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Stamate, D., Kim, M., Proitsi, P., Weestwood, S., Baird, A., Nevado-Holgado, A., . . . Legido-Quigley, C. (2019). A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood: Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort. Alzheimer's & Dementia: Translational Research & Clinical Interventions, 5(C), 933-938
Open this publication in new window or tab >>A metabolite-based machine learning approach to diagnose Alzheimer-type dementia in blood: Results from the European Medical Information Framework for Alzheimer disease biomarker discovery cohort
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2019 (English)In: Alzheimer's & Dementia: Translational Research & Clinical Interventions, ISSN 2352-8737, Vol. 5, no C, p. 933-938Article in journal (Refereed) Published
Abstract [en]

Introduction

Machine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when compared to CSF biomarkers.

Methods

This study analyzed samples from 242 cognitively normal (CN) people and 115 with AD‐type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).

Results

On the test data, DL produced the AUC of 0.85 (0.80–0.89), XGBoost produced 0.88 (0.86–0.89) and RF produced 0.85 (0.83–0.87). By comparison, CSF measures of amyloid, p‐tau and t‐tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.

Discussion

This study showed that plasma metabolites have the potential to match the AUC of well‐established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
EMIF‐AD, Alzheimer's disease, Metabolomics, Biomarkers, Machine‐Learning
National Category
Medical and Health Sciences Geriatrics Neurosciences
Identifiers
urn:nbn:se:oru:diva-79714 (URN)10.1016/j.trci.2019.11.001 (DOI)31890857 (PubMedID)2-s2.0-85076456435 (Scopus ID)
Note

Funding: The present study was conducted as part of the EMIF‐AD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007–2013) and EFPIA companies' in‐kind contribution. The DESCRIPA study was funded by the European Commission within the fifth framework program (QLRT‐2001‐2455). The EDAR study was funded by the European Commission within the fifth framework program (contract no. 37670). The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01. 41142.001.H). Kristel Sleegers is supported by the Research Fund of the University of Antwerp. Daniel Stamate is supported by the Alzheimer's Research UK (ARUK‐PRRF2017‐012).

Available from: 2020-02-03 Created: 2020-02-03 Last updated: 2020-02-05Bibliographically approved
van Maurik, I. S., Vos, S. J., Bos, I., Bouwman, F. H., Teunissen, C. E., Scheltens, P., . . . van der Flier, W. M. (2019). Biomarker-based prognosis for people with mild cognitive impairment (ABIDE): a modelling study. Lancet Neurology, 18(11), 1034-1044
Open this publication in new window or tab >>Biomarker-based prognosis for people with mild cognitive impairment (ABIDE): a modelling study
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2019 (English)In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 18, no 11, p. 1034-1044Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Biomarker-based risk predictions of dementia in people with mild cognitive impairment are highly relevant for care planning and to select patients for treatment when disease-modifying drugs become available. We aimed to establish robust prediction models of disease progression in people at risk of dementia.

METHODS: In this modelling study, we included people with mild cognitive impairment (MCI) from single-centre and multicentre cohorts in Europe and North America: the European Medical Information Framework for Alzheimer's Disease (EMIF-AD; n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI; n=829), Amsterdam Dementia Cohort (ADC; n=666), and the Swedish BioFINDER study (n=233). Inclusion criteria were a baseline diagnosis of MCI, at least 6 months of follow-up, and availability of a baseline Mini-Mental State Examination (MMSE) and MRI or CSF biomarker assessment. The primary endpoint was clinical progression to any type of dementia. We evaluated performance of previously developed risk prediction models-a demographics model, a hippocampal volume model, and a CSF biomarkers model-by evaluating them across cohorts, incorporating different biomarker measurement methods, and determining prognostic performance with Harrell's C statistic. We then updated the models by re-estimating parameters with and without centre-specific effects and evaluated model calibration by comparing observed and expected survival. Finally, we constructed a model combining markers for amyloid deposition, tauopathy, and neurodegeneration (ATN), in accordance with the National Institute on Aging and Alzheimer's Association research framework.

FINDINGS: We included all 2611 individuals with MCI in the four cohorts, 1007 (39%) of whom progressed to dementia. The validated demographics model (Harrell's C 0·62, 95% CI 0·59-0·65), validated hippocampal volume model (0·67, 0·62-0·72), and updated CSF biomarkers model (0·72, 0·68-0·74) had adequate prognostic performance across cohorts and were well calibrated. The newly constructed ATN model had the highest performance (0·74, 0·71-0·76).

INTERPRETATION: We generated risk models that are robust across cohorts, which adds to their potential clinical applicability. The models could aid clinicians in the interpretation of CSF biomarker and hippocampal volume results in individuals with MCI, and help research and clinical settings to prepare for a future of precision medicine in Alzheimer's disease. Future research should focus on the clinical utility of the models, particularly if their use affects participants' understanding, emotional wellbeing, and behaviour.

Place, publisher, year, edition, pages
The Lancet Publishing Group, 2019
National Category
Geriatrics Neurology
Identifiers
urn:nbn:se:oru:diva-77105 (URN)10.1016/S1474-4422(19)30283-2 (DOI)000489517000016 ()31526625 (PubMedID)2-s2.0-85072867961 (Scopus ID)
Available from: 2019-10-09 Created: 2019-10-09 Last updated: 2019-10-24Bibliographically approved
Bos, I., Vos, S., Verhey, F., Scheltens, P., Teunissen, C., Engelborghs, S., . . . Visser, P. J. (2019). Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum. Alzheimer's & Dementia, 15(5), 644-654
Open this publication in new window or tab >>Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum
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2019 (English)In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 15, no 5, p. 644-654Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: We investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau).

METHODS: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ- vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition.

RESULTS: Ng and T-tau distinguished between Aβ+ from Aβ- individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum.

DISCUSSION: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
APOE, Alzheimer's disease, Amyloid-β, Cerebrospinal fluid, Cognition, Neurofilament light, Neurogranin, YKL-40
National Category
Medical and Health Sciences Neurology
Identifiers
urn:nbn:se:oru:diva-74036 (URN)10.1016/j.jalz.2019.01.004 (DOI)000467220800005 ()30853464 (PubMedID)
Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-06-19Bibliographically approved
Shi, L., Freund-Levi, Y. & Nevado-Holgado, A. J. (2019). Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay. Alzheimer's & Dementia, 15(11), 1478-1488
Open this publication in new window or tab >>Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay
2019 (English)In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 15, no 11, p. 1478-1488Article in journal (Refereed) Published
Abstract [en]

Introduction: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins.

Methods: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid.

Results: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) e4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization.

Discussion: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Amyloid beta, SOMAscan assay, Plasma proteomics, Replication, Causal relationship, Tau
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-78371 (URN)10.1016/j.jalz.2019.06.4951 (DOI)000496951600011 ()31495601 (PubMedID)2-s2.0-85071719989 (Scopus ID)
Note

Funding Agencies:

Innovative Medicines Initiative Joint Undertaking under EMIF grant 115372

European Union (EU)

EFPIA companies'  

European Commission Joint Research Centre QLRT-2001-245537670

Stichting voor Alzheimer Onderzoek 11020 13007 15005

Department of Health of the Basque Government 17.0.1.08.12.0000.2.454.01.41142.001.H

University of Antwerp Research Fund  

NIHR biomedical research centre at UCLH  

DPUK through MRC MR/L023784/2

Medical Research Council UK (MRC) MC_PC_17215

Available from: 2019-12-03 Created: 2019-12-03 Last updated: 2019-12-03Bibliographically approved
Vermunt, L., Sikkes, S. A. M., van den Hout, A., Handels, R., Bos, I., van der Flier, W. M., . . . Visser, P. J. (2019). Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype. Alzheimer's & Dementia, 15(7), 888-898
Open this publication in new window or tab >>Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype
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2019 (English)In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 15, no 7, p. 888-898Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration.

METHODS: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration.

RESULTS: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE ε4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage.

DISCUSSION: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
APOE, Alzheimer's disease, Clinical setting, Dementia, Disease duration, Multistate model, Preclinical, Prodromal, Progression
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-75631 (URN)10.1016/j.jalz.2019.04.001 (DOI)000475846300004 ()31164314 (PubMedID)2-s2.0-85066298869 (Scopus ID)
Note

Funding Agency:

NIA NIH HHS

Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved
Jernerén, F., Cederholm, T., Refsum, H., Smith, A. D., Turner, C., Palmblad, J., . . . Freund-Levi, Y. (2019). Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer's Disease: The OmegAD Study. Journal of Alzheimer's Disease, 69(1), 189-197
Open this publication in new window or tab >>Homocysteine Status Modifies the Treatment Effect of Omega-3 Fatty Acids on Cognition in a Randomized Clinical Trial in Mild to Moderate Alzheimer's Disease: The OmegAD Study
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2019 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 69, no 1, p. 189-197Article in journal (Refereed) Published
Abstract [en]

Background: Trials of supplementation with omega-3 fatty acids (omega 3-FAs) in patients with mild cognitive impairment or Alzheimer's disease (AD) have produced inconsistent effects on cognitive decline. There is evidence of an interaction between B vitamin status and omega 3-FAs in relation to brain atrophy and cognitive decline.

Objective: We investigated whether baseline levels of plasma total homocysteine (tHcy), a marker of B vitamin status, modify the effects of omega 3-FAs supplementation on cognitive performance in moderate AD.

Methods: This post hoc analysis of the OmegAD trial included 171 community-based patients with AD (MMSE >= 15): 88 patients received daily doses of 1.7 g docosahexaenoic acid and 0.6 g eicosapentaenoic acid for 6 months. Treatment outcome on cognition was analyzed according to baseline levels of tHcy using a general linear model and ANCOVA.

Results: We found significant interactions between omega 3-FA supplementation and tHcy on cognition and clinical stage assessed by MMSE (p = 0.040), global CDR (p = 0.059), and CDRsob (p = 0.023), but not on ADAS-cog (p = 0.649). In patients with tHcy levels <11.7 mu mol/L, omega 3-FA supplementation improved cognitive performance as measured by MMSE (+7.1%, 95% CI: 0.59 to 13.7%, p = 0.033) and clinical status as measured by CDRsob (-22.3%, 95% CI: -5.8 to -38.7%, p = 0.009) compared with placebo.

Conclusion: The effect of omega 3-FA supplementation on MMSE and CDR appears to be influenced by baseline tHcy, suggesting that adequate B vitamin status is required to obtain beneficial effects of omega 3-FA on cognition.

Place, publisher, year, edition, pages
IOS Press, 2019
Keywords
Alzheimer's disease, B vitamins, cognition, dementia, homocysteine, omega-3 fatty acids
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-74426 (URN)10.3233/JAD-181148 (DOI)000467519100017 ()30958356 (PubMedID)2-s2.0-85065659695 (Scopus ID)
Funder
Stockholm County CouncilThe Karolinska Institutet's Research FoundationThe Dementia Association - The National Association for the Rights of the DementedStiftelsen Gamla TjänarinnorThe Swedish Brain FoundationSwedish Nutrition Foundation (SNF)Gun och Bertil Stohnes StiftelseÅke Wiberg Foundation
Note

Funding Agencies:

Funds of Capio

Swedish Alzheimer Foundation  

Norwegian Research Council  

Odd Fellows 

Swedish Society of Physicians  

Lion's Sweden 

Available from: 2019-05-28 Created: 2019-05-28 Last updated: 2019-05-28Bibliographically approved
Lleó, A., Alcolea, D., Martínez-Lage, P., Scheltens, P., Parnetti, L., Poirier, J., . . . Blennow, K. (2019). Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study. Alzheimer's & Dementia, 15(6), 742-753
Open this publication in new window or tab >>Longitudinal cerebrospinal fluid biomarker trajectories along the Alzheimer's disease continuum in the BIOMARKAPD study
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2019 (English)In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 15, no 6, p. 742-753Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Within-person trajectories of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD) are not well defined.

METHODS: We included 467 subjects from the BIOMARKAPD study with at least two serial CSF samples. Diagnoses were subjective cognitive decline (n = 75), mild cognitive impairment (n = 128), and AD dementia (n = 110), and a group of cognitively unimpaired subjects (n = 154) were also included. We measured baseline and follow-up CSF levels of total tau (t-tau), phosphorylated tau (p-tau), YKL-40, and neurofilament light (NfL). Median CSF sampling interval was 2.1 years.

RESULTS: CSF levels of t-tau, p-tau, NfL, and YKL-40 were 2% higher per each year of baseline age in controls (P <.001). In AD, t-tau levels were 1% lower (P <.001) and p-tau levels did not change per each year of baseline age. Longitudinally, only NfL (P <.001) and YKL-40 (P <.02) increased during the study period.

DISCUSSION: All four CSF biomarkers increase with age, but this effect deviates in AD for t-tau and p-tau.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Alzheimer, Amyloid, CSF, Inflammation, Neurofilaments, Tau, YKL-40
National Category
Medical and Health Sciences Neurology
Identifiers
urn:nbn:se:oru:diva-79152 (URN)10.1016/j.jalz.2019.01.015 (DOI)000470084500002 ()30967340 (PubMedID)2-s2.0-85063904370 (Scopus ID)
Funder
Swedish Research CouncilEU, European Research Council, 681712
Note

Funding Agencies:

Ministry of Health, Italy, Appeared in article as Italian Ministry of Health

Netherlands Organization for Health Research and Development, Appeared in article as Netherlands Organization for Health, Research and Development (ZonMw)

Instituto de Salud Carlos III, Appeared in article as Instituto de Salud Carlos III, Grant numbers PI14/1561, PI17/1895

Fondo Europeo de Desarrollo Regional (FEDER), Union Europea, "Una manera de hacer Europa"

Federal Ministry of Education & Research (BMBF), Appeared in article as Bundesministerium fur Bildung und Forschung (BMBF), Germany

Swedish Research Council, Appeared in article as Swedish Research Council

Innovation Fund Denmark, Grant number 0603-00470B

Fonds de Recherche du Quebec-Sante (FRQS)

J. L. Levesque Foundation  

Department of Health of the Basque Government, Grant number 2016111096

Instituto de Salud Carlos III, Appeared in article as Carlos III Institute of Health, Grant number PI15/00919

"Obra Social Kutxa Fundazioa"

European Research Council (ERC), Appeared in article as European Research Council, Grant number 681712

Swedish Research Council, Appeared in article as Swedish Research Council, Grant number 2013-2546

Torsten Soderberg Foundation at the Royal Swedish Academy of Sciences  

European Union (EU), Appeared in article as European Commission as part of the 6th Framework Program, Grant number 37670

Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-21Bibliographically approved
Kim, M., Snowden, S., Suvitaival, T., Ali, A., Merkler, D. J., Ahmad, T., . . . Legido-Quigley, C. (2019). Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort. Alzheimer's & Dementia, 15(6), 817-827
Open this publication in new window or tab >>Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort
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2019 (English)In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 15, no 6, p. 817-827Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.

METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.

RESULTS: Eight metabolites were associated with amyloid β and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.

DISCUSSION: PFAMs have been found increased and associated with amyloid β burden in CSF and clinical measures.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Alzheimer's disease, Amyloid, Biomarkers, Brain volume measurements, CSF, Cognitive function measurements, Dementia, EMIF-AD, Metabolomics, Tau
National Category
Medical and Health Sciences Neurology
Identifiers
urn:nbn:se:oru:diva-79153 (URN)10.1016/j.jalz.2019.03.004 (DOI)000470084500009 ()31078433 (PubMedID)2-s2.0-85066602218 (Scopus ID)
Note

Funding Agencies:

Innovative Medicines Initiative Joint Undertaking under EMIF, Grant number 115372

European Union (EU), Appeared in article as European Union

EFPIA companies  

European Commission Joint Research Centre, Appeared in article as European Commission, Grant number QLRT-2001-245537670

Department of Health of the Basque Government, Grant number  17.0.1.08.12.0000.2.454.01.41142.001.H

United States Department of Health & Human Services

National Institutes of Health (NIH) - USA, Appeared in article as National Institutes of Health, Grant number R15-GM107864

Available from: 2020-01-14 Created: 2020-01-14 Last updated: 2020-01-21Bibliographically approved
Bos, I., Vos, S. J. B., Jansen, W. J., Vandenberghe, R., Gabel, S., Estanga, A., . . . Visser, P. J. (2018). Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data.. Frontiers in Aging Neuroscience, 10, Article ID 193.
Open this publication in new window or tab >>Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data.
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2018 (English)In: Frontiers in Aging Neuroscience, ISSN 1663-4365, E-ISSN 1663-4365, Vol. 10, article id 193Article in journal (Refereed) Published
Abstract [en]

We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
Alzheimer's disease, amyloid-beta, cognition, neuropsychological examination, normative data, tau
National Category
Neurology
Identifiers
urn:nbn:se:oru:diva-74037 (URN)10.3389/fnagi.2018.00193 (DOI)000436126300002 ()29988624 (PubMedID)
Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-06-18Bibliographically approved
Jansen, W. J., Visser, P. J. & Amyloid Biomarker Study Group, . (2018). Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia. JAMA psychiatry, 75(1), 84-95
Open this publication in new window or tab >>Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia
2018 (English)In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 75, no 1, p. 84-95Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Medical Association, 2018
National Category
Medical and Health Sciences Gerontology, specialising in Medical and Health Sciences
Identifiers
urn:nbn:se:oru:diva-79268 (URN)10.1001/jamapsychiatry.2017.3391 (DOI)000419177700014 ()29188296 (PubMedID)2-s2.0-85040468555 (Scopus ID)
Note

Funding Agencies:

United States Department of Health & Human Services National Institutes of Health (NIH) - USA, NIH National Center for Research Resources (NCRR), Appeared in article as NCRR NIH HHS, Grant number: C06 RR018898

United States Department of Health & Human Services National Institutes of Health (NIH) - USA, NIH National Institute on Aging (NIA), Appeared in article as NIA NIH HHS, Grant numbers: R01 AG045611, RF1 AG025516, P50 AG005133, P01 AG026276, P50 AG005681, P01 AG003991, P30 AG010124, P50 AG023501, P01 AG025204

Available from: 2020-01-20 Created: 2020-01-20 Last updated: 2020-01-20Bibliographically approved
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