The Swedish BioFINDER - Memory Clinic Study (Validate)

The diagnosis of diseases causing memory difficulties or dementia is often challenging. Without the use of advanced methods such as cerebrospinal fluid tests, approximately 25-30% do not receive a correct diagnosis today. However, we have recently developed new blood biomarkers with high diagnostic accuracy, and we now want to investigate whether they can eventually replace cerebrospinal fluid tests. This is because blood tests are much more cost-effective and significantly easier for patients compared to cerebrospinal fluid tests.

In this study, 1200 patients undergoing clinical evaluations at the Memory Clinic, Skåne University Hospital in Malmö, are included for blood and cerebrospinal fluid sample collection. The blood samples are sent for analysis using the new blood biomarkers. Subsequently, the results are compared with those from the clinical analysis of cerebrospinal fluid to determine how well they perform in routine clinical practice as an alternative to cerebrospinal fluid tests and whether the blood test improves patient care. This comparison is carried out by the attending physician in three steps:

1. Assessment without access to the results of either the blood test or cerebrospinal fluid test.
2. Assessment with access to only the results of the blood test.
3. Assessment with access to the results of both the blood test and cerebrospinal fluid test.

Aim 1) To prospectively validate plasma AD biomarkers for diagnosis of patients with cognitive symptoms who are evaluated in a specialist memory clinic.

Aim 2) Determine whether blood AD biomarkers improve patient management in specialist memory clinic settings.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease; Frontotemporal Degeneration; Mild Cognitive Impairment; Lewy Body Disease; Vascular Dementia; SCD; Mild Dementia
• Intervention / Treatment: Diagnostic test: Plasma APS 2 score; Diagnostic test: Plasma ptau217/nptau217; Diagnostic test: Plasma ptau217; Diagnostic test: Plasma NfL; Diagnostic test: Plasma Ab42/Ab40

Detailed Description

The diagnosis of diseases causing memory difficulties or dementia is often challenging. Without the use of advanced methods such as cerebrospinal fluid tests, approximately 25-30% do not receive a correct diagnosis today. However, we have recently developed new blood biomarkers with high diagnostic accuracy, and we now want to investigate whether they can eventually replace cerebrospinal fluid tests. This is because blood tests are much more cost-effective and significantly easier for patients compared to cerebrospinal fluid tests.

In this study, 1200 patients undergoing clinical evaluations at the Memory Clinic, Skåne University Hospital in Malmö, are included for blood and cerebrospinal fluid sample collection. The blood samples are sent for analysis using the new blood biomarkers. Subsequently, the results are compared with those from the clinical analysis of cerebrospinal fluid to determine how well they perform in routine clinical practice as an alternative to cerebrospinal fluid tests and whether the blood test improves patient care. This comparison is carried out by the attending physician in three steps:

1. Assessment without access to the results of either the blood test or cerebrospinal fluid test.
2. Assessment with access to only the results of the blood test.
3. Assessment with access to the results of both the blood test and cerebrospinal fluid test.

Aim 1) To prospectively validate plasma AD biomarkers for diagnosis of patients with cognitive symptoms who are evaluated in a specialist memory clinic. We here intend to study the clinical robustness and accuracy of plasma AD biomarkers in real-world settings by using high-performing plasma assays over 2-3 years, focusing on a specialist memory clinic population (n=1200). 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/at study closure). We 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., presence of AD brain pathology as determined with CSF Aβ42/Aβ40 [Lumipulse; Fujirebio] and CSF P-tau217 [Eli Lilly]). We will strive to recruit diverse and representative populations of patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI) and mild dementia. The effects of potential confounders (such as kidney function) on diagnostic accuracy will also be studied. We will only use really top-performing plasma assays for each biomarker, including p-tau217 and Ab42/Ab40.

Expected outcomes: We will 1) determine the diagnostic accuracy of different plasma AD biomarkers, 2) establish an optimal combination of plasma biomarkers for detection of AD brain pathology and 3) identify the effects of different potential confounding factors (e.g., kidney function) on the performance of different plasma biomarkers, when used prospectively in both real-world specialist and primary care populations.

Aim 2) Determine whether blood AD biomarkers improve patient management in specialist memory clinic settings. 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, we study whether the most promising plasma biomarkers for symptomatic AD (including plasma p-tau217) will improve AD diagnosis beyond what is currently done as part of clinical practice. The dementia experts 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 plasma p-tau217 results, and the pre- and posttest diagnosis will be compared to the reference standard (i.e., presence of AD brain pathology as determined with CSF Aβ42/Aβ40 [Lumipulse; Fujirebio] and CSF P-tau217 [Eli Lilly]). Change in treatment and care of the patient after evaluating the p-tau217 results will also be recorded similar to how amyloid-PET was evaluated in the IDEAS study.

Expected outcomes: We will determine whether the addition of plasma AD biomarkers to current clinical practice in memory clinics and/or primary care improves diagnosis and management of patients with SCD, MCI or mild dementia.

• Study Type: Observational
• Enrollment (Estimated): 1200

Contacts and Locations

• Study Contact: Name: Oskar Hansson, MD, PhD; Phone Number: +46-40-331000; Email: oskar.hansson@med.lu.se
• Study Contact Backup: Name: Erik Stomrud, MD, PhD; Phone Number: +46-40-331000; Email: erik.stomrud@med.lu.se

Study Locations

• Sweden
  • Malmö, Sweden
    • Recruiting
    • Skåne University Hospital
    • Contact: Erik Stomrud, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with cognitive symptoms (SCD, MCI or dementia) at a secondary memory clinic.

Description

Inclusion Criteria:

1. Under investigation for cognitive symptoms at the Memory clinic.
2. Cerebrospinal fluid and blood sampling is planned to be done as part of clinical practice even if the patient is not taking part of this study.

Exclusion Criteria:

1. Not undergoing CSF or blood sampling as part of clinical practice.
2. Not undergoing cognitive testing as part of clinical practice.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients in secondary care with cognitive symptoms

Diagnostic test: Plasma APS 2 score; APS 2 score (combination of ptau217/nptau217 and Ab42/Ab40). The cut off will be predefined. The samples will be analysed prospectively every two weeks.; Diagnostic test: Plasma ptau217/nptau217; The cut off will be predefined. The samples will be analysed prospectively every two weeks.; Diagnostic test: Plasma ptau217; The cut off will be predefined. The samples will be analysed prospectively every two weeks.; Diagnostic test: Plasma NfL; The cut off will be predefined. The samples will be analysed prospectively every two weeks.; Diagnostic test: Plasma Ab42/Ab40; The cut off will be predefined. The samples will be analysed prospectively every two weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain AD pathology as determined by CSF AD biomarkers	CSF Ab42/Ab40 and p-tau217	At baseline (cross-sectional)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical diagnosis supported by CSF biomarkers	Clinical diagnosis based on DSM-5 but supported by CSF biomarkers	At baseline (cross-sectional)
Brain AD pathology as determined by tau PET imaging	Tau PET imaging	At baseline (cross-sectional)
Change in patient management	Change in suggested diagnosis, treatment, referral or ordered diagnostic tests	At baseline (cross-sectional)
Change in diagnostic confidence	Change in diagnostic confidence of the treating physician	At baseline (cross-sectional)
Brain AD pathology as determined by amyloid amyloid PET imaging	Amyloid PET imaging	At baseline (cross-sectional)
Progression to AD dementia in patients with SCD or MCI at baseline	Development of AD dementia during follow-up diagnosed using DSM-5 and supported by CSF biomarkers	At baseline (cross-sectional)

Collaborators and Investigators

• Sponsor: Skane University Hospital
• Collaborators: Lund University

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 2, 2023
• First Submitted That Met QC Criteria: November 2, 2023
• First Posted (Estimated): November 8, 2023

Study Record Updates

• Last Update Posted (Estimated): November 8, 2023
• Last Update Submitted That Met QC Criteria: November 2, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Neurocognitive Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Tauopathies; Cognition Disorders; Intracranial Arterial Diseases; Intracranial Arteriosclerosis; Leukoencephalopathies; Dementia; Alzheimer Disease; Cognitive Dysfunction; Lewy Body Disease; Dementia, Vascular
• Other Study ID Numbers: VALIDATE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: Within one year after study completion
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No