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1. Quantitative neuroimaging biomarkers in a series of 20 adult patients with POLG mutations.

Author

Masingue M, Adanyeguh I, Tchikviladzé M, Maisonobe T, Jardel C, Galanaud D, and Mochel F

Subjects
Adolescent, Adult, Aged, Animals, Basal Ganglia pathology, Brain Stem pathology, Female, Gyrus Cinguli pathology, Humans, Male, Middle Aged, Myography methods, Retrospective Studies, Young Adult, Biomarkers analysis, DNA Polymerase gamma genetics, Diffusion Tensor Imaging methods, Mitochondrial Diseases diagnostic imaging, Mutation
Abstract

Mutations in the gene encoding polymerase gamma (POLG) are a common cause of mitochondrial diseases in adults. We retrospectively analyzed volumetric and diffusion tensor imaging data from 20 adult POLG-mutated patients compared to healthy controls. We used an original clinical binary load score and electroneuromyography to evaluate disease severity. Patients showed atrophy in the basal ganglia, amygdala, and brainstem (p < 0.05) compared to controls, as well as decreased fractional anisotropy (FA) in the cingulate gyrus, the internal capsule and the corona radiata (p < 0.05). Clinical scores correlated with decreased FA and increased radial diffusivity in several brain regions (p < 0.05)., (Copyright © 2018 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Published
2019
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2. New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Author

Pilliod J, Moutton S, Lavie J, Maurat E, Hubert C, Bellance N, Anheim M, Forlani S, Mochel F, N'Guyen K, Thauvin-Robinet C, Verny C, Milea D, Lesca G, Koenig M, Rodriguez D, Houcinat N, Van-Gils J, Durand CM, Guichet A, Barth M, Bonneau D, Convers P, Maillart E, Guyant-Marechal L, Hannequin D, Fromager G, Afenjar A, Chantot-Bastaraud S, Valence S, Charles P, Berquin P, Rooryck C, Bouron J, Brice A, Lacombe D, Rossignol R, Stevanin G, Benard G, Burglen L, Durr A, Goizet C, and Coupry I

Subjects
Adolescent, Adult, Cell Culture Techniques, Child, Cohort Studies, Female, Fibroblasts, Heat-Shock Proteins genetics, Humans, Male, Middle Aged, Muscle Spasticity genetics, Muscle Spasticity pathology, Muscle Spasticity physiopathology, Mutation, Spinocerebellar Ataxias diagnosis, Spinocerebellar Ataxias genetics, Spinocerebellar Ataxias pathology, Spinocerebellar Ataxias physiopathology, Young Adult, Biomarkers, Heat-Shock Proteins physiology, Mitochondria metabolism, Mitochondria pathology, Mitochondria physiology, Muscle Spasticity diagnosis, Spinocerebellar Ataxias congenital
Abstract

Objective: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the SACS gene. SACS encodes sacsin, a protein whose function remains unknown, despite the description of numerous protein domains and the recent focus on its potential role in the regulation of mitochondrial physiology. This study aimed to identify new mutations in a large population of ataxic patients and to functionally analyze their cellular effects in the mitochondrial compartment., Methods: A total of 321 index patients with spastic ataxia selected from the SPATAX network were analyzed by direct sequencing of the SACS gene, and 156 patients from the ATAXIC project presenting with congenital ataxia were investigated either by targeted or whole exome sequencing. For functional analyses, primary cultures of fibroblasts were obtained from 11 patients carrying either mono- or biallelic variants, including 1 case harboring a large deletion encompassing the entire SACS gene., Results: We identified biallelic SACS variants in 33 patients from SPATAX, and in 5 nonprogressive ataxia patients from ATAXIC. Moreover, a drastic and recurrent alteration of the mitochondrial network was observed in 10 of the 11 patients tested., Interpretation: Our results permit extension of the clinical and mutational spectrum of ARSACS patients. Moreover, we suggest that the observed mitochondrial network anomalies could be used as a trait biomarker for the diagnosis of ARSACS when SACS molecular results are difficult to interpret (ie, missense variants and heterozygous truncating variant). Based on our findings, we propose new diagnostic definitions for ARSACS using clinical, genetic, and cellular criteria., (© 2015 American Neurological Association.)

Published
2015
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3. Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency.

Author

Engelke UF, Zijlstra FS, Mochel F, Valayannopoulos V, Rabier D, Kluijtmans LA, Perl A, Verhoeven-Duif NM, de Lonlay P, Wamelink MM, Jakobs C, Morava E, and Wevers RA

Subjects
Adolescent, Animals, Butyrates chemistry, Child, Preschool, Fumarates chemistry, Fumarates urine, Gas Chromatography-Mass Spectrometry, Heptoses chemistry, Heptoses urine, Humans, Infant, Infant, Newborn, Ketoglutaric Acids chemistry, Ketoglutaric Acids urine, Magnetic Resonance Spectroscopy, Mice, Mice, Knockout, Molecular Structure, Pentose Phosphate Pathway, Ribitol chemistry, Ribitol urine, Sugar Alcohols chemistry, Sugar Alcohols urine, Transaldolase genetics, Biomarkers urine, Butyrates urine, Mitochondria metabolism, Transaldolase deficiency
Abstract

Background: Sedoheptulose, arabitol, ribitol, and erythritol have been identified as key diagnostic metabolites in TALDO deficiency., Method: Urine from 6 TALDO-deficient patients and TALDO-deficient knock-out mice were analyzed using ¹H-NMR spectroscopy and GC-mass spectrometry., Results: Our data confirm the known metabolic characteristics in TALDO-deficient patients. The β-furanose form was the major sedoheptulose anomer in TALDO-deficient patients. Erythronic acid was identified as a major abnormal metabolite in all patients and in knock-out TALDO mice implicating an as yet unknown biochemical pathway in this disease. A putative sequence of enzymatic reactions leading to the formation of erythronic acid is presented. The urinary concentration of the citric acid cycle intermediates 2-oxoglutaric acid and fumaric acid was increased in the majority of TALDO-deficient patients but not in the knock-out mice., Conclusion: Erythronic acid is a novel and major hallmark in TALDO deficiency. The pathway leading to its production may play a role in healthy humans as well. In TALDO-deficient patients, there is an increased flux through this pathway. The finding of increased citric acid cycle intermediates hints toward a disturbed mitochondrial metabolism in TALDO deficiency., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Published
2010
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4. Elevated CSF N-acetylaspartylglutamate suggests specific molecular diagnostic abnormalities in patients with white matter diseases.

Author

Mochel F, Boildieu N, Barritault J, Sarret C, Eymard-Pierre E, Seguin F, Schiffmann R, and Boespflug-Tanguy O

Subjects
Adolescent, Adult, Canavan Disease diagnosis, Canavan Disease genetics, Child, Child, Preschool, Dipeptides chemistry, Female, Gene Duplication, Humans, Magnetic Resonance Spectroscopy methods, Male, Molecular Structure, Myelin Proteolipid Protein genetics, Organic Anion Transporters genetics, Pelizaeus-Merzbacher Disease diagnosis, Pelizaeus-Merzbacher Disease genetics, Point Mutation, Sensitivity and Specificity, Symporters genetics, Biomarkers cerebrospinal fluid, Canavan Disease cerebrospinal fluid, Dipeptides cerebrospinal fluid, Pelizaeus-Merzbacher Disease cerebrospinal fluid
Abstract

Background: In order to identify biomarkers useful for the diagnosis of genetic white matter disorders we compared the metabolic profile of patients with leukodystrophies with a hypomyelinating or a non-hypomyelinating MRI pattern., Methods: We used a non-a priori method of in vitro ¹H-NMR spectroscopy on CSF samples of 74 patients with leukodystrophies., Results: We found an elevation of CSF N-acetylaspartylglutamate (NAAG) in patients with Pelizaeus-Merzbacher disease (PMD)-PLP1 gene, Pelizaeus-Merzbacher-like disease-GJC2 gene and Canavan disease-ASPA gene. In the PMD group, NAAG was significantly elevated in the CSF of all patients with PLP1 duplication (19/19) but was strictly normal in 6 out of 7 patients with PLP1 point mutations. Additionally, we previously reported increased CSF NAAG in patients with SLC17A5 mutations., Conclusions: Elevated CSF NAAG is a biomarker that suggests specific molecular diagnostic abnormalities in patients with white matter diseases. Our findings also point to unique pathological functions of the overexpressed PLP in PMD patients with duplication of this gene., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Published
2010
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5. Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression.

Author

Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, Perin L, Le Bouc Y, Gervais C, Carcelain G, Vassault A, Feingold J, Rabier D, and Durr A

Subjects
Adult, Aged, Aged, 80 and over, Amino Acids blood, Body Weight, Cognition Disorders genetics, Disease Progression, Female, Heterozygote, Humans, Huntington Disease blood, Huntington Disease physiopathology, Loss of Heterozygosity, Male, Middle Aged, Motor Activity, Mutation, Predictive Value of Tests, Reference Values, Weight Loss genetics, Biomarkers blood, Energy Metabolism, Huntington Disease genetics, Huntington Disease metabolism
Abstract

Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD has not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. (1)H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA), valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide.

Published
2007
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7. Biomarker-guided clustering of Alzheimer's disease clinical syndromes

Author

Toschi, Nicola, Lista, Simone, Lamari, Foudil, Genthon, Remy, Habert, Marie-Odile, Dubois, Bruno, Floris, Roberto, Garaci, Francesco, Vergallo, Andrea, Hampel, Harald, group, INSIGHT-preAD study, Initiative, Alzheimer Precision Medicine, Baldacci, Filippo, Bakardjian, Hovagim, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Boukerrou, Nadia, Cavedo, Enrica, Chiesa, Patrizia, Colliot, Olivier, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Houot, Marion, Kas, Aurélie, Levy, Marcel, Zetterberg, Henrik, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Andrade, Katia Santos, Sole, Marine, Blennow, Kaj, Surtee, Mohmed, Thiebaut de Schotten, Michel, Younsi, Nadjia, Kilimann, Ingo, Teipel, Stefan J, Melo Dos Santos, Antonio, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CCSD, Accord Elsevier, Università degli Studi di Roma Tor Vergata [Roma], Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), University of Pisa - Università di Pisa, University of Gothenburg (GU), University of Rostock, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre pour l'Acquisition et le Traitement des Images (CATI), Eisai, and Hovagim Bakardjian, Habib Benali, Hugo Bertin, Joel Bonheur, Laurie Boukadida, Nadia Boukerrou, Enrica Cavedo, Patrizia Chiesa, Olivier Colliot, Bruno Dubois, Marion Dubois, Stéphane Epelbaum, Geoffroy Gagliardi, Remy Genthon, Marie-Odile Habert, Harald Hampel, Marion Houot, Aurélie Kas, Foudil Lamari, Marcel Levy, Simone Lista, Christiane Metzinger, Fanny Mochel, Francis Nyasse, Catherine Poisson, Marie-Claude Potier, Marie Revillon, Antonio Santos, Katia Santos Andrade, Marine Sole, Mohmed Surtee, Michel Thiebaut de Schotten, Andrea Vergallo, Nadjia Younsi

Subjects
Male, 0301 basic medicine, Oncology, Aging, [SDV]Life Sciences [q-bio], cerebrospinal fluid [Amyloid beta-Peptides], Disease, 0302 clinical medicine, Risk Factors, General Neuroscience, Precision medicine, diagnosis [Alzheimer Disease], Alzheimer's disease, Middle Aged, Pathophysiology, 3. Good health, [SDV] Life Sciences [q-bio], cerebrospinal fluid [Alzheimer Disease], cerebrospinal fluid [Cognitive Dysfunction], cerebrospinal fluid [Biomarkers], Biomarker (medicine), Female, Biomarker-guided categorization, Clustering, medicine.medical_specialty, tau Proteins, Neuropathology, 03 medical and health sciences, Settore MED/36 - Diagnostica per Immagini e Radioterapia, Alzheimer Disease, Internal medicine, medicine, Humans, Dementia, Cognitive Dysfunction, ddc:610, cerebrospinal fluid [Peptide Fragments], Cluster analysis, Aged, Amyloid beta-Peptides, business.industry, medicine.disease, Settore FIS/07 - Fisica Applicata(Beni Culturali, Ambientali, Biol.e Medicin), Peptide Fragments, 030104 developmental biology, diagnosis [Cognitive Dysfunction], cerebrospinal fluid [tau Proteins], Spatial clustering, Neurology (clinical), Geriatrics and Gerontology, business, Biomarkers, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; Alzheimer's disease (AD) neuropathology is extremely heterogeneous, and the evolution from preclinical to mild cognitive impairment until dementia is driven by interacting genetic/biological mechanisms not fully captured by current clinical/research criteria. We characterized the heterogeneous "construct" of AD through a cerebrospinal fluid biomarker-guided stratification approach. We analyzed 5 validated pathophysiological cerebrospinal fluid biomarkers (Aβ1-42, t-tau, p-tau181, NFL, YKL-40) in 113 participants (healthy controls [N = 20], subjective memory complainers [N = 36], mild cognitive impairment [N = 20], and AD dementia [N = 37], age: 66.7 ± 10.4, 70.4 ± 7.7, 71.7 ± 8.4, 76.2 ± 3.5 years [mean ± SD], respectively) using Density-Based Spatial Clustering of Applications with Noise, which does not require a priori determination of the number of clusters. We found 5 distinct clusters (sizes: N = 38, 16, 24, 14, and 21) whose composition was independent of phenotypical groups. Two clusters showed biomarker profiles linked to neurodegenerative processes not associated with classical AD-related pathophysiology. One cluster was characterized by the neuroinflammation biomarker YKL-40. Combining nonlinear data aggregation with informative biomarkers can generate novel patient strata which are representative of cellular/molecular pathophysiology and may aid in predicting disease evolution and mechanistic drug response.

Published
2019

8. Multiparametric characterization of white matter alterations in early stage Huntington disease

Author

Adanyeguh, Isaac M., Branzoli, Francesca, Delorme, Cécile, Méneret, Aurélie, Monin, Marie-Lorraine, Luton, Marie-Pierre, Durr, Alexandra, Sabidussi, Emanoel, Mochel, Fanny, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], HAL-SU, Gestionnaire, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Center for NeuroImaging Research - CENIR, Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Adult, Male, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Science, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, Neuroimaging, Huntington's disease, Middle Aged, White Matter, Article, Diffusion Magnetic Resonance Imaging, Huntington Disease, Case-Control Studies, Disease Progression, Humans, Medicine, Female, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Huntington's disease (HD) is a monogenic, fully penetrant neurodegenerative disorder. Widespread white matter damage affects the brain of patients with HD at very early stages of the disease. Fixel-based analysis (FBA) is a novel method to investigate the contribution of individual crossing fibers to the white matter damage and to detect possible alterations in both fiber density and fiber-bundle morphology. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS), on the other hand, quantifies the motion of brain metabolites in vivo, thus enabling the investigation of microstructural alteration of specific cell populations. The aim of this study was to identify novel specific microstructural imaging markers of white matter degeneration in HD, by combining FBA and DW-MRS. Twenty patients at an early stage of HD and 20 healthy controls were recruited in a monocentric study. Using diffusion imaging we observed alterations to the brain microstructure and their morphology in patients with HD. Furthermore, FBA revealed specific fiber populations that were affected by the disease. Moreover, the mean diffusivity of the intra-axonal metabolite N-acetylaspartate, co-measured with N-acetylaspartylglutamate (tNAA), was significantly reduced in the corpus callosum of patients compared to controls. FBA and DW-MRS of tNAA provided more specific information about the biological mechanisms underlying HD and showed promise for early investigation of white matter degeneration in HD.

Published
2021

9. MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

Author

Vergallo, Andrea, Lista, Simone, group, INSIGHT-preAD study, Lucía, Alejandro, Mango, Dalila, Mapstone, Mark, Neri, Christian, Nisticò, Robert, O'Bryant, Sid E, Palermo, Giovanni, Perry, George, Ritchie, Craig, Rossi, Simone, Initiative, Alzheimer Precision Medicine, Saidi, Amira, Santarnecchi, Emiliano, Schneider, Lon S, Sporns, Olaf, Toschi, Nicola, Valenzuela, Pedro L, Vellas, Bruno, Verdooner, Steven R, Villain, Nicolas, Giudici, Kelly Virecoulon, Bakardjian, Hovagim, Watling, Mark, Welikovitch, Lindsay A, Woodcock, Janet, Younesi, Erfan, Zugaza, José L, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Boukerrou, Nadia, Cavedo, Enrica, Chiesa, Patrizia, Zhao, Yuhai, Colliot, Olivier, Dubois, Bruno, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Hampel, Harald, Houot, Marion, Kas, Aurélie, Lemercier, Pablo, Lamari, Foudil, Levy, Marcel, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Santos, Antonio, Teipel, Stefan J, Andrade, Katia Santos, Sole, Marine, Surtee, Mohmed, de Schotten, Michel Thiebaut, Younsi, Nadjia, Afshar, Mohammad, Aguilar, Lisi Flores, Akman-Anderson, Leyla, Arenas, Joaquín, Ávila, Jesús, Babiloni, Claudio, Baldacci, Filippo, Batrla, Richard, Benda, Norbert, Black, Keith L, Bokde, Arun L W, Bonuccelli, Ubaldo, Broich, Karl, Cacciola, Francesco, Caraci, Filippo, Caruso, Giuseppe, Castrillo, Juan, Ceravolo, Roberto, Chiesa, Patrizia A, Corbo, Massimo, Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L, Depypere, Herman, Duggento, Andrea, Emanuele, Enzo, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A, Garaci, Francesco, Lukiw, Walter J, Geerts, Hugo, Giacobini, Ezio, Giorgi, Filippo S, Goetzl, Edward J, Graziani, Manuela, Haberkamp, Marion, Hänisch, Britta, Herholz, Karl, Hernandez, Felix, Imbimbo, Bruno P, Kapogiannis, Dimitrios, Karran, Eric, Kiddle, Steven J, Kim, Seung H, Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehéricy, Stéphane, Llavero, Francisco, Lorenceau, Jean, Ministre de l'Enseignement Supérieur, de la Recherche et de l'Innovation (France), Sorbonne Université, AXA Research Fund, Fondation partenariale, Fondation pour la Recherche sur Alzheimer, Investissement d’Avenir French program, Vergallo, Andrea [0000-0002-0208-6384], Apollo - University of Cambridge Repository, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Louisiana State University (LSU), University of Rostock, Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CATI Multicenter Neuroimaging Platform (CATI), Service de médecine nucléaire [CHU Pitié-Salpétrière], Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Department of Psychiatry, Psychosomatic Medicine and Psychotherapy [Goethe Universität], Goethe-Universität Frankfurt am Main, HAL-SU, Gestionnaire, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Service de Médecine nucléaire [CHU Pitié-Salpétrière], Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France, Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)

Subjects
Apolipoprotein E, Aging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Disease, miRNAs plasma concentrations, Alzheimer's Disease, amyloid-β (Aβ)-positron emission tomography (Aβ-PET), Prognostic markers, 0302 clinical medicine, Medicine, Psychology, Aetiology, education.field_of_study, MicroARNs, Settore FIS/07, amyloid, Brain, Pathophysiology, ALZHEIMERS-DISEASE, Psychiatry and Mental health, Alzheimer's disease (AD), Public Health and Health Services, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MiRNA, medicine.medical_specialty, 18F-fluorodeoxyglucose-PET (18F-FDG-PET), BIOMARKERS, Neurociencias, Clinical Sciences, Molecular neuroscience, Predictive markers, Article, VESICLES, lcsh:RC321-571, 03 medical and health sciences, Memory, Clinical Research, Alzheimer Disease, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], microRNA, Genetics, Humans, education, Biological Psychiatry, Prevention, Memory, MiRNA, Alzheimer, biological markers, amyloid, 030104 developmental biology, Endocrinology, Cross-Sectional Studies, Positron-Emission Tomography, CELLS, Dementia, diagnostic imaging [Alzheimer Disease], INSIGHT-preAD study group, 030217 neurology & neurosurgery, [SDV.NEU.SC] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, 0301 basic medicine, genetics [Alzheimer Disease], Pilot Projects, Neurodegenerative, Medicine and Health Sciences, 2.1 Biological and endogenous factors, genetics [MicroRNAs], MIR-125B, screening and diagnosis, PLASMA, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Detection, Real-time polymerase chain reaction, Neurological, medicine.symptom, biological markers, Biotechnology, EXPRESSION, Population, metabolism [Amyloid beta-Peptides], Asymptomatic, Salud mental, Cellular and Molecular Neuroscience, ADULT, Fluorodeoxyglucose F18, Internal medicine, Acquired Cognitive Impairment, ddc:610, Allele, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, diagnostic imaging [Brain], Psiquiatría, Amyloid beta-Peptides, Enfermedad de alzheimer, business.industry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neurosciences, Alzheimer Precision Medicine Initiative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, 4.1 Discovery and preclinical testing of markers and technologies, MicroRNAs, metabolism [Brain], Alzheimer, business, Psychiatric disorders
Abstract

There is substantial experimental evidence for dysregulation of several microRNA (miRNA) expression levels in Alzheimer’s disease (AD). MiRNAs modulate critical brain intracellular signaling pathways and are associated with AD core pathophysiological mechanisms. First, we conducted a real-time quantitative PCR-based pilot study to identify a set of brain-enriched miRNAs in a monocentric cohort of cognitively normal individuals with subjective memory complaints, a condition associated with increased risk of AD. Second, we investigated the impact of age, sex, and the Apolipoprotein E ε4 (APOE ε4) allele, on the identified miRNA plasma concentrations. In addition, we explored the cross-sectional and longitudinal association of the miRNAs plasma concentrations with regional brain metabolic uptake using amyloid-β (Aβ)-positron emission tomography (Aβ-PET) and F-fluorodeoxyglucose-PET (F-FDG-PET). We identified a set of six brain-enriched miRNAs—miRNA-125b, miRNA-146a, miRNA-15b, miRNA-148a, miRNA-26b, and miRNA-100. Age, sex, and APOE ε4 allele were not associated with individual miRNA abundance. MiRNA-15b concentrations were significantly lower in the Aβ-PET-positive compared to Aβ-PET-negative individuals. Furthermore, we found a positive effect of the miRNA-15b*time interaction on regional metabolic F-FDG-PET uptake in the left hippocampus. Plasma miRNA-125b concentrations, as well as the miRNA-125b*time interaction (over a 2-year follow-up), were negatively associated with regional Aβ-PET standard uptake value ratio in the right anterior cingulate cortex. At baseline, we found a significantly negative association between plasma miRNA-125b concentrations and F-FDG-PET uptake in specific brain regions. In an asymptomatic at-risk population for AD, we show significant associations between plasma concentrations of miRNA-125b and miRNA-15b with core neuroimaging biomarkers of AD pathophysiology. Our results, coupled with existing experimental evidence, suggest a potential protective anti-Aβ effect of miRNA-15b and a biological link between miRNA-125b and Aβ-independent neurotoxic pathways., “Investissement d’Avenir” (ANR-10-AIHU-06) French program. The study was promoted in collaboration with the “CHU de Bordeaux” (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/Lilly. CATI is a French neuroimaging platform funded by the French Plan Alzheimer (available at http://cati-neuroimaging.com). A.V. is an employee of Eisai Inc. This work has been performed during his previous position at Sorbonne University, Paris, France. H.H. is an employee of Eisai Inc. This work has been performed during his previous position at Sorbonne University, Paris, France. At Sorbonne University he was supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université” and the “Fondation pour la Recherche sur Alzheimer

Published
2021

10. Plasma tau correlates with basal forebrain atrophy rates in people at risk for alzheimer disease

Author

Cavedo, Enrica, Lista, Simone, Dubois, Bruno, Mapstone, Mark, Neri, Christian, Nistico, Robert, O'Bryant, Sid E., Palermo, Giovanni, Perry, George, Ritchie, Craig, Rossi, Simone, Saidi, Amira, Santarnecchi, Emilian, Hampel, Harald, Schneider, Lon S., Sporns, Olaf, Toschi, Nicola, Verdooner, Steven R., Vergallo, Andrea, Villain, Nicolas, Welikovitch, Lindsay A., Woodcock, Janet, Younesi, Erfan, Group, INSIGHT-preAD Study, Alzheimer Precision Medicine Initiative, Bakardjian, Hovagim, Benali, Habib, Bertin, Hugo, Bonheur, Joel, Boukadida, Laurie, Houot, Marion, Chiesa, Patrizia, Colliot, Olivier, Dubois, Marion, Epelbaum, Stéphane, Gagliardi, Geoffroy, Genthon, Remy, Habert, Marie-Odile, Hampe, Harald, Kas, Auréli, Lamari, Foudil, Levy, Marcel, Metzinger, Christiane, Mochel, Fanny, Nyasse, Francis, Poisson, Catherine, Potier, Marie-Claude, Revillon, Marie, Grothe, Michel J, Santos, Antonio, Andrade, Katia Santos, Sole, Marine, Thiebaud de Schotten, Michel, Andrea, Vergallo, Nadjia, Yonsi, Afshar, Mohammad, Aguilar, Lisi Flores, Akman-Anderson, Leyla, Teipel, Stefan, Arenas, Joaquín, Avila, Jesus, Babiloni, Claudio, Baldacci, Filippo, Batrla, Richard, Benda, Norbert, Black, Keith L., Bokde, Arun L. W., Bonuccelli, Ubaldo, Broich, Karl, Zetterberg, Henrik, Caccilola, Francesco, Caraci, Filippo, Castrillo, Juan, Ceravolo, Roberto, Chiesa, Patrizia A., Corvol, Jean-Christophe, Cuello, Augusto Claudio, Cummings, Jeffrey L., Depypere, Herman, Blennow, Kaj, Duggent, Andrea, Emanuele, Enzo, Escott-Price, Valentina, Federoff, Howard, Ferretti, Maria Teresa, Fiandaca, Massimo, Frank, Richard A., Garaci, Francesco, Geerts, Hugo, Giorgi, Filippo S., Goetzl, Edward J., Graziani, Manuela, Haberkamp, Marion, Herholz, Karl, Hernandez, Felix, Kapogiannis, Dimitrios, Karran, Eric, Potier, Marie C, Kidddle, Stephen J, Kim, Seung H., Koronyo, Yosef, Koronyo-Hamaoui, Maya, Langevin, Todd, Lehericy, Stéphane, Lucia, Alejandro, Lorenceau, Jean, and Mango, Dalila

Subjects
0301 basic medicine, Apolipoprotein E, Male, blood [Neurofilament Proteins], Cohort Studies, pathology [Alzheimer Disease], 0302 clinical medicine, pathology [Prosencephalon], Neurofilament Proteins, blood [Amyloid beta-Peptides], Basal forebrain, pathology [Parasympathetic Nervous System], Magnetic Resonance Imaging, Predictive value of tests, Cohort, Female, Alzheimer's disease, Cohort study, blood [tau Proteins], medicine.medical_specialty, tau Proteins, 03 medical and health sciences, aged, alzheimer disease, amyloid beta-peptides, apolipoproteins e, atrophy, biomarkers, cohort studies, female, humans, magnetic resonance imaging, male, neurofilament proteins, parasympathetic nervous system, positron-emission tomography, predictive value of tests, prosencephalon, tau proteins, Atrophy, blood [Alzheimer Disease], Apolipoproteins E, Prosencephalon, Alzheimer Disease, Parasympathetic Nervous System, Predictive Value of Tests, Internal medicine, medicine, Dementia, Humans, ddc:610, Aged, Amyloid beta-Peptides, business.industry, diagnostic imaging [Prosencephalon], medicine.disease, 030104 developmental biology, Endocrinology, Positron-Emission Tomography, genetics [Apolipoproteins E], Neurology (clinical), business, diagnostic imaging [Alzheimer Disease], 030217 neurology & neurosurgery, Biomarkers
Abstract

ObjectiveTo investigate whether baseline concentrations of plasma total tau (t-tau) and neurofilament light (NfL) chain proteins are associated with annual percent change (APC) of the basal forebrain cholinergic system (BFCS) in cognitively intact older adults at risk for Alzheimer disease (AD).MethodsThis was a large-scale study of 276 cognitively intact older adults from the monocentric INSIGHT-preAD (Investigation of Alzheimer's Predictors in Subjective Memory Complainers) cohort. Participants underwent baseline assessment of plasma t-tau and NfL concentrations as well as baseline and 24-month follow-up MRI scans. Linear models with and without influential observations (calculated using the Cook distance) were carried out to investigate the effect of plasma NfL and t-tau concentrations, and their interaction effect with β-amyloid status and APOE genotype, on the APC of the whole BFCS and its anterior (Ch1/2) and posterior (Ch4) subdivisions separately.ResultsHigher plasma t-tau concentrations at baseline were associated with higher BFCS rate of atrophy (model without influencers: n = 251, F value = 4.6815; p value = 0.031). Subregional analyses showed similar results for both the APC of the Ch1/2 (model without influencers: n = 256, F value = 3.9535, p corrected = 0.047) and Ch4 BFCS sectors (model without influencers: n = 253, F value = 4.9090, p corrected = 0.047). Baseline NfL, β-amyloid load, and APOE ε4 carrier status did not affect APC of the BFCS.ConclusionIncreased concentrations of baseline plasma t-tau may predict in vivo structural BFCS atrophy progression in older adults at risk for AD, independently of β-amyloid status and APOE genotype.

Published
2020

11. Outline of metabolic diseases in adult neurology

Author

Mochel, Fanny, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Administateur, HAL Sorbonne Université

Subjects
Biomarqueurs, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Erreurs innées du métabolisme, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Therapeutics, Inborn errors of metabolism, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Traitement, Biomarkers, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Introduction : Inborn errors of metabolism (IEM) are traditionally defined by enzymatic deficiencies or defects in proteins involved in cellular metabolism. Historically discovered and characterized in children, a growing number of IEM are described in adults, and especially in the field of neurology. In daily practice, it is important to recognize emergency situations as well as neurodegenerative diseases for which a metabolic disease is likely, especially when therapeutic interventions are available.Objectives : Here, the goal is to provide simple clinical, imaging and biochemical tools that can first orientate towards and then confirm the diagnosis of IEM. General guidelines are presented to treat the most common IEM during metabolic crises – acute encephalopathies with increased plasma ammonia, lactate or homocystein, as well as rhabdomyolysis. Examples of therapeutic strategies currently applied to chronic neurometabolic diseases are also provided – GLUT1 deficiency, adrenoleukodystrophy, cerebrotendinous xanthomatosis, Niemann-Pick type C and Wilson disease. Genetic counseling is mandatory in some X-linked diseases – ornithine transcarbamylase deficiency and adrenoleukodystrophy – and recommended in maternally inherited mitochondrial diseases – mutations of mitochondrial DNA.Conclusion : Besides these practical considerations, the contribution of metabolism to the field of adult neurology and neurosciences is much greater: first, with the identification of blood biomarkers that are progressively changing our diagnostic strategies thanks to lipidomic approaches, as illustrated in the field of spastic paraplegia and atypical psychiatric presentations; and second, through the understanding of pathophysiological mechanisms involved in common neurological diseases thanks to the study of these rare diseases., Introduction : Les erreurs innées du métabolisme (EIM) correspondent classiquement à des déficits enzymatiques ou des altérations protéiques ayant un rôle dans le métabolisme cellulaire. Historiquement découvertes et décrites chez les enfants, un nombre croissant d’EIM sont identifiées chez les adultes, en particulier en neurologie. En pratique clinique, il est important de reconnaître les situations d’urgence et les maladies neurodégénératives pour lesquelles une maladie métabolique est probable, en particulier s’il existe des options thérapeutiques.Objectifs : Le but ici est de décrire des outils cliniques, d’imagerie et biochimiques qui peuvent orienter puis confirmer le diagnostic d’EIM. Des recommandations générales sont proposées pour le traitement des décompensations des EIM les plus fréquentes – encéphalopathies aiguës avec hyperammoniémie, hyperlactacidémie ou hyperhomocystéinémie et rhabdomyolyse. Sont également présentés des exemples de stratégies thérapeutiques appliquées à des maladies neurométaboliques chroniques – déficit en GLUT1, adrénoleucodystrophie, xanthomatose cérébrotendineuse, Niemann-Pick de type C, maladie de Wilson. Le conseil génétique est nécessaire dans certaines pathologies liées à l’X – déficit en ornithine transcarbamylase et adrénoleucodystrophie – et recommandé dans les maladies mitochondriales avec hérédité maternelle – mutations de l’ADN mitochondrial.Conclusion : En dehors de ces considérations pratiques, la contribution du métabolisme au domaine de la neurologie et des neurosciences est bien plus grande : d’abord avec l’identification de biomarqueurs sanguins qui changent progressivement nos stratégies diagnostiques grâce à l’essor de la lipidomique, notamment dans le domaine des paraparésies spastiques et des présentations psychiatriques atypiques ; mais aussi grâce à la compréhension de mécanismes physiopathologiques dans des maladies neurologiques communes au travers de l’étude de ces maladies rares.

Published
2015

12. A recessive ataxia diagnosis algorithm for the next generation sequencing era.

Author

Renaud, Mathilde, Tranchant, Christine, Martin, Juan Vicente Torres, Mochel, Fanny, Synofzik, Matthis, van de Warrenburg, Bart, Pandolfo, Massimo, Koenig, Michel, Kolb, Stefan A., Anheim, Mathieu, Alonso, Isabel, Azzedine, Hamid, Barbot, Clara, Bereau, Matthieu, Berkovic, Sam, Bernard, Geneviéve, Bindoff, Laurence A., Bompaire, Flavie, Bonneau, Dominique, and Bonneau, Patrizia

Subjects
CEREBELLAR ataxia, ELECTROMYOGRAPHY, NUCLEOTIDE sequencing, MAGNETIC resonance imaging of the brain, BIOMARKERS, DIAGNOSIS, ALGORITHMS, DIFFERENTIAL diagnosis, LONGITUDINAL method, SEQUENCE analysis
Abstract

Objective: Differential diagnosis of autosomal recessive cerebellar ataxias can be challenging. A ranking algorithm named RADIAL that predicts the molecular diagnosis based on the clinical phenotype of a patient has been developed to guide genetic testing and to align genetic findings with the clinical context.Methods: An algorithm that follows clinical practice, including patient history, clinical, magnetic resonance imaging, electromyography, and biomarker features, was developed following a review of the literature on 67 autosomal recessive cerebellar ataxias and personal clinical experience. Frequency and specificity of each feature were defined for each autosomal recessive cerebellar ataxia, and corresponding prediction scores were assigned. Clinical and paraclinical features of patients are entered into the algorithm, and a patient's total score for each autosomal recessive cerebellar ataxia is calculated, producing a ranking of possible diagnoses. Sensitivity and specificity of the algorithm were assessed by blinded analysis of a multinational cohort of 834 patients with molecularly confirmed autosomal recessive cerebellar ataxia. The performance of the algorithm was assessed versus a blinded panel of autosomal recessive cerebellar ataxia experts.Results: The correct diagnosis was ranked within the top 3 highest-scoring diagnoses at a sensitivity and specificity of >90% for 84% and 91% of the evaluated genes, respectively. Mean sensitivity and specificity of the top 3 highest-scoring diagnoses were 92% and 95%, respectively. The algorithm outperformed the panel of ataxia experts (p = 0.001).Interpretation: Our algorithm is highly sensitive and specific, accurately predicting the underlying molecular diagnoses of autosomal recessive cerebellar ataxias, thereby guiding targeted sequencing or facilitating interpretation of next-generation sequencing data. Ann Neurol 2017;82:892-899. [ABSTRACT FROM AUTHOR]

Published
2017
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13. Evolution of structural neuroimaging biomarkers in a series of adult patients with Niemann-Pick type C under treatment.

Author

Masingue, Marion, Adanyeguh, Isaac, Nadjar, Yann, Sedel, Frédéric, Galanaud, Damien, and Mochel, Fanny

Subjects
BRAIN imaging, NIEMANN-Pick diseases, MAGNETIC resonance imaging, ATROPHY, CORPUS callosum, BRAIN, GLYCOSIDASES, NEURORADIOLOGY, CASE-control method, PIPERIDINE, CHEMICAL inhibitors, THERAPEUTICS
Abstract

Background: Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by a wide clinical spectrum and non-specific conventional magnetic resonance imaging (MRI) signs. As substrate reduction therapy with miglustat is now used in almost all patients, its efficacy and the course of the disease are sometimes difficult to evaluate. Neuroimaging biomarkers could prove useful in this matter. We first performed a retrospective analysis of volumetric and diffusion tensor imaging (DTI) data on 13 adult NPC patients compared to 13 controls of similar age and sex. Eleven NPC patients were then studied using the same neuroimaging modalities over a mean of 5 years. The NPC composite score was used to evaluate disease severity.Results: NPC patients showed atrophy in basal ganglia - pallidum (p = 0.029), caudate nucleus (p = 0.022), putamen (p = 0.002) and thalamus (p < 0.001) - cerebral peduncles (p = 0.003) and corpus callosum (p = 0.006), compared to controls. NPC patients also displayed decreased fractional anisotropy (FA) in several regions of interest - corona radiata (p = 0.015), internal capsule (p = 0.007), corpus callosum (p = 0.032) and cingulate gyrus (p = 0.002) - as well as a broad increase in radial diffusivity (p < 0.001), compared to controls. Over time, 3 patients worsened clinically, including 2 patients who interrupted treatment, while 8 patients remained stable. With miglustat, no significant volumetric change was observed but FA improved after 2 years in the corpus callosum and the corona radiata of NPC patients (n = 4; p = 0.029) - although that was no longer observed at further time points.Conclusion: This is the first study conducted on a series of adult NPC patients using two neuroimaging modalities and followed under treatment. It confirmed that NPC patients displayed cerebral atrophy in several regions of interest compared to controls. Furthermore, miglustat showed an early effect on diffusion metrics in treated patients. DTI can detect brain microstructure alterations caused by neurometabolic dysfunction. Its potential as a biomarker in NPC shall be further evaluated in upcoming therapeutic trials. [ABSTRACT FROM AUTHOR]

Published
2017
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