Alzheimer's Disease, Mild Cognitive Impairment
Conditions
Keywords
Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Neuroinflammation, Mild Cognitive Impairment, Alzheimer's Disease, Minocycline
Brief summary
Cognitively normal individuals, patients with Mild Cognitive Impairment (MCI) or Alzheimer's Disease (AD) will undergo clinical screening, neuropsychological tests, blood and urine analyses, quantitative magnetic resonance imaging (MRI) and proton (1H ) and carbon 13 (13C) magnetic resonance spectroscopy (MRS). Each individual will receive minocycline oral administration for 4 weeks initially, after which MRI, MRS and neuropsychological results will be recorded. If no adverse side effects occur, subjects will continue minocycline administration for an additional 5 months.
Detailed description
In the course of on-going trials of novel MRI procedures for Neurological Diagnosis, the investigators have established non-invasive BIOMARKERS (Note: Biomarkers are objective Laboratory tests used in, but not replacing Clinical diagnostic criteria of any disease,in this case age-related dementia of the Alzheimer type and its pre-clinical forms including Mild Cognitive Impairment - MCI) which significantly assist in the Diagnosis of Alzheimer's Disease. MRS, rather like blood tests which are applied for screening and exclusion of medical disorders, provides a pattern of brain chemicals from which this and many other diagnoses have become available (see: Magnetic Resonance Spectroscopy in Neurological Diagnosis: E.R Danielsen and B.D. Ross, Marcel Dekker New York, 1999). Diagnosis of Alzheimer's Disease has hitherto been exclusively a clinical diagnosis, made on the basis of non-specific tests by the treating physician/neurologist. Furthermore, treatments have been of limited efficacy so that the pressure for conclusive diagnosis or an objective characterization of disease progression (or better, regression) has not been a priority. This conservative approach to Alzheimer's Disease changed in 2010 with the Report of National Institutes of Aging. First: The failures of treatment have been ascribed to introduction only in patients with advanced disease (dementia). Second: A preliminary form of AD, known as pre-clinical or Mild Cognitive Impairment, has been recognized, distinct from, and generally earlier in the disease course. Third: A new set of diagnostic criteria, which include objective 'biomarkers', from cerebrospinal fluid, genetic and imaging analyzes, has been accepted by the Expert Panel. Finally, Clinical trials of existing and new drugs for Alzheimer's Disease are expected to yield better results if initiated earlier - in the pre-clinical phase - and the outcomes evaluated by the earlier changes in an approved panel of biomarkers.
Interventions
DRUGMinocycline
50mg, twice daily for 6 months.
Sponsors
Huntington Medical Research Institutes
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
55 Years to 90 Years
Healthy volunteers
Yes
Inclusion criteria
* Cognitively normal elderly subjects between the ages of 55-90 and patients aged 55 - 90 years who have mild cognitive impairment (MCI) or clinically defined Alzheimer's disease.
Exclusion criteria
* Any person with medical devices such as cardiac pacemakers/defibrillators or neuro-implants as they are contra-indications for MRI/MRS exam. * Since the effects of MRI are unknown to the fetus or unborn child, any person who is or may be pregnant will be excluded from the study. * History of known allergy or intolerance to minocycline or any other tetracycline * Impaired renal function (plasma Creatinine) or blood urea nitrogen (BUN) levels exceeds twice normal upper limit which can result in higher serum levels of tetracycline, azotemia, hyperphosphatemia and acidosis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline values, 1-3 Months Values (averaged), 4-6 Months Values (averaged) | RBANS is a brief neurocognitive battery with four alternate forms, measuring immediate and delayed memory, attention, language, and visuospatial skills. RBANS was developed as a stand-alone core battery for the detection and neurocognitive characterization of dementia and as a brief neurocognitive battery for the detection and tracking of neurocognitive deficits in a variety of disorders. (Reference: http://rbans.com/) Qualitative Description of Index Scores: Index Score Classification 130 and above Very Superior 120-129 Superior 110-119 High Average 90-109 Average 80-89 Low Average 70-79 Borderline 69 and below Extremely Low Psychometric range for RBANS: AD 0 - 77 MCI 78 - 99 Normal \> 100 Range of scores: Minimum = 0, Maximum = 130 Values are reported below for Baseline, averaged for 1-3 months, and averaged for 4-6 months during minocycline administration. |
| Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Baseline values, 1-3 Months Values (averaged), 4-6 Months Values (averaged) | Using magnetic resonance images acquired, hippocampal volume was measured monthly for 6 months. Normal range for hippocampal volume in aged-matched controls is 6.6 - 8.8 cm\^3. Values are reported below for Baseline, averaged for 1-3 months, and averaged for 4-6 months during minocycline administration. |
| Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Baseline values, 1-3 Months Values (averaged), 4-6 Months Values (averaged) | It has been demonstrated in numerous studies over the past decade that magnetic resonance spectroscopy (MRS) can be used for the diagnosis of Alzheimer's disease. By measuring an area within the posterior cingulate gyrus, one can obtain a biochemical signature of that region in AD whereby NAA is reduced and mI is increased. These two biomarkers, N-acetylaspartate (NAA, a neuronal marker) and myo-inositol (mI, a glial marker) were quantified and then used to calculate NAA/mI (an index currently widely used for AD and MCI diagnosis). Scale of MRS biomarkers for aged-matched controls: NAA = 1.43, mI = 0.60, NAA/mI = 2.38. Any value lower than NAA/mI of 2.38 are considered not normal. Values are reported below for Baseline, averaged for 1-3 months, and averaged for 4-6 months during minocycline administration. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from local physicians, through Clinical Trials website and the AD association.
Participants by arm
| Arm | Count |
|---|---|
| Minocycline Subjects administered 50mg minocycline twice daily for 6 months | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Minocycline |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 73.5 years STANDARD_DEVIATION 8.8 |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC)
It has been demonstrated in numerous studies over the past decade that magnetic resonance spectroscopy (MRS) can be used for the diagnosis of Alzheimer's disease. By measuring an area within the posterior cingulate gyrus, one can obtain a biochemical signature of that region in AD whereby NAA is reduced and mI is increased. These two biomarkers, N-acetylaspartate (NAA, a neuronal marker) and myo-inositol (mI, a glial marker) were quantified and then used to calculate NAA/mI (an index currently widely used for AD and MCI diagnosis). Scale of MRS biomarkers for aged-matched controls: NAA = 1.43, mI = 0.60, NAA/mI = 2.38. Any value lower than NAA/mI of 2.38 are considered not normal. Values are reported below for Baseline, averaged for 1-3 months, and averaged for 4-6 months during minocycline administration.
Time frame: Baseline values, 1-3 Months Values (averaged), 4-6 Months Values (averaged)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Minocycline AD | Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Averaged Values for Months 1-3 | 1.78 Ratio | Standard Deviation 0.61 |
| Minocycline AD | Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Baseline Values | 1.69 Ratio | Standard Deviation 0.38 |
| Minocycline AD | Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Averaged Values for Months 4-6 | 1.84 Ratio | Standard Deviation 0.61 |
| Minocycline MCI | Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Averaged Values for Months 1-3 | 1.80 Ratio | — |
| Minocycline MCI | Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Baseline Values | 1.87 Ratio | — |
| Minocycline MCI | Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Averaged Values for Months 4-6 | 2.08 Ratio | — |
| Minocycline NC | Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Baseline Values | 2.42 Ratio | Standard Deviation 0.08 |
| Minocycline NC | Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Averaged Values for Months 4-6 | 2.47 Ratio | Standard Deviation 0.41 |
| Minocycline NC | Biomarker NAA/mI Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC) | Averaged Values for Months 1-3 | 2.44 Ratio | Standard Deviation 0.26 |
Primary
Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC).
Using magnetic resonance images acquired, hippocampal volume was measured monthly for 6 months. Normal range for hippocampal volume in aged-matched controls is 6.6 - 8.8 cm\^3. Values are reported below for Baseline, averaged for 1-3 months, and averaged for 4-6 months during minocycline administration.
Time frame: Baseline values, 1-3 Months Values (averaged), 4-6 Months Values (averaged)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Minocycline AD | Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Averaged Values for Months 4-6 | 4.94 cm^3 | Standard Deviation 1.2 |
| Minocycline AD | Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Averaged Values for Months 1-3 | 5.42 cm^3 | Standard Deviation 1.06 |
| Minocycline AD | Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Baseline Values | 5.49 cm^3 | Standard Deviation 1.14 |
| Minocycline MCI | Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Averaged Values for Months 4-6 | 7.60 cm^3 | — |
| Minocycline MCI | Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Baseline Values | 6.35 cm^3 | — |
| Minocycline MCI | Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Averaged Values for Months 1-3 | 6.30 cm^3 | — |
| Minocycline NC | Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Averaged Values for Months 1-3 | 6.92 cm^3 | Standard Deviation 0.48 |
| Minocycline NC | Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Baseline Values | 6.98 cm^3 | Standard Deviation 1.18 |
| Minocycline NC | Hippocampal Volumes Measured in Three Groups: Alzheimer Disease (AD), Mild Cognitive Impairment (MCI) and Normal, Age-matched Controls (NC). | Averaged Values for Months 4-6 | 6.82 cm^3 | Standard Deviation 0.45 |
Primary
Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
RBANS is a brief neurocognitive battery with four alternate forms, measuring immediate and delayed memory, attention, language, and visuospatial skills. RBANS was developed as a stand-alone core battery for the detection and neurocognitive characterization of dementia and as a brief neurocognitive battery for the detection and tracking of neurocognitive deficits in a variety of disorders. (Reference: http://rbans.com/) Qualitative Description of Index Scores: Index Score Classification 130 and above Very Superior 120-129 Superior 110-119 High Average 90-109 Average 80-89 Low Average 70-79 Borderline 69 and below Extremely Low Psychometric range for RBANS: AD 0 - 77 MCI 78 - 99 Normal \> 100 Range of scores: Minimum = 0, Maximum = 130 Values are reported below for Baseline, averaged for 1-3 months, and averaged for 4-6 months during minocycline administration.
Time frame: Baseline values, 1-3 Months Values (averaged), 4-6 Months Values (averaged)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Minocycline AD | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Averaged Values for Months 1-3 | 32.5 units on a scale | Standard Deviation 3.4 |
| Minocycline AD | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline Values | 49 units on a scale | Standard Deviation 8 |
| Minocycline AD | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Averaged Values for Months 4-6 | 32.9 units on a scale | Standard Deviation 4.2 |
| Minocycline MCI | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Averaged Values for Months 1-3 | 58.7 units on a scale | — |
| Minocycline MCI | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline Values | 81 units on a scale | — |
| Minocycline MCI | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Averaged Values for Months 4-6 | 63.8 units on a scale | — |
| Minocycline NC | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Baseline Values | 106 units on a scale | Standard Deviation 13 |
| Minocycline NC | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Averaged Values for Months 4-6 | 123.6 units on a scale | Standard Deviation 37.1 |
| Minocycline NC | Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) | Averaged Values for Months 1-3 | 108.4 units on a scale | Standard Deviation 26 |