| 1. |
- Bartl, Michael, et al.
(författare)
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Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid of de novo Parkinson's disease
- 2024
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Ingår i: NPJ PARKINSONS DISEASE. - 2373-8057. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Lysosomal and synaptic dysfunctions are hallmarks in neurodegeneration and potentially relevant as biomarkers, but data on early Parkinson's disease (PD) is lacking. We performed targeted mass spectrometry with an established protein panel, assessing autophagy and synaptic function in cerebrospinal fluid (CSF) of drug-na & iuml;ve de novo PD, and sex-/age-matched healthy controls (HC) cross-sectionally (88 PD, 46 HC) and longitudinally (104 PD, 58 HC) over 10 years. Multiple markers of autophagy, synaptic plasticity, and secretory pathways were reduced in PD. We added samples from prodromal subjects (9 cross-sectional, 12 longitudinal) with isolated REM sleep behavior disorder, revealing secretogranin-2 already decreased compared to controls. Machine learning identified neuronal pentraxin receptor and neurosecretory protein VGF as most relevant for discriminating between groups. CSF levels of LAMP2, neuronal pentraxins, and syntaxins in PD correlated with clinical progression, showing predictive potential for motor- and non-motor symptoms as a valid basis for future drug trials.
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| 2. |
- Filograna, Roberta, et al.
(författare)
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PARKIN is not required to sustain OXPHOS function in adult mammalian tissues
- 2024
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Ingår i: npj Parkinson's Disease. - : Springer Nature. - 2373-8057. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function variants in the PRKN gene encoding the ubiquitin E3 ligase PARKIN cause autosomal recessive early-onset Parkinson’s disease (PD). Extensive in vitro and in vivo studies have reported that PARKIN is involved in multiple pathways of mitochondrial quality control, including mitochondrial degradation and biogenesis. However, these findings are surrounded by substantial controversy due to conflicting experimental data. In addition, the existing PARKIN-deficient mouse models have failed to faithfully recapitulate PD phenotypes. Therefore, we have investigated the mitochondrial role of PARKIN during ageing and in response to stress by employing a series of conditional Parkin knockout mice. We report that PARKIN loss does not affect oxidative phosphorylation (OXPHOS) capacity and mitochondrial DNA (mtDNA) levels in the brain, heart, and skeletal muscle of aged mice. We also demonstrate that PARKIN deficiency does not exacerbate the brain defects and the pro-inflammatory phenotype observed in mice carrying high levels of mtDNA mutations. To rule out compensatory mechanisms activated during embryonic development of Parkin-deficient mice, we generated a mouse model where loss of PARKIN was induced in adult dopaminergic (DA) neurons. Surprisingly, also these mice did not show motor impairment or neurodegeneration, and no major transcriptional changes were found in isolated midbrain DA neurons. Finally, we report a patient with compound heterozygous PRKN pathogenic variants that lacks PARKIN and has developed PD. The PARKIN deficiency did not impair OXPHOS activities or induce mitochondrial pathology in skeletal muscle from the patient. Altogether, our results argue that PARKIN is dispensable for OXPHOS function in adult mammalian tissues.
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| 7. |
- Pedersen, Camilla Christina, et al.
(författare)
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Serum neurofilament light at diagnosis: a prognostic indicator for accelerated disease progression in Parkinson's Disease
- 2024
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Ingår i: NPJ PARKINSONS DISEASE. - 2373-8057. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Neurofilament light chain (NFL) is elevated in neurodegenerative diseases, including Parkinson's disease (PD). This study aimed to investigate serum NFL in newly diagnosed PD and its association with cognitive and motor decline over 10 years. Serum NFL levels were measured in PD patients and controls from the ParkWest study at diagnosis (baseline) and after 3 and 5 years. Mixed-effects regression analyzed changes in NFL and the association with annual changes in MMSE and UPDRS-III scores over 10 years. PD patients had elevated serum NFL at all visits and a faster annual increase over 5 years compared to controls (0.09 pg/mL per year; p = 0.029). Higher baseline NFL predicted faster cognitive decline beta -0.77 transformed MMSE; p = 0.010), and a 40% NFL increase predicted future motor decline (beta 0.28 UPDRS-III; p = 0.004). Elevated serum NFL in early PD is linked to faster cognitive and motor impairment, suggesting its prognostic value in PD biomarker panels.
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| 8. |
- Sauerbier, A., et al.
(författare)
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Predictors of short-term anxiety outcome in subthalamic stimulation for Parkinson’s disease
- 2024
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Ingår i: npj Parkinson's Disease. - 2373-8057. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson’s disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month follow-up postoperatively. We assessed the Hospital Anxiety and Depression Scale (HADS-anxiety and depression subscales), Unified PD Rating Scale-motor examination, Scales for Outcomes in PD-motor (SCOPA-M)-activities of daily living (ADL) and -motor complications, Non-Motor Symptom Scale (NMSS), PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose. We tested changes at follow-up with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We identified patients with a clinically relevant anxiety improvement of anxiety based on a designated threshold of ½ standard deviation of baseline HADS-anxiety. Moreover, we investigated predictors of HADS-anxiety changes with correlations and linear regressions. We included 50 patients with clinically relevant baseline anxiety (i.e., HADS-anxiety ≥ 8) aged 63.1 years ± 8.3 with 10.4 years ± 4.5 PD duration. HADS-anxiety improved significantly at 6-month follow-up as 80% of our cohort experienced clinically relevant anxiety improvement. In predictor analyses, worse baseline SCOPA-ADL and NMSS-urinary domain were associated with greater HADS-anxiety improvements. HADS-anxiety and PDQ-8 changes correlated moderately. Worse preoperative ADL and urinary symptoms predicted favourable postoperative anxiety outcome, which in turn was directly proportionate to greater QoL improvement. This study highlights the importance of detailed anxiety assessments alongside other non-motor and motor symptoms when advising and monitoring patients undergoing STN-DBS for PD. © The Author(s) 2024.
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| 9. |
- Vinding, Mikkel C., et al.
(författare)
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Oscillatory and non-oscillatory features of the magnetoencephalic sensorimotor rhythm in Parkinson's disease
- 2024
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Ingår i: npj Parkinson's Disease. - : Springer Nature. - 2373-8057. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson’s disease (PD) is associated with changes in neural activity in the sensorimotor alpha and beta bands. Using magnetoencephalography (MEG), we investigated the role of spontaneous neuronal activity within the somatosensory cortex in a large cohort of early- to mid-stage PD patients (N = 78) on Parkinsonian medication and age- and sex-matched healthy controls (N = 60) using source reconstructed resting-state MEG. We quantified features of the time series data in terms of oscillatory alpha power and central alpha frequency, beta power and central beta frequency, and 1/f broadband characteristics using power spectral density. Furthermore, we characterised transient oscillatory burst events in the mu-beta band time-domain signals. We examined the relationship between these signal features and the patients’ disease state, symptom severity, age, sex, and cortical thickness. PD patients and healthy controls differed on PSD broadband characteristics, with PD patients showing a steeper 1/f exponential slope and higher 1/f offset. PD patients further showed a steeper age-related decrease in the burst rate. Out of all the signal features of the sensorimotor activity, the burst rate was associated with increased severity of bradykinesia, whereas the burst duration was associated with axial symptoms. Our study shows that general non-oscillatory features (broadband 1/f exponent and offset) of the sensorimotor signals are related to disease state and oscillatory burst rate scales with symptom severity in PD.
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