scholarly journals Memory decline accompanies subthreshold amyloid accumulation

Neurology ◽  
2018 ◽  
Vol 90 (17) ◽  
pp. e1452-e1460 ◽  
Author(s):  
Susan M. Landau ◽  
Andy Horng ◽  
William J. Jagust ◽  
Keyword(s):  
Executive Function ◽  
Sex Education ◽  
Memory Performance ◽  
Standardized Uptake Value ◽  
Hippocampal Volume ◽  
Older Individuals ◽  
Memory Decline ◽  
Domain Specific ◽  
Amyloid Accumulation ◽  
Amyloid Aβ

ObjectiveExtensive cortical β-amyloid (Aβ positivity) has been linked to cognitive decline, but the clinical significance of elevations in Aβ within the negative range is unknown.MethodsWe examined amyloid and cognitive trajectories (memory, executive function) in 142 cognitively normal older individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative who were Aβ-negative at baseline and who had at least 2 [18F]-florbetapir PET scans over 3.9 ± 1.4 years. We determined whether Aβ accumulation was associated with longitudinal changes in memory or executive function.ResultsAmong baseline-negative individuals, florbetapir slope (mean annual increase 0.002 ± 0.008 standardized uptake value ratio units/y) was not related to age, sex, education, APOE4 status, baseline memory or executive function, temporoparietal glucose metabolism, baseline hippocampal volume, or hippocampal volume change; but it was related to higher baseline cortical florbetapir, indicating that Aβ accumulation was ongoing at baseline in those who accumulated during the study. Over the course of follow-up, 13 individuals converted to florbetapir+ and 14 nearly nonoverlapping individuals converted to mild cognitive impairment or Alzheimer disease. Amyloid accumulation among baseline-negative individuals was associated with poorer longitudinal memory performance (p = 0.019), but it was not associated with changes in executive function. Reducing the sample to individuals with at least 3 timepoints to estimate the florbetapir slope strengthened the relationship further between florbetapir accumulation and memory decline (p = 0.007).ConclusionsMemory decline accompanies Aβ accumulation in otherwise healthy, Aβ-negative older adults. Amyloid increases within the negative range may represent the earliest detectable indication of pathology with domain-specific cognitive consequences.

scholarly journals APOE genotype and early β-amyloid accumulation in older adults without dementia

Neurology ◽  
2017 ◽  
Vol 89 (10) ◽  
pp. 1028-1034 ◽  
Author(s):  
Yen Ying Lim ◽  
Elizabeth C. Mormino ◽  
Keyword(s):  
Older Adults ◽  
Apoe Genotype ◽  
Standardized Uptake Value ◽  
Older Age ◽  
Older Individuals ◽  
Participant Selection ◽  
Amyloid Accumulation ◽  
Ε4 Allele ◽  
Amyloid Aβ ◽  
Β Amyloid

Objective:To clarify associations between APOE ε4 allele and age on longitudinal rates of β-amyloid (Aβ) accumulation within Aβ+ and Aβ− older individuals without dementia.Methods:We analyzed 595 older adults without dementia classified cross-sectionally as Aβ− (n = 325) and Aβ+ (n = 270) using longitudinal florbetapir PET. The influence of age and APOE genotype on longitudinal accumulation of Aβ was examined with linear mixed models.Results:APOE ε4 and older age were associated with higher risk of being classified as Aβ+ at baseline. The annual rate of Aβ accumulation was significantly greater than zero for Aβ− ε3 (0.0021 ± 0.0007 standardized uptake value ratio [SUVR] units) and Aβ− ε4 (0.0044 ± 0.0010 SUVR units), as well as Aβ+ ε3 (0.0141 ± 0.0019 SUVR units) and Aβ+ ε4 (0.0126 ± 0.0018 SUVR units). Aβ accumulation was significantly faster in Aβ− ε4 compared to Aβ− ε3 and Aβ− ε2. Rates of Aβ accumulation did not differ significantly between Aβ+ APOE groups. Older age was associated with higher rates of Aβ accumulation in the Aβ− group.Conclusions:APOE ε4 carriage and older age were predictors of longitudinal Aβ accumulation within the Aβ− group but not the Aβ+ group. APOE ε2 carriage was protective against longitudinal Aβ accumulation within the Aβ− group. APOE genotype in conjunction with chronologic age may aid in participant selection for primary prevention trials aimed at halting Aβ accumulation before abnormal levels are reached.

Hippocampal volume is more related to patient-reported memory than objective memory performance in early multiple sclerosis

2020 ◽  
pp. 135245852092283
Author(s):  
Lisa Glukhovsky ◽  
Rachel Brandstadter ◽  
Victoria M Leavitt ◽  
Stephen Krieger ◽  
Korhan Buyukturkoglu ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Memory Performance ◽  
Hippocampal Volume ◽  
Magnetic Resonance Images ◽  
Longitudinal Assessment ◽  
Subjective Memory ◽  
Cross Sectional ◽  
Memory Decline ◽  
Patient Reported ◽  
Partial Correlations

Background: When persons with multiple sclerosis (MS) report memory decline but objective memory performance is normal, there is a bias toward believing objective test results. Objective: Investigate whether subjective memory decline or objective memory performance is more related to hippocampal and hippocampal subfield volumes in early MS. Methods: Persons with early MS ( n = 185; ⩽5.0 years diagnosed) completed a subjective memory questionnaire; an objective memory composite was derived from four memory tests. Total hippocampal and subfield volumes were derived from high-resolution 3.0 T magnetic resonance images (MRIs). Partial correlations assessed links between hippocampal volumes and both subjective and objective memory, controlling for age, sex, mood, and pre-morbid intelligence quotient (IQ). Results: Lower total hippocampal and CA1 volumes were related to worse subjective memory but not objective memory (controlling for multiple comparisons). Correlations between subjective memory and both CA1 and subiculum were significantly stronger than were correlations between objective memory and these subfields. Patients in the worst tertile of subjective memory complaints (but not objective memory) had lower hippocampal volumes than 35 demographically similar healthy controls. Conclusion: Patient-report is inherently a longitudinal assessment of within-person memory change in everyday life, which may be more sensitive to subtle disease-related changes than cross-sectional objective tests. Findings align with the aging literature.

scholarly journals The presubiculum links incipient amyloid and tau pathology to memory function in older persons

Neurology ◽  
2020 ◽  
Vol 94 (18) ◽  
pp. e1916-e1928
Author(s):  
Heidi I.L. Jacobs ◽  
Jean C. Augustinack ◽  
Aaron P. Schultz ◽  
Bernard J. Hanseeuw ◽  
Joseph Locascio ◽  
...  
Keyword(s):  
Memory Performance ◽  
Memory Function ◽  
Hippocampal Volume ◽  
Cognitive Testing ◽  
Pet Scan ◽  
Aging Brain ◽  
Amyloid Pet ◽  
Older Individuals ◽  
Amyloid Burden ◽  
Tau Pathology

ObjectiveTo identify the hippocampal subregions linking initial amyloid and tau pathology to memory performance in clinically normal older individuals, reflecting preclinical Alzheimer disease (AD).MethodsA total of 127 individuals from the Harvard Aging Brain Study (mean age 76.22 ± 6.42 years, 68 women [53.5%]) with a Clinical Dementia Rating score of 0, a flortaucipir tau-PET scan, a Pittsburgh compound B amyloid-PET scan, a structural MRI scan, and cognitive testing were included. From these images, we calculated neocortical, hippocampal, and entorhinal amyloid pathology; entorhinal and hippocampal tau pathology; and the volumes of 6 hippocampal subregions and total hippocampal volume. Memory was assessed with the selective reminding test. Mediation and moderation analyses modeled associations between regional markers and memory. Analyses included covariates for age, sex, and education.ResultsNeocortical amyloid, entorhinal tau, and presubiculum volume univariately associated with memory performance. The relationship between neocortical amyloid and memory was mediated by entorhinal tau and presubiculum volume, which was modified by hippocampal amyloid burden. With other biomarkers held constant, presubiculum volume was the only marker predicting memory performance in the total sample and in individuals with elevated hippocampal amyloid burden.ConclusionsThe presubiculum captures unique AD-related biological variation that is not reflected in total hippocampal volume. Presubiculum volume may be a promising marker of imminent memory problems and can contribute to understanding the interaction between incipient AD-related pathologies and memory performance. The modulation by hippocampal amyloid suggests that amyloid is a necessary, but not sufficient, process to drive neurodegeneration in memory-related regions.

scholarly journals 1H-MRS metabolites and rate of β-amyloid accumulation on serial PET in clinically normal adults

Neurology ◽  
2017 ◽  
Vol 89 (13) ◽  
pp. 1391-1399 ◽  
Author(s):  
Zuzana Nedelska ◽  
Scott A. Przybelski ◽  
Timothy G. Lesnick ◽  
Christopher G. Schwarz ◽  
Val J. Lowe ◽  
...  
Keyword(s):  
Older Adults ◽  
Standardized Uptake Value ◽  
Resonance Spectroscopy ◽  
1H Mrs ◽  
Mixed Effect ◽  
Clinically Normal ◽  
Mixed Effect Models ◽  
Amyloid Accumulation ◽  
Amyloid Aβ ◽  
Β Amyloid

Objective:To assess whether noninvasive proton magnetic resonance spectroscopy (1H-MRS) tissue metabolite measurements at baseline can predict an increase in the rate of β-amyloid (Aβ) accumulation on serial PET in clinically normal (CN) older adults.Methods:Consecutive participants aged 60 years and older (n = 594) from the Mayo Clinic Study of Aging who were CN at baseline and who underwent 1H-MRS from the posterior cingulate voxel and longitudinal 11C-Pittsburgh compound B (PiB)–PET were included. The rate of Aβ accumulation by serial cortical PiB standardized uptake value ratios was estimated as a function of baseline 1H-MRS metabolite ratios and time using mixed-effect models adjusted for age, sex, and APOE ε4. Effect of APOE ε4 on the relationship between baseline MRS and an increased rate of Aβ accumulation was also assessed.Results:Among all participants, a higher myo-inositol (mI)/creatine (p = 0.011) and a lower N-acetylaspartate/mI (p = 0.006) at baseline were associated with an increased Aβ accumulation over time after adjusting for age, sex, and APOE ε4. APOE ε4 did not modify the association of baseline 1H-MRS metabolite ratios and rate of Aβ accumulation. However, APOE ε4 carriers accumulated Aβ faster than noncarriers regardless of the baseline Aβ load (p = 0.001).Conclusion:Among CN older adults, early metabolic alterations on 1H-MRS and APOE ε4 status are independently associated with an increased rate of Aβ accumulation. Our findings could have important implications for early diagnosis and identification of individuals for secondary prevention trials, because an increased rate of Aβ accumulation in CN older adults may confer a higher risk for cognitive decline and mild cognitive impairment.

scholarly journals Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Stephanie L Leal ◽  
Susan M Landau ◽  
Rachel K Bell ◽  
William J Jagust
Keyword(s):  
Cognitive Decline ◽  
Memory Performance ◽  
Memory Task ◽  
Synaptic Activity ◽  
Longitudinal Change ◽  
Neural Function ◽  
Amyloid Accumulation ◽  
Hippocampal Activity ◽  
Proposed Model ◽  
Amyloid Aβ

The amyloid hypothesis suggests that beta-amyloid (Aβ) deposition leads to alterations in neural function and ultimately to cognitive decline in Alzheimer’s disease. However, factors that underlie Aβ deposition are incompletely understood. One proposed model suggests that synaptic activity leads to increased Aβ deposition. More specifically, hyperactivity in the hippocampus may be detrimental and could be one factor that drives Aβ deposition. To test this model, we examined the relationship between hippocampal activity during a memory task using fMRI and subsequent longitudinal change in Aβ using PIB-PET imaging in cognitively normal older adults. We found that greater hippocampal activation at baseline was associated with increased Aβ accumulation. Furthermore, increasing Aβ accumulation mediated the influence of hippocampal activation on declining memory performance, demonstrating a crucial role of Aβ in linking hippocampal activation and memory. These findings support a model linking increased hippocampal activation to subsequent Aβ deposition and cognitive decline.

scholarly journals The effects of bilingualism on hippocampal volume in ageing bilinguals

2022 ◽  
Author(s):  
Toms Voits ◽  
Holly Robson ◽  
Jason Rothman ◽  
Christos Pliatsikas
Keyword(s):  
Second Language ◽  
Language Learning ◽  
Memory Performance ◽  
Hippocampal Volume ◽  
Older Age ◽  
Protective Effects ◽  
Older Individuals ◽  
Neuroprotective Effects ◽  
Wide Range

AbstractLong-term management of more than one language has been argued to contribute to changes in brain and cognition. This has been particularly well documented in older age, where bilingualism has been linked to protective effects against neurocognitive decline. Since memory difficulties are key aspects of this decline, herein we examine potential effects of bilingualism on the hippocampus, a brain structure related to memory that is particularly vulnerable to cognitive ageing. Hippocampal volume has been shown to increase as a result of second language learning and use in younger adults. However, it is unknown if this is maintained throughout the lifespan. We examine hippocampal volume and episodic memory performance in a participant sample consisting of healthy older individuals with a wide range of experiences in exposure and using a second language. Results reveal greater hippocampal volume calibrated to degree of quantified dual language use. Our results mirror those of immersive active bilingualism in younger populations, suggesting that long-term active bilingualism leads to neuroprotective effects in the hippocampus. We discuss this in the context of literature proposing bilingualism-induced brain reserve in the older age.

scholarly journals Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults

Neurology ◽  
2018 ◽  
Vol 91 (19) ◽  
pp. e1809-e1821 ◽  
Author(s):  
Michelle E. Farrell ◽  
Xi Chen ◽  
Melissa M. Rundle ◽  
Micaela Y. Chan ◽  
Gagan S. Wig ◽  
...  
Keyword(s):  
Episodic Memory ◽  
Sex Education ◽  
Linear Models ◽  
Standardized Uptake Value ◽  
Future Research ◽  
Sequence Of Events ◽  
Amyloid Accumulation ◽  
Cortical Regions ◽  
Disease Signature ◽  
Middle Aged Adults

ObjectiveTo assess whether global or regional changes in amyloid burden over 4 years predict early declines in episodic memory in initially amyloid-negative adults.MethodsOne hundred twenty-six initially amyloid-negative, cognitively normal participants (age 30–89 years) were included from the Dallas Lifespan Brain Study who completed florbetapir PET and a cognitive battery at baseline and 4-year follow-up. Standardized uptake value ratio (SUVR) change was computed across 8 bilateral regions of interest. Using general linear models, we examined the relationship between change in global and regional SUVR and change in episodic memory, controlling for baseline SUVR, baseline memory, age, sex, education, and APOE status.ResultsIn initially amyloid-negative adults, we detected a regionally specific relationship between declining episodic memory and increasing amyloid accumulation across multiple posterior cortical regions. In addition, these amyloid-related changes in memory persisted when we focused on middle-aged adults only and after controlling for atrophy in global cortical, hippocampal, and Alzheimer disease signature cortical volume.ConclusionOur results indicate that assessing regional changes in amyloid, particularly in posterior cortical regions, can aid in the early detection of subclinical amyloid-related decline in episodic memory as early as middle age. Future research incorporating tau and other markers of neurodegeneration is needed to clarify the sequence of events that lead to this early, subclinical memory decline.

Improved Prediction of Imminent Progression to Clinically Significant Memory Decline Using Surface Multivariate Morphometry Statistics and Sparse Coding

2021 ◽  
pp. 1-12
Author(s):  
Cynthia M. Stonnington ◽  
Jianfeng Wu ◽  
Jie Zhang ◽  
Jie Shi ◽  
Robert J. Bauer III ◽  
...  
Keyword(s):  
Sex Education ◽  
Sparse Coding ◽  
Prediction Accuracy ◽  
Binary Logistic Regression ◽  
Hippocampal Volume ◽  
Memory Decline ◽  
Subject Selection ◽  
Clinically Significant ◽  
E4 Allele ◽  
Leave One Out

Background: Besides their other roles, brain imaging and other biomarkers of Alzheimer’s disease (AD) have the potential to inform a cognitively unimpaired (CU) person’s likelihood of progression to mild cognitive impairment (MCI) and benefit subject selection when evaluating promising prevention therapies. We previously described that among baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD, hippocampal volume was the best predictor of incident MCI within 2 years (79%sensitivity/78%specificity), using standard automated MRI volumetric algorithmic programs, binary logistic regression, and leave-one-out procedures. Objective: To improve the same prediction by using different hippocampal features and machine learning methods, cross-validated via two independent and prospective cohorts (Arizona and ADNI). Methods: Patch-based sparse coding algorithms were applied to hippocampal surface features of baseline TI-MRIs from 78 CU adults who subsequently progressed to amnestic MCI in approximately 2 years (“progressors”) and 80 matched adults who remained CU for at least 4 years (“nonprogressors”). Nonprogressors and progressors were matched for age, sex, education, and apolipoprotein E4 allele dose. We did not include amyloid or tau biomarkers in defining MCI. Results: We achieved 92%prediction accuracy in the Arizona cohort, 92%prediction accuracy in the ADNI cohort, and 90%prediction accuracy when combining the two demographically distinct cohorts, as compared to 79%(Arizona) and 72%(ADNI) prediction accuracy using hippocampal volume. Conclusion: Surface multivariate morphometry and sparse coding, applied to individual MRIs, may accurately predict imminent progression to MCI even in the absence of other AD biomarkers.

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