Health Technology Assessment of Diagnostic Approaches in Alzheimer's Disease

Study Overview
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Brief Summary
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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.

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

Conditions
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Neurodegenerative Diseases, Memory Disturbances

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| total patient group<br>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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, Diagnosis, Costs, Benefits, subjective and/or objective memory complaints