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  • 1.
    Abu Hamdeh, Sami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Waara, Erik Rollman
    Möller, Christer
    Söderberg, Linda
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic Neuroscience AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rapid amyloid-β oligomer and protofibril accumulation in traumatic brain injury2017In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639Article in journal (Refereed)
    Abstract [en]

    Deposition of amyloid-β (Aβ) is central to Alzheimer's disease (AD) pathogenesis and associated with progressive neurodegeneration in traumatic brain injury (TBI). We analyzed predisposing factors for Aβ deposition including monomeric Aβ40, Aβ42 and Aβ oligomers/protofibrils, Aβ species with pronounced neurotoxic properties, following human TBI. Highly selective ELISAs were used to analyze N-terminally intact and truncated Aβ40 and Aβ42, as well as Aβ oligomers/protofibrils, in human brain tissue, surgically resected from severe TBI patients (n = 12; mean age 49.5 ± 19 years) due to life-threatening brain swelling/hemorrhage within one week post-injury. The TBI tissues were compared to post-mortem AD brains (n = 5), to post-mortem tissue of neurologically intact (NI) subjects (n = 4) and to cortical biopsies obtained at surgery for idiopathic normal pressure hydrocephalus patients (iNPH; n = 4). The levels of Aβ40 and Aβ42 were not elevated by TBI. The levels of Aβ oligomers/protofibrils in TBI were similar to those in the significantly older AD patients and increased compared to NI and iNPH controls (P < 0.05). Moreover, TBI patients carrying the AD risk genotype Apolipoprotein E epsilon3/4 (APOE ε3/4; n = 4) had increased levels of Aβ oligomers/protofibrils (P < 0.05) and of both N-terminally intact and truncated Aβ42 (P < 0.05) compared to APOE ε3/4-negative TBI patients (n = 8). Neuropathological analysis showed insoluble Aβ aggregates (commonly referred to as Aβ plaques) in three TBI patients, all of whom were APOE ε3/4 carriers. We conclude that soluble intermediary Aβ aggregates form rapidly after TBI, especially among APOE ε3/4 carriers. Further research is needed to determine whether these aggregates aggravate the clinical short- and long-term outcome in TBI.

  • 2.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alzheimerin tauti: (Alzheimer’s sjukdom)2012In: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, p. 1029-1031Chapter in book (Other academic)
  • 3.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alzheimer's disease-related lesions2013In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 33, no Suppl 1, p. S173-S179Article, review/survey (Refereed)
    Abstract [en]

    The invitation to contribute to "Alzheimer's Disease: Advances for a New Century" gave me an opportunity to briefly summarize my personal opinions about how the field of neuropathology has evolved. The goal is to briefly exemplify the changes that have influenced the way we conduct our diagnostic work as well as the way we interpret our results. From an era of histological stains, we have moved to visualization of altered proteins in predicted brain regions; we have also realized that in many aged subjects, not one but a plethora of co-pathologies are seen, and finally, we have become aware that the degenerative process is initiated much earlier than we ever suspected.

  • 4.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Frontotemporaaliset lobaariset degeneraatiot: (Frontoremporal degeneration)2012In: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, p. 1032-1033Chapter in book (Other academic)
  • 5.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Neuropatologinen tutkimus: Neuropatologisk undersökning2010In: Muistisairaudet: (Minnestörningar) / [ed] Erkinjuntti T, Rinne J, Soininen H, Helsingfors: Duodecim , 2010, 1, p. 438-446Chapter in book (Other academic)
  • 6.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Neuropatologinen tutkimus: Neuropatologisk undersökning2015In: Muistisairaudet: (Minnestörningar) / [ed] Erkinjuntti T, Rinne J, Soininen H, Helsingfors: Duodecim , 2015, 2, p. 426-434Chapter in book (Other academic)
  • 7.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Parkinsonin tauti ja lewynkappaledementia: (Parkinsons sjukdom)2012In: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, p. 1031-1032Chapter in book (Other academic)
  • 8.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Rapeuttavat aivosairaudet: (Degenerativa hjärnsjukdomar)2012In: Patologia: (Patologi) / [ed] Mäkinen M, Carpen O, Kosma VM, Lehto VP, Paavonen T, Stenbäck F, Helsingfors: Duodecim , 2012, 1, p. 1023-1028Chapter in book (Other academic)
  • 9.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Tau pathology in aging and AD: beyond neurofibrillary tangles (grains, astrocytes, etc.)2014In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 24, no S1, p. 20-21Article in journal (Other academic)
  • 10.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Gelpi, E.
    Al-Sarraj, S.
    Arzberger, T.
    Attems, J.
    Bodi, I.
    Bogdanovic, N.
    Budka, H.
    Bugiani, O.
    Englund, E.
    Ferrer, I.
    Gentleman, S.
    Giaccone, G.
    Graeber, M. B.
    Hortobagyi, T.
    Höftberger, R.
    Ironside, J. W.
    Jellinger, K.
    Kavantzas, N.
    King, A.
    Korkolopoulou, P.
    Kovács, G. G.
    Meyronet, D.
    Monoranu, C.
    Parchi, P.
    Patsouris, E.
    Roggendorf, W.
    Rozemuller, A.
    Seilhean, D.
    Streichenberger, N.
    Thal, D. R.
    Wharton, S. B.
    Kretzschmar, H.
    The need to unify neuropathological assessments of vascular alterations in the ageing brain: Multicentre survey by the BrainNet Europe consortium2012In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 47, no 11, p. 825-833Article in journal (Refereed)
    Abstract [en]

    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.

  • 11.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Parkkinen, Laura
    Staged pathology in Parkinson's disease2014In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 20, no Suppl. 1, p. S57-S61Article in journal (Refereed)
    Abstract [en]

    There has been a tremendous development since a regional progression of pathology in subjects with Lewy bodies (LB) was initially proposed 30 years ago. The entity of dementia with Lewy bodies has been acknowledged, the main protein constituent of LBs--aggregated α-synuclein (αS)--has been identified and a stepwise progression of the pathology has been reported. Implementation of the staging strategies published provides a common ground for handling a case with a suspected α-synucleinopathy. It is always important to state the staging strategy implemented while assessing a case, as the strategy applied might influence both the reported stage of LB pathology and, ultimately, the final diagnosis of the patient.

  • 12.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pikkarainen, M
    Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
    Parkkinen, L
    Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
    Synucleinopathies2015In: Neuropathology of neurodegenerative diseases: A practical guide / [ed] Gabor G Kovacs, Cambridge University Press, 2015, p. 149-175Chapter in book (Refereed)
    Abstract [en]

    Definition, structure and biochemical background Similar to other “proteinopathies,” the process that links α-synuclein (αS) protein to disease pathogenesis originated from the discovery that a single point mutation in the αS gene (i.e. SNCA) can cause autosomal-dominant Parkinson’s disease (PD) [1]. This was followed by the breakthrough finding that the actual transcribed protein was a major fibrillar component of pathological hallmarks known as Lewy bodies (LBs), Lewy neurites (LNs) and glial cytoplasmic inclusions characterizing a heterogeneous group of diseases, now collectively referred to as “synucleinopathies,” i.e. PD, PD with dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) [2, 3]. Currently, there are five missense mutations (pA53T, p.A30P, p.E46K, p.H50Q and p.G51D) [1, 4–8] and multiplication mutations (SNCA duplication and triplication) [9–11] that are genetically linked to clinical parkinsonism (Table 9.1). This genetic and pathological linkage establishes αS as an important player in the development of these disorders.

  • 13.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pikkarainen, Maria
    Univ Eastern Finland, Dept Clin Med, Kuopio, Finland.
    Neumann, Manuela
    Univ Tubingen, German Ctr Neurodegenerat Dis, Dept Neuropatol, Tubingen, Germany; DZNE, Tubingen, Germany.
    Arzberger, Thomas
    Univ Munich, Ctr Neuropathol & Prion Res, Munich, Germany.
    Al-Sarraj, Safa
    Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England; MRC, London Neurodegenerat Dis Brain Bank, London, England.
    Bodi, Istvan
    Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England; MRC, London Neurodegenerat Dis Brain Bank, London, England.
    Bogdanovic, Nenad
    Univ Oslo, Inst Clin Med, Dept Geriatr, Oslo, Norway.
    Bugiani, Orso
    IRCSS Fdn Ist Neurol Carlo Besta, Div Neuropathol & Neurol 5, Milan, Italy.
    Ferrer, Isidro
    Univ Barcelona, CEBERNED, Bellvitge Univ Hosp, Inst Neuropathol, Barcelona, Spain.
    Gelpi, Ellen
    Biobanc Hosp Clin IDIBAPS, Neurol Tissue Bank, Barcelona, Spain.
    Gentleman, Stephen
    Univ London Imperial Coll Sci Technol & Med, Dept Med, Neuropathol Unit, London, England.
    Giaccone, Giorgio
    IRCSS Fdn Ist Neurol Carlo Besta, Div Neuropathol & Neurol 5, Milan, Italy.
    Graeber, Manuel B.
    Univ Sydney, Fac Med, Sydney, NSW 2006, Australia; Univ Sydney, Fac Hlth Sci, Brain & Mind Res Inst, Sydney, NSW 2006, Australia.
    Hortobagyi, Tibor
    Univ Debrecen, Instutute Pathol, Dept Neuropathol, Debrecen, Hungary.
    Ince, Paul G.
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England.
    Ironside, James W.
    Univ Edinburgh, Western Gen Hosp, Natl CJD Res & Surveillance Unit, Edinburgh, Midlothian, Scotland.
    Kavantzas, Nikolaos
    Natl & Capodistrian Univ Athens, Dept Pathol, Athens, Greece.
    King, Andrew
    Kings Coll Hosp London, Inst Psychiat, Dept Clin Neuropathol, London, England; MRC, London Neurodegenerat Dis Brain Bank, London, England.
    Korkolopoulou, Penelope
    Natl & Capodistrian Univ Athens, Dept Pathol, Athens, Greece.
    Kovács, Gábor G.
    Med Univ Vienna, Inst Neurol, Vienna, Austria.
    Meyronet, David
    Univ Lyon, Hosp Civils Lyon, Ctr Pathol & Neuropathol Est, Lyon Neurosci Res Ctr, Lyon, France.
    Monoranu, Camelia
    Univ Wurzburg, Abt Neuropathol, Pathol Inst, D-97070 Wurzburg, Germany.
    Nilsson, Tatjana
    Karolinska Inst, Dept Geriatr, Stockholm, Sweden.
    Parchi, Piero
    Univ Bologna, Ist Sci Neurol, Dept Biomed & Neuromotor Sci, IRCCS, Bologna, Italy.
    Patsouris, Efstratios
    Natl & Capodistrian Univ Athens, Dept Pathol, Athens, Greece.
    Revesz, Tamas
    UCL Inst Neurol, Queen Sq Brain Bank, Dept Mol Neurosci, London, England.
    Roggendorf, Wolfgang
    Univ Wurzburg, Abt Neuropathol, Pathol Inst, D-97070 Wurzburg, Germany.
    Rozemuller, Annemieke
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands.
    Seilhean, Danielle
    Univ Paris 06, AP HP, Lab Neuropathol Raymond Escourolle, Paris, France; INSERM, Paris, France.
    Streichenberger, Nathalie
    Univ Lyon, Hosp Civils Lyon, Ctr Pathol & Neuropathol Est, Lyon Neurosci Res Ctr, Lyon, France.
    Thal, Dietmar R.
    Univ Ulm, Inst Pathol, Neuropathol Lab, D-89069 Ulm, Germany.
    Wharton, Stephen B.
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England.
    Kretzschmar, Hans
    Univ Munich, Ctr Neuropathol & Prion Res, Munich, Germany.
    Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium2015In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 122, no 7, p. 957-972Article in journal (Refereed)
    Abstract [en]

    The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.

  • 14.
    Alafuzoff, Irina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Popova, Svetlana N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wanders, Alkwin
    Department of Clinical Pathology and Cytology, Umea University Hospital, Umea, Sweden.
    Veress, Bela
    Department of Clinical Pathology and Cytology, Skane University Hospital, Malmo, Sweden.
    Neuronal Protein Alteration in Enteric Dysmotility Syndrome2016In: Journal of Alzheimer’s Disease & Parkinsonism, ISSN 2161-0460, Vol. 6, no 1, article id 1000212Article in journal (Other academic)
  • 15. Amirian, E Susan
    et al.
    Armstrong, Georgina N
    Zhou, Renke
    Lau, Ching C
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill S
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S
    Jenkins, Robert B
    Lachance, Daniel
    Olson, Sara H
    Bernstein, Jonine L
    Merrell, Ryan T
    Wrensch, Margaret R
    Davis, Faith G
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I
    Scheurer, Michael E
    Aldape, Kenneth
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Brännström, Thomas
    Broholm, Helle
    Collins, Peter
    Giannini, Caterina
    Rosenblum, Marc
    Tihan, Tarik
    Melin, Beatrice S
    Bondy, Melissa L
    The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium2016In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 183, no 2, p. 85-91Article in journal (Refereed)
    Abstract [en]

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions.

  • 16. Arzberger, Thomas
    et al.
    Giese, Armin
    Edbauer, Dieter
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ferrer, Isidro
    Special Issue: Research on Brain Bank Material - From Ethical Issues to Biomolecular Studies2015In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 122, no 7, p. 933-936Article in journal (Other academic)
  • 17.
    Berntsson, Shala Ghaderi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Falk, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Savitcheva, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Godau, Andrea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Perfusion and diffusion MRI combined with (11)C-methionine PET in the preoperative evaluation of suspected adult low-grade gliomas2013In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 114, no 2, p. 241-249Article in journal (Refereed)
    Abstract [en]

    Perfusion and diffusion magnetic resonance imaging (pMRI, dMRI) are valuable diagnostic tools for assessing brain tumors in the clinical setting. The aim of this study was to determine the correlation of pMRI and dMRI with (11)C-methionine positron emission tomography (MET PET) in suspected low-grade gliomas (LGG) prior to surgery. Twenty-four adults with suspected LGG were enrolled in an observational study and examined by MET PET, pMRI and dMRI. Histological tumor diagnosis was confirmed in 23/24 patients (18 gliomas grade II, 5 gliomas grade III). The maximum relative cerebral blood volume (rCBVmax) and the minimum mean diffusivity (MDmin) were measured in tumor areas with highest MET uptake (hotspot) on PET by using automated co-registration of MRI and PET scans. A clearly defined hotspot on PET was present in all 23 tumors. Regions with rCBVmax corresponded with hotspot regions in all tumors, regions with MDmin corresponded with hotspot regions in 20/23 tumors. The correlation between rCBVmax (r = 0.19, P = 0.38) and MDmin (r = -0.41, P = 0.053) with MET uptake in the hotspot was not statistically significant. Taken into account the difficulties of measuring perfusion abnormalities in non-enhancing gliomas, this study demonstrates that co-registered MET PET and pMRI facilitates the identification of regions with rCBVmax. Furthermore, the lack of a clear positive correlation between tumor metabolism in terms of MET uptake and tumor vascularity measured as rCBVmax suggests that combined pMRI/PET provides complementary baseline imaging data in these tumors.

  • 18.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Heck, Ansgar
    Schulz, Stefan
    Nesland, Jahn Marthin
    Ramm-Pettersen, Jon
    Lekva, Tove
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Bollerslev, Jens
    Expression of SSTR2a, but not of SSTRs 1, 3, or 5 in Somatotroph Adenomas Assessed by Monoclonal Antibodies Was Reduced by Octreotide and Correlated With the Acute and Long-Term Effects of Octreotide2013In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 11, p. E1730-E1739Article in journal (Refereed)
    Abstract [en]

    Context: Reduced expression of somatostatin receptors (SSTRs) in somatotroph adenomas and their potential down-regulation after medical treatment may explain the unsatisfactory response to octreotide in particular acromegalic patients. The expression of SSTRs other than SSTR2a has not been studied in large, unselected cohorts using novel rabbit monoclonal antibodies. Objective: We aimed to determine the expression of SSTRs 1, 2a, 3, and 5 in somatotroph adenomas, to correlate expression with clinical characteristics and the response to octreotide, and to ascertain whether preoperative octreotide treatment affected SSTR expression. Design, Setting, Patients: The study included 78 adenomas from patients operated on consecutively during 2000 to 2010. After exclusion of 13 patients, immunohistochemical analysis with rabbit monoclonal antibodies against SSTRs 1, 2a, 3, and 5 (clones UMB-7, -1, -5, and -4) was performed on 65 adenomas. Intervention: Twenty-eight patients received preoperative octreotide, and 37 patients were operated on without pretreatment. Twenty-six patients were randomized to direct surgery (n = 13) or to octreotide pretreatment (n = 13). Main Outcome Measure: SSTR expression was evaluated using a 12-grade scoring system. The responses to the octreotide test dose (GH reduction) and to 6 months of octreotide (IGF-I reduction) were measured. Results: The majority of adenomas showed membranous expression of SSTRs 2a and 5. SSTR2a expression was reduced in the pretreated group and correlated with the acute octreotide test results and the effect of octreotide treatment. In a linear regression model with SSTR2 a expression as the determinant, the correlation with the acute test response improved after adjustment for medical pretreatment. Conclusion: Rabbit monoclonal antibodies are reliable markers of SSTRs in somatotroph adenomas. SSTR2a expression correlated with the response to octreotide and was reduced after octreotide treatment, indicating the need for adjustment when SSTR2a expression is correlated with baseline characteristics. Evaluation of SSTR subtypes may be an important aspect of improving the medical treatment for acromegaly.

  • 19. Crary, John F.
    et al.
    Trojanowski, John Q.
    Schneider, Julie A.
    Abisambra, Jose F.
    Abner, Erin L.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Arnold, Steven E.
    Attems, Johannes
    Beach, Thomas G.
    Bigio, Eileen H.
    Cairns, Nigel J.
    Dickson, Dennis W.
    Gearing, Marla
    Grinberg, Lea T.
    Hof, Patrick R.
    Hyman, Bradley T.
    Jellinger, Kurt
    Jicha, Gregory A.
    Kovacs, Gabor G.
    Knopman, David S.
    Kofler, Julia
    Kukull, Walter A.
    Mackenzie, Ian R.
    Masliah, Eliezer
    McKee, Ann
    Montine, Thomas J.
    Murray, Melissa E.
    Neltner, Janna H.
    Santa-Maria, Ismael
    Seeley, William W.
    Serrano-Pozo, Alberto
    Shelanski, Michael L.
    Stein, Thor
    Takao, Masaki
    Thal, Dietmar R.
    Toledo, Jonathan B.
    Troncoso, Juan C.
    Vonsattel, Jean Paul
    White, Charles L., III
    Wisniewski, Thomas
    Woltjer, Randall L.
    Yamada, Masahito
    Nelson, Peter T.
    Primary age-related tauopathy (PART): a common pathology associated with human aging2014In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 128, no 6, p. 755-766Article in journal (Refereed)
    Abstract [en]

    We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (A beta) plaques. For these "NFT+/A beta-aEuroe brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of A beta accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.

  • 20.
    Dieterich, Lothar C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mellberg, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Langenkamp, Elise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Zieba, Agata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Salomäki, Henriikka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Teichert, M.
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Kraus, T.
    Augustin, H. G.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Molema, G.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Georgii-Hemming, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization2012In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 228, no 3, p. 378-390Article in journal (Refereed)
    Abstract [en]

    Glioblastoma are aggressive astrocytic brain tumours characterized by microvascular proliferation and an abnormal vasculature, giving rise to brain oedema and increased patient morbidity. Here, we have characterized the transcriptome of tumour-associated blood vessels and describe a gene signature clearly associated with pleomorphic, pathologically altered vessels in human glioblastoma (grade IV glioma). We identified 95 genes differentially expressed in glioblastoma vessels, while no significant differences in gene expression were detected between vessels in non-malignant brain and grade II glioma. Differential vascular expression of ANGPT2, CD93, ESM1, ELTD1, FILIP1L and TENC1 in human glioblastoma was validated by immunohistochemistry, using a tissue microarray. Through qPCR analysis of gene induction in primary endothelial cells, we provide evidence that increased VEGF-A and TGFβ2 signalling in the tumour microenvironment is sufficient to invoke many of the changes in gene expression noted in glioblastoma vessels. Notably, we found an enrichment of Smad target genes within the distinct gene signature of glioblastoma vessels and a significant increase of Smad signalling complexes in the vasculature of human glioblastoma in situ. This indicates a key role of TGFβ signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGFβ2 may represent a new target for vascular normalization therapy.

  • 21.
    Elobeid, Adila
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Laurell, Katarina
    Cesarini, Kristina Giuliana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Correlations Between Mini-Mental State Examination Score, Cerebrospinal Fluid Biomarkers, and Pathology Observed in Brain Biopsies of Patients With Normal-Pressure Hydrocephalus2015In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 74, no 5, p. 470-479Article in journal (Refereed)
    Abstract [en]

    Alzheimer disease (AD)-related pathology was assessed in cortical biopsy samples of 111 patients with idiopathic normal-pressure hydrocephalus. Alzheimer disease hallmark lesions-beta-amyloid (A beta) and hyperphosphorylated tau (HPtau)-were observed in 47% of subjects, a percentage consistent with that for whole-brain assessment reported postmortem in unselected cohorts. Higher-immunostained area fraction of AD pathology corresponded with lower preoperative mini-mental state examination scores. Concomitant A beta and HPtau pathology, reminiscent of that observed in patients with AD, was observed in 22% of study subjects. There was a significant correlation between A beta-immunostained area fraction in tissue and A beta 42 (42-amino-acid form of A beta) in cerebrospinal fluid (CSF). Levels of A beta 42 were significantly lower in CSF in subjects with concomitant A beta and HPtau pathology compared with subjects lacking pathology. Moreover, a significant correlation between HPtau-immunostained area fraction and HPtau in CSF was noted. Both HPtau and total tau were significantly higher in CSF in subjects with concomitant A beta and HPtau pathology compared with subjects lacking pathology. The 42-amino-acid form of A beta (A beta 42) and HPtau in CSF were the most significant predictors of the presence of AD pathology in cortical biopsies. Long-term follow-up studies are warranted to assess whether all patients with idiopathic normal-pressure hydrocephalus with AD pathology progress to AD and to determine the pathologic substrate of idiopathic normal-pressure hydrocephalus.

  • 22.
    Elobeid, Adila
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Leino, Marina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Popova, Svetlana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Altered proteins in the aging brain2016In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 75, no 4, p. 316-325Article in journal (Refereed)
    Abstract [en]

    We assessed the prevalence of common altered brain proteins in 296 cognitively unimpaired subjects ranging from age 50 to 102 years. The incidence and the stage of hyperphosphorylated-tau (HP tau), beta-amyloid, alpha-synuclein (alpha S), and transactive response DNA (TDP) binding protein 43 (TDP43)-immunoreactivity (-IR) increased with age. HP tau-IR was observed in 98% of the subjects; the locus coeruleus was solely affected in 46%, and 79% of the subjects were in Braak stages a to II. beta-Amyloid was seen in 47% of subjects and the Thal phase correlated with the HP tau Braak stage and age. Intermediate Alzheimer disease-related pathology (ADRP) was seen in 12%; 52% of the subjects with HP tau-IR fulfilled criteria for definite primary age-related tauopathy (PART). The incidence of concomitant pathology (alpha S, TDP43) did not differ between those with PART and those with ADRP but the former were younger. TDP43-IR was observed in 36%; the most frequently affected region was the medulla; alpha S-IR was observed in 19% of subjects. In 41% of the subjects from 80 to 89 years at death, 3 altered proteins were seen in the brain. Thus, altered proteins are common in the brains of cognitively unimpaired aged subjects; this should be considered while developing diagnostic biomarkers, particularly for identifying subjects at early stages of neurodegenerative diseases.

  • 23.
    Elobeid, Adila
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Rantakomi, Sanna
    Soininen, Hilkka
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alzheimer's disease-related plaques in nondemented subjects2014In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 10, no 5, p. 522-529Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) pathology was assessed in 587 nondemented subjects, with age at death at or more than 50 years. In 307 subjects, amyloid-beta (A beta) immunoreactive (IR) plaques were seen; in 192 subjects, neuritic plaques (NPs) stained with modified Bielschowsky silver stain (mBky) were observed. In 20% of the whole cohort and in 62% of the 192 subjects with NPs in mBky, hyperphosphorylated tau (HPtau) IR NPs were seen. In most cases in this nondemented cohort, the HPtau IR NPs were observed either sparsely or to a moderate extent. The correlation between the NP score and Braak stage was best (r = 0.6, P < .001) when HPtau immunohistochemistry was used. Eighty-three percent of the subjects could not be categorized following the 1997 National Institute on Aging and the Reagan Institute (NIA-RI) recommendations, whereas the 2012 National Institute on Aging Alzheimer's Association (NIA-AA) guidelines were applicable for all study subjects. Twenty-eight subjects had an intermediate level of AD neuropathological change according to the 2012 NIA-AA guidelines, and 25 of these 28 subjects displayed HPtau IR NPs in the temporal cortex. It is noteworthy, however, that as many as 119 out of the 192 subjects with NPs in mBky displayed HPtau IR NPs in the temporal cortex. Ninety-four of these 119 subjects with neocortical HPtau IR NPs had a low level of neuropathological AD change according to the 2012 NIA-AA guidelines because they were in Braak stages I and II. Thus, 94 subjects were not acknowledged as being at risk for AD when applying the 2012 NIA-AA guidelines. We suggest that to identify all subjects with cortical HPtau pathology and, consequently, probably being at risk for developing AD, in addition to the level of AD neuropathological change as recommended by the 2012 NIA-AA guidelines, assessment of HPtau IR NPs in the neocortex should be carried out.

  • 24. Elobeid, Adila
    et al.
    Soininen, Hilkka
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Hyperphosphorylated tau in young and middle-aged subjects2012In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 123, no 1, p. 97-104Article in journal (Refereed)
    Abstract [en]

    The brain tissue obtained from ninety-five cognitively unimpaired subjects, with ages ranging from 22 to 50 years upon death, were immunohistochemically assessed for neurodegenerative changes, i.e., hyperphosphorylated tau (HP tau) and beta-amyloid (A beta) pathology in predilection neuroanatomical areas. HP tau pathology was observed in the transentorhinal cortex and/or the locus coeruleus (LC) in 33% of the subjects, without any obvious risk factors known to alter the microtubule-associated protein. HP tau pathology was noted in the LC in 25 out of 83 subjects (30%), lacking concomitant cortical A beta or transentorhinal HP tau pathology. This observation was present even when assessing only one routine section of 7 mu m thickness. The recent suggestion of prion-like propagation of neurodegeneration and the finding of neurodegeneration being quite common in middle-aged persons is alarming. It is noteworthy, however, that a substantial number of neurologically unimpaired subjects even at a very old age display only sparse to modest extent of neurodegenerative pathology. Thus, only a subset of subjects with neurodegenerative changes early in life seem to progress to a symptomatic disease with ageing. This observation brings forth the notion that other, yet unknown modifying factors influence the progression of degeneration that leads to a symptomatic disorder. The known association between alterations in the LC and mood disorders, and the finding of the LC being frequently affected with HP tau pathology suggest that clinicopathological studies on young subjects both with or without mood disorders are warranted.

  • 25.
    Elsir, Tamador
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Edqvist, Per-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlson, Joseph
    Ribom, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Popova, Svetlana N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nistér, Monica
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    A study of embryonic stem cell-related proteins in human astrocytomas: Identification of Nanog as a predictor of survival2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 134, no 5, p. 1123-1131Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO grade II) and 98 high-grade human gliomas (WHO grade III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low- and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n=42) with high levels of Nanog protein (p=0.0067) and of Klf4 protein (p=0.0368), in high-grade astrocytomas (n=85) with high levels of Nanog (p=0.0042), Klf4 (p=0.0447), and c-Myc (p=0.0078) and in glioblastomas only (n=71) with high levels of Nanog (p=0.0422) and of c-Myc (p= 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p=0.0039), high-grade astrocytomas (p=0.0124) and glioblastomas only (p=0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.

  • 26.
    Falk Delgado, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Markus, Nilsson
    Bioimaging center, Lunds Universitet.
    Ghaderi Berntsson, Shala
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    van Westen, Danielle
    Clinical Sciences, Lunds Universitet.
    Lätt, Jimmy
    MR Department, Center for medical imaging and physiology, Lund University Hospital.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Preoperative diffusion kurtosis imaging in suspected low-grade gliomas: A prospective study of diffusional properties in tumour and perilesional regions with histopathological correlationsManuscript (preprint) (Other academic)
  • 27.
    Falk Delgado, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Nilsson, Markus
    Lund Univ, Bioimaging Ctr, Lund, Sweden..
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Libard, Sylwia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    van Westen, Danielle
    Lund Univ, Clin Sci Lund, Diagnost Radiol, Lund, Sweden..
    Lätt, Jimmy
    Skane Univ Healthcare, Dept Imaging & Funct, Lund, Sweden..
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Diffusion kurtosis imaging of gliomas grades II and III: a study of perilesional tumor infiltration, tumor grades and subtypes at clinical presentation2017In: Radiology and Oncology, ISSN 1318-2099, E-ISSN 1581-3207, Vol. 51, no 2, p. 121-129Article in journal (Refereed)
    Abstract [en]

    Background. Diffusion kurtosis imaging (DKI) allows for assessment of diffusion influenced by microcellular structures. We analyzed DKI in suspected low-grade gliomas prior to histopathological diagnosis. The aim was to investigate if diffusion parameters in the perilesional normal-appearing white matter (NAWM) differed from contralesional white matter, and to investigate differences between glioma malignancy grades II and III and glioma subtypes (astrocytomas and oligodendrogliomas).

    Patients and methods. Forty-eight patients with suspected low-grade glioma were prospectively recruited to this institutional review board-approved study and investigated with preoperative DKI at 3T after written informed consent. Patients with histologically proven glioma grades II or III were further analyzed (n=35). Regions of interest (ROIs) were delineated on T2FLAIR images and co-registered to diffusion MRI parameter maps. Mean DKI data were compared between perilesional and contralesional NAWM (student's t-test for dependent samples, Wilcoxon matched pairs test). Histogram DKI data were compared between glioma types and glioma grades (multiple comparisons of mean ranks for all groups). The discriminating potential for DKI in assessing glioma type and grade was assessed with receiver operating characteristics (ROC) curves.

    Results. There were significant differences in all mean DKI variables between perilesional and contralesional NAWM (p=< 0.000), except for axial kurtosis (p=0.099). Forty-four histogram variables differed significantly between glioma grades II (n=23) and III (n=12) (p=0.003-0.048) and 10 variables differed significantly between ACs (n=18) and ODs (n=17) (p=0.011-0.050). ROC curves of the best discriminating variables had an area under the curve (AUC) of 0.657-0.815.

    Conclusions. Mean DKI variables in perilesional NAWM differ significantly from contralesional NAWM, suggesting altered microstructure by tumor infiltration not depicted on morphological MRI. Histogram analysis of DKI data identifies differences between glioma grades and subtypes.

  • 28.
    Falk Delgado, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Nilsson, Markus
    Latini, Francesco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Mårtensson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Berntsson, Shala G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lätt, Jimmy
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Preoperative Quantitative MR Tractography Compared with Visual Tract Evaluation in Patients with Neuropathologically Confirmed Gliomas Grades II and III: A Prospective Cohort Study2016In: Radiology Research and Practice, ISSN 2090-1941, E-ISSN 2090-195X, article id 7671854Article in journal (Refereed)
    Abstract [en]

    Background and Purpose. Low-grade gliomas show infiltrative growth in white matter tracts. Diffusion tensor tractography can noninvasively assess white matter tracts. The aim was to preoperatively assess tumor growth in white matter tracts using quantitative MR tractography (3T). The hypothesis was that suspected infiltrated tracts would have altered diffusional properties in infiltrated tract segments compared to noninfiltrated tracts. Materials and Methods. Forty-eight patients with suspected low-grade glioma were included after written informed consent and underwent preoperative diffusion tensor imaging in this prospective review-board approved study. Major white matter tracts in both hemispheres were tracked, segmented, and visually assessed for tumor involvement in thirty-four patients with gliomas grade II or III (astrocytomas or oligodendrogliomas) on postoperative neuropathological evaluation. Relative fractional anisotropy (rFA) and mean diffusivity (rMD) in tract segments were calculated and compared with visual evaluation and neuropathological diagnosis. Results. Tract segment infiltration on visual evaluation was associated with a lower rFA and high rMD in a majority of evaluated tract segments (89% and 78%, resp.). Grade II and grade III gliomas had similar infiltrating behavior. Conclusion. Quantitative MR tractography corresponds to visual evaluation of suspected tract infiltration. It may be useful for an objective preoperative evaluation of tract segment involvement.

  • 29.
    Flygt, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Gumucio, Astrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala Univ, Dept Publ Hlth & Caring Sci, Geriatr, Uppsala, Sweden..
    Skoglund, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Holm, Jonatan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Human Traumatic Brain Injury Results in Oligodendrocyte Death and Increases the Number of Oligodendrocyte Progenitor Cells2016In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 75, no 6, p. 503-515Article in journal (Refereed)
    Abstract [en]

    Oligodendrocyte (OL) death may contribute to white matter pathology, a common cause of network dysfunction and persistent cognitive problems in patients with traumatic brain injury (TBI). Oligodendrocyte progenitor cells (OPCs) persist throughout the adult CNS and may replace dead OLs. OL death and OPCs were analyzed by immunohistochemistry of human brain tissue samples, surgically removed due to life-threatening contusions and/or focal brain swelling at 60.6 +/- 75 hours (range 4-192 hours) postinjury in 10 severe TBI patients (age 51.7 +/- 18.5 years). Control brain tissue was obtained postmortem from 5 age-matched patients without CNS disorders. TUNEL and CC1 co-labeling was used to analyze apoptotic OLs, which were increased in injured brain tissue (p < 0.05), without correlation with time from injury until surgery. The OPC markers Olig2, A2B5, NG2, and PDGFR-alpha were used. In contrast to the number of single-labeled Olig2, A2B5, NG2, and PDGFR-alpha-positive cells, numbers of Olig2 and A2B5 co-labeled cells were increased in TBI samples (p < 0.05); this was inversely correlated with time from injury to surgery (r = -0.8, p < 0.05). These results indicate that severe focal human TBI results in OL death and increases in OPCs postinjury, which may influence white matter function following TBI.

  • 30. Gallagher, Michael D.
    et al.
    Suh, Eunran
    Grossman, Murray
    Elman, Lauren
    McCluskey, Leo
    Van Swieten, John C.
    Al-Sarraj, Safa
    Neumann, Manuela
    Gelpi, Ellen
    Ghetti, Bernardino
    Rohrer, Jonathan D.
    Halliday, Glenda
    Van Broeckhoven, Christine
    Seilhean, Danielle
    Shaw, Pamela J.
    Frosch, Matthew P.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Antonell, Anna
    Bogdanovic, Nenad
    Brooks, William
    Cairns, Nigel J.
    Cooper-Knock, Johnathan
    Cotman, Carl
    Cras, Patrick
    Cruts, Marc
    De Deyn, Peter P.
    DeCarli, Charles
    Dobson-Stone, Carol
    Engelborghs, Sebastiaan
    Fox, Nick
    Galasko, Douglas
    Gearing, Marla
    Gijselinck, Ilse
    Grafman, Jordan
    Hartikainen, Paivi
    Hatanpaa, Kimmo J.
    Highley, J. Robin
    Hodges, John
    Hulette, Christine
    Ince, Paul G.
    Jin, Lee-Way
    Kirby, Janine
    Kofler, Julia
    Kril, Jillian
    Kwok, John B. J.
    Levey, Allan
    Lieberman, Andrew
    Llado, Albert
    Martin, Jean-Jacques
    Masliah, Eliezer
    McDermott, Christopher J.
    McKee, Ann
    McLean, Catriona
    Mead, Simon
    Miller, Carol A.
    Miller, Josh
    Munoz, David G.
    Murrell, Jill
    Paulson, Henry
    Piguet, Olivier
    Rossor, Martin
    Sanchez-Valle, Raquel
    Sano, Mary
    Schneider, Julie
    Silbert, Lisa C.
    Spina, Salvatore
    van der Zee, Julie
    Van Langenhove, Tim
    Warren, Jason
    Wharton, Stephen B.
    White, Charles L., III
    Woltjer, Randall L.
    Trojanowski, John Q.
    Lee, Virginia M. Y.
    Van Deerlin, Vivianna
    Chen-Plotkin, Alice S.
    TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions2014In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 127, no 3, p. 407-418Article in journal (Refereed)
    Abstract [en]

    Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.

  • 31. Giaccone, Giorgio
    et al.
    Arzberger, Thomas
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Al-Sarraj, Safa
    Budka, Herbert
    Duyckaerts, Charles
    Falkai, Peter
    Ferrer, Isidro
    Ironside, James W.
    Kovacs, Gabor G.
    Meyronet, David
    Parchi, Piero
    Patsouris, Efstratios
    Revesz, Tomas
    Riederer, Peter
    Rozemuller, Annemieke
    Schmitt, Andrea
    Winblad, Bengt
    Kretzschmar, Hans
    New lexicon and criteria for the diagnosis of Alzheimer's disease2011In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 10, no 4, p. 298-299Article in journal (Refereed)
  • 32.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Melin, Beatrice
    Umeå Univ, Dept Radiat Sci, Umeå.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Beskow, Anna H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Björ, Ove
    Umeå Univ, Dept Radiat Sci, Umeå.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Henriksson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jonsson, Håkan
    Umeå Univ, Dept Radiat Sci, Umeå.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljuslinder, Ingrid
    Umeå Univ, Dept Radiat Sci, Umeå.
    Mindus, Stephanie
    Akad Sjukhuset, Lung & Allergy Clin, Uppsala.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Riklund, Katrine
    Umeå Univ, Dept Radiat Sci, Umeå.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sandin, Fredrik
    Uppsala Univ Hosp, RCC Uppsala Örebro, Uppsala.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Solna.
    Stenling, Roger
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Stålberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Thellenberg Karlsson, Camilla
    Umeå Univ, Dept Radiat Sci, Umeå.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergh, Anders
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Palmqvist, Richard
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 33. Grünblatt, Edna
    et al.
    Monoranu, Camelia Maria
    Apfelbacher, Manuela
    Keller, Daniela
    Michel, Tanja M
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Department of Clinical Medicine, Kuopio University, Kuopio, Finland.
    Ferrer, Isidro
    Al-Saraj, Safa
    Keyvani, Kathy
    Schmitt, Andrea
    Falkai, Peter
    Schittenhelm, Jens
    McLean, Catriona
    Halliday, Glenda M
    Harper, Clive
    Deckert, Jürgen
    Roggendorf, Wolfgang
    Riederer, Peter
    Tryptophan is a marker of human postmortem brain tissue quality2009In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 110, no 5, p. 1400-1408Article in journal (Refereed)
    Abstract [en]

    Postmortem human brain tissue is widely used in neuroscience research, but use of tissue originating from different brain bank centers is considered inaccurate because of possible heterogeneity in sample quality. There is thus a need for well-characterized markers to assess the quality of postmortem brain tissue. Toward this aim, we determined tryptophan (TRP) concentrations, phosphofructokinase-1 and glutamate decarboxylase activities in 119 brain tissue samples. These neurochemical parameters were tested in samples from autopsied individuals, including control and pathological cases provided by 10 different brain bank centers. Parameters were assessed for correlation with agonal state, postmortem interval, age and gender, brain region, preservation and freezing methods, storage conditions and storage time, RNA integrity, and tissue pH value. TRP concentrations were elevated significantly (p = 0.045) with increased postmortem interval; which might indicate increased protein degradation. Therefore, TRP concentration might be one useful and convenient marker for estimating the quality of human postmortem brain tissue.

  • 34. Hanisch, Katja
    et al.
    Soininen, Hilkka
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hoffmann, Ralf
    Analysis of human tau in cerebrospinal fluid2010In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 9, no 3, p. 1476-1482Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease (AD) is the most common form of dementia. Neuropathologically, it is characterized by two major hallmarks: neurofibrillary tangles (NFT) formed from hyperphosphorylated versions of the tau-protein, and neuritic plaques (NP) containing mostly beta-amyloid peptides (A beta) that are formed from the amyloid precursor protein (APP) by enzymatic cleavage. Despite much progress in recent years, the causes of sporadic (i.e., nonfamiliar) AD are still unclear and its valid diagnosis still relies on autopsy. Clinically used biomarkers present in cerebrospinal fluid (CSF), that is, unphosphorylated or phosphorylated tau and A beta-peptides of different lengths, lack the necessary specificity and sensitivity. Here, we describe a novel strategy to characterize tau versions present in CSF with respect to their molecular mass and isoelectric point. Aliquots of 1 mL CSF (i.e., 700 to 1300 pg tau) from nondemented persons and histopathologically confirmed AD cases were depleted for six dominant proteins, separated by two-dimensional gel electrophoresis, and then electro-transferred onto PVDF-membranes. Tau was detected with monoclonal antibody (mAb) HT7 conjugated with horseradish peroxidase (HRP). In this way, a complex tau pattern was identified in CSF that was very similar to the tau preparations from autopsy brain samples. The presented strategy enables the analysis of the phosphorylation and processing status of tau in CSF samples from healthy people and patients diagnosed with different neurological disorders. This more-detailed information on circulating tau versions and their clearance rates may facilitate the development of new diagnostic tools.

  • 35. Hartikainen, Päivi H
    et al.
    Pikkarainen, Maria
    Hänninen, Tuomo
    Soininen, Hilkka
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Unusual clinical presentation and neuropathology in two subjects with fused-in sarcoma (FUS) positive inclusions2012In: Neuropathology (Kyoto. 1993), ISSN 0919-6544, E-ISSN 1440-1789, Vol. 32, no 1, p. 60-68Article in journal (Refereed)
    Abstract [en]

    We report two unusual autopsy cases with frontotemporal lobar degeneration (FTLD) that were hyperphosphorylated-tau- and TAR DNA binding protein 43 (TDP-43)- negative. The behavioral symptoms in both cases were compatible with frontotemporal dementia, but they exhibited more prominent speech and language related symptoms than previously reported. Moreover, they displayed a short duration of the disease; the male case had a disease onset age of 45 years, and duration of 5 years, and the female case suffered even shorter disease duration and a later onset of the symptoms, at the age of 67 years. Moreover, the motor functions had deteriorated in different ways in these cases. The male patient showed progressive motor symptoms, weakness of extremities and bulbar muscles suggesting motor neuron disease with a muscle biopsy supporting neurogenic deficits, whereas the female patient exhibited dyskinesias and tremor with progressive swallowing disorders. The father of the male case displayed dementia of similar type at the age of 68 years. In both cases, neuropathological examination showed fused-in sarcoma (FUS)-positive pathology. The male patient had intensely FUS-positive cytoplasmic and intranuclear inclusions that resembled the characteristics previously reported in FTLD FUS, whereas the female patient did not exhibit any cytoplasmic inclusions but had roundish, dense FUS-positive intranuclear inclusions. She also displayed a plethora of other pathologies including α-synuclein, hyperphosphorylated-tau, β-amyloid aggregation and some neuronal polyglutamine aggregation (1C2) but no well-demarcated inclusions were observed. We conclude that clinical phenotypes of FUS pathologies also include elderly patients and are more variable with motor and speech disorders than previously reported.

  • 36. Herukka, Sanna-Kaisa
    et al.
    Rummukainen, Jaana
    Ihalainen, Jouni
    Fraunberg, Mikael von und Zu
    Koivisto, Anne M.
    Nerg, Ossi
    Puli, Lakshman K.
    Seppala, Toni T.
    Zetterberg, Henrik
    Pyykko, Okko T.
    Helisalmi, Seppo
    Tanila, Heikki
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hiltunen, Mikko
    Rinne, Jaakko
    Soininen, Hilkka
    Jaaskelainen, Juha E.
    Leinonen, Ville
    Amyloid-beta and Tau Dynamics in Human Brain Interstitial Fluid in Patients with Suspected Normal Pressure Hydrocephalus2015In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 46, no 1, p. 261-269Article in journal (Refereed)
    Abstract [en]

    Background: Amyloid-beta (A beta(1-42)), total tau (T-tau), and phosphorylated tau (P-tau(181)) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer's disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble A beta decreases with increasing age and advanced A beta pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. A beta(1-42) and P-tau(181) remained stable during the experiment (n = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while A beta(1-42) levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r = 0.70, p = 0.017) and P-tau(181) (r = 0.64, p = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF A beta(1-42) levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF A beta and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease.

  • 37.
    Hopp, Sarah
    et al.
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany.;Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Albert-Weissenberger, Christiane
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany.;Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Mencl, Stine
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany..
    Bieber, Michael
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany.;Univ Hosp Wurzburg, Comprehens Heart Failure Ctr DZHI, D-97080 Wurzburg, Germany..
    Schuhmann, Michael K.
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany..
    Stetter, Christian
    Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Nieswandt, Bernhard
    Univ Wurzburg, Rudolf Virchow Ctr, German Res Soc, Res Ctr Expt Biomed, D-97070 Wurzburg, Germany..
    Schmidt, Peter M.
    CSL Ltd, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic, Australia..
    Monoranu, Camelia-Maria
    Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Inst Pathol, Dept Neuropathol, D-97070 Wurzburg, Germany..
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Nolte, Marc W.
    CSL Behring, Marburg, Germany..
    Siren, Anna-Leena
    Univ Hosp Wurzburg, Dept Neurosurg, D-97080 Wurzburg, Germany..
    Kleinschnitz, Christoph
    Univ Hosp Wurzburg, Dept Neurol, Josef Schneider Str 11, D-97080 Wurzburg, Germany..
    Targeting Coagulation Factor XII as a Novel Therapeutic Option in Brain Trauma2016In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 79, no 6, p. 970-982Article in journal (Refereed)
    Abstract [en]

    Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.

    Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.

    Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.

    Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.

  • 38. Jellinger, Kurt A.
    et al.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Attems, Johannes
    Beach, Thomas G.
    Cairns, Nigel J.
    Crary, John F.
    Dickson, Dennis W.
    Hof, Patrick R.
    Hyman, Bradley T.
    Jack, Clifford R., Jr.
    Jicha, Gregory A.
    Knopman, David S.
    Kovacs, Gabor G.
    Mackenzie, Ian R.
    Masliah, Eliezer
    Montine, Thomas J.
    Nelson, Peter T.
    Schmitt, Frederick
    Schneider, Julie A.
    Serrano-Pozo, Albert
    Thal, Dietmar R.
    Toledo, Jonathan B.
    Trojanowski, John Q.
    Troncoso, Juan C.
    Vonsattel, Jean Paul
    Wisniewski, Thomas
    PART, a distinct tauopathy, different from classical sporadic Alzheimer disease2015In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 129, no 5, p. 757-762Article in journal (Refereed)
  • 39.
    Jiang, Yiwen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Marinescu, Voichita Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Xie, Yuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Maturi, Naga Prathyusha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Olofsson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindberg, Nanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olofsson, Tommie
    Natl Board Forens Med, Dept Forens Med, Box 1024, S-75140 Uppsala, Sweden..
    Leijonmarck, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin2017In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, no 4, p. 977-990Article in journal (Refereed)
    Abstract [en]

    The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

  • 40. Jutila, Leena
    et al.
    Aikia, Marja
    Immonen, Arto
    Mervaala, Esa
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Kalviainen, Reetta
    Long-term memory performance after surgical treatment of unilateral temporal lobe epilepsy (TLE)2014In: Epilepsy Research, ISSN 0920-1211, E-ISSN 1872-6844, Vol. 108, no 7, p. 1228-1237Article in journal (Refereed)
    Abstract [en]

    Long-term cognitive and memory performance after surgical treatment of unilateral temporal lobe epilepsy (TLE) was investigated in a series of 98 patients. Neuropsychological evaluation was performed preoperatively and after one and three years postoperatively. Fifty-eight patients (59%) became seizure-free (Engel's class I). Verbal learning and memory declined in long-term follow-up in both left and right TLE groups. Visual memory remained stable. Ongoing postoperative seizures were related to decline in the immediate recall of logical prose, and postoperative seizure-freedom to improvement in verbal fluency in patients with left TLE. There was significant variability in the individual postoperative long-term memory performance. Left side of surgery, better baseline performance and older age at surgery were identified as risk factors for individual decline in delayed verbal memory. Selected patients undergoing surgery for drug-resistant TLE are at risk for significant postoperative memory decline especially after left temporal lobe surgery. Preoperative counseling and long-term follow-up of cognitive performance in individual patients is recommended. Additionally, more accurate predictors of individual postoperative memory performance would be needed.

  • 41. Karamanakos, Petros N.
    et al.
    Jaaskelainen, Juha E.
    Alafuzoff, Irina
    Department of Clinical Pathology, University Hospital, Kuopio, Finland.
    Pirinen, Elina
    Vanninen, Ritva
    Silvennoinen, Sanna
    Sankilampi, Ulla
    Immonen, Arto
    Malignant giant cell tumor in the posterior fossa of a neonate: case report2010In: Journal of Neurosurgery: Pediatrics, ISSN 1933-0707, E-ISSN 1933-0715, Vol. 5, no 3, p. 277-282Article in journal (Refereed)
    Abstract [en]

    Giant cell tumors (GCTs) of the bone are rare, usually benign but locally aggressive neoplasms that primarily occur in the epiphyses of long bones. They seldom develop in the cranium; when they do, they involve principally the sphenoid and temporal bones. These tumors usually affect young adults, and few reports in children have been published. Primary malignant GCTs of the skull are even more uncommon. The 3 published cases all involved adults over 40 years of age. Herein, the authors present a case of a highly aggressive primary malignant GCT of the posterior fossa in a 5-week old preterm infant. One month after the gross-total resection of the tumor found in the bone, the infant's condition rapidly deteriorated and she died. Magnetic resonance imaging and postmortem examination revealed a tumor larger than it had been before the operation, with expansion toward the brain. To the best of the authors' knowledge, this is the youngest patient reported with a primary malignant GCT of the skull, and actually the first case in a pediatric patient. In addition, the extremely high growth rate of the tumor in the postoperative period renders this case the most aggressive primary malignant GCT of the cranium described so far.

  • 42. Koivisto, Anne M
    et al.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Savolainen, Sakari
    Sutela, Anna
    Rummukainen, Jaana
    Kurki, Mitja
    Jääskeläinen, Juha E
    Soininen, Hilkka
    Rinne, Jaakko
    Leinonen, Ville
    Poor Cognitive Outcome in Shunt-Responsive Idiopathic Normal Pressure Hydrocephalus2013In: Neurosurgery, ISSN 0148-396X, E-ISSN 1524-4040, Vol. 72, no 1, p. 1-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:: Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive decline that can be alleviated by shunting, but long-term outcome studies are scarce. OBJECTIVE:: To elucidate the long-term cognitive condition of shunt-responsive iNPH patients. METHODS:: The follow-up data (Kuopio University Hospital NPH Registry) of 146 patients diagnosed with iNPH by clinical and radiological examination, 24-hour intraventricular pressure monitoring, frontal cortical biopsy, and response to the shunt were analyzed for signs of dementia. The Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, and specified memory disorder criteria were used. Median follow-up was 4.8 years. RESULTS:: At the end of follow-up, 117 (80%) of the 146 iNPH patients had cognitive decline and 67 (46%) had clinical dementia. The most common clinical diagnoses were Alzheimer disease and vascular dementia. In multivariate analysis of the 146 iNPH patients, memory deficit as a first symptom before shunt (odds ratio [OR] 18.3; 95% confidence interval [CI] 1.9-175), male sex (OR 3.29; 95% CI 1.11-9.73), age (OR 1.17 year; 95% CI 1.07-1.28), and follow-up time (OR 1.20 year; 95% CI 1.02-1.40) predicted dementia. Interestingly, 8 (5%) iNPH patients had dementia without any signs of other neurodegenerative diseases in clinical, neuroradiological, or brain biopsy evaluation. These patients initially presented a full triad of symptoms, with gait disturbance being the most frequent initial symptom followed by deterioration in cognition. CONCLUSION:: The novel findings were (a) a significant risk of dementia in iNPH initially responsive to cerebrospinal fluid shunt, (b) cognitive impairment most commonly due to iNPH-related dementia followed by concurrent degenerative brain disease, and (c) a subgroup with dementia related to iNPH without comorbidities. ABBREVIATIONS:: Aβ, amyloid betaAD, Alzheimer diseaseCI, confidence intervalHPτ, hyperphosphorylated tauICP, intracranial pressureiNPH, idiopathic normal pressure hydrocephalusKUH, Kuopio University HospitalNPH, normal pressure hydrocephalusVaD, vascular dementia.

  • 43.
    Koivisto, Anne M.
    et al.
    Univ Eastern Finland, Inst Clin Med, Neurol Unit, Kuopio, Finland.;Kuopio Univ Hosp, Neurol NeuroCtr, SF-70210 Kuopio, Finland..
    Kurki, Mitja I.
    Kuopio Univ Hosp, Neurosurg NeuroCtr, SF-70210 Kuopio, Finland..
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sutela, Anna
    Kuopio Univ Hosp, Dept Radiol, SF-70210 Kuopio, Finland..
    Rurnmukainen, Jaana
    Kuopio Univ Hosp, Dept Pathol, SF-70210 Kuopio, Finland..
    Savolainen, Sakari
    Kuopio Univ Hosp, Neurosurg NeuroCtr, SF-70210 Kuopio, Finland..
    Vanninen, Ritva
    Kuopio Univ Hosp, Dept Radiol, SF-70210 Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Unit Clin Radiol, Kuopio, Finland..
    Jaaskelainen, Juha E.
    Kuopio Univ Hosp, Neurosurg NeuroCtr, SF-70210 Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Unit Neurosurg, Kuopio, Finland..
    Soininen, Hilkka
    Univ Eastern Finland, Inst Clin Med, Neurol Unit, Kuopio, Finland.;Kuopio Univ Hosp, Neurol NeuroCtr, SF-70210 Kuopio, Finland..
    Leinonen, Ville
    Kuopio Univ Hosp, Neurosurg NeuroCtr, SF-70210 Kuopio, Finland.;Univ Eastern Finland, Inst Clin Med, Unit Neurosurg, Kuopio, Finland..
    High Risk of Dementia in Ventricular Enlargement with Normal Pressure Hydrocephalus Related Symptoms2016In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 52, no 2, p. 497-507Article in journal (Refereed)
    Abstract [en]

    Background: Differential diagnosis of ventricular enlargement with normal pressure hydrocephalus (NPH) related symptoms is challenging. Patients with enlarged ventricles often manifest cognitive deterioration but their long-term outcome is not well known. Objectives: We aim to evaluate long-term cognitive outcome in patients with enlarged ventricles and clinically suspected NPH. Methods: A neurologist and a neurosurgeon clinically evaluated 468 patients with enlarged ventricles and suspected NPH using radiological methods, intraventricular pressure monitoring, and frontal cortical brain biopsy. The neurologist confirmed final diagnoses after a median follow-up interval of 4.8 years. Results: Altogether, 232 patients (50%) with enlarged ventricles did not fulfill the criteria for shunt surgery. The incidence of dementia among patients with enlarged ventricles, and at least one NPH-related symptom with adequate follow-up data (n = 446) was high, varying from 77 (iNPH, shunt responders) to 141/1000 person-years (non-shunted patients with enlarged ventricles). At the end of the follow-up, 59% of all these patients were demented. The demented population comprised 73% of non-shunted patients with enlarged ventricles, 63% of shunted iNPH patients that did not respond to treatment, and 46% of iNPH patients that were initially responsive to shunting. The most common cause of dementia was Alzheimer's disease (n = 94, 36%), followed by vascular dementia (n= 68, 26%). Conclusions: One-half of patients with enlarged ventricles and clinically suspected NPH were not shunted after intraventricular pressure monitoring. Dementia caused by various neurodegenerative diseases was frequently seen in patients with ventricular enlargement. Thus, careful diagnostic evaluation in collaboration with neurologists and neurosurgeons is emphasized.

  • 44.
    Kok, Eloise H.
    et al.
    Univ Tampere, Dept Forens Med, Tampere 33014, Finland..
    Karppinen, Toni T.
    Univ Tampere, Dept Forens Med, Tampere 33014, Finland..
    Luoto, Teemu
    Tampere Univ Hosp, Dept Neurosci & Rehabil, Tampere, Finland..
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Univ Uppsala Hosp, Dept Pathol, Uppsala, Sweden.;Univ Eastern Finland, Inst Clin Med, Neurol Unit, Kuopio, Finland..
    Karhunen, Pekka J.
    Univ Tampere, Dept Forens Med, Tampere 33014, Finland..
    Beer Drinking Associates with Lower Burden of Amyloid Beta Aggregation in the Brain: Helsinki Sudden Death Series2016In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 40, no 7, p. 1473-1478Article in journal (Refereed)
    Abstract [en]

    BackgroundControversy surrounds the effect of alcohol consumption on the development of dementia and cognitive impairment. We investigated the association between consumption of different alcoholic beverages and -amyloid (A) aggregation in the brain, 1 of the neuropathological lesions of Alzheimer's disease. MethodsIn total, 125 males of the Helsinki Sudden Death autopsy Series were included with an age range at death 35 to 70years. The consumption of alcohol, A aggregation in the brain, and Apolipoprotein E (APOE) genotype were assessed. Relatives answered a questionnaire to gather alcohol consumption history, and A was visualized by implementing immunohistochemical staining of brain sections. A immunoreactivity (IR) was assessed in a dichotomized (yes/no) fashion and as a stained area fraction (%). APOE genotype was assessed in DNA extracted from paraffin-embedded cardiac muscle samples. ResultsIncreased age (p=0.001; odds ratio [OR]=1.09, confidence interval [CI]=1.04 to 1.15) was associated with higher prevalence of A-IR. Beer drinking decreased (p=0.024; OR=0.35, CI=0.14 to 0.87) the prevalence of A-IR and was associated with a significantly lower extent of A-IR (p=0.022). The amount of alcohol consumed was not linked with A aggregation and neither was spirit nor wine consumption. ConclusionsBeer consumption may protect against A aggregation in brain. Further studies are necessary to fully understand the effects of alcohol on A pathology seen in brain tissue.

  • 45.
    Kovacs, Gabor G
    et al.
    Institute of Neurology, Medical University of Vienna, Vienna, Austria.
    Ferrer, Isidro
    Institute of Neuropathology, Bellvitge University Hospital, University of Barcelona, Spain.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Concomitant pathologies II: neurodegenerative conditions2015In: Neuropathology of neurodegenerative diseases A practical guide / [ed] Gabor G Kovacs, Cambridge University Press, 2015, p. 292-298Chapter in book (Refereed)
    Abstract [en]

    Introduction The term “mixed or concomitant” pathologies in neurodegenerative disease means that, in addition to the hallmark lesions of a neurodegenerative disease entity, further pathological alterations can be observed in the same brain. The term mixed pathology was originally used when describing accompanying vascular pathology. Later, Lewy body pathology was also described as concomitant pathology when seen together with other neurodegenerative diseases. Currently, we classify neurodegenerative diseases according to the predominant protein that shows pathological depositions in the brain. During the diagnostic process, detecting hallmark lesions of a certain disease, like neuritic plaques in the cortex, spongiform change in the cortex, globose tangles in the brainstem nuclei or Lewy bodies in the brainstem or cortex, can lead to negligence of further lesions or performance of further stains. However, deposition of multiple proteins, in addition to co-occurrence of non-neurodegenerative pathology (e.g. vascular, metabolic), is a frequent event. In fact, overlapping neurodegeneration may be more the rule than the exception. This concept is supported by observations in genetic forms of neurodegenerative disorders where various proteins may show pathological deposits in the same brain [1–3]. Complex constellations of clinical symptoms (movement disorders and cognitive decline) may associate with the accompanying presence of diverse neurodegenerative disorders. There are several factors determining overlap between neurodegenerative disorders as proposed by Armstrong et al. [4]): (i) historical factors, which means that the original descriptions of key disorders were based on the descriptions of relatively small numbers of cases; furthermore, the original investigators interpreted these as ‘syndromes’ rather than distinct diseases; (ii) disease heterogeneity; (iii) age-related changes;(iv) apolipoprotein ɛ genotype, especially in cases with significant Aβ deposition but without further features of Alzheimer’s disease (AD); (v) co-occurrence of common diseases, like AD and Parkinson’s disease (PD), as both are more likely to occur in the elderly and thus are more likely to co-occur.

  • 46. Kovacs, Gabor G.
    et al.
    Ferrer, Isidro
    Univ Barcelona, Bellvitge Univ Hosp, Hosp Llobregat, Inst Neuropathol, Barcelona, Spain.;Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA..
    Grinberg, Lea T.
    Univ Sao Paulo, Sch Med, Dept Pathol, Sao Paulo, Brazil..
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Attems, Johannes
    Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Budka, Herbert
    Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland..
    Cairns, Nigel J.
    Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA..
    Crary, John F.
    Icahn Sch Med Mt Sinai, Friedman Brain Inst, Dept Pathol, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, New York, NY 10029 USA..
    Duyckaerts, Charles
    Univ Paris 04, UPMC, Hop La Salpetriere, AP HP,Neuropathol Dept, Paris, France..
    Ghetti, Bernardino
    Indiana Univ, Sch Med, Dept Pathol & Lab Med, Indianapolis, IN 46204 USA..
    Halliday, Glenda M.
    GMH Neurosci Res Australia, Sydney, NSW, Australia.;Univ New S Wales, Sydney, NSW, Australia..
    Ironside, James W.
    Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Love, Seth
    Univ Bristol, Southmead Hosp, Inst Clin Neurosci, Bristol, Avon, England..
    Mackenzie, Ian R.
    Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada..
    Munoz, David G.
    St Michaels Hosp, Div Pathol, Toronto, ON M5B 1W8, Canada..
    Murray, Melissa E.
    Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA..
    Nelson, Peter T.
    Univ Kentucky, Dept Pathol, Lexington, KY 40536 USA.;Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA..
    Takahashi, Hitoshi
    Niigata Univ, Dept Pathol, Brain Res Inst, Niigata 9518585, Japan..
    Trojanowski, John Q.
    Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res,Inst Aging, Philadelphia, PA 19104 USA..
    Ansorge, Olaf
    John Radcliffe Hosp, Dept Neuropathol, Oxford OX3 9DU, England..
    Arzberger, Thomas
    Univ Munich, Dept Psychiat & Psychotherapy, Ctr Neuropathol & Prion Res, Munich, Germany..
    Baborie, Atik
    Walton Ctr, Dept Neuropathol, Liverpool, Merseyside, England..
    Beach, Thomas G.
    Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ 85351 USA..
    Bieniek, Kevin F.
    Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA..
    Bigio, Eileen H.
    Northwestern Univ, Feinberg Sch Med, Northwestern ADC Neuropathol Core, Chicago, IL 60611 USA..
    Bodi, Istvan
    Kings Coll Hosp London, London Neurodegenerat Brain Bank, Clin Neuropathol, London, England..
    Dugger, Brittany N.
    Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ 85351 USA.;Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA..
    Feany, Mel
    Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA USA..
    Gelpi, Ellen
    Biobank Hosp Clin IDIBAPS, Inst Invest Biomed August Pi & Sunyer, Neurol Tissue Bank, Barcelona, Spain..
    Gentleman, Stephen M.
    Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England..
    Giaccone, Giorgio
    IRCCS Fdn Carlo Besta Neurol Inst, Milan, Italy..
    Hatanpaa, Kimmo J.
    Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA..
    Heale, Richard
    Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England..
    Hof, Patrick R.
    Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Friedman Brain Inst, Fishberg Dept Neurosci, New York, NY 10029 USA..
    Hofer, Monika
    John Radcliffe Hosp, Dept Neuropathol, Oxford OX3 9DU, England..
    Hortobagyi, Tibor
    Univ Debrecen, Fac Med, Inst Pathol, Dept Neuropathol, H-4032 Debrecen, Hungary..
    Jellinger, Kurt
    Inst Clin Neurobiol, A-1150 Vienna, Austria..
    Jicha, Gregory A.
    Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA.;Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA..
    Ince, Paul
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England..
    Kofler, Julia
    Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA..
    Koevari, Enikoe
    Univ Hosp, Dept Mental Hlth & Psychiat, Geneva, Switzerland.;Univ Geneva, Sch Med, Geneva, Switzerland..
    Kril, Jillian J.
    Univ Sydney, Sydney Med Sch, Discipline Pathol, Sydney, NSW 2006, Australia..
    Mann, David M.
    Univ Manchester, Fac Med & Hlth Sci, Inst Brain Behav & Mental Hlth, Manchester, Lancs, England..
    Matej, Radoslav
    Thomayer Hosp, Dept Pathol & Mol Med, Prague 4, Czech Republic..
    McKee, Ann C.
    Boston Univ, Sch Med & VA Healthcare Syst, Dept Neurol & Pathol, Boston, MA 02118 USA..
    McLean, Catriona
    Alfred Hosp, Dept Anat Pathol, Prahran, Vic 3004, Australia..
    Milenkovic, Ivan
    Med Univ Vienna, Neurol, A-1097 Vienna, Austria.;Med Univ Vienna, Dept Neurol, Vienna, Austria..
    Montine, Thomas J.
    Univ Washington, Dept Pathol, Seattle, WA 98195 USA..
    Murayama, Shigeo
    Tokyo Metropolitan Geriatr Hosp, Dept Neuropathol, Brain Bank Aging Res, Tokyo 173, Japan.;Inst Gerontol, Tokyo, Japan..
    Lee, Edward B.
    Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res,Inst Aging, Philadelphia, PA 19104 USA..
    Rahimi, Jasmin
    Med Univ Vienna, Neurol, A-1097 Vienna, Austria..
    Rodriguez, Roberta D.
    Univ Sao Paulo, Sch Med, Brazilian Aging Brain Study Grp LIM22, Physiopathol Aging Lab, Sao Paulo, Brazil..
    Rozemuller, Annemieke
    Vrije Univ Amsterdam, Med Ctr, Netherlands Brainbank, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Med Ctr, Dept Pathol, Amsterdam, Netherlands..
    Schneider, Julie A.
    Rush Univ, Med Ctr, Dept Pathol, Chicago, IL 60612 USA.;Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA..
    Schultz, Christian
    Heidelberg Univ, Ctr Biomed & Med Technol Mannheim, Inst Neuroanat, Heidelberg, Germany.;Heidelberg Univ, Med Fac Mannheim, Heidelberg, Germany..
    Seeley, William
    Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94143 USA..
    Seilhean, Danielle
    Univ Paris 04, UPMC, Hop La Salpetriere, AP HP,Neuropathol Dept, Paris, France..
    Smith, Colin
    Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Tagliavini, Fabrizio
    IRCCS Fdn Carlo Besta Neurol Inst, Milan, Italy..
    Takao, Masaki
    Saitama Med Univ, Int Med Ctr, Dept Neurol, Saitama, Japan..
    Thal, Dietmar Rudolf
    Univ Ulm, Inst Pathol, Neuropathol Lab, D-89081 Ulm, Germany.;Katholieke Univ Leuven, Dept Neurosci, B-3000 Louvain, Belgium..
    Toledo, Jon B.
    Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Ctr Neurodegenerat Dis Res,Inst Aging, Philadelphia, PA 19104 USA..
    Tolnay, Markus
    Univ Basel Hosp, Inst Pathol, CH-4031 Basel, Switzerland..
    Troncoso, Juan C.
    Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA..
    Vinters, Harry V.
    Univ Calif Los Angeles, Med Ctr, Brain Res Inst, Sect Neuropathol,Dept Pathol & Lab Med, Los Angeles, CA 90024 USA.;Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA.;Univ Calif Los Angeles, Med Ctr, Brain Res Inst, Dept Neurol, Los Angeles, CA 90095 USA..
    Weis, Serge
    Johannes Kepler Univ Linz, Kepler Univ Hosp, Sch Med, Dept Pathol & Neuropathol,Lab Neuropathol, A-4040 Linz, Austria..
    Wharton, Stephen B.
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England..
    White, Charles L., III
    Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA..
    Wisniewski, Thomas
    NYU, Sch Med, Dept Neurol, Ctr Cognit Neurol, New York, NY 10016 USA.;NYU, Sch Med, Dept Pathol, Ctr Cognit Neurol, New York, NY 10016 USA.;NYU, Sch Med, Dept Psychiat, Ctr Cognit Neurol, New York, NY 10016 USA..
    Woulfe, John M.
    Univ Ottawa, Ottawa Hosp, Res Inst, Dept Pathol & Lab Med,Ctr Canc Therapeut, Ottawa, ON, Canada..
    Yamada, Masahito
    Kanazawa Univ, Grad Sch Med Sci, Dept Neurol & Neurobiol Aging, Kanazawa, Ishikawa, Japan..
    Dickson, Dennis W.
    Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA..
    Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy2016In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 131, no 1, p. 87-102Article in journal (Refereed)
    Abstract [en]

    Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.

  • 47. Kovacs, Gabor G
    et al.
    Rozemuller, Annemieke J M
    van Swieten, John C
    Gelpi, Ellen
    Majtenyi, Katalin
    Al-Sarraj, Safa
    Troakes, Claire
    Bódi, István
    King, Andrew
    Hortobágyi, Tibor
    Esiri, Margaret M
    Ansorge, Olaf
    Giaccone, Giorgio
    Ferrer, Isidre
    Arzberger, Thomas
    Bogdanovic, Nenad
    Nilsson, Tatjana
    Leisser, Irene
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Ironside, James W
    Kretzschmar, Hans
    Budka, Herbert
    Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: A study of the BrainNet Europe Consortium2013In: Neuropathology and Applied Neurobiology, ISSN 0305-1846, E-ISSN 1365-2990, Vol. 39, no 2, p. 166-178Article in journal (Refereed)
    Abstract [en]

    Aims: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurons. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. Methods: We evaluated immunoreactivity for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. Results: Mean age at death was 68.2 years (range 49 to 96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of FTD, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein immunoreactivity was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurons. Aβ immunoreactivity was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. Conclusions: 1) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; 2) even minor deviation from these morphological criteria suggests a different disorder; and 3) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.

  • 48. Kovacs, Gabor G.
    et al.
    Wagner, Uta
    Dumont, Benoit
    Pikkarainen, Maria
    Osman, Awad A.
    Streichenberger, Nathalie
    Leisser, Irene
    Verchère, Jérémy
    Baron, Thierry
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Budka, Herbert
    Perret-Liaudet, Armand
    Lachmann, Ingolf
    An antibody with high reactivity for disease-associated α-synuclein reveals extensive brain pathology2012In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 124, no 1, p. 37-50Article in journal (Refereed)
    Abstract [en]

    α-Synuclein is the major protein associated with Lewy body dementia, Parkinson's disease and multiple system atrophy. Since α-synuclein is present in the brain in physiological conditions as a presynaptic protein, it is crucial to characterize disease-associated modifications to develop an in vivo biomarker. With the aim to develop antibodies showing high specificity and sensitivity for disease-associated α-synuclein, synthetic peptides containing different amino acid sequences were used for immunization of mice. After generation of α-synuclein aggregates, ELISA and immunoblotting were used to test the specificity of antibodies. Tissue microarray sections originating from different human α-synucleinopathies were used to compare immunostaining with other, commercially available antibodies. Immunization of mice with the peptide TKEGVVHGVATVAE (amino acid 44-57 of α-synuclein) resulted in the generation of a monoclonal antibody (5G4), which was able to bind aggregated α-synuclein preparation in sandwich ELISA or coated on magnetic beads. 5G4 proved to be superior to other antibodies in comparative immunohistochemical studies by revealing more widespread and distinct α-synuclein pathology. Immunoblotting of human brain tissue revealed an additional band seen in dementia with Lewy bodies, whereas the band representing monomeric α-synuclein was very weak or lacking. In summary, the 5G4 antibody is most promising for re-evaluation of archival material and may offer new perspective for the development of in vivo diagnostic assays for detecting disease-associated α-synuclein in body fluids.

  • 49.
    Kovacs, Gabor G.
    et al.
    Med Univ Vienna, Inst Neurol, AKH 4J,Wahringer Gurtel 18-20, A-1097 Vienna, Austria.;Univ Penn, Ctr Neurodegenerat Dis Res, Inst Aging, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA..
    Xie, Sharon X.
    Univ Penn, Dept Biostat & Epidemiol, Ctr Brain Injury & Repair, Philadelphia, PA 19104 USA..
    Lee, Edward B.
    Univ Penn, Ctr Neurodegenerat Dis Res, Inst Aging, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA..
    Robinson, John L.
    Univ Penn, Ctr Neurodegenerat Dis Res, Inst Aging, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA..
    Caswell, Carrie
    Univ Penn, Dept Biostat & Epidemiol, Ctr Brain Injury & Repair, Philadelphia, PA 19104 USA..
    Irwin, David J.
    Univ Penn, Ctr Neurodegenerat Dis Res, Inst Aging, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA..
    Toledo, Jon B.
    Univ Penn, Ctr Neurodegenerat Dis Res, Inst Aging, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA..
    Johnson, Victoria E.
    Univ Penn, Dept Neurosurg, Ctr Brain Injury & Repair, Philadelphia, PA 19104 USA..
    Smith, Douglas H.
    Univ Penn, Dept Neurosurg, Ctr Brain Injury & Repair, Philadelphia, PA 19104 USA..
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Attems, Johannes
    Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne, Tyne & Wear, England..
    Bencze, Janos
    Univ Debrecen, Dept Neuropathol, Inst Pathol, Fac Med, Debrecen, Hungary..
    Bieniek, Kevin F.
    Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA..
    Bigio, Eileen H.
    Northwestern Univ, Feinberg Sch Med, Northwestern ADC Neuropathol Core, Chicago, IL 60611 USA..
    Bodi, Istvan
    Kings Coll Hosp London, Clin Neuropathol, London, England.;London Neurodegenerat Brain Bank, London, England..
    Budka, Herbert
    Med Univ Vienna, Inst Neurol, AKH 4J,Wahringer Gurtel 18-20, A-1097 Vienna, Austria.;Univ Hosp Zurich, Inst Neuropathol, Zurich, Switzerland..
    Dickson, Dennis W.
    Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA..
    Dugger, Brittany N.
    Univ Calif San Francisco, Inst Neurodegenerat Dis, San Francisco, CA 94143 USA..
    Duyckaerts, Charles
    UPMC Sorbonne Univ, Dept Neuropathol, Hop La Salpetriere, AP HP, Paris, France..
    Ferrer, Isidro
    Univ Barcelona, Inst Neuropathol, Bellvitge Univ Hosp, CIBERNED, Barcelona, Spain..
    Forrest, Shelley L.
    Univ Sydney, Sydney Med Sch, Discipline Pathol, Sydney, NSW, Australia..
    Gelpi, Ellen
    Inst Invest Biomed Pi &, Neurol Tissue Bank, Biobank Hosp Clin IDIBAPS, Barcelona, Spain..
    Gentleman, Stephen M.
    Imperial Coll London, Dept Med, London, England..
    Giaccone, Giorgio
    IRCCS Fdn Carlo Besta Neurol Inst, Milan, Italy..
    Grinberg, Lea T.
    Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA USA.;Univ Sao Paulo, Sch Med, LIM, Dept Pathol, Sao Paulo, Brazil..
    Halliday, Glenda M.
    Univ Sydney, Brain & Mind Ctr, Sydney Med Sch, Sydney, NSW, Australia.;UNSW Med & NeuRA, Sydney, NSW, Australia..
    Hatanpaa, Kimmo J.
    Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX USA..
    Hof, Patrick R.
    Icahn Sch Med Mt Sinai, Fishberg Dept Neurosci, Friedman Brain Inst, New York, NY 10029 USA.;Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, New York, NY 10029 USA..
    Hofer, Monika
    John Radcliffe Hosp, Dept Neuropathol, Oxford, England..
    Hortobagyi, Tibor
    Univ Debrecen, Dept Neuropathol, Inst Pathol, Fac Med, Debrecen, Hungary..
    Ironside, James W.
    Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    King, Andrew
    Kings Coll Hosp London, Clin Neuropathol, London, England.;London Neurodegenerat Brain Bank, London, England..
    Kofler, Julia
    Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA..
    Kovari, Eniko
    Univ Hosp, Dept Mental Hlth & Psychiat, Geneva, Switzerland.;Univ Geneva, Sch Med, Geneva, Switzerland..
    Kril, Jillian J.
    Univ Sydney, Sydney Med Sch, Discipline Pathol, Sydney, NSW, Australia..
    Love, Seth
    Univ Bristol, Inst Clin Neurosci, Southmead Hosp, Learning & Res Level 2, Bristol, Avon, England..
    Mackenzie, Ian R.
    Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC, Canada..
    Mao, Qinwen
    Northwestern Univ, Feinberg Sch Med, Northwestern ADC Neuropathol Core, Chicago, IL 60611 USA..
    Matej, Radoslav
    Thomayer Hosp, Dept Pathol & Mol Med, Prague, Czech Republic.;Charles Univ Prague, Dept Pathol, Med Fac 1, Prague, Czech Republic..
    McLean, Catriona
    Alfred Hosp, Dept Anat Pathol, Prahran, Vic, Australia..
    Munoz, David G.
    St Michaels Hosp, Div Pathol, Toronto, ON, Canada..
    Murray, Melissa E.
    Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA..
    Neltner, Janna
    Univ Kentucky, Dept Pathol, Lexington, KY USA.;Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA..
    Nelson, Peter T.
    Univ Kentucky, Dept Pathol, Lexington, KY USA.;Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA..
    Ritchie, Diane
    Univ Edinburgh, Ctr Clin Brain Sci, Edinburgh, Midlothian, Scotland..
    Rodriguez, Roberta D.
    Univ Sao Paulo, Sch Med, Physiopathol Aging Lab, Brazilian Aging Brain Study Grp LIM22, Sao Paulo, Brazil.;Univ Sao Paulo, Behav & Cognit Neurol Unit, Dept Neurol, Sao Paulo, Brazil..
    Rohan, Zdenek
    Thomayer Hosp, Dept Pathol & Mol Med, Prague, Czech Republic.;Charles Univ Prague, Dept Pathol, Med Fac 1, Prague, Czech Republic..
    Rozemuller, Annemieke
    Netherlands Brainbank, Amsterdam, Netherlands.;Vrije Univ Amsterdam, Dept Pathol, Med Ctr, Amsterdam, Netherlands..
    Sakai, Kenji
    Kanazawa Univ, Grad Sch Med Sci, Dept Neurol & Neurobiol Aging, Kanazawa, Ishikawa, Japan..
    Schultz, Christian
    Heidelberg Univ, Inst Neuroanat, Ctr Biomed & Med Technol Mannheim, Med Fac Mannheim, Heidelberg, Germany..
    Seilhean, Danielle
    UPMC Sorbonne Univ, Dept Neuropathol, Hop La Salpetriere, AP HP, Paris, France..
    Smith, Vanessa
    Univ Kentucky, Dept Pathol, Lexington, KY USA.;Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA..
    Tacik, Pawel
    Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA.;Univ Bonn, Med Ctr, Dept Neurodegenerat Dis & Gerontopsychiat, Bonn, Germany..
    Takahashi, Hitoshi
    Niigata Univ, Brain Res Inst, Dept Pathol, Niigata, Japan..
    Takao, Masaki
    Saitama Med Univ, Int Med Ctr, Dept Neurol, Saitama, Japan..
    Thal, Dietmar Rudolf
    Katholieke Univ Leuven, Dept Neurosci, Leuven, Belgium.;Univ Ziekenhuizen Leuven, Dept Pathol, Leuven, Belgium..
    Weis, Serge
    Johannes Kepler Univ Linz, Neuropathol Lab, Dept Pathol & Neuropathol, Kepler Univ Hosp,Med Sch, Linz, Austria..
    Wharton, Stephen B.
    Univ Sheffield, Sheffield Inst Translat Neurosci, Sheffield, S Yorkshire, England..
    White, Charles L., III
    Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, Dallas, TX USA..
    Woulfe, John M.
    Univ Ottawa, Dept Pathol & Lab Med, Ctr Canc Therapeut, Ottawa Hosp,Res Inst, Ottawa, ON, Canada..
    Yamada, Masahito
    Kanazawa Univ, Grad Sch Med Sci, Dept Neurol & Neurobiol Aging, Kanazawa, Ishikawa, Japan..
    Trojanowski, John Q.
    Univ Penn, Ctr Neurodegenerat Dis Res, Inst Aging, Perelman Sch Med, Philadelphia, PA 19104 USA.;Univ Penn, Dept Pathol & Lab Med, Perelman Sch Med, Philadelphia, PA USA..
    Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG)2017In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 76, no 7, p. 605-619Article in journal (Refereed)
    Abstract [en]

    Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was > 60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (> 90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.

  • 50. Kämäläinen, Anna
    et al.
    Viswanathan, Jayashree
    Natunen, Teemu
    Helisalmi, Seppo
    Kauppinen, Tarja
    Pikkarainen, Maria
    Pursiheimo, Juha-Pekka
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Kivipelto, Miia
    Haapasalo, Annakaisa
    Soininen, Hilkka
    Herukka, Sanna-Kaisa
    Hiltunen, Mikko
    GRN Variant rs5848 Reduces Plasma and Brain Levels of Granulin in Alzheimer's Disease Patients.2013In: Journal of Alzheimer's disease : JAD, ISSN 1875-8908, Vol. 33, no 1, p. 23-7Article in journal (Refereed)
    Abstract [en]

    Genetic variants in the granulin (GRN) gene have been shown to increase the risk of Alzheimer's disease (AD). Here, we report that the A allele of rs5848 in GRN reduces plasma granulin levels in a dose-dependent manner in a clinically-defined AD sample cohort. Similarly, the mRNA levels of granulin were decreased with respect to A allele of rs5848 in the inferior temporal cortex of neuropathologically confirmed AD patients. Our findings suggest that the A allele of rs5848 is functionally relevant by reducing the expression of granulin.

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