115 results on '"Moda F"'
Search Results
2. MACHINE LEARNING EARLY DIAGNOSIS OF ALZHEIMER’S DISEASE WITH SURFACE-ENHANCED RAMAN SCATTERING ON A-BETA SPECIES IN THE CEREBROSPINAL FLUID
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Barucci, A., primary, D’Andrea, C., additional, Banchelli, M., additional, Farnesi, E., additional, Panagis, P., additional, Marzi, C., additional, Bistaffa, E., additional, Cazzaniga, F., additional, Tiraboschi, P., additional, De Angelis, M., additional, Moda, F., additional, and Matteini, P., additional
- Published
- 2023
- Full Text
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3. “Heróis” por necessidade: entregadores por aplicativos em tempos de covid-19
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OLIVEIRA, M. A. G., primary, MODA, F. B., additional, and ACCORSI, André, additional
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- 2020
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4. PC-09.2 - MACHINE LEARNING EARLY DIAGNOSIS OF ALZHEIMER’S DISEASE WITH SURFACE-ENHANCED RAMAN SCATTERING ON A-BETA SPECIES IN THE CEREBROSPINAL FLUID
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Barucci, A., D’Andrea, C., Banchelli, M., Farnesi, E., Panagis, P., Marzi, C., Bistaffa, E., Cazzaniga, F., Tiraboschi, P., De Angelis, M., Moda, F., and Matteini, P.
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- 2023
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5. Identification of early and peripheral biomarkers predictive of Parkinson’s disease and dementia with Lewy bodies in patients with isolated REM sleep behavior disorders
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Didato, G., primary, De Luca, C.M.G., additional, Cazzaniga, F., additional, Consonni, A., additional, Elia, A., additional, Baggi, F., additional, Tiraboschi, P., additional, and Moda, F., additional
- Published
- 2022
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6. Supplement to: Prions in the urine of patients with variant Creutzfeldt-Jakob disease.
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Moda, F, Gambetti, P, and Notari, S
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- 2014
7. Tau-Centric Multitarget Approach for Alzheimer's Disease: Development of First-in-Class Dual Glycogen Synthase Kinase 3 beta and Tau-Aggregation Inhibitors
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Gandini A, Bartolini M, Tedesco D, Martinez-Gonzalez L, Roca C, Campillo NE, Zaldivar-Diez J, Perez C, Zuccheri G, Miti A, Feoli A, Castellano S, Petralla S, Monti B, Rossi M, Moda F, Legname G, Martinez A, and Bolognesi ML
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ASSAY INTERFERENCE COMPOUNDS ,AMYLOID CASCADE HYPOTHESIS ,TARGET-DIRECTED LIGANDS ,BLOOD-BRAIN-BARRIER ,GSK-3-BETA INHIBITORS ,DRUG DISCOVERY ,NEURODEGENERATIVE DISEASES ,ACTIVITY PROFILES ,COMPOUNDS PAINS ,PROTEIN-TAU - Abstract
Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3? and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC50 values toward GSK-3?, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 ?M, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.
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- 2018
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8. Altered Brain Hemoglobin Gene Expression in the Frontal Cortex of Patients with Alzheimer’s and Acquired Creutzfeldt-Jakob’s Disease
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Vanni, S, Zattoni, M, Moda, F, Tagliavini, F, Halk, S, Deslys, Jp, Zanusso, G, Ironside, Jw, Ferrer, I, Kovacs, G, and Legname, G.
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Creutzfeldt-Jakob’s Disease ,Alzheimer’s - Published
- 2017
9. Differential overexpression of SERPINA3 in human prion diseases
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Vanni, S., primary, Moda, F., additional, Zattoni, M., additional, Bistaffa, E., additional, De Cecco, E., additional, Rossi, M., additional, Giaccone, G., additional, Tagliavini, F., additional, Haïk, S., additional, Deslys, J. P., additional, Zanusso, G., additional, Ironside, J. W., additional, Ferrer, I., additional, Kovacs, G. G., additional, and Legname, G., additional
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- 2017
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10. Targeting ß-amyloid by the A2V Aß variant: a novel disease-modifying strategy for the treatment of Alzheimer’s disease
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Di Fede, G, Diomede, L, Catania, M, Maderna, E, Moda, F, Ruggerone, M, Romeo, M, Morbin, M, Palamara, L, Campagnani, I, Colombo, L, Rossi, A, Cagnotto, A, Messa, M, De Luigi, A, MANCINI, SIMONA, Stravalaci, M, Gobbi, M, Borsello, T, Salmona, M, Tagliavini, F., Di Fede, G, Diomede, L, Catania, M, Maderna, E, Moda, F, Ruggerone, M, Romeo, M, Morbin, M, Palamara, L, Campagnani, I, Colombo, L, Rossi, A, Cagnotto, A, Messa, M, De Luigi, A, Mancini, S, Stravalaci, M, Gobbi, M, Borsello, T, Salmona, M, and Tagliavini, F
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Neurology ,Animal ,Medicine (all) ,Dementia ,Human - Published
- 2014
11. Treatment with a non-toxic, self-replicating anti-prion delays or prevents prion disease in vivo
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Diaz-Espinoza, R, primary, Morales, R, additional, Concha-Marambio, L, additional, Moreno-Gonzalez, I, additional, Moda, F, additional, and Soto, C, additional
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- 2017
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12. Alzheimer disease: APP mutations are associated with high percentage of cerebral amyloid deposits containing Aβ40
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Marcon, G, Giaccone, G, Indaco, A, Moro, M, Moda, F, Cupidi, C, Bruni, A, Demarchi, A, Bogdanovic, N, Ghetti, B, Tagliavini, F, Marcon, G, Giaccone, G, Indaco, A, Moro, M, Moda, F, Cupidi, C, Bruni, A, Demarchi, A, Bogdanovic, N, Ghetti, B, and Tagliavini, F
- Published
- 2011
13. MM2-Thalamic Creutzfeldt-Jacob Disease: Neuropathological, Biochemical and Transmission Studies Identify a Distinctive Prion Strain
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Moda, F., Suardi, S., Di Fede, G., Indaco, A., Limido, L., Vimercati, C., Ruggerone, M., Campagnani, I., Langeveld, J.P.M., Terruzzi, A., Brambilla, A., Zerbi, P., Fociani, P., Bishop, T., Will, G.W., Manson, J.C., Giaccone, G., and Tagliavini, F.
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prpsc types ,animal diseases ,brain ,scrapie ,coexistence ,degeneration ,Bacteriology, Host Pathogen Interaction & Diagnostics ,nervous system diseases ,cooccurrence ,classification ,variant ,mental disorders ,Bacteriologie, Host Pathogen Interactie & Diagnostiek ,sporadic fatal insomnia ,protein - Abstract
In CreutzfeldtJakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrPSc) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrPSc and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrPSc are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrPSc. Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrPSc, a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form.
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- 2012
14. Brain delivery of AVV9 expressing anti-PrP molecules delays prion disease onsite in mice
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Moda, F, Vimercati, C, Campagnani, I, Ruggerone, M, Mobin, M, Giaccone, G, Zentilin, L, Giacca, M, Legname, Giuseppe, and Tagliavini, F.
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Prion - Published
- 2011
15. Discrimination between prion-infected and normal brain with monoclonal antibodies specific for C-terminally truncated PrP fragment
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Koren, S, Kosmač, M, Giachin, G, Moda, F, Vranac, T, Gennaro, R, Bresjanac, M, Tagliavini, F, Legname, Giuseppe, and Čurin Šerbec, V.
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- 2009
16. Engineered adeno-associated-viruses as new therapeutic strategy for prion diseases
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Moda, F, Legname, Giuseppe, Zentilin, L, Giacca, M, Vimercati, C, Suardi, S, Campagnani, I, Ruggerone, M, Zucca, I, and Tagliavini, F.
- Published
- 2009
17. Treatment with a non-toxic, self-replicating anti-prion delays or prevents prion disease in vivo
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Diaz-Espinoza, R, Morales, R, Concha-Marambio, L, Moreno-Gonzalez, I, Moda, F, and Soto, C
- Abstract
Transmissible spongiform encephalopathies (TSEs) are fatal neurological disorders caused by prions, which are composed of a misfolded protein (PrPSc) that self-propagates in the brain of infected individuals by converting the normal prion protein (PrPC) into the pathological isoform. Here, we report a novel experimental strategy for preventing prion disease based on producing a self-replicating, but innocuous PrPSc-like form, termed anti-prion, which can compete with the replication of pathogenic prions. Our results show that a prophylactic inoculation of prion-infected animals with an anti-prion delays the onset of the disease and in some animals completely prevents the development of clinical symptoms and brain damage. The data indicate that a single injection of the anti-prion eliminated ~99% of the infectivity associated to pathogenic prions. Furthermore, this treatment caused significant changes in the profile of regional PrPScdeposition in the brains of animals that were treated, but still succumbed to the disease. Our findings provide new insights for a mechanistic understanding of prion replication and support the concept that prion replication can be separated from toxicity, providing a novel target for therapeutic intervention.
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- 2018
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18. Homeopathic clinical studies in allergology and otorhinolaringology
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Moda, F., Caniato, R., and Bellavite, Paolo
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Allergology ,otolaryngology ,homeopathy - Published
- 1999
19. Human α-Synuclein Fibrils Induce α-Synuclein Aggregation In Vitro And Behavioral Alterations In Vivo Upon Inoculation In Wildtype Mice
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Tran, Ahn, Ntt, Le, Moda, F, Zucca, P, Tagliavini, F, Gustincich, Stefano, and Legname, Giuseppe
20. Biochemical and biophysical comparison of human and mouse beta-2 microglobulin reveals the molecular determinants of low amyloid propensity
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Alfonso De Simone, Xiao Han, Rita Grandori, Jeremie Buratto, Adnane Achour, Carlo Camilloni, Chiara De Luca, Alberto Barbiroli, Carlo Santambrogio, Luca Broggini, Cristina Visentin, Fabio Moda, Renhua Sun, Tatyana Sandalova, Stefano Ricagno, Pietro Sormanni, Achour, A, Broggini, L, Han, X, Sun, R, Santambrogio, C, Buratto, J, Visentin, C, Barbiroli, A, De Luca, C, Sormanni, P, Moda, F, De Simone, A, Sandalova, T, Grandori, R, Camilloni, C, Ricagno, S, Achour, A., Broggini, L., Han, X., Sun, R., Santambrogio, C., Buratto, J., Visentin, C., Barbiroli, A., De Luca, C. M. G., Sormanni, P., Moda, F., De Simone, A., Sandalova, T., Grandori, R., Camilloni, C., and Ricagno, S.
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0301 basic medicine ,crystal structure ,Amyloid ,Protein Folding ,Protein aggregation ,Molecular Dynamics Simulation ,Biochemistry ,protein aggregation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,medicine ,structural biology ,Animals ,Humans ,Molecular Biology ,Gene ,Chemistry ,Beta-2 microglobulin ,Animal ,Protein Stability ,Amyloidosis ,molecular dynamic ,Cell Biology ,medicine.disease ,In vitro ,030104 developmental biology ,Structural biology ,030220 oncology & carcinogenesis ,Biophysics ,Protein Multimerization ,beta 2-Microglobulin ,Human - Abstract
The molecular bases of amyloid aggregation propensity are still poorly understood, especially for proteins that display a stable folded native structure. A prototypic example is human beta-2 microglobulin (β2m), which, when accumulated in patients, gives rise to dialysis-related amyloidosis. Interestingly, although the physiologic concentration of β2m in mice is five times higher than that found in human patients, no amyloid deposits are observed in mice. Moreover, murine β2m (mβ2m) not only displays a lower amyloid propensity both invivo and invitro but also inhibits the aggregation of human β2m invitro. Here, we compared human and mβ2m for their aggregation propensity, ability to form soluble oligomers, stability, three-dimensional structure and dynamics. Our results indicate that mβ2m low-aggregation propensity is due to two concomitant aspects: the low-aggregation propensity of its primary sequence combined with the absence of high-energy amyloid-competent conformations under native conditions. The identification of the specific properties determining the low-aggregation propensity of mouse β2m will help delineate the molecular risk factors which cause a folded protein to aggregate.
- Published
- 2019
21. Structural and dynamical determinants of a β-sheet-enriched intermediate involved in amyloid fibrillar assembly of human prion protein
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Luigi Russo, Giulia Salzano, Andrea Corvino, Edoardo Bistaffa, Fabio Moda, Luigi Celauro, Gianluca D'Abrosca, Carla Isernia, Danilo Milardi, Gabriele Giachin, Gaetano Malgieri, Giuseppe Legname, Roberto Fattorusso, Russo, L., Salzano, G., Corvino, A., Bistaffa, E., Moda, F., Celauro, L., D'Abrosca, G., Isernia, C., Milardi, D., Giachin, G., Malgieri, G., Legname, G., and Fattorusso, R.
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General Chemistry - Abstract
The N-ter domain in HuPrP regulates the folding mechanism by tuning the long-range μs–ms dynamics. Removal of the N-ter domain triggers the formation of a stable β-enriched intermediate state inducing amyloid aggregates with HuPrPSc seeding activity.
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- 2022
22. COVID‐19‐associated immune‐mediated encephalitis mimicking acute‐onset Creutzfeldt‐Jakob disease
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Simone Beretta, Michela Bombino, Giuseppe Citerio, Roberto Rona, Jacopo C. DiFrancesco, A. Patruno, Fabio Moda, Graziella Bogliun, Andrea Stabile, Giuseppe Foti, Carlo Ferrarese, Cristina Capraro, Francesca Andreetta, Paola Cavalcante, Claudia Balducci, Beretta, S, Stabile, A, Balducci, C, Difrancesco, J, Patruno, A, Rona, R, Bombino, M, Capraro, C, Andreetta, F, Cavalcante, P, Moda, F, Citerio, G, Foti, G, Bogliun, G, and Ferrarese, C
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Pathology ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Disease ,Electroencephalography ,Immune system ,COVID‐19 ,Aphasia ,mental disorders ,medicine ,RC346-429 ,medicine.diagnostic_test ,Case Study ,business.industry ,General Neuroscience ,medicine.disease ,Hyperintensity ,nervous system diseases ,encephalitsi ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,medicine.symptom ,business ,Myoclonus ,Encephalitis ,RC321-571 - Abstract
We report a subtype of immune‐mediated encephalitis associated with COVID‐19, which closely mimics acute‐onset sporadic Creutzfeldt–Jakob disease. A 64‐year‐old man presented with confusion, aphasia, myoclonus, and a silent interstitial pneumonia. He tested positive for SARS‐CoV‐2. Cognition and myoclonus rapidly deteriorated, EEG evolved to generalized periodic discharges and brain MRI showed multiple cortical DWI hyperintensities. CSF analysis was normal, except for a positive 14‐3‐3 protein. RT‐QuIC analysis was negative. High levels of pro‐inflammatory cytokines were present in the CSF and serum. Treatment with steroids and intravenous immunoglobulins produced EEG and clinical improvement, with a good neurological outcome at a 6‐month follow‐up.
- Published
- 2021
23. Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models
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Matteo Staderini, Silvia Vanni, Arianna Colini Baldeschi, Gabriele Giachin, Marco Zattoni, Luigi Celauro, Chiara Ferracin, Edoardo Bistaffa, Fabio Moda, Daniel I. Pérez, Ana Martínez, M. Antonia Martín, Olmo Martín-Cámara, Ángel Cores, Giulia Bianchini, Robert Kammerer, J. Carlos Menéndez, Giuseppe Legname, Maria Laura Bolognesi, Associazione Italiana Encefalopatie da Prioni, Ministero della Salute, Ministerio de Ciencia e Innovación (España), Staderini, Matteo, Vanni, Silvia, Colini Baldeschi, Arianna, Giachin, Gabriele, Zattoni, Marco, Celauro, Luigi, Ferracin, Chiara, Bistaffa, Edoardo, Moda, F., Pérez, Daniel I., Martínez, Ana, Martín, M. Antonia, Martín-Cámara, Olmo, Cores, Ángel, Kammerer, Robert, Menéndez, J. Carlos, Legname, G., and Bolognesi, Maria Laura
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Pharmacology ,Sheep ,Prions ,Optical Imaging ,Organic Chemistry ,Carbazoles ,Química orgánica ,General Medicine ,GN8 ,Prion protein ,Theranostics ,Prion Diseases ,Mice ,Drug Discovery ,Química farmaceútica ,Humans ,Animals ,Scrapie - Abstract
14 p.-11 fig., Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four-step route, and a representative member was confirmed to have native fluorescence, including a band in the near-infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cell lines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrPC levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain-independent anti-prion compounds., This work was partially supported by Associazione Italiana Encefalopatie da Prioni (AIEnP) and the Italian Ministry of Health (RRC) to FM. Financial support from Ministerio de Ciencia e Innovación, Spain, through grants RTI2018-097662-B-I00 and PID2021-124983OB-I00 (to JCM) and PID2019-105600RB-I00 (to AM), is also gratefully acknowledged.
- Published
- 2022
24. Validation of Revised International Creutzfeldt-Jakob Disease Surveillance Network Diagnostic Criteria for Sporadic Creutzfeldt-Jakob Disease
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Neil Watson, Peter Hermann, Anna Ladogana, Angeline Denouel, Simone Baiardi, Elisa Colaizzo, Giorgio Giaccone, Markus Glatzel, Alison J. E. Green, Stéphane Haïk, Daniele Imperiale, Janet MacKenzie, Fabio Moda, Colin Smith, David Summers, Dorina Tiple, Luana Vaianella, Gianluigi Zanusso, Maurizio Pocchiari, Inga Zerr, Piero Parchi, Jean-Philippe Brandel, Suvankar Pal, Watson N., Hermann P., Ladogana A., Denouel A., Baiardi S., Colaizzo E., Giaccone G., Glatzel M., Green A.J.E., Haik S., Imperiale D., Mackenzie J., Moda F., Smith C., Summers D., Tiple D., Vaianella L., Zanusso G., Pocchiari M., Zerr I., Parchi P., Brandel J.-P., and Pal S.
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Male ,revision ,accuracy ,diagnosis ,sporadic Creutzfeldt-Jakob disease ,specificity ,Diagnostic Techniques, Neurological ,General Medicine ,sensitivity ,Magnetic Resonance Imaging ,Sensitivity and Specificity ,Creutzfeldt-Jakob Syndrome ,United Kingdom ,Italy ,Retrospective Studie ,Germany ,Population Surveillance ,diagnostic criteria ,Humans ,Female ,Autopsy ,France ,Retrospective Studies ,Aged ,Human - Abstract
Importance: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly lethal disease. Rapid, accurate diagnosis is imperative for epidemiological surveillance and public health activities to exclude treatable differentials and facilitate supportive care. In 2017, the International CJD Surveillance Network diagnostic criteria were revised to incorporate cortical ribboning on magnetic resonance imaging and the real-time quaking-induced conversion (RT-QuIC) assay, developments that require multicenter evaluation. Objective: To evaluate the accuracy of revised diagnostic criteria through the retrospective diagnosis of autopsy-confirmed cases (referred to as in-life diagnosis). Design, Setting, and Participants: This diagnostic study used a 3-year clinicopathological series using all cases of autopsy-confirmed sCJD and a noncase group with alternative neuropathological diagnoses from national surveillance centers in the United Kingdom, France, Germany, and Italy. Data were collected from January 2017 to December 2019 and analyzed from January 2020 to November 2021. Main Outcomes and Measures: Sensitivity and specificity of revised diagnostic criteria and diagnostic investigations. Secondary analyses assessing sCJD subgroups by genotype, pathological classification, disease duration, and age. Results: A total of 501 sCJD cases and 146 noncases were included. Noncase diagnoses included neurodegenerative diseases, autoimmune encephalitis, and cerebral insults such as anoxia. Participants in the sCJD cases cohort were younger (mean [SD] age, 68.8 [9.8] years vs 72.8 [10.9] years; P .99). Among 223 cases and 52 noncases with the full panel of investigations performed, sensitivity of revised criteria (97.8%; 95% CI, 94.9%-99.3%) was increased compared with prior criteria (76.2%; 95% CI, 70.1%-81.7%; P .99). In 455 cases and 111 noncases, cortical ribboning was 67.9% sensitive (95% CI, 63.4%-72.2%) and 86.5% specific (95% CI, 78.7%-92.2%). In 274 cases and 77 noncases, RT-QuIC was 91.6% sensitive (95% CI, 87.7%-94.6%) and 100% specific (95% CI, 96.2%-100%). Investigation sensitivity varied with genetic and pathological features, disease duration, and age. Conclusions and Relevance: This diagnostic study demonstrated significantly improved sensitivity of revised sCJD diagnostic criteria with unaltered specificity. The revision has enhanced diagnostic accuracy for clinical care and surveillance..
- Published
- 2022
25. Animal Models of Autosomal Recessive Parkinsonism
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Guendalina Bastioli, Jenny Sassone, Edoardo Bistaffa, Letizia Zanetti, Maria Regoni, Chiara De Luca, Flavia Valtorta, Federico Angelo Cazzaniga, Fabio Moda, Bastioli, G., Regoni, M., Cazzaniga, F., De Luca, C. M. G., Bistaffa, E., Zanetti, L., Moda, F., Valtorta, F., and Sassone, J.
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0301 basic medicine ,Parkinson's disease ,autosomal recessive Parkinsonism ,QH301-705.5 ,Medicine (miscellaneous) ,Substantia nigra ,Review ,Disease ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Dopamine ,medicine ,Animal model ,Dopaminer-gic neurons ,Biology (General) ,dopaminergic neurons ,Pars compacta ,business.industry ,animal model ,Autosomal recessive Parkinsonism ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Parkinson’s disease ,Neuron ,Neuron death ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. The neuropathological hallmark of the disease is the loss of dopamine neurons of the substantia nigra pars compacta. The clinical manifestations of PD are bradykinesia, rigidity, resting tremors and postural instability. PD patients often display non-motor symptoms such as depression, anxiety, weakness, sleep disturbances and cognitive disorders. Although, in 90% of cases, PD has a sporadic onset of unknown etiology, highly penetrant rare genetic mutations in many genes have been linked with typical familial PD. Understanding the mechanisms behind the DA neuron death in these Mendelian forms may help to illuminate the pathogenesis of DA neuron degeneration in the more common forms of PD. A key step in the identification of the molecular pathways underlying DA neuron death, and in the development of therapeutic strategies, is the creation and characterization of animal models that faithfully recapitulate the human disease. In this review, we outline the current status of PD modeling using mouse, rat and non-mammalian models, focusing on animal models for autosomal recessive PD.
- Published
- 2021
26. Novel screening approaches for human prion diseases drug discovery
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Fabio Moda, Maria Laura Bolognesi, Giuseppe Legname, Moda F., Bolognesi M.L., and Legname G.
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Protein Folding ,Prions ,Computational biology ,Disease ,Biology ,Prion Diseases ,03 medical and health sciences ,Mice ,0302 clinical medicine ,PMCA ,Drug Development ,Settore BIO/10 - Biochimica ,Drug Discovery ,Screening method ,Animals ,Humans ,drug screening ,Prion protein ,Animal species ,030304 developmental biology ,0303 health sciences ,Drug discovery ,RT-QuIC ,Reproducibility of Results ,Human prion disease ,030220 oncology & carcinogenesis ,Expert opinion ,Disease Progression ,Protein Misfolding Cyclic Amplification ,Human prion diseases - Abstract
Introduction: Human prion diseases are rare fatal neurodegenerative diseases caused by the misfolding and aggregation of the prion protein in the form of infectious prions. So far, these diseases are incurable. One of the major difficulties in identifying suitable drugs is the availability of robust preclinical screening methods. All molecules identified have been screened using cell-based assays and in vivo murine models. The existence of a continuum of prion strains has hampered the identification of efficacious molecules modulating the progression of different forms of the disease. Areas covered: The advent of new in vitro screening methodologies is allowing for novel strategies to develop new compounds that could interfere with a broad range of diseases. In particular, two innovative techniques named Real Time Quaking Induced Conversion (RT-QuIC) and Protein Misfolding Cyclic Amplification (PMCA) have opened new venues for testing compounds in a rapid a reproducible way. These are discussed within. Expert opinion: For human prion diseases, one major hurdle has been a well-defined screening methodology. In other animal species, cell-based assays have been employed that could replicate animal prions indefinitely. Such a tool for human prion diseases is still missing. Therefore, the advent of RT-QuIC and PMCA has proven instrumental to overcome this limitation.
- Published
- 2019
27. Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State
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Stefano Ricagno, Francesca Malagrinò, Lorenzo Visconti, Stefano Gianni, Angelo Toto, Chiara De Luca, Luca Broggini, Fabio Moda, Visconti, L., Malagrino, Francesca, Broggini, L., De Luca, C. M. G., Moda, F., Gianni, S., Ricagno, S., and Toto, A.
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folding ,0301 basic medicine ,Protein Denaturation ,binding ,Amyloid ,Equilibrium unfolding ,Mutant ,Protein aggregation ,medicine.disease_cause ,Protein Aggregation, Pathological ,Catalysis ,Article ,protein aggregation ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,Protein Aggregates ,0302 clinical medicine ,medicine ,Physical and Theoretical Chemistry ,lcsh:QH301-705.5 ,Molecular Biology ,denatured state ,Spectroscopy ,Alleles ,Protein Unfolding ,Mutation ,Chemistry ,Beta-2 microglobulin ,Amyloidosis ,Organic Chemistry ,Osmolar Concentration ,Wild type ,experiments ,General Medicine ,Hydrogen-Ion Concentration ,medicine.disease ,Recombinant Proteins ,Computer Science Applications ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Amino Acid Substitution ,protein stability ,Biophysics ,beta 2-Microglobulin ,030217 neurology & neurosurgery - Abstract
Beta-2 microglobulin (&beta, 2m) is a protein responsible for a pathologic condition, known as dialysis-related amyloidosis (DRA), caused by its aggregation and subsequent amyloid formation. A naturally occurring mutation of &beta, 2m, D76N, presents a higher amyloidogenic propensity compared to the wild type counterpart. Since the three-dimensional structure of the protein is essentially unaffected by the mutation, the increased aggregation propensity of D76N has been generally ascribed to its lower thermodynamic stability and increased dynamics. In this study we compare the equilibrium unfolding and the aggregation propensity of wild type &beta, 2m and D76N variant at different experimental conditions. Our data revealed a surprising effect of the D76N mutation in the residual structure of the denatured state, which appears less compact than that of the wild type protein. A careful investigation of the structural malleability of the denatured state of wild type &beta, 2m and D76N pinpoint a clear role of the denatured state in triggering the amyloidogenic propensity of the protein. The experimental results are discussed in the light of the previous work on &beta, 2m and its role in disease.
- Published
- 2018
28. Molecular subtypes of Alzheimer’s disease
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Marcella Catania, Anna Paterlini, Giuseppe Di Fede, Edoardo Bistaffa, Laura Colombo, Giorgio Giaccone, Bernardino Ghetti, Stefano Sorrentino, Roberta Ghidoni, Ilaria Campagnani, Elisa Tonoli, Emanuela Maderna, Fabio Moda, Fabrizio Tagliavini, Adriana Maria Kubis, Luisa Benussi, Di Fede, G, Catania, M, Maderna, E, Ghidoni, R, Benussi, L, Tonoli, E, Giaccone, G, Moda, F, Paterlini, A, Campagnani, I, Sorrentino, S, Colombo, L, Kubis, A, Bistaffa, E, Ghetti, B, and Tagliavini, F
- Subjects
0301 basic medicine ,Amyloid ,Proteases ,Chemical Phenomena ,lcsh:Medicine ,Molecular neuroscience ,Disease ,Protein aggregation ,Protein Aggregation, Pathological ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Biological property ,Animals ,Humans ,lcsh:Science ,Amyloid beta-Peptides ,Multidisciplinary ,Chemistry ,lcsh:R ,Brain ,Phenotype ,Cerebral Amyloid Angiopathy ,Disease Models, Animal ,030104 developmental biology ,Biochemistry ,lcsh:Q ,Protein folding ,030217 neurology & neurosurgery - Abstract
Protein misfolding and aggregation is a central feature of several neurodegenerative disorders including Alzheimer’s disease (AD), in which assemblies of amyloid β (Aβ) peptides accumulate in the brain in the form of parenchymal and/or vascular amyloid. A widely accepted concept is that AD is characterized by distinct clinical and neuropathological phenotypes. Recent studies revealed that Aβ assemblies might have structural differences among AD brains and that such pleomorphic assemblies can correlate with distinct disease phenotypes. We found that in both sporadic and inherited forms of AD, amyloid aggregates differ in the biochemical composition of Aβ species. These differences affect the physicochemical properties of Aβ assemblies including aggregation kinetics, resistance to degradation by proteases and seeding ability. Aβ-amyloidosis can be induced and propagated in animal models by inoculation of brain extracts containing aggregated Aβ. We found that brain homogenates from AD patients with different molecular profiles of Aβ are able to induce distinct patterns of Aβ-amyloidosis when injected into mice. Overall these data suggest that the assembly of mixtures of Aβ peptides into different Aβ seeds leads to the formation of distinct subtypes of amyloid having distinctive physicochemical and biological properties which result in the generation of distinct AD molecular subgroups.
- Published
- 2018
29. MRI abnormalities found 1 year prior to symptom onset in a case of Creutzfeldt–Jakob disease
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Federico Verde, Andrea Falini, Vincenzo Silani, Fabio Moda, Elisa Scola, Floriano Girotti, Stefano Messina, Luca Maderna, Fabrizio Tagliavini, Narghes Calcagno, Nicola Ticozzi, Verde, F, Ticozzi, N, Messina, S, Calcagno, N, Girotti, F, Maderna, L, Moda, F, Scola, E, Falini, Andrea, Tagliavini, F, and Silani, V.
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0301 basic medicine ,medicine.medical_specialty ,Pediatrics ,Neurology ,business.industry ,MEDLINE ,Posterior reversible encephalopathy syndrome ,Disease ,Ideomotor apraxia ,Creutzfeldt-Jakob Syndrome ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Medicine ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Neuroradiology ,Visual agnosia - Published
- 2016
30. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model
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Dario Brunetti, Carla Giordano, Fabio Moda, Giulia d'Amati, Sabrina Dusi, Michela Morbin, Ilaria D'Amato, Susan J. Hayflick, Valeria Tiranti, Anna Cozzi, Sonia Levi, Andrea Uggetti, Brunetti, Dario, Dusi, Sabrina, Morbin, Michela, Uggetti, Andrea, Moda, Fabio, D'Amato, Ilaria, Giordano, Carla, D'Amati, Giulia, Cozzi, Anna, Levi, Sonia, Hayflick, Susan, Tiranti, Valeria, Brunetti, D, Dusi, S, Morbin, M, Uggetti, A, Moda, F, D'Amato, I, Giordano, C, D'Amati, G, Cozzi, A, Levi, SONIA MARIA ROSA, Hayflick, S, and Tiranti, V.
- Subjects
Central Nervous System ,Retinal degeneration ,Neurodegeneration with brain iron accumulation ,Mitochondrion ,Biology ,Membrane Potential ,Pantothenate kinase-associated neurodegeneration ,Membrane Potentials ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genetic ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Cellular localization ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Neurodegenerative Disease ,Animal ,Neurodegeneration ,Neurodegenerative Diseases ,Oxidative Stre ,Articles ,General Medicine ,PANK2 ,medicine.disease ,Mitochondria ,Cell biology ,Oxidative Stress ,Phosphotransferases (Alcohol Group Acceptor) ,Biochemistry ,Mitochondrial Membranes ,Knockout mouse ,Mitochondrial Membrane ,030217 neurology & neurosurgery ,Human - Abstract
Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of this disorder is poorly understood and, although PANK2 is a mitochondrial protein, perturbations in mitochondrial bioenergetics have not been reported. A knock-out (KO) mouse model of PKAN exhibits retinal degeneration and azoospermia, but lacks any neurological phenotype. The absence of a clinical phenotype has partially been explained by the different cellular localization of the human and murine PANK2 proteins. Here we demonstrate that the mouse Pank2 protein localizes to mitochondria, similar to its human orthologue. Moreover, we show that Pank2-defective neurons derived from KO mice have an altered mitochondrial membrane potential, a defect further corroborated by the observations of swollen mitochondria at the ultra-structural level and by the presence of defective respiration. © The Author 2012.Published by Oxford University Press.
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- 2012
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31. Engineered adeno associated-viruses expressing anti-prp molecules and polyelectrolyte gold nanoparticles as new therapeutic strategies for prion diseases in mouse models
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MODA, FABIO and Moda, F
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MED/26 - NEUROLOGIA ,Protein Misfolding ,Gene therapy ,Nanomedicine ,Prion ,Prion disease ,TSE ,Neurodegeneration - Abstract
The prion diseases are neurodegenerative disorders of humans and animals that are sporadic or inherited in origin and can be transmitted. Despite remarkable differences in phenotypic expression, these disorders share a similar pathogenic mechanism, i.e. a posttranslational modification of the prion protein from a normal cellular isoform (PrPC) to insoluble and protease-resistant disease-specific species (termed PrPSc). PrPSc accumulates in the brain and, according to prion hypothesis, is responsible for the propagation of the pathologic process and transmissibility of the disease, by converting PrPC into a likeness of itself. In a model of prion replication, direct interaction between PrPSc template and the endogenous PrPC is proposed to drive the formation of nascent infectious prions. For these reasons therapies to prevent prion diseases can be targeted towards the selective binding of PrPC or PrPSc and the process of conversion. Many compounds have been proposed as potential therapies in the treatment of prion diseases. With the development of novel gene delivery system and nanomedicine, it has been possible to design innovative in vitro therapies effective in cure chronically prion infected cells. ScFvD18, an antibody fragment composed by the variable regions of the heavy and light chains, already resulted in efficient clearing PrPSc in prion infected cells. Fo this reason, ScFvD18 was engineered in Adeno-Associated Viral vectors (AAVs) serotype 9 (AAV9-ScFvD18) and inoculated into the brain of prion infected mice to assess its effectiveness in modify disease progression. Also polyelectrolyte covered gold nanoparticles (AuNPs) are excellent therapeutic compounds due to the intrinsic properties as being non-toxic, inert to most chemical reactions and easy to prepare. In vitro experiments showed that even picomolar amount of AuNPs with layer-wise deposition of oppositely charged synthetic polyelectrolytes, such as polyallylamine hydrochloride (PAH)and polystyrenesulfonate (PSS), were able to hamper the accumulation of PrPSc in cell culture. The efficacy of these nanogold particles was further assessed in prion infected mice.
- Published
- 2010
32. Transmission of Norwegian reindeer CWD to sheep by intracerebral inoculation results in an unusual phenotype and prion distribution.
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Harpaz E, Cazzaniga FA, Tran L, Vuong TT, Bufano G, Salvesen Ø, Gravdal M, Aldaz D, Sun J, Kim S, Celauro L, Legname G, Telling GC, Tranulis MA, Benestad SL, Espenes A, Moda F, and Ersdal C
- Subjects
- Animals, Sheep, Norway, Brain metabolism, Phenotype, Sheep Diseases transmission, Wasting Disease, Chronic transmission, Reindeer, Prions metabolism
- Abstract
Chronic wasting disease (CWD), a prion disease affecting cervids, has been known in North America (NA) since the 1960s and emerged in Norway in 2016. Surveillance and studies have revealed that there are different forms of CWD in Fennoscandia: contagious CWD in Norwegian reindeer and sporadic CWD in moose and red deer. Experimental studies have demonstrated that NA CWD prions can infect various species, but thus far, there have been no reports of natural transmission to non-cervid species. In vitro and laboratory animal studies of the Norwegian CWD strains suggest that these strains are different from the NA strains. In this work, we describe the intracerebral transmission of reindeer CWD to six scrapie-susceptible sheep. Detection methods included immunohistochemistry (IHC), western blot (WB), enzyme-linked immunosorbent assay (ELISA), real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA). In the brain, grey matter vacuolation was limited, while all sheep exhibited vacuolation of the white matter. IHC and WB conventional detection techniques failed to detect prions; however, positive seeding activity with the RT-QuIC and PMCA amplification techniques was observed in the central nervous system of all but one sheep. Prions were robustly amplified in the lymph nodes of all animals, mainly by RT-QuIC. Additionally, two lymph nodes were positive by WB, and one was positive by ELISA. These findings suggest that sheep can propagate reindeer CWD prions after intracerebral inoculation, resulting in an unusual disease phenotype and prion distribution with a low amount of detectable prions., (© 2024. The Author(s).)
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- 2024
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33. From Protein Misfolding to Dementia: Basic Research, Innovative Diagnosis and Early Biomarkers.
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Bacınoğlu MB, Ciullini A, Giaccone G, and Moda F
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- Humans, Proteostasis Deficiencies metabolism, Proteostasis Deficiencies diagnosis, Protein Folding, Alzheimer Disease metabolism, Alzheimer Disease diagnosis, Biomarkers metabolism, Dementia metabolism, Dementia diagnosis
- Abstract
Competing Interests: The authors declare no conflict of interest. Given the role as Guest Editor member of FBL, Fabio Moda and Giorgio Giaccone had no involvement in the peer-review of this editorial and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to Graham Pawelec.
- Published
- 2024
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34. Tau seeding activity in skin biopsy differentiates tauopathies from synucleinopathies.
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Dellarole IL, Vacchi E, Ruiz-Barrio I, Pinton S, Raimondi A, Rossi S, Morandi S, Bianco G, Begum Bacinoglu M, Lombardo A, Celauro L, Staedler C, Galati S, Pagonabarraga J, Kulisevsky J, Legname G, Gobbi C, Kaelin-Lang A, Moda F, and Melli G
- Abstract
Most neurodegenerative diseases lack definitive diagnostic tests, and the identification of easily accessible and reliable biomarkers remains a critical unmet need. Since tau protein is highly expressed in skin of tauopathies patients, we aimed to exploit the ultrasensitive seeding activity assay (SAA) to assess tau seeding activity in skin of patients with tauopathies. In this multicentric, case-control study, patients with tauopathies and synucleinopathies were consecutively recruited and sex-matched to healthy controls (HC). Subjects underwent a double 3 mm skin biopsy in cervical area and ankle. Skin tau-SAA, using TauK18 and TauK19 as reaction substrates for 4R and 3R isoforms, seeding score, clinical scales, biochemical and morphological characterization of SAA end-products were evaluated. We analyzed 58 subjects: 24 tauopathies (18 progressive supranuclear palsy, PSP, and 6 corticobasal degeneration, CBD), 20 synucleinopathies (14 Parkinson's disease, PD, and 6 multiple system atrophy, MSA), and 14 HC. PSP and CBD showed higher tau seeding activity at both anatomical sites. A greater sensitivity of 4R-SAA than 3R-SAA was observed. 4R tau-SAA identified tauopathies with 71% sensitivity and 93% specificity. Accuracy was higher for PSP than CBD: PSP vs HC / PD (AUC 0.825), while CBD vs HC / PD (AUC 0.797), and PSP vs MSA (AU 0.778). SAA end-products showed differences in biochemical and morphological characterization according to the anatomical site. Skin tau-SAA identifies tauopathies with good accuracy and can be used to implement the in-vivo clinical diagnosis of patients with neurodegenerative diseases. Further characterization of peripheral tau seed in skin may elucidate the structure of tau deposits in brain., (© 2024. The Author(s).)
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- 2024
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35. Combined 18F-FDG PET-CT markers in dementia with Lewy bodies.
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Mattoli MV, Cocciolillo F, Chiacchiaretta P, Dotta F, Trevisi G, Carrarini C, Thomas A, Sensi S, Pizzi AD, Nicola ADD, Crosta AD, Mammarella N, Padovani A, Pilotto A, Moda F, Tiraboschi P, Martino G, and Bonanni L
- Abstract
Introduction:
18 F-Fluoro-deoxyglucose-positron emission tomography (FDG-PET) is a supportive biomarker in dementia with Lewy bodies (DLB) diagnosis and its advanced analysis methods, including radiomics and machine learning (ML), were developed recently. The aim of this study was to evaluate the FDG-PET diagnostic performance in predicting a DLB versus Alzheimer's disease (AD) diagnosis., Methods: FDG-PET scans were visually and semi-quantitatively analyzed in 61 patients. Radiomics and ML analyses were performed, building five ML models: (1) clinical features; (2) visual and semi-quantitative PET features; (3) radiomic features; (4) all PET features; and (5) overall features., Results: At follow-up, 34 patients had DLB and 27 had AD. At visual analysis, DLB PET signs were significantly more frequent in DLB, having the highest diagnostic accuracy (86.9%). At semi-quantitative analysis, the right precuneus, superior parietal, lateral occipital, and primary visual cortices showed significantly reduced uptake in DLB. The ML model 2 had the highest diagnostic accuracy (84.3%)., Discussion: FDG-PET is a valuable tool in DLB diagnosis, having visual and semi-quantitative analyses with the highest diagnostic accuracy at ML analyses., Competing Interests: All authors report no conflicts of interest., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)- Published
- 2023
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36. Detection of prions in the urine of patients affected by sporadic Creutzfeldt-Jakob disease.
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Pritzkow S, Ramirez F, Lyon A, Schulz PE, Appleby B, Moda F, Ramirez S, Notari S, Gambetti P, and Soto C
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- Humans, Brain metabolism, Creutzfeldt-Jakob Syndrome diagnosis, Prions
- Abstract
Objective: Currently, it is unknown whether infectious prions are present in peripheral tissues and biological fluids of patients affected by sporadic Creutzfeldt-Jakob disease (sCJD), the most common prion disorder in humans. This represents a potential risk for inter-individual prion infection. The main goal of this study was to evaluate the presence of prions in urine of patients suffering from the major subtypes of sCJD., Methods: Urine samples from sCJD patients spanning the six major subtypes were tested. As controls, we used urine samples from people affected by other neurological or neurodegenerative diseases as well as healthy controls. These samples were analyzed blinded. The presence of prions was detected by a modified version of the PMCA technology, specifically optimized for high sensitive detection of sCJD prions., Results: The PMCA assay was first optimized to detect low quantities of prions in diluted brain homogenates from patients affected by all subtypes of sCJD spiked into healthy urine. Twenty-nine of the 81 patients affected by sCJD analyzed in this study were positive by PMCA testing, whereas none of the 160 controls showed any signal. These results indicate a 36% sensitivity and 100% specificity. The subtypes with the highest positivity rate were VV1 and VV2, which combined account for about 15-20% of all sCJD cases, and no detection was observed in MV1 and MM2., Interpretation: Our findings indicate that potentially infectious prions are secreted in urine of some sCJD patients, suggesting a possible risk for inter-individual transmission. Prion detection in urine might be used as a noninvasive preliminary screening test to detect sCJD., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2023
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37. Ambroxol as a disease-modifying treatment to reduce the risk of cognitive impairment in GBA -associated Parkinson's disease: a multicentre, randomised, double-blind, placebo-controlled, phase II trial. The AMBITIOUS study protocol.
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Colucci F, Avenali M, De Micco R, Fusar Poli M, Cerri S, Stanziano M, Bacila A, Cuconato G, Franco V, Franciotta D, Ghezzi C, Gastaldi M, Elia AE, Romito L, Devigili G, Leta V, Garavaglia B, Golfrè Andreasi N, Cazzaniga F, Reale C, Galandra C, Germani G, Mitrotti P, Ongari G, Palmieri I, Picascia M, Pichiecchio A, Verri M, Esposito F, Cirillo M, Di Nardo F, Aloisio S, Siciliano M, Prioni S, Amami P, Piacentini S, Bruzzone MG, Grisoli M, Moda F, Eleopra R, Tessitore A, Valente EM, and Cilia R
- Abstract
Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA -related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF)., Methods and Analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat., Ethics and Dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences., Trial Registration Numbers: NCT05287503, EudraCT 2021-004565-13., Competing Interests: Competing interests: RC has received speaking honoraria from Zambon Italia; Zambon SAU; Bial Italia Srl; advisory board fees from Bial; research support from the Italian Ministry of Health; he is Editor-in-Chief of the neuromuscular and movement disorders section of Brain Sciences (MDPI); Associate Editor of Parkinsonism and Related Disorders (Elsevier) and Frontiers in Ageing Neuroscience., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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38. Secondary Protein Aggregates in Neurodegenerative Diseases: Almost the Rule Rather than the Exception.
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Moda F, Ciullini A, Dellarole IL, Lombardo A, Campanella N, Bufano G, Cazzaniga FA, and Giaccone G
- Subjects
- Humans, Aged, Protein Aggregates, tau Proteins metabolism, Amyloid beta-Peptides, Neurodegenerative Diseases pathology, Lewy Body Disease metabolism, Lewy Body Disease pathology, Synucleinopathies, Alzheimer Disease metabolism, Parkinson Disease metabolism, Prion Diseases, Frontotemporal Lobar Degeneration
- Abstract
The presence of protein aggregates is a hallmark of many neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Traditionally, each disease has been associated with the aggregation of specific proteins, which serve as disease-specific biomarkers. For example, aggregates of α-synuclein (α-syn) are found in α-synucleinopathies such as PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Similarly, AD is characterized by aggregates of amyloid-beta (Aβ) and tau proteins. However, it has been observed that these protein aggregates can also occur in other neurodegenerative diseases, contributing to disease progression. For instance, α-syn aggregates have been detected in AD, Down syndrome, Huntington's disease, prion diseases, and various forms of FTLD. Similarly, Aβ aggregates have been found in conditions like DLB and PD. Tau aggregates, in addition to being present in primary tauopathies, have been identified in prion diseases, α-synucleinopathies, and cognitively healthy aged subjects. Finally, aggregates of TDP-43, typically associated with FTLD and amyotrophic lateral sclerosis (ALS), have been observed in AD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), MSA, DLB, and other neurodegenerative diseases. These findings highlight the complexity of protein aggregation in neurodegeneration and suggest potential interactions and common mechanisms underlying different diseases. A deeper understating of this complex scenario may eventually lead to the identification of a better elucidation of the pathogenetic mechanisms of these devastating conditions and hopefully new therapeutic stragegies., Competing Interests: The authors declare no conflict of interest. Given their role as Guest Editor member of FBL, Fabio Moda and Giorgio Giaccone had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to Antoni Camins., (© 2023 The Author(s). Published by IMR Press.)
- Published
- 2023
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39. Different tau fibril types reduce prion level in chronically and de novo infected cells.
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Celauro L, Burato A, Zattoni M, De Cecco E, Fantuz M, Cazzaniga FA, Bistaffa E, Moda F, and Legname G
- Subjects
- Humans, Amyloidogenic Proteins, Prion Proteins, Neurodegenerative Diseases, Prion Diseases metabolism, Prions metabolism, tau Proteins metabolism
- Abstract
Neurodegenerative diseases are often characterized by the codeposition of different amyloidogenic proteins, normally defining distinct proteinopathies. An example is represented by prion diseases, where the classical deposition of the aberrant conformational isoform of the prion protein (PrP
Sc ) can be associated with tau insoluble species, which are usually involved in another class of diseases called tauopathies. How this copresence of amyloidogenic proteins can influence the progression of prion diseases is still a matter of debate. Recently, the cellular form of the prion protein, PrPC , has been investigated as a possible receptor of amyloidogenic proteins, since its binding activity with Aβ, tau, and α-synuclein has been reported, and it has been linked to several neurotoxic behaviors exerted by these proteins. We have previously shown that the treatment of chronically prion-infected cells with tau K18 fibrils reduced PrPSc levels. In this work, we further explored this mechanism by using another tau construct that includes the sequence that forms the core of Alzheimer's disease tau filaments in vivo to obtain a distinct fibril type. Despite a difference of six amino acids, these two constructs form fibrils characterized by distinct biochemical and biological features. However, their effects on PrPSc reduction were comparable and probably based on the binding to PrPC at the plasma membrane, inhibiting the pathological conversion event. Our results suggest PrPC as receptor for different types of tau fibrils and point out a role of tau amyloid fibrils in preventing the pathological PrPC to PrPSc conformational change., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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40. Impact of seed amplification assay and surface-enhanced Raman spectroscopy combined approach on the clinical diagnosis of Alzheimer's disease.
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D'Andrea C, Cazzaniga FA, Bistaffa E, Barucci A, de Angelis M, Banchelli M, Farnesi E, Polykretis P, Marzi C, Indaco A, Tiraboschi P, Giaccone G, Matteini P, and Moda F
- Subjects
- Humans, Spectrum Analysis, Raman, Machine Learning, Seeds, Alzheimer Disease diagnosis, Cognitive Dysfunction
- Abstract
Background: The current diagnosis of Alzheimer's disease (AD) is based on a series of analyses which involve clinical, instrumental and laboratory findings. However, signs, symptoms and biomarker alterations observed in AD might overlap with other dementias, resulting in misdiagnosis., Methods: Here we describe a new diagnostic approach for AD which takes advantage of the boosted sensitivity in biomolecular detection, as allowed by seed amplification assay (SAA), combined with the unique specificity in biomolecular recognition, as provided by surface-enhanced Raman spectroscopy (SERS)., Results: The SAA-SERS approach supported by machine learning data analysis allowed efficient identification of pathological Aβ oligomers in the cerebrospinal fluid of patients with a clinical diagnosis of AD or mild cognitive impairment due to AD., Conclusions: Such analytical approach can be used to recognize disease features, thus allowing early stratification and selection of patients, which is fundamental in clinical treatments and pharmacological trials., (© 2023. The Author(s).)
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- 2023
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41. Correction to: Sporadic Fatal Insomnia presenting with agrypnia excitata and rapidly progressive dementia: a case report.
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Cannizzaro M, Pieri V, Curti DG, Gueye M, Rugarli G, Napoli G, Cardamone R, Falini A, Perani D, Zucconi M, Casoni F, Giaccone G, Moda F, Di Fede G, Magnani G, Caso F, and Filippi M
- Published
- 2023
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42. Sporadic Fatal Insomnia presenting with agrypnia excitata and rapidly progressive dementia: a case report.
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Cannizzaro M, Pieri V, Curti DG, Gueye M, Rugarli G, Napoli G, Cardamone R, Falini A, Perani D, Zucconi M, Casoni F, Giaccone G, Moda F, Di Fede G, Magnani G, Caso F, and Filippi M
- Subjects
- Humans, Polysomnography, Sleep Initiation and Maintenance Disorders complications, Dementia complications
- Published
- 2023
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43. Cerebrospinal fluid lipoproteins inhibit α-synuclein aggregation by interacting with oligomeric species in seed amplification assays.
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Bellomo G, Paciotti S, Concha-Marambio L, Rizzo D, Wojdaƚa AL, Chiasserini D, Gatticchi L, Cerofolini L, Giuntini S, De Luca CMG, Ma Y, Farris CM, Pieraccini G, Bologna S, Filidei M, Ravera E, Lelli M, Moda F, Fragai M, Parnetti L, and Luchinat C
- Subjects
- Humans, alpha-Synuclein chemistry, Lipoproteins, Synucleinopathies, Parkinson Disease diagnosis
- Abstract
Background: Aggregation of α-synuclein (α-syn) is a prominent feature of Parkinson's disease (PD) and other synucleinopathies. Currently, α-syn seed amplification assays (SAAs) using cerebrospinal fluid (CSF) represent the most promising diagnostic tools for synucleinopathies. However, CSF itself contains several compounds that can modulate the aggregation of α-syn in a patient-dependent manner, potentially undermining unoptimized α-syn SAAs and preventing seed quantification., Methods: In this study, we characterized the inhibitory effect of CSF milieu on detection of α-syn aggregates by means of CSF fractionation, mass spectrometry, immunoassays, transmission electron microscopy, solution nuclear magnetic resonance spectroscopy, a highly accurate and standardized diagnostic SAA, and different in vitro aggregation conditions to evaluate spontaneous aggregation of α-syn., Results: We found the high-molecular weight fraction of CSF (> 100,000 Da) to be highly inhibitory on α-syn aggregation and identified lipoproteins to be the main drivers of this effect. Direct interaction between lipoproteins and monomeric α-syn was not detected by solution nuclear magnetic resonance spectroscopy, on the other hand we observed lipoprotein-α-syn complexes by transmission electron microscopy. These observations are compatible with hypothesizing an interaction between lipoproteins and oligomeric/proto-fibrillary α-syn intermediates. We observed significantly slower amplification of α-syn seeds in PD CSF when lipoproteins were added to the reaction mix of diagnostic SAA. Additionally, we observed a decreased inhibition capacity of CSF on α-syn aggregation after immunodepleting ApoA1 and ApoE. Finally, we observed that CSF ApoA1 and ApoE levels significantly correlated with SAA kinetic parameters in n = 31 SAA-negative control CSF samples spiked with preformed α-syn aggregates., Conclusions: Our results describe a novel interaction between lipoproteins and α-syn aggregates that inhibits the formation of α-syn fibrils and could have relevant implications. Indeed, the donor-specific inhibition of CSF on α-syn aggregation explains the lack of quantitative results from analysis of SAA-derived kinetic parameters to date. Furthermore, our data show that lipoproteins are the main inhibitory components of CSF, suggesting that lipoprotein concentration measurements could be incorporated into data analysis models to eliminate the confounding effects of CSF milieu on α-syn quantification efforts., (© 2023. The Author(s).)
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- 2023
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44. Corrigendum: PMCA-based detection of prions in the olfactory mucosa of patients with sporadic Creutzfeldt-Jakob disease.
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Cazzaniga FA, Bistaffa E, De Luca CMG, Portaleone SM, Catania M, Redaelli V, Tramacere I, Bufano G, Rossi M, Caroppo P, Giovagnoli AR, Tiraboschi P, Di Fede G, Eleopra R, Devigili G, Elia AE, Cilia R, Fiorini M, Bongianni M, Salzano G, Celauro L, Quarta FG, Mammana A, Legname G, Tagliavini F, Parchi P, Zanusso G, Giaccone G, and Moda F
- Abstract
[This corrects the article DOI: 10.3389/fnagi.2022.848991.]., (Copyright © 2023 Cazzaniga, Bistaffa, De Luca, Portaleone, Catania, Redaelli, Tramacere, Bufano, Rossi, Caroppo, Giovagnoli, Tiraboschi, Di Fede, Eleopra, Devigili, Elia, Cilia, Fiorini, Bongianni, Salzano, Celauro, Quarta, Mammana, Legname, Tagliavini, Parchi, Zanusso, Giaccone and Moda.)
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- 2023
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45. Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models.
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Staderini M, Vanni S, Baldeschi AC, Giachin G, Zattoni M, Celauro L, Ferracin C, Bistaffa E, Moda F, Pérez DI, Martínez A, Martín MA, Martín-Cámara O, Cores Á, Bianchini G, Kammerer R, Menéndez JC, Legname G, and Bolognesi ML
- Subjects
- Animals, Mice, Cell Line, Optical Imaging, Carbazoles chemistry, Carbazoles pharmacology, Carbazoles therapeutic use, Prion Diseases diagnosis, Prion Diseases drug therapy, PrPC Proteins antagonists & inhibitors, PrPC Proteins chemistry, Protein Aggregates drug effects
- Abstract
Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrP
Sc ) of the cellular prion protein (PrPC ). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four-step route, and a representative member was confirmed to have native fluorescence, including a band in the near-infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc . Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cell lines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrPC levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain-independent anti-prion compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2023
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46. Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort.
- Author
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Rossi G, Salvi E, Mehmeti E, Ricci M, Villa C, Prioni S, Moda F, Di Fede G, Tiraboschi P, Redaelli V, Coppola C, Koch G, Canu E, Filippi M, Agosta F, Giaccone G, and Caroppo P
- Abstract
Semantic and right temporal variant of frontotemporal dementia (svFTD and rtvFTD) are rare clinical phenotypes in which, in most cases, the underlying pathology is TDP-43 proteinopathy. They are usually sporadic disorders, but recent evidences suggest a higher frequency of genetic mutations for the right temporal versus the semantic variant. However, the genetic basis of these forms is not clear. In this study we performed a genetic screening of a single-center cohort of svFTD and rtvFTD patients, aiming at identifying the associated genetic variants. A panel of 73 dementia candidate genes has been analyzed by NGS target sequencing including both causal and risk/modifier genes in 23 patients (15 svFTD and 8 rtvFTD) and 73 healthy age-matched controls. We first performed a single variant analysis considering rare variants and then a gene-based aggregation analysis to evaluate the cumulative effects of multiple rare variants in a single gene. We found 12 variants in nearly 40% of patients (9/23), described as pathogenic or classified as VUS/likely pathogenic. The overall rate was higher in svFTD than in rtvFTD. Three mutations were located in MAPT gene and single mutations in the following genes: SQSTM1, VCP, PSEN1, TBK1, OPTN, CHCHD10, PRKN, DCTN1 . Our study revealed the presence of variants in genes involved in pathways relevant for the pathology, especially autophagy and inflammation. We suggest that molecular analysis should be performed in all svFTD and rtvFTD patients, to better understand the genotype-phenotype correlation and the pathogenetic mechanisms that could drive the clinical phenotypes in FTD., Competing Interests: EC has received research supports from the Italian Ministry of Health. MF is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). FA is Section Editor of NeuroImage: Clinical; has received speaker honoraria from Biogen Idec, Roche and Zambon; and receives or has received research supports from the Italian Ministry of Health, AriSLA (Fondazione Italiana di Ricerca per la SLA), the European Research Council and the Foundation Research on Alzheimer Disease. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rossi, Salvi, Mehmeti, Ricci, Villa, Prioni, Moda, Di Fede, Tiraboschi, Redaelli, Coppola, Koch, Canu, Filippi, Agosta, Giaccone and Caroppo.)
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- 2022
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47. Approaching the Gut and Nasal Microbiota in Parkinson's Disease in the Era of the Seed Amplification Assays.
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Consonni A, Miglietti M, De Luca CMG, Cazzaniga FA, Ciullini A, Dellarole IL, Bufano G, Di Fonzo A, Giaccone G, Baggi F, and Moda F
- Abstract
Parkinson's disease (PD) is a neurodegenerative disorder often associated with pre-motor symptoms involving both gastrointestinal and olfactory tissues. PD patients frequently suffer from hyposmia, hyposalivation, dysphagia and gastrointestinal dysfunctions. During the last few years it has been speculated that microbial agents could play a crucial role in PD. In particular, alterations of the microbiota composition (dysbiosis) might contribute to the formation of misfolded α-synuclein, which is believed to be the leading cause of PD. However, while several findings confirmed that there might be an important link between intestinal microbiota alterations and PD onset, little is known about the potential contribution of the nasal microbiota. Here, we describe the latest findings on this topic by considering that more than 80% of patients with PD develop remarkable olfactory deficits in their prodromal disease stage. Therefore, the nasal microbiota might contribute to PD, eventually boosting the gut microbiota in promoting disease onset. Finally, we present the applications of the seed amplification assays to the study of the gut and olfactory mucosa of PD patients, and how they could be exploited to investigate whether pathogenic bacteria present in the gut and the nose might promote α-synuclein misfolding and aggregation.
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- 2022
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48. Correction to: The cognitive phenotypes of Creutzfeldt‑Jakob disease: comparison with secondary metabolic encephalopathy.
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Giovagnoli AR, Di Fede G, Rossi G, Moda F, Grisoli M, and Bugiani O
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- 2022
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49. Structural and dynamical determinants of a β-sheet-enriched intermediate involved in amyloid fibrillar assembly of human prion protein.
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Russo L, Salzano G, Corvino A, Bistaffa E, Moda F, Celauro L, D'Abrosca G, Isernia C, Milardi D, Giachin G, Malgieri G, Legname G, and Fattorusso R
- Abstract
The conformational conversion of the cellular prion protein (PrP
C ) into a misfolded, aggregated and infectious scrapie isoform is associated with prion disease pathology and neurodegeneration. Despite the significant number of experimental and theoretical studies the molecular mechanism regulating this structural transition is still poorly understood. Here, via Nuclear Magnetic Resonance (NMR) methodologies we investigate at the atomic level the mechanism of the human HuPrP(90-231) thermal unfolding and characterize the conformational equilibrium between its native structure and a β-enriched intermediate state, named β-PrPI. By comparing the folding mechanisms of metal-free and Cu2+ -bound HuPrP(23-231) and HuPrP(90-231) we show that the coupling between the N- and C-terminal domains, through transient electrostatic interactions, is the key molecular process in tuning long-range correlated μs-ms dynamics that in turn modulate the folding process. Moreover, via thioflavin T (ThT)-fluorescence fibrillization assays we show that β-PrPI is involved in the initial stages of PrP fibrillation, overall providing a clear molecular description of the initial phases of prion misfolding. Finally, we show by using Real-Time Quaking-Induced Conversion (RT-QuIC) that the β-PrPI acts as a seed for the formation of amyloid aggregates with a seeding activity comparable to that of human infectious prions., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)- Published
- 2022
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50. α-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies: The Way Forward.
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Bellomo G, De Luca CMG, Paoletti FP, Gaetani L, Moda F, and Parnetti L
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- Humans, Kinetics, alpha-Synuclein metabolism, Lewy Body Disease pathology, Multiple System Atrophy pathology, Parkinson Disease pathology, Prions, Synucleinopathies diagnosis
- Abstract
Parkinson disease (PD) is the second most common neurodegenerative disease, and the most common synucleinopathy, as alpha-synuclein (α-syn), a prion-like protein, plays an important pathophysiologic role in its onset and progression. Although neuropathologic changes begin many years before the onset of motor manifestations, diagnosis still relies on the identification of the motor symptoms, which hinders to formulate an early diagnosis. Because α-syn misfolding and aggregation precede clinical manifestations, the possibility to identify these phenomena in patients with PD would allow us to recognize the disease at the earliest, premotor phases, as a consequence of the transition from a clinical to a molecular diagnosis. Seed amplification assays (SAAs) are a group of techniques that currently support the diagnosis of prion subacute encephalopathies, namely Creutzfeldt-Jakob disease. These techniques enable the detection of minimal amounts of prions in CSF and other matrices of affected patients. Recently, SAAs have been successfully applied to detect misfolded alpha-synuclein (α-syn) in CSF, olfactory mucosa, submandibular gland biopsies, skin, and saliva of patients with Parkinson disease (PD) and other synucleinopathies. In these categories, they can differentiate PD and dementia with Lewy bodies (DLBs) from control subjects, even in the prodromal stages of the disease. In differential diagnosis, SAAs satisfactorily differentiated PD, DLB, and multiple system atrophy (MSA) from nonsynucleinopathy parkinsonisms. The kinetic analysis of the SAA fluorescence profiles allowed the identification of synucleinopathy-dependent α-syn fibrils conformations, commonly referred to as strains, which have demonstrated diagnostic potential in differentiating among synucleinopathies, especially between Lewy body diseases (LBDs) (PD and DLB) and MSA. In front of these highly promising data, which make the α-syn seeding activity detected by SAAs as the most promising diagnostic biomarker for synucleinopathies, there are still preanalytical and analytical issues, mostly related to the assay standardization, which need to be solved. In this review, we discuss the key findings supporting the clinical application of α-syn SAAs to identify PD and other synucleinopathies, the unmet needs, and future perspectives., (© 2022 American Academy of Neurology.)
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- 2022
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