Introduction: The study aimed to determine the room for improvement of a perfect cerebrospinal fl... more Introduction: The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment. Methods: A decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add-on test when current practice concluded the presence or absence of AD. Results: The simulated MCI population was aged on average 68.3 and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, V33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3-year delay in dementia conversion. Discussion: The results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses explored different CSF positions.
Keywords: Early diagnosis service use dementia mild cognitive impairment latent class analysis a ... more Keywords: Early diagnosis service use dementia mild cognitive impairment latent class analysis a b s t r a c t Objectives: Understanding which persons most likely use particular combinations of service types is important as this could lead to a better understanding of care pathways. The aim of this study is to identify combinations of service use within a sample of community-dwelling people with mild cognitive impairment (MCI) and dementia and identify factors related to these service use combinations. Methods: A latent class analysis performed at baseline on a merged dataset (n ¼ 530) was used to classify care recipients based on following service use types: general practitioner visits, physiotherapist visits, hospital outpatient specialist visits, emergency room visits, hospital inpatient visits with stay over, day care visits, use of domestic homecare, use of personal homecare, and informal care on (instrumental) activities of daily living. Multinomial logistic regression was performed to identify factors associated with service use combinations using clinical characteristics of the care recipient and demographic characteristics of the care recipient and caregiver. Results: Three service use classes were identified; a formal homecare class (10% of participants), an informal care class (46% of participants), and a low user class (44% of participants). Factors increasing the likelihood of being in the formal homecare class compared with the low service use class included a diagnosis of MCI or dementia, activities of daily living impairment, older age of the care recipient, and care recipient not living together with the caregiver. Conclusions: Besides a diagnosis of MCI or dementia, other factors (activities of daily living impairment, age, and living situation) were associated with service use. We recommend using these factors alongside the diagnostic label for care indication.
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 9, 2015
The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biom... more The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment. A decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add-on test when current practice concluded the presence or absence of AD. The simulated MCI population was aged on average 68.3% and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, €33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3-year delay in dementia conversion. The results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 9, 2015
The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biom... more The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment. A decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add-on test when current practice concluded the presence or absence of AD. The simulated MCI population was aged on average 68.3% and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, €33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3-year delay in dementia conversion. The results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses...
Disease modifying drugs for Alzheimer's disease (AD) are likely to be most effective when given i... more Disease modifying drugs for Alzheimer's disease (AD) are likely to be most effective when given in non-demented subjects. In this review we summarized biomarkers in cerebrospinal fluid (CSF) and blood that can predict AD-type dementia in subjects with mild cognitive impairment (MCI). In addition, we investigated whether these markers could reduce sample size and costs if used to select subjects for trials on the prevention of AD in subjects with MCI. A meta-analysis of markers that had been investigated in multiple studies showed that the combination of amyloid-β (Aβ)1−42 and tau in CSF had the best predictive accuracy for AD (odds ratio (OR) 18.1, 95% confidence interval (CI) 9.6-32.4). Aβ1−42, total tau, and phosphorylated tau in CSF also predicted conversion, but with lower accuracy (OR 7.5 to 8.1). Plasma levels of Aβ1−40, Aβ1−42, the ratio Aβ1−42/Aβ1−40 and homocysteine did not predict outcome. In a fictive trial design, the use of the combination of Aβ1−42 and tau in CSF in the selection of subjects could reduce sample size by 67% and trial costs by 60% compared to a trial in which unselected subjects with MCI would be enrolled. In conclusion, the combination of Aβ1−42 and tau in CSF is useful to select subjects for trials that aim to slow down the progression from MCI to AD-type dementia.
Background: In the absence of a gold standard, a panel of experts can be invited to assign a refe... more Background: In the absence of a gold standard, a panel of experts can be invited to assign a reference diagnosis for use in research. Available literature offers limited guidance on assembling and working with an expert panel for this purpose. We aimed to develop a protocol for an expert panel consensus diagnosis and evaluated its applicability in a pilot project. Methods: An adjusted Delphi method was used, which started with the assessment of clinical vignettes by 3 experts individually, followed by a consensus discussion meeting to solve diagnostic discrepancies. A panel facilitator ensured that all experts were able to express their views, and encouraged the use of argumentation to arrive at a specific diagnosis, until consensus was reached by all experts. Eleven vignettes of patients suspected of having a primary neurodegenerative disease were presented to the experts. Clinical information was provided stepwise and included medical history, neurological, physical and cognitive function, brain MRI scan, and follow-up assessments over 2 years. After the consensus discussion meeting, the procedure was evaluated by the experts. Results: The average degree of consensus for the reference diagnosis increased from 52% after individual assessment of the vignettes to 94% after the consensus discussion meeting. Average confidence in the diagnosis after individual assessment was 85%. This did not increase after the consensus discussion meeting. The process evaluation led to several recommendations for improvement of the protocol. Conclusion: A protocol for attaining a reference diagnosis based on expert panel consensus was shown feasible in research practice.
Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)... more Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (A)1-42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF A1-42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF A1-42/tau increased predictive accuracy in subjects with normal HCV (p Ͻ 0.001) and abnormal HCV (p ϭ 0.025). HCV increased predictive accuracy only in subjects with normal CSF A1-42/tau (p ϭ 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD.
atrophy, lower BMI, worse cognition, higher tau, and lower Ab 42 . We found that delayed onset in... more atrophy, lower BMI, worse cognition, higher tau, and lower Ab 42 . We found that delayed onset in AD subjects was related to decreased tau, lower BMI, and better cognitive performance (Table 3, ). We then grouped subjects into "extraordinary delayers" -25 AD and 38 non-AD subjects who had at least a five-year delay between predicted and actual onsetcompared to all other 380 subjects. "Delayers" had significantly lower BMI, lower cognitive performance, lower Ab 42, and more AD-like atrophy . Since the high proportion of AD subjects was a potential confound, we repeated this analysis with just the non-AD subjects. Only lower BMI remained significantly different in the "delayer" group. Conclusions: It was possible to forecast the age of clinical symptoms with a correlation of over 0.3 using variation in the APOE gene. Contrary to previous evidence implicating hypertension in increased risk, we found no clear relationship with blood pressure and accelerated onset. We found no protective effect from more years of education. We also found a consistent relationship that lower BMI is associated with delayed onset ). In other cohorts, a higher risk of developing dementia was associated with mid-life obesity (Profenno 2010), but this relationship may reverse in old age, due to weight loss associated with dementia (Buchman 2005; Tolppanen 2014). However, our results suggest that lower BMI is protective, even in subjects without AD.
Background: New research criteria for the diagnosis of Alzheimer's disease (AD) have recently bee... more 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 MRI, PET and CSF, 2) perform a cost-consequence analysis and 3) assess long-term cost-effectiveness by an economic model. Methods/design: In a cohort design 241 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, costs and emerging biomarkers are gathered. Diagnostic test accuracy is determined by relating the clinical practice and new research criteria diagnoses to a 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 built 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.
The objective of this study is to systematically review the literature on economic evaluations of... more The objective of this study is to systematically review the literature on economic evaluations of interventions for the early diagnosis of Alzheimer's disease (AD) and related disorders and to describe their general and methodological characteristics. We focused on the diagnostic aspects of the decision models to assess the applicability of existing decision models for the evaluation of the recently revised diagnostic research criteria for AD. PubMed and the National Institute for Health Research Economic Evaluation database were searched for English-language publications related to economic evaluations on diagnostic technologies. Trial-based economic evaluations were assessed using the Consensus on Health Economic Criteria list. Modeling studies were assessed using the framework for quality assessment of decision-analytic models. The search retrieved 2109 items, from which eight decision-analytic modeling studies and one trial-based economic evaluation met all eligibility criteria. Diversity among the study objective and characteristics was considerable and, despite considerable methodological quality, several flaws were indicated. Recommendations were focused on diagnostic aspects and the applicability of existing models for the evaluation of recently revised diagnostic research criteria for AD.
[(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET... more [(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET measure fibrillar amyloid-β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population. One hundred fifty-four patients underwent paired dynamic [(11)C]PIB and static [(18)F]FDG PET scans shortly after completing a standard dementia screening. Two-year clinical follow-up data were available for 39 patients. Parametric PET images were assessed visually and results were reported to the neurologists responsible for the initial diagnosis. Outcome measures were (change in) clinical diagnosis and confidence in that diagnosis before and after disclosing PET results. [(11)C]PIB scans were positive in 40 of 66 (61%) patients with a clinical diagnosis of Alzheimer's disease (AD), 5 of 18 (28%) patients with frontotemporal dementia (FTD), 4 of 5 (80%) patients with Lewy body dementia, and 3 of 10 (30%) patients with other dementias. [(18)F]FDG uptake patterns matched the clinical diagnosis in 38 of 66 (58%) of AD patients, and in 6 of 18 (33%) FTD patients. PET results led to a change in diagnosis in 35 (23%) patients. This only occurred when prior diagnostic certainty was <90%. Diagnostic confidence increased from 71 ± 17% before to 87 ± 16% after PET (p < .001). Two-year clinical follow-up (n = 39) showed that [(11)C]PIB and [(18)F]FDG predicted progression to AD for patients with mild cognitive impairment, and that the diagnosis of dementia established after PET remained unchanged in 96% of patients. In a memory clinic setting, combined [(11)C]PIB and [(18)F]FDG PET are of additional value on top of the standard diagnostic work-up, especially when prior diagnostic confidence is low.
Dementia causes a high burden on patients, caregivers, and societies. Decision analytic models to... more Dementia causes a high burden on patients, caregivers, and societies. Decision analytic models to support allocation of resources are often developed making use of cost-of-illness (COI) studies. However, current COI study estimates are highly variable due to care setting and methodological issues. We aim to explore variables explaining the variation of (formal and informal) health care costs of cognitive disorders, using a broad spectrum of variables, including patient, caregiver, and social context variables. A bottom-up COI study design was used in which a societal viewpoint and a validated method to measure and value informal care was applied. Data were analyzed using univariate, multivariate, and forward regression analyses. The average 1-year health care sector costs were &OV0556;26,140 ($34,505 or £17,775) and &OV0556;11,931 ($15,749 or £8113) for patient and family. The analyses indicated that cognitive functioning, caregiver burden, patient sex, and instrumental activities of daily living were significantly associated with care costs independently. Cognitive functioning and instrumental activities of daily living are important variables to include in health care decision models. We recommend also including caregiver burden and patient sex in decision models for health policy decision makers to fully reflect the heterogeneity of the disease progression of cognitive disorders.
Introduction: The study aimed to determine the room for improvement of a perfect cerebrospinal fl... more Introduction: The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment. Methods: A decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add-on test when current practice concluded the presence or absence of AD. Results: The simulated MCI population was aged on average 68.3 and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, V33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3-year delay in dementia conversion. Discussion: The results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses explored different CSF positions.
Keywords: Early diagnosis service use dementia mild cognitive impairment latent class analysis a ... more Keywords: Early diagnosis service use dementia mild cognitive impairment latent class analysis a b s t r a c t Objectives: Understanding which persons most likely use particular combinations of service types is important as this could lead to a better understanding of care pathways. The aim of this study is to identify combinations of service use within a sample of community-dwelling people with mild cognitive impairment (MCI) and dementia and identify factors related to these service use combinations. Methods: A latent class analysis performed at baseline on a merged dataset (n ¼ 530) was used to classify care recipients based on following service use types: general practitioner visits, physiotherapist visits, hospital outpatient specialist visits, emergency room visits, hospital inpatient visits with stay over, day care visits, use of domestic homecare, use of personal homecare, and informal care on (instrumental) activities of daily living. Multinomial logistic regression was performed to identify factors associated with service use combinations using clinical characteristics of the care recipient and demographic characteristics of the care recipient and caregiver. Results: Three service use classes were identified; a formal homecare class (10% of participants), an informal care class (46% of participants), and a low user class (44% of participants). Factors increasing the likelihood of being in the formal homecare class compared with the low service use class included a diagnosis of MCI or dementia, activities of daily living impairment, older age of the care recipient, and care recipient not living together with the caregiver. Conclusions: Besides a diagnosis of MCI or dementia, other factors (activities of daily living impairment, age, and living situation) were associated with service use. We recommend using these factors alongside the diagnostic label for care indication.
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 9, 2015
The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biom... more The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment. A decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add-on test when current practice concluded the presence or absence of AD. The simulated MCI population was aged on average 68.3% and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, €33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3-year delay in dementia conversion. The results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 9, 2015
The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biom... more The study aimed to determine the room for improvement of a perfect cerebrospinal fluid (CSF) biomarker and the societal incremental net monetary benefit of CSF in subjects with mild cognitive impairment (MCI) assuming a hypothetical disease-modifying Alzheimer's disease (AD) treatment. A decision model compared current practice to a perfect biomarker and to two strategies positioning CSF as add-on test when current practice concluded the presence or absence of AD. The simulated MCI population was aged on average 68.3% and 49% had AD. The room for improvement by the perfect CSF test was 0.39 quality adjusted life years, €33,622 ($43,372) savings, 2.0 potential beneficial treatment years, and 1.3-year delay in dementia conversion. The results indicated more potential benefit from a biomarker positioned to verify subjects who are not expected to have AD (i.e., to prevent undertreatment) rather than to verify subjects expected to have AD (prevent overtreatment). Sensitivity analyses...
Disease modifying drugs for Alzheimer's disease (AD) are likely to be most effective when given i... more Disease modifying drugs for Alzheimer's disease (AD) are likely to be most effective when given in non-demented subjects. In this review we summarized biomarkers in cerebrospinal fluid (CSF) and blood that can predict AD-type dementia in subjects with mild cognitive impairment (MCI). In addition, we investigated whether these markers could reduce sample size and costs if used to select subjects for trials on the prevention of AD in subjects with MCI. A meta-analysis of markers that had been investigated in multiple studies showed that the combination of amyloid-β (Aβ)1−42 and tau in CSF had the best predictive accuracy for AD (odds ratio (OR) 18.1, 95% confidence interval (CI) 9.6-32.4). Aβ1−42, total tau, and phosphorylated tau in CSF also predicted conversion, but with lower accuracy (OR 7.5 to 8.1). Plasma levels of Aβ1−40, Aβ1−42, the ratio Aβ1−42/Aβ1−40 and homocysteine did not predict outcome. In a fictive trial design, the use of the combination of Aβ1−42 and tau in CSF in the selection of subjects could reduce sample size by 67% and trial costs by 60% compared to a trial in which unselected subjects with MCI would be enrolled. In conclusion, the combination of Aβ1−42 and tau in CSF is useful to select subjects for trials that aim to slow down the progression from MCI to AD-type dementia.
Background: In the absence of a gold standard, a panel of experts can be invited to assign a refe... more Background: In the absence of a gold standard, a panel of experts can be invited to assign a reference diagnosis for use in research. Available literature offers limited guidance on assembling and working with an expert panel for this purpose. We aimed to develop a protocol for an expert panel consensus diagnosis and evaluated its applicability in a pilot project. Methods: An adjusted Delphi method was used, which started with the assessment of clinical vignettes by 3 experts individually, followed by a consensus discussion meeting to solve diagnostic discrepancies. A panel facilitator ensured that all experts were able to express their views, and encouraged the use of argumentation to arrive at a specific diagnosis, until consensus was reached by all experts. Eleven vignettes of patients suspected of having a primary neurodegenerative disease were presented to the experts. Clinical information was provided stepwise and included medical history, neurological, physical and cognitive function, brain MRI scan, and follow-up assessments over 2 years. After the consensus discussion meeting, the procedure was evaluated by the experts. Results: The average degree of consensus for the reference diagnosis increased from 52% after individual assessment of the vignettes to 94% after the consensus discussion meeting. Average confidence in the diagnosis after individual assessment was 85%. This did not increase after the consensus discussion meeting. The process evaluation led to several recommendations for improvement of the protocol. Conclusion: A protocol for attaining a reference diagnosis based on expert panel consensus was shown feasible in research practice.
Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)... more Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (A)1-42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF A1-42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF A1-42/tau increased predictive accuracy in subjects with normal HCV (p Ͻ 0.001) and abnormal HCV (p ϭ 0.025). HCV increased predictive accuracy only in subjects with normal CSF A1-42/tau (p ϭ 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD.
atrophy, lower BMI, worse cognition, higher tau, and lower Ab 42 . We found that delayed onset in... more atrophy, lower BMI, worse cognition, higher tau, and lower Ab 42 . We found that delayed onset in AD subjects was related to decreased tau, lower BMI, and better cognitive performance (Table 3, ). We then grouped subjects into "extraordinary delayers" -25 AD and 38 non-AD subjects who had at least a five-year delay between predicted and actual onsetcompared to all other 380 subjects. "Delayers" had significantly lower BMI, lower cognitive performance, lower Ab 42, and more AD-like atrophy . Since the high proportion of AD subjects was a potential confound, we repeated this analysis with just the non-AD subjects. Only lower BMI remained significantly different in the "delayer" group. Conclusions: It was possible to forecast the age of clinical symptoms with a correlation of over 0.3 using variation in the APOE gene. Contrary to previous evidence implicating hypertension in increased risk, we found no clear relationship with blood pressure and accelerated onset. We found no protective effect from more years of education. We also found a consistent relationship that lower BMI is associated with delayed onset ). In other cohorts, a higher risk of developing dementia was associated with mid-life obesity (Profenno 2010), but this relationship may reverse in old age, due to weight loss associated with dementia (Buchman 2005; Tolppanen 2014). However, our results suggest that lower BMI is protective, even in subjects without AD.
Background: New research criteria for the diagnosis of Alzheimer's disease (AD) have recently bee... more 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 MRI, PET and CSF, 2) perform a cost-consequence analysis and 3) assess long-term cost-effectiveness by an economic model. Methods/design: In a cohort design 241 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, costs and emerging biomarkers are gathered. Diagnostic test accuracy is determined by relating the clinical practice and new research criteria diagnoses to a 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 built 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.
The objective of this study is to systematically review the literature on economic evaluations of... more The objective of this study is to systematically review the literature on economic evaluations of interventions for the early diagnosis of Alzheimer's disease (AD) and related disorders and to describe their general and methodological characteristics. We focused on the diagnostic aspects of the decision models to assess the applicability of existing decision models for the evaluation of the recently revised diagnostic research criteria for AD. PubMed and the National Institute for Health Research Economic Evaluation database were searched for English-language publications related to economic evaluations on diagnostic technologies. Trial-based economic evaluations were assessed using the Consensus on Health Economic Criteria list. Modeling studies were assessed using the framework for quality assessment of decision-analytic models. The search retrieved 2109 items, from which eight decision-analytic modeling studies and one trial-based economic evaluation met all eligibility criteria. Diversity among the study objective and characteristics was considerable and, despite considerable methodological quality, several flaws were indicated. Recommendations were focused on diagnostic aspects and the applicability of existing models for the evaluation of recently revised diagnostic research criteria for AD.
[(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET... more [(11)C]Pittsburgh compound B ([(11)C]PIB) and [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) PET measure fibrillar amyloid-β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population. One hundred fifty-four patients underwent paired dynamic [(11)C]PIB and static [(18)F]FDG PET scans shortly after completing a standard dementia screening. Two-year clinical follow-up data were available for 39 patients. Parametric PET images were assessed visually and results were reported to the neurologists responsible for the initial diagnosis. Outcome measures were (change in) clinical diagnosis and confidence in that diagnosis before and after disclosing PET results. [(11)C]PIB scans were positive in 40 of 66 (61%) patients with a clinical diagnosis of Alzheimer's disease (AD), 5 of 18 (28%) patients with frontotemporal dementia (FTD), 4 of 5 (80%) patients with Lewy body dementia, and 3 of 10 (30%) patients with other dementias. [(18)F]FDG uptake patterns matched the clinical diagnosis in 38 of 66 (58%) of AD patients, and in 6 of 18 (33%) FTD patients. PET results led to a change in diagnosis in 35 (23%) patients. This only occurred when prior diagnostic certainty was <90%. Diagnostic confidence increased from 71 ± 17% before to 87 ± 16% after PET (p < .001). Two-year clinical follow-up (n = 39) showed that [(11)C]PIB and [(18)F]FDG predicted progression to AD for patients with mild cognitive impairment, and that the diagnosis of dementia established after PET remained unchanged in 96% of patients. In a memory clinic setting, combined [(11)C]PIB and [(18)F]FDG PET are of additional value on top of the standard diagnostic work-up, especially when prior diagnostic confidence is low.
Dementia causes a high burden on patients, caregivers, and societies. Decision analytic models to... more Dementia causes a high burden on patients, caregivers, and societies. Decision analytic models to support allocation of resources are often developed making use of cost-of-illness (COI) studies. However, current COI study estimates are highly variable due to care setting and methodological issues. We aim to explore variables explaining the variation of (formal and informal) health care costs of cognitive disorders, using a broad spectrum of variables, including patient, caregiver, and social context variables. A bottom-up COI study design was used in which a societal viewpoint and a validated method to measure and value informal care was applied. Data were analyzed using univariate, multivariate, and forward regression analyses. The average 1-year health care sector costs were &OV0556;26,140 ($34,505 or £17,775) and &OV0556;11,931 ($15,749 or £8113) for patient and family. The analyses indicated that cognitive functioning, caregiver burden, patient sex, and instrumental activities of daily living were significantly associated with care costs independently. Cognitive functioning and instrumental activities of daily living are important variables to include in health care decision models. We recommend also including caregiver burden and patient sex in decision models for health policy decision makers to fully reflect the heterogeneity of the disease progression of cognitive disorders.
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Papers by Ron Handels