| 1. |
- Nilsson, Johanna, 1993, et al.
(författare)
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Cerebrospinal fluid biomarkers of synaptic dysfunction are altered in Parkinson's disease and related disorders
- 2023
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Ingår i: Movement Disorders. - : John Wiley & Sons. - 0885-3185 .- 1531-8257. ; 38:2, s. 267-277
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Tidskriftsartikel (refereegranskat)abstract
- Background: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects.Objective: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders.Methods: Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n1 = 51, n2 = 101), corticobasal degeneration (CBD) (n1 = 11, n2 = 3), progressive supranuclear palsy (PSP) (n1 = 22, n2 = 21), multiple system atrophy (MSA) (n1 = 31, n2 = 26), and healthy control (HC) (n1 = 48, n2 = 30) participants, as well as Alzheimer's disease (AD) (n2 = 23) patients in the second cohort.Results: Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25–0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β-estimate = −0.025 to −0.038, P < 0.05) and cognitive decline (NPTX2; β-estimate = 0.32, P = 0.021).Conclusions: These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD.
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| 2. |
- Constantinescu, Clara, 1995, et al.
(författare)
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Persons with suspicious onset of multiple sclerosis but with undetermined diagnosis had persistent lower cognition and reduced quality of life
- 2021
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Ingår i: Multiple Sclerosis and Related Disorders. - : Elsevier BV. - 2211-0348. ; 52
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Tidskriftsartikel (refereegranskat)abstract
- Backgound: Differential diagnosis of multiple sclerosis (MS) includes a variety of disorders and misdiagnosis is common. Objective: To follow-up persons with suspected onset of MS but in whom the diagnostic investigation was negative. Methods: In a prospective study including 271 persons with clinical features of suspected MS onset, 136 persons were diagnosed with MS or clinically isolated syndrome (PwMS), 46 had other disorders, and 89 persons had a negative diagnostic work-up, i.e. persons with undetermined diagnosis (PwUD). They underwent diagnostic reassessment, and those who remained without a diagnosis were investigated for signs of pathology including cognitive tests and assessments of quality of life (QoL). Results were compared with those of PwMS and 24 age and sex matched healthy controls (HC). Results: After reassement 55 (20%) persons still had undetermined diagnosis (PwUD). They had similar age and gender distribution as PwMS. In 76% of PwUD, the suspected clinical onset included sensory symptoms. PwUD and PwMS scored similarly in cognitive tests and QoL but significantly lower than HC. At 3 years follow-up, PwMS and PwUD improved in most test parameters, but PwUD scored lower than PwMS in cognition. Conclusion: PwUD constituted the dominating differential diagnosis in persons with suspected clinical onset of MS. QoL and cognition were comparable with those of PwMS but significantly lower than in HC.
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| 3. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Cerebrospinal fluid biomarkers in patients with neurological symptoms but without neurological diseases
- 2019
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Elevated levels of the cerebrospinal fluid (CSF) neuronal injury markers (neurofilament light chain [NF-L] and total tau protein [t-tau]) and of the astroglial marker glial fibrillary acidic protein (GFAP) are found in etiologically different neurological disorders affecting the peripheral and the central nervous system. Aims: To explore the role of CSF biomarkers in the clinical management of patients admitted for alarming neurological symptoms, but in whom neurological disorders could be excluded. Methods: Study participants were patients seeking medical attention for neurological symptoms primarily considered to be caused by a neurological diagnosis and investigated according to clinical routine. Demographic, clinical, and CSF data were extracted retrospectively from medical records. Patients with a final neurological diagnosis were excluded. Results: Out of 990 patients, 900 with a neurological diagnosis were excluded leaving 90 patients without a final neurological diagnosis. Sixty-eight (75.6%) were females. Median (range) age at lumbar puncture was 34.7 (16.9-65.1)years. Age-adjusted CSF-NF-L, CSF-t-tau, and CSF-GFAP concentrations were normal in 89 (98.9%), 86 (95.6%), and 87 (96.7%) patients, respectively. Conclusion: In patients with significant neurological symptoms but in whom a neurological diagnosis could not be made, the CSF markers NF-L, t-tau, and GFAP did not indicate signs of neuronal or astroglial cell damage close to symptom onset. Consequently, increased levels of CSF markers are not expected in this patient group and, if present, should raise suspicion of underlying neurological disorders and motivate further investigations. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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| 4. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Proteomic profiling of cerebrospinal fluid in parkinsonian disorders.
- 2010
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Ingår i: Parkinsonism & related disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; :16, s. 545-49
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) and atypical parkinsonian disorders (APD), including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), are a group of neurodegenerative diseases sharing many similar signs and symptoms but distinguished by their particular clinical features, treatment response, prognosis and mortality. The differential diagnosis may be challenging, especially in early disease stages. Considering the importance of an accurate diagnosis both for clinical management and for research, new diagnostic tools are needed. In this study, we investigated 56 PD, 42 MSA, 39 PSP, 9 CBD patients, and 24 healthy controls. After screening the cerebrospinal fluid (CSF) proteome using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), we identified 4 proteins (ubiquitin [mass-to-charge ratio (m/z) 8590], beta2-microglobulin [m/z 11730], and 2 secretogranin 1 [chromogranin B] fragments [m/z 7260 and m/z 6250]) that differentiated healthy controls and PD patients from patients with APD. However, they could not differentiate PD patients from controls. As none of these changes were APD subgroup-specific, they most likely reflect the intensity and/or extent of the neurodegenerative process in general.
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| 5. |
- Fernandes Gomes, Bárbara, et al.
(författare)
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α-Synuclein seed amplification assay as a diagnostic tool for parkinsonian disorders.
- 2023
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Ingår i: Parkinsonism & related disorders. - 1873-5126. ; 117
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Tidskriftsartikel (refereegranskat)abstract
- Synucleinopathies such as Parkinson's disease (PD) and multiple system atrophy (MSA) can be challenging to diagnose due to the symptom overlap with, for example, atypical parkinsonisms like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Seed amplification assays (SAA), developed for the detection of α-synuclein (αSyn) aggregates in CSF, have been successful when used as a biomarker evaluation for synucleinopathies. In this study, we investigated the potential of this assay to not only detect αSyn seeds in CSF, but also discriminate between movement disorders.The αSyn-SAA was tested in a Scandinavian cohort composed of 129 CSF samples from patients with PD (n=55), MSA (n=27), CBD (n=7), and PSP (n=16), as well as healthy controls (HC, n=24).The αSyn seed amplification assay (αSyn-SAA) was able to correctly identify all PD samples as positive (sensitivity of 100%) while also discriminating the PD group from HC (70.8% specificity, p<0.0001) and tauopathies [CBD (71% specificity) and PSP (75% specificity), p<0.0001)]. The αSyn-SAA was also able to identify almost all MSA samples as positive for αSyn aggregation (sensitivity of 92.6%). In general, this assay is able to discriminate between the synucleinopathies and tauopathies analyzed herein (p<0.0001) despite the overlapping symptoms in these diseases.These findings suggest the αSyn-SAA is a useful diagnostic tool for differentiating between different parkinsonian disorders, although further optimization may be needed.
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| 6. |
- Rudenholm, Magnus, et al.
(författare)
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Cerebrospinal Fluid Biomarkers in DM1: a 14-year Follow Up Study.
- 2019
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Ingår i: IDMC-12, Göteborg 2019, Konferensprogram.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: DM1 affects cognition, but worsening over time and relation to cerebrospinal fluid (CSF) biomarkers is yet unclear. The aim of this study was to investigate this further. Methods: CSF levels of beta amyloid 1-42 (Aβ42), total- and phosphorylated tau protein (t-tau/p-tau), neurofilament light chain (NFL), glial fibrillary acid protein (GFAP) and cognitive performance on neuropsychological tests were measured in 17 patients with DM1 at baseline 2004 and follow up 2018. Results: CSF-Aβ42 was decreased in 1 patient (5.9%) at follow up compared to 6 patients (35%) at baseline (p <0.001). Remaining biomarkers were without change or pathology. Patients scored worse on cognitive measures at follow-up, unrelated to CSF biomarkers. Conclusions: Cognitive decline was observed but could not be related to disturbance in CSF-biomarkers. This suggesting a neurodegenerative process not intense enough to be observable using the employed biomarkers.
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| 7. |
- Stevens-Jones, Oskar, et al.
(författare)
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Presence of neural surface and onconeural autoantibodies in cerebrospinal fluid and serum in neurological diseases presents a potential risk for misdiagnosis
- 2023
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Ingår i: European Journal of Neurology. - 1351-5101. ; 30:9, s. 2602-2610
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: Autoantibodies have been found to contribute to pathology and are used in the diagnosis of some neurological diseases. We examined the prevalence of autoantibodies in patients with various neurological diseases and whether patients who had autoantibodies differed in age, sex, or disability from those who did not.Methods: We examined the prevalence of neural surface and onconeural autoantibodies in cerebrospinal fluid (CSF) and serum from patients with multiple sclerosis (n = 64), Parkinson disease plus atypical parkinsonism (n = 150), amyotrophic lateral sclerosis (n = 43), or autoimmune encephalitis (positive control; n = 7) and a healthy control group (n = 37). A total of 12 onconeural autoantibodies and six neural surface autoantibodies were tested in all participants.Results: Autoantibodies were present in all cohorts. The prevalence of autoantibodies was high (>80%) in the autoimmune encephalitis cohort but low (<20%) in all other cohorts. When comparing patients within cohorts who were positive for autoantibodies to patients who were not, there was no difference in age, sex, and disability. This was apart from the multiple sclerosis and Parkinson disease plus atypical parkinsonism cohorts, where those with positivity for autoantibodies in the CSF were significantly older.Conclusions: The presence of the autoantibodies examined does not appear to have a substantial clinical impact within the diseases examined in this study. The presence of autoantibodies in all cohorts presents a risk for misdiagnosis when the method is used incorrectly on patients with atypical clinical presentation.
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| 8. |
- Weiner, Sophia, et al.
(författare)
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SCRN1: A cerebrospinal fluid biomarker correlating with tau in Alzheimer's disease
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:10, s. 4609-4618
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Secernin-1 (SCRN1) is a neuronal protein that co-localizes with neurofibrillary tangles in Alzheimer's disease (AD), but not with tau inclusions in corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or Pick's disease. METHODS: We measured SCRN1 concentration in cerebrospinal fluid (CSF) using a novel mass spectrometric parallel reaction monitoring method in three clinical cohorts comprising patients with neurochemically characterized AD (n=25) and controls (n=28), clinically diagnosed Parkinson's disease (PD; n=38), multiple system atrophy (MSA; n=31), PSP (n=20), CBD (n=8), healthy controls (n=37), and neuropathology-confirmed AD (n=47). RESULTS: CSF SCRN1 was significantly increased in AD (P<0.01, fold change=1.4) compared to controls (receiver operating characteristic area under the curve=0.78) but not in CBD, PSP, PD, or MSA. CSF SCRN1 positively correlated with CSF total tau (R=0.78, P=1.1×10−13), phosphorylated tau181 (R=0.64, P=3.2×10−8), and Braak stage and negatively correlated with Mini-Mental State Examination score. DISCUSSION: CSF SCRN1 is a candidate biomarker of AD, reflecting tau pathology. HIGHLIGHTS: We developed a parallel reaction monitoring assay to measure secernin-1 (SCRN1) in cerebrospinal fluid (CSF). CSF SCRN1 was increased in Alzheimer's disease compared to healthy controls. CSF SCRN1 remained unchanged in Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, or corticobasal degeneration compared to controls. CSF SCRN1 correlated strongly with CSF phosphorylated tau and total tau. CSF SCRN1 increased across Braak stages and negatively correlated with Mini-Mental State Examination score.
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| 9. |
- Aghanavesi, Somayeh, 1981-, et al.
(författare)
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A multiple motion sensors index for motor state quantification in Parkinson's disease
- 2020
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Ingår i: Computer Methods and Programs in Biomedicine. - : Elsevier BV. - 0169-2607 .- 1872-7565. ; 189
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To construct a Treatment Response Index from Multiple Sensors (TRIMS) for quantification of motor state in patients with Parkinson's disease (PD) during a single levodopa dose. Another aim was to compare TRIMS to sensor indexes derived from individual motor tasks. Method: Nineteen PD patients performed three motor tests including leg agility, pronation-supination movement of hands, and walking in a clinic while wearing inertial measurement unit sensors on their wrists and ankles. They performed the tests repeatedly before and after taking 150% of their individual oral levodopa-carbidopa equivalent morning dose.Three neurologists blinded to treatment status, viewed patients’ videos and rated their motor symptoms, dyskinesia, overall motor state based on selected items of Unified PD Rating Scale (UPDRS) part III, Dyskinesia scale, and Treatment Response Scale (TRS). To build TRIMS, out of initially 178 extracted features from upper- and lower-limbs data, 39 features were selected by stepwise regression method and were used as input to support vector machines to be mapped to mean reference TRS scores using 10-fold cross-validation method. Test-retest reliability, responsiveness to medication, and correlation to TRS as well as other UPDRS items were evaluated for TRIMS. Results: The correlation of TRIMS with TRS was 0.93. TRIMS had good test-retest reliability (ICC = 0.83). Responsiveness of the TRIMS to medication was good compared to TRS indicating its power in capturing the treatment effects. TRIMS was highly correlated to dyskinesia (R = 0.85), bradykinesia (R = 0.84) and gait (R = 0.79) UPDRS items. Correlation of sensor index from the upper-limb to TRS was 0.89. Conclusion: Using the fusion of upper- and lower-limbs sensor data to construct TRIMS provided accurate PD motor states estimation and responsive to treatment. In addition, quantification of upper-limb sensor data during walking test provided strong results. © 2019
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| 10. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Cerebrospinal fluid biomarker candidates for Parkinsonian disorders
- 2013
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Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 3 JAN
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Tidskriftsartikel (refereegranskat)abstract
- The Parkinsonian disorders are a large group of neurodegenerative diseases including idiopathic Parkinson's disease (PD) and atypical Parkinsonian disorders (APD), such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies. The etiology of these disorders is not known although it is considered to be a combination of genetic and environmental factors. One of the greatest obstacles for developing efficacious disease-modifying treatment strategies is the lack of biomarkers. Reliable biomarkers are needed for early and accurate diagnosis, to measure disease progression, and response to therapy. In this review several of the most promising cerebrospinal biomarker candidates are discussed. Alpha-synuclein seems to be intimately involved in the pathogenesis of synucleinopathies and its levels can be measured in the cerebrospinal fluid and in plasma. In a similar way, tau protein accumulation seems to be involved in the pathogenesis of tauopathies. Urate, a potent antioxidant, seems to be associated to the risk of developing PD and with its progression. Neurofilament light chain levels are increased in APD compared with PD and healthy controls. The new "omics" techniques are potent tools offering new insights in the patho-etiology of these disorders. Some of the difficulties encountered in developing biomarkers are discussed together with future perspectives. © 2013 Constantinescu and Mondello.
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| 11. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Cerebrospinal fluid markers of neuronal and glial cell damage in patients with autoimmune neurologic syndromes with and without underlying malignancies.
- 2017
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Ingår i: Journal of neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 306, s. 25-30
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune neurologic syndromes can be paraneoplastic (associated with malignancies and/or onconeural antibodies), or non-paraneoplastic. Their clinical presentation is often similar. As prognosis is related to malignancy treatment, better biomarkers are needed to identify patients with malignancy. We investigated cerebrospinal fluid (CSF) markers of neuronal (neurofilament light chain, NFL and total tau protein, T-tau) and glial (glial fibrillary acidic protein) damage. CSF-NFL and T-tau were increased in both paraneoplastic and non-paraneoplastic autoimmune syndromes. Patients with manifest malignancies were older, had less epilepsy, more focal central and peripheral neurological signs and symptoms, and worse long-term outcome, than those without malignancy. CSF-NFL-levels predicted long-term outcome but were not diagnostic for malignancy, after age adjustment.
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| 12. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Cerebrospinal fluid markers of neuronal and glial cell damage to monitor disease activity and predict long-term outcome in patients with autoimmune encephalitis
- 2016
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101. ; 23:4, s. 796-806
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Tidskriftsartikel (refereegranskat)abstract
- Background and purposeClinical symptoms and long-term outcome of autoimmune encephalitis are variable. Diagnosis requires multiple investigations, and treatment strategies must be individually tailored. Better biomarkers are needed for diagnosis, to monitor disease activity and to predict long-term outcome. The value of cerebrospinal fluid (CSF) markers of neuronal [neurofilament light chain protein (NFL), and total tau protein (T-tau)] and glial cell [glial fibrillary acidic protein (GFAP)] damage in patients with autoimmune encephalitis was investigated. MethodsDemographic, clinical, magnetic resonance imaging, CSF and antibody-related data of 25 patients hospitalized for autoimmune encephalitis and followed for 1 year were retrospectively collected. Correlations between these data and consecutive CSF levels of NFL, T-tau and GFAP were investigated. Disability, assessed by the modified Rankin scale, was used for evaluation of disease activity and long-term outcome. ResultsThe acute stage of autoimmune encephalitis was accompanied by high CSF levels of NFL and T-tau, whereas normal or significantly lower levels were observed after clinical improvement 1 year later. NFL and T-tau reacted in a similar way but at different speeds, with T-tau reacting faster. CSF levels of GFAP were initially moderately increased but did not change significantly later on. Final outcome (disability at 1 year) directly correlated with CSF-NFL and CSF-GFAP levels at all time-points and with CSF-T-tau at 3 1 months. This correlation remained significant after age adjustment for CSF-NFL and T-tau but not for GFAP. ConclusionIn autoimmune encephalitis, CSF levels of neuronal and glial cell damage markers appear to reflect disease activity and long-term disability.
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| 13. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Cerebrospinal fluid neurofilament light and tau protein as mortality biomarkers in parkinsonism
- 2019
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 140:2, s. 147-156
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Tidskriftsartikel (refereegranskat)abstract
- - Background: Mortality is increased in parkinsonian disorders, moderately in Parkinson's disease (PD) but markedly in atypical parkinsonian disorders (APD), including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Still, there are no reliable quantitative biomarkers for mortality. The cerebrospinal fluid (CSF) neurodegeneration biomarkers such as neurofilament light chain (NF-L), total tau (t-tau), and the tau pathology marker phosphorylated tau (p-tau) are related to mortality in other neurological disorders (eg, amyotrophic lateral sclerosis, Alzheimer's disease), but have not been investigated in this respect in parkinsonian disorders. Aims: To investigate the CSF biomarkers' (NF-L, t-tau, and p-tau) relationship to mortality in parkinsonian disorders. Methods: Demographic, mortality, and CSF data were collected from 68 PD and 83 APD patients. Survival analysis was conducted using Cox regression, with age at lumbar puncture, gender, diagnosis, and levels of CSF biomarkers as predictors. Results: NF-L in CSF was associated with increased mortality in synucleinopathies (PD, MSA; HR 3.698 [2.196-6.228, 95% confidence interval (CI)], P<0.001), in PSP (HR 2.767 [1.126-6.802 95% CI], P=0.027), and in the entire cohort (HR 1.661 [1.082-2.55, 95% CI], P=0.02). t-Tau in CSF was associated with increased mortality in PSP (HR 9.587 [1.143-80.418], P=0.037). p-Tau in CSF was associated with decreased mortality in synucleinopathies (HR 0.196 [0.041-0.929, 95% CI], P=0.040). Atypical parkinsonian disorders and tauopathies were associated with higher mortality (HR 8.798 [4.516-17.14, 95% CI] and HR 3.040 [1.904-4.854], respectively, P<0.001). Conclusion: NF-L and tau protein in CSF might be useful for mortality prognosis in patients with parkinsonian disorders and should be investigated in larger studies. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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| 14. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Cerebrospinal fluid protein markers in PD patients after DBS-STN surgery—A retrospective analysis of patients that underwent surgery between 1993 and 2001
- 2018
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Ingår i: Clinical neurology and neurosurgery. - : Elsevier BV. - 0303-8467. ; 174, s. 174-179
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Tidskriftsartikel (refereegranskat)abstract
- Objective Cerebrospinal fluid (CSF) markers of neurodegeneration [neurofilament light chain (NFL), total Tau (T-Tau)], tau pathology [phosphorylated tau (p-Tau)], glial cell damage or activation [glial fibrillary acidic protein (GFAP)], and brain amyloidosis [β-amyloid 1-42 (Aβ42)] are useful for diagnosis and prognosis in several neurodegenerative disorders. In this paper we investigate these markers and their relationship to key clinical milestones in patients with advanced Parkinson´s disease (PD) operated at our center with subthalamic nucleus deep brain stimulation (STN-DBS) for at least 15 years ago. Patients and methods Retrospective analysis of available cerebrospinal fluid and clinical data in PD-patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska University Hospital before January 1, 2001, were regularly assessed until January 10, 2018, or until death, or until lost to follow-up. Results Twenty three PD patients were operated with STN-DBS. Sixteen of these (six females and ten males) underwent at least one lumbar puncture (LP) immediately prior to or after STN-DBS. Their age at the latest available LP was 64 (55–75) years [median (range)], PD duration 20 (11–33) years, and Hoehn & Yahr (H&Y) stage 3 (2–4). Time between DBS operation and the last LP was 4.5 (0.3–10.8) years. Time from the last LP to the last follow up was 6 (0.1–18) years, and for the entire cohort 115 person-years. On January 10, 2018, four PD-patients (25%) were still alive. All preoperative CSF marker levels were normal. Between two days and six months after DBS, NFL and GFAP levels increased sharply but they normalized thereafter in most patients, and were normal up to almost 11 years after neurosurgery. Over time, all patients deteriorated slowly. At the last follow up, H&Y was 5 (3–5) and 12/16 were demented. There was no significant correlation between postoperative (> 6 months) CSF NFL, GFAP, T-Tau, p-Tau, β-amyloid levels and the presence of dementia, psychosis, inability to walk or need for nursing home at the time for LP, nor for presence of dementia at the last follow up or for death as of January 10, 2018. Conclusion CSF protein biomarkers remain normal despite long PD duration, severe disability, and chronic STN-DBS. They cannot be used for PD staging or prognostication but may indicate brain damage caused by other pathological factors.
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| 15. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Key clinical milestones 15 years and onwards after DBS-STN surgery-A retrospective analysis of patients that underwent surgery between 1993 and 2001
- 2017
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Ingår i: Clinical Neurology and Neurosurgery. - : Elsevier BV. - 0303-8467. ; 154, s. 43-48
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for motor fluctuations in Parkinson's disease (PD), but does not halt disease progression. The long-term deterioration of key functions such as cognition, speech, ability to swallow, gait, urinary bladder control, orientation and reality perception is decisive for patients' independency in daily life. In this paper we investigated patients with advanced PD operated at our center with STN-DBS for at least 15 years ago, in respect to key clinical milestones reflecting their overall function in daily living. Patients and methods: Retrospective analysis of clinical data concerning key clinical milestones including death in PD-patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska Hospital before January 1, 2001, were regularly assessed until death, dropout, or January 11, 2016. Results: Sixteen men and seven women with a median (range) disease duration of 18 (10-28) years were operated with STN-DBS. The median (range) follow-up time post-surgery was 12 (2-18) years and 692 person-years of disease duration were observed. In January 2016, nine PD-patients (39%) were still alive (eight with active STN-DBS). Initially, motor symptoms improved in all patients. Sustained benefit (implying active stimulation at the last follow up) was maintained in 19 of them (83%) but STN-DBS was inactivated in four (17%) due to inefficacy. Over time, all patients deteriorated slowly, and a majority developed severe non-motor and axial symptoms such as dementia, inability to talk, swallow and walk, urinary incontinence, psychosis, and need for nursing home care. At the last follow up, 16/23 (70%) patients were treated with antidepressants. Conclusion: A majority of PD-patients experience sustained motor benefit with continuous STN-DBS. However, over time, non-motor and axial symptoms slowly and severely restrict PD-patients' function in their daily living. (C) 2017 Elsevier B.V. All rights reserved.
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| 16. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Levels of brain related proteins in cerebrospinal fluid: An aid in the differential diagnosis of parkinsonian disorders.
- 2009
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Ingår i: Parkinsonism & related disorders. - : Elsevier BV. - 1353-8020. ; 15:3, s. 205-12
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Forskningsöversikt (refereegranskat)abstract
- Parkinsonian disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), are a large group of common neurodegenerative diseases. The initial differential diagnosis can be extremely challenging with major implications for prognosis. The 42 amino acid fragment of amyloid-beta (Abeta42), neurofilament light chain (NFL), neurofilament heavy chain (pNFH), tau protein, glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE), S-100B protein, and myelin basic protein (MBP) are brain related proteins (BRP) present in neurons and glia cells. They are released in the cerebrospinal fluid (CSF) after brain tissue damage caused by a variety of neurological diseases, including the parkinsonian disorders. A review of the literature shows that, carefully interpreted, the CSF levels of BRP can be of value in the differential diagnosis of parkinsonian disorders.
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| 17. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Levels of the light subunit of neurofilament triplet protein in cerebrospinal fluid in Huntington's disease.
- 2009
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Ingår i: Parkinsonism & related disorders. - : Elsevier BV. - 1353-8020. ; 15:3, s. 245-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neurofilaments are major structural elements of neuronal cells. The light subunit of neurofilament triplet protein (NFL) has been shown to be increased in several neurological diseases (e.g. vascular, infectious, neurodegenerative), indicating axonal damage. METHODS: In this study we analyzed the NFL levels in all (N=35) available cerebrospinal fluid (CSF) samples from a clinical trial in Huntington's disease (HD) and compared them to age and gender matched controls. RESULTS: The CSF-NFL levels were significantly higher in HD subjects compared with age and genders matched controls, and were correlated with scores on the Unified Huntington's Disease Rating Scale Total Functional Capacity assessment. The potential of CSF-NFL levels as a disease activity marker in HD needs to be further investigated.
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| 18. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Light subunit of neurofilament triplet protein in the cerebrospinal fluid after subthalamic nucleus stimulation for Parkinson's disease.
- 2011
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Ingår i: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 124:3, s. 206-10
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Tidskriftsartikel (refereegranskat)abstract
- Constantinescu R, Holmberg B, Rosengren L, Corneliusson O, Johnels B, Zetterberg H. Light subunit of neurofilament triplet protein in the cerebrospinal fluid after subthalamic nucleus stimulation for Parkinson's disease.Acta Neurol Scand: DOI: 10.1111/j.1600-0404.2010.01451.x.© 2010 John Wiley & Sons A/S. Objectives-Cerebrospinal fluid (CSF) levels of neurofilament triplet protein (NFL), a non-specific marker of neuronal damage, are normal in Parkinson's disease (PD) but increased after brain trauma and in several neurological disorders. Using longitudinal CSF-NFL measurements as an indicator of neuronal damage, this study investigated the impact of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on the brain, directly following the surgical intervention and in chronically treated patients with PD. Materials and methods-CSF-NFL levels were measured consecutively in eight patients with PD before and after STN-DBS treatment. Results-CSF-NFL levels were normal prior to STN-DBS and increased sharply during the first 2weeks post-operatively, but normalized after 12months or more. Conclusion-The STN-DBS procedure leads to an acute but limited neuronal damage, as expected. However, normal CSF-NFL levels at 12months post-operatively and beyond suggest the absence of any long-term neuronal damage caused by long-term STN-DBS stimulation.
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| 19. |
- Constantinescu, Radu, 1966, et al.
(författare)
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Serum and cerebrospinal fluid urate levels in synucleinopathies versus tauopathies
- 2013
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314. ; 127:2
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Tidskriftsartikel (refereegranskat)abstract
- Background Low levels of serum urate are associated with a higher risk of Parkinson's disease (PD). Higher serum and cerebrospinal fluid (CSF) urate levels are associated with slower rates of clinical decline in PD and in multiple system atrophy (MSA). Aims To compare CSF and blood urate levels in healthy controls, patients with synucleinopathies and with tauopathies. Methods We investigated urate levels in serum and CSF from 18 healthy controls, 19 patients with synucleinopathies (six patients with PD and 13 with MSA), and 24 patients with tauopathies (18 with progressive supranuclear palsy and six with corticobasal degeneration). None of the patients were treated with dopaminergic medications. Results No significant differences were seen when comparing serum and CSF urate levels from controls across the parkinsonian diagnostic groups. However, in men, serum urate levels were significantly lower in the synucleinopathy group compared with the tauopathy group (P = 0.046), although with a broad overlap. Conclusion Our study suggests that urate levels might provide new insights into the potential pathophysiological mechanisms underlying Parkinsonism and thereby contribute to the future management of these disorders.
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| 20. |
- Constantinescu, Radu, 1966
(författare)
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Update on the use of pramipexole in the treatment of Parkinson's disease.
- 2008
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Ingår i: Neuropsychiatric disease and treatment. - 1176-6328. ; 4:2, s. 337-52
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Tidskriftsartikel (refereegranskat)abstract
- Pramipexole is a non-ergot dopamine agonist shown to be efficacious in the treatment of Parkinson's disease (PD). This review addresses the literature concerning pramipexole's efficacy in treating motor and non-motor symptoms in PD, its impact on the development of dyskinesias and response fluctuations, the issue of neuroprotection, and the risk for developing adverse events such as increased somnolence, attacks of sudden onset of sleep, cardiac valvulopathy and impulse control disturbances.
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| 21. |
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| 22. |
- Hansson, Oskar, et al.
(författare)
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Blood-based NfL : A biomarker for differential diagnosis of parkinsonian disorder
- 2017
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Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 88:10, s. 930-937
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To determine if blood neurofilament light chain (NfL) protein can discriminate between Parkinson disease (PD) and atypical parkinsonian disorders (APD) with equally high diagnostic accuracy as CSF NfL, and can therefore improve the diagnostic workup of parkinsonian disorders. Methods: The study included 3 independent prospective cohorts: the Lund (n = 278) and London (n = 117) cohorts, comprising healthy controls and patients with PD, progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and multiple system atrophy (MSA), as well as an early disease cohort (n = 109) of patients with PD, PSP, MSA, or CBS with disease duration ≤3 years. Blood NfL concentration was measured using an ultrasensitive single molecule array (Simoa) method, and the diagnostic accuracy to distinguish PD from APD was investigated. Results: We found strong correlations between blood and CSF concentrations of NfL (ρ ≥ 0.73-0.84, p ≤ 0.001). Blood NfL was increased in patients with MSA, PSP, and CBS (i.e., all APD groups) when compared to patients with PD as well as healthy controls in all cohorts (p < 0.001). Furthermore, in the Lund cohort, blood NfL could accurately distinguish PD from APD (area under the curve [AUC] 0.91) with similar results in both the London cohort (AUC 0.85) and the early disease cohort (AUC 0.81). Conclusions: Quantification of blood NfL concentration can be used to distinguish PD from APD. Blood-based NfL might consequently be included in the diagnostic workup of patients with parkinsonian symptoms in both primary care and specialized clinics. Classification of evidence: This study provides Class III evidence that blood NfL levels discriminate between PD and APD.
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| 23. |
- Jeppsson, Anna, et al.
(författare)
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CSF biomarkers distinguish idiopathic normal pressure hydrocephalus from its mimics
- 2019
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:10, s. 1117-1123
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine the differential diagnostic significance of cerebrospinal fluid (CSF) biomarkers reflecting Alzheimer's disease-related amyloid β (Aβ) production and aggregation, cortical neuronal damage, tau pathology, damage to long myelinated axons and astrocyte activation, which hypothetically separates patients with idiopathic normal pressure hydrocephalus (iNPH) from patients with other neurodegenerative disorders. Methods: The study included lumbar CSF samples from 82 patients with iNPH, 75 with vascular dementia, 70 with Parkinson's disease, 34 with multiple system atrophy, 34 with progressive supranuclear palsy, 15 with corticobasal degeneration, 50 with Alzheimer's disease, 19 with frontotemporal lobar degeneration and 54 healthy individuals (HIs). We analysed soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ), Aβ species (Aβ38, Aβ40 and Aβ42), total tau (T-tau), phosphorylated tau, neurofilament light and monocyte chemoattractant protein 1 (MCP-1). Results: Patients with iNPH had lower concentrations of tau and APP-derived proteins in combination with elevated MCP-1 compared with HI and the non-iNPH disorders. T-tau, Aβ40 and MCP-1 together yielded an area under the curve of 0.86, differentiating iNPH from the other disorders. A prediction algorithm consisting of T-tau, Aβ40 and MCP-1 was designed as a diagnostic tool using CSF biomarkers. Conclusions: The combination of the CSF biomarkers T-tau, Aβ40 and MCP-1 separates iNPH from cognitive and movement disorders with good diagnostic sensitivity and specificity. This may have important implications for diagnosis and clinical research on disease mechanisms for iNPH. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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| 24. |
- Kloberg, A., et al.
(författare)
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Tolerability and efficacy of the monoaminergic stabilizer (-)-OSU6162 (PNU-96391A) in Huntington's disease: A double-blind cross-over study
- 2014
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press. - 0924-2708 .- 1601-5215. ; 26:5, s. 298-306
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Tidskriftsartikel (refereegranskat)abstract
- Objective To evaluate the safety (primary objective) and efficacy (secondary objective) of (-)-OSU6162 in Huntington's disease (HD). Methods In a double-blind, cross-over trial, patients with HD were randomly assigned to start treatment on either (-)-OSU6162 or placebo. After 4 weeks, those patients who initially received active drug were switched to placebo for another 4 weeks, and vice versa. During the first week the (-)-OSU6162 dose was 15 mg twice daily, during the second week 30 mg twice daily, and during the last 2 weeks 45 mg twice daily. Motor, cognitive, mental and social functions were rated by the clinical investigator or by self-assessment, using established rating scales. Results Fifteen patients fulfilling inclusion and exclusion criteria completed the study. (-)-OSU6162 was well tolerated by all patients and no adverse effects were observed. (-)-OSU6162 treatment significantly improved the Short Form 36 Vitality score, mainly due to an improvement of the individual item 'worn-out' (VT3). In addition, an improvement of depressive symptoms was found using Beck Depression Inventory. In contrast to a general trend of improvement in several non-motor variables only small and non-significant differences between (-)-OSU6162 and placebo were found regarding motor functions. Conclusions (-)-OSU6162 offers promise for the treatment of HD, as a drug with good tolerability, capable of improving the patients' experienced non-motor functions such as energy and mood and thus alleviating symptoms of great importance for their quality of life. © © Scandinavian College of Neuropsychopharmacology 2014.
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| 25. |
- Korpela, Sara, et al.
(författare)
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Cerebrospinal fluid glial fibrillary acidic protein, in contrast to amyloid beta protein, is associated with disease symptoms in Huntington's disease
- 2024
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Ingår i: Journal of the Neurological Sciences. - : Elsevier. - 0022-510X .- 1878-5883. ; 459
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Huntington's disease (HD) is a hereditary neurodegenerative disease, currently lacking disease-modifying treatments. Biomarkers are needed for objective assessment of disease progression. Evidence supports both complex protein aggregation and astrocyte activation in HD. This study assesses the 42 amino acid long amyloid beta (Aβ42) and glial fibrillary acidic protein (GFAP) as potential biomarkers in the cerebrospinal fluid (CSF) of HD mutation carriers.Methods: CSF from participants was obtained from three sites in Sweden. Clinical symptoms were graded with the composite Unified Huntington's disease rating scale (cUHDRS). Protein concentrations were measured using ELISA. Pearson correlations were calculated to assess disease progression association. Results were adjusted for age and collection site.Results: The study enrolled 28 manifest HD patients (ManHD), 13 premanifest HD gene-expansion carriers (PreHD) and 20 controls. Aβ42 levels did not differ between groups and there was no correlation with measures of disease progression. GFAP concentration was higher in ManHD (424 ng/l, SD 253) compared with both PreHD (266 ng/l, SD 92.4) and controls (208 ng/l, SD 83.7). GFAP correlated with both cUHDRS (r = -0.77, p < 0.001), and 5-year risk of disease onset (r = 0.70, p = 0.008).Conclusion: We provide evidence that indicates CSF Aβ42 has limited potential as a biomarker for HD. GFAP is a potential biomarker of progression in HD. Validation in larger cohorts measuring GFAP in blood and CSF would be of interest.
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| 26. |
- Lancaster, Eric, et al.
(författare)
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Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen.
- 2010
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Ingår i: Lancet neurology. - 1474-4465. ; 9:1, s. 67-76
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Some encephalitides or seizure disorders once thought idiopathic now seem to be immune mediated. We aimed to describe the clinical features of one such disorder and to identify the autoantigen involved. METHODS: 15 patients who were suspected to have paraneoplastic or immune-mediated limbic encephalitis were clinically assessed. Confocal microscopy, immunoprecipitation, and mass spectrometry were used to characterise the autoantigen. An assay of HEK293 cells transfected with rodent GABA(B1) or GABA(B2) receptor subunits was used as a serological test. 91 patients with encephalitis suspected to be paraneoplastic or immune mediated and 13 individuals with syndromes associated with antibodies to glutamic acid decarboxylase 65 were used as controls. FINDINGS: All patients presented with early or prominent seizures; other symptoms, MRI, and electroencephalography findings were consistent with predominant limbic dysfunction. All patients had antibodies (mainly IgG1) against a neuronal cell-surface antigen; in three patients antibodies were detected only in CSF. Immunoprecipitation and mass spectrometry showed that the antibodies recognise the B1 subunit of the GABA(B) receptor, an inhibitory receptor that has been associated with seizures and memory dysfunction when disrupted. Confocal microscopy showed colocalisation of the antibody with GABA(B) receptors. Seven of 15 patients had tumours, five of which were small-cell lung cancer, and seven patients had non-neuronal autoantibodies. Although nine of ten patients who received immunotherapy and cancer treatment (when a tumour was found) showed neurological improvement, none of the four patients who were not similarly treated improved (p=0.005). Low levels of GABA(B1) receptor antibodies were identified in two of 104 controls (p<0.0001). INTERPRETATION: GABA(B) receptor autoimmune encephalitis is a potentially treatable disorder characterised by seizures and, in some patients, associated with small-cell lung cancer and with other autoantibodies. FUNDING: National Institutes of Health.
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| 27. |
- Luk, C., et al.
(författare)
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Development and assessment of sensitive immuno-PCR assays for the quantification of cerebrospinal fluid three- and four-repeat tau isoforms in tauopathies
- 2012
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; 123:3, s. 396-405
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Tidskriftsartikel (refereegranskat)abstract
- Characteristic tau isoform composition of the insoluble fibrillar tau inclusions define tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal dementia with parkinsonism linked to chromosome 17/frontotemporal lobar degeneration-tau (FTDP-17/FTLD-tau). Exon 10 splicing mutations in the tau gene, MAPT, in familial FTDP-17 cause elevation of tau isoforms with four microtubule-binding repeat domains (4R-tau) compared to those with three repeats (3R-tau). On the basis of two well-characterised monoclonal antibodies against 3R- and 4R-tau, we developed novel, sensitive immuno-PCR assays for measuring the trace amounts of these isoforms in CSF. This was with the aim of assessing if CSF tau isoform changes reflect the pathological changes in tau isoform homeostasis in the degenerative brain and if these would be relevant for differential clinical diagnosis. Initial analysis of clinical CSF samples of PSP (n = 46), corticobasal syndrome (CBS; n = 22), AD (n = 11), Parkinson's disease with dementia (PDD; n = 16) and 35 controls revealed selective decreases of immunoreactive 4R-tau in CSF of PSP and AD patients compared with controls, and lower 4R-tau levels in AD compared with PDD. These decreases could be related to the disease-specific conformational masking of the RD4-binding epitope because of abnormal folding and/or aggregation of the 4R-tau isoforms in tauopathies or increased sequestration of the 4R-tau isoforms in brain tau pathology.
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| 28. |
- Lukkarinen, H., et al.
(författare)
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Cerebrospinal fluid biomarkers that reflect clinical symptoms in idiopathic normal pressure hydrocephalus patients
- 2022
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Ingår i: Fluids and Barriers of the Cns. - : Springer Science and Business Media LLC. - 2045-8118. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The relationship between cerebrospinal fluid (CSF) biomarkers and the clinical features of idiopathic normal pressure hydrocephalus (iNPH) has been inconclusive. We aimed to evaluate CSF biomarkers reflecting Alzheimer’s disease (AD)-related amyloid β (Aβ) aggregation, tau pathology, neuroinflammation and axonal degeneration in relation to the clinical features of pre- and post-shunt surgery in iNPH patients. Methods: Mini Mental State Examination (MMSE) scores and gait velocity were evaluated pre- and postoperatively in cohorts of 65 Finnish (FIN) and 82 Swedish (SWE) iNPH patients. Lumbar CSF samples were obtained prior to shunt surgery and analysed for soluble amyloid precursor protein alpha (sAPPα) and beta (sAPPβ); amyloid-β isoforms of 42, 40 and 38 (Aβ42, Aβ40, Aβ38); total tau (T-tau); phosphorylated tau (P-tau181); neurofilament light (NfL) and monocyte chemoattractant protein 1 (MCP1). Results: Preoperative patient characteristics showed no significant differences between patients in the FIN and SWE cohorts. Patients in both cohorts had significantly improved gait velocity after shunt surgery (p < 0.0001). Low CSF T-tau and absence of apolipoprotein E ε4 predicted over 20% gait improvement postoperatively (p = 0.043 and p = 0.008). Preoperative CSF T-tau, P-tau181 and NfL correlated negatively with MMSE scores both pre- (p < 0.01) and post-surgery (p < 0.01). Furthermore, T-tau, NfL and Aβ42 correlated with MMSE outcomes (p < 0.05). Low preoperative CSF P-tau181 (p = 0.001) and T-tau with NfL (p < 0.001 and p = 0.049) best predicted pre- and postoperative MMSE scores greater than or equal to 26. Conclusions: CSF biomarkers of neurodegeneration appeared to correlate with pre- and postoperative cognition, providing a window into neuropathological processes. In addition, preoperative CSF neurodegeneration biomarkers may have potential in the prediction of gait and cognitive outcomes after shunt surgery. © 2022, The Author(s).
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| 29. |
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| 30. |
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| 31. |
- Mondello, Stefania, et al.
(författare)
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CSF α-synuclein and UCH-L1 levels in Parkinson's disease and atypical parkinsonian disorders.
- 2014
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Ingår i: Parkinsonism & related disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 20:4, s. 382-387
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Tidskriftsartikel (refereegranskat)abstract
- There is an unmet need for biomarkers for Parkinson's disease (PD) and atypical parkinsonian disorders (APD). α-Synuclein, linked to the pathogenesis of PD, is a promising biomarker candidate in need of further investigation. The ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a pivotal component of the ubiquitin proteasome system which seems to be disturbed in PD, may also be involved in the pathogenesis of this disorder.
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| 32. |
- Niemelä, Valter, et al.
(författare)
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Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease
- 2021
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:2, s. 481-491
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Tidskriftsartikel (refereegranskat)abstract
- Objective Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies. Methods We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 pre-manifest (preHD), and 38 controls. A biologically plausible and significant possible biomarker was validated in samples from a separate cohort of patients and controls consisting of 23 ManHD patients and 23 controls. Results In ManHD compared to preHD, 10 proteins were downregulated and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin were closely linked to HD symptom severity, whereas levels of 15 upregulated proteins were associated with symptom severity. The decreased PENK levels were replicated in the separate cohort where absolute quantitation was performed. Conclusions We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD. (c) 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
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| 33. |
- Nutu, Magdalena, 1967, et al.
(författare)
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Aβ1-15/16 as a potential diagnostic marker in neurodegenerative diseases.
- 2013
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Ingår i: Neuromolecular medicine. - : Springer Science and Business Media LLC. - 1559-1174 .- 1535-1084. ; 15:1, s. 169-79
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) reflect brain biochemistry. Using combined immunoprecipitation and mass spectrometry, we have shown that amyloid beta 1-15 (Aβ1-15) is produced by concerted β- and α-secretase cleavage of amyloid precursor protein (APP) and that the relative levels of Aβ1-16 in AD compared to controls are increased. Furthermore, drug-induced γ-secretase inhibition enhances the relative levels of Aβ1-15 and Aβ1-16. Here, we investigate a novel immunoassay for Aβ1-15/16 in a broad range of neurodegenerative conditions. The CSF level of Aβ1-15/16 was measured by the bead-based amplified luminescent proximity homogeneous assay (Alpha technology). Concentrations of Aβ1-15/16 were analyzed in subjects with Parkinson disease (PD; n = 90), PD with dementia (PDD) (n = 32), dementia with Lewy bodies (DLB) (n = 68), AD (n = 48), progressive supranuclear palsy (PSP) (n = 45), multiple system atrophy (MSA) (n = 46), and corticobasal degeneration (CBD) (n = 12). The detecting antibody is specific to the C-terminal epitope of Aβ15. We found that a carboxypeptidase (CPB) present in fetal bovine serum (FBS), a component of the buffers used, degrades Aβ1-16 to Aβ1-15, which is then detected by the Aβ1-15/16 assay. Significantly, lower levels of Aβ1-15/16 were detected in PD, PDD, PSP, and MSA compared to other neurodegenerative diseases and controls. Using the specific Aβ1-15/16 assay, a reliable quantification of Aβ1-15 or Aβ1-15/16 in CSF samples is obtained. We found reduced levels of Aβ1-15 in parkinsonian disease groups. The molecular mechanism behind this reduction is at present unknown.
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| 34. |
- Nyhlén, Jakob, et al.
(författare)
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Problems associated with fluid biomarkers for Parkinson's disease.
- 2010
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Ingår i: Biomarkers in medicine. - : Future Medicine Ltd. - 1752-0371 .- 1752-0363. ; 4:5, s. 671-81
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Forskningsöversikt (refereegranskat)abstract
- This article focuses on biochemical markers that may be used in the diagnostics of Parkinson's disease and associated disorders, and to identify early cases and stratify patients into subgroups. We present an updated account of some currently available candidate fluid biomarkers, and discuss their diagnostic performance and limitations. We also discuss some of the general problems with Parkinson's disease biomarkers and possible ways of moving forward. It may be concluded that a diagnostically useful fluid biomarker for Parkinson's disease is yet to be identified. However, some interesting candidates exist and may prove useful in the future, alone or when analyzed together in patterns.
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| 35. |
- Nyholm, Dag, et al.
(författare)
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Comparison of apomorphine and levodopa infusions in four patients with Parkinson's disease with symptom fluctuations.
- 2009
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Ingår i: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 119:5, s. 345-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Motor fluctuations in patients with advanced Parkinson's disease may be successfully treated with subcutaneous apomorphine infusion or intraduodenal levodopa/carbidopa infusion. No comparative trials of these two alternatives were performed. AIMS OF THE STUDY: We present a subanalysis from a randomized crossover clinical trial where levodopa infusion as monotherapy was compared with any other combination of pharmacotherapy in fluctuating patients. Four patients used apomorphine infusion and oral levodopa in the comparator arm. The results of these four patients are presented in detail. METHODS: The duration of the trial was 3 + 3 weeks. Patients were video-recorded half-hourly on two non-consecutive days of both treatment arms. Blinded video ratings were used. Patient self-assessments of motor function and quality-of-life (QoL) parameters were captured using an electronic diary. RESULTS: Ratings in moderate to severe "off" state ranged 0-44% on apomorphine infusion and 0-6% on levodopa infusion. Moderate to severe dyskinesias were not recorded in any of the treatments. QoL was reported to be improved in all patients on duodenal levodopa infusion. CONCLUSIONS: Monotherapy with duodenal infusion of levodopa was more efficacious and brought greater QoL than combination therapy with apomorphine infusion in these fluctuating patients.
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| 36. |
- Olsson, Bob, 1969, et al.
(författare)
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The glial marker YKL-40 is decreased in synucleinopathies.
- 2013
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Ingår i: Movement disorders : official journal of the Movement Disorder Society. - : Wiley. - 1531-8257. ; 28:14, s. 1882-1885
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Tidskriftsartikel (refereegranskat)abstract
- Microglia are resident immunosurveillant cells in the central nervous system, and astrocytes are important for blood flow, plasticity, and neurotransmitter regulation. The aim of this study was to investigate whether astrocyte and microglial activation, estimated through markers in cerebrospinal fluid and serum, differed between synucleinopathies, tauopathies, and controls.
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| 37. |
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| 38. |
- Senek, Marina, et al.
(författare)
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Levodopa/carbidopa microtablets in Parkinson's disease : a study of pharmacokinetics and blinded motor assessment
- 2017
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Ingår i: European Journal of Clinical Pharmacology. - Heidelberg, Germany : Springer. - 0031-6970 .- 1432-1041 .- 0014-2999. ; 73:5, s. 563-571
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Tidskriftsartikel (refereegranskat)abstract
- Background: Motor function assessments with rating scales in relation to the pharmacokinetics of levodopa may increase the understanding of how to individualize and fine-tune treatments.Objectives: This study aimed to investigate the pharmacokinetic profiles of levodopa-carbidopa and the motor function following a single-dose microtablet administration in Parkinson’s disease.Methods: This was a single-center, open-label, single-dose study in 19 patients experiencing motor fluctuations. Patients received 150% of their individual levodopa equivalent morning dose in levodopa-carbidopa microtablets. Blood samples were collected at pre-specified time points. Patients were video recorded and motor function was assessed with six UPDRS part III motor items, dyskinesia score, and the treatment response scale (TRS), rated by three blinded movement disorder specialists.Results: AUC0–4/dose and Cmax/dose for levodopa was found to be higher in Parkinson’s disease patients compared with healthy subjects from a previous study, (p = 0.0008 and p = 0.026, respectively). The mean time to maximum improvement in sum of six UPDRS items score was 78 min (±59) (n = 16), and the mean time to TRS score maximum effect was 54 min (±51) (n = 15). Mean time to onset of dyskinesia was 41 min (±38) (n = 13).Conclusions: In the PD population, following levodopa/carbidopa microtablet administration in fasting state, the Cmax and AUC0–4/dose were found to be higher compared with results from a previous study in young, healthy subjects. A large between subject variability in response and duration of effect was observed, highlighting the importance of a continuous and individual assessment of motor function in order to optimize treatment effect.
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| 39. |
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| 40. |
- Stevens-Jones, Oskar, et al.
(författare)
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Paraneoplastic or not? Sirtuin 2 in anti-N-methyl-D-aspartate receptor encephalitis
- 2023
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Ingår i: European Journal of Neurology. - 1351-5101. ; 30:10, s. 3228-3235
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: N-methyl- d- aspartate receptor (NMDAR) and leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis are important types of autoimmune encephalitis (AE) with significant morbidity. In this study, we used a proteomic approach in search of novel clinically relevant biomarkers in these types of encephalitides. Methods: Swedish and Czech tertiary neuroimmunology centers collaborated in this retrospective exploratory study. Fifty-eight cerebrospinal fluid (CSF) samples of 28 patients with AE (14 definite NMDAR, 14 with definite LGI1 encephalitis) and 30 controls were included. CSF samples were analyzed using proximity extension assay technology (Olink Target 96 Inflammation panel). For each CSF sample, 92 proteins were measured. Clinical variables were retrospectively collected, and correlations with protein levels were statistically analyzed. Results: Patients and controls differed significantly in the following 18 biomarkers: TNFRSF9, TNFRSF12, TNFRSF14, TNF beta, TNF alpha, IL7, IL10, IL12B, IFN gamma, CD5, CD6, CASP8, MMP1, CXCL8, CXCL10, CXCL11, IL20RA, and sirtuin 2 (SIRT2). In LGI1 encephalitis, no clinically useful association was found between biomarkers and clinical variables. In the NMDAR encephalitis group, SIRT2, TNF beta, and CD5 were significantly associated with ovarian teratoma. For SIRT2, this was true even for the first patients' CSF sample (SIRT2 without vs. with tumor, mean +/- SD = 2.2 +/- 0.29 vs. 2.88 +/- 0.48; p = 0.007, 95% confidence interval = -1.15 to -0.22; r statistic in point-biserial correlation (rpb) = 0.66, p = 0.011). SIRT2 was positively correlated with age (rpb = 0.39, p = 0.018) and total hospital days (r = 0.55, p = <0.001). Conclusions: SIRT2 should be investigated as a biomarker of paraneoplastic etiology in NMDAR encephalitis.
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| 41. |
- Thomas, Ilias, et al.
(författare)
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Using measurements from wearable sensors for automatic scoring of Parkinson's disease motor states : Results from 7 patients
- 2017
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Ingår i: 2017 39th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). - New York : IEEE. - 1094-687X. - 9781509028092 - 9781509028108 ; , s. 131-134
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Konferensbidrag (refereegranskat)abstract
- The objective of this study was to investigate the validity of an objective gait measure for assessment of different motor states of advanced Parkinson's disease (PD) patients. Seven PD patients performed a gait task up to 15 times while wearing sensors on their upper and lower limbs. Each task was performed at specific points during a test day, following a single dose of levodopa-carbidopa. At the time of the tasks the patients were video recorded and three movement disorder experts rated their motor function on three clinical scales: a treatment response scale (TRS) that ranged from −3 (very bradykinetic) to 0 (ON) to +3 (very dyskinetic), a dyskinesia score that ranged from 0 (no dyskinesia) to 4 (extreme dyskinesia), and a bradykinesia score that ranged from 0 (no bradykinesia) to 4 (extreme bradykinesia). Raw accelerometer and gyroscope data of the sensors were processed and analyzed with time series analysis methods to extract features. The utilized features quantified separate limb movements as well as movement symmetries between the limbs. The features were processed with principal component analysis and the components were used as predictors for separate support vector machine (SVM) models for each of the three scales. The performance of each model was evaluated in a leave-one-patient out setting where the observations of a single patient were used as the testing set and the observations of the other 6 patients as the training set. Root mean square error (RMSE) and correlation coefficients for the predictions showed a good ability of the models to map the sensor data into the rating scales. There were strong correlations between the SVM models and the mean ratings of TRS (0.79; RMSE=0.70), bradykinesia score (0.79; RMSE=0.47), and bradykinesia score (0.78; RMSE=0.46). The results presented in this paper indicate that the use of wearable sensors when performing gait tasks can generate measurements that have a good correlation to subjective expert assessments.
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| 42. |
- Thordstein, Magnus, et al.
(författare)
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Possibly lifesaving, noninvasive, EEG-guided neuromodulation in anesthesia-refractory partial status epilepticus
- 2012
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Ingår i: Epilepsy & Behavior. - : Elsevier BV. - 1525-5050. ; 25:3, s. 468-472
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to investigate the effect of low frequency repetitive transcranial magnetic stimulation (rTMS) guided as to localization and effect by continuous EEG on a super-refractory status epilepticus unresponsive to conventional treatment for 44 days including repeated deep sedation. Repetitive transcranial magnetic stimulation was delivered for one-hour sessions to the most active of two EEG foci for 8 days. From the third day of stimulation, the EEG pathology markedly decreased in parallel to clinical improvement. The patient could be weaned off the respirator, transferred to an ordinary ward then to a rehabilitation clinic. This is the first report of a positive outcome of rTMS treatment in super-refractory status epilepticus. In the context of refractory partial status epilepticus, neuromodulation through rTMS is a safe treatment option. If performed along the lines herein described, it may also be more efficient than conventional treatment. Repetitive transcranial magnetic stimulation may be an underused treatment option for status epilepticus. (C) 2012 Elsevier Inc. All rights reserved.
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| 43. |
- Zelano, Johan, 1981, et al.
(författare)
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Neuronal antibodies in adult patients with new-onset seizures: A prospective study
- 2019
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Ingår i: Brain and Behavior. - : Wiley. - 2162-3279. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Immunotherapy in addition to antiepileptic drugs can improve seizure freedom rates in autoimmune epilepsy, highlighting the importance of early diagnosis. A diagnosis of autoimmune epilepsy can be supported by presence of serum antibodies to neuronal antigens. We asked how often neuronal antibodies are found in the serum of unselected adult patients with new-onset seizures and whether such testing could improve detection of autoimmune epilepsy. Material and Methods We included 44 patients over the age of 25 presenting after at least one unprovoked seizure to the Neurology Clinic at Sahlgrenska University Hospital, Gothenburg, Sweden. The median time between the first-ever seizure in life and the serum sampling was 50 days (range 22-11,000). Antibody testing in serum was performed according to the manufacturer's instructions. The patients were followed for at least 1 year. Results Epilepsy could be diagnosed already at the first visit in 21/44 patients (47.7%). Two patients (4.5%) were positive for neuronal antibodies: one against contactin-associated protein 2 (CASPR-2) and one against glutamate acid decarboxylase (GAD). Three patients (6.7%) displayed very weak immunoreactivity that was deemed clinically insignificant. One of the antibody-positive patients had only a single seizure. The other had a focal cortical dysplasia and was seizure-free on levetiracetam. None of the five patients with antibodies or immunoreactivity displayed any feature of autoimmune epilepsy. Conclusions We conclude that indiscriminate testing in patients presenting to a first seizure clinic with new-onset seizures or epilepsy is unlikely to improve detection of autoimmune epilepsy.
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