The Relationship Between Neuropsychological Testing and MRI, PET and COBRE - Project 1: AIM 2 (GE-180)

Parkinson Disease Clinical Trial

Official title:

The Relationship Between Neuropsychological Testing and MRI, PET and Blood Biomarkers in Neurodegenerative Disease (COBRE - Project 1): AIM 2

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03702816
• Other study ID #: 15-888
• Status: Terminated
• Phase: Phase 2
• Start date: December 13, 2018
• Est. completion date: September 29, 2019

Study information

• Verified date: April 2023
• Source: The Cleveland Clinic
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The complex pathological cascades leading to both Alzheimer's disease (AD) and Parkinson's disease (PD) involve, at various points, inflammation. Since inflammation is a treatable symptom, understanding how and when it impacts the brain, and where specifically in the brain, would offer important guidance in the development of new treatments, sorely needed in both diseases.

Microglia play an important anti-inflammatory role, and produce a substance, mitochondrial translocator protein (TSPO), whose presence can be used as a marker of regional inflammation. GE180 is a newly developed PET ligand which binds to TSPO and hence can be used in imaging studies to analyze regional inflammation in living patients. In prior studies it has shown regional specificity in multiple sclerosis and brain injury. In the current study, the investigators will be using GE180 to analyze regional and global inflammation in the brains of patients with AD and PD at a single time point.

The results of the current study will provide enriched understanding of inflammation in these conditions, and potentially provide preliminary data to inform design of future interventional trials.

Description:

This study will involve a cohort that is currently being established at the Cleveland Clinic Lou Ruvo Center for Brain Health. The cohort has been established under the NIH Center of Biomedical Research Excellence (COBRE) grant and involves annual collection of detailed neuropsychological testing and biomarkers (blood and neuroimaging) from all participants annually. Data are filed in a registry (CNTN). Participants include healthy controls, participants with PD (with and without mild cognitive impairment (MCI)) and patients with MCI (with or without positive florbetapir scan, which demonstrates underlying AD changes likely causing the cognitive impairment) and patients with AD. For the current study, we will focus on patients with MCI with associated underlying AD or PD.

Participants will undergo GE180 PET one time during the study. The approach to PET data collection and analysis will be similar to work done previously with an earlier generation ligand (Edison et al., 2008) and to other work with this tracer (Fan et al., 2016). Participants will complete ECGs and have their vitals taken prior to and immediately following injections. Briefly, the ligand will be injected, there will be a 90 minute uptake period, and scan acquisition will commence for 30 minutes, and will be collected in list mode and rebinned into 18 time frames post acquisition.

The total duration of the study visit will be around 4 hours, and the participants will receive $50 compensation for the visit.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 24
• Est. completion date: September 29, 2019
• Est. primary completion date: September 29, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 55 Years to 90 Years

Eligibility

Inclusion Criteria:

1. Be enrolled in CNTN

2. Aged 55 to 90

3. Available study partners

4. Willing and able to participate in longitudinal follow-up study

5. For MCI patients, fit criteria based in Movement Disorders Task Force or NIA

Exclusion Criteria:

1. Significant neurological disorders other than AD or PD;

2. Unstable medical conditions

3. History of major psychiatric diseases

4. MRI evidence of infarction or other focal lesion or multiple lacunes

5. Clinically significant abnormalities in B12 or TSH

6. Identified as having a common polymorphism (rs6971) in the TSPO gene which has been shown to reduce binding affinity of tracers similar to GE180. This testing will be done as part of their CNTN participation.

Related Conditions & MeSH terms

• Alzheimer Disease
• Inflammation
• Parkinson Disease

Intervention

Drug:
• GE180 PET Scan
GE180 PET Scan

Locations

Country	Name	City	State
United States	Lou Ruvo Center for Brain Health	Las Vegas	Nevada

Sponsors (1)

Lead Sponsor	Collaborator
Aaron Ritter, MD

Country where clinical trial is conducted

United States, 

References & Publications (15)

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Boutin H, Murray K, Pradillo J, Maroy R, Smigova A, Gerhard A, Jones PA, Trigg W. 18F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke. Eur J Nucl Med Mol Imaging. 2015 Mar;42(3):503-11. doi: 10.1007/s00259-014-2939-8. Epub 2014 Oct 29. — View Citation

Calsolaro V, Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions. Alzheimers Dement. 2016 Jun;12(6):719-32. doi: 10.1016/j.jalz.2016.02.010. Epub 2016 May 11. — View Citation

Chauveau F, Boutin H, Van Camp N, Dolle F, Tavitian B. Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imaging. 2008 Dec;35(12):2304-19. doi: 10.1007/s00259-008-0908-9. Epub 2008 Oct 1. — View Citation

Dickens AM, Vainio S, Marjamaki P, Johansson J, Lehtiniemi P, Rokka J, Rinne J, Solin O, Haaparanta-Solin M, Jones PA, Trigg W, Anthony DC, Airas L. Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med. 2014 Mar;55(3):466-72. doi: 10.2967/jnumed.113.125625. Epub 2014 Feb 10. — View Citation

Edison P, Archer HA, Gerhard A, Hinz R, Pavese N, Turkheimer FE, Hammers A, Tai YF, Fox N, Kennedy A, Rossor M, Brooks DJ. Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis. 2008 Dec;32(3):412-9. doi: 10.1016/j.nbd.2008.08.001. Epub 2008 Aug 15. — View Citation

Fan Z, Calsolaro V, Atkinson RA, Femminella GD, Waldman A, Buckley C, Trigg W, Brooks DJ, Hinz R, Edison P. Flutriciclamide (18F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein. J Nucl Med. 2016 Nov;57(11):1753-1759. doi: 10.2967/jnumed.115.169078. Epub 2016 Jun 3. — View Citation

Ji K, Miyauchi J, Tsirka SE. Microglia: an active player in the regulation of synaptic activity. Neural Plast. 2013;2013:627325. doi: 10.1155/2013/627325. Epub 2013 Nov 3. — View Citation

Kim YS, Joh TH. Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp Mol Med. 2006 Aug 31;38(4):333-47. doi: 10.1038/emm.2006.40. — View Citation

Liu B, Le KX, Park MA, Wang S, Belanger AP, Dubey S, Frost JL, Holton P, Reiser V, Jones PA, Trigg W, Di Carli MF, Lemere CA. In Vivo Detection of Age- and Disease-Related Increases in Neuroinflammation by 18F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice. J Neurosci. 2015 Nov 25;35(47):15716-30. doi: 10.1523/JNEUROSCI.0996-15.2015. — View Citation

Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, Lamb BT, Bhaskar K. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015 Jun;138(Pt 6):1738-55. doi: 10.1093/brain/awv081. Epub 2015 Mar 31. — View Citation

Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, StJean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012 Jan;32(1):1-5. doi: 10.1038/jcbfm.2011.147. Epub 2011 Oct 19. — View Citation

Rizzo G, Veronese M, Tonietto M, Zanotti-Fregonara P, Turkheimer FE, Bertoldo A. Kinetic modeling without accounting for the vascular component impairs the quantification of [(11)C]PBR28 brain PET data. J Cereb Blood Flow Metab. 2014 Jun;34(6):1060-9. doi: 10.1038/jcbfm.2014.55. Epub 2014 Mar 26. — View Citation

Turkheimer FE, Rizzo G, Bloomfield PS, Howes O, Zanotti-Fregonara P, Bertoldo A, Veronese M. The methodology of TSPO imaging with positron emission tomography. Biochem Soc Trans. 2015 Aug;43(4):586-92. doi: 10.1042/BST20150058. Epub 2015 Aug 3. — View Citation

Yokokura M, Mori N, Yagi S, Yoshikawa E, Kikuchi M, Yoshihara Y, Wakuda T, Sugihara G, Takebayashi K, Suda S, Iwata Y, Ueki T, Tsuchiya KJ, Suzuki K, Nakamura K, Ouchi Y. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2011 Feb;38(2):343-51. doi: 10.1007/s00259-010-1612-0. Epub 2010 Sep 16. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frontal GE180 Standardized Uptake Value Ratio (SUVR)	Frontal SUVR- GE180 binding potential in the frontal cortical ROI, as a marker of frontal neuroinflammation. Frontal neuroinflammation would be expected to relate to frontal lobe AD pathology, and given known frontal lobe role in executive system function, is hypothesized to relate to measures of executive function in particular, and also to memory and language dysfunction, as these have executive components. Greater frontal lobe GE180 is expected to relate to poorer cognitive function.	Baseline (Single scan)
Primary	Cingulate GE180 Standardized Uptake Value Ratio (SUVR)	Cingulate SUVR- GE180 binding potential in the cingulate ROI, as a marker of cingulate neuroinflammation. Cingulate neuroinflammation would be expected to relate to cingulate AD pathology, and given known cingulate lobe role in executive system function, is hypothesized to relate to measures of executive function in particular, with greater cingulate GE180 relating to poorer cognitive function.	Baseline (Single scan)
Primary	Parietal GE180 Standardized Uptake Value Ratio (SUVR)	Parietal SUVR - GE180 binding potential in the parietal cortical ROI, as a marker of parietal neuroinflammation. Parietal neuroinflammation would be expected to relate to parietal lobe AD pathology, and given known parietal lobe role in visual and executive system function, is hypothesized to relate to measures of visuospatial and executive skills in particular, with greater parietal lobe GE180 relating to poorer cognitive function.	Baseline (Single scan)
Primary	Temporal GE180 Standardized Uptake Value Ratio (SUVR)	Temporal SUVR-- GE180 binding potential in the temporal cortical ROI, as a marker of temporal neuroinflammation. Temporal neuroinflammation would be expected to relate to temporal lobe AD pathology, and given known temporal lobe role in memory and language system function, is hypothesized to relate to measures of memory in particular, with greater temporal lobe GE180 relating to poorer memory and language function.	Baseline (Single scan)
Primary	Whole Brain GE180 Standardized Uptake Value Ratio (SUVR)	Whole Brain GE180- GE180 binding potential in the whole brain, as a marker of global neuroinflammation. Global neuroinflammation would be expected to relate to more widespread pathology on average, and is hypothesized to relate to global measures of cognition, including the MoCA and DRS, with greater whole brain GE180 relating to poorer cognitive function overall.	Baseline (Single scan)
Primary	Memory Composite Score (Z-score)	The memory composite score is comprised from data from two gold-standard clinical measures of verbal and nonverbal memory (Rey Auditory Verbal Learning Test, delayed recall score; Brief Visuospatial Memory Test, Revised, delayed recall score). The raw score for each individual assessment is corrected for age based on published normative data for each test. These adjusted scores (T scores and/or scaled scores) are converted to z-scores, then the two z-scores are averaged together to create the composite score. A higher value is indicative of better memory function, a lower value is indicative of worse memory function. A z-score of 0 represents the sample mean. Composite Z-scores do not have direct clinical relevance.	Baseline (Pre-scan)
Primary	Executive Function Composite Score (Z-score)	The executive function composite score is comprised from data from two gold-standard clinical measures of set-shifting and inhibition (Trail Making Test, part B; Delis Kaplan Executive Functioning Scale Color Word Inhibition, inhibition score). The raw score for each individual assessment is corrected for age based on published normative data for each test. These adjusted scores (T scores and/or scaled scores) are converted to z-scores, then the two z-scores are averaged together to create the composite score. A higher value is indicative of better executive function, a lower value is indicative of worse executive function. A z-score of 0 represents the sample mean. Composite Z-scores do not have direct clinical relevance.	Baseline (Pre-scan)
Primary	Speed Composite Score (Z-score)	The speed composite score is comprised from data from two gold-standard clinical measures of speeded attention and psychomotor speed (Trail Making Test, part A; Symbol Digit Modalities Test, oral version). The raw score for the Symbol Digit Modalities Test, oral version is converted directly to a z-score based on published normative data. The Trail making Test, part A is corrected for age based on published normative data, resulting in a T-score, which is then converted to a z-score. Then the two z-scores are averaged together to create the composite score. A higher value is indicative of better speed function, a lower value is indicative of worse speed function. A z-score of 0 represents the sample mean. Composite Z-scores do not have direct clinical relevance.	Baseline (Pre-scan)
Primary	Language Composite Score (Z-score)	The language composite score is comprised from data from two gold-standard clinical measures of confrontation naming and semantic fluency (Boston Naming Test; Animal Naming Test). The raw score for the Animal Naming Test is converted directly to a z-score based on published normative data. The Boston Naming Test is corrected for age based on published normative data, resulting in a scaled score, which is then converted to a z-score. Then the two z-scores are averaged together to create the composite score. A higher value is indicative of better language function, a lower value is indicative of worse language function. A z-score of 0 represents the sample mean. Composite Z-scores do not have direct clinical relevance.	Baseline (Pre-scan)
Primary	Dementia Rating Score	DRS- The Dementia Rating Scale is a comprehensive, but relatively brief assessment of overall cognitive functioning. The measure consists of items testing memory, attention, executive skills, and visuospatial skill, for a total of 144 points. A score of less than 124 is indicative of dementia level cognitive functioning. A higher score indicates a better outcome.	Baseline (Pre-scan)
Primary	Montreal Cognitive Assessment Score (MoCA)	MoCA -The Montreal Cognitive Assessment is a brief screening tool, originally designed to detect patients with MCI in a memory disorders clinic [10]. Standard administration consists of 12 individual tasks grouped into seven cognitive domains (visuospatial/executive, naming; attention, language, abstraction, memory, and orientation). Task performance is summed generating both domain and a total score. An education correction of one point is added to the total score for individuals with 12 years of education or less. Scores range from 0-30, with a score of 26 or less indicating cognitive impairment.	Baseline (Pre-scan)