Format

Send to

Choose Destination
JAMA Psychiatry. 2018 Jan 1;75(1):84-95. doi: 10.1001/jamapsychiatry.2017.3391.

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

Jansen WJ1, Ossenkoppele R2,3,4,5, Tijms BM2, Fagan AM6, Hansson O7, Klunk WE8, van der Flier WM2,9, Villemagne VL10, Frisoni GB11,12, Fleisher AS13,14,15, Lleó A16, Mintun MA17, Wallin A18, Engelborghs S19, Na DL20, Chételat G21, Molinuevo JL22, Landau SM5, Mattsson N7, Kornhuber J23, Sabri O24, Rowe CC6,10, Parnetti L25, Popp J26, Fladby T27, Jagust WJ5, Aalten P1, Lee DY28, Vandenberghe R29, Resende de Oliveira C30, Kapaki E31, Froelich L32, Ivanoiu A33, Gabryelewicz T34, Verbeek MM35, Sanchez-Juan P36, Hildebrandt H37, Camus V38, Zboch M39, Brooks DJ40, Drzezga A41, Rinne JO42, Newberg A43, de Mendonça A44, Sarazin M45, Rabinovici GD4, Madsen K46, Kramberger MG47, Nordberg A48, Mok V49, Mroczko B50, Wolk DA51, Meyer PT52, Tsolaki M53, Scheltens P2, Verhey FRJ1, Visser PJ1,2; Amyloid Biomarker Study Group, Aarsland D54, Alcolea D16, Alexander M55, Almdahl IS27, Arnold SE51, Baldeiras I30, Barthel H24, van Berckel BNM3, Blennow K18,56, van Buchem MA57, Cavedo E11,58,59, Chen K13, Chipi E25, Cohen AD8, Förster S60, Fortea J16, Frederiksen KS61, Freund-Levi Y62, Gkatzima O53, Gordon MF63, Grimmer T64, Hampel H58,59,65, Hausner L32, Hellwig S66, Herukka SK67, Johannsen P68, Klimkowicz-Mrowiec A69, Köhler S1, Koglin N70, van Laere K71, de Leon M72, Lisetti V25, Maier W73, Marcusson J74, Meulenbroek O75, Møllergård HM27, Morris JC6, Nordlund A18, Novak GP76, Paraskevas GP31, Perera G55,77, Peters O78, Ramakers IHGB1, Rami L22, Rodríguez-Rodríguez E36, Roe CM6, Rot U47, Rüther E79, Santana I30, Schröder J80, Seo SW20, Soininen H67, Spiru L81, Stomrud E7, Struyfs H19, Teunissen CE82, Vos SJB1, van Waalwijk van Doorn LJC35, Waldemar G60, Wallin ÅK7, Wiltfang J79, Zetterberg H18,56,83.

Author information

1
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands.
2
Department of Neurology and Alzheimer Center, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
3
Department of Radiology and Nuclear Medicine, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
4
Department of Neurology, Memory and Aging Center, University of California, San Francisco.
5
Helen Wills Neuroscience Institute, University of California, Berkeley.
6
Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
7
Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden.
8
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
9
Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
10
Department of Nuclear Medicine and Centre for PET, Austin Health, Melbourne, Australia.
11
Laboratory of Alzheimer's Neuroimaging and Epidemiology, IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
12
Memory Clinic and LANVIE-Laboratory of Neuroimaging of Aging, University Hospitals, and University of Geneva, Geneva, Switzerland.
13
Banner Alzheimer's Institute, Phoenix, Arizona.
14
Eli Lilly and Company, Indianapolis, Indiana.
15
Department of Neurosciences, University of California, San Diego.
16
Neurology Department, Hospital de Sant Pau, Barcelona, Spain.
17
Avid Radiopharmaceuticals, Philadelphia, Pennsylvania.
18
Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
19
Reference Center for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium.
20
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
21
Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Caen, Caen, France.
22
Alzheimer's Disease and Other Cognitive Disorders Unit, IDIBAPS, Clinic University Hospital, Barcelona, Spain.
23
Department of Psychiatry and Psychotherapy, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
24
Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.
25
Section of Neurology, Center for Memory Disturbances, University of Perugia, Perugia, Italy.
26
Department of Psychiatry, Service of Old Age Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland.
27
Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
28
Department of Neuropsychiatry, Seoul National University, College of Medicine, Seoul, South Korea.
29
Laboratory for Cognitive Neurology and Alzheimer Research Centre KU Leuven, Catholic University Leuven, Leuven, Belgium.
30
Center for Neuroscience and Cell Biology, Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra, Portugal.
31
First Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
32
Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
33
Memory Clinic and Neurochemistry Laboratory, Saint Luc University Hospital, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.
34
Department of Neurodegenerative Disorders, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland.
35
Departments of Neurology and Laboratory Medicine, Donders Institute for Brain, Cognition and Behaviour, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands.
36
Neurology Service, Universitary Hospital Marqués de Valdecilla, IDIVAL, Santander, Spain.
37
Center for Neurology, Hospital of Bremen-Ost, Bremen, Germany.
38
CHRU de Tours, CIC INSERM 1415, INSERM U930, and Université François Rabelais de Tours, Tours, France.
39
Alzheimer Center, Wroclaw Medical University, Scinawa, Poland.
40
Division of Neuroscience, Medical Research Council Clinical Sciences Centre, Imperial College London, London, England.
41
Department of Nuclear Medicine, University of Cologne, Cologne, Germany.
42
Turku PET Centre and Division of Clinical Neurosciences Turku, University of Turku and Turku University Hospital, Turku, Finland.
43
Myrna Brind Center of Integrative Medicine, Thomas Jefferson University and Hospital, Philadelphia, Pennsylvania.
44
Institute of Molecular Medicine and Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
45
Neurologie de la Mémoire et du Langage, Centre Hospitalier Sainte-Anne, Université Paris 5, Paris, France.
46
Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark.
47
Center for Cognitive Impairments, University Medical Centre Ljubljana, Ljubljana, Slovenia.
48
Department NVS, Center for Alzheimer Research, Translational Alzheimer Neurobiology, Karolinska Institutet, and Geriatric Medicine, Karolinska University Hospital, Stockholm, Sweden.
49
Lui Che Woo Institute of Innovative Medicine, Department of Medicine and Therapeutics, Therese Pei Fong Chow Research Centre for Prevention of Dementia, Hong Kong.
50
Department of Neurodegeneration Diagnostics, Leading National Research Centre in Białystok (KNOW), Medical University of Białystok, Białystok, Poland.
51
Department of Neurology, University of Pennsylvania, Philadelphia.
52
Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.
53
Third Department of Neurology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
54
Center for Age-Related Medicine, Stavanger University Hospital, Stavanger, Norway.
55
Roche Products, Welwyn Garden City, United Kingdom.
56
Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
57
Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
58
Département de Neurologie, Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Hôpital Pitié-Stijmsalpêtrière, Boulevard de l'hôpital, F-75013, Paris, France.
59
AXA Research Fund & UPMC Chair, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Inserm, CNRS, Institut du Cerveau et de la Moelle Épinière, Paris, France.
60
Department of Nuclear Medicine, Technische Universitaet München, Munich, Germany.
61
Danish Dementia Research Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
62
Department of Geriatrics, Karolinska University Hospital Huddinge, Section of Clinical Geriatrics, Institution of NVS, Karolinska Institutet, Stockholm, Sweden.
63
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut.
64
Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universitaet München, Munich, Germany.
65
Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Maximilian University, Munich, Germany.
66
Center of Geriatrics and Gerontology, University Hospital Freiburg, Freiburg, Germany.
67
Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
68
Memory Clinic, Danish Dementia Research Center, Rigshospitalet, Copenhagen, Denmark.
69
Jagiellonian University College of Medicine, Krakow, Poland.
70
Piramal Imaging GmbH, Berlin, Germany.
71
Department of Imaging and Pathology, Catholic University Leuven, Leuven, Belgium.
72
School of Medicine, Center for Brain Health, New York University, New York.
73
Department of Psychiatry and Psychotherapy, University of Bonn, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
74
Geriatric Medicine, Department of Clinical and Experimental Medicine, University of Linköping, Linköping, Sweden.
75
Department of Geriatric Medicine, Radboud Alzheimer Center, Radboud University Medical Center, Nijmegen, the Netherlands.
76
Janssen Research and Development, Titusville, New Jersey.
77
Department of Psychological Medicine, Institute of Psychiatry, Kings College London, London, United Kingdom.
78
Department of Psychiatry and Psychotherapy, Charité Berlin, German Center for Neurodegenrative Diseases (DZNE), Berlin, Germany.
79
Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August University, Göttingen, Germany.
80
Sektion Gerontopsychiatrie, Universität Heidelberg, Heidelberg, Germany.
81
Department of Geriatrics-Gerontology-Gerontopsychiatry, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
82
Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
83
UCL Institute of Neurology, Queen Square, London, United Kingdom.

Erratum in

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.

PMID:
29188296
PMCID:
PMC5786156
DOI:
10.1001/jamapsychiatry.2017.3391
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center