Association of cortical microstructure with amyloid-β and tau: impact on cognitive decline, neurodegeneration, and clinical progression in older adults

AbstractNoninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer’s disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-β and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, 11C-Pittsburgh compound-B-PET, 18F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-β, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-β, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-β, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-β and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-β, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.

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Links Between Metabolic and Structural Changes in the Brain of Cognitively Normal Older Adults: A 4-Year Longitudinal Follow-Up

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2019.00015 ◽

2019 ◽

Vol 11 ◽

Cited By ~ 7

Author(s):

Christian-Alexandre Castellano ◽

Carol Hudon ◽

Etienne Croteau ◽

Mélanie Fortier ◽

Valérie St-Pierre ◽

...

Keyword(s):

Older Adults ◽

Structural Changes ◽

Cognitively Normal ◽

The Brain

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Social Engagement and Amyloid-β-Related Cognitive Decline in Cognitively Normal Older Adults

American Journal of Geriatric Psychiatry ◽

10.1016/j.jagp.2019.05.005 ◽

2019 ◽

Vol 27 (11) ◽

pp. 1247-1256 ◽

Cited By ~ 9

Author(s):

Kelsey D. Biddle ◽

Federico d'Oleire Uquillas ◽

Heidi I.L. Jacobs ◽

Benjamin Zide ◽

Dylan R. Kirn ◽

...

Keyword(s):

Older Adults ◽

Cognitive Decline ◽

Social Engagement ◽

Amyloid Β ◽

Cognitively Normal

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Superior Memory Reduces 8-year Risk of Mild Cognitive Impairment and Dementia But Not Amyloid β-Associated Cognitive Decline in Older Adults

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acy078 ◽

2018 ◽

Vol 34 (5) ◽

pp. 585-598 ◽

Cited By ~ 2

Author(s):

Christa Dang ◽

Karra D Harrington ◽

Yen Ying Lim ◽

David Ames ◽

Jason Hassenstab ◽

...

Keyword(s):

Older Adults ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Episodic Memory ◽

Cognitive Decline ◽

Sex Education ◽

Verbal Memory ◽

Amyloid Β ◽

Clinical Progression ◽

Age Related

Abstract Objective To prospectively examine 8-year risk of clinical disease progression to mild cognitive impairment (MCI)/dementia in older adults ≥60 with superior episodic memory (SuperAgers) compared to those cognitively normal for their age (CNFA). Additionally, to determine the extent to which SuperAgers were resilient to the negative effects of elevated amyloid-beta (Aβ+) on cognition. Method Participants were classified as SuperAgers based on episodic memory performance consistent with younger adults aged 30–44 and no impairment on non-memory tests (n = 179), and were matched with CNFA on age, sex, education, and follow-up time (n = 179). Subdistribution hazard models examined risk of clinical progression to MCI/dementia. Linear mixed models assessed the effect of Aβ on cognition over time. Results Prevalence of Aβ+ and APOE ε4 was equivalent between SuperAgers and CNFA. SuperAgers had 69%–73% reduced risk of clinical progression to MCI/dementia compared to CNFA (HR: 0.27–0.31, 95% CI: 0.11–0.73, p < .001). Aβ+ was associated with cognitive decline in verbal memory and executive function, regardless of SuperAger/CNFA classification. In the absence of Aβ+, equivalent age-related changes in cognition were observed between SuperAgers and CNFA. Conclusions SuperAgers displayed resilience against clinical progression to MCI/dementia compared to CNFA despite equivalent risk for Alzheimer’s disease (AD); however, SuperAgers had no greater protection from Aβ+ than CNFA. The deleterious effects of Aβ on cognition persist regardless of baseline cognitive ability. Thus, superior cognitive performance does not reflect resistance against the neuropathological processes associated with AD, and the observed resilience for SuperAgers may instead reflect neuropsychological criteria for cognitive impairment.

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SPON1 Is Associated with Amyloid-β and APOE ε4-Related Cognitive Decline in Cognitively Normal Adults

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-200246 ◽

2021 ◽

Vol 5 (1) ◽

pp. 111-120

Author(s):

Shane Fernandez ◽

Samantha C. Burnham ◽

Lidija Milicic ◽

Greg Savage ◽

Paul Maruff ◽

...

Keyword(s):

Older Adults ◽

Cognitive Decline ◽

Amyloid Β ◽

Independent Effect ◽

Imaging Biomarkers ◽

Cognitively Normal ◽

Study Results ◽

Global Cognition ◽

Mixed Modelling ◽

Normal Adults

Abstract. Background: Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer’s disease. Objective: The aim of this study was to assess whether the association was present in cognitively normal older adults. Methods: Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study. Results: No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ4/rs11023139-A carriers declined significantly faster than APOE ɛ4/rs11023139-G_G carriers in measures of global cognition (p = 0.011) and verbal episodic memory (p = 0.020). Conclusion: These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ4 cognitively normal older adults with a high neocortical amyloid-β burden.

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P3-305: SYNERGISTIC ADVERSE EFFECTS OF WIDOWHOOD AND AMYLOID-β ON COGNITIVE DECLINE IN COGNITIVELY NORMAL OLDER ADULTS

Alzheimer s & Dementia ◽

10.1016/j.jalz.2019.06.3337 ◽

2019 ◽

Vol 15 ◽

pp. P1054-P1054

Author(s):

Kelsey D. Biddle ◽

Federico d'Oleire Uquillas ◽

Benjamin Zide ◽

Dylan Kirn ◽

Heidi IL. Jacobs ◽

...

Keyword(s):

Older Adults ◽

Adverse Effects ◽

Cognitive Decline ◽

Amyloid Β ◽

Cognitively Normal

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Cortical tau deposition follows patterns of entorhinal functional connectivity in aging

eLife ◽

10.7554/elife.49132 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 5

Author(s):

Jenna N Adams ◽

Anne Maass ◽

Theresa M Harrison ◽

Suzanne L Baker ◽

William J Jagust

Keyword(s):

Older Adults ◽

Functional Connectivity ◽

Resting State ◽

Amyloid Β ◽

Resting State Fmri ◽

Aging Brain ◽

Functional Specialization ◽

Tau Pathology ◽

Cognitively Normal ◽

Neural Connections

Tau pathology first appears in the transentorhinal and anterolateral entorhinal cortex (alEC) in the aging brain. The transition to Alzheimer’s disease (AD) is hypothesized to involve amyloid-β (Aβ) facilitated tau spread through neural connections. We contrasted functional connectivity (FC) of alEC and posteromedial EC (pmEC), subregions of EC that differ in functional specialization and cortical connectivity, with the hypothesis that alEC-connected cortex would show greater tau deposition than pmEC-connected cortex. We used resting state fMRI to measure FC, and PET to measure tau and Aβ in cognitively normal older adults. Tau preferentially deposited in alEC-connected cortex compared to pmEC-connected or non-connected cortex, and stronger connectivity was associated with increased tau deposition. FC-tau relationships were present regardless of Aβ, although strengthened with Aβ. These results provide an explanation for the anatomic specificity of neocortical tau deposition in the aging brain and reveal relationships between normal aging and the evolution of AD.

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Social isolation, rather than loneliness, is associated with cognitive decline in older adults: the China Health and Retirement Longitudinal Study

Psychological Medicine ◽

10.1017/s0033291720001026 ◽

2021 ◽

pp. 1-8

Author(s):

Bin Yu ◽

Andrew Steptoe ◽

Yongjie Chen ◽

Xiaohua Jia

Keyword(s):

Older Adults ◽

Longitudinal Study ◽

Cognitive Function ◽

Episodic Memory ◽

Cognitive Decline ◽

Social Isolation ◽

Mental Status ◽

Chinese Older Adults ◽

Confounding Variables

Abstract Background Social isolation and loneliness have each been associated with cognitive decline, but most previous research is limited to Western populations. This study examined the relationships of social isolation and loneliness on cognitive function among Chinese older adults. Methods This study used two waves of data (2011 and 2015) from the China Health and Retirement Longitudinal Study and analyses were restricted to those respondents aged 50 and older. Social isolation, loneliness, and cognitive function were measured at baseline. Follow-up measures on cognitive function were obtained for 7761 participants (mean age = 60.97, s.d. = 7.31; male, 50.8%). Lagged dependent variable models adjusted for confounding factors were used to evaluate the association between baseline isolation, loneliness, and cognitive function at follow-up. Results Loneliness was significantly associated with the cognitive decline at follow-up (episodic memory: β = −0.03, p < 0.01; mental status: β = −0.03, p < 0.01) in the partially adjusted models. These associations became insignificant after additional confounding variables (chronic diseases, health behaviors, disabilities, and depressive symptoms) were taken into account (all p > 0.05). By contrast, social isolation was significantly associated with decreases in all cognitive function measures at follow-up (episodic memory: β = −0.05, p < 0.001; mental status: β = −0.03, p < 0.01) even after controlling for loneliness and all confounding variables. Conclusions Social isolation is associated with cognitive decline in Chinese older adults, and the relationships are independent of loneliness. These findings expand our knowledge about the links between social relationships and the cognitive function in non-Western populations.

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Elevated plasma growth and differentiation factor 15 predicts incident anemia in older adults aged 60 years and older

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa324 ◽

2020 ◽

Author(s):

Yuko Yamaguchi ◽

Marta Zampino ◽

Toshiko Tanaka ◽

Stefania Bandinelli ◽

Yusuke Osawa ◽

...

Keyword(s):

Older Adults ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Differentiation Factor ◽

Hazards Model ◽

Increased Risk ◽

The Relationship

Abstract Background Anemia is common in older adults and associated with greater morbidity and mortality. The causes of anemia in older adults have not been completely characterized. Although elevated circulating growth and differentiation factor 15 (GDF-15) has been associated with anemia in older adults, it is not known whether elevated GDF-15 predicts the development of anemia. Methods We examined the relationship between plasma GDF-15 concentrations at baseline in 708 non-anemic adults, aged 60 years and older, with incident anemia during 15 years of follow-up among participants in the Invecchiare in Chianti (InCHIANTI) Study. Results During follow-up, 179 (25.3%) participants developed anemia. The proportion of participants who developed anemia from the lowest to highest quartile of plasma GDF-15 was 12.9%, 20.1%, 21.2%, and 45.8%, respectively. Adults in the highest quartile of plasma GDF-15 had an increased risk of developing anemia (Hazards Ratio 1.15, 95% Confidence Interval 1.09, 1.21, P<.0001) compared to those in the lower three quartiles in a multivariable Cox proportional hazards model adjusting for age, sex, serum iron, soluble transferrin receptor, ferritin, vitamin B12, congestive heart failure, diabetes mellitus, and cancer. Conclusions Circulating GDF-15 is an independent predictor for the development of anemia in older adults.

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Association of Brain Natriuretic Peptide With Mortality in Exceptionally Long-Lived Families

Innovation in Aging ◽

10.1093/geroni/igaa057.681 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 211-211

Author(s):

Allison Kuipers ◽

Robert Boudreau ◽

Mary Feitosa ◽

Angeline Galvin ◽

Bharat Thygarajan ◽

...

Keyword(s):

Older Adults ◽

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Sex Education ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Time To Event ◽

Healthy Older Adults ◽

Secondary Analyses

Abstract Natriuretic peptides are produced within the heart and released in response to increased chamber wall tension and heart failure (HF). N-Terminal prohormone Brain Natriuretic Peptide (NT-proBNP) is a specific natriuretic peptide commonly assayed in persons at risk for HF. In these individuals, NT-proBNP is associated with future disease prognosis and mortality. However, its association with mortality among healthy older adults remains unknown. Therefore, we determined the association of NT-proBNP with all-cause mortality over a median follow-up of 10 years in 3253 individuals free from HF at baseline in the Long Life Family Study, a study of families recruited for exceptional longevity. We performed cox proportional hazards analysis (coxme in R) for time-to event (mortality), adjusted for field center, familial relatedness, age, sex, education, smoking, alcohol, physical activity, BMI, diabetes, hypertension, and cancer. In addition, we performed secondary analyses among individuals (N=2457) within the normal NT-proBNP limits at baseline (<125pg/ml aged <75 years; <450pg/ml aged ≥75 years). Overall, individuals were aged 32-110 years (median 67 years; 44% male), had mean NT-proBNP of 318.5 pg/ml (median 91.0 pg/ml) and 1066 individuals (33%) died over the follow-up period. After adjustment, each 1 SD greater baseline NT-proBNP was associated with a 1.30-times increased hazard of mortality (95% CI: 1.24-1.36; P<0.0001). Results were similar in individuals with normal baseline NT-proBNP (HR: 1.21; 95% CI: 1.11-1.32; P<0.0001). These results suggest that NT-proBNP is a strong and specific biomarker for mortality in older adults independent of current health status, even in those with clinically-defined normal NT-proBNP.

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Cognitive decline and alcohol consumption adjusting for functional status over a 3-year period in French speaking community living older adults

Journal of Public Health ◽

10.1093/pubmed/fdy126 ◽

2018 ◽

Vol 41 (2) ◽

pp. e177-e184 ◽

Cited By ~ 1

Author(s):

Helen-Maria Vasiliadis ◽

Marie-Christine Payette ◽

Djamal Berbiche ◽

Sébastien Grenier ◽

Carol Hudon

Keyword(s):

Older Adults ◽

Alcohol Consumption ◽

Cognitive Decline ◽

Functional Status ◽

Repeated Measures ◽

Service Use ◽

High Functioning ◽

French Speaking ◽

Changing Patterns

AbstractBackgroundThe effect of alcohol consumption on cognitive decline is not clear. We aimed to study the association between alcohol consumption and cognitive functioning controlling for functional heath status.MethodsA total of 1610 older adults with a score ≥26 on the Mini-Mental State Examination (MMSE) were followed to assess the change in scores at the 3-year follow-up. Information on alcohol consumption as well as socio-demographic, lifestyle, psychosocial and clinical factors, as well as health service use were assessed at baseline and 3-year follow-up interviews. Linear mixed models with repeated measures were used stratifying by functional status.ResultsClose to 73% reported consuming alcohol in the past 6 months, of which 11% were heavy drinkers (≥11 and ≥16 drinks for women and men). A significant decrease in MMSE scores was observed in low functioning non-drinkers (−1.48; 95% CI: −2.06, −0.89) and light to moderate drinkers (−0.99; 95% CI: −1.54, −0.44) and high functioning non-drinkers (−0.51; 95% CI: −0.91, −0.10).ConclusionsAlcohol consumption did not contribute to cognitive decline. Cognitive decline was greater in individuals reporting low functional status. Research should focus on the interaction between changing patterns of alcohol consumption and social participation in individuals with low and high functioning status.

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