University of Groningen
Improving outcomes of patients with Alzheimer's disease Droogsma, Hinderika
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Improving outcomes of patients with Alzheimer’s disease
long-term disease course and nutritional status in a ‘real-life’ setting
Hinderika Droogsma
© Copyright 2015: H. Droogsma
No parts of this thesis may be reproduced or transmitted in any forms or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system, without permission of the author
ISBN: 978-90-367-8162-6
Lay-out: Peter van der Sijde, Proefschriftgroningen.nl Printed by: Dekker drukwerken te Leeuwarden
Improving outcomes of patients with Alzheimer’s disease
long-term disease course and nutritional status in a ‘real-life’ setting
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op maandag 23 november 2015 om 15.00 uur
door
Hinderika Droogsma geboren op 19 december 1986
te Sneek
Promotor Prof. dr. P.P. De Deyn
Copromotor Dr. D. van Asselt
Beoordelingscommissie Prof. dr. H.W.G.M. Boddeke Prof. dr. H.P.H. Kremer Prof. dr. M.G.M. Olde Rikkert
Paranimfen Susanne Lubbers Marloes Prins
6
1. General introduction, aims and outline of this thesis 9 2. Long-term course of Alzheimer’s disease in patients treated in a ‘real-life’ setting 19 2.1 Long-term course of Alzheimer’s disease in patients treated according to the 19
Dutch dementia guideline at a memory clinic: a ‘real-life’ study
2.2 Initial cognitive response to cholinesterase inhibitors and subsequent long-term 37 course in patients with mild Alzheimer’s disease
3. Alzheimer’s disease and nutritional status 53
3.1 Nutritional status of community-dwelling elderly with newly diagnosed 53 Alzheimer’s disease: prevalence of malnutrition and the relation of various factors to nutritional status
3.2 The relation of weight change trajectory with medial temporal lobe atrophy in 65 patients with mild Alzheimer’s disease: results from a cohort study
3.3 Effect of long-term treatment with galantamine on weight of patients with 85 Alzheimer’s dementia
3.4 Nutritional interventions in community-dwelling Alzheimer patients with (risk of) 79 undernutrition: a systematic review
4. Main outcomes and general discussion 111
5. Summary/samenvatting/gearfetting 125
5.1 Summary in English 127
5.2 Samenvatting in het Nederlands 131
5.3 Gearfetting yn it Frysk 135
6. Appendices 141
6.1 List of publications 143
6.2 About the author 145
6.3 Dankwoord 147
Table of content
8
Chapter 1
General Introduction, aims and outline
of this thesis
10
Alzheimer’s disease
It is estimated that by 2030 about 65 million people will be affected by dementia worldwide1.
Dementia has been declared as a public health priority by the World Health Organization as it is a costly condition in its social, economic, and health dimensions2. Alzheimer’s Disease (AD) is the most frequent cause of dementia3-5 and characterized by cognitive impairment, functional decline and neuropsychiatric symptoms5,6. As a consequence, AD has substantial effects on the quality of life of patients and their caregivers7.
The cause of AD is to a large extent unknown; it is thought that AD develops as a result of multiple factors rather than a single cause5. Several risk factors are linked to AD such as age, family history, apolipoprotein (Apo) E4 status and head injury5. In addition, it is believed that the clinical features of AD are associated with brain pathology, including amyloid plaques and neurofibrillary tangles5,6. Plaques are deposits of amyloid, a small protein with a beta-sheet structure8. Tangles consist of accumulation of tau, a microtubule-associated protein9. These microscopic abnormalities may lead to macroscopic brain atrophy, which can been seen on structural brain imaging such as Magnetic Resonance Imaging (MRI) of the brain10-12.
Diagnosing Alzheimer’s disease
In the Netherlands, memory clinics have been established for the diagnosis and treatment of dementia. A memory clinic is an ambulatory facility with multidisciplinary teams that focus on diagnosis, treatment and counselling of patients with cognitive impairment, especially dementia13.
The role of research within a memory clinic is very important because memory clinics provide an appropriate setting for standardized inclusion of patients. In addition, memory clinics are important settings for the implementation of new interventions and evaluation of the effect of these new interventions13,14.
The Dutch memory clinics provide care according to the Dutch dementia guideline15,16.
According to this guideline, patients are evaluated by a physician and a specialized geriatric nurse.
Anamnesis, heteroanamnesis, physical-, neurological-, and cognitive assessment are performed, including cognitive screening tests such as the Mini Mental State Examination (MMSE)17 and the clock-drawing test18. When a diagnosis can not be established, additional tests are ordered such as extensive neuropsychological testing and brain imaging15,16. When the diagnosis probable or possible AD, according to the criteria of the National Institute of Neurological and Communicative Diseases-Alzheimer’s Disease and Related Disorder Association (NINCDS-ADRDA)19 is established, patients are offered pharmacological and non-pharmacological interventions15,16 and outpatient visits are scheduled to evaluate the effect of these interventions.
Pharmacological and non-pharmacological interventions for Alzheimer’s disease
Unfortunately, there is currently no curative treatment for AD. Since the 1990s, two types of symptomatic pharmacologic treatments are available: the N-Methyl-D-aspartate glutamatereceptor
antagonist memantine and the cholinesterase inhibitors (ChEIs) rivastigmine, galantamine and donepezil20. ChEIs are recommended for the management of mild to moderate AD15,16,21, memantine for moderate to severe AD15,16,21. ChEIs and memantine influence neurotransmitter systems associated with the underlying degenerative processes. ChEIs increase the amount of acetylcholine at the synaptic cleft by preventing its breakdown by the enzyme acetylcholinesterase20. Memantine is believed to act by reducing glutamate mediated toxicity20.
Randomised controlled trials (RCTs) have shown beneficial effects of ChEIs on cognition, global clinical state, activities of daily living and behaviour22,23. However, it is difficult to draw firm conclusions about their long-term effectiveness as most trials lasted on average six months20,22,23.
In addition, RCTs are performed in selected groups of patients with strict inclusion and exclusion criteria. Consequently, AD patients enrolled in RCTs may not be representative of AD patients treated in a ‘real-life’ setting, limiting the external validity of the results24,25. Moreover, in the past years, it is not just the pharmacological treatment that has changed the management of AD. Drugs are given in addition to multiple non-pharmacological interventions such as dementia case management, respite care and occupational therapy15,16. Knowledge of the long-term course of AD in light of current pharmacological and non-pharmacological interventions provided in a ‘real-life’ setting, i.e.
outside of clinical trials, is scarce. This knowledge is of great importance as it gives the possibility to asses the long-term effect of these interventions and to plan future care.
In addition, it is important to know what clinicians should do in case of absence of an initial response to ChEI treatment. Some guidelines on the management of AD propose to evaluate the effect of ChEI treatment three or six months after the ChEI is started15,26,27. In case of deterioration of global, cognitive, functional or behavioral function during the first months of treatment, the patient is considered to be a non-responder and discontinuation of treatment is recommended15,26,28.
However, the evidence demonstrating that it is appropriate to stop treatment in non-responders is limited27. In contrast, it has been shown that the beneficial effects of ChEIs disappear within six weeks after discontinuation29. Understanding the relation between the initial response to ChEI treatment and the subsequent course of AD is relevant given the potential negative consequences of stopping treatment29. Hence, it may help clinicians, patients and their caregivers to make an informed decision.
Alzheimer’s disease and nutritional status
Since there is no curative treatment for AD, it is of crucial importance to seize every opportunity to improve the outcomes for AD patients. In 1907, Alois Alzheimer described weight loss in his first patient30 and weight loss is currently recognized as a clinical feature of AD19. Weight loss, a characteristic of undernutrition31, has been described in approximately 20% to 45% of community- dwelling AD patients32-37 and is associated with an accelerated progression of cognitive decline32,34,38,39, increased dependency34,38,39, a higher incidence of behavioural problems38, increased morbidity32, decrease in quality of life of the patient and his caregiver32, a higher rate of institutionalization40 and
12
Chapter 1
increased mortality41-43.
Although weight loss is frequently described in AD patients and its association with the mentioned adverse outcomes, little is known about the prevalence of undernutrition in community- dwelling AD patients, especially in newly diagnosed AD patients. Early detection of poor nutritional status, and its causes, is crucial for adequate interventions to prevent or diminish the adverse outcomes. Nevertheless, in the current guidelines on diagnosis and treatment of AD15,16,26,44,45, no attention is given to what clinicians should do in case of poor nutritional status in community- dwelling AD patients. In general, there are various interventions to increase nutritional intake in individuals who are undernourished or at risk of undernutrition, such as dietary fortifi cation and oral nutritional supplements (ONS)46. Before implementation of such interventions in AD guidelines, fundamental questions about their eff ectiveness in community-dwelling AD patients need to be addressed systematically. There are several guidelines and studies on the treatment of weight loss and undernutrition in older people without AD47,48. However, these results can not be extrapolated to AD patients because the mechanisms and causes of weight loss in AD patients are probably not the same as in individuals without AD.
The various hypotheses regarding the causes and mechanisms for weight loss in AD patients are summarized in fi gure 130,32,49-52. The factors that may contribute to weight loss in AD patients can be divided in primary and secondary factors51,52. Primary or disease-related factors are related to AD, such as cognitive disturbances, behavioural problems and an altered taste and smell function (fi gure 1)51,52. Secondary factors are general factors that may contribute to weight loss, such as adverse eff ects of medication and comorbidity (fi gure 1)51,52. These primary and secondary factors may lead to loss of appetite, inability to shop and prepare meals, refusal to eat, fi nally resulting in an imbalance between energy intake on the one hand, and energy expenditure on the other hand, and hence in weight loss (fi gure 1)30,32,49-52.
Weight loss
appetit
Including ChEIs4 Primary factors
Factors related to Alzheimer’s disease that may contribute to weight loss Factors related to Alzheimer’s disease that may contribute to weight loss
Secondary factors General factors that may contribute to weight loss General factors that may contribute to weight
Cognitive
disturbances Behavioural
disturbances Medial temporal lobe atrophy Biological
Disturbances2
Taste and smell dysfunction
Motor
disturbances3 Side effects of medication Social
factors5 Comorbidity
Loss of
appetite Inability to carry out complex activities,
for example preparing meals Increased energy expenditure Forgetting
to eat Refusal to eat
Imbalance between energy intake and energy expenditure
Figure 1: Hypotheses regarding the causes and mechanisms for weight loss in patients with Alzheimer’s disease1 Figure 1 is based on the following studies: 3⁰,32,⁴⁹-⁵2
2 Biological disturbances: hormonal changes, infl ammatory abnormalities, endocrine and metabolic changes; 3 Motor disturbances: restlessness, pacing, repetitive tasks; 4 ChEIs: cholinesterase inhibitors; 5 Social factors: increasing age, no social support, loneliness, poverty.
General introduction, aims and outline of this thesis
1
None of the proposed mechanisms or causes of weight loss in AD has been proven. A better understanding of the causes and mechanisms of weight loss in AD patients is relevant given its adverse outcomes. As shown in figure 1, some authors hypothesized that AD patients lose weight as a result of atrophy of the medial temporal lobe30,32,49,53,54. The medial temporal lobe is a brain area which is involved in the regulation of food intake53-55 and a site where AD pathology is typically present12. In addition, it is supposed that ChEIs may contribute to weight loss due to gastrointestinal side effects such as nausea, vomiting and diarrhea49, which may be caused by the cholinergic action of ChEIs on stomach and intestine56. Given the increasing number of patients treated with a ChEI57,58, it is important to establish the role of ChEIs as a potentially contributing factor to weight loss
Aims of this thesis
Since Alzheimer’s disease is one of the most disabling and burdensome health conditions worldwide3, it is of crucial importance to improve the outcomes for AD patients. In order to improve the outcomes for AD patients, this thesis will focus on the long-term course of AD in patients treated in a ‘real-life’
setting and their nutritional status. We used data from the Frisian Alzheimer’s Disease Cohort Study, a ‘real-life’ study of the long-term course of AD in patients treated with pharmacological (i.e. ChEIs) and non-pharmacological (i.e. case management, respite care) interventions provided according to the Dutch Dementia guideline at the memory clinic of the Medical Center Leeuwarden. In addition, for one study we used data of AD patients seen at the memory clinic of the Slingeland Hospital in Doetinchem. These patients were also treated according the Dutch Dementia guideline.
The research aims of this thesis are:
1. Providing insight in the long-term course of AD in patients treated with pharmacological and non-pharmacological interventions in a ‘real-life’ setting.
2. Investigate the relation between the initial response to treatment with ChEIs and the subsequent long-term course of AD.
3. Determine the prevalence of undernutrition and the relation of various factors to nutritional status in newly diagnosed AD patients.
4. Elucidate the possible role of the medial temporal lobe and ChEIs as mechanisms of weight loss in AD patients.
5. Assess the current evidence regarding the effect of nutritional interventions in community- dwelling AD patients with a poor nutritional status.
Outline of this thesis
The first research aim is addressed in chapter 2.1 of this thesis. We investigated the disease course of 576 patients from the Frisian Alzheimer’s Disease Cohort Study. Disease course was described by changes in cognition and number of types of professional care during 3.5 years. In addition, behaviour and psychological symptoms, proportion of nursing home admission and deaths were
14
Chapter 1
investigated.
The relation between the initial response to ChEI treatment and the subsequent long-term course of AD is explored in chapter 2.2 by comparing the long-term course of cognition between initial non-responders and responders.
In chapter 3.1, we determined the prevalence of undernutrition and its relation to various factors in 312 community-dwelling elderly with newly diagnosed AD seen at the memory clinic of the Slingeland Hospital in Doetinchem. To determine the prevalence of undernutrition, we used the Mini Nutritional Assessment (MNA), which is specifically developed and validated to identify undernutrition in older people59-62.
In chapter 3.2 and 3.3, we focus on causes and mechanisms of weight loss in AD patients of the Frisian Alzheimer’s Disease Cohort. In chapter 3.2, we explored the role of atrophy of the medial temporal lobe in weight loss in AD patients. The role of ChEIs as a potentially contributing factor in weight loss is examined in chapter 3.3.
Chapter 3.4 describes the current (lack of) evidence regarding the effect of nutritional interventions in community-dwelling AD patients with a poor nutritional status.
Chapter 4 summarizes our main findings and discusses the clinical and scientific implications of the results.
General introduction, aims and outline of this thesis
R
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39. Vellas B, Lauque S, Gillette-Guyonnet S, et al. (2005) Impact of nutritional status on the evolution of Alzheimer’s disease and on response to acetylcholinesterase inhibitor treatment. The Journal of Nutrition,
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48. American Dietetic Association. (2009) Unintended weight loss (UWL) in older adults evidence-based nutrition practice guideline. Chicago. Available at: http://andevidencelibrary.com/topic.cfm?cat=3653 49. Gillette-Guyonnet S, Abellan van Kan G, Alix E, et al. (2007) IANA (International Academy on Nutrition and
Aging) Expert group: weight loss and Alzheimer’s disease. J Nutr Health Aging 11(1):38-48
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61. Gianluca I, Mario B, Aimonino-Ricauda N, et al. (2011) Malnutrition in patients with dementia. J Am Geriatr Soc 59(4):774-775
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Chapter 2.1
Long-term course of Alzheimer’s disease in patients treated according to the Dutch
dementia guideline at a memory clinic:
a ‘real-life’ study
Erika Droogsma1 Dieneke van Asselt1 Jolanda van Steijn1 Marjolein Diekhuis1 Nic Veeger2,3 Peter Paul De Deyn4,5
1 Department of Geriatric Medicine, Medical Center Leeuwarden, Leeuwarden, the Netherlands
2 Department of Epidemiology, Medical Center Leeuwarden, Leeuwarden, the Netherlands
3 Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
4 Department of Neurology and Alzheimer Research Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
5 Department of Neurology and Memory Clinic,
ZNA and Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
Alzheimer Dis Assoc Disord. 2015 Mar 6
20
Chapter 2.1
A
bstRAct
Introduction: There is little knowledge of the long-term course of Alzheimer’s disease (AD) in light of current pharmacological and non-pharmacological interventions provided in a ‘real-life’ setting.
Methods: The Frisian Alzheimer’s Disease Cohort study is a ‘real-life’ study of the course of AD in patients (n=576) treated with pharmacological (i.e. cholinesterase inhibitors (ChEIs)) and non- pharmacological (i.e. case management, respite care) interventions. Disease course was described by changes in cognition (MMSE, clock-drawing test (CDT)) and number of types of professional care applying a repeated measures analysis using a marginal model (population based average model). In addition, behavioural and psychological symptoms (BPS), proportions of nursing home admissions and deaths were investigated.
Results: During 3.5 years, the average MMSE decreased from 22.24 to 18.91, the CDT score increased from 3.38 to 4.05, the number of types of professional care increased from 0.85 to 2.64 and the patients with BPS increased from 29.0% to 70.2%. The proportion of patients admitted to a nursing home was 40.8% and 41.0% died.
Conclusion: Cognition and behaviour of AD patients deteriorated accompanied with an increase in care-dependency during 3.5 years. Nevertheless, compared to the pre-ChEI-era, current pharmacological and non-pharmacological interventions appear to slow cognitive decline, which emphasizes that they seem to have a favorable effect.
Long-term course of Alzheimer’s disease
2 I
ntRoductIonAlzheimer’s disease (AD), the most frequent cause of dementia1, is characterized by cognitive impairment, functional decline, and neuropsychiatric symptoms2. Consequently, AD has substantial effects on the quality of life of patients and their caregivers3.
There is no curative treatment for AD. Since the 1990s, two types of symptomatic pharmacologic treatments are available: the N-Methyl-D-aspartate glutamatereceptor antagonist memantine (approved in 2002) and the cholinesterase inhibitors (ChEIs) rivastigmine, galantamine and donepezil4,5. ChEIs are recommended for the management of mild to moderate AD, memantine for moderate to severe AD5,6. Randomised controlled trials (RCTs) have shown beneficial effects of ChEIs on cognition, global clinical state, activities of daily living and behaviour7. However, it is difficult to draw firm conclusions about the long term effectiveness as most trials lasted on average six months4,7. In addition, RCTs are performed in selected groups of patients with strict inclusion and exclusion criteria. Consequently, AD patients enrolled in RCTs may not be representative of AD patients treated in a ‘real-life’ setting, limiting the external validity of the results8,9.
In the past years, it is not just the pharmacological treatment that has changed the management of AD. Drugs are given in addition to multiple non-pharmacological interventions such as dementia case management, respite care and occupational therapy6. In the Netherlands, memory clinics have been established to provide and monitor these pharmacological and non-pharmacological interventions. They provide care according to the Dutch dementia guideline, and ChEIs and memantine are reimbursed if patients are treated accordingly6.
Knowledge of the long-term course of AD in light of current pharmacological and non- pharmacological interventions provided in a ‘real-life’ setting, i.e. outside of clinical trials, is scarce.
A better understanding of the long-term course is of great importance as it gives the possibility to assess the effect of these interventions and to plan future needs for care. This may contribute to an improvement of outcomes for AD patients. This ‘real-life’ study aims to describe the long-term course of AD in patients treated with pharmacological and non-pharmacological interventions according to the Dutch dementia guideline at a memory clinic.
M
ethodsStudy design & setting
The Frisian Alzheimer’s Disease Cohort study is a retrospective longitudinal ‘real-life’ study of the long-term course of AD in patients treated with pharmacological and non-pharmacological interventions according to the Dutch Dementia guideline at our memory clinic. Patients were evaluated by a physician and a specialized geriatric nurse. A comprehensive geriatric assessment (CGA)10 was performed including cognitive screening tests such as the Mini Mental State Examination (MMSE) and the clock-drawing test (CDT). When a diagnosis could not be established,
22
Chapter 2.1
additional tests were ordered such as neuropsychological testing and brain imaging. When the diagnosis probable or possible AD, according to the criteria of the National Institute of Neurological and Communicative Diseases –Alzheimer’s Disease and Related Disorder Association (NINCDS- ADRDA)11, mild to moderate (MMSE≥10) was established, patients were offered treatment with a ChEI. During the first three months of treatment, a specialized nurse had contact by telephone with the patient and/or his caregiver to discuss possible ChEI related side-effects. After the diagnosis, most patients were referred to dementia case management. When appropriate, other forms of non- pharmacological interventions were implemented. The guideline recommendation to evaluate patients every six months was adjusted to yearly evaluations due to our large patient population.
If required, the frequency of visits was increased for certain patients. During outpatient visits, the overall condition of the patient was assessed based on the oral information provided and the outcomes of the MMSE and CDT. When necessary, care was arranged, counselling provided and medications adjusted. Outpatient visits ended when treatment with ChEIs and/or memantine was terminated or in case of nursing home admission.
Participants
AD patients who visited the memory clinic between 2002 to 2012, aged 65 years or older, living at home or in residential care at the time of diagnosis and who started with a ChEI, were included. Patients were naïve to ChEIs at baseline and were not treated with a ChEI before AD diagnosis. Patients were excluded if they did not meet the inclusion criteria. Data were retrospectively collected and entered into a database by a research fellow. Disease course was described by changes in cognition, number of types of professional care and behavioural and psychological symptoms (BPS) of dementia for a period of 3.5 years. In addition, the number and characteristics of patients admitted to a nursing home and the number of deaths
were investigated. The study was approved by the local ethics committee of the Medical Center Leeuwarden.
Measurements
Socio-demographic characteristics
Age, gender, living status, and use of informal care were recorded. Comorbidity was evaluated by the Cumulative Illness Rating Scale (CIRS) with a total score ranging from 0 (no impairment) to 56 (extremely severe impairment)12. AD as index disease was not included in the CIRS score. The number of medications beside the ChEI was recorded. Polypharmacy was defined as use of 4 or more medications beside the ChEI.
Cognitive functioning
Cognitive functioning was assessed by the MMSE13 and the CDT. We used the scoring system of Shulman 1993, in which the total score ranges from 1 to 6, and a score of 3 or more indicates cognitive impairment14.
Long-term course of Alzheimer’s disease
2
Use of professional care
For research purposes, Instrumental Activities of Daily Living (IADL) would ideally be operationalized with a measurement instrument. However, in our memory clinic, IADL was not measured with an instrument. Therefore, for this study, we used the number of types of professional care as indirect measure of IADL, since loss of ability to perform (I)ADLs is associated with increased need for professional care15,16. Five types were distinguished: dementia case management, domestic help, homecare, respite care (i.e. daycare center) and meals at home services.
Behavioural and psychological symptoms (BPS) of dementia
Based on self reported patient and caregiver information, we recorded whether BPS were present or absent. Since BPS was not operationalized with a measurement instrument, it was not possible to report the severity, nature nor frequency of BPS.
Type and dosage of ChEI
At each outpatient visit, type and dosage of ChEI, and if applicable memantine, were recorded. At our memory clinic, galantamine retard is the treatment of choice for patients with mild to moderate AD. The retard form of galantamine is prescribed since 2005, before 2005, galantamine was given twice daily. Patients start with 8 milligram (mg) galantamine per day for at least four weeks, followed by 16 mg/day for at least four weeks and, if necessary, the dose was increased to the maintenance dose of 24 mg/day.
Nursing home admission and mortality
At one point in time, December 2012, we checked the place of residency (i.e. at home or nursing home) of all patients included in our cohort and whether the patient had died. If possible, the date of nursing home admission and/or death was recorded.
Statistical Analysis
Data were analysed with Statistical Package for the Social Sciences (SPSS) 16.0 and Statistical Analysis Software (SAS) 9.2. All hypothesis tests were two-tailed. A probability (p) value of less than 0.05 was considered statistically significant. Descriptive statistics are presented as means ± standard deviations for normally distributed variables. For skewed distributed variables, median and 25th – 75th percentiles are given. We used the Kolmogorov Smirnov test to establish the normality of distribution of the variables. Number and proportion are given for categorical variables.
The course of cognition and professional care were assessed applying a repeated measures analysis using a marginal model (population based averaged model) and SAS proc mixed procedure with time as repeated statement and unstructured covariance structure. The repeated measures analysis has been developed for the analysis of longitudinal, continuous, dependent data. It gives an estimate of change in the dependent variable over time. The analyses were performed with all available data from patients with a baseline assessment and at least one follow-up assessment, over a period of maximally 3.5 years (five measurements). From the 6th measurement moment, it was not possible to give a reliable estimate of change in the dependent variable due to the small
24
Chapter 2.1
number of patients at that moment. Three analyses were performed, with MMSE score, CDT score and the number of types of professional care as dependent variable. Within these analyses, time (i.e. the number of measurement moments) was included as independent variable. Because BPS is a dichotomous variable, no repeated measures analysis could be performed. Therefore, the course of BPS was described by comparing the percentage of patients with BPS at each measurement moment to the percentage of patients with BPS at baseline, using the McNemar test.
Various characteristics were compared between patients admitted to a nursing home vs.
patients who were not admitted to a nursing home, respectively between patients who died vs.
those who survived and between patients who dropped out in the first six months (i.e. who did not complete the first assessment) versus patients who completed at least one follow-up assessment.
The independent sample t-test was performed to compare normally distributed variables. We employed the Mann-Whitney U test to compare skewed distributed variables. The Pearson Chi- square or Fisher’s exact test was used to compare categorical variables.
R
esultsPatient characteristics
Table 1 shows the patient characteristics of the 576 enrolled patients at the time of AD diagnosis. At baseline, median age was 80 years, median MMSE score 23 and median CDT score 3. More than half of the patients (51.4%) were dependent of professional care and 83% were dependent of informal care. Nearly a third (29%) of the patients had BPS. Of all patients, 96.4% started with galantamine and 3.6% with rivastigmine. During follow-up, memantine was added in 81 patients (14.1%) and 18 patients (3.1%) switched to monotherapy with memantine.
Follow-up
The number of outpatient visits per patient ranged from 1 to 11, the median number was 3 (25th – 75th percentile 2 - 5). Median time from starting a ChEI to the first subsequent outpatient visit was 6.3 months (25th – 75th percentile 5.5 – 7.3). Median time between subsequent visits was 10.6 months (25th – 75th percentile 10.1 – 11.7). Although the first patient was included in 2002, most patients were diagnosed with AD between 2006 and 2010 (87.3%). Median follow-up time between the date of diagnosis and December 2012 was 49 months (4.1 years) (25th – 75th percentile 37 – 66 months).
Drop-out
The number of patients that remained in the study at the different visits was: 576 at visit 1 (baseline), 447 patients at visit 2, 344 at visit 3, 242 at visit 4, 149 at visit 5, 73 at visit 6, 30 at visit 7, 11 at visit 8, 4 at visit 9, 1 at visit 10 and 1 at visit 11, respectively. Of the 576 patients that started using a ChEI, 171 patients (29.7%) are still waiting for their next outpatient clinic visit. 405 Patients (70.3%) did not show up at the next clinic visit at a given moment during follow-up. The main reasons patient
Long-term course of Alzheimer’s disease
2
did not show up were nursing home admission (n = 151, 37.3%) and discontinuation of treatment with a ChEI (n = 90, 22.2%). Most of the patients who discontinued ChEI treatment did so because of gastrointestinal side effects (n = 28, 31.1%). Of the 576 patients, 125 dropped out in the first six months and 451 patients completed at least one follow-up assessment. Patients who dropped out in the first six months were older, had a higher score on the CDT, had more often BPS and were more dependent on professional and informal care, compared to patients who had a least one follow-up assessment. There were no differences between the two groups with regard to gender, social status, MMSE score, comorbidity, ChEI wich was used and the number of medications beside the ChEI (see Table, Supplemental Digital Content 1, http://links.lww.com/WAD/A112) .
Course of cognition expressed by MMSE and CDT score
The course of the MMSE score is presented in table 2 and figure 1. There was no interaction between baseline MMSE score and time. Mean MMSE score at baseline was 22.24. During the first 6 months, the MMSE score remained stable. During the following three years, the MMSE score decreased to 18.91. The decrease in MMSE score equals to an average decrease of 1.1 points/year.
Table 1. Patient characteristics at baseline
Age (year): n, median [25th -75th percentile] 576, 80 [75 – 84]
Women, n (%) 362 (62.8)
Living status alone, n (%) with partner, n (%) other, n (%)
237 (42.5) 306 (54.9) 14 (2.5%) CIRS (score): n, median [25th -75th percentile] 575, 6.0 [4.0- 8.0]
Number of medications beside ChEI ≤ 4, n (%)
>4 (polypharmacy), n (%) 325 (57.0)
245 (43.0)
Use of informal care, n (%) 472 (83.0)
MMSE (score): n, median [25th -75th percentile]
MMSE score ≤ 24, n (%)
546, 23 [20 – 25]
375 (68.7) Clock-drawing test (score): n, median [25th -75th percentile]
clock-drawing test score ≥ 3: n (%)
463, 3.0 [2.0-5.0]
339 (73.1) Number of types of professional care
none, n (%) 1, n (%) 2, n (%) 3, n (%) 4, n (%) 5, n (%)
262 (48.6) 138 (25.6) 96 (17.8) 37 (6.9) 6 (1.1) 0 (0.0)
Presence of BPS, n (%) 163 (29.0)
ChEI which was started galantamine, n (%)
rivastigmine, n (%) 555 (96.4)
21 (3.6)
Abbreviations: CIRS: Cumulative Illness Rating Scale, BPS: Behavioural and psychological symptoms, ChEI:
cholinesterase inhibitor, MMSE: Mini Mental State Examination, n: number of patients
26
Chapter 2.1
At baseline, the mean CDT score was 3.38 (table 2 and figure 1). The score did not change in the first 6 months. After 3.5 years, the score increased with 0.67 points compared to baseline.
Over the follow-up period of 3.5 years, AD patients deteriorated on cognition, operationalized with both the MMSE (p<0.001) and the CDT (p=0.009).
Table 2. Course of AD expressed by MMSE score, CDT score and number of types of professional care:
results from the repeated measures analysis Measurement
moment n Mean (95% CI) ∆ ± SE P
MMSE 1: Baseline 546 22.24 (21.91 – 22.57)
2: 6 months 342 22.16 (21.52 – 22.80) -0.08 ± 0.16 0.61 3: 18 months 282 20.38 (19.63 – 21.14) -1.86 ± 0.22 <0.001*
4: 30 months 184 19.91 (19.09 – 20.73) -2.33 ± 0.25 <0.001*
5: 42 months 124 18.91(18.96 – 19.87) -3.33 ± 0.17 <0.001*
Clock-drawing test 1: Baseline 463 3.38 (3.24 – 3.52)
2: 6 months 300 3.29 (3.02 – 3.56) -0.09 ± 0.07 0.192 3: 18 months 250 4.06 (3.03 – 5.10) 0.68 ± 0.46 0.133 4: 30 months 165 4.39 (3.16 – 5.62) 1.01 ± 0.55 0.069 5: 42 months 117 4.05 (3.36 – 4.75) 0.67 ± 0.28 0.018*
Number of types of
professional care 1: Baseline 539 0.85 (0.77 – 0.94)
2: 6 months 397 1.94 (1.76 – 2.12) 1.08 ± 0.05 <0.001*
3: 18 months 299 2.21 (2.02 – 2.41) 1.36 ± 0.06 <0.001*
4: 30 months 198 2.40 (2.18 – 2.62) 1.55 ± 0.07 <0.001*
5: 42 months 125 2.64 (2.40 – 2.89) 1.79 ± 0.08 <0.001*
Abbreviations: MMSE: Mini Mental State Examination, n: number of remaining patients, CI:
Confidence Interval, ∆: estimated change from baseline, SE: Standard Error, *: significant compared to baseline
Course of IADL expressed by use of professional care
At baseline the mean number of types of professional care was 0.85 (table 2, figure 2). The increase in number of types of care was the greatest during the first 6 months (i.e. 1.08) and increased more gradually thereafter with a mean number of types of professional care of 2.64 after 3.5 years (p<0.001).
Course of behavioural functioning expressed by BPS
During 3.5 years of follow-up, the prevalence of BPS increased from 29.0% at baseline to 41.4% at 6 months, to 54.3% at 18 months, to 59.6% at 30 months and to 70.2% at 42 months (p<0.001).
Long-term course of Alzheimer’s disease
2
Course of AD expressed by proportions of nursing home admissions and deaths
For 476 patients (83.6%), the place of residency could be determined. Of these patients, 194 (40.8%) were admitted to a nursing home during a median follow-up time of 4.1 years. The date of nursing home admission was available for 39 patients (20.1%). Median time to nursing home placement for Figure 1. Course of cognition: results from the repeated measures analysis.
(a) Course of the Mini Mental State Examination (MMSE) score in the Frisian Alzheimer’s Disease Cohort.
(b) Course of the score on the clock-drawing test in the Frisian Alzheimer’s Disease Cohort.
(c) Course of the MMSE score in the Frisian Alzheimer’s Disease Cohort vs. in historical pre-ChEI-era cohorts.
CI: Confidence Interval, : significant compared to baseline.
Figure 2. Course of the number of types of professional care: results from the repeated measures analysis.
CI: Confidence Interval, : significant compared to baseline.
28
Chapter 2.1
these patients was 24 months (25th – 75th percentile 8.0 – 33.0). Patients admitted to a nursing home had poorer cognition, more BPS and used more professional care at baseline compared to those who remained at home (see Table, Supplemental Digital Content 2, http://links.lww.com/WAD/
A113). In addition, the proportion of deaths was higher in patients admitted to a nursing home.
Median follow-up time for patients admitted to a nursing home was 5.5 months longer compared to patients who were not admitted (p=0.002) (see Table, Supplemental Digital Content 2, http://links.
lww.com/WAD/A113) .
For 478 patients, it was possible to determine whether they died or not. Of these patients, 196 (41.0%) died during a median follow-up time of 4.1 years. Median time until death after diagnosis was 32.2 months (25th – 75th percentile 17.3 – 45.5). Patients who died had poorer cognition, used more types of professional care, had more comorbidity and more polypharmacy at baseline than survivors (see Table, Supplemental Digital Content 2, http://links.lww.com/WAD/A113). Median follow-up for patients who died was 15 months longer compared to those who survived (p=0.000).
d
IscussIonTo our knowledge, this is one of the largest ‘real-life’ studies of the long-term disease course of newly diagnosed AD patients treated at a memory clinic, and the first from the Netherlands. Our results show that, with the pharmacological and non-pharmacological interventions, provided according to the Dutch dementia guideline, cognition and behaviour deteriorated accompanied with an increase in care-dependency during 3.5 years of follow-up.
The estimated rate of decline in MMSE score (1.1 point/year) was lower than in historical pre- ChEI-era cohorts, with an estimated rate of decline of 3.3 point/year (95% confidence interval 2.9 – 3.7)17 (figure 1). The mean annual decline in our study was also lower compared to other long-term,
‘real-life’ ChEI-era cohorts, where the decline in MMSE score ranged from 1.3 to 2.5 points/year18-
20. However, the interpretation of these comparisons must be performed with caution, because of differences in patient characteristics and study methodology. In the ‘Swedish Alzheimer Treatment Study’ (SATS) cohort, mean annual decline in MMSE score was 1.3 points18. These patients were younger compared to the patients in our cohort, which might have contributed to the faster decline in MMSE score in the SATS cohort21. In ‘The REseau sur la maladie d’Alzheimer Français’ (REAL.FR) cohort, mean annual decline in MMSE score was 2.419. However, these patients had been diagnosed with AD over a year, while we investigated newly-diagnosed patients. In addition, differences in geographical position, reflecting differences in cultural and health care system can influence the outcome. We do not know details on how the care for people with dementia in France and Sweden is organized. Although, ‘The Impact of Cholinergic Treatment Use’ (ICTUS) study showed that the progression of AD was similar across 12 European countries (including France, Sweden and the Netherlands), despite different health care systems20. Patients from the ICTUS cohort were diagnosed with AD for 0.4 years. The MMSE declined in the first year 1.5 points and in the second year 2.5
Long-term course of Alzheimer’s disease
2
points20. However, 10% of the patients from the ICTUS cohort received not continuous treatment with a ChEI after inclusion. This may have contributed to the difference in mean annual decline in MMSE score between the ICTUS cohort and our cohort. Irrespective of possible differences, the results of the SATS18, REAL.FR19 and ICTUS20 cohort are in line with our finding that the rate of decline in MMSE score is slower than in historical pre-ChEI-era cohorts17, suggesting that long- term treatment with pharmacological and non-pharmacological interventions in a ‘real-life’ setting appears to slow cognitive decline in AD patients.
Little is known about changes in CDT score over time. Shulman et al. reported an increase in CDT score with 0.33 points in demented patients from the pre-ChEI-era during 18 months of follow-up.
This is less compared to our increase with 0.67 points in 18 months. The lower increase in CDT score reported by Shulman et al. could be explained by a ceiling effect since their patients had severe dementia (MMSE score 15.77), though their baseline score on the CDT was 3.3014. Shulman et al.
concluded that the CDT can be helpful in the monitoring of dementia14. To our knowledge, there are no studies that investigated the responsiveness of the CDT. Our results suggest that the CDT is able to detect changes over time in AD patients. The decrease in MMSE score and increase in CDT score in the present study, demonstrate that cognitive functions as measured by the MMSE deteriorate over time, but also as measured by the CDT, including executive functions.
Describing the use of professional care provides valuable information as it might help to plan the use of professional care and estimate future health care costs. To our knowledge, the use of professional care was investigated in one other ChEI-era AD cohort16. In this cohort, the use of professional care increased gradually over time16. In our study, the increase in use of professional care was the greatest during the first six months of ChEI treatment. This is most likely explained by the fact that we investigated newly diagnosed patients for whom pharmacological and non- pharmacological interventions, including professional care, were initiated after the diagnosis. Thus, the steep rise in number of professional types of care in the first six months is not a reliable measure for the severity of IADL limitations in our cohort.
The long-term course of BPS has been investigated in three other ChEI-era cohorts19,20,22. They reported similar results, namely that BPS gradually increased over time19,20,22. We have found no studies on the course of BPS from the pre-ChEI-era. Based on our results, we can not be conclusive whether treatment with ChEIs, in addition to non-pharmacological interventions, reduces behavioural problems. Though, there is evidence showing some benefit of ChEIs with regard to BPS7.
The proportion of patients admitted to a nursing home (40.8%) is higher than in other ChEI-era cohorts, with proportions of 12.4% in 2 years20 and 34% in 4 years19. The higher proportion in our cohort is possibly explained by our longer follow-up time, which could be as long as 10 years for some patients, though the median follow-up time was 4.1 years. To our knowledge, the proportion of patients admitted to a nursing home was investigated in two pre-ChEI-era cohorts23,24. In the pre- ChEI-era cohort of Yaffe et al., the proportion of patients admitted to a nursing home was higher, i.e.
30
Chapter 2.1
52% after 3 years23. However, this proportion is based on patients with more advanced dementia23. Smith et al. concluded that proportions of nursing home admission of approximately 10% per year could be expected in pre-ChEI-era dementia patients24, which equals the proportion of our cohort. Therefore, based on our results, it is not possible to be conclusive as to whether the current interventions reduce nursing home admission. Though, the proportion of patients admitted to a nursing home in the other ChEI-era cohorts is lower compared to the pre-ChEI-era cohorts of Yaffe et al. and Smith et al., possibly reflecting the benefits of the pharmacological and non-pharmacological interventions with regard to nursing home admission. Patients admitted to a nursing home were characterized by a more severe AD at baseline compared to patients who remained at home. This finding is consistent with other studies19,25,26. In addition, the proportion of deaths was higher in patients admitted to a nursing home, which is in agreement with other studies27. Our finding that BPS is associated with nursing home admission is also in line with other studies23,28 and emphasizes the importance of more research to treatment options for BPS in AD.
The proportion of deaths in our study (41%) is higher than in other ChEI-era cohorts, with proportions of 3.6% in 3 years29 and 23% in 4 years19. The higher proportion in our cohort is possibly explained by our longer follow-up time. In addition, the patients in the cohort where the proportion of deaths was 3.6%29, were seven years younger than our patients. As far as we know, the proportion of deaths was investigated in two pre-ChEI-era cohorts30,31. In one of these cohorts, the proportion of deaths was 17% during 4 years of follow-up30. In the pre-ChEI study of Holmes et al., the proportion of deaths was 70.5% after 3 years of follow-up31. Because of differences in patient characteristics between these cohorts and the present study, it is not possible to be conclusive about the effect of ChEIs, in addition to non-pharmacological interventions, on mortality. For example, patients in the cohort from Holmes et al. had advanced dementia with mean baseline MMSE score of 9.9. However, there is some evidence that galantamine reduces mortality. A recent trial in 2051 AD patients showed that galantamine was associated with lower mortality compared to placebo32. Patients who died during our study were characterized by a more severe AD at baseline. In addition, they had more comorbidity and polypharmacy. This suggests that mortality is related to the overall health status of AD patients, whereas admission to a nursing home is related to the dementia itself.
Strengths of our study are that we investigated patient-relevant outcomes in a relatively large group of AD patients with a long follow-up. In addition, the ‘real-life’ setting avoids the limitations of most AD clinical trials, increasing the external validity of the results. Another strength is that the disease course was described by a wide spectrum of domains. In addition, we investigated the course of cognition by change in the CDT. Statistical analysis of longitudinal data is primarily complicated because of intra-individual correlation and, particularly in older AD patients, drop out of patients33. A repeated measures analysis is specifically developed for the analysis of longitudinal dependent data. All data contribute to the longitudinal analysis and even data from patients who dropped out can be used. By applying a repeated measures analysis in our study we could maximize the use of all available data of a large number of patients with a long follow-up.
Long-term course of Alzheimer’s disease
2
Some limitations of the study must be considered. Firstly, all our AD patients were treated with a ChEI. Therefore, we compared our results with data derived from historical pre-ChEI-era AD cohorts. These comparisons have shortcomings because of differences in methodology and clinical characteristics. A placebo-controlled study is the ideal way to assess the effect of long-term treatment with ChEIs embedded in the current package of care. However, such a study can no longer be performed because of ethical reasons and would not reflect a ‘real-life’ setting. Furthermore, the decision to start the patient on a ChEI was made by the physicians of the memory clinic. This may have contributed to selection bias. A third limitation is the retrospective design of our study.
Hence, IADL and BPS were not measured using validated questionnaires. In addition, not all the non-pharmacological interventions were recorded (for example, it was not recorded if patients used occupational therapy). Moreover, for some patients data regarding nursing home admission and mortality could not be determined. Hence, it was not possible to perform a survival analysis, which thoroughly estimates incidences of nursing home admission and mortality and takes into account differences in follow-up, as was the case in our study. The fourth limitation is that the disease course was described by various rating scales for which a definition of a worthwhile clinical response is lacking. We can not assume that the statistically significant changes in test scores would be considered clinically relevant by patients, caregivers or health care professionals. Development of scales that can describe the course of AD for all relevant domains and provides worthwhile clinical changes are needed. Recently, such a scale was developed: the Relevant Outcome Scale for Alzheimer’s Disease (ROSA)34, which may be a promising tool for the future.
In conclusion, the present ‘real-life’ study provides insight in the long-term course of AD patients treated according to the Dutch dementia guideline at a memory clinic. Despite pharmacological and non-pharmacological interventions, cognition and BPS deteriorated accompanied with an increase in care-dependency during 3.5 years of follow-up. Compared to the disease progression in the period before ChEIs were available, long-term treatment appears to slow cognitive decline.
This emphasizes that the combination of pharmacological and non-pharmacological interventions seem to have a favorable effect on the long-term course of AD.
More data regarding the course of AD should be collected in well established registries using appropriate and validated scales. This offers the opportunity to use ‘benchmarking’ in order to improve the care for AD patients. With benchmarking, the clinical approaches of institutions with excellent clinical outcomes can be identified and used for the improvement of the quality of care and outcomes of other institutions35.
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R
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