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      Amyloid duration is associated with preclinical cognitive decline and tau PET

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          Abstract

          Introduction

          This study applies a novel algorithm to longitudinal amyloid positron emission tomography (PET) imaging to identify age‐heterogeneous amyloid trajectory groups, estimate the age and duration (chronicity) of amyloid positivity, and investigate chronicity in relation to cognitive decline and tau burden.

          Methods

          Cognitively unimpaired participants ( n = 257) underwent one to four amyloid PET scans (Pittsburgh Compound B, PiB). Group‐based trajectory modeling was applied to participants with longitudinal scans ( n = 171) to identify and model amyloid trajectory groups, which were combined with Bayes theorem to estimate age and chronicity of amyloid positivity. Relationships between chronicity, cognition, clinical progression, and tau PET (MK‐6240) were investigated using regression models.

          Results

          Chronicity explained more heterogeneity in amyloid burden than age and binary amyloid status. Chronicity was associated with faster cognitive decline, increased risk of abnormal cognition, and higher entorhinal tau.

          Discussion

          Amyloid chronicity provides unique information about cognitive decline and neurofibrillary tangle development and may be useful to investigate preclinical Alzheimer's disease.

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          Frequent amyloid deposition without significant cognitive impairment among the elderly.

          Howard Aizenstein, Robert Nebes, Judith Saxton … (2008)
          To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests. Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs). University medical center. From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included. Regional PiB retention and cognitive test performance. Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.
          Article 0 comments Cited 291 times – based on 0 reviews     Review now
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            Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer's disease.

            Kerryn E Pike, Greg Savage, Victor Villemagne … (2007)
            Beta-amyloid (Abeta) deposition is pathognomic for Alzheimer's disease (AD), but may occur in normal elderly people without apparent cognitive effect. Episodic memory impairment is an early and prominent sign of AD, but its relationship with Abeta burden in non-demented persons and in AD patients is unclear. We examined this relationship using 11C-PIB-PET as a quantitative marker of Abeta burden in vivo in healthy ageing (HA), mild cognitive impairment (MCI) and AD. Thirty-one AD, 33 MCI and 32 HA participants completed neuropsychological assessment and a 11C-PIB-PET brain scan. Multiple linear regression analyses were conducted relating episodic memory performance and other cognitive functions to Abeta burden. Ninety-seven percent of AD, 61% of MCI and 22% of HA cases had increased cortical PIB binding, indicating the presence of Abeta plaques. There was a strong relationship between impaired episodic memory performance and PIB binding, both in MCI and HA. This relationship was weaker in AD and less robust for non-memory cognitive domains. Abeta deposition in the asymptomatic elderly is associated with episodic memory impairment. This finding, together with the strong relationship between PIB binding and the severity of memory impairment in MCI, suggests that individuals with increased cortical PIB binding are on the path to Alzheimer's disease. The data also suggests that early intervention trials for AD targeted to non-demented individuals with cerebral Abeta deposition are warranted.
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              Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects.

              E Mormino, J Kluth, C Madison … (2009)
              Although beta-amyloid (Abeta) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Abeta and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Abeta deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Abeta deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Abeta-induced hippocampus atrophy.
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                Author and article information

                Contributors
                Sterling C. Johnson: scj@medicine.wisc.edu
                Journal
                Journal ID (nlm-ta): Alzheimers Dement (Amst)
                Journal ID (iso-abbrev): Alzheimers Dement (Amst)
                Journal ID (doi): 10.1002/(ISSN)2352-8729
                Journal ID (publisher-id): DAD2
                Title: Alzheimer's & Dementia : Diagnosis, Assessment & Disease Monitoring
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2352-8729
                Publication date (Electronic): 13 February 2020
                Publication date Collection: 2020
                Volume: 12
                Issue: 1 ( doiID: 10.1002/dad2.v12.1 )
                Electronic Location Identifier: e12007
                Affiliations
                [ 1 ] Wisconsin Alzheimer's Institute University of Wisconsin School of Medicine and Public Health Madison Wisconsin
                [ 2 ] Department of Medicine University of Wisconsin School of Medicine and Public Health Madison Wisconsin
                [ 3 ] Wisconsin Alzheimer's Disease Research Center University of Wisconsin School of Medicine and Public Health Madison Wisconsin
                [ 4 ] Geriatric Research Education and Clinical Center William S. Middleton Memorial Veterans Hospital Madison Wisconsin
                [ 5 ] Department of Neurology University of Wisconsin School of Medicine and Public Health Madison Wisconsin
                [ 6 ] Department of Medical Physics University of Wisconsin‐Madison Madison Wisconsin
                [ 7 ] Waisman Laboratory for Brain Imaging and Behavior University of Wisconsin‐Madison Madison Wisconsin
                Author notes
                [*] [* ] Correspondence

                Sterling C. Johnson, Wisconsin Alzheimer's Disease Research Center, University of Wisconsin‐Madison, School of Medicine and Public Health, 600 Highland Avenue, K6/438, Clinical Sciences Center, Madison, WI 53792, USA.

                Email: scj@ 123456medicine.wisc.edu

                [†]

                Rebecca L. Koscik and Tobey J. Betthauser contributed equally to this study.

                Article
                Publisher ID: DAD212007
                DOI: 10.1002/dad2.12007
                PMC ID: 7085284
                PubMed ID: 32211502
                SO-VID: 7b12de3a-5d3a-4758-bc5d-ed810976b1b2
                Copyright © © 2020 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, Inc. on behalf of the Alzheimer's Association.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 19 September 2019
                Date revision received : 20 November 2019
                Page count
                Figures: 4, Tables: 2, Pages: 10, Words: 6419
                Funding
                Funded by: National Institutes of Health , open-funder-registry 10.13039/100000002;
                Award ID: R01 AG021155 y6‐y13
                Award ID: R01 AG027161 y1‐y11
                Award ID: P50 AG033514 y1‐y11
                Award ID: U54 HD090256 y1‐y4
                Funded by: Alzheimer's Association , open-funder-registry 10.13039/100000957;
                Award ID: AARF‐19‐614533
                Award ID: 2019
                Funded by: Wisconsin Alzheimer's Institute Lou Holland Fund
                Categories
                Subject: Neuroimaging
                Subject: Neuroimaging
                Custom metadata
                source-schema-version-number 2.0
                cover-date 2020
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.8 mode:remove_FC converted:17.03.2020

                Keywords: alzheimer's disease,alzheimer's,beta‐amyloid,biomarker,chronicity,group‐based trajectory modeling,positron emission tomography,tau,trajectory modeling
                Data availability:
                Keywords: alzheimer's disease, alzheimer's, beta‐amyloid, biomarker, chronicity, group‐based trajectory modeling, positron emission tomography, tau, trajectory modeling

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