Objective: To compare brain mitochondrial respiratory Complex-1 (mito-C1) between Parkinson’s disease (PD) and PD dementia/Dementia with Lewy Bodies (PDD/DLB) participants and unimpaired controls, using ¹⁸F-BCPP-EF, a PET radioligand targeting mito-C1 [1, 2]. In this pilot study, we tested the hypotheses that ¹⁸F-BCPP-EF PET imaging would detect decreased mito-C1 in relevant brain regions in PD compared to controls, and that cognitive impairment would show a unique mitochondrial signature.

Background: Growing evidence suggests mitochondrial dysfunction is central to PD pathogenesis, and this may initiate with specific dysfunction of mito-C1. However, until the development of ¹⁸F-BCPP-EF, mito-C1 activity could not be studied in the living human brain. ¹⁸F-BCPP-EF binds specifically to mito-C1 and has optimized properties for brain imaging [1, 2].

Method: Control (n=9), cognitively unimpaired PD (n=15), and PDD/DLB (n=8) participants underwent neurologic evaluation, MRI, and ¹⁸F-BCPP-EF PET imaging. Standardized uptake value ratios (SUVR) were computed for ¹⁸F-BCPP-EF target regions normalized to subcortical white matter (centrum semiovale) [3] .

Results: There was no significant difference in mean age (sd) between control 70.3 (4.6), PD 71.3 (7.6), and PDD/DLB 73.4 (5.1), and no correlation between either age or MDS-UPDRS motor score and ¹⁸F-BCPP-EF SUVR in any region. Overall, ¹⁸F-BCPP-EF SUVR was not significantly different between control (n=9) and all PD (n=18;15 PD + 3 PDD) in midbrain, caudate, putamen, or anterior ventral striatum. However, the data revealed a negative correlation (Pearson’s R) between disease duration and ¹⁸F-BCPP-EF SUVR in anterior putamen (R= -0.619, p = 0.0008) posterior putamen (R= -0.517, p = 0.0058), and precommisural dorsal caudate (R= -0.382, p=0.0357). In some cases early in disease course, elevated ¹⁸F-BCPP-EF binding was observed in these regions. PDD/DLB brains showed reduced ¹⁸F-BCPP-EF binding specifically in occipital lobe compared to controls (ANOVA followed by Tukey’s HSD testing p= 0.042), which was not observed in cognitively intact PD (¹⁸F-BCPP-EF mean SUVR (SEM): Control 2.97 (0.09); PD 2.91 (0.09); DLB/PDD 2.52 (0.20)).

Conclusion: Our pilot data support a role for mitochondrial dysfunction in PD that may change as disease progresses. In PDD/DLB, occipital loss of mito-C1 suggests distinct localized mitochondrial impairment.

References: 1. Tsukada H, Nishiyama S, Fukumoto D, Kanazawa M, Harada N. Novel PET probes 18F-BCPP-EF and 18F-BCPP-BF for mitochondrial complex I: a PET study in comparison with 18F-BMS-747158-02 in rat brain. J Nucl Med 2014;55:473-480.
2. Harada N, Nishiyama S, Kanazawa M, Tsukada H. Development of novel PET probes, [18F]BCPP-EF, [18F]BCPP-BF, and [11C]BCPP-EM for mitochondrial complex 1 imaging in the living brain. J Labelled Comp Radiopharm 2013;56:553-561.
3. Mansur A, Rabiner EA, Tsukada H, Comley RA, Lewis Y, Huiban M, Passchier J, Gunn RN. Test-retest variability and reference region-based quantification of [18F]BCPP-EF for imaging mitochondrial complex I in the human brain. J Cereb Blood Flow Metab 2021, 41:771-779.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mitochondrial-complex-i-brain-imaging-in-parkinsons-disease-and-lewy-body-dementia/