The Swedish BioFINDER Study

Mild Cognitive Impairment Clinical Trial

Official title:

The Swedish BioFINDER Study: Early Diagnosis of Alzheimer's Disease - a Multidisciplinary Approach

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01208675
• Other study ID #: TiDiS-2010
• Status: Active, not recruiting
• Start date: September 2010
• Est. completion date: December 2024

Study information

• Verified date: November 2023
• Source: Skane University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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:

1. 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%.

2. 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.

3. 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.

4. 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.

Description:

1. 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.

2. 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.

3. 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.

4. 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 1150
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease
• Cognitive Dysfunction
• Dementia
• Dementia With Lewy Bodies
• Dementia, Vascular
• Lewy Body Disease
• Mild Cognitive Impairment
• Vascular Dementia

Locations

Country	Name	City	State
Sweden	Memory Clinic, Hospital of Ängelholm	Ängelholm
Sweden	Memory Clinic, Skåne University Hospital	Malmö

Sponsors (2)

Lead Sponsor	Collaborator
Skane University Hospital	Lund University

Country where clinical trial is conducted

Sweden, 

References & Publications (24)

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. Cerebrova — View Citation

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 — View Citation

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. — View Citation

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. — View Citation

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. Neu — View Citation

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 patholo — View Citation

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/srep2680 — View Citation

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 Alzheim — View Citation

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. Apolip — View Citation

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: 10.1 — View Citation

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. — View Citation

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. Neuro — View Citation

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 stu — View Citation

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 Alzheime — View Citation

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 Neuroche — View Citation

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. — View Citation

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 2 — View Citation

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: — View Citation

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. — View Citation

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. — View Citation

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; — View Citation

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( — View Citation

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. — View Citation

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 — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 zero equals the baseline visit. All subjects will subsequently attend follow-up visits every year for approximately 4-6 years after baseline.
Secondary	Rate of cognitive decline as measured by various cognitive tests, Activities of Daily Living (FAQ) and Global Deterioration Scale.		Time zero equals the baseline visit. All subjects will subsequently attend follow-up visits every year for approximately 10 years after baseline.
Secondary	Group differences for imaging and wet biomarker measurements.		At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
Secondary	Rate of volume change of structural MRI measures and amyloid PET		At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
Secondary	Rates of change on each specified biochemical biomarker		At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
Secondary	Correlations between biomarkers and biomarker change		At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.
Secondary	Subgroups analyses: Abnormal CSF biomarkers, positive amyloid imaging, APOE genotype.		At baseline, 1 years, 2 years, 3 years, 4 years, 6 years, 8 years and 10 years.