| 21. |
- 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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| 22. |
- Gorges, Martin, et al.
(författare)
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Hypothalamic atrophy is related to body mass index and age at onset in amyotrophic lateral sclerosis
- 2017
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 88:12, s. 1033-1041
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Our objective was to study the hypothalamic volume in a cohort of patients with amyotrophic lateral sclerosis (ALS) including symptomatic and presymptomatic ALS mutation carriers.Methods: High-resolution three-dimensional T1-weighted MRI datasets from 251 patients with sporadic ALS, 19 symptomatic and 32 presymptomatic ALS mutation carriers and 112 healthy controls (HC) were retrospectivally registered for manual delineation of the hypothalamus. The volume of the hypothalamus, in total or subdivided, was normalised to the intracranial volume and adjusted to age. Correlation analyses were performed with clinical and metabolic outcomes. Pathologically defined ALS stages were determined in vivo by diffusion tensor imaging (DTI).Results: We observed a severe atrophy of the hypothalamus both in patients with sporadic ALS (-21.8%, p<0.0001) and symptomatic ALS mutation carriers (-13.4%, p<0.001). The atrophy in patients with sporadic ALS was observed in both the anterior (-27.6% p<0.0001) and the posterior parts of the hypothalamus (-17.7%, p<0.0001). Notably, this atrophy was also observed in presymptomatic ALS mutation carriers (-15.5%, p<0.001) and was unrelated to whole brain volume atrophy or disease stage as assessed using DTI or functional status. Hypothalamic volume was correlated with body mass index (BMI) in patients with sporadic ALS (p=0.0434, Ρ=+0.1579), and this correlation was much stronger in patients with familial ALS (fALS) (p=0.0060, Ρ=+0.6053). Anterior hypothalamic volume was correlated with age at onset, but not with survival after MRI.Conclusions: Hypothalamus is atrophied in ALS, even in premorbid stages, and correlates with BMI, especially in fALS. Decreased anterior hypothalamic volume is associated with earlier onset of disease.
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| 23. |
- Hamano, Tsuyoshi, et al.
(författare)
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Depression, stroke and gender: evidence of a stronger association in men.
- 2015
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 86:3, s. 319-323
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Tidskriftsartikel (refereegranskat)abstract
- Depression is associated with an increased risk for stroke. The aim of this study was to examine whether demographic and socioeconomic factors modify this association.
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| 24. |
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| 25. |
- 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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| 26. |
- 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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| 27. |
- 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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| 28. |
- Juneja, M, et al.
(författare)
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PFN2 and GAMT as common molecular determinants of axonal Charcot-Marie-Tooth disease
- 2018
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Ingår i: Journal of neurology, neurosurgery, and psychiatry. - : BMJ. - 1468-330X .- 0022-3050. ; 89:8, s. 870-878
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Tidskriftsartikel (refereegranskat)abstract
- Charcot-Marie-Tooth type 2 (CMT2) neuropathy is characterised by a vast clinical and genetic heterogeneity complicating its diagnosis and therapeutic intervention. Identification of molecular signatures that are common to multiple CMT2 subtypes can aid in developing therapeutic strategies and measuring disease outcomes.MethodsA proteomics-based approach was performed on lymphoblasts from CMT2 patients genetically diagnosed with different gene mutations to identify differentially regulated proteins. The candidate proteins were validated through real-time quantitative PCR and western blotting on lymphoblast samples of patients and controls, motor neurons differentiated from patient-derived induced pluripotent stem cells (iPSCs) and sciatic nerves of CMT2 mouse models.ResultsProteomic profiling of patient lymphoblasts resulted in the identification of profilin 2 (PFN2) and guanidinoacetate methyltransferase (GAMT) as commonly downregulated proteins in different genotypes compared with healthy controls. This decrease was also observed at the transcriptional level on screening 43 CMT2 patients and 22 controls, respectively. A progressive decrease in PFN2 expression with age was observed in patients, while in healthy controls its expression increased with age. Reduced PFN2 expression was also observed in motor neurons differentiated from CMT2 patient-derived iPSCs and sciatic nerves of CMT2 mice when compared with controls. However, no change in GAMT levels was observed in motor neurons and CMT2 mouse-derived sciatic nerves.ConclusionsWe unveil PFN2 and GAMT as molecular determinants of CMT2 with possible indications of the role of PFN2 in the pathogenesis and disease progression. This is the first study describing biomarkers that can boost the development of therapeutic strategies targeting a wider spectrum of CMT2 patients.
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| 29. |
- Lerche, Stefanie, et al.
(författare)
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Parkinson's disease : Evolution of cognitive impairment and CSF Aβ1-42 profiles in a prospective longitudinal study
- 2019
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:2, s. 165-170
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the evolution of cognitive impairment in relation to cerebrospinal fluid (CSF) profiles of amyloid-β (Aβ), total-Tau and phosphorylated-Tau in Parkinson's disease (PD). Methods: Prospective, longitudinal, observational study up to 10 years with follow-up every 2 years. We assessed CSF profiles in 415 patients with sporadic PD (median age 66; 63% men) and 142 healthy controls (median age 62; 43% men). Results: Patients with PD with low CSF Aβ1-42 levels at baseline were more often cognitively impaired than patients with intermediate and high Aβ1-42 levels. Sixty-seven per cent of the patients with low Aβ1-42 levels at baseline and normal cognition developed cognitive impairment during follow-up, compared with 41% and 37% of patients having intermediate and high CSF Aβ1-42 levels. Kaplan-Meier survival curves and Cox regression revealed that patients with low CSF Aβ1-42 levels at baseline developed cognitive impairment more frequently and earlier during follow-up. Conclusion: We conclude that in patients with sporadic PD, low levels of Aβ1-42 are associated with a higher risk of developing cognitive impairment earlier in the disease process at least in a subgroup of patients.
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| 30. |
- Magdalinou, N. K., et al.
(författare)
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A panel of nine cerebrospinal fluid biomarkers may identify patients with atypical parkinsonian syndromes
- 2015
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Ingår i: Journal of Neurology Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 86:11, s. 1240-1247
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Tidskriftsartikel (refereegranskat)abstract
- Background Patients presenting with parkinsonian syndromes share many clinical features, which can make diagnosis difficult. This is important as atypical parkinsonian syndromes (APSs) such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal syndrome (CBS) carry a poor prognosis, compared with patients with Parkinson's disease (PD). In addition, there is overlap between APS and dementia diseases, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Objective To use a panel of cerebrospinal fluid (CSF) biomarkers to differentiate patients with APS from PD and dementia. Methods A prospective cohort of 160 patients and 30 control participants were recruited from a single specialist centre. Patients were clinically diagnosed according to current consensus criteria. CSF samples were obtained from patients with clinical diagnoses of PD (n=31), PSP (n=33), CBS (n=14), MSA (n=31), AD (n=26) and FTD (n=16). Healthy, elderly participants (n=30) were included as controls. Total tau (t-tau), phosphorylated tau (p-tau), beta-amyloid 1-42 (A beta 42), neurofilament light chain (NFL), alpha-synuclein (alpha-syn), amyloid precursor protein soluble metabolites alpha and beta (soluble amyloid precursor protein (sAPP)alpha, sAPP beta) and two neuroinflammatory markers (monocyte chemoattractant protein-1 and YKL-40) were measured in CSF. A reverse stepwise regression analysis and the false discovery rate procedure were used. Results CSF NFL (p<0.001), sAPP alpha (p<0.001) and a-syn (p=0.003) independently predicted diagnosis of PD versus APS. Together, these nine biomarkers could differentiate patients with PD from APS with an area under the curve of 0.95 and subtypes of APS from one another. There was good discriminatory power between parkinsonian groups, dementia disorders and healthy controls. Conclusions A panel of nine CSF biomarkers was able to differentiate APS from patients with PD and dementia. This may have important clinical utility in improving diagnostic accuracy, allowing better prognostication and earlier access to potential disease-modifying therapies.
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