A contribution to the current discussion on anti-dementia drugs in Germany

In Germany, the role of acetylcholinesterase inhibitors in the treatment of Alzheimer's disease (AD) has become a topic of recent discussion. The present article addresses issues which, in the opinion of the authors, have not received sufficient attention. These include the distinction between statistical and clinical significance, outcome parameters, the duration of clinical trials, variability in treatment response and the definition of treatment responders. The authors argue that these issues need to be considered in an in-depth evaluation of acetylcholinesterase inhibitors in the treatment of AD.     

Experimental research on nitric oxide and the therapy of Alzheimer disease: a challenging bridge

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment due to neuronal death. Although the lost of cognitive function is the main problem for AD subjects, death occurs due to secondary issues such as concomitant infections, respiratory complications or multi-organ failure. Current drugs used in AD are acetylcholinesterase inhibitors and antagonists of the N-methyl-D-aspartate receptor. These drugs may only slightly improve cognitive functions but have only very limited impact on the clinical course of the disease. Over the last 5 years, new targets were identified and innovative drugs against AD have been designed and developed. Worthy of mention are β-secretase inhibitors, monoclonal antibodies against amyloid-β-peptide and tau inhibitors. However, although promising beneficial effects were highlighted in the data from preclinical studies, only few of these new drugs improved cognitive functions for a significant time frame in AD subjects. Controversial is the therapeutic effect on AD obtained through the manipulation of the nitric oxide synthase/nitric oxide system since the potential toxic effects on brain function could overcome the beneficial effects. The aim of this review is to analyze from a pharmacologic point of view both old and new drugs developed for the treatment of AD. In addition, the risk/benefit ratio related to the modulation of the nitric oxide synthase/nitric oxide system in AD brain will be analyzed.     

CSF markers for incipient Alzheimer's disease

Early diagnosis of Alzheimer's disease (AD) is needed to initiate symptomatic treatment with acetylcholinesterase inhibitors, and will be of even greater significance if drugs aimed at slowing down the degenerative process, such as vaccination regimes and beta-secretase and gamma-secretase inhibitors, prove to affect AD pathology and to have clinical effect. However, there is no clinical method to determine in which patients mild cognitive impairment (MCI) will progress to AD with dementia, and in which patients MCI is benign. Hence, there is a great clinical need for biomarkers to identify incipient AD in patients with MCI. The CSF biomarkers total tau protein, phosphorylated tau protein, and the 42 amino-acid residue form of amyloid-beta may, if put in the right clinical context, prove to have high enough diagnostic accuracy to meet this challenge.     

Treatment of Alzheimer's disease: current status and new perspectives

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the most prevalent cause of dementia with ageing. Pharmacological treatment of AD is based on the use of acetylcholinesterase inhibitors, which have beneficial effects on cognitive, functional, and behavioural symptoms of the disease, but their role in AD pathogenesis is unknown. Other pharmacological therapies are becoming available--including the recently approved drug memantine, an NMDA channel blocker indicated for advanced AD. Here, we review clinical features of the available cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) including their pharmacological properties, the evidence for switching from one agent to another, "head to head" studies, and the emerging evidence for the use of memantine in AD. New therapeutic approaches--including those more closely targeted to the pathogenesis of the disease--will also be reviewed. These potentially disease modifying treatments include amyloid-beta-peptide vaccination, secretase inhibitors, cholesterol-lowering drugs, metal chelators, and anti-inflammatory agents.     

Correlates of dropout,efficacy, and adverse events in treatment with acetylcholinesterase inhibitors in Korean patients with Alzheimer's disease

The correlates of dropout, efficacy, and adverse events in the treatment of Alzheimer's disease (AD) with acetylcholinesterase inhibitors (ChEI) are unclear. To investigate these issues, a 26-week prospective, randomized, open-labeled trial with donepezil or rivastigmine was undertaken. Sixty-four Korean patients with AD were recruited, and data on sociodemographic and clinical characteristics and several assessment scales were collected. Characteristics of available caregivers were also gathered. Information on adverse events and dropout was recorded. Thirty-five (55%) patients dropped out during treatment with ChEI, for reasons mainly related to financial burden of caregivers. Of the 29 patients who completed the 26-week trial, 16 (55%) were responsive to ChEI. Lower scores on the Clinical Dementia Rating and Blessed Dementia Scale at baseline were associated with the efficacy of ChEI. Of the total participants, 26 (41%) experienced adverse events, although these seemed to be mild and appeared to be associated with the psychological state of patients or coadministration of psychotropic drugs. In conclusion, ChEI seemed to be effective and well tolerated in the treatment of Korean patients with AD, but the use of this drug was limited mainly by the financial burden of caregivers.     

New therapeutic approaches in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects a large proportion of the elderly population. It causes a progressive decline in memory and other cognitive functions. There is no effective treatment of AD despite the great effort in trying to find one. Herein new therapeutic approaches including those closely targeting the pathogenesis of the disease have been discussed. Potential disease modifying treatments that are being considered as future treatment of AD include avaccination, secretase inhibitors, cholesterol lowering drugs, metal chelators and anti- inflammatory agents. According to Evidence Based Dementia Practice, only inhibitors of acetylcholinesterase (AChE) are approved in mild and moderate stages of AD treatment. From the end of 2003, FDA also approved memantine for much severer phases of AD. When all the presented possibilities are taken into account, the most important target for scientists and physicians is not only to find ways for causative cure of AD, but also to be ready for that moment. There is a great need for finding routine biomarkers and sensitive enough clinical tests for diagnosis of AD in which the lasting pathological process does not destroy too many neurones.     

Clinical trials in mild cognitive impairment: lessons for the future

Mild cognitive impairment (MCI) is an operational definition for a cognitive decline in individuals with a greater risk of developing dementia. The amnestic subtype of MCI is of particular interest because these individuals most likely progress to Alzheimer's disease (AD). Currently hypothesised therapeutic approaches in MCI are mainly based on AD treatment strategies. Long term secondary prevention randomised clinical trials have been completed in amnestic MCI populations, encompassing agents with various mechanisms of action: acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), antioxidants (vitamin E), anti-inflammatories (rofecoxib), and nootropics (piracetam). The design of clinical trials in MCI is influenced by study objectives and definition of primary end points: time to clinical diagnosis of dementia, and AD in particular, or symptom progression. As none of the drugs previously shown to have clinical efficacy in AD trials or benefit in everyday practice have met the primary objectives of the respective trials, design of future clinical trials in MCI should be further developed particularly as regards the selection of more homogeneous samples at entry, optimal treatment duration, and multidimensional and reliable outcomes.     

Is pharmacotherapy feasible for mild cognitive impairment?

The feasibility of pharmacotherapy with cholinesterase inhibitors, which have been approved as the treatment agent for Alzheimer's disease (AD), for mild cognitive impairment (MCI) is discussed together with the results of previous studies. The clinical trials of cholinesterase inhibitors in patients with early or mild AD are reviewed first, because some cases of MCI may be regarded as cases of very early‐stage AD or very mild AD. Clinical trials for MCI treatment are then analyzed, although only preliminary results of data analysis have been reported. In addition, the methodological issues in the clinical trials for MCI treatment are discussed. The author points out that there should be focus on the observation period of trials, patient inclusion and exclusion criteria and subtypes of MCI, and that the suitability of cognitive measurements need to be further discussed.     

Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors

Neurological Sciences - In order to evaluate the biochemical effects of long-term treatment with inhibitors of acetylcholinesterase (AChE) in patients with Alzheimer's disease (AD), we measured...     

Empirical evidence of neuroprotection by dual cholinesterase inhibition in Alzheimer's disease

Brain grey matter density changes were quantified using voxel based morphometry in 26 patients with minimal to mild Alzheimer's disease (AD) treated with three cholinesterase inhibitors over 20 weeks. Patients whose drug treatment also inhibited butyrylcholinesterase did not show the widespread cortical atrophic changes in parietotemporal regions invariably reported in untreated AD patients, and which were detectable in the subgroups treated with selective acetylcholinesterase inhibition. This finding is the first empirical evidence that dual cholinesterase inhibition may have neuroprotective potential in AD.     

Pharmacologic treatment expectations in the management of dementia with Lewy bodies

Recently recognized as an entity separate from Alzheimer's disease (AD) and Parkinson's disease with dementia, dementia with Lewy bodies (DLB) is a frequent cause of dementia. It is characterized by progressive cognitive decline and attention deficits, but in contrast to AD, the cognitive changes typically fluctuate over time. Patients with DLB often experience Parkinson-like spontaneous motor features as well as recurrent visual hallucinations. Another frequent finding in DLB is rapid eye movement (REM) sleep disorder. Ideally, each of the major symptom domains associated with DLB (behavioral, motor, and cognitive) would be treated, but drug interactions in these patients are a serious concern. In addition, many patients with DLB are hypersensitive to neuroleptics, which can induce severe extrapyramidal and other symptoms--sometimes ending in death. Compared with conventional neuroleptics, the newer atypical antipsychotic agents may be associated with lower rates of extrapyramidal side effects. Cholinergic deficits in DLB are even more severe than in AD, whereas the extent of cerebral atrophy and neuronal damage may be less. These observations and emerging clinical data support the treatment of DLB with acetylcholinesterase inhibitors. Encouraging results have been obtained from studies of DLB patients treated with rivastigmine, donepezil, and galantamine, but large-scale, controlled trials are needed to confirm the efficacy and safety of acetylcholinesterase inhibitors in patients with DLB.     

Worsening of motor function and mood in a patient with Parkinson's disease after pharmacologic challenge with oral rivastigmine

Patients with Parkinson's disease (PD) can experience cognitive impairment. There are currently no medications indicated for the treatment of cognitive impairment in PD. Clinicians are faced with the dilemma as to whether or not to treat patients with PD with the acetylcholinesterase inhibitors that are currently approved for use in Alzheimer's disease (AD) and that have shown promise in clinical trials of Dementia with Lewy bodies (DLB). Although these medications may help cognition, there is a theoretical concern that by increasing acetylcholine relative to dopamine, they might worsen motor function. We report the case of a patient with PD and cognitive impairment who developed a marked worsening of motor function, mood, and anxiety in the setting of a pharmacologic challenge study using a 3-mg oral dose of the acetylcholinesterase inhibitor, rivastigmine. We believe that the mechanism of the motor and perhaps psychiatric worsening was increased central cholinergic tone. We conclude that further studies should be done to evaluate the efficacy and tolerability of these agents in this illness but that caution should be exercised when using acetylcholinesterase inhibitors in patients with PD.     

Dementia of the Alzheimer type in women

Within the different kinds of dementia, Alzheimer's Disease (AD) obviously is the only one showing relevant gender differences, concerning epidemiology, risk factors and cognitive deficits. Women more often suffer from AD, achieve lower Mini Mental Status Test scores when demented and show lower verbal skills. The possibility of using estrogen as a therapeutic agent, either only or as an augmentation to acetylcholinesterase inhibitors, could become more important for clinical practice, as it is said to cause distinct improvements of cognitive skills. Epidemiological studies were able to show that estrogen replacement therapy in menopausal women lowers risk of AD.     

The prediction and prevention of Alzheimer's disease--towards a research agenda

This paper sets a research agenda for the prediction and prevention of future onset of Alzheimer's disease (AD). From a MEDLINE review of the literature, the authors found age to be a predictor of AD. The literature also indicates that memory and attentional impairments predict AD, although the relative risk is relatively low. Late-onset depression may also predict AD, but these data are limited by a lack of cohort studies. Studying cognitively impaired subjects with late-onset depression may identify a high-risk group, facilitating prevention trials. Characteristics of an "ideal" preventive agent are suggested. There is a biologic rationale, and preliminary evidence, that non-steroidal anti-inflammatory drugs (including ASA), estrogen and vitamin E may play a preventive role in AD. Other compounds (such as acetylcholinesterase inhibitors) are also promising, but costs, side effects, and lack of other health benefits may preclude their use in all but very high-risk groups.     

Treating apathy in Alzheimer's disease

Apathy, a syndrome of decreased initiation and motivation, affects over 70% of individuals with Alzheimer's disease (AD) and is the most common neuropsychiatric symptom reported in AD patients. The syndrome of apathy is associated with functional impairment among patients and elevated stress among their caregivers. Apathy is one of the primary neuropsychiatric manifestations of frontal system dysfunction, and AD-related apathy is thought to reflect the interaction between cholinergic deficiency and neuropathological changes in frontal brain regions. This article reviews the assessment and treatment of apathy in AD, with emphasis on the utility of acetylcholinesterase inhibitors for reducing apathy in AD. The potential benefits of other pharmacologic agents and combined pharmacologic-behavioral interventions are also discussed, and recommendations for future research are provided.     

Predicting cognitive decline in Alzheimer disease. Role of platelet amyloid precursor protein

An altered pattern of platelet amyloid precursor protein (APP) forms, consisting of a reduced ratio of the upper (130 kDa) to the lower (110 to 106 kDa) immunoreactivity band (APPr), is associated with Alzheimer disease (AD), although in the early stages of AD this pattern shows high variability. To explore whether APPr values at baseline may predict the rate of cognitive decline, we evaluated patients with mild AD before and after 1 year of treatment with acetylcholinesterase inhibitors. Lower APPr at baseline was the only predictor of progressive cognitive decline, suggesting that this biomarker might be a useful indicator of prognosis for patients with AD.     

Increase of BDNF serum concentration during donepezil treatment of patients with early Alzheimer’s disease

Alzheimer's disease (AD) can be treated with inhibitors of the enzyme acetylcholinesterase (AChE). Recent pre-clinical and clinical studies gave evidence that AChE-inhibitors have neuroprotective effects and thereby a disease-modifying potential. The mechanism of this action is still discussed. In an animal model oral administration of an AChE-inhibitor lead to an increase of brain derived neurotrophic factor (BDNF) in hippocampus and cortex. Recent studies have found a decrease of BDNF in the serum and brain of AD patients with potentially consecutive lack of neurotrophic support and contribution to progressive neurodegeneration. BDNF serum concentrations were assessed by ELISA in 19 AD patients and 20 age-matched healthy controls at baseline and in the AD patients after 15 months of treatment with donepezil 10 mg per day (one patient received just 5 mg). Before treatment with donepezil we found in AD significantly decreased BDNF serum concentrations (19.2 +/- 3.7 ng/ml) as compared to healthy controls (23.2 +/- 6.0 ng/ml, P = 0.015). After 15 months of treatment the BDNF serum concentration increased significantly in the AD patients (23.6 +/- 7.0 ng/ml, P = 0.001) showing no more difference to the healthy controls (P = 0.882). The results of the present study confirm data of prior investigations that a down-regulation of BDNF in serum and brain of AD patients seems to begin with the first clinical symptoms and to be persistent. A treatment with the AChE-inhibitor donepezil is accompanied with an increase of BDNF serum concentration in AD patients reaching the level of healthy controls. Thus, up-regulation of BDNF might be part of a neuroprotective effect of AChE-inhibitors. The molecular mechanism of this potentially disease-modifying mechanism of action of donepezil should be clarified.     

The clinical significance of plasmatic amyloid A{beta}-40 peptide levels in Alzheimer's disease patients treated with galantamine

To date there are no conclusive reports on the usefulness of determining amyloid peptides in the serum of patients with Alzheimer's disease (AD). Only anecdotal works deal with the changes in the peptides produced by cholinesterase inhibitors. In this study, the authors investigated and studied the clinical significance of plasmatic Abeta-40 and Abeta-42 peptide levels in a series of 34 consecutive patients with AD. The baseline levels of the Abeta-40 peptide correlated negatively with the Mini Examen Cognoscitivo (Spanish version of the Mini-Mental test) score. Complete follow-up was possible in 22 patients. After 6 months of treatment with galantamine, the mean Abeta-40 peptide levels decreased from 31.86 to 24.22 pg/mL. The baseline levels of Abeta-40 were predictive of response to treatment in the Alzheimer's Disease Assessment Scale-Cognitive Subscale. The authors conclude that determining plasmatic Abeta-40 peptide levels could be useful in predicting and monitoring response to treatment in AD.     

Review of the next generation of Alzheimer's disease therapeutics: challenges for drug development

1. AD is believed to stem from dysfunctional cholinergic signaling in the regions of the brain associated with memory and cognition. 2. The occurrence of AD in afflicted individuals correlates with an increase in the accumulation of A beta-rich senile plaques and neurofibrillary tangles in the brain. 3. Currently, the only FDA-approved AD therapies are a group of acetylcholinesterase inhibitors which slow the turnover of the neurotransmitter acetylcholine in the synapse. 4. Many other compounds which target other aspects of the disease, such as reducing neuronal damage and limiting oxidation, are in clinical trials. These include monoamine oxidase (MAO-B) inhibitors, NSAIDs, antioxidants and estrogen, among others. 5. Recent research discoveries have more completely defined the molecular nature of AD, and are generating new approaches for treatment. One idea is to limit the ability of the protein tau to become phosphorylated in hopes that this will limit the formation of neurofibrillary tangles in the brain. 6. A separate approach that is being pursued is to prevent formation and accumulation of A beta plaques. This may be accomplished by either regulating gamma-secretase activity, or using anti-beta-amyloid antibodies to reduce the size of existing plaques. 7. Employing improved procedural and technological approaches during clinical trials, such as bridging studies, dynabridge studies and PET analysis, promises to streamline the drug development process. 8. The use of biomarkers and MRI analysis may be an effective means by which to identify the disease early. Consequently, early intervention treatment therapies may be an effective way of delaying onset of the disease. 9. Long term AD studies, particularly those focusing on the MCI population, are likely to provide statistically valid results using a smaller study population.     

Treating Alzheimer's disease: do clinical trial methods produce unnecessary practitioner dilemmas?

Recent clinical trials and critical reviews of Alzheimer's disease (AD) research discourage already relatively sparing clinical uses of cholinesterase inhibitors (ChEIs) considering the prevalence of AD. As evidence against use of this class of drugs, detractors cite critical reviews of ChEIs and lack of long-term health benefits found in one long-term clinical trial. This paper describes the use of standard error of measurement to allow investigators to design clinical trials that address these issues. The new clinical trial procedures afford sufficient precision for two purposes. First, practitioners can assess individual patients with precision and certainty in their observations. Second, clinical trial researchers can study how short-term drug effects on individual patients predict long-term benefits from continued treatment. With these more clinically informative clinical trial designs, investigators would be able to avoid uncertainties currently raised by conflicts between short- and long-term AD clinical trials.