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

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

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

GE180 has limited Blood - brain barrier permeation, reducing its utility in neuroinflammation. COVID19 created supply chain issues, impacting enrollment.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Inclusion Criteria: Be enrolled in CNTN Aged 55 to 90 Available study partners Willing and able to participate in longitudinal follow-up study For MCI patients, fit criteria based in Movement Disorders Task Force or NIA Exclusion Criteria: Significant neurological disorders other than AD or PD; Unstable medical conditions History of major psychiatric diseases MRI evidence of infarction or other focal lesion or multiple lacunes Clinically significant abnormalities in B12 or TSH 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.

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