Assessing Mild Cognitive Impairment with Amyloid and Dopamine Terminal Molecular Imaging

Journal of Nuclear Medicine, published on April 9, 2013 as doi:10.2967/jnumed.112.112599 Assessing Mild Cognitive Impairment with Amyloid and Dopamine Terminal Molecular Imaging Roger L. Albin1–4, James F. Burke1,3,5, Robert A. Koeppe6, Bruno Giordani4,7, Sid Gilman1, and Kirk A. Frey1,6 1Department of Neurology, University of Michigan, Ann Arbor, Michigan; 2Geriatrics Research, Education, and Clinical Center, VAAAHS, Ann Arbor, Michigan; 3Neurology Service, VAAAHS, Ann Arbor, Michigan; 4Michigan Alzheimer Disease Center, Ann Arbor, Michigan; 5Robert Wood Johnson Clinical Scholars Program, University of Michigan, Ann Arbor, Michigan; 6Department of Radiology, University of Michigan, Ann Arbor, Michigan; and 7Department of Psychiatry, University of Michigan, Ann Arbor, Michigan have a progressive course, and others may improve over We evaluated PET-based classification of neurodegenerative time (8–12). Clinical trials enrolling MCI subjects face pathology in mild cognitive impairment (MCI). Methods: Our the same challenge as trials involving subjects with early study was a cross-sectional and prospective evaluation of a co- dementias: the strong likelihood of enrolling heteroge- hort of 27 MCI subjects drawn from a university-based cognitive neous subject populations, plus the problem of enrolling disorders clinic. We compared expert clinical consensus classification of MCI at entry and possible dementia at follow-up subjects who will not go on to develop dementia. The de- with molecular imaging–based classification using 11C-dihydo- velopment of PET ligands identifying characteristic patho- tetrabenazine PET measurement of striatal dopamine terminal logic features of different neurodegenerative dementias integrity and 11C-Pittsburgh compound B (11C-PiB) PET measure- offers the possibility of a minimally invasive subclassification ment of cerebral amyloid burden. Results: Eleven subjects were of MCI subjects based on well-characterized correlates of initially classified clinically as amnestic MCI, 7 as multidomain pathology (13,14). Because potential treatments to prevent MCI, and 9 as nonamnestic MCI. At a mean follow-up of 3 y, or delay onset of dementia are likely to target specific path- 18 subjects converted to dementia. PET imaging evidence of significant cerebral amyloid deposition or nigrostriatal denervation ologic processes, the identification of subject groups with was a strong predictor of conversion to dementia. There was only specific underlying pathologic features is likely to improve moderate concordance between expert clinical classifications the statistical power of clinical trials. and PET-based classifications of dementia subtypes. Con- There are 3 primary causes of neurodegenerative clusion: Combined PET molecular imaging of cerebral amy- dementias—Lewy body dementia (LBD), Alzheimer disease loid burden and striatal dopamine terminal integrity may be (AD), and frontotemporal dementias (FTDs). LBD is charac- useful for identifying subjects at high risk for progression to terized by substantial loss of nigrostriatal dopaminergic ter- dementia and in defining neurochemically differentiated sub- sets of MCI subjects. minals, together with cerebrocortical Lewy bodies and Lewy Key Words: dementia; Alzheimer disease; Lewy body dementia; neurites. AD and a significant percentage of LBD subjects frontotemporal dementia exhibit neuritic plaques composed of fibrillar amyloid pre- cursor protein fragments (Ab amyloid). FTDs generally lack J Nucl Med 2013; 54:1–7 DOI: 10.2967/jnumed.112.112599 these features and are characterized by deposition of a va- riety of protein species including t-protein and TAR-DNA- binding protein-43. Studies correlating amyloid imaging results with the postmortem assessments of amyloid burden indicate a good Mild cognitive impairment (MCI) is recognized as correlation between imaging and pathologic measures of a substantial risk factor for subsequent development of amyloid burden (15). Prior postmortem studies evaluating dementia (1). There is considerable interest in MCI subjects nigrostriatal degeneration in pathologically defined AD and as suitable target populations for clinical trials aimed at de- LBD samples indicated a high specificity for substantial loss laying dementia onset. MCI, however, is a heterogeneous of nigrostriatal dopaminergic terminals as a marker for LBD entity caused by all major neurodegenerative pathologies (16,17). These results, and others, indicate that molecular and vascular etiologies (1–7). Some MCI subjects do not imaging with amyloid and nigrostriatal dopamine terminal ligands may identify characteristic pathologic features of Received Aug. 9, 2012; revision accepted Dec. 4, 2012. neurodegenerative dementias. For correspondence or reprints contact: Roger L. Albin, 5023 BSRB, 109 We previously reported PET imaging–based classification Zina Pitcher Pl., Ann Arbor, MI, 48109-2200. E-mail: [email protected] of early, mild dementias with amyloid and dopamine terminal Published online nnnn. molecular imaging. We demonstrated only moderate (Cohen’s COPYRIGHT ª 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc. k 5 0.39) concordance between molecular imaging–based 11C-PIB AND 11C-DTBZ PET IN MCI • Albin et al. 1 jnm112599-pm n 4/5/13 Copyright 2013 by Society of Nuclear Medicine. classifications and expert consensus–based clinical classifica- procedure and the same raters, who were masked to the initial clin- tions (18). To clarify the potential role of this imaging-based ical consensus evaluations. Consensus assessment included evalua- approach in the subclassification of MCI and to evaluate the tion of progression to dementia. Subjects with persistent MCI were prediction of progression to dementia, we report the results of classified as described above. Subjects converting to dementia were combined PET imaging with the nigrostriatal dopamine ter- then classified as 1 of the 3 major forms of neurodegenerative dementia using standard criteria for AD, LBD, and FTD (20–22). minal marker 11C-dihydotetrabenazine and the Ab amyloid 11 11 marker C-Pittsburgh compound B ( C-PiB) in a cohort PET Imaging of MCI subjects. Subjects underwent 11C-PiB and 11C-dihydotetrabenazine PET imagingonaSiemensECATHR1 camera operated in 3-dimensional MATERIALS AND METHODS mode (septa retracted), and they were scanned within 2–3 wk of Subjects initial evaluation. The 2 radiotracer scans were usually performed on Twenty-seven subjects with primary symptoms of cognitive the same half day, with at least 2 h between scans to allow for impairment were recruited from the University of Michigan Cognitive physical decay of the first tracer before the second scan. 11C-PiB DisordersClinic.Thiswasaconvenience sample of subjects meeting was administered as an intravenous bolus of 45% of the total mass criteria for MCI and satisfying the following inclusion and exclusion dosage over 30 s, followed by constant infusion of the remaining criteria (18). Included subjects were over the age of 40, had cogni- 55% of the dose over the 80-min study duration (23). 11C-PiB PET tive symptoms for longer than 9 mo, and were capable of completing images were acquired as a dynamic series of 17 scan frames over neuropsychologic testing and research neuroimaging. Subjects with a total of 80 min as follows: 4 · 30 s, 3 · 1min,2· 2.5 min, a modified Hachinski scale score greater than 4 or meeting NINDS- 2 · 5min,and6· 10 min. Parametric 11C-PiB distribution volume AIREN (National Institute of Neurological Disorders and Stroke and ratio (DVR) images were computed by averaging the last 4 scan Association Internationale pour la Recherché et l’Enseignement en frames (40–80 min) normalized to the mean value in the cerebellar Neurosciences) criteria suggesting vascular dementia were excluded. hemisphere cortical gray matter. (1)-11C-dihydotetrabenazine was Subjects were excluded also if a finding suggested the following administered intravenously as a bolus containing 55% of the total possible nonneurodegenerative causes of cognitive decline: clin- mass dose over 30 s, followed by continuous infusion of the remain- ically significant abnormality on screening blood tests including ing 45% of the dose over the 60-min study duration (24). A dynamic · · vitamin B12 level and thyroid function tests, a Geriatric Depres- series of PET images was acquired over 60 min: 4 30 s, 3 1min, sion Score greater than 6, a history of seizure disorder, a history 2 · 2.5 min, 2 · 5min,and4· 10 min. Parametric 11C-dihydote- of cranial radiation therapy, a history of mental retardation, a re- trabenazine DVR images were computed by averaging the last 3 cent history of focal brain injury, focal neurologic deficits that de- scan frames (30–60 min) and normalized to the mean value in the veloped simultaneously with cognitive complaints, or the presence occipital cerebral cortex. This bolus-plus-infusion approach leads to of a systemic or medical illness that would confound the diagnosis steady-state or equilibrium conditions, and the tissue concentration of a degenerative dementia. The Institutional Review Board of the ratio yields DVR directly. University of Michigan (IRBMED) approved this investigation, and all participants signed an IRBMED-approved written informed PET Neuroimaging Classifications consent. PET image classifications were made by an expert familiar with the biodistributions of the tracers in normal and relevant pathologic Clinical Classification conditions. Following the procedure used in our prior study and the Clinical classification was

Load more