Clinical meaningfulness of subtle cognitive decline on longitudinal testing in preclinical AD

Background: The utility of subjective cognitive decline (SCD) as an indicator of preclinical AD is overshadowed by its inconsistent association with objective cognition. Objective: This study examines if manipulations of SCD measurement affect its association with early cognitive dysfunction characteristic of preclinical AD. Methods: Cognitively healthy older adults (n = 110) completed SCD questionnaires that elicited complaints in general, compared to 5 years ago (retrospective SCD) and compared to their peers (age-anchored SCD) in binary and Likert scales. Outcome cognitive tasks included an associative memory task (Face-Name Test), a visual short-term memory binding task (STMB test), and a clinical neuropsychological list learning test (Selective Reminder Test). Results: SCD complaints, when compared to age-matched peers (age-anchored SCD) were endorsed less frequently than complaints compared to 5 years ago (retrospective SCD) (p < 0.01). In demographically adjusted regressions, age-anchored ordinal-rated SCD was associated with short term memory binding (β= –0.22, p = 0.040, CI = –0.45, –0.01), associative memory (β= –0.26, p = 0.018, CI = –0.45, –0.06), and list learning (β= –0.31, p = 0.002, CI = –0.51, –0.12). Retrospective and general ordinal-rated SCD was associated with associative memory (β= –0.25, p = 0.012, CI = –0.44, –0.06; β= –0.29, p = 0.003, CI = –0.47, –0.10) and list learning only (β= –0.25, p = 0.014, CI = –0.45, –0.05; β= –0.28, p = 0.004, CI = –0.48, –0.09). Conclusion: Ordinal age-anchored SCD appears better suited than other SCD measurements to detect early cognitive dysfunction characteristic of preclinical AD.

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FACEHBI: A PROSPECTIVE STUDY OF RISK FACTORS, BIOMARKERS AND COGNITION IN A COHORT OF INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE. STUDY RATIONALE AND RESEARCH PROTOCOLS

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2016.122 ◽

2016 ◽

pp. 1-9

Author(s):

O. Rodriguez-Gomez ◽

A. Sanabria ◽

A. Perez-Cordon ◽

D. Sanchez-Ruiz ◽

C. Abdelnour ◽

...

Keyword(s):

Risk Factor ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Diffusion Tensor ◽

Subjective Cognitive Decline ◽

Long Term Study ◽

Research Protocols ◽

Preclinical Ad ◽

Multimodal Biomarkers

Background: Long-term longitudinal studies with multimodal biomarkers are needed to delve into the knowledge of preclinical AD. Subjective cognitive decline has been proposed as a risk factor for the development of cognitive impairment. Thus, including individuals with SCD in observational studies may be a cost-effective strategy to increase the prevalence of preclinical AD in the sample. Objectives: To describe the rationale, research protocols and baseline characteristics of participants in the Fundació ACE Healthy Brain Initiative (FACEHBI). Design: FACEHBI is a clinical trial (EudraCT: 2014-000798-38) embedded within a long-term observational study of individuals with SCD. Setting: Participants have been recruited at the memory clinic of Fundació ACE (Barcelona) from two different sources: patients referred by a general practitioner and individuals from an Open House Initiative. Participants: 200 individuals diagnosed with SCD with a strictly normal performance in a comprehensive neuropsychological battery. Measurements: Individuals will undergo an extensive neuropsychological protocol, risk factor assessment and a set of multimodal biomarkers including florbetaben PET, structural and functional MRI, diffusion tensor imaging, determination of amyloid species in plasma and neurophthalmologic assessment with optical coherence tomography. Results: Two hundred individuals have been recruited in 15 months. Mean age was 65.9 years; mean MMSE was 29.2 with a mean of 14.8 years of education. Conclusions: FACEHBI is a long-term study of cognition, biomarkers and lifestyle that has been designed upon an innovative symptom-based approach using SCD as target population. It will shed light on the pathophysiology of preclinical AD and the role of SCD as a risk marker for the development of cognitive impairment.

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P2-550: PLASMA MEASURES OF INFLAMMATION ASSOCIATED WITH CLINICAL PROGRESSION AND COGNITIVE DECLINE DURING PRECLINICAL AD

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.2958 ◽

2019 ◽

Vol 15 ◽

pp. P831-P831

Author(s):

Alden L. Gross ◽

Keenan A. Walker ◽

Abhay Moghekar ◽

Corinne Pettigrew ◽

Anja Soldan ◽

...

Keyword(s):

Cognitive Decline ◽

Clinical Progression ◽

Preclinical Ad

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Genetic Effects on Longitudinal Cognitive Decline During the Early Stages of Alzheimer's Disease

10.21203/rs.3.rs-149163/v1 ◽

2021 ◽

Author(s):

Atul Kumar ◽

Maryam Shoai ◽

Sebastian Palmqvist ◽

Erik Stomrud ◽

John Hardy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Genome Wide Association Study ◽

Early Stage ◽

Cognitive Change ◽

Preclinical Ad ◽

Genome Wide ◽

A Genome ◽

Polygenic Scores

Abstract Background Cognitive decline in early-stage Alzheimer’s disease (AD) may depend on genetic variability. Methods In the Swedish BioFINDER study, we used polygenic scores (PGS) (for AD, intelligence and educational attainment), and genetic variants (in a genome-wide association study [GWAS]) to predict longitudinal cognitive change (measured by MMSE) over a mean of 4.2 years. We included 555 β-amyloid (Aβ) negative cognitively unimpaired (CU) individuals, 206 Aβ-positive CU (preclinical AD), 110 Aβ-negative mild cognitive impairment (MCI) patients, and 146 Aβ-positive MCI patients (prodromal AD). Results Polygenic scores for AD (in Aβ-positive individuals) and intelligence (independent of Aβ-status) were associated with cognitive decline. Eight genes were associated with cognitive decline in GWAS (3 independent of Aβ-status). Conclusions AD risk genes may influence cognitive decline in early AD, while genes related to intelligence may modulate cognitive decline irrespective of disease. Therapies targeting the implicated biological pathways may modulate the clinical course of AD.

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Altered Frequency-Dependent Brain Activation and White Matter Integrity Associated With Cognition in Characterizing Preclinical Alzheimer’s Disease Stages

Frontiers in Human Neuroscience ◽

10.3389/fnhum.2021.625232 ◽

2021 ◽

Vol 15 ◽

Author(s):

Siyu Wang ◽

Jiang Rao ◽

Yingying Yue ◽

Chen Xue ◽

Guanjie Hu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

White Matter ◽

Cognitive Decline ◽

Brain Activation ◽

Amnestic Mild Cognitive Impairment ◽

White Matter Integrity ◽

Correlation Analyses ◽

Preclinical Ad

BackgroundSubjective cognitive decline (SCD), non-amnestic mild cognitive impairment (naMCI), and amnestic mild cognitive impairment (aMCI) are regarded to be at high risk of converting to Alzheimer’s disease (AD). Amplitude of low-frequency fluctuations (ALFF) can reflect functional deterioration while diffusion tensor imaging (DTI) is capable of detecting white matter integrity. Our study aimed to investigate the structural and functional alterations to further reveal convergence and divergence among SCD, naMCI, and aMCI and how these contribute to cognitive deterioration.MethodsWe analyzed ALFF under slow-4 (0.027–0.073 Hz) and slow-5 (0.01–0.027 Hz) bands and white matter fiber integrity among normal controls (CN), SCD, naMCI, and aMCI groups. Correlation analyses were further utilized among paired DTI alteration, ALFF deterioration, and cognitive decline.ResultsFor ALFF calculation, ascended ALFF values were detected in the lingual gyrus (LING) and superior frontal gyrus (SFG) within SCD and naMCI patients, respectively. Descended ALFF values were presented mainly in the LING, SFG, middle frontal gyrus, and precuneus in aMCI patients compared to CN, SCD, and naMCI groups. For DTI analyses, white matter alterations were detected within the uncinate fasciculus (UF) in aMCI patients and within the superior longitudinal fasciculus (SLF) in naMCI patients. SCD patients presented alterations in both fasciculi. Correlation analyses revealed that the majority of these structural and functional alterations were associated with complicated cognitive decline. Besides, UF alterations were correlated with ALFF deterioration in the SFG within aMCI patients.ConclusionsSCD shares structurally and functionally deteriorative characteristics with aMCI and naMCI, and tends to convert to either of them. Furthermore, abnormalities in white matter fibers may be the structural basis of abnormal brain activation in preclinical AD stages. Combined together, it suggests that structural and functional integration may characterize the preclinical AD progression.

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Monthly At-Home Computerized Cognitive Testing to Detect Diminished Practice Effects in Preclinical Alzheimer's Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.800126 ◽

2022 ◽

Vol 13 ◽

Author(s):

Roos J. Jutten ◽

Dorene M. Rentz ◽

Jessie F. Fu ◽

Danielle V. Mayblyum ◽

Rebecca E. Amariglio ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Pet Imaging ◽

Cognitive Testing ◽

Practice Effects ◽

Aging Brain ◽

Amyloid Burden ◽

Preclinical Ad ◽

At Home

Introduction: We investigated whether monthly assessments of a computerized cognitive composite (C3) could aid in the detection of differences in practice effects (PE) in clinically unimpaired (CU) older adults, and whether diminished PE were associated with Alzheimer's disease (AD) biomarkers and annual cognitive decline.Materials and Methods:N = 114 CU participants (age 77.6 ± 5.0, 61% female, MMSE 29 ± 1.2) from the Harvard Aging Brain Study completed the self-administered C3 monthly, at-home, on an iPad for one year. At baseline, participants underwent in-clinic Preclinical Alzheimer's Cognitive Composite-5 (PACC5) testing, and a subsample (n = 72, age = 77.8 ± 4.9, 59% female, MMSE 29 ± 1.3) had 1-year follow-up in-clinic PACC5 testing available. Participants had undergone PIB-PET imaging (0.99 ± 1.6 years before at-home baseline) and Flortaucipir PET imaging (n = 105, 0.62 ± 1.1 years before at-home baseline). Linear mixed models were used to investigate change over months on the C3 adjusting for age, sex, and years of education, and to extract individual covariate-adjusted slopes over the first 3 months. We investigated the association of 3-month C3 slopes with global amyloid burden and tau deposition in eight predefined regions of interest, and conducted Receiver Operating Characteristic analyses to examine how accurately 3-month C3 slopes could identify individuals that showed >0.10 SD annual decline on the PACC-5.Results: Overall, individuals improved on all C3 measures over 12 months (β = 0.23, 95% CI [0.21–0.25], p < 0.001), but improvement over the first 3 months was greatest (β = 0.68, 95% CI [0.59–0.77], p < 0.001), suggesting stronger PE over initial repeated exposures. However, lower PE over 3 months were associated with more global amyloid burden (r = −0.20, 95% CI [−0.38 – −0.01], p = 0.049) and tau deposition in the entorhinal cortex (r = −0.38, 95% CI [−0.54 – −0.19], p < 0.001) and inferior-temporal lobe (r = −0.23, 95% CI [−0.41 – −0.02], p = 0.03). 3-month C3 slopes exhibited good discriminative ability to identify PACC-5 decliners (AUC 0.91, 95% CI [0.84–0.98]), which was better than baseline C3 (p < 0.001) and baseline PACC-5 scores (p = 0.02).Conclusion: While PE are commonly observed among CU adults, diminished PE over monthly cognitive testing are associated with greater AD biomarker burden and cognitive decline. Our findings imply that unsupervised computerized testing using monthly retest paradigms can provide rapid detection of diminished PE indicative of future cognitive decline in preclinical AD.

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Accelerated decline in white matter microstructure in subsequently impaired older adults and its relationship with cognitive decline.

10.1101/2020.09.23.20187450 ◽

2020 ◽

Author(s):

Owen A Williams ◽

Andrea T Shafer ◽

Evian Perez Rivra ◽

Yang An ◽

Bennett Allen Landman ◽

...

Keyword(s):

Older Adults ◽

White Matter ◽

Cognitive Decline ◽

Processing Speed ◽

Verbal Memory ◽

Diffusion Tensor ◽

Neuropsychological Testing ◽

Longitudinal Diffusion ◽

Preclinical Ad ◽

The Right

INTRODUCTION: Little is known about longitudinal decline in white matter (WM) microstructure and its associations with cognition in preclinical Alzheimers disease (AD). METHODS: Longitudinal diffusion tensor imaging and neuropsychological testing from 50 older adults who subsequently developed mild cognitive impairment or dementia (subsequently impaired, SI) and 200 cognitively normal controls. Rates of WM decline were compared between groups using voxel-wise linear mixed-effects models. Associations between change in WM and cognition were examined. RESULTS: SI had faster decline in fractional anisotropy (FA) in the right inferior fronto-occipital fasciculus (R.IFOF) and bilateral splenium of the corpus callosum. Decline in R.IFOF FA was related to decline in verbal memory, visuospatial ability, processing speed, and MMSE (p≤ 0.05). Decline in bilateral splenium FA was related to decline in verbal fluency, processing speed, and MMSE (p≤ 0.05). DISCUSSION: Accelerated regional WM decline is characteristic of preclinical AD and related to domain specific cognitive decline.

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P3-031: CLINICAL MEANINGFULNESS OF SHORT-TERM COGNITIVE DECLINE ON THE PRECLINICAL ALZHEIMER'S COGNITIVE COMPOSITE-5 (PACC-5) IN NORMAL OLDER ADULTS WITH ELEVATED β-AMYLOID

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.3057 ◽

2019 ◽

Vol 15 ◽

pp. P937-P938

Author(s):

Kate V. Papp ◽

Rachel F. Buckley ◽

Elizabeth C. Mormino ◽

Paul Maruff ◽

Victor L. Villemagne ◽

...

Keyword(s):

Older Adults ◽

Cognitive Decline ◽

Short Term ◽

Β Amyloid ◽

Clinical Meaningfulness

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The Association between Insomnia-like Sleep Pattern Changes and Cognitive Dysfunction: Possible Mechanism and Therapeutic Strategy

Current Alzheimer Research ◽

10.2174/1567205018666211207095048 ◽

2021 ◽

Vol 18 ◽

Author(s):

Kangzhi Chen ◽

Yefan Lv ◽

Xiaoyan Long ◽

Weiping Liu ◽

Jinxia Zhou

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

Sleep Disorders ◽

Cognitive Dysfunction ◽

Therapeutic Strategy ◽

Sleep Architecture ◽

Sleep Pattern ◽

Sleep Patterns ◽

Preclinical Ad ◽

The Relationship

: The prevalence of sleep disorders and cognitive dysfunction has overwhelmingly increased, with insomnia and Alzheimer’s disease (AD) being the most common form. A multitude of studies have linked the alterations in sleep continuity or sleep architecture with cognitive impairment bilaterally, but the management of disrupted sleep patterns in preclinical AD could be more beneficial since there is no cure for AD. This review mainly focuses on the altered sleep patterns in insomnia, and summarizes potential pathways underlying the relationship between insomnia and cognitive impairment, aiming to establish certain sleep pattern changes as biomarkers for cognitive decline and explore potential therapeutic targets based on evidence from research advances.

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Evidence for Reduced Autobiographical Memory Episodic Specificity in Cognitively Normal Middle-Aged and Older Individuals at Increased Risk for Alzheimer’s Disease Dementia

Journal of the International Neuropsychological Society ◽

10.1017/s1355617718000577 ◽

2018 ◽

Vol 24 (10) ◽

pp. 1073-1083 ◽

Cited By ~ 14

Author(s):

Matthew D. Grilli ◽

Aubrey A. Wank ◽

John J. Bercel ◽

Lee Ryan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Older Individuals ◽

Autobiographical Memories ◽

Middle Aged ◽

Cognitively Normal ◽

Preclinical Ad ◽

Increased Risk ◽

And Gender

AbstractObjectives: Alzheimer’s disease (AD) typically eludes clinical detection for years, if not decades. The identification of subtle cognitive decline associated with preclinical AD would not only advance understanding of the disease, but also provide clinical targets to assess preventative and early intervention treatments. Disrupted retrieval of detailed episodic autobiographical memories may be a sensitive indicator of subtle cognitive decline, because this type of memory taxes a core neural network affected by preclinical AD neuropathology. Methods: To begin to address this idea, we assessed the episodic specificity of autobiographical memories retrieved by cognitively normal middle-aged and older individuals who are carriers of the apolipoprotein E ε4 allele – a population at increased risk for subtle cognitive decline related to neuropathological risk factors for AD. We compared the ε4 carriers to non-carriers of ε4 similar in age, education, and gender. Results: The ε4 carriers did not perform worse than the non-carriers on a comprehensive battery of neuropsychological tests. In contrast, as a group, the ε4 carriers generated autobiographical memories that were reduced in “internal” or episodic details relative to non-carriers. Conclusions: These findings support the notion that reduced autobiographical episodic detail generation may be a marker of subtle cognitive decline associated with AD. (JINS, 2018, 24, 1073–1183)

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