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Authors: Otto, Markus | Wiltfang, Jens

Article Type: Research Article

Abstract: In principle, two research approaches can be considered for the laboratory diagnosis of transmissible spongiform encephalopathies (TSE): (i) the direct detection of PrP^{Sc} and (ii) the detection of surrogate markers in biological materials that show an altered pattern of expression in early stages of the disease or are used in the differential diagnosis of other dementias and thus enable an exclusion diagnosis. This review concentrates on the second approach. It was shown that a single determination of just a few markers (tau-protein, S-100B, 14-3-3-protein) was already sufficient to achieve a high degree of diagnostic certainty in the diagnosis of CJD. …On the basis of the available data, it is to be expected that a combination of these markers will bring improved diagnostic strength with regard to the differential diagnosis of dementias as a whole. This especially applies to some of the subtypes of CJD and Alzheimer's dementia (AD). Show more

Citation: Restorative Neurology and Neuroscience, vol. 21, no. 3-4, pp. 191-209, 2003

Authors: Barba, Lorenzo | Otto, Markus | Abu-Rumeileh, Samir

Article Type: Article Commentary

Abstract: Concomitant Alzheimer’s disease (AD) pathology can be observed in approximately 10–15% of cases with amyotrophic lateral sclerosis (ALS). ALS-AD patients have a higher prevalence of amnestic cognitive disturbances, which may often precede motor symptoms. Cerebrospinal fluid (CSF) AD core biomarkers usually show no or slightly significant changes in ALS, whereas blood phosphorylated tau protein might be increased independently from AD copathology. Neurofilament proteins are consistently elevated in CSF and blood of ALS, but have been poorly investigated in ALS-AD. All these issues should be taken into account when using fluid biomarkers as inclusion criteria or secondary endpoints in clinical trials.

Keywords: Alzheimer’s disease, amyloid-β, amyotrophic lateral sclerosis, biomarker, copathology, neurofilament light chain

DOI: 10.3233/JAD-230900

Citation: Journal of Alzheimer's Disease, vol. 95, no. 4, pp. 1401-1404, 2023

Authors: Jesse, Sarah | Steinacker, Petra | Cepek, Lukas | Arnim, Christine V. | Tumani, Hayrettin | Lehnert, Stefan | Kretzschmar, Hans A. | Baier, Michael | Otto, Markus

Article Type: Research Article

Abstract: Glial fibrillary acidic protein (GFAP) and protein S-100B are established indicators of astrogliosis in neuropathology. As GFAP and S-100B are expressed in different cell populations, variable cerebrospinal fluid (CSF) concentrations of these proteins might reflect disease-specific pathological profiles. Therefore we investigated CSF of patients with Alzheimer's disease (AD), patients with Creutzfeldt-Jakob disease (CJD), and non-demented control patients (CON). Measurement of GFAP and S-100B in CSF was performed by commercially available ELISA. Our results show that, in AD, there are significantly higher levels of GFAP concentrations, compared to CON (p = 0.001) and CJD patients (p = 0.009), whereas S-100B is …much higher in CJD, compared to AD (p = 0.001) and CON (p = 0.001). In conclusion, GFAP and S-100B represent astroglial markers and the different levels of these proteins in CSF of AD and CJD patients might point to a distinct pathophysiological involvement in these diseases. Apart from pathophysiological aspects, GFAP in particular might serve as an additional diagnostic tool for AD, due to the fact that this protein does not correlate to established markers like tau and amyloid-β such that analysis of GFAP may be useful for further differential diagnostic approaches in neurodegenerative diseases. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, Creutzfeldt-Jakob disease, glial fibrillary acidic protein, neurochemical diagnosis, S-100B

DOI: 10.3233/JAD-2009-1075

Citation: Journal of Alzheimer's Disease, vol. 17, no. 3, pp. 541-551, 2009

Authors: Mollenhauer, Brit | Esselmann, Herrmann | Trenkwalder, Claudia | Schulz-Schaeffer, Walter | Kretzschmar, Hans | Otto, Markus | Wiltfang, Jens | Bibl, Mirko

Article Type: Research Article

Abstract: Appropriate treatment of dementia requires biomarkers that provide an exact and differential diagnosis. We recently presented differentially expressed amyloid-β (Aβ) peptide patterns in cerebrospinal fluid (CSF) as biomarker candidates for neurochemical diagnosis of Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The objective of the present study was to investigate CSF Aβ peptide patterns in both neuropathologically and clinically defined diagnostic groups of AD and DLB. Using the quantitative Aβ-SDS-PAGE/immunoblot, we analyzed CSF samples of neuropathologically defined patients with AD (definite AD, dAD; n = 11) and DLB (definite, dDLB; n = 12). We compared absolute and relative quantities …of CSF Aβ-peptides with a larger cohort of clinically diagnosed patients with probable AD (pAD; n = 71), probable DLB (pDLB; n = 32), and non-demented controls (NDC; n = 71). Each neuropathologically and clinically defined diagnostic group showed a similar relative distribution of CSF Aβ-peptides (Aβ1-X% . Aβ1-42% was lowered in dAD compared to NDC (p = 1.6 × 10−7 , but did not differ between dAD and pAD. Aβ1-40ox% was elevated in dDLB as compared to NDC (p = 1.8 × 10−5 , but did not differ between dDLB and pDLB. Thus, we were able to confirm previous results on Aβ peptide patterns in neuropathologically characterized patients with AD and DLB. Our results underline the usefulness of the CSF Aβ1-42% and Aβ1-40ox% as diagnostic biomarkers for AD and DLB, respectively. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, cerebrospinal fluid, dementia with Lewy bodies, neuropathologically confirmed diagnosis

DOI: 10.3233/JAD-2011-101551

Citation: Journal of Alzheimer's Disease, vol. 24, no. 2, pp. 383-391, 2011

Authors: Steinacker, Petra | Klafki, Hans | Lehnert, Stefan | Jesse, Sarah | v. Arnim, Christine A.F. | Tumani, Hayrettin | Pabst, Alice | Kretzschmar, Hans A. | Wiltfang, Jens | Otto, Markus

Article Type: Research Article

Abstract: The clinical diagnosis of Creutzfeldt-Jakob disease (CJD) can be supported by several biochemical markers in cerebrospinal fluid (CSF) such as 14-3-3 proteins and tau protein. Unfortunately, none of the currently known markers are suited for screening or seems to be directly related to the pathophysiological process. A marker fulfilling these criteria might facilitate the early detection and might also serve in monitoring drug efficacy. Recently, the extracellular signal-regulated kinase ERK1/2 was detected in CSF of patients with neuropsychiatric disorders. Furthermore, ERK1/2 was reported to be activated in brains of animals infected with pathological prion protein. Therefore, we investigated CSF of …19 patients with CJD, 23 patients with other dementias including patients with Alzheimer's disease, and 12 patients with other neurological disorders. The measurement of ERK1/2 in the CSF samples was performed with an electrochemiluminescence assay and Western immunoblot. ERK1/2 and doubly phosphorylated ERK1/2 (pERK1/2) were detected in all patient groups. Significantly elevated mean levels of total ERK1/2 and pERK1/2 were found in the CJD patients. This increase was also observed in a CJD case that was negative for 14-3-3 protein or in CJD cases that had low levels of tau protein. Western immunoblot analysis suggested that ERK2 was the predominant form of ERKs present in our CSF samples. This pilot study suggests that ERK1/2 is a potential CSF biomarker for CJD, directly associated with the pathophysiological processes. Analysis of larger sample cohorts including other diseases with rapid neurodegeneration are required to confirm our findings. Show more

Keywords: Alzheimer's disease, biomarker, cerebrospinal fluid, Creutzfeldt-Jakob disease, duplex electrochemiluminescence assay, extracellular signal-regulated kinase ERK1/2

DOI: 10.3233/JAD-2010-100030

Citation: Journal of Alzheimer's Disease, vol. 22, no. 1, pp. 119-128, 2010

Authors: Oeckl, Patrick | Halbgebauer, Steffen | Anderl-Straub, Sarah | Steinacker, Petra | Huss, André M. | Neugebauer, Hermann | von Arnim, Christine A.F. | Diehl-Schmid, Janine | Grimmer, Timo | Kornhuber, Johannes | Lewczuk, Piotr | Danek, Adrian | Consortium for Frontotemporal Lobar Degeneration German | Ludolph, Albert C. | Otto, Markus

Article Type: Short Communication

Abstract: Reliable blood biomarkers for Alzheimer’s disease (AD) are missing. We measured astroglial GFAP in patients with AD (n  = 28), frontotemporal dementia (bvFTD, n  = 35), Parkinson’s disease (n  = 11), Lewy body dementias (n  = 19), and controls (n  = 34). Serum GFAP was increased in AD (p  < 0.001) and DLB/PDD (p  < 0.01), and cerebrospinal fluid GFAP was increased in all neurodegenerative diseases (p  < 0.001). Serum GFAP correlated with the Mini-Mental State Examination score (r = –0.42, p  < 0.001) and might be a follow-up marker in clinical trials. Sensitivity and specificity of serum GFAP for AD versus bvFTD was 89% and 79% and might be …the first blood biomarker in the differential diagnosis of AD and bvFTD. Show more

Keywords: Alzheimer’s disease, astrocyte, biomarker, cerebrospinal fluid, differential diagnosis, frontotemporal dementia, GFAP, Lewy body dementia, Parkinson’s disease, serum

DOI: 10.3233/JAD-180325

Citation: Journal of Alzheimer's Disease, vol. 67, no. 2, pp. 481-488, 2019

Authors: Boström, Gustaf | Freyhult, Eva | Virhammar, Johan | Alcolea, Daniel | Tumani, Hayrettin | Otto, Markus | Brundin, Rose-Marie | Kilander, Lena | Löwenmark, Malin | Giedraitis, Vilmantas | Lleó, Alberto | von Arnim, Christine A.F. | Kultima, Kim | Ingelsson, Martin

Article Type: Research Article

Abstract: Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for …age, gender, collection unit, and multiple testing. Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14–1.53, q  = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20–1.94, q  = 0.045; and FTD: FC = 1.42, 95% CI 1.10–1.83, q  = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q  < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q  < 0.05). Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, mild cognitive impairment, neuroinflammation, proteomics

DOI: 10.3233/JAD-201565

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 629-640, 2021

Authors: de Boer, Sterre C.M. | Riedl, Lina | van der Lee, Sven J. | Otto, Markus | Anderl-Straub, Sarah | Landin-Romero, Ramon | Sorrentino, Federica | Fieldhouse, Jay L.P. | Reus, Lianne M. | Vacaflor, Blanca | Halliday, Glenda | Galimberti, Daniela | Diehl-Schmid, Janine | Ducharme, Simon | Piguet, Olivier | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: Background: Reported sex distributions differ between frontotemporal dementia (FTD) cohorts. Possible explanations are the evolving clinical criteria of FTD and its subtypes and the discovery of FTD causal genetic mutations that has resulted in varying demographics. Objective: Our aim was to determine the sex distribution of sporadic and genetic FTD cases and its subtypes in an international cohort. Methods: We included 910 patients with behavioral variant frontotemporal dementia (bvFTD; n  = 654), non-fluent variant primary progressive aphasia (nfvPPA; n  = 99), semantic variant primary progressive aphasia (svPPA; n  = 117), and right temporal variant frontotemporal dementia (rtvFTD; n  = 40). We compared sex distribution …between genetic and sporadic FTD using χ 2 -tests. Results: The genetic FTD group consisted of 51.2% males, which did not differ from sporadic FTD (57.8% male, p  = 0.08). In the sporadic bvFTD subgroup, males were predominant in contrast to genetic bvFTD (61.6% versus 52.9% males, p  = 0.04). In the other clinical FTD subgroups, genetic cases were underrepresented and within the sporadic cases the sex distribution was somewhat equal. Conclusion: The higher male prevalence in sporadic bvFTD may provide important clues for its differential pathogenesis and warrants further research. Show more

Keywords: Behavioral variant frontotemporal dementia, genetic, non-fluent variant primary progressive aphasia, right temporal variant frontotemporal dementia, semantic variant primary progressive aphasia, sex differences, sex distribution, sporadic

DOI: 10.3233/JAD-210688

Citation: Journal of Alzheimer's Disease, vol. 84, no. 3, pp. 1153-1161, 2021

Authors: Premi, Enrico | Costa, Tommaso | Gazzina, Stefano | Benussi, Alberto | Cauda, Franco | Gasparotti, Roberto | Archetti, Silvana | Alberici, Antonella | van Swieten, John C. | Sanchez-Valle, Raquel | Moreno, Fermin | Santana, Isabel | Laforce, Robert | Ducharme, Simon | Graff, Caroline | Galimberti, Daniela | Masellis, Mario | Tartaglia, Carmela | Rowe, James B. | Finger, Elizabeth | Tagliavini, Fabrizio | de Mendonça, Alexandre | Vandenberghe, Rik | Gerhard, Alexander | Butler, Chris R. | Danek, Adrian | Synofzik, Matthis | Levin, Johannes | Otto, Markus | Ghidoni, Roberta | Frisoni, Giovanni | Sorbi, Sandro | Peakman, Georgia | Todd, Emily | Bocchetta, Martina | Rohrer, Johnathan D. | Borroni, Barbara | GENFI Consortium Members

Collaborators: Afonso, Sónia | Rosario Almeida, Maria | Anderl-Straub, Sarah | Andersson, Christin | Antonell, Anna | Arighi, Andrea | Balasa, Mircea | Barandiaran, Myriam | Bargalló, Nuria | Bartha, Robart | Bender, Benjamin | Benussi, Luisa | Bessi, Valentina | Binetti, Giuliano | Black, Sandra | Borrego-Ecija, Sergi | Bras, Jose | Bruffaerts, Rose | Caroppo, Paola | Cash, David | Castelo-Branco, Miguel | Convery, Rhian | Cope, Thomas | de Arriba, María | Di Fede, Giuseppe | Díaz, Zigor | Duro, Diana | Fenoglio, Chiara | Ferrari, Camilla | B. Ferreira, Catarina | Fox, Nick | Freedman, Morris | Fumagalli, Giorgio | Gabilondo, Alazne | Gauthier, Serge | Giaccone, Giorgio | Gorostidi, Ana | Greaves, Caroline | Guerreiro, Rita | Heller, Carolin | Hoegen, Tobias | Indakoetxea, Begoña | Jelic, Vesna | Jiskoot, Lize | Karnath, Hans-Otto | Keren, Ron | Langheinrich, Tobias | João Leitão, Maria | Lladó, Albert | Lombardi, Gemma | Loosli, Sandra | Maruta, Carolina | Mead, Simon | Meeter, Lieke | Miltenberger, Gabriel | van Minkelen, Rick | Mitchell, Sara | Moore, Katrina | Nacmias, Benedetta | Nicholas, Jennifer | Öijerstedt, Linn | Olives, Jaume | Panman, Jessica | Papma, Janne | Pievani, Michela | Pijnenburg, Yolande | Polito, Cristina | Prioni, Sara | Prix, Catharina | Rademakers [as London Ontario geneticist], Rosa | Redaelli, Veronica | Rittman, Tim | Rogaeva, Ekaterina | Rosa-Neto, Pedro | Rossi, Giacomina | Rossor, Martin | Santiago, Beatriz | Scarpini, Elio | Schönecker, Sonja | Semler, Elisa | Shafei, Rachelle | Shoesmith, Christen | Tábuas-Pereira, Miguel | Tainta, Mikel | Taipa, Ricardo | Tang-Wai, David | L Thomas, David | Thompson, Paul | Thonberg, Hakan | Timberlake, Carolyn | Tiraboschi, Pietro | Van Damme, Philip | Vandenbulcke, Mathieu | Veldsman, Michele | Verdelho, Ana | Villanua, Jorge | Warren, Jason | Wilke, Carlo | Woollacott, Ione | Wlasich, Elisabeth | Zetterberg, Henrik | Zulaica, Miren

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD). Objectives: To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD. Methods: 84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.2±16.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded. Results: Prediction accuracy was high for each considered brain region (i.e., prefrontal region, real CT at follow-up versus predicted CT …at follow-up, mean error ≤1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power = 0.80, alpha = 0.05). Conclusion: The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself. Show more

Keywords: Frontotemporal dementia, granulin, magnetic resonance imaging, mutation, preclinical, presymptomatic

DOI: 10.3233/JAD-215447

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 205-218, 2022

Authors: Serpente, Maria | Fenoglio, Chiara | Arcaro, Marina | Carandini, Tiziana | Sacchi, Luca | Pintus, Manuela | Rotondo, Emanuela | Borracci, Vittoria | Ghezzi, Laura | Bouzigues, Arabella | Russell, Lucy L. | Foster, Phoebe H. | Ferry-Bolder, Eve | van Swieten, John C. | Jiskoot, Lize C. | Seelaar, Harro | Sánchez Valle, Raquel | Laforce, Robert | Graff, Caroline | Vandenberghe, Rik | de Mendonça, Alexandre | Tiraboschi, Pietro | Santana, Isabel | Gerhard, Alexander | Levin, Johannes | Sorbi, Sandro | Otto, Markus | Pasquier, Florence | Ducharme, Simon | Butler, Chris R. | Le Ber, Isabelle | Finger, Elizabeth | Tartaglia, Maria Carmela | Masellis, Mario | Rowe, James B. | Synofzik, Matthis | Moreno, Fermin | Borroni, Barbara | Rohrer, Jonathan D. | Arighi, Andrea | Galimberti, Daniela | Alberici, Antonella | Afonso, Sónia | Alves, Patricia | Anderl-Straub, Sarah | Antonell, Anna | Balasa, Mircea | Barandiaran, Myriam | Bargalló, Nuria | Bartha, Robert | Bender, Benjamin | Bernhardt, Alexander Maximilian | Bertoux, Maxime | Bertrand, Anne | Bessi, Valentina | Black, Sandra | Bocca, Giorgio | Bocchetta, Martina | Borrego-Ecija, Sergi | Brice, Alexis | Bruffaerts, Rose | Buccellato, Francesca R | Buratti, Emanuele | Cantoni, Valentina | Caroppo, Paola | Cash, David | Castelo-Branco, Miguel | Colliot, Olivier | Convery, Rhian | Cope, Thomas | Costa-Coelho, Tiago | Croitoru, Ioana | Camuzat, Agnès | D’Anca, Marianna | de Boer, Liset | de Houwer, Julie | Deramecourt, Vincent | Durães, João | Di Fede, Giuseppe | Ferrari, Camilla | Florio, Graziana | Frascotti, Marta | Freedman, Morris | Funkiewiez, Aurélie | Gabilondo, Alazne | Gasparotti, Roberto | Giaccone, Giorgio | Giannini, Lucia | Goldsmith, Sophie | Graf, Lisa | Jelic, Vesna | Keren, Ron | Krüger, Johanna | Kuchcinski, Gregory | Langheinrich, Tobias | Lebouvier, Thibaud | Leitão, Maria João | Lemos, João | Lima, Marisa | Lladó, Albert | Lombardi, Gemma | Lombardi, Jolina | Malpetti, Maura | Maruta, Carolina | Mengel, David | Miltenberger, Gabriel | Mitchell, Sara | Montembault, Maxime | Nacmias, Benedetta | Nilsson, Mattias | Öijerstedt, Linn | Olives, Jaume | Papma, Janne M. | Pijnenburg, Yolande | Poesen, Koen | Polito, Cristina | Poos, Jackie | Premi, Enrico | Prioni, Sara | Prix, Catharina | Redaelli, Veronica | Rittman, Timothy | Rademakers, Rosa | Rinaldi, Daisy | Rogaeva, Ekaterina | Rollin, Adeline | Rosa-Neto, Pedro | Almeida, Maria Rosario | Rossi, Giacomina | Samra, Kiran | Saracino, Dario | Sayah, Sabrina | Scarpini, Elio | Schönecker, Sonja | Shoesmith, Christen | Simões do Couto, Frederico | Stockbauer, Anna | Tábuas-Pereira, Miguel | Tang-Wai, David | Taheri Rydell, Melissa | Tainta, Mikel | Thomas, David L | Vandenbulcke, Mathieu | Van Damme, Philip | van Minkelen, Rick | Verdelho, Ana | Viklund, Henrik | Vimercati, Roberto | Vogels, Annick | Wagemann, Olivia | Wlasich, Elisabeth

Article Type: Research Article

Abstract: Background: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72 ), Microtubule Associated Protein Tau (MAPT ), and Progranulin (GRN ) genes are not well understood. Objective: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI). Methods: Fifty-three lncRNAs were analyzed with the OpenArray Custom panel, in 131 patients with mutations in C9ORF72 , MAPT , and …GRN , including 68 symptomatic mutation carriers (SMC) and 63 presymptomatic mutation carriers (PMC), compared with 40 non-carrier controls (NC). Results: Thirty-eight lncRNAs were detectable; the relative expression of NEAT1 and NORAD was significantly higher in C9ORF72 SMC as compared with NC. GAS5 expression was instead significantly lower in the GRN group versus NC. MAPT carriers showed no significant deregulations. No significant differences were observed in PMC. Disease duration did not correlate with lncRNA expression. Conclusions: NEAT1 and NORAD are upregulated in C9ORF72 SMC and GAS5 levels are downregulated in GRN SMC, underlining lncRNAs’ relevance in FTD and their potential for biomarker development. Further validation and mechanistic studies are crucial for clinical implications. Show more

Keywords: Alzheimer’s disease, chromosome 9 open reading frame 72, frontotemporal dementia, long non-coding RNA, microtubule associated protein tau, progranulin

DOI: 10.3233/JAD-240557

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S187-S196, 2024