Evaluation of [123I]CLINDE and SPECT as a Marker of Inflammation in Subjects With PD or AD and in Healthy Subjects
| Status: | Terminated |
|---|---|
| Conditions: | Alzheimer Disease, Healthy Studies, Parkinsons Disease, Neurology, Multiple Sclerosis |
| Therapuetic Areas: | Neurology, Other |
| Healthy: | No |
| Age Range: | 30 - 50 |
| Updated: | 4/5/2019 |
| Start Date: | January 2008 |
| End Date: | November 1, 2009 |
Evaluation of [123I]CLINDE and SPECT as a Marker of Inflammation in Subjects With Parkinson Disease or Alzheimer Disease and in Healthy Subjects
To assess the dynamic uptake and washout of 123-I CLINDE, a potential imaging biomarker for
inflammatory changes in brain, using single photon emission computed tomography (SPECT) in
similarly aged healthy controls and subjects with Alzheimer (AD) or Parkinson disease (PD).
To perform blood metabolite characterization of 123-I CLINDE in healthy and subjects with AD
or PD to determine the nature of metabolites in assessment of 123-I CLINDE as a single photon
computed tomography (SPECT) brain imaging agent.
Evaluate the test/retest reproducibility of 123-I CLINDE, and SPECT in AD and PD subjects and
healthy controls
inflammatory changes in brain, using single photon emission computed tomography (SPECT) in
similarly aged healthy controls and subjects with Alzheimer (AD) or Parkinson disease (PD).
To perform blood metabolite characterization of 123-I CLINDE in healthy and subjects with AD
or PD to determine the nature of metabolites in assessment of 123-I CLINDE as a single photon
computed tomography (SPECT) brain imaging agent.
Evaluate the test/retest reproducibility of 123-I CLINDE, and SPECT in AD and PD subjects and
healthy controls
When microglia become activated they express peripheral benzodiazepine receptors (PBR) or
binding sites on their mitochondrial membrane. PBRs are functionally and structurally
distinct from central benzodiazepine receptors associated with y-aminiobutric acid
(GABA)-regulated chloride channels. PBRs are found in abundance in peripheral organs and
hematologic cells, but are present at only very low levels in the normal central nervous
system (Banati, 2002). CLINDE is a phenylimidazopyridine and appears to bind selectively to
the PBR. In the absence of excessive blood in the CNS an increase CLINDE binding to PBR is a
potential marker of microglial activation in the CNS. The increase in CLINDE binding may be
an indicator of the transition of microglia from a resting to an activated state. When
labeled with 123-I and used as a SPECT radiotracer, CLINDE may serve as an in vivo marker of
microglial activation in Alzheimer disease and Parkinson disease.
The 123-I radioactive tag offers distinct advantages for large-scale clinical imaging studies
of anti-inflammatory targeted treatments as a marker of microglial activation and efficacy of
therapeutic intervention. The half-life (13.1 h) of 123-I permits imaging in multiple
subjects in a single research-dedicated imaging center, with multiple research subjects per
day. This minimizes variability introduced in multi-center 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 CLINDE as a biomarker of microglial activation in
neurodegenerative diseases requires human validation studies. Expanding upon our previous
work with b-amyloid ligands (123I-IMPY, 123-I MNI-187) for AD and dopamine transporter
ligands (123-I B-CIT, Altropane) for PD, we desire to develop and characterize 123-I CLINDE
as a potential marker for microglial activation in association with neuronal damage that may
be applicable to multiple neurodegenerative diseases. Ultimately a marker of microglial
activation could be used for large-scale quantitative brain imaging trials in AD or PD,
specifically to investigate the agent as an objective biomarker in treatments aimed at
reducing inflammatory changes in these conditions. The significance of this work lies in
applying state-of-art quantitative neuroimaging tools to develop a relevant biomarker in
individuals with neurodegenerative diseases with the intention of using this efficiently in
large clinical imaging trials.
binding sites on their mitochondrial membrane. PBRs are functionally and structurally
distinct from central benzodiazepine receptors associated with y-aminiobutric acid
(GABA)-regulated chloride channels. PBRs are found in abundance in peripheral organs and
hematologic cells, but are present at only very low levels in the normal central nervous
system (Banati, 2002). CLINDE is a phenylimidazopyridine and appears to bind selectively to
the PBR. In the absence of excessive blood in the CNS an increase CLINDE binding to PBR is a
potential marker of microglial activation in the CNS. The increase in CLINDE binding may be
an indicator of the transition of microglia from a resting to an activated state. When
labeled with 123-I and used as a SPECT radiotracer, CLINDE may serve as an in vivo marker of
microglial activation in Alzheimer disease and Parkinson disease.
The 123-I radioactive tag offers distinct advantages for large-scale clinical imaging studies
of anti-inflammatory targeted treatments as a marker of microglial activation and efficacy of
therapeutic intervention. The half-life (13.1 h) of 123-I permits imaging in multiple
subjects in a single research-dedicated imaging center, with multiple research subjects per
day. This minimizes variability introduced in multi-center 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 CLINDE as a biomarker of microglial activation in
neurodegenerative diseases requires human validation studies. Expanding upon our previous
work with b-amyloid ligands (123I-IMPY, 123-I MNI-187) for AD and dopamine transporter
ligands (123-I B-CIT, Altropane) for PD, we desire to develop and characterize 123-I CLINDE
as a potential marker for microglial activation in association with neuronal damage that may
be applicable to multiple neurodegenerative diseases. Ultimately a marker of microglial
activation could be used for large-scale quantitative brain imaging trials in AD or PD,
specifically to investigate the agent as an objective biomarker in treatments aimed at
reducing inflammatory changes in these conditions. The significance of this work lies in
applying state-of-art quantitative neuroimaging tools to develop a relevant biomarker in
individuals with neurodegenerative diseases with the intention of using this efficiently in
large clinical imaging trials.
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 probable 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 < 25.
- Modified Hachinski Ischemia Scale score of ≤ 4.
- Geriatric Depression Scales (GDS) ≤ 10.
- For females, non-child bearing potential a negative urine or blood pregnancy test on
day of 123-I CLINDE injection.
Parkinson's Subject Selection. Subjects who have a clinical diagnosis of mild to moderate
Parkinson disease will be recruited for this study. The following criteria will be met for
inclusion of PD subjects in this study:
- The participant is 30 years or older.
- Written informed consent is obtained.
- Participants have a clinical diagnosis of Parkinson disease (at least two of the three
cardinal symptoms: resting tremor, rigidity, bradykinesia).
- Geriatric Depression Scales (GDS) ≤ 10.
- Hoehn and Yahr ≤4.
- For females, non-child bearing potential a negative urine or blood pregnancy test on
day of 123-I CLINDE 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 30 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 a negative urine or blood pregnancy test on
day of 123-I CLINDE injection.
Exclusion Criteria:
Alzheimer's subjects will be excluded from participation for the following reasons:
- The subject has a 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 evidence of clinically significant gastrointestinal, cardiovascular,
hepatic, renal, hematological, neoplastic, endocrine, neurological, immunodeficiency,
pulmonary, or other disorder or disease.
- Pregnancy
- Positive urine drug test.
Parkinson's 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 evidence of clinically significant gastrointestinal, cardiovascular,
hepatic, renal, hematological, neoplastic, endocrine, neurological, immunodeficiency,
pulmonary, or other disorder or disease.
- Pregnancy
- Positive urine drug test.
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 evidence of clinically significant gastrointestinal, cardiovascular,
hepatic, renal, hematological, neoplastic, endocrine, neurological, immunodeficiency,
pulmonary, or other disorder or disease.
- Pregnancy
- Positive urine drug test.
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