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1.
  • Brunnström, Hans, et al. (författare)
  • Correlations of CSF tau and amyloid levels with Alzheimer pathology in neuropathologically verified dementia with Lewy bodies.
  • 2013
  • Ingår i: International Journal of Geriatric Psychiatry. - : Wiley. - 1099-1166 .- 0885-6230. ; 28:7, s. 738-744
  • Tidskriftsartikel (refereegranskat)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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2.
  • Londos, Elisabet, et al. (författare)
  • Extreme sleep pattern in Lewy body dementia : A hypothalamic matter?
  • 2019
  • Ingår i: BMJ Case Reports. - : BMJ. - 1757-790X. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Excessive sleep during the night and for >2 hours during the day is part of the fluctuating wakefulness criterion of dementia with Lewy bodies (DLB). The phenomenon â € sleep days' is not uncommon in nursing homes. Here, we describe a woman who, for months, slept for 3 days and nights in a row and thereafter was awake for 3 days and nights. Electroencephalogram (EEG) showed slow background activity and increased delta activity. No epileptiform activity was detected. Polysomnography showed a severely disturbed, markedly fragmented sleep pattern. On her death, neuropathology revealed degeneration and loss of neurons along with α-synuclein-containing Lewy body inclusions and neurites in the substantia nigra, locus coeruleus, hypothalamus, and neocortex, thus fulfilling the criteria of DLB, cortical type. We propose that the hypothalamic degeneration contributed significantly to the clinical profile in this case. We suggest that patients with sleep days should be investigated for other DLB signs.
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4.
  • Adler, Aleksandra, 1983- (författare)
  • Cognitive load in dialogue interpreting : Experience and directionality
  • 2023
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This dissertation investigates the effect of experience and language direction on cognitive load in dialogue interpreting. The general objective of the study is to contribute to a better understanding of cognitive processes involved in dialogue interpreting. The present inquiry employs a multi- and mixed- method design and seeks to investigate disfluency measures as indicators of cognitive load in dialogue interpreting. Furthermore, the study aims to explore whether blink-based measures are sensitive to changes in cognitive load of dialogue interpreters. The present study is positioned within cognitive translation and interpreting studies (CTIS) and employs cognitive translatology as a framework, encompassing both cognitive and psycholinguistic approaches to translation and interpreting. Chen’s multidimensional theoretical construct of cognitive load in interpreting is explored in the study and remodeled to fit the context of dialogue interpreting and the assumptions of cognitive translatology. The data were collected from 17 dialogue interpreters during simulated interpreted encounters that recreated a situation commonly arising in a public service context in Sweden. The 10 inexperienced and 7 experienced interpreters all had Swedish as their working language, and the other working languages were French, Polish, and Spanish. Following the revised cognitive load model, the analyses of cognitive load focus on interpreter characteristics (interpreting experience) and on task and environmental characteristics (directionality). The results of analyses show that, in line with previous research, both interpreting experience and directionality modulate cognitive load of dialogue interpreters. Specifically, interpreting experience is demonstrated to attenuate cognitive load. In terms of directionality, interpreting into L2 is shown to be more cognitively demanding than interpreting into L1. Moreover, blink rate and blink rate variability (BRV) are explored as possible indicators of cognitive load. The analyses of blink measures suggest that no meaningful relationship can be found between blink measures and cognitive load.Finally, the complementary analyses of disfluency types in the utterances of the Polish interpreters (n=4) point to multifunctionality of disfluency in dialogue interpreting and to the multiple origins of cognitive load in interpreting dialogues. The analysis is performed from the perspective of the functional-cognitive view of disfluency proposed in the dissertation, whereby three disfluency context categories are identified and applied (cognitive-monitoring, cognitive-pragmatic, and cognitive-processing). Lexical access and rendition planning are identified as recurrent causes of cognitive load in dialogue interpreting. The study also makes theoretical and methodological contributions, primarily by revising the theoretical model of cognitive load in interpreting, which allows for operationalization of cognitive load with additional measures, in both experimental and naturalistic settings. Practical implications are a contribution to the understanding of the challenges interpreting into L2, and the impact of interpreters’ experience on interpreting. Overall, the study contributes to the emerging cognitive profile of dialogue interpreters.
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5.
  • Ahlenius, Henrik, et al. (författare)
  • Adaptor Protein LNK Is a Negative Regulator of Brain Neural Stem Cell Proliferation after Stroke.
  • 2012
  • Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:15, s. 5151-5164
  • Tidskriftsartikel (refereegranskat)abstract
    • Ischemic stroke causes transient increase of neural stem and progenitor cell (NSPC) proliferation in the subventricular zone (SVZ), and migration of newly formed neuroblasts toward the damaged area where they mature to striatal neurons. The molecular mechanisms regulating this plastic response, probably involved in structural reorganization and functional recovery, are poorly understood. The adaptor protein LNK suppresses hematopoietic stem cell self-renewal, but its presence and role in the brain are poorly understood. Here we demonstrate that LNK is expressed in NSPCs in the adult mouse and human SVZ. Lnk(-/-) mice exhibited increased NSPC proliferation after stroke, but not in intact brain or following status epilepticus. Deletion of Lnk caused increased NSPC proliferation while overexpression decreased mitotic activity of these cells in vitro. We found that Lnk expression after stroke increased in SVZ through the transcription factors STAT1/3. LNK attenuated insulin-like growth factor 1 signaling by inhibition of AKT phosphorylation, resulting in reduced NSPC proliferation. Our findings identify LNK as a stroke-specific, endogenous negative regulator of NSPC proliferation, and suggest that LNK signaling is a novel mechanism influencing plastic responses in postischemic brain.
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6.
  • Alafuzoff, Irina, et al. (författare)
  • The need to unify neuropathological assessments of vascular alterations in the ageing brain : Multicentre survey by the BrainNet Europe consortium
  • 2012
  • Ingår i: Experimental Gerontology. - : Elsevier BV. - 0531-5565 .- 1873-6815. ; 47:11, s. 825-833
  • Tidskriftsartikel (refereegranskat)abstract
    • Here, we summarise the results after carrying out a large survey regarding the assessment of vascular alterations, both vessel changes and vascular lesions in an inter-laboratory setting. In total, 32 neuropathologists from 22 centres, most being members of BrainNet Europe (BNE), participated by filling out a questionnaire with emphasis on assessment of common vascular alterations seen in the brains of aged subjects. A certain level of harmonisation has been reached among BNE members regarding sectioning of the brain, harvesting of brain tissue for histology and staining used when compared to the survey carried out in 2006 by Pantoni and colleagues. The most significant variability was seen regarding the assessment of severity and of clinical significance of vascular alterations. Two strategies have recently been recommended regarding the assessment of vascular alterations in aged and demented subjects. The National Institute on Aging - Alzheimer's Association (NIA-AA) recommends the assessment of hippocampal sclerosis, vascular brain injury and microvascular lesions in 12 regions. Although this strategy will be easy to follow, the recommendations do not inform how the load of observed alterations should be assessed and when the observed lesions are of significance. Deramecourt and his colleagues recommend an assessment and semiquantitative grading of various pathologies in 4 brain regions. This strategy yielded a total score of 0 to 20 as an estimate of pathology load. It is, however, not clear which score is considered to be of clinical significance. Furthermore, in several BNE trials the semiquantitative assessment has yielded poor agreement rates; an observation that might negatively influence the strategy proposed by Deramecourt and his colleagues. In line with NIA-AA, a dichotomised approach of easily recognisable lesions in a standardised set of brain regions harvested for neuropathological assessment and applying reproducible sampling and staining strategies is recommended by BNE. However, a simple strategy regarding assessment of load of alteration is urgently needed to yield reproducible, and at the same time, comparable results between centres.
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7.
  • Allard, Per, et al. (författare)
  • Caudate nucleus dopamine D-2 receptors in vascular dementia
  • 2002
  • Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 14:1, s. 22-25
  • Tidskriftsartikel (refereegranskat)abstract
    • Caudate nucleus dopamine (DA) D-2 receptors were studied in patients with vascular dementia (VaD) and in a control group using [H-3]raclopride as a radioligand. There was no significant difference in the number of DA D-2 receptors in the VaD group as compared with controls. The binding affinity was significantly lower in the VaD group. When the VaD group was subdivided into subjects with or without neuroleptic treatment, there were no differences in the numbers of receptors as compared with controls, and the significant differences in binding affinity remained for both VaD subgroups. The present results are. discussed with reference to the previous finding of a reduced density of caudate nucleus DA uptake sites in the same VaD group and to results from studies on DA D-2 receptors in Alzheimer's disease and Parkinson's disease. Copyright (C) 2002 S. Karger AG, Basel.
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8.
  • Andersson, Elin Möller, et al. (författare)
  • Clinicopathological concordance in cognitive disease diagnostics
  • 2020
  • Ingår i: Clinical Neuropathology. - 0722-5091. ; 39:3, s. 99-104
  • Tidskriftsartikel (refereegranskat)abstract
    • Neurocognitive disorder encompasses many separate diagnoses, such as frontotemporal dementia (FTD), Alzheimer's disease (AD), Lewy body dementia (LBD), vascular dementia (VaD), and mixed dementia (MD). Because of the many variations between and within each subtype, it may be a challenge to clinically diagnose each condition. In a previous study on 176 dementia patients in a university hospital cohort between the years 1996 and 2006, a full diagnostic concordance of 49% was demonstrated between clinical diagnoses and pathological morphology [1]. The aims of this study were to do a follow-up on diagnostic concordance from the subsequent 10 years (2007 - 2016) and to compare the results with the previous study from 2009. In all cases of neuropathologically diagnosed dementia disorders (n = 324), the clinical records were searched for information on the clinical diagnosis of dementia, including on subtype. All individuals who had been diagnosed by a specialist were selected (n = 210). In this study, a full concordance between clinical diagnoses and neuropathological morphology was found in 61% of individuals, with marked variations between subgroups, including the lowest (31%) in the group of VaD. Vigilance in clinicopathological concordance is important for quality maintenance as well as the improvement of skills in diagnostic work. In light of the previous study, VaD one decade later remains elusive. The unmasking of this complicated and multifaceted disorder may be beneficial to the overall diagnostic accuracy in cognitive disease investigations.
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9.
  • Andin, Ulla, et al. (författare)
  • Alzheimer's disease (AD) with and without white matter pathology-clinical identification of concurrent cardiovascular disorders.
  • 2007
  • Ingår i: Archives of Gerontology and Geriatrics. - : Elsevier BV. - 1872-6976 .- 0167-4943. ; 44, s. 277-286
  • Tidskriftsartikel (refereegranskat)abstract
    • Clinical vascular features, either as manifest vascular disease or as cardiovascular risk factors were compared in AD with and without neuropathological white matter disease (WMD). The aim of the study was to investigate whether the presence of WMD and the severity of either AD pathology or WMD were associated with different cardiovascular profiles. A total of 44 AD cases were retrospectively studied. All the cases were neuropathologically diagnosed as AD with WMD (n = 22) and as AD without WMD (n = 22), respectively. The patients' medical records were studied with regard to their medical history and to somatic and neurological findings including arrhythmia, congestive heart failure, angina, myocardial infarctions, signs of TIA/stroke, diabetes mellitus, and blood pressure abnormalities, such as hypertension and orthostatic hypotension. In AD-WMD, hypertension, orthostatic hypotension as well as dizziness/unsteadiness were significantly more common than in AD without WMD. Cardiovascular symptoms were more frequent in AD-WMD than in the other group, though the difference did not reach statistical significance. Hypothetically, abnormal and unstable blood pressure levels underlie recurrent cerebral hypoperfusion, which may in turn leave room for the development of WMD. Furthermore, dizziness/unsteadiness may be a symptom reflecting the presence of WMD. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
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10.
  • Arcini, Caroline, et al. (författare)
  • Intracranial Atherosclerosis in Medieval Scandinavia
  • 2023
  • Ingår i: The Bioarchaeology of Cardiovascular Disease. - : Cambridge University Press. - 9781108648561 - 9781108480345 ; , s. 164-173
  • Bokkapitel (refereegranskat)abstract
    • In past human populations, atherosclerosis has been identified in mummies from different regions of the world, and from a range of chronological periods (for extensive reviews see Chapters 3 and 4). This current study from Sweden aims to contribute to the limited evidence for atherosclerosis associated with human skeletal remains by presenting examples of atherosclerosis in another part of the body. We describe two well-preserved cemeteries in Åhus and Skänninge (1237-1536 CE) in present-day Sweden where several individuals with atherosclerosis of the internal carotid artery were discovered.
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11.
  • Arvidsson, Ida, et al. (författare)
  • Early terminal complement blockade and C6 deficiency are protective in enterohemorrhagic Escherichia coli-infected mice
  • 2016
  • Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 197:4, s. 1276-1286
  • Tidskriftsartikel (refereegranskat)abstract
    • Complement activation occurs during enterohemorrhagic Escherichia coli (EHEC) infection and may exacerbate renal manifestations. In this study, we show glomerular C5b-9 deposits in the renal biopsy of a child with EHEC-associated hemolytic uremic syndrome. The role of the terminal complement complex, and its blockade as a therapeutic modality, was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice were treated with monoclonal anti-C5 i.p. on day 3 or 6 after intragastric inoculation and monitored for clinical signs of disease and weight loss for 14 d. All infected untreated mice (15 of 15) or those treated with an irrelevant Ab (8 of 8) developed severe illness. In contrast, only few infected mice treated with anti-C5 on day 3 developed symptoms (three of eight, p < 0.01 compared with mice treated with the irrelevant Ab on day 3) whereas most mice treated with anti-C5 on day 6 developed symptoms (six of eight). C6-deficient C57BL/6 mice were also inoculated with E. coli O157:H7 and only 1 of 14 developed disease, whereas 10 of 16 wild-type mice developed weight loss and severe disease (p < 0.01). Complement activation via the terminal pathway is thus involved in the development of disease in murine EHEC infection. Early blockade of the terminal complement pathway, before the development of symptoms, was largely protective, whereas late blockade was not. Likewise, lack of C6, and thereby deficient terminal complement complex, was protective in murine E. coli O157:H7 infection.
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12.
  • Badian, Reza A., et al. (författare)
  • Comparison of novel wide-field in vivo corneal confocal microscopy with skin biopsy for assessing peripheral neuropathy in type 2 diabetes
  • 2023
  • Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 72:7, s. 908-917
  • Tidskriftsartikel (refereegranskat)abstract
    • Diabetic peripheral neuropathy (DPN) is a serious complication of diabetes, where skin biopsy assessing intraepi-dermal nerve fiber density (IENFD) plays an important diagnostic role. In vivo confocal microscopy (IVCM) of the corneal subbasal nerve plexus has been proposed as a noninvasive diagnostic modality for DPN. Direct compari-sons of skin biopsy and IVCM in controlled cohorts are lacking, as IVCM relies on subjective selection of images depicting only 0.2% of the nerve plexus. We compared these diagnostic modalities in a fixed-age cohort of 41 participants with type 2 diabetes and 36 healthy participants using machine algorithms to create wide-field image mosaics and quantify nerves in an area 37 times the size of prior studies to avoid human bias. In the same partici-pants, and at the same time point, no correlation between IENFD and corneal nerve density was found. Corneal nerve density did not correlate with clinical measures of DPN, including neuropathy symptom and disability scores, nerve conduction studies, or quantitative sensory tests. Our findings indicate that corneal and intraepidermal nerves likely mirror different aspects of nerve degeneration, where only intraepidermal nerves appear to reflect the clinical status of DPN, suggesting that scrutiny is warranted concerning methodologies of studies using corneal nerves to assess DPN.
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15.
  • Björkman-Burtscher, Isabella, et al. (författare)
  • Proton MR spectroscopy and preoperative diagnostic accuracy: an evaluation of intracranial mass lesions characterized by stereotactic biopsy findings
  • 2000
  • Ingår i: AJNR. - 1936-959X. ; 21:1, s. 84-93
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND PURPOSE: MR imaging has made it easier to distinguish among the different types of intracranial mass lesions. Nevertheless, it is sometimes impossible to base a diagnosis solely on clinical and neuroradiologic findings, and, in these cases, biopsy must be performed. The purpose of this study was to evaluate the hypothesis that proton MR spectroscopy is able to improve preoperative diagnostic accuracy in cases of intracranial tumors and may therefore obviate stereotactic biopsy. METHODS: Twenty-six patients with intracranial tumors underwent MR imaging, proton MR spectroscopy, and stereotactic biopsy. MR spectroscopic findings were evaluated for the distribution pattern of pathologic spectra (NAA/Cho ratio < 1) across the lesion and neighboring tissue, for signal ratios in different tumor types, and for their potential to improve preoperative diagnostic accuracy. RESULTS: Gliomas and lymphomas showed pathologic spectra outside the area of contrast enhancement while four nonastrocytic circumscribed tumors (meningioma, pineocytoma, metastasis, and germinoma) showed no pathologic spectra outside the region of enhancement. No significant correlation was found between different tumor types and signal ratios. MR spectroscopy improved diagnostic accuracy by differentiating infiltrative from circumscribed tumors; however, diagnostic accuracy was not improved in terms of differentiating the types of infiltrative or circumscribed lesions. CONCLUSION: MR spectroscopy can improve diagnostic accuracy by differentiating circumscribed brain lesions from histologically infiltrating processes, which may be difficult or impossible solely on the basis of clinical or neuroradiologic findings.
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16.
  • Bocci, Matteo, et al. (författare)
  • Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients.
  • 2021
  • Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067 .- 1661-6596. ; 22:21
  • Tidskriftsartikel (refereegranskat)abstract
    • A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood-brain barrier.
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17.
  • Boza-Serrano, Antonio, et al. (författare)
  • Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease
  • 2019
  • Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 251-273
  • Tidskriftsartikel (refereegranskat)abstract
    • Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.
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18.
  • Brabec, Jan, et al. (författare)
  • Coregistered histology sections with diffusion tensor imaging data at 200 µm resolution in meningioma tumors
  • 2023
  • Ingår i: Data in Brief. - 2352-3409. ; 48
  • Tidskriftsartikel (refereegranskat)abstract
    • A significant problem in diffusion MRI (dMRI) is the lack of understanding regarding which microstructural features account for the variability in the diffusion tensor imaging (DTI) parameters observed in meningioma tumors. A common assumption is that mean diffusivity (MD) and fractional anisotropy (FA) from DTI are inversely proportional to cell density and proportional to tissue anisotropy, respectively. Although these associations have been established across a wide range of tumors, they have been challenged for interpreting within-tumor variations where several additional microstructural features have been suggested as contributing to MD and FA.To facilitate the investigation of the biological underpinnings of DTI parameters, we performed ex-vivo DTI at 200 µm isotropic resolution on 16 excised meningioma tumor samples. The samples exhibit a variety of microstructural features because the dataset includes meningiomas of six different meningioma types and two different grades. Diffusion-weighted signal (DWI) maps, DWI maps averaged over all directions for given b-value, signal intensities without diffusion encoding (S0) as well as DTI parameters: MD, FA, in-plane FA (FAIP), axial diffusivity (AD) and radial diffusivity (RD), were coregistered to Hematoxylin & Eosin- (H&E) and Elastica van Gieson-stained (EVG) histological sections by a non-linear landmark-based approach.Here, we provide DWI signal and DTI maps coregistered to histology sections and describe the pipeline for processing the raw DTI data and the coregistration. The raw, processed, and coregistered data are hosted by Analytic Imaging Diagnostics Arena (AIDA) data hub registry, and software tools for processing are provided via GitHub. We hope that data can be used in research and education concerning the link between the meningioma microstructure and parameters obtained by DTI.
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  • Brabec, Jan, et al. (författare)
  • Histogram analysis of tensor-valued diffusion MRI in meningiomas : Relation to consistency, histological grade and type
  • 2022
  • Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 33
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Preoperative radiological assessment of meningioma characteristics is of value for pre- and post-operative patient management, counselling, and surgical approach.PURPOSE: To investigate whether tensor-valued diffusion MRI can add to the preoperative prediction of meningioma consistency, grade and type.MATERIALS AND METHODS: 30 patients with intracranial meningiomas (22 WHO grade I, 8 WHO grade II) underwent MRI prior to surgery. Diffusion MRI was performed with linear and spherical b-tensors with b-values up to 2000 s/mm2. The data were used to estimate mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK) and its components-the anisotropic and isotropic kurtoses (MKA and MKI). Meningioma consistency was estimated for 16 patients during resection based on ultrasonic aspiration intensity, ease of resection with instrumentation or suction. Grade and type were determined by histopathological analysis. The relation between consistency, grade and type and dMRI parameters was analyzed inside the tumor ("whole-tumor") and within brain tissue in the immediate periphery outside the tumor ("rim") by histogram analysis.RESULTS: Lower 10th percentiles of MK and MKA in the whole-tumor were associated with firm consistency compared with pooled soft and variable consistency (n = 7 vs 9; U test, p = 0.02 for MKA 10 and p = 0.04 for MK10) and lower 10th percentile of MD with variable against soft and firm (n = 5 vs 11; U test, p = 0.02). Higher standard deviation of MKI in the rim was associated with lower grade (n = 22 vs 8; U test, p = 0.04) and in the MKI maps we observed elevated rim-like structure that could be associated with grade. Higher median MKA and lower median MKI distinguished psammomatous type from other pooled meningioma types (n = 5 vs 25; U test; p = 0.03 for MKA 50 and p = 0.03 and p = 0.04 for MKI 50).CONCLUSION: Parameters from tensor-valued dMRI can facilitate prediction of consistency, grade and type.
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20.
  • Brabec, Jan, et al. (författare)
  • Meningioma microstructure assessed by diffusion MRI : An investigation of the source of mean diffusivity and fractional anisotropy by quantitative histology
  • 2023
  • Ingår i: NeuroImage: Clinical. - : Elsevier BV. - 2213-1582. ; 37
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Mean diffusivity (MD) and fractional anisotropy (FA) from diffusion MRI (dMRI) have been associated with cell density and tissue anisotropy across tumors, but it is unknown whether these associations persist at the microscopic level.PURPOSE: To quantify the degree to which cell density and anisotropy, as determined from histology, account for the intra-tumor variability of MD and FA in meningioma tumors. Furthermore, to clarify whether other histological features account for additional intra-tumor variability of dMRI parameters.MATERIALS AND METHODS: We performed ex-vivo dMRI at 200 μm isotropic resolution and histological imaging of 16 excised meningioma tumor samples. Diffusion tensor imaging (DTI) was used to map MD and FA, as well as the in-plane FA (FA IP). Histology images were analyzed in terms of cell nuclei density (CD) and structure anisotropy (SA; obtained from structure tensor analysis) and were used separately in a regression analysis to predict MD and FA IP, respectively. A convolutional neural network (CNN) was also trained to predict the dMRI parameters from histology patches. The association between MRI and histology was analyzed in terms of out-of-sample (R 2 OS) on the intra-tumor level and within-sample R 2 across tumors. Regions where the dMRI parameters were poorly predicted from histology were analyzed to identify features apart from CD and SA that could influence MD and FA IP, respectively. RESULTS: Cell density assessed by histology poorly explained intra-tumor variability of MD at the mesoscopic level (200 μm), as median R 2 OS = 0.04 (interquartile range 0.01-0.26). Structure anisotropy explained more of the variation in FA IP (median R 2 OS = 0.31, 0.20-0.42). Samples with low R 2 OS for FA IP exhibited low variations throughout the samples and thus low explainable variability, however, this was not the case for MD. Across tumors, CD and SA were clearly associated with MD (R 2 = 0.60) and FA IP (R 2 = 0.81), respectively. In 37% of the samples (6 out of 16), cell density did not explain intra-tumor variability of MD when compared to the degree explained by the CNN. Tumor vascularization, psammoma bodies, microcysts, and tissue cohesivity were associated with bias in MD prediction based solely on CD. Our results support that FA IP is high in the presence of elongated and aligned cell structures, but low otherwise. CONCLUSION: Cell density and structure anisotropy account for variability in MD and FA IP across tumors but cell density does not explain MD variations within the tumor, which means that low or high values of MD locally may not always reflect high or low tumor cell density. Features beyond cell density need to be considered when interpreting MD.
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22.
  • Brunnström, Hans, et al. (författare)
  • A 76-year-old man with cognitive and neurological symptoms
  • 2009
  • Ingår i: Brain Pathology. - : Wiley. - 1750-3639 .- 1015-6305. ; 19:4, s. 4-731
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • A 76-year-old man presented with cognitive symptoms, followed by headache and weakness of the lower limbs and left arm. The clinical course was progressive but fluctuating. On magnetic resonance imaging (MRI), a contrast-enhancing lesion 1 cm in diameter was seen in the left temporal lobe. This lesion became attenuated and a new contrast-enhancing lesion 1 x 2 cm was seen in the left frontal lobe on a subsequent MRI. Following additional tests, treatment with corticosteroids for presumptive neurosarcoidosis was started, however, he soon expired. At autopsy, there was a tumor-like mass in the left frontal lobe. Pathologic evaluation revealed a primary T-cell lymphoma of the central nervous system (CNS). CNS T-cell lymphomas may be difficult to diagnose, even histologically, due to their frequent small cell morphology and lack of significant atypia.
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23.
  • Brunnström, Hans, et al. (författare)
  • Cause of death in patients with dementia disorders.
  • 2009
  • Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 16, s. 488-492
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Investigations on cause of death may provide valuable information about life expectancy and on conditions of terminal dementia care, which perhaps can be ameliorated. Methods: The autopsy reports were studied on all patients (n = 524; 55.3% females; median age 80 years) with a clinically and neuropathologically diagnosed dementia disorder who underwent a complete autopsy at the University Hospital in Lund, Sweden, during 1974-2004. Results: The two most common causes of death were bronchopneumonia (38.4%) and ischaemic heart disease (23.1%), whilst neoplastic diseases were uncommon (3.8%). In a general population of elderly studied for comparison, bronchopneumonia accounted for 2.8%, ischaemic heart disease for 22.0%, and neoplasm for 21.3% of the deaths. Amongst the demented patients, circulatory and respiratory system diseases were the causes of death in 23.2% and 55.5% of the Alzheimer patients, respectively, whilst the corresponding figures were 54.8% and 33.1% for the patients with vascular dementia. Conclusions: In patients with dementia, pneumonia as the immediate cause of death may reflect a terminal stage in which patient care and feeding is difficult to manage well. Knowledge about what actually causes death is of value in the terminal care of patients with dementia disorders.
  •  
24.
  • Brunnström, Hans, et al. (författare)
  • Cerebrospinal fluid biomarker results in relation to neuropathological dementia diagnoses.
  • 2010
  • Ingår i: Alzheimer's & dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:2, s. 104-109
  • Tidskriftsartikel (refereegranskat)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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25.
  • Brunnström, Hans, et al. (författare)
  • Clinicopathological concordance in dementia diagnostics.
  • 2009
  • Ingår i: The American Journal of Geriatric Psychiatry. - 1545-7214. ; 17:8, s. 664-670
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Accurate distinction between dementia subtypes is important for patient care and pharmacological treatment. Continuing systematic comparisons of clinical and neuropathological dementia diagnoses may provide a basis for further improvement of the diagnostic procedure. The purpose of this study was to investigate concordance between clinical dementia diagnosis and neuropathological findings in the specialized dementia care. METHODS: Inclusion required 1) a clinical dementia disorder diagnosed at a hospital-based memory clinic and 2) a neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1996-2006. A total of 176 consecutive patients fulfilled the criteria and were thus included. Clinical dementia diagnoses were obtained from the medical records and compared with the neuropathological findings. RESULTS: The clinical and pathological dementia diagnoses were in full accordance in 86 (49%) of the patients (kappa 0.37). In an additional 24 (14%) cases, the clinical diagnosis corresponded with some but not all pathological components judged to contribute to the dementia disorder. Of the patients with clinical Alzheimer disease, 84% (46/55) had a significant Alzheimer component with or without other significant pathology at neuropathological examination. The corresponding figure for vascular dementia (VaD) was 59% (24/41), for frontotemporal dementia 74% (20/27), for combined Alzheimer and VaD 25% (4/16), and for dementia with Lewy bodies 67% (6/9). CONCLUSIONS: This study shows that clinical dementia diagnoses do not always correspond with neuropathological changes. It stresses the importance of neuropathological examination in research and in daily clinical practice.
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26.
  • Brunnström, Hans, et al. (författare)
  • Comparison of four neuropathological scales for Alzheimer's disease.
  • 2011
  • Ingår i: Clinical Neuropathology. - 0722-5091. ; 30:2, s. 56-69
  • Tidskriftsartikel (refereegranskat)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.
  •  
27.
  • Brunnström, Hans, et al. (författare)
  • Differential degeneration of the locus coeruleus in dementia subtypes.
  • 2011
  • Ingår i: Clinical Neuropathology. - 0722-5091. ; 30:3, s. 104-110
  • Tidskriftsartikel (refereegranskat)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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28.
  • Brunnström, Hans, et al. (författare)
  • History of depression prior to Alzheimer's disease and vascular dementia verified post-mortem.
  • 2013
  • Ingår i: Archives of Gerontology and Geriatrics. - : Elsevier BV. - 1872-6976 .- 0167-4943. ; 56:1, s. 80-84
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to analyze the medical history, with regards to previous remote depression, in patients with neuropathologically verified Alzheimer's disease (AD), vascular dementia (VaD) and mixed AD/VaD. The 201 patients included (115 AD, 44 VaD and 42 mixed AD/VaD) had been referred to the Psychogeriatric/Psychiatric Department, Lund University Hospital, for psychogeriatric investigation and were followed-up with clinical records and detailed information on psychiatric history prior to the onset of dementia. Depression was considered to exist when the patient had consulted a psychiatrist or physician and had been diagnosed with a "depressive episode" or "depression" and when anti-depressants and/or other specific treatments had been prescribed. Twenty patients (10%) had suffered from depression earlier in life well before the onset of dementia. Eight of the 9 AD patients with a previous diagnosis of depression had suffered from only one depressive episode and all had responded well to treatment, with complete recovery. In the VaD group, 8 out of 9 patients suffered two or more depressive episodes and only two recovered completely. Events with a possible significant relationship to depression were seen in 8 of the 9 AD patients but in only 1 of the 9 VaD patients. Psychotic symptoms were more common in VaD than in the AD group. The treatment modality of depression was similar in the groups. In conclusion, a history of depression prior to dementia is more common and more therapy-resistant in VaD than in AD.
  •  
29.
  • Brunnström, Hans, et al. (författare)
  • Prevalence of dementia subtypes: A 30-year retrospective survey of neuropathological reports.
  • 2009
  • Ingår i: Archives of Gerontology and Geriatrics. - : Elsevier BV. - 1872-6976 .- 0167-4943. ; Aug 7, s. 146-149
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated the distribution of neuropathologically defined dementia subtypes among individuals with dementia disorder. The neuropathological reports were studied on all patients (n=524; 55.3% females; median age 80, range 39-102 years) with clinically diagnosed dementia disorder who underwent complete autopsy including neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1974-2004. The neuropathological diagnosis was Alzheimer's disease (AD) in 42.0% of the cases, vascular dementia (VaD) in 23.7%, dementia of combined Alzheimer and vascular pathology in 21.6%, and frontotemporal dementia in 4.0% of the patients. The remaining 8.8% of the patients had other dementia disorders, including combinations other than combined Alzheimer and vascular pathology. The registered prevalence of dementia subtypes depends on many variables, including referral habits, clinical and neuropathological judgments and diagnostic traditions, all of these variables potentially changing over time. This, however, does not seem to obscure the delineation of the major dementia subgroups. In this material of 30 years from Lund in the south of Sweden, AD by far dominated among dementia subtypes, while cerebrovascular pathology corresponded with the dementia disorder, either entirely or partly, in almost half of the demented patients.
  •  
30.
  • Brunnström, Hans, et al. (författare)
  • Response to letter to the editor.
  • 2010
  • Ingår i: The American Journal of Geriatric Psychiatry. - 1545-7214. ; 18:1, s. 92-93
  • Tidskriftsartikel (refereegranskat)
  •  
31.
  • Brunnström, Hans, et al. (författare)
  • Staging of Lewy-related pathology in dementia
  • 2012
  • Ingår i: Clinical Neuropathology. - 0722-5091. ; 31:4, s. 216-223
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Lewy-related pathology is the characteristic feature of Parkinson's disease with and without dementia and dementia with Lewy bodies (DLB). There are two neuropathological staging systems for Lewy-related pathology commonly employed today: the staging system for Parkinson-related pathology by Braak et al., and the staging system by the Consortium on DLB. There are also several modified systems based on these two scales. Methods: We applied a total of eight different staging systems for Lewy-related pathology to 36 consecutive demented patients with various dementia disorders. Results: The staging systems varied considerably in number of unclassifiable cases (range 0 - 16 out of 36 cases), while the diagnostic agreement between the systems that were able to classify all or the very majority of cases varied only slightly (weighted kappa 0.86 - 0.92 and Spearman's sigma 0.80 - 1.0). Conclusion: The different staging systems for Lewy-related pathology that exist today vary in staging procedure and proportion of unclassifiable cases. The choice of system may affect the stage of Lewy-related pathology and ultimately final diagnosis.
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32.
  • Burguillos Garcia, Miguel, et al. (författare)
  • Caspase signalling controls microglia activation and neurotoxicity.
  • 2011
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 472, s. 214-319
  • Tidskriftsartikel (refereegranskat)abstract
    • Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson's disease (PD) and the frontal cortex of individuals with Alzheimer's disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.
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33.
  • Burguillos Garcia, Miguel, et al. (författare)
  • Microglia-Secreted Galectin-3 Acts as a Toll-like Receptor 4 Ligand and Contributes to Microglial Activation.
  • 2015
  • Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 10:9, s. 1626-1638
  • Tidskriftsartikel (refereegranskat)abstract
    • Inflammatory response induced by microglia plays a critical role in the demise of neuronal populations in neuroinflammatory diseases. Although the role of toll-like receptor 4 (TLR4) in microglia's inflammatory response is fully acknowledged, little is known about endogenous ligands that trigger TLR4 activation. Here, we report that galectin-3 (Gal3) released by microglia acts as an endogenous paracrine TLR4 ligand. Gal3-TLR4 interaction was further confirmed in a murine neuroinflammatory model (intranigral lipopolysaccharide [LPS] injection) and in human stroke subjects. Depletion of Gal3 exerted neuroprotective and anti-inflammatory effects following global brain ischemia and in the neuroinflammatory LPS model. These results suggest that Gal3-dependent-TLR4 activation could contribute to sustained microglia activation, prolonging the inflammatory response in the brain.
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34.
  • Carlén, Birgitta, et al. (författare)
  • Diagnostic value of electron microscopy in a case of juvenile neuronal ceroid lipofuscinosis
  • 2001
  • Ingår i: Ultrastructural Pathology. - : Informa UK Limited. - 1521-0758 .- 0191-3123. ; 25:4, s. 285-288
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuronal ceroid lipofuscinoses (NCLs) represent a large group of inherited neurodegenerative disorders characterized by an abnormal accumulation of lipopigment in neuronal and extraneuronal cells. The authors present a case of juvenile neuronal ceroid lipofuscinosis in a 7-year-old boy. Ultrastructural examination of a skin biopsy disclosed deposits of curvilinear profiles and fingerprint-like structures in epithelial cells of sweat glands, endothelial cells, peripheral nerve endings, and fibroblasts, These findings allowed specific confirmation of the assumed diagnosis of juvenile neuronal ceroid lipofuscinosis. Due to the genotypic and phenotypic variability within the group of NCLs, the clinical investigation may be long and complicated. With the NCL disorders in mind, an accurate diagnosis based on ultrastructural examination of a skin biopsy may shorten this investigation, thus benefitting the patient.
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35.
  • Ceberg, Crister, et al. (författare)
  • Photon activation therapy of RG2 glioma carrying Fischer rats using stable thallium and monochromatic synchrotron radiation.
  • 2012
  • Ingår i: Physics in Medicine and Biology. - : IOP Publishing. - 1361-6560 .- 0031-9155. ; 57:24, s. 8377-8391
  • Tidskriftsartikel (refereegranskat)abstract
    • 75 RG2 glioma-carrying Fischer rats were treated by photon activation therapy (PAT) with monochromatic synchrotron radiation and stable thallium. Three groups were treated with thallium in combination with radiation at different energy; immediately below and above the thallium K-edge, and at 50 keV. Three control groups were given irradiation only, thallium only, or no treatment at all. For animals receiving thallium in combination with radiation to 15 Gy at 50 keV, the median survival time was 30 days, which was 67% longer than for the untreated controls (p = 0.0020) and 36% longer than for the group treated with radiation alone (not significant). Treatment with thallium and radiation at the higher energy levels were not effective at the given absorbed dose and thallium concentration. In the groups treated at 50 keV and above the K-edge, several animals exhibited extensive and sometimes contra-lateral edema, neuronal death and frank tissue necrosis. No such marked changes were seen in the other groups. The results were discussed with reference to Monte Carlo calculated electron energy spectra and dose enhancement factors.
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36.
  • Chen, Dongfeng, et al. (författare)
  • Better Prognosis of Patients with Glioma Expressing FGF2-Dependent PDGFRA Irrespective of Morphological Diagnosis.
  • 2013
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
  • Tidskriftsartikel (refereegranskat)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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37.
  • Chen, Dongfeng, et al. (författare)
  • Glioma Cell Proliferation Controlled by ERK Activity-Dependent Surface Expression of PDGFRA.
  • 2014
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
  • Tidskriftsartikel (refereegranskat)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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38.
  • Clayton, Emma L., et al. (författare)
  • Early microgliosis precedes neuronal loss and behavioural impairment in mice with a frontotemporal dementia-causing CHMP2B mutation
  • 2017
  • Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 26:5, s. 873-887
  • Tidskriftsartikel (refereegranskat)abstract
    • Frontotemporal dementia (FTD)-causing mutations in the CHMP2B gene lead to the generation of mutant C-terminally truncated CHMP2B. We report that transgenic mice expressing endogenous levels of mutant CHMP2B developed late-onset brain volume loss associated with frank neuronal loss and FTD-like changes in social behaviour. These data are the first to show neurodegeneration in mice expressing mutant CHMP2B and indicate that our mouse model is able to recapitulate neurodegenerative changes observed in FTD. Neuroinflammation has been increasingly implicated in neurodegeneration, including FTD. Therefore, we investigated neuroinflammation in our CHMP2B mutant mice. We observed very early microglial proliferation that develops into a clear pro-inflammatory phenotype at late stages. Importantly, we also observed a similar inflammatory profile in CHMP2B patient frontal cortex. Aberrant microglial function has also been implicated in FTD caused by GRN, MAPT and C9orf72 mutations. The presence of early microglial changes in our CHMP2B mutant mice indicates neuroinflammation may be a contributing factor to the neurodegeneration observed in FTD.
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39.
  • Cronberg, Tobias, et al. (författare)
  • Neuron-specific enolase correlates with other prognostic markers after cardiac arrest.
  • 2011
  • Ingår i: Neurology. - 1526-632X. ; 77:7, s. 623-630
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Therapeutic hypothermia (TH) is a recommended treatment for survivors of cardiac arrest. Prognostication is complicated since sedation and muscle relaxation are used and established indicators of a poor prognosis are lacking. This prospective, observational study describes the pattern of commonly used prognostic markers in a hypothermia-treated cohort of cardiac arrest patients with prolonged coma. METHODS: Among 111 consecutive patients, 19 died, 58 recovered, and 34 were in coma 3 days after normothermia (4.5 days after cardiac arrest), defined as prolonged coma. All patients were monitored with continuous amplitude-integrated EEG and repeated samples of neuron-specific enolase (NSE) were collected. In patients with prolonged coma, somatosensory evoked potentials (SSEP) and brain MRI were performed. A postmortem brain investigation was undertaken in patients who died. RESULTS: Six of the 17 patients (35%) with NSE levels <33 μg/L at 48 hours regained the capacity to obey verbal commands. By contrast, all 17 patients with NSE levels >33 failed to recover consciousness. In the >33 NSE group, all 10 studied with MRI had extensive brain injury on diffusion-weighted images, 12/16 lacked cortical responses on SSEP, and all 6 who underwent autopsy had extensive severe histologic damage. NSE levels also correlated with EEG pattern, but less uniformly, since 11/17 with NSE <33 had an electrographic status epilepticus (ESE), only one of whom recovered. A continuous EEG pattern correlated to NSE <33 and awakening. CONCLUSIONS: NSE correlates well with other markers of ischemic brain injury. In patients with no other signs of brain injury, postanoxic ESE may explain a poor outcome.
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40.
  • Dragancea, Irina, et al. (författare)
  • The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest.
  • 2013
  • Ingår i: Resuscitation. - : Elsevier BV. - 1873-1570 .- 0300-9572. ; 84:3, s. 337-342
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Brain injury is considered the main cause of death in patients who are hospitalized after cardiac arrest (CA). Induced hypothermia is recommended as neuroprotective treatment after (CA) but may affect prognostic parameters. We evaluated the effect of delayed neurological prognostication on the mode of death in hypothermia-treated CA-survivors. STUDY DESIGN: Retrospective study at a Swedish university hospital, analyzing all in-hospital and out-of-hospital CA-patients treated with hypothermia during a 5-year period. Cause of death was categorized as brain injury, cardiac disorder or other. Multimodal neurological prognostication and decision on level of care was performed in comatose patients 72hours after rewarming. Neurological function was evaluated by Cerebral Performance Categories scale (CPC). RESULTS: Among 162 patients, 76 survived to hospital discharge, 65 of whom had a good neurological outcome (CPC 1-2), and 11 were severely disabled (CPC 3). No patient was in vegetative state. The cause of death was classified as brain injury in 61 patients, cardiac disorder in 14 and other in 11. Four patients were declared brain dead and became organ donors. They were significantly younger (median 40 years) and with long time to ROSC. Active intensive care was withdrawn in 50 patients based on a statement of poor neurological prognosis at least 72h after rewarming. These patients died, mainly from respiratory complications, at a median 7 days after CA. CONCLUSION: Following induced hypothermia and delayed neurological prognostication, brain injury remains the main cause of death after CA. Most patients with a poor prognosis statement died within two weeks.
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41.
  • Durmo, Faris, et al. (författare)
  • Assessment of Amide proton transfer weighted (APTw) MRI for pre-surgical prediction of final diagnosis in gliomas
  • 2020
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:12
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Radiological assessment of primary brain neoplasms, both high (HGG) and low grade tumors (LGG), based on contrast-enhancement alone can be inaccurate. We evaluated the radiological value of amide proton transfer weighted (APTw) MRI as an imaging complement for pre-surgical radiological diagnosis of brain tumors.METHODS: Twenty-six patients were evaluated prospectively; (22 males, 4 females, mean age 55 years, range 26-76 years) underwent MRI at 3T using T1-MPRAGE pre- and post-contrast administration, conventional T2w, FLAIR, and APTw imaging pre-surgically for suspected primary/secondary brain tumor. Assessment of the additional value of APTw imaging compared to conventional MRI for correct pre-surgical brain tumor diagnosis. The initial radiological pre-operative diagnosis was based on the conventional contrast-enhanced MR images. The range, minimum, maximum, and mean APTw signals were evaluated. Conventional normality testing was performed; with boxplots/outliers/skewness/kurtosis and a Shapiro-Wilk's test. Mann-Whitney U for analysis of significance for mean/max/min and range APTw signal. A logistic regression model was constructed for mean, max, range and Receiver Operating Characteristic (ROC) curves calculated for individual and combined APTw signals.RESULTS: Conventional radiological diagnosis prior to surgery/biopsy was HGG (8 patients), LGG (12 patients), and metastasis (6 patients). Using the mean and maximum: APTw signal would have changed the pre-operative evaluation the diagnosis in 8 of 22 patients (two LGGs excluded, two METs excluded). Using a cut off value of >2.0% for mean APTw signal integral, 4 of the 12 radiologically suspected LGG would have been diagnosed as high grade glioma, which was confirmed by histopathological diagnosis. APTw mean of >2.0% and max >2.48% outperformed four separate clinical radiological assessments of tumor type, P-values = .004 and = .002, respectively.CONCLUSIONS: Using APTw-images as part of the daily clinical pre-operative radiological evaluation may improve diagnostic precision in differentiating LGGs from HGGs, with potential improvement of patient management and treatment.
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42.
  • Durmo, Faris, et al. (författare)
  • Brain Tumor Characterization Using Multibiometric Evaluation of MRI
  • 2018
  • Ingår i: Tomography : a journal for imaging research. - : MDPI AG. - 2379-1381. ; 4:1, s. 14-25
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim was to evaluate volume, diffusion, and perfusion metrics for better presurgical differentiation between high-grade gliomas (HGG), low-grade gliomas (LGG), and metastases (MET). For this retrospective study, 43 patients with histologically verified intracranial HGG (n = 18), LGG (n = 10), and MET (n = 15) were chosen. Preoperative magnetic resonance data included pre- and post-gadolinium contrast-enhanced T1-weighted fluid-attenuated inversion recover, cerebral blood flow (CBF), cerebral blood volume (CBV), fractional anisotropy, and apparent diffusion coefficient maps used for quantification of magnetic resonance biometrics by manual delineation of regions of interest. A binary logistic regression model was applied for multiparametric analysis and receiver operating characteristic (ROC) analysis. Statistically significant differences were found for normalized-ADC-tumor (nADC-T), normalized-CBF-tumor (nCBF-T), normalized-CBV-tumor (nCBV-T), and normalized-CBF-edema (nCBF-E) between LGG and HGG, and when these metrics were combined, HGG could be distinguished from LGG with a sensitivity and specificity of 100%. The only metric to distinguish HGG from MET was the normalized-ADC-E with a sensitivity of 68.8% and a specificity of 80%. LGG can be distinguished from MET by combining edema volume (Vol-E), Vol-E/tumor volume (Vol-T), nADC-T, nCBF-T, nCBV-T, and nADC-E with a sensitivity of 93.3% and a specificity of 100%. The present study confirms the usability of a multibiometric approach including volume, perfusion, and diffusion metrics in differentially diagnosing brain tumors in preoperative patients and adds to the growing body of evidence in the clinical field in need of validation and standardization.
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43.
  • Durmo, Faris, et al. (författare)
  • Multivoxel 1H-MR Spectroscopy Biometrics for Preoprerative Differentiation Between Brain Tumors
  • 2018
  • Ingår i: Tomography : a journal for imaging research. - : MDPI AG. - 2379-1381. ; 4:4, s. 172-181
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigated multivoxel proton magnetic resonance spectroscopy (1H-MRS) biometrics for preoperative differentiation and prognosis of patients with brain metastases (MET), low-grade glioma (LGG) and high-grade glioma (HGG). In total, 33 patients (HGG, 14; LGG, 9; and 10 MET) were included. 1H-MRS imaging (MRSI) data were assessed and neurochemical profiles for metabolites N-acetyl aspartate (NAA) + NAAG(NAA), Cr + PCr(total creatine, tCr), Glu + Gln(Glx), lactate (Lac), myo-inositol(Ins), GPC + PCho(total choline, tCho), and total lipids, and macromolecule (tMM) signals were estimated. Metabolites were reported as absolute concentrations or ratios to tCho or tCr levels. Voxels of interest in an MRSI matrix were labeled according to tissue. Logistic regression, receiver operating characteristic, and Kaplan-Meier survival analysis was performed. Across HGG, LGG, and MET, average Ins/tCho was shown to be prognostic for overall survival (OS): low values (≤1.29) in affected hemisphere predicting worse OS than high values (>1.29), (log rank < 0.007). Lip/tCho and Ins/tCho combined showed 100% sensitivity and specificity for both HGG/LGG (P < .001) and LGG/MET (P < .001) measured in nonenhancing/contrast-enhancing lesional tissue. Combining tCr/tCho in perilesional edema with tCho/tCr and NAA/tCho from ipsilateral normal- appearing tissue yielded 100% sensitivity and 81.8% specificity (P < .002) for HGG/MET. Best single biomarker: Ins/tCho for HGG/LGG and total lipid/tCho for LGG/MET showed 100% sensitivity and 75% and 100% specificity, respectively. HGG/MET; NAA/tCho showed 75% sensitivity and 84.6% specificity. Multivoxel 1H-MRSI provides prognostic information for OS for HGG/LGG/MET and a multibiometric approach for differentiation may equal or outperform single biometrics.
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44.
  • Eckermann, Marina, et al. (författare)
  • 3d phase-contrast nanotomography of unstained human skin biopsies may identify morphological differences in the dermis and epidermis between subjects
  • 2021
  • Ingår i: Skin Research and Technology. - : Wiley. - 0909-752X .- 1600-0846. ; 27:3, s. 316-323
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Enteric neuropathy is described in most patients with gastrointestinal dysmotility and may be found together with reduced intraepidermal nerve fiber density (IENFD). The aim of this pilot study was to assess whether three-dimensional (3d) imaging of skin biopsies could be used to examine various tissue components in patients with gastrointestinal dysmotility. Material and methods: Four dysmotility patients of different etiology and two healthy volunteers were included. From each subject, two 3-mm punch skin biopsies were stained with antibodies against protein gene product 9.5 or evaluated as a whole with two X-ray phase-contrast computed tomography (CT) setups, a laboratory µCT setup and a dedicated synchrotron radiation nanoCT end-station. Results: Two patients had reduced IENFD, and two normal IENFD, compared with controls. µCT and X-ray phase-contrast holographic nanotomography scanned whole tissue specimens, with optional high-resolution scans revealing delicate structures, without differentiation of various fibers and cells. Irregular architecture of dermal fibers was observed in the patient with Ehlers-Danlos syndrome and the patient with idiopathic dysmotility showed an abundance of mesenchymal ground substance. Conclusions: 3d phase-contrast tomographic imaging may be useful to illustrate traits of connective tissue dysfunction in various organs and to demonstrate whether disorganized dermal fibers could explain organ dysfunction.
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45.
  • Ek Olofsson, Henric, et al. (författare)
  • Are cortical microvascular raspberries caused by cerebral hypoperfusion? An exploratory pathological study
  • 2021
  • Ingår i: Cerebral Circulation - Cognition and Behavior. - : Elsevier BV. - 2666-2450. ; 2
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: This retrospective study investigated a cortical microvascular formation, termed a ‘raspberry’ due to its appearance under a bright-field microscope. We examined whether there is support for the hypothesis that raspberry formation is an angiogenic process induced by cerebral hypoperfusion. Materials and Methods: Raspberries were manually quantified in haematoxylin and eosin-stained cortical sections from the anterior frontal lobe of deceased individuals who had undergone a diagnostic neuropathological examination at the Department of Pathology, Lund, Sweden, during April 2019–January 2021. Subjects represented consecutively received cases during this 22-month period. The raspberry density was compared between subjects according to variables collected from medical records and autopsy reports: age, sex, hypertension, diabetes mellitus, atrial fibrillation, orthostatic hypotension, chronic heart failure, acute circulatory failure, aortic atherosclerosis, atherosclerosis of the basal cerebral arteries (referred to as ‘cerebral atherosclerosis’), cerebral small vessel disease, cerebral amyloid angiopathy, cerebral infarction, and ischaemic white matter disease. Results: 62 subjects were included. The mean age was 71.9 years (range 46–97 years). 21 subjects (33.9%) were female. Independent-samples t-test showed a higher raspberry density in subjects with cerebral atherosclerosis (p = 0.029; 95% CI 0.7, 11.6 raspberries/cm²). The higher raspberry density in subjects with cerebral atherosclerosis remained in multiple linear regression (p = 0.003; 95% CI 2.3, 11.1 raspberries/cm²). Conclusion: This exploratory study indicates that cortical raspberries could be associated with cerebral atherosclerosis. The remaining results were inconclusive but motivate further examination of variables such as acute circulatory failure.
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46.
  • Ek Olofsson, Henric, et al. (författare)
  • Cortical microvascular raspberries and ageing : an independent but not exclusive relationship
  • 2023
  • Ingår i: Acta Neuropathologica Communications. - 2051-5960. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Raspberries are cerebral microvascular formations of unknown origin, defined as three or more transversally sectioned vascular lumina surrounded by a common perivascular space. We have previously demonstrated an increased raspberry density in the cortex of patients with vascular dementia and cerebral atherosclerosis, while studies by other authors on overlapping and synonymously defined vascular entities mainly associate them with advancing age. The aim of the present study was to examine the relationship between raspberries and age in a large study sample while including multiple potential confounding factors in the analysis.Materials and methods: Our study sample consisted of 263 individuals aged 20–97 years who had undergone a clinical autopsy including a neuropathological examination. The cortical raspberry density had either been quantified as part of a previous study or was examined de novo in a uniform manner on haematoxylin- and eosin-stained tissue sections from the frontal lobe. The medical records and autopsy reports were assessed regarding neurodegeneration, cerebral infarcts, cerebral atherosclerosis and small vessel disease, cardiac hypertrophy, nephrosclerosis, hypertension, and diabetes mellitus. With the patients grouped according to 10-year age interval, non-parametric tests (the Kruskal–Wallis test, followed by pairwise testing with Bonferroni-corrected P values) and multiple linear regression models (not corrected for multiple tests) were performed.Results: The average raspberry density increased with advancing age. The non-parametric tests demonstrated statistically significant differences in raspberry density when comparing the groups aged 60–99 years and 70–99 years to those aged 20–29 years (P < 0.012) and 30–59 years (P < 0.011), respectively. The multiple linear regression models demonstrated positive associations with age interval (P < 0.001), cerebral atherosclerosis (P = 0.024), cardiac hypertrophy (P = 0.021), hypertension subgrouped for organ damage (P = 0.006), and female sex (P = 0.004), and a tendency towards a negative association with Alzheimer’s disease neuropathologic change (P = 0.048).Conclusion: The raspberry density of the frontal cortex increases with advancing age, but our results also indicate associations with acquired pathologies. Awareness of the biological and pathological context where raspberries occur can guide further research on their origin.
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47.
  • Ek Olofsson, Henric, et al. (författare)
  • On the regional distribution of cerebral microvascular ‘raspberries’ and their association with cerebral atherosclerosis and acute circulatory failure
  • 2023
  • Ingår i: Cerebral Circulation - Cognition and Behavior. - : Elsevier BV. - 2666-2450. ; 4, s. 1-5
  • Tidskriftsartikel (refereegranskat)abstract
    • IntroductionIn this follow-up study, cerebral microvascular formations termed ‘raspberries’ were quantified according to cerebral atherosclerosis (C-ASCL) and acute circulatory failure (ACF). We also examined the regional distribution of raspberries throughout the brain.Materials and methodsThe study population consisted of adult individuals who had undergone a diagnostic neuropathological autopsy. Groups were formed to examine the association between raspberries, C-ASCL and ACF (control group, C-ASCL group, C-ASCL+ACF group [n = 47 per group] and a combined C-ASCL-tot group [n = 94]). To examine the regional distribution, additional groups were formed based on previously known raspberry densities of the frontal cortex (high-, medium- and low-density group [n = 6 per group]). Raspberries were quantified on scanned haematoxylin-eosin-stained sections.ResultsCortical raspberry density did not differ at a statistically significant level between the control group, the C-ASCL group and the C-ASCL+ACF group (P = 0.10) but did so between the control group and the C-ASCL-tot group (P = 0.033). The total raspberry density of the high-, medium- and low-density groups differed at a statistically significant level (P = 0.005), which remained in group-to-group comparisons of the high- and medium-density groups (P = 0.015) and the high- and low-density groups (P = 0.002). Raspberries were rare in cerebral white matter and in the cerebellum.ConclusionAn association between raspberry density and C-ASCL is supported but is weaker than previously indicated. An association with ACF is not indicated. The raspberry density of the frontal cortex provides an approximation of the brain's total raspberry density.
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48.
  •  
49.
  • Ekman, Linnéa, et al. (författare)
  • Evaluation of small nerve fiber dysfunction in type 2 diabetes
  • 2020
  • Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 141:1, s. 38-46
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: To assess potential correlations between intraepidermal nerve fiber densities (IENFD), graded with light microscopy, and clinical measures of peripheral neuropathy in elderly male subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM), respectively. Materials and methods: IENFD was assessed in thin sections of skin biopsies from distal leg in 86 men (71-77 years); 24 NGT, 15 IGT, and 47 T2DM. Biopsies were immunohistochemically stained for protein gene product (PGP) 9.5, and intraepidermal nerve fibers (IENF) were quantified manually by light microscopy. IENFD was compared between groups with different glucose tolerance and related to neurophysiological tests, including nerve conduction study (NCS; sural and peroneal nerve), quantitative sensory testing (QST), and clinical examination (Total Neuropathy Score; Neuropathy Symptom Score and Neuropathy Disability Score). Results: Absent IENF was seen in subjects with T2DM (n = 10; 21%) and IGT (n = 1; 7%) but not in NGT. IENFD correlated weakly negatively with HbA1c (r = −.268, P =.013) and Total Neuropathy Score (r = −.219, P =.042). Positive correlations were found between IENFD and sural nerve amplitude (r =.371, P =.001) as well as conduction velocity of both the sural (r =.241, P =.029) and peroneal nerve (r =.258, P =.018). Proportions of abnormal sural nerve amplitude became significantly higher with decreasing IENFD. No correlation was found with QST. Inter-rater reliability of IENFD assessment was good (ICC = 0.887). Conclusions: Signs of neuropathy are becoming more prevalent with decreasing IENFD. IENFD can be meaningfully evaluated in thin histopathological sections using the presented technique to detect neuropathy.
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50.
  • Ekman, Linnéa, et al. (författare)
  • Temporal trend of small nerve fibre degeneration in people with and without type 2 diabetes mellitus
  • 2022
  • Ingår i: Diabetic Medicine. - : John Wiley & Sons. - 0742-3071 .- 1464-5491. ; 39:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: We investigated the long-term temporal trend of intraepidermal nerve fibre density (IENFD) and the association between changes in IENFD and metabolic factors in individuals with and without type 2 diabetes. Methods: A total of 66 participants were enrolled in this longitudinal population-based study, at baseline consisting of 35 individuals (median 61 years) without diabetes and 31 individuals with type 2 diabetes mellitus. Participants underwent clinical and electrophysiological examinations, as well as a skin biopsy both at baseline and at the follow-up visit (mean 8.1 ± 0.5 years). IENFD was assessed in thin sections of 5 μm, stained with the protein gene product 9.5-antibody and compared between the groups. Results: IENFD decreased during the period in both groups, with a greater decline in the group without diabetes than in type 2 diabetes (−2.3 and −0.6 fibres/mm respectively; p < 0.001). While IENFD at baseline was significantly reduced in type 2 diabetes relative to people without (p < 0.001), no difference in IENFD was found between groups at the follow-up (p = 0.183). Linear mixed model analysis indicated that age, weight and HbA1c were associated with decrease in IENFD in the total population (p < 0.007). IENFD also decreased with increasing age and weight, but not with HbA1c, in the separate groups (p < 0.049). Conclusions: Despite lower IENFD levels at baseline in type 2 diabetes, IENFD was equal between the groups at follow-up. A decrease in IENFD is to a limited extent affected by body weight, and HbA1c, but age seems to be the long-term determinant of IENFD in an elderly population.
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