Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium

Alafuzoff, Irina; Pikkarainen, Maria; Neumann, Manuela; Arzberger, Thomas; Al‐Sarraj, Safa; Bódi, István; Bogdanović, Nenad; Bugiani, Orso; Ferrer, Isidro; Gelpí, Ellen; Gentleman, Stephen M.; Giaccone, Giorgio; Graeber, Manuel B.; Hortobágyi, Tibor; Ince, Paul G.; Ironside, James W.; Kavantzas, Nikolaos; King, Andrew; Korkolopoulou, Penelope; Kovács, Gábor G.; Meyronet, David; Monoranu, Camelia; Nilsson, Tony; Parchi, Piero; Patsouris, Efstratios; Révész, Tamás; Roggendorf, Wolfgang; Rozemüller, Annemieke; Seilhean, Danielle; Streichenberger, Nathalie; Thal, Dietmar Rudolf; Wharton, Stephen B.; Kretzschmar, Hans A.

doi:10.1007/s00702-014-1304-1

Cited by 26 publications

(16 citation statements)

References 41 publications

(85 reference statements)

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“…Analysis of formalin-fixed and paraffin-embedded tissue from different parts of the brain was performed, including the frontal cortex (F2), temporal pole cortex, parietal cortex (superior and inferior lobule), occipital pole cortex, amygdala, and the hippocampus, essentially CA1 and entorhinal area of the parahippocampal gyrus. Staging of pathology was evaluated according to a modified assessment of Braak and Alafuzoff and the Aβ staging of Thal [2, 9, 57]. For cases with and without clinical neurological disease, diagnosis was processed identically.…”

Section: Methodsmentioning

confidence: 99%

Immunological memory to hyperphosphorylated tau in asymptomatic individuals

et al. 2017

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Several reports have described the presence of antibodies against Alzheimer’s disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG+ memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs. In total, 52 somatically mutated tau-binding antibodies were identified, corresponding to 35 unique clonal families. Forty-one of these antibodies recognize epitopes in the proline-rich and C-terminal domains, and binding of 26 of these antibodies is strictly phosphorylation dependent. Thirteen antibodies showed inhibitory activity in a P301S lysate seeded in vitro tau aggregation assay. Two such antibodies, CBTAU-7.1 and CBTAU-22.1, which bind to the proline-rich and C-terminal regions of tau, respectively, were characterized in more detail. CBTAU-7.1 recognizes an epitope that is similar to that of murine anti-PHF antibody AT8, but has different phospho requirements. Both CBTAU-7.1 and CBTAU-22.1 detect pathological tau deposits in post-mortem brain tissue. CBTAU-7.1 reveals a similar IHC distribution pattern as AT8, immunostaining (pre)tangles, threads, and neuritic plaques. CBTAU-22.1 shows selective detection of neurofibrillary changes by IHC. Taken together, these results suggest the presence of an ongoing antigen-driven immune response against tau in healthy individuals. The wide range of specificities to tau suggests that the human immune repertoire may contain antibodies that can serve as biomarkers or be exploited for therapy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1705-y) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Immunological memory to hyperphosphorylated tau in asymptomatic individuals

et al. 2017

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“…Although most FTLD‐TDP cases can easily be assigned to one of the common subtypes (A–D), several studies have found that a minority of cases are difficult to classify; either because the pattern of pathology is felt not to fit with any of the existing subtypes or because it shows overlapping features of more than one subtype . A recent study that evaluated the TDP‐43 pathology in a large series of cases using an unbiased semiquantitative approach found that 19% had the positive pathological features of both type A and type B .…”

Section: Ftld‐tdpmentioning

confidence: 99%

Review: Neuropathology of non‐tau frontotemporal lobar degeneration

Neumann

Mackenzie

2019

Neuropathology Appl Neurobio

111

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Frontotemporal dementia (FTD) is a heterogeneous clinical syndrome associated with frontotemporal lobar degeneration (FTLD) as a relatively consistent neuropathological hallmark feature. However, the discoveries in the past decade of many of the relevant pathological proteins aggregating in human FTD brains in addition to several new FTD causing gene mutations underlined that FTD is a diverse condition on the neuropathological and genetic basis. This resulted in a novel molecular classification of these conditions based on the predominant protein abnormality and allows most cases of FTD to be placed now into one of three broad molecular subgroups; FTLD with tau, TAR DNA‐binding protein 43 or FET protein accumulation (FTLD‐tau, FTLD‐TDP and FTLD‐FET respectively). This review will provide an overview of the molecular neuropathology of non‐tau FTLD, insights into disease mechanisms gained from the study of human post mortem tissue as well as discussion of current controversies in the field.

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“…Consequently, IHC diagnosis of TDP-43-proteinopathies finds greater concordance among neuropathologists when the anti-phosphorylated-TDP-43 antibody has been applied. 33 , 34 …”

Section: Discussionmentioning

confidence: 99%

Distinct Phospho-TDP-43 brain distribution in two cases of FTD, one associated with ALS

Guedes

Santin

Costa

et al. 2017

Dement. neuropsychol.

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INTRODUCTION:TDP-43 is an intranuclear protein involved in many cellular processes. When altered, it shows a change in pattern of distribution, as well as in functioning, throughout the Central Nervous System structures. Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are examples of TDP-43 proteinopathy. These disorders form a clinical spectrum, with some patients having a pure cognitive disorder while others also exhibit motor features.METHODS:We studied two donated brains from patients with a diagnosis of Frontotemporal Dementia (FTD), one of which was associated with ALS (ALS-FTD). After fixation and macroscopic examinations, sample analyses were performed. Specific regions were chosen for the application of immunohistochemistry (IHC) with anti-Aβ, AT8, anti-α-synuclein and anti-phospho-TDP-43.RESULTS:Both brains presented anti-phospho-TDP-43 positivity, but this was not equally distributed throughout the encephalic zones. In the FTD case, the studied brain presented phosphorylated TDP-43- in the frontal cortex, hippocampus, entorhinal cortex and mesencephalon; in the ALS-FTD case, the abnormal protein was also seen in the pons and medulla oblongata. The brain in the ALS-FTD case presented Aβ and AT8 positivity in the hippocampus and entorhinal cortex (Braak I and II).DISCUSSION:The hypothesis supported by scientific literature that these neurodegenerative diseases can have the same etiology with distinct encephalic region involvement is corroborated by the present study.

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Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium

Cited by 26 publications

References 41 publications

Immunological memory to hyperphosphorylated tau in asymptomatic individuals

Immunological memory to hyperphosphorylated tau in asymptomatic individuals

Review: Neuropathology of non‐tau frontotemporal lobar degeneration

Distinct Phospho-TDP-43 brain distribution in two cases of FTD, one associated with ALS

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