| 1. |
- Pourhamidi, Kaveh, et al.
(author)
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Evaluation of clinical tools and their diagnostic use in distal symmetric polyneuropathy
- 2014
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In: Primary care diabetes. - : Elsevier. - 1878-0210 .- 1751-9918. ; 8:1, s. 77-84
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Journal article (peer-reviewed)abstract
- AIMS: To compare the diagnostic usefulness of tuning fork, monofilament, biothesiometer and skin biopsies in peripheral neuropathy in individuals with varying glucose metabolism.METHODS: Normoglycaemic, impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) individuals were recruited. Nerve conduction studies (NCS) and thermal threshold tests were performed. Vibrotactile sense was tested with a biothesiometer and a 128-Hz tuning fork. Touch/pressure perception was examined with a 10-g monofilament. Skin biopsies were performed and intraepidermal nerve fibres were quantified. Distal symmetric polyneuropathy (DSPN) was defined as neuropathy disability score ≥2 and abnormal NCS. Thermal threshold tests were used to define small nerve fibre neuropathy (sDSPN) in cases where NCS (large nerve fibres) were normal.RESULTS: The prevalence of DSPN and sDSPN in the whole group (n=119) was 18% and 23%, respectively. For the biothesiometer, a cut-off of ≥24.5V had a sensitivity of 82% and specificity of 70% (AUC=0.81, 95% CI 0.71-0.91) when evaluating DSPN. An intraepidermal nerve fibre density cut-off of ≤3.39fibres/mm showed a sensitivity of 74% and specificity of 70% in the detection of sDSPN, whereas the sensitivity of the tuning fork and the biothesiometer were relatively low, 46% and 67%, respectively. When combining skin biopsies with the tuning fork, 10 more sDSPN cases were identified. Adding skin biopsy to the combination of the tuning fork and biothesiometer increased the sensitivity of finding sDSPN cases, but not DSPN, from 81% to 93%.CONCLUSION: Using a biothesiometer in clinical routine might be a sensitive method to detect large nerve fibre dysfunction in the lower extremity, whereas skin biopsies in combination with methods measuring vibrotactile sense could increase the diagnostic sensitivity of detecting peripheral neuropathy at an early stage.
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| 2. |
- Gustafson, Lars, et al.
(author)
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A factor analytic approach to symptom patterns in dementia.
- 2010
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In: International Journal of Alzheimer's Disease. - : Hindawi Limited. - 2090-0252 .- 2090-8024.
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Journal article (peer-reviewed)abstract
- Previous publications have shown a high diagnostic sensitivity and specificity of three short clinical rating scales for Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VaD) validated against neuropathological (NP) diagnoses. In this study, the aim was to perform an exploratory factor analysis of the items in these clinical rating scales. The study included 190 patients with postmortem diagnoses of AD (n = 74), VaD (n = 33), mixed AD/VaD (n = 31), or FTD (n = 52). The factor analysis produced three strong factors. Factor 1 contained items describing cerebrovascular disease, similar to the Hachinski Ischemic Score. Factor 2 enclosed major clinical characteristics of FTD, and factor 3 showed a striking similarity to the AD scale. A fourth symptom cluster was described by perception and expression of emotions. The factor analyses strongly support the construct validity of the diagnostic rating scales.
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| 3. |
- Pourhamidi, Kaveh, et al.
(author)
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No difference in small or large nerve fiber function between individuals with normal glucose tolerance and impaired glucose tolerance
- 2013
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 36:4, s. 962-964
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Journal article (peer-reviewed)abstract
- OBJECTIVE To assess small and large nerve fiber function in people with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D).RESEARCH DESIGN AND METHODS Participants were recruited consecutively from a population-based cohort: NGT (n = 39), IGT (n = 29), and T2D (n = 51). Electrophysiological measures included nerve conduction studies and thermal thresholds. Intraepidermal nerve fiber density (IENFD) in skin biopsies was calculated.RESULTS There was no difference between IGT and NGT in sural nerve conduction, IENFD, and thermal thresholds. IENFD was significantly lower in T2D (median = 2.8 fibers/mm [Interquartile range 1.1–4.7 fibers/mm]) than NGT individuals (4.5 fibers/mm [3.4–6.1 fibers/mm]; P < 0.05). T2D participants had poorer nerve conduction and higher heat thresholds than NGT and IGT.CONCLUSIONS Large and small nerve function in people with IGT did not differ from those with NGT. Our finding does not support the existence of neuropathy in a prediabetic stage.
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| 4. |
- Landqvist, Maria, et al.
(author)
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Cerebrospinal fluid neurofilament light chain protein levels in subtypes of frontotemporal dementia
- 2013
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In: BMC Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 13
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Journal article (peer-reviewed)abstract
- Background: Frontotemporal dementia (FTD) is recognised as a clinically and morphologically heterogeneous group of interrelated neurodegenerative conditions. One of the subtypes within this disease spectrum is the behavioural variant FTD (bvFTD). This is known to be a varied disorder with a mixture of tau-positive and tau-negative underlying pathologies. The other subtypes include semantic dementia (SD), which generally exhibits tau-negative pathology, and progressive non-fluent aphasia (PNFA), which is usually tau-positive. As the clinical presentation of these subtypes may overlap, a specific diagnosis can be difficult to attain and today no specific biomarker can predict the underlying pathology. Neurofilament light chain protein (NFL), a cytoskeletal constituent of intermediate filaments, is thought to reflect neuronal and axonal death when appearing in the cerebrospinal fluid (CSF). NFL has been shown to be elevated in CSF in patients with FTD compared with AD and controls. Our hypothesis was that the levels of NFL also differ between the subtypes of FTD and may indicate the underlying pathological subtype. Methods: We retrospectively analysed data from previous CSF analyses in 34 FTD cases (23 bvFTD, seven SD, four PNFA), 20 AD cases, and 26 healthy controls. A separate group of 10 neuropathologically verified and subtyped FTD cases (seven tau-negative, three tau-positive) were also analysed. Result: NFL levels were significantly higher in FTD compared with both AD (p<0.001) and controls (p<0.001). The NFL levels of SD and bvFTD were significantly higher (p<0.001) compared with AD. The biomarker profiles of PNFA and AD were similar. In the neuropathologically verified FTD cases, NFL was higher in the tau-negative than in the tau-positive cases (exact p=0.017). Conclusions: The marked NFL elevation in some but not all FTD cases is likely to reflect the different underlying pathologies. The highest NFL values found in the SD group as well as in the neuropathologically verified tau-negative cases may be of subtype diagnostic value, if corroborated in larger patient cohorts. In bvFTD, a mixture of tau-positive and tau-negative underlying pathologies could possibly explain the intermediate NFL values.
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| 5. |
- Brunnström, Hans, et al.
(author)
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Correlations of CSF tau and amyloid levels with Alzheimer pathology in neuropathologically verified dementia with Lewy bodies.
- 2013
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In: International Journal of Geriatric Psychiatry. - : Wiley. - 1099-1166 .- 0885-6230. ; 28:7, s. 738-744
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The presence of concomitant Alzheimer pathology has been linked to earlier death in cases with dementia with Lewy bodies (DLB). Recently, elevated cerebrospinal fluid (CSF) tau protein levels have been reported to be associated with shorter survival in clinically diagnosed DLB. Correlations between CSF biomarkers and neuropathological findings in DLB are missing. The aim of this study was to investigate correlations between CSF biomarker levels and histopathological findings, with a focus on concomitant Alzheimer pathology, in neuropathologically verified DLB cases. METHODS: The extent of neurofibrillary pathology (Braak stage), neuritic plaques (CERAD stage), Alzheimer pathology (PPAD9 stage) and cerebral amyloid angiopathy was assessed in 16 cases with DLB in whom total tau (T-tau), hyperphosphorylated tau and amyloid beta 1-42 (Aβ42) protein levels in CSF had been analyzed in vivo. Demographic and clinical data were collected. RESULTS: Both Braak and PPAD9 stages were inversely correlated with Aβ42 levels, whereas CERAD stage showed no significant correlations. Cerebral amyloid angiopathy correlated positively with T-tau and T-tau/Aβ42 ratio, and inversely with Aβ42 levels, but the group showed a very heterogeneous extent of cerebral amyloid angiopathy. CONCLUSIONS: The burden of concomitant Alzheimer pathology correlates with CSF Aβ42 but not with T-tau levels in cases with neuropathologically defined DLB. Copyright © 2012 John Wiley & Sons, Ltd.
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| 6. |
- Chen, Dongfeng, et al.
(author)
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Better Prognosis of Patients with Glioma Expressing FGF2-Dependent PDGFRA Irrespective of Morphological Diagnosis.
- 2013
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
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Journal article (peer-reviewed)abstract
- Signaling of platelet derived growth factor receptor alpha (PDGFRA) is critically involved in the development of gliomas. However, the clinical relevance of PDGFRA expression in glioma subtypes and the mechanisms of PDGFRA expression in gliomas have been controversial. Under the supervision of morphological diagnosis, analysis of the GSE16011 and the Repository of Molecular Brain Neoplasia Data (Rembrandt) set revealed enriched PDGFRA expression in low-grade gliomas. However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression. SNP analysis in Rembrandt data set and FISH analysis in eleven low passage glioma cell lines showed infrequent amplification of PDGFRA. Using in vitro culture of these low passage glioma cells, we tested the hypothesis of gliogenic factor dependent expression of PDGFRA in glioma cells. Fibroblast growth factor 2 (FGF2) was able to maintain PDGFRA expression in glioma cells. FGF2 also induced PDGFRA expression in glioma cells with low or non-detectable PDGFRA expression. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Further, concordant expression patterns of FGF2 and PDGFRA were detected in glioma samples by immunohistochemical staining. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas with younger age at disease onset and longer patient survival regardless of their morphological diagnosis.
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| 7. |
- Chen, Dongfeng, et al.
(author)
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Glioma Cell Proliferation Controlled by ERK Activity-Dependent Surface Expression of PDGFRA.
- 2014
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Journal article (peer-reviewed)abstract
- Increased PDGFRA signaling is an essential pathogenic factor in many subtypes of gliomas. In this context the cell surface expression of PDGFRA is an important determinant of ligand sensing in the glioma microenvironment. However, the regulation of spatial distribution of PDGFRA in glioma cells remains poorly characterized. Here, we report that cell surface PDGFRA expression in gliomas is negatively regulated by an ERK-dependent mechanism, resulting in reduced proliferation of glioma cells. Glioma tumor tissues and their corresponding cell lines were isolated from 14 patients and analyzed by single-cell imaging and flow cytometry. In both cell lines and their corresponding tumor samples, glioma cell proliferation correlated with the extent of surface expression of PDGFRA. High levels of surface PDGFRA also correlated to high tubulin expression in glioma tumor tissue in vivo. In glioma cell lines, surface PDGFRA declined following treatment with inhibitors of tubulin, actin and dynamin. Screening of a panel of small molecule compounds identified the MEK inhibitor U0126 as a potent inhibitor of surface PDGFRA expression. Importantly, U0126 inhibited surface expression in a reversible, dose- and time-dependent manner, without affecting general PDGFRA expression. Treatment with U0126 resulted in reduced co-localization between PDGFRA and intracellular trafficking molecules e.g. clathrin, RAB11 and early endosomal antigen-1, in parallel with enhanced co-localization between PDGFRA and the Golgi cisternae maker, Giantin, suggesting a deviation of PDGFRA from the endosomal trafficking and recycling compartment, to the Golgi network. Furthermore, U0126 treatment in glioma cells induced an initial inhibition of ERK1/2 phosphorylation, followed by up-regulated ERK1/2 phosphorylation concomitant with diminished surface expression of PDGFRA. Finally, down-regulation of surface PDGFRA expression by U0126 is concordant with reduced glioma cell proliferation. These findings suggest that manipulation of spatial expression of PDGFRA can potentially be used to combat gliomas.
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| 8. |
- Brunnström, Hans, et al.
(author)
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Cerebrospinal fluid biomarker results in relation to neuropathological dementia diagnoses.
- 2010
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In: Alzheimer's & dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:2, s. 104-109
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Journal article (peer-reviewed)abstract
- BACKGROUND: Clinical dementia diagnoses are not always consistent with neuropathological findings. As correct diagnosis is important for treatment and care, new diagnostic possibilities for dementia are in demand. Cerebrospinal fluid biomarkers should ideally be able to identify ongoing processes in the brain, but need to be further compared with neuropathological findings for evaluation of their diagnostic validity. METHODS: This study included 43 patients with a clinical dementia disorder. All patients were neuropathologically examined at the University Hospital in Lund, Sweden, during the years 2001-2008, and all had a lumbar puncture carried out as part of the clinical investigation during the time of cognitive impairment. RESULTS: Of eight patients, five with Alzheimer's disease had elevated total tau protein (T-tau) and decreased amyloid beta 1-42 protein (Abeta42), while both values for the other three patients were normal. Slightly elevated T-tau and/or decreased Abeta42 were also seen in several patients with other dementia diagnoses such as Lewy body disease, frontotemporal lobar degeneration and vascular dementia. Furthermore, T-tau levels did not differ markedly between patients with morphologically tau-positive and tau-negative frontotemporal lobar degeneration. Also, seven of nine patients with Creutzfeldt-Jacob disease exhibited pronounced elevation in T-tau concentration. CONCLUSION: From this rather limited study, being the first of its kind in Sweden, we may conclude that there is no perfect concordance between cerebrospinal fluid biomarker levels and pathological findings, which should be taken into account in the clinical diagnostic setting.
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| 9. |
- Brunnström, Hans, et al.
(author)
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Comparison of four neuropathological scales for Alzheimer's disease.
- 2011
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In: Clinical Neuropathology. - 0722-5091. ; 30:2, s. 56-69
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Journal article (peer-reviewed)abstract
- Objective: There are several neuropathological scales for staging of Alzheimer pathology. The system proposed by Braak and Braak is based on the topographic distribution of neurofibrillary tangles and neuropil threads, while that of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) is based on the quantity of neocortical neuritic plaques. A combination of the Braak and CERAD staging scales was recommended by the National Institute on Aging and Reagan Institute (NIA-RI). The Poly-Pathology Alzheimer's Disease assessment, nine areas (PPAD9) is a staging system based on the extent of neuronal degeneration, microvacuolization, cytoarchitectural disorder and gliosis, in addition to neurofibrillary tangles and neuritic plaques, in nine cerebral regions. The aim of the present study was to critically compare these four neuropathological staging scales. Methods: We assessed the Alzheimer pathology, using the four scales, in 43 patients with various dementia disorders, with focus on concordance and differences between the staging systems. Results: Comparing the staging systems, the Spearman's rho value for PPAD9 vs. Braak was 0.65, for PPAD9 vs. CERAD 0.72, for PPAD9 vs. NIA-RI 0.67, and for Braak vs. CERAD 0.46. Conclusion: The correlation between the neuropathological staging systems was suboptimal, and we conclude that the choice of staging system affects the evaluation of Alzheimer pathology, and hence the final diagnosis.
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| 10. |
- Brunnström, Hans, et al.
(author)
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Differential degeneration of the locus coeruleus in dementia subtypes.
- 2011
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In: Clinical Neuropathology. - 0722-5091. ; 30:3, s. 104-110
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Journal article (peer-reviewed)abstract
- Objective: Neuronal loss in the locus coeruleus (LC) is common in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). The aims of the present study were to investigate LC degeneration in different dementia disorders including vascular dementia (VaD) and frontotemporal lobar degeneration (FTLD), to compare LC degeneration with severity of pathology in AD and DLB/PDD, to further evaluate the usefulness of a previously presented scoring system and to examine the predictive value of macroscopic assessment of the LC. Methods: A horizontal mid-level section of the pons was examined in 200 neuropathologically examined cases with clinical dementia. A previous macroscopic assessment of the LC was performed in 149 of the cases. Results: Cases with DLB/ PDD and AD presented with the highest microscopic LC degeneration scores, with significant differences compared to combined AD + VaD, in turn with a higher score than VaD, FTLD and other dementia disorders. Interrater agreement (weighted kappa;) for LC degeneration scoring was 0.83 - 0.91. DLB/ PDD, AD and AD + VaD were the diagnoses for 85% of the cases with macroscopic LC depigmentation. Conclusion: LC degeneration, which may be macroscopically noted, often indicates synuclein and/or Alzheimer pathology among demented. When clinical information is scarce or inconsistent, a macroscopic assessment of the LC may facilitate focusing of the subsequent neuropathological investigation. Also, the semiquantitative scoring system is a reliable tool for histological assessment of LC degeneration.
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