A Pilot Study of Inflammatory Markers in Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this study is to examine the cerebrospinal fluid (CSF) of patients with Alzheimer's disease for biomarkers of inflammation and their response to the antibiotics doxycycline and rifampin. The results of this preliminary analysis will be used in defining the direction of further research.

Detailed Description
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Doxycycline and rifampicin are two antibiotics which may be useful in the treatment of Alzheimer's disease (AD). Besides their antimicrobial effects they may also decrease specific contributors to AD pathology including: 1. amyloid beta, 2. inflammatory mediators, 3. proteolytic enzymes, and 4. metal ions. Evidence indicates an inflammatory response in AD. This includes complement activation, elevated C-reactive protein (CRP), elevated pro-inflammatory cytokines (including IL-1-beta, IL-6, TNF-α, TGF-β, S100-β), chemokine alterations (IL-8, MIP-1-alpha, MIP-1-beta, MCP-1), and microglial activation. In our previous study of AD patients treated with combined doxycycline and rifampicin versus placebo, we demonstrated that antibiotic treatment significantly delayed progression of clinical impairment. Treatment also reduced blood CRP levels suggesting an anti-inflammatory role of these antibiotics. In this study we suggest analysis of biomarkers including both pro and anti-inflammatory cytokines TNF-alpha, IL-1beta, IL-4, IL-10,the chemokine MCP-1 and other inflammatory markers in both the cerebrospinal fluid (CSF) and blood from AD patients and age-matched controls. AD patients are participants in a 12 month randomized clinical trial of doxycyline and rifampin or placebo (DARAD) for treatment of AD. Each patient is asked if they wish to contribute a sample of CSF and blood at baseline and at 12 months when treatment is completed. About half the patients are consenting to this. Since consent is given to the lumbar puncture before the double-blinded DARAD treatment is initiated, we expect the distribution of samples collected to be random among the four treatment groups. We will compare CSF biomarker levels among the four treatment groups. Ten age-matched healthy controls are also being asked to contribute CSF and blood samples for comparison. The controls are not participants in the DARAD trial. We feel that this is an important pilot study to determine whether there are any differences in blood or CSF concentrations of commonly studied cytokines between AD patients and normal controls. As such, this study could contribute to the search for a diagnostic biomarker. Also, it could provide a solid foundation for future studies aimed at elucidating the effects of antibiotics on various biomarkers in the blood and CSF of AD patients. From this, we may be able to correlate previous findings that antibiotics delay progression of clinical outcome in AD with changes in blood or CSF biomarker levels.

Official Title
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A Pilot Study Comparing Inflammatory Biomarkers in Blood and CSF in Patients With Alzheimer's Disease and Age-Matched Controls

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: doxycycline
* Drug: rifampin
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Giving informed consent to lumbar puncture Participation in the DARAD clinical trial which requires the following: diagnosis of probable Alzheimer's disease SMMSE 14-26 inclusive community-dwelling age 50 or greater caregiver to monitor study medication and report on ADLs, behaviour, etc. adequate English literacy to complete neuropsychological testing generally stable level of health Exclusion Criteria: Contraindication to lumbar puncture DARAD exclusion criteria as follows: dementia due to other neurodegenerative diseases cognitive impairment due to head trauma, etc. stroke or significant cerebrovascular disease clinically significant cardiac disease such as recent MI, uncontrolled hypertension taking other anti-dementia treatments or investigational drugs allergy to doxycycline or rifampin significant psychiatric conditions like depression cancer

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 AD doxycycline + rifampin<br>Participants with AD allocated to doxycycline 100 mg bid od and rifampin 300 mg od for 12 months | Drug: doxycycline<br>* capsule, 100 mg, b.i.d., 12 months<br>* Other names: Apo-doxy;Drug: rifampin<br>* capsule, 300 mg, od, 12 months<br>* Other names: Rifadin;|
| Active Comparator: 2 AD doxycycline<br> | Drug: doxycycline<br>* capsule, 100 mg, b.i.d., 12 months<br>* Other names: Apo-doxy;Drug: placebo<br>* placebo matched to rifampin; placebo matched to doxycycline<br>|
| Active Comparator: 3 AD rifampin<br>Participants with AD allocated to rifampin 300 mg od od and placebo matched to doxycycline bid for 12 months | Drug: rifampin<br>* capsule, 300 mg, od, 12 months<br>* Other names: Rifadin;Drug: placebo<br>* placebo matched to rifampin; placebo matched to doxycycline<br>|
| Placebo Comparator: 4 AD placebo<br>Participants with AD allocated to placebo matched to doxycycline and placebo matched to rifampin for 12 months | Drug: placebo<br>* placebo matched to rifampin; placebo matched to doxycycline<br>|
| No Intervention: 5 Control<br>Age-matched cognitively healthy participants (untreated) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IL-1beta |  | baseline and 12 months | 
| TNF-alpha |  | baseline and 12 months | 
| MCP-1 |  | baseline and 12 months | 
| IL-4 |  | baseline and 12 month | 
| IL-10 |  | baseline and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Other inflammatory markers. |  | Baseline and 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, dementia, inflammation, cytokine, biomarker, cerebrospinal fluid, serum, doxycycline, rifampin