| 1. |
- Eusebi, Paolo, et al.
(författare)
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Cerebrospinal fluid biomarkers for the diagnosis and prognosis of Parkinson's disease : protocol for a systematic review and individual participant data meta-analysis
- 2017
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 7:11, s. 018177-018177
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder related to α-synuclein misfolding and aggregation. For this reason, it belongs to the family of 'synucleinopathies', which also includes some other neurological diseases. Although imaging and ancillary investigations may be helpful in the diagnostic workup, the diagnosis of PD mostly relies on the clinician's expertise. Furthermore, there is a need today for markers that can track the disease progression in PD that might improve the evaluation of novel disease-modifying therapies. The cerebrospinal fluid (CSF) has been widely investigated with the purpose of finding useful diagnostic and prognostic biomarkers for PD.METHODS AND ANALYSIS: This systematic review protocol has been developed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocol 2015 statement and was registered on the PROSPERO international prospective register of systematic reviews. An international collaboration will be established. We will search the Cochrane Library, Web of Science, Medline and Embase from inception, using appropriate search strategies. Individual participant data from all included studies will be merged into a single database. We will include any study assessing the diagnostic and prognostic role of CSF biomarkers in PD. To evaluate the risk of bias and applicability of primary diagnostic accuracy studies, we will use Quality Assessment of Diagnostic Accuracy Studies-2 and Quality in Prognostic Studies. We will use standard meta-analytic procedures. We will first explore the utility of each CSF biomarker in turn. For each biomarker, we will assess its diagnostic and prognostic utility by means of receiver operating characteristic analysis and regression models. We will then move towards a multivariate approach considering different panels of biomarkers.ETHICS AND DISSEMINATION: Our study will not include confidential data, and no intervention will be involved, so ethical approval is not required. The results of the study will be reported in international peer-reviewed journals.
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| 2. |
- Majbour, Nour K, et al.
(författare)
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Increased levels of CSF total but not oligomeric or phosphorylated forms of alpha-synuclein in patients diagnosed with probable Alzheimer's disease
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Several studies reported an association between CSF alpha-synuclein (α-syn) and tau in Alzheimer's disease (AD), and demonstrated the significance of α-syn in improving the diagnostic sensitivity/specificity of classical AD CSF biomarkers. In the current study, we measured CSF levels of different α-syn species in a cohort of AD patients (n = 225) who showed a CSF profile typical of AD at baseline as well as in cognitively intact controls (n = 68). CSF total α-syn (t-α-syn) significantly increased in the AD group (p < 0.0001) compared to controls, while oligomeric- and phosphorylated-Ser129-α-syn did not change significantly. ROC analysis showed a sensitivity of 85% and a specificity of 84% (AUC = 0.88) in distinguishing AD from controls. T-α-syn levels correlated positively with tau species in AD group and negatively with baseline MMSE score. Our data support the added value of measurement of CSF α-syn species for further characterization of the CSF AD profile.
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| 3. |
- Majbour, Nour K., et al.
(författare)
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Longitudinal changes in CSF alpha-synuclein species reflect Parkinson's disease progression
- 2016
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 31:10, s. 1535-1542
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Tidskriftsartikel (refereegranskat)abstract
- Background: Parkinson's disease (PD) diagnosis is mainly based on clinical criteria, with a high risk of misdiagnosis. The identification of reliable biomarkers for disease diagnosis and progression has a key role for developing disease-modifying therapies. In this article, we investigated the longitudinal changes of CSF α-synuclein species in early PD patients and explored the potential use of these species as surrogate biomarkers for PD progression. Methods: We used our newly developed enzyme-linked immunosorbent assay systems for measuring different forms of α-synuclein, such as oligomeric-α-synuclein, phosphorylated-α-synuclein at serine 129, or total-α-synuclein in CSF from the longitudinal Deprenyl and Tocopherol Antioxidative Therapy for Parkinsonism study cohort (n = 121). CSF Alzheimer's disease biomarkers (total-tau, phosphorylated-tau, Aβ40, and Aβ42) were also measured for this cohort. Results: Interestingly, total-α-synuclein and oligomeric-α-synuclein levels significantly increased during the 2-year Deprenyl and Tocopherol Antioxidative Therapy for Parkinsonism study follow-up period, whereas phosphorylated-α-synuclein at serine 129 levels showed a longitudinal decrease. We have also noted an association between a change of the oligomeric-α-synuclein/total-α-synuclein ratio and a worsening of motor signs, in particular in the postural-instability and gait-difficulty dominant PD group. A strong positive correlation between the changes in CSF total-α-synuclein and oligomeric-α-synuclein during the 2-year Deprenyl and Tocopherol Antioxidative Therapy for Parkinsonism study was also noted (r = 0.84, P <.001). Conclusion: Our data show that CSF α-synuclein species have a dynamic pattern along the course of the disease, supporting their possible role as progression biomarkers for PD and their link with PD clinical phenotypes.
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| 4. |
- Parnetti, Lucilla, et al.
(författare)
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CSF and blood biomarkers for Parkinson's disease.
- 2019
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Ingår i: The Lancet. Neurology. - 1474-4465 .- 1474-4422. ; 18:6, s. 573-586
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Tidskriftsartikel (refereegranskat)abstract
- In the management of Parkinson's disease, reliable diagnostic and prognostic biomarkers are urgently needed. The diagnosis of Parkinson's disease mostly relies on clinical symptoms, which hampers the detection of the earliest phases of the disease-the time at which treatment with forthcoming disease-modifying drugs could have the greatest therapeutic effect. Reliable prognostic markers could help in predicting the response to treatments. Evidence suggests potential diagnostic and prognostic value of CSF and blood biomarkers closely reflecting the pathophysiology of Parkinson's disease, such as α-synuclein species, lysosomal enzymes, markers of amyloid and tau pathology, and neurofilament light chain. A combination of multiple CSF biomarkers has emerged as an accurate diagnostic and prognostic model. With respect to early diagnosis, the measurement of CSF α-synuclein aggregates is providing encouraging preliminary results. Blood α-synuclein species and neurofilament light chain are also under investigation because they would provide a non-invasive tool, both for early and differential diagnosis of Parkinson's disease versus atypical parkinsonian disorders, and for disease monitoring. In view of adopting CSF and blood biomarkers for improving Parkinson's disease diagnostic and prognostic accuracy, further validation in large independent cohorts is needed.
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| 5. |
- Chiasserini, Davide, et al.
(författare)
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CSF Levels of Heart Fatty Acid Binding Protein are Altered During Early Phases of Alzheimer's Disease.
- 2010
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 22:4, s. 1281-8
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Tidskriftsartikel (refereegranskat)abstract
- Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimer's disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-β (Aβ)1-42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n=41), AD (n=32), and subjects with other neurological diseases without dementia (OND, n=25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC=0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Aβ1-42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC=0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC=0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Aβ1-42 ratio (cut-off=0.7). A significant correlation between HFABP/Aβ1-42 ratio and MMSE annual decrease rate was also documented (p< 0.0001). HFABP /Aβ1-42 ratio might be a useful predictor of conversion in MCI patients.
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| 6. |
- Crittenden, Jill R., et al.
(författare)
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CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors
- 2021
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Ingår i: Neurobiology of Disease. - Maryland Heights, MO, United States : Academic Press. - 0969-9961 .- 1095-953X. ; 158
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Tidskriftsartikel (refereegranskat)abstract
- CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntingtons disease and levodopa-induced dyskinesia in Parkinsons disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the selfadministration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGIs therapeutic potential.
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| 7. |
- Errico, Francesco, et al.
(författare)
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Higher free d-aspartate and N-methyl-d-aspartate levels prevent striatal depotentiation and anticipate 1-DOPA-induced dyskinesia
- 2011
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 232:2, s. 240-250
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Tidskriftsartikel (refereegranskat)abstract
- In Parkinson's disease (PD) progressive alteration of striatal N-methyl-D-aspartate receptors (NMDARs) signaling has emerged as a considerable factor for the onset of the adverse motor effects of long-term levodopa (L-DOPA) treatment. In this regard, the NMDAR channel blocker amantadine is so far the only drug available for clinical use that attenuates L-DOPA-induced dyskinesia (LID). In this study, we examined the influence of a basal corticostriatal hyper-glutamatergic transmission in the appearance of dyskinesia, using a genetic mouse model lacking D-Aspartate Oxidase (DDO) enzyme (Ddo(-/-)mice). We found that, in Ddo(-/-)mice, non-physiological, high levels of the endogenous free D-amino acids D-aspartate (D-Asp) and NMDA, known to stimulate NMDAR transmission, resulted in the loss of corticostriatal synaptic depotentiation and precocious expression of LID. Interestingly, the block of depotentiation precedes any change in dopaminergic transmission associated to 6-OHDA lesion and L-DOPA treatment. Indeed, lesioned mutant mice display physiological L-DOPA-dependent enhancement of striatal D1 receptor/PKA/protein phosphatase-1 and ERK signaling. Moreover, in line with synaptic rearrangements of NMDAR subunits occurring in dyskinetic animal models, a short L-DOPA treatment produces a dramatic and selective reduction of the NR2B subunit in the striatal post-synaptic fraction of Ddo(-/-) lesioned mutants but not in controls. These data indicate that a preexisting hyper-glutamatergic tone at NMDARs in Ddo(-/-) mice produce abnormal striatal synaptic changes that, in turn, facilitate the onset of LID. (C) 2011 Elsevier Inc. All rights reserved.
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| 8. |
- Pedrelli, Matteo, et al.
(författare)
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Vasculoprotective Properties of Plasma Lipoproteins from Brown Bears (Ursus arctos)
- 2021
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Ingår i: Journal of Lipid Research. - : American Society for Biochemistry and Molecular Biology. - 0022-2275 .- 1539-7262. ; 62
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cholesterol and triglyceride levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early-stage atherosclerosis development when adult. To explore this apparent paradox, we analysed plasma lipoproteins from the same ten bears in winter (hibernation) and in summer using size exclusion chromatography, ultracentrifugation and electrophoresis. LDL cholesterol binding to arterial proteoglycans, and plasma cholesterol efflux capacity were also evaluated. The data collected and analysed from bears were also compared with those from healthy humans. In bears the cholesterol esters, unesterified cholesterol, triglyceride and phospholipid content of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans, but did not change seasonally in bears. Bear LDL was larger, richer in triglycerides, showed pre-beta electrophoretic mobility and had 5-10 times lower binding to arterial proteoglycans than human LDL. Finally, plasma cholesterol efflux capacity was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL cholesterol for arterial proteoglycans and an elevated cholesterol efflux capacity of bear plasma.
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| 9. |
- Pedrelli, Matteo, et al.
(författare)
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Vasculoprotective properties of plasma lipoproteins from brown bears (Ursus arctos)
- 2021
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Ingår i: Journal of Lipid Research. - : Elsevier. - 0022-2275 .- 1539-7262. ; 62
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Tidskriftsartikel (refereegranskat)abstract
- Plasma cholesterol and triglyceride (TG) levels are twice as high in hibernating brown bears (Ursus arctos) than healthy humans. Yet, bears display no signs of early stage atherosclerosis development when adult. To explore this apparent paradox, we analyzed plasma lipoproteins from the same 10 bears in winter (hibernation) and summer using size exclusion chromatography, ultracentrifugation, and electrophoresis. LDL binding to arterial proteoglycans (PGs) and plasma cholesterol efflux capacity (CEC) were also evaluated. The data collected and analyzed from bears were also compared with those from healthy humans. In bears, the cholesterol ester, unesterified cholesterol, TG, and phospholipid contents of VLDL and LDL were higher in winter than in summer. The percentage lipid composition of LDL differed between bears and humans but did not change seasonally in bears. Bear LDL was larger, richer in TGs, showed prebeta electrophoretic mobility, and had 5-10 times lower binding to arterial PGs than human LDL. Finally, plasma CEC was higher in bears than in humans, especially the HDL fraction when mediated by ABCA1. These results suggest that in brown bears the absence of early atherogenesis is likely associated with a lower affinity of LDL for arterial PGs and an elevated CEC of bear plasma.
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| 10. |
- Plantone, Domenico, et al.
(författare)
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Clinically relevant increases in serum neurofilament light chain and glial fibrillary acidic protein in patients with Susac syndrome
- 2023
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Ingår i: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331. ; 30:10, s. 3256-3264
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed. Methods: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age-and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit. Results: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013). Conclusion: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS.
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| 11. |
- Rylander, Daniella, et al.
(författare)
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Region-specific restoration of striatal synaptic plasticity by dopamine grafts in experimental parkinsonism.
- 2013
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:46, s. 4375-4384
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Tidskriftsartikel (refereegranskat)abstract
- Intrastriatal transplantation of dopaminergic neurons can restore striatal dopamine levels and improve parkinsonian deficits, but the mechanisms underlying these effects are poorly understood. Here, we show that transplants of dopamine neurons partially restore activity-dependent synaptic plasticity in the host striatal neurons. We evaluated synaptic plasticity in regions distal or proximal to the transplant (i.e., dorsolateral and ventrolateral striatum) and compared the effects of dopamine- and serotonin-enriched grafts using a rat model of Parkinson disease. Naïve rats showed comparable intrinsic membrane properties in the two subregions but distinct patterns of long-term synaptic plasticity. The ventrolateral striatum showed long-term potentiation using the same protocol that elicited long-term depression in the dorsolateral striatum. The long-term potentiation was linked to higher expression of postsynaptic AMPA and N2B NMDA subunits (GluN2B) and was dependent on the activation of GluN2A and GluN2B subunits and the D1 dopamine receptor. In both regions, the synaptic plasticity was abolished after a severe dopamine depletion and could not be restored by grafted serotonergic neurons. Solely, dopamine-enriched grafts could restore the long-term potentiation and partially restore motor deficits in the rats. The restoration could only be seen close to the graft, in the ventrolateral striatum where the graft-derived reinnervation was denser, compared with the distal dorsolateral region. These data provide proof of concept that dopamine-enriched transplants are able to functionally integrate into the host brain and restore deficits in striatal synaptic plasticity after experimental parkinsonism. The region-specific restoration might impose limitations in symptomatic improvement following neural transplantation.
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| 12. |
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| 13. |
- Tschiderer, Lena, et al.
(författare)
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Association of Intima-Media Thickness Measured at the Common Carotid Artery With Incident Carotid Plaque : Individual Participant Data Meta-Analysis of 20 Prospective Studies
- 2023
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Ingår i: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 12:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development.Methods and Results: We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I-2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I-2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I-2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques).Conclusions: Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.
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