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Aggressive course of disease in dementia
Alzheimer’s & Dementia 2 (2006) 210 –217
Review Articles
Aggressive course of disease in dementia Serge Gauthier,a,* Bruno Vellas,b Martin Farlow,c David Burnd a
McGill Centre for Studies in Aging, Verdun, Quebec, Canada b CHU de Toulouse Hôpital La Grave, Toulouse, France c Indiana University School of Medicine, Indianapolis, IN, USA d Newcastle General Hospital, Newcastle upon Tyne, UK
Abstract
The rate of disease progression in Alzheimer’s disease (AD) patients is variable. A significant proportion of AD patients appear to experience an aggressive course of disease, and this has a major impact on prognosis, the patients, and their caregivers and society in general. Here we review the current literature on an aggressive course of disease in dementia and how it can be recognized in clinical practice. We also discuss the options available for treating patients with this condition. © 2006 The Alzheimer’s Association. All rights reserved.
Keywords:
Alzheimer’s disease; Dementia; Aggressive course of disease; Rapid decline; Rapid progression
1. Introduction
2. What is an “Aggressive” Course of Disease?
Neurodegenerative dementias such as Alzheimer’s disease (AD) are long-term, progressive conditions. However, the rate of progression can be highly variable between individual patients [1]. Whereas some decline gradually over time, others may experience an aggressive course of disease. These patients deteriorate rapidly and are likely to have a poorer prognosis than those with slower progression rates [1,2]. When dementia is diagnosed, patients often ask how fast their disease will progress. The ability to differentiate rates of decline would help patients and caregivers plan for the future and physicians decide how to best manage patients. However, although several methods of identifying patients with an aggressive course of disease have evolved in clinical research settings, there is no standard methodology or definition for use in clinical practice. Here we review the current literature on an aggressive course of disease in dementia, how this may be anticipated, and the options available for treating patients with this condition.
The concept of an “aggressive course of disease” is still relatively new. Although some studies on the rate of decline in dementia were conducted in the 1990s [3,4], the majority of research on the subject has taken place in the last 5 years. The definition of an aggressive course of disease in the literature has varied, including “rapid cognitive decline,” “rapid progression,” and “rapid cognitive loss.” These terms have been used to describe patients who experience a greater than average or expected loss on specified dementia assessment scales over set periods of time. However, the efficacy measures and the time periods used differ between studies (Table 1). Several studies have based measurement of an aggressive course of disease on the Mini-Mental State Examination (MMSE). The average annual MMSE decline in AD is 2 to 3 points [5]. In one of the first studies to look at the rate of decline in dementia, Doody et al [1] used the time taken to reach a 5-point decrease in MMSE score, which was thought to be a clinically meaningful deterioration, to identify patients with rapid disease progression. In this study, patients were divided at baseline into slow (0- to 1.9-point decline in MMSE per year), intermediate (2- to 4.9-point decline per year), or rapid progressors (ⱖ5-point decline per year) using predicted preprogression rates based on their initial MMSE scores. During the study, rapid progressors
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S. Gauthier et al. / Alzheimer’s & Dementia 2 (2006) 210 –217 Table 1 Definitions of an aggressive course of disease in dementia based on cognitive decline Study
No.
% patients with Aggressive Course of Disease
Definition of Aggressive Course of Disease
Doody et al [1] Farlow et al [11]
298 235
22 45
Dumont et al [7]
340
54
Atchison et al [10]
189
39
Farlow et al [12]
679
36
Dumont et al [8]
312
25
Time to 5-pt MMSE decline ⬎4 pt loss on ADAS-cog in 6 months ⬎3-pt loss on MMSE in 6 months MMSE tertiles based on monthly change ⬎4-pt loss on ADAS-cog in 6 months ⬎4-pt MMSE loss in 6 months
reached a further 5-point decline in MMSE score in a mean of 1.6 years compared with 2.3 years for slow progressors. Similarly, O’Hara et al [6] proposed a definition of “rapid decline” as a loss of 3 MMSE points or more in 1 year. In more recent studies, suggested definitions have included a 3-point or more decline on the MMSE in 6 months [7], a loss of 4 or more MMSE points in 6 months [8], a loss of 4 or more MMSE points in 6 months associated with loss of at least 1 point in the next 6 months [9]. Atchison et al [10] divided 211 AD patients into fast, intermediate, and slow decliners based on the monthly rate of change on the MMSE, at the points that left the most equal group sizes. Fast decliners had an average monthly MMSE decline of 0.58 points. Another efficacy measure that has been used to study the rate of progression in AD is the Alzheimer’s Disease Assessment Scale cognitive component (ADAS-cog) [11,12]. The ADAS-cog is often used to assess cognition in clinical trials but is not suitable for clinical practice because of the time taken to complete the test. Farlow et al [12] used a 4-point or greater decline on the ADAScog in 6 months to identify patients with an aggressive course of disease in placebo-treated patients from clinical trials of rivastigmine in AD (Fig. 1). However, although an aggressive course of disease is characterized by a decline in cognition, it is also associated with deterioration in other domains such as behavior and function in activities of daily living. Farlow et al [11] also used the Progressive Deterioration Scale (PDS), a measure of activities of daily living, to measure decline. A worsening of 10% or greater on the PDS in 6 months was used to categorize rapidly progressive patients. A general, but clinically useful, definition of an aggressive course of disease may be “a significant deterioration in patient status within a short time period (6 to 12 months).”
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3. Prevalence of Aggressive Course of Disease Because of the different definitions used in studies of aggressive course of disease in dementia, there is considerable variation in the reported frequency of patients with the condition (Table 1). Doody et al [1] reported that 22% of their 336 AD patients were rapid progressors, whereas 54% of patients in the REAL.FR study (n ⫽ 340) were classified as having rapid cognitive decline [7]. These differences are largely caused by the lack of a standard definition for an aggressive course of disease and the fact that different studies used different inclusion criteria to select populations. Nevertheless, based on the available data, at least a third of dementia patients may be regarded as experiencing an aggressive course of disease. 4. Prognosis The frequencies of an aggressive course of disease reported in clinical studies (Table 1) suggest that these patients represent a large proportion of the overall dementia population. The fact that these patients may have a worse prognosis is therefore of considerable clinical importance. It has been suggested that the rate of disease progression may be more important than the severity of disease for predicting the time to reach significant endpoints such as institutionalization or death [13]. In a 4-year study of 354 AD patients, patients were divided into quartiles according to their rate of decline in global cognition score derived from a battery of 17 cognitive tests [2]. Compared with those with the least decline, the risk of mortality was increased 3-fold for patients with mild decline, 5-fold for moderate decline, and 8-fold for those with the most rapid rate of decline. Consistent with this finding, it had previously been reported that AD patients with aggressive course of disease reached clinical mile-
Fig. 1. Mean change in ADAS-cog scores in rapid and slow progressing placebo-treated patients with mild to moderate AD over 26 weeks [12]. Patients were divided into slow and fast progressors on the basis of their decline on placebo treatment over 6 months: rapid progressors declined by ⱖ 4 points (n ⫽ 240); slow progressors declined by ⬍ 4 points (n ⫽ 432).
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Table 2 Possible predictors of an aggressive course of disease Predictors of an Aggressive Course of Disease Demographics Deficits in executive function and attention at time of diagnosis Poor nutritional status High educational attainment Young age of onset Clinical symptoms Extrapyramidal symptoms (eg, tremor, rigidity, bradykinesia) Psychotic symptoms (eg, delusions, hallucinations [particularly visual]) Subcortical symptoms (eg, apathy, attention or executive function deficits) AD pathology with symptoms of LB pathology Genetics BuChE wild-type allele APOE ⑀4 allele
stones sooner than those with slower rates of decline [1]. Patients who had baseline rates of decline that were more rapid than average (ⱖ 5 MMSE points per year) continued to experience more rapid decline than patients who had slow or average rates of disease progression. Furthermore, a longitudinal study of 91 AD patients showed that the course of deterioration tended to stay constant over time [14]. Patients who experienced rapid progression from the time of diagnosis to the time of next assessment were unlikely to shift to a slow progression rate in the following 12 to 24 months. This could imply that the tempo of the pathophysiologic process is predetermined at the outset by a combination of biological or environmental factors. 5. Recognition of Aggressive Course of Disease Given the poorer prognosis for dementia patients with an aggressive course of disease, it is important to be able to recognize and treat these patients as early as possible. Considerable efforts have been directed toward identifying patients at risk of rapid disease progression (Table 2). 5.1. Demographics as predictors of an aggressive course of disease The cognitive status of the patient at the time of diagnosis may be a useful predictor of an aggressive course of disease. Atchison et al [10] found that AD patients (n ⫽ 189) showing significantly impaired performance on measures of attention and executive function at baseline, had a more rapid decline over 1 year on the MMSE than those who did not, despite equivalent MMSE scores at baseline for both groups. Impaired performances at baseline on other neuropsychological measures, including letter and category fluency tests, naming tests, and language tests, may also predict a faster rate of decline in AD patients [15–18]. Poor nutritional status may also predict an aggressive course of disease. A study of 312 AD patients who experienced rapid loss of cognition over 1 year aimed to identify
predictive factors for an aggressive course of disease [8]. Rapid cognitive loss was defined as a 4-point or greater loss in MMSE score in 6 months. A multivariate analysis showed that the Mini Nutritional Assessment (MNA) score correlated with the rate of decline (p ⫽ 0.002). This may reflect the underlying frailty of these patients, who were also significantly more dependent on activities of daily living compared with slower progressors. Education may provide a “cognitive reserve” that must be depleted to a certain threshold before dementia becomes clinically manifest. At higher levels of education, AD pathology may therefore be more advanced before dementia symptoms are manifest, so these patients subsequently experience a more rapid clinical progression. In support of this hypothesis, Stern et al [19] reported a correlation between the number of years of education and the severity of AD pathology. For a given clinical severity of dementia, parieto-temporal blood flow was reduced further in patients with higher levels of education, indicating more severe pathology. In a further study [20], AD patients with a higher educational level experienced a more rapid decline in memory measured using the Selective Reminding Test, compared with patients with lower levels of education (p ⬍ 0.057). A similar result was seen when patients with high occupational attainment were compared with low-attainment patients (p ⬍ 0.02). Furthermore, in a recent prospective study of 1,050 healthy elderly patients, highly educated subjects had higher initial scores on the MMSE and 4 neuropsychological measures but experienced a more rapid cognitive decline during the 3 years preceding diagnosis of dementia compared with less educated subjects [21]. A younger age at the onset of AD may also be a predictor of an aggressive course of disease. In a study of 127 AD patients, those with an onset of AD before the age of 65 (n ⫽ 44, mean age of onset 58.8 years) declined significantly faster than late-onset patients (n ⫽ 83, mean age of onset 74.1 years) over 2 years on the modified MMSE (p⬍0.001) [4]. Regression analyses showed that age at symptom onset was a strong predictor of the rate of cognitive decline. Decline in functional capacity measured using the Blessed Dementia Rating Scale (BDRS) was also more rapid in the younger patient group (p⬍0.05). Furthermore, in AD and dementia with Lewy bodies (DLB), patients younger in age at onset had more severe pathology and aggressive disease. A comparison of 28 DLB patients age 70 or younger with the same number of patients older than 70 years showed that early-onset patients declined more rapidly and had more severe pathology. Similar findings were seen in 178 AD patients [22]. 5.2. Clinical symptoms as predictors of an aggressive course of disease Alzheimer’s disease patients who present extrapyramidal signs (EPS), such as tremor, rigidity, and bradykinesia may
S. Gauthier et al. / Alzheimer’s & Dementia 2 (2006) 210 –217
Fig. 2. Visual hallucinations as a predictor of an aggressive course of disease in PDD patients [30]. Based on change in ADAS-cog in mild to moderate PDD patients with and without visual hallucinations at baseline receiving placebo for 6 months.
be at high risk of an aggressive course of disease. The presence of EPS symptoms at baseline significantly predicts faster cognitive decline in AD patients [23]. In 67 patients with probable AD, patients with EPS reached endpoints on the BDRS factor VI, a measure of basic self-care, earlier than those who did not (p⬍0.05) [3]. Moreover, in a study of 81 AD patients, those with EPS symptoms deteriorated 67% faster on the MMSE than those with no EPS symptoms [24]. EPS signs in AD patients have also been associated with a more rapid functional decline [25,26]. Patients with psychotic symptoms, including delusions, at baseline also experience more rapid cognitive decline, reaching endpoints on the Blessed Dementia Rating Scale (BDRS) factor I sooner than those without psychosis (p⬍0.001) [3]. Wilson et al [27] examined the association between delusions and hallucinations and the rate of cognitive decline over 4 years in 410 AD patients. Both hallucinations (present in 41% of patients) and delusions (present in 55%) were common at baseline. Patients with hallucinations at baseline declined more rapidly on a composite measure of cognitive function, which included the MMSE. Chui et al [23] also showed that hallucinations at baseline in AD patients predicted a shorter time to reach endpoints on the MMSE (n ⫽ 135; p ⫽ 0.01). Hallucinations are common in the neurodegenerative dementias, developing in 30% to 40% of patients with AD [27], and 60% to 80% of patients with Parkinson’s disease dementia (PDD) [28], and DLB [29]. Hallucinations have been associated with rapid cognitive and functional decline in PDD and DLB as well as in AD patients [27,29 –31]. In a randomized, controlled trial of rivastigmine in PDD, decline in the ADAS-cog over 24 weeks was 2.1 in placebotreated patients with visual hallucinations at baseline (n ⫽ 70) compared with 0.1 points in placebo-treated nonvisual hallucinators (n ⫽ 109; Fig. 2) [30]. Evidence suggests that hallucinations, particularly visual hallucinations, relate to
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cholinergic and possibly dopaminergically mediated cortical dysfunction. The presence of apathy has been linked with a greater placebo decline in PDD patients on measures of cognition, behavior, attention, and executive function [32]. Apathy has also been associated with an increased likelihood of progression to AD in subjects with mild cognitive impairment (MCI) [33,34]. Apathy is thought to be a feature of frontosubcortical pathology [35]. Extrapyramidal, psychotic, and subcortical symptoms are common in patients with Lewy body dementia. Kraybill et al [36] confirmed that AD patients with symptoms of LB pathology may be more likely to have an aggressive course of disease compared with patients with AD or LB pathology alone. The rate of decline in AD patients with symptoms of LB pathology (n ⫽ 65) was significantly faster on the Mattis Dementia Rating Scale over 18 months (p⬍0.03) and MMSE over 6 months (p⬍0.04) compared with AD (n ⫽ 48) or LB (n ⫽ 22) patients. Similar relationships between the rate of cognitive decline and symptoms suggestive of Lewy body dementia have been noted in other studies [37– 39]. 5.3. Genetics as a predictor of aggressive course of disease Whereas younger age, more advanced education, poorer nutritional status, hallucinations, and EPS may be clinical markers for an aggressive course of disease, genetic factors may be the underlying cause of the variations in the differential rates of decline in dementia patients. Genetic factors that have been linked with the rate of progression of disease include the APOE ⑀4 allele. Carriers of APOE ⑀4 with mild AD (MMSE score 22 to 26) declined faster on the ADAScog over 6 months compared with noncarriers, whereas moderate AD APOE ⑀4 carriers (MMSE score 10 to 21) declined slower than those without the allele [40]. However, a majority of studies have failed to link the presence of APOE ⑀4 to rate of progression, possibly owing to the fact that it is disease severity stage dependent [41] and that the rate of cognitive decline fits nonlinear models better [42]. Butyrylcholinesterase (BuChE) genotype affects the rate of disease progression in dementia [43– 45]. BuChE, like acetylcholinesterase (AChE), is involved in the hydrolysis of acetylcholine in the brain, but unlike AChE, the level of BuChE activity increases in the brain as the disease progresses in AD patients [45]. The K and A variants of BuChE encode for lower expression or lower activity of the BuChE enzyme in the plasma. In 57 patients with AD or DLB, BuChE wild-type homozygotes had a more rapid progression on the Cambridge Cognitive Examination schedule (CAMCOG) over 2 to 3 years compared with carriers of the K or A variants of BuChE (Fig. 3) [44]. After this, Perry et al [45] showed that the antemortem rate of cognitive decline correlated with the level of BuChE activ-
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6. Treatment options
Fig. 3. An aggressive course of disease in BuChE wild-type homozygous patients with AD or DLB: a prospective study [44]. Based on annual mean change from baseline in CAMCOG in 57 patients with moderate to severe AD and DLB.
ity in the temporal cortex of patients with DLB. A further study showed that the rate of cognitive decline in severe AD patients (baseline MMSE ⱕ 8) carrying the K variant allele of BuChE was slower compared with patients with wildtype BuChE (mean annual MMSE decline of 0.2 compared with 1.8 in BuChE wild-type homozygotes) [43]. The distribution of BuChE in the brain is greater in subcortical structures. BuChE-positive neurons in subcortical nuclei that project to prefrontal cortical areas have been implicated in attention, executive function, and certain behaviors [46]. The presence of BuChE wt/wt correlates with worse attentional function at baseline in patients with DLB [43]. In PDD, a greater decline in BuChE wt/wt patients (n ⫽ 176) on the D-KEFS verbal fluency test, a measure of executive function, was seen over 24 weeks compared with carriers of one K variant allele (n ⫽ 96) (Fig. 4) [32]. Similar findings were also seen on the Cognitive Drug Research Power of Attention measure of focussed attention. These studies suggest that higher levels of BuChE may be associated with an accelerated rate of cognitive decline in dementia and that patients possessing variant alleles that encode for less expression of the enzyme are less likely to experience an aggressive course of disease. In particular, higher levels of BuChE may induce greater progression of deficits related to subcortical pathology, in keeping with the predominant subcortical distribution of BuChE in the brain [32]. There may be many other genetic variations influencing rate of decline in dementia, and further research in this area may also increase our understanding of the pathophysiology.
Once a patient with an aggressive course of disease has been identified, treatment should be initiated as soon as possible to delay progression of symptoms. Effective treatment may also reduce caregiver stress associated with the condition. However, there has been limited research on treatment of patients with an aggressive course of disease. A 26-week, double-blind, placebo-controlled trial of the ChE-I rivastigmine, a dual inhibitor of AChE and BuChE, in AD patients, was followed by an open-label extension study for a further 26 weeks [11]. The response to rivastigmine was studied in 187 patients who had received placebo during the original trial and who continued with open-label rivastigmine therapy. Patients identified as rapid progressors using the PDS and ADAS-cog during the double-blind trial showed significantly greater responses to rivastigmine treatment compared with slow progressors on measures of cognition (Rapid progressors baseline [week 26] score 17.5, change from baseline to endpoint 2.01; slow progressors [week 26] baseline score 33.5; change from baseline to endpoint ⫺0.90; p⬍0.05, rapid versus slow progressors). Greater responses to treatment in rapid progressors were also seen on activities of daily living (rapid progressors baseline [week 26] score 38.5, change from baseline to endpoint 0.34; slow progressors [week 26] baseline score 61.0; change from baseline to endpoint ⫺2.54; p⬍0.05, rapid versus slow progressors). This study was included in a meta-analysis of 4 6-month, double-blind, placebo-controlled studies of rivastigmine, in which rapidly progressive patients also showed greater responses to therapy compared with slowly progressive patients [12]. Patients who experi-
Fig. 4. More rapid decline in executive function in mild to moderate PDD patients with BuChE wild-type genotype (n ⫽ 176) compared with BuChE-K variant carriers (n ⫽ 96) [32]. Changes shown are least square mean calculations of change from baseline at 24 weeks (ITT-RDO analysis).
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enced a decline of 4 or more points on the ADAS-cog during 26 weeks of placebo treatment showed a mean improvement over baseline of 4.97 points after 12 weeks of rivastigmine therapy. This was significantly better than the change seen in patients who had declined by less than 4 points in the first 26 weeks (p⬍0.001). These are the only published studies showing a relationship between response to ChE-I therapy and the rate of AD progression. Furthermore, patients who exhibit predictors of an aggressive course of disease in Lewy Body (LB) dementias have also been shown to have differential responses to ChE-I treatment. Greater responses to rivastigmine have also been seen in PDD and DLB patients with hallucinations, which have been shown to be indicative of an aggressive course of disease [29,30]. In a retrospective analysis of rivastigmine in 120 DLB patients, greater improvements in attention were seen in patients who had hallucinations at baseline [29]. On Power of Attention, significant treatment benefits of rivastigmine were seen in patients with hallucinations (p⫽0.002) but not in nonhallucinating patients. In a prospective, randomized, placebo-controlled trial of rivastigmine in PDD, patients with visual hallucinations (n ⫽ 188) showed greater treatment–placebo differences than patients without visual hallucinations (n ⫽ 348), on measures of cognition (ADAS-cog), global change (Alzheimer’s Disease Assessment Scale Clinician’s Global Impression of Change [ADAS-CGIC]), attention and executive function (D-KEFS verbal fluency, Choice Reaction Time and Power of Attention), and behavior (Neuropsychiatric inventory [NPI-10]). In a recent, large, double-blind study of rivastigmine and the AChE selective inhibitor donepezil in moderate AD patients, significantly greater functional responses to rivastigmine therapy were seen in the two thirds of patients with a BuChE wt/wt genotype compared with donepezil therapy [47]. These differential effects were particularly apparent in younger AD patients (⬍75 years of age) with the BuChE wt/wt genotype [48]. Differential effects were not seen in BuChE K variant carriers, possibly owing to greater tolerability problems in these patients resulting in a significantly lower mean daily dose of rivastigmine [49] (Fig. 5). Patients with symptoms suggestive of concomitant LB disease, including hallucinations, fluctuating cognition, and extrapyramidal symptoms also showed greater benefits of rivastigmine treatment [50]. To date, rivastigmine is the only drug in which the response of patients with an aggressive course of disease has been studied. Patients receiving other ChE-I inhibitors who experience an aggressive course of disease may benefit from switching to rivastigmine [51]. However, it remains to be confirmed whether these effects are caused by the additional inhibition of BuChE as well as the sustained inhibition of AChE, by rivastigmine.
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Fig. 5. Greater response to rivastigmine therapy on Alzheimer’s Disease Cooperative Study Activities of Daily Living scale (ADCS-ADL) in homozygous butyrylcholinesterase (BuChE) wild-type patients with moderate AD over 2 years (ITT-LOCF analysis) [47].
7. Discussion A significant proportion of people with dementia have an aggressive course of disease, and this has major deleterious effects on caregivers and society in general, as well as on patients. Currently, there is no clear definition of an aggressive course of disease, but there are several factors that may predict the condition. Cognitive status, young age at disease onset, presence of EPS, fluctuating cognition, psychotic symptoms and hallucinations, prominent subcortical pathology with attention and executive deficits, poor nutrition, and high previous educational attainment may identify at-risk patients in the clinic. There is a need for a clinical assessment tool, which must include caregiver input, for the detection of an aggressive course of disease in newly diagnosed patients. Further prospective studies may also permit the development of a clinically based algorithm to predict rate of disease progression. Given the poor prognosis of patients with an aggressive course of disease, it is important to initiate treatment as soon as possible. The only therapy in which the response in patients with an aggressive course of disease has been studied is rivastigmine, which may be particularly effective in these patients. It has not yet been confirmed whether the same response is seen with other ChE-Is, but evidence suggests that the sustained inhibition of BuChE and AChE by rivastigmine might provide greater benefits in these patients compared with AChE selective inhibitors. Genetic variations, such as APOE ⑀4 and BuChE genotypes, may determine susceptibility to rapidly progressive disease, and their influence may change over the course of
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the disease. Rapid disease progression may be caused by multiple factors, and further research is required to better understand the pathophysiology of an aggressive course of disease and to develop optimum therapeutic approaches. When a patient has dementia diagnosed, physicians should always be alert to the possibility of an aggressive course of disease and should assess each individual patient based on their symptoms and demographics. If an aggressive course of disease is suspected, then appropriate treatment should be initiated immediately to keep symptoms at a manageable level and to minimize the impact of this distressing condition on both patient and carer for as long as possible.
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S. Gauthier et al. / Alzheimer’s & Dementia 2 (2006) 210 –217 [35] Benoit M, Clairet S, Koulibaly PM, Darcourt J, Robert PH. Brain perfusion correlates of the Apathy Inventory dimensions of Alzheimer’s disease. Int J Geriatr Psychiatry 2004;19:864 –9. [36] Kraybill MI, Larson EB, Tsuang DW, Teri L, McCormick WC, Bowen JD, et al. Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both. Neurology 2005;64:2069 –73. [37] Olichney JM, Galasko D, Salmon DP, Hofstetter CR, Hansen LA, Katzman R, et al. Cognitive decline is faster in Lewy body variant than in Alzheimer’s disease. Neurology 1998;51:351–7. [38] Scarmeas N, Albert M, Brandt J, Blacker D, Hadjigeorgiou G, Papadimitriou A, et al. Motor signs predict poor outcomes in Alzheimer disease. Neurology 2005;64:1696 –703. [39] Tsuang DW, Purganan K, Steinbart E, et al. Concomitant Lewy body pathology a marker for more aggressive course in familial Alzheimer’s disease. 57th Annual Meeting of the American Academy of Neurology, Miami, FL, USA, 9 –16 April 2005 (P06.074). [40] Lane R, Farlow M. Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer’s disease. J Lipid Res 2005;46:949 – 68. [41] Holmes C. Genotype and phenotype in Alzheimer’s disease. Br J Psychiatry 2002;180:131– 4. [42] Martins CAR, Oulhaj A, de Jager CA, Williams JH. APOE alleles predict the rate of cognitive decline in Alzheimer disease. Neurology 2005;65:1888 –93. [43] Holmes C, Ballard C, Lehmann D, David Smith A, Beaumont H, Day IN, et al. Rate of progression of cognitive decline in Alzheimer’s disease: Effect of butyrylcholinesterase K gene variation. J Neurol Neurosurg Psychiatry 2005;76:640 –3.
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[44] O’Brien KK, Saxby BK, Ballard CG, Grace J, Harrington F, Ford GA, et al. Regulation of attention and response to therapy in dementia by butyrylcholinesterase. Pharmacogenetics 2003;13:231–9. [45] Perry E, McKeith I, Ballard C. Butyrylcholinesterase and progression of cognitive deficits in dementia with Lewy bodies. Neurology 2003; 60:1852–3. [46] Darvesh S, Hopkins DA. Differential distribution of butyrylcholinesterase and acetylcholinesterase in the human thalamus. J Comp Neurol 2003;463:25– 43. [47] Bullock R, Touchon J, Bergman H, Gambina G, He Y, Rapatz G, et al. Rivastigmine and donepezil treatment in moderate to moderatelysevere Alzheimer’s disease over a 2-year period. Curr Med Res Opin 2005;21:1317–27. [48] Bullock R, Bergman H, Touchon J, Gambina G, He Y, Nagel J, et al. Effect of age on response to rivastigmine or donepezil in patients with Alzheimer’s disease Curr Med Res Opin 2006;22:48394. [49] Blesa R, Bullock R, He Y, Bergman H, Gambina G, Meyer J, et al. Effect of BuChE genotype on response to rivastigmine or donepezil in younger patients with Alzheimer’s disease. Pharmacogenet Genomics (in press). [50] Touchon J, Bergman H, Bullock R, Rapatz G, Nagel J, Lane R. Response to rivastigmine or donepezil in patients with Alzheimer’s disease and symptoms suggestive of concomitant Lewy body pathology. Curr Med Res Opin 2006;22:49 –59. [51] Auriacombe S, Pere J-J, Loria-Kanza Y, Vellas B. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease who failed to benefit from treatment with donepezil. Curr Med Res Opin 2002;18: 129 –38.
Review Articles
Aggressive course of disease in dementia Serge Gauthier,a,* Bruno Vellas,b Martin Farlow,c David Burnd a
McGill Centre for Studies in Aging, Verdun, Quebec, Canada b CHU de Toulouse Hôpital La Grave, Toulouse, France c Indiana University School of Medicine, Indianapolis, IN, USA d Newcastle General Hospital, Newcastle upon Tyne, UK
Abstract
The rate of disease progression in Alzheimer’s disease (AD) patients is variable. A significant proportion of AD patients appear to experience an aggressive course of disease, and this has a major impact on prognosis, the patients, and their caregivers and society in general. Here we review the current literature on an aggressive course of disease in dementia and how it can be recognized in clinical practice. We also discuss the options available for treating patients with this condition. © 2006 The Alzheimer’s Association. All rights reserved.
Keywords:
Alzheimer’s disease; Dementia; Aggressive course of disease; Rapid decline; Rapid progression
1. Introduction
2. What is an “Aggressive” Course of Disease?
Neurodegenerative dementias such as Alzheimer’s disease (AD) are long-term, progressive conditions. However, the rate of progression can be highly variable between individual patients [1]. Whereas some decline gradually over time, others may experience an aggressive course of disease. These patients deteriorate rapidly and are likely to have a poorer prognosis than those with slower progression rates [1,2]. When dementia is diagnosed, patients often ask how fast their disease will progress. The ability to differentiate rates of decline would help patients and caregivers plan for the future and physicians decide how to best manage patients. However, although several methods of identifying patients with an aggressive course of disease have evolved in clinical research settings, there is no standard methodology or definition for use in clinical practice. Here we review the current literature on an aggressive course of disease in dementia, how this may be anticipated, and the options available for treating patients with this condition.
The concept of an “aggressive course of disease” is still relatively new. Although some studies on the rate of decline in dementia were conducted in the 1990s [3,4], the majority of research on the subject has taken place in the last 5 years. The definition of an aggressive course of disease in the literature has varied, including “rapid cognitive decline,” “rapid progression,” and “rapid cognitive loss.” These terms have been used to describe patients who experience a greater than average or expected loss on specified dementia assessment scales over set periods of time. However, the efficacy measures and the time periods used differ between studies (Table 1). Several studies have based measurement of an aggressive course of disease on the Mini-Mental State Examination (MMSE). The average annual MMSE decline in AD is 2 to 3 points [5]. In one of the first studies to look at the rate of decline in dementia, Doody et al [1] used the time taken to reach a 5-point decrease in MMSE score, which was thought to be a clinically meaningful deterioration, to identify patients with rapid disease progression. In this study, patients were divided at baseline into slow (0- to 1.9-point decline in MMSE per year), intermediate (2- to 4.9-point decline per year), or rapid progressors (ⱖ5-point decline per year) using predicted preprogression rates based on their initial MMSE scores. During the study, rapid progressors
*Corresponding author. Tel.:514-766-2010; Fax:514-888-4050 E-mail address: [email protected]
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S. Gauthier et al. / Alzheimer’s & Dementia 2 (2006) 210 –217 Table 1 Definitions of an aggressive course of disease in dementia based on cognitive decline Study
No.
% patients with Aggressive Course of Disease
Definition of Aggressive Course of Disease
Doody et al [1] Farlow et al [11]
298 235
22 45
Dumont et al [7]
340
54
Atchison et al [10]
189
39
Farlow et al [12]
679
36
Dumont et al [8]
312
25
Time to 5-pt MMSE decline ⬎4 pt loss on ADAS-cog in 6 months ⬎3-pt loss on MMSE in 6 months MMSE tertiles based on monthly change ⬎4-pt loss on ADAS-cog in 6 months ⬎4-pt MMSE loss in 6 months
reached a further 5-point decline in MMSE score in a mean of 1.6 years compared with 2.3 years for slow progressors. Similarly, O’Hara et al [6] proposed a definition of “rapid decline” as a loss of 3 MMSE points or more in 1 year. In more recent studies, suggested definitions have included a 3-point or more decline on the MMSE in 6 months [7], a loss of 4 or more MMSE points in 6 months [8], a loss of 4 or more MMSE points in 6 months associated with loss of at least 1 point in the next 6 months [9]. Atchison et al [10] divided 211 AD patients into fast, intermediate, and slow decliners based on the monthly rate of change on the MMSE, at the points that left the most equal group sizes. Fast decliners had an average monthly MMSE decline of 0.58 points. Another efficacy measure that has been used to study the rate of progression in AD is the Alzheimer’s Disease Assessment Scale cognitive component (ADAS-cog) [11,12]. The ADAS-cog is often used to assess cognition in clinical trials but is not suitable for clinical practice because of the time taken to complete the test. Farlow et al [12] used a 4-point or greater decline on the ADAScog in 6 months to identify patients with an aggressive course of disease in placebo-treated patients from clinical trials of rivastigmine in AD (Fig. 1). However, although an aggressive course of disease is characterized by a decline in cognition, it is also associated with deterioration in other domains such as behavior and function in activities of daily living. Farlow et al [11] also used the Progressive Deterioration Scale (PDS), a measure of activities of daily living, to measure decline. A worsening of 10% or greater on the PDS in 6 months was used to categorize rapidly progressive patients. A general, but clinically useful, definition of an aggressive course of disease may be “a significant deterioration in patient status within a short time period (6 to 12 months).”
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3. Prevalence of Aggressive Course of Disease Because of the different definitions used in studies of aggressive course of disease in dementia, there is considerable variation in the reported frequency of patients with the condition (Table 1). Doody et al [1] reported that 22% of their 336 AD patients were rapid progressors, whereas 54% of patients in the REAL.FR study (n ⫽ 340) were classified as having rapid cognitive decline [7]. These differences are largely caused by the lack of a standard definition for an aggressive course of disease and the fact that different studies used different inclusion criteria to select populations. Nevertheless, based on the available data, at least a third of dementia patients may be regarded as experiencing an aggressive course of disease. 4. Prognosis The frequencies of an aggressive course of disease reported in clinical studies (Table 1) suggest that these patients represent a large proportion of the overall dementia population. The fact that these patients may have a worse prognosis is therefore of considerable clinical importance. It has been suggested that the rate of disease progression may be more important than the severity of disease for predicting the time to reach significant endpoints such as institutionalization or death [13]. In a 4-year study of 354 AD patients, patients were divided into quartiles according to their rate of decline in global cognition score derived from a battery of 17 cognitive tests [2]. Compared with those with the least decline, the risk of mortality was increased 3-fold for patients with mild decline, 5-fold for moderate decline, and 8-fold for those with the most rapid rate of decline. Consistent with this finding, it had previously been reported that AD patients with aggressive course of disease reached clinical mile-
Fig. 1. Mean change in ADAS-cog scores in rapid and slow progressing placebo-treated patients with mild to moderate AD over 26 weeks [12]. Patients were divided into slow and fast progressors on the basis of their decline on placebo treatment over 6 months: rapid progressors declined by ⱖ 4 points (n ⫽ 240); slow progressors declined by ⬍ 4 points (n ⫽ 432).
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Table 2 Possible predictors of an aggressive course of disease Predictors of an Aggressive Course of Disease Demographics Deficits in executive function and attention at time of diagnosis Poor nutritional status High educational attainment Young age of onset Clinical symptoms Extrapyramidal symptoms (eg, tremor, rigidity, bradykinesia) Psychotic symptoms (eg, delusions, hallucinations [particularly visual]) Subcortical symptoms (eg, apathy, attention or executive function deficits) AD pathology with symptoms of LB pathology Genetics BuChE wild-type allele APOE ⑀4 allele
stones sooner than those with slower rates of decline [1]. Patients who had baseline rates of decline that were more rapid than average (ⱖ 5 MMSE points per year) continued to experience more rapid decline than patients who had slow or average rates of disease progression. Furthermore, a longitudinal study of 91 AD patients showed that the course of deterioration tended to stay constant over time [14]. Patients who experienced rapid progression from the time of diagnosis to the time of next assessment were unlikely to shift to a slow progression rate in the following 12 to 24 months. This could imply that the tempo of the pathophysiologic process is predetermined at the outset by a combination of biological or environmental factors. 5. Recognition of Aggressive Course of Disease Given the poorer prognosis for dementia patients with an aggressive course of disease, it is important to be able to recognize and treat these patients as early as possible. Considerable efforts have been directed toward identifying patients at risk of rapid disease progression (Table 2). 5.1. Demographics as predictors of an aggressive course of disease The cognitive status of the patient at the time of diagnosis may be a useful predictor of an aggressive course of disease. Atchison et al [10] found that AD patients (n ⫽ 189) showing significantly impaired performance on measures of attention and executive function at baseline, had a more rapid decline over 1 year on the MMSE than those who did not, despite equivalent MMSE scores at baseline for both groups. Impaired performances at baseline on other neuropsychological measures, including letter and category fluency tests, naming tests, and language tests, may also predict a faster rate of decline in AD patients [15–18]. Poor nutritional status may also predict an aggressive course of disease. A study of 312 AD patients who experienced rapid loss of cognition over 1 year aimed to identify
predictive factors for an aggressive course of disease [8]. Rapid cognitive loss was defined as a 4-point or greater loss in MMSE score in 6 months. A multivariate analysis showed that the Mini Nutritional Assessment (MNA) score correlated with the rate of decline (p ⫽ 0.002). This may reflect the underlying frailty of these patients, who were also significantly more dependent on activities of daily living compared with slower progressors. Education may provide a “cognitive reserve” that must be depleted to a certain threshold before dementia becomes clinically manifest. At higher levels of education, AD pathology may therefore be more advanced before dementia symptoms are manifest, so these patients subsequently experience a more rapid clinical progression. In support of this hypothesis, Stern et al [19] reported a correlation between the number of years of education and the severity of AD pathology. For a given clinical severity of dementia, parieto-temporal blood flow was reduced further in patients with higher levels of education, indicating more severe pathology. In a further study [20], AD patients with a higher educational level experienced a more rapid decline in memory measured using the Selective Reminding Test, compared with patients with lower levels of education (p ⬍ 0.057). A similar result was seen when patients with high occupational attainment were compared with low-attainment patients (p ⬍ 0.02). Furthermore, in a recent prospective study of 1,050 healthy elderly patients, highly educated subjects had higher initial scores on the MMSE and 4 neuropsychological measures but experienced a more rapid cognitive decline during the 3 years preceding diagnosis of dementia compared with less educated subjects [21]. A younger age at the onset of AD may also be a predictor of an aggressive course of disease. In a study of 127 AD patients, those with an onset of AD before the age of 65 (n ⫽ 44, mean age of onset 58.8 years) declined significantly faster than late-onset patients (n ⫽ 83, mean age of onset 74.1 years) over 2 years on the modified MMSE (p⬍0.001) [4]. Regression analyses showed that age at symptom onset was a strong predictor of the rate of cognitive decline. Decline in functional capacity measured using the Blessed Dementia Rating Scale (BDRS) was also more rapid in the younger patient group (p⬍0.05). Furthermore, in AD and dementia with Lewy bodies (DLB), patients younger in age at onset had more severe pathology and aggressive disease. A comparison of 28 DLB patients age 70 or younger with the same number of patients older than 70 years showed that early-onset patients declined more rapidly and had more severe pathology. Similar findings were seen in 178 AD patients [22]. 5.2. Clinical symptoms as predictors of an aggressive course of disease Alzheimer’s disease patients who present extrapyramidal signs (EPS), such as tremor, rigidity, and bradykinesia may
S. Gauthier et al. / Alzheimer’s & Dementia 2 (2006) 210 –217
Fig. 2. Visual hallucinations as a predictor of an aggressive course of disease in PDD patients [30]. Based on change in ADAS-cog in mild to moderate PDD patients with and without visual hallucinations at baseline receiving placebo for 6 months.
be at high risk of an aggressive course of disease. The presence of EPS symptoms at baseline significantly predicts faster cognitive decline in AD patients [23]. In 67 patients with probable AD, patients with EPS reached endpoints on the BDRS factor VI, a measure of basic self-care, earlier than those who did not (p⬍0.05) [3]. Moreover, in a study of 81 AD patients, those with EPS symptoms deteriorated 67% faster on the MMSE than those with no EPS symptoms [24]. EPS signs in AD patients have also been associated with a more rapid functional decline [25,26]. Patients with psychotic symptoms, including delusions, at baseline also experience more rapid cognitive decline, reaching endpoints on the Blessed Dementia Rating Scale (BDRS) factor I sooner than those without psychosis (p⬍0.001) [3]. Wilson et al [27] examined the association between delusions and hallucinations and the rate of cognitive decline over 4 years in 410 AD patients. Both hallucinations (present in 41% of patients) and delusions (present in 55%) were common at baseline. Patients with hallucinations at baseline declined more rapidly on a composite measure of cognitive function, which included the MMSE. Chui et al [23] also showed that hallucinations at baseline in AD patients predicted a shorter time to reach endpoints on the MMSE (n ⫽ 135; p ⫽ 0.01). Hallucinations are common in the neurodegenerative dementias, developing in 30% to 40% of patients with AD [27], and 60% to 80% of patients with Parkinson’s disease dementia (PDD) [28], and DLB [29]. Hallucinations have been associated with rapid cognitive and functional decline in PDD and DLB as well as in AD patients [27,29 –31]. In a randomized, controlled trial of rivastigmine in PDD, decline in the ADAS-cog over 24 weeks was 2.1 in placebotreated patients with visual hallucinations at baseline (n ⫽ 70) compared with 0.1 points in placebo-treated nonvisual hallucinators (n ⫽ 109; Fig. 2) [30]. Evidence suggests that hallucinations, particularly visual hallucinations, relate to
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cholinergic and possibly dopaminergically mediated cortical dysfunction. The presence of apathy has been linked with a greater placebo decline in PDD patients on measures of cognition, behavior, attention, and executive function [32]. Apathy has also been associated with an increased likelihood of progression to AD in subjects with mild cognitive impairment (MCI) [33,34]. Apathy is thought to be a feature of frontosubcortical pathology [35]. Extrapyramidal, psychotic, and subcortical symptoms are common in patients with Lewy body dementia. Kraybill et al [36] confirmed that AD patients with symptoms of LB pathology may be more likely to have an aggressive course of disease compared with patients with AD or LB pathology alone. The rate of decline in AD patients with symptoms of LB pathology (n ⫽ 65) was significantly faster on the Mattis Dementia Rating Scale over 18 months (p⬍0.03) and MMSE over 6 months (p⬍0.04) compared with AD (n ⫽ 48) or LB (n ⫽ 22) patients. Similar relationships between the rate of cognitive decline and symptoms suggestive of Lewy body dementia have been noted in other studies [37– 39]. 5.3. Genetics as a predictor of aggressive course of disease Whereas younger age, more advanced education, poorer nutritional status, hallucinations, and EPS may be clinical markers for an aggressive course of disease, genetic factors may be the underlying cause of the variations in the differential rates of decline in dementia patients. Genetic factors that have been linked with the rate of progression of disease include the APOE ⑀4 allele. Carriers of APOE ⑀4 with mild AD (MMSE score 22 to 26) declined faster on the ADAScog over 6 months compared with noncarriers, whereas moderate AD APOE ⑀4 carriers (MMSE score 10 to 21) declined slower than those without the allele [40]. However, a majority of studies have failed to link the presence of APOE ⑀4 to rate of progression, possibly owing to the fact that it is disease severity stage dependent [41] and that the rate of cognitive decline fits nonlinear models better [42]. Butyrylcholinesterase (BuChE) genotype affects the rate of disease progression in dementia [43– 45]. BuChE, like acetylcholinesterase (AChE), is involved in the hydrolysis of acetylcholine in the brain, but unlike AChE, the level of BuChE activity increases in the brain as the disease progresses in AD patients [45]. The K and A variants of BuChE encode for lower expression or lower activity of the BuChE enzyme in the plasma. In 57 patients with AD or DLB, BuChE wild-type homozygotes had a more rapid progression on the Cambridge Cognitive Examination schedule (CAMCOG) over 2 to 3 years compared with carriers of the K or A variants of BuChE (Fig. 3) [44]. After this, Perry et al [45] showed that the antemortem rate of cognitive decline correlated with the level of BuChE activ-
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6. Treatment options
Fig. 3. An aggressive course of disease in BuChE wild-type homozygous patients with AD or DLB: a prospective study [44]. Based on annual mean change from baseline in CAMCOG in 57 patients with moderate to severe AD and DLB.
ity in the temporal cortex of patients with DLB. A further study showed that the rate of cognitive decline in severe AD patients (baseline MMSE ⱕ 8) carrying the K variant allele of BuChE was slower compared with patients with wildtype BuChE (mean annual MMSE decline of 0.2 compared with 1.8 in BuChE wild-type homozygotes) [43]. The distribution of BuChE in the brain is greater in subcortical structures. BuChE-positive neurons in subcortical nuclei that project to prefrontal cortical areas have been implicated in attention, executive function, and certain behaviors [46]. The presence of BuChE wt/wt correlates with worse attentional function at baseline in patients with DLB [43]. In PDD, a greater decline in BuChE wt/wt patients (n ⫽ 176) on the D-KEFS verbal fluency test, a measure of executive function, was seen over 24 weeks compared with carriers of one K variant allele (n ⫽ 96) (Fig. 4) [32]. Similar findings were also seen on the Cognitive Drug Research Power of Attention measure of focussed attention. These studies suggest that higher levels of BuChE may be associated with an accelerated rate of cognitive decline in dementia and that patients possessing variant alleles that encode for less expression of the enzyme are less likely to experience an aggressive course of disease. In particular, higher levels of BuChE may induce greater progression of deficits related to subcortical pathology, in keeping with the predominant subcortical distribution of BuChE in the brain [32]. There may be many other genetic variations influencing rate of decline in dementia, and further research in this area may also increase our understanding of the pathophysiology.
Once a patient with an aggressive course of disease has been identified, treatment should be initiated as soon as possible to delay progression of symptoms. Effective treatment may also reduce caregiver stress associated with the condition. However, there has been limited research on treatment of patients with an aggressive course of disease. A 26-week, double-blind, placebo-controlled trial of the ChE-I rivastigmine, a dual inhibitor of AChE and BuChE, in AD patients, was followed by an open-label extension study for a further 26 weeks [11]. The response to rivastigmine was studied in 187 patients who had received placebo during the original trial and who continued with open-label rivastigmine therapy. Patients identified as rapid progressors using the PDS and ADAS-cog during the double-blind trial showed significantly greater responses to rivastigmine treatment compared with slow progressors on measures of cognition (Rapid progressors baseline [week 26] score 17.5, change from baseline to endpoint 2.01; slow progressors [week 26] baseline score 33.5; change from baseline to endpoint ⫺0.90; p⬍0.05, rapid versus slow progressors). Greater responses to treatment in rapid progressors were also seen on activities of daily living (rapid progressors baseline [week 26] score 38.5, change from baseline to endpoint 0.34; slow progressors [week 26] baseline score 61.0; change from baseline to endpoint ⫺2.54; p⬍0.05, rapid versus slow progressors). This study was included in a meta-analysis of 4 6-month, double-blind, placebo-controlled studies of rivastigmine, in which rapidly progressive patients also showed greater responses to therapy compared with slowly progressive patients [12]. Patients who experi-
Fig. 4. More rapid decline in executive function in mild to moderate PDD patients with BuChE wild-type genotype (n ⫽ 176) compared with BuChE-K variant carriers (n ⫽ 96) [32]. Changes shown are least square mean calculations of change from baseline at 24 weeks (ITT-RDO analysis).
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enced a decline of 4 or more points on the ADAS-cog during 26 weeks of placebo treatment showed a mean improvement over baseline of 4.97 points after 12 weeks of rivastigmine therapy. This was significantly better than the change seen in patients who had declined by less than 4 points in the first 26 weeks (p⬍0.001). These are the only published studies showing a relationship between response to ChE-I therapy and the rate of AD progression. Furthermore, patients who exhibit predictors of an aggressive course of disease in Lewy Body (LB) dementias have also been shown to have differential responses to ChE-I treatment. Greater responses to rivastigmine have also been seen in PDD and DLB patients with hallucinations, which have been shown to be indicative of an aggressive course of disease [29,30]. In a retrospective analysis of rivastigmine in 120 DLB patients, greater improvements in attention were seen in patients who had hallucinations at baseline [29]. On Power of Attention, significant treatment benefits of rivastigmine were seen in patients with hallucinations (p⫽0.002) but not in nonhallucinating patients. In a prospective, randomized, placebo-controlled trial of rivastigmine in PDD, patients with visual hallucinations (n ⫽ 188) showed greater treatment–placebo differences than patients without visual hallucinations (n ⫽ 348), on measures of cognition (ADAS-cog), global change (Alzheimer’s Disease Assessment Scale Clinician’s Global Impression of Change [ADAS-CGIC]), attention and executive function (D-KEFS verbal fluency, Choice Reaction Time and Power of Attention), and behavior (Neuropsychiatric inventory [NPI-10]). In a recent, large, double-blind study of rivastigmine and the AChE selective inhibitor donepezil in moderate AD patients, significantly greater functional responses to rivastigmine therapy were seen in the two thirds of patients with a BuChE wt/wt genotype compared with donepezil therapy [47]. These differential effects were particularly apparent in younger AD patients (⬍75 years of age) with the BuChE wt/wt genotype [48]. Differential effects were not seen in BuChE K variant carriers, possibly owing to greater tolerability problems in these patients resulting in a significantly lower mean daily dose of rivastigmine [49] (Fig. 5). Patients with symptoms suggestive of concomitant LB disease, including hallucinations, fluctuating cognition, and extrapyramidal symptoms also showed greater benefits of rivastigmine treatment [50]. To date, rivastigmine is the only drug in which the response of patients with an aggressive course of disease has been studied. Patients receiving other ChE-I inhibitors who experience an aggressive course of disease may benefit from switching to rivastigmine [51]. However, it remains to be confirmed whether these effects are caused by the additional inhibition of BuChE as well as the sustained inhibition of AChE, by rivastigmine.
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Fig. 5. Greater response to rivastigmine therapy on Alzheimer’s Disease Cooperative Study Activities of Daily Living scale (ADCS-ADL) in homozygous butyrylcholinesterase (BuChE) wild-type patients with moderate AD over 2 years (ITT-LOCF analysis) [47].
7. Discussion A significant proportion of people with dementia have an aggressive course of disease, and this has major deleterious effects on caregivers and society in general, as well as on patients. Currently, there is no clear definition of an aggressive course of disease, but there are several factors that may predict the condition. Cognitive status, young age at disease onset, presence of EPS, fluctuating cognition, psychotic symptoms and hallucinations, prominent subcortical pathology with attention and executive deficits, poor nutrition, and high previous educational attainment may identify at-risk patients in the clinic. There is a need for a clinical assessment tool, which must include caregiver input, for the detection of an aggressive course of disease in newly diagnosed patients. Further prospective studies may also permit the development of a clinically based algorithm to predict rate of disease progression. Given the poor prognosis of patients with an aggressive course of disease, it is important to initiate treatment as soon as possible. The only therapy in which the response in patients with an aggressive course of disease has been studied is rivastigmine, which may be particularly effective in these patients. It has not yet been confirmed whether the same response is seen with other ChE-Is, but evidence suggests that the sustained inhibition of BuChE and AChE by rivastigmine might provide greater benefits in these patients compared with AChE selective inhibitors. Genetic variations, such as APOE ⑀4 and BuChE genotypes, may determine susceptibility to rapidly progressive disease, and their influence may change over the course of
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the disease. Rapid disease progression may be caused by multiple factors, and further research is required to better understand the pathophysiology of an aggressive course of disease and to develop optimum therapeutic approaches. When a patient has dementia diagnosed, physicians should always be alert to the possibility of an aggressive course of disease and should assess each individual patient based on their symptoms and demographics. If an aggressive course of disease is suspected, then appropriate treatment should be initiated immediately to keep symptoms at a manageable level and to minimize the impact of this distressing condition on both patient and carer for as long as possible.
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