Mild worry symptoms predict decline in learning and memory in healthy older adults: a 2-year prospective cohort study.

OBJECTIVE: : Theoretical models of cognitive aging are increasingly recognizing the importance of anxiety and depressive symptoms in predicting age-related cognitive changes and early dementia. This study examined the association between mild worry and depressive symptoms, and cognitive function in healthy, community-dwelling older adults. METHOD: : A total of 263 healthy older adults participated in an observational prospective cohort study that assessed worry and depression symptoms, and a broad range of cognitive functions over a 2-year period. RESULTS: : Older adults with mildly elevated worry symptoms at baseline performed worse than older adults with minimal worry symptoms on measures of visual and paired associate learning. They were also more likely to show clinically significant (> 1.5 standard deviation) decline in visual learning and memory at a 2-year follow-up assessment (9.4% versus 2.5%; odds ratio = 3.8). CONCLUSION: : Assessment of worry symptoms, even mild levels, may have utility in predicting early cognitive decline in healthy, community-dwelling older adults.

Intraindividual cognitive decline using a brief computerized cognitive screening test.

BACKGROUND: Progressive intraindividual decline in memory and cognition is characteristic of dementia and may be useful in detecting very early Alzheimer's disease pathology. METHODS: This study evaluated the slopes of cognitive performance over a 12-month period in 263 healthy, community-dwelling, adult volunteers aged ≥50 years. Participants completed a brief computerized battery of cognitive tests (CogState) at baseline and during 3-, 6-, 9-, and 12-month follow-up assessments. Linear mixed models were used to estimate age-adjusted mean slopes and 95% confidence intervals of change for each of the cognitive measures. RESULTS: By defining age-adjusted mean slopes, and 95% confidence intervals for a measure of episodic memory, individuals with greater than expected decline (equal to or lower than the fifth percentile level of decline) were identified. From these, four individuals completed a full medical, neurologic, and neuropsychological evaluation, with none of them fulfilling criteria for mild cognitive impairment, but three (75%) having positive amyloid-positron emission tomographic scans. CONCLUSIONS: Intraindividual decline in cognitive performance can be detected in otherwise healthy, community-dwelling, older persons, and this may deserve further study as a potential indicator of early Alzheimer's disease pathology.

A comparison of statistical approaches used to evaluate change in cognitive function following pharmacologic challenge: an example with lorazepam.

BACKGROUND: Neuropsychological tests are commonly used in psychopharmacological research to understand the nature and the magnitude of cognitive effects of licensed and novel compounds. While the science of cognitive change assessment has advanced considerably, statistical techniques used to guide inferences about differences in cognitive change have not been considered in the same detail, especially in light of recent advances in modeling repeated data. METHODS: Data from a randomized, placebo-controlled, crossover study of the effect of an acute dose of lorazepam on cognitive function in healthy adults were analyzed using five statistical approaches (paired sample t-test, area under curve (AUC), repeated measures analysis of variance (ANOVA), change from baseline, and linear mixed models (LMM)). Results of significance tests and effect sizes were compared at maximum concentration (C(max)) and over the ascending slopes of cognitive performance. RESULTS: LMM approaches were superior to other statistical approaches with respect to results of significance testing and magnitudes of estimated effect size change. CONCLUSIONS: Results of this study suggest that employment of LMM, which permit examination of specific fixed effects (e.g., time, treatment, treatment x time) and that are not confounded by between-subject variability, provide a sensitive approach to detecting the cognitive effects of pharmacologic challenges, even with small samples.

The use of effect sizes to characterize the nature of cognitive change in psychopharmacological studies: an example with scopolamine.

Drug induced cognitive change is generally investigated using small sample sizes. In terms of null hypothesis significance testing (NHST) this can render a meaningful change non-significant, as a result of insufficient power in the statistical model. NHST leads to 'all or none' thinking, where a non-significant result is interpreted as an absence of change. An effect size calculation indicates the magnitude of change which has occurred post-intervention, and therefore whether a significant result is meaningful. We used a scopolamine challenge to demonstrate the usefulness of effect sizes. The aim of the study was to determine how effect sizes could describe the cognitive changes that occur following administration of subcutaneous scopolamine (s.c. scopolamine). Twenty four healthy young males (M = 32.6, sd = 4.5 years) were administered placebo and 0.2 mg, 0.4 mg & 0.6 mg of s.c. scopolamine using a 4-way crossover design. Memory, learning, psychomotor function, attention and executive function were assessed. Scopolamine significantly impaired performance on all tasks in a dose and time related manner. These results demonstrate the functionality of change scores to draw comparisons between different times and doses. This methodology overcomes the limitations of comparisons between studies using different tasks, doses and time at which cognitive functions are measured.

Cognitive recovery during and after treatment for volatile solvent abuse.

BACKGROUND: Cognitive impairment reflecting CNS disruption in chronic solvent abusers can resolve within two years of abstinence. However, the specific time course for recovery has yet to be determined empirically. This study monitored cognition among solvent (i.e., gasoline) abusers throughout 8 weeks of residential treatment. It also investigated the extent to which solvent-related cognitive impairments persisted following discharge. METHODS: Non-drug using healthy controls (n=33) and solvent abusers (n=29) who had inhaled gasoline, regularly or episodically, for an average of 4.3 years (SD=2.7) were assessed. Using linear mixed model analyses, solvent abusers were compared to healthy controls throughout treatment at baseline, two weeks, four weeks and six weeks, on visual motor, attention, learning, memory, and executive function tasks. Ten users who maintained abstinence were reassessed an average of 12 months later (SD=2.8) and were compared to healthy controls (n=12) retested at the same time interval using ANCOVA while controlling for age and baseline performance. RESULTS: At baseline, solvent abusers showed cognitive deficits on visual motor, learning and memory, paired associate learning, and executive functions. Paired associate learning performance improved within 6 weeks of abstinence, however, impairments in visual motor speed, learning and memory, and executive function persisted throughout and in some cases beyond treatment. CONCLUSIONS: Cognitive deficits exist for solvent abusers upon treatment entry. Some impairments resolve within weeks of abstinence, while memory and executive function improves gradually over months to years of abstinence, and might never fully recover.

Spatial memory and executive functions in children.

A computerized hidden pathway maze-learning task was used to examine the development of spatial memory and executive functions in 6- to 9-year-olds. Pathway length was manipulated to investigate the impact of increases in maze matrix size on these abilities. Analysis showed that maze matrix size (and ipso facto pathway length) and age interacted to affect executive functions but not spatial memory. Executive errors differed as a function of age on the most difficult maze. Results are discussed in terms of factors affecting the development of executive functions and spatial memory.

Reliability, stability, and sensitivity to change and impairment in acoustic measures of timing and frequency.

Assessment of the voice for supporting classifications of central nervous system (CNS) impairment requires a different practical, methodological, and statistical framework compared with assessment of the voice to guide decisions about change in the CNS. In experimental terms, an understanding of the stability and sensitivity to change of an assessment protocol is required to guide decisions about CNS change. Five experiments (N = 70) were conducted using a set of commonly used stimuli (eg, sustained vowel, reading, extemporaneous speech) and easily acquired measures (eg, f0-f4, percent pause). Stability of these measures was examined through their repeated application in healthy adults over brief and intermediate retest intervals (ie, 30 seconds, 2 hours, and 1 week). Those measures found to be stable were then challenged using an experimental model that reliably changes voice acoustic properties (ie, the Lombard effect). Finally, adults with an established CNS-related motor speech disorder (dysarthria) were compared with healthy controls. Of the 61 acoustic variables studied, 36 showed good stability over all three stability experiments (eg, number of pauses, total speech time, speech rate, f0-f4. Of the measures with good stability, a number of frequency measures showed a change in response to increased vocal effort resulting from the Lombard effect challenge. Furthermore, several timing measures significantly separated the control and motor speech impairment groups. Measures with high levels of stability within healthy adults, and those that show sensitivity to change and impairment may prove effective for monitoring changes in CNS functioning.

Episodic memory decline predicts cortical amyloid status in community-dwelling older adults.

Intra-individual decline in memory and cognition is characteristic of prodromal Alzheimer's disease (AD) and may allow detection of very early AD pathology. Episodic memory task scores on a brief computerized cognitive battery (CogState) were prospectively evaluated at baseline, and 3-, 6-, 9-, 12-, and 24-months post-baseline. Linear mixed models were conducted to compute age-adjusted slopes. Subjects with slopes declining ≥90th percentile ("memory decliners") and age- and gender-matched subjects without such decline ("non-decliners") were studied with clinical, neuropsychological, and neuroimaging evaluations. Of 195 who completed 24-month evaluation (age 51 to 80 years), 15 memory decliners (mean age 62.7 years, SD 7.6) were identified, and matched with 33 non-decliners (mean age 63.3 years, SD 8.2). Amyloid-PET imaging was qualitatively abnormal with excess cortical amyloid accumulation in 7 memory decliners (46.7%) and 4 (12.1%) non-decliners (odds ratio 6.34), and quantitatively abnormal with standardized uptake value ratios >1.4 in 5 memory decliners (33.3%) and 2 (6.1%) non-decliners (odds ratio 8.3). One of the memory decliners and none of the non-decliners fulfilled criteria for mild cognitive impairment, but the groups did not differ with respect to subjective memory impairment, neuropsychological evidence of episodic memory impairment, or MRI imaging abnormalities. Intra-individual decline in episodic memory can be detected using a brief computerized cognitive performance test optimized to detect change in community-dwelling non-demented older persons and appears predictive of the presence of cerebral amyloid in about half of these persons. This approach may help detect early prodromal AD pathology in wider-scale community screening programs.