Rachel F. Buckley

Factors affecting subjective memory complaints in the AIBL aging study: biomarkers, memory, affect, and age.

BACKGROUND The prognostic value of subjective memory complaints (SMCs) in the diagnosis of dementia of the Alzheimers type is unclear. While some studies have found an association between SMCs and cognitive decline, many have found a stronger association with depression, which raises questions about their diagnostic utility. METHODS We examined the cross-sectional association between SMC severity (as measured using the MAC-Q, a brief SMC questionnaire) and affect, memory, and Alzheimers disease (AD) biomarkers (β-amyloid deposition and the apolipoprotein E ε4 (APOEε4) allele) in healthy elderly controls (HC; M = 78.74 years, SD = 6.7) and individuals with mild cognitive impairment (MCI; M = 72.74 years, SD = 8.8). We analyzed a subset of individuals drawn from the Australian Imaging Biomarkers and Lifestyle (AIBL) Study of Aging. RESULTS SMCs were more severe in MCI patients than in HCs. SMC severity was related to affective variables and the interaction between age and group membership (HC/MCI). Within the HC group, SMC severity was related to affective variables only, while severity correlated only with age in the MCI group. SMCs were not related to cognitive variables or AD biomarkers. CONCLUSION SMCs were related to solely by poorer mood (greater depressive and anxious symptomatology) in the cognitively healthy elderly however mean levels were subclinical. This finding argues for the assessment of affective symptomatology in conjunction with cognitive assessment in elderly memory complainers. Future AIBL research will focus on assessing other AD biomarkers, such as brain atrophy and Aβ plasma markers, in relation to complaint severity. Once our 36-month follow-up data are collected, we propose to assess whether SMCs can predict future cognitive decline.

Implementation of subjective cognitive decline criteria in research studies

Subjective cognitive decline (SCD) manifesting before clinical impairment could serve as a target population for early intervention trials in Alzheimers disease (AD). A working group, the Subjective Cognitive Decline Initiative (SCD‐I), published SCD research criteria in the context of preclinical AD. To successfully apply them, a number of issues regarding assessment and implementation of SCD needed to be addressed.

Amyloid-β Related Memory Decline is not Associated with Subjective or Informant Rated Cognitive Impairment in Healthy Adults

BACKGROUND The detection of early Alzheimers disease (AD) can rely on subjective and informant reports of cognitive impairment. However, relationships between subjective cognitive impairment, objectively measured cognitive function, and amyloid-β (Aβ) biomarkers remain unclear. OBJECTIVE To determine the extent to which impairment or decline in subjective and informant rated cognitive impairment was associated with memory in healthy older adults with high Aβ. METHODS Healthy older adults (n = 289) enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were studied at baseline. Pittsburgh Compound B was used to determine Aβ status at baseline. At baseline and 18 months assessments, subjective memory impairment was assessed using the Memory Complaint Questionnaire and the Short Form of the Informant Questionnaire on Cognitive Decline in the Elderly. Cognition was measured using the Cogstate Brief Battery. RESULTS At baseline, there were no differences between low and high Aβ groups in subjective or informant-rated cognitive impairment, depressive and anxiety symptoms, or cognitive function. Longitudinal analyses showed moderate decline in learning and working memory over the 18 months in the high Aβ group. However there was no change over time in subjective or informant-rated cognitive impairment, depressive and anxiety symptoms, or cognition in either Aβ group. CONCLUSIONS Although healthy older adults with high Aβ levels show decline in learning and working memory over 18 months, subjective or informant ratings of cognitive impairment do not change over the same period suggesting subjective cognitive impairment may have limited utility for the very early identification of AD.

Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals

Alzheimers disease (AD) is characterized by two hallmark molecular pathologies: amyloid aβ1–42 and Tau neurofibrillary tangles. To date, studies of functional connectivity MRI (fcMRI) in individuals with preclinical AD have relied on associations with in vivo measures of amyloid pathology. With the recent advent of in vivo Tau-PET tracers it is now possible to extend investigations on fcMRI in a sample of cognitively normal elderly humans to regional measures of Tau. We modeled fcMRI measures across four major cortical association networks [default-mode network (DMN), salience network (SAL), dorsal attention network, and frontoparietal control network] as a function of global cortical amyloid [Pittsburgh Compound B (PiB)-PET] and regional Tau (AV1451-PET) in entorhinal, inferior temporal (IT), and inferior parietal cortex. Results showed that the interaction term between PiB and IT AV1451 was significantly associated with connectivity in the DMN and salience. The interaction revealed that amyloid-positive (aβ+) individuals show increased connectivity in the DMN and salience when neocortical Tau levels are low, whereas aβ+ individuals demonstrate decreased connectivity in these networks as a function of elevated Tau-PET signal. This pattern suggests a hyperconnectivity phase followed by a hypoconnectivity phase in the course of preclinical AD. SIGNIFICANCE STATEMENT This article offers a first look at the relationship between Tau-PET imaging with F18-AV1451 and functional connectivity MRI (fcMRI) in the context of amyloid-PET imaging. The results suggest a nonlinear relationship between fcMRI and both Tau-PET and amyloid-PET imaging. The pattern supports recent conjecture that the AD fcMRI trajectory is characterized by periods of both hyperconnectivity and hypoconnectivity. Furthermore, this nonlinear pattern can account for the sometimes conflicting reports of associations between amyloid and fcMRI in individuals with preclinical Alzheimers disease.

Subjective memory decline predicts greater rates of clinical progression in preclinical Alzheimer's disease.

The objective of this study was to determine the utility of subjective memory decline (SMD) to predict episodic memory change and rates of clinical progression in cognitively normal older adults with evidence of high β‐amyloid burden (CN Aβ+).

Phenomenological characterization of memory complaints in preclinical and prodromal Alzheimer’s disease.

OBJECTIVE To explore the subjective experience of memory change in groups at risk of dementia (those with mild cognitive impairment MCI or high β-amyloid (Aβ+) burden) to determine the existence of potential phenomenological typologies. METHOD We recruited 123 healthy controls (HC) and individuals with MCI from the Australian Imaging, Biomarker and Lifestyle (AIBL) study. Sixty-7 (HC = 47,MCI = 20) had Aβ scans available for analysis. Semistructured interviews were administered, transcribed, and meaningful phrases extracted from transcripts. Twelve themes were defined and compared across diagnostic status and Aβ status. RESULTS MCI endorsed more complaints of burdensome coping strategies, increasing frequency, sense of predomination, poor contextualization, progression, dependency, impact on affect, and dismissive attitudes. HCAβ+ acknowledged a progressive memory decline compared to HCAβ-, while MCIAβ+ expressed more burdensome coping strategies, dismissive attitudes, and dependency comparative to either healthy group. Depression was more likely to be related to complaint themes in HCs, while complaint themes were associated with poorer list-learning performance in individuals with MCI. CONCLUSION Complaint themes in those with MCI align with the MCI symptom complex, particularly when accompanied with high Aβ load. Healthy Aβ+ individuals acknowledged progressive memory change, suggesting they are aware of memory changes not yet detectable via neuropsychological measures. Depressive symptomatology associated with HC complaints, suggesting certain themes are affect-driven, while complaints in MCI are associated with organically driven functional impairment. Qualitative analysis of SMCs can inform the earliest clinical manifestations of Alzheimers disease. Our findings can inform diagnostic approaches to the clinical evaluation of memory complaints in the nondemented elderly.

Subjective Memory Complaints in APOEɛ4 Carriers are Associated with High Amyloid-β Burden.

BACKGROUND APOEɛ4 genotype and aging have been identified as risk factors for Alzheimers disease (AD). In addition, subjective memory complaints (SMC) might be a first clinical expression of the effect of AD pathology on cognitive functioning. OBJECTIVE To assess whether APOEɛ4 genotype, age, SMC, and episodic memory are risk factors for high amyloid-β (Aβ) burden in cognitively normal elderly. METHODS 307 cognitively normal participants (72.7 ± 6.8 years, 53% female, 55% SMC) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study underwent amyloid PET and APOE genotyping. Logistic regression analyses were performed to determine the association of APOEɛ4 genotype, age, SMC, and episodic memory with Aβ pathology. RESULTS Odds of high Aβ burden were greater at an older age (OR = 3.21; 95% CI = 1.68-6.14), when SMC were present (OR = 1.90; 95% CI = 1.03-3.48), and for APOEɛ4 carriers (OR = 7.49; 95% CI = 3.96-14.15), while episodic memory was not associated with odds of high Aβ burden. Stratified analyses showed that odds of SMC for high Aβ burden were increased in specifically APOEɛ4 carriers (OR = 4.58, 95% CI = 1.83-11.49) and younger participants (OR = 3.73, 95% CI = 1.39-10.01). CONCLUSION Aging, APOEɛ4 genotype, and SMC were associated with high Aβ burden. SMC were especially indicative of high Aβ burden in younger participants and in APOEɛ4 carriers. These findings suggest that selection based on the presence of SMC, APOEɛ4 genotype and age may help identify healthy elderly participants with high Aβ burden eligible for secondary prevention trials.

Segmentation of the mouse hippocampal formation in magnetic resonance images

The hippocampal formation plays an important role in cognition, spatial navigation, learning, and memory. High resolution magnetic resonance (MR) imaging makes it possible to study in vivo changes in the hippocampus over time and is useful for comparing hippocampal volume and structure in wild type and mutant mice. Such comparisons demand a reliable way to segment the hippocampal formation. We have developed a method for the systematic segmentation of the hippocampal formation using the perfusion-fixed C57BL/6 mouse brain for application in longitudinal and comparative studies. Our aim was to develop a guide for segmenting over 40 structures in an adult mouse brain using 30 μm isotropic resolution images acquired with a 16.4 T MR imaging system and combined using super-resolution reconstruction.

Functional network integrity presages cognitive decline in preclinical Alzheimer disease

Objective: To 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). Methods: A total of 237 clinically normal older adults (aged 63–90 years, Clinical Dementia Rating 0) underwent baseline β-amyloid (Aβ) 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 Aβ burden. Median neuropsychological follow-up was 3 years. Results: Baseline 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 Aβ burden in predicting decline, with combined higher Aβ and lower connectivity predicting the steepest curvilinear decline in PACC performance. Conclusions: In clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased Aβ 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.

Region-Specific Association of Subjective Cognitive Decline With Tauopathy Independent of Global β-Amyloid Burden

Importance The ability to explore associations between reports of subjective cognitive decline (SCD) and biomarkers of early Alzheimer disease (AD) pathophysiologic processes (accumulation of neocortical &bgr;-amyloid [A&bgr;] and tau) provides an important opportunity to understand the basis of SCD and AD risk. Objective To examine associations between SCD and global A&bgr; and tau burdens in regions of interest in clinically healthy older adults. Design, Setting, and Participants This imaging substudy of the Harvard Aging Brain Study included 133 clinically healthy older participants (Clinical Dementia Rating Scale global scores of 0) participating in the Harvard Aging Brain Study who underwent cross-sectional flortaucipir F 18 (previously known as AV 1451, T807) positron emission tomography (FTP-PET) imaging for tau and Pittsburgh compound B carbon 11–labeled PET (PiB-PET) imaging for A&bgr;. The following 2 regions for tau burden were identified: the entorhinal cortex, which exhibits early signs of tauopathy, and the inferior temporal region, which is more closely associated with AD-related pathologic mechanisms. Data were collected from June 11, 2012, through April 7, 2016. Main Outcomes and Measures Subjective cognitive decline was measured using a previously published method of z-transforming subscales from the Memory Functioning Questionnaire, the Everyday Cognition battery, and a 7-item questionnaire. The A&bgr; level was measured according to a summary distribution volume ratio of frontal, lateral temporal and parietal, and retrosplenial PiB-PET tracer uptake. The FTP-PET measures were computed as standardized uptake value ratios. Linear regression models focused on main and interactive effects of A&bgr;, entorhinal cortical, and inferior temporal tau on SCD, controlling for age, sex, educational attainment, and Geriatric Depression Scale score. Results Of the 133 participants, 75 (56.3%) were women and 58 (43.6%) were men; mean (SD) age was 76 (6.9) years (range, 55-90 years). Thirty-nine participants (29.3%) exhibited a high A&bgr; burden. Greater SCD was associated with increasing entorhinal cortical tau burden (&bgr; = 0.35; 95% CI, 0.19-.52; P < .001) and A&bgr; burden (&bgr; = 0.24; 95% CI, 0.08-.40; P = .005), but not inferior temporal tau burden (&bgr; = 0.10; 95% CI, −0.08 to 0.28; P = .27). This association between entorhinal cortical tau burden and SCD was largely unchanged after accounting for A&bgr; burden (&bgr; = 0.36; 95% CI, 0.15-.58; P = .001), and no interaction influenced SCD (&bgr; = −0.36; 95% CI, −0.34 to 0.09; P = .25). An exploratory post hoc whole-brain analysis also indicated that SCD was predominantly associated with greater tau burden in the entorhinal cortex. Conclusions and Relevance Subjective cognitive decline is indicative of accumulation of early tauopathy in the medial temporal lobe, specifically in the entorhinal cortex, and to a lesser extent, elevated global levels of A&bgr;. Our findings suggest multiple underlying pathways that motivate SCD that do not necessarily interact to influence SCD endorsement. As such, multiple biological factors must be considered when assessing SCD in clinically healthy older adults.