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Sökning: WFRF:(Ohrfelt Annika)

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1.
  • Brinkmalm, Ann, et al. (författare)
  • SNAP-25 is a promising novel cerebrospinal fluid biomarker for synapse degeneration in Alzheimer's disease
  • 2014
  • Ingår i: Molecular Neurodegeneration. - BioMed Central (BMC). - 1750-1326. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Synaptic degeneration is an early pathogenic event in Alzheimer's disease, associated with cognitive impairment and disease progression. Cerebrospinal fluid biomarkers reflecting synaptic integrity would be highly valuable tools to monitor synaptic degeneration directly in patients. We previously showed that synaptic proteins such as synaptotagmin and synaptosomal-associated protein 25 (SNAP-25) could be detected in pooled samples of cerebrospinal fluid, however these assays were not sensitive enough for individual samples. Results: We report a new strategy to study synaptic pathology by using affinity purification and mass spectrometry to measure the levels of the presynaptic protein SNAP-25 in cerebrospinal fluid. By applying this novel affinity mass spectrometry strategy on three separate cohorts of patients, the value of SNAP-25 as a cerebrospinal fluid biomarker for synaptic integrity in Alzheimer's disease was assessed for the first time. We found significantly higher levels of cerebrospinal fluid SNAP-25 fragments in Alzheimer's disease, even in the very early stages, in three separate cohorts. Cerebrospinal fluid SNAP-25 differentiated Alzheimer's disease from controls with area under the curve of 0.901 (P < 0.0001). Conclusions: We developed a sensitive method to analyze SNAP-25 levels in individual CSF samples that to our knowledge was not possible previously. Our results support the notion that synaptic biomarkers may be important tools for early diagnosis, assessment of disease progression, and to monitor drug effects in treatment trials.
2.
  • Brinkmalm, Gunnar, et al. (författare)
  • Soluble amyloid precursor protein α and β in CSF in Alzheimer's disease.
  • 2013
  • Ingår i: Brain research. - 1872-6240. ; 1513, s. 117-26
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Cerebral accumulation of amyloid beta (A beta) is a pathological hallmark of Alzheimer's disease (AD). Proteolytic processing of amyloid precursor protein (APP) by alpha- or beta-secretase results in two soluble metabolites, sAPP alpha and sAPP beta, respectively. However, previous data have shown that both alpha- and beta-secretase have multiple cleavage sites. The aim of this study was to characterize the C-termini of sAPP alpha and sAPP beta in cerebrospinal fluid (CSF) by mass spectrometry (MS) and to evaluate whether different combinations of these fragments better separate between AD patients and controls by comparing two different sAPP immunoassays. Methods: Using immunoprecipitation and high resolution MS, the APP species present in CSF were investigated. CSF levels of sAPP alpha and sAPP beta from patients with AD (n=43) and from non-demented controls (n=44) were measured using AlphaLISA and MSD immunoassays that employ different antibodies for C-terminal recognition of sAPP alpha. Results: Four different C-terminal forms of sAPP were identified, sAPP beta-M671, sAPP beta-Y681, sAPP alpha-Q686, and 5APP alpha-K687 (APP770 numbering). Neither immunoassay for the sAPP species could separate the two patient groups. The correlation (R-2) between the two immunoassays was 0.41 for sAPP alpha and 0.45 for sAPP beta. Conclusion: Using high resolution MS, we show here for the first time that sAPP alpha in CSF ends at Q686 and K687. The findings also support the conclusion from several previous studies that sAPP alpha and sAPP beta levels are unaltered in AD. (C) 2013 Elsevier B.V. All rights reserved.
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3.
  • Hall, Sara, et al. (författare)
  • Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders.
  • 2012
  • Ingår i: Archives of neurology. - 1538-3687. ; 69:11, s. 1445-52
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To assess the ability of 5 cerebrospinal fluid (CSF) biomarkers to differentiate between common dementia and parkinsonian disorders. Design: A cross-sectional, clinic-based study. Participants: Cerebrospinal fluid samples (N=453) were obtained from healthy individuals serving as controls and from patients with Parkinson disease (PD), PD with dementia (PDD), dementia with Lewy bodies (DLB), Alzheimer disease (AD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), or corticobasal degeneration (CBD). Setting: Neurology and memory disorder clinics. Main Outcome Measures: Cerebrospinal fluid biomarker levels in relation to clinical diagnosis. Results: Cerebrospinal fluid levels of alpha-synuclein were decreased in patients with PD, PDD, DLB, and MSA but increased in patients with AD. Cerebrospinal fluid levels of beta-amyloid 1-42 were decreased in DLB and even further decreased in AD. Cerebrospinal fluid levels of total tau and hyperphosphorylated tau were increased in AD. Multivariate analysis revealed that these biomarkers could differentiate AD from DLB and PDD with an area under the curve of 0.90, with alpha-synuclein and total tau contributing most to the model. Cerebrospinal fluid levels of neurofilament light chain were substantially increased in atypical parkinsonian disorders (ie, PSP, MSA, and CBD), and multivariate analysis revealed that the level of neurofilament light chain alone could differentiate PD from atypical parkinsonian disorders, with an area under the curve of 0.93. Conclusions: Ascertainment of the alpha-synuclein level in CSF somewhat improves the differential diagnosis of AD vs DLB and PDD when combined with established AD biomarkers. The level of neurofilament light chain alone may differentiate PD from atypical parkinsonian disorders.
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4.
  • Hall, Sara, et al. (författare)
  • CSF biomarkers and clinical progression of Parkinson disease.
  • 2015
  • Ingår i: Neurology. - American Academy of Neurology. - 1526-632X. ; 84:1, s. 57-63
  • Tidskriftsartikel (refereegranskat)abstract
    • To investigate whether certain CSF biomarkers at baseline can predict future progression of motor symptoms and cognitive decline in patients with Parkinson disease (PD).
5.
6.
  • Nutu, Magdalena, et al. (författare)
  • Evaluation of the Cerebrospinal Fluid Amyloid-beta(1-42)/Amyloid-beta(1-40) Ratio Measured by Alpha-LISA to Distinguish Alzheimer's Disease from Other Dementia Disorders
  • 2013
  • Ingår i: Dementia and Geriatric Cognitive Disorders. - Karger. - 1420-8008. ; 36:1-2, s. 99-110
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The well-established core biomarkers used to identify Alzheimer's disease (AD) overlap with other dementia disorders such as dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). This study aimed to evaluate whether the cerebrospinal fluid (CSF) amyloid-beta (A beta)(1-42)/A beta(1-40) ratio, measured by a novel method, could improve the differential diagnosis of AD, DLB and PDD. Method: CSF levels of A beta(1-40) and A beta(1-42) in patients with PDD, DLB, AD, Parkinson's disease and controls were analyzed using an amplified luminescent proximity homogenous immunoassay along with conventional immunoassays. Results: The CSF A beta(1-42)/A beta(1-40) ratio increased discrimination of AD from PDD and DLB compared with either of the two A beta biomarkers individually. Conclusion: The use of the A beta(1-42)/A beta(1-40) ratio could improve the differentiation of AD from PDD and DLB. (C) 2013 S. Karger AG, Basel
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7.
  • Hansson, Oskar, et al. (författare)
  • Levels of cerebrospinal fluid α-synuclein oligomers are increased in Parkinson's disease with dementia and dementia with Lewy bodies compared to Alzheimer's disease
  • 2014
  • Ingår i: Alzheimer's Research & Therapy. - BioMed Central. - 1758-9193. ; 6:3
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>INTRODUCTION:</strong> The objective was to study whether α-synuclein oligomers are altered in the cerebrospinal fluid (CSF) of patients with dementia, including Parkinson disease with dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD), compared with age-matched controls.</p><p><strong>METHODS:</strong> In total, 247 CSF samples were assessed in this study, including 71 patients with DLB, 30 patients with PDD, 48 patients with AD, and 98 healthy age-matched controls. Both total and oligomeric α-synuclein levels were evaluated by using well-established immunoassays.</p><p><strong>RESULTS:</strong> The levels of α-synuclein oligomers in the CSF were increased in patients with PDD compared with the controls (P &lt; 0.05), but not in patients with DLB compared with controls. Interestingly, the levels of α-synuclein oligomers in the CSF were also significantly higher in patients with PDD (P &lt; 0.01) and DLB (P &lt; 0.05) compared with patients with AD. The levels of CSF α-synuclein oligomers and the ratio of oligomeric/total-α-synuclein could distinguish DLB or PDD patients from AD patients, with areas under the curves (AUCs) of 0.64 and 0.75, respectively. In addition, total-α-synuclein alone could distinguish DLB or PDD patients from AD patients, with an AUC of 0.80.</p><p><strong>CONCLUSIONS:</strong> The levels of α-synuclein oligomers were increased in the CSF from α-synucleinopathy patients with dementia compared with AD cases.</p>
8.
  • Nutu, Magdalena, et al. (författare)
  • Evaluation of the cerebrospinal fluid amyloid-β1-42/amyloid-β1-40 ratio measured by alpha-LISA to distinguish Alzheimer's disease from other dementia disorders.
  • 2013
  • Ingår i: Dementia and Geriatric Cognitive Disorders. - 1420-8008 .- 1421-9824. ; 36:1-2, s. 99-110
  • Tidskriftsartikel (refereegranskat)abstract
    • <p><strong>BACKGROUND:</strong> The well-established core biomarkers used to identify Alzheimer's disease (AD) overlap with other dementia disorders such as dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD). This study aimed to evaluate whether the cerebrospinal fluid (CSF) amyloid-β (Aβ)1-42/Aβ1-40 ratio, measured by a novel method, could improve the differential diagnosis of AD, DLB and PDD.</p><p><strong>METHOD:</strong> CSF levels of Aβ1-40 and Aβ1-42 in patients with PDD, DLB, AD, Parkinson's disease and controls were analyzed using an amplified luminescent proximity homogenous immunoassay along with conventional immunoassays.</p><p><strong>RESULTS:</strong> The CSF Aβ1-42/Aβ1-40 ratio increased discrimination of AD from PDD and DLB compared with either of the two Aβ biomarkers individually.</p><p><strong>CONCLUSION:</strong> The use of the Aβ1-42/Aβ1-40 ratio could improve the differentiation of AD from PDD and DLB.</p>
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9.
  • Öhrfelt Olsson, Annika, 1973-, et al. (författare)
  • Cerebrospinal fluid alpha-synuclein in neurodegenerative disorders-a marker of synapse loss?
  • 2009
  • Ingår i: Neuroscience letters. - 0304-3940. ; 450:3, s. 332-5
  • Tidskriftsartikel (refereegranskat)abstract
    • The association of alpha-synuclein (alpha-syn) neuropathology with Parkinson's disease (PD) and several related disorders has led to an intense research effort to develop cerebrospinal fluid (CSF)- or blood-based alpha-syn biomarkers for these types of diseases. Recent studies show that alpha-syn is present in CSF and possible to measure using enzyme-linked immunosorbent assay (ELISA). Here, we describe a novel ELISA that allows for quantification of alpha-syn in CSF down to 50pg/mL. The diagnostic value of the test was assessed using CSF samples from 66 Alzheimer's disease (AD) patients, 15PD patients, 15 patients with dementia with Lewy bodies (DLB) and 55 cognitively normal controls. PD and DLB patients and controls displayed similar CSF alpha-syn levels. AD patients had significantly lower alpha-syn levels than controls (median [inter-quartile range] 296 [234-372] and 395 [298-452], respectively, p<0.001). Moreover, AD patients with mini-mental state examination (MMSE) scores below 20 had significantly lower alpha-syn than AD patients with MMSE scores of 20 or higher (p=0.02). There was also a tendency towards a negative correlation between alpha-syn levels and disease duration in the AD group (r=-0.247, p=0.06). Altogether, our results speak against CSF alpha-syn as a reliable biomarker for PD and DLB. The lower alpha-syn levels in AD, as well as the association of alpha-syn reduction with AD severity, approximated by MMSE, suggests that it may be a general marker of synapse loss, a hypothesis that warrants further investigation.
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10.
  • Öhrfelt Olsson, Annika, 1973-, et al. (författare)
  • Identification of Novel α-Synuclein Isoforms in Human Brain Tissue by using an Online NanoLC-ESI-FTICR-MS Method.
  • 2011
  • Ingår i: Neurochemical research. - 1573-6903. ; 36:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are neurodegenerative diseases that are characterized by intra-neuronal inclusions of Lewy bodies in distinct brain regions. These inclusions consist mainly of aggregated α-synuclein (α-syn) protein. The present study used immunoprecipitation combined with nanoflow liquid chromatography (LC) coupled to high resolution electrospray ionization Fourier transform ion cyclotron resonance tandem mass spectrometry (ESI-FTICR-MS/MS) to determine known and novel isoforms of α-syn in brain tissue homogenates. N-terminally acetylated full-length α-syn (Ac-α-syn(1-140)) and two N-terminally acetylated C-terminally truncated forms of α-syn (Ac-α-syn(1-139) and Ac-α-syn(1-103)) were found. The different forms of α-syn were further studied by Western blotting in brain tissue homogenates from the temporal cortex Brodmann area 36 (BA36) and the dorsolateral prefrontal cortex BA9 derived from controls, patients with DLB and PD with dementia (PDD). Quantification of α-syn in each brain tissue fraction was performed using a novel enzyme-linked immunosorbent assay (ELISA).
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