Neuropsychiatric Disease and Treatment 2007:3(2) 211���218 �� 2007 Dove Medical Press Limited. All rights reserved 211 E X P E RT O P I N I O N Rivastigmine in the treatment of patients with Alzheimer���s disease Thomas M��ller Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Germany Correspondence: Thomas M��ller Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany Tel +49 234 509 2426 Fax +49 234 509 2414 Email thomas.mueller@ruhr-uni-bochum.de Abstract: Impairment of attention and memory in patients with Alzheimer���s disease (AD) is associated with signifi cantly lower levels of acetylcholine. Inhibition of the breakdown of acetylcholine by blocking the enzymes acetylcholinesterase and butyrylcholinesterase with rivastigmine improves this cholinergic depletion. Thus rivastigmine administration provides established, effective, long-term symptomatic treatment in AD and Parkinson���s disease (PD) patients with dementia. A sustained treatment with cholinesterase inhibitors in general may also induce a certain deterioration of fi ne motor behavior, which may play a crucial role in the treatment of PD patients with dementia. Recent studies show that this altered balance between dopamine and acetylcholine due to cholinesterase inhibition, with its possible negative impact on motion behaviour, does not present a major problem in clinical practice in AD patients and may be compensated for by modifi cation of dopaminergic substitution in PD patients with dementia. However, progression of neurodegeneration increases the vulnerability for psychosis in AD and PD patients with dementia in combination with dehydration and often requires additional application of neuroleptics. Since classical neuroleptics increase extrapyramidal symptoms, atypical neuroleptics are used. Out of these, quetiapine shows a distinct lower anticholinergic (muscarinergic) potency with benefi cial effects on cognition. This favors its use in combination with rivastigmine. Keywords: neurodegeneration, Alzheimer���s disease, rivastigmine, movement Introduction Alzheimer���s disease (AD) is the commonest cause of dementia affecting older people. Research advances have enabled a detailed understanding of the molecular pathogenesis of the hallmarks of the disease, ie, plaques, composed of amyloid beta, and tangles, composed of hyperphosphorylated tau. The neurodegenerative AD process is histopathologically characterized by nerve cell loss, extracellular deposits of beta amyloid protein, and intraneuronal formation of neurofi brillary tangles. These changes do not exclusively occur in the cerebral cortex but also in several subcortical nuclei. The nucleus basalis of Meynert is most severely affected. Its neurons are cholinergic and project into many cortical areas. Loss of these nerve cells results in a widespread reduction of the cholinergic activity in the cortex. Cholinergic depletion is associated with impairment of attention and memory therefore the cholinergic defi cit in AD presumably contributes to some of the core symptoms. However, as knowledge increases so does also the appreciation for the pathogenic complexity of the disorder. Familial AD is a very rare autosomal dominant disease with early onset, caused by mutations in the amyloid precursor protein and presenilin genes, both linked to amyloid beta metabolism. By contrast with familial disease, sporadic AD is very common with more than 15 million people affected worldwide (Blount et al 2002 Cummings 2005 Alva and Potkin 2003). The cause of the sporadic form of the disease is unknown,

Neuropsychiatric Disease and Treatment 2007:3(2) 212 M��ller probably because the dementia and AD in particular is heterogeneous, caused by aging in concert with a complex interaction of both genetic and environmental risk factors (Blennow et al 2006). The common mode of action of cholinesterase inhibitors (ChEI) Pathological changes in AD involve cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. These pathways are thought to be intricately involved in memory, attention, learning, and other cognitive processes. These are accomplished by decreased concentrations of acetylcholine, which are modulated by the enzyme cholinesterase. This enzyme is of neuronal origin and functions to metabolize acetylcholine at synapses throughout the nervous system. Cholinesterase breaks down acetylcholine, a neurotransmitter which assists in human memory and cognition processes. By inhibiting cholinesterase, more acetylcholine is available to the patient for memory and cognitive functioning. This is effective in treatment of AD, since acetylcholine is at signifi cantly lower levels in AD patients than in normally functioning people. These drugs block the enzyme that inactivates the transmitter in the synaptic cleft. It should be noted that ChEI are a symptomatic, not causal, treatment of AD. ChEI increase the concentration of acetylcholine in the brain. As AD progresses and cortical neurons are lost, levels of acetylcholinesterase progressively decline, while levels of butyrylcholinesterase increase. Butyrylcholinesterase can and does take over the function of metabolizing acetylcholine at the synapse, when acetylcholinesterase is lost, a phenomenon that has been demonstrated in an acetylcholinesterase knockout mouse model and which probably occurs in AD (Polinsky 1998). Rivastigmine, but not its competitors, inhibits both acetylcholinesterase and butyrylcholinesterase by covalently binding to active sites on these enzymes, blocking their function. Breaking of these covalent bonds is the fi rst and most important step in the degradation of rivastigmine, which is not metabolized in the liver (Greig et al 2002 Darvesh et al 2003 Eskander et al 2005). Symptomatic drug treatment approaches Since the introduction of the first ChEI in 1997, most clinicians and probably most patients would consider the cholinergic drugs donepezil, galantamine, and rivastigmine to be the fi rst-line pharmacotherapy for mild to moderate AD. These drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the clinical manifestations, in particular the cognitive impairment, of AD. Moreover there is accumulating evidence that they also improve additional affected domains of global functioning, such as activities of daily living or behavior (Cummings 2000 Bonner and Peskind 2002 Clegg et al 2002). Objective Objective is to review the effi cacy of rivastigmine in the treatment of AD and to provide an outlook of its effect in the treatment of dementia in Parkinson���s disease (PD). Essential clinical AD trials with rivastigmine The safety and effi cacy of rivastigmine were investigated in several placebo-controlled investigations (see Table 1). Participants, all AD patients, were evaluated in terms of their cognitive performance using the Alzheimer���s Disease Assessment Scale (ADAS-cog) and the Clinician���s Interview Based Impression of Change (CIBIC-Plus). The ADAS-cog considers elements of memory, orientation, attention, reasoning, language, and praxis. Improvement in global functioning was measured by the CIBIC-Plus. This instrument of evaluation considers overall patient cognition, behaviour, and functioning. The patient population for these studies tried to refl ect a real world population, since most of the patients used concomitant medications to treat other conditions during the studies. In a 26-week, US study, patients were divided into three groups, each receiving 1���4 mg/day of rivastigmine, 6���12 mg/day of rivastigmine, or placebo. At the end of the treatment period, both ADAS-cog scores and CIBIC-Plus ratings for those treated in either dose-group of rivastigmine were signifi cantly superior to the scores of those who took placebo. Furthermore, the higher-dosage group had better ADAS-cog scores and CIBIC-Plus ratings than the lower-dosage group. Better scores in these assessments indicate greater improvement and less worsening in cognitive function (such as memory, recognition, ability to speak, and other symptoms of dementia) than the average placebo- treated patient. In another 26-week, global study, patients were divided into similar groups. Results of this study also indicated that the 6���12 mg/day group showed signifi cantly