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1. Multicenter Analytical Validation of Aβ40 Immunoassays

Author

Linda J. C. van Waalwijk van Doorn, Luka Kulic, Marleen J. A. Koel-Simmelink, H. Bea Kuiperij, Alexandra A. M. Versleijen, Hanne Struyfs, Harry A. M. Twaalfhoven, Anthony Fourier, Sebastiaan Engelborghs, Armand Perret-Liaudet, Sylvain Lehmann, Marcel M. Verbeek, Eugeen J. M. Vanmechelen, and Charlotte E. Teunissen

Subjects
method validation, Alzheimer’s disease, cerebrospinal fluid, amyloid, Immunoassays, Neurology. Diseases of the nervous system, RC346-429
Abstract

BackgroundBefore implementation in clinical practice, biomarker assays need to be thoroughly analytically validated. There is currently a strong interest in implementation of the ratio of amyloid-β peptide 1-42 and 1-40 (Aβ42/Aβ40) in clinical routine. Therefore, in this study, we compared the analytical performance of six assays detecting Aβ40 in cerebrospinal fluid (CSF) in six laboratories according to a recently standard operating procedure (SOP) developed for implementation of ELISA assays for clinical routine.MethodsAβ40 assays of six vendors were validated in up to three centers per assay according to recently proposed international consensus validation protocols. The performance parameters included sensitivity, precision, dilutional linearity, recovery, and parallelism. Inter-laboratory variation was determined using a set of 20 CSF samples. In addition, test results were used to critically evaluate the SOPs that were used to validate the assays.ResultsMost performance parameters of the different Aβ40 assays were similar between labs and within the predefined acceptance criteria. The only exceptions were the out-of-range results of recovery for the majority of experiments and of parallelism by three laboratories. Additionally, experiments to define the dilutional linearity and hook-effect were not executed correctly in part of the centers. The inter-laboratory variation showed acceptable low levels for all assays. Absolute concentrations measured by the assays varied by a factor up to 4.7 for the extremes.ConclusionAll validated Aβ40 assays appeared to be of good technical quality and performed generally well according to predefined criteria. A novel version of the validation SOP is developed based on these findings, to further facilitate implementation of novel immunoassays in clinical practice.

Published
2017
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2. Prevalence of the apolipoprotein E E4 allele in amyloid B positive subjects across the spectrum of Alzheimer's disease

Author

Dong Young Lee, Vincent Camus, Sudesh Prabhakar, Anne M. Fagan, Aleksandra Klimkowicz-Mrowiec, Julius Popp, Frans R.J. Verhey, Victor L. Villemagne, David J. Brooks, Susan M. Landau, Kewei Chen, Johannes Kornhuber, Duk L. Na, Linda J C van Waalwijk van Doorn, Mony J. de Leon, Ann D. Cohen, Charlotte E. Teunissen, Eloy Rodríguez-Rodríguez, Erik Stomrud, Philip Scheltens, Wiesje M. van der Flier, Adrian Ivanoiu, Anders Wallin, Eckart Rüther, Adam S. Fleisher, Isabel Santana, Ramesh Kandimalla, Tormod Fladby, Åsa K. Wallin, Peter Johannsen, Stefan Förster, Sang W. Seo, Gaël Chételat, Koen Van Laere, Ina S. Almdahl, Mark M. Mintun, Dag Aarsland, Sanna-Kaisa Herukka, Harald Hampel, Magda Tsolaki, Henrik Zetterberg, Kristian Steen Frederiksen, John C. Morris, David A. Wolk, Marie Sarazin, Hilkka Soininen, Catherine M. Roe, Sebastiaan Engelborghs, Juha O. Rinne, Hanne Struyfs, Daniel Alcolea, Pieter Jelle Visser, Oliver Peters, Willemijn J. Jansen, Alberto Lleó, Bart N.M. van Berckel, Kiran Dip Gill, Arto Nordlund, Jens Wiltfang, Kaj Blennow, Timo Grimmer, Johannes Schröder, Pauline Aalten, Colin Groot, Pascual Sánchez-Juan, Jan Marcusson, Inês Baldeiras, Mark A. van Buchem, Niklas Mattsson, Christopher C. Rowe, Rik Ossenkoppele, Wolfgang Maier, Agneta Nordberg, Rik Vandenberghe, William E. Klunk, Hanne M. Møllergård, José Luis Molinuevo, Stephanie J.B. Vos, Olymbia Gkatzima, Alexander Drzezga, Oskar Hansson, Lorena Rami, Giovanni B. Frisoni, Karen M. Rodrigue, Olga Meulenbroek, Barbara Mroczko, Marcel M. Verbeek, Juan Fortea, Gil D. Rabinovici, William J. Jagust, Yvonne Freund-Levi, Luiza Spiru, Gunhild Waldemar, Catarina R. Oliveira, Enrica Cavedo, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), Frisoni, Giovanni, Popp, Julius, Neurology, Amsterdam Neuroscience - Neurodegeneration, Laboratory Medicine, Radiology and nuclear medicine, APH - Personalized Medicine, and APH - Methodology

Subjects
0301 basic medicine, Apolipoprotein E, Male, NATIONAL INSTITUTE, Neurology, Epidemiology, Apolipoprotein E4, LONGITUDINAL COHORT, Disease, metabolism [Cognitive Dysfunction], ddc:616.89, 0302 clinical medicine, Prevalence, Geographical location, genetics [Apolipoprotein E4], APOE GENOTYPE, Health Policy, GLUCOSE-METABOLISM, CEREBROSPINAL-FLUID BIOMARKERS, Alzheimer's disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, Europe, Psychiatry and Mental health, cerebrospinal fluid [Biomarkers], Biomarker (medicine), lipids (amino acids, peptides, and proteins), Female, Sex, ASSOCIATION WORKGROUPS, metabolism [Alzheimer Disease], APOE, medicine.medical_specialty, Amyloid, CSF BIOMARKERS, metabolism [Amyloid beta-Peptides], CSF, ta3112, Education, 03 medical and health sciences, Cellular and Molecular Neuroscience, Age, Developmental Neuroscience, Alzheimer Disease, Internal medicine, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, ddc:610, Allele, OLDER-ADULTS, Biology, Alleles, Aged, Amyloid beta-Peptides, business.industry, Mild cognitive impairment, medicine.disease, nervous system diseases, 030104 developmental biology, Endocrinology, PET, Positron-Emission Tomography, ddc:618.97, Subjective cognitive decline, DIAGNOSTIC GUIDELINES, Human medicine, Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Introduction: Apolipoprotein E (APOE) epsilon 4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta(A beta) pathology. Methods: We included 3451 A beta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon 4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE epsilon 4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in A beta+ cognitively normal and A beta+ mild cognitive impairment (P

Published
2018
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3. Association of Cerebral Amyloid-Β Aggregation With Cognitive Functioning in Persons Without Dementia

Author

Myriam Alexander, Steven E. Arnold, Stephanie J.B. Vos, Viviana Lisetti, Gunhild Waldemar, Marzena Zboch, David A. Wolk, Sebastiaan Engelborghs, Sabine Hellwig, Adrian Ivanoiu, José Luis Molinuevo, Duk L. Na, Sebastian Köhler, Elisabeth Kapaki, Catarina R. Oliveira, Enrica Cavedo, Ina S. Almdahl, Karine Madsen, Mark A. Mintun, Frans R.J. Verhey, Juha O. Rinne, John C. Morris, Hanne Struyfs, George P. Paraskevas, Oliver Peters, Ann D. Cohen, Philip Scheltens, Willemijn J. Jansen, Linda J C van Waalwijk van Doorn, Eckart Rüther, Sanna-Kaisa Herukka, Osama Sabri, Mark Forrest Gordon, Yvonne Freund-Levi, Rik Vandenberghe, Lucrezia Hausner, Marie Sarazin, Kristian Steen Frederiksen, Inês Baldeiras, William E. Klunk, Susan M. Landau, Timo Grimmer, Lutz Froelich, Betty M. Tijms, Dong Young Lee, Peter Johannsen, Aleksandra Klimkowicz-Mrowiec, Charlotte E. Teunissen, Kaj Blennow, Mony J. de Leon, Christopher C. Rowe, Alberto Lleó, Uroš Rot, Pascual Sánchez-Juan, Daniel Alcolea, Henryk Barthel, Wiesje M. van der Flier, Olga Meulenbroek, Tomasz Gabryelewicz, Tormod Fladby, Andrew B. Newberg, Åsa K. Wallin, Marcel M. Verbeek, Lucilla Parnetti, Bart N.M. van Berckel, Vincent Mok, Oskar Hansson, Victor L. Villemagne, David J. Brooks, Helmut Hildebrandt, Koen Van Laere, Dag Aarsland, Inez H.G.B. Ramakers, Harald Hampel, Elena Chipi, Henrik Zetterberg, Erik Stomrud, Hilkka Soininen, Juan Fortea, Gil D. Rabinovici, Anders Wallin, Vincent Camus, Gayan Perera, Julius Popp, Pieter Jelle Visser, Magda Tsolaki, Johannes Kornhuber, Anne M. Fagan, Niklas Mattsson, William J. Jagust, Luiza Spiru, Hanne M. Møllergård, Adam S. Fleisher, Isabel Santana, Jens Wiltfang, Jan Marcusson, Alexander Drzezga, Giovanni B. Frisoni, Catherine M. Roe, Mark A. van Buchem, Norman Koglin, Johannes Schröder, Pauline Aalten, Olymbia Gkatzima, Lorena Rami, Wolfgang Maier, Agneta Nordberg, Alexandre de Mendonça, Gerald Novak, Gaël Chételat, Arto Nordlund, Milica G. Kramberger, Rik Ossenkoppele, Barbara Mroczko, Kewei Chen, Eloy Rodríguez-Rodríguez, Stefan Förster, Sang W. Seo, Philipp T. Meyer, Clinical sciences, Neurology, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychiatrie & Neuropsychologie, MUMC+: MA Med Staf Spec Psychiatrie (9), Amyloid Biomarker Study Group, Frisoni, Giovanni, Popp, Julius, Amsterdam Neuroscience - Neurodegeneration, APH - Personalized Medicine, APH - Methodology, Radiology and nuclear medicine, Laboratory Medicine, and CCA - Imaging and biomarkers

Subjects
0301 basic medicine, PRECLINICAL ALZHEIMERS-DISEASE, Male, psychology [Alzheimer Disease], physiopathology [Cognitive Dysfunction], cerebrospinal fluid [Amyloid beta-Peptides], physiopathology [Brain], ddc:616.89, 0302 clinical medicine, Reference Values, 10. No inequality, Episodic memory, ta515, Original Investigation, LIFE-SPAN, Medicine(all), Geriatrics, Cerebral Amyloid-β Aggregation, diagnosis [Alzheimer Disease], Brain, Cognition, IMPAIRMENT, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Mental Status and Dementia Tests, Cognitive test, Psychiatry and Mental health, physiopathology [Cognition Disorders], Female, psychology [Cognitive Dysfunction], Alzheimer's disease, BURDEN, APOE, medicine.medical_specialty, Memory, Episodic, psychology [Cognition Disorders], ta3112, physiopathology [Alzheimer Disease], 03 medical and health sciences, AGE, Alzheimer Disease, Internal medicine, mental disorders, medicine, Dementia, Humans, Cognitive Dysfunction, Effects of sleep deprivation on cognitive performance, Cognitive skill, ddc:610, METAANALYSIS, Aged, diagnosis [Cognition Disorders], DECLINE, Amyloid beta-Peptides, business.industry, MEMORY PERFORMANCE, Correction, medicine.disease, ta3124, INDIVIDUALS, 030104 developmental biology, Cross-Sectional Studies, diagnosis [Cognitive Dysfunction], Positron-Emission Tomography, Human medicine, business, Cognition Disorders, 030217 neurology & neurosurgery, dementia
Abstract

Contains fulltext : 190311.pdf (Publisher’s version ) (Closed access) Importance: Cerebral amyloid-beta aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials. Objective: To investigate whether amyloid-beta aggregation is associated with cognitive functioning in persons without dementia. Design, Setting, and Participants: This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017. Main Outcomes and Measures: Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score

Published
2018
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4. Improved Cerebrospinal Fluid-Based Discrimination between Alzheimer's Disease Patients and Controls after Correction for Ventricular Volumes

Author

João Pereira, Enrica Cavedo, Isabel Santana, Miguel Castelo-Branco, Erden Eren, Sermin Genc, Philip Scheltens, Albert Lladó, Catarina R. Oliveira, Giovanni B. Frisoni, Chiara Fenoglio, H. Bea Kuiperij, Marco Bozzali, Andrea Urbani, Andrea Arighi, Yawu Liu, Raquel Sánchez-Valle, Magda Tsolaki, Linda J C van Waalwijk van Doorn, Åsa K. Wallin, Flavio Nobili, Roberto Tarducci, Görsev Yener, Nicola Salvadori, Maria Pikkarainen, Juan Fortea Ormaechea, Yvonne Freund-Levi, Eduard Vilaplana, Viviana Greco, Harald Hampel, Pieter Jelle Visser, Elio Scarpini, Hilkka Soininen, Kaj Blennow, Agnese Picco, Derya Durusu Emek-Savaş, Marcel M. Verbeek, Lucilla Parnetti, Kader Karli Oguz, Daniela Galimberti, Sanna-Kaisa Herukka, Jurgen A.H.R. Claassen, Alberto Lleó, Inês Baldeiras, Juan Domingo Gispert, Esen Saka, José Luis Molinuevo, Charlotte E. Teunissen, Olga Meulenbroek, Paolo Eusebi, Lucia Farotti, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Psychiatrie & Neuropsychologie, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Clinical chemistry

Subjects
Male, NATIONAL INSTITUTE, 0301 basic medicine, MILD COGNITIVE IMPAIRMENT, Pathology, Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1], Neurology, Hippocampus, RECOMMENDATIONS, Cerebral Ventricles, Pattern Recognition, Automated, ddc:616.89, Computer-Assisted, 0302 clinical medicine, Cerebrospinal fluid, BRAIN ATROPHY, Alzheimer’s disease, amyloid biomarkers, cerebrospinal fluid, lateral ventricles, tau protein, medicine.diagnostic_test, biology, DEMENTIA, General Neuroscience, Organ Size, General Medicine, Middle Aged, Alzheimer's disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Magnetic Resonance Imaging, Clinical Psychology, Psychiatry and Mental Health, Area Under Curve, Population study, Female, ASSOCIATION WORKGROUPS, Geriatrics and Gerontology, AD-CSF-INDEX, Algorithms, Automated, medicine.medical_specialty, BIOMARKERS, Tau protein, tau Proteins, Pattern Recognition, 03 medical and health sciences, Atrophy, Alzheimer Disease, Statistical significance, Image Interpretation, Computer-Assisted, mental disorders, medicine, Humans, Cognitive Dysfunction, Image Interpretation, Settore BIO/10 - BIOCHIMICA, Aged, Amyloid beta-Peptides, business.industry, Magnetic resonance imaging, medicine.disease, Peptide Fragments, 030104 developmental biology, ROC Curve, biology.protein, DIAGNOSTIC GUIDELINES, TAU, Nuclear medicine, business, 030217 neurology & neurosurgery
Abstract

Cerebrospinal fluid (CSF) biomarkers may support the diagnosis of Alzheimer's disease (AD). We studied if the diagnostic power of AD CSF biomarker concentrations, i.e., Aβ42, total tau (t-tau), and phosphorylated tau (p-tau), is affected by differences in lateral ventricular volume (VV), using CSF biomarker data and magnetic resonance imaging (MRI) scans of 730 subjects, from 13 European Memory Clinics. We developed a Matlab-algorithm for standardized automated segmentation analysis of T1 weighted MRI scans in SPM8 for determining VV, and computed its ratio with total intracranial volume (TIV) as proxy for total CSF volume. The diagnostic power of CSF biomarkers (and their combination), either corrected for VV/TIV ratio or not, was determined by ROC analysis. CSF Aβ42 levels inversely correlated to VV/TIV in the whole study population (Aβ42: r=-0.28; p42 alone (AUC: 0.75 versus 0.81) or in combination with t-tau (AUC: 0.81 versus 0.91). In conclusion, differences in VV may be an important confounder in interpreting CSF Aβ42 levels.

Published
2017
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5. Validation of soluble amyloid-β precursor protein assays as diagnostic CSF biomarkers for neurodegenerative diseases

Author

Harry Twaalfhoven, Philip Scheltens, Eugeen Vanmechelen, Hanne Struyfs, Linda J C van Waalwijk van Doorn, Charlotte E. Teunissen, Marleen J.A. Koel-Simmelink, Philipp Linning, H. Bea Kuiperij, Hans Klafki, Hans-Joachim Knölker, Sebastiaan Engelborghs, Marcel M. Verbeek, Jens Wiltfang, Ute Haußmann, Clinical sciences, Neurology, Clinical chemistry, and Amsterdam Neuroscience - Neurodegeneration

Subjects
0301 basic medicine, Laboratory Proficiency Testing, Pathology, medicine.medical_specialty, Amyloid β, Operating procedures, Medizin, Enzyme-Linked Immunosorbent Assay, Subjective memory, Computational biology, Sensitivity and Specificity, Biochemistry, Alzheimer Disease/cerebrospinal fluid, Meso scale, Amyloid beta-Protein Precursor, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Humans, Medicine, Biomarkers/cerebrospinal fluid, Medicine(all), Memory Disorders, business.industry, solubility, Neurodegenerative Diseases/cerebrospinal fluid, Clinical performance, Neurodegenerative Diseases, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Peptide Fragments, Amyloid beta-Protein Precursor/cerebrospinal fluid, 030104 developmental biology, Frontotemporal Dementia, Csf biomarkers, Biomarker (medicine), Memory Disorders/cerebrospinal fluid, Reagent Kits, Diagnostic, reproducibility of results, Frontotemporal Dementia/cerebrospinal fluid, Peptide Fragments/cerebrospinal fluid, business, Biomarkers, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 168259.pdf (Publisher’s version ) (Closed access) Analytical validation of a biomarker assay is essential before implementation in clinical practice can occur. In this study, we analytically validated the performance of assays detecting soluble amyloid-beta precursor protein (sAPP) alpha and beta in CSF in two laboratories according to previously standard operating procedures serving this goal. sAPPalpha and sAPPbeta ELISA assays from two vendors (IBL-international, Meso Scale Diagnostics) were validated. The performance parameters included precision, sensitivity, dilutional linearity, recovery, and parallelism. Inter-laboratory variation, biomarker comparison (sAPPalpha vs. sAPPbeta) and clinical performance was determined in three laboratories using 60 samples of patients with subjective memory complaints, Alzheimer's disease, or frontotemporal dementia. All performance parameters of the assays were similar between labs and within predefined acceptance criteria. The only exceptions were minor out-of-range results for recovery at low concentrations and, despite being within predefined acceptance criteria, non-comparability of the results for evaluation of the dilutional linearity and hook-effect. Based on the inter-laboratory correlation between Lab #1 and Lab #2, the IBL-international assays were more robust (sAPPalpha: r(2) = 0.92, sAPPbeta: r(2) = 0.94) than the Meso Scale Diagnostics (MSD) assay (sAPPalpha: r(2) = 0.70, sAPPbeta: r(2) = 0.80). Specificity of assays was confirmed using assay-specific peptide competitors. Clinical validation showed consistent results across the clinical groups in the different laboratories for all assays. The validated sAPP assays appear to be of sufficient technical quality and perform well. Moreover, the study shows that the newly developed standard operating procedures provide highly useful tools for the validation of new biomarker assays. A recommendation was made for renewed instructions to evaluate the dilutional linearity and hook-effect. We analytically validated the performance of assays detecting soluble amyloid-beta precursor protein (sAPP) alpha and beta in CSF according to SOPs in agreement with ISO15189 guidelines. The validated sAPP assays appear to be of sufficient technical quality and perform well. Moreover, this study proofs that the newly developed SOPs, with a minor modification, provide highly useful tools for the validation of new biomarker assays.

Published
2016
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6. P4‐229: Improved CSF‐based discrimination between Alzheimer's disease patients and controls after correction for ventricular volumes

Author

Hawra Kadhim, Marcel M. Verbeek, Olga Meulenbroek, Linda J C van Waalwijk van Doorn, Juan Domingo Gispert, José-Luis Molinuevo, and H. Bea Kuiperij

Subjects
Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Internal medicine, medicine, Cardiology, Neurology (clinical), Geriatrics and Gerontology, business
Published
2015
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7. P1‐120: Standardization of a method for diagnostic biomarker validation for neurodegenerative diseases: App assays as example

Author

Marleen J.A. Koel-Simmelink, Linda J C van Waalwijk van Doorn, Hans Klafki, Charlotte E. Teunissen, Hans‐Joachim Knoelker, Marcel M. Verbeek, Hanne Struyfs, Sebastiaan Engelborghs, Philipp Linning, H. Bea Kuiperij, Ute Haußmann, Jens Wiltfang, Eugeen Vanmechelen, and Harry Twaalfhoven

Subjects
0303 health sciences, Standardization, Epidemiology, business.industry, Health Policy, Computational biology, 03 medical and health sciences, Psychiatry and Mental health, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Diagnostic biomarker, Medicine, Biomarker (medicine), Neurology (clinical), Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, 030304 developmental biology
Published
2015
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8. P4‐270: CORRELATIONS OF CSF BIOMARKER LEVELS WITH LATERAL VENTRICULAR CSF VOLUMES

Author

Hawra Kadhim, Marcel M. Verbeek, Linda J C van Waalwijk van Doorn, Olga Meulenbroek, Juan Domingo Gispert Lopez, H. Bea Kuiperij, and José Luis Molinuevo

Subjects
Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Ventricular CSF, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Csf biomarkers, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published
2014
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