Dataset Information

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.

ABSTRACT: Importance:Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective:To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants:This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures:Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype. Results:Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P < .001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P < .001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years. Conclusions and Relevance:Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.

SUBMITTER: Jansen WJ

PROVIDER: S-EPMC5786156 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.

Jansen Willemijn J WJ Ossenkoppele Rik R Tijms Betty M BM Fagan Anne M AM Hansson Oskar O Klunk William E WE van der Flier Wiesje M WM Villemagne Victor L VL Frisoni Giovanni B GB Fleisher Adam S AS Lleó Alberto A Mintun Mark A MA Wallin Anders A Engelborghs Sebastiaan S Na Duk L DL Chételat Gäel G Molinuevo José Luis JL Landau Susan M SM Mattsson Niklas N Kornhuber Johannes J Sabri Osama O Rowe Christopher C CC Parnetti Lucilla L Popp Julius J Fladby Tormod T Jagust William J WJ Aalten Pauline P Lee Dong Young DY Vandenberghe Rik R Resende de Oliveira Catarina C Kapaki Elisabeth E Froelich Lutz L Ivanoiu Adrian A Gabryelewicz Tomasz T Verbeek Marcel M MM Sanchez-Juan Páscual P Hildebrandt Helmut H Camus Vincent V Zboch Marzena M Brooks David J DJ Drzezga Alexander A Rinne Juha O JO Newberg Andrew A de Mendonça Alexandre A Sarazin Marie M Rabinovici Gil D GD Madsen Karine K Kramberger Milica G MG Nordberg Agneta A Mok Vincent V Mroczko Barbara B Wolk David A DA Meyer Philipp T PT Tsolaki Magda M Scheltens Philip P Verhey Frans R J FRJ Visser Pieter Jelle PJ Aarsland Dag D Alcolea Daniel D Alexander Myriam M Almdahl Ina S IS Arnold Steven E SE Baldeiras Inês I Barthel Henryk H van Berckel Bart N M BNM Blennow Kaj K van Buchem Mark A MA Cavedo Enrica E Chen Kewei K Chipi Elena E Cohen Ann D AD Förster Stefan S Fortea Juan J Frederiksen Kristian S KS Freund-Levi Yvonne Y Gkatzima Olymbia O Gordon Mark Forrest MF Grimmer Timo T Hampel Harald H Hausner Lucrezia L Hellwig Sabine S Herukka Sanna-Kaisa SK Johannsen Peter P Klimkowicz-Mrowiec Aleksandra A Köhler Sebastian S Koglin Norman N van Laere Koen K de Leon Mony M Lisetti Viviana V Maier Wolfgang W Marcusson Jan J Meulenbroek Olga O Møllergård Hanne M HM Morris John C JC Nordlund Arto A Novak Gerald P GP Paraskevas George P GP Perera Gayan G Peters Oliver O Ramakers Inez H G B IHGB Rami Lorena L Rodríguez-Rodríguez Eloy E Roe Catherine M CM Rot Uros U Rüther Eckart E Santana Isabel I Schröder Johannes J Seo Sang W SW Soininen Hilkka H Spiru Luiza L Stomrud Erik E Struyfs Hanne H Teunissen Charlotte E CE Vos Stephanie J B SJB van Waalwijk van Doorn Linda J C LJC Waldemar Gunhild G Wallin Åsa K ÅK Wiltfang Jens J Zetterberg Henrik H

JAMA psychiatry 20180101 1

<h4>Importance</h4>Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.<h4>Objective</h4>To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.<h4>Design, setting, and participants</h4>This cross-sectio ...[more]

PMID: 29188296

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Project description:Importance:Aging is associated with excessive daytime sleepiness (EDS), which has been linked to cognitive decline in the elderly. However, whether EDS is associated with the pathologic processes of Alzheimer disease remains unclear. Objective:To investigate whether EDS at baseline is associated with a longitudinal increase in regional β-amyloid (Aβ) accumulation in a cohort of elderly individuals without dementia. Design, Setting, and Participants:This prospective analysis included participants enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study in Olmsted County, Minnesota. Of 2900 participants, 2172 (74.9%) agreed to undergo carbon 11-labeled Pittsburgh compound B positron emission tomography (PiB-PET). We included 283 participants 70 years or older without dementia who completed surveys assessing sleepiness at baseline and had at least 2 consecutive PiB-PET scans from January 1, 2009, through July 31, 2016, after excluding 45 (13.7%) who had a comorbid neurologic disorder. Main Outcomes and Measures:Excessive daytime sleepiness was defined as an Epworth Sleepiness Scale score of at least 10. The difference in Aβ levels between the 2 consecutive scans (ΔPiB) in Aβ-susceptible regions (prefrontal, anterior cingulate, posterior cingulate-precuneus, and parietal) was determined. Multiple linear regression models were fit to explore associations between baseline EDS and ΔPiB while adjusting for baseline age, sex, presence of the apolipoprotein E ε4 allele, educational level, baseline PiB uptake, global PiB positivity (standardized uptake value ratio ≥1.4), physical activity, cardiovascular comorbidities (obesity, hypertension, hyperlipidemia, and diabetes), reduced sleep duration, respiratory symptoms during sleep, depression, and interval between scans. Results:Of the initial 283 participants, mean (SD) age was 77.1 (4.8) years; 204 (72.1%) were men and 79 (27.9%) were women. Sixty-three participants (22.3%) had EDS. Baseline EDS was significantly associated with increased regional Aβ accumulation in the anterior cingulate (B coefficient = 0.031; 95% CI, 0.001-0.061; P = .04), posterior cingulate-precuneus (B coefficient = 0.038; 95% CI, 0.006-0.069; P = .02), and parietal (B coefficient = 0.033; 95% CI, 0.001-0.065; P = .04) regions. Association of EDS with longitudinal Aβ accumulation was stronger in participants with baseline global PiB positivity in the anterior cingulate (B coefficient = 0.065; 95% CI, 0.010-0.118; P = .02) and cingulate-precuneus (B coefficient = 0.068; 95% CI, 0.009-0.126; P = .02) regions. Conclusions and Relevance:Baseline EDS was associated with increased longitudinal Aβ accumulation in elderly persons without dementia, suggesting that those with EDS may be more vulnerable to pathologic changes associated with Alzheimer disease. Further work is needed to elucidate whether EDS is a clinical marker of greater sleep instability, synaptic or network overload, or neurodegeneration of wakefulness-promoting centers. Early identification of patients with EDS and treatment of underlying sleep disorders could reduce Aβ accumulation in this vulnerable group.

Project description:ImportanceCerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.ObjectiveTo use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).Data sourcesRelevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.Study selectionStudies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.Data extraction and synthesisIndividual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.Main outcomes and measuresPrevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.ResultsThe prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.Conclusions and relevanceAmong persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Project description:ImportanceTau accumulation in Alzheimer disease (AD) is closely associated with cognitive impairment. Quantitating tau accumulation by positron emission tomography (PET) will be a useful outcome measure for future clinical trials in the AD spectrum.ObjectiveTo investigate the association of β-amyloid (Aβ) on PET with subsequent tau accumulation on PET in persons who were cognitively unimpaired (CU) to gain insight into temporal associations between Aβ and tau accumulation and inform clinical trial design.Design, setting, and participantsThis cohort study included individuals aged 65 to 85 years who were CU and had participated in the Mayo Clinic Study of Aging, with serial cognitive assessments, serial magnetic resonance imaging, 11C-Pittsburgh compound B (Aβ) PET scans, and 18F-flortaucipir PET scans, collected from May 2015 to March 2020. Persons were excluded if they lacked follow-up PET scans. A similarly evaluated CU group from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were also studied. These data were collected from September 2015 to March 2020.ExposuresParticipants were stratified by index Aβ levels on PET into low Aβ (≤8 centiloid [CL]), subthreshold Aβ (9-21 CL), suprathreshold Aβ (22-67 CL), and high Aβ (≥68 CL).Main outcomes and measuresChanges over a mean of 2.7 (range, 1.1-4.1) years in flortaucipir PET in entorhinal, inferior temporal, and lateral parietal regions of interest and an AD meta-region of interest (ROI).ResultsA total of 167 people were included (mean age, 74 [range, 65-85] years; 75 women [44.9%]); 101 individuals were excluded lacking follow-up, and 114 individuals from the ADNI were also studied (mean [SD] age, 74.14 [5.29] years; 64 women [56.1%]). In the Mayo Clinic Study of Aging, longitudinal flortaucipir accumulation rates in the high Aβ group were greater than the suprathreshold, subthreshold, and low Aβ groups in the entorhinal ROI (suprathreshold, 0.025 [95% CI, 0.013-0.037] standardized uptake value ratio [SUVR] units; subthreshold, 0.026 [95% CI, 0.014-0.037] SUVR units; low Aβ, 0.034 [95% CI, 0.02-0.049] SUVR units), inferior temporal ROI (suprathreshold, 0.025 [95% CI, 0.014-0.035] SUVR units; subthreshold, 0.027 [95% CI, 0.017-0.037] SUVR units; low Aβ, 0.035 [95% CI, 0.022-0.047] SUVR units), and the AD meta-ROI (suprathreshold, 0.023 [95% CI, 0.013-0.032] SUVR units; subthreshold, 0.025 [95% CI, 0.016-0.034] SUVR units; low Aβ, 0.032 [95% CI, 0.021-0.043] SUVR units) (all P < .001). Flortaucipir accumulation rates in the subthreshold and suprathreshold Aβ groups in temporal regions were nonsignificantly elevated compared with the low Aβ group. In the ADNI cohort, the variance was larger than in the Mayo Clinic Study of Aging but point estimates for annualized flortaucipir accumulation in the inferior temporal ROI were very similar. An estimated 216 participants who were CU per group with PET Aβ of 68 CL or more would be needed to detect a 25% annualized reduction in flortaucipir accumulation rate in the AD meta-ROI with 80% power.Conclusions and relevanceSubstantial flortaucipir accumulation in temporal regions is greatest in persons aged 65 to 85 years who were CU and had high initial Aβ PET levels, compared with those with lower Aβ levels. Recruiting persons who were CU and exhibiting Aβ of 68 CL or more on an index Aβ PET is a feasible strategy to recruit for clinical trials in which a change in tau PET signal is an outcome measure.

Project description:BackgroundPrevious publications indicate that Alzheimer's Disease (AD) related cortical atrophy may develop in asymmetric patterns, with accentuation of the left hemisphere. Since fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the regional cerebral metabolic rate of glucose (rCMRgl) provide a sensitive and specific marker of neurodegenerative disease progression, we sought to investigate the longitudinal pattern of rCMRgl in amyloid-positive persons with mild cognitive impairment (MCI) and dementia, hypothesizing asymmetric declines of cerebral glucose metabolism.MethodsUsing florbetapir PET and cerebrospinal fluid (CSF) measures to define amyloid-β (Aβ) positivity, 40 Aβ negative (Aβ-) cognitively unimpaired controls (CU; 76 ± 5y), 76 Aβ positive (Aβ+) persons with MCI (76 ± 7y) and 51 Aβ + persons with probable AD dementia (75 ± 7y) from the AD Neuroimaging Initiative (ADNI) were included in this study with baseline and 2-year follow-up FDG PET scans. The degree of lateralization of longitudinal rCMRgl declines in subjects with Aβ + MCI and AD in comparison with Aβ- CU were statistically quantified via bootstrapped lateralization indices [(LI); range - 1 (right) to 1 (left)].ResultsCompared to Aβ- CU, Aβ + MCI patients showed marked left hemispheric lateralization (LI: 0.78). In contrast, modest right hemispheric lateralization (LI: -0.33) of rCMRgl declines was found in Aβ + persons with probable AD dementia. Additional comparisons of Aβ + groups (i.e. MCI and probable AD dementia) consequently indicated right hemispheric lateralization (LI: -0.79) of stronger rCMRgl declines in dementia stages of AD. For all comparisons, voxel-based analyses confirmed significant (pFWE<0.05) declines of rCMRgl within AD-typical brain regions. Analyses of cognitive data yielded predominant decline of memory functions in both MCI and dementia stages of AD.ConclusionsThese data indicate that in early stages, AD may be characterized by a more lateralized pattern of left hemispheric rCMRgl declines. However, metabolic differences between hemispheres appear to diminish with further progression of the disease.

Project description:IntroductionWe comprehensively evaluated how self- and informant-reported neuropsychiatric symptoms (NPS) were differentially associated with cerebral amyloid-beta (Aβ) PET levels in older adults without dementia.MethodsTwo hundred and twenty-one participants (48% female, age = 73.4 years ± 8.4, Clinical Dementia Rating = 0 [n = 184] or 0.5 [n = 37]) underwent an Aβ-PET scan (florbetapir or PIB), comprehensive neuropsychological testing, and self-reported (Geriatric Depression Scale - 30 item [GDS-30]) and informant-reported interview (Neuropsychiatric Inventory Questionnaire [NPI-Q]) of NPS. Cerebral Aβ burden was quantified using centiloids (CL). NPI-Q and GDS-30 queried the presence of NPS within 4 subdomains and 6 subscales, respectively. Regression models examined the relationship between NPS and Aβ-PET CL.ResultsBoth higher self- and informant-reported NPS were associated with higher Aβ burden. Among specific NPI-Q subdomains, informant-reported changes in depression, anxiety, and irritability were all associated with higher Aβ-PET. Similarly, self-reported (GDS-30) subscales of depression, apathy, anxiety, and cognitive concern were associated with higher Aβ-PET. When simultaneously entered, only self-reported cognitive concern was associated with Aβ-PET in the GDS-30 model, while both informant-reported anxiety and depression were associated with Aβ-PET in the NPI-Q model. Clinical status moderated the association between self-reported NPS and Aβ-PET such that the positive relationship between self-perceived NPS and Aβ burden strengthened with increasing functional difficulties.ConclusionsIn a cohort of older adults without dementia, both self- and informant-reported measures of global NPS, particularly patient-reported cognitive concerns and informant-reported anxiety and depression, corresponded with cerebral Aβ burden. NPS may appear early in the prodromal disease state and relate to initial AD proteinopathy burden, a relationship further exaggerated in those with greater clinical severity.

Dataset Information

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.

Publications

Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.

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