Evaluation of [123I] MNI-340 and SPECT as a Marker of Beta-Amyloid Protein Deposition
| Status: | Terminated |
|---|---|
| Conditions: | Alzheimer Disease |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 50 - Any |
| Updated: | 4/5/2019 |
| Start Date: | April 2008 |
| End Date: | July 2008 |
Evaluation of [123I] MNI-340 and SPECT as a Marker of Beta-amyloid Protein Deposition in Subjects With Alzheimer Disease in Comparison to Healthy Subjects
The main objectives of this proposal are as follows:
To assess the dynamic uptake and washout of 123-I MNI-340, a potential imaging biomarker for
β-amyloid burden in brain, using single photon emission computed tomography (SPECT) in
similarly aged Alzheimer's (AD) subjects and healthy controls
To perform blood metabolite characterization of 123-I MNI-340 in healthy and AD subjects to
determine the metabolic fate and nature of metabolites in assessment of 123-I MNI-340 as a
single photon computed tomography (SPECT) brain imaging agent
To assess the dynamic uptake and washout of 123-I MNI-340, a potential imaging biomarker for
β-amyloid burden in brain, using single photon emission computed tomography (SPECT) in
similarly aged Alzheimer's (AD) subjects and healthy controls
To perform blood metabolite characterization of 123-I MNI-340 in healthy and AD subjects to
determine the metabolic fate and nature of metabolites in assessment of 123-I MNI-340 as a
single photon computed tomography (SPECT) brain imaging agent
Background:
Alzheimer's dementia (AD) is a common disorder of the aging brain causing progressive and
irreversible impairment in memory and cognitive function. Beginning with the initial
description of Alzheimer's dementia (AD) in 1906 when abnormal accumulations of plaques and
tangles in the brain of a woman with severe cognitive impairment were first noted, the
pathophysiology of AD has been intimately associated with a progressive neuropathologic
process involving abnormal protein deposition in brain. More recent work has implicated the
accumulation of β-amyloid as an early feature of AD, which may be directly responsible for
some of the clinical manifestations of the disease. Pathologic studies suggest levels of
β-amyloid are elevated even in cases classified as having questionable dementia (CDR score =
0.5), and increases in amyloid are strongly correlated with cognitive decline. Increases in
β-amyloid precede significant tau pathology suggesting the formation of plaques early in the
disease may be of clinical importance.
Until recently post-mortem examination of brain tissues was the only means available for
directly evaluating the changes occurring in the brain in AD and related neurodegenerative
diseases. In the last decade, the development of highly specific techniques for imaging the
brain in AD has expanded our ability to measure the process of the disease over time in a
living individual. Briefly, these techniques involve intravenous administration of
radioactively-labeled compounds which bind to selective target sites in brain. The
scintigraphic imaging methods PET (positron emission tomography) or SPECT (single photon
emission computed tomography) are able to detect the spatial distribution of the radioactive
compound in the brain and can be used as an objective, sensitive, and accurate method to
quantify the concentration of the targets site in different brain regions.
Using these techniques, β-amyloid aggregates have been successfully imaged in several studies
in AD patients using high affinity 11-C and 18-F-labeled PET tracers (PIB and FDDNP, AV-1).
More recently, another tracer, based on a thioflavin-S derivative,
6-iodo-2-(4'-dimethylamino-)phenyl-imidazol[1,2-a]pyridine, IMPY, labeled with 123-I has been
used to image amyloid. MNI-340 has a similar structure to PIB, but the 123-I radioactive tag
offers distinct advantages for large-scale clinical imaging studies of β -amyloid plaque
targeted treatments as a marker of plaque burden and efficacy of therapeutic intervention.
The longer half-life (13.1 h) of 123-I permits imaging in multiple subjects in a single
research-dedicated imaging center. This minimizes variability introduced in multicenter
quantitative imaging trials where different cameras, image processing methods, and QA
procedures all conspire to increase the variance imaging biomarkers. Using this model, our
group pioneered a method to evaluate the loss of dopamine function in Parkinson's disease
using a radioactive drug 123-I β-CIT, which binds directly to dopamine nerve terminals.
The adaptation of imaging agents like 123-I MNI-340 as a biomarker of β-amyloid deposition in
AD patients for assessing disease requires human validation studies. The purpose of this
study is to develop and characterize 123-I MNI-340 as an objective biomarker in AD. The
significance of this work lies in applying state-of-art quantitative neuroimaging tools to
develop a relevant biomarker in living AD patients. In this context we propose to investigate
the feasibility of applying this technique as an imaging biomarker of disease in AD patients.
Research Plan:
General Design and Methods. The underlying goal of this study is to assess 123-I MNI-340
SPECT imaging as a tool to detect ß-amyloid deposition in the brain of AD research
participants and age- and gender-matched healthy subjects. All study procedures will be
conducted at the Institute for Neurodegenerative Disorders (IND) and Molecular NeuroImaging
(MNI) in New Haven, CT. Approximately 10 patients with Alzheimers disease (AD) and 10
similarly aged healthy controls will be recruited to participate in this study. Healthy
controls will be screened to ensure that there is no evidence of cognitive decline or
significant neurological deficit.
Informed consent will be obtained for all subjects. All subjects will undergo a screening
evaluation including baseline clinical laboratory testing, a baseline physical and
neurological evaluation and baseline cognitive evaluations. Subjects will be given a bolus
injection of 123-I MNI-340 in an antecubital vein. Subjects will undergo serial SPECT imaging
scans and serial venous plasma sampling for measurement of 123-I MNI-340 in plasma (both
protein bound and free) over a period of up to 8 hours. The quantitative and visual imaging
analyses will be performed by an image-processing specialist who will remain blinded to any
clinical information.including diagnosis. The primary imaging outcome measure will be the
brain regional distribution volumes expressed as a brain tissue to plasma ratio of the
radioligand, 123-I MNI-340. Time to the peak uptake and amplitude of the peak uptake will be
evaluated for all brain regions and the results for the AD patients and controls will be
compared.
Alzheimer's dementia (AD) is a common disorder of the aging brain causing progressive and
irreversible impairment in memory and cognitive function. Beginning with the initial
description of Alzheimer's dementia (AD) in 1906 when abnormal accumulations of plaques and
tangles in the brain of a woman with severe cognitive impairment were first noted, the
pathophysiology of AD has been intimately associated with a progressive neuropathologic
process involving abnormal protein deposition in brain. More recent work has implicated the
accumulation of β-amyloid as an early feature of AD, which may be directly responsible for
some of the clinical manifestations of the disease. Pathologic studies suggest levels of
β-amyloid are elevated even in cases classified as having questionable dementia (CDR score =
0.5), and increases in amyloid are strongly correlated with cognitive decline. Increases in
β-amyloid precede significant tau pathology suggesting the formation of plaques early in the
disease may be of clinical importance.
Until recently post-mortem examination of brain tissues was the only means available for
directly evaluating the changes occurring in the brain in AD and related neurodegenerative
diseases. In the last decade, the development of highly specific techniques for imaging the
brain in AD has expanded our ability to measure the process of the disease over time in a
living individual. Briefly, these techniques involve intravenous administration of
radioactively-labeled compounds which bind to selective target sites in brain. The
scintigraphic imaging methods PET (positron emission tomography) or SPECT (single photon
emission computed tomography) are able to detect the spatial distribution of the radioactive
compound in the brain and can be used as an objective, sensitive, and accurate method to
quantify the concentration of the targets site in different brain regions.
Using these techniques, β-amyloid aggregates have been successfully imaged in several studies
in AD patients using high affinity 11-C and 18-F-labeled PET tracers (PIB and FDDNP, AV-1).
More recently, another tracer, based on a thioflavin-S derivative,
6-iodo-2-(4'-dimethylamino-)phenyl-imidazol[1,2-a]pyridine, IMPY, labeled with 123-I has been
used to image amyloid. MNI-340 has a similar structure to PIB, but the 123-I radioactive tag
offers distinct advantages for large-scale clinical imaging studies of β -amyloid plaque
targeted treatments as a marker of plaque burden and efficacy of therapeutic intervention.
The longer half-life (13.1 h) of 123-I permits imaging in multiple subjects in a single
research-dedicated imaging center. This minimizes variability introduced in multicenter
quantitative imaging trials where different cameras, image processing methods, and QA
procedures all conspire to increase the variance imaging biomarkers. Using this model, our
group pioneered a method to evaluate the loss of dopamine function in Parkinson's disease
using a radioactive drug 123-I β-CIT, which binds directly to dopamine nerve terminals.
The adaptation of imaging agents like 123-I MNI-340 as a biomarker of β-amyloid deposition in
AD patients for assessing disease requires human validation studies. The purpose of this
study is to develop and characterize 123-I MNI-340 as an objective biomarker in AD. The
significance of this work lies in applying state-of-art quantitative neuroimaging tools to
develop a relevant biomarker in living AD patients. In this context we propose to investigate
the feasibility of applying this technique as an imaging biomarker of disease in AD patients.
Research Plan:
General Design and Methods. The underlying goal of this study is to assess 123-I MNI-340
SPECT imaging as a tool to detect ß-amyloid deposition in the brain of AD research
participants and age- and gender-matched healthy subjects. All study procedures will be
conducted at the Institute for Neurodegenerative Disorders (IND) and Molecular NeuroImaging
(MNI) in New Haven, CT. Approximately 10 patients with Alzheimers disease (AD) and 10
similarly aged healthy controls will be recruited to participate in this study. Healthy
controls will be screened to ensure that there is no evidence of cognitive decline or
significant neurological deficit.
Informed consent will be obtained for all subjects. All subjects will undergo a screening
evaluation including baseline clinical laboratory testing, a baseline physical and
neurological evaluation and baseline cognitive evaluations. Subjects will be given a bolus
injection of 123-I MNI-340 in an antecubital vein. Subjects will undergo serial SPECT imaging
scans and serial venous plasma sampling for measurement of 123-I MNI-340 in plasma (both
protein bound and free) over a period of up to 8 hours. The quantitative and visual imaging
analyses will be performed by an image-processing specialist who will remain blinded to any
clinical information.including diagnosis. The primary imaging outcome measure will be the
brain regional distribution volumes expressed as a brain tissue to plasma ratio of the
radioligand, 123-I MNI-340. Time to the peak uptake and amplitude of the peak uptake will be
evaluated for all brain regions and the results for the AD patients and controls will be
compared.
Inclusion Criteria:
- Alzheimer's Subject Selection. Subjects who have a clinical diagnosis of mild to
moderate Alzheimer's disease will be recruited for this study. The following criteria
will be met for inclusion of AD subjects in this study:
- The participant is 50 years or older.
- Written informed consent is obtained.
- Participants have a clinical diagnosis of Alzheimer's disease based on National
Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's
Disease and Related Disorders Association (NINCDS/ADRDA) criteria.
- Mini-Mental Status Exam score > 16 and < 25.
- Modified Hachinski Ischemia Scale score of ≤ 4.
- Geriatric Depression Scales (GDS) ≤ 10.
- For females, non-child bearing potential or negative urine and blood pregnancy
test on day of 123-I MNI-340 injection.
- Healthy Control Subject Selection: Healthy control subjects who have no neurological
disease will be recruited for this study. The following criteria will be met for
inclusion of healthy control subjects in this study:
- The participant is 50 years or older.
- Written informed consent is obtained.
- Negative history of neurological or psychiatric illness based on evaluation by a
research physician.
- Mini-Mental Status Exam score ≥28.
- For females, non-child bearing potential or negative urine and blood pregnancy
test on day of 123-I MNI-340 injection.
Exclusion Criteria:
- Alzheimer's subjects will be excluded from participation for the following reasons:
- The subject has signs or symptoms of another neurodegenerative disease including
Parkinson's disease, diffuse Lewy body dementia, or history of significant
cerebrovascular disease.
- The subject has a clinically significant abnormal laboratory value and/or
clinically significant unstable medical or psychiatric illness
- The subject has any disorder that may interfere with drug absorption
distribution, metabolism, or excretion (including gastrointestinal surgery).
- The subject has evidence of clinically significant gastrointestinal,
cardiovascular, hepatic, renal, hematological, neoplastic, endocrine,
neurological, immunodeficiency, pulmonary, or other disorder or disease.
- The subject has participated in another clinical study within the previous 30
days.
- Clinically significant MRI evidence of vascular disease or alternative neurologic
disorder
- Pregnancy
- Healthy control subjects will be excluded from participation for the following
reasons:
- The subject has a clinically significant abnormal laboratory value and/or
clinically significant unstable medical or psychiatric illness.
- The subject has any disorder that may interfere with drug absorption
distribution, metabolism, or excretion (including gastrointestinal surgery).
- The subject has evidence of clinically significant gastrointestinal,
cardiovascular, hepatic, renal, hematological, neoplastic, endocrine,
neurological, immunodeficiency, pulmonary, or other disorder or disease.
- The subject has participated in another clinical study within the previous 30
days.
- Pregnancy
- Clinically significant MRI evidence of vascular disease or neurologic disorder
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