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Clinicopathologic Correlations and Neuroimaging Biomarkers in Primary Progressive Aphasia

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Clinicopathologic Correlations and Neuroimaging Biomarkers in Primary Progressive Aphasia ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Clinicopathologic correlations and neuroimaging biomarkers in primary progressive aphasia Doctoral student Miguel Ángel Santos Santos Directors Maria Luisa Gorno-Tempini Juan Fortea Ormaechea Antonio Escartín Siquer Programa de doctorat en Medicina con el Real Decreto 1393 Departament de Medicina. Facultat de Medicina. Universidad Autònoma de Barcelona. 2017 CERTIFICATE OF DIRECTION Maria Luisa Gorno-Tempini, Doctor in Neuroscience by University College London and Professor of Neurology at the University of California San Francisco, Juan Fortea Ormaechea, Doctor in Medicine by the Universidad de Barcelona and specialist in Neurology at the Hospital Sant Pau Memory Unit, and Antonio Escartín Siquer, Doctor in Medicine by the Universidad Autonoma de Barcelona and Professor of Neurology in the Department of Medicine at the Universidad Autonoma de Barcelona, CERTIFY: That the thesis titled “Clinicopathologic correlations and neuroimaging biomarkers in primary progressive aphasia” was carried out under our supervision and meets all the requirements necessary for the doctoral candidate to proceed to its defense before the corresponding tribunal. Maria Luisa Gorno- Juan Fortea Antonio Escartín Tempini Ormaechea Siquer Memory Unit, Hospital Professor of Neurology, Memory and Aging de la Santa Creu i Sant Hospital de la Santa Center, University of California San Francisco Pau Creu i Sant Pau June 27th, 2017 To the patients and families whose amazing effort and patience made this research possible A mi familia, a mis dos princesitas TABLE OF CONTENTS I. INDEX OF TABLES & FIGURES II. GLOSSARY OF ABBREVIATIONS III. INTRODUCTION [p1] a. Definition and history of primary progressive aphasia [p2] b. Pathophysiology, genetics, and epidemiology [p5] c. Diagnostic criteria [p7] d. Clinical characterization of the three most common variants [p9] e. Neuroanatomy of cognitive symptoms in primary progressive aphasia [p14] f. Clinicopathologic correlation in primary progressive aphasia [p24] IV. JUSTIFICATION, HYPOTHESES, OBJECTIVES & OUTLINE [p27] a. Justification [p28] b. Hypotheses [p30] c. Objectives [p31] d. Outline [p32] V. MATERIALS AND METHODS [p34] VI. RESULTS [p41] a. Rates and significance of amyloid imaging positivity in a prospective cohort of primary progressive aphasia [p42] b. Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration [p60] c. Cognitive and neuroanatomical features predictive of amyloid imaging status in primary progressive aphasia [p75] VII. DISCUSSION [p84] a. PPA variant classification according to 2011 consensus diagnostic criteria improves reliability of clinico-pathologic correlations b. Characteristics of PPA with “discordant” (amyloid positive svPPA and nfvPPA, and amyloid negative lvPPA) amyloid status. c. Characteristics of patients with mixed-PPA syndrome. d. Language profiles were predictive of AD biomarker status in patients that did not meet root PPA criteria. e. Issues regarding classification according to current PPA consensus criteria. f. Advances in clinicopathologic correlation in nfvPPA. g. Clinical and neuroanatomical characteristics that predict underlying AD pathology. h. Laterality of amyloid deposition and GM atrophy were not correlated in lvPPA VIII. CONCLUSIONS [p104] IX. BIBLIOGRAPHY [p109] X. ANNEX #1 [p139] a. Rates and significance of amyloid imaging positivity in a prospective cohort of primary progressive aphasia (under review JAMA Neurology) XI. ANNEX #2 [p167] a. Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration (published in JAMA Neurology: JAMA Neurol. 2016 Jun 1;73(6):733-42. doi: 10.1001/jamaneurol.2016.0412) INDEX OF TABLES & FIGURES III. INTRODUCTION [p1] a. Figure 3.1: Pattern of atrophy in Primary Progressive Aphasia Variants versus Controls [p4] b. Table 3.1: 2011 International consensus PPA diagnostic criteria [p8] c. Figure 3.2: Probabilistic maps of the language-related tracts from 48 subjects [p16] VI. RESULTS [p41] a. Rates and significance of amyloid imaging positivity in a prospective cohort of primary progressive aphasia [p42] i. Figure-6.1.1: Study cohort flow chart [p44] ii. Table-6.1.1: Excluded patients that did not meet root PPA criteria [p45] iii. Table-6.1.2: Demographics, amyloid imaging, genetic and clinical data in svPPA, nfvPPA, lvPPA, and PPAm [p48] iv. Figure-6.1.2: Scatter plot depicting PET PIB standardized uptake value ratios (SUVr) [p52] v. Table-6.1.3: Pathological diagnoses and amyloid imaging for all PPA [p53] vi. Figure-6.1.3: Voxel-based morphometry of grey matter atrophy patterns for amyloid negative svPPA, amyloid negative nfvPPA, and amyloid positive lvPPA groups [p57] vii. Figure-6.1.4: Voxel-based morphometry of grey matter atrophy patterns for PPA mixed (PPAm) [p58] b. Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration [p60] i. Table-6.2.1: Demographic and cognitive data in nfvPPA-PSP, nfvPPA-CBD, and controls at initial visit [p61] ii. Table 6.2.2: Cognitive data at baseline and 1 year follow-up evaluation [p65] iii. Table-6.3.3: Neurological symptoms and signs at presentation, 1 year, >1 year follow-up evaluations and overall [p66] iv. Figure-6.2.1: Cross-sectional VBM at presentation of nfvPPA: 4R tau (n=14), PSP (n=5), and CBD (n=9) [p70] v. Figure-6.2.2: Longitudinal VBM of nfvPPA: 4R tau (n=10), PSP (n=5), and CBD (n=5) [p71] c. Cognitive and neuroanatomical features predictive of amyloid imaging status in primary progressive aphasia [p75] i. Table-6.3.1: Clinical features discriminating amyloid status in PPA [p77] ii. Figure-6.3.1: Neuroanatomical features predictive of amyloid-PET status [p78] iii. Table-6.3.2: PIB and GM asymmetry indexes in amyloid positive lvPPA [p79] iv. Table-6.3.3: PIB and GM raw values correlation in amyloid positive lvPPA [p80] v. Figure-6.3.2: Box plot depicting relationship between PIB and grey matter volume asymmetry indexes [p81] GLOSSARY OF ABBREVIATIONS AD Alzheimer’s disease APOE apolipoprotein E gene CBD corticobasal degeneration CSF cerebral spinal fluid [18F]AV45 florbetapir compound FTLD frontotemporal lobar degeneration FUS fused-in-sarcoma (FUS) protein GM grey matter (brain) lvPPA logopenic variant primary progressive aphasia nfvPPA non-fluent/agrammatic variant primary progressive aphasia PPA primary progressive aphasia PET Positron Emission Tomography PIB or [11C]PIB Pittsburgh compound B PSP progressive supranuclear palsy SUVr standardized uptake value ratios svPPA semantic variant primary progressive aphasia TDP-43 TAR DNA-binding protein of 43 kDa VBM Voxel based morphometry WM white matter (brain) III. INTRODUCTION III. Introduction INTRODUCTION A. DEFINITION & HISTORY Primary progressive aphasia (PPA) is a clinical entity differentiated from other forms of neurodegenerative disease in that language difficulty is the most prominent clinical feature as well as the primary cause of functional impairment at onset and during the first years of disease. It is caused by degeneration of the language network and recent neuroimaging studies have established the association between particular patterns of neuroanatomic damage and clinical presentation (Gorno-Tempini, Dronkers, et al., 2004). The term aphasia denotes a heterogeneous clinical disorder characterized by impaired language function due to lesions of the brain. The neural network responsible for language function is composed of different areas whose dysfunction results in differentiable behavioral manifestations. These differences have been extensively studied since Paul Broca’s first description in the 1890s of a patient who could understand language but couldn’t speak due to a lesion in the inferior part of his left frontal lobe caused by a stroke. Clinical aphasiology has progressed greatly in this last century, primarily from the study of stroke patients as neurovascular disease is the most common cause of aphasia. Our knowledge of the biology of language has evolved alongside clinical aphasiology, and, as a result, is biased towards explaining the mechanisms of the symptoms presented by “stroke aphasics.” Aphasia due to neurodegenerative disease appears gradually and then advances progressively in contrast to a strokes abrupt onset, maximum initial impairment, and later recovery. The pathological mechanisms at work in degenerative disease are not determined by the anatomy of the neurovascular system and thus injure other areas of the language network, resulting in different clinical presentations. 2 III. Introduction Arnold Pick published the first case of a progressive disorder of language associated to atrophy of the left frontal and temporal lobes in the 1890s (Pick, 1892), but these forms
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