GENERAL AIMS:
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.
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.
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.
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.
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").
MOTOR ASSESSMENTS Motor aspects are evaluated as part of the sub-study Motor-ACT, which
includes detailed motor assessments (including dual tasking): clinical assessments
(administered by a physiotherapist), patient-reported outcomes and digital measures (see
outcome measures).
Detailed motor assessments are included in the following cohorts: B (older healthy
controls), C (SCD/MCI with suspicion of incipient neurocognitive disorder) and E
(parkinsonian disorders).
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.