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Journal of Alzheimer’s Disease 42 (2014) 1311–1324 DOI 10.3233/JAD-131556 IOS Press

Alzheimer’s Disease Costs: What We Know and What We Should Take into Account Luisa Coluccia,b , Massimiliano Boscob , Angiola Maria Fasanarob , Giuseppe Lucio Gaetac , Giovanna Riccid and Francesco Amentaa,∗ a Centro

Ricerche Cliniche, Telemedicina e Telefarmacia, Universit`a di Camerino, Camerino, Italy

b Unit` a Valutativa Alzheimer e Malattie Involutive Cerebrali, Azienda Ospedaliera Rilievo Nazionale A. Cardarelli,

Napoli, Italy di Scienze Sociali ed Umane, Universit`a di Napoli l’Orientale, Napoli, Italy di Giurisprudenza, Universit`a di Camerino, Camerino, Italy

c Dipartimento d Scuola

Handling Associate Editor: Richard Dodel

Accepted 8 May 2014

Abstract. Background/Objective: Alzheimer’s disease (AD) is a very costly pathology. Total costs of AD result from the sum of direct and indirect costs. Intangible costs represent an additional burden that is difficult to quantify. This paper has reviewed the evaluation of the costs of AD and the methodologies to estimate them, and proposes the use of some tools which may be useful in establishing the financial weight of the disease. Method: A systematic literature search was conducted using the Pubmed and Medline databases as a source of published papers. Results: In AD, direct and indirect costs and their sum (total costs) are very high and tend to increase parallel with the evolution of the pathology. The evolution of AD is characterized by the loss of functional autonomy, the onset of behavioral and sleep disorders, and the development of delusions and hallucinations. This requires more frequent medical examinations and hospitalizations resulting in higher direct costs, which become the relevant weight. None of the papers reviewed investigated intangible cost. Conclusion: The calculation of costs of AD is frequently based on cognitive decline and the degree of dependence of patients. The evaluation of intangible costs (psychological pain of the patient and of the unpaid caregivers’ and their impaired quality of life) is a missing aspect in all reviewed studies. Due to the complexity of AD, it will be necessary to adopt cost evaluation systems including the different dimensions of the problem and its various aspects. Keywords: Costs of Alzheimer’s disease, direct costs, evaluation costs, indirect costs, intangible costs, total costs

INTRODUCTION “If dementia care were a country, it would be the world’s 18th largest economy” [1]. This statement of the Alzheimer’s Association highlights the magnitude of the economic burden of dementia which is doomed to increase dramatically in the near future. It was been estimated that 35.6 million people live ∗ Correspondence to: Francesco Amenta, Centro Ricerche Cliniche, Telemedicina e Telefarmacia, Universit`a di Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Italy. Tel.: +39 0737 403 311; Fax: +39 0737 403 325; E-mail: [email protected].

with dementia worldwide [2]. They are estimated to be 65.7 million in 2030 and 115.4 million in 2050 [2], and this disease will probably reach third place in terms of total costs after cancer and cardiovascular disorders [3]. Alzheimer’s disease (AD) therefore represents a very relevant challenge both from a medical and an economical perspective. Several studies have tried to evaluate the costs related to the disease with the vast majority dividing them between direct and indirect costs. Direct costs are related to the money spent on the diagnosis, follow up, and treatment of patients. They include the expenses for health services,

ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved

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pharmacotherapy, and hospitalization, as well as those of the possible institutionalization. Indirect costs are related to the resources lost because of the disease, such as the loss of productivity in case patients still work. They also include the reduced productivity in those family members who provide unpaid assistance to the ill person. The sum of direct and indirect costs represents the total costs of the disease. However, other costs should be included in the global economic evaluation: they are related to the psychological pain of the patient and of the unpaid caregivers’ and to their impaired quality of life. These aspects, even if difficult to translate in economic values, are relevant and deserve attention [4]. Their monetary assessment, in fact, not only reflects an important aspect of the disease burden, but may significantly encourage families to postpone or avoid as much as possible the institutionalization of their relatives. Several reviews articles have analyzed the costs of the disease and discussed methods adopted and cost-effectiveness of different drug treatments. These reviews confirm the costly character of AD: with the annual total cost per patient varying from 2,935 to 52,954 US dollars ($) [5]. The annual total costs increase with disease severity. Direct costs are associated with cognitive and functional status; the functional status is also associated with indirect costs [6]. Similar results were reported by another work of J¨onsson that emphasized the need to standardize methods for assessing costs [7]. The aim of this paper was to offer an updated and systematic analysis of the literature on the costs related to AD and, in general, to adult-onset dementia disorders and on the tools used for their evaluation. Differently from previous review articles, we limited our analysis to clinical trials on the topic. The relevant limits found in the studies examined in terms of scarce consideration given to intangible costs are also highlighted. In conclusion, some methods which might be applied to acquire a better knowledge of AD’s total cost are suggested.

STUDIES SELECTION A systematic literature search was conducted on the PubMed and Medline databases using the following entries: “direct costs in AD”, “indirect costs in AD”, “total costs in AD”, “intangible costs in AD” and the MeSH terms listed below: Alzheimer Disease/economics, Cost of Illness/Alzheimer, Health Expenditures/Alzheimer, Health Care Costs/Alzhei-

mer. Limits applied were: English language, at least one keyword corresponding to the above entries in the title/abstract, and study based on the evaluation of clinical trials. The analysis was carried out in November 2013 and included the 5-year period between 2008 and 2013. All articles were selected to obtain a costs evaluation of AD. Identified papers were further selected using the criteria of the Newcastle-Ottawa Scale that allows the assessment of the methodological quality of comparative studies and of case control studies. Overall study quality was defined as poor (score 0–4), moderate (5–6), or good (7–9) [8]. Excluded articles are summarized in Table 1. The main findings obtained in eligible studies were summarized in a tabular format. On the whole, we have found 4 papers for MeSH terms (Table 2) and 13 papers for others keys words such as “direct costs”, “total costs”, and “indirect cost” (Tables 3 and 4).

REVIEW OF SELECTED STUDIES Patient-level cost of illness studies A summary of the most relevant features of the patient-level cost of illness studies analyzed is reported in Table 3. Gustavsson and coworkers [9] provided an empirical assessment of direct and indirect societal costs of AD using data collected through a survey carried out in four countries (Spain, Sweden, the United Kingdom, and the United States) and involving 1,222 patients. Direct and indirect costs were calculated by measuring the patients’ health care resource utilization during the 30 days before the visit. Medical care (AD medication, hospitalizations, emergency care, and outpatient care visits), community care (patient accommodation, respite care, and other community care services), and informal care were considered. Direct costs were calculated looking at the prices of resources that were consumed. Informal care value was considered the loss of productivity for the caregivers who gave up work to care for the patient and the value of leisure time for the remainder caregiving time. Mean cost estimates vary across countries and increase with the severity of disease for patients in community dwellings. Estimates range from 1,000 UK Pounds (£) (real £ using the Purchasing Price Parity adjusted to the real exchange rates in 2007) per patient and month for mild patients living in the community, to 5,000£ for patients living in residential care settings.

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Table 1 List of papers excluded from analysis because they did not estimate the costs of AD Keyword

Articles excluded

Alzheimer/Economics Van Houtven CH et al., Gerontologist, 2013 Pitk¨al¨a KH et al., JAMA Intern Med, 2013 Søgaard R et al., BMC Health Serv Res, 2009 Cost of Illness/Alzheimer Glueckauf RL et al., Rehabil Psychol, 2012 Frakey LL et al., J Clin Psychiatry, 2012 Cheng ST et al., Trials, 2012 Meeuwsen EJ et al., BMJ, 2012 Van Houtven CH et al., Gerontologist, 2013 Mohamed S et al., J Clin Psychiatry, 2012 Montgomery RJ et al., J Gerontol B Psychol Sci Soc Sci, 2011 Vreugdenhil A et al., Scand J Caring Sci, 2012 Mart´ın-Carrasco M et al., Int J Geriatr Psychiatry, 2009 Lavretsky H et al., Am J Geriatr Psychiatry, 2010 Martin-Carrasco M et al., Aging Ment Health, 2010 Health Care Costs/Alzheimer Van Houtven CH et al., Gerontologist, 2013 Pitkala K et al., Trials, 2010 Kopits IM et al., Genet Test Mol Biomarkers, 2011 Pitk¨al¨a KH et al., JAMA Intern Med, 2013 Søgaard R et al., BMC Health Serv Res, 2009 Health Expenditures/Alzheimer Van Houtven CH et al., Gerontologist, 2013 Direct Costs/Alzheimer Zhu CW et al., J Am Geriatr Soc, 2013 Frakey LL et al., J Clin Psychiatry, 2012 Van Houtven CH et al., Gerontologist, 2013 Bergvall N et al., Int Psychogeriatr, 2011 Voisin T et al., J Nutr Health Aging, 2010 Zhu CW et al., J Nutr Health Aging, 2009 Lachaine J et al., Can J Psychiatry, 2011 Indirect Costs/Alzheimer Glueckauf RL et al., Rehabil Psychol, 2012 Grammas P et al., J Neuroinflammation, 2011 Pfeil AM et al., Swiss Med Wkly, 2012 Total Costs/Alzheimer Chiatti C et al., Trials, 2013 Pitk¨al¨a KH et al., JAMA Intern Med, 2013 Mielke MM et al., Neurology, 2012 Cheng ST et al., Trials, 2012 Cummings JL, Neurobiol Aging, 2010 Wilson RS et al., Arch Neurol, 2010 Kunik ME et al., J Clin Psychiatry, 2010 Wolfs CA et al., Arch Gen Psychiatry, 2009 Zhu CW et al., J Am Geriatr Soc, 2013 Lin PJ et al., Med Care, 2009

A statistical analysis was carried out to identify the most important drivers of these costs. The main predictors were the disease severity measures [i.e. Mini-Mental State Examination (MMSE), Disability Assessment in Dementia (DAD), and Neuropsychiatric Inventory (NPI)]. These tests were used together with covariates such as patients’ characteristics, caregivers’ characteristics, and country fixed effects. The DAD was the most important predictor of costs of care of community dwelling patients. A one-point decrease

on the DAD scale resulted in a 1.4 to 2% increase in costs on average, 32 or a 45% increase from a standard deviation decrease on DAD. NPI-severity and MMSE as well had a significant impact on costs but the effects sizes were smaller. Miller and coworkers [10] provided an estimation of AD direct costs using data collected through the Clinical Antipsychotic Trial of Intervention Effectiveness. Analysis was made in 42 sites in the United States involving 421 ambulatory outpatients with a diagnosis

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L. Colucci et al. / Costs of AD Table 2 Papers evaluated for mesh terms

First Author Gustavsson [9] Miller [10] Coduras [15] Reese [17]

Mesh terms Alzheimer Disease/economics Alzheimer Disease/economics Alzheimer Disease/economics Alzheimer Disease/economics

of AD (MMSE 5–26) who lived with at least one caregiver. Data collection was longitudinal and each patient was interviewed three times over nine months. Interviews allowed to collect information concerning the patients’ use over the last 30 days of a wide variety of services, including nights spent in hospitals, nursing homes, and residential care facilities, other forms of community supports, mental health services, medical and surgical visits, and ancillary medications. All these services/goods were assigned a cost looking at unitary costs derived from published reports and administrative data sets in order to carry out the estimation of direct (health care system perspective) costs of AD. The results indicated an average of AD total direct costs of 1,205 US Dollars ($)/month per patient. Institutional care represented the 62.6% of monthly total costs; outpatient care the 20.1%; and ancillary drugs the 17.3%. In general, nursing home, residential care, and drug costs increased steadily through the 9 months considered, reflecting the progression of cognitive impairment as documented by average declines in MMSE and AD Cooperative Study – Activities of Daily Living (ADCS-ADL). The authors also carried out a statistical analysis looking for covariates significantly related with the estimated total costs. A wide set of covariates, including measures of patients’ social-demographic characteristics, global cognitive functioning, psychiatric symptoms, physical functioning, quality of life, and quality of health, was assessed. Improvement of the individual health status as measured by the Health Utilities Index (HUI)-III, is associated with reduction in total costs. A one-point increase on the quality of life as measured by the AD-Related Quality of Life Scale (ADRQoL index) is significantly associated with increases in ancillary drug purchase and total costs. A rise of activities of daily living (as measured by the ADCS-ADL index) was significantly associated with declines in total costs. Gillespie and coworkers [11] estimated the costs of formal and informal care for AD using data gathered through the Enhancing Care in AD (ECAD) study [12]. Data were collected using structured questionnaires and medical assessments involving a sample of 100

Irish patients with AD or mild cognitive impairment interviewed in 2009 over a period of 6 months. Formal health and social care costs were calculated as resulting from general practice visits, hospitalizations, outpatient clinic consultations, accident and emergency visits, respite care, meals on wheels services, and additional health and social care professional consultations. All these services/goods were estimated using unit cost data calculated from a variety of national Irish data sources. Moreover, informal care costs were considered as resulting from caregiving hours provided by the primary carer for each patient, measured by the Resource Utilization in Dementia Lite (RUD) instrument [13]. Hours of informal care provided by employed carers were valued using the opportunity cost method whereas those provided by the unemployed were valued at opportunity cost of leisure time, proxied as a percentage (25%) of the average industrial wage per hour. The study reported that the average total cost for was 6,955 European Union Euros (D ) per patient over six months (1,845 D for health and social care plus 4,959 D for informal care, all data are expressed at 2008 currency value). A multivariate generalized linear model regression framework was adopted to explore the effects on total costs of a wide set of independent variables. Patient dependence measured by the dependence scale (DS), patient function (DAD scale), MMSE, and a range of other clinical and sociodemographic measures. The results show that both DS and DAD scores are positively and significantly associated with total cost over 6 months. Rapp and coworkers [14] used data drawn from the PLASA study (Plan de Soin et d’Aide sp´ecifique a` la maladie d’Alzheimer), a large randomized trial involving 1,131 patients with mild to moderate AD recruited between June 2003 and July 2005 from 50 French memory clinics. The data are longitudinal: each patient was interviewed three times over 2 years. The authors provide an estimation of AD total per patient cost as resulting from the sum of direct medical costs, direct non-medical costs, and informal costs. Direct medical and non-medical costs include the use of day care, alarm services, home help, and day/night surveillance. Medical costs included costs associated with inpatient and outpatient hospital visits, physician visits, speech therapist visits, physical therapist visits, nurse visits, and medication use. Informal costs arose from surveillance, Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL). During each interview, the use of the above resource/goods for the previous month was registered. The value of

Herrmann et al. [16]

903 patients (Canada)

Coduras et 560 patients al. [15] (Spain)

Rapp et al. 1,131 patients [14] (France)

Diagnosis of possible Societal or probable AD, consistent with DSM-IV 290.00 or 290.10 and NINCDS-ADRDA criteria. DSM-IV, diagnosis of Societal dementia.

Diagnosis of probable Societal or possible AD (according to the NINCDS-ADRDA criteria) or MCI (according to international consensus criteria) and aged >50 y. Diagnosis of AD mild Societal or moderate.

Yes

Yes

Yes

Yes

100 patients (Ireland)

Gillespie et al. [11]

Health care system

Yes

Dementia of the Alzheimer’s type (DSM-IV) and probable AD.

Yes

Yes

Yes

Yes

No

Yes

Perspective

Perspective

Perspective

Perspective

Perspective

Retrospective

Direct Indirect Type of costs costs analysis

421 patients (USA)

Cost perspective

Miller et al. [10]

Diagnosis used to select patients Yes

Sample size

Gustavsson 1,222 patients Clinical diagnosis of Societal et al. [9] (Spain, Sweden, possible or probable UK, USA) AD.

Authors

Total cost estimate

Detailed resource use questionnaires C$367/month per patient for patients were used. Patients were with very mild AD (GDS = 2), interviewed at baseline and every 6 C$4,063/month per patient for months over a total of 36 months. patients with severe or very severe AD (2000 Canadian $).

The RUD 2.0 questionnaire was used. Patients were interviewed three times over 2 years.

EU D 2,918/ month per patient at baseline, EU D 3,112/month per patient at year 1, and EU D 4,101/month per patient at year 2 (2007 euros). The RUD questionnaire was used. EU D 1,425.73/month per patient Three visits: baseline, 6 and 12 (2006 euros). It increased by months after inclusion in the study, 10.08% at the end of the study. with an additional visit 4–8 weeks after initiating the study.

The Resource Use in Dementia UK £1,000/month per patient for (RUD) Lite questionnaire was used mild patients living in the to interview the patients about their community (real pounds sterling health care resource utilization using Purchasing Price Parity during the 30 days before the visit. adjusted real exchange rates per 2007). UK £5,000 for patients living in residential care settings. A structured questionnaire was used. $1,205/month per patient (2002 US Patients were interviewed three $). times over nine months and asked about the use of a wide variety of services over the last 30 days. A structured questionnaire was used. EU D 6,955 per patient over six Patients were interviewed over a months (2008 Euros). EU D 1,845 period of 6 months. for health and social care and EU D 4,959 for informal care.

Tools for data collection

Table 3 Studies considering the cost of the disease at the patient level considered. Summary of main features

L. Colucci et al. / Costs of AD 1315

395 patients (Germany)

Reese et al. [17]

Cost perspective

AD + CHF = 240 Diagnosis of AD patients, AD (ICD-9 294.10, only = 664, CHF 294.11, 331.0) only = 712, controls = 2,904 (USA)

Diagnosis of dementia determined with the use of a detailed in-home cognitive assessment.

Health care system

Diagnostic criteria for Societal AD as defined by NINCDS-ADRDA

Diagnosis used to select patients

Yes

Yes

Yes

No

Yes

Yes

Retrospective

Perspective

Retrospective

Direct Indirect Type of costs costs analysis

Total cost estimate

Standardized questionnaires were EU D 3,300 per patient for a three used to collect data concerning all months period (2009 euros). costs associated with AD that Average annual cost is about EU incurred over the prior three D 13,080 per patient. months. Questionnaire used is not specified. $41,689/year per patient when the Data were extracted from the valuation of forgone wages was Health and Retirement Study, an used to cost informal care (2010 American nationally representative US dollars) and $56,290/year per longitudinal survey of persons. patient when the valuation of replacement cost was used to cost informal care. Health resource utilization data and $20,888/y for AD + CHF group (2000 Medicare reimbursements (costs) US dollars), $5473/y for only AD for all care provided and paid for group, $17,700/y for only CHF each person were extracted from group and $4,578/y for the control databases such as the MEDPAR group (no-AD and no-CHF). inpatient care, Outpatient Standard Analytical Files, home health and hospice care and carrier files.

Tools for data collection

AD, Alzheimer’s Disease; CHF, congestive heart failure; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; EU, European Union; ICD-9, International Classification of Diseases, 9th revision; MCI, mild cognitive impairment; MEDPAR, Medicare Provider Analysis and Review; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and the Stroke and Alzheimer’s Disease and Related Disorders Association; RUD, Resource Use in Dementia; UK, United Kingdom; USA, United States of America.

Chhatrea et al. [19]

Hurd et al. 856 patients [18] (USA)

Sample size

Authors

Table 3 (Continued)

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Disease definition Cost perspective

dementia as societal defined by the World Alzheimer Report 2009 and the WHO dementia report

Worldwide

The 27 EU countries in 2008

Prevalence

Prevalence

Indirect costs

Total cost estimate

Data sources

i) Health care costs ii) Social care costs iii) research funding

189 billion D per year The number of people with Opportunity cost of dementia in each of the (2007 value) for the unpaid care, and EU-15 countries was 15 EU countries valued in terms of the time that carers considered; The obtained from a report corresponding annual published by Alzheimer’s provide for their spouses, friends, or per patient social care Disease International. and healthcare cost is Data concerning relatives suffering from dementia. 9,904 D resources’ use and costs Productivity losses were extracted from EUROSTAT and due to mortality and country-specific studies. morbidity Resources used in the Informal care 160 billion D (2008 Data on the number of medical (e.g., hospital (resource use and value) for the 27 EU people affected by care) and costs of caring for a countries considered. dementia in each country non-medical (e.g., demented person). The corresponding were drawn from a home help, nursing per patient and year meta-analysis carried out home care) sectors. cost is 22,000 D by the Eurocode group. Country-specific per-capita direct and indirect cost data were extracted from fourteen papers from key countries. Missing data were imputed. Direct medical costs Informal care (care 604 billion $ in 2010 Number of people affected related to the medical input by family (2010 value) by dementia in a number care system, such as members, friends, of regions of the world costs of hospital care, and others). drawn from the World medication, and visits Alzheimer Report 2009 to clinics. Direct and the dementia report social care costs are by the WHO. for formal services Country-specific provided outside of per-capita direct and the medical care indirect cost data are system, including extracted from a detailed community services literature review. Missing such as home care, data were imputed. food supply, and transport, and residential or nursing home care.

EpidemiologicalDirect costs approach

The 15 EU countries Prevalence in 2007: Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Netherlands, Portugal, Spain, Sweden, UK.

Countries considered

AD, Alzheimer’s Disease; EU, European Union; UK, United Kingdom; WHO, World Health Organization.

Wimo et al. [22]

LuengoAD defined as Societal, (top-down) Fernandez International et al. Statistical [20] Classification of Diseases and Related Health Problems 10th Revision (ICD-10) F00-F03 and G30. Wimo et dementia as societal al. [21] defined by the Eurocode group.

Authors

Table 4 Studies considering the country-level cost of the disease considered. Summary of relevant features

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resources included in direct costs was calculated using unit costs collected using the French consumer price index. The replacement wage method was applied to calculate costs of informal caregiving, assuming that the unit cost was equal to the average hourly wage in French private industries. The mean total cost of AD per month was 2,918 D at baseline, 3,112 D at year 1, and 4,101 D at year 2. Informal cost was the largest component per month, and its importance in total costs increased over time from 2,334 D at baseline, to 2,510 D at year 1, and 3,373 D at year 2. Regression analyses were carried out in order to explore the determinants of total costs. Covariates included cognitive status (measured by MMSE), functional status measured by the Katz Index of Independence in Activities of Daily Living (Katz ADL scale), the severity and frequency of a wide range of behavioral reactions measured by the NPI, sociodemographic variables such as patients’ age, gender, education level, time since AD diagnosis, and informal caregivers’ subjective burden measured by the Zarit Burden Interview index (ZBI). Possible biases in assessing relationship between MMSE, ADL, NPI, ZBI and AD costs were evaluated by estimation of instrumental variables. For these calculations lagged value of total costs, patients’ level of education, and a categorical variable measuring whether another informal caregiver provided help rarely, sometimes, or always, were considered. The study showed that the most important predictors of costs were functional and cognitive declines. A marginal decrease in MMSE score was associated with a 7% increase in total costs while a marginal loss in ADL was associated with a 28.65% increase in total costs. Caregivers’ subjective burden and the severity and frequency of behavioral reactions were found to be slightly positively associated with total costs. The study highlighted that the relationship between MMSE and costs could lead to a large underestimation of the impact of MMSE on costs, being a marginal decrease in MMSE score associated with a 29.30% increase in the total cost of care. Coduras and coworkers [15] used data drawn from the ECO study which is a multi-center, prospective, 12- month, observational study, conducted in Spain between 2003 and 2006. This study involved 560 patients at different stages of AD who were interviewed in three different dates over the time of the trial. The analysis has calculated AD direct costs resulting from the use of healthcare resources (medical visits, drugs and concomitant treatments, complementary and diagnostic tests, institutionalization, and use of

home-nursing facilities) and non-healthcare resources (inventory materials, consumables, professional and non-professional caregivers’ time for care and supervision) assessed according to 2006 prices taken from the Pharmacist Colleges General Council catalogue for drugs. Indirect costs were also computed, with the substitution costs method being applied by multiplying the number of days of work absence in the case of informal caregivers by the mean salary earning declared by the caregiver. Monthly average costs per patient were 1,425.73 D , and increased by the 10.08% at the end of the study. Non-healthcare costs (1,059 D being the 74.30% of total cost) decreased by 4.30 D /month (0.40%) at the end of the year, while healthcare costs, which presented a total average of 366.66 D , increased by 136.94 D at the time of observation (54.06%), mainly due to cost of drugs, nursing home utilization, and institutionalization. The caregivers’ total burden represented 70.86% of the overall cost of illness. A statistical analysis was also carried out to investigate how monthly progression of costs over the course of the study is linked to a wide set of caregiver-specific sociodemographic covariates such as age, gender, marital status, living arrangements, years of education, level of education, and income. Analysis included a wide set of clinical variables such as Clinical Dementia Rating Scale (CDR), Blessed Dementia Rating Scale (BDRS), Health Utilities Index-Mark 3 (HUI-3), ZBI, and MMSE. The results showed that when the caregiver is the spouse or partner, divorced/separated, or has a university level of education, the monthly cost is higher. In terms of clinical variables, the MMSE and mainly the BDRS scores showed a statistically significant effect on the average monthly cost. The CDR and HUI-3 scales and the ZBI did not correlate significantly with costs. Herrmann and coworkers [16] analyzed data collected during the Canadian Outcomes Study in Dementia (COSID), a prospective observational study conducted in Canada between 2000 and 2003 involving 903 dementia-diagnosed patients and their caregivers who were interviewed at baseline and every 6 months over a total of 36 months. The authors adopted a societal perspective assessment and estimated both direct (medical and non-medical) and indirect costs of AD. Direct costs result from expenditures for visits to a family doctor, general practitioner, specialist, day surgery, psychiatric nurse, home care nurse, counselor or psychologist, laboratory or diagnostic tests, hospitalizations, support group, meals on wheels, etc. The use of these resources was registered using detailed questionnaires and valued by prices extracted from a

L. Colucci et al. / Costs of AD

comprehensive cost dictionary considering many service providers. Medication costs were obtained from a British Columbia-based wholesale pharmacy 2000 price list. Indirect costs were calculated by determining the number of days the patient and (or) caregiver was prevented from performing their regular activities and determining the market value of the informal care provided by looking at the data provided by the Canada Statistics 1997 on domestic help hourly wage. The results showed that total costs are significantly higher with greater disease severity. The mean total cost to treat patients with very mild AD (Global Deterioration Scale (GDS) = 2) was 367 Canadian Dollars (C$) per month (value of the currency in 2000), compared with 4,063 C$ per month for patients with severe or very severe AD (GDS = 6). The largest component of total cost was represented by indirect costs. Medication costs were more relevant in patients with very mild AD. A statistical analysis revealed that female gender, poorer function, and more neuropsychiatric symptoms are significant predictors of total cost. A wide set of severity measures such as GDS, MMSE, and Functional Autonomy Measurement System (SM AF) showed a highly significant positive association with total costs of AD. Reese and coworkers [17] used data gathered through a cross-sectional survey done in 2009 involving 395 patients who were recruited in the region of Marburg-Biedenkopf in Germany. Recruited subjects were asked for a retrospective evaluation of the costs incurred over the prior three months. The study estimated total, direct, and indirect cost of AD. Direct costs included outpatient care, inpatient care, drug costs, and costs of nursing home. The use of health care resources by patients was recorded through standardized questionnaires. Calculation of the costs of outpatient care was based on the cost values related to specialists. Costs for inpatient care were calculated based on the mean daily costs for the specific departments. Drugs costs were calculated on the basis of the official German price list of drugs. Costs for patients living in nursing homes were obtained from the official tariff lists published by each institution. Finally, indirect costs were calculated both for patients and caregivers in terms of productivity losses due to a) early retirement, b) inability to work, c) unemployment, d) sick leave, and e) reduction of labor time caused by AD. Using the human capital approach, costs due to productivity lost were calculated on the basis of the Statistical Year Book 2009 for the Federal Republic of Germany. The average total cost for a three-month period was approximately 3,300 D (2009 value) and the average

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annual cost was about 13,080 D . The total annual costs was approximately 25,500 D in patients living in longterm care facilities and 7,450 D for patients still living at home. The most important cost component was long-term care, constituting about 43% of total costs. Indirect costs represented about the 18% of total costs and were mainly due to reductions in working time of caregivers. A bivariate and multivariate analysis was made to estimate empirically the effects of a number of clinical characteristics, such as depression (measured by Geriatric Depression Scale), general cognition measured by MMSE and Alzheimer’s Disease Assessment Scale (ADAS-Cog), activities of daily living (ADCSADL), neuropsychiatric symptoms (measured by NPI) on the total cost of illness. The study concluded that impaired activities of daily living (ADCS-ADL) are the most important predictor of costs. Hurd and coworker [18] provided an estimation of monetary costs of dementia based on 2010 data collected from a subsample (856 persons) of the population involved in the Health and Retirement Study, a nationally representative prospective study carried out in the US from 1992. The market costs associated with care for persons with dementia were determined on the basis of self-reported out-of-pocket spending (e.g., nursing home stays, hospital stays, medical visits, outpatient surgery etc.), spending recorded by the Federal Government social insurance program Medicare (e.g., durable-medical-equipment purchases, skilled nursing-facility care), spending for home nursing and for formal/ informal home care. Informal care was evaluated using a replacement cost approach and, alternatively, by means of the forgone wage approach. To isolate the costs directly attributable to dementia from those due to other coexisting diseases, authors used a multivariate regression model relating cost components to the patients’ predicted probability of dementia (calculated according to personal and household characteristics), to coexisting conditions and to a set of demographic characteristics. The results indicate that attributable yearly cost per person, including those of care purchased in the marketplace and those cost of informal care, were 41,689 $ (2010 values) when the evaluation of forgone wages was used and 56,290 $ when the evaluation of replacement cost was used. The main component of the costs attributable to dementia is the cost for institutional and home-based long-term care rather than the costs of medical services. Calculating the value of informal home care in terms of forgone wages yielded an estimate of the cost of unpaid caregiving that was 31% of the total cost. Calculation of the value of informal

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home care in terms of the replacement cost yielded an estimate of 49%. Chhatrea and coworkers [19] provided a retrospective case-control study whose aim was to assess health resource utilization and direct cost of care in the elderly with AD and with or without concomitant congestive heart failure (CHF). A group of 904 patients with a diagnosis of AD and an AD free control group (n = 3,616) were recruited for this study over 1999 and 2000 in the US. The AD and non-AD groups were further subdivided into those with and without a diagnosis of CHF (AD + CHF = 240 patients), AD only (664 patients), CHF only (712 patients) and control group (2,904 patients). Data were gathered through an administrative database of a large urban academic health care system (PICARD). Authors obtained data of health care resources utilization data and Medicare reimbursements for inpatient costs, outpatient costs, inpatient pharmacy costs, length of stay, number of emergency room visits, number of inpatient admissions, number of outpatient visits, number of diagnostic, lab procedures, and home health and hospice care. All these data were extracted from databases such as the Medicare Provider Analysis and Review (MEDPAR) inpatient care, Outpatient Standard Analytical Files (SAF) home health and hospice care and carrier files. The study calculated a mean annual cost of 20,888 $ (2007 value) for the ADCHF group, 5,473 $ for the AD-only group, 17,700 $ for the CHF-only group, and 4,578 $ for the control group (no-AD and no-CHF). Hence, the direct cost of AD was higher than the one observed for the control group, but the total cost of caring for persons with CHF alone was higher. As expected, a co-occurring diagnosis of AD and CHF is accompanied by substantial increases in all medical care costs, mainly inpatient care. Log-linear regressions were run in order to investigate the impact on costs of a number of personal variables such as age, race, gender, subsample epidemiology (AD only, CHF only, AD+CHF, control group) and co-morbidity. Compared with the reference group (control group), the total cost for those belonging to the AD + CHF group were 8-fold higher, while for those belonging to the CHF-only group it was 5-fold higher and co-morbidity had an obvious effect on total costs rise. Country-level cost of illness studies The most relevant features of the country-level cost of illness studies analyzed are summarized in Table 4.

Luengo-Fernandez and coworkers [20] provided estimates of the societal perspective economic burden of AD across the 15 European Union member states in 2004. In this study, which adopted a prevalence approach, AD was defined according to the International Statistical Classification of Diseases and Related Health Problems (10th Revision). Data on the number of dementia patients were extracted from a report published by Alzheimer’s Disease International. Cost estimations are based on patient-level studies and aggregate data on morbidity, mortality, health and social care use extracted from various sources. Five typologies of costs were considered: i) health care costs: primary care (dementia-related visits to general practitioners, together with general practitioner visits to patients’ homes, and visits to or by a primary care nurse); accident and emergency care (dementia-specific hospital emergency visits); hospital outpatient care (specialist consultations taking place in outpatient wards, clinics, or patients’ homes); hospital inpatient care; and medications. To account for private expenditure on health care in countries where data was only available on public expenditure, cost estimates were inflated using the total proportion of private expenditure on health care; ii) social care costs (number of dementia-related weeks spent in care homes); iii) informal care costs as resulting from country-specific data on the time spent by relatives and friends providing unpaid care for dementia patients multiplied for caregivers’ wages; iv) productivity losses due to mortality and morbidity. These are valued by looking at value. The number of working years lost due to premature mortality was estimated using expected working years left by age group and the number of deaths stratified by age and gender; and v) governments’ and charities expenditure for research funding in the European Union 15 countries as resulting from data published by the Resource Allocation to Brain Research in Europe study (RABRE). The resulting total annual cost of dementia is 189 billion D per year (2007 euros) for the 15 countries considered. Social care services are 49 billion D , 26% of total cost, whereas healthcare costs accounted for 10 billion D (5%). The corresponding annual per patient social care and healthcare cost is 9,904 D . Informal care accounted for 105 billion D , 64% of total cost, representing 11.9 billion hours of unpaid care provided by relatives and friends of dementia patients. Productivity losses, including mortality and morbidity losses, accounted for 2.2 billion D , only 1% of total cost, mainly because dementia occurs in old non-working patients. Moreover, the study shows that cost compo-

L. Colucci et al. / Costs of AD

sition significantly varies across European countries. The proportion of total costs due to informal care is about 75% in in Southern European countries while it represents around 50% of total costs in Northern countries where long-term institutional care is significantly higher. Wimo and coworkers [21] published an empirical study whose aim is to calculate the societal, prevalence-based total economic impact of dementia in the 27 countries part of the European Union in 2008. Data on the number of people affected by dementia in each country was drawn from the a meta-analysis carried out by the Eurocode group while country-specific per-capita direct (medical, e.g., hospital care, and nonmedical, e.g., home help, nursing home care sectors) and indirect (informal care) cost data was extracted from a detailed literature review including fourteen papers from key countries. Imputation was used for countries where no cost figures were available. The total estimated cost of dementia in the 27 countries of the European Union in 2008 is 160 billion D , of which 56% are costs of informal care. The corresponding per patient and year cost is 22,000 D . Consistent with the paper by Luengo-Fernandez et al. [20], the results show that in Northern Europe the direct costs are considerable while in southern Europe the major cost component is the one related to the informal care. The latter study was updated by Wimo and coworkers [22] who have done a societal, prevalence based estimation of total costs of dementia worldwide. In this study the authors use data on the number of people affected by dementia in a number of regions of the world drawn from the World Alzheimer Report 2009 and the dementia report by the World Health Organization. Following their previous paper [21], country-specific per-capita direct and indirect cost data are extracted from a detailed literature review and imputed in case of missing country information. Direct medical costs were considered those of hospital care, medication, and visits to clinics. Direct social care costs include formal services provided outside of the medical care system, including community services such as home care, food supply, and transport, and residential or nursing home care. Finally, informal costs concern care input by family members, friends, and others. The total estimated worldwide costs of dementia is 604 billion $ in 2010. The costs are distributed unevenly: about 70% of them occurred in western Europe and North America. In such high-income regions, costs of informal care and the direct costs of social care contribute sim-

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ilar proportions of total costs (40–45%), while the direct medical costs were much lower. In low and middle-income countries the majority of costs are related to informal care accounts while direct costs are negligible. DISCUSSION What do we know? The evaluation of AD costs allows us to understand the extent of the present economic burden of illness to society and to predict its dimension in the near future, when the number of patients will significantly increase [3]. AD is only one of a number of diseases leading to dementia, which may also be due to other neurodegenerative disorders such as frontotemporal dementia, Lewy body disease, vascular dementia, and other less frequent forms of adult-onset dementias. Dementia is, in fact, an “umbrella” term under which different pathologies are grouped. However, a neat clinical differentiation of AD by other disorders is difficult in many cases, and AD is by far the most frequent adultonset dementia. Consequently, our review has included papers that estimate costs associated to AD (8 papers) [9–11, 14, 15, 17, 19, 20], together with those investigate costs of dementia more generally speaking (4 papers) [16, 18, 21, 22]. The same approach is adopted by the majority of review articles published in this field [7, 23, 24]. As already mentioned above, 9 papers provided a patient-level estimation of costs [9, 14–19] while 3 [20–22] focused on the investigation of country-level cost of the disease. Among the papers we reviewed, 10 adopted a societal perspective [9, 11, 14–18, 20–22] and 2 [10, 19] adopted a health care system perspective. Only one study [20] adopted a top-down approach in estimating the total cost of illness; all the other studies rely on data collected through interviews with patients who were asked about the quantity of health inputs used. Among these latter studies, the majority employs standard questionnaires, such as the RUD questionnaire, to collect data through interviews. Most of the studies estimate both direct and indirect costs. The only exceptions are represented by Miller and coworkers [11] and Chhatrea and coworkers [19] who centered their analysis on direct costs. Analysis of the studies that provide patient-level total (direct + indirect) cost of illness estimates, showed that the cost per patient and month is highly variable; ranging from 347 C$ for patients with very mild AD [16] to 4,690 $ for the American patients [18]. Looking at

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European studies, the lowest cost per patient and month is reported by the German study [17] which found a value of 1,100 D (monetary value similar to the one found by the Irish study [11]. The highest is calculated by the French study [14] who registered a mean total cost of 2,918 D per patient and month. The variability of costs depends, at least partially, by different voices of direct and indirect costs included in the studies reviewed. In the French study [14], the direct costs refer to day care, hospital and physicians visits, medical treatments, and expenses due to speech and physical therapists; the Spanish study, instead, apart from the day care and the medical and nurse interventions, also includes the institutionalization. On the other hand, some studies consider as indirect costs the loss of productive of patients and caregivers [17], but others studies include only the lost production for the caregivers [9]. The same variability is found when looking at country-level estimates. Ten studies (83% of the papers examined) report the relative contribution of the direct and indirect costs to the total amount [9, 11, 14–18, 20–22] while 2 studies are without this differentiation [11, 19]. Direct and indirect costs (and therefore total costs) are very high in AD and their distribution changes during the progression of disease. Informal cost is the largest cost component and these costs increase over the time [14, 16, 20–22]. In the US, the mean of direct costs is 1,205 $/month per patient [10]. In Europe the mean of direct costs seems to be inferior than in the US (about 800 D /month per patient) [17, 20]. In terms of indirect costs, the mean of cost per patient and month in Europe is about 500 D [17] while in the US the same costs are apparently higher (about 1,000 $/month per patient) [18]. Different variables are found to be significant determinants of cost. Cognitive decline represents an important variable in the costs rise, and its severity causes higher costs [11, 14–16]. MMSE, and more generally the score of cognitive tests (as GDS, ADAS-Cog) [16, 17] allowing an objective evaluation of the cognitive impairment over time, are the most used cognitive variables. Costs vary according to the loss of autonomy of the patients, and thus to the results of the functional scales [11, 25], the most employed being the SM AF-B ADL [16], the DS [11], the DAD [9], the BDRS [15], and the ADL [14]. The DAD is indicated as the most important predictor of the costs of care [9], of total costs [11], and of caregiver time [25], while the DS is significantly related with total costs [11]. The BDRS and the SM AF are also important predictors of total costs [15, 16],

while the ADL is associated with both total cost and medical and non-medical costs [14]. Recently introduced scales to evaluate the caregivers’ burden, as the ZARIT, are useful in measuring this determinant variable of indirect costs [14]. What should we know better? The evaluation of the intangible costs is a missing aspect in all reviewed studies, none of which has specifically indicated them. However, the pain, anxiety and other factors such as the difficulty in maintaining personal relationships, or having leisure time, can negatively influence the quality of life of both caregivers and patients, thus constituting an aspect that should be accurately taken into account. Specific methodologies have been developed to this aim. Some, as the Health-Related Quality of Life, have been essentially designed to evaluate the impact of the informal caregiving on caregivers health [26]. Others, such as the EuroQoL [27], and the Care-Related Quality of Life (CarerQoL) [28], are aimed at measuring a more comprehensive aspect, that is the well-being (happiness) of the caregivers in relationship to their activity. Well-being is a wider concept than health, and seems more adequate to capture the complexity of the effects related to the caregiving. Furthermore, the CarerQoL includes within its numerous dimensions the level of the satisfaction that may derive from the giving of care, an aspect often reported by the caregivers, to which this tool assigns, thus, a fair value. The Caregivers’ Quality of Life Index is quite a similar instrument, which evaluates three standard dimensions of the caregiving, but which has a higher complexity [29]. The Caregiver Burden Inventory, an easy questionnaire aimed at evaluating the psychological, physical, social and emotional aspects of the caregiving, is a well-known and widely applied measure which takes into account the objective and the subjective aspects of care [30]. Subjective aspects, which refer to the caregiver’s perception of their own caring activity, have been particularly highlighted by other instruments as the Caregiver Strain Index [31], the Caregiver Reaction Assessment [32] and the Sense of Competence [33]. These instruments are however more designed to register than to measure the burden, so that they should be first translated into monetary terms. The Self-Rated Burden [34] includes also an evaluation measure. The intangible costs as well refer to the patients, even if the assessment of their quality of life by ques-

L. Colucci et al. / Costs of AD

tionnaires is, obviously, less easy. Patients may be, in fact, partially or totally unaware of their disease and its effects. However, they or some of them, can usually express themselves in the emotional dimension [35], and thus be evaluated with scales such as the Life-Alzheimer’s Disease Scale [36]. Once the evaluation of life quality has been obtained it is possible to apply methodologies borrowed from social finances studies [37] to achieve an economic translation of these intangible aspects. The Contingent Evaluations method [38] is an option. It consists in the attribution of a value established through a direct survey and the creation of a hypothetical market. In this case, the payment accessibility and its amount would be evaluated according to the heterogeneity of the object, and the values would depend from the simulated market. They might thus be influenced by the uncertainty and the vulnerability of the evaluation. Another option is the Conjoint Measurement [39], where the caregivers are required to evaluate different attributes of the caregiving (suffering, psychological stress, limitations to social relationships etc.) to provide a measure of the impact of caregiving on life quality. Evaluations would be more reliable if they really took into account the heterogeneity of the disease and of its assistance, nevertheless, they should allow the conversion of the scores into monetary values, thus allowing the measurement of intangible costs.

ACKNOWLEDGMENTS The present work was supported by an institutional grant of Camerino University for Life Sciences PhD activities. Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=2332).

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Conclusions More detailed models for the evaluations of costs and more accurate methodological standardization are necessary for properly calculating the costs of AD. They would be useful to allow policy makers to define their choices according to the economic and social situations of their countries [20]. For instance, it is reasonable to suggest that in developing countries, where AD prevalence will dramatically increase in the next decades, according to the sharp increase in life expectancy, programs focused on lifestyles should be launched as soon as possible. In the industrialized western world, where life expectancy is already high, it is more reasonable to invest in different strategies such as, for example, support programs [40]. Whatever strategy is chosen, it is necessary to evaluate it adopting costs evaluation systems that include all the numerous and different dimensions of the problem and the various components of it. This will require interdisciplinary efforts in which physicians, neuropsychologists and economists should work together.

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