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Meeting ReportOral - PhysicianPharm

Human hippocampal [18F]nifene binding to nicotinic acetylcholinergic α4β2* receptors is reduced in postmortem Alzheimer’s disease brains

Jogeshwar Mukherjee, Christopher Liang, Anthony Campoy, Harsimran Kaur, Amina Syed and Tram Danh
Journal of Nuclear Medicine May 2021, 62 (supplement 1) 121;
Jogeshwar Mukherjee
1Radiological Sciences University of California-Irvine Irvine CA United States
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Christopher Liang
1Radiological Sciences University of California-Irvine Irvine CA United States
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Anthony Campoy
1Radiological Sciences University of California-Irvine Irvine CA United States
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Harsimran Kaur
1Radiological Sciences University of California-Irvine Irvine CA United States
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Amina Syed
2Radiological Sciences Univ of Calfornia - Irvine Irvine CA United States
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Tram Danh
1Radiological Sciences University of California-Irvine Irvine CA United States
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Abstract

121

Objectives: Hippocampus (HP) in the human brain is innervated with α4β2* nicotinic acetylcholine receptors (nAChRs). This receptor system is involved in cognition, learning and memory and may be adversely affected in Alzheimer’s disease (AD). Neurofibrillary tangle (NFT) PET imaging has confirmed initial accumulation of NFT in AD HP which progressively spreads to cortical regions and may be related to Braak stages and clinical diagnosis of AD. We have previously reported suitability of [18F]Nifene human PET studies in normal subjects. In our efforts to consider translational use of [18F]Nifene PET in AD, we have carried out quantitative autoradiographic evaluation of nicotinic α4β2* nAChRs using HP (CA1/subiculum plus) in postmortem AD (n=16) and compared to control (ND, n=16) brains using [18F]Nifene.

Methods: Well-characterized human post-mortem brain tissue sections (10 μm thick) consisting of HP CA1-subiculum regions, (AD, n=8F and 8M and ND =8F and 8M) were obtained from Banner Health, Sun City, Arizona. Brain slices were incubated [18F]Nifene (1 μCi/cc) in Tris/pH 7.4 buffer at 25 oC for 1 hr. Nonspecific binding was measured using 300 μM nicotine. Adjacent sections were tested for NFT using [125I]IPPI (0.1 μCi/cc) in PBS pH 7.4 buffer at 25 oC for 1 hr using our previously published protocols. Additionally, slices were tested for Aβ plaques using [3H]PIB. Anti-tau and anti-Aβ immunostaining was carried out on adjacent slices. Using the Optiquant program (Packard Instruments Co), regions of interest were drawn and digital light units/ mm2 (DLU/mm2) were used to quantify the percentage change in binding of [18F]Nifene, [125I]IPPI and [3H]PIB.

Results: All ND subjects exhibited significant [18F]Nifene binding in the HP CA1-SUB regions compared to the lower binding in adjacent white matter (WM) regions. This is consistent with our PET [18F]Nifene results in healthy human subjects. Average HP ratio (n=16) of GM/WM = 4.38 in the ND HP CA1-SUB, while it was lower in the AD HP CA1-SUB (n=16), GM/WM=2.76. Using the ratios, a 37% reduction in [18F]Nifene AD HP CA1-SUB was measured. Since WM binding in ND and AD subjects was similar, using HP CA1-SUB total binding alone (Avg DLU/mm2 ND=4571 and AD=2997) also indicated a 34% decrease in AD HP CA1-SUB. Male-female [18F]Nifene HP CA1-SUB differences in the brain sections were not significant, both in ND and AD subjects. Howvever, this will have to be ascertained in PET studies. Nicotine displaced [18F]Nifene binding from these brain regions. As expected, [18F]Nifene binding in the AD subjects was inversely correlated to [125I]IPPI and [3H]PIB binding in HP CA1-SUB. Conclusions: Cholinergic pathway deficits in AD have been associated with cognitive impairment. Our results with [18F]Nifene show α4β2* nAChRs are reduced significantly in HP CA1-SUB of the postmortem AD brain. The extent of reduction is significantly greater in AD compared to the 5-10% test-retest error found in human [18F]Nifene PET, which requires a PET scan of less than 60 minutes. Thus, [18F]Nifene PET may potentially have a complementary role along with ongoing NFT PET studies in AD subjects. Information on the status of the α4β2* nAChR system may be useful in treatment planning using acetylcholinesterase inhibitors.Research Support: NIH/NIA RF1 AG029479

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Journal of Nuclear Medicine
Vol. 62, Issue supplement 1
May 1, 2021
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Human hippocampal [18F]nifene binding to nicotinic acetylcholinergic α4β2* receptors is reduced in postmortem Alzheimer’s disease brains
Jogeshwar Mukherjee, Christopher Liang, Anthony Campoy, Harsimran Kaur, Amina Syed, Tram Danh
Journal of Nuclear Medicine May 2021, 62 (supplement 1) 121;

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Human hippocampal [18F]nifene binding to nicotinic acetylcholinergic α4β2* receptors is reduced in postmortem Alzheimer’s disease brains
Jogeshwar Mukherjee, Christopher Liang, Anthony Campoy, Harsimran Kaur, Amina Syed, Tram Danh
Journal of Nuclear Medicine May 2021, 62 (supplement 1) 121;
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