Depression screening in cognitively normal older adults: Measurement bias according to subjective memory decline, brain amyloid burden, cognitive function, and sex
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ABSTRACT:
SUBMITTER: Thompson L
PROVIDER: S-EPMC7521597 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Alterations in parietal and temporal white matter microstructure derived from diffusion tensor imaging occur in preclinical and clinical Alzheimer's disease. Amyloid beta (Aβ) deposition and such white matter alterations are two pathological hallmarks of Alzheimer's disease. However, the relationship between these pathologies is not yet understood, partly since conventional diffusion MRI methods cannot distinguish between cellular and extracellular processes. Thus, we studied Aβ-associated longitudinal diffusion MRI changes in Aβ-positive (N = 21) and Aβ-negative (N = 51) cognitively normal elderly obtained from the Alzheimer's Disease Neuroimaging Initiative dataset using linear mixed models. Aβ-positivity was based on Alzheimer's Disease Neuroimaging Initiative amyloid-PET recommendations using a standardized uptake value ratio cut-off of 1.11. We used free-water imaging to distinguish cellular and extracellular changes. We found that Aβ-positive subjects had increased baseline right uncinate fasciculus free-water fraction (FW), associated with worse baseline Alzheimer's disease assessment scale scores. Furthermore, Aβ-positive subjects showed faster decrease in fractional anisotropy (FW-corrected) in the right uncinate fasciculus and faster age-dependent right inferior longitudinal fasciculus FW increases over time. Right inferior longitudinal fasciculus FW increases were associated with greater memory decline. Importantly, these results remained significant after controlling for gray and white matter volume and hippocampal volume. This is the first study to illustrate the influence of Aβ burden on early longitudinal (in addition to baseline) white matter changes in cognitively normal elderly individuals at-risk of Alzheimer's disease, thus underscoring the importance of longitudinal studies in assessing microstructural alterations in individuals at risk of Alzheimer's disease prior to symptoms onset.
| S-EPMC6501192 | biostudies-literature
Project description:BackgroundMotor slowing is associated with risk of Alzheimer's disease. Whether ?-amyloid (A?) burden is associated with motor decline, independent of cognitive decline, is unknown.MethodsAbout 59 cognitively unimpaired older participants had baseline PET-PiB scans and repeated measures of lower (usual gait speed, 400-m time, Health ABC Physical Performance Battery (HABCPPB) score, total standing balance time) and upper (mean tapping time) extremity performance during a mean follow-up of 4.7 years. Linear mixed effect models examined the relationship between baseline A? burden and motor decline, adjusting for age, sex, body mass index, cardiovascular risk, APOE ?4 status, memory decline, depressive symptoms, ankle-arm index, processing speed, executive function, and cerebrovascular disease.ResultsHigher mean cortical A? burden was associated with greater declines in gait speed and HABCPPB score and a greater increase in 400-m time. Higher A? of putamen was associated with declines in all lower extremity measures, including balance. Higher A? of dorsolateral prefrontal cortex and lateral temporal lobe was associated with declines of gait speed and 400-m time, and of precuneus with a greater increase in 400-m time. Associations remained similar after further adjustment.ConclusionsIn cognitively unimpaired older adults, A? burden overall and in specific brain regions are risk factors for lower extremity motor decline, independent of memory function. These findings provide the first empirical evidence that A? burden is a risk factor for mobility decline in older adults.
| S-EPMC6075426 | biostudies-literature
Project description:OBJECTIVE:Subjective cognitive complaints in otherwise normal aging are common but may be associated with preclinical Alzheimer disease in some individuals. Little is known about who is mostly likely to show associations between cognitive complaints and preclinical Alzheimer pathology. We sought to demonstrate associations between subjective complaints and brain amyloid-? in cognitively normal older adults; and to explore personality factors as potential moderators of this association. DESIGN:Cross-sectional observational study. SETTING:Clinical neuroimaging research center. PARTICIPANTS:Community volunteer sample of 92 healthy older adults, screened for normal cognition with comprehensive neuropsychological evaluation. MEASUREMENTS:Subjective cognitive self-report measures included the Memory Functioning Questionnaire (MFQ), Cognitive Failures Questionnaire, and the Subjective Cognitive Complaint Scale. Personality was measured with the NEO Five Factor Inventory. Brain amyloid-? deposition was assessed with Pittsburgh compound B (PiB)-PET imaging. RESULTS:One of three cognitive complaint measures, the MFQ, was associated with global PiB retention (standardized beta = -0.230, p = 0.046, adjusting for age, sex and depressive symptoms). Neuroticism moderated this association such that only high neuroticism individuals showed the predicted pattern of high complaint-high amyloid-? association. CONCLUSION:Evidence for association between subjective cognition and brain amyloid-? deposition in healthy older adults is demonstrable but measure-specific. Neuroticism may moderate the MFQ-amyloid-? association such that it is observed in the context of higher trait neuroticism. Subjective cognitive complaints and neuroticism may reflect a common susceptibility toward psychological distress and negative affect, which are in turn risk factors for cognitive decline in aging and incident Alzheimer disease.
| S-EPMC4532656 | biostudies-literature
Project description:Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later Alzheimer-related cognitive decline.To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid.Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).Individuals were classified at baseline as having normal (n?=?243) or elevated (n?=?202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid ?.Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 [worst] to 30 [best] points), Clinical Dementia Rating Sum of Boxes (CDR-Sum of Boxes; 0 [best] to 18 [worst] points), and Logical Memory Delayed Recall (0 [worst] to 25 [best] story units).Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR-Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points [95% CI, 0.94-2.10]; P?<?.001), MMSE (mean difference, 0.56 points [95% CI, 0.32-0.80]; P?<?.001), and CDR-Sum of Boxes (mean difference, 0.23 points [95% CI, 0.08-0.38]; P?=?.002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units [95% CI, -0.02 to 1.48]; P?=?.056).Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.
| S-EPMC5736301 | biostudies-literature
Project description:OBJECTIVE:Public health recommendations promote social engagement to reduce risk of cognitive decline and dementia. The objective of this study was to evaluate the longitudinal associations of social engagement and cognition in cognitively normal older adults with varying levels of neocortical amyloid-β, the Alzheimer's disease (AD) pathologic marker. METHODS:Two hundred seventeen men and women, age 63-89 underwent assessments for social engagement and cognitive performance at baseline and 3 years later using the Community Healthy Activities Model Program for Seniors questionnaire and the Preclinical Alzheimer Cognitive Composite (PACC). Amyloid-β was measured using Pittsburgh compound B-PET. Multivariable regression models estimated main and interactive effects of baseline social engagement and amyloid-β on cognitive change. Reciprocal models estimated main and interactive effects of baseline cognitive performance and amyloid-β on change in social engagement. RESULTS:Baseline social engagement was associated with PACC change as a modifier but not as a main effect. Lower baseline social engagement was associated with greater amyloid-β-related PACC decline, while higher baseline social engagement was associated with relative preservation of PACC scores (β = 0.05, p = 0.03). Reciprocally, lower baseline PACC score was associated with decline in social engagement score (β = 1.1, p = 0.02). This association was not modified by amyloid-β, and there was no direct association of amyloid-β with change in social engagement. CONCLUSIONS:Low social engagement may be a marker of neurocognitive vulnerability in older adults who are cognitively normal but have evidence of AD pathophysiologic change. Understanding changes in social engagement in older adults may lead to earlier diagnosis of AD and advances in evidence-based prevention and treatment.
| S-EPMC6778491 | biostudies-literature
Project description:ObjectiveTo investigate the relationship between amyloid-β (Aβ) deposition and markers of brain structure on cognitive decline in oldest-old individuals with initial normal cognition.MethodsWe studied cognitive functioning in four domains at baseline and change over time in fifty-seven cognitively intact individuals from the EMIF-AD 90+ study. Predictors were Aβ status determined by [18 F]-flutemetamol PET (normal = Aβ - vs. abnormal = Aβ+), cortical thickness in 34 regions and hippocampal volume. Mediation analyses were performed to test whether effects of Aβ on cognitive decline were mediated by atrophy of specific anatomical brain areas.ResultsSubjects had a mean age of 92.7 ± 2.9 years, of whom 19 (33%) were Aβ+. Compared to Aβ-, Aβ+ individuals showed steeper decline on memory (β ± SE = -0.26 ± 0.09), and processing speed (β ± SE = -0.18 ± 0.08) performance over 1.5 years (P < 0.05). Furthermore, medial and lateral temporal lobe atrophy was associated with steeper decline in memory and language across individuals. Mediation analyses revealed that part of the memory decline observed in Aβ+ individuals was mediated through parahippocampal atrophy.InterpretationThese results show that Aβ abnormality even in the oldest old with initially normal cognition is not part of normal aging, but is associated with a decline in cognitive functioning. Other pathologies may also contribute to decline in the oldest old as cortical thickness predicted cognitive decline similarly in individuals with and without Aβ pathology.
| S-EPMC7886045 | biostudies-literature
Project description:BackgroundCurrent methods of amyloid PET interpretation based on the binary classification of global amyloid signal fail to identify early phases of amyloid deposition. A recent analysis of 18F-florbetapir PET data from the Alzheimer's disease Neuroimaging Initiative cohort suggested a hierarchical four-stage model of regional amyloid deposition that resembles neuropathologic estimates and can be used to stage an individual's amyloid burden in vivo. Here, we evaluated the validity of this in vivo amyloid staging model in an independent cohort of older people with subjective memory complaints (SMC). We further examined its potential association with subtle cognitive impairments in this population at elevated risk for Alzheimer's disease (AD).MethodsThe monocentric INSIGHT-preAD cohort includes 318 cognitively intact older individuals with SMC. All individuals underwent 18F-florbetapir PET scanning and extensive neuropsychological testing. We projected the regional amyloid uptake signal into the previously proposed hierarchical staging model of in vivo amyloid progression. We determined the adherence to this model across all cases and tested the association between increasing in vivo amyloid stage and cognitive performance using ANCOVA models.ResultsIn total, 156 participants (49%) showed evidence of regional amyloid deposition, and all but 2 of these (99%) adhered to the hierarchical regional pattern implied by the in vivo amyloid progression model. According to a conventional binary classification based on global signal (SUVRCereb = 1.10), individuals in stages III and IV were classified as amyloid-positive (except one in stage III), but 99% of individuals in stage I and even 28% of individuals in stage II were classified as amyloid-negative. Neither in vivo amyloid stage nor conventional binary amyloid status was significantly associated with cognitive performance in this preclinical cohort.ConclusionsThe proposed hierarchical staging scheme of PET-evidenced amyloid deposition generalizes well to data from an independent cohort of older people at elevated risk for AD. Future studies will determine the prognostic value of the staging approach for predicting longitudinal cognitive decline in older individuals at increased risk for AD.
| S-EPMC6357385 | biostudies-literature
Project description:ObjectivesSecondary prevention trials in subjects with preclinical Alzheimer disease may require documentation of brain amyloidosis. The identification of inexpensive and noninvasive screening variables that can identify individuals who have significant amyloid accumulation would reduce screening costs.MethodsA total of 483 cognitively normal (CN) individuals, aged 70-92 years, from the population-based Mayo Clinic Study of Aging, underwent Pittsburgh compound B (PiB)-PET imaging. Logistic regression determined whether age, sex, APOE genotype, family history, or cognitive performance was associated with odds of a PiB retention ratio >1.4 and >1.5. Area under the receiver operating characteristic curve (AUROC) evaluated the discrimination between PiB-positive and -negative subjects. For each characteristic, we determined the number needed to screen in each age group (70-79 and 80-89) to identify 100 participants with PiB >1.4 or >1.5.ResultsA total of 211 (44%) individuals had PiB >1.4 and 151 (31%) >1.5. In univariate and multivariate models, discrimination was modest (AUROC ∼0.6-0.7). Multivariately, age and APOE best predicted odds of PiB >1.4 and >1.5. Subjective memory complaints were similar to cognitive test performance in predicting PiB >1.5. Indicators of PiB positivity varied with age. Screening APOE ε4 carriers alone reduced the number needed to screen to enroll 100 subjects with PIB >1.5 by 48% in persons aged 70-79 and 33% in those aged 80-89.ConclusionsAge and APOE genotype are useful predictors of the likelihood of significant amyloid accumulation, but discrimination is modest. Nonetheless, these results suggest that inexpensive and noninvasive measures could significantly reduce the number of CN individuals needed to screen to enroll a given number of amyloid-positive subjects.
| S-EPMC3475629 | biostudies-literature
Project description:ImportanceEmotional and behavioral symptoms in cognitively normal older people may be direct manifestations of Alzheimer disease (AD) pathophysiology at the preclinical stage, prior to the onset of mild cognitive impairment. Loneliness is a perceived state of social and emotional isolation that has been associated with cognitive and functional decline and an increased risk of incident AD dementia. We hypothesized that loneliness might occur in association with elevated cortical amyloid burden, an in vivo research biomarker of AD.ObjectiveTo determine whether cortical amyloid burden is associated with greater loneliness in cognitively normal older adults.Design, setting, and participantsCross-sectional analyses using data from the Harvard Aging Brain Study of 79 cognitively normal, community-dwelling participants. A continuous, aggregate measure of cortical amyloid burden, determined by Pittsburgh Compound B-positron emission tomography (PiB-PET), was examined in association with loneliness in linear regression models adjusting for age, sex, apolipoprotein E ε4 (APOEε4), socioeconomic status, depression, anxiety, and social network (without and with the interaction of amyloid and APOEε4). We also quantified the association of high amyloid burden (amyloid-positive group) to loneliness (lonely group) using logistic regression, controlling for the same covariates, with the amyloid-positive group and the lonely group, each composing 32% of the sample (n = 25).Main outcomes and measuresLoneliness, as determined by the 3-item UCLA Loneliness Scale (possible range, 3-12, with higher score indicating greater loneliness).ResultsThe 79 participants included 43 women and 36 men with a mean (SD) age of 76.4 (6.2) years. Mean (SD) cortical amyloid burden via PiB-PET was 1.230 (0.209), and the mean (SD) UCLA-3 loneliness score was 5.3 (1.8). Twenty-two (28%) had positive APOEε4 carrier status, and 25 (32%) were in the amyloid-positive group with cortical PiB distribution volume ratio greater than 1.2. Controlling for age, sex, APOEε4, socioeconomic status, depression, anxiety, and social network, we found that higher amyloid burden was significantly associated with greater loneliness: compared with individuals in the amyloid-negative group, those in the amyloid-positive group were 7.5-fold (95% CI, 1.7-fold to 34.0-fold) more likely to be classified as lonely than nonlonely (β = 3.3, partial r = 0.4, P = .002). Furthermore, the association of high amyloid burden and loneliness was stronger in APOEε4 carriers than in noncarriers.Conclusions and relevanceWe report a novel association of loneliness with cortical amyloid burden in cognitively normal older adults, suggesting that loneliness is a neuropsychiatric symptom relevant to preclinical AD. This work will inform new research into the neural underpinnings and disease mechanisms involved in loneliness and may enhance early detection and intervention research in AD.
| S-EPMC5257284 | biostudies-literature
Project description:A single nucleotide polymorphism, rs17070145, in the KIdney and BRAin expressed protein (KIBRA) gene has been associated with cognition and hippocampal volume in cognitively normal (CN) individuals. However, the impact of rs17070145 on longitudinal cognitive decline and hippocampal atrophy in CN adults at greatest risk of developing Alzheimer's disease is unknown. We investigated the impact rs17070145 has on the rate of cognitive decline and hippocampal atrophy over six years in 602 CN adults, with known brain Aβ-amyloid levels and whether there is an interactive effect with APOE genotype. We reveal that whilst limited independent effects of KIBRA genotype were observed, there was an interaction with APOE in CN adults who presented with high Aβ-amyloid levels across study duration. In comparison to APOE ε4-ve individuals carrying the rs17070145-T allele, significantly faster rates of cognitive decline (global, p = 0.006; verbal episodic memory, p = 0.004), and hippocampal atrophy (p = 0.04) were observed in individuals who were APOE ε4 + ve and did not carry the rs17070145-T allele. The observation of APOE effects in only non-carriers of the rs17070145-T allele, in the presence of high Aβ-amyloid suggest that carriers of the rs17070145-T allele are conferred a level of resilience to the detrimental effects of high Aβ-amyloid and APOE ε4.
| S-EPMC5794989 | biostudies-literature