067-72 antibiotics in dementia

DERLEME/REVIEW
Gelifl Tarihi/Received: 27/02/2009 - Kabul Edilifl Tarihi/Accepted: 09/03/2009 Antibiotics in Dementia: What’s Next?The DARAD Trial Demansta Antibiyotikler: S›rada Ne Var?
DARAD Çal›flmas›
Burcu Balam Yavuz1, Tim Standish2, Elizabeth Almeida2, Alwin Cunje3, Paula DiLoreto2, Ainsley Moore4, Brandon Kucher2, Monica Marchese2, Mohammed Warsi5, Alexander J. Molloy6, D. William Molloy2
1 Division of Geriatric Medicine, Department of Internal Medicine, Faculty of Medicine, 1 Hacettepe Üniversitesi T›p Fakültesi, ‹ç Hastal›klar› Anabilim Dal›, Geriatri Ünitesi, Ankara, Türkiye2 Department of Internal Medicine, McMaster University, Hamilton, Ontario, Canada 2 McMaster Üniversitesi, ‹ç Hastal›klar› Anabilim Dal›, Hamilton, Ontario, Kanada3 Department of Internal Medicine, Memorial University, St. John’s, Newfoundland, Canada3 Memorial Üniversitesi, ‹ç Hastal›klar› Anabilim Dal›, St. John’s, Newfoundland, Kanada4 Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada 4 McMaster Üniversitesi, Aile Hekimli¤i Anabilim Dal›, Hamilton, Ontario, Kanada5 Department of Psychiatry, McMaster University, Hamilton, Ontario, Canada5 McMaster Üniversitesi, Psikiyatri Anabilim Dal›, Hamilton, Ontario, Kanada6 McMaster University, Hamilton, Ontario, Canada6 McMaster Üniversitesi, Hamilton, Ontario, Kanada ABSTRACT
The main mechanism for the underlying pathogenesis of Alzheimer’s disease (AD) is the amyloid cascade hypothesis. A therape-utic agent that reduced amyloid deposition would be a disease modifying agent. Chlamydia pneumoniae has been suggested tohave an etiologic role in AD. This finding raised the possibility of using long term antibiotics to prevent or treat AD. Doxycylineand rifampicin have been identified as potential disease-modifying agents. They are safe, inexpensive, and widely availableagents. Besides their antimicrobial effects, they have non-antimicrobial properties which may account for their effects in the tre-atment of AD. These non-antimicrobial properties are anti-amyloidogenic, anti-tau, anti-inflammatory, anti-proteolytic, anti-oxi-dant, and metal ion chelator effects. To test the hypothesis that doxycycline and rifampicin reduce cognitive decline in AD pati-ents; a pilot randomized controlled trial was conducted and the results showed significantly less decline in cognitive function. Totest the efficacy of doxycycline and rifampicin in the treatment of AD, a multi-centre, randomized, controlled trial (DARAD Trial: Yaz›flma Adresi/Address for Correspondence
Hacettepe Üniversitesi T›p Fakültesi, ‹ç Hastal›klar› Anabilim Dal›, Geriatri Ünitesi, S›hhiye 06100 Ankara/Türkiyee-posta: bbdogu@gmail.com Yavuz BB, Standish T, Almeida E, Cunje A, DiLoreto P, Moore A, Kucher B, Marchese M, Warsi M, Molloy AJ, Molloy DW. Antibiotics in Dementia: What’s Next? The DARAD Trial Doxycycline and Rifampicin for Alzheimer’s Disease) is being conducted in 14 centers in Canada. The primary objective of thisstudy is to determine the impact of rifampicin and doxycycline, over a one year period, on cognition, function, mood, and beha-viour. The secondary objective is to determine if treatment with either doxycycline or rifampicin alone is as efficacious as the com-bined treatment. The target sample size is 500 patients with probable AD. Blood analyses and cerebrospinal fluid (CSF) biomar-kers will be measured before and after treatment as a sub study to find out which markers are affected. MRI using SusceptibilityWeighted Imaging (SWI) will also be performed in 100 patients. On February 3, 2009, 302 patients were enrolled in the study.
The drugs are well tolerated and currently about 90% of the patients complete 12 months of treatment. Within the CSF/bloodsub study of the DARAD, 79 baseline and 38 12 month samples have been collected to date. The DARAD trial will culminate 13years of study into the effects of these antibiotics, as potential disease modifying agents, in AD. The last patient will be throughin 2011. CSF analyses may be available sooner. We eagerly await these results to guide further inquiry and exploration. Key Words: Alzheimer’s disease, antibiotic, dementia, chlamydia pneumonia, doxycycline, rifampicin.
Alzheimer hastal›¤› (AH)’n›n patogenezinde altta yatan temel mekanizma amiloid hipotezidir. Amiloid birikimini engelleyecek birajan hastal›¤› modifiye edici bir tedavi olacakt›r. Chlamydia pneumoniae’n›n AH etyolojisinde rolü olabilece¤i öne sürülmüfltür.
Bu bulgu AH’›n önlenmesi ve tedavisinde uzun süreli antibiyotik kullan›m› ihtimalini do¤urmufltur. Doksisiklin ve rifampisin po-tansiyel hastal›¤› modifiye edici ajanlar olarak tan›mlanm›flt›r. Güvenli, ucuz ve kolay bulunabilir ajanlard›r. Antimikrobiyal et-kilerinin yan› s›ra AH tedavisindeki etkilerini aç›klayabilecek nonantimikrobiyal etkileri de mevcuttur. Bu nonantimikrobiyal et-kiler antiamiloidojenik, anti-tau, antiinflamatuvar, antiproteolitik, antioksidan ve metal iyon flelatör etkileridir. Doksisiklin ve ri-fampisinin AH’da kognitif düflüflü yavafllatt›¤› hipotezinin test edilmesi için randomize kontrollü bir pilot çal›flma yap›lm›flt›r vesonuçlar kognitif fonksiyonda daha az düflüfl oldu¤unu göstermifltir. Doksisiklin ve rifampisinin AH tedavisindeki etkinli¤ini testetmek için Kanada’da 14 merkezde randomize, kontrollü çok merkezli bir çal›flma (DARAD Çal›flmas›: Doxycycline and Rifampi-cin for Alzheimer’s Disease) yürütülmektedir. Bu çal›flman›n primer amac› rifampisin ve doksisiklinin bir y›ll›k bir sürede kogni-tif fonksiyon, fonksiyonel durum, duygudurum ve davran›fl üzerine etkilerini tespit etmektir. Sekonder amaç ise doksisiklin veyarifampisin ile tedavinin kombine tedavi kadar etkin olup olmad›¤›n›n tespit edilmesidir. Hedef 500 muhtemel Alzheimer hastas›-na ulaflmakt›r. Bir alt çal›flma olarak hangi mark›rlar›n tedaviden etkilendi¤ini bulmak için kan ve beyin omurilik s›v›s› (BOS) bi-yomark›r analizleri tedavi öncesi ve sonras›nda yap›lmaktad›r. “Susceptibility Weighted Imaging (SWI)” tekni¤i kullan›larakmanyetik rezonans görüntüleme yöntemi de 100 hastaya uygulanacakt›r. 03 fiubat 2009 tarihi itibariyle çal›flmaya 302 hastaal›nm›flt›r. fiu ana kadar ilaçlar iyi tolere edilmifl ve %90 hasta 12 ayl›k tedaviyi tamamlam›flt›r. DARAD’›n BOS/kan alt çal›flma-s›nda flu ana kadar 79 bazal ve 38 12. ay örnekleri toplanm›flt›r. DARAD çal›flmas›nda bu antibiyotiklerin AH’da potansiyel has-tal›k modifiye edici ajanlar olarak etkisinin ölçülmesi 13 y›lda tamamlanabilecektir. Son hastan›n takiplerinin 2011 y›l›nda sonaerece¤i düflünülmektedir. BOS analizleri daha erken bitebilecektir. Daha ileri inceleme ve araflt›rmalar yapmak için bu sonuçla-r› hevesle beklemekteyiz. Anahtar Kelimeler: Alzheimer hastal›¤›, antibiyotik, demans, klamidya pnömoni, doksisiklin, rifampisin.
INTRODUCTION
Some possible therapeutic agents that would play a Pathogenesis of Alzheimer’s Disease and
role in reducing amyloid beta deposition are inhibiting Treatment Strategies
beta or gamma secretase inhibit amyloid beta aggrega- tion and/or increase clearance of amyloid beta fibrils Alzheimer’s disease (AD) is a neurodegenerative are being investigated (1-7). These possible therapeutic disease that causes progressive cognitive deteriorati- agents are immunotherapy, beta and gamma secretase on, decline in activities of daily living, behavioral inhibitors, alpha secretase stimulators, glycosami- changes and neuropsychiatric symptoms. The patho- noglycan mimetics, and tau kinase inhibitors. Cur- logical hallmarks of AD are amyloid beta deposition rently, the treatments being used for AD are sympto- and tau protein abnormalities. The main mechanism matic. A therapeutic agent that reduced amyloid depo- for the underlying pathogenesis of the disease conti- sition would be a disease modifying agent. nues to be the amyloid cascade hypothesis. Clinical studies are ongoing to find therapies that target amy- Doxycycline and rifampicin have been identified as potential disease-modifying agents. To test their effects Yavuz BB, Standish T, Almeida E, Cunje A, DiLoreto P, Moore A, Kucher B, Marchese M, Warsi M, Molloy AJ, Molloy DW. Demansta Antibiyotikler: S›rada Ne Var? DARAD Çal›flmas› in the treatment of AD, a multi-centre, randomized, cont- mized controlled trial was conducted between 1999 rolled trial examining the efficacy of the antibiotics and 2001 (15). This study examined the effects of doxycycline and rifampicin is being conducted in 14 cen- doxycycline and rifampicin in AD patients who were gi- ters in Canada. This trial, the DARAD Trial (Doxycycline ven three months of treatment. They were followed for and Rifampicin for Alzheimer’s Disease) examines the one year, the last nine months off treatment. Assess- effect of these antibiotics on outcomes of AD patients.
ments of cognition, activities of daily living (ADL), be- They are safe, inexpensive, and widely available agents. havior and mood were performed at 3, 6, and 12 Chlamydia pneumoniae and
months. Cognitive function was the primary outcome.
Alzheimer’s Disease
The results showed significantly less decline in Stan- dardized Alzheimer’s Disease Assessment Scale –cog- C. pneumoniae, a common respiratory pathogen has nitive subscale (SADAS-cog) scores in the active treat- been suggested to have an etiologic role in AD (4). It has ment group compared to placebo at 6 months, and a been isolated from AD brains and has been shown to in- statistically significant improvement in Standardized duce Alzheimer-like plaque formation in the brains of Mini-Mental State Examination (SMMSE) scores in the BALB/c mice (4,6,8). Other studies conducted to detect treatment group at 12 months. The change in SADAS- Chlamydia pneumonia in brains of AD patients had conf- cog scores from baseline between rifampicin + licting results (4,9,10). These findings raised the possibi- doxycycline and placebo groups is shown in Figure 1.
lity of using long term antibiotics to prevent or treat AD. A statistically significant change in depression, behavi- Mechanisms of Doxycycline and
or, caregiver burden, and ADL occurred at 3 months.
Rifampicin That May Affect AD
These differences were not significant at six or 12 Doxycycline and rifampicin are used against C. pne- months. C. pneumoniae serology was not significantly umoniae and mycobacterial infections, respectively. Be- different between groups and did not show any reduc- sides their antimicrobial effects, these antibiotics have nonantimicrobial properties which may account for the- The results of this study suggest that these drugs ir effects in the treatment of AD. The nonantimicrobial slow the progression of clinical decline and have dise- properties of doxycycline and rifampicin that may af- ase modifying effects. At present, it is unclear if this ef- fect AD pathogenesis are their anti-amyloidogenic, anti- fect is due to doxycycline, rifampicin, or both. The pos- tau, anti-inflammatory (IL-1β, TNF-α, IL-4, IL-10), anti- sible mechanisms underlying this result may reduce ne- proteolytic (MMP-2 and MMP-9), anti-oxidant, and me- urofibrillary tangle formation and/or increase anti-inf- tal ion chelator effects. Furthermore, they both penetra- te the blood brain barrier. Both rifampicin and doxycyc- This study was underpowered and the effects on be- line interfere with the accumulation of amyloid beta havior and mood were transient. A further study with peptide and formation of amyloid beta fibrils. Rifampi- larger numbers, with a longer period of treatment, was cin inhibits aggregation of amyloid beta fibrils and ne- undertaken. Blood and cerebrospinal fluid (CSF) is be- urotoxicity in vitro (11,12). This activity was correlated ing taken to measure biomarkers to explore different with rifampicin’s radical-scavenging ability of hydroxyl effects and mechanisms of the treatment in this study.
free radicals (11). Tetracyclines disassemble amyloid beta fibrils (13). Doxycycline also suppresses mutant DARAD Trial
tau production in transgenic mice (14). Based on this This larger randomized controlled trial, funded by evidence showing inhibition of the formation of these to- Canadian Institutes of Health Research (CIHR), is na- xic amyloid beta polymers, it was hypothesized that med the DARAD Trial (Doxycycline and Rifampicin for doxycycline and rifampicin could play a role in the tre- Alzheimer’s disease). Physicians’ Services Incorpora- atment of AD as disease modifying agents. ted Foundation (PSI) provided additional funding to CLINICAL TRIALS of DOXYCYCLINE
examine biomarkers in the CSF and serum, to explore and RIFAMPICIN
the effects of doxycycline and rifampicin on these bi- Pilot Randomized Controlled Trial
The primary objective of this study is to determine To test the hypothesis that doxycycline and rifam- the impact of rifampicin and doxycycline, over a one ye- picin reduce cognitive decline in AD patients; a rando- Yavuz BB, Standish T, Almeida E, Cunje A, DiLoreto P, Moore A, Kucher B, Marchese M, Warsi M, Molloy AJ, Molloy DW. Antibiotics in Dementia: What’s Next? The DARAD Trial ar period, on cognition, function, mood, and behaviour.
Inclusion criteria are: Age ≥ 50, probable AD.
The central hypothesis of the DARAD trial is that SMMSE score 14-26 inclusive, consenting patient, con- doxycycline and/or rifampicin have beneficial effects in senting caregiver, sufficient English to complete stan- patients with AD by acting as antiinflammatory agents dardized testing in English, with stable health where by modulating inflammatory biomarkers in the blood the patient is reasonably expected to complete a 1 ye- and CSF and/or by modifying tau formation and/or changing the amyloid cascade. These effects will be tes- Exclusion criteria are: Other neuro-degenerative
ted by comparing the levels of inflammatory cytokines diseases such as Lewy body, Parkinson’s, fronto-tem- in serum and CSF between patients with AD and normal poral, Huntington’s Chorea, Down’s Syndrome or Cre- age-matched controls. The effects of these antibiotics utzfeld Jacob Disease; cognitive impairment due to on the biomarkers including amyloid beta 40 and 42 in acute cerebral trauma, subdural hematoma, injuries the serum and CSF and total-tau (T-tau) and phosphory- from chronic trauma, hypoxic cerebral damage; B12 lated-tau (P-tau) in the CSF will also be tested to exami- deficiency, cancer or infections; endocrine deficiencies; ne the mechanism of action of these drugs in AD.
hypercalcemia, hypothyroidism, hyperparathyroidism, The secondary objective is to determine if treat- Cushing’s syndrome, severe renal failure, poorly cont- ment with either doxycycline or rifampicin alone is as rolled diabetes mellitus, pituitary disease; mental re- efficacious as the combined treatment. A comparison tardation; significant cerebrovascular disease or multi- of combined and single therapies versus placebo will infarct dementia; intra-cranial pathology, tumour or determine if the effects are caused by one drug or the hydrocephalus; history of epilepsy or convulsions; clini- cally significant psychiatric conditions or moderate to METHODS of DARAD TR‹AL
severe behavioural disturbances; clinically significant cardiac, hepatic, renal, pulmonary, metabolic or endoc- Study Patients
rine diseases; history of drug or alcohol abuse; history The DARAD is a multi-centre, blinded, randomized, of myasthenia gravis; clinically significant cardiac di- controlled trial comparing different regimens of the an- sease such as cardiac surgery in the past six months, tibiotics doxycycline and rifampicin in the treatment of unstable angina or poorly controlled congestive heart AD. This study is ongoing with 14 centers in Canada failure, uncontrolled hypertension with systolic pressu- participating. The target sample size is 500 patients re greater that 180 mmHg or diastolic pressure greater SADAS-Cog Change From Baseline for Doxycycline and Rifampin vs. Placebo
SADAS-Cog Score
Figure 1. The change in SADAS-cog scores from baseline for doxycycline + rifampicin and placebo groups in the
pilot randomized controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease.
Yavuz BB, Standish T, Almeida E, Cunje A, DiLoreto P, Moore A, Kucher B, Marchese M, Warsi M, Molloy AJ, Molloy DW. Demansta Antibiyotikler: S›rada Ne Var? DARAD Çal›flmas› that 110 mmHg anti-dementia treatments except done- cog is an objective measure of cognition and the CDR pezil, galantamine, rivastigmine, memantine, ASA up is a measure of global function. The secondary outco- to 650 mg, vitamin E up to 400 IU, multi B vitamins, mes are Standardized Mini-Mental State Examination gingko biloba, Cox II inhibitors or statins (if doses are (SMMSE), AB Cognitive Screen 100 (ABCS 100), Geriat- stable for at least three months and will be stable du- ric Depression Scale (GDS), activities of daily living ring the trial); other investigational drugs; long-term (Lawton Scale), and Dysfunctional Behaviour Rating antibiotics; allergy to doxycycline or rifampicin.
Instrument (DBRI). Clinical outcomes are assessed at Clinical Outcomes
Patients are treated for 12 months in four treat- CSF and Blood Biomarkers
Blood analyses and CSF biomarkers will be measu- red before and after one year of treatment as a sub study of the DARAD trial to find out which markers doxycycline and rifampicin affect. CSF biomarkers will be used to follow the disease progress and to identify 4. Placebo-doxycycline + placebo-rifampicin.
the mechanisms of these drugs’ effects in AD. Blood Doxycycline is given in 100 mg twice a day and ri- and 10 mL of CSF samples are obtained from 100 pa- fampicin 300 mg is taken once a day. Placebos matc- tients and analyzed for changes in biomarkers of AD hed to both doxycycline and rifampicin are used to ma- before and after treatment. These biomarkers are amy- intain the blinding. The co-primary outcomes of the loid beta (1-40), amyloid beta (1-42), P-tau, T-tau, APP study are the Standardized Alzheimer’s Disease As- isoforms (β-sAPP and α-sAPP), matrix metalloproteina- sessment Scale-Cognitive Subscale (SADAS-cog), and ses (MMP-2, MMP-9), metal ions (copper, iron, zinc, man- the Clinical Dementia Rating scale (CDR). The SADAS- ganese), pro-inflammatory cytokines (IL-1β, TNF-α), and DARAD Enrollment
Patients
Months to Recruit
Figure 2. Number of patients enrolled in DARAD trial.
Yavuz BB, Standish T, Almeida E, Cunje A, DiLoreto P, Moore A, Kucher B, Marchese M, Warsi M, Molloy AJ, Molloy DW. Antibiotics in Dementia: What’s Next? The DARAD Trial antiinflammatory cytokines (IL-4 and IL-10). The corre- Chang WP, Koelsch G, Wong S, Downs D, Da H, Weerasena V etal. In vivo inhibition of Abeta production by memapsin 2 (beta- lation between the changes in CSF biomarkers and the secretase) inhibitors. Journal of Neurochemistry 2004; 89: clinical outcomes will be assessed. These observations will provide insight into the effects of doxycycline and Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Ga- rifampicin on AD pathology and clinical outcomes. dient R, et al. Modulation of notch processing by ?-Secretase in- The CSF and serum biomarkers will also be compa- hibitors causes intestinal goblet cell metaplasia and induction ofgenes known to specify gut secretory lineage differentiation. To- red with an age-matched control group, without AD.
xicological Sciences 2004; 82: 341-58. This correlation of biomarkers between non-AD and AD Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLe- patients may help to identify a biomarker that could be an CA, et al. Treatment with a copper-zinc chelator markedly used in the diagnosis and/or to monitor activity/prog- and rapidly inhibits [beta]-amyloid accumulation in alzheimer's disease transgenic mice. Neuron 2001;30: 665-76. Neuroimaging
Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M,MacGregor L, et al. Metal-protein attenuation with iodoch- MRI using Susceptibility Weighted Imaging (SWI) lorhydroxyquin (clioquinol) targeting Abeta amyloid deposition will also be performed at baseline and after the one ye- and toxicity in Alzheimer disease: A pilot phase 2 clinical trial.
Arch Neurol 2003; 60: 1685-91. ar of treatment in 100 patients. The changes in the ne- uroimaging findings will be correlated with the clinical Aisen PA, Mehran M, Poole R, Lavoie I, Gervais F, Briand R, etal. Clinical data on Alzhemed(TM) after 12 months of treatment and biological markers in blood and CSF.
in patients with mild to moderate Alzheimer's disease. Neurobi- PROGRESS of DARAD TRIAL to DATE
Fourteen centers in Canada are recruiting patients Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, etal. Immunization with amyloid-beta attenuates Alzheimer-dise- to DARAD trial. On February 3, 2009, 302 patients we- ase-like pathology in the DA mouse. Nature 1999; 400: 173-7. re enrolled in the study (Figure 2). The study drugs are Gerard HC, Wildt KL, Whittum-Hudson JA, Lai Z, Ager J, Hud- well tolerated and currently about 90% of the patients son AP. The load of Chlamydia pneumoniae in the Alzheimer's complete 12 months of study treatment.
brain varies with APOE genotype. Microbial Pathogenesis 2005; Within the CSF/blood sub study of the DARAD, 79 baseline and 38-12 month samples have been collected Nochlin D, Shaw CM, Campbell LA, Kuo CC. Failure to detectChlamydia pneumoniae in brain tissues of Alzheimer's disease. CONCLUSION
10. Gieffers J, Reusche E, Solbach W, Maass M. Failure to detect The DARAD trial will culminate 13 years of study Chlamydia pneumoniae in brain sections of Alzheimer's disease into the effects of these antibiotics, as potential dise- patients. J Clin Microbiol 2000; 38: 881-2. ase modifying agents, in AD. The drugs are well known, 11. Tomiyama T, Shoji A, Kataoka K, Suwa Y, Asano S, Kaneko H, Endo N. Inhibition of amyloid beta protein aggregation and ne- easily available and well tolerated. The trial will recru- urotoxicity by rifampicin. Its possible function as a hydroxyl ra- it another 150 patients in 2009 and 2010. The last pa- dical scavenger. J Biol Chem 1996; 271: 6839-44. tient will be through sometime in 2011. CSF analyses 12. Tomiyama T, Asano S, Suwa Y, Morita T, Kataoka K, Mori H, En- may be available sooner because these samples are do N. Rifampicin prevents the aggregation and neurotoxicity of blinded again with only treatments known. In this way amyloid beta protein in vitro. Biochem Biophys Res Commun they can be analysed even before the main clinical tri- als ends. We eagerly await these results to guide furt- 13. Forloni G, Colombo L, Girola L, Tagliavini F, Salmona M. Anti- amyloidogenic activity of tetracyclines: Studies in vitro. FEBSLett 2001; 487: 404-7. 14. Santa Cruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, et al. Tau Suppression in a Neurodegenerative Mouse Model REFERENCES
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