Health Technology Assessment of Diagnostic Approaches in Alzheimer's Disease

Novel Diagnostic Approaches for the Diagnosis of Alzheimer's Disease: Technology Assessment and Clinical Effectiveness

Background: New research criteria for the diagnosis of Alzheimer's disease (AD) have recently been developed to enable an early diagnosis of AD pathophysiology by relying on emerging biomarkers. To enable efficient allocation of health care resources, evidence is needed to support decision makers on the adoption of emerging biomarkers in clinical practice. The research goals are to 1) assess the diagnostic test accuracy (of current clinical diagnostic work-up and emerging biomarkers in Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET) and Cerebrospinal Fluid (CSF), 2) perform a cost-consequence analysis and 3) assess long-term cost-effectiveness by an economic model.

Methods/design: In a cohort design 304 consecutive patients suspected of having a primary neurodegenerative disease are approached in four academic memory clinics and followed for two years. Clinical data and data on quality of life data, costs and emerging biomarkers are gathered.

Diagnostic test accuracy is determined by relating the clinical practice and new research criteria diagnoses to the reference diagnosis. The clinical practice diagnosis at baseline is reflected by a consensus procedure among experts using clinical information only (no biomarkers). The diagnosis based on the new research criteria is reflected by decision rules that combine clinical and biomarker information. The reference diagnosis is determined by a consensus procedure among experts based on clinical information on the course of symptoms over a two-year time period.

A decision analytic model is build combining available evidence from different resources among which (accuracy) results from the study, literature and expert opinion to assess long-term cost-effectiveness of the emerging biomarkers.

Discussion: Several other multi-centre trials study the relative value of new biomarkers for early evaluation of AD and related disorders. The uniqueness of this study is the assessment of resource utilization and quality of life to enable an economic evaluation. The study results are generalizable to a population of patients who are referred to a memory clinic due to their memory problems.

Study Overview

• Status: Completed
• Conditions: Neurodegenerative Diseases; Memory Disturbances

• Study Type: Observational
• Enrollment (Actual): 304

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1100 DD
    • VU University Medical Center
  • Leiden, Netherlands, 2333 ZA
    • Leiden University Medical Center
  • Maastricht, Netherlands, 6200 MD
    • Maastricht University Medical Center
  • Nijmegen, Netherlands, 6500 HC
    • Radboud University Nijmegen Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

304 consecutive patients, of four academic memory clinics specialized in the diagnosis and treatment of memory disorders, who were suspected of having a primary neurodegenerative disease were approached for participating in the study. This included all patients with subjective and/or objective memory complaints. Eligibility criteria were chosen to represent current clinical situation and enable generalisability to clinical practice.

Description

Inclusion Criteria:

• All new consecutive patients of the participating memory clinics who are suspected of having a primary neurodegenerative disease. This means all patients with subjective and/or objective memory complaints.
• CDR 0, 0.5 or 1
• MMSE score must be 20 or higher.
• Availability of a reliable informer or proxy (who visits or contacts the patient at least once a week).

Exclusion Criteria:

• Normal Pressure Hydrocephalus (NPH)
• Huntington's disease
• Recent Transient Ischaemic Attack (TIA) (<2 years) or Cerebral Vascular Accident (CVA) or TIA/CVA followed by cognitive impairment (within 3 months)
• History of Schizophrenia, other psychotic disorders (< 12 months)
• Major depression (< 12 months)
• Alcohol abuse
• Brain-tumor, epilepsy, encephalitis
• Absence of a reliable informant
• Probably not available for follow-up

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
total patient group; all new consecutive patients of the participating memory clinics who are suspected of having a primary neurodegenerative disease, meaning that all patients with subjective as well as objective memory complaints are included

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic accuracy of Magnetic Resonance Imaging (MRI)	Diagnostic test accuracy (in terms of sensitivity and specificity) of three MRI markers (Whole brain and hippocampal volume, white matter integrity, and functional connectivity) is determined by relating the particular marker to a reference diagnosis. The reference diagnosis is determined by a consensus procedure among experts based on clinical information on the course of symptoms over a two-year time period.	baseline
Change in cognition at 2 years	Measured by the Mini-mental state examination (MMSE).	baseline, 1 year follow up, 2 year follow up
Change in dementia severity at 2 years	Measured by the clinical dementia rating (CDR) scale.	baseline, 1 year follow up, 2 year follow up
Change in quality of life at 2 years	Measured by the Euro-Qol-5D both by the patient and caregiver and measured by the Quality of life Alzheimer's disease state (QoL-AD) both by the patient and caregiver.	baseline, 3 months follow up, 1 year follow up, 2 year follow up
Health care resource use during 2 years	By means of questionnaires the health care resource usage is measured by the Resource Utilization in Dementia-questionnaire (RUD-lite) over a period of 2 years using 4 measurement moments to interpolate the data.	baseline, 3 months follow up, 1 year follow up, 2 year follow up
Change in productivity at 2 years	Work status, income, and productivity losses of both the patient and caregiver are assessed by the adjusted PRODISQ (PROductivity and DISease Questionnaire). The consequences of informal caregiving on paid or unpaid work are assessed by the Health and Labour Questionnaire.	baseline, 3 months follow up, 1 year follow up, 2 year follow up
Diagnostic accuracy of cerebrospinal fluid (CSF)	Diagnostic test accuracy (in terms of sensitivity and specificity) of three CSF markers (CSF total tau, CSF phosphorylated tau, and CSF Aβ1-42) is determined by relating the particular marker to a reference diagnosis. The reference diagnosis is determined by a consensus procedure among experts based on clinical information on the course of symptoms over a two-year time period.	baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Demographic changes at 2 years	Course of cognitive symptoms, Civil status, and Living situation are assessed.	baseline, 1 year follow up, 2 year follow up
General clinical changes at 2 years	Smoking behaviour, alcohol intake, length, weight, blood pressure, neuropsychological problems, and co-morbidities are assessed.	baseline, 1 year follow up, 2 year follow up
Change in behavioural and psychological problems at 2 years	Measured by the Neuropsychiatric Inventory (NPI).	baseline, 1 year follow up, 2 year follow up
Change in basic and instrumental activities in daily activities at 2 years	Measured by the Disability assessment for Dementia (DAD).	baseline, 1 year follow up, 2 year follow up
Change in depression at 2 years	Measured by the geriatric depression scale 15 (GDS-15).	baseline, 1 year follow up, 2 year follow up
Change in cognitive functioning at 2 years	A neuropsychological examination is performed using the: Rey's Verbal Learning Test, Visual Association Test, and Digit-Span to assess memory;; Letter Digit Substitution Test to assess mental processing rate; and; Stroop Color-Word Test and Trail Making Test to assess attention, concentration and interference.	baseline, 1 year follow up, 2 year follow up
Change in sense of competence at 2 years	Measured by the Sense of Competence Questionnaire (SoCQ).	baseline, 1 year follow up, 2 year follow up
Change in Care-related quality of life	Assessed by the CarerQol by the informal caregiver.	baseline, 3 months follow up, 1 year follow up, 2 year follow up

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: Radboud University Medical Center; Amsterdam UMC, location VUmc; Leiden University Medical Center; Center for Translational Molecular Medicine

Publications and helpful links

General Publications

• Handels RL, Aalten P, Wolfs CA, OldeRikkert M, Scheltens P, Visser PJ, Joore MA, Severens JL, Verhey FR. Diagnostic and economic evaluation of new biomarkers for Alzheimer's disease: the research protocol of a prospective cohort study. BMC Neurol. 2012 Aug 10;12:72. doi: 10.1186/1471-2377-12-72.

Helpful Links

• organizational framework for the study

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: September 20, 2011
• First Submitted That Met QC Criteria: October 10, 2011
• First Posted (Estimate): October 12, 2011

Study Record Updates

• Last Update Posted (Estimate): May 28, 2015
• Last Update Submitted That Met QC Criteria: May 27, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Alzheimer's disease; Diagnosis; Costs; Benefits; subjective and/or objective memory complaints
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Dementia; Tauopathies; Alzheimer Disease; Neurodegenerative Diseases
• Other Study ID Numbers: 09-3-038; 02N-101 (Other Grant/Funding Number: Center for Translational Molecular Medicine (CTMM))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No