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Cholinergic deficiency and inflammation in cognitive dysfunction
Lemstra, A.W.
Publication date
2008
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Final published version
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Lemstra, A. W. (2008). Cholinergic deficiency and inflammation in cognitive dysfunction.
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Cholinergic deficiency and inflammation
in cognitive dysfunction
© A.W. Lemstra, Amsterdam, The Netherlands, 2008
Printed by: PrintPartners Ipskamp, Enschede Lay-out: A.W. Lemstra
This thesis was prepared at the Department of Neurology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
Publication of this thesis was made possible by financial support of the Memory Clinic AMC, Department of Neurology AMC, Alzheimer Nederland, Internationale Stichting Alzheimer Onderzoek, Stichting het Remmert Adriaan Laan fonds.
Cholinergic deficiency and inflammation in
cognitive dysfunction
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor aan de Universiteit van Amsterdam op gezag van de Rector Magnificus
prof dr. D.C. van den Boom
ten overstaan van een door het college voor promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel
op dinsdag 22 april 2008, te 12.00 uur
door
Afina Willemina Lemstra
Promotor : Prof dr. W.A. van Gool
Co-promotor : Prof dr. P. Eikelenboom
Overige leden: Prof dr. M. Vermeulen Prof dr. B.A. Schmand Prof dr. T. van der Poll Prof dr. R.G.J. Westendorp Prof dr. R.C. van der Mast Prof dr. J.P.J. Slaets
Contents
Ch.1 Introduction 9
Part I Cholinergic deficiency Ch. 2 The cholinergic deficiency syndrome and its therapeutic 19
implications Ch. 3 Identification of responders to rivastigmine: 31
a prospective cohort study Ch. 4 Can quantitative spectral electroencephalography 47
be of use to predict response to rivastigmine in patients with dementia? Ch. 5 The association of neuroleptic sensitivity in Dementia 57
with Lewy bodies with false positive clinical diagnosis of Creutzfeldt-Jakob disease Ch. 6 Cholinesterase inhibitors in dementia: yes, no or maybe 67
Part II Inflammation and delirium Ch. 7 Pre-operative inflammatory markers and the risk of 77
postoperative delirium in elderly patients Ch. 8 Microglia activation in sepsis: a case-control study 89
Ch. 9 General discussion 103
Summary 121
Samenvatting 127
Dankwoord 131
Chapter 1
Dementia is a non-specific term encompassing a spectrum of clinical syndromes of cognitive decline and behavioral disturbances caused by a variety of disease processes. Alzheimer’s disease (AD) is the most common pathologic entity causing dementia, followed by vascular dementia, Dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). Parkinson’s disease dementia (PD) and Creutzfeldt-Jakob disease (CJD) represent other examples of diseases that are accompanied by dementia. At the moment the number of patients with dementia in the Netherlands is approximately 200.000. With the rising life expec-tancy the prevalence of dementia in the Netherlands is estimated to reach 400.000 in 20501. Although dementia is in the top 10 of diseases leading to death
in the Western world and subject of intense research activities throughout the world, many questions are still unanswered. Among these questions are: ’which processes contribute to the symptoms that ruin the lives of patients suffering from these diseases’ and ‘how can we optimally manage these symptoms’. This thesis aims to contribute to answering some aspects concerning these questions.
Cholinergic deficiency
The renaissance of the interest in AD in the 1970’s led to intensified investigations into the etiology of this disease2. Although nowadays much more is
understood of the molecular and genetic basis of the different disease mecha-nisms causing dementia, the therapies that are currently available are founded on the research of decades ago. An important line of research in the 1970-1980’s was focused on the relationship between neurotransmitters and cognitive (dys)function. Fuelled by the success of the discovery of the involvement of the dopaminergic system in PD and the subsequent relieve of symptoms by sub-stitution of dopamine, different neurotransmitter systems were investigated for their role in cognitive deficits. One of the findings that attracted intense scrutiny was the loss of cholinergic neurons in the basal forebrain in postmortem examina-tion of brains of patients with AD3. Drachmann and Leavitt were among the first to
describe the relationship between the central cholinergic system and cognitive functions by studying the effects of cholinergic and anti-cholinergic agents in human subjects4. Administration of the anticholinergic agent scopolamine
revealed a sequence of symptoms resembling that seen in patients with dementia. The cholinergic hypothesis became a widespread trigger for research in the AD-field and culminated -5 to 10 years later- in the demonstration that cholin-esterase inhibitors could indeed lead to some improvement of symptoms in patients with AD5. Numerous clinical trials followed in want of proving that finally a rational treatment was available for this devastating disease. But after years of
extensive clinical research one has to conclude that the effect of cholinesterase inhibitors in AD is truly limited. If strict responder criteria are used, and putative placebo effects are accounted for, CEI therapy is successful in only 5 to 15% of AD patients, whereas patients who are treated with CEIs frequently encounter serious side-effects (Cochrane reviews)6-8. With the advancing scientific insights in disease mechanisms it is now known that AD is a highly heterogeneous entity. Currently, beta-amyloïd and presenilins are considered by many to be the most important factors in the process that leads to widespread degeneration of cortical networks underlying dementia in AD9. It is widely acknowledged that loss of cholinergic transmission alone cannot account for the whole clinicopathological picture of AD. Notwithstanding these new insights in the pathogenesis, CEIs are the only available drugs that are licensed. Across numerous clinical trials there is a consistent effect of CEIs, not only in patients with AD but also with other forms of dementia such as DLB and Parkinson’s disease dementia (PDD).
Factors that might a priori predict a response to cholinesterase inhibitors have not yet been identified10. In the first part of this thesis we discuss the issue of
cholinergic deficiency and response to CEI therapy in different ways. In Chapter 2 it is hypothesized that a cholinergic deficiency syndrome can be delineated that may occur in various forms of dementia and that can serve as indication for therapy with CEIs. Based on literature this syndrome is suggested to resemble the symptoms seen in delirium. In Chapter 3 a prospective study is described that investigates in detail the clinical characteristics of responders to therapy with the CEI rivastigmine. These features are thought to constitute the hallmarks of the cholinergic deficiency syndrome. Chapter 4 describes the role of electro-encephalography in identifying responders to CEI-therapy in addition to clinical measures. A putative clinical correlate of the cholinergic deficiency syndrome is discussed in Chapter 5 where neuroleptic sensitivity as a manifestation of cholinergic deficiency leads to a false diagnosis of Creutzfeldt-Jakob disease. Rational and cost-effective use of CEIs has also been the subject of the guidance of the United Kingdom’s National Institute of Clinical Excellence and health (NICE). This guideline caused a major uproar in societal and political sense in the UK in 2007. Chapter 6 is a reaction to these events. This paper advocates the concept of the cholinergic deficiency syndrome as indication for therapy with CEIs and urges pharmaceutical companies to release trial data in order to gain more insight into the clinical characteristics of responders to CEI-treatment.
Inflammation
Not long after the intense interest in the role of specific neurotransmitter systems subsided, a new area which focused the attention in the field of dementia research developed. Availability of specific antibodies in the 1980’s stimulated increasing insight in the immune system and inflammatory processes. It became clear that inflammatory processes in the brain affect cognitive functioning.
This was based on the discovery of three disease mechanisms. First, neurodege-nerative diseases are accompanied by an inflammatory response. Pathological studies showed that microglia, the macrophages of the brain, become activated and release cytokines. Whether these inflammatory mediators have a primarily causative, a facilitating or counter-regulatory function remains controversial11. It is
remarkable in this context that the pathological hallmarks of neurodegenerative disease such as amyloid-beta plaques in AD, tau in FTD or alpha-synucleïne-pathology in DLB, do not completely explain the clinical symptoms12. Second, it became widely acknowledged that aging itself is accompanied by a low-grade inflammatory state expressed by alterations in concentrations of circulating pro- and anti-inflammatory cytokines in serum11,13. This is associated with age-related
diseases such as atherosclerosis, diabetes mellitus and AD. In the brain similar immunological changes occur as a result of aging as expressed by the presence of activated microglia14. This could be elicited by other pathological changes in the
brain as mentioned before. Alternatively it has been proposed that microglia activation in elderly is a result of aging of the microglia themselves. It is proposed that inflammation in combination with neuro-endocrinological changes and sarcopenia, conceptualized as frailty, put an older person at risk for adverse outcomes15. This concept, however, is still in need of support by robust evidence
from observational or experimental studies.
Important to the understanding of the role of inflammatory markers and cognitive function was the elaborate research on infectious processes. Inflammation in peripheral tissue is accompanied by a systemic reaction of release of cytokines in the blood. As a result of the infection the body creates a new homeostasis accompanied by fever, reduced appetite, and neurobehavioral changes, collectively known as sickness behavior16. It is now well established that raised
levels of circulating cytokines induce these behavioral changes through interaction with the brain, especially via interleukin-1. Several pathways have been proposed that may play a role in this cross-talk between the peripheral immune system and the brain, but the activation of microglia in the brain parenchyma seems to be pivotal 17,18.
The current knowledge leaves several issues to be elucidated. In what way does systemic inflammation influence the brain? Are immunological changes in the brain responsible for cognitive impairments and what is the mechanism? In the second part of this thesis we address some of these problems.
In Chapter 7 the hypothesis is tested that raised inflammatory markers in elderly subjects mediate vulnerability as based on the frailty concept. It is investigated whether these markers are an independent risk factor for the development of delirium. In Chapter 8 microglia activation in postmortem brains of patients who died with sepsis are compared with controls. This could be the first step in identi-fying the mechanism(s) in humans of the interplay between systemic inflammatory changes and the brain, since animal experiments have suggested that activation of microglia occurs in sepsis. In the discussion section the results of the various studies described in part I and II are put in perspective and suggestions for future research are made. A possible link between inflammation, cholinergic deficiency and cognitive dysfunction is hypothesized.
References
1. NationaalKompasVolksgezondheid.
http://www.rivm.nl/vtv/object_document/o1470n17535.html
2. Mesulam M. The cholinergic lesion of Alzheimer's disease: pivotal factor or side show? Learn Mem. 2004; 11:43-49
3. Mesulam MM, Geula C. Nucleus basalis (Ch4) and cortical cholinergic innervation in the human brain: observations based on the distribution of acetylcholinesterase and choline acetyltransferase. J Comp Neurol. 1988; 275:216-240
4. Drachman DA, Leavitt J. Human memory and the cholinergic system. A relationship to aging? Arch Neurol. 1974; 30:113-121
5. Summers WK, Majovski LV, Marsh GM et al. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. N Engl J Med. 1986; 315:1241-1245 6. Birks J. Cholinesterase inhibitors for Alzheimer's disease. Cochrane Database Syst Rev.
2006;CD005593
7. Maidment I, Fox C, Boustani M. Cholinesterase inhibitors for Parkinson's disease demen-tia. Cochrane Database Syst Rev. 2006;CD004747
8. Malouf R, Birks J. Donepezil for vascular cognitive impairment. Cochrane Database Syst Rev. 2004;CD004395
9. Selkoe DJ. Alzheimer's disease: genes, proteins, and therapy. Physiol Rev. 2001; 81:741-766
10. Liberini P, Valerio A, Memo M et al. Lewy-body dementia and responsiveness to choli-nesterase inhibitors: a paradigm for heterogeneity of Alzheimer's disease? Trends Phar-macol Sci. 1996; 17:155-160
11. Krabbe KS, Pedersen M, Bruunsgaard H. Inflammatory mediators in the elderly. Exp Gerontol. 2004; 39:687-699
12. Rozemuller JM, Stam FC, Eikelenboom P. Acute phase proteins are present in amor-phous plaques in the cerebral but not in the cerebellar cortex of patients with Alzheimer's disease. Neurosci Lett. 1990; 119:75-78
13. Godbout JP, Johnson RW. Age and neuroinflammation: a lifetime of psychoneuroimmune consequences. Neurol Clin. 2006; 24:521-538
14. Conde JR, Streit WJ. Microglia in the aging brain. J Neuropathol Exp Neurol. 2006; 65:199-203
15. Fried LP, Tangen CM, Walston J et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001; 56:M146-M156
16. Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci. 2002; 25:154-159
17. Dantzer R. Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol. 2004; 500:399-411
18. Perry VH. The influence of systemic inflammation on inflammation in the brain: implica-tions for chronic neurodegenerative disease. Brain Behav Immun. 2004; 18:407-413
Part I
C
hapter 2
The cholinergic deficiency syndrome and its
therapeutic implications
A.W. Lemstra P. Eikelenboom W.A. van Gool
ABSTRACT
Cholinesterase inhibitors are licensed for treatment of dementia in Alzheimer’s disease. However, the effects of these drugs on the cognitive symptoms of dementia are very small. We suggest that symptoms like impairment of attention and concentration, anxiety, restlessness and hallucinations, delineate a specific central cholinergic deficiency syndrome (CDS), that may be a much better target for such treatment. Changes in the quantitative electro-encephalogram, muscarinic subtype radioimaging and serum anticholinergic activity may potentially help to diagnose the CDS. CDS is suggested to occur in various neurodegenerative diseases like Alzheimer’s disease, Dementia with Lewy bodies and Parkinson’s disease and to respond well to cholinesterase inhibitor therapy.
INTRODUCTION
World-wide cholinesterase inhibitors (CEIs) like donepezil, rivastigmine and galantamine have been licensed for symptomatic therapy in Alzheimer’s disease (AD). This development has brought a little hope in a previously desperate clinical situation, but the therapeutic response to CEIs and the severity of side-effects vary widely between AD patients1-4. If strict responder criteria are used, CEI
therapy is successful in only 5 to 15% of AD patients5. On the other hand,
case-reports and a single randomised controlled trial suggest that neuropsychiatric symptoms like hallucinations, anxiety and agitation in patients with Dementia with Lewy bodies (DLB) or Parkinson’s disease (PD) may respond well to this type of drug6-9. Therefore, despite their official label stating that CEIs are licensed for ‘the
treatment of mild to moderate dementia of the Alzheimer’s type, it is highly ques-tionable if the cognitive deficits of dementia represent the most appropriate target of CEIs and also if use of these drugs should be restricted to AD only.
The cholinergic hypothesis in Alzheimer’s disease
AD is a devastating neurodegenerative disorder characterised by neuritic plaques, neurofibrillary tangles and loss of neurons and synapses. Since the early 1970s, brains of patients with AD have been extensively examined hoping to find a neurochemical deficit underlying the disease, analogous to PD and dopamine10.
The first clues on specific neurochemical systems affected in AD, became avail-able when Drachmann and Leavitt showed that cognitive impairments resembling the deficits observed in elderly people with primary degenerative dementias, could be produced by antagonists of muscarinic acetylcholine receptors (for example scopolamine)11.
The cholinergic transmission is one of the most important neuromodulating systems in the brain. All sectors of the human cerebral cortex receive dense cholinergic input. The origin of this projection is located in the magnocellular neurons of the basal forebrain, the nucleus basalis of Meynert and the substantia innominata. These extensive cholinergic projections influence nearly all aspects of cognitive functions, especially the domains of attention, memory and emotion12,13.
Several laboratories demonstrated a significant reduction in markers of cholinergic transmission in AD, including the synthetic and degradative enzymes choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), respectively. Sub-sequent discoveries of reduced choline uptake, acetylcholine (ACh) release, and loss of cholinergic cells in the septal nuclei and basal forebrain established the cholinergic hypothesis of AD14-18. According to this hypothesis, the cholinergic
dysfunction in AD is mainly due to loss of cholinergic innervation, rather than to reduction in postsynaptic receptivity to the effects of ACh release19-21.
The cholinergic hypothesis as an explanation for the syndrome of dementia in AD has been challenged over the last 20 years. Indeed, numerous studies have documented important cholinergic deficits in AD10,19. However, by their nature,
most postmortem studies were performed in AD patients with end-stage disease. Recent studies of AD patients representing the complete spectrum of disease indicate that loss of cholinergic markers can not be detected in individuals with mild AD and is not present until relatively late in the course of the disease22-24.
Many other neurotransmitter deficits have been identified in AD brain tissue. It became increasingly clear that AD did not involve degeneration of a single neurotransmitter but was highly heterogeneous. Currently, beta-amyloïd and presenilins are considered by many to be important factors in the process that leads to widespread degeneration of cortical networks underlying dementia in AD. At the moment it is widely acknowledged that loss of cholinergic transmission alone cannot account for the whole clinicopathological picture of AD. The lack of robust clinical benefit in most patients treated with cholinergic drugs is consistent with these insights25.
Cholinergic therapy
Development of CEIs was inspired by the cholinergic hypothesis of AD stating that selective degeneration of cholinergic neurons in the basal forebrain is responsible for dementia in this disease. However, the prior probability that all cognitive deficits of dementia would respond favourably to CEI therapy is low, considering the discussion above. In general, the rationale behind the choice for a specific therapeutic target is based on a clear description of the disease or complex of symptoms, but this has not been the case for the use of CEIs in AD26. In his
original description of Auguste D., Alzheimer emphasised aphasia, apraxia, agno-sia and acalculia in addition to memory deficits27. A neurologically based model of
human cognition, as suggested by Albert, distinguishes between instrumental functions such as language, perception and praxis, and fundamental functions such as set shifting, attention, concentration, and rate of information processing28.
This instrumental/fundamental dichotomy, that was later expanded by Cummings to include anatomic, ontogenetic and neurochemical dimensions, may be helpful in characterising the symptoms of AD29. Thus, Auguste, as the prototypical patient
with AD, suffered mainly from impairments of instrumental functions with relatively intact fundamental functions, as is the case in most patients with AD. The consistent, albeit small effects of CEIs in AD, can be understood by the limited contribution of cholinergically mediated fundamental functions to the symptoms of AD (figure 1). Rather than serving specific instrumental cortical functions, the
Parkinson’s disease
diffusely organised cortical cholinergic input system serves the more fundamental role of detection, selection, discriminating and processing of sensory stimuli and higher processes13,30.
Substantial evidence has accumulated in support of the notion that demands in attentional processing are mediated via cortical cholinergic inputs31. Deficiencies
in these inputs impair discriminatory processes, the efficiency of cortical processing and responsiveness to relevant and new stimuli. Performance on neuropsychological tasks requiring perception, language or praxis can be modulated by factors such as motivation, attention and concentration. Therefore, in addition to extensive cortical damage in AD resulting in severe instrumental impairments, some deficits in the fundamental processes associated with degene-ration in the cholinergic projection system, may to some extent also contribute to the symptomatology of AD (figure 1).
From the recent clinical trials with CEI it can be concluded that patients with AD can be divided in at least two different groups: responders and non-responders to CEI26.Although small, the effects of CEIs on cognitive test scores in groups of AD
were statistically significant and very consistent across various trials with different CEIs in AD1-4. Liberini et al note in a comprehensive review on cholinergic therapy
• aphasia • apraxia • agnosia • acalculia
• impairment of attention and concentra-tion
• difficulties with stimulus detection • anxiety, restlessness • tremor • rigidity • hypokinesia • postural imbalance
focal
cortical
impairments
Cholinergic
deficiency syndrome
acutechronic (delirium)
motor
symptoms
Figure 1. Schematic display of distribution of instrumental and fundamental dysfunctions in
dementia syndromes in which loss of cholinergic neurons occur. Thickness of arrows indicate degree of deficit.
Dementia with Lewy bodies Alzheimer’s disease
that the variability of the response to CEI may be related to individual differences in the pharmocokinetics. On the other hand the differential response to CEI may be related to the clinical heterogeneity of degenerative dementia26.
Neurochemical reductions in cholinergic enzymes and/or loss of neurons from the basal nucleus are apparent in many other brain disorders associated with neuro-psychiatric symptoms like DLB, PD, progressive supranuclear palsy and Down’s syndrome32-34. Neuropathological studies show that the neuronal damage to the
nucleus basalis of Meynert of DLB patients is greater than in that of patients with Alzheimer disease. In addition, neurochemical examinations of autopsy material from DLB cases have shown an extensive deficit in cholinergic input to the frontal, parietal and temporal cortices, with reductions in ChAT activity greater than those seen in AD26,35-37. The basal nucleus is also severely depleted in PD patients with
dementia38. The cholinergic deficits in PD and DLB are not accompanied by
wide-spread cortical changes and they may even exceed the changes in the cholinergic system found in AD.
In a clinical trial with rivastigmine in DLB patients significant reductions of apathy, anxiety, delusions and hallucinations that exceeded the changes on cognitive test scores9. Hallucinations and confusional states are frequent and disabling
compli-cations also of PD. Although, excess of dopamine resulting from pharmaco-therapy is usually presumed to cause hallucinations, several observations cast doubt on this explanation. Hallucinations in PD are known from the time before dopamine therapy became available, the relationship between high levels of levodopa and neuropsychiatric manifestations has never been documented directly, and Goetz et al. failed to provoke hallucinations with a high-dose intra-venous challenge with levodopa in PD patients39,40. In PD anticholinergics may
elicit confusional states and hallucinations whereas preliminary observations suggest that CEI therapy does not increase parkinsonism and can be benificial 7,41-43. Conventional antipsychotics are associated with considerable side effects in
these patients, therefore, CEI therapy deserves consideration also for the neuro-psychiatric symptoms associated with PD.
Central cholinergic deficiency syndrome
It seems somewhat paradoxical to restrict use of symptomatic therapy to a single
nosological entity. Symptomatic therapy with hypnotics, antipsychotics and
anti-depressants is prescribed for sleep, psychotic or affective disorders irrespective of the specific disease a patient is suffering from. So why not treat all patients with an apparent deficit of the cholinergically mediated fundamental functions with CEIs irrespective of the neurodegenerative disorder they are suffering from? The question is, if there is something like a clinical syndrome that results from central
cholinergic deficiency how can clinicians recognise it? There is not a clear description of the clinical picture of cholinergic deficiency which could be distin-guished in patients with various neurodegenerative disorders. Despite the numerous trials with CEIs, factors that might a priori predict a response to cholinesterase inhibitors have not yet been identified26. Symptom profiles of neurodegenerative diseases affecting the cholinergic system are not very well suited to define exactly the functional consequences of cholinergic impairment, because these effects are difficult to separate from additional neuropathological ramifications that are sometimes only partially known. Therefore, for this purpose it may be better to refer to other sources of knowledge.
In their 1958 paper advocating atropine coma as a save alternative for insulin coma in the treatment of psychosis, Forrer and Miller described ‘restlessness, occasionally mild excitement, confusion’ as a result of anticholinergic treatment and at higher doses ‘memory disturbance, disorientation, clouded consciousness, illusions and most frequently visual hallucinations44. Itil and Fink reported
depression, impaired consciousness, perceptual distortion, disturbances of thought and association, severe anxiety and restlessness45. Interestingly, they
report that upon administration of the CEI tetrahydroaminoacridine, currently better known as tacrine, this neuropsychiatric syndrome completely reversed within minutes. At that time, ‘broadening of attention’ indicating difficulties with filtering out distracting stimuli was identified as the most salient effect of anti-cholinergic treatment46. These descriptions of the cholinergic deficiency syndrome
(CDS) caused by anticholinergic treatment resemble more closely the state of delirium or acute confusion than that of dementia in AD. The emphasis is more on global behavioral symptoms rather than on specific focal cognitive disturbances as in AD. This is consistent with the extensive literature on the role of the cholinergic system in delirium, however the CDS in neurodegenerative diseases is of a more gradual onset and longer duration47,48.
HYPOTHESIS
Here, we propose that to the benefit of patients a neuropsychiatric syndrome can be delineated that develops as a consequence of cholinergic deficiency in the central nervous system. The CDS is characterised clinically by loss of attention, impaired concentration and reduced capacity to detect and select relevant stimuli. As a consequence, patients become restless, anxious and confused. Maybe as a result of impaired binding with the real world, there is a propensity to develop misidentifications, pseudo-hallucinations or frank hallucinations and delusions. On formal tests of cognition, test scores are im-paired, but on closer examination there are no outstanding focal cortical deficits.
The specific features of cholinergic deficiency may be quantified and/or qualified by a limited set of neuropsychological tests. This set of tests can measure vigilance, selective and sustained attention etc. In neurodegenerative diseases CDS may coincide with dementia, but for treatment purposes it should be distin-guished from focal cortical deficits (figure 1). We speculate that ancillary
investiga-tions may help to characterise this CDS. Reducinvestiga-tions of the power in the alpha2-band on quantitative analysis of the electroencephalogram (qEEG)
follow-ing administration of scopalamine, suggest that central cholinergic dysfunction is associated with specific EEG changes49. Analogous effects in animal experiments on low voltage fast EEG activity of either atropine injection or lesions of the substantia innominata support this notion50. Other methods that are potentially of
interest in attempts to characterise the functional status of cholinergic system in patients are imaging of presynaptic muscarinic (M2-)subtype receptor with
radio-labelled ligands or measurements of serum anticholinergic activity48,51.
Direct testing of our hypothesis would require prospective studies of patients from various disease categories that are subjected to CEI therapy. Our hypothesis would predict that a beneficial therapeutic response will be associated with the presence of clinical symptoms of CDS outlined above independent of the presence of important focal cognitive deficits, reductions of alpha2-frequency in
the qEEG, low M2-receptor subtype binding and presence of serum anticholinergic
activity, irrespective of the specific disease that was diagnosed before initiating therapy.
To summarise, ‘dementia’ may be a poor descriptor of the target for CEI therapy and the same holds for a diagnosis of AD. Perhaps patients have much to gain if the indication for CEI treatment is based on the identification of a specific clinical syndrome, rather than a single disease category. A syndrome characterised by impairments of attention and concentration, restlessness, hallucinations and anxiety, as symptoms of the CDS could be a much better indication for this kind of treatment. Cognitive deficits may be secondary to this CDS, but the syndrome is sometimes superimposed on the dementia in AD. Acute delirium shares many features with CDS and future studies will have to clarify to what extent they overlap and if CEIs may be effective also in this condition. There may be a new role for qEEG, radioimaging of presynaptic cholinergic markers or measurement of serum anti-cholinergic activity in diagnosing CDS, thus helping to identify patients across different classical disease categories that may benefit optimally from CEI therapy.
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C
hapter 3
Identification of responders to rivastigmine:
a prospective cohort study
A.W. Lemstra R.B. Kuiper B. Schmand W.A. van Gool
ABSTRACT
Although the overall effects of cholinesterase inhibitors (CEIs) are limited, there could be a subpopulation of patients who experience unequivocal benefit. This study aimed to describe a clinical profile based on a combination of specific neuropsychological test scores and clinical symptoms associated with a favourable response to rivastigmine.
A prospective cohort study was conducted in 53 patients who started rivastigmine treatment. Neuropsychological evaluation was performed at baseline and after 6 months of treatment. Patients were labelled responders and non-responders based on change scores after 6 months in 3 clinical domains: cognition, activities of daily living and behaviour.
After 6 months 19 responders and 15 non-responders were identified. Variability in reaction time and Continuous Performance Test (CPT) scores differed significantly at baseline between groups. A previously defined cluster of 4 items of the Neuropsychiatric Inventory was correlated with therapeutic response.
These findings suggest that patients who respond well to CEI therapy can be identified by deficits in attention, combined with a cluster of behavioural symptoms, including hallucinations, apathy, anxiety and psychomotor distur-bances. This may constitute the clinical profile of cholinergic deficiency. Further prospective studies in larger populations are warranted to investigate if this profile can be used to select patients who will benefit from CEIs.
INTRODUCTION
Cholinesterase inhibitors (CEIs) are widely prescribed for patients with cognitive deficits. Randomised controlled trials established modest therapeutic effects of these drugs in Alzheimer’s disease (AD), Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD)1-3. However, the therapeutic response to CEIs and the severity of side effects vary widely between patients. This has fuelled discussions on licensing and reimbursement of CEIs in several countries. In the UK e.g., the National Institute for Health and Clinical Excellence (NICE) recommends CEIs only for a subgroup of AD-patients, namely only those with moderate disease severity4. This vigorously discussed decision points to a
more general awareness that the original license for CEIs, namely dementia de-fined in global terms, may not be the most appropriate target of this class of drugs. However, to date the subgroup of patients that suffer from (cholinergic) deficits that are amenable to treatment with CEIs cannot be clearly delineated on clinical grounds. In an early retrospective study, Mega et al pointed out that a pre-treatment behavioural profile may be helpful in predicting a response to done-pezil5. Several other studies investigated possible predictors of a favourable CEI
response: clinical characteristics such as disease severity, fluctuating cognition, a diagnosis of DLB or PDD, and older age have been described as possible predictors of beneficial therapeutic response in retrospective studies6-9. Based on
post-hoc analyses of trial data in various populations it is proposed that patients with visual hallucinations and specific behavioural symptoms as described by clusters of items of the Neuropsychiatric Inventory (NPI) are more likely to respond to CEI treatment10-12. A prospective cohort study linked response to attentional deficits as measured by the Digit Symbol Substitution Test13. A recent
study by Saumier et al showed that response to donepezil in AD patients was predicted by a better performance on visual-spatial motor tasks and the Boston naming test14. Neurophysiological measures and findings on neuroimaging could
also have some association with response to CEI therapy, but these techniques are not widely applicable yet15-19.
The observations described above indicate that although overall effect of CEIs in unselected groups of patients may be limited, there could be a specific subpopula-tion of patients with a more satisfactory response than has been reported up till now in clinical trials. The question is: how can these patients can best identified in clinical practice? We proposed earlier that a neuropsychiatric syndrome may be delineated that develops as a consequence of cholinergic deficiency in the central nervous system20. Based on early reports in psychiatric literature on effects of
anticholinergic medication, this cholinergic deficiency syndrome can be character-ised clinically by attentional deficits, anxiety and confusion with hallucinations and
delusions21,22. Potentially, this cholinergic deficiency syndrome can occur in any
neurodegenerative disease affecting the cholinergic system and it may be associated with a specific profile of cognitive deficits. The cholinergic deficiency syndrome may offer a more rational indication for CEI treatment than a specific disease category or subgroups of patients arbitrarily defined by a range of Mini Mental State Examination (MMSE) values.
In this study, our goal was to describe the clinical profile that is associated with a favourable response to rivastigmine, based on a combination of neuropsychologi-cal impairments and clinineuropsychologi-cal symptoms, regardless the underlying nosologineuropsychologi-cal entity. This profile could be helpful in discerning patients with a high level of cholinergic deficiency who will benefit most from therapy with CEIs.
METHODS Patients
A prospective cohort was recruited between January 2002 and January 2006, from the outpatient clinics of the Academic Medical Centre in Amsterdam, the Medical Centre Alkmaar in Alkmaar and Parnassia Psycho-medical Centre in The Hague. Patients were included when they had suffered from progressive cognitive decline for more than 6 months as reported by patient, caregiver and referring physician. Cognitive decline had to be accompanied by neuropsychiatric features, because the prior probability of suffering from significant cholinergic deficits in these patients was estimated to be higher than in an unselected group of patients solely defined by dementia. This assumption is based on experiments with anticholinergic drugs in the past which conveyed that an anticholinergic state resembles closely the clinical picture of delirium 20-22.
Patients were required to have contact with a responsible caregiver on at least 5 days a week. The referring physician decided if there was an indication for therapy with rivastigmine. When the study was designed, rivastigmine was the only licensed CEI available in the Netherlands. Exclusion criteria were: a MMSE score of less than 1223; bedridden; asthma; fever; metabolic disorders;
pre-existing psychiatric disease or other causes that could explain the cognitive symptoms; use of neuroleptics, anticholinergic medication or previous use of cholinesterase inhibitors; alcohol or drug misuse.
This study was approved by the local ethical committees. Patients and their caregivers gave written informed consent before entering the study.
Evaluation
All patients referred for the study underwent routine physical and neurological examination by one of the investigators (AWL). Diagnoses made by the referring physician were verified by using the appropriate international classification criteria for the specific diseases (AD: NINCDS-ARDA24; Vascular dementia (VaD): NINDS-AIREN25; DLB: consensus criteria suggested by the consortium on DLB26;
PDD: established Parkinson’s disease according to UK Parkinson's disease brain bank criteria27 in combination with dementia according to Diagnostic and
Stati-stical Manual of Mental Disease (fourth edition) – criteria28).
Routine laboratory tests were performed (ESR, haemoglobin, WBC, thrombo-cytes, sodium, potassium, creatinine, ureum, liver enzymes, glucose, cholesterol, TSH, vitamin B1 & B12, folic acid, syphilis serology) to exclude other causes for neuropsychiatric symptoms. Patients were evaluated clinically by the same neurologist (AWL) at baseline, at 3 months and 6 months after receiving rivastig-mine. Clinical tests included: MMSE; Interview for Deterioration in Daily Living (IDDD), an 11-item paper-and-pencil questionnaire, which is completed by the caregiver, covering self-care activities such as dressing and eating, and complex instrumental activities such as shopping and taking care of financial affairs, total scores range from 0 (no assistance required for any activity) to 44 (always assis-tance required for all activities)29; Neuropsychiatric Inventory (NPI), a widely used
measure of dementia-associated neuropsychiatric disturbances30; Unified
Parkinson Disease Rating Scale-Motor part (UPDRS-III)31; and the Clinician
Assessment of Fluctuation (CAF), a series of screening questions regarding fluctuating confusion and impaired consciousness, producing a severity score from 0-12 (0 representing no fluctuating confusion, 12 representing severe fluctuating confusion)32. Medication doses and side effects were noted separately.
A standardised, partially computerised neuropsychological evaluation was performed independently by a neuropsychologist, who was not aware of the findings of the neurologist, at baseline, and 3 and 6 months after therapy. The following neuropsychological tests were included: Stroop-test (I, II and III)33;
simple visual reaction time measurement (VRT), part of the FePsy computerized neuropsychological test battery34,34; Expanded Mental Control Test (EMCT)
consisting of 12 serial items of increasing difficulty35; Continuous Performance
Test (CPT), an adaptation from the Paced Auditory Serial Addition Task (PASAT)36and the Visual Association Test (VAT)37. These tests were selected for
their specific characteristics. The Stroop test, VRT, EMCT and CPT were selected for their ability to detect deficits in selective attention, mental processing speed, sustained attention and vigilance. As a control task we included a task that we did
not expect to correlate cholinergic deficits or with treatment response: the VAT, a measure of associative memory.
Analysis
After 6 months of therapy with rivastigmine patients were divided into 2 groups, responders and non-responders. Unequivocal responders were patients who showed no change or an improvement of change scores after 6 months in all 3 clinical domains: cognition (MMSE), activities of daily living (IDDD) and behaviour (NPI). Although we did not include a subjective measure of response, we believe that the criterion of consistency among all change scores in 3 domains reliably reflects true benefit of the treatment. Patients who did not fulfil this criterion were labelled as non-responders. This also included patients who had only a partial response, for example improvement on the MMSE and NPI, but worsening on the IDDD. We choose not to divide the study-population in more than two groups because of the limited number of patients in our study.
The UPDRS-score was used to evaluate progression of parkinsonism. Neuro-psychological test scores at baseline, NPI items and CAF-scores at base-line were compared between the responders and the non-responders to find potential predictors for response.
Two clusters of NPI-items were evaluated that have been suggested to be associated with favourable therapeutic response before: the NPI-items 2, 3, 7 &10 (hallucinations, anxiety, apathy & abnormal motor behaviour) defined by Herrmann et al and a cluster of NPI-items 1, 2, 4 & 7 (delusions, hallucinations, depression and apathy) as suggested by McKeith et al3,11.
Statistical analysis
Statistical analysis was performed using SPSS 11.0 package for Windows. Data were tested for normal distribution. For not normally distributed numerical data Mann-Whitney U test was used to compare variables between groups, otherwise Student’s t-test was applied. In order to obtain a single value reflecting the overall change in the severity of dementia for individual patients, change scores on MMSE, IDDD and NPI were transformed to z-scores and a mean z-score of change of dementia severity was calculated. This sum z-score was used to analyse relationships between relevant variables and response using correlation and regression analysis, in addition to the responders/non-responders dichotomy. A value of P <0.05 was considered statistically significant for all statistical analyses.
RESULTS
A total of 68 patients were referred for the study and screened (see figure 1). Fifty-six patients were eligible of which 3 withdrew consent before start-ing rivastigmine therapy. DLB and PDD were the most prevalent diagnoses in this study population (Table 1). During treatment, a total of 10 (19%) patients dropped out due to adverse events, of which gastrointestinal symptoms were most frequently observed. The final analysis was performed on the data of 34 patients who completed 6 months of rivastigmine treatment. The baseline data of these patients are comparable to the data of the whole group at the beginning of the study (53 patients + 3 patients who withdrew consent before starting with the treatment) with respect to age (mean 71,4 yrs) gender M:F = 44:12), and MMSE-score (21, range 14-28).
Responders versus non-responders
Patients were labelled responders and non-responders to rivastigmine according to the responder-criteria as defined in the method section. Of the 34 patients, 19 patients showed improvement or no change in all three domains; only one patient had a change score of 0 on the MMSE and two patients had a change
53 started with rivastigmine
42 evaluated at 3 months
37 evaluated at 6 months
34 patients analysed
9 no indication for therapy 3 withdraw consent before therapy 3 excluded (1 blind, 2 MMSE < 12)
7 adverse events 3 withdraw consent 1 died (cerebral hemorrhage)
3 adverse events 2 withdraw consent
3 missing data, no change scores 68 patients screened
score of 0 on the IDDD; all other 54 change scores were positive in these patients. This is a response rate of 56%, according to the strict criteria of the present study. The remaining 15 patients were non-responders (Table 1).
Of the responders, about half of the patients had a clinical diagnosis of probable DLB. In the group of non-responders there were 4 DLB-patients, 8 PDD-patients, 2 AD-patients and 1 patient with vascular dementia. There was a difference in mean age between the responders and non-responders (75.3 and 66.4 years, respectively; see also section below). After 6 months of therapy there was no difference in change on the UPDRS (p = 0.257) which could have explained deterioration on the IDDD in some of the non-responders.
Fluctuation in cognitive function as measured by the CAF did not differ between responders or non-responders at baseline or after therapy. However, for the whole group the CAF improved after 6 months of rivastigmine therapy (p = 0.002).
Table 1. Characteristics of responders and non-responders
Responders (n=19) Non-responders (n=15)
Baseline
Age, yrs (range) 75.3 (50-89) 66.4 (45-83)
Sex, M:F 15 : 4 13 : 2 Diagnosis* AD 4 2 PDD 5 8 DLB 10 4 VaD - 1
MMSE*, median (range) 19 (14 -26) 23 (15 -28) IDDD*, median (range) 17 (5 -29) 15 (0 – 39) NPI*, median (range) 26 (4 – 70) 21 (0 -43) UPDRS*, median (range) 24 (10 - 67) 26 (2 - 51)
Change scores at 6 months**
∆ MMSE, median (range) + 4 (0 - 11) + 2 (- 4 to +12)
∆ IDDD, median (range) + 3 (0 - 16) - 3 (-10 to +4)
∆ NPI, median (range) + 16 (1 - 58) + 6 (-19 to +18)
* AD: Alzheimer’s disease; PDD: Parkinson’s disease dementia; DLB: Dementia with Lewy Bodies; VaD: vascular dementia; MMSE: Mini Mental State Examination; IDDD: Interview for Deterioration in Daily living; NPI: Neuropsychiatric Inventory; UPDRS: Unified Parkinson’s Disease Rating Scale
** + = true positive change, indicating improvement; - = true negative change, indicating worsening
Mean dose of rivastigmine at 3 months was 8.1 and 7.9 mg and at 6 months 8.8 and 9.6 mg for responders and non-responders, respectively. Side effects proba-bly related to rivastigmine were reported 15 times in 8 responders and 11 times in 10 non-responders. Nausea was the most frequent complaint. None of these side effects were severe. Atypical neuroleptics were taken by 2 patients, 1 in each group, benzodiazepines were taken by 5 patients in the responder-group (all sleeping tablets) and by none in the nonresponder-group, and SSRI’s were taken by 2 of the responders and by 3 of the non-responders.
Neuropsychological tests
Baseline test-scores of the VRT, its standard deviation in individual patients (VRT-sd), Stroop 1, 2 & 3, CPT, EMCT and the VAT were compared between responders and non-responders using the Mann-Whitney U test. Median scores and significance levels are displayed in Table 2.
Table 2. Baseline neuropsychological test-scores in responders and non-responders
VRT* VRT-sd* Stroop1 Stroop2 Stroop3 EMCT* CPT* VAT*
R 525.5 733.5 86 138 655 14 58 6
(281-3578) (114-1504) (56-370) (52-302) (162-885) (2-24) (31-61) (0-12)
NR 388 325 64 100 320 14 61 9.5
(240-4000) (41-1392) (36-218) (63-262) (78-885) (2-24) (46-61) (1-12)
p-value 0.212 0.015 0.103 0.111 0.171 0.647 0.022 0.162
R= responders, NR= non-responders; displayed are median and (range)
* VRT= visual reaction time; VRT-sd=VRT-standard deviation; EMCT= expanded mental control test; CPT=continuous performance test; VAT-visual association test
Significant differences in baseline test-scores for responders and non-responders were found for the VRT-sd and the CPT (respectively, 0.015 and 0.022). The median VRT-sd of the responders was more than twice as high as of the non-responders, indicating a much higher intra-individual variability in reaction times. Together with lower CPT scores this suggests poorer sustained attention abilities in the responder-group. No distinct differences were found for the other neuro-psychological tests the VRT, Stroop 1, 2 & 3, EMCT and VAT. Baseline median scores in VRT, VRT-sd, Stroop3, CPT and change over time in both groups are shown in figure 2. Figure 2 clearly shows that there is not only a difference at
baseline but also more improvement over time on the VRT-sd and CPT in the responder-group.
Based on z-scores for the change on the 3 clinical outcome scales a mean z-score was calculated for individual patients. This mean z-score (Zsum) as an overall measure of therapeutic response correlated with the baseline scores of both the VRT-sd (ρ 0.48; p=0.005) and CPT (ρ -0.44; p=0.010). There was no significant correlation between Zsum and age (Pearson’s r 0.241; p = 0.170).
NPI-clusters
We compared the two predefined NPI-clusters and total NPI-score between responders and responders at baseline using Mann-Whitney U non-parametric tests. None of these three measures were significantly different between responders and non-responders, but for the cluster described by Herrmann et al11 (NPI-items hallucination, anxiety, apathy and abnormal motor
behaviour), there was a trend towards higher baseline scores in responders (p = 0.079). Exploring the correlation of this cluster with response as indicated by Zsum, using Spearman correlation coefficient, we found a positive correlation of 0.378; p = 0.027. Stroop3 0 200 400 600 800 1000 baseline 3 m 6 m ti m e (s) CPT 52 54 56 58 60 62 baseline 3 m 6 m n u m b er o f co rr ec t an sw er s
Visual reaction time
0 400 800 1200 1600 baseline 3 m 6 m ti m e (s) VRT-sd 0 400 800 1200 1600 baseline 3 m 6 m ti m e (s)
Figure 2. Graphic display of 4 tests of the neuropsychological test battery.
Changes of median scores in time from baseline at 3 and 6 months in responders and non-responders are shown. VRT-sd and CPT scores were significantly different at baseline between the groups. Vertical bars indicate interquartile range (25 -75%).
DISCUSSION
This was a prospective cohort study in patients treated with rivastigmine aimed at the delineation of a baseline clinical profile that predicts a beneficial response to CEI-therapy. Neuropsychological tests scores and clinical symptoms were used to define this clinical profile. Since cholinergic neuronal loss occurs in various degenerative diseases causing dementia we did not limit our study to a single disease entity. In this study strict criteria were applied in order to distinguish clinical relevant response to treatment. Our results show that fluctuations in reaction time tasks and poor sustained attention at baseline are features that are associated with a favourable response to treatment with rivastigmine. In the course of rivastigmine treatment the large baseline differences in attentional performance between responders and non-responders disappeared (figure 2). This supports the idea that the impairments as reflected in these two measures are sensitive to the effect of cholinesterase inhibition. Moreover, our results suggest that a cluster of behavioural symptoms, including hallucinations, apathy, anxiety and psychomotor disturbances, coexists with these attentional deficits in patients that respond well to CEI therapy.
The findings of this study agree with previous hypotheses and observations that cholinergic deficiency is best identified by impairments in attention and concen-tration accompanied by features such as confusion and hallucinations20,22,38.
In the few clinical trials on efficacy of CEIs that assessed behavioural symptoms and attention as primary outcome measures, beneficial effects in favour of CEI treatment-groups were observed39-41. The presence of hallucinations predicted
greater improvement in attention in DLB12. In PDD-patients treatment effects were more marked if patients suffered from hallucinations10. The fact that we were able
to find strong correlations between baseline VRT-sd and CPT and, to a certain degree, between NPI-items at baseline and subsequent therapeutic response even in a small study population as in the present study support these notions. The small number of patients may render some of our conclusions prone to a type II error: some of the baseline differences that did not reach statistical significance may do so in the studies of larger patient groups. For example, in contrast to previous reports we did not find a difference in fluctuating cognition as measured by the CAF7.
The same may hold for the fact that the correlation between age and therapeutic response (expressed by Zsum) was not significant, although mean age was higher in the group of responders. Van der Putt et al. described earlier a baseline difference in age between responders and non-responders, in which responders to CEI-treatment were older9. This effect of age may imply that attentional deficits and behavioural disturbances are more prominent in older patients with dementia.
Our conclusions are based on correlation analysis. Due to the small cohort no reliable cluster analysis or regression modelling could be performed to obtain stronger evidence of specific features that are independently associated with response to CEIs. Further prospective studies in larger cohorts need to be performed for this purpose. To improve face-validity these future studies should preferably be carried out in heterogeneous populations which have a more representative distribution of dementias than our study did.
In our study the drop-out rate was lower than the rates reported in clinical trials and also the overall response rate was considerably higher (>50%) than reported in randomised trials2,3,42,43. These effects are probably due to the specific
selec-tion of patients that were included in the present study. Although worsening of parkinsonism, especially tremor, due to use of cholinesterase inibitors has been described, we found no significant difference in change of UPDRS scores over 6 months’ treatment between the two groups44,45.
Our study was a hypothesis-driven exploration to seek a clinical profile that may serve as a more sensible and reliable target for CEI-therapy than a nosological entity per se or subgroups of patients within an arbitrarily defined range of MMSE scores, as suggested by the recent NICE guidelines. This small open-label study has limited value in defining this profile in very specific terms but gives a hint of the direction that can be taken to explore new ways of administering CEIs in a group of patients suffering from very disturbing symptoms. Independent prospective studies in larger cohorts of patients, with various neurodegenerative diseases should be performed to determine the true value of this or similar risk profiles. Ideally, this should converge to a specific clinical profile in patients with cholinergic deficiency, which can be easily recognised by a small set of simple tests in the physician’s office.
In conclusion, a profile based on a combination of few behavioural symptoms and simple neuropsychological tests that focus on attention, could potentially contribute to a better selection of patients that will unequivocally benefit from treatment with CEIs.
References
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2. Emre M, Aarsland D, Albanese A et al. Rivastigmine for dementia associated with Parkin-son's disease. N Engl J Med. 2004; 351:2509-2518
3. McKeith I, Del ST, Spano P et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet. 2000; 356:2031-2036
