Current and Future Treatments for Alzheimer's Disease

Konstantina G. Yiannopoulou, MD, Sokratis G. Papageorgiou, PhD, MD

Disclosures

Ther Adv Neurol Disorders. 2013;6(1):19-33. 

 

 Abstract and Introduction

Abstract

Alzheimer's dementia (AD) is increasingly being recognized as one of the most important medical and social problems in older people in industrialized and nonindustrialized nations. To date, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance. Three cholinesterase inhibitors (CIs) are currently available and have been approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine, an N-methyl- D-aspartate receptor noncompetitive antagonist. Treatments capable of stopping or at least effectively modifying the course of AD, referred to as 'disease-modifying' drugs, are still under extensive research. To block the progression of the disease they have to interfere with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, inflammation, oxidative damage, iron deregulation and cholesterol metabolism. In this review we discuss current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I–III trials.

Introduction

Dementia is increasingly being recognized as one of the most important medical problems in older people with a prevalence rising from 1% at the age of 60 to at least 35% at the age of 90 [Ferri et al.2005]. Within the spectrum of dementias, Alzheimer's disease (AD) is the most prevalent subtype, accounting for about 60% of all dementias. It is characterized clinically by progressive memory and orientation loss and other cognitive deficits, including impaired judgment and decision making, apraxia and language disturbances. These are typically accompanied by various neuropsychiatric symptoms (i.e. depression, apathy, anxiety, agitation, delusions, hallucinations). The continuing expansion of life expectancy, leading to a fast growing number of patients with dementia, particularly AD, has led to an enormous increase in research focused on the discovery of drugs for primary, secondary or tertiary prevention of the disease. Despite all scientific efforts, at the moment there are no effective pharmacotherapeutic options for prevention and treatment of AD.

To date, established treatments are only symptomatic in nature, trying to counterbalance the neurotransmitter disturbance of the disease. Three cholinesterase inhibitors (CIs) are approved for the treatment of mild to moderate AD [Birks, 2006]. A further therapeutic option available for moderate to severe AD is memantine [McShane et al. 2006]. At the same time antipsychotic and antidepressant treatments are used for the behavioral symptoms of the disease [Ballard and Corbett, 2010].

Treatments under research include compounds that act on the pathological substrate of the disease: extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). In this review, current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I–III trials are discussed.

Current Symptomatic Approaches to Alzheimer's Disease

Cholinesterase Inhibitors

The cholinergic hypothesis of AD concludes that cholinergic systems in the basal forebrain are affected early in the disease process, including loss of acetylcholine neurons, loss of enzymatic function for acetylcholine synthesis and degradation, resulting in memory loss and deterioration of other cognitive and noncognitive functions such as neuropsychiatric symptoms [Bartus et al. 1982; Cummings and Back, 1998]. A strategy to enhance the cholinergic transmission by using CIs to delay the degradation of acetylcholine between the synaptic cleft has been proposed. To date, three CIs are approved for the treatment of mild to moderate AD: donepezil (Pfizer, New York, NY, USA), rivastigmine (Novartis, Basel, Switzerland) and galantamine (Janssen, Beerse, Belgium) [Farlow, 2002]. These drugs have been regarded as the standard and first-line treatment for AD. Systemic reviews including many double- blind, randomized, placebo-controlled trials (RCTs) of these three CIs all showed benefit on cognitive functions, activities of daily living (ADL), and global function for patients with mild to moderate AD; there was no significant difference of efficacy between individual CIs [Farlow, 2002; Birks, 2006]. In addition, donepezil is now also approved for the treatment of severe AD in the USA [Cummings et al. 2010]. Although tacrine (First Horizon Pharmaceuticals, Alpharetta, Georgia, USA) was the first CI drug approved for AD in 1993, it is no longer used due to hepatotoxicity [Alfirevic et al. 2007]. Related systemic reviews showed that the incidence of gastrointestinal adverse effects, such as nausea, vomiting, diarrhea and abdominal cramp, was lower with donepezil than with rivastigmine and galantamine [Alva and Cummings, 2008]. The incidence of adverse effects was associated with higher therapeutic dose. However, it may be that galantamine and rivastigmine may be equal to donepezil in tolerability if a careful and gradual titration routine of more than 3 months is used. The dermal form of rivastigmine provides a lower dose with fewer adverse effects but comparable efficacy, and is was preferred by some caregivers [Blesa et al. 2007]. Use of CIs is also reported to be associated with increased rates of syncope, bradycardia and pacemaker insertion. The risk of these adverse events must be weighed carefully against the drugs' benefits [Gill et al. 2009].

Reviews and meta-analyses on CIs that have recently been published showed that they delay the decline in cognitive function as measured by the AD Assessment Scale – cognitive subscale (ADAS-cog), global clinical rating, behavior and ADL over 6–12-month periods. These benefits seem to be applicable to mild, moderate and severe AD [Birks, 2006; Hansen et al 2008; Qaseem et al. 2008]. Compared with those on placebo treatment, patients on CIs generally show an initial mild improvement in cognitive functions over the first 3 months. Thereafter, the mean decline in cognitive functions was also less rapid over the subsequent 3–9 months. At 6 months, the cognitive improvement (versusplacebo) was 2.7 points over the Mid range of ADAS-cog [Birks, 2006; Hansen et al. 2008]. Symptoms that were improved included attention, thinking, memory, praxis, language comprehension and communication [Qaseem et al. 2008].

Initiation of CI treatment in the early stages of AD is preferred. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe AD reported that patients with AD who started the CI 6 months later achieved lower cognitive performance than those who started the drug immediately after the diagnosis [Farlow et al. 2000]. Preserved cognitive function was also observed after 12 months of treatment with rivastigmine in patients with mild AD in comparison to untreated patients who markedly worsened in cognition during the same period [Almkvist et al. 2004].

N-methyl-D-aspartate Antagonist

A further therapeutic option for moderate to severe AD is memantine (Lundbeck, Valby, Denmark). This drug is an uncompetitive, moderate- affinity N-methyl-D-aspartate (NMDA) antagonist believed to protect neurons from excitotoxicity. A systemic review of double-blind, parallel- group, RCT studies of memantine showed improvement in cognition, ADL and behaviors in people with moderate to severe AD after 6 months of use [McShane et al. 2006]. Another systemic review which included six RCT studies indicated that memantine may reduce behavioral and psychological symptoms of dementia [Maidment et al. 2008]. The most frequently reported adverse events in memantine trials were dizziness, headache and confusion. A small group of patients might develop agitation [Alva and Cummings, 2008].

Combination Therapy

RCT studies on parallel groups of patients with moderate to severe AD showed a significant benefit in cognitive function, language, ADL, behaviors and global state from combination use of memantine and donepezil over the placebo group (memantine and placebo) [Tariot et al. 2004; Feldman et al.2006; Howard et al. 2012]. However, such benefit was not demonstrated in patients with mild to moderate AD [Farlow et al. 2010].

Treatment of Behavioral and Psychological Symptoms of Dementia in Alzheimer's Disease

Noncognitive neuropsychiatric symptoms or behavioral and psychological symptoms of dementia (BPSD) are common in all clinical stages of AD and even in amnestic mild cognitive impairment (MCI) (the predementia stage of AD) with increasing prevalence when dementia progresses. They are the main determining factors for increased caregiver burden and institutionalization of patients. According to a large observational study, BPSD may be grouped into four major symptom clusters with high prevalence: psychosis (38% of the patients, e.g. delusions), affective symptoms (59%, anxiety and depression), hyperactivity (64%, e.g. aggression, disinhibition) and apathy (65%) [Zec and Burkett, 2008].

CIs and memantine may have an effect on behavioral symptoms [Farlow, 2002; Birks, 2006; Maidmentet al. 2008]. However, when BPSD become more severe, these antidementia drugs may not be as effective and other drugs also need to be given.

Serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine) are largely considered to be among the most efficient antidepressants to treat comorbid depression in AD dementia [Zec and Burkett, 2008]. Mirtazapine, venlafaxine and duloxetine, which are combined selective noradrenalin and serotonin inhibitors (SNRIs), and bupropion are other widely used antidepressants in this population.

A few RCTs with limited numbers of patients as well as meta-analyses support their efficacy to treat depression in AD dementia [Ballard and Corbett, 2010]. SSRIs may also be taken into consideration for the treatment of agitation and psychosis in AD dementia [Zec and Burkett, 2008]. However, a recent randomized, multicenter, double-blind, placebo-controlled trial of sertraline or mirtazapine for depression in dementia (HTA-SADD) showed absence of benefit compared with placebo and increased risk of adverse events. The trial concluded that the current practice of using these antidepressants, with usual care, for first-line treatment of depression in Alzheimer's disease should be reconsidered [Banerjee et al. 2011].

Psychotic symptoms and agitation/aggression are commonly treated with antipsychotics in patients with AD dementia. Atypical agents (olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole) are preferred due to their milder parkinsonian effects [Ballard and Corbett, 2010]. The use of antipsychotics has been discussed controversially, as cerebrovascular morbidity and higher mortality have been found in patients with dementia taking antipsychotics. Furthermore, the use of antipsychotics may be associated with a higher risk of hip fracture and pneumonia, as well as worsening cognitive impairment. The increased mortality may be reduced if antipsychotics are only given over a short period, as stopping the antipsychotic medication may not be associated with a subsequent increase in BPSD [Zec and Burkett, 2008].

Benzodiazepines are used to reduce agitation and anxiety. However, they can also trigger further agitation in older people. An association of greater benzodiazepine use with more rapid cognitive and functional decline has been reported in AD and indeed in older people in general [Zec and Burkett, 2008].

Anticonvulsant drugs like carvamazepine can also reduce BPSD in AD to some degree [Ballard et al.2009].

It is obvious that drugs currently used for the treatment of AD have weak beneficial effects on cognitive function or offer some relief of BPSD. The discovery of new drugs that act during the early stages of AD could be considered a 'medical need' [Mancuso et al. 2011]. Early intervention is critical because a delay in treatment is associated with nonreversible symptom progression.

The Amyloid Hypothesis

The primary histopathologic lesions of Alzheimer's pathology are amyloid plaques, NFTs and neuronal loss. Mature plaques consist of a central amyloid core with surrounding degenerating neurons affected by the toxic effect of the Aβ. NFTs consist of hyperphosphorylated tau protein that has assumed a double helical filament conformation [Cummings, 2008b].

The Aβ derives from the amyloid precursor protein (APP) through sequential proteolysis by β secretase (BACE1) in the extracellular domain and γ secretase in the transmembrane region.

Full-length APP undergoes sequential proteolytic processing. It is first cleaved by α secretase (nonamyloidogenic pathway) or β secretase (amyloidogenic pathway) within the luminal domain, resulting in the shedding of nearly the entire ectodomain and the generation of α or β C-terminal fragments (CTFs). The major neuronal β secretase, named BACE1 (β-site APP cleaving enzyme), is a transmembrane aspartyl protease that cleaves APP within the ectodomain, generating the N-terminus of Aβ. The second proteolytic event in APP processing involves intramembranous cleavage of α and β CTFs by γ secretase. Major sites of γ-secretase cleavage correspond to positions 40 and 42 of Aβ. Amyloidogenic processing is the favored pathway of APP metabolism in neurons because of the greater abundance of BACE1, whereas the nonamyloidogenic pathway predominates in other cells [Vassar, 2004].

According to the 'amyloid hypothesis' Aβ production in the brain initiates a cascade of events leading to the clinical syndrome of Alzheimer's dementia [Golde, 2005]. Aβ is a protein consisting of two major forms, Aβ40 and Aβ42. Aβ42 is the most soluble form and has the tendency to aggregate into fibrils that form the major composite of amyloid plaques. It is the predominant form found in the brain parenchyma of patients with AD. Aβ40 is mostly found in the cerebral vasculature as part of 'cerebral amyloid angiopathy'. Aβ has a tendency to cluster into oligomers. Oligomers can form Aβ-fibrils and protofibrils that will eventually form amyloid plaques, which are believed to be nontoxic. It is the forming of amyloid oligomers to which neurotoxicity is attributed and initiates the amyloid cascade. The elements of the cascade include local inflammation, oxidation, excitoxicity (excessive glutamate) and tau hyperphosphorylation. As a result of this process, tau proteins fold into intraneuronic tangles, which results in cell death. Progressive neuronal destruction leads to shortage and imbalance between various neurotransmitters (e.g. acetylcholine, dopamine, serotonin) and to the cognitive deficiencies seen in AD [Cummings, 2008a; Golde, 2005].

On the basis of findings on AD pathogenesis, novel treatments under development aim to interfere with the pathogenic steps previously mentioned in an attempt to block the course of the disease in its early stages [Galimberti and Scarpini, 2011; Golde, 2005]. For this reason they have been termed 'disease-modifying' drugs. In this review, possible strategies for the development of novel disease-modifying therapies will be discussed.

Disease-modifying Approaches to Alzheimer's Disease

The production of Aβ, which is a crucial step in AD pathogenesis, is the result of cleavage of APP, which is overexpressed in AD [Griffin, 2006]. Aβ forms highly insoluble and proteolysis-resistant fibrils known as senile plaques (SPs). NFTs are composed of the tau protein. In healthy subjects, tau is a component of microtubules, which are the internal support structures for the transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Microtubules also stabilize growing axons necessary for the development and growth of neurons [Griffin, 2006]. In AD, tau protein is abnormally hyperphosphorylated and forms insoluble fibrils, causing deposits within the cell.

Thus, both Aβ and tau are prime targets for disease- modifying therapies in AD. From this point of view, AD could be prevented or effectively treated by decreasing the production of Aβ and tau; preventing aggregation or misfolding of these proteins; neutralizing or removing the toxic aggregate or misfolded forms of these proteins; or a combination of these modalities.

A number of additional pathogenic mechanisms have been described, possibly overlapping with Aβ plaques and NFT formation, including inflammation [Griffin, 2006], oxidative damage [Reddy et al. 2009], iron deregulation [Adlard and Bush, 2006] and cholesterol metabolism [Stefani and Liguri, 2009].

Disease-modifying Treatments: Modulation of Amyloid Deposition Drugs Interfering with Amyloid β Deposition.

Anti-amyloid Aggregation Agents The hypothesis that aggregation of Aβ leads to toxic oligomeres has driven research into studying compounds that could prevent this aggregation ( Table 1 ) [Cummings, 2008b; Golde, 2005].

The only Aβ aggregation inhibitor reaching phase III is the synthetic glycosaminoglycan 3-amino- 1-propaneosulfonic acid (3APS, tramiprosate) [Gauthier et al. 2009]. It is designed to interfere with the binding of glycosaminoglycanes and Aβ. Disappointing results of the North American phase III trial in the year 2007 have led to discontinuation of the European phase III trial. Nevertheless, 3APS will now be commercialized as a branded nutraceutical. However, recent data suggest that tramiprosate promotes an abnormal aggregation of the tau protein in neuronal cells [Santa-Maria et al. 2007]. These results emphasize the importance of testing the potential drugs for the treatment of AD on both types of pathology (amyloid and tau).

Another molecule undergoing testing is colostrinin, a proline-rich polypeptide complex derived from sheep colostrum (O-CLN; ReGen Therapeutics, London, UK). Colostrinin inhibits Aβ aggregation and neurotoxicity in cellular assays and improves cognitive performance in animal models. Although a phase II trial demonstrated modest improvements in Mini Mental State Evaluation scores for patients with mild AD over a treatment period of 15 months, this beneficial effect was not sustained during an additional 15 months of continued treatment [Bilikiewicz and Gaus, 2004].

Another compound named scyllo-inositol is able to stabilize oligomeric aggregates of Aβ and inhibit Aβ toxicity in mouse hippocampus. An 18-month, randomized, double-blind, placebocontrolled, dose-ranging, safety and efficacy study of oral scyllo-inositol (ELND005) in participants with mild to moderate AD has been carried out by Transition Therapeutics (Toronto, ON, Canada)/Elan (Dublin, Ireland). A long-term follow-up class II study in subjects with AD provided insufficient evidence to support or refute a benefit of ELND005.

Primary clinical efficacy outcomes were not significant. The safety and cerebrospinal fluid (CSF) biomarker results will guide selection of the optimal dose for future studies, which will target earlier stages of AD [Salloway et al. 2011].

Drugs Interfering With Metals Zinc (Zn) and copper (Cu) are both involved in the aggregation of Aβ42. Several chelators of Zn/Cu have been shown to inhibit Aβ aggregation in vitro and in animal studies. PBT2 is a second-generation 8-OH quinoline metal-protein-attenuating compound that affects the Cu2⁺-mediated and Zn2⁺- mediated toxic oligomerization of Aβ. A recent phase IIa study concluded that the safety profile is favorable for the ongoing development of PBT2. The effect on putative biomarkers for AD in CSF but not in plasma suggests a central effect of the drug on Aβ metabolism. Cognitive efficacy was restricted to two measures of executive function. In the post hoc analysis, the cognitive, blood marker and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg and PBT2 250 mg revealed that the proportions of patients showing improvement were significantly greater in the PBT2 250 mg group than in the placebo group. These findings further encourage larger-scale testing of PBT2 for AD [Faux et al. 2010].

Selective Aβ42-lowering Agents. Aβ is generated through proteolytic processing of the transmembrane peptide APP. APP can be cleaved by two competing proteases, α secretase and β secretase. Only cleavage by β secretase, followed by γ-secretase cleavage, which in AD is the dominant pathway, will lead to production of Aβ40 and Aβ42. By inhibiting β secretase and γ secretase or by increasing α-secretase cleavage, Aβ production may be reduced [Cummings, 2008a].

β-site AP-cleaving Enzyme Inhibition The β-secretase enzyme BACE1 is a promising therapeutic target, although the development of a BACE1 inhibitor therapy is problematic for two reasons. First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood–brain barrier. Many of compounds able to inhibit BACE are still in the preclinical phase. Inhibitors based on the peptidomimetic strategy suffer from well known difficulties associated with polypeptides, such as blood–brain barrier crossing, poor oral bioavailability and susceptibility to P-glycoprotein transport. Efforts to overcome these problems led to the design of new nonpeptidomimetic β-secretase inhibitors that show high selectivity over BACE2 (BACE1/BACE2 selectivity >100) and other human proteases (cathD, pepsin and renin). Their weak or nonpeptidic character favors CNS penetration and oral bioavailability [Silvestri, 2009]. A ligand-based computational approach is currently used to identify the molecular chemical features required for the inhibition of BACE1 enzyme [John et al. 2011].

Only a few β-secretase inhibitors have entered clinical trials to date. The first publicly announced phase I clinical trial on a β-secretase inhibitor CTS-21166 was conducted by CoMentis (South San Francisco, USA) [Hey et al. 2008; Albert, 2008; Panza, 2009]. Phase I clinical trials on CTS-21166 have been carried out in healthy young men and evaluated for safety and preliminary Aβ responses. In these clinical trials, β-secretase inhibitor has been shown to reduce human plasma Aβ [Hey et al. 2008]. Clearly, the hope for the next step would be to develop inhibitors with better pharmaceutical properties and to carry out well designed efficacy trials to determine if they can rescue cognitive decline in patients with AD [Ghosh et al. 2012].

γ-Secretase Inhibition γ Secretase is a nucleoprotein complex with at least four different proteins from which preseniline PS-1 and PS-2 seem to be responsible for the enzymatic action on APP. Unfortunately, besides APP, γ secretase has many other substrates and cleaves several other transmembrane proteins, including the Notch receptor 1, which is necessary for growth and development. Notch-related side effects of γ-secretase inhibition (severe gastrointestinal and hemopoetic side effects) have been hampering the development of clinically useful γ-secretase inhibitors so far [Wong et al. 2004]. The most studied γ-secretase inhibitor, which is semagacestat (LY-450139), was shown to dosedependently decrease the generation of Aβ in the CSF of healthy people [Siemers et al. 2005]. Unfortunately, two large phase III clinical trials of semagacestat in patients with mild to moderate AD were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared with those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aβ (the C-terminal fragment of APP or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP [Imbimbo and Giardina, 2011]. Two large phase III studies in patients with mild AD with tarenflurbil (or R-flurbiprofen), which is a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notchsparing γ-secretase inhibitors and more potent and brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks [Imbimbo and Giardina, 2011].

A potent γ-secretase inhibitor, BMS-708163 (avagacestat; Bristol-Myers Squibb, New York, NY, USA), was tested in a phase I clinical trial. After 18 days, BMS-708163 caused a decrease in CSF Aβ40 and Aβ42 of 30% following a daily dose of 100mg as well as a decrease of 60% at a daily dose of 150mg. A phase II study is ongoing [Tong et al 2012].

α-Secretase Potentiation Etazolate (EHT 0202; ExonHit Therapeutics, Paris, France) stimulates the neurotrophic α-secretase (nonamyloidogenic) pathway and inhibits Aβ-induced neuronal death, providing symptomatic relief and modifying disease progression. The recent pilot, randomized, double-blind, placebo-controlled, parallel group, multicentre, phase IIA study was conducted in 159 randomized patients with mild to moderate AD. EHT0202 was shown to be safe and generally well tolerated. These first encouraging safe results support further development of EHT0202 to assess its clinical efficacy and to confirm its tolerability in a larger cohort of patients with AD and for a longer period of time [Vella et al.2011].

Immunotherapy. Immunotherapy is one of the strategies being studied by most pharmaceutical companies. The mechanism behind amyloid clearance by immunotherapy has not been fully elucidated. At least six mechanisms that are not mutually exclusive are considered to elicit a humoral response: First, by direct disassembly of plaques by conformation-selective antibodies; second, by antibody-induced activation of microglial cells and phagocytosis of pathological protein deposits; third, by noncomplement-mediated phagocytosis activation of microglial cells; fourth, by neutralization of toxic soluble oligomers; fifth, by a shift in equilibrium toward efflux of specific proteins from the brain, creating a peripheral sink by clearance of circulating Aβ cell-mediated immune responses; and finally, immunoglobulin M (IgM)-mediated hydrolysis. All these mechanisms may play roles depending on the specific immunotherapeutic scenario [Wisniewski and Konietzko, 2008] (Figure 2).

Both active immunization (vaccination) and passive immunization (monoclonal antibodies) are being studied. After promising preclinical results in animal studies, one of the first active vaccination trials was initiated using human Aβ1-42 (AN-1792) in conjunction with a T-helper adjuvant (QS-21). Unfortunately, in 2002, the phase II vaccination trial was discontinued because of the occurrence of meningoencephalitis (6%) [Gilman et al. 2005]. Additionally, only 19.7% of the AN-1792-treated patients developed the predetermined antibody response.

Double-blind assessment was maintained for 12 months, demonstrating no significant differences in cognition between antibody responders and the placebo group. In a small subset of patients, CSF tau levels were decreased in antibody responders but Aβ levels were unchanged [Gilman et al. 2005]. Long-term follow up of treated patients and further analysis of autopsy data modified and moderated the negative impact of the first results, encouraging additional clinical attempts. Subsequent observations of AN1792- vaccinated patients or transgenic models, and of brain tissue taken from mice and humans using a new tissue amyloid immunoreactive method suggested that antibodies against Aβ-related epitopes are capable of slowing down the progression of neuropathology in AD. In a recent 4-year study, Hock and Nitsch followed 30 patients who received a primary and booster immunization in the first year after vaccination, providing further support for continuation of the investigation of antibody treatment in AD [Hock and Nitsch, 2005].

The occurrence of encephalitis led to the development of new vaccines, which lack the amino acid parts thought to be responsible for the T-cell response mediated encephalitis, but retain the residues (4–10) required for antibodies to bind to Aβ. Most of these vaccines are now being tested in phase I and II trials: the CAD-106 trial led by Novartis/Cytos (Basel, Switzerland) and the V950 trial initiated by Merck (Whitehouse Station, NJ, USA) [Brody and Holtzman, 2008]. Additional antibodies under testing include ACC- 001 (Wyeth, New Jersey, USA, two phase II studies ongoing in the USA and Japan), MABT5102A (Genentech, San Francisco, California, USA, phase I completed), PF-04360365 (Pfizer, phase I completed), R1450 (Hoffman-LaRoche, Basel, Switzerland, phase I completed), GSK933776A (GlaxoSmithKline, London, UK, phase I completed) [ClinicalTrials. gov; Galimberti and Scarpini, 2011].

Given the adverse reactions of the active immunization and the variable antibody response to vaccines in older individuals, passive immunization directed against various domains of Aβ emerged as an alternative immunotherapeutic strategy. A point of concern in these therapies is the occurrence of cerebral microhemorrhages. The underlying mechanism is probably related to vascular amyloid deposits (congophilic amyloid angiopathy), present in nearly all patients with AD. The need for vascular repair and regeneration during Aβ immunotherapy is another argument for early treatment and subtle clearance over a long period of time [Wilcock et al. 2007].

More advanced is the Elan/Wyeth trial of AAB- 001 monoclonal antibody (bapineuzumab), which entered phase III testing in 2007. This approach involves passive immunization with an Aβ N-terminal directed, humanized monoclonal antibody. The murine version of this antibody binds to both soluble and aggregated Aβ. The multiple-dose phase II trial including 240 participants did not attain statistical significance on the primary efficacy endpoints in the whole study population. Some patients in the treatment group had a vasogenic edema, which is a serious side effect. However, in the subgroup of participants who did not have the apolipoprotein E (ApeE) ε4 allele, clinically significant benefits were recorded in several scales and magnetic resonance imaging showed smaller loss of brain volume. Looking at the best result of different groupings, it seemed that a small subset of patients, the ApoE noncarriers who received the second lowest of the four doses six times, responded really well in 78 weeks. Therefore the phase III study was initiated in ApoE4 noncarriers with mild to moderate AD [Wisniewski and Konietzko, 2008].

The next most advanced trial to our knowledge is the Eli Lilly and Co. (Indianapolis, IN, USA) phase II trial of LY2062430 (solanezumab), which involves passive vaccination with an Aβ central domain directed, humanized monoclonal antibody. Systemic administration of the closely related central domain mouse monoclonal antibody m266 rapidly improved behavioral performance and decreased plaque formation in preclinical studies. However, this antibody did not worsen intracerebral hemorrhage or vascular pathology in older APP transgenic mice. The phase II results have been reported and no safety concerns were raised; a phase III study is being conducted [Brody and Holtzman, 2008].

Finally, natural antiamyloid antibodies have been found in human intravenous immunoglobulins (IVIgs) obtained from the pooled plasma of healthy blood donors. In light of these observations, a phase I trial has been carried out in the USA. Eight patients with AD were treated with IVIg (Gammagard S/D immune globulin intravenous human) donated by Baxter Healthcare Corporation (Deerfield, IL, USA). Seven patients completed the study. After 6 months, cognitive function stopped declining in all seven patients and improved in six. In 2009, a phase III clinical trial involving more than 360 patients with AD was initiated and may provide conclusive evidence for the effect of IVIg as a treatment option for AD [Dodelet al. 2010].

Passive vaccination requires repeated infusions, which have a high cost. Therefore active vaccination is always taken into consideration.

Data from preclinical studies regarding mice suggest that novel immunotherapeutic strategies like DNA epitope vaccine [Qu et al. 2010], antibodies against the β-secretase cleavage site of the APP [Rakoveret al. 2007] and mucosal vaccination [Hara et al. 2011] could be used as safe and effective methods for AD therapy. DNA epitope vaccines have received substantial interest because of the ease of selectively designing them to elicit specific immune responses. Mucosal vaccination is an alternative way to achieve humoral response. Its mechanism is based on the presence of lymphocytes in the mucosa of the nasal cavity and gastrointestinal tract. It produces primarily secretory IgA antibodies, but when the antigen is coadministered with adjuvants such as cholera toxin subunit B and heat labile Escherichia colienterotoxin, substantial serum IgM titers can be achieved. It has a more limited humoral response with little or no cell-mediated immunity. The last developed mucosal immunotherapy for AD by nasal administration used a recombinant Sendai virus vector carrying Aβ1-43 and mouse interleukin- 10 cDNA. It induced good antibody responses to Aβ. When APP transgenic mice (Tg2576) received this vaccine once nasally, the Aβ plaque burden was significantly decreased 8 weeks later, without inducing inflammation in the brain. Tg2576 mice showed significant improvement in cognitive functions when examined 3 months after the vaccination [Hara et al. 2011].

Disease-modifying Treatments: Modulation of Tau Deposition

Drugs Interfering With Tau Deposition Multiple compounds have been identified through cell culture or in vitro screens as tau aggregation inhibitors ( Table 2 ). A phenothiazine, methylene blue (MB) or methylthioninium chloride, has previously been used in humans and is currently being evaluated in AD trials. The problem with this drug is that urine is colored blue, resulting in a lack of blinding. However, promising results have emerged from a phase II clinical trial testing MB as a potential therapy for AD, as improvements in cognitive function of patients with AD after 6 months of MB administration have been reported [Gura, 2008].

Drugs Interfering With Tau Phosphorylation. The intriguing link between phosphorylation and tau pathology has provided the boost to examine the role of kinase inhibitors as potential therapeutics targeting tau. Kinases induce the hyperphosphorylation of tau [Yiannopoulou et al. 2009]. Despite the large number of tau phosphorylation sites and the ability of multiple kinases to phosporylate individual sites, glycogen synthase kinase 3 (GSK3β) has emerged as a potential therapeutic target. The most studied compound able to inhibit GSK3 is lithium, but several other compounds are under development, including pyrazolopyrazines, pyrazolopyridines, the aminothiazole AR-A014418, and sodium valproate [Martinez and Perez, 2008]. In recent studies, the effect of short-term treatment on cognitive and biological outcomes in people with amnestic MCI was shown and supports the notion that lithium has disease-modifying elements with potential clinical implications in the prevention of AD [Forlenza et al.2011].

Immunotherapy. Vaccination approaches targeting tau have been considered, but the development of a successful therapy is complicated because tau protein is intracellular [Galimberti and Scarpini, 2011].

Disease-modifying Treatments: Modulation of Inflammation and Oxidative Damage

Anti-inflammatory Drugs Epidemiological evidence suggests that long-term use of NSAIDs protects against the development of AD. Despite this premise, prospective studies showed lack of efficacy [Aisenet al. 2002, 2003] or treatmentlimiting gastrointestinal toxicity [Rogers et al. 1993].

Molecules Addressing Oxidative Damage. Potential antioxidants include mitoquinone, vitamin E, Ginkgo biloba, natural polyphenols such as green tea, wine, blueberries and curcumin, ω3 fatty acids, folate, vitamin B6 and vitamin B12 supplementation. A trial to determine whether the reduction of homocysteine levels with highdose folate, vitamin B6 and vitamin B12 supplementation can slow the rate of cognitive decline in subjects with AD had no beneficial effect on the primary cognitive measure, the rate of change in ADAS-cog score over 18 months, or on any secondary measures, although the vitamin supplement regimen was effective in reducing homocysteine levels [Aisen et al. 2006]. Clinical trials with vitamin E and ω3 fatty acids did not show beneficial effects in patients with AD [Barten and Albright, 2008].

More recent data have revealed that tumor necrosis factor (TNF), one of the few gliotransmitters, has strikingly acute effects on synaptic physiology. These complex influences on neural health suggest that manipulation of this cytokine might have important impacts on diseases characterized by glial activation, cytokine-mediated neuroinflammation and synaptic dysfunction. Toward such manipulation in AD, a 6-month study was conducted with 15 patients with probable AD who were treated weekly with perispinal injection of etanercept, an FDA-approved TNF inhibitor that is now widely used for the treatment of rheumatoid arthritis and other systemic diseases associated with inflammation. The results demonstrated that perispinal administration of etanercept could provide sustained improvement in cognitive function for patients with AD. Additionally, the authors were impressed by the striking rapidity with which these improvements occurred in the study patients. Nevertheless, etanercept merits further study in RCTs [Griffin, 2008].

Disease-modifying Treatments: Additional Approaches

Modulation ofCcholesterol and Vascular-related Risk Factors. A link between hypercholesterolemia, cardiovascular diseases and AD has also been suggested. Additional vascular-related risk factors for AD include hypertension, atrial fibrillation, hyperhomocysteinemia, atherosclerosis and stroke [Hooijmans and Kiliaan, 2008]. Epidemiological studies have indicated that patients treated for cardiovascular disease with cholesterol-lowering therapy (statins) showed a decreased prevalence of AD [Jick et al. 2000]. The Lipitor's Effect in Alzheimer's Dementia (LEADe) study tested the hypothesis that a statin (atorvastatin 80mg daily) is beneficial to patients with mild to moderate AD receiving background therapy of donepezil 10mg daily. Despite a promising premise, there were no significant differences in the coprimary or secondary endpoints, although atorvastatin was generally well tolerated [Feldman et al. 2010].

Simvastatin metabolites are high-affinity 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, reducing the quantity of mevalonic acid, a precursor of cholesterol. Cholesterol Lowering Agent (simvastatin) to Slow Progression (CLASP) of Alzheimer's Disease Study is an ongoing randomized, double-blind, placebo-controlled, parallel-assignment phase III trial that investigates the safety and effectiveness of simvastatin in slowing down the progression of AD. It has not yet published its results [McGuinness et al. 2010]. However, a randomized, doubleblind, placebo-controlled recent trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol [Sano et al. 2011].

Final Remarks

Currently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease. However, these therapies demonstrate modest, but particularly consistent, benefit for cognition, global status and functional ability [Herrmann et al. 2011].

The search for disease-modifying interventions has focused largely on compounds targeting the Aβ pathway. To date, many treatments targeting this pathway, such as tarenflurbil, tramiprosate and semagacestat, have been unsuccessful in demonstrating efficacy in the final clinical stages of testing [Gauthier et al. 2009; Imbimbo and Giardina, 2011].

However, colostrinin, scyllo-inositol, PBT2, avagacestat, etazolate and active and passive immunization methods, treatments also targeting the Aβ pathway, are being tested in advanced clinical trials.

At the same time, other possible neuronal mechanisms that seem to play important roles in the pathophysiology of this multifactorial disorder, such as tau deposition and hyperphosphorylation, neuroinflammation and oxidative stress, are being researched as promising therapeutic targets. Clinical trials with drugs interfering with tau deposition or phosphorylation (lithium) are ongoing [Martinez and Perez, 2008]. Clinical trials of potential antioxidants such as vitamin E and ω3 fatty acids did not show beneficial effects in patients with AD [Barten and Albright, 2008].

Etanercept, a TNF inhibitor that is now widely used for the treatment of systemic diseases associated with inflammation, provided sustained improvement in cognitive function in patients with mild to severe AD after perispinal administration in a 6-month, open-label pilot study. However, etanercept merits further study in RCTs [Griffin, 2008].

Modulation of cholesterol and vascular-related risk factors is an additional possible disease-modifying approach. CLASP is an ongoing phase III trial investigating the effectiveness of simvastatin in slowing down the progression of AD [McGuinness et al. 2010].

The development of disease-modifying drugs for AD is recognized as a worldwide necessity. These must presumably be drugs that will modify, either by stabilizing or slowing, the molecular pathological steps leading to neurodegeneration and finally dementia.

The required design of clinical trials to test this concept raises many questions regarding the study populations, the duration of trials, the necessary primary and secondary endpoints, including biomarkers [Vellas et al. 2007]. It has been recognized that, to modify AD, which has recently been redefined to have presymptomatic and symptomatic phases, one must attempt to treat patients when neuronal dysfunction is far from full blown and largely irreversible [Dubois et al. 2010; Sperling et al. 2011].

The following considerations have emerged that should be taken into account when planning future clinical trials:

1. The mechanisms underlying the pathogenesis of AD need to be thoroughly investigated before focusing on the development of novel disease-modifying compounds. Despite promising premises related to different pathogenic mechanisms, large phase III trials with potentially disease-modifying properties have failed to demonstrate any effect on cognition. It is of crucial importance to better understand the relationship between tau, Aβ and other factors to develop successful disease-modifying drugs [Galimberti and Scarpini, 2011].
2. Treatments of AD appear effective only in certain phases of the disease. A few disease- modifying compounds have shown some benefits in mild but not moderate AD or even in MCI. Therapeutic trials should therefore be carried out as early as possible during the course of the disease, which requires the identification of more accurate tools for early diagnosis. New criteria for the diagnosis of AD have enlarged the window for the detection of the early stages of the disease and include biomarkers mechanistically related to AD pathology. Adoption of these early biomarkers in implementing design of future studies is highly desirable [Galimberti and Scarpini, 2011; Salomone et al. 2011].
3. AD is heterogeneous in clinical presentation, underlying neuropathology and mixed causes (especially in late-onset AD). This fact is one more reason to improve our tools for detecting patients with amnestic MCI at high risk of converting to AD before the different full-blown clinical features of the disease appear. A major challenge will also be to identify subgroups with homogeneous biomarkers. At present, the focus in AD drug development is shifting from treatment to prevention [Salomone et al. 2011; Vellas et al. 2011].
4. Indicators useful as surrogate outcome measures (surrogate biomarkers like magnetic resonance imaging, CSF tau and Aβ, and amyloid positron emission tomography) should be identified to have substitutes for clinical endpoints (i.e. neuropsychological testing), tools able to predict clinical benefit or the opposite, and to demonstrate whether the drug has disease- modifying properties [Galimberti and Scarpini, 2011].
5. Prolonged development times delay effective therapies from reaching patients in need. Several strategies are promising for answering the crucial question of, 'How much information is sufficient to proceed to phase III without excessive risk for failure?' Phase II proof of concept (POC) (IIa) and dose-finding (IIb) studies represent major challenges in drug development. Biomarkers, population enrichment with risk factors, clinical measures with greater sensitivity than standard trial instruments and adaptive dose–response designs might represent other strategies applicable to POC studies. All of these strategies are being considered as means of shortening phase IIb studies and creating a seamless interface with phase III. None of these strategies have been validated in a successful drug development program [Cummings, 2008b].

In conclusion, the new strategies seem to focus on examining the potential neuroprotective activity of disease-modifying drugs in the presymptomatic stages of AD, with the help of biomarkers that predict disease progression before development of overt dementia.

 

 

Neurostimulation Has Benefits in Early Parkinson's Disease

Megan Brooks

Feb 15, 2013

 

 Subthalamic nucleus deep brain stimulation (DBS) offers benefits earlier in the course of Parkinson's disease (PD), before the appearance of severe disabling motor complications, according to results of a randomized controlled trial.

In a group of patients with relatively mild early motor complications of PD, subthalamic stimulation plus medical therapy was superior to medical therapy alone on several key measures of quality of life and motor function.

Results of the Controlled Trial of Deep Brain Stimulation in Early Patients with Parkinson's Disease (EARLYSTIM) were published February 14 in the New England Journal of Medicine.

"The result of our study is that a new group of patients can do better with neurostimulation than with medication," study investigator Gunther Deuschl, MD, from Christian Albrechts University in Kiel, Germany, told Medscape Medical News.

A Second Honeymoon?

Levodopa remains the most effective current treatment for parkinsonian motor symptoms. But after an initial "honeymoon" period, which may last several years, the beneficial effects are hampered by levodopa-induced motor complications, which progressively compromise quality of life, the researchers note. For patients with advanced PD with medically intractable motor fluctuations and dyskinesia, neurostimulation of the subthalamic nucleus effectively reduces motor disability and improves quality of life and has become an established treatment option.

The EARLYSTIM study suggests that neurostimulation "may be a therapeutic option for patients at an earlier stage than current recommendations suggest," Dr. Deuschl and colleagues say.

In this 2-year trial, 251 patients with PD and early motor complications were randomly assigned to subthalamic nucleus stimulation plus medical therapy or medical therapy alone. The patients had a mean age of 52 years and had had PD for a mean of 7.5 years.

The intention-to-treat population included 124 patients assigned to neurostimulation (120 of whom underwent implantation and completed the study) and 128 assigned to medical therapy alone (125 underwent medical therapy and 123 completed the study).

In the intention-to-treat population, the primary outcome — Parkinson's Disease Questionnaire (PDQ-39) summary index score — was improved from baseline to 24 months by 7.8 points (26%) in the neurostimulation group but worsened by 0.2 point (1%) in the medical therapy group.

In this population, the between-group difference in the mean change from baseline was 8.0% (95% confidence interval, 4.2% - 11.9%; P = .002), which was similar to the between-group differences in the per-protocol population.

Neurostimulation was also superior to medical therapy with respect to the major secondary outcomes, with significant mean differences achieved in parkinsonian motor disability, activities of daily living, levodopa-induced motor complications (all P < .001), and time with good mobility and no dyskinesia (P = .01).

An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of patients in the neurostimulation group and 94.5% in the medical therapy group.

It appears from this study, therefore, that neurostimulation in combination with medical therapy can "improve motor symptoms better than medical therapy alone at this earlier stage," the authors say.

Monitor for Suicide

Serious adverse events occurred in 54.8% of patients in the neurostimulation group and in 44.1% of those in the medical therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. A total of 26 serious adverse events were related directly to surgery or the implanted devices; 25 of them resolved completely, and 1 left a cutaneous scar.

The authors say serious adverse events in the medical therapy group were more often related to problems of mobility and adverse effects of medications, including hallucinations and behavioral problems, whereas major depression occurred more often among patients with neurostimulation, despite an overall improvement in mood at the end of the trial.

There were 3 suicides in study patients (2 in the neurostimulation group and 1 in the medical therapy group), as well as 4 suicide attempts (2 in the neurostimulation group and 2 in the medical therapy group). The frequency of suicidal behavior, including suicide, was high but did not differ between treatment groups, the authors note.

The study "did not suggest that neurostimulation is associated with a higher risk of suicide than medical therapy," they write. The authors hypothesize that the decision to eventually undergo neurostimulation may select a specific subgroup of patients with a higher risk for suicidal behavior than the general population. During the study, they established monitoring procedures for suicide, which they say may be useful in the future.

In a linked editorial, Caroline M. Tanner, MD, PhD, from the Parkinson's Institute, Sunnyvale, California, and Stanford University School of Medicine, Palo Alto, California, points out that suicide has "previously been associated with stimulation of the subthalamic nucleus but less so with other surgical targets."

Dr. Tanner says the EARLYSTIM study is one of the "most rigorously" conducted trials of neurostimulation, but she cautioned that patients in the trial do not match most patients with PD. All were 60 years of age or younger at the time of surgery, were in good general health, and had a good response to a levodopa challenge.

"Very few" patients with PD meet these criteria, she points out. Only 11% of cases of PD are diagnosed before age 60, and on average 30% of patients have dementia. "Whether these results would be obtained in older patients with PD or in less-experienced medical centers is not known," she writes.

Potential Candidates

Dr. Tanner also notes that little is known about the long-term efficacy of neurostimulation. But she notes that a study published in Archives of Neurology in 2011 and reported by Medscape Medical Newsshowed that motor improvement is sustained for as long as 10 years in a small number of selected patients. "This would argue in favor of using neurostimulation in carefully chosen, young patients with a recent onset of motor fluctuations," Dr. Tanner says.

Dr. Deuschl told Medscape Medical News that potential candidates for earlier neurostimulation include patients beyond the first years when medications do very well and the patients are close to normal (honeymoon period). "They are in a disease stage which we call 'intermediate period' (followed many years later or decades later by the 'late period')," he explained.

The mobility of these patients has been fluctuating for about 1.5 years on average and dyskinesias are developing over that time, although they are still able to participate in activities related to work, family, and sports, he said. "These patients have on average a disease duration of 7.5 years and do better with DBS. I think age should also play a role and younger patients have most likely a lower risk to have complications due to the surgery," Dr. Deuschl said.

The study was funded by the German Ministry of Research, the French Programme Hospitalier de Recherche Clinique National, and by Medtronic. Dr. Deuschl and several coauthors have disclosed financial relationships with Medtronic and other pharmaceutical companies. A complete list for study authors and Dr. Tanner can be found at www.NEJM.org.

N Engl J Med. 2013;368:610-622, 675-676. Abstract Editorial

Short Course of Aspirin, Clopidogrel Cuts Stroke Risk

Pauline Anderson

Feb 11, 2013

 .

Results of the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial were presented here at the International Stroke Conference (ISC) 2013.

The CHANCE trial, carried out exclusively in China, is a few steps ahead of a similar trial, the Platelet Oriented Inhibition in New TIA and stroke (POINT) trial, now enrolling mostly in the United States.

Although CHANCE was a "well done" trial and its results showed "a larger treatment effect," it's important to note that healthcare in China is different from that in the United States, said CHANCE co–principal investigator, S. Claiborne Johnston, MD, PhD, professor, neurology, and director, Stroke Service, University of California, San Francisco.

"Secondary prevention practices are not as robust there as they are in Europe and in North America, and that could have impacted the trial," he told Medscape Medical News. "Also, usually genetic differences don't matter, but in this case, they might because there are differences in polymorphisms that affect clopidogrel metabolism in Asian populations.

For these reasons, although American neurologists might see the CHANCE trial as a signal to go ahead and use combined therapy, "I think it's wise for us to wait for a confirmatory trial outside of China, said Dr. Johnston, who is also co–principal investigator of the POINT trial.

CHANCE co–principal investigator was Yongjun Wang, MD, professor of neurology and vice-president of Beijing TianTan Hospital, Capital Medical University, who presented the full results here.

High Risk for Hemorrhage

The study enrolled 5170 patients at least 40 years of age who had sustained a TIA or minor stroke. Within 24 hours of their symptom onset, they were randomly assigned to 1 of 2 groups: aspirin (1 day loading dose of 75 to 300 mg, followed by 75 mg/day) plus placebo, or the same aspirin regimen plus clopidogrel (loading dose of 300 mg followed by 75 mg/day).

Patients in the combination group were taken off aspirin at 21 days because of the concern that Chinese patients, as with other Asian populations, are at relatively high risk for hemorrhage. "Frankly, that belief comes from epidemiological studies, but the epidemiology may just reflect underlying risk factors and not a true propensity for it," said Dr. Johnston. He pointed out that the studies testing this have not been in the acute period.

The study showed that stroke occurred less frequently in those receiving both aspirin and clopidogrel. At 90 days, the hazard ratio (HR) for survival free of stroke — either ischemic or hemorrhagic — in the combination group was 0.68 (95% confidence interval [CI], 0.57 - 0.81; P < .001).

For the secondary outcome of combined events (stroke, myocardial infarction, vascular death), the HR was 0.69 (95% CI, 0.58 - 0.82; P < .001). The risk for hemorrhagic stroke was the same in the 2 groups (0.3%).

Notably, severe bleeding events occurred at a similar rate in the 2 groups (0.2% in each). Although mild bleeding occurred more often in the combination group (1.2% versus 0.7%), Dr. Johnston noted that these events included nose bleeds. "We did not see a signal that the combination was unsafe."

Both aspirin and clopidogrel affect platelets, but through different pathways. "Together, the 2 are much more powerful than either one alone," said Dr. Johnston.

CHANCE was the first trial to focus on the acute period in TIA and minor stroke, which Dr. Johnston emphasized is not being seen nearly enough in the emergency department. "People with TIA and minor stroke are not coming in acutely or they're calling the office and being seen in clinic," he said. "We need to remind people that this really is an emergency and it should be treated right away."

Asked whether the combination therapy would be an acceptable approach for more severe strokes, Dr. Johnston said it's impossible to know "where to draw the line." The researchers will do more subgroup analyses looking at stroke severity, but Dr. Johnston pointed out that "there was no difference between the TIA and stroke in terms of rates of hemorrhagic stroke or in the efficacy of the combination."

Compared with elsewhere in the world, the risk for stroke is very high in China. "There are a whole lot more strokes in China than there are in the US and even if you add Europe, you still have more strokes in China," said Dr. Johnston.

Healthcare Differences

Because the trial was so large and because standards for clinical research have improved dramatically in China, the CHANCE results are "incredibly important" and should have a major effect on public health around the world, said Dr. Johnston. However, there are important differences between healthcare in China and that in the United States.

For example, Dr. Johnston noted that about two thirds of the Chinese patients in the study had hypertension and less than half were receiving any drug for hypertension during follow-up. Undertreatment, he said, could "certainly" affect the absolute effect size that's seen in the trial.

It's probably wise to await what happens with the POINT trial before changing treatment approaches here in North America, said Dr. Johnston, who is that study's principal investigator. Interim POINT results will be available in May, he said. "That will provide an opportunity to say it's very important to continue POINT or it's not important to continue POINT."

The POINT trial, which is about a third of the way through recruitment, differs slightly from CHANCE, said Dr. Johnston. For example, it includes a higher loading dose of clopidogrel and requires enrollment within 12 hours instead of 24 hours. As well, patients in the combination group continue with aspirin for 90 days instead of stopping at 21 days as in the CHANCE study.

Dr. Johnston pointed out a graph showing times for survival free of stroke for the treatment groups. "Most of the separation in the 2 curves occurs just in the first couple of days, so certainly by 21 days, the curves are almost parallel."

POINT includes mainly centers in the United States, although some sites have been added internationally.

The idea of comparing aspirin plus clopidogrel in a North American trial dates back more than a decade, but the researchers ran into funding difficulties when the drug manufacturer pulled its backing. This, said Dr. Johnston, substantially delayed the start of the trial.

When asked about next steps for CHANCE, Dr. Johnston said the Chinese researchers will look at ancillary studies of biomarkers and subtyping based on vascular imaging. As well, they plan to provide outcomes at 1 year that will include results related to cognition.

Helpful Information

Invited to comment on the CHANCE trial results, Larry B. Goldstein, MD, professor, medicine, Division of Neurology, and director, Duke Stroke Center, Duke University, Durham, North Carolina, and a POINT investigator, said the information is "quite helpful" and could eventually alter the current treatment practice, which is to being aspirin alone. "This would suggest that aspirin with clopidogrel over a relatively short course may have some benefit."

He added that the "key" is the short course of the combination aspirin plus clopidogrel treatment. He pointed out that other trials, including SPS3 and MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients), found that long-term combinations are associated with an increased risk for major bleeding complications.

The lack of increased risk of bleeding, at least in the short term, "is quite encouraging," said Dr. Goldstein. He added that bleeding complications are more of a concern in Asia than in the United States, which has a much more ethnically diverse population and where the proportion of Asians is relatively low."Over the longer term, the addition of a more potent antiplatelet drug, or combinations in general, seem to carry a much higher risk of bleeding that attenuates any benefit they have in reducing ischemic stroke risk," said Dr. Goldstein. "In our current guidelines, there is actually a contraindication for the combination for long-term secondary stroke prevention."

Dr. Johnston has conflicts of interest. Other than being a POINT investigator, Dr. Goldstein has disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2013. Abstract LB11. Presented February 8, 2013.

 

Clinical Features of Dopamine Agonist Withdrawal Syndrome in a Movement Disorders Clinic

Margarita Pondal, Connie Marras, Janis Miyasaki, Elena Moro, Melissa J Armstrong, Antonio P Strafella, Binit B Shah, Susan Fox, L K Prashanth, Nicolas Phielipp, Anthony E Lang

Disclosures

J Neurol Neurosurg Psychiatry. 2013;84(2):130-135. 

 Abstract and Introduction

 Abstract and Introduction

Abstract

Background Recently, symptoms similar to addictive drug withdrawal have been reported in a structured longitudinal study of patients with idiopathic Parkinson's Disease (PD) withdrawing from dopamine agonists (DA): the dopamine agonist withdrawal syndrome (DAWS).

Objectives The objective of this study was to establish the frequency, predictors, and outcomes of DAWS in a movement disorders clinic.

Methods We conducted a retrospective chart review of a sample of patients with a clinical diagnosis of PD treated with DA in whom withdrawal or attempted withdrawal of DA was carried out because of adverse effects, or for any other reason. Out of 487 PD patient charts reviewed, 84 were withdrawn from the agonists and were evaluable.

Results Thirteen patients (15.5%) met criteria for DAWS (DAWS+) and 71 did not (DAWS−). DAWS developed upon withdrawal from pergolide, pramipexole and ropinirole, and did not respond to levodopa. DAWS outcomes included recovery in less than 6 months in 61%, in more than a year in 23%, and an inability to discontinue DA in 15% of patients. Development of impulse control disorders was the reason for DA withdrawal in all DAWS+, but only in 41% of DAWS− patients (p<0 .0001="" and="" daws="" did="" differ="" in="" not="" other="" p="" patients="" variables.="">

Conclusion DAWS is a disabling complication of DA use. Critical features of the syndrome are the strong link with impulse control disorders, possibly the independence of DA dosage and type, and the resistance to treatment, including levodopa. Further studies are required to characterise those at risk as well as to define an effective treatment.

Introduction

Dopamine is a critical neurotransmitter in mesocorticolimbic circuits involved in reward.^[1–3] Drugs that stimulate this circuit, such as amphetamines and cocaine, are a major societal cause of addiction.^[4–6]Dopamine replacement therapies (DRT) replenish the nigrostriatal pathway to control the motor symptoms of Parkinson's disease (PD), but also stimulate mesocorticolimbic circuits that are relatively intact,^[2–5] resulting in several addiction-related syndromes.^[4,7]

Among substance addiction syndromes reported in patients with PD on DRT, the dopamine dysregulation syndrome (DDS) is characterised by compulsive drug consumption accompanied by psychomotor agitation and euphoria, drug-related dyskinesias, resistance to dose reduction and withdrawal symptoms characterised by depression, anxiety and impairment in occupational and social functioning.^[3,8,9]

Impulse control disorders (ICD), commonly involving pathological gambling, hypersexuality, compulsive buying and compulsive eating, constitute a second type of DRT-related disinhibitory psychopathology considered a behavioural addition.^[4,10] ICD appear much more commonly in patients treated with dopamine agonists (DA), in whom they are reported in 14–17% of cases, while in patients with levodopa treatment the frequency ranges from 0.7% to 7%.^[4,6,10]

The clinical manifestations of dopamine agonist withdrawal syndrome (DAWS) resemble other psychostimulant withdrawal syndromes and the observed lack of response to levodopa, antidepressants and anxiolytics and the improvement with DA replacement are consistent with a drug-specific withdrawal syndrome.^[7] Rabinak and Nirenberg^[7] postulated that the patients with DAWS belong to a 'mesocorticolimbic variant' of PD, with disproportionate mesocorticolimbic versus nigrostriatal dopaminergic dysfunction, increased vulnerability to DAWS and ICD.

Most patients with ICD do not use DRT in a compulsive manner.^[11–14] On the other hand, the dose escalation in DDS patients can be accompanied by the development of ICD.^[4] Okai et al ^[15] reviewed the problems of diagnosing and assessing the severity of ICD and proposed an extension to the criteria for DDS diagnosis.

We aimed to determine the frequency of DAWS, the determinants for developing this syndrome, and the outcome of DAWS in a population of PD patients followed in a movement disorders clinic.The apathy that develops in PD patients following subthalamic nucleus stimulation has been linked to the drastic reduction in medication after surgery, and can be considered a DRT-related withdrawal syndrome.^[16] In contrast to this restricted postsurgical withdrawal syndrome, in a cohort of PD patients enrolled in a structured longitudinal study, Rabinak and Nirenberg^[7] reported symptoms similar to addictive drug withdrawal developing on withdrawal or attempted withdrawal of DA. They defined the DAWS as a severe stereotyped cluster of physical and psychological symptoms that correlate with DA withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other PD medications, and cannot be attributed to other clinical factors.^[7]DAWS comprises psychiatric symptoms such as anxiety, panic attacks, depression, agitation, irritability, dysphoria, insomnia, fatigue, generalised pain, and drug cravings and autonomic signs and symptoms such as orthostatic hypotension, dizziness, nausea and diaphoresis.^[7]

Methods

We carried out a retrospective chart review of PD patients attending a large movement disorders clinic at the Toronto Western Hospital. The study project was approved by the Research Ethics Board of University Health Network, Toronto, Ontario, Canada.

Patient selection was carried out searching our database for a diagnosis of PD among patients with ongoing follow-up. All the information present in the chart was evaluated by a neurologist assessor. If clarification was required, and in all patients in whom DAWS was suspected, the case was discussed in detail with the attending neurologist. The inclusion criteria were a clinical diagnosis of PD using UK Parkinson's Disease Society brain bank criteria^[17] with a history of DA treatment for more than 3 months, in whom withdrawal of a DA had been carried out. Exclusion criteria were dementia as a clinical diagnosis stated in the chart, a history of functional neurosurgery for treatment of PD temporally close to withdrawal and insufficient information on DA treatment or withdrawal.

All data collection was completed before rendering a diagnosis of DAWS, which was retrospectively applied, upon reviewing the clinical information and the opinion of the patient's neurologist, using the criteria proposed by Rabinak and Nirenberg:^[7] a severe stereotyped cluster of physical and psychological symptoms that correlated with DA withdrawal in a dose-dependent manner, caused clinically significant distress or social/occupational dysfunction, were refractory to levodopa and other PD medications (apart from DA), and could not be attributed to other clinical factors. Psychiatric symptoms included anxiety, panic attacks, depression, agitation, irritability, dysphoria, insomnia, fatigue, generalised pain, and drug cravings and autonomic signs and symptoms included orthostatic hypotension, dizziness, nausea and diaphoresis.^[7] The symptoms did not improve with levodopa, even in the 'on' state, but did improve with DA repletion. Finally, the symptoms could not be explained by other clinical factors.^[7]

According to the chart description of functional impairment by the patients themselves, their family and caregivers, and patients' follow-up, the severity of DAWS was classified by the assessor as either mild–moderate if impairment was limited to demanding activities or if it had some impact on the patient's and family daily life, or severe if there was considerable disruption of the patient's and family daily life or inability to perform basic activities of daily life. The duration of DAWS symptoms was classified as remitting and lasting less than 6 months, 6 months to 1 year, or over a year, or not remitting and unable to withdraw from DA.

In addition to the gender and marital status, the following clinical variables were recorded: age at DA withdrawal, age at PD onset, PD duration at withdrawal time, history of smoking, and smoking at DA withdrawal time, ICD before PD, illicit drug use before PD. On the state unified Parkinson's disease rating scale (UPDRS) motor subscale scores were recorded during routine visits at DA withdrawal time. The levodopa equivalent daily dose (LEDD) was calculated as: regular levodopa plus 0.75 times the dose of continuous release levodopa plus 1.3 times the dose of levodopa/entacapone plus 100 times the dose of pramipexole dihydrocloride or pergolide mesylate plus 20 times the dose of ropinirole hydrochloride.^[7,18] Treatment variables recorded were: reason for DA withdrawal, specific DA withdrawn, dosage of levodopa (LD-LEDD), dosage of DA (DA-LEDD), total LEDD (DA-LEDD plus LD-LEDD) at withdrawal, cumulative dose exposure for DA (maintenance DA-LEDD times years of treatment), levodopa treatment duration and DA treatment duration in years.

Categorical variables were compared using the χ² test if the number expected in each cell was five or greater, and utilising Fisher's exact test otherwise. Continuous variables with a normal distribution as determined by the Kolmogorov–Smirnov test were compared by Student's t test, and otherwise by the non-parametric Mann–Whitney U test. No correction for multiple comparisons was applied. Statistical analysis was carried out using SPSS V.13.0 for Windows statistical software. Significance was set at p<0 .05.="" span="">The ICD diagnosis was clinical, rendered by the patient's neurologist, and registered in the chart when appropriate symptoms were reported by patients, their families and caregivers. In patients with ICD as the cause of withdrawal, the speed of DA withdrawal (DA-LEDD decrease per week), previous ICD with other DA, type of ICD, and duration of ICD before withdrawal were recorded. Patients with a diagnosis of DAWS (DAWS+) were compared with patients without (DAWS−); this was done for all patients, and a second comparison was restricted to patients withdrawn from DA due to ICD.

Results

Four hundred and eighty-seven active charts were reviewed; 297 patients (61%) had been treated with a DA, and in 98 (33%) of these DA were discontinued. Fourteen of these 98 patients were excluded from analysis, 10 because of insufficient data on treatment or withdrawal follow-up, two because they underwent PD surgery close to the time of DA withdrawal, and two because they had dementia at the time of DA withdrawal (figure 1).

(Enlarge Image)

Figure 1.

Patient flow chart. DA, dopamine agonist.

Five patients had a remote history of functional PD surgery before withdrawal; none of them was withdrawn from DA because of ICD. ICD were the most common reason for DA withdrawal, representing 50% of the withdrawals (n=42). Other causes were hypersomnia (thirteen), hallucinations (seven), worsening PD symptoms (five), nausea (five), cognitive impairment (five), hypotension (four), limb oedema (two) and isolated anxiety (one).

Out of 84 patients analysed, 13 (15.5%) fulfilled the diagnostic criteria for DAWS, and 71 patients did not develop DAWS on withdrawal from DA (figure 1).

ICD were the reason for DA withdrawal in all 13 DAWS+ patients (100%), compared to an ICD frequency of 41% in DAWS− patients (29 of 71), (p<0 .0001="" p="">

Each patient with DAWS had at least four (mean 4.9, median 5) of the 13 clinical manifestations suggestive of DAWS observed. These symptoms represented a change from their previous functioning level and were related in time to DA discontinuation. The most common of these were depressed mood in eleven patients (84%), fatigue in ten (77%), anxiety in nine (69%) and insomnia in eight (61%). Autonomic dysfunction was recorded in six patients (46%) including diaphoresis, dizziness, nausea and flushed face; four patients (31%) had panic attacks, four (31%) generalised pain, three (23%) irritability, three (23%) drug cravings and one loss of interest (8%). One patient voiced suicidal thoughts during the withdrawal period.

None of the clinical or treatment variables evaluated (see Methods section) significantly differed between DAWS+ and DAWS− patients ( Table 1 ).

DAWS was observed in subjects withdrawn from pergolide (one), pramipexole (five) and ropinirole (seven); there was no statistically significant difference in the frequency of DAWS between the specific DA. In the group of patients withdrawn from DA because of ICD there was a trend towards a more frequent use of ropinirole than other DA (Fisher's exact test 0.043).

The levodopa dose was increased in all patients at the time of withdrawal. Three of the DAWS+ patients increased levodopa dosages by 15–20% above the dose recommended by their physician in an attempt to treat DAWS symptoms after DA withdrawal: one of them had a history of DDS years before DA withdrawal and another developed DDS approximately 1 year after recovering from DAWS. Among the DAWS− patients who were withdrawn from DA because of ICD, just one had a history of DDS. DAWS symptoms were not abated in any patient by increasing the dose of levodopa. The degree of functional impairment was classified as mild–moderate in seven patients and severe in six ( Table 2 ).

Forty-two patients underwent DA withdrawal because of ICD, 13 DAWS+ and 29 DAWS−. Table 3 shows the frequencies of ICD in DAWS+ and DAWS− patients. There were no statistical differences in the type of ICD between the DAWS+ and DAWS− groups ( Table 3 ).There was no evident relationship between either the degree of functional impairment or the evolution of DAWS and the LD-LEDD, DA-LEDD, cumulative DA-LEDD or total LEDD at withdrawal. Regarding the evolution of DAWS, eight patients recovered in less than 6 months, no patient had a resolution of symptoms between 6 months and 12 months, recovery took over a year in three patients, and two patients were unable to remain off of DA due to disabling symptoms of DAWS. These patients had persistent, chronic ICD associated with an inability to wean the DA ( Table 2 ).

Among the multiple demographic, clinical and treatment variables compared, the only differences within the group of patients withdrawn from DA because of ICD were that DAWS+ patients were taking higher doses of levodopa (expressed in LEDD) at the time of DA withdrawal (p<0 .02="" a="" and="" frequent="" had="" history="" href="" more="" nbsp="" p="" smoking="" style="color: #5757a6; text-decoration: initial;">Table 4

 ).

Discussion

Our retrospective chart review in a clinic practice setting confirms the concept of DAWS as identified by Rabinak and Nirenberg.^[7] Using the same diagnostic criteria, we found a very similar frequency of the syndrome among those patients in whom DA were withdrawn, 15.5% in our series versus 19% in theirs. A frequency of 7.8% of patients withdrawn from DA was reported in the only other study that we are aware of that examined DAWS.^[19] Unlike our study and that of Rabinak and Nirenberg,^[7] that series included subjects who had undergone deep brain stimulation (DBS) surgery while DA were discontinued, and thus some confusion with the postsurgical apathy-related features (see below) may have been possible.

Similarities in the results of our study and that of Rabinak and Nirenberg^[7] include the frequency of ICD as the cause of withdrawal from DA (50% vs 58%), the proportion of subjects who developed DAWS when ICD were the reason for DA withdrawal (approximately one third in both series), and the 100% association between DAWS and ICD, contrasting with the 34% reported by Limotai et al. ^[19]Previous ICD were significantly more common in DAWS+ than in DAWS− cases (p<0 .0001="" all="" at="" compared="" effect="" either="" magnitude="" marginal="" most="" of="" or="" other="" p="" significance.="" studied="" the="" this="" to="" variables="" were="" without="">

In our study the patients who attempted to improve their withdrawal symptoms by increasing their levodopa dose by 15–20% more than prescribed by their physician did not have other clinical manifestations suggestive of DDS at this time. DAWS symptoms did not disappear with equivalent or higher doses of dopaminergic medications other than DA, as previously reported.^[7] We cannot exclude the possibility that there may be a milder group of 'treatable DAWS' patients who had subtle DAWS symptoms and who responded to levodopa adjustment. Mild self-limited withdrawal symptoms not meeting the DAWS criteria of Rabinak and Nirenberg^[7] that we used in our study were included in a recent report of patients tapering DA.^[20] These patients would have been diagnosed as DAWS− in our study and it is not at all clear that the reported milder symptoms of low mood or apathy have the same pathogenic basis as the more complex psychostimulant drug withdrawal-like symptoms of DAWS. Self-medication with supratherapeutic doses of levodopa in an attempt to alleviate DAWS symptoms^[7] and the significant association reported in one series between DAWS and DDS^[19] suggest an overlapping vulnerability to DDS in the DAWS+ patients. This tendency of DAWS+ patients to escalate levodopa dosage is also consistent with 'negative reinforcement' models of addiction.^[2] Okai et al ^[15] considered that patients with DDS and even non-DDS patients often take extra medication to avoid the distress and dysphoria that appears during the off state, and propose that this pattern is similar to that of DAWS. In our opinion the two entities differ in that DAWS is related to a drug withdrawal situation, in contrast to the steady or escalating dose of levodopa in DDS patients, and the spectrum of symptoms of DAWS is broader and more typical of an addictive drug withdrawal. The symptoms of DAWS were extremely disruptive to the patients and their families: in almost 40% of patients, DAWS symptoms were either associated with a protracted course, taking over a year to withdraw the offending agent fully, or they were refractory to attempts to withdraw DA; these patients required ongoing treatment with the result that their ICD continued unabated.

The average age of PD onset in our series of patients is just over 50 years and below that expected in the general population.^[21] The presence of dementia as a clinical diagnosis stated in the chart as one of the exclusion criteria could have contributed to reducing the number of older patients included in our series. Our study was not designed to determine the frequency of ICD in PD patients treated with DA. Pathological gambling was the type of ICD most commonly observed, as reported by Voon et al. ^[13] The frequency of multiple ICD, observed in 28% of all our ICD patients, is similar to the one quarter^[6] and one third^[22] reported in other surveys. On the other hand, in patients with DAWS Rabinak and Nirenberg^[7] observed a much higher (80%) frequency of multiple ICD than our 30%. Among patients with ICD, there was no difference in the type or multiplicity of ICD between DAWS+ and DAWS− in our study, suggesting that the presence of DA-induced ICD, rather than the type or complexity, is the relevant predictor for the development of DAWS.

A significantly lower UPDRS motor score (suggesting a less severe form or earlier PD stage) in DAWS+ patients was reported previously,^[7] but we could not confirm this using on-state UPDRS scores obtained during routine clinic visits. Our failure to demonstrate a difference in motor symptomatology between DAWS+ and DAWS− patients does not exclude a role of the mesocorticolimbic system in the pathogenesis of DAWS. However, we did not find evidence to support a disproportionate sparing of the motor circuit in these patients.

In contrast to other studies, we did not find either a higher baseline dose of DA in DAWS patients^[7] or higher DA cumulative exposure,^[7,19] although a statistical trend towards higher cumulative DA-LEDD was observed (p=0.08). When we restricted the comparison to the group with ICD, DAWS patients had a higher LD-LEDD at DA withdrawal (p<0 .02="" associated="" be="" daws.="" development="" higher="" icd="" is="" ld-ledd="" of="" patients="" reported="" similarly="" style="font-size: 0.85em; line-height: 0;" sup="" than="" the="" to="" with="" without="">[6]

 however, ICD can develop irrespective of DA dosage,^[6] and even with very low DA cumulative exposure in patients with restless legs syndrome.^[23–25]

All DAWS+ patients in the original report of Rabinak and Nirenberg^[7] were using pramipexole. We extend the concept of DAWS by describing this syndrome with other DA. We did not find statistically significant differences among the specific DA drugs in the frequency of development of DAWS in the total sample of 84 patients; however, the small numbers in each treatment group limit interpretation. Although in the group of patients withdrawn from DA because of ICD there was a trend towards a more frequent use of ropinirole than other DA (Fisher's exact test 0.043), we do not consider this result relevant because of the marginal significance. The RR of developing ICD with pramipexole compared to other DA has been disputed in the literature, but it is clear that several DA can induce the syndrome, and the general consensus is that this is a class effect.^[6,26–28] While reported cases of ICD in PD secondary to bromocriptine are scarce,^[29] the two patients withdrawn from bromocriptine in our series had ICD.

Among patients with ICD, a history of smoking (considered an addictive behaviour) was present more often in DAWS+ than in DAWS− patients (p<0 .03="" p="">

We did not correct for multiple comparisons. With this caveat it is interesting to note the trend we found in patients with ICD towards higher doses of dopamine replacement treatments and addictive behaviour in the DAWS+ group compared to the DAWS− group. Our study has two major limitations. First, it is a retrospective chart review with all the acknowledged problems inherent with this approach. Second, it is purely clinical, and thus contributes no insights into the pathophysiological mechanisms or the genetic risk factors for the development of DAWS.

Further prospective studies are required to determine the frequency and spectrum of severity of DAWS, and to define effective treatment for DAWS, given the potential for considerable disability and extended course experienced by many patients.In conclusion, DAWS is an important clinical problem with manifestations resembling those of other drug withdrawal syndromes and a relevant concept in the management of patients with PD. The individual tendency to develop ICD in response to exposure to any DA, rather than other treatment or demographic factors, may be the major determinant in the development of DAWS. The fact that a smoking history in the ICD group increases the likelihood of developing DAWS suggests a susceptibility to addiction in these patients. A higher dose of levodopa may also contribute to the development of DAWS in patients with ICD.

 

«