ArticlesEffect of hydroxychloroquine on progression of dementia in early Alzheimer's disease: an 18-month randomised, double-blind, placebo-controlled study
Introduction
Three independent lines of evidence suggest that endogenous inflammatory responses have a role in the pathogenesis of Alzheimer's disease. First, cytokines, acute phase reactants, and complement activation fragments are seen in close association with senile plaques in the neuropathology of Alzheimer's disease.1 Microglial cells, the brain-resident cells of the mononuclear phagocyte system that cluster around plaques, express complement receptors and produce inflammatory proteins.1 Messenger RNA concentrations for complement proteins are strongly upregulated in the brain of patients with Alzheimer's disease.2 Second, results of in-vitro studies show that the major constituent of plaques, the β-amyloid protein, can activate the complement system and potentiate cytokine secretion, which might trigger an inflammatory response in the absence of immune complexes or cellular mediated response.3, 4 Finally, findings of numerous cross-sectional and some longitudinal epidemiological studies have shown that anti-inflammatory drugs might delay or even prevent the onset of Alzheimer's disease.5, 6 Therefore, since the 1990s many scientists believe that the inflammatory process in the brain of patients with Alzheimer's disease is a compelling target for therapeutic intervention, an opinion which can be tested with available drugs.7 Indeed, results of a small, early clinical study suggested a beneficial effect of indometacin after 6 months of treatment.8
Since the 1950s, the antimalarials chloroquine and hydroxychloroquine have also been used to treat inflammatory diseases. In vitro, aminoquinoline compounds are specifically effective against β-amyloid protein induced neurotoxicity.9 Hydroxychloroquine suppresses acute-phase reactants, lymphocyte responsiveness, macrophage function, and cytokine release.10 In rheumatoid arthritis, this drug is a well established, slow-acting, disease-modifying treatment. Hydroxychloroquine is generally well tolerated in elderly people, and the risk of retinopathy among patients receiving appropriate doses of the drug is low.11 Because of its broad scope of anti-inflammatory activity, its safety profile, and its ability to cross the blood-brain barrier,10 we chose to test whether hydroxychloroquine could slow the rate of decline in patients with early Alzheimer's disease.
Section snippets
Patients
We recruited patients through four memory clinics in Amsterdam between December, 1996, and October, 1998. Individuals were eligible if they fulfilled criteria for a diagnosis of probable Alzheimer's disease, as outlined by the National Institute of Neurological and Communicative Disorders and Alzheimer's Disease and Related Disorders.12 The severity of dementia had to be minimal or mild according to the guidelines for the gradation of dementia in the Cambridge Examination for Mental Disorders
Results
Figure 1 shows the trial profile, and table 1 shows baseline demographic and clinical characteristics of patients. The IDDD and ADAS-cog scores at baseline show that we were successful in recruitment of patients with early Alzheimer's disease. The ADAS-cog scores in our study are substantially lower than in other clinical trial reports in Alzheimer's disease. The mean IDDD score of about 11 suggests that the typical participant of this trial required (three IDDD points) assistance with taking
Discussion
In our study, hydroxychloroquine did not slow the progression of dementia over 18 months. Furthermore, we did not identify any subgroups, defined by sex, age, genotype, education, or baseline degree of deterioration, which had benefited from treatment. Hydroxychloroquine was well tolerated and did not cause clinically important ophthalmological problems at the cumulative dose used. Our findings suggest that long-term studies with a low drop-out rate are feasible in the early stages of
References (32)
- et al.
The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases
Brain Res Rev
(1995) - et al.
Up-regulated production and activation of the complement system in Alzheimer's disease brain
Am J Pathol
(1999) - et al.
Complement C1q does not bind monomeric beta-amyloid
Exp Neurol
(1994) Microglia and the immune pathology of Alzheimer disease
Am J Hum Genet
(1999)Hydroxychloroquine and retinal safety
Lancet
(1998)Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate
Am J Med
(1983)- et al.
Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs
Neurobiol Aging
(1995) - et al.
Atherosclerosis, apolipoprotein E and the prevalence of dementia and Alzheimer's disease in the Rotterdam study
Lancet
(1997) - et al.
Effects of naproxen and nabumetone on serum cholesterol levels in patients with osteoarthritis
Clin Ther
(1995) Effects of nonsteroidal anti-inflammatory therapy on platelets
Am J Med
(1999)
Betaamyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain
J Immunol
Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies
Neurology
Reduced prevalence of AD in users of NSAIDs and H2 receptor antagonists: the Cache County study
Neurology
Possible pharmacological approaches to slowing down Alzheimer's disease progression
Neurobiol Aging
Clinical trial of indomethacin in Alzheimer's disease
Neurology
Inflammatory mechanisms in Alzheimer's disease: implications for therapy
Am J Psychiatry
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