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1. Longitudinal neuroanatomical and cognitive progression of posterior cortical atrophy

Author

Timothy J. Shakespeare, Nick C. Fox, Keir Yong, Alexandra L. Young, Ross W. Paterson, Jason D. Warren, Amelia Carton, Aida Suarez-Gonzalez, Eulogio Gil-Néciga, Basil H. Ridha, Razvan V. Marinescu, Alexander J.M. Foulkes, Ivanna M. Pavisic, Daniel C. Alexander, Sebastien Ourselin, Elizabeth K. Warrington, Neil P. Oxtoby, Natalie S. Ryan, Dilek Ocal, Manja Lehmann, Nicholas C. Firth, Catherine F. Slattery, Marc Modat, Martin N. Rossor, Gil D. Rabinovici, Silvia Primativo, Bruce L. Miller, M. Jorge Cardoso, Jonathan M. Schott, Sebastian J. Crutch, Alzheimer's Research UK, Economic and Social Research Council (UK), Engineering and Physical Sciences Research Council (UK), Alzheimer Society of Canada, Brain Research Trust, Wolfson Foundation, National Institute for Health Research (UK), National Institutes of Health (US), and European Commission

Subjects
Male, Aging, Brain atrophy, Pathology, Neuropsychological Tests, Neurodegenerative, Alzheimer's Disease, Medical and Health Sciences, 0302 clinical medicine, Models, 2.1 Biological and endogenous factors, Longitudinal Studies, Aetiology, Cognitive decline, Cerebral Cortex, 0303 health sciences, medicine.diagnostic_test, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Neurological, Disease Progression, Female, Mental health, Abnormality, Alzheimer’s disease, medicine.medical_specialty, Models, Neurological, 03 medical and health sciences, Atrophy, Alzheimer Disease, Clinical Research, Memory, Acquired Cognitive Impairment, medicine, Posterior cortical atrophy syndrome, Humans, Dementia, Cognitive Dysfunction, 030304 developmental biology, Neurology & Neurosurgery, business.industry, Working memory, Psychology and Cognitive Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Posterior cortical atrophy, Magnetic resonance imaging, Original Articles, medicine.disease, Brain Disorders, Editor's Choice, Structural MRI, Case-Control Studies, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

In the first multicentre, international longitudinal investigation of disease progression in posterior cortical atrophy, Firth et al. reveal distinct trajectories of cognitive decline and patterns of tissue loss compared to typical Alzheimer’s disease. Mapping this heterogeneity provides a basis for understanding the factors underlying variability in neurodegenerative disease expression., Posterior cortical atrophy is a clinico-radiological syndrome characterized by progressive decline in visual processing and atrophy of posterior brain regions. With the majority of cases attributable to Alzheimer’s disease and recent evidence for genetic risk factors specifically related to posterior cortical atrophy, the syndrome can provide important insights into selective vulnerability and phenotypic diversity. The present study describes the first major longitudinal investigation of posterior cortical atrophy disease progression. Three hundred and sixty-one individuals (117 posterior cortical atrophy, 106 typical Alzheimer’s disease, 138 controls) fulfilling consensus criteria for posterior cortical atrophy-pure and typical Alzheimer’s disease were recruited from three centres in the UK, Spain and USA. Participants underwent up to six annual assessments involving MRI scans and neuropsychological testing. We constructed longitudinal trajectories of regional brain volumes within posterior cortical atrophy and typical Alzheimer’s disease using differential equation models. We compared and contrasted the order in which regional brain volumes become abnormal within posterior cortical atrophy and typical Alzheimer’s disease using event-based models. We also examined trajectories of cognitive decline and the order in which different cognitive tests show abnormality using the same models. Temporally aligned trajectories for eight regions of interest revealed distinct (P < 0.002) patterns of progression in posterior cortical atrophy and typical Alzheimer’s disease. Patients with posterior cortical atrophy showed early occipital and parietal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion leading to tissue loss of comparable extent later. Hippocampal, entorhinal and frontal regions underwent a lower rate of change and never approached the extent of posterior cortical involvement. Patients with typical Alzheimer’s disease showed early hippocampal atrophy, with subsequent higher rates of temporal atrophy and ventricular expansion. Cognitive models showed tests sensitive to visuospatial dysfunction declined earlier in posterior cortical atrophy than typical Alzheimer’s disease whilst tests sensitive to working memory impairment declined earlier in typical Alzheimer’s disease than posterior cortical atrophy. These findings indicate that posterior cortical atrophy and typical Alzheimer’s disease have distinct sites of onset and different profiles of spatial and temporal progression. The ordering of disease events both motivates investigation of biological factors underpinning phenotypic heterogeneity, and informs the selection of measures for clinical trials in posterior cortical atrophy.

Published
2019
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2. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study

Author

Healy, Daniel G., Mario, Falchi, O'Sullivan, Sean S., Bonifati, Vincenzo, Alexandra, Durr, Susan, Bressman, Alexis, Brice, Jan, Aasly, Zabetian, Cyrus P., Stefano, Goldwurm, Ferreira, Joaquim J., Eduardo, Tolosa, Kay, Denise M., Christine, Klein, Williams, David R., Connie, Marras, Lang, Anthony E., Wszolek, Zbigniew K., Jose, Berciano, Schapira, Anthony H. V., Timothy, Lynch, Bhatia, Kailash P., Thomas, Gasser, Lees, Andrew J., Wood, Nicholas W., International Lrrk Consortium, Collaborators, Tazir, M., Ysmail Dahlouk, F., Belarbi, S., Hecham, N., Barbosa, E., Chien, H. F., Rieder, C. R., Jardim, L. B., Rogaeva, E., Lesage, S., Lohmann, E., Vidailhet, M., Bonnet, A. M., Agid, Y., Pollak, P., Tison, F., Durif, F., Broussolle, E., Berg, D., Hagenah, J., Gosal, D., Gibson, M., Vanacore, Nicola, Berardelli, Alfredo, Fabbrini, Giovanni, Fabrizio, E., Meco, Giuseppe, Stocchi, F., Dalla Libera, A., De Mari, M., Lamberti, P., Cossu, G., Pezzoli, G., Zini, M., Tesei, S., Zecchinelli, A., Sironi, F., Antonini, A., Mariani, C., Sacilotto, G., Meucci, N., Canesi, M., Di Fonzo, A., Oostra, B., Correia Guedes, L., Rosa, Mm, Coelho, M., Sampaio, C., Gaig, C., C. S., Lu, Wu Chou, Y. H., Quinn, N. P., Abou Sleiman, P. M., Muqit, M. M., Khan, N. L., Gandhi, S., Vaughan, J., Payami, H., Nutt, J. J., Factor, S. A., Higgins, D. S., Farrer, M. J., Hulihan, M., Brown, L., Mata, I. F., Samii, A., Yearout, D., Griffith, A., Leis, B. C., Roberts, J. W., Clinical Genetics, Department of Clinical Neurosciences, University College of London [London] (UCL)-Institute of Neurology, Genomic Medicine, Imperial College London-Kings College, Reta Lila Weston Institute for Neurological Studies, Queen Mary University of London (QMUL), Department of Clinical Genetics (DCG), Erasmus University Medical Centre, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Beth Israel Medical Centre- Albert Einstein College of Medicine [New York], St. Olav's Hospital, University of Washington [Seattle], Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, Parkinson Institute, Istituti Clinici di Perfezionamento, Neurological Clinic Research Unit, Institute of Molecular Medicine-Lisbon School of Medicine, Neurology Service, Institut Clinic Maltias del Sistema Nervios-Hospital Clinic Universitari-University of Barcelona, Division of Genetic Disorders, New York State Department of Health [Albany], University of Luebeck, Faculty of Medicine (Neurosciences), Monash University [Clayton], University of Toronto, Mayo Clinic Jacksonville, Service of Neurology, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC)-Instituto de Salud Carlos III [Madrid] (ISC), Mater Misericordiae University Hospital (The Mater Hospital), Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Department of Neurodegenerative Diseases, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen-Hertie-Institut for Clinical Brain Research, Department of Molecular Pathogenesis, UK Medical Research Council, UK Parkinson's Disease Society, UK Brain Research Trust, Internationaal Parkinson Fonds, Volkswagen Foundation, National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging, Udall Parkinson's Disease Centre of Excellence, Pacific Alzheimer Research Foundation Centre, Italian Telethon Foundation, Fondazione Grigioni per il Morbo di Parkinson, Michael J Fox Foundation for Parkinson's Research, Safra Global Genetics Consortium, US Department of Veterans Affairs, French Agence Nationale de la Recherche., ANR-05-NEUR-0019,LRRK2 in PD,Pathologie moléculaire et modèles murins du gène LRRK2, impliqué dans la maladie de Parkinson(2005), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Beth Israel Medical Centre- Albert Einstein College of Medicine, CIBER de Enfermedades Neurodegenerativas (CIBERNED), Mater Misericordiae University Hospital, Eberhard Karls Universität Tübingen-Hertie-Institut for Clinical Brain Research, ANR-05-NEURO-019,ANR-05-NEURO-019, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Gerontology, Male, Risk, Pediatrics, medicine.medical_specialty, Parkinson's disease, Genotype, International Cooperation, DNA Mutational Analysis, Glycine, Clinical Neurology, Penetrance, Disease, Protein Serine-Threonine Kinases, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Severity of Illness Index, 03 medical and health sciences, 0302 clinical medicine, medicine, Serine, Humans, Genetic Predisposition to Disease, Genetic Testing, Age of Onset, 030304 developmental biology, Genetic testing, Family Health, 0303 health sciences, medicine.diagnostic_test, business.industry, Case-control study, Age Factors, Parkinson Disease, medicine.disease, LRRK2, 3. Good health, nervous system diseases, Dyskinesia, Case-Control Studies, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neurology (clinical), genetics, parkinson, Age of onset, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Summary Background Mutations in LRRK2 , the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2 -associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2 ? Methods Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2 -associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. Findings Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2 -associated PD were more benign than those of idiopathic PD. Interpretation Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. Funding UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.

Published
2008
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