The Swedish BioFINDER 2 Study

Brief Title

The Swedish BioFINDER 2 Study

Official Title

The Swedish BioFINDER 2 Study

Brief Summary

      The Swedish BioFINDER 2 study is a new study that will launch in 2017 and extends the
      previous cohorts of BioFINDER 1 study (www.biofinder.se). BioFINDER 1 is used e.g. to
      characterize the role of beta-amyloid pathology in early diagnosis of Alzheimer's disease
      (AD) using amyloid-PET (18F-Flutemetamol) and Aβ analysis in cerebrospinal fluid samples. The
      BioFINDER 1 study has resulted in more than 40 publications during the last three years, many
      in high impact journals, and some the of the results have already had important implications
      for the diagnostic work-up patients with AD in the clinical routine practice.

      The original BioFINDER 1 cohort started to include participants in 2008. Since then there has
      been a rapid development of biochemical and neuroimaging technologies which enable novel ways
      to the study biological processes involved in Alzheimer's disease in living people. There has
      also been a growing interest in the earliest stages of AD and other neurodegenerative
      diseases. With the advent of new tau-PET tracers there is now an opportunity to elucidate the
      role of tau pathology in the pathogenesis of AD and other tauopathies. The Swedish BioFINDER
      2 study has been designed to complement the BioFINDER 1 study and to e.g. address issues
      regarding the role of tau pathology in different dementias and in preclinical stages of
      different dementia diseases. Further, the clinical assessments and MRI methods have been
      further optimized compared to BioFINDER 1.
    

Detailed Description

      GENERAL AIMS:

        1. Develop methods for early and accurate diagnosis of different dementia disorders. This
           is important not only for the clinical diagnostic work-up, but also for selection of
           patients to clinical trials. Because dementia is very common among the elderly, but
           often misdiagnosed, we need to develop minimally invasive, reliable and affordable
           biomarkers for use in a primary care setting. This could include blood-based biomarkers
           which could be used to identify patients at high risk for a neurodegenerative disease.
           We also aim to develop new diagnostic algorithms using advanced imaging techniques and
           cerebrospinal fluid (CSF) biomarkers to diagnose patients prior to overt symptoms (when
           brain dysfunction is still limited and potentially reversible) in order to identify
           individuals more likely to respond to new disease-modifying therapies.

        2. Develop biomarkers and imaging techniques to monitor early effects of new
           disease-modifying therapies. Methods are needed that can reliably detect relevant
           changes in the turnover of Aβ, tau and α-synuclein. In the present study one focus will
           be to study the annual change in the retention of Tau PET ligands during both the
           prodromal and dementia stages of AD. Further, we need biomarkers that detect the
           intensity of ongoing synaptic/neuronal degeneration. Imaging methods revealing the
           functional and structural integrity of different brain networks might also be relevant.

        3. Investigate the heterogeneity of dementia and parkinsonian disorders to assist in the
           development of a new pathology-based disease classification. Current diagnostic work-up
           is based on symptomatology. However, the diseases (e.g. Alzheimer's and Parkinson's
           diseases) are heterogeneous with respect to clinical features and underlying
           pathologies. Moreover, there is also significant overlap between the diseases. Hence,
           today's symptom-based clinical diagnostic criteria are likely too crude to provide an
           etiologically meaningful classification of patients. We will therefore work towards a
           pathology-based disease classification, using in vivo biomarkers that reflect the
           underlying brain pathologies, e.g. Aβ or tau. This will be especially useful for the
           development of new disease-modifying therapies, which are aimed at specific brain
           pathologies.

        4. Define the temporal evolution of pathologies in the predementia phases of Alzheimer's
           disease. One of the last decade's paradigm shifts in neuroscience has been the
           realization that AD, and likely also other neurodegenerative diseases, starts with a
           prolonged predementia phase. AD even starts with an asymptomatic phase, when brain
           pathology is present in the absence of clinical symptoms. It has become clear that we
           need to better understand the temporal sequence of pathologic events in these disorders
           to be able to select the optimal disease stages for interventions in clinical trials
           with different disease-modifying therapies directed at specific pathologies.

        5. Investigate the underlying disease mechanisms of dementia disorders in humans aiming at
           finding new relevant drug targets. Drug discovery using the currently available cell and
           animal models, has not translated to human research as indicated by failed phase II and
           III trials. There are several possible reasons for these failures. First, it is possible
           that previous trials may have focused on the wrong drug targets, since findings from
           cell and animal models of dementias may not have accurately captured essential aspects
           of the disease mechanisms in humans. BioFINDER2 will be a translational study where we
           will attempt to bridge the knowledge gap between cell/animal studies and studies in
           humans, by using biomarkers that reflect biological mechanisms that may be studied
           across model systems. Second, another reason of the failed trials may be that they
           included patients in too advanced disease stages for the treatments to be effective, or
           that they partly included patients with unspecific diseases, since they did not use
           biomarker-based methods for inclusion of participants. BioFINDER2 will inform on the
           design of future clinical trials by providing detailed data about cognitive and
           functional changes over time in people with well-defined biomarker-characterized brain
           pathologies.

      STUDY PLAN To reach the objectives above, we include well-characterized and clinically
      relevant populations of patients with dementia and/or parkinsonian symptoms and healthy
      individuals. We apply several state of the art methodologies in order to develop new brain
      imaging techniques, new biomarkers in blood and CSF as well as novel methods of assessing
      important clinical symptoms.

      COGNITIVE TESTING Attention and executive function will be assessed with the Trail Making
      Test A and B (TMT), Symbol Digit Modalities Test (SDMT), and A Quick Test of cognitive speed
      (AQT). Visuospatial ability will be measured by two subtests from the Visual Objects and
      Space Perception (VOSP) battery, incomplete letters and cube analysis. Memory will be
      assessed with the Free and Cued Selective Reminding Test (FCSRT) in cohorts A and B. It will
      be complemented with the 10-word delayed recall test from ADAS-cog, including a recognition
      part. Verbal ability will be evaluated with the animal and letter S fluency tests and the
      15-item short version of the Boston Naming Test. Global cognition will be assessed with the
      Mini-Mental State Examination (MMSE). In cohort A and B, a computerized cognitive battery
      focusing on memory and attention will also be performed.

      ASSESSMENTS OF SYMPTOMS, FUNCTIONAL ABILITIES AND GLOBAL FUNCTION Cognitive symptoms. All
      subjects will rate his or her memory and attention/executive function in relation to others
      of the same age according the Brief Anosognosia Scale (BAS). We have also added similar
      questions to cover the other cognitive domains. These questions have been validated against
      neuropsychological testing but there are data indicating that self-reported cognitive
      complaints are only valid in a lesser degree of cognitive impairment. To assess a broader
      range of cognitive complaints, the Subjective Cognitive Decline questionnaire (SCD-q) will be
      administered to the research subjects. Subjects from cohorts C, D and E will be assessed with
      cognitive impairment questionnaire (CIMP-QUEST; filled out by an informant).

      Functional ability. This will be evaluated with the informant-based Functional Activities
      Questionnaire (FAQ) or the Amsterdam IADL scale, both focus on instrumental activities of
      daily living (IADL) known to be affected early in cognitive decline.

      Global function. The global cognitive status will be evaluated using the sum of boxes score
      from the Clinical Dementia Rating scale (CDR) and the global deterioration scale (GDS).

      Behavioral and psychological symptoms in dementia (BPSD). BPSD will be assessed by clinicians
      using the Neuropsychiatric Inventory - Clinician rating scale (NPI-C) developed by Jeffrey
      Cummings. Mood and anxiety will be further assessed with the Hospital Anxiety and Depression
      scale (HADS). Frontal Behavioral Inventory (FBI) will be done in FTD-related conditions.

      Quality of Life (QoL). The overall health status will be rated by the subjects using the
      EQ-5D from Euro-QoL. In demented patients this will also be rated by an informant, spouse or
      close relative.

      Sleep. The presence of REM sleep behavior disorder will be evaluated with a single validated
      composite question derived from the Mayo Sleep Questionnaire. Sleep quality is assessed with
      the Sleep Scale from the Medical Outcome Study (MOS).

      Cognitive reserve. Premorbid cognition and cognitive reserve is approximated from the
      Cognitive Reserve Index questionnaire (CRI-q; subitems "Education" and "Working activity",
      not "Leisure time").

      CEREBROSPINAL FLUID (CSF) AND BLOOD SAMPLING AND ANALYZES Lumbar CSF samples will be
      collected according to a standardized protocol and will follow the principles of the
      Alzheimer's Association Flow Chart for CSF biomarkers. In short, lumbar puncture will be done
      between 9-12 am. 20-30 ml of CSF will be collected in Low Binding polypropylene tubes, which
      are stored on ice for 5-20 min until the CSF samples will be centrifuged (2000g, +4°C, 10
      min). Thereafter, the CSF will be aliquoted in ca 1 ml portions into Low Binding
      polypropylene tubes followed by storage at -80°C until batch analyses.

      Plasma collection will be done at the same visit as the lumbar puncture. Blood will be drawn
      into tubes containing either EDTA (5 x 6 ml tubes) or Lithium heparin (3 x 3 ml tubes) as
      anticoagulant. After centrifugation (2000g, +4°C, 10 min), plasma samples will be aliquoted
      into polypropylene tubes and stored at -80°C pending biochemical analyses. Further,
      EDTA-blood (2 x 6 ml) will also be obtained for genetic DNA analyses.

      MAGNETIC RESONANCE IMAGING 3 Tesla MRI (Siemens Prisma) will be done in all study cohorts. A
      wide variety of magnetic resonance imaging (MRI) techniques will be used to study regional
      brain volume (three-dimensional magnetization-prepared rapid acquisition with gradient echo
      (3D MPRAGE)), metabolism (MR spectroscopy (MRS)), structural and functional connectivity of
      different brain regions (diffusion tensor imaging (DTI) and functional MRI (fMRI)), regional
      blood flow (arterial spin labeling (ASL)), iron deposition (susceptibility-weighted imaging
      (SWI)) and the presence of small vessel disease (MPRAGE, SWI and fluid-attenuated inversion
      recovery (FLAIR)). The protocol will take approximately 60 min to perform. No
      contrast-enhancing agent will be used.

      PET IMAGING

      Tau PET. PET imaging of tau aggregates will be done in all the included cohorts at baseline.
      In the present study, Tau PET imaging will be performed using 18F-RO6958948 developed by
      Hoffmann-La Roche that will provide the precursor for this PET ligand. This tau PET imaging
      agent has been shown to accurately detect tau pathology in cases with AD when compared to
      controls. We will perform a 20-30 min PET scan approximately 60 min post intravenous
      injection of 18F-RO6958948. The impact of the investigation on clinical diagnostic accuarcy
      and patient care will be investigated. 18F-RO6958948 has not yet been approved for use in
      clinical routine practice in Sweden, and can only be used in research studies, such as the
      present study.

      Amyloid PET. PET imaging of Aβ aggregates (including 18F-flutemetamol PET) has been approved
      for use in clinical routine practice in Sweden. In the present study, 18F-flutemetamol PET
      will be done in non-demented cases only. In the cases with dementia CSF Aβ will be enough to
      determine the presence or absence of brain amyloid pathology. However, in the cognitively
      healthy cases and in the patients with SCD or MCI we are interested in following the spread
      of amyloid pathology throughout the brain during the preclinical stages of AD and the spatial
      relationship to tau pathology. Therefore, Amyloid PET will be done according to clinical
      routine procedures in addition to CSF Aβ measurements in these groups. In the present study
      Amyloid PET will be performed using 18F-flutemetamol. GE Healthcare will provide the
      precursor for 18F-flutemetamol. A 20 min scan will be performed between 90-110 min post
      injection of 18F-flutemetamol.

      FDOPA PET FDOPA PET is often used as part of clinical routine examinations of patients with
      parkinsonism to confirm the diagnosis. Here DaTSCAN will be done according to clinical
      routine procedures in cases with PD, PDD, DLB, MSA, PSP and CBD to confirm the clinical
      diagnosis if it has not been done in clinical routine praxis within one year from the
      baseline visit.
    


Study Type

Interventional


Primary Outcome

Clinical diagnosis

Secondary Outcome

 Rate of cognitive decline as measured by MMSE.

Condition

Dementia

Intervention

Flutemetamol F18 Injection

Study Arms / Comparison Groups

 COHORT A: Cognitively healthy younger individuals (40-65 y)
Description:  We will recruit 300 cognitively healthy individuals from the Malmö Offspring study, which is an epidemiological study. The participants will be stratified according to a) family history of dementia in first degree relatives (with onset before 80 years of age) and b) APOE 4 genotype; i.e. 25% will have no family history and no APOE4 allele, 25% will have a family history and no APOE 4 allele, 25% will have no family history and at least one APOE 4 allele, 25% will have a family history and at least one APOE 4 allele.
FOLLOW-UP FOR 8 YEARS Every 2 years new clinical, cognitive, neurological, and psychiatric assessments will be performed as well as CSF/blood sampling.
MRI, Tau PET and Amyloid PET will be done every 4 years in all cases, and Tau PET and MRI every two years if the subject is amyloid positive at baseline.
An auxiliary cohort (termed "Cohort A2") of 40 healthy individuals aged 20-40 years of age will also be included.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

1505

Start Date

May 15, 2017

Completion Date

December 31, 2028

Primary Completion Date

December 31, 2028

Eligibility Criteria

        COHORT A: Cognitively healthy younger individuals (40-65 years of age) INCLUSION CRITERIA

          -  Age 40-65 years

          -  Absence of cognitive symptoms as assessed by a physician with special interest in
             cognitive disorders.

          -  MMSE score 27-30 at screening visit.

          -  Do not fulfill the criteria for MCI or any dementia according to DSM-V.

          -  Speaks and understands Swedish to the extent that an interpreter is not necessary for
             the patient to fully understand the study information and cognitive tests.

        EXCLUSION CRITERIA

          -  Significant unstable systemic illness or organ failure, such as terminal cancer, that
             makes it difficult to participate in the study.

          -  Current significant alcohol or substance misuse.

          -  Significant neurological or psychiatric illness.

          -  Refusing lumbar puncture, MRI or PET.

        COHORT B: Cognitively healthy elderly individuals (66-100 years of age) INCLUSION CRITERIA

          -  Age 66-100 years

          -  Absence of cognitive symptoms as assessed by a physician with special interest in
             cognitive disorders.

          -  MMSE score 26-30 at screening visit.

          -  Do not fulfill the criteria for MCI or any dementia according to DSM-V.

          -  Speaks and understands Swedish to the extent that an interpreter is not necessary for
             the patient to fully understand the study information and cognitive tests.

        EXCLUSION CRITERIA

          -  Significant unstable systemic illness or organ failure, such as terminal cancer, that
             makes it difficult to participate in the study.

          -  Current significant alcohol or substance misuse.

          -  Significant neurological or psychiatric illness.

          -  Refusing lumbar puncture, MRI or PET.

        COHORT C: Subjective cognitive decline and mild cognitive impairment INCLUSION CRITERIA

          -  Age 40-100 years.

          -  Referred to the memory clinics due to cognitive symptoms experienced by the patient
             and/or informant. These symptoms do not have to be memory complaints, but could also
             be executive, visuospatial, language, praxis, psychomotor or social cognitive
             complaints.

          -  MMSE score of 24 - 30 points.

          -  Do not fulfill the criteria for any dementia (major neurocognitive disorder) according
             to DSM-V.

          -  The medical doctor (after clinical assessments, cognitive testing, CSF analyses and
             structural brain imaging) believes the cognitive complaints are caused by an incipient
             neurocognitive disorder of any sort. This is defined as any case fulfilling the
             criteria above (i.e. both SCD and MCI) with an abnormal CSF Aβ42/40 ratio, which is
             strongly associated with brain Aβ pathology and prodromal Alzheimer's disease.
             Further, cases with MCI (=minor neurocognitive impairment) due to either Parkinson's
             disease, Lewy body disease, vascular neurocognitive disorder or frontotemporal
             dementia (please see Appendix below for clinical criteria and references) can also be
             included.

          -  Speaks and understands Swedish to the extent that an interpreter is not necessary for
             the patient to fully understand the study information and cognitive tests.

        EXCLUSION CRITERIA

          -  Significant unstable systemic illness or organ failure, such as terminal cancer, that
             makes it difficult to participate in the study.

          -  Current significant alcohol or substance misuse.

          -  Refusing lumbar puncture, MRI or PET.

        COHORT D: Dementia due to Alzheimer's disease INCLUSION CRITERIA

          -  Age 40-100 years.

          -  Referred to the memory clinics due to cognitive symptoms experienced by the patient
             and/or informant. These symptoms do not have to be memory complaints, but could also
             be executive, visuospatial, language, praxis or psychomotor complaints.

          -  MMSE score of 12-26 points.

          -  Fulfill the criteria for dementia (major neurocognitive disorder) due to Alzheimer's
             disease (DSM-V).

          -  Speaks and understands Swedish to the extent that an interpreter was not necessary for
             the patient to fully understand the study information and cognitive tests.

        EXCLUSION CRITERIA

          -  Significant unstable systemic illness or organ failure, such as terminal cancer, that
             makes it difficult to participate in the study.

          -  Current significant alcohol or substance misuse.

          -  Refusing lumbar puncture, MRI or PET.

        COHORT E: Other dementias INCLUSION CRITERIA

          -  Age 40-100 years.

          -  Fulfill the criteria for dementia (major neurocognitive disorder) due to FTD, PDD, DLB
             or subcortical VaD alternatively the criteria for PD, PSP, MSA or CBS.

          -  Speaks and understands Swedish to the extent that an interpreter was not necessary for
             the patient to fully understand the study information and cognitive tests.

        EXCLUSION CRITERIA

          -  Significant unstable systemic illness or organ failure, such as terminal cancer, that
             makes it difficult to participate in the study.

          -  Current significant alcohol or substance misuse.

          -  Refusing lumbar puncture, MRI or PET.
      

Gender

All

Ages

20 Years - 100 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Oskar Hansson, MD, Professor, +46 (0)40 335036, [email protected]

Location Countries

Sweden

Location Countries

Sweden

Administrative Informations


NCT ID

NCT03174938

Organization ID

BioFINDER 2


Responsible Party

Principal Investigator

Study Sponsor

Skane University Hospital

Collaborators

 Lund University

Study Sponsor

Oskar Hansson, MD, Professor, Principal Investigator, Skåne University Hospital, and Lund University


Verification Date

February 2021