Alzheimer’s Research & Therapy (May 2023)
Phenotype and imaging features associated with APP duplications
- Lou Grangeon,
- Camille Charbonnier,
- Aline Zarea,
- Stephane Rousseau,
- Anne Rovelet-Lecrux,
- David Bendetowicz,
- Marion Lemaitre,
- Cécile Malrain,
- Muriel Quillard-Muraine,
- Kevin Cassinari,
- David Maltete,
- Jeremie Pariente,
- Olivier Moreaud,
- Eloi Magnin,
- Benjamin Cretin,
- Marie-Anne Mackowiak,
- Adeline Rollin Sillaire,
- Martine Vercelletto,
- Elsa Dionet,
- Olivier Felician,
- Pauline Rod-Olivieri,
- Catherine Thomas-Antérion,
- Gaelle Godeneche,
- Mathilde Sauvée,
- Leslie Cartz-Piver,
- Isabelle Le Ber,
- Valérie Chauvire,
- Therèse Jonveaux,
- Anna-Chloé Balageas,
- Annie Laquerriere,
- Charles Duyckaerts,
- Anne Vital,
- Andre Maues de Paula,
- David Meyronet,
- Lucie Guyant-Marechal,
- Didier Hannequin,
- Elisabeth Tournier-Lasserve,
- Dominique Campion,
- CNR-MAJ collaborators,
- Gaël Nicolas,
- David Wallon
Affiliations
- Lou Grangeon
- Department of Neurology and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- Camille Charbonnier
- Department of Genetics and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- Aline Zarea
- Department of Neurology and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- Stephane Rousseau
- Department of Genetics and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- Anne Rovelet-Lecrux
- Department of Genetics and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- David Bendetowicz
- Neurology Department, Sorbonne Université, Paris Brain Institute – ICM, Inserm, CNRS and APHP, Hôpital de la Pitié-Salpétrière APHP
- Marion Lemaitre
- Geriatric department, Seclin-Carvin Hospital
- Cécile Malrain
- Department of Neurology, Rennes Hospital
- Muriel Quillard-Muraine
- Laboratoire de biochimie, Rouen University Hospital and University of Rouen
- Kevin Cassinari
- Department of Genetics and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- David Maltete
- Department of Neurology and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- Jeremie Pariente
- Neurology Department, Toulouse University Hospital and Toulouse NeuroImaging Center (ToNIC) INSERM-Univeristy of Toulouse Paul Sabatier
- Olivier Moreaud
- Department of Neurology, Grenoble Hospital
- Eloi Magnin
- Department of Neurology, Besancon Hospital
- Benjamin Cretin
- Department of Neurology, Hautepierre Hospital
- Marie-Anne Mackowiak
- Univ. Lille, CHU Lille, CNRMAJ
- Adeline Rollin Sillaire
- Univ. Lille, CHU Lille, CNRMAJ
- Martine Vercelletto
- Department of Neurology, Nantes University Hospital
- Elsa Dionet
- Department of Neurology, Clermont-Ferrand Hospital
- Olivier Felician
- APHM, Service de Neurologie et Neuropsychologie, CHU Timone
- Pauline Rod-Olivieri
- Neurology Department, Hôpital Saint Anne APHP
- Catherine Thomas-Antérion
- Department of Neurology, Lyon University Hospital
- Gaelle Godeneche
- Department of Neurology, La Rochelle Hospital
- Mathilde Sauvée
- Department of Neurology, Grenoble Hospital
- Leslie Cartz-Piver
- Centre Mémoire Ressources et Recherche (CMRR), Limoges University Hospital
- Isabelle Le Ber
- Neurology Department, Sorbonne Université, Paris Brain Institute – ICM, Inserm, CNRS and APHP, Hôpital de la Pitié-Salpétrière APHP
- Valérie Chauvire
- Department of Neurology, Angers University Hospital
- Therèse Jonveaux
- Department of Neurology, Nancy University Hospital
- Anna-Chloé Balageas
- CHRU Tours, Centre Mémoire Ressources et Recherche (CMRR)
- Annie Laquerriere
- Department of Neuropathology, F 76000, Normandy Center for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital
- Charles Duyckaerts
- Sorbonne Unviersité, INSERM, CNRS U1127, ICM and Laboratoire de Neuropathologie R. Escourolle, Hospital Pitie-Salpêtrière
- Anne Vital
- Department of Pathology, University Hospital
- Andre Maues de Paula
- Department of Pathology, La Timone University Hospital
- David Meyronet
- Department of Pathology, Hopital Civil University Hospital
- Lucie Guyant-Marechal
- Department of Genetics and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- Didier Hannequin
- Department of Neurology and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- Elisabeth Tournier-Lasserve
- AP-HP, Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, INSERM UMR 1141, NeuroDiderot, Université de Paris
- Dominique Campion
- Department of Genetics and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- CNR-MAJ collaborators
- Gaël Nicolas
- Department of Genetics and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- David Wallon
- Department of Neurology and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen
- DOI
- https://doi.org/10.1186/s13195-023-01172-2
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 12
Abstract
Abstract Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.
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