Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05067192 |
| Other study ID # |
A-synuclein-PET-study |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 15, 2021 |
| Est. completion date |
September 1, 2021 |
Study information
| Verified date |
September 2021 |
| Source |
Skane University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The aim of the project is to develop the first alpha-synuclein (a-syn)-specific PET tracer.
The research phase will exploit ACI's proprietary MorphomerTM library and extensively
optimized screening workflow.
Promising PET-tracer candidates will be tested for their ability in detecting a-syn pathology
in patients with a range of Parkinsonian conditions with different a-syn levels and
distributions, comprising hereditary forms of PD and other synucleinopathies.
Description:
Aims:
Today there is no way of detecting a-synuclein pathology in life, and thus the diagnoses of
Parkinson's Disease (PD) and the closely related synucleinopathies Dementia with Lewy Bodies
(DLB) and Multiple system atrophy (MSA) are clinical diagnoses, that can be supported by
dopamine (F-DOPA) imaging and biomarkers (f.ex cerebrospinal fluid neurofilament light
chain), but where the ultimate diagnosis is not certain until at post mortem investigation of
the brain.
The general aim of this study is to assess a newly developed positron emission tomography
(PET) tracers for a-synuclein and to study the ability of the tracer in detecting the
underlying pathology in PD, DLB and MSA. If the PET tracers can detect the pathology reliably
our hope is that this tracers can assist in future clinical trials for PD, DLB and MSA.
Primary aim
• to assess the brain a-synuclein load in vivo using [18F]ACI-3847 PET in MSA, DLB and
Parkinson's disease
Secondary aims
- to explore the correlation in these patients between a-synuclein load assessed by
[18F]ACI-3847 PET and clinical features including cognitive impairment and severity of
neurological symptoms
- to detect a-synuclein pathology assessed by [18F]ACI-3847 PET in Parkinson cases with a
duplication in the gene coding for a-synuclein
Background:
Clinical presentation: Neurodegenerative disorders mainly affect the elderly population and
approximately 1% of the population above 60 are affected by PD. DLB is likely underdiagnosed,
but represent approximately 10% of the patients in a specialist dementia center setting. MSA
is more uncommon and is often mistaken for PD, but carries a much worse prognosis. Due to the
poor prognosis of MSA it is important to as early as possible be able to give a correct
diagnosis.
The diagnoses of PD, DLB and MSA are today mainly clinical diagnoses. The diagnosis of PD is
based on the triad of symptoms: rigidity, resting tremor and bradykinesia of movement,
followed by a rapid and sustained response of symptoms to levodopa treatment. Further, the
loss of dopaminergic neurons can be visualized with PET-imaging of dopamine storage capacity
(18F-DOPA PET). At symptom onset of PD it has been estimated that 50-70% of dopaminergic
cells are already lost, making it more difficult to successfully treat the disease to halt or
slow down disease progression. MSA causes similar symptoms as PD, and is often mistaken for
PD, but patients gradually also develop autonomic failure, with varying heart rate and
blodpressure, causing falls due to ortostatic drops in blood pressure. F-DOPA PET again shows
a loss of dopaminergic cells in the midbrain, but the levodopa response is much attenuated in
MSA. DLB shows similar symptoms of bradykinesia and rigidity, but also early on changes in
cognition and visual hallucinations.
Neuropathology: PD, DLB and MSA are all caused by aggregation of a-synuclein in the brain.
The midbrain and the brainstem is first affected in PD, and later in the disease the
pathology spreads throughout the neocortex. In DLB the a-synuclein often also involves the
occipital neocortex and limbic brain structures in addition to the midbrain. In MSA the
pathology affects the brain stem and basal ganglia, but also often the cerebellum.
Diagnostic work-up: As stated earlier there is today no reliable way to verify the diagnoses
or the a-synuclein in life. In this study we will include also 18F-DOPA PET that is today the
state-of-the-art technique for detecting a loss of dopamine producing cells in the midbrain.
18F-DOPA PET will strengthen the diagnostic accuracy, but there are still pitfalls even when
using 18F-DOPA PET for diagnosis. For example the Parkinson-related disorders Progressive
Supranuclear Palsy (PSP) and Corticobasal Degeneration (CDB), that both show dopamine cell
loss and a decreased 18F-DOPA retention in addition to PD-like symptoms like bradykinesia and
rigidity, but that both are caused by tau pathology and not a-synuclein pathology. It is well
known that the diagnostic accuracy of some of the diagnoses with parkinsonism is at best
moderate and that many diagnoses will have to be corrected at autopsy.
Our hope is that [18F]ACI-3847 PET in the long run will help in the differential diagnosis
against PSP and CBD, but also that the different patterns of a-synuclein accumulation in PD,
DLB and MSA will provide a useful tool in tracking disease progression within the
synucleinopathies.
Treatment trials: There are currently no treatments that slow down or stop PD, DLB or MSA.
There are large efforts to develop therapies (e.g. immunotherapies) that remove aggregated
a-synuclein from the brains of the affected patients. However, there is no methods available
today that can be used to study whether such treatments really affect the levels of abnormal
a-synuclein in the living human brain. If [18F]ACI-3847 PET can visualize the a-synuclein
aggregates, then it might be used in the future to evaluate whether novel therapies can
remove a-synuclein from the brain of living humans.
Participants:
Patients with PD, DLB, MSA, PSP and CBD and Healthy controls.
Inclusion criteria - patients
- Age 50-100 years.
- Fulfill the criteria for PD, DLB, MSA, PSP 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 - patients
- 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 MRI or PET.
Inclusion criteria - healthy controls
- Age 50-100 years
- Absence of cognitive symptoms or parkinsonism as assessed by a physician with special
interest in cognitive disorders.
- 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 - healthy controls
- Significant unstable systemic illness or organ failure, such as terminal cancer, that
makes it difficult to participate in the study.
- No significant neurological or psychiatric disease.
- Current significant alcohol or substance misuse.
- Refusing MRI or PET.
Methods:
Positron Emission Tomography [18F]ACI-3847 PET (a-synuclein PET) will be performed in all
participants. 185 MBq (5 mCi) [18F]ACI-3847 is injected intravenously via an intravenous
cathether. Data acquisition is started at the time of injection and continues over 100
minutes (0-100 min). During this time the patient will need to keep as still as possible.
Image data will be collected on GE Discovery MI PET/CT cameras as LIST mode data (raw data)
and be reconstructed after acquisition and attenuation correction. Arterial sampling will be
performed in a subset of individuals.
[18F]DOPA PET for assessment of remaining dopamine producing cells will be performed by
intravenous injection of 185 MBq (5 mCi) [18F]DOPA. Data acquisition is started at either at
the time of injection and continues over 110 minutes, or starts 90 min after injection and
continues for 20 minutes. No arterial blood sampling is needed for this scan.
Magnetic Resonance Imaging 3 Tesla MRI (Siemens Prisma) will be done in all participants. No
contrast-enhancing agent will be used.
