scales, Affiliation and Exhibition, were shown to be both sensitive to criteria and resistant to demand effects, and as such may be useful as outcome measures in non-controlled clinical settings.     

Considerations in the design of clinical trials for cognitive aging

What will it take to develop interventions for the treatment of age-related cognitive decline? Session V of the Summit provided perspectives on the design of clinical trials to evaluate promising but unproven interventions, and some of the steps needed to accelerate the discovery and evaluation of promising treatments. It considered strategies to further characterize the biological and cognitive changes associated with normal aging and their translation into the development of new treatments. It provided regulatory, scientific, and clinical perspectives about neurocognitive aging treatments, their potential benefits and risks, and the strategies and endpoints needed to evaluate them in the most rapid, rigorous, and clinically meaningful way. It considered lessons learned from the study of Alzheimer's disease, the promising roles of biomarkers in neurocognitive aging research, and ways to help galvanize the scientific study and treatment of neurocognitive aging.     

Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease

OBJECTIVE: To examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI). BACKGROUND: Previous cross-sectional studies examining the relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI. METHODS: Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability. RESULTS: Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline. CONCLUSIONS: Results suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.     

Memory failure has different mechanisms in subcortical stroke and Alzheimer's disease

Patients with extensive subcortical cerebrovascular disease may have impaired memory, often despite the absence of medial temporal or diencephalic strokes. In this group, episodic memory failure may arise from frontal lobe dysfunction based on disruption of frontosubcortical loops caused by lacunae. We tested this idea by studying cognitively impaired subcortical stroke (CIS) patients and Alzheimer's disease (AD) patients with [18F]-fluorodeoxyglucose positron emission tomography using a continuous verbal memory task during the period of tracer uptake. Patients were matched on severity of cognitive impairment and overall memory task performance. As hypothesized, we found a double dissociation in the relations between metabolism and memory in these groups, such that memory in CIS (but not in AD) correlates with prefrontal lobe metabolism, whereas in AD (but not in CIS), memory correlates with left hippocampal and temporal lobe metabolism. Analysis of memory subscores showed that CIS patients made more errors on short-delay trials, which is consistent with working memory failure. It seems that different pathogenic mechanisms underlie episodic memory failure in subcortical cerebrovascular disease and AD.     

Assessment of disruptive behavior associated with dementia: the Disruptive Behavior Rating Scales

Disruptive behavior associated with dementia is a major clinical problem, but there has been limited methodology for assessing it. This study describes the development of a set of rating scales used to measure four dimensions of disruptive behavior that present frequent problems in patients with dementia: physical aggression, verbal aggression, agitation, and wandering. In addition, a total disruptive behavior scale is derived by averaging scores from these four scales. A sample of 16 patients in a skilled nursing facility was used to test interrater reliability and validity of this instrument. Interrater reliability was quite favorable for all scales. There was clear evidence for convergent validity of all scales except the verbal aggression scale, where a substantial correlation was found with one relevant external measure but not the other. There was also favorable evidence of discriminant validity for all scales except the verbal aggression scale. Psychometric properties of this instrument appear to be promising and indicate that it has potential utility for further research on causes and treatments for disruptive behavior in demented patients.     

Effect of haloperidol on a symbol digit substitution task in normal adult males

Two groups of normal male volunteers were administered oral haloperidol at two dose levels: 4 mg (n = 12), and 10 mg (n = 9). Subjects were administered the Symbol-Digit Substitution Test (SDST) prior to drug administration (0 hours) and at the following intervals after administration: 1, 3, 4, 6, 14, 24, and 36 hours. Overall performance of the 10-mg group was poorer than that of the 4-mg group. Both groups showed a significant time-dependent decrease in performance, with the effects for the 10-mg group being apparent earlier and lasting longer. The time course for this decrease corresponded to the time course of elevation of prolactin by haloperidol in these subjects. Performance on the Flexibility of Closure Test was unimpaired in subjects receiving 10 mg haloperidol, indicating that the impairment in performance on the SDST was not exclusively due to nonspecific factors such as sedation or psychomotor retardation. Extrapyramidal side effects could have contributed to impairment on the SDST, but the time course of these effects was different than that of performance impairment. Results indicate that haloperidol may have dose-dependent differential adverse effects on task performance when administered on a short-term basis, although little is known about the exact nature of these effects and their relationship to antipsychotic activity of the drug. Even though these effects may clear with repeated administration, their presence even for a short time may contribute adversely to the risk-benefit profile of neuroleptic medication.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influences of lobar gray matter and white matter lesion load on cognition and mood

Depressed mood is a frequent co-morbidity of dementia suggesting that they might share a common neuropathological substrate. Gray matter (GM) atrophy and white matter lesions (WML) have been described in both conditions. Our aims were to determine the relationship of GM and WML with cognition and depressed mood in the same population. Structural brain images were obtained from 42 controls, 20 Alzheimer's disease (AD) patients and 32 subjects with cognitive impairment/dementia due to subcortical cerebrovascular disease (vascCIND/IVD). Images were segmented to obtain lobar GM, white matter and WML volumes. Lobar WML had a negative effect on GM in all lobes in controls, on frontal, parietal and occipital GM in AD and on frontal GM in vascCIND/IVD. Frontal, temporal and hippocampal GM were associated with cognitive functions and frontal WML load with depressed mood. Cognitive function is associated with GM atrophy and depressed mood is associated with frontal WML. This indicates that although both often occur together, depressed mood and cognitive impairment have different pathological correlates.