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  • 1.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Ince, Paul G.
    Arzberger, Thomas
    Al-Sarraj, Safa
    Bell, Jeanne
    Bodi, Istvan
    Bogdanovic, Nenad
    Bugiani, Orso
    Ferrer, Isidro
    Gelpi, Ellen
    Gentleman, Stephen
    Giaccone, Giorgio
    Ironside, James W.
    Kavantzas, Nikolaos
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G.
    Meyronet, David
    Monoranu, Camelia
    Parchi, Piero
    Parkkinen, Laura
    Patsouris, Efstratios
    Roggendorf, Wolfgang
    Rozemuller, Annemieke
    Stadelmann-Nessler, Christine
    Streichenberger, Nathalie
    Thal, Dietmar R.
    Kretzschmar, Hans
    Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe Consortium2009In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 117, no 6, p. 635-652Article in journal (Refereed)
    Abstract [en]

    When 22 members of the BrainNet Europe (BNE) consortium assessed 31 cases with alpha-synuclein (alphaS) immunoreactive (IR) pathology applying the consensus protocol described by McKeith and colleagues in 2005, the inter-observer agreement was 80%, being lowest in the limbic category (73%). When applying the staging protocol described by Braak and colleagues in 2003, agreement was only 65%, and in some cases as low as 36%. When modifications of these strategies, i.e., McKeith's protocol by Leverenz and colleagues from 2009, Braak's staging by Müller and colleagues from 2005 were applied then the agreement increased to 78 and 82%, respectively. In both of these modifications, a reduced number of anatomical regions/blocks are assessed and still in a substantial number of cases, the inter-observer agreement differed significantly. Over 80% agreement in both typing and staging of alphaS pathology could be achieved when applying a new protocol, jointly designed by the BNE consortium. The BNE-protocol assessing alphaS-IR lesions in nine blocks offered advantages over the previous modified protocols because the agreement between the 22 observers was over 80% in most cases. Furthermore, in the BNE-protocol, the alphaS pathology is assessed as being present or absent and thus the quality of staining and the assessment of the severity of alphaS-IR pathology do not alter the inter-observer agreement, contrary to other assessment strategies. To reach these high agreement rates an entity of amygdala-predominant category was incorporated. In conclusion, here we report a protocol for assessing alphaS pathology that can achieve a high inter-observer agreement for both the assignment to brainstem, limbic, neocortical and amygdala-predominant categories of synucleinopathy and the Braak stages.

  • 2.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Pikkarainen, Maria
    Arzberger, Thomas
    Thal, Dietmar R
    Al-Sarraj, Safa
    Bell, Jeanne
    Bodi, Istvan
    Budka, Herbert
    Capetillo-Zarate, Estibaliz
    Ferrer, Isidro
    Gelpi, Ellen
    Gentleman, Stephen
    Giaccone, Giorgio
    Kavantzas, Nikolaos
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G
    Meyronet, David
    Monoranu, Camelia
    Parchi, Piero
    Patsouris, Efstratios
    Roggendorf, Wolfgang
    Stadelmann, Christine
    Streichenberger, Nathalie
    Tagliavini, Fabricio
    Kretzschmar, Hans
    Inter-laboratory comparison of neuropathological assessments of beta-amyloid protein: a study of the BrainNet Europe consortium.2008In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 115, no 5, p. 533-46Article in journal (Refereed)
    Abstract [en]

    Amyloid-beta-protein (Abeta) is generally assessed by neuropathologists in diagnostics. This BrainNet Europe ( http://www.brainnet-europe.org/ ) (15 centres and 26 participants) study was carried out to investigate the reliability of such an assessment. In the first part of this trial, tissue microarray sections were stained with the antibody of each centre's choice. Reflecting the reality, seven antibodies and a plethora of pretreatment strategies were used. Ninety-two percent of the stainings were of good/acceptable quality and the estimation of presence of Abeta aggregates yielded good results. However, a poor agreement was reached particularly regarding quantitative (density) and qualitative (diffuse/cored plaques) results. During a joint meeting, the clone 4G8 was determined to label best the fleecy/diffuse plaques, and thus, this clone and the formic acid pretreatment technique were selected for the second part of this study. Subsequently, all stained sections were of good/acceptable quality and again a high level of concordance of the dichotomized (presence/absence) assessment of plaques and CAA was achieved. However, even when only one antibody was used, the type of Abeta-aggregates (diffuse/cored), type of vessel and Vonsattel grade, were not reliably assigned. Furthermore, the quantification of lesions was far from reliable. In line with the first trial, the agreement while assessing density (some, moderate and many) was unimpressive. In conclusion, we can confirm the utility of immunohistochemical detection of Abeta-protein in diagnostics and research. It is noteworthy that to reach reproducible results a dichotomized assessment of Abeta-immunoreactivity rather than quantification and assignment of various types of lesions should be applied, particularly when comparing results obtained by different neuropathologists.

  • 3.
    Alafuzoff, Irina
    et al.
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Thal, Dietmar R.
    Arzberger, Thomas
    Bogdanovic, Nenad
    Al-Sarraj, Safa
    Bodi, Istvan
    Boluda, Susan
    Bugiani, Orso
    Duyckaerts, Charles
    Gelpi, Ellen
    Gentleman, Stephen
    Giaccone, Giorgio
    Graeber, Manuel
    Hortobagyi, Tibor
    Höftberger, Romana
    Ince, Paul
    Ironside, James W.
    Kavantzas, Nikolaos
    King, Andrew
    Korkolopoulou, Penelope
    Kovács, Gábor G.
    Meyronet, David
    Monoranu, Camelia
    Nilsson, Tatjana
    Parchi, Piero
    Patsouris, Efstratios
    Pikkarainen, Maria
    Revesz, Tamas
    Rozemuller, Annemieke
    Seilhean, Danielle
    Schulz-Schaeffer, Walter
    Streichenberger, Nathalie
    Wharton, Stephen B.
    Kretzschmar, Hans
    Assessment of beta-amyloid deposits in human brain: a study of the BrainNet Europe Consortium2009In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 117, no 3, p. 309-320Article in journal (Refereed)
    Abstract [en]

    beta-Amyloid (A-beta) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as iota and alpha synuclein related lesions, also A-beta related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of A-beta, i.e. phase 1 = deposition of A-beta exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of A-beta phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of A-beta-phases as a diagnostic tool while analyzing subjects with suspected Alzheimer's disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the A-beta phase in AD is feasible even in large scale retrospective studies.

  • 4. Bell, Jeanne E
    et al.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Al-Sarraj, Safa
    Arzberger, Thomas
    Bogdanovic, Nenad
    Budka, Herbert
    Dexter, David T
    Falkai, Peter
    Ferrer, Isidro
    Gelpi, Elena
    Gentleman, Steven M
    Giaccone, Giorgio
    Huitinga, Inge
    Ironside, James W
    Klioueva, Natasja
    Kovacs, Gabor G
    Meyronet, David
    Palkovits, Miklos
    Parchi, Piero
    Patsouris, Efstatios
    Reynolds, Richard
    Riederer, Peter
    Roggendorf, Wolfgang
    Seilhean, Danielle
    Schmitt, Andrea
    Schmitz, Peer
    Streichenberger, Nathalie
    Schwalber, Ameli
    Kretzschmar, Hans
    Management of a twenty-first century brain bank: experience in the BrainNet Europe consortium.2008In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 115, no 5, p. 497-507Article in journal (Refereed)
    Abstract [en]

    Collections of human postmortem brains gathered in brain banks have underpinned many significant developments in the understanding of central nervous system (CNS) disorders and continue to support current research. Unfortunately, the worldwide decline in postmortem examinations has had an adverse effect on research tissue procurement, particularly from control cases (non-diseased brains). Recruitment to brain donor programmes partially addresses this problem and has been successful for dementing and neurodegenerative conditions. However, the collection of brains from control subjects, particularly from younger individuals, and from CNS disorders of sudden onset, remains a problem. Brain banks need to adopt additional strategies to circumvent such shortages. The establishment of brain bank networks allows data on, and access to, control cases and unusual CNS disorders to be shared, providing a larger resource for potential users. For the brain banks themselves, inclusion in a network fosters the sharing of protocols and development of best practice and quality control. One aspect of this collective experience concerns brain bank management, excellence in which is a prerequisite not only for gaining the trust of potential donors and of society in general, but also for ensuring equitable distribution to researchers of high quality tissue samples. This review addresses the legal, ethical and governance issues, tissue quality, and health and safety aspects of brain bank management and data management in a network, as well as the needs of users, brain bank staffing, donor programs, funding issues and public relations. Recent developments in research methodology present new opportunities for researchers who use brain tissue samples, but will require brain banks to adopt more complex protocols for tissue collection, preparation and storage, with inevitable cost implications for the future.

  • 5.
    Casar-Borota, Olivera
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jacobsen, Eva Astrid
    Scheie, David
    Bilateral atypical choroid plexus papillomas in cerebellopontine angles mimicking neurofibromatosis 2.2006In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 111, no 5, p. 500-2Article in journal (Refereed)
  • 6. 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.

  • 7. 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.

  • 8. 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.

  • 9.
    Ingelsson, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ramasamy, Karunya
    Cantuti-Castelvetri, Ippolita
    Skoglund, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Matsui, Toshifumi
    Orne, Jennifer
    Kowa, Hasimoto
    Raju, Susan
    Vanderburg, Charles R
    Augustinack, Jean C
    de Silva, Rohan
    Lees, Andrew J
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Growdon, John H
    Frosch, Matthew P
    Standaert, David G
    Irizarry, Michael C
    Hyman, Bradley T
    No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer's disease brain2006In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 112, no 4, p. 439-449Article in journal (Refereed)
    Abstract [en]

    Defective splicing of tau mRNA, promoting a shift between tau isoforms with (4R tau) and without (3R tau) exon 10, is believed to be a pathological consequence of certain tau mutations causing frontotemporal dementia. By assessing protein and mRNA levels of 4R tau and 3R tau in 27 AD and 20 control temporal cortex, we investigated whether altered tau splicing is a feature also in Alzheimer's disease (AD). However, apart from an expected increase of sarcosyl-insoluble tau in AD, there were no significant differences between the groups. Next, by laser-capture microscopy and quantitative PCR, we separately analyzed CA1 hippocampal neurons with and without neurofibrillary pathology from six of the AD and seven of the control brains. No statistically significant differences in 4R tau/3R tau mRNA were found between the different subgroups. Moreover, we confirmed the absence of significant ratio differences in a second data set with laser-captured entorhinal cortex neurons from four AD and four control brains. Finally, the 4R tau/3R tau ratio in CA1 neurons was roughly half of the ratio in temporal cortex, indicating region-specific differences in tau mRNA splicing. In conclusion, this study indicated region-specific and possibly cell-type-specific tau splicing but did not lend any support to overt changes in alternative splicing of tau exon 10 being an underlying factor in AD pathogenesis.

  • 10.
    Ingelsson, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ramasamy, Karunya
    Russ, Carsten
    Freeman, Stefanie H
    Orne, Jennifer
    Raju, Susan
    Matsui, Toshifumi
    Growdon, John H
    Frosch, Matthew P
    Ghetti, Bernardino
    Brown, Robert H
    Irizarry, Michael C
    Hyman, Bradley T
    Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains2007In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 114, no 5, p. 471-479Article in journal (Refereed)
    Abstract [en]

    Some cases of familial frontotemporal dementia (FTD) leading to frontotemporal lobar degeneration (FTLD) are caused by mutations in tau on chromosome 17 (FTDP-17). Certain mutations alter the ratio between four (4R tau) and three (3R tau) repeat tau isoforms whereas cases with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) mainly have 4R tau brain pathology. We assessed tau mRNA and protein levels in frontal cortex from 15 sporadic FTLD, 21 PSP, 5 CBD, 15 Alzheimer’s disease (AD) and 16 control brains. Moreover, we investigated the disease association and possible tau splicing effects of the tau H1 haplotype. Cases with FTLD and PSP had lower tau mRNA levels than control brains. When analyzing 4R tau and 3R tau mRNA separately, control subjects displayed a 4R tau/3R tau ratio of 0.48. Surprisingly, FTLD brains displayed a more elevated ratio (1.32) than PSP brains (1.12). Also, several FTLD and PSP cases had higher 4R tau/3R tau mRNA than FTDP-17 cases, included as reference tissues, and the ratio increase was seen regardless of underlying histopathology, i.e. both for tau-positive and tau-negative FTLD cases. Furthermore, total tau protein levels were slightly decreased in both FTLD and AD as compared to control subjects. Finally, we confirmed the association of tau H1 with PSP, but could not find any haplotype-related effect on tau exon 10 splicing. In conclusion, we demonstrated increased but largely variable 4R tau/3R tau mRNA ratios in FTLD and PSP cases, suggesting heterogeneous pathophysiological processes within these disorders.

  • 11. 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)
  • 12. 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.

  • 13. 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.

  • 14.
    Lindqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Penisson-Besnier, Isabelle
    Iwamoto, Hiroyuki
    Li, Meishan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Yagi, Naoto
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    A myopathy-related actin mutation increases contractile function2012In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 123, no 5, p. 739-746Article in journal (Refereed)
    Abstract [en]

    Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure. To decipher them, in the present study, we originally recorded and analysed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibres with a particular peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an unexpected cascade of molecular and cellular events. During contraction, p.Phe352Ser greatly enhances the strain of individual cross-bridges. Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by altering the rate of myosin head attachment to actin monomers. Overall, at the cell level, these divergent mechanisms conduct to an improved steady-state force production. Such results provide new surprising scientific insights and crucial information for future therapeutic strategies.

  • 15. Mackenzie, Ian R. A.
    et al.
    Neumann, Manuela
    Bigio, Eileen H.
    Cairns, Nigel J.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Kril, Jillian
    Kovacs, Gabor G.
    Ghetti, Bernardino
    Halliday, Glenda
    Holm, Ida E.
    Ince, Paul G.
    Kamphorst, Wouter
    Revesz, Tamas
    Rozemuller, Annemieke J. M.
    Kumar-Singh, Samir
    Akiyama, Haruhiko
    Baborie, Atik
    Spina, Salvatore
    Dickson, Dennis W.
    Trojanowski, John Q.
    Mann, David M. A.
    Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update2010In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 119, no 1, p. 1-4Article in journal (Refereed)
  • 16. Mackenzie, Ian R. A.
    et al.
    Neumann, Manuela
    Bigio, Eileen H.
    Cairns, Nigel J.
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Kril, Jillian
    Kovacs, Gabor G.
    Ghetti, Bernardino
    Halliday, Glenda
    Holm, Ida E.
    Ince, Paul G.
    Kamphorst, Wouter
    Revesz, Tamas
    Rozemuller, Annemieke J. M.
    Kumar-Singh, Samir
    Akiyama, Haruhiko
    Baborie, Atik
    Spina, Salvatore
    Dickson, Dennis W.
    Trojanowski, John Q.
    Mann, David M. A.
    Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations2009In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 117, no 1, p. 15-18Article in journal (Refereed)
  • 17. Mangerel, Joshua
    et al.
    Price, Aryeh
    Castelo-Branco, Pedro
    Brzezinski, Jack
    Buczkowicz, Pawel
    Rakopoulos, Patricia
    Merino, Diana
    Baskin, Berivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Wasserman, Jonathan
    Mistry, Matthew
    Barszczyk, Mark
    Picard, Daniel
    Mack, Stephen
    Remke, Marc
    Starkman, Hava
    Elizabeth, Cynthia
    Zhang, Cindy
    Alon, Noa
    Lees, Jodi
    Andrulis, Irene L.
    Wunder, Jay S.
    Jabado, Nada
    Johnston, Donna L.
    Rutka, James T.
    Dirks, Peter B.
    Bouffet, Eric
    Taylor, Michael D.
    Huang, Annie
    Malkin, David
    Hawkins, Cynthia
    Tabori, Uri
    Alternative lengthening of telomerases is enriched in, and impacts survival of TP53 mutant pediatric malignant brain tumors2014In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 128, no 6, p. 853-862Article in journal (Refereed)
    Abstract [en]

    Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.

  • 18.
    Neumann, Julia E.
    et al.
    Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany..
    Johansson, Fredrik K.
    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.
    Schueller, Ulrich
    Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany.;Univ Med Ctr Hamburg Eppendorf, Dept Pediat Hematol & Oncol, Hamburg, Germany.;Res Inst Childrens Canc Ctr, Martinistr 52, D-20251 Hamburg, Germany..
    Medulloblastoma: experimental models and reality2017In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 134, no 5, p. 679-689Article, review/survey (Refereed)
    Abstract [en]

    Medulloblastoma is the most frequent malignant brain tumor in childhood, but it may also affect infants, adolescents, and young adults. Recent advances in the understanding of the disease have shed light on molecular and clinical heterogeneity, which is now reflected in the updated WHO classification of brain tumors. At the same time, it is well accepted that preclinical research and clinical trials have to be subgroup-specific. Hence, valid models have to be generated specifically for every medulloblastoma subgroup to properly mimic molecular fingerprints, clinical features, and responsiveness to targeted therapies. This review summarizes the availability of experimental medulloblastoma models with a particular focus on how well these models reflect the actual disease subgroup. We further describe technical advantages and disadvantages of the models and finally point out how some models have successfully been used to introduce new drugs and why some medulloblastoma subgroups are extraordinary difficult to model.

  • 19. Parkkinen, Laura
    et al.
    Pirttilä, Tuula
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland .
    Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance.2008In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 115, no 4, p. 399-407Article in journal (Refereed)
    Abstract [en]

    In Parkinson's disease (PD) and dementia with Lewy bodies (DLB) alpha-synuclein (alphaS) pathology is seen that displays a predictable topographic distribution. There are two staging/categorization systems, i.e. Braak's and McKeith's, currently in use for the assessment of alphaS pathology. The aim of these diagnostic strategies in pathology is, in addition to assess the stage/severity of pathology, to assess the probabilities of the related clinical symptomatology i.e. dementia and extrapyramidal symptoms (EPS). Herein, we assessed the applicability of these two staging/categorization systems and the frequency of dementia and EPS in a cohort of 226 alphaS-positive-subjects. These subject were selected from a large autopsy sample (n = 1,720), irrespective of the clinical presentation, based on the detection of alphaS-immunoreactivity (IR) in one of the most vulnerable nuclei; in the dorsal motor nucleus of vagus, substantia nigra and basal forebrain. The frequency of alphaS-IR lesions in this large cohort was 14% (248 out of 1,720). If applicable, each of the 226 subjects with all required material available was assigned a neuropathological stage/category of PD/DLB and finally the neuropathological data was analyzed in relation to dementia and EPS. 83% of subjects showed a distribution pattern of alphaS-IR that was compatible with the current staging/categorization systems. Around 55% of subjects with widespread alphaS pathology (Braak's PD stages 5-6) lacked clinical signs of dementia or EPS. Similarly, in respect to those subjects that fulfilled the McKeith criteria for diffuse neocortical category and displaying only mild concomitant Alzheimer's disease-related pathology, only 48% were demented and 54% displayed EPS. It is noteworthy that some subjects (17%) deviated from the suggested caudo-rostral propagation suggesting alternative routes of progression, perhaps due to concomitant diseases and genetic predisposition. In conclusion, our results do indeed confirm that current staging/categorization systems can readily be applied to most of the subjects with alphaS pathology. However, finding that around half of the subjects with abundant alphaS pathology remain neurologically intact is intriguing and raises the question whether we do assess the actual disease process.

  • 20.
    Qu, Mingqi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Olofsson, Tommie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sigurdardottir, Sunna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    You, Chao
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nistér, Monica
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Ren, Zhi-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Genetically distinct astrocytic and oligodendroglial components in oligoastrocytomas2007In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 113, no 2, p. 129-136Article in journal (Refereed)
    Abstract [en]

    Oligoastrocytomas are glial tumours consisting of a mixture of neoplastic astrocytic and oligodendroglial cells. Genetic alterations of oligoastrocytomas include loss of heterozygosity of chromosomes 1p and/or 19q (LOH 1p/19q), typically occurring in oligodendrogliomas, and mutations of TP53, frequently occurring in astrocytomas. To investigate whether these neoplastic cell types in oligoastrocytomas have different genetic profiles, we examined the two different components of oligoastrocytomas in comparison with the histological diagnosis of the specific tumour area for LOH 1p/19q and TP53 mutations by using microdissection technique. We found a variety of lost markers for 1p and 19q, and the presence of two different TP53 mutations in the tumour samples. In the majority of cases (9/11), the oligodendroglial and astrocytic components of an individual oligoastrocytoma displayed the same genotype. We present two cases of biphasic oligoastrocytomas with aberrant findings, suggesting the coexistence of genetically and morphologically distinct tumour cell clones in these tumours. In one case, the oligodendroglial part of the tumour showed LOH19q, whereas the astrocytic part showed TP53 mutation (codon 273). In another case, we found LOH 1p/19q in the oligodendroglial component, but two retained areas on chromosome 1p in the astrocytic component of the tumour. No evidence was found for the coexistence of tumour cells with the two genotypical changes within the same morphological region of one individual tumour. The two cases of biphasic oligoastrocytomas in our sample that display a different genotype in the astrocytic and oligodendroglial part of the tumour show that different components of an oligoastrocytoma may be derived from different cell clones during neoplastic transformation.

  • 21.
    Reyes, Juan F.
    et al.
    Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Sackmann, Christopher
    Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Hoffmann, Alana
    Univ Hosp Erlangen, Dept Mol Neurol, Erlangen, Germany.
    Svenningsson, Per
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Winkler, Jürgen
    Univ Hosp Erlangen, Dept Mol Neurol, Erlangen, Germany.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hallbeck, Martin
    Linkoping Univ, Dept Clin Pathol, Linkoping, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden.
    Binding of alfa-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes2019In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 138, no 1, p. 23-47Article in journal (Refereed)
    Abstract [en]

    The intercellular transfer of alpha-synuclein (-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of -syn oligomeric assemblies (o-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and o-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked o-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with -syn accumulation. Notably, we could alsodemonstrate a direct interaction between -syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related -synucleinopathies.

  • 22.
    Sarkisyan, Daniil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Watanabe, Hiroyuki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kononenko, Olga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schumann, Gunter
    Kings Coll London, Inst Psychiat, London, England..
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Damaged reward areas in human alcoholics: neuronal proportion decline and astrocyte activation2017In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 133, no 3, p. 485-487Article in journal (Refereed)
  • 23.
    Sinha, Maitrayee Sardar
    et al.
    Linkoping Univ, Dept Pathol, Dept Clin & Expt Med, Linkoping, Sweden.
    Ansell-Schultz, Anna
    Linkoping Univ, Dept Pathol, Dept Clin & Expt Med, Linkoping, Sweden.
    Civitelli, Livia
    Linkoping Univ, Dept Pathol, Dept Clin & Expt Med, Linkoping, Sweden.
    Hildesjo, Camilla
    Linkoping Univ, Dept Pathol, Dept Clin & Expt Med, Linkoping, Sweden.
    Larsson, Max
    Linkoping Univ, Dept Pathol, Dept Clin & Expt Med, Linkoping, Sweden.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. BioArctic AB, Stockholm, Sweden.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hallbeck, Martin
    Linkoping Univ, Dept Pathol, Dept Clin & Expt Med, Linkoping, Sweden.
    Alzheimer's disease pathology propagation by exosomes containing toxic amyloid-beta oligomers2018In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, no 1, p. 41-56Article in journal (Refereed)
    Abstract [en]

    The gradual deterioration of cognitive functions in Alzheimer's disease is paralleled by a hierarchical progression of amyloid-beta and tau brain pathology. Recent findings indicate that toxic oligomers of amyloid-beta may cause propagation of pathology in a prion-like manner, although the underlying mechanisms are incompletely understood. Here we show that small extracellular vesicles, exosomes, from Alzheimer patients' brains contain increased levels of amyloid-beta oligomers and can act as vehicles for the neuron-to-neuron transfer of such toxic species in recipient neurons in culture. Moreover, blocking the formation, secretion or uptake of exosomes was found to reduce both the spread of oligomers and the related toxicity. Taken together, our results imply that exosomes are centrally involved in Alzheimer's disease and that they could serve as targets for development of new diagnostic and therapeutic principles.

  • 24.
    Sjöstedt, Evelina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Bollerslev, Jens
    Oslo Univ Hosp, Rikshosp, Dept Specialized Endocrinol, Oslo, Norway.; Univ Oslo, Fac Med, Oslo, Norway.
    Mulder, Jan
    KTH Royal Inst Technol, Sci Life Lab, Stockholm, Sweden.
    Lindskog, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Casar Borota, Olivera
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Oslo Univ Hosp, Dept Pathol, Oslo, Norway.
    A specific antibody to detect transcription factor T-Pit: a reliable marker of corticotroph cell differentiation and a tool to improve the classification of pituitary neuroendocrine tumours2017In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 134, no 4, p. 675-677Article in journal (Other academic)
  • 25.
    Zhang, Xiao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Wang, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    O'Callaghan, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hjertstrom, Elina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Jia, Juan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gong, Feng
    Zcharia, Eyal
    Nilsson, Lars N. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Vlodavsky, Israel
    Lindahl, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-beta in murine brain2012In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 124, no 4, p. 465-478Article in journal (Refereed)
    Abstract [en]

    Neuroinflammation is typically observed in neurodegenerative diseases such as Alzheimer's disease, as well as after traumatic injury and pathogen infection. Resident immune cells, microglia and astrocytes, are activated and joined by blood-borne monocytes that traverse the blood-brain barrier and convert into activated macrophages. The activated cells express various cytokines, chemokines and proteolytic enzymes. To study the role of heparan sulfate proteoglycans in neuroinflammation, we employed a transgenic mouse overexpressing heparanase, an endoglucuronidase that specifically degrades heparan sulfate side chains. Neuroinflammation was induced by systemic challenge with lipopolysaccharide, or by localized cerebral microinjection of aggregated amyloid-beta peptide, implicated in Alzheimer's disease. Lipopolysaccharide-treated control mice showed massive activation of resident microglia as well as recruitment of monocyte-derived macrophages into the brain parenchyma. Microinjection of aggregated amyloid-beta elicited a similar inflammatory response, albeit restricted to the injection site, which led to dispersion and clearance of the amyloid. In the heparanase-overexpressing mice, all aspects of immune cell recruitment and activation were significantly attenuated in both inflammation models, as was amyloid dispersion. Accordingly, an in vitro blood-brain barrier model constructed from heparanase-overexpressing cerebral vascular cells showed impaired transmigration of monocytes compared to a corresponding assembly of control cells. Our data indicate that intact heparan sulfate chains are required at multiple sites to mediate neuroinflammatory responses, and further point to heparanase as a modulator of this process, with potential implications for Alzheimer's disease.

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