Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06120361 |
| Other study ID # |
ADetect |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2020 |
| Est. completion date |
December 31, 2028 |
Study information
| Verified date |
November 2023 |
| Source |
Skane University Hospital |
| Contact |
Sebastian Palmqvist, MD, PhD |
| Phone |
+46-40-331000 |
| Email |
Sebastian.Palmqvist[@]med.lu.se |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The overall aim of the study is to improve the diagnostic accuracy of AD and cognitive
impairment in primary care settings to ensure better care and treatment as well as facilitate
correct referrals to specialized memory clinics. The investigators will strive to recruit
diverse and representative populations of patients with subjective cognitive decline (SCD),
mild cognitive impairment (MCI) and mild dementia. The specific aims of the study are to:
1. Improve the detection of mild cognitive impairment (MCI) and dementia in primary care.
2. Develop and evaluate cognitive tests, blood-based biomarkers and brain imaging methods
that are suitable for accurate and early diagnosis of Alzheimer's disease (AD) in
primary care.
3. To prospectively validate plasma AD biomarkers for diagnosis of patients with cognitive
symptoms who are evaluated in primary care.
4. Determine whether blood AD biomarkers improve patient management in primary care.
Description:
AIMS
The overall aim of the study is to improve the diagnostic accuracy of AD and cognitive
impairment in primary care settings to ensure better care and treatment as well as facilitate
correct referrals to specialized memory clinics. The investigators will strive to recruit
diverse and representative populations of patients with subjective cognitive decline (SCD),
mild cognitive impairment (MCI) and mild dementia. The specific aims of the study are to:
1. Improve the detection of mild cognitive impairment (MCI) and dementia in primary care.
Early detection of cognitive impairment can lead to improved care, optimized treatments,
and highlight issues regarding decision making, incorrect utilizations of healthcare
resources and driving ability.Despite this, primary care still uses the same tools as
30-40 years ago, which have a low sensitivity for MCI. In this project, the
investigators will identify the optimal cognitive screening tests by doing head-to-head
comparisons of novel and traditional cognitive tests including computerized tests and
smartphone apps that can run daily tests of memory and executive function.
2. Develop and evaluate cognitive tests, blood-based biomarkers and brain imaging methods
that are suitable for accurate and early diagnosis of Alzheimer's disease (AD) in
primary care.
AD is the most common dementia (causing about 70% of all dementia cases) and there are
currently 4 registered symptomatic treatments that improve cognition, activities of
daily function and may delay the time to nursing homes. Detection of AD is therefore
essential in order to start the treatment. Further, promising trials suggest that
disease-modifying AD treatments might be available in the future targeting Aβ (the cause
and hallmark pathology of AD). In this scenario, it essential that AD is identified at
an early stage before neurodegeneration is wide-spread. To tackle this, the
investigators will develop and validate methods that can accurately detect people with
early AD in a primary care setting, including i) cognitive screening tests (e.g.
computerized tests and smartphone apps); ii) novel blood-based biomarkers (e.g. mass
spectrometry based plasma p-tau217 and Ab42/40 measures as well as the combination of
these two biomarkers in C2N Diagnostics' PrecivityAD2 test), and iii) widely available
brain imaging methods (including a comparison between computed tomography scan [CT] and
Magnetic resonance imaging scan [MRI]). The ultimate goal is to develop brief and
cost-effective diagnostic algorithms. The investigators will both validate a previous
algorithm that the investigators have published as well as test new ones, including the
PrecivityAD2 test result known as the Amyloid Probability Score 2 (APS2, ranging from
0-100 for the likelihood of brain amyloid plaques).
3. To prospectively validate plasma AD biomarkers for diagnosis of patients with cognitive
symptoms who are evaluated in primary care. The investigators here intend to study the
clinical robustness and accuracy of plasma AD biomarkers in real-world settings by using
high-performing plasma assays over a 2-3 year time period. In this study, plasma samples
are collected as part of clinical praxis and analyzed on a bi-weekly basis throughout
the study period (and not in single batches). The investigators will (1) use pre-defined
cut offs for each biomarker (similar to real world clinical practice), and (2) use an
accurate reference standard (i.e., cerebrospinal fluid (CSF)/Positron emission
tomography (PET) AD biomarkers). The effects of potential confounders (such as kidney
function) on diagnostic accuracy will also be studied. The investigators will only use
really top-performing plasma assays for each biomarker including for p-tau217 and
Ab42/Ab40.
4. Determine whether blood AD biomarkers improve patient management in primary care.
As often noted by regulatory authorities, it is important to know if novel diagnostic
methods improve the actual management of patients in real world settings. Consequently,
the investigators study whether the most promising plasma biomarkers for symptomatic AD
(including the APS2) will improve AD diagnosis beyond what is currently done as part of
clinical practice. The physician will document the most likely diagnosis (and the
certainty of the diagnosis) after having performed an interview with the patient and
informant, as well as evaluated the patient's cognitive test results, routine blood
tests and structural brain imaging. The physician will then re-evaluate the diagnosis
(and certainty of diagnosis) after having obtained the APS2, plasma p-tau217 and
Ab42/Ab40 results, and the pre- and post-test diagnosis will be compared to the
reference standard (i.e. presence of AD brain pathology as determined with biomarkers).
Change in treatment and care of the patient after evaluating blood-based biomarkers will
also be recorded similar to how amyloid-PET was evaluated in the IDEAS study.
PARTICIPANTS
The study will consecutively recruit 1200 patients seeking medical care due to mild
cognitive symptoms in primary care units. They will be recruited at approximately 20-30
primary care facilities in Skåne. The patients will as usual first meet a general
practitioner who performs a basic investigation of the patient to rule out other obvious
causes causing the cognitive symptoms other than a dementia disorder, such as
depression, sleep deprivation, etc. The patients, whose cognitive symptoms are not
clearly explained by psychiatric or somatic conditions, will be assessed with cognitive
tests by a dementia nurse or occupational therapist at the primary care unit.
ASSESSMENTS AT THE PRIMARY CARE UNIT
At the primary care units, the investigators will collect data to be able to design
optimal and cost-effective diagnostic algorithms for dementia disorder, especially AD.
In order to do that the investigators will perform different cognitive tests, including
smartphone-based tests, to determine impairment of global cognition as well as different
cognitive domains. Informed consent is signed before the study begins.
i) Cognitive Testing at the primary care unit The primary care tests are summarized
below. These include tradition and novel pen and paper tests, iPad tests,
smartphone-based tests for home-based testing and the use of a digital pen.
The Montreal Cognitive Assessment (MoCA)
Mini-Mental State Examination (MMSE)
The 10-word list from the Alzheimer's Disease Assessment Scale-Cognitive Subscale
(ADAS-cog) (immediate, delayed and recognition recall)
Symbol Digit Modalities Test (SDMT)
Animal Fluency
Cube copying
The clock drawing test
Immediate and delayed recall of pictures test
Trail Making Test A and B
Mini-Cog
CANTAB Paired Associate Learning (iPad)
CANTAB Reaction Time (iPad)
Mezurio Gallery game (smartphone)
Mezurio Tilt Task (smartphone)
Digital Clock Test
Speech recognition tests (ki elements)
In-house developed iPad test battery
Cognitive Function Instrument (CFI)
Amsterdam iADL scale
ii) Blood sampling at the primary care unit Recent breakthroughs by our group and others
show that it is possible to accurately detect cerebral Aβ and tau using blood-based
biomarkers. Blood will be collected in 10 mL EDTA tubes, which are centrifuged (2000g)
within 1 hour. Plasma will then be aliquoted into LoBind tubes and sent by ordinary
transport to the Clinical Chemistry unit either in Malmö or Lund for storage at -80°C.
Some of these plasma samples will be analysed prospectively every two weeks.
iii) Brain imaging ordered by the primary care unit A short a short MRI examination and
a CT scan of the brain will be ordered by the primary care unit, and performed at the
local hospital. The brain atrophy pattern may reveal the type of underlying dementia
disorder that is the cause of cognitive symptoms.
iv) Assessment of change in management and diagnosis After the initial basic dementia
investigation (current clinical practice) the primary care physician will 1) note the
most likely diagnosis of the patient, 2) rate his/her confidence in the diagnosis of the
patient and 3) note the plans for further investigations and treatment. Thereafter, the
clinician will get access to the newly developed APS2 diagnostic algorithm that includes
prospectively measured plasma p-tau217 ratio and Ab42/40 levels). After obtaining the
results of the APS2 algorithm the medical doctor will again 1) note the most likely
diagnosis of the patient, 2) rate his/her confidence in the diagnosis of the patient and
3) note the plans for further investigations and treatment. This will allow us to
evaluate what impact the new cognitive and blood tests have on physicians' decision
making and if the clinical diagnostic accuracy was improved.
ESTABLISHMENT OF THE STANDARD OF TRUTH - ASSESSMENT OF THE MEMORY CLINIC
After the visit at the primary care unit, the patient will be referred to the Memory
Clinic to determine the cognitive function and clinical diagnosis, which will be blinded
to all investigations done at the primary care unit (besides the CT scan). The following
will be performed:
1. Extensive cognitive testing by an experienced neuropsychologist using the
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
neuropsychological battery that does not overlap with the cognitive tests at the
primary care units. These tests are done according to clinical routine practice at
our Memory clinic.
2. Cognitive, neurological and psychiatric assessments by a physician specialized in
cognitive disorders. These assessments are done according to clinical routine
practice at our Memory clinic.
3. Detection of brain amyloid pathology by either cerebrospinal fluid AD biomarkers
(CSF Aβ42/Aβ40 [Lumipulse; Fujirebio] and CSF p-tau217 [Eli Lilly]), alternatively
18F-flutemetamol PET will be used if there are contraindications for lumbar
puncture. These assessments are done according to clinical routine practice at our
Memory clinic.
A consensus diagnosis will be established based on the neuropsychological, medical
history, and CSF data (blinded to the cognitive test data from the primary care unit and
the blood-based biomarker data). Analysis of CSF Aβ42/Aβ40 [Lumipulse; Fujirebio] and
CSF p-tau217 [Eli Lilly] will be used to determine if the patient is AD pathology
negative or positive (alternatively amyloid PET if there are contraindications for LP).
Patients will also be followed over 3-5 years to determine the rate of cognitive decline
and progression to AD dementia in those with either SCD or MCI at baseline.
