Objective: To investigate the time course of modifications in dopaminergic terminals during the premotor phase in LRRK2 genetically determined Parkinson’s disease (PD).

Background: Increased dopamine metabolism has been suggested as a compensatory mechanism in the premotor phase of PD. Little is known about the delay between compensatory mechanisms and motor symptoms onset. Here, we report the longitudinal investigation of PET scan brain imaging in a family with LRRK2-R1441H mutation including one participant who converted nine years after inclusion

Method: Four family members were included: two patients with PD (aged 67 and 59, PD duration 11 and 8 years) carrying the mutation (LRRK2+PD+), one unaffected sibling carrying the mutation (age 61, LRRK2+PD-) and one unaffected non-carrier (age 61, LRRK2-PD-). Subjects underwent clinical evaluation and PET-scan for dopamine transporter binding (¹¹C-PE2I) and L-DOPA uptake (¹⁸F-DOPA) repeatedly at two years interval.

Results: At baseline, LRRK2+PD+ patients had -77% and -82% decrease of ¹¹C-PE2I binding, and -81% and -70% decrease of ¹⁸F-DOPA uptake in the most affected putamen relative to normal data. The LRRK2+PD- participant had -57% decrease of ¹¹C-PE2I binding in the left putamen (right binding in the normal range), whereas ¹⁸F-DOPA uptake was not altered (-21%) but decreased progressively over time, reaching -51% at the time of conversion, 9 years after inclusion. PET imaging parameters of the LRRK2-PD- subject were normal values and remained stable during follow-up.

Conclusion: This observation confirms the early upregulation of L-DOPA metabolism compensating dopaminergic nerve terminal loss up to nine years before conversion to clinical PD. This is the first report associating evolution of distinct presynaptic markers and clinical evaluation over 9 years before PD diagnosis.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/premotor-compensatory-mechanisms-in-parkinsons-disease-with-lrrk2-r1441h-mutation/