Forschungszentrum DZNEMay 25
New paper out: PinkyCaMP: an mScarlet-based calcium sensor with enhanced brightness, photostability and multiplexing capabilities.: Fink, Ryan; Imai, Shosei; Gockel, Nala Eileen; et al.
Nature methods Vol. 23, no. 5, p. 998 - 1010 http://dlvr.it/TSjDQj | Please share #dzne #papers
PinkyCaMP: an mScarlet-based calcium sensor with enhanced brightness, photostability and multiplexing capabilities. - DZNEPUB

Genetically encoded calcium (Ca2+) indicators (GECIs) are essential tools for monitoring neuronal activity, but the performance of red fluorescent GECIs has remained limited. In particular, many red indicators are relatively dim, produce low signal-to-noise ratios and can undergo unwanted photoswitching when exposed to blue light, restricting their use in all-optical experiments that combine imaging with optogenetics or multicolor imaging. Here we show the development of PinkyCaMP, a Ca2+ sensor based on the bright red fluorescent protein mScarlet. PinkyCaMP exhibits markedly improved brightness, photostability and signal-to-noise ratio compared to existing red GECIs, while remaining fully compatible with blue-light-based optogenetic and dual-color imaging approaches. PinkyCaMP is well-tolerated by neurons, showing no detectable toxicity or aggregation, both in vitro and in vivo. PinkyCaMP enables a broad spectrum of imaging modalities, including single-photon methods, such as fiber photometry, widefield imaging and miniature microscopy imaging, as well as two-photon imaging in awake mice. Fink, Ryan; Imai, Shosei; Gockel, Nala Eileen; Lauer, German; Renken, Kim; Wietek, Jonas; Lamothe-Molina, Paul J; Fuhrmann, Falko; Mittag, Manuel; Ziebarth, Tim; Canziani, Annika; Kubitschke, Martin; Kistmacher, Vivien; Kretschmer, Anny; Sebastian, Eva; Ottens, Jana; Schmitz, Dietmar; Terai, Takuya; Gründemann, Jan; Hassan, Sami I; Patriarchi, Tommaso; Reiner, Andreas; Fuhrmann, Martin; Campbell, Robert E; Masseck, Olivia Andrea

Forschungszentrum DZNEMay 24
New paper out: The In Vivo Microstructural Profile of Human Hippocampal Subfield CA1 and Its Relation to Memory Performance.: Hayek, Dayana; Höpker-Fernandes, Joseph; Vockert, Niklas; et al.
Human brain mapping Vol. 47, no. 7, p. e70542 http://dlvr.it/TShtQD | Please share #dzne #papers
The In Vivo Microstructural Profile of Human Hippocampal Subfield CA1 and Its Relation to Memory Performance. - DZNEPUB

The hippocampal CA1 subregion supports learning, memory formation, and spatial navigation. Although its three-layered architecture has been described in ex vivo investigations, the in vivo microstructural profile of CA1 and its relation to individual variations in memory performance remain poorly characterized. In this study, we used ultra-high field structural MRI at 7 Tesla to investigate the depth-dependent myelination patterns (measured by quantitative T1) of CA1 in younger adults, their relation to the local arterial architecture, and their association with individual differences in cognitive functions, specifically memory performance. Results show that left and right CA1 present depth-dependent patterns of myelination, with the outer and inner compartments showing higher myelination than the middle compartment. No significant relationship between layer-specific myelination of CA1 and distance to the nearest artery was observed. Right CA1 was found to be more myelinated than left CA1. Pairwise correlations and regression models showed that higher left CA1 myelination is linked to higher accuracy in object localization. Together, our data demonstrate the feasibility of describing the three-layered myelin architecture of CA1 in vivo, and provide information on how alterations in the architecture of CA1 may relate to alterations in cognitive performance in younger adults. Hayek, Dayana; Höpker-Fernandes, Joseph; Vockert, Niklas; Garcia-Garcia, Berta; Mattern, Hendrik; Behrenbruch, Niklas; Fischer, Larissa; Kalyani, Avinash; Doehler, Juliane; Hämmerer, Dorothea; Yi, Yeo-Jin; Schreiber, Stefanie; Maass, Anne; Kuehn, Esther

Forschungszentrum DZNEMay 24
New paper out: Arbeitsbedingungen von beruflich Pflegenden und deren Folgen, Teil 3: Schmidt, Sascha G.; Dichter, Martin; Hasselhorn, Hans M.
Lebenswelt Heim  http://dlvr.it/TShlrx | Please share #dzne #papers
Arbeitsbedingungen von beruflich Pflegenden und deren Folgen, Teil 3 - DZNEPUB

Schmidt, Sascha G.; Dichter, Martin; Hasselhorn, Hans M.

Forschungszentrum DZNEMay 24
New paper out: DNA methylation signatures of bilateral hippocampal volume, asymmetry and atrophy: a cross-omics analysis in the general population.: Liu, Dan; Talevi, Valentina; Tavares, Juliana F; et al.
EBioMedicine Vol. 128, p. 106289 - http://dlvr.it/TShd6T | Please share #dzne #papers
DNA methylation signatures of bilateral hippocampal volume, asymmetry and atrophy: a cross-omics analysis in the general population. - DZNEPUB

Left-right hippocampal volumetric asymmetry and atrophy are implicated in neurodegenerative and neuropsychiatric disorders, yet their molecular basis in healthy adults remains poorly understood.We conducted a meta-analysis of epigenome-wide association studies across six population-based cohorts (n = 8156; 53% women; mean age = 60.7 years) to identify DNA methylation signatures associated with left and right hippocampal volumes (LHCV, RHCV) and hippocampal asymmetry (i.e, differences between left and right volumes divided by their sums).We identified five CpGs and 262 differentially methylated regions associated with LHCV, nine CpGs and 246 regions with RHCV, one CpG and 16 regions with asymmetry. Cross-omics integration uncovered 15 LHCV-related and 13 RHCV-related methylation-gene expression pairs, with five overlapping genes primarily involved in immune regulation. LHCV-specific genes were involved in cellular signalling, and Mendelian randomisation (MR) analyses supported a potential causal association between brain expression of DIP2C and increased risk of major depressive disorder. RHCV-specific genes were involved in neuronal differentiation pathways, with MR analyses suggesting that brain-tissue expression of BAIAP2, MACF1, SLC16A5, and CORO1B was associated with neuropsychiatric disorders. We also identified sex-specific patterns with hippocampal asymmetry. Notably, baseline methylation at these sites predicted hippocampal atrophy rates, explaining >10% of the variation. Associations with multiple healthy dietary patterns suggest modifiable influences on hippocampal structure.These findings highlight distinct methylation profiles as potential biomarkers or therapeutic targets for neuropsychiatric and neurodegenerative conditions.Institutional funds, Federal Ministry of Education and Research of Germany, Alzheimer's Association. Liu, Dan; Talevi, Valentina; Tavares, Juliana F; Wang, Ruiqi; Imtiaz, Mohammed A; Melas, Konstantinos; Teumer, Alexander; Wittfeld, Katharina; Hillary, Robert F; Vojinovic, Dina; Beekman, Marian; Armstrong, Nicola J; Estrada, Santiago; Völzke, Henry; Bülow, Robin; Royle, Natalie A; Wardlaw, Joanna M; Wen, Wei; Sachdev, Perminder S; Mather, Karen A; Slagboom, P Eline; Cox, Simon R; Grabe, Hans Jörgen; Yang, Qiong; Aziz, N Ahmad; Breteler, Monique M B

Forschungszentrum DZNEMay 23
New paper out: New evidence on the clinical, genetic, and biochemical bases of GBA1-Parkinson's disease: prospects for treatment.: Menozzi, Elisa; Toffoli, Marco; Deleidi, Michela; et al.
The lancet Vol. 25, no. 6, p. 602 - 614 http://dlvr.it/TShKP5 | Please share #dzne #papers
New evidence on the clinical, genetic, and biochemical bases of GBA1-Parkinson's disease: prospects for treatment. - DZNEPUB

GBA1 variants are common genetic risk factors for Parkinson's disease and also for dementia with Lewy bodies. New evidence highlights the relationship between the different GBA1 variants and their associated clinical presentation and disease progression, although penetrance is low and the majority of carriers do not develop a synucleinopathy. The clinical profile of GBA1-associated Parkinson's disease is characterised by a faster rate of progression with more severe cognitive and autonomic dysfunction than idiopathic Parkinson's disease, particularly in those carrying severe pathogenic variants. The mechanisms involved in phenotypic conversion and disease progression in carriers of GBA1 variants are being elucidated, and this knowledge could be translated into clinically relevant biomarker profiles. GBA1 has become a target for intervention for both GBA1-associated Parkinson's disease and idiopathic Parkinson's disease, with therapeutic strategies aiming to prevent or slow disease progression via pharmacological chaperones, enzymatic allosteric activators, metabolic interventions, and modulation of gene expression. Menozzi, Elisa; Toffoli, Marco; Deleidi, Michela; Di Monte, Donato A; Blandini, Fabio; Krainc, Dimitri; Sidransky, Ellen; Schapira, Anthony H V

Forschungszentrum DZNEMay 23
New paper out: IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity.: Askin, Bilge; Kilic, Cagla; Cordero Gómez, César; et al.
Science advances Vol. 12, no. 20, p. eaec2042 http://dlvr.it/TSh9fW | Please share #dzne #papers
IgLON5 autoimmune antibodies activate Tau via neuronal hyperactivity. - DZNEPUB

Anti-IgLON5 disease is an autoimmune disease, in which autoantibodies (AABs) against the neuronal cell surface protein IgLON5 lead to profound brain dysfunction and Tau pathology. How α-IgLON5 AABs cause neuronal Tau protein pathology and neurodegeneration remains unclear. We find that patient-derived α-IgLON5 AABs cluster IgLON5 proteins with other cell surface proteins, leading to neuronal hyperactivity that triggers pathological Tau missorting and phosphorylation, typically observed early in Tau-related neurodegenerative diseases. In wild-type mice, α-IgLON5 AABs induce hippocampal Tau phosphorylation and neuroinflammatory responses. Our findings establish a causal link between the α-IgLON5 AABs and Tau pathology in anti-IgLON5 disease patients and highlight the role of neuronal hyperactivity as a disease-overarching driver of Tau pathology and provide a potential target for therapeutic intervention. Askin, Bilge; Kilic, Cagla; Cordero Gómez, César; Duong, Sophie Lan-Linh; Domingues-Baquero, Alvaro; Goihl, Alexander; Nalbach, Karsten; Petushi, Joana; Grundschöttel, Pia; Wagner, Jessica; Thomas, Valentine; Lamberty, Janne; Withers, Emily; Huber, Hanna; Hübschmann, Sabrina; Semenova, Ekaterina; Turko, Paul; Newman, Andrew G; Diez, Lisa; Beyer, Marc; De Domenico, Elena; Körtvelyessy, Peter; Reinhold, Dirk; Schneider, Anja; Neher, Jonas J; Ulas, Thomas; Lichtenthaler, Stefan F; Rost, Benjamin R; Schmitz, Dietmar; Prüss, Harald; Wegmann, Susanne

Forschungszentrum DZNEMay 23
New paper out: Phenotypic spectrum of FGF14-related late-onset ataxia: predominant tremor and cognitive decline as key features of SCA27A.: Möller, Meret; Fienemann, André; Trinh, Joanne; et al.
Journal of neurology Vol. 273, no. 6, p. 309 http://dlvr.it/TSh1td | Please share #dzne #papers
Phenotypic spectrum of FGF14-related late-onset ataxia: predominant tremor and cognitive decline as key features of SCA27A. - DZNEPUB

Möller, Meret; Fienemann, André; Trinh, Joanne; Much, Christoph; Falkenburger, Björn H; Schniewind, Iñaki; Hellenbroich, Yorck; Brüggemann, Norbert; Klein, Christine; Balck, Alexander

Forschungszentrum DZNEMay 22
New paper out: APTw CEST MRI in therapy-naive IDH-wildtype glioblastoma: insights into tumor heterogeneity and molecular subtypes.: Zeyen, Thomas; Decker, Andreas; Krause, Inga; et al.
Journal of neuro-oncology Vol. 178, no. 1, p. 9 http://dlvr.it/TSgclX | Please share #dzne #papers
APTw CEST MRI in therapy-naive IDH-wildtype glioblastoma: insights into tumor heterogeneity and molecular subtypes. - DZNEPUB

Advanced MRI techniques may provide non-invasive insight into the molecular heterogeneity of glioblastoma. Amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) MRI reflects endogenous protein and peptide content, but its clinical and molecular correlates in therapy-naive glioblastoma, IDH-wildtype, remain incompletely understood.This retrospective single-center study included 53 adult patients with therapy-naive glioblastoma, IDH-wildtype, who underwent preoperative APTw MRI. Median time between imaging and tissue sampling was two days. Median and 90th percentile (p90) APTw signal intensities were extracted from contrast-enhancing (T1-CE) tumor regions and FLAIR-hyperintense regions using automated deep learning-based segmentation with manual quality control. Histological and molecular analyses included MGMT promoter methylation, Ki-67 index, and DNA methylation-based subclassification. Associations were assessed using non-parametric tests, multivariable linear regression, and Cox regression analyses.APTw signal intensity was significantly higher in T1-CE tumor regions than in FLAIR-hyperintense regions (p < 0.0001). Within the T1-CE region, higher APTw signal intensity was modestly associated with younger age. Glioblastomas of the mesenchymal methylation subtype demonstrated significantly higher median and p90 APTw signal intensity compared with RTK1 and RTK2 subtypes, independent of MGMT status and Ki-67 index. APTw signal intensity was not independently associated with PFS or OS.APTw CEST MRI reflects molecular heterogeneity in therapy-naive IDH-wildtype glioblastoma, with potentially increased signal intensity in the mesenchymal subtype. These findings support its possible role as a complementary imaging biomarker for non-invasive molecular characterization. Zeyen, Thomas; Decker, Andreas; Krause, Inga; Kroh, Florian; Scheuble, Julia; Friker, Lea L; Pietsch, Torsten; Regnery, Sebastian; Effland, Alexander; Weller, Johannes; Schäfer, Niklas; Radbruch, Alexander; Herrlinger, Ulrich; Paech, Daniel

Forschungszentrum DZNEMay 22
New paper out: Potential proteomic biomarkers for monitoring clinical studies in Duchenne/Becker muscular dystrophy.: Dowling, Paul; Bouragba, Dounia; Negroni, Elisa; et al.
Expert review of proteomics Vol. 23, no. 4-5, p. 109 - 120 http://dlvr.it/TSgP5P | Please share #dzne #papers
Potential proteomic biomarkers for monitoring clinical studies in Duchenne/Becker muscular dystrophy. - DZNEPUB

Clinical proteomics is an evolving discipline that aims to identify new biomarker candidates of human disease to improve diagnosis, prognosis, treatment monitoring and the discovery of novel therapeutic targets. This article outlines the pathoproteomic characterization of dystrophinopathies, which are classified as muscle wasting diseases due to mutations in the DMD gene.The Special Report focuses on the proteomic profiling of progressive Duchenne muscular dystrophy of early childhood and more benign and later-onset Becker muscular dystrophy. The literature search on proteomics and biomarker discovery in dystrophinopathies was conducted with the standard scientific literature databases PubMed and Google Scholar for the preparation of the general text of this article.This report has outlined the biomedical value of the systematic proteomic characterization of tissue specimens and associated biofluids to establish novel biomarkers for monitoring clinical studies in muscular dystrophy. Both, mass spectrometry-based profiling approaches and high-plex/high-throughput proteomics platforms were shown to be suitable for the systematic study of complex changes versus adaptations in dystrophinopathy. The verification of promising disease indicators, especially minimally invasive biofluid markers of myonecrosis, chronic inflammation, disturbed energy metabolism and myofibrosis, using orthogonal methodology holds great potential for future clinical applications such as therapeutic monitoring. Dowling, Paul; Bouragba, Dounia; Negroni, Elisa; Trollet, Capucine; Zweyer, Margit; Swandulla, Dieter; Ohlendieck, Kay

Forschungszentrum DZNEMay 22
New paper out: Minor neuropsychological deficits and stage 2 of Alzheimer's disease.: Stark, Melina; Wagner, Michael; Kuhn, Elizabeth; et al.
Alzheimer's and dementia Vol. 22, no. 5, p. e71458 http://dlvr.it/TSg94Q | Please share #dzne #papers
Minor neuropsychological deficits and stage 2 of Alzheimer's disease. - DZNEPUB

Subtle symptoms, like subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD), can improve the risk stratification in preclinical Alzheimer´s disease (AD) but their importance is insufficiently elaborated.We pooled data from cognitively normal individuals participating in three longitudinal cohort studies (N = 13,192, 8,359[63.3%] female, mean [SD] age 71.0[8.4]).Compared to participants without SCD and MNPD (SCD-/MNPD-), SCD-/MNPD+, SCD+/MNPD-, and SCD+/MNPD+ participants had an increased risk for mild cognitive impairment (MCI) and dementia, including in amyloid-positive individuals. Focusing on SCD+/MNPD+ participants triples the positive predictive value of amyloid biomarker testing for the 5-year prediction of MCI and reduces the required samples size for trials in preclinical AD to one fourth, compared to considering all cognitively normal participants regardless of subtle symptoms.SCD and MNPD offer a powerful approach for risk stratification in preclinical AD, which can improve clinical trial designs, risk counseling, and future case identifications for early treatment. Stark, Melina; Wagner, Michael; Kuhn, Elizabeth; Roeske, Sandra; Amthauer, Holger; Bartels, Claudia; Boecker, Henning; Brosseron, Frederic; Buchert, Ralph; Buerger, Katharina; Daamen, Marcel; Drzezga, Alexander; Düzel, Emrah; Ersözlü, Ersin; Essler, Markus; Ewers, Michael; Fliessbach, Klaus; Glanz, Wenzel; Hellmann-Regen, Julian; Incesoy, Enise I; Janowitz, Daniel; Kafali, Konstantinia; Kilimann, Ingo; Krause, Bernd Joachim; Kronmüller, Marie; Laske, Christoph; Maier, Franziska; Maurer, Angelika; Michely, Jochen; Perneczky, Robert; Peters, Oliver; Preis, Lukas; Priller, Josef; Rauchmann, Boris Stephan; Reimold, Matthias; Rominger, Axel; Schmid, Matthias; Schneider, Anja; Sodenkamp, Sebastian; Spottke, Annika; Spruth, Eike Jakob; Teipel, Stefan; Wiltfang, Jens; Initiative, Alzheimer´s Disease Neuroimaging; Jessen, Frank; Kleineidam, Luca