| 1. |
- Blennow, Kaj, 1958, et al.
(författare)
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- CSF neurogranin as a neuronal damage marker in CJD: A comparative study with AD
- 2019
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:8
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Tidskriftsartikel (refereegranskat)abstract
- - Objective: To investigate whether cerebrospinal fluid (CSF) neurogranin concentrations are altered in sporadic Creutzfeldt-Jakob disease (CJD), comparatively with Alzheimer's disease (AD), and associated with neuronal degeneration in brain tissue. Methods: CSF neurogranin, total tau, neurofilament light (NFL) and 14-3-3 protein were measured in neurological controls (NCs, n=64), AD (n=46) and CJD (n=81). The accuracy of neurogranin discriminating the three diagnostic groups was evaluated. Correlations between neurogranin and neurodegeneration biomarkers, demographic, genetic and clinical data were assessed. Additionally, neurogranin expression in postmortem brain tissue was studied. Results: Compared with NC, CSF neurogranin concentrations were increased in CJD (4.75 times of NC; p<0.001, area under curve (AUC), 0.96 (95% CI 0.93 to 0.99) and AD (1.94 times of NC; p<0.01, AUC 0.73, 95% CI 0.62 to 0.82), and were able to differentiate CJD from AD (p<0.001, AUC 0.85, 95% CI 0.78 to 0.92). CSF tau was increased in CJD (41 times of NC) and in AD (3.1 times of NC), both at p<0.001. In CJD, neurogranin positively correlated with tau (r=0.55, p<0.001) and was higher in 14-3-3-positivity (p<0.05), but showed no association with NFL (r=0.08, p=0.46). CJD-MM1/MV1 cases displayed higher neurogranin levels than VV2 cases. Neurogranin was increased at early CJD disease stages and was a good prognostic marker of survival time in CJD. In brain tissue, neurogranin was detected in the cytoplasm, membrane and postsynaptic density fractions of neurons, with reduced levels in AD, and more significantly in CJD, where they correlated with synaptic and axonal markers. Conclusions: Neurogranin is a new biomarker of prion pathogenesis with diagnostic and prognostic abilities, which reflects the degree of neuronal damage in brain tissue in a CJD subtype manner. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
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| 2. |
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| 3. |
- Farahmand, Dan, et al.
(författare)
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Intracranial pressure in hydrocephalus: impact of shunt adjustments and body positions
- 2015
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 86:2, s. 222-228
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Tidskriftsartikel (refereegranskat)abstract
- Background The association between intracranial pressure (ICP) and different shunt valve opening pressures in relation to body positions is fundamental for understanding the physiological function of the shunt. Objective To analyse the ICP and ICP wave amplitude (AMP) at different shunt settings and body positions in patients with hydrocephalus. Methods In this prospective study 15 patients with communicating hydrocephalus were implanted with a ligated adjustable ventriculoperitoneal shunt. They also received a portable intraparenchymatous ICP-monitoring device. Postoperative ICP and AMP were recorded with the patients in three different body positions (supine, sitting and walking) and with the shunt ligated and open at high, medium and low valve settings. In each patient 12 10 min segments were coded, blinded and analysed for mean ICP and mean AMP using an automated computer algorithm. Results Mean ICP and mean AMP were lower at all three valve settings compared with the ligated shunt state (p<0.001). Overall, when compared with the supine position, mean ICP was 11.5 +/- 1.1 (mean +/- SD) mm Hg lower when sitting and 10.5 +/- 1.1 mm Hg lower when walking (p<0.001). Mean ICP was overall 1.1 mm Hg higher (p=0.042) when walking compared with sitting. The maximal adjustability difference (highest vs lowest valve setting) was 4.4 mm Hg. Conclusions Changing from a supine to an upright position reduced ICP while AMP only increased at trend level. Lowering of the shunt valve opening pressure decreased ICP and AMP but the difference in mean ICP in vivo between the highest and lowest opening pressures was less than half that previously observed in vitro.
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| 4. |
- Foiani, Martha S, et al.
(författare)
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Plasma tau is increased in frontotemporal dementia.
- 2018
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 89:8, s. 804-807
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is familial with mutations inGRN,MAPTandC9orf72being the major genetic causes. Robust biomarkers of the underlying pathology are still lacking in FTD with no markers currently being able to distinguish those with tau and TDP-43 inclusions during life.This study used an ultrasensitive single molecule methodology to measure plasma tau concentrations in 176 participants: 71 with bvFTD, 83 with PPA and 22 healthy controls. The patient group included 36 with pathogenic mutations in eitherMAPT(n=12),GRN(n=9) orC9orf72(n=15). Group comparisons were performed between clinical and genetic groups and controls using a linear regression model with bias-corrected bootstrap CIs. Correlative analyses were performed to investigate associations with measures of disease severity and progression.Higher plasma tau concentrations were seen in bvFTD (mean 1.96 (SD 1.07) pg/mL) and PPA (2.65 (2.15) pg/mL) compared with controls (1.67 (0.50) pg/mL). Investigating the PPA group further showed significantly higher levels compared with controls in each of the PPA subtypes (non-fluent, semantic and logopenic variants, as well as a fourth group not meeting criteria for one of the three main variants). In the genetic groups, only theMAPTgroup had significantly increased concentrations (2.62 (1.39) pg/mL) compared with controls. No significant correlations were seen with cross-sectional or longitudinal brain volumes, serum neurofilament light chain concentrations or disease duration.Plasma tau levels are increased in FTD in all clinical groups, but in the genetic subtypes only inMAPTmutations, the group of patients who definitively have tau pathology at postmortem. Future studies will be required in pathologically confirmed cohorts to investigate this association further, and whether plasma tau will be helpful in differentiating patients with FTD with tau from those with other pathologies.
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| 5. |
- Foiani, M. S., et al.
(författare)
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Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: An elusive quest
- 2019
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:7, s. 740-746
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Tidskriftsartikel (refereegranskat)abstract
- Background: Frontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer's disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD. Methods: 86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau (181) ). Patients with FTD were grouped based on their Aβ 42 level into those likely to have underlying Alzheimer's disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology. Results: Significantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau (181) /T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109. Conclusions: Despite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.
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| 6. |
- Gaetani, L., et al.
(författare)
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Neurofilament light chain as a biomarker in neurological disorders
- 2019
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:8, s. 870-881
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Tidskriftsartikel (refereegranskat)abstract
- In the management of neurological diseases, the identification and quantification of axonal damage could allow for the improvement of diagnostic accuracy and prognostic assessment. Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and blood proportionally to the degree of axonal damage in a variety of neurological disorders, including inflammatory, neurodegenerative, traumatic and cerebrovascular diseases. New immunoassays able to detect biomarkers at ultralow levels have allowed for the measurement of NfL in blood, thus making it possible to easily and repeatedly measure NfL for monitoring diseases' courses. Evidence that both CSF and blood NfL may serve as diagnostic, prognostic and monitoring biomarkers in neurological diseases is progressively increasing, and NfL is one of the most promising biomarkers to be used in clinical and research setting in the next future. Here we review the most important results on CSF and blood NfL and we discuss its potential applications and future directions.
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| 7. |
- Gazzina, S, et al.
(författare)
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Education modulates brain maintenance in presymptomatic frontotemporal dementia
- 2019
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 90:10, s. 1124-1130
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Tidskriftsartikel (refereegranskat)abstract
- Cognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time.MethodsTwo-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling.ResultsHighly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers.ConclusionsThis longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.
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| 8. |
- Jabbari, E., et al.
(författare)
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Proximity extension assay testing reveals novel diagnostic biomarkers of atypical parkinsonian syndromes
- 2019
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:7, s. 768-773
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Tidskriftsartikel (refereegranskat)abstract
- Objective The high degree of clinical overlap between atypical parkinsonian syndromes (APS) and Parkinson's disease (PD) makes diagnosis challenging. We aimed to identify novel diagnostic protein biomarkers of APS using multiplex proximity extension assay (PEA) testing. Methods Cerebrospinal fluid (CSF) samples from two independent cohorts, each consisting of APS and PD cases, and controls, were analysed for neurofilament light chain (NF-L) and Olink Neurology and Inflammation PEA biomarker panels. Whole-cohort comparisons of biomarker concentrations were made between APS (n=114), PD (n=37) and control (n=34) groups using logistic regression analyses that included gender, age and disease duration as covariates. Results APS versus controls analyses revealed 11 CSF markers with significantly different levels in cases and controls (p<0.002). Four of these markers also reached significance (p<0.05) in APS versus PD analyses. Disease-specific analyses revealed lower group levels of FGF-5, FGF-19 and SPOCK1 in multiple system atrophy compared with progressive supranuclear palsy and corticobasal syndrome. Receiver operating characteristic curve analyses suggested that the diagnostic accuracy of NF-L was superior to the significant PEA biomarkers in distinguishing APS, PD and controls. The biological processes regulated by the significant proteins include cell differentiation and immune cell migration. Delta and notch-like epidermal growth factor-related receptor (DNER) had the strongest effect size in APS versus controls and APS versus PD analyses. DNER is highly expressed in substantia nigra and is an activator of the NOTCH1 pathway which has been implicated in the aetiology of other neurodegenerative disorders including Alzheimer's disease. Conclusions PEA testing has identified potential novel diagnostic biomarkers of APS.
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| 9. |
- Jabbari, E., et al.
(författare)
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Tracking and predicting disease progression in progressive supranuclear palsy: CSF and blood biomarkers
- 2017
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 88:10, s. 883-888
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Tidskriftsartikel (refereegranskat)abstract
- Progressive supranuclear palsy (PSP) is a rare and progressive neurodegenerative condition characterised pathologically by neuronal cell loss due to abnormal tau deposits. Clinically, the condition manifests as parkinsonism with the addition of progressive balance, speech, swallowing, eye movement and cognitive impairment, ultimately leading to death. Measuring change over time in neurodegenerative conditions is central to defining the effects of therapeutic intervention and disease biology. The current gold standard for measuring clinical disease progression in PSP is the PSP Rating Scale score. However, such scales may be affected by intrarater and inter-rater variability. In addition, their use in clinical trials may be hindered by differences in the time interval between pathological disease progression/response to therapeutics and change in clinical state. Therefore, the need for reliable disease progression biomarkers to complement clinical rating scales is clear. Here we discuss the benefits of using biomarkers to predict and track disease progression in both clinical and research settings. Through reviewing the literature to date on the role of cerebrospinal fluid (CSF) and blood biomarkers, we highlight data that reveals the ability of CSF and plasma neurofilament light chain (NF-L) to predict and track clinical disease progression in PSP. We also discuss the need for large-scale longitudinal studies to identify novel biomarkers.
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| 10. |
- 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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