242 research outputs found
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Potential implications of practice effects in Alzheimer's disease prevention trials.
IntroductionPractice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome.MethodsWe investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline.ResultsOn average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run-in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design.DiscussionAssuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials
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Women can bear a bigger burden: ante- and post-mortem evidence for reserve in the face of tau.
In this study, we aimed to assess whether women are able to withstand more tau before exhibiting verbal memory impairment. Using data from 121 amyloid-β-positive Alzheimer's Disease Neuroimaging Initiative participants, we fit a linear model with Rey Auditory Verbal Learning Test score as the response variable and tau-PET standard uptake value ratio as the predictor and took the residuals as an estimate of verbal memory reserve for each subject. Women demonstrated higher reserve (i.e. residuals), whether the Learning (t = 2.78, P = 0.006) or Delay (t = 2.14, P = 0.03) score from the Rey Auditory Verbal Learning Test was used as a measure of verbal memory ability. To validate these findings, we examined 662 National Alzheimer's Coordinating Center participants with a C2/C3 score (Consortium to Establish a Registry for Alzheimer's Disease) at autopsy. We stratified our National Alzheimer's Coordinating Center sample into Braak 1/2, Braak 3/4 and Braak 5/6 subgroups. Within each subgroup, we compared Logical Memory scores between men and women. Men had worse verbal memory scores within the Braak 1/2 (Logical Memory Immediate: β = -5.960 ± 1.517, P < 0.001, Logical Memory Delay: β = -5.703 ± 1.677, P = 0.002) and Braak 3/4 (Logical Memory Immediate: β = -2.900 ± 0.938, P = 0.002, Logical Memory Delay: β = -2.672 ± 0.955, P = 0.006) subgroups. There were no sex differences in Logical Memory performance within the Braak 5/6 subgroup (Logical Memory Immediate: β = -0.314 ± 0.328, P = 0.34, Logical Memory Delay: β = -0.195 ± 0.287, P = 0.50). Taken together, our results point to a sex-related verbal memory reserve
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APOE Genotype Influences Functional Status among Elderly without Dementia
The presence of apolipoprotein-ϵ4 (APOE-ϵ4) significantly increases the risk of Alzheimer's disease (AD). The association between APOE-ϵ4 status and functional abilities was explored further in a multicultural sample of community-dwelling, non-demented elders. The sample was limited to cognitively-intact, community-dwelling elders, who were free of stroke or other neurologic disability. In 218 elders who met research criteria, the presence of APO-ϵ4 was associated with poorer functional status, apart from the effects of neuropsychological performance, gender, age, and education (OR = 2.5, 95% CI: 1.3, 4.9). In 158 subjects without an APOE-ϵ4 allele, 50% reported no functional limitation; in the 60 subjects with an ϵ4 allele, only 28% reported no functional limitation (P < .01). The relationship was not explained by the distribution of co-morbidities. The association between poorer function and the presence of an APOE-ϵ4 allele was evident in each ethnic group. In path analyses, the presence of an APOE-ϵ4 allele was associated with decreased functional ability in non-demented elders not simply through an association with poorer cognitive status, but also independently. These results suggest that the APOE-ϵ4 genotype is associated with functional deficit in people with normal neuropsychological profiles
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Participation in Clinical Trials and Long-Term Outcomes in Alzheimer's Disease
The objective of this study was to determine whether participation in clinical trials affects long-term outcomes in Alzheimer's disease (AD). Participation in clinical trials for persons with dementia is often justified on the grounds that patients benefit from the medical oversight typical of trials, even when experimental agents do not demonstrate short-term benefits. This claim has not been rigorously assessed. Of 215 community-resident subjects enrolled in a prospective study of outcomes in AD, 101 participated in randomized clinical trials (RCTs) during the first 2 years of follow-up. These subjects were compared with subjects who met eligibility requirements for RCTs but did not participate (N = 57) and with subjects who were ineligible (N = 57), over a total of 3.5 years of follow-up. Survival analyses assessed risk of death, nursing home placement, and incident functional deficit end points, adjusting for baseline differences. Subjects who participated in RCTs were younger and more highly educated. Mortality, risk of hospitalization, number of medical examinations conducted by study physicians, and onset of severe functional deficit did not differ between the groups, but risk of nursing home admission was significantly lower among RCT participants compared with eligible nonparticipants and ineligible subjects (16.8% versus 36.8% and 31.6%, respectively [p = 0.01]). The difference in risk of nursing home placement may represent a long-term, drug-related benefit to patients, a selection effect (caregivers of patients who participate in RCTs differ from caregivers of patients who do not), or a positive effect on caregivers (greater contact with a medical service may be associated with better care-giving outcomes). Further research is required to assess these effects
Short-term memory binding and semantic network strength reinforce prospective memory in older adults
Objective Prospective memory (Pro-M), or remembering to carry out a future task, is critical to everyday functioning, but is not assessed by traditional neuropsychological measures. In this study, we investigated neurocognitive mechanisms underlying Pro-M ability in older adults. Participants and Methods 48 nondemented older adults (M age=75.2; SD=2.1) were recruited from the UCSD Alzheimer’s Disease Research Center (ADRC). Participants were 60% female and averaged 17.2 years (SD=2.1) of education. The Memory for Intentions Screening Test (MIST; Raskin et al., 2010) and a visual short-term memory (STM) binding task (Parra et al., 2017) were administered in a single session. Results were compared with scores on traditional neuropsychological measures from a recent ADRC annual assessment. Results Overall performance on the MIST was significantly correlated with shape-color binding accuracy (r=0.38; p 0.10). Analysis of errors on MIST time-cued tasks revealed the most common error was performing an incorrect task at the prescribed time (61%), whereas performing the prescribed task at the incorrect time was relatively infrequent (13%). Conclusions Performance of non-demented older adults on Pro-M was associated with STM binding and category fluency but not episodic memory or executive functioning. These results suggest that Pro-M is a unique aspect of memory functioning that is distinct from episodic memory and requires synthesizing multiple cognitive strategies. Participants with a stronger semantic network may be able to create a strong association for the intention at the time of encoding, while Pro-M failures could be explained by a failure to adequately bind the semantic components of the encoded intention and the future action
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Longitudinal Study of Quality of Life in People with Advanced Alzheimer's Disease
The authors examined three indicators of health-related quality of life in people with advanced Alzheimer's disease ([AD]; N = 150): confinement to home, null activity, and null positive affect, as reported by patient proxies. Dementia severity predicted time-to-onset for all three disease milestones in models that controlled for sociodemographic indicators, nursing home status, and death in the follow-up period. Patients whose dementia worsened over follow-up were more likely to reach each milestone. These outcomes represent key milestones in the care of patients; they are sensitive to disease progression, and they are likely to be useful for studying treatment in advanced AD
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Word-List Intrusion Errors Predict Progression to Mild Cognitive Impairment
OBJECTIVE: Preclinical Alzheimer\u27s disease (AD) defined by a positive AD biomarker in the presence of normal cognition is presumed to precede mild cognitive impairment (MCI). Subtle cognitive deficits and cognitive inefficiencies in preclinical AD may be detected through process and error scores on neuropsychological tests in those at risk for progression to MCI.
METHOD: Cognitively normal participants (n = 525) from the Alzheimer\u27s Disease Neuroimaging Initiative were followed for up to 5 years and classified as either stable normal (n = 305) or progressed to MCI (n = 220). Cox regressions were used to determine whether baseline process scores on the Rey Auditory Verbal Learning Test (AVLT; intrusion errors, learning slope, proactive interference, retroactive interference) predicted progression to MCI and a Clinical Dementia Rating (CDR) score of 1 after considering demographic characteristics, apolipoprotein E ε4 status, cerebrospinal fluid AD biomarkers, ischemia risk, mood, functional difficulty, and standard neuropsychological total test scores for the model.
RESULTS: Baseline AVLT intrusion errors predicted progression to MCI (hazard ratio = 1.04, 95% confidence interval 1.01-1.07, p = .008) and improved model fit after the other valuable predictors were already in the model, χ2(df = 1) = 6.330, p = .012. AVLT intrusion errors also predicted progression to CDR = 1 (hazard ratio = 1.10, 95% confidence interval 1.02-1.18, p = .016) and again improved model fit, χ2(df = 1) = 4.682, p = .030.
CONCLUSIONS: Intrusion errors on the AVLT contribute unique value for predicting progression from normal cognition to MCI and normal cognition to mild dementia (CDR = 1). Intrusion errors appear to reflect subtle change and inefficiencies in cognition that precede impairment detected by neuropsychological total scores
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Predicting Time to Nursing Home Care and Death in Individuals with Alzheimer Disease
Objective. —To develop and validate an approach that uses clinical features that can be determined in a standard patient visit to estimate the length of time before an individual patient with Alzheimer disease (AD) requires care equivalent to nursing home placement or dies. Design. —Prospective cohort study of 236 patients, followed up semiannually for up to 7 years. A second validation cohort of 105 patients was also followed. Setting. —Three AD research centers. Patients. —All patients met National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD and had mild dementia at the initial visit. Intervention. —Predictive features, ascertained at the initial visit, were sex, duration of illness, age at onset, modified Mini-Mental State Examination (mMMS) score, and the presence or absence of extrapyramidal signs or psychotic features.Main Outcome Measures. —(1) Requiring the equivalent of nursing home placement and (2) death. Results. —Prediction algorithms were constructed for the 2 outcomes based on Cox proportional hazard models. For each algorithm, a predictor index is calculated based on the status of each predictive feature at the initial visit. A table that specifies the number of months in which 25%, 50%, and 75% of patients with any specific predictor index value are likely to reach the end point is then consulted.Survival curves for time to need for care equivalent to nursing home placement and for time to death derived from the algorithms for selected predictor indexes fell within the 95% confidence bands of actual survival curves for patients.When the predictor variables from the initial visit for the validation cohort patients were entered into the algorithm, the predicted survival curves for time to death fell within the 95% confidence bands of actual survival curves for the patients. Conclusions. —The prediction algorithms are a first but promising step toward providing specific prognoses to patients, families, and practitioners. This approach also has clear implications for the design and interpretation of clinical trials in patients with AD
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Predicting Time to Nursing Home Care and Death in Individuals with Alzheimer Disease
Objective. —To develop and validate an approach that uses clinical features that can be determined in a standard patient visit to estimate the length of time before an individual patient with Alzheimer disease (AD) requires care equivalent to nursing home placement or dies. Design. —Prospective cohort study of 236 patients, followed up semiannually for up to 7 years. A second validation cohort of 105 patients was also followed. Setting. —Three AD research centers. Patients. —All patients met National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD and had mild dementia at the initial visit. Intervention. —Predictive features, ascertained at the initial visit, were sex, duration of illness, age at onset, modified Mini-Mental State Examination (mMMS) score, and the presence or absence of extrapyramidal signs or psychotic features.Main Outcome Measures. —(1) Requiring the equivalent of nursing home placement and (2) death. Results. —Prediction algorithms were constructed for the 2 outcomes based on Cox proportional hazard models. For each algorithm, a predictor index is calculated based on the status of each predictive feature at the initial visit. A table that specifies the number of months in which 25%, 50%, and 75% of patients with any specific predictor index value are likely to reach the end point is then consulted.Survival curves for time to need for care equivalent to nursing home placement and for time to death derived from the algorithms for selected predictor indexes fell within the 95% confidence bands of actual survival curves for patients.When the predictor variables from the initial visit for the validation cohort patients were entered into the algorithm, the predicted survival curves for time to death fell within the 95% confidence bands of actual survival curves for the patients. Conclusions. —The prediction algorithms are a first but promising step toward providing specific prognoses to patients, families, and practitioners. This approach also has clear implications for the design and interpretation of clinical trials in patients with AD
Impact of HIV and antiretroviral drug exposure on lung growth and function over 2 years in an African Birth Cohort.
OBJECTIVE: To assess the impact of HIV and antiretroviral exposure without infection on lung growth and function over the first 2 years of life. DESIGN: Prospective observational study of an African birth cohort, Drakenstein Child Health Study. METHOD: Infants enrolled antenatally had lung function measured at 6 weeks, 1 and 2 years. HIV-infected women received antiretroviral therapy (ART) as per local guidelines. The association between HIV and antiretroviral exposure with lung function was assessed using mixed effects modelling. RESULTS: Of 1143 infants born, two HIV-infected infants were excluded from analysis; 909 (80%) infants had lung function collected at 6 weeks [190 (21%) were HIV-exposed uninfected (HEU)]; 782 (69%) at 1 year and 741 (65%) at 2 years. At 6 weeks HEU infants had larger tidal volume compared with HIV-unexposed infants (1.13?ml, confidence interval: 0.02-2.23, P?=?0.045). High maternal viral load was associated with a 17% lower expiratory flow over 2 years (0.17, confidence interval 0.00-0.34, P?=?0.046). First-line ART initiated during pregnancy was associated with lower infant tidal volume at 6 weeks compared with those who initiated ART before pregnancy (-2.7?ml, -5.31 to -0.10, P?=?0.042), and low maternal CD4 cell counts associated with lower infant tidal over 2 years (-11.1?ml, -18.58-3.58, P?=?0.004). CONCLUSION: HIV exposure is associated with altered lung function in early life, with a vulnerable HEU subgroup based on maternal disease severity, immunological compromise and ART exposure. These data highlight the importance of ongoing surveillance of respiratory health in HEU children
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