This is a one-year, double-blind placebo-controlled randomized clinical trial that compares montelukast to placebo in individuals with mild cognitive impairment (MCI) and early Alzheimer's disease (AD) dementia. The measures include cognitive function, cerebrospinal fluid (CSF) biomarkers and neuroimaging (cerebral perfusion and markers of vascular brain damage). Participants will be treated with montelukast (escalating doses:10, 20 to 40 mg) or matched placebo.
Treatment options for Alzheimer's disease (AD) remain limited, especially treatments linking neurovascular and neuroinflammatory changes with clinical manifestations of the disease. Prior research studies have documented a positive effect of cysteinyl leukotriene type 1 (cysLT-1) receptor antagonist, particularly Montelukast, on inflammatory processes in the brain and on neuronal injury, blood-brain-barrier (BBB) integrity, and amyloid-β42 (Aβ) protein accumulation. Although montelukast is currently in use for the treatment of inflammatory diseases e.g. bronchial asthma and exercise-induced bronchospasm, its effects on memory and thinking abilities and on AD biomarkers are yet to be fully understood. This is a single site randomized controlled trial at Emory University that compares the effects of montelukast vs. placebo on memory and thinking abilities, as well as on brain imaging and markers of brain degeneration. Each participant will undergo a screening process following informed consent to determine if they meet study eligibility criteria. Participants will be enrolled in the study for 1 year.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
32
Participants in this arm will take a pill of Montelukast daily on escalating doses: 10, 20 to 40 mg. All participants will be initiated on 10 mg. The dose will be increased in 2-week increments to 20 mg and 40 mg as long as participants report no intolerable symptoms or adverse events.
Participants in this arm will take a matched placebo pill daily
Emory Clinic
Atlanta, Georgia, United States
Emory University Hospital Clinical Research Network
Atlanta, Georgia, United States
Executive Park
Atlanta, Georgia, United States
Wesley Woods
Atlanta, Georgia, United States
Number of Participants With Any Gastrointestinal (GI) Symptoms
Number of participants with any GI symptoms reported: diarrhea, nausea, vomiting
Time frame: Baseline, 1 year
Number of Participants With Reported Anaphylaxis
Number of participants with reported anaphylaxis during follow up time
Time frame: Baseline, 1 year
Number of Participants With Elevated Liver Enzymes
Number of participants with elevated liver enzymes during follow up
Time frame: Baseline, 1 year
Prothrombin Time (PT)/ International Normalized Ratio (INR)
Prothrombin time (PT)/ international normalized ratio (INR) will be measured at baseline and 1 year.
Time frame: Baseline, 1 year
Neuropsychiatric Inventory Questionnaire (NPI-Q) Score
The NPI-Q is designed to be a self-administered questionnaire completed by informants about patients for whom they care. Each of the 12 NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain. Initial responses to each domain question are "Yes" (present) or "No" (absent). If the response to the domain question is "No", the informant goes to the next question. If "Yes", the informant then rates both the Severity of the symptoms present within the last month on a 3-point scale and the associated impact of the symptom manifestations on them (i.e. Caregiver Distress) using a 5-point scale. The NPI-Q provides symptom Severity and Distress ratings for each symptom reported, and total Severity and Distress scores reflecting the sum of individual domain scores. NPI-Q Severity score range: 0-36 (lower is better).
Time frame: Baseline, 1 year
Number of Patients With Seizures
Number of participants that reported seizures during follow up time
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Time frame: Baseline, 1 year
Number of Discontinuations From Montelukast
Number of participants that stopped taking Montelukast during follow up time
Time frame: Baseline, 1 year
CSF Amyloid
A lumbar puncture will be done at baseline and at 12 months follow up Approximately 30-45 ml of CSF will be collected using sterile polypropylene collection tubes. Amyloid-β42 is reported as pg/ml.
Time frame: Baseline, 1 year
CSF Tau Levels
CSF tau protein (CSF-tau) is found in most patients with Alzheimer's disease. A lumbar puncture will be done at baseline and at 12 months follow up. Approximately 30-45 ml of CSF will be collected using sterile polypropylene collection tubes. Results will be reported as Phospho tau (p-tau181) in pg/ml.
Time frame: Baseline, 1 year
Clinical Dementia Rating (CDR) Score
The CDR rates each of the six general domains (or boxes) involving memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care, and a global rating is then generated, ranging from 0 to 3. A score of 0 = normal, 0.5 = very mild dementia, 1 = mild dementia, 2 = moderate dementia, and 3 = severe dementia.
Time frame: Baseline, 1 year
NIH Toolbox Cognition Battery (NIHTB-CB)
The NIH Toolbox® is a computer-based comprehensive set of neuro-behavioral measurements that reliably and validly assesses neurocognitive sub-domains in clinical trials, including working memory, episodic memory, processing speed, language, attention and executive function. The fluid cognitive composite (FCC) score is derived by averaging the standard scores of each of the fluid tests (Picture Sequence Memory, List Sorting, Pattern Comparison, Flanker, and Dimensional Change Card Sort.), and then deriving standard scores based on this new distribution. The fully-adjusted FCC T-score is reported. Higher score indicates with better performance. The score ranged from a minimum of 19 (0th percentile) to a maximum of 58 (79th percentile) in this sample. The population-level T-score and percentile rank range from 23 (0.3th percentile) to 77 (99.6th percentile) with mean=50 and SD=10.
Time frame: Baseline, 1 year