PET Imaging of Cerebral Nicotinic Acetylcholine Receptors (nAchRs) in Early Alzheimer's Disease (AD) Assessed with the New Radioligand (-)-[18F]-Norchloro-Fluoro-Homoepibatidine (NCFHEB)

Objectives:

Post mortem studies have shown a degeneration of cholinergic neurons in the brain of AD-patients. Further evidence suggests that the loss of nAChRs is a major contributor to the cognitive deterioration in AD, whereby the alpha4beta2-nAChR subtype is thought to be the most severely reduced in the onset of AD. Using 2-[18F]F-A85380 PET we showed a significant decline in alpha4beta2-nAChRs in early AD-patients which correlated significantly with the loss of cognitive function (1, 2). However, this tracer was not well suited as a biomarker in a routine clinical set-up for early AD-diagnosis because of unfavourable properties (slow kinetics, long acquisition times up to 7 hours, limited alpha4beta2-receptor selectivity). We, therefore, developed the new radiotracer [18F]NCFHEB (epibatidine derivative without toxicity in humans) with significantly improved brain uptake, nAChR affinity and selectivity (3). Here, we present the results of the worldwide first ongoing NCFHEB-PET study in humans.
Methods:
6 mild AD-patients (NINCDS-ADRDA, age 76.7±5.9, MMSE 23.8±3.0) and 5 age-matched healthy controls (HC, age 71.1±5.3, MMSE 28.4±1.1) underwent NCFHEB-PET (370 MBq, 3D-acquisition, ECAT Exact HR+). All were nonsmokers and naïve for central acting medication. In each subject, 4 scans (41 frames) were acquired from 0-270 min post injection and motion correction was performed with SPM2. Kinetic modelling was applied to the VOI-based tissue-activity curves generated for 29 brain regions (irregularly anatomically defined via MRI co-registration) using a one tissue compartment model with measured arterial input-function. Total distribution volume (DV) and binding potential (BP, reference region: corpus callosum) werde used to characterize specific binding. Additionally, parametric images of DV were computed (Logan plot).
Results:
Image quality of NCFHEB scans was clearly superior to 2-[18F]F-A85380, and a 20 minutes scan already adequate for visual analysis. All 29 regions were well described with one tissue compartment. PET data acquired over only 90 minutes were sufficient to estimate all kinetic parameters precisely indicating a fast receptor binding kinetic (much faster than for 2-[18F]F-A85380). DVs in HCs increase as expected with receptor density: Corpus callosum (DV: 4.81±0.32), posterior cingulate (8.92±0.66), temporal (9.03±0.44), pons (11.00±1.19), thalamus (24.32±2.96). The AD-patients showed extensive BP reductions in frontal, parietal, temporal, anterior and posterior cingulated cortices, caudate, and hippocampus (all p<0.05) compared to HCs.
Conclusions:
Due to the significant shorter acquisition time and superior image quality NCFHEB appears to be a much more valuable tracer than 2-[18F]F-A85380 to image alpha4beta2-nAChRs in humans. Early AD-patients show significant declines of alpha4beta2-nAChRs in brain regions typically affected by AD-pathology. These results indicate that NCFHEB-PET has a great potential to be tested as a biomarker for early AD-diagnosis.
References:
1. O. Sabri,..P. Brust: Acetylcholine receptors in dementia and mild cognitive impairment. Eur J Nucl Med Mol Imaging 2008; 35 (Suppl. 1): 30-45.
2. K. Kenziorra,..O. Sabri: Decreased cerebral α4β2 nicotinic acetylcholine receptors in living patients with mild cognitive impairment and Alzheimer disease with positron emission tomography.
Eur J Nucl Med Mol Imaging 2010; DOI 10.1007/s00259-010-1644-5.
3. P. Brust,..O. Sabri: In-vivo measurement of nicotinic acetylcholine receptors with [18F]norchloro-fluoro-homoepibatidine (NCFHEB). Synapse 2008; 62: 205-218.