Rates of decline in Alzheimer disease decrease with age.
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ABSTRACT:
SUBMITTER: Holland D
PROVIDER: S-EPMC3410919 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Measures of neuronal damage/dysfunction are likely good surrogates for disease progression in Alzheimer disease (AD). CSF markers of neuronal injury may offer utility in predicting disease progression and guiding prognostic and outcome assessments in therapeutic trials. Visinin-like protein-1 (VILIP-1) has demonstrated potential utility as a marker of neuronal injury. We here investigate the utility of VILIP-1 and VILIP-1/A?42 in predicting rates of cognitive decline in early AD.Individuals with a clinical diagnosis of very mild or mild AD (n = 60) and baseline CSF measures of VILIP-1, tau, p-tau181, and A?42 were followed longitudinally for an average of 2.6 years. Annual assessments included the Clinical Dementia Rating (CDR), CDR-sum of boxes (CDR-SB), and global composite scores. Mixed linear models assessed the ability of CSF biomarker measures to predict rates of cognitive decline over time.Baseline CSF VILIP-1 and VILIP-1/A?42 levels predicted rates of future decline in CDR-SB and global composite scores over the follow-up period. Individuals with CSF VILIP-1 ?560 pg/mL (corresponding to the upper tercile) progressed much more rapidly in CDR-SB (1.61 boxes/year; p = 0.0077) and global scores (-0.53 points/year; p = 0.0002) than individuals with lower values (0.85 boxes/year and -0.15 points/year, respectively) over the follow-up period. CSF tau, p-tau181, tau/A?42, and p-tau181/A?42 also predicted more rapid cognitive decline in CDR-SB and global scores over time.These findings suggest that CSF VILIP-1 and VILIP-1/A?42 predict rates of global cognitive decline similarly to tau and tau/A?42, and may be useful CSF surrogates for neurodegeneration in early AD.
| S-EPMC3306162 | biostudies-literature
Project description:Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from Wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich diet and via subsequent inbreeding of highly susceptible rats. Currently, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which means early development of a phenotype similar to human geriatric disorders, including accelerated brain aging. In recent years, our group found strong evidence that OXYS rats are a promising model for studies of the mechanisms of brain aging and neurodegenerative processes similar to those seen in Alzheimer disease (AD). The manifestation of behavioral alterations and learning and memory deficits develop since the fourth week of age, i.e., simultaneously with first signs of neurodegeneration detectable on magnetic resonance imaging and under a light microscope. In addition, impaired long-term potentiation has been demonstrated in OXYS rats by the age of 3 months. With age, neurodegenerative changes in the brain of OXYS rats become amplified. We have shown that this deterioration happens against the background of overproduction of amyloid precursor protein (A?PP), accumulation of ?-amyloid (A?), and hyperphosphorylation of the tau protein in the hippocampus and cortex. The development of AMD-like retinopathy in OXYS rats is also accompanied by increased accumulation of A? in the retina. These published data suggest that the OXYS strain may serve as a spontaneous rat model of AD-like pathology and could help to decipher the pathogenesis of AD.
| S-EPMC3984313 | biostudies-other
Project description:ObjectiveTo determine the time required for a preclinical Alzheimer disease population to decline in a meaningful way, use estimates of decline to update previous clinical trial design assumptions, and identify factors that modify β-amyloid (Aβ)-related decline.MethodsIn 1,120 cognitively unimpaired individuals from 3 international cohorts, we estimated the relationship between Aβ status and longitudinal changes across multiple cognitive domains and assessed interactions between Aβ and baseline factors. Power analyses were performed to explore sample size as a function of treatment effect.ResultsCognitively unimpaired Aβ+ participants approach mild cognitive impairment (MCI) levels of performance 6 years after baseline, on average. Achieving 80% power in a simulated 4-year treatment trial, assuming a 25% treatment effect, required 2,000 participants/group. Multiple factors interacted with Aβ to predict cognitive decline; however, these findings were all cohort-specific. Despite design differences across the cohorts, with large sample sizes and sufficient follow-up time, the Aβ+ groups declined consistently on cognitive composite measures.ConclusionsA preclinical AD population declines to the cognitive performance of an early MCI population in 6 years. Slowing this rate of decline by 40%-50% delays clinically relevant impairment by 3 years-a potentially meaningful treatment effect. However, assuming a 40%-50% drug effect highlights the difficulties in preclinical AD trial design, as a more commonly assumed treatment effect of 25% results in a required sample size of 2,000/group. Designers of preclinical AD treatment trials need to prepare for larger and longer trials than are currently being considered. Interactions with Aβ status were inconsistent and not readily generalizable.
| S-EPMC6669933 | biostudies-literature
Project description:Alzheimer disease results in progressive functional decline, leading to loss of independence.To determine whether collaborative care plus 2 years of home-based occupational therapy delays functional decline.Randomized, controlled clinical trial. (ClinicalTrials.gov: NCT01314950).Urban public health system.180 community-dwelling participants with Alzheimer disease and their informal caregivers.All participants received collaborative care for dementia. Patients in the intervention group also received in-home occupational therapy delivered in 24 sessions over 2 years.The primary outcome measure was the Alzheimer's Disease Cooperative Study Group Activities of Daily Living Scale (ADCS ADL); performance-based measures included the Short Physical Performance Battery (SPPB) and Short Portable Sarcopenia Measure (SPSM).At baseline, clinical characteristics did not differ significantly between groups; the mean Mini-Mental State Examination score for both groups was 19 (SD, 7). The intervention group received a median of 18 home visits from the study occupational therapists. In both groups, ADCS ADL scores declined over 24 months. At the primary end point of 24 months, ADCS ADL scores did not differ between groups (mean difference, 2.34 [95% CI, -5.27 to 9.96]). We also could not definitively demonstrate between-group differences in mean SPPB or SPSM values.The results of this trial are indeterminate and do not rule out potential clinically important effects of the intervention.The authors could not definitively demonstrate whether the addition of 2 years of in-home occupational therapy to a collaborative care management model slowed the rate of functional decline among persons with Alzheimer disease. This trial underscores the burden undertaken by caregivers as they provide care for family members with Alzheimer disease and the difficulty in slowing functional decline.National Institute on Aging.
| S-EPMC5554402 | biostudies-literature
Project description:ObjectiveTo determine whether a decline in cued recall is observable in the preclinical stage of Alzheimer disease (AD) in clinically normal older adults with elevated ?-amyloid (A?) burden on PET imaging.MethodsClinically normal older adults underwent baseline neuroimaging (PET to assess A?+/- status and MRI) and annual neuropsychological testing. Cox proportional hazards models were used to assess the relative risk of cued memory decline (drop of 1, 2, 3, or 4 points on the total score of the Free and Cued Selective Reminding Test) in relation to neuroimaging measures, functional status, age, sex, and education.ResultsA total of 276 older adults (Clinical Dementia Rating = 0, mean Mini-Mental State Examination score = 29 ± 1.06) were followed up for a mean of 3.6 ± 1.2 years. Despite the infrequency of cued memory decline (only 19% of participants scored ?46/48 in total recall by year 3), A?+ participants were 3.55 times (95% confidence interval = 1.77-7.12) more likely to exhibit decline in total recall (?46/48) compared with their A?- peers. Furthermore, A?+ participants who scored ?46/48 had smaller hippocampal volumes (t = 3.37, p = 0.001) and evidence of early functional decline, i.e., greater risk of progression to global Clinical Dementia Rating of 0.5 (?2 = 14.30, p < 0.001), compared with their A?+ peers with intact total recall.ConclusionsCued memory decline in healthy older adults may be particularly indicative of A?-related decline during the preclinical stage of AD and useful for identifying A?+ clinically normal individuals at greatest risk of short-term clinical progression.
| S-EPMC5386436 | biostudies-literature
Project description:Lack of clear understanding remains on the overlapping atrophy patterns of aging and early Alzheimer disease (AD) pathology in gray matter (GM) of the brain in vivo.To evaluate the independent and overlapping patterns of GM atrophy in normal aging and AD.A total of 169 cognitively normal subjects and 33 persons with probable AD enrolled in the longitudinal Cardiovascular Health Study-Cognition Study underwent 3-dimensional volumetric MRI scans. Controls remained cognitively normal for at least 5 years after their MRI scans and the probable AD subjects were relatively early in their clinical course with an average modified Mini-Mental State Examination score of 76/100. The scans were analyzed using voxel-based morphometry adjusting for total intracranial volume, gender, education, and race.With older age, GM volume was lower in the sensorimotor and heteromodal association areas in frontal, temporal, occipital, and parietal lobes, as well as in the cerebellum (false discovery rate p = 0.05). Additional atrophy was observed in the posterior hippocampus, thalamus, and middle cingulate gyrus. By contrast, atrophy was seen in subjects with AD in the anterior hippocampal/parahippocampal regions and the precuneus. Normal aging and AD overlapped in the hippocampal body and the entorhinal cortex.Brain atrophy with aging was observed in supratentorial and infratentorial areas, as well in primary motor, sensory, and heteromodal association regions. Age and Alzheimer disease exert independent gray matter atrophy patterns but these effects overlapped substantially in the hippocampus and entorhinal cortex.
| S-EPMC2788799 | biostudies-literature
Project description:ObjectiveTo determine the association between age at surgical menopause and both cognitive decline and Alzheimer disease (AD) pathology in 2 longitudinal cohorts.MethodsFemale subjects from 2 longitudinal studies of cognitive decline (Religious Orders Study and Rush Memory and Aging Project) were included (total n = 1,884). The primary analysis examined the association between age at surgical menopause and decline in a global cognition score. Secondary analyses examined additional outcomes: 1) decline in 5 cognitive subdomains and 2) a global measure of the burden of AD pathology. In exploratory analyses, we examined the effect of hormone replacement therapy (HRT). We adjusted all models for age, education, smoking, and cohort and stratified by surgical vs natural menopause.ResultsFor the 32% of subjects with surgical menopause, earlier age at menopause was associated with faster decline in global cognition (p = 0.0007), specifically episodic memory (p = 0.0003) and semantic memory (p = 0.002). Earlier age at menopause was also associated with increased AD neuropathology (p = 0.038), in particular neuritic plaques (p = 0.013). HRT use for at least 10 years, when administered within a 5-year perimenopausal window, was associated with decreased decline in global cognition. No associations were seen in women who had natural menopause.ConclusionsEarly age at surgical menopause was associated with cognitive decline and AD neuropathology. Ongoing studies should clarify the potential effect of HRT on this relationship.
| S-EPMC3902759 | biostudies-literature
Project description:ObjectiveTo examine the utility of resting-state functional connectivity MRI (rs-fcMRI) measurements of network integrity as a predictor of future cognitive decline in preclinical Alzheimer disease (AD).MethodsA total of 237 clinically normal older adults (aged 63-90 years, Clinical Dementia Rating 0) underwent baseline ?-amyloid (A?) imaging with Pittsburgh compound B PET and structural and rs-fcMRI. We identified 7 networks for analysis, including 4 cognitive networks (default, salience, dorsal attention, and frontoparietal control) and 3 noncognitive networks (primary visual, extrastriate visual, motor). Using linear and curvilinear mixed models, we used baseline connectivity in these networks to predict longitudinal changes in preclinical Alzheimer cognitive composite (PACC) performance, both alone and interacting with A? burden. Median neuropsychological follow-up was 3 years.ResultsBaseline connectivity in the default, salience, and control networks predicted longitudinal PACC decline, unlike connectivity in the dorsal attention and all noncognitive networks. Default, salience, and control network connectivity was also synergistic with A? burden in predicting decline, with combined higher A? and lower connectivity predicting the steepest curvilinear decline in PACC performance.ConclusionsIn clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased A? burden. Among examined networks, default, salience, and control networks were the strongest predictors of rate of change in PACC scores, with the inflection point of greatest decline beyond the fourth year of follow-up. These results suggest that rs-fcMRI may be a useful predictor of early, AD-related cognitive decline in clinical research settings.
| S-EPMC5496516 | biostudies-literature
Project description:ObjectiveTo measure the cognitive consequences of incident Alzheimer disease (AD) in older African American and white subjects.MethodsData are from the Chicago Health and Aging Project, a longitudinal cohort study of older white and black persons residing in a geographically defined community. At 3-year intervals, the entire study population completed 4 brief cognitive tests, from which a previously established composite measure of global cognition was derived, and a subset underwent detailed clinical evaluation that supported clinical classification of mild cognitive impairment, dementia, and AD. We used mixed-effects models to examine change in cognitive function following the diagnostic evaluation.ResultsOn clinical evaluation, 614 persons were found to have no cognitive impairment, 395 had mild cognitive impairment, and 149 had AD (88.5% mild); 10 persons with other dementias were excluded from analyses. During up to 11 years of observation following the clinical evaluation (mean = 5.5, SD = 2.5), the composite measure of global cognition declined a mean of 0.042 unit per year (SE = 0.008, p < 0.001) in those with no cognitive impairment. In comparison to the no cognitive impairment group, the annual rate of decline was increased more than twofold in mild cognitive impairment (estimate = 0.086, SE = 0.011, p < 0.001) and more than fourfold in AD (estimate = 0.173, SE = 0.020, p < 0.001). Results did not reliably vary by race, sex, or age.ConclusionsAlzheimer disease has a devastating impact on cognition, even in its prodromal stages, with comparable effects in African American and white persons.
| S-EPMC2848102 | biostudies-literature
Project description:ObjectivesThe aim of this study was to determine whether use of diuretics, angiotensin-1 receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACE-I), calcium channel blockers (CCB), or β-blockers (BB) was associated with a reduced risk of Alzheimer disease (AD) dementia in participants with normal cognition or mild cognitive impairment (MCI).MethodsSecondary longitudinal data analysis of the Ginkgo Evaluation of Memory Study in older adults at least 75 years of age with normal cognition (n = 1,928) or MCI (n = 320) over a median 6.1-year period using Cox proportional hazard models after adjusting for confounders.ResultsDiuretic use was reported by 15.6%, ARB 6.1%, ACE-I 15.1%, CCB 14.8%, and BB 20.5%. Of the 2,248 participants, 290 (13%) developed AD dementia. Hazard ratio for incident AD dementia among participants with normal cognition was 0.51 in diuretic (95% confidence interval [CI] 0.31-0.82), 0.31 in ARB (95% CI 0.14-0.68), 0.50 in ACE-I (95% CI 0.29-0.83), 0.62 in CCB (95% CI 0.35-1.09), and 0.58 in BB (95% CI 0.36-0.93) users and was not significantly altered when mean systolic blood pressure was above 140 mm Hg. In participants with MCI, only diuretic use was associated with decreased risk (hazard ratio = 0.38, 95% CI 0.20-0.73).ConclusionsDiuretic, ARB, and ACE-I use was, in addition to and/or independently of mean systolic blood pressure, associated with reduced risk of AD dementia in participants with normal cognition, while only diuretic use was associated with reduced risk in participants with MCI.
| S-EPMC3885216 | biostudies-literature