| 1. |
- Fazio, Patrik
(författare)
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In vivo imaging markers for the characterization of molecular changes in Parkinson and Huntington's disease
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) and Huntington’s disease (HD) are neurodegenerative disorders characterized by a progressive multi-systemic accumulation of misfolded proteins associated with neuronal dysfunction and neuronal loss. The rationale of this thesis is to examine, by means ofthe state of the art Positron emission tomography (PET) methodology combined with the use of high resolution MRI image molecular changes associated to the early stages of PD and HD. PET is a molecular imaging technique that, due to recent advancements in terms ofradioligand development and PET instrumentation, such as the high-resolution research tomograph (HRRT) and PET quantification, may contribute to examine in vivo the distribution and availability of different biochemical targets. The work included in the thesis can be subdivided into two projects. The first project is dedicated to PD and to the study of two relevant molecular targets (dopamine and serotonin transporters), examined respectively with the radioligands [18F]FEPE2I and [11C]MADAM. In paper I, it is shown that [18F]FE-PE2I represents a reliable imaging biomarker to study the dopamine transporter (DAT) in the striatum and in the substantia nigra in PD. In paper II, a validation of a new approach to examine the serotonin transporter protein in small brainstem structures is presented. In paper III, [18F]FE-PE2I was used to study the entire nigro-striatal dopaminergic system, including dopamine projections, in a larger group of PD patients. The study was able to show a prominent involvement of the dopamine transporter in the striatum, a relatively milder reduction of DAT in the substantia nigra and a relative preservation of the protein along the nigro-striatal projections. The second project is dedicated to the evaluation of Phosphodiesterase 10A as new molecular target for HD. This project includes two studies in which the radioligand [18F]MNI-659 has been used as radioligand for PDE10A and the D2/3 receptors radioligand [11C]raclopride that has been used as internal reference. In paper IV, it is shown that aging is associated with a considerable reduction of PDE10A. In Paper V, the same targets are examined in selected cohorts of HD subjects in pre-manifest and manifest stages. The study shows that PDE10A was preserved in early pre-manifest HD subjects and progressively decreased in late premanifest and manifest HD stages. In conclusion the presented applications of new PET molecular imaging probes provided relevant information that contributes to measure early changes of molecular targets associated with the onset and progression of neuronal loss occurring in PD and HD.
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| 2. |
- Huttunen, Henri J., et al.
(författare)
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Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double-Blind, Multicenter Phase 1 Trial
- 2023
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Ingår i: Movement Disorders. - : John Wiley & Sons. - 0885-3185 .- 1531-8257. ; 38:7, s. 1209-1222
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). Objective: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. Methods: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo-controlled, double-blind, 6-month main study followed by an active-treatment 6-month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18F]FE-PE2I. Results: Drug-related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. Conclusions: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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| 3. |
- Jonasson, My, et al.
(författare)
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Striatal dopamine transporter and receptor availability correlate with relative cerebral blood flow measured with [11C]PE2I, [18F]FE-PE2I and [11C]raclopride PET in healthy individuals
- 2023
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016. ; 43:7, s. 1206-1215
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [11C]PE2I (n = 20) and [18F]FE-PE2I (n = 20) and the D2/3 tracer [11C]raclopride (n = 18). Subjects with a [11C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [11C]DASB. Binding potential (BPND) and relative tracer delivery (R1) values were calculated on regional and voxel-level. Striatal R1 and BPND values were correlated, using either an MRI-based volume of interest (VOI) or an isocontour VOI based on the parametric BPND image. An inter-tracer comparison between [11C]PE2I BPND and [11C]DASB R1 was done on a VOI-level and simulations were performed to investigate whether the constraints of the modeling could cause correlation of the parameters. A positive association was found between BPND and R1 for all three dopamine tracers. A similar correlation was found for the inter-tracer correlation between [11C]PE2I BPND and [11C]DASB R1. Simulations showed that this relationship was not caused by cross-correlation between parameters in the kinetic model. In conclusion, these results suggest an association between resting-state striatal dopamine function and relative blood flow in healthy subjects.
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| 4. |
- Kerstens, Vera S, et al.
(författare)
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Reliability of dopamine transporter PET measurements with [18F]FE-PE2I in patients with Parkinson's disease.
- 2020
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Ingår i: EJNMMI Research. - : Springer Nature. - 2191-219X. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Reliable quantification of dopamine transporter (DAT), a biomarker for Parkinson's disease (PD), is essential for diagnostic purposes as well as for evaluation of potential disease-modifying treatment. Due to degeneration of dopaminergic neurons and thus lower expected radioligand binding to DAT, higher measurement variability in PD patients might be expected than earlier reproducibility results in healthy controls. Therefore, we aimed to examine the test-retest properties of [18F]FE-PE2I-PET in PD patients.METHODS: Nine patients with PD (Hoehn and Yahr stage < 3) were included (men/women 6/3; mean age 65.2 ± 6.8 years). Each patient underwent two [18F]FE-PE2I-PET measurements within 7-28 days. The outcome measure was non-displaceable binding potential generated using wavelet-aided parametric imaging with cerebellum as reference region. We assessed test-retest performance using estimates of reliability and repeatability. Regions for primary analysis were caudate, putamen, ventral striatum, and substantia nigra. Exploratory analysis was performed for functional subdivisions of the striatum. We also compared the more vs. less affected side.RESULTS: [18F]FE-PE2I showed absolute variability estimates of 5.3-7.6% in striatal regions and 11% in substantia nigra and ICCs of 0.74-0.97 (median 0.91). The absolute variability for functional striatal subdivisions was 6.0-9.6% and ICCs of 0.76-0.91 (median 0.91). The less affected substantia nigra exhibited greater consistency than the more affected side. According to power calculations based on the current sample size, DAT changes of 5-11% in the striatum and 28% in the substantia nigra can be detected with a power of 0.8 (p < 0.0125).CONCLUSION: DAT-PET measurements with [18F]FE-PE2I in PD patients showed good repeatability and reliability. The slightly lower reliability in the substantia nigra in patients may be explained by lower DAT density and smaller anatomical size. Power calculations suggest that [18F]FE-PE2I PET is a suitable marker for longitudinal DAT decline in PD.TRIAL REGISTRATION: EudraCT 2017-003327-29.
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| 5. |
- Landtblom, Anne-Marie, et al.
(författare)
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The first case history of multiple sclerosis: Augustus dEst, (1794-1848)
- 2010
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Ingår i: NEUROLOGICAL SCIENCES. - : Springer Science and Business Media LLC. - 1590-1874 .- 1590-3478. ; 31:1, s. 29-33
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Tidskriftsartikel (refereegranskat)abstract
- The personal diary of Sir Augustus dEst,, born 1794 grandson of King George III of England, reveals a medical history strongly suggesting that Augustus suffered from multiple sclerosis (MS). It could well be the first record of a person having this disease. Charcot coined the term scl,rose en plaques 20 years after the death of this patient in 1848. The onset of this mans MS seems to have been in 1822 with bilateral optic neuritis, the disease gradually developing in the classic manner with bouts derived from different loci in the central nervous system and eventually a secondary progressive form with paraparesis, sphincter incontinence, urinary problems and impotence. In 1941, Firth highlighted the case of Augustus dEst, and later wrote a description of the pathology including a discussion on the aetiology of MS. No previous medical records have given such a characteristic picture of MS as this.
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