- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01208675
The Swedish BioFINDER Study
The Swedish BioFINDER Study: Early Diagnosis of Alzheimer's Disease - a Multidisciplinary Approach
The present study aims at combining biochemical methods with various types of imaging techniques to identify the pathophysiology of Alzheimer's disease (AD). The main interest is to find markers associated with the very early steps in the pathology of this disease. The investigators shall thus screen for i) molecules in cerebrospinal fluid (CSF) and plasma specific for AD, and ii) brain imaging markers (e.g. MRI and PET) that correlate to detailed clinical assessments.
Biomarkers of interest would then be useful to:
- Enable accurate detection of the disease early on. Such biomarkers need to specifically reflect the very early pathophysiology of AD and distinguish it from disorders with similar symptomatology, such as other types of dementia and major depression. The sensitivity and specificity of these biomarkers in combination with clinical assessment should be of at least 90%.
- Enable prediction of the course of events of the disease, such as the disease rate in individual patients. Biomarkers that can predict the pattern of future symptoms will be extremely valuable.
- Allow monitoring of early effects of new disease-modifying therapies (so-called surrogate biomarkers). Currently clinical therapeutic trials for AD require large patient groups together with long-term treatment. Both size of the groups and treatment time will be reduced with the help of surrogate biomarkers.
- Study the pathogenesis of the disease. Biomarkers can be used to investigate in detail early alterations in AD patients. For instance, changes in the levels of certain molecules in CSF together with genetic predisposition could then be correlated to clinical signs and changes detectable by brain imaging. This can lead to identification of new therapeutic targets that could easily be monitored in future trials.
Study Overview
Status
Detailed Description
Baseline investigations of patients with mild cognitive deficits
We are conducting a prospective, longitudinal study in which we consecutively include patients with mild cognitive deficits (MCI), who seek medical care at the Neuropsychiatric Clinic (Malmö, Sweden) or Unit for Cognitive Medicine (Lund, Sweden). At baseline the MCI patients undergo detailed neurological and psychiatric examination, including assessment of depressive symptoms and ADL-capacity as well as cognitive and motor tests. Patients are also genotyped for APOE. Samples of plasma, blood (for DNA and mRNA) and CSF are also collected. All patients undergo an advanced MRI scan of the brain. A subset will undergo 18F-Flutemetamol PET. We will include patients over a period of three years.
1.2 Follow-up of MCI patients
Thereafter, we follow patients for up to 10 years with repeated testing and clinical evaluation. During clinical follow-up we estimate how many of the patients develop any type of dementia, for instance AD. Moreover we also estimate how aggressive the progression of the disease is in those patients that develop AD with the help of repeated cognitive testing.
Baseline investigations of healthy elderly volunteers
To answer the question if new biomarkers could detect early signs of AD in healthy people, we have included cognitively healthy elderly subjects. These people are recruited from a population-based study in Malmö ("Malmö Kost Cancer") where people without memory problems or cognitive difficulties, and who performs well on cognitive tests, are offered to participate. These individuals will undergo the same baseline studies that MCI patients (see above), including cognitive tests, psychiatric assessment, lumbar puncture, blood tests and MRI scan. A subset is also examined with 18F-Flutemetamol PET.
2.1 Follow-up of elderly volunteers
This population will also be followed-up for 10 years with repeated cognitive tests to determine which subjects develop cognitive impairment (e.g. memory problems) over this period of time.
Analyses of CSF and plasma/blood
CSF and plasma/blood sampling is done at baseline, 2, 4, 6 and 10 years of follow-up. To find novel and better biomarkers to predict AD in both healthy and MCI patients, the CSF, plasma and blood will be analyzed by various biomedical techniques. We will also screen for biomarkers that can help us to predict how fast the disease will progress. We will use two different approaches, namely: a) analysis of various candidate biomarkers and b) unbiased screening using proteomics.
- Magnetic resonance imaging (MRI) MRI is done at baseline, 2, 4 and 6 years of follow-up, using the same MRI scanner. We will evaluate the potential benefits of new MRI protocols for prediction of future AD. MRI will also be used to study the pathogenesis of AD. These new approaches include: 3D-MP RAGE, T2* GRE, DTI/DTT, ASL and MRS.
Study Type
Enrollment (Actual)
Contacts and Locations
Study Locations
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Malmö, Sweden, 20502
- Memory Clinic, Skåne University Hospital
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Ängelholm, Sweden
- Memory Clinic, Hospital of Ängelholm
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Sampling Method
Study Population
Description
Inclusion Criteria:
Healthy elderly subjects
- No cognitive symptoms reported by patient and/or informant
- Normal performance on cognitive tests
- General cognition and functional performance preserved such that a diagnosis of MCI or dementia cannot be made by physician at the time of the baseline visit
- Between 60 and 90 years of age
- Fluent in Swedish
- Agrees to at least one lumbar puncture, and neuropsychological testing.
Mild cognitive impairment
- Cognitive symptoms reported by patient and/or informant
- Between 60 and 80 years of age
- Mini-Mental State Exam score between 24 and 30
- General cognition and functional performance sufficiently preserved such that a diagnosis of dementia cannot be made by physician at the time of the baseline visit
- Fluent in Swedish
- Agrees to at least one lumbar puncture, and neuropsychological testing.
Exclusion Criteria (for both MCI and healthy elderly):
- Any significant neurologic disease other than dementia disorders, such as Huntington's disease, normal pressure hydrocephalus, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.
- Major depression as described in DSM-IV.
- History of schizophrenia or other recurrent psychotic disorder
- History of alcohol or substance abuse or dependence within the past 5 years
Study Plan
How is the study designed?
Design Details
Cohorts and Interventions
Group / Cohort |
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Mild cognitive impairment
550 patients with mild cognitive impairment or subjective cognitive symptoms at baseline.
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Healthy elderly subjects
650 elderly subjects, who are cognitively healthy at baseline.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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To compare the time to conversion to clinically probable AD in MCI subjects or healthy elderly subjects with normal and abnormal biomarkers (CSF, blood, MRI, PET)
Time Frame: Time zero equals the baseline visit. All subjects will subsequently attend follow-up visits every year for approximately 4-6 years after baseline.
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Time zero equals the baseline visit. All subjects will subsequently attend follow-up visits every year for approximately 4-6 years after baseline.
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Rate of cognitive decline as measured by various cognitive tests, Activities of Daily Living (FAQ) and Global Deterioration Scale.
Time Frame: Time zero equals the baseline visit. All subjects will subsequently attend follow-up visits every year for approximately 10 years after baseline.
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Time zero equals the baseline visit. All subjects will subsequently attend follow-up visits every year for approximately 10 years after baseline.
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Group differences for imaging and wet biomarker measurements.
Time Frame: At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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Rate of volume change of structural MRI measures and amyloid PET
Time Frame: At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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Rates of change on each specified biochemical biomarker
Time Frame: At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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Correlations between biomarkers and biomarker change
Time Frame: At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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Subgroups analyses: Abnormal CSF biomarkers, positive amyloid imaging, APOE genotype.
Time Frame: At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Oskar Hansson, MD, PhD, Lund University
Publications and helpful links
General Publications
- Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U, Norgren N, Linder J, Forsgren L, Constantinescu R, Zetterberg H, Blennow K; Swedish BioFINDER study. Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017 Mar 7;88(10):930-937. doi: 10.1212/WNL.0000000000003680. Epub 2017 Feb 8.
- Janelidze S, Hertze J, Nagga K, Nilsson K, Nilsson C; Swedish BioFINDER Study Group; Wennstrom M, van Westen D, Blennow K, Zetterberg H, Hansson O. Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype. Neurobiol Aging. 2017 Mar;51:104-112. doi: 10.1016/j.neurobiolaging.2016.11.017. Epub 2016 Dec 5.
- Smith R, Scholl M, Honer M, Nilsson CF, Englund E, Hansson O. Tau neuropathology correlates with FDG-PET, but not AV-1451-PET, in progressive supranuclear palsy. Acta Neuropathol. 2017 Jan;133(1):149-151. doi: 10.1007/s00401-016-1650-1. Epub 2016 Nov 29. No abstract available.
- Mattsson N, Zetterberg H, Janelidze S, Insel PS, Andreasson U, Stomrud E, Palmqvist S, Baker D, Tan Hehir CA, Jeromin A, Hanlon D, Song L, Shaw LM, Trojanowski JQ, Weiner MW, Hansson O, Blennow K; ADNI Investigators. Plasma tau in Alzheimer disease. Neurology. 2016 Oct 25;87(17):1827-1835. doi: 10.1212/WNL.0000000000003246. Epub 2016 Sep 30.
- Hahn A, Schain M, Erlandsson M, Sjolin P, James GM, Strandberg OT, Hagerstrom D, Lanzenberger R, Jogi J, Olsson TG, Smith R, Hansson O. Modeling Strategies for Quantification of In Vivo 18F-AV-1451 Binding in Patients with Tau Pathology. J Nucl Med. 2017 Apr;58(4):623-631. doi: 10.2967/jnumed.116.174508. Epub 2016 Oct 20.
- Smith R, Schain M, Nilsson C, Strandberg O, Olsson T, Hagerstrom D, Jogi J, Borroni E, Scholl M, Honer M, Hansson O. Increased basal ganglia binding of 18 F-AV-1451 in patients with progressive supranuclear palsy. Mov Disord. 2017 Jan;32(1):108-114. doi: 10.1002/mds.26813. Epub 2016 Oct 6.
- Smith R, Puschmann A, Scholl M, Ohlsson T, van Swieten J, Honer M, Englund E, Hansson O. 18F-AV-1451 tau PET imaging correlates strongly with tau neuropathology in MAPT mutation carriers. Brain. 2016 Sep;139(Pt 9):2372-9. doi: 10.1093/brain/aww163. Epub 2016 Jun 29.
- Surova Y, Lampinen B, Nilsson M, Latt J, Hall S, Widner H; Swedish BioFINDER study; van Westen D, Hansson O. Alterations of Diffusion Kurtosis and Neurite Density Measures in Deep Grey Matter and White Matter in Parkinson's Disease. PLoS One. 2016 Jun 30;11(6):e0157755. doi: 10.1371/journal.pone.0157755. eCollection 2016.
- Pannee J, Portelius E, Minthon L, Gobom J, Andreasson U, Zetterberg H, Hansson O, Blennow K. Reference measurement procedure for CSF amyloid beta (Abeta)1-42 and the CSF Abeta1-42 /Abeta1-40 ratio - a cross-validation study against amyloid PET. J Neurochem. 2016 Nov;139(4):651-658. doi: 10.1111/jnc.13838. Epub 2016 Sep 30.
- Janelidze S, Stomrud E, Palmqvist S, Zetterberg H, van Westen D, Jeromin A, Song L, Hanlon D, Tan Hehir CA, Baker D, Blennow K, Hansson O. Plasma beta-amyloid in Alzheimer's disease and vascular disease. Sci Rep. 2016 May 31;6:26801. doi: 10.1038/srep26801.
- van Westen D, Lindqvist D, Blennow K, Minthon L, Nagga K, Stomrud E, Zetterberg H, Hansson O. Cerebral white matter lesions - associations with Abeta isoforms and amyloid PET. Sci Rep. 2016 Feb 9;6:20709. doi: 10.1038/srep20709.
- Smith R, Wibom M, Olsson T, Hagerstrom D, Jogi J, Rabinovici GD, Hansson O. Posterior Accumulation of Tau and Concordant Hypometabolism in an Early-Onset Alzheimer's Disease Patient with Presenilin-1 Mutation. J Alzheimers Dis. 2016;51(2):339-43. doi: 10.3233/JAD-151004.
- Hall S, Surova Y, Ohrfelt A; Swedish BioFINDER Study; Blennow K, Zetterberg H, Hansson O. Longitudinal Measurements of Cerebrospinal Fluid Biomarkers in Parkinson's Disease. Mov Disord. 2016 Jun;31(6):898-905. doi: 10.1002/mds.26578. Epub 2016 Feb 16.
- Voevodskaya O, Sundgren PC, Strandberg O, Zetterberg H, Minthon L, Blennow K, Wahlund LO, Westman E, Hansson O; Swedish BioFINDER study group. Myo-inositol changes precede amyloid pathology and relate to APOE genotype in Alzheimer disease. Neurology. 2016 May 10;86(19):1754-61. doi: 10.1212/WNL.0000000000002672. Epub 2016 Apr 15.
- Janelidze S, Zetterberg H, Mattsson N, Palmqvist S, Vanderstichele H, Lindberg O, van Westen D, Stomrud E, Minthon L, Blennow K; Swedish BioFINDER study group; Hansson O. CSF Abeta42/Abeta40 and Abeta42/Abeta38 ratios: better diagnostic markers of Alzheimer disease. Ann Clin Transl Neurol. 2016 Jan 1;3(3):154-65. doi: 10.1002/acn3.274. eCollection 2016 Mar.
- Palmqvist S, Zetterberg H, Mattsson N, Johansson P; Alzheimer's Disease Neuroimaging Initiative; Minthon L, Blennow K, Olsson M, Hansson O; Swedish BioFINDER Study Group. Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology. 2015 Oct 6;85(14):1240-9. doi: 10.1212/WNL.0000000000001991. Epub 2015 Sep 9.
- Lindqvist D, Prokopenko I, Londos E, Middleton L, Hansson O. Associations between TOMM40 Poly-T Repeat Variants and Dementia in Cases with Parkinsonism. J Parkinsons Dis. 2016;6(1):99-108. doi: 10.3233/JPD-150693.
- Gustavsson AM, Stomrud E, Abul-Kasim K, Minthon L, Nilsson PM, Hansson O, Nagga K. Cerebral Microbleeds and White Matter Hyperintensities in Cognitively Healthy Elderly: A Cross-Sectional Cohort Study Evaluating the Effect of Arterial Stiffness. Cerebrovasc Dis Extra. 2015 May 20;5(2):41-51. doi: 10.1159/000377710. eCollection 2015 May-Aug.
- Hall S, Surova Y, Ohrfelt A, Zetterberg H, Lindqvist D, Hansson O. CSF biomarkers and clinical progression of Parkinson disease. Neurology. 2015 Jan 6;84(1):57-63. doi: 10.1212/WNL.0000000000001098. Epub 2014 Nov 19.
- Palmqvist S, Zetterberg H, Blennow K, Vestberg S, Andreasson U, Brooks DJ, Owenius R, Hagerstrom D, Wollmer P, Minthon L, Hansson O. Accuracy of brain amyloid detection in clinical practice using cerebrospinal fluid beta-amyloid 42: a cross-validation study against amyloid positron emission tomography. JAMA Neurol. 2014 Oct;71(10):1282-9. doi: 10.1001/jamaneurol.2014.1358.
- Lautner R, Palmqvist S, Mattsson N, Andreasson U, Wallin A, Palsson E, Jakobsson J, Herukka SK, Owenius R, Olsson B, Hampel H, Rujescu D, Ewers M, Landen M, Minthon L, Blennow K, Zetterberg H, Hansson O; Alzheimer's Disease Neuroimaging Initiative. Apolipoprotein E genotype and the diagnostic accuracy of cerebrospinal fluid biomarkers for Alzheimer disease. JAMA Psychiatry. 2014 Oct;71(10):1183-91. doi: 10.1001/jamapsychiatry.2014.1060.
- Silajdzic E, Constantinescu R, Holmberg B, Bjorkqvist M, Hansson O. Flt3 ligand does not differentiate between Parkinsonian disorders. Mov Disord. 2014 Sep;29(10):1319-22. doi: 10.1002/mds.25948. Epub 2014 Jul 16.
- Lindqvist D, Hall S, Surova Y, Nielsen HM, Janelidze S, Brundin L, Hansson O. Cerebrospinal fluid inflammatory markers in Parkinson's disease--associations with depression, fatigue, and cognitive impairment. Brain Behav Immun. 2013 Oct;33:183-9. doi: 10.1016/j.bbi.2013.07.007. Epub 2013 Jul 31.
- Surova Y, Szczepankiewicz F, Latt J, Nilsson M, Eriksson B, Leemans A, Hansson O, van Westen D, Nilsson C. Assessment of global and regional diffusion changes along white matter tracts in parkinsonian disorders by MR tractography. PLoS One. 2013 Jun 13;8(6):e66022. doi: 10.1371/journal.pone.0066022. Print 2013.
- Johansson M, Stomrud E, Johansson PM, Svenningsson A, Palmqvist S, Janelidze S, van Westen D, Mattsson-Carlgren N, Hansson O. Development of Apathy, Anxiety, and Depression in Cognitively Unimpaired Older Adults: Effects of Alzheimer's Disease Pathology and Cognitive Decline. Biol Psychiatry. 2022 Jul 1;92(1):34-43. doi: 10.1016/j.biopsych.2022.01.012. Epub 2022 Jan 31.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Mental Disorders
- Cardiovascular Diseases
- Vascular Diseases
- Cerebrovascular Disorders
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Arteriosclerosis
- Arterial Occlusive Diseases
- Neurocognitive Disorders
- Parkinsonian Disorders
- Basal Ganglia Diseases
- Movement Disorders
- Synucleinopathies
- Neurodegenerative Diseases
- Tauopathies
- Cognition Disorders
- Intracranial Arterial Diseases
- Intracranial Arteriosclerosis
- Leukoencephalopathies
- Dementia
- Alzheimer Disease
- Cognitive Dysfunction
- Lewy Body Disease
- Dementia, Vascular
Other Study ID Numbers
- TiDiS-2010
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