How Modifiable Are Modifiable Dementia Risk Factors? A Framework for Considering the Modifiability of Dementia Risk Factors.

Many risk factors for dementia, identified from observational studies, are potentially modifiable. This raises the possibility that targeting key modifiable dementia risk factors may reduce the prevalence of dementia, which has led to the development of dementia risk reduction and prevention strategies, such as intervention trials or dementia prevention guidelines. However, what has rarely been considered in the studies that inform these strategies is the extent to which modifiable dementia risk factors can (1) be identified by individuals, and (2) be readily modified by individuals. Characteristics of modifiable dementia risk factors such as readiness of identification and targeting, as well as when they should be targeted, can influence the design, or success of strategies for reducing dementia risk. This review aims to develop a framework for classifying the degree of modifiability of dementia risk factors for research studies. The extent to which these modifiable dementia risk factors could be modified by an individual seeking to reduce their dementia risk is determined, as well as the resources that might be needed for both risk factor identification and modification, and whether modification may be optimal in early-life (aged <45 years), midlife (aged 45-65 years) or late-life (aged >65 years). Finally, barriers that could influence the ability of an individual to engage in risk factor modification and, ultimately, dementia risk reduction are discussed.

Two-Year Prognostic Utility of Plasma p217+tau across the Alzheimer's Continuum.

BACKGROUND: Plasma p217+tau has shown high concordance with cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid-ß (Aß) and tau in Alzheimer's Disease (AD). However, its association with longitudinal cognition and comparative performance to PET Aß and tau in predicting cognitive decline are unknown. OBJECTIVES: To evaluate whether p217+tau can predict the rate of cognitive decline observed over two-year average follow-up and compare this to prediction based on Aß (18F-NAV4694) and tau (18F-MK6240) PET. We also explored the sample size required to detect a 30% slowing in cognitive decline in a 2-year trial and selection test cost using p217+tau (pT+) as compared to PET Aß (A+) and tau (T+) with and without p217+tau pre-screening. DESIGN: A prospective observational cohort study. SETTING: Participants of the Australian Imaging, Biomarker and Lifestyle Flagship Study of Ageing (AIBL) and Australian Dementia Network (ADNeT). PARTICIPANTS: 153 cognitively unimpaired (CU) and 50 cognitively impaired (CI) individuals. MEASUREMENTS: Baseline p217+tau Simoa® assay, 18F-MK6240 tau-PET and 18F-NAV4694 Aß-PET with neuropsychological follow-up (MMSE, CDR-SB, AIBL-PACC) over 2.4 ± 0.8 years. RESULTS: In CI, p217+tau was a significant predictor of change in MMSE (ß = -0.55, p < 0.001) and CDR-SB (ß =0.61, p < 0.001) with an effect size similar to Aß Centiloid (MMSE ß = -0.48, p = 0.002; CDR-SB ß = 0.43, p = 0.004) and meta-temporal (MetaT) tau SUVR (MMSE: ß = -0.62, p < 0.001; CDR-SB: ß = 0.65, p < 0.001). In CU, only MetaT tau SUVR was significantly associated with change in AIBL-PACC (ß = -0.22, p = 0.008). Screening pT+ CI participants into a trial could lead to 24% reduction in sample size compared to screening with PET for A+ and 6-13% compared to screening with PET for T+ (different regions). This would translate to an 81-83% biomarker test cost-saving assuming the p217+tau test cost one-fifth of a PET scan. In a trial requiring PET A+ or T+, p217+tau pre-screening followed by PET in those who were pT+ would cost more in the CI group, compared to 26-38% biomarker test cost-saving in the CU. CONCLUSIONS: Substantial cost reduction can be achieved using p217+tau alone to select participants with MCI or mild dementia for a clinical trial designed to slow cognitive decline over two years, compared to participant selection by PET. In pre-clinical AD trials, p217+tau provides significant cost-saving if used as a pre-screening measure for PET A+ or T+ but in MCI/mild dementia trials this may add to cost both in testing and in the increased number of participants needed for testing.

Associations between Participant Characteristics and Participant Feedback about an Unsupervised Online Cognitive Assessment in a Research Registry.

BACKGROUND: This study aims to understand whether and how participant characteristics (age, gender, education, ethnocultural identity) are related to their feedback about taking a remote, unsupervised, online cognitive assessment. METHODS: The Brain Health Registry is a public online registry which includes cognitive assessments. Multivariable ordinal regressions assessed associations between participant characteristics and feedback responses of older (55+) participants (N=11,553) regarding their Cogstate Brief Battery assessment experience. RESULTS: Higher age, secondary education or less, Latino identity, and female gender were associated with a poorer assessment experience; higher age and a non-White identity were associated with experiencing the assessment instructions as less clear; and higher age, non-White identity, and secondary education or less were associated with rating additional human support with the assessment as more useful. DISCUSSION: Our findings highlight the importance of improving the design and instructions of unsupervised, remote, online cognitive assessments to better suit the needs of diverse communities.

Unsupervised Performance of the CogState Brief Battery in the Brain Health Registry: Implications for Detecting Cognitive Decline.

INTRODUCTION: The feasibility and validity of unsupervised, longitudinal brief computerized cognitive batteries is unknown. METHODS: Participants aged 56-90 (N = 19476) from the Brain Health Registry (BHR) completed the CogState Brief Battery (CBB) at 6-month intervals over a period of 5 years. We used linear mixed-effects models to assess whether cross-sectional and longitudinal performance on CBB within BHR was associated with demographic and cognitive characteristics. We also defined a group of CBB decliners based on subject-specific slopes and estimated associations between decliner status and participant characteristics. RESULTS: We found weak associations between longitudinal change in CBB and participant characteristics. Cross-sectional CBB scores were significantly associated with participant characteristics such as age, gender, ethnicity, self-reported disease status, and memory concern. CBB decliners were more likely to self-report mild cognitive impairment (MCI) and memory concerns. DISCUSSION: Cross-sectional, remote CBB shows evidence of construct validity, but our results suggest that longitudinal assessment may not provide additional value for identifying those at risk for and with cognitive impairment.

Longitudinal Cognitive Decline in Patients With Mild Cognitive Impairment or Dementia Due to Alzheimer's Disease.

Sensitive cognitive assessments accurately detect and track cognitive decline in Alzheimer's disease. The Cogstate battery was used to measure cognitive change in cognitively normal participants and in individuals with mild cognitive impairment and mild Alzheimer's disease enrolled in the Australian Imaging, Biomarker and Lifestyle Rate of Change Substudy. Over 18 months, verbal episodic memory performance declined for mild cognitive impairment and mild Alzeheimer's disease groups when compared to cognitively normal participants. Frequent assessments of episodic memory may facilitate early detection of cognitive decline due to Alzheimer's disease.

The Computerized Cognitive Composite (C3) in an Alzheimer's Disease Secondary Prevention Trial.

BACKGROUND: Computerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers. OBJECTIVE: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3). DESIGN: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD). SETTING: Multi-center international study. PARTICIPANTS: Clinically normal (CN) older adults (65-85; n=4486). MEASUREMENTS: Participants underwent florbetapir-Positron Emission Tomography for Aß+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer's Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aß+/- groups (n=1323/3163) and PACC. RESULTS: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aß+ performed worse on C3 compared with Aß- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants. CONCLUSIONS: These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.

Application of the NIA-AA Research Framework: Towards a Biological Definition of Alzheimer's Disease Using Cerebrospinal Fluid Biomarkers in the AIBL Study.

BACKGROUND: The National Institute on Aging and Alzheimer's Association (NIA-AA) have proposed a new Research Framework: Towards a biological definition of Alzheimer's disease, which uses a three-biomarker construct: Aß-amyloid, tau and neurodegeneration AT(N), to generate a biomarker based definition of Alzheimer's disease. OBJECTIVES: To stratify AIBL participants using the new NIA-AA Research Framework using cerebrospinal fluid (CSF) biomarkers. To evaluate the clinical and cognitive profiles of the different groups resultant from the AT(N) stratification. To compare the findings to those that result from stratification using two-biomarker construct criteria (AT and/or A(N)). DESIGN: Individuals were classified as being positive or negative for each of the A, T, and (N) categories and then assigned to the appropriate AT(N) combinatorial group: A-T-(N)-; A+T-(N)-; A+T+(N)-; A+T-(N)+; A+T+(N)+; A-T+(N)-; A-T-(N)+; A-T+(N)+. In line with the NIA-AA research framework, these eight AT(N) groups were then collapsed into four main groups of interest (normal AD biomarkers, AD pathologic change, AD and non-AD pathologic change) and the respective clinical and cognitive trajectories over 4.5 years for each group were assessed. In two sensitivity analyses the methods were replicated after assigning individuals to four groups based on being positive or negative for AT biomarkers as well as A(N) biomarkers. SETTING: Two study centers in Melbourne (Victoria) and Perth (Western Australia), Australia recruited MCI individuals and individuals with AD from primary care physicians or tertiary memory disorder clinics. Cognitively healthy, elderly NCs were recruited through advertisement or via spouses of participants in the study. PARTICIPANTS: One-hundred and forty NC, 33 MCI participants, and 27 participants with AD from the AIBL study who had undergone CSF evaluation using Elecsys® assays. INTERVENTION (if any): Not applicable. MEASUREMENTS: Three CSF biomarkers, namely amyloid ß1-42, phosphorylated tau181, and total tau, were measured to provide the AT(N) classifications. Clinical and cognitive trajectories were evaluated using the AIBL Preclinical Alzheimer Cognitive Composite (AIBL-PACC), a verbal episodic memory composite, an executive function composite, California Verbal Learning Test - Second Edition; Long-Delay Free Recall, Mini-Mental State Examination, and Clinical Dementia Rating Sum of Boxes scores. RESULTS: Thirty-eight percent of the elderly NCs had no evidence of abnormal AD biomarkers, whereas 33% had biomarker levels consistent with AD or AD pathologic change, and 29% had evidence of non-AD biomarker change. Among NC participants, those with biomarker evidence of AD pathology tended to perform worse on cognitive outcome assessments than other biomarker groups. Approximately three in four participants with MCI or AD had biomarker levels consistent with the research framework's definition of AD or AD pathologic change. For MCI participants, a decrease in AIBL-PACC scores was observed with increasing abnormal biomarkers; and increased abnormal biomarkers were also associated with increased rates of decline across some cognitive measures. CONCLUSIONS: Increasing biomarker abnormality appears to be associated with worse cognitive trajectories. The implementation of biomarker classifications could help better characterize prognosis in clinical practice and identify those at-risk individuals more likely to clinically progress, for their inclusion in future therapeutic trials.

Monitoring cognitive change in multiple sclerosis using a computerized cognitive battery.

BACKGROUND: Cognitive monitoring that can detect short-term change in multiple sclerosis is challenging. Computerized cognitive batteries such as the CogState Brief Battery can rapidly assess commonly affected cognitive domains. OBJECTIVES: The purpose of this study was to establish the acceptability and sensitivity of the CogState Brief Battery in multiple sclerosis patients compared to controls. We compared the sensitivity of the CogState Brief Battery to that of the Paced Auditory Serial Addition Test over 12 months. METHODS: Demographics, Expanded Disability Status Scale scores, depression and anxiety scores were compared with CogState Brief Battery and Paced Auditory Serial Addition Test performances of 51 patients with relapsing-remitting multiple sclerosis, 19 with secondary progressive multiple sclerosis and 40 healthy controls. Longitudinal data in 37 relapsing-remitting multiple sclerosis patients were evaluated using linear mixed models. RESULTS: Both the CogState Brief Battery and the Paced Auditory Serial Addition Test discriminated between multiple sclerosis and healthy controls at baseline (p<0.001). CogState Brief Battery tasks were more acceptable and caused less anxiety than the Paced Auditory Serial Addition Test (p<0.001). In relapsing-remitting multiple sclerosis patients, reaction time slowed over 12 months (p<0.001) for the CogState Brief Battery Detection (mean change -34.23 ms) and Identification (-25.31 ms) tasks. Paced Auditory Serial Addition Test scores did not change over this time. CONCLUSIONS: The CogState Brief Battery is highly acceptable and better able to detect cognitive change than the Paced Auditory Serial Addition Test. The CogState Brief Battery could potentially be used as a practical cognitive monitoring tool in the multiple sclerosis clinic setting.

APOE and BDNF polymorphisms moderate amyloid ß-related cognitive decline in preclinical Alzheimer's disease.

Accumulation of ß-amyloid (Aß) in the brain is associated with memory decline in healthy individuals as a prelude to Alzheimer's disease (AD). Genetic factors may moderate this decline. We examined the role of apolipoprotein E (ɛ4 carrier[ɛ4(+)], ɛ4 non-carrier[ɛ4(-)]) and brain-derived neurotrophic factor (BDNF(Val/Val), BDNF(Met)) in the extent to which they moderate Aß-related memory decline. Healthy adults (n=333, Mage=70 years) enrolled in the Australian Imaging, Biomarkers and Lifestyle study underwent Aß neuroimaging. Neuropsychological assessments were conducted at baseline, 18-, 36- and 54-month follow-ups. Aß positron emission tomography neuroimaging was used to classify participants as Aß(-) or Aß(+). Relative to Aß(-)ɛ4(-), Aß(+)ɛ4(+) individuals showed significantly faster rates of cognitive decline over 54 months across all domains (d=0.40-1.22), while Aß(+)ɛ4(-) individuals showed significantly faster decline only on verbal episodic memory (EM). There were no differences in rates of cognitive change between Aß(-)ɛ4(-) and Aß(-)ɛ4(+) groups. Among Aß(+) individuals, ɛ4(+)/BDNF(Met) participants showed a significantly faster rate of decline on verbal and visual EM, and language over 54 months compared with ɛ4(-)/BDNF(Val/Val) participants (d=0.90-1.02). At least two genetic loci affect the rate of Aß-related cognitive decline. Aß(+)ɛ4(+)/BDNF(Met) individuals can expect to show clinically significant memory impairment after 3 years, whereas Aß(+)ɛ4(+)/BDNF(Val/Val) individuals can expect a similar degree of impairment after 10 years. Little decline over 54 months was observed in the Aß(-) and Aß(+) ɛ4(-) groups, irrespective of BDNF status. These data raise important prognostic issues in managing preclinical AD, and should be considered in designing secondary preventative clinical trials.

A combination of physical activity and computerized brain training improves verbal memory and increases cerebral glucose metabolism in the elderly.

Physical exercise interventions and cognitive training programs have individually been reported to improve cognition in the healthy elderly population; however, the clinical significance of using a combined approach is currently lacking. This study evaluated whether physical activity (PA), computerized cognitive training and/or a combination of both could improve cognition. In this nonrandomized study, 224 healthy community-dwelling older adults (60-85 years) were assigned to 16 weeks home-based PA (n=64), computerized cognitive stimulation (n=62), a combination of both (combined, n=51) or a control group (n=47). Cognition was assessed using the Rey Auditory Verbal Learning Test, Controlled Oral Word Association Test and the CogState computerized battery at baseline, 8 and 16 weeks post intervention. Physical fitness assessments were performed at all time points. A subset (total n=45) of participants underwent [(18)F] fluorodeoxyglucose positron emission tomography scans at 16 weeks (post-intervention). One hundred and ninety-one participants completed the study and the data of 172 participants were included in the final analysis. Compared with the control group, the combined group showed improved verbal episodic memory and significantly higher brain glucose metabolism in the left sensorimotor cortex after controlling for age, sex, premorbid IQ, apolipoprotein E (APOE) status and history of head injury. The higher cerebral glucose metabolism in this brain region was positively associated with improved verbal memory seen in the combined group only. Our study provides evidence that a specific combination of physical and mental exercises for 16 weeks can improve cognition and increase cerebral glucose metabolism in cognitively intact healthy older adults.

Barriers to repeated assessment of verbal learning and memory: a comparison of international shopping list task and rey auditory verbal learning test on build-up of proactive interference.

Proactive interference (PI) that remains unidentified can confound the assessment of verbal learning, particularly when its effects vary from one population to another. The International Shopping List Task (ISLT) is a new measure that provides multiple forms that can be equated for linguistic factors across cultural groups. The aim of this study was to examine the build-up of PI on two measures of verbal learning-a traditional test of list learning (Rey Auditory Verbal Learning Test, RAVLT) and the ISLT. The sample consisted of 61 healthy adults aged 18-40. Each test had three parallel forms, each recalled three times. Results showed that repeated administration of the ISLT did not result in significant PI effects, unlike the RAVLT. Although these PI effects, observed during short retest intervals, may not be as robust under normal clinical administrations of the tests, the results suggest that the choice of the verbal learning test should be guided by the knowledge of PI effects and the susceptibility of particular patient groups to this effect.

Computerized cognitive remediation training for schizophrenia: an open label, multi-site, multinational methodology study.

A recent single-site study (Fisher et al., 2009. Am J Psychiatry. 166 (7) 805-11) showed that repeated training with the Brain Fitness Program (BFP) improved performance on a battery of neuropsychological tasks. If replicated these data suggest an important non-pharmacological method for ameliorating cognitive impairment in schizophrenia. Our study evaluated the BFP training effects in an open-label, multi-site, multinational clinical trial. Fifty-five stable adult patients with schizophrenia on regular antipsychotic medication completed ≥ 32 BFP training sessions over 8-10 weeks. Training effects on cognitive performance and functional capacity outcome measures were measured using CogState® schizophrenia battery, UCSD Performance based Skills Assessment (UPSA-2) and Cognitive Assessment Interview (CAI). BFP training showed a large and significant treatment effect on a training exercise task (auditory processing speed), however this effect did not generalize to improved performance on independent CogState® assessment. There were no significant effects on UPSA-2 or CAI scores. Our study demonstrated the feasibility of implementing BFP training in a multi-site study. However, BFP training did not show significant treatment effects on cognitive performance or functional capacity outcome measures despite showing large and significant effects on a training exercise.

The effect of acute increase in urge to void on cognitive function in healthy adults.

AIMS: In healthy adults, voluntary inhibition of micturition is associated with an increasing sensation in the urge to void and pain, and acute pain has been associated with transient deterioration in aspects of cognitive function. METHODS: Eight healthy young adults consumed 250 ml of water every 15 min until they could no longer inhibit voiding. Performance on standardized measures of cognitive function was measured at hourly intervals which were classified as baseline, when individuals reported an increase in the urge to void, a strong increase in the urge to void, an extreme increase in the urge to void and postmicturition. RESULTS: Sensations of the urge to void and pain increased with time of inhibition of urge to void and with amount of water consumed. Having an extreme urge to void exerted a large negative effect on attentional and working memory functions (d>0.8). These cognitive functions returned to normal levels after micturition. CONCLUSION: The magnitude of decline in cognitive function associated with an extreme urge to void was as large and equivalent or greater than the cognitive deterioration observed for conditions known to be associated with increased accident risk.

Cerebral function tests reveal differences in HIV-infected subjects with and without chronic HCV co-infection.

Neurocognitive impairment (NCI) remains prevalent in HIV-infected subjects despite effective combination antiretroviral therapy (CART). In subjects without evidence of hepatic decompensation, NCI is also a feature of chronic HCV infection. The present study aimed to examine cerebral function and establish differences between HIV-HCV co-infected (HCVco) and HIV mono-infected (HIVmo) individuals. Neurologically asymptomatic subjects with chronic HCVco were eligible and underwent computerized neurocognitive testing (CogState; CogState Ltd, Melbourne, Australia), a dementia assessment [International HIV Dementia Scale (IHDS)] and memory assessment [the Prospective and Retrospective Memory Questionnaire (PRMQ)]. Historic control data were available for 45 HIVmo individuals and differences between study groups were assessed. Twenty-seven HCVco subjects were recruited. Plasma HIV RNA was <50 copies/mL in 25/27 of HCVco subjects and all HIVmo subjects and nadir CD4+ cell count (mean ± SD) was 214 ± 166 cells/µL and 180 ± 130 cells/µL, in HCVco and HIVmo subjects, respectively. No statistically significant differences in neurocognitive parameters or PRMQ scores were observed between groups. However, a trend towards poorer executive function score was observed in HCVco subjects (p 0.106). IHDS score (mean ± SD) was poorer in HCVco subjects (10.48 ± 1.25) vs. HIVmo subjects (11.51 ± 0.76), (p <0.001). In a multivariate model, increasing age and HCVco were the only factors significantly associated with poorer IHDS scores (p 0.039 and <0.001, respectively). In HIV-infected subjects stable on CART, statistically significantly poorer performance in the IHDS score was observed in subjects with HCVco, although no differences were observed after neurocognitive testing or memory assessment.

Cognitive function in patients undergoing coronary angiography.

OBJECTIVE: To measure cognition in patients before and after coronary angiography. DESIGN: Prospective observational cohort study. SETTING: University teaching hospital. PATIENTS: 56 patients presenting for elective coronary angiography. MAIN OUTCOME MEASURES: Computerised cognitive test battery administered before coronary angiography, before discharge from hospital and 7 days after discharge. A matched healthy control group was used as a comparator. RESULTS: When analysed by group, coronary angiography patients performed worse than matched controls at each time point. When the cognitive change was examined for each individual, of the 48 patients tested at discharge, 19 (39.6%) were classified as having a new cognitive dysfunction, and of 49 patients tested at day 7, six (12.2%) were classified as having a new cognitive dysfunction. CONCLUSIONS: The results confirm that cognitive function is decreased in patients who have cardiovascular disease. Furthermore, coronary angiography may exacerbate this impaired cognition in some patients.

Evaluation of the usability of a brief computerized cognitive screening test in older people for epidemiological studies.

BACKGROUND: Computerized cognitive testing has the potential to be an effective way to assess and monitor cognition in large neuroepidemiological studies. CogState is a game-like computerized test with demonstrated validity and reliability that has shown sensitivity to decline in older individuals over time. This study aimed to evaluate the serial usability of the test specifically within an older community cohort. METHODS: The test battery was administered to healthy volunteers aged 50 years and above at 3-month intervals over 12 months in a community setting. Test usability was examined in terms of acceptability, efficiency and stability. RESULTS: Of 301 subjects (age: 61.9 +/- 7.2 years), 87% completed the study. In addition, 85% completed the first test within the allowed time and passed integrity criteria with their performance improving and stabilizing at subsequent visits. The computerized battery required 15 min for administration on average, allowing 263 patients to be assessed on 5 occasions by 2 assessors. All tasks showed stability and a high test-retest reliability with serial administration. CONCLUSIONS: This computerized test was shown to have good acceptability, efficiency and stability for the repeated assessment of cognitive function in older people. Together with its demonstrated sensitivity to cognitive impairment and cognitive change, these data suggest that it would be a useful tool for application in neuroepidemiological studies.

Methodological improvements in quantifying cognitive change in clinical trials: an example with single-dose administration of donepezil.

OBJECTIVES: Change in cognitive function in response to a pharmacologic challenge can be observed with greater sensitivity by employing cognitive tests with optimal psychometric properties and a statistical approach that more accurately accounts for individual variability in performance. To demonstrate this approach we examined the cognitive effects of a single acute dose administration of an acetylcholinesterase inhibitor, donepezil, in healthy older adults and in older adults with mild Alzheimer's disease (AD). DESIGN: Placebo-controlled crossover study with three separate testing days: baseline, placebo, and donepezil, with assessments at baseline, and 1-, 2-, 3-, 6-, and 8-hrs post-dosing on each day. SETTING: Early phase I clinical trial. PARTICIPANTS: 15 healthy older adults; 14 older adults with mild Alzheimer's disease. INTERVENTION: Single acute dose of 5mg donepezil. MEASUREMENTS: Performance on the Groton Maze Learning Test (GMLT), a computerized neuropsychological measure of spatial working memory and error monitoring. RESULTS: A single acute dose of donepezil improved GMLT performance in healthy older adults (effect size: 0.83 at 6 hrs post-dosing) and older adults with mild AD (effect size: 0.58 at 3 hrs post-dosing). CONCLUSION: The GMLT detected cognitive improvement following a single, acute dose administration of donepezil in healthy older adults and older adults with mild AD. The choice of cognitive tests designed for repeated administration, as well as an analytic approach that emphasizes individual-level change in cognitive function, provides a sensitive approach to detecting central nervous system drug penetration and activity of cognitive-enhancing agents.

The nature of cognitive complaints in healthy older adults with and without objective memory decline.

Cognitive and memory complaints were assessed in 100 healthy older adults on two occasions over 2.5 years as part of a 6-year study assessing cognition, mood, and general health factors. Diminished memory for names and actions and lapses in concentration were common complaints, regardless of the individuals' actual cognitive status. No change in cognitive complaints occurred over time, even for individuals whose memory had declined over 6 years. Cognitive complaints correlated with anxiety, depression, and general mental health but not with objectively measured memory or cognition, education or age. Complaints did not differ with gender, apolipoprotein E epsilon4 genotype, cardiovascular risk factors, or intake of sedating medications. Thus, cognitive complaints could not differentiate memory-declining older adults from cognitively normal older adults and were more closely associated with mood and general mental health than actual cognitive status, age, or potential risk factors for Alzheimer's disease. Thus, the evaluation of cognitive complaints must be broad and must consider the correspondence of complaints not only to relevant measurable cognitive abilities but also to the affect of the individual.

Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer's disease.

Approximately 30% of healthy persons aged over 75 years show Abeta deposition at autopsy. It is postulated that this represents preclinical Alzheimer's disease (AD). We evaluated the relationship between Abeta burden as assessed by PiB PET and cognitive decline in a well-characterized, non-demented, elderly cohort. PiB PET studies and cognitive tests were performed on 34 elderly participants (age 73+/-6) from the longitudinal Melbourne Healthy Aging Study (MHAS). Subjects were classified as being cognitively 'stable' or 'declining' by an independent behavioural neurologist based on clinical assessment and serial word-list recall scores from the preceding 6-10 years. Decline was calculated from the slope of the word-list recall scores. Abeta burden was quantified using Standardized Uptake Value normalized to cerebellar cortex. Ten subjects were clinically classified as declining. At the time of the PET scans, three of the declining subjects had mild cognitive impairment, one had AD, and six were declining but remained within the normal range for age on cognitive tests. Declining subjects were much more likely to show cortical PiB binding than stable subjects (70% vs. 17%, respectively). Neocortical Abeta burden correlated with word-list recall slopes (r=-0.78) and memory function (r=-0.85) in the declining group. No correlations were observed in the stable group. Abeta burden correlated with incident memory impairment and the rate of memory decline in the non-demented ageing population. These observations suggest that neither memory decline nor Abeta deposition are part of normal ageing and likely represent preclinical AD. Further longitudinal observations are required to confirm this hypothesis.

Improved cognitive function as a consequence of hepatitis C virus treatment.

OBJECTIVE: The aim of the study was to investigate the impact of treatment-related clearance of hepatitis C virus (HCV) on cognitive function. METHODS: A prospective study was conducted in 19 HCV-monoinfected and 15 HIV/HCV-coinfected individuals undergoing pegylated interferon alpha-2a and ribavirin therapy between April 2003 and August 2005. Neuropsychological, mood, and health-related quality of life (HRQOL) effects were assessed using computer-based battery, Trail Making Tests, Depression Anxiety Stress Scales and the Short Form-36 health survey. RESULTS: Pretreatment cognitive function, mood status, and HRQOL were similar between the HCV patient groups. Sustained virological response (SVR) rates were similar between HCV-monoinfected (68%) and HIV/HCV-coinfected (73%) groups. SVR was associated with significant improvements in some measures of cognitive function, independent of HRQOL improvement. CONCLUSIONS: Our findings provide evidence to support cognitive effects of HCV independent of mood status and HRQOL profiles.