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Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs.

ABSTRACT: Impairment of the ubiquitin proteasome system has been implicated in Parkinson's disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. Göttingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port. Minipigs were imaged at baseline and after cumulative doses of 200 and 400??g lactacystin, respectively. Main radioligands included [11C]-DTBZ (vesicular monoamine transporter type 2) and [11C]-yohimbine (?2-adrenoceptor). [11C]-DASB (serotonin transporter) and [11C]-PK11195 (activated microglia) became available later in the study and we present their results in a smaller subset of animals for information purposes only. Striatal [11C]-DTBZ binding potentials decreased significantly by 16% after 200??g compared to baseline, but the decrease was not sustained after 400??g (n?=?6). [11C]-yohimbine volume of distribution increased by 18-25% in the pons, grey matter and the thalamus after 200??g, which persisted at 400??g (n?=?6). In the later subset of minipigs, we observed decreased [11C]-DASB (n?=?5) and increased [11C]-PK11195 (n?=?3) uptake after 200??g. These changes may mimic monoaminergic changes and compensatory responses in early Parkinson's disease.

SUBMITTER: Lillethorup TP

PROVIDER: S-EPMC6200778 | biostudies-other | 2018 Oct

REPOSITORIES: biostudies-other

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Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs.

Lillethorup Thea P TP Glud Andreas N AN Alstrup Aage K O AKO Noer Ove O Nielsen Erik H T EHT Schacht Anna C AC Landeck Natalie N Kirik Deniz D Orlowski Dariusz D Sørensen Jens Christian H JCH Doudet Doris J DJ Landau Anne M AM

Scientific reports 20181024 1

Impairment of the ubiquitin proteasome system has been implicated in Parkinson's disease. We used positron emission tomography to investigate longitudinal effects of chronic intracerebroventricular exposure to the proteasome inhibitor lactacystin on monoaminergic projections and neuroinflammation. Göttingen minipigs were implanted in the cisterna magna with a catheter connected to a subcutaneous injection port. Minipigs were imaged at baseline and after cumulative doses of 200 and 400 μg lactacy ...[more]

PMID: 30356172

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Project description:Primary progressive apraxia of speech (PPAOS) is a term used to describe a neurodegenerative condition in which apraxia of speech (AOS; a planning and/or programming deficit) occurs in the absence of aphasia (a language deficit). PPAOS is strongly associated with 4-repeat tau pathology. Elevated flortaucipir ([18F]AV-1451; FTP) uptake has been observed cross-sectionally in patients with PPAOS and those with aphasia. Here, we evaluated longitudinal changes in previously-identified regions of uptake and their relationship with clinical presentation. Thirteen patients who were diagnosed with PPAOS (5 female) at presentation underwent FTP PET imaging at two visits (mean 1 year interval). Median age was 72, with a median of 4 years disease duration at initial testing. Beta-amyloid status was assessed with Pittsburgh Compound B (PiB), where a global PiB ratio>1.48 was deemed amyloid positive (n = 4). FTP uptake was assessed as cortical to cerebellar crus ratios (SUVr) in cortical regions of interest. A single hierarchical linear model (HLM) compared PPAOS patients to 52 cognitively unimpaired controls of similar age and sex. Annualized SUVr change was the outcome, predicted by region, clinical status, and age. Person-specific effects accounted for intra-patient correlations and contralateral regions were included as repeated measures. Changes in clinical measures were assessed using Wilcoxon signed-rank tests; statistically significant changes in the Montreal Cognitive Assessment, MDS-UPDRS, motor section, and PSP Rating Scale were noted between visits. Changes in FTP SUVr were greater for patients than controls. The strongest changes in PPAOS patients were in the precentral gyrus, pallidum, and mid and superior frontal gyri, per the HLM. Qualitatively, larger changes were seen in patients who had developed aphasia by the time of their baseline scan (n = 5). While the biological mechanisms of FTP signal in non-AD tauopathies are unknown, this study demonstrates the utility of FTP in tracking disease progression in 4R tauopathies.

Dataset Information

Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs.

Publications

Longitudinal monoaminergic PET imaging of chronic proteasome inhibition in minipigs.

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