Podcasts about ftld

References Front. Immunol., 19 October 2022 Brain. 2023 Sep 13:awad309. doi:10.1093/brain/awad309 --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.14.549089v1?rss=1 Authors: Reich, M., Simon, M. J., Polke, B., Werner, G., Schrader, C., Paris, I., Robinson, S., Davis, S. S., Lunkes de Melo, G., Schlaphoff, L., Spieth, L., Berghoff, S., Logan, T., Nuscher, B., Buschmann, K., Edbauer, D., Simons, M., Suh, J., Sandmann, T., Kariolis, M. S., DeVos, S. L., Lewcock, J. W., Paquet, D., Capell, A., Di Paolo, G., Haass, C. Abstract: Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant (AAV(L):bPGRN) in two mouse models of FTLD-GRN, namely Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs while maintaining sustained levels of PGRN in the brain following a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRN associated disease pathologies including severe motor function deficits, aberrant TDP-43 solubility and phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis and neurodegeneration in the brain. Translatability of our findings was confirmed in a novel human in vitro model using co-cultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies can ameliorate FTLD-GRN relevant phenotypes including TDP-43 pathology, neurodegeneration and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRN and potentially other CNS disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.21.546009v1?rss=1 Authors: San Gil, R., Pascovici, D., Venturato, J., Brown-Wright, H., Mehta, P., Madrid San Martin, L., Wu, J., Chui, Y. K., Bademosi, A., Swaminathan, S., Luan, W., Berning, B. A., Wright, A. L., Keating, S. S., Lee, A., Morsch, M., Chung, R. S., Lisowski, L., Mirzaei, M., Walker, A. K. Abstract: Understanding the mechanisms that drive TDP-43 pathology is integral to combating neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To address this, we sought to determine the timeline of proteomic alterations across disease course in TDP-43 proteinopathy. Using longitudinal quantitative proteomics analysis of cortex samples from the cytoplasmic TDP-43 rNLS8 mouse model of ALS and FTLD, we identified several distinct protein subsets characterized by temporal alterations in protein abundance across diverse biological pathways, including protein folding, intracellular transport, myelination, and neuronal synaptic function. Remarkably, neurons in the rNLS8 cortex elicited a transitory response primarily comprising protein-folding factors prior to and in the earliest stages of disease progression. This response included increased levels of DnaJ homolog subfamily B member 5, DNAJB5, and proof-of-concept studies showed that DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures. Conversely, knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in the brains and spinal cords of mice. Lastly, the late disease proteomic signatures of rNLS8 mouse cortex strongly correlated with changes in human autopsy-derived TDP-43 proteinopathy tissues, indicating commonality of disease processes. Together, these findings reveal molecular mechanisms that regulate protein levels through distinct stages of ALS and FTLD progression, and suggest that protein folding factors that combat cytoplasmic TDP-43 protein aggregation could be protective in disease. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.06.535844v1?rss=1 Authors: Du, H., Yang, C., Nana, A. L., Seeley, W. W., Smolka, M. B., Hu, F. Abstract: Mutations in the granulin (GRN) gene, resulting in haploinsufficiency of the progranulin (PGRN) protein, are a leading cause of frontotemporal lobar degeneration (FTLD) and PGRN polymorphisms are associated with Alzheimer's disease (AD) and Parkinson's disease (PD). PGRN is a key regulator of microglia-mediated inflammation but the mechanism is still unknown. Here we report that PGRN interacts with sPLA2-IIA, a secreted phospholipase involved in inflammatory responses, to downregulate sPLA2-IIA activities and levels. sPLA2-IIA expression modifies PGRN deficiency phenotypes in mice and sPLA2-IIA inhibition rescues inflammation and lysosomal abnormalities in PGRN deficient mice. Furthermore, FTLD patients with GRN mutations show increased levels of sPLA2-IIA in astrocytes. Our data support sPLA2-IIA as a critical target for PGRN and a novel therapeutic target for FTLD-GRN. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.21.513088v1?rss=1 Authors: Fodder, K., Murthy, M., Rizzu, P., Toomey, C. E., Hasan, R., Humphrey, J., Raj, T., Lunnon, K., Mill, J., Heutink, P., Lashley, T., Bettencourt, C. Abstract: Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, namely Alzheimer's disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (228 individuals), generated using the Illumina 450K or EPIC arrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differential methylated loci across FTLD subgroups/subtypes. Additionally, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. The EWAS meta-analysis revealed four differentially methylated loci in FTLD, some of which showed altered gene and protein expression in FTLD. Two of the meta-analysis hits, OTUD4 and CEBPZ, were found to be co-methylated within signatures strongly associated with FTLD. These signatures were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dr. Philip Wade Tipton discusses his paper, "Differences in Motor Features of C9orf72, MAPT, or GRN Variant Carriers With Familial Frontotemporal Lobar Degeneration". Show references: https://n.neurology.org/content/early/2022/06/29/WNL.0000000000200860 This podcast is sponsored by argenx. Visit www.vyvgarthcp.com for more information.

Dr. Matt Barrett talks with Dr. Philip Tipton about differences in motor features of C9orf72, MAPT, and GRN variant carriers with familial frontotemporal lobar degeneration. Read the full article in Neurology. This podcast is sponsored by argenx. Visit www.vyvgarthcp.com for more information.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.08.371922v1?rss=1 Authors: Alquezar, C., Schoch, K. M., Geier, E. G., Ramos, E. M., Scrivo, A., Li, K., Argouarch, A. R., Mlynarski, E. E., Dombroski, B., Yokoyama, J. S., Cuervo, A. M., Burlingame, A. L., Schellenberg, G. D., Miller, T. M., Miller, B. L., Kao, A. W. Abstract: Age-associated neurodegenerative disorders demonstrating tau-laden intracellular inclusions, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and progressive supranuclear palsy (PSP), are collectively known as tauopathies. The vast majority of human tauopathies accumulate non-mutant tau rather than mutant forms of the protein, yet cell and animal models for non-mutant tauopathies are lacking. We previously linked a monoallelic mutation in the TSC1 gene to tau accumulation and FTLD. Now, we have identified new variants in TSC1 that predisposed to other tauopathies such as AD and PSP. These new TSC1 risk variants significantly decreased the half-life of TSC1/hamartin in vitro. Cellular and murine models of TSC1 haploinsufficiency (TSC1+/-) accumulated tau protein that exhibited aberrant acetylation on six lysine residues. Tau acetylation hindered its degradation via chaperone-mediated autophagy leading to neuronal tau accumulation. Enhanced tau acetylation in TSC1+/- models was achieved through both an increase in p300 acetyltransferase activity and a decrease in SIRT1 deacetylase levels. Pharmacological modulation of either enzyme restored tau levels. Together, these studies substantiate TSC1 as a novel tauopathy risk gene and advance TSC1 haploinsufficiency as a new genetic model for tauopathy. In addition, these results promote acetylated tau as a rational target for diagnostic and therapeutic modalities in multiple tauopathies. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.04.282855v1?rss=1 Authors: Small, C., Martinez-Marmol, R., Wallis, T., Gormal, R., Götz, J., Meunier, F. Abstract: Fyn is a Src kinase that controls critical signalling cascades and its postsynaptic enrichment underpins synaptotoxicity in Alzheimer's disease (AD) and frontotemporal dementia (FTLD-tau). Previously, we found that pathogenic FTLD tau mutant (P301L) expression promotes aberrant trapping of Fyn in nanoclusters within hippocampal dendrites via an unknown mechanism (Padmanabhan et al., 2019). Here, we imaged Fyn-mEos2 using single particle tracking photoactivated localization microscopy (sptPALM) to demonstrate that nanoclustering of Fyn in hippocampal dendrites is promoted by Fyn's open, primed conformation. Disrupting the auto-inhibitory, closed conformation of Fyn through phospho-inhibition, and perturbation of Fyn's SH3 domain increases, Fyn's nanoscale trapping. However, inhibition of Fyn's catalytic domain has no impact on its mobility. Tau-P301L promotes Fyn lateral trapping via Fyn opening and ensuing increased catalytic activation. Pathogenic tau may therefore drive synaptotoxicity by locking Fyn in an open, catalytically active conformation, leading to postsynaptic entrapment and aberrant signalling cascades. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.04.187997v1?rss=1 Authors: Kang, S.-G., Han, Z. Z., Daude, N., McNamara, E., Wohlgemuth, S., Safar, J. G., Mok, S.-A., Westaway, D. Abstract: Recent studies show that a single MAPT gene mutation can promote alternative tau misfolding pathways engendering divergent forms of frontotemporal dementia and that under conditions of molecular crowding, the repertoire of tau forms can include liquid-liquid phase separation (LLPS). We show here that following pathogenic seeding, tau condenses on the nuclear envelope (NE) and disrupts nuclear-cytoplasmic transport (NCT). Interestingly, NE fluorescent tau signals and small fluorescent inclusions behaved as demixed liquid droplets in living cells. Thioflavin S-positive intracellular aggregates were prevalent in tau-derived inclusions with a size bigger than 3 m2, indicating that a threshold of critical mass in the liquid state condensation may drive liquid-solid phase transitions. Our findings indicate that tau undergoing LLPS is more toxic amongst a spectrum of alternative conformers; LLPS droplets on the NE that disrupt NCT serve to trigger cell death and can act as nurseries for fibrillar structures abundantly detected in end-stage disease. Copy rights belong to original authors. Visit the link for more info

You've spent your entire life wiring your brain to make you ...  you! So, if your brain changes, you change - right? On this episode, Melissa and Swapna chat with Dr. Carmela Tartaglia, a Clinician-Investigator at the Krembil Neuroscience Centre at Toronto Western Hospital, to shed light on a form of early onset dementia - frontotemporal lobar degeneration (FTLD). Dr. Tartaglia is also the Marion and Gerald Soloway Chair in Brain Injury and Concussion Research and she brings to light some common misconceptions about the diagnosis, prevalence, and treatment of concussion. In hopes of understanding how exercise can benefit those with neurodegenerative disease, James sits down with Dennis Hunkin, and learns how he has taken up boxing to fight back in his battle against Parkinson’s. Finally, Anton explores a taboo, yet prevalent societal issue of intimate partner violence induced concussions, with leading expert Dr. Eve Valera from Harvard Medical School. Definitely one you won't want to miss! Until next time, keep it raw!

You've spent your entire life wiring your brain to make you ...  you! So, if your brain changes, you change - right? On this episode, Melissa and Swapna chat with Dr. Carmela Tartaglia, a Clinician-Investigator at the Krembil Neuroscience Centre at Toronto Western Hospital, to shed light on a form of early onset dementia - frontotemporal lobar degeneration (FTLD). Dr. Tartaglia is also the Marion and Gerald Soloway Chair in Brain Injury and Concussion Research and she brings to light some common misconceptions about the diagnosis, prevalence, and treatment of concussion. In hopes of understanding how exercise can benefit those with neurodegenerative disease, James sits down with Dennis Hunkin, and learns how he has taken up boxing to fight back in his battle against Parkinson’s. Finally, Anton explores a taboo, yet prevalent societal issue of intimate partner violence induced concussions, with leading expert Dr. Eve Valera from Harvard Medical School. Definitely one you won't want to miss! Until next time, keep it raw!

Boris Rogelj, Institute Joseph Stefan, Ljubljana, SLOVENIA speaks on "RNA binding proteins in ALS and FTLD". This movie has been recorded by ICGEB Trieste .

A look at two industry-specific domain names. Craig Schwartz, formerly with ICANN, is managing director of fTLD. Unlike other new top level domain name companies, fTLD was set up by industry associations to run the .bank and .insurance domain names for the benefit of its members. Craig discusses this approach and its success so far, […] Post link: Craig Schwartz – DNW Podcast #81 © DomainNameWire.com 2020. This is copyrighted content. Domain Name Wire full-text RSS feeds are made available for personal use only, and may not be published on any site without permission. If you see this message on a website, contact editor (at) domainnamewire.com. Latest domain news at DNW.com: Domain Name Wire.

Mon, 4 Apr 2016 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/19381/ https://edoc.ub.uni-muenchen.de/19381/1/Hasenkamp_Laura-Carolin.pdf Hasenkamp, Laura-Carolin ddc:610, ddc:600, Medizinische Fakultät

Frontotemporal lobar degeneration (FTLD) is a fatal neurodegenerative disease with presenile onset. Clinically, it mainly presents with language disorders or personality and behavioural changes whereas pathologically patients Show atrophy of the frontal and temporal lobes of the brain. Like in other neurodegenerative disorders, abnormal protein deposition can be detected in the affected areas of the brain nervous system. However, several different proteins have been identified to be the main component of These inclusions accordingly leading to the differentiation of so far five distinct types of FTLD, namely FTLD-tau, FTLD-TDP (TAR DNA-binding protein 43), FTLD-FUS (Fused in Sarcoma), FTLD-PR (dipeptide repeat protein) and FTLDUPS (ubiquitin-proteasome system). FTLD-TDP comprises 45 % of all FTLD cases and thus represents one of the two main pathological subtypes of FTLD. In the last few years, tremendous progress has been made in the identification of the genetic causes for FTLD-subtypes; among them, the identification of mutations in the progranulin (GRN) gene in FTLD-TDP. Interestingly, even though haploinsufficiency of progranulin was demonstrated to be causative for FTLD-TDP, the same GRN mutation could present with different ages of disease onset in different patients. This argued for additional factors that might modulate disease onset. In order to identify such genetic factors, a genome-wide association study was performed in genetically or pathologically confirmed FTLD-TDP cases. Thereby, twelve single-nucleotide polymorphisms mapped to a 68 kb interval located on chromosome 7p21.3 implicating that this might be a common genetic susceptibility locus for FTLD-TDP. This region only comprised one gene encoding for the transmembrane protein 106B (TMEM106B). Interestingly, the risk allele of TMEM106B was especially associated with FTLD risk in patients carrying a GRN mutation which suggested a functional relationship between those two proteins. However, TMEM106B was an uncharacterized protein of unknown function. Thus, the Motivation of my study was to investigate the biochemical features of TMEM106B, followed by examining the relationship between TMEM106B and GRN and finally, by investigating TMEM106B function. In the first part of this study, Membrane orientation, cellular localization and the glycosylation status of TMEM106B were determined and tools developed. By sequential inactivation of the five predicted N-glycosylation motifs, TMEM106B was demonstrated to be a type II transmembrane protein that is N-glycosylated at the amino acid positions 146 (N1), 152 (N2), 165 (N3), 184 (N4)and 257 (N5). Moreover, only N4 and N5 proved to be complex glycosylated whereas N1, N2 and N3 did not. By immunofluorescence, TMEM106B was determined to be a lysosomal protein. Interestingly, mutants where one of the two complex glycosylation motifs was deleted showed a different intracellular localization whereas deleting the non-complex glycosylation motifs did not change TMEM106B localization. This indicated that complex glycosylation was essential for correct TMEM106B positioning in the cell. In the second part of this study, the influence of TMEM106B expression on GRN levels was analysed in various cell lines. However, neither overexpression nor knockdown of TMEM106B changed intracellular or secreted GRN levels indicating that both proteins probably do not influence each other directly. However, interestingly, bafilomycin A1 (BafA1) treatment which inhibits lysosomal acidification and thus lysosomal function increased both GRN and TMEM106B protein levels suggesting that both proteins might act in a common pathway or might be located in the same compartment. Since treatment with proteasomal inhibitors did not increase TMEM106B levels, this observation further indicated that TMEM106B is mainly degraded by the lysosome. In the third part of this study, the endogenous function of TMEM106B was investigated using siRNA-mediated TMEM106B knockdown in a cell culture model. Thereby, TMEM106B knockdown was shown to change lysosomal positioning as lysosomes clustered tightly at the microtubule-organizing center instead of being distributed throughout the cell. A rescue experiment, where endogenous TMEM106B was knocked down first and then, additionally, either a control vector or exogenous TMEM106B was transfected, proved that lysosomal clustering was the result of TMEM106B loss and not a side effect of siRNA transfection. Furthermore, lysosomal clustering upon TMEM106B knockdown was shown to be dependent on functional retrograde transport and an intact microtubule network. In addition, lysosomes were demonstrated to be still acidic and, in principle, functional upon TMEM106B knockdown. Interestingly, however, lysosomal and autophagosomal protein levels increased significantly upon TMEM106B knockdown, suggesting that the autophagic pathway might be affected by TMEM106B levels. Since GRN had been implicated in playing an important role for lysosomal function and thus in the autophagic pathway, the finding that TMEM106B also has an impact on this pathway might explain why TMEM106B polymorphisms are especially associated with GRN mutation carriers but also why TMEM106B is a general risk factor for FTLD. Changes in the autophagic pathway seem to be common in neurodegenerative disorders as for example in Alzheimer’s, Parkinson’s and Huntington’s disease, the autophagic pathway has been reported to be impaired in the course of disease. My findings would support the notion that also in FTLD, autophagy plays an essential part in disease progression.

Frontotemporal dementia is the second most common neurodegenerative disease in people younger than 65 years. Patients suffer from behavioral changes, language deficits and speech impairment. Unfortunately, there is no effective treatment available at the moment. Cytoplasmic inclusions of the DNA/RNA-binding protein TDP-43 are the pathological hallmark in the majority of FTLD cases, which are accordingly classified as FTLD-TDP. Mutations in GRN, the gene coding for the trophic factor progranulin, are responsible for the majority of familiar FTLD-TDP cases. The first genome-wide association study performed for FTLD-TDP led to the identification of risk variants in the so far uncharacterized gene TMEM106B. Initial cell culture studies revealed intracellular localization of TMEM106B protein in lysosomes but its neuronal function remained elusive. Based on these initial findings, I investigated the physiological function of TMEM106B in primary rat neurons during this thesis. I demonstrated that endogenous TMEM106B is localized to late endosomes and lysosomes in primary neurons, too. Notably, knockdown of the protein does neither impair general neuronal viability nor the protein level of FTLD associated proteins, such as GRN or TDP-43. However, shRNA-mediated knockdown of TMEM106B led to a pronounced withering of the dendritic arbor in developing and mature neurons. Moreover, the strong impairment of dendrite outgrowth and maintenance was accompanied by morphological changes and loss of dendritic spines. To gain mechanistic insight into the loss-of-function phenotypes, I searched for coimmunoprecipitating proteins by LC-MS/MS. I specifically identified the microtubule-binding protein MAP6 as interaction partner and was able to validate binding. Strikingly, overexpression of MAP6 in primary neurons phenocopied the TMEM106B knockdown effect on dendrites and loss of MAP6 restored dendritic branching in TMEM106B knockdown neurons, indicating functional interaction of the two proteins. The link between a lysosomal and a microtubule-binding protein made me study the microtubule dependent transport of dendritic lysosomes. Remarkably, live cell imaging studies revealed enhanced movement of dendritic lysosomes towards the soma in neurons devoid of TMEM106B. Again, MAP6 overexpression phenocopied and MAP6 knockdown rescued this effect, strengthening the functional link. The MAP6-independent rescue of dendrite outgrowth by enhancing anterograde lysosomal movement provided additional evidence that dendritic arborization is directly controlled by lysosomal trafficking. From these findings I suggest the following model: TMEM106B and MAP6 together act as a molecular brake for the retrograde transport of dendritic lysosomes. Knockdown of TMEM106B and (the presumably dominant negative) overexpression of MAP6 release this brake and enhance the retrograde movement of lysosomes. Subsequently, the higher protein turnover and the net loss of membranes in distal dendrites may cause the defect in dendrite outgrowth. The findings of this study suggest that lysosomal misrouting in TMEM106B risk allele carrier might further aggravate lysosomal dysfunction seen in patients harboring GRN mutations and thereby contribute to disease progression. Taken together, I discovered the first neuronal function for the FTLD-TDP risk factor TMEM106B: This lysosomal protein acts together with its novel, microtubule-associated binding partner MAP6 as molecular brake for the dendritic transport of lysosomes and thereby controls dendrite growth and maintenance.

Boris Rogelj, Department of Biotechnology B3, Jozef Stefan Institute, Ljubljana - SLOVENIA speaks on "RNA-binding proteins that bind ALS- and FTLD-associated hexanucleotide repeat expansion mutation. This seminar has been recorded at Area Science Park Trieste by ICGEB Trieste

Robert Baloh, Cedars-Sinai, Director, Neuromuscular Medicine, ALS Program, Neurodegenerative Diseases Laboratory, Advanced Health Sciences Pavilion Los Angeles - USA speaks on "Cellular and animal models to understand C9ORF72 repeat expansion in ALS and FTLD - RNA Metabolism: Changing Paradigms in Neurodegeneration” This seminar has been recorded at Area Science Park Trieste by ICGEB Trieste

Antonella Alberici, A.O. Spedali Civili di Brescia, U.O. Neurologia 2, Brescia, - ITALY speaks on "Clinical and neuroimaging phenotypes in monogenic FTLD - RNA Metabolism: Changing Paradigms in Neurodegeneration". This seminar has been recorded at Area Science Park Trieste by ICGEB Trieste

In the last JNNP podcast of 2012, we look at what jelly beans and the Andalucian mountains have done for neurology and psychiatry.Alan Emery, emeritus professor, Green Temple College, University of Oxford, describes studying the family that led him to delineate Emery-Dreifuss muscular dystrophy.And Jason Warren and Rohani Omar, UCL Institute of Neurology, talk about what their study into flavour identification in frontotemporal lobar degeneration reveals.See also:Impact commentary: Unusual type of benign X linked muscular dystrophy http://tinyurl.com/aszzjtyOriginal paper: Unusual type of benign X linked muscular dystrophy http://tinyurl.com/bjadyodFlavour identification in frontotemporal lobar degeneration http://tinyurl.com/a8zh35u

Background/Aims: The diagnostic accuracy of the German version of the revised Addenbrooke's Cognitive Examination (ACE-R) in identifying mild cognitive impairment (MCI), mild dementia in Alzheimer's disease (AD) and mild dementia in frontotemporal lobar degeneration (FTLD) in comparison with the conventional Mini Mental State Examination (MMSE) was assessed. Methods: The study encompasses 76 cognitively healthy elderly individuals, 75 patients with MCI, 56 with AD and 22 with FTLD. ACE-R and MMSE were validated against an expert diagnosis based on a comprehensive diagnostic procedure. Statistical analysis was performed using the receiver operating characteristic method and regression analyses. Results: The optimal cut-off score for the ACE-R for detecting MCI, AD, and FTLD was 86/87, 82/83 and 83/84, respectively. ACE-R was superior to MMSE only in the detection of patients with FTLD {[}area under the curve (AUC): 0.97 vs. 0.92], whilst the accuracy of the two instruments did not differ in identifying MCI and AD. The ratio of the scores of the memory ACE-R subtest to verbal fluency subtest contributed significantly to the discrimination between AD and FTLD (optimal cut-off score: 2.30/2.31, AUC: 0.77), whereas the MMSE and ACE-R total scores did not. Conclusion: The German ACE-R is superior to the most commonly employed MMSE in detecting mild dementia in FTLD and in the differential diagnosis between AD and FTLD. Thus it might serve as a valuable instrument as part of a comprehensive diagnostic workup in specialist centres/clinics contributing to the diagnosis and differential diagnosis of the cause of dementia. Copyright (C) 2010 S. Karger AG, Basel

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.14.041863v1?rss=1 Authors: Nogueras-Ortiz, C. J., Mahairaki, V., Delgado-Peraza, F. M., Das, D., Avgerinos, K., Hentschel, M., Goetzl, E. J., Mattson, M. P., Kapogiannis, D. Abstract: We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer's disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurodegeneration, we assessed the neurotoxicity of immunocaptured AEVs (with anti-GLAST antibody), neuronal-origin NEVs (with anti-L1CAM antibody), and multicellular-origin (with anti-CD81 antibody) EVs from the plasma of AD, frontotemporal lobar degeneration (FTLD) and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons, membrane disruption, reduced neurite density, and decreased cell viability in rat cortical neurons and human IPSC-derived neurons. Neurodegenerative effects were not produced by multicellular-origin EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and suggest that neuronal MAC deposition is necessary for AEV/NEV-mediated neurodegeneration in AD. Copy rights belong to original authors. Visit the link for more info