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Cortical thickness in presymptomatic GRN and C9ORF72 mutation carriers Dowds, Emma Frances 2014

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 CORTICAL THICKNESS IN PRESYMPTOMATIC GRN AND C9ORF72 MUTATION CARRIERS   by   Emma Frances Dowds    A THESIS SUBMITTED IN PARTIAL FULLFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF    MASTER OF SCIENCE    in    THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES    (Neuroscience)    THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)    July 2014  © Emma Frances Dowds, 2014 	   ii	  Abstract   Objective: This thesis aimed to investigate cortical thickness in presymptomatic GRN and C9ORF72 mutation carriers prior to the onset of frontotemporal dementia (FTD).  Methods: Subjects were recruited from 16 families with a family history of FTD caused by GRN or C9ORF72 mutations. The C9ORF72 group consisted of 8 mutation carriers (age 50.25 ± 6.90 years), 11 non-carrier family member controls (age 52.82 ± 17.15 years), and 3 affected carriers (age 55.00 ± 1.00 years). The GRN group consisted of 6 mutation carriers (age 53.33 ± 9.67 years) and 9 non-carrier family member controls (age 52.11 ± 8.82). Between group differences in cortical thickness were assessed using a surface based vertex-by-vertex model correcting for age, sex, MMSE and years to mean age of family onset. Significant clusters are reported at 10mm, 15mm and 20mm of smoothing and those identified at all three, two consecutive or one smoothing level are reported with strong, moderate and weak confidence, respectively.  Results: Compared to non-carrier control family members, the C9ORF72 mutation carriers exhibited no difference in cognitive domain scores, but presented with strong to moderate asymmetrical patterns of thinning in the right temporoinsular and left mediofrontal and temporal regions. Compared to non-carrier controls, the GRN mutation carriers exhibited decreased performance on domains of working memory (p = 0.02) and executive function (p = 0.01), with a trend towards reduced language (p = 0.06) and visuospatial (p = 0.08) domains, but did not exhibit any difference in cortical thickness when compared to the non-carrier control family members.  	   iii	   Conclusions: With the use of genetic screening and neuroimaging analyses this thesis demonstrated that grey matter atrophy occurs prior to cognitive decline in C9ORF72 mutation carriers, while GRN carriers exhibit subtle changes in cognitive domains prior to cortical grey matter atrophy. These findings could prove to be highly valuable as they suggest that the mechanism of disease progression between the two mutations may differ. As such, each mutation may require specific neuroimaging methods to track morphological changes prior to cognitive decline and clinical onset.   	   iv	  Preface   The imaging and clinical data used in this thesis was collected by the UBC Alzheimer’s Disease and Related Disorder’s Clinic from 2006-2013. Methodologies were reviewed and approved by the UBC Clinical Research Ethics Board (Frontotemporal Dementia with Ubiquinated Inclusions: Clinical, Genetic and Pathological Characterization, H05-70283).    The study described within this thesis was submitted in abstract format for presentation at the 2014 International Conference on Frontotemporal Dementia, but was otherwise not submitted for publication at the time of thesis submission.  I, Emma Dowds, was the primary investigator on the project, responsible for MRI quality control processing, collection of past clinical data, imaging and statistical analyses, and manuscript composition. Dr. Hsiung and the UBC clinic staff were involved in clinical data collection and MRI scanning between 2006-2013. Dr. Karteek Popuri, of Simon Fraser University, assisted with formatting matlab scripts, which I then customized and executed in the Surfstat cortical thickness analyses. Dr. Robin Hsiung was the supervisory author on the project and helped with study design and thesis revisions. Dr. Faisal Beg, of Simon Fraser University, contributed to the study design and supervision of the MRI analyses.   .    	   v	  Table of Contents  Abstract ........................................................................................................................... ii Preface ........................................................................................................................... iv Table of Contents ........................................................................................................... v List of Tables ............................................................................................................... viii List of Figures ................................................................................................................ ix List of Abbreviations ...................................................................................................... x Acknowledgements ....................................................................................................... xi Dedication ..................................................................................................................... xii Chapter 1: Introduction .................................................................................................. 1 1.1 General introduction ............................................................................................... 1 1.2 Cortical thickness .................................................................................................... 2 1.1.1 Effect of brain volume, sex and age on cortical thickness ............................ 3 1.1.2 Utility of cortical thickness in neurodegenerative disease ............................ 5 1.3 Frontotemporal dementia ........................................................................................ 6 1.3.1 Clinical phenotypes  ..................................................................................... 6 1.3.2 Clinical diagnosis  ......................................................................................... 7 1.3.3 Genetics  ...................................................................................................... 8 1.4 Neuroimaging and anatomical features of FTD  ................................................... 10 1.4.1 Behavioral variant  ...................................................................................... 10 1.4.2 Language variants: SD and PNFA  ............................................................ 14 	   vi	  1.4.3 Affected GRN and C9ORF72 mutation carriers ......................................... 15 1.4.4 Presymptomatic GRN and C9ORF72 mutation carriers  ............................ 16 1.5 Overview of the study ........................................................................................... 18 1.5.1 Aims and purpose  ...................................................................................... 18 1.5.2 Hypotheses  ................................................................................................ 19 1.5.3 Further considerations  ............................................................................... 19 Chapter 2: Methods ...................................................................................................... 20 2.1 Subjects ................................................................................................................ 20 2.1.1 Clinical assessment .................................................................................... 21 2.1.2 Inclusion criteria .......................................................................................... 23 2.2 Image acquisition .................................................................................................. 23 2.3 Image processing ................................................................................................. 23 2.3.1 Quality control process ............................................................................... 24 2.3.2 Template registration .................................................................................. 26 2.4 Statistical analysis ................................................................................................ 26 2.5 Study design ......................................................................................................... 26 Chapter 3: Results ........................................................................................................ 28 3.1 Demographic and clinical data .............................................................................. 28 3.2 Cortical thickness between groups ....................................................................... 31 3.2.1 GRN carriers versus GRN non-carrier controls .......................................... 32 3.2.2 C9ORF72 carriers versus C9ORF72 non-carrier controls .......................... 33 3.2.3 Affected C9ORF72 mutation carriers versus presymptomatic C9ORF72 mutation carriers and non-carrier controls ................................................... 38 	   vii	  3.2.4 GRN mutation carriers versus C9ORF72 mutation carriers ....................... 43 3.3 Correlation between cortical thickness and clinical scores ................................... 45 3.3.1 C9ORF72 mutation carriers and non-carrier controls ................................. 45 Chapter 4: Discussion .................................................................................................. 46 4.1 Presymptomatic C9ORF72 mutation carrier cortical thinning ............................... 47 4.1.1 bvFTD neuroanatomical features ............................................................... 48 4.1.2 Language variant neuroanatomical features .............................................. 51 4.1.3 Motor neuroanatomical features ................................................................. 52 4.2 Cortical thinning in affected C9ORF72 mutation carriers ..................................... 53 4.3 Between group analyses of the GRN groups ....................................................... 54 4.4 Between group analysis of the GRN and C9ORF72 carrier groups  .................... 55 4.5 Molecular mechanisms  ........................................................................................ 55 4.5.1 GRN deficiency and white matter abnormalities ......................................... 56 4.5.2 C9OR72 molecular mechanisms of neuronal loss ..................................... 58 4.6 Limitations ............................................................................................................. 58 4.7 Future directions ................................................................................................... 59 4.8 Conclusions .......................................................................................................... 60 References .................................................................................................................... 61   	   viii	  List of Tables  Table 1      FTD neuropsychological test battery and cognitive domains assessed ...... 22 Table 2  Group demographic data, clinical scores and composite domain scores (z-scores) ......................................................................................................... 29 Table 3  Demographic data, clinical scores and composite domain scores (z-scores) of the mutation carriers ................................................................................ 30  Table 4  Regions of significant cortical thinning in the C90RF72 mutation carriers compared to the non-carrier controls .......................................................... 37          	   ix	  List of Figures  Figure 1   A sample quickcheck image of the right hemisphere with a segmentation error detected in the first sagittal image ...................................................... 25 Figure 2   Mean cortical thickness maps at 15mm of smoothing ................................. 31 Figure 3   T-maps of GRN carriers versus GRN non-carrier controls .......................... 32 Figure 4  T-maps of C9ORF72 carriers versus C9ORF72 non-carrier controls  ........ 34 Figure 5  Regions of significant cortical thinning in the C9ORF72 mutation carriers compared to the C9ORF72 non-carrier controls ......................................... 35 Figure 6 Cortical thinning of the right anterior and posterior dorsal insula in the C9ORF72 mutation carrier group  ............................................................... 36  Figure 7  T-maps of C9ORF72 mutation carriers versus affected C9ORF72 mutation carriers ........................................................................................................ 39 Figure 8   Regions of significant cortical thinning in the affected C9ORF72 mutation carriers compared to the presymptomatic C9ORF72 mutation carriers ...... 40 Figure 9   T-maps of affected C9ORF72 mutation carriers versus C9ORF72 non-carrier controls ............................................................................................. 41 Figure 10   Regions of significant cortical thinning in the affected C9ORF72 mutation carriers compared to the C9ORF72 non-carrier controls ............................ 42 Figure 11  T-maps of C9ORF72 mutation carriers versus GRN mutation carriers  ...... 44   	   x	  List of Abbreviations  ACC: Anterior cingulate cortex AD: Alzheimer’s disease ANOVA: Analysis of variance ANCOVA: Analysis of co-variance bvFTD: behavioural variant Frontotemporal dementia C9ORF72: chromosome 9 open reading frame 72 CVLT: California Verbal Learning Test DTI: Diffusion tensor imaging FTD: Frontotemporal dementia GRN: Progranulin MMSE: Mini Mental State Exam MRI: Magnetic resonance imaging PFC: Prefrontal cortex PNFA: Progressive non-fluent aphasia ROI: Region of interest SD: semantic dementia TDP-43: TAR DNA-binding protein 43   	   xi	  Acknowledgements  I would like to thank my supervisor Dr. Robin Hsiung for his ongoing support and guidance through my studies. I would also like to thank Dr. Faisal Beg and the staff and students in the Medical Imaging Analysis Lab at Simon Fraser University for their assistance in helping me to develop an understanding and appreciation for imaging analysis tools. In particular, the incredible patience of Dr. Karteek Parpouri was invaluable to the progress of this thesis.  I would like to extend a special thank you to the staff of the UBC Clinic for Alzheimer’s Disease and Related Disorders for their assistance and support in gathering the clinical data required to complete this thesis.   	   xii	  Dedication      To my family, I dedicate this thesis to you. 	   1	  Chapter 1: Introduction    1.1 General introduction Frontotemporal Dementia (FTD) is a neurodegenerative disease that presents with progressive alterations in behaviour, personality and/or language (Neary et al., 1998; McKhann et al., 2001), and accounts for as much as 20% of all dementias (Ratnavalli et al., 2002). Deficits in language and changes in personality and behaviour are caused by progressive atrophy of the frontal and temporal lobes (Grossman, 2002; Weder et al., 2007). The heterogeneous clinical symptoms of FTD broadly divide the disease into three phenotypic variants: behavioral-variant (bvFTD), progressive non-fluent aphasia (PNFA), and semantic dementia (SD) (Neary et al., 1998). FTD is the second most common dementia in people younger than 65 years of age and has a strong genetic basis with upwards of 50% of affected individuals having a positive family history, often with an autosomal dominant inheritance pattern (Rohrer et al., 2009a; Seelaar et al., 2008). The pathology of FTD spans two broad categories, tauopathies and TAR DNA-binding protein 43 (TDP-43) neuronal inclusions. FTD with tauopathies can be caused by a mutation in the microtubule associated protein tau gene (MAPT) (Poorkaj et al., 1998), and most frequently results in bvFTD (Miller, 2014). Tauopathies of unknown genetic cause can also lead to Pick’s disease, corticobasal degeneration and progressive supranuclear palsy (Miller, 2014). FTD associated with TDP-43 pathology can have genetic causes including C9ORF72 (DeJesus-Hernandez et al., 2011) and progranulin (GRN) mutations (Baker et al., 2006; Cruts et al., 2006). This thesis will be examining the presymptomatic neuroimaging features of these two 	   2	  mutations; therefore, the remainder of this introduction will focus on their corresponding clinical phenotypes and neuroanatomical features.  Since the discovery of these two genes, structural MRI studies have proved useful in identifying broad patterns of atrophy associated with each of the GRN and C9ORF72 mutations in affected individuals (Sha et al., 2012; Whitwell et al., 2012). However, few studies have examined the structural changes prior to disease onset in GRN mutation carriers (Borroni et al., 2008; Rohrer et al. 2008; Cruchaga et al., 2009; Borroni et al., 2012; Jacova et al., 2013) and none have been published on C9ORF72 mutation carriers. Thus, it is currently unknown what the earliest morphological changes in preclinical C9ORF72 mutations are, how they progress in the trajectory towards FTD, whether they can be measured with structural neuroimaging methods, and whether there are differences between GRN and C9ORF72 mutation carriers. Evidence suggests that abnormalities in white matter and functional connectivity occur prior to the clinical onset of GRN associated FTD (Borroni et al., 2008; Rohrer et al., 2008; Borroni et al., 2012; Jacova et al., 2013). However, further investigation is necessary to better understand when grey matter atrophy begins. As such, the aim of the current thesis is to utilize cortical thickness analyses to examine the neuroimaging characteristics of presymptomatic FTD caused by GRN and C9ORF72 mutations.  1.2  Cortical thickness The cerebral cortex is a highly folded sheet of grey matter with variable thickness that changes with normal aging (Salat et al., 2004). The cortical mantle, for the most part, is organized into six horizontal layers of distinct cellular composition and density. 	   3	  The six horizontal layers, beginning at the outer pial surface, include the following: (I) the acellular molecular layer, consisting of dendrites of neurons deeper in the cortex; (II) the external granule cell layer, consisting of granule cells; (III) the external pyramidal layer, consisting of pyramidal cells; (IV) the internal granule cell layer, which is similar to layer II; (V) the internal pyramidal cell layer, which is similar to layer III; and (VI) the polymorphic layer, containing spindleform cells. Laminar organization facilitates precise organization of outputs and inputs to and from various cortical and subcortical regions (von Economo and Koskinas, 1925; Kandel et al., 2000). Neuroimaging-based cortical thickness measures are inclusive of all layers spanning from the outer pial grey matter surface to the inner grey-white matter border. The first detailed study of cortical thickness in 1925 found an average thickness of 2.5mm, ranging from 1.5 - 4.5mm thick with the anterior temporal lobes and pre-central gyrus having the thickest cortex, and the post-central gyrus and the occipital lobes having the thinnest (von Economo and Koskinas, 1925; Kandal et al., 2000). von Economo and Koskinas also found variation within the gyri, with the thickest and thinnest values found in the crown and fundi, respectively. Since then, comparable mean cortical thickness values have been reproduced using MRI-based cortical thickness measurement tools (Fischl and Dale, 2000).  1.1.1 Effects of brain volume, sex and age on cortical thickness  Studies have found that as brain size increases, as does cortical surface area, sulcal depth and gyrification (Im et al., 2008; Toro et al., 2008). The corresponding increase in surface area and gyrification occurs throughout the entire cortex, with the 	   4	  greatest increase in folding occurring in the prefrontal cortex (Toro et al., 2008). Cortical thickness, on the other hand, only increases minimally with a larger brain volume (Pakkenberg and Gundersen, 1997; Im et al., 2008).   On average, men have a larger brain volume than women (8-10%) due to a larger body size and, therefore, a larger cranial cavity (Giedd et al., 1996; Peters et al., 1998; Sowell et al., 2007). Studies of whole brain grey matter, when controlling for brain size, have reported variable sex differences including no significant difference (Courchesne et al., 2000; Good et al., 2001), increased grey matter in females (Lemaitre et al., 2005) and increased grey matter in males (Resnick et al., 2000; Sullivan et al., 2004). When examined at the region-specific level, cortical thickness analyses have shown that women have a thicker cortical mantle in the parietal and temporal lobes (Im et al., 2006; Luders et al., 2006; Sowell et al., 2006). Differences at the regional level and variable results in whole brain grey matter indicate the importance in controlling for sex differences when analyzing group wise differences in cortical thickness. Age-related cortical thinning has been measured at a rate of 0.016mm per decade, with more significant age-related thinning in the occipital lobe (calcarine region), pre- and post-central gyrus, central sulcus, and association cortices (Salat et al., 2004). Age-related thinning of the prefrontal and orbitofrontal cortices (Jernigan et al., 2001; Sowell et al., 2003; Salat et al., 2004) with relative sparing of the temporal lobes have also been observed (DeCarli et al., 1994; Salat et al., 2004). Men and women have been shown to exhibit no significant difference in age-related cortical thinning (Salat et al., 2004).  It is evident that cortical thinning is a measurable and 	   5	  normal age-related change that must be considered when examining cortical thickness across independent groups.  1.1.2 Utility of measuring cortical thickness in neurodegenerative disease Automated tools that measure cortical thickness from in-vivo MRI are precise and have the capability to quantitatively measure the cortical mantle in both clinical and normal populations (Salat et al., 2004; Rosas et al., 2008; Sowell et al., 2008). Cortical thickness has also been suggested to be a more sensitive measure of minute changes when compared to voxel-based morphometry (VBM), specifically in age-associated grey matter thinning (Hutton et al., 2009) and therefore, may be the more suitable method of choice when measuring small amounts of cortical thinning, as is expected to be the case in presymptomatic genetic FTD. Cortical thickness methods have been widely used to measure neurodegenerative cortical thinning in Alzheimer’s disease (Du et al., 2007; Im et al., 2008; Richards et al., 2009), Huntington's disease (Rosas et al., 2008), Parkinson’s disease (Ibarretxe-Bilbeo et al., 2012; Zarei et al., 2013) and amyotrophic lateral sclerosis (ALS)  (Mezzapesa et al., 2013; Schuster et al., 2014). Utilizing cortical thickness methods to identify disease-specific regional thinning, such as thinning of the primary motor cortex in ALS patients with higher upper motor neuron burden (Mezzapesa et al., 2013), can provide valuable insight into the progression of a disease and may aid in predicting symptomology early in disease onset.  Cortical thickness analyses are becoming increasingly used in FTD neuroimaging studies. A study of the language variants, SD and PNFA, found that SD presented with left-greater-than-right asymmetrical temporal lobe thinning and that 	   6	  PNFA presented with left-sided superior temporal, inferior frontal and insular atrophy (Rohrer et al., 2009b), which is consistent with reports utilizing alternative neuroimaging modalities (Gorno-Tempini et al., 2004; Brambati et al., 2007, Schroeter et al., 2007). Not only did the findings of Rohrer and colleagues identify distinct cortical thickness patterns that accurately distinguished SD and PNFA, but they also identified longitudinal changes in cortical thinning consistent with the clinical progression of each variant (Rohrer et al., 2009b). A second study of the language variants was also successful in identifying distinct patterns of cortical thinning, particularly in the early to moderate stage of the disease (Rogalski et al., 2011). Cortical thickness analyses have also been utilized in comparative AD-FTD studies. One such study found that significantly thinner precuneus and parietal cortices differentiated the AD group from the FTD group (Du et al., 2007), while another demonstrated disease specific patterns of cortical thinning in AD and FTD compared to controls (Richards et al., 2009).    1.3  Frontotemporal dementia 1.3.1 Clinical phenotypes  FTD can have broad neurological and clinical features most commonly characterized by dysfunction in behavior, language and executive function (Neary et al., 1998; McKhann et al., 2001). Despite the heterogeneity of FTD symptoms, individuals affected by FTD generally exhibit deficits in executive function and working memory, reflecting the underlying distribution of neurodegeneration (Neary et al., 2005; Weder et al., 2007). bvFTD is characterized by alterations in social behaviour including 	   7	  disinhibition, impulsivity, apathy and loss of empathy (Bathgate et al., 2001; Grossman, 2002) and is the most common phenotype, with approximately half of all patients exhibiting symptoms of bvFTD (Johnson et al., 2005). Although behavioural changes are often the most prominent, FTD can also impair language. The two language variants, SD and PNFA, are clinically identified by primary progressive aphasia. SD is associated with left anterior temporal lobe atrophy and/or hypometabolism causing the progressive loss of semantic knowledge with relative preservation of grammar and episodic memory (Hodges et al., 1992; Gorno-Tempini et al., 2011). As the disease progresses, cortical degeneration can spread to the orbitofrontal and anterior cingulate cortices causing patients to exhibit bvFTD-like symptoms, in addition to their initial language deficits (Seeley et al., 2005). PNFA patients typically present with preserved single-word comprehension and object knowledge, but exhibit agrammatism and apraxia of speech caused by left frontoinsular atrophy and/or hypometabolism (Gorno-Tempini et al., 2011). As with the SD variant, PNFA atrophy can progress into more frontal regions causing the onset of bvFTD-like symptoms (Miller et al., 2014).  1.3.2 Clinical diagnosis  The diagnosis of FTD is achieved through the use of neuropsychological testing, neuropsychiatric assessment, and neuroimaging (Grossman, 2002).  Although the Mini-Mental State Examination (MMSE) is one of the most widely used neuropsychological tests in clinic, studies show that it has a relatively low sensitivity for distinguishing FTD from other types of dementias (Gregory et al., 1997, Mathuranath et al., 2000). The diagnosis of bvFTD is made based on clinical symptoms and neuroimaging features 	   8	  defined in the updated international consensus criteria (Rascovsky et al., 2011). Patients who initially present with prominent language deficits are diagnosed according to the language variant international consensus criteria (Gorno-Tempini et al., 2011).  Despite the utility of the language variant criteria, early in the disease the PNFA variant can be difficult to differentiate from the Alzheimer’s disease phenotype logopenic primary progressive aphasia, which is characterized by word retrieval difficulties causing slowed speech and sentence repetition deficits (reviewed by Gorno-Tempini et al., 2011). Although both consensus criteria support the clinical diagnosis of FTD, the pathological cause of the disease cannot be determined clinically, as each phenotype can have various underlying pathologies. For example, PNFA is associated with both tauopathies (Mesulam et al., 2008; Deramecourt et al., 2010) and TDP-43 pathology (Mesulam et al., 2008; Grossman et al., 2010).   1.3.3 Genetics   FTD has a strong genetic basis with approximately 50% of affected individuals having a positive family history of dementia, often with autosomal dominant inheritance pattern (Chow et al., 1999; Mackenzie et al., 2009). The two most common genetic causes of TDP-43 pathology are C9ORF72 (DeJesus-Hernandez et al., 2011) and GRN mutations (Baker et al., 2006; Cruts et al., 2006).  GRN encodes the protein progranulin, a growth factor and anti-inflammatory factor expressed in a variety of tissues throughout the body. In the CNS, progranulin is primarily produced by mature neurons and activated microglia (Daniel et al., 2000; Mackenzie et al., 2006; Petkau et al., 2010). Familial FTD caused by a GRN mutation 	   9	  results in haploinsufficiency and eventual TDP-43 pathology (Baker et al., 2006; Mackenzie et al., 2006; Benussi et al., 2009). However, the underlying mechanism by which progranulin haploinsufficienty causes the accumulation of TDP-43 neuronal inclusions remains unclear. The mean age of onset in GRN mutation carriers is 60 years, but can range by a much as 20 years even within families (Seelar et al., 2008; van Swieten et al., 2008). Approximately 90% of mutation carriers manifest symptoms by 75 years of age (Cruts et al., 2006) with the most common phenotypes being bvFTD and PNFA (Snowden et al., 2006; Rademakers et al., 2007 LeBer et al., 2008). After onset, the mean survival time is 8 years, but this is also considerably variable and can range from 3 to 22 years (Seelar, 2008).   The C9ORF72 genetic mutation is the most common cause of familial FTD and familial ALS, and encodes a protein of unknown function (DeJesus-Hernandez et al., 2011). One study reported 96% of carriers presented with bvFTD and that 26.9% also exhibit FTD/ALS (DeJesus-Hernandez et al., 2011), while a second study corroborated the prominence of bvFTD (64.0%), but also found expression of PNFA (26.7%) and SD (9.3%) within a C9ORF72 mutation carrier population (Renton et al., 2011). C9ORF72 trends towards an earlier ago of onset, approximately 56 years of age (DeJesus-Hernandez et al., 2011), compared to non-carrier FTD patients (Arighi et al., 2012; Irwin et al., 2013; Van Langenhove et al., 2013). Furthermore, patients with the mutation exhibit more psychiatric symptoms including delusions, hallucinations and severe anxiety compared to non-carrier FTD patients (Dobson-Stone et al., 2012).   	   10	  1.4  Neuroimaging and anatomical features of FTD 	  Volumetric MRI, DTI and resting-state fMRI are useful neuroimaging modalities that have helped to characterize clinical and genetic FTD. Volumetric MRI provides measures of grey matter loss in both cortical and subcortical regions, DTI investigates white matter tract integrity and resting-state fMRI detects functional connectivity of brain networks. Resting-state fMRI studies of the salience network are of particular interest, as this network is involved in processing salient internal and external stimuli associated with social-emotional processing, and is structurally based in the frontoinsula and anterior cingulate cortex (ACC) (Seeley et al., 2007b). Dysfunction in this network corresponds to bvFTD-specific atrophy patterns and may be connected to the social and behavioural symptoms of FTD (Whitwell et al., 2007a; Seeley et al., 2009; Zhou et al., 2010).  The remainder of section 1.4 will review the common neuroimaging features of genetically unclassified bvFTD, PNFA an SD, followed by a review of the neuroimaging features of affected and presymptomatic GRN and C9ORF72 mutation carriers.  1.4.1 Behavioral variant    bvFTD is the most widely studied phenotype of FTD. Studies of cortical grey matter volume in bvFTD, without specification of genetic status, are anatomically heterogeneous, yet general patterns of bilateral orbitofrontal, dorsolateral and medial frontal atrophy, as well as anterior temporal lobe involvement are commonly observed (Rosen et al., 2002a; Kreuger et al., 2010; Frings et al., 2012). A VBM study by Whitwell and colleagues identified four anatomical patterns of bvFTD presentation including: 	   11	  frontal dominant, frontotemporal dominant, temporal dominant and temporofrontoparietal dominant. A comparison of cognitive scores across the four anatomical subtypes showed group deficits characteristic of the anatomical regions affected. The frontal and frontotemporal subtypes performed the worst on executive function tasks, while the temporal-dominant group had the lowest scores on naming and memory tasks. Conversely, the frontal-dominant group performed best on memory and naming tasks (Whitwell et al., 2009). Several other studies also suggest that the anatomical regions affected are what drive the clinical syndrome of bvFTD. Apathy is thought to be largely frontal, however, the specific neuroanatomical correlate remains unclear with studies indicating the dorsolateral prefrontal cortex (Zamboni et al., 2008) and medial prefrontal cortex (Rosen et al., 2005), particularly the ACC (Zamboni et al., 2008; Massimo et al., 2009). Disinhibition and impulsivity are associated with atrophy of the medial orbitofrontal cortex (Rosen et al., 2005; Peters et al., 2006; Massimo et al., 2009). Obsessive-compulsive behaviors in bvFTD and have been correlated with atrophy in the lentiform nucleus and lateral temporal lobe (Perry et al., 2012), while changes in eating habits have been linked to the right anterior insula and orbitofrontal cortex (Whitwell et al., 2007b; Woolley et al., 2007). Increasing severity of repetitive movements is suggested to correlate with progressive atrophy of the right supplementary motor region (Rosen et al., 2002a, Rosen et al., 2005). Lastly, the dorsolateral prefrontal cortex (PFC), which is responsible for mediating executive skills (Possin et al., 2009), is often spared in early bvFTD, which may explain the later onset of executive dysfunction (Gorno-Tempini et al., 2011; Miller, 2014).   	   12	   Seeley and colleagues have done some of the most extensive work on the early anatomical changes in bvFTD. Findings of early focal atrophy of the right ACC and frontoinsula in bvFTD (Rosen et al., 2002; Schroeter et al., 2008) led to them to the hypothesis that two unique cell populations localized to these regions are specifically targeted early in disease progression (Seeley et al., 2006). Von Economo neurons (VENs), large bipolar neurons localized to layer 5 within the ACC and frontoinsula (von Economo, 1926), and fork cells, neurons in layer 5 of the frontoinsula (Ngowyang, 1923), are abundant in humans and great apes and increase in size and density with phylogenetic proximity to humans (Nimchinsky et al., 1999).  As such, these neurons are suggested to play an important role in the social and emotional capacities distinct to human cognition (reviewed by Seeley et al., 2006).  A comparative study of FTD and AD found that VENs were selectively affected early in FTD, with 74% reduction; whereas AD subjects exhibited normal VEN counts (Seeley et al., 2006). Seeley and colleagues have found that VEN and fork cell numbers begin to fall early in bvFTD, particularly in the frontoinsula, suggesting that atrophy of these regions initiate the decline in social-emotional processing (Seeley, 2008; Seeley et al., 2009; Zhou et al., 2010). A significant decline in VEN and fork cell numbers in the right frontoinsula, and to a lesser extent the ACC, were correlated with worsening symptoms of dishinibition in bvFTD (Kim et al., 2011), further supporting the theory of early focal ACC and frontoinsula atrophy as an underling cause of bvFTD symptom onset. More recently, VENs have been identified in the dorsolateral PFC (BA 9)(Fajardo et al., 2008), but the selective vulnerability of this population of VENs in FTD has yet to be examined.   	   13	   In addition to grey matter atrophy, structural and functional connectivity abnormalities have been measured in bvFTD patients. Degeneration of white matter tracts, primarily of in the frontal and temporal lobes, include: the superior longitudinal fasciculus, which connects the frontal, temporal and parietal lobes; the anterior cingulum, which connects to limbic structures; the anterior corpus callosum, which connects the frontal lobes; the uncinate fasciculus, which connects frontal and temporal lobes; and the inferior longitudinal fasciculus, which connects the temporal and occipital lobes (Zhang et al., 2009; Whitwell et al., 2010; Agosta et al., 2011). Decreased functional connectivity of the salience network has also been observed in bvFTD (Seeley et al., 2007a), with areas affected including the frontoinsular, cingulate, striatal thalamic and brainstem regions (Zhou et al., 2010). The right frontoinsula is suggested to be a critical integration hub necessary in the proper functioning of the salience network (Sridharan et al., 2008), indicating that atrophy in this region, and other regions associated with the salience network, may cause network dysfunction leading to a decline in social-emotional processing (Seeley et al., 2009; Zhou et al., 2010). However, some studies suggest that functional abnormalities precede structural atrophy (Whitwell et al., 2011; Dopper et al., 2013).  Based on the literature, it is evident that structural and functional connectivity changes affect bvFTD patients, however, what remains unclear is the chronology of the onset these structural and functional changes. Whether functional connectivity, grey matter atrophy or white matter atrophy initiates functional decline in bvFTD remains to be elucidated. Research into the earliest changes prior to symptom onset may prove valuable in better understanding the natural progression of bvFTD.    	   14	  1.4.2 Language variants: SD and PNFA    Clinically, SD patients initially present with deficits in word finding and single word comprehension (Gorno-Tempini et al., 2011), with structural MRI typically revealing asymmetrical atrophy predominantly in the left anterior and inferior temporal lobe (Mummery et al., 2000; Grossman et al., 2004; Rohrer et al., 2012). Despite prominent left temporal lobe involvement, greater right anterior temporal lobe atrophy at baseline has been observed, suggesting that in a subset of individuals the disease begins on the right side, but then progresses more rapidly in the left (Brambati et al., 2009; Josephs et al., 2009). Patients with this pattern of atrophy exhibit early signs of decreased empathy and difficulty with facial recognition, which is consistent with right temporal lobe atrophy (Perry et al., 2001; Rankin et al., 2006). Atrophy of the left fusiform and anterior temporal lobe is associated with object naming difficulties (Binney et al., 2010; Mion et al., 2010). White matter abnormalities in SD include the uncinate fasciculus and inferior longitudinal fasciculus, which is consistent the left temporal lobe atrophy (Whitwell et al., 2010; Galantucci et al., 2011; Agosta et al., 2012). As disease severity progresses, atrophy can spread from the left temporal lobe to the orbitofrontal, inferior frontal, insula and anterior cingulate cortices, causing bvFTD-like symptoms (Rohrer et al., 2009b).  PNFA patients typically present with expressive aphasia (agrammatism) and/or apraxia of speech, with focal asymmetrical atrophy of the left inferior frontal and anterior insula (Gorno-Tempini et al., 2011) and white matter degeneration of the left superior longitudinal fasciculus (Whitwell et al., 2010; Galantucci et al., 2011). There is no consensus on the anatomical correlate of apraxia of speech, with studies suggesting 	   15	  regionalization to left fronto-opercular area (Jordan and Hillis, 2006), the left anterior insula (Ogar et al., 2006) and the left dorsal pre-motor and supplementary motor cortices (Josephs et al., 2006). The neuroanatomical substrate of agrammatism is suggested to be in the anterior perisylvian area (Josephs et al., 2006).  1.4.3 Affected GRN and C9ORF72 mutation carriers Affected carriers of C9ORF72 exhibit diffuse anterior-to-posterior symmetrical atrophy in the frontal lobe, most prominently in the medial, dorsolateral and orbitofrontal regions, followed by atrophy in the anterior temporal lobe, parietal lobe and cerebellum (Boxer et al., 2011; Mahoney et al., 2012; Whitewell et al., 2012). Diffuse bilateral white matter abnormalities in the superior and inferior longitudinal fascisuli, cingulum, thalamic radiations, corticospinal tract and corpus callosum are also observed (Mahoney et al., 2012). A comparative study between sporadic bvFTD patients and C9ORF72 mutation carriers with bvFTD showed similarities in frontal and temporal lobe involvement, however, carriers exhibited greater posterior insular atrophy. The same study found that C9ORF72 mutation carriers with FTD/ALS exhibited greater atrophy in cerebellum and the right dorsofrontal and posterior cortical regions when compared to non-carrier FTD/ALS patients (Sha et al., 2012). GRN mutations are associated with asymmetric patterns of atrophy in the frontal, insular, cingulate, temporal and parietal cortices (Whitwell, 2009; Rohrer et al., 2010) and exhibit faster rates of atrophy than C9ORF72 mutation carriers (Mahoney et al., 2012). A right-side dominant presentation is associated with emotional and behavioural changes, whereas a left-side dominant pattern of atrophy results in executive 	   16	  dysfunction (bvFTD) and/or language impairments (PNFA) (Miller, 2014). A direct comparison across GRN and C9ORF72 groups found no regions of greater loss in the C9ORF72 carriers. The GRN group did, however, exhibited more atrophy than the C9ORF72 group in the left inferior temporal lobe and bilateral parietal lobes, suggesting that the parietal lobe involvement may be a GRN-specific marker (Whitwell et al., 2012).  1.4.4 Presymptomatic GRN and C9ORF72 mutation carriers A limited number of studies have examined the presymptomatic features of GRN mutation carriers, while no studies of presymptomatic C9ORF72 mutation carriers have been published. Presymptomatic GRN neuroimaging reports are mostly case studies or small sample studies examining white matter connectivity, resting-state fMRI and/or grey matter atrophy.   The literature to date suggests that structural and functional connectivity changes occur prior to grey matter atrophy in asymptomatic GRN mutation carriers (Borroni et al., 2008; Borroni et al., 2012; Dopper et al., 2013; Jacova et al., 2013), while the timing of subtle neuropsychological changes remains unclear. One study reported widespread white matter involvement including the right uncinate fasciculus, superior and inferior longitudinal fasciculi, corona radiata, external capsule, internal capsule, bilateral forceps minor, anterior thalamic radiation, inferior frontooccipital fasciculus and the body of the corpus callosum (Dopper et al., 2013). A smaller second study observed abnormalities in the left uncinate fasciculus and inferior frontooccipital fasciculus, which was suggestive of an underlying language phenotype (Borroni et al., 2008), as both of these white matter tracts are part of the perisilvian language system (Catani et al., 2005). 	   17	  Disruptions in presymptomatic functional connectivity, measured using resting-state fMRI, shows decreased anterior mid-cingulate connectivity and diminished connectivity between the frontoinsula and anterior mid-cingulate, suggesting early salience network dysfunction (Dopper et al., 2013). In contrast to these findings, a study of GRN carriers on average 20 years from the mean age of family onset, with no cortical loss, showed increased connectivity in the salience network, which was suggested to be a compensatory mechanism prior to network dysfunction (Borroni et al., 2012). Lastly, decreased glucose metabolism has been recorded in presymptomatic GRN mutation carriers in the right medial and ventral frontal lobe and insula without visible signs of grey matter atrophy (Jacova et al., 2013).   Of the few studies that have reported grey matter atrophy in presymptomatic GRN mutation carriers, findings suggest that atrophy occurs closer to the time of clinical onset. A study of GRN subjects with a family history of PNFA observed atrophy in the superior and inferior frontal gyri, left middle temporal gyrus, and superior and inferior parietal lobe at the time of onset of subtle language deficits (Cruchaga et al., 2009). Prior to a bvFTD diagnosis, a single GRN mutation carrier exhibited left side dominant asymmetrical atrophy of the frontal, temporal and parietal lobes 18 months before symptomatic onset (Rohrer et al., 2008). Although further research will be necessary to better understand the progression of GRN, the literature is strongly suggestive of early white matter and functional connectivity changes in presymptomatic GRN mutation followed by grey matter atrophy nearing clinical onset.   	   18	   Presymptomatic performance on neuropsychological testing also contributes to the understanding of disease progression in GRN mutation carriers. The findings to date are varied, which may be the results of small sample sizes and underlying clinical heterogeneity. Neuropsychological findings in presymptomatic GRN carrier have reported no measurable change in cognitive or language doamins (Borroni et al., 2008; Dopper et al., 2013), executive dysfunction (Geschwind et al., 2001) and decreased scores on tests of attention, mental flexibility and language (Barandiarn et al., 2012; Hallam et al., 2014).  Although Dopper and colleagues found no differences between controls and mutation carriers, an age-associated decline in tests of executive function and social cognition in the carrier group, but not the controls, suggested that impairment of these tasks may occur closer to disease onset (Dopper et al., 2013).   1.5 Overview of the study  1.5.1 Aims and purpose    Characterization of presymptomatic changes in white matter, functional connectivity and grey matter atrophy of C9ORF72 and GRN mutation carriers remains an important field of study as it may eventually contribute to the development of distinct genetic and/or phenotypic presymptomatic profiles. Morphological profiles would be invaluable in the counseling and management of mutation carriers, and in the tracking of morphological changes should future therapies specifically directed at TDP-43 proteinopathies become available. Thus, the primary aim of the current study is to contribute to the presymptomatic characterization of C9ORF72 and GRN mutation carriers by evaluating cortical grey matter thickness prior to the clinical onset of FTD. A 	   19	  secondary aim is to evaluate the status of several cognitive domains within each carrier group.   1.5.2 Hypotheses  I) Neuroanatomical changes in GRN and C9ORF72 mutation carriers begin prior to the onset of clinical FTD and can be measured using structural MRI cortical thickness analyses.  II) Presymptomatic changes in cortical thickness in GRN and C9ORF72 carriers will drive subtle differences in performance on neuropsychological and/or motor function tests.   1.5.3 Further considerations  A significant challenge faced by this thesis is the possibility of multiple underlying phenotypes within each carrier group. Since the population studied is presymptomatic, they remain clinically unclassified; therefore, the discussion of the results, as they relate to clinical phenotypes, is largely speculative. After disease progression and phenotype confirmation, a longitudinal follow-up with a retrospective analysis of the results will be necessary to fully appreciate the presymptomatic implications of C9ORF72 cortical thinning and decreased cognitive domain performance in GRN. 	   20	  Chapter 2: Methods  2.1 Subjects The FTD cohort included 37 participants recruited between 2006 and 2013 through the University of British Columbia (UBC) Clinic for Alzheimer Disease and Related Disorders. Subjects were recruited from 16 families with a GRN or C9ORF72 family history of FTD. GRN and C9ORF72 carrier status was determined after enrollment and remain blinded to the subjects and to investigators who performed the clinical assessments. The cohort included 6 GRN mutation carriers and 9 non-carriers from 5 GRN families, and 8 C9ORF72 mutation carriers and 11 non-carriers from 11 C9ORF72 families. An additional 3 affected C9ORF72 carrier images were available and included in the study as a separate group. The fully affected group consisted of one bvFTD subject and two FTD/ALS subjects. The carrier status was determined by DNA extraction from peripheral blood and sequencing was performed at the Mayo Clinic, Jacksonville, Florida, using standard protocols (Baker et al., 2006; Frackowiak et al., 2004; DeJesus-Hernandez et al., 2011). Subjects with a mutation were classified as unaffected mutation carriers, affected carriers or non-carrier controls, in accordance with the family history. From here on, ‘C9ORF72 carriers’ refers to the unaffected group and ‘affected C9ORF72 carriers’ refers to the fully affected group. Demographic data was collected at the time of imaging and included age, sex, years of education, and years to mean age of FTD onset within the family.     	   21	  2.1.1 Clinical assessment A neuropsychological battery was administered and measures were converted to composite z-scores by domains of attention, language, visuospatial skill, verbal memory, non-verbal memory, working memory and executive function (Table 1). Clinical data was collected within seven days of the magnetic resonance imaging (MRI) study with exception of one GRN and one C9ORF72 non-carrier control where the clinical data was collected three weeks and three months prior to MRI acquisition, respectively. The following tests were administered to all participants: Trails A and B, Stroop Colour Naming/Interference, Flanker Task, CVLT-II, WMS-III, Gambling Task, Wisconsin Card Sort-64, Fluency (design, verbal, category), WAIS-III, Pyramid & Palm Trees, Boston Diagnostic Aphasia Exam, Boston Naming Test, Peabody Picture Vocabulary Test-III, PALPA Reading, Benton Facial Recognition, Beck Depression Inventory-II/Geriatric Depression Scale, State-Trait Anxiety Inventory, Judgment of Line Orientation and Brief Visuospatial Memory Test.   Standard protocol approvals and patient consents were obtained and the UBC Ethics Board approved the study. Written informed consent was obtained from each participant. 	   22	  Table 1.  FTD neuropsychological test battery and cognitive domains assessed Domain Test Attention  Trail Making, Part A Stroop Colour Naming WAIS-III Digit Span Forward WMS-III Spatial Span Forward  Visuospatial WAIS-III Block Design Modified Rey Figure Copy WMS-III Visual Reproduction Copy Verbal Memory CVLT-II SF short and long delay WMS-III Logical Memory Immediate and Delayed Recall Trial Working Memory CVLT-II SF, Trial I WAIS-III Digit and Spatial Span Backward WAIS-III Digit Symbol Language  Controlled Oral Word Association Test (C-F-L) Category Fluency Test Boston Naming Test, short version  Non-verbal Memory WMS-III Visual Reproduction I (Immediate Recall Trial) WMS-III Visual Reproduction II (Delayed Recall) Modified Rey Figure Delayed Recall Trial  Executive Function Trail Making, Part B Ruff Design Fluency Wisconsin Card Sorting Test – Preservative Errors WAIS-II Similarities, Matrix Reasoning WAIS-III = Wechsler Adult Intelligence Scale, WMS-III = Wechsler Memory Scale, CVLT-II SF = California Verbal Learning Test Short Form. 	   23	  2.1.2 Inclusion criteria For inclusion in the study, all subjects had to a) have a genetically confirmed family history of FTD due to either GRN or C9ORF72, b) undergo a neuropsychiatric battery and clinical examination and exhibit normal neurological examination and no evidence of dementia and c) be able to provide consent. The combination of both test scores and clinical assessments were used to classify subjects as either unaffected or affected. Patients with MMSE scores below 26, but otherwise normal, were excluded from the unaffected and non-carrier control groups.    2.2 Image acquisition All carrier and control subjects underwent a structural MRI using a 1.5T GE Signa scanner located in the UBC Hospital MRI Research Centre. The scan parameters were: 1) Localizers (0:25 min): sagittal/coronal and axial;  2) Fast Gradient TR 5.4, TE 1.6, 1 average, FOV 22 cm, 256 x 128 matrix; 3D T1-Fast Spoiled gradient echo IR Prepped (8:35 min): axial, TR/TE (ms) = 10.3/4.8, 256 x 256 matrix, 170 partitions, 8o flip angle.  2.3 Image processing Images were processed and the cortex parcellated using the FreeSurfer Surface Analysis pipeline (http://surfer.nmr.mgh.harvard.edu/). The automated procedure has been previously described in detail and validated (Dale et al., 1999; Fischl and Dale, 2000). Briefly, the pipeline involves intensity normalization, registration to Talairach space, skull stripping, segmentation of white matter, tessellation of the white matter 	   24	  boundary, smoothing of the tessellated surface and automatic topology correction. The tessellated surface is utilized for the surface algorithm in finding the white and pial boundary of the cortical mantle (Dale et al., 1999; Fischl and Dale, 2000).  2.3.1 Quality control process After automated cortical parcellation, all images were passed through a quality control process to identify and correct parcellation errors. The quality control phase involved examining each MRI for cortical parcellation errors, manually correcting errors, re-parcellating the MRI in the automated pipeline, followed by a final pass of the corrected MRI through the quality control process. The first step in the quality control assessment involved generating two quickcheck images per MRI, one per hemisphere, for a total of 74 quickcheck images. Figure 1 is a sample quickcheck that demonstrates the comprehensive overview of each hemisphere including 9 images per plane of view, for a total of 27 images per hemisphere. Every quickcheck was examined for segmentation errors generated in the automated pipeline. The only errors detected were the result of incomplete skull stripping causing partial inclusion of the skull and/or dura at the pial border. Errors were manually corrected by removing the excess skull and dura using the FreeSurfer Freeview application. After manual removal of the excess material, images were reprocessed in the cortical thickness pipeline and reviewed in a second quickcheck to ensure that the segmentation error was corrected, and to ensure that no additional errors were generated.     	   25	  Figure 1. A sample quickcheck image of the right hemisphere with a segmentation error detected in the first sagittal image. 	   26	  2.3.2 Template registration After all images passed the quality control phase, images were registered to common space using the FreeSurfer fsaverage template. Following registration, surface maps were generated and smoothed using a 10mm, 15mm and 20mm full-width at half maximum Gaussian kernel.  2.4 Statistical analysis Statistics Package for the Social Sciences (version 20) was used to compare groups on demographic and clinical variables. To compare means across groups the significance was set at p < 0.05. For continuous variables a one-way analysis of variance (ANOVA) was used, a chi-square tests was used for categorical variables, and Studentʼs t-test for two independent samples. Pearson correlations were conducted to compare mean cortical thickness and cognitive domain z-scores. Freesurfer image processing and registration to a common space results in 327684 vertices across the cortical surface. Using the program SurfStat (Worsley et al., 2009) cortical thickness was analyzed using a vertex-by-vertex general linear model to examine differences in cortical thickness between groups while controlling for age, sex, MMSE and years to mean age of onset within the family.   2.5 Study design Cross sectional whole brain analyses were conducted to examine group wise differences in cortical thickness. The cluster threshold was set at p < 0.05, using random field theory correction for multiple comparisons, and only clusters consisting of 	   27	  more than 50 nodes were reported. Cortical thickness data was collected at 10mm, 15mm and 20mm of full width half maximum smoothing and was reported using confidence intervals based the trends across all three analyses. Significant clusters identified at all three, two consecutive or one smoothing level are reported with strong, moderate and weak confidence, respectively. The decision to report all three smoothing levels in the current study is aimed at providing a systematic approach whereby the result with moderate to strong confidence can be reported with greater certainty that the findings are due to an underlying cortical thickness difference, and not the result of a smoothing effect, as may be the case in the weak confidence interval.  To compare clusters across the three smoothing levels, an ROI naming system was employed to identify the gyri that contributed to each significant cluster. As each vertex on the fsaverage template surface is associated with a specific ROI in the Freesurfer Desikan-Killiany atlas, the vertices of a significant cluster were grouped according their ROI location in accordance with the atlas’ ROI naming conventions (Desikan et al., 2006). Thus, clusters that spanned large cortical areas were more accurately defined by multiple specific anatomical locations. Both the p-value and number of vertices in the regions of significant clusters were recorded in order to track cluster sizes across the three smoothing analyses (Table 4).  At each of the 10mm, 15mm and 20mm smoothing analyses, mean cortical thickness of the ROIs contributing to the significant clusters was recorded for every individual within the group. Lastly, a correlation analysis was conducted to examine the relationship between cognitive domain z-scores and mean cortical thickness at the significant cluster ROIs.  	   28	   Chapter 3: Results   3.1 Demographic and clinical data The demographic data and clinical assessment scores collected at the time of imaging for the C9ORF72 and GRN groups are listed in Table 2. The individual carrier and affected subject scores in are listed in Table 3. There was no significant difference in age, years of education or years to mean age of family onset between the mutation carriers and their respective non-carrier control group. The GRN mutation carriers performed significantly worse on domains of working memory (p = 0.02) and executive function (p = 0.01). The executive function t-test was re-evaluated with exclusion of an outlier (second GRN carrier listed in Table 2), yet remained significant (p = 0.037). Furthermore, there was a trend towards decreased performance in the GRN mutation carrier group on domains of language (p = 0.06) and visuospatial skills (p = 0.08). There was no difference in cognitive domain composite scores between the C9ORF72 carrier and non-carrier control groups. Between the two carrier groups and between the two control groups there was no significant difference in demographic data or cognitive scores. Although the affected C9ORF72 carrier group was not significantly older than the C9ORF72 carrier group, they were closer to the mean age of onset within the family (p = 0.03). The affected C9ORF72 mutation carriers performed significantly worse than the presymptomatic C9ORF72 mutation carriers on test of language (p = 0.04), the ALS-Functional Rating Scale (p = 0.05) and the ALS Bulbar Scale (p = 0.007).	   29	  Table 2. Group demographic data, clinical scores and composite domain scores (z-scores).   GRN- n=9 Mean ± SD GRN+ n=6 Mean ± SD P* C9ORF72- n=11 Mean ± SD C9ORF72+ n=8 Mean ± SD P* C9ORF72 affected n=3 Mean ± SD P** Age at scan, years 52.11 ± 8.82 53.33 ± 9.67 0.80 52.82 ± 17.15 50.25 ± 6.90 0.70 55.00 ± 1.00 0.70 Sex (M:F) 4:5 1:5 0.26 7:4 5:3 0.96 3:0 0.21 Education, years 13.00 ± 2.00 11.83 ± 1.33 0.23 14.73 ± 3.00 14.50 ± 4.14 0.89 13.33 ± 2.31 0.66 Years to mean age of onset within family -6.78 ± 7.24 -6.33 ± 10.39 0.92 -4.18 ± 15.02 -8.00 ± 5.66 0.51  0.33 ± 1.53 0.03  MMSE 29.44 ± 0.53 29.33 ± 0.82 0.75 28.82 ± 0.98 29.50 ± 0.75 0.12 27.67 ± 2.08 0.24 FAB 17.56 ± 0.73 17.67 ± 0.82 0.79 16.18 ± 2.14 16.00 ± 1.93 0.85 13.33 ± 4.73 0.43 Attention 0.22 ± 0.67 -0.17± 0.75 0.31 0.18± 0.75 0.00 ± 0.76 0.61 -1.33 ± 2.08 0.38 Working Memory 0.56 ± 0.53 -0.33 ± 0.82 0.02 0.27 ± 0.65 0.38 ± 0.52 0.72 -0.33 ± 1.16 0.40 Language 0.67 ± 0.50 0.17 ± 0.41 0.06 0.18 ± 0.60 0.50 ± 0.76 0.32 -0.67 ± 0.58 0.04 Visuospatial 0.22 ± 0.67 -0.50± 0.84 0.08 0.36 ± 0.67 0.00 ± 1.04 0.29 0.00 ± 0.00 1.00 Verbal Memory 0.67 ± 0.71 0.50 ± 1.05 0.72 0.55 ± 0.82 0.75 ± 1.04 0.64 0.00 ± 2.00 0.42 Non-verbal Memory 0.33 ± 1.00 0.00 ± 0.63 0.48 0.18 ± 1.17 -0.25 ± 0.71 0.37 0.00 ± 1.00 0.65 Executive 0.44 ± 0.53 -0.33 ± 0.52 0.01 0.00 ± 0.78 0.13 ± 0.84 0.74 -0.67 ± 1.53 0.29 ALS-FRS 20.00 ± 0.00 20.00 ± 0.00 1 19.73 ± 0.47 19.88 ± 0.35 0.46 19.00 ± 1.00 0.05 ALS Bulbar Scale 38.89 ± 0.33 39.00 ± 0.00 0.44 38.82 ± 0.41 39.00 ± 0.00 0.17 30.33 ± 7.77 0.007 MMSE = Mini Mental State Examination. FAB = Frontal Assessment Battery. ALS-FRS = ALS-Functional Rating Scale.               * t-test for continuous variables, chi-square test for categorical variables. ** C9ORF72 mutation carriers compared to affected C9ORF72 mutation carriers.  	   30	  Table 3. Demographic data, clinical scores and composite domain scores (z-scores) of the mutation carriers.  Genetics Sex Age Onset MMSE FAB ALS FRS ALS BST Cognitive Domain Scores Attn WM Lang VSP VM N-VM Exec Presymptomatic C9ORF72     F 50 -12 30 16 20 39 0.61 0.64 1.54 0.55 1.92 0.4 0.41 C9ORF72 F 57 -7 29 18 20 39 0.07 0.97 1.11 1 0.33 -0.26 0.82 C9ORF72 M 55 -1 28 15 19 39 -1.39 -0.35 -0.27 -0.68 -0.67 -0.04 -0.59 C9ORF72 M 49 -4 30 18 20 39 0.27 0.41 -0.03 -0.13 -0.13 -0.92 -0.01 C9ORF72 M 37 -14 30 18 20 39 0.95 0.24 -0.13 0.11 0.75 0.73 0.86 C9ORF72 M 45 -17 29 13 20 39 0.21 0.27 0.38 -1.14 0.79 -0.7 0.41 C9ORF72 F 58 -4 30 14 20 39 -0.61 -0.36 0.22 -0.24 0.67 -0.69 -0.56 C9ORF72 M 51 -5 30 16 20 39 0.07 0.73 1.34 0.43 1.54 0.31 0.58 GRN F 66 7 29 18 - - 0.6 0.79 -0.04 -0.71 0.59 -0.09 0.23 GRN F 54 -5 28 16 - - -0.82 -0.63 -0.47 -0.7 -0.83 -1.14 -1.35 GRN F 46 -17 29 18 - - 0.12 -0.66 -0.12 -1.36 0.13 -0.48 0.27 GRN F 39 -20 30 18 - - -0.7 -0.76 -0.48 -0.67 1.5 0.4 -0.51 GRN M 55 -4 30 18 - - -0.39 -0.17 0.23 0.81 0.46 1.18 0.39 GRN F 60 1 30 18 - - 0.44 0.33 0.56 0 0.63 0.3 0.39 Affected C9ORF72 M 54 2 30 17 20 39 0.92 0.62 -0.45 -0.45 1.88 1.06 0.59 C9ORF72 M 55 -1 27 15 18 28 -1.76 -0.78 -1.37 0 0 -0.47 -1.49 C9ORF72 M 56 0 26 8 19 24 -2.74 -1.33 -0.86 0 -1.5 -1.46 -2.25 Onset = years to mean age of family onset; MMSE = Mini Mental State Exam; FAB = Frontal Assessment Battery; ALS-FRS = ALS-Functional Rating Scale; ALS-BST = ASL Bulbar Scale total; Attn = Attention; WM = Working memory; Lang = Language; VSP = Visuospatial; N-VM = Nonverbal memory; Exec = Executive function. 	  	   31	  3.2 Cortical thickness between groups Vertex-wise analyses of cortical thickness differences between carrier, control and affected groups controlling for age, sex, MMSE scores and years to mean age of family onset are reported. Figure 2 displays the whole-brain mean cortical thickness at 15mm of smoothing of the following groups: all non-carrier controls (n = 17), GRN carriers (n = 6), C9ORF72 carriers (n = 9) and affected C9ORF72 carriers (n = 3).  Figure 2. Mean cortical thickness maps at 15mm of smoothing. 	  	   32	  3.2.1 GRN carriers versus GRN non-carrier controls The cortical thickness comparison between the GRN carriers and non-carrier controls showed no regions of significant difference at the 10mm, 15mm or 20mm smoothing levels. T-maps indicate cortical thickness variability between the groups (Figure 3), but exhibited no major pattern. A repeated analysis at all smoothing values without inclusion of covariates also revealed negative findings.     Figure 3. T-maps of GRN carriers versus GRN non-carrier controls.  The colour bar indicates the t-statistic with cooler colours signifying areas of thinner cortex in the GRN mutation carrier group and warmer colours indicating regions of thinner cortex in the non-carrier control group. None of the regions reached statistical significance. A) 10mm smoothing; B) 15mm smoothing; C) 20mm smoothing.  	   33	  3.2.2 C9ORF72 carriers versus C9ORF72 non-carrier controls Compared to the non-carrier controls, cortical thickness in the C9ORF72 carriers was widely reduced (Figure 4) with a number of statistically significant regions at each of the 10mm, 15mm and 20mm smoothing analyses (Figure 5). No region of the cortex was significantly thicker in C9ORF72 carrier group than the non-carrier control group. Table 4 lists the regions that were significantly thinner in the C9ORF72 carrier group by confidence intervals. Clusters that were significant across all three, two consecutive or only one smoothing level are reported with strong, moderate and weak confidence, respectively. When examining the significant regions with moderate to strong confidence of more than 1000 nodes at each significant measure, a pattern of right temporoinsular and left dorsal mediofrontal and temporal cortical thinning in the C9ORF72 carrier group is observed (Table 4).  The most extensive regions affected in the right temporoinsular area in the carrier group of strong confidence include the superior temporal gyrus (mean number of nodes (MN) = 3297), banks of the superior temporal sulcus (MN = 1563) and middle temporal gyrus (MN = 1235), with moderate confidence in the insula (MN = 1630). Visual inspection of an inflated template surface revealed significant cortical thinning of the right insula regionalized to the dorsal-anterior and dorsal-posterior surfaces at both 15mm (p<0.01) and 20mm (p<0.05) smoothing (Figure 6).  The left dorsal mediofrontal region exhibited strong confidence at the superior frontal gyrus (MN = 8387) and pre-central gyrus (MN = 2181), while the left temporal pattern is comprised of moderate confidence at the fusiform gyrus (MN  = 3448), inferior 	   34	  temporal gyrus (MN= 2279), middle temporal gyrus (MN = 1137) and superior temporal sulcus (MN= 1715).    Figure 4. T-maps of C9ORF72 carriers versus C9ORF72 non-carrier controls.  The colour bar indicates the t-statistic with cooler colours indicating areas of thinner cortex in the C9ORF72 carrier group, while warmer colours denote regions of thinner cortex in the non-carrier control group. A) 10mm smoothing; B) 15mm smoothing; C) 20mm smoothing.  	   35	  Figure 5. Regions of significant cortical thinning in the C9ORF72 mutation carriers compared to the C9ORF72 non-carrier controls.  Analysis controlling for age, sex, MMSE and years to mean age of family onset. All significant regions are thinner in the C9ORF72 carrier group. A)10mm; smoothing; B) 15mm smoothing; C) 20mm smoothing. 	   36	  Figure 6. Cortical thinning of the right anterior and posterior dorsal insula in the C9ORF72 mutation carrier group.  Analysis controlling for age, sex, MMSE and years to mean age of family onset.           A) 15mm smoothing; B) 20mm smoothing.	   37	  Table 4. Regions of significant cortical thinning in the C90RF72 mutation carriers compared to the non-carrier controls. Cluster Region 10mm 15mm 20mm P-value Nodes P-value Nodes P-value  Nodes Strong L_Caudal middle frontal <0.001 175 <0.01 210 <0.001 3156 L_Paracentral <0.001 208 <0.01 237 <0.001 586 L_Posterior cingulate <0.001 219 <0.01 446 <0.001 1490 L_Precentral <0.001 1563 <0.01 2176 <0.001 2803 L_Superior frontal <0.001 6939 <0.01 8320 <0.001 9604 R_Bankssts <0.01 1241 <0.01 1666 <0.05 1783 R_Inferior parietal <0.01 51 <0.01 190 <0.05 299 R_Middle temporal <0.01 1097 <0.01 1244 <0.05 1364 R_Supramarginal <0.01 79 <0.01 2205 <0.05 3264 R_Superior temporal <0.01 2003 <0.01 3567 <0.05 4320 Moderate L_Bankssts - - <0.01 1567 <0.001 1862 L_Entorhinal - - <0.01 514 <0.001 726 L_Fusiform - - <0.01 3156 <0.001 3740 L_Inferior parietal - - <0.01 124 <0.001 144 L_Inferior temporal - - <0.01 1878 <0.001 2679 L_Lingual - - <0.01 126 <0.001 1667 L_Middle temporal - - <0.01 1196 <0.001 1077 L_Parahippocampal - - <0.01 506 <0.001 1156 L_Supramarginal - - <0.01 352 <0.001 307 L_Superior temporal - - <0.01 1463 <0.001 911 L_Temporal pole - - <0.01 74 <0.001 100 R_Insula - - <0.01 1502 <0.05 1758  R_Lateral orbitofrontal - - <0.01 56 <0.05 64 R_Parsopercularis - - <0.01 151 <0.05 233 R_Parstriangularis - - <0.01 349 <0.05 391 R_Postcentral - - <0.01 648 <0.05 879 R_Precentral - - <0.01 455 <0.05 493 R_Transverse temporal - - <0.01 51 <0.05 83 Weak L_Caudal anterior cingulate - - - - <0.001 241 L_Cuneus - - - - <0.001 309 L_Isthmus cingulate - - - - <0.001 1593 L_Parsopercularis - - - -  <0.001 471 L_Pericalcarine - - - - <0.001 326 L_Precuneus - - - - <0.001 2310 L_Rostral middle frontal - - - - <0.001 3160 R_Frontal pole <0.05 187 - - - - R_Medial orbitofrontal <0.05 817 - - - - R_Rostral middle frontal <0.05 224 - - - - Only clusters greater than 50 nodes are reported. bankssts = banks of the superior temporal sulcus.   	   38	  3.2.3 Affected C9ORF72 mutation carriers versus presymptomatic C9ORF72 mutation carriers and non-carrier controls Cortical thickness in the affected C9ORF72 carrier group exhibited diffuse areas of thinning when compared to the C9ORF72 carrier group, particularly in the right medial temporal lobe and the left frontal operculum and anterior insula (Figure 7). Numerous areas reached statistical significance (Figure 8), but did not survive the inclusion of age, sex, MMSE, or years to means of family onset covariates, likely due to the small sample size of the affected group (n = 3).   When compared to the C9ORF72 non-carrier control group, the affected C9ORF72 carriers displayed widespread anterior-to-posterior bilateral cortical thinning (Figure 9) with relatively symmetrical distribution, with the exception of greater thinning in dorsomedial PFC of the right hemisphere (Figure 10).  	   39	  Figure 7. T-maps of C9ORF72 mutation carriers versus affected C9ORF72 mutation carriers. The colour bar indicates the t-statistic without controlling for age, sex, MMSE or years to mean age of family onset. Warmer colours denote areas of thinner cortex in the affected C9ORF72 mutation carrier group and cooler colours specify regions of thinning in the presymptomatic C9ORF72 mutation carrier group. A) 10mm smoothing; B) 15mm smoothing; C) 20mm smoothing.   	   40	   Figure 8. Regions of significant cortical thinning in the affected C9ORF72 mutation carriers compared to the presymptomatic C9ORF72 mutation carriers.            Significant clusters of cortical thinning without controlling for age, sex, MMSE or years to mean age of family onset. A) 10mm smoothing; B) 15mm smoothing; C) 20mm smoothing	   41	  Figure 9. T-maps of affected C9ORF72 mutation carriers versus C9ORF72 non-carrier controls.  The colour bar indicates the t-statistic with cooler colours signifying areas of thinner cortex in the affected C9ORF72 mutation carrier group and warmer colours indicating regions of thinner cortex in the non-carrier control group. A) 10mm smoothing; B) 15mm smoothing; C) 20mm smoothing.	   42	  Figure 10. Regions of significant cortical thinning in the affected C9ORF72 mutation carriers compared to the C9ORF72 non-carrier controls.     Analysis controlling for age, sex, MMSE and years to mean age of family onset. All regions are significantly thinner in the affected C9ORF72 mutation carrier group. A) 10mm smoothing. B) 15mm smoothing. C) 20mm smoothing.  	   43	   3.2.4 GRN mutation carriers versus C9ORF72 mutation carriers Figure 11 displays the spatial distribution of cortical thickness differences between the GRN mutation carriers and C9ORF72 mutation carriers. A trend towards thinning of the caudal medial frontal region (left>right) in the C9ORF72 carriers group is apparent on visual inspection of the t-maps (Figure 11), however, no cortical region reached statistical significant at 10mm, 15mm or 20mm of smoothing. Repeated analyses excluding the covariates also found no significant difference between the two carrier groups. 	   44	   Figure 11. T-maps of C9ORF72 mutation carriers versus GRN mutation carriers. The colour bar indicates the t-statistic with warmer colours signifying areas of thinner cortex in the C9ORF72 mutation carrier group and cooler colours indicating regions of thinner cortex in the GRN mutation carrier group. None of the regions reached statistical significance. A)10mm smoothing; B) 15mm smoothing; C) 20mm smoothing.	   45	  3.3 Correlation between cortical thickness and clinical scores 3.3.1 C9ORF72 mutation carriers and C9ORF72 non-carrier controls A Pearson correlation was conducted to assess the relationship between mean cortical thickness of the strong, moderate and weakly significant clusters at each smoothing level and the cognitive domain composite scores. Non-verbal memory scores were positively correlated with left hemisphere regions including the paracentral gyrus (r=0.49 and 0.50 at 15mm and 20mm, p<0.05), inferior temporal gyrus (r= 0.62 and 0.63, p<0.001 at 15mm and 20mm), lingual gyrus (r = 0.62 and 0.63 at 15mm and 20mm, p<0.001) and middle temporal gyrus (r = 0.56 and 0.59 at 15mm and 20mm; p<0.05). Verbal memory correlated with cortical thickness of the left middle temporal gyrus (r = 0.66 and 0.68 at 15mm and 20mm; p<0.01), while attention scores correlated with the left paracentral gyrus (r = 0.62 at 10mm, 15mm and 20mm; p<0.01).   	   46	  Chapter 4: Discussion  The aim of this thesis was to investigate cortical thickness in presymptomatic C9ORF72 and GRN mutation carriers with specific aims to a) examine cortical thickness differences between mutation carriers and non-carrier control family members, b) examine the differences between presymptomatic C9ORF72 mutation carriers and affected C9ORF72 mutation carriers and c) determine the relationship between early cognitive and/or motor changes with regions of significant cortical thinning. With the use of genetic screening and neuroimaging analyses this thesis demonstrated that grey matter thinning occurred prior to cognitive domain changes in the C9ORF72 mutation carriers, while the GRN mutation carriers exhibited decreased performance on domains of working memory and executive function, with a trend towards decreased performance on language and visuospatial domains, prior to cortical grey matter atrophy. These findings are significant as they suggest that each mutation progresses towards FTD along different mechanisms. Thus, GRN and C9ORF72 mutations may require specific neuroimaging methods to track morphological changes prior to cognitive decline. In C9ORF72 mutation carriers, cortical grey matter atrophy may prove to be a useful tool in tracking and/or predicting disease progression, whereas the negative atrophy findings in the GRN mutation group indicates that alternative neuroimaging modalities may prove to be more useful in understanding early disease progression in presymptomatic GRN mutation carriers. These alternative neuroimaging modalities and their possible utility in understanding early GRN progression are discussed further in sections 4.3 and 4.6.  	   47	   4.1 Presymptomatic C9ORF72 mutation carrier cortical thinning  Studies of affected C9ORF72 mutation carriers generally report symmetrical patterns of frontal, temporal, insular, and posterior cortical atrophy (Boeve et al., 2012; Mahoney et al., 2012; Sha et al., 2012; Whitwell et al., 2012; Whitwell et al., 2013), however, no published works have reported on presymptomatic cortical thickness in C9ORF72 mutation carriers. A major finding of the current work is the C9ORF72 mutation carrier cortical thinning prior to the onset of cognitive and/or motor deficits. However, since the specific clinical phenotypes within the group remains to be elucidated, the observed patterns of cortical thinning may be driven by a combination of bvFTD, FTD/ALS and/or language variants. Thus, the interpretations of the patterns of atrophy in the current study remain largely speculative. Only with longitudinal follow-up and retrospective analysis can the functional implication of these patterns be more fully understood. Despite this challenge, the findings of the current study provide valuable insight into disease progression and provide numerous reasons and rationale for longitudinal study of the C9ORF72 carrier group. The overall pattern of presymptomatic atrophy was asymmetrical, which contrasts the symmetrical pattern observed in symptomatic patients, yet the regions affected in each hemisphere (right temporoinsular and left mediofrontal and superior temporal) are consistent with studies of affected C9ORF72 mutation carriers (Boeve et al., 2012; Mahoney et al., 2012; Sha et al., 2012; Whitwell et al., 2012; Whitwell et al., 2013). The involvement of the right insula is of particular interest, as this is consistent with the work of Seeley and colleagues that suggests neuropathology of FTD begins in 	   48	  the frontoinsular and paralimbic regions (Seeley et al., 2008; Seeley et al., 2010). The other regions affected also reflect several areas functionally related to early behavioral symptoms of bvFTD in C9ORF72 mutation carriers, including behavioral disinhibition, apathy, decreased motivation and initiative, loss of empathy, and changes in dietary habits (Boeve et al., 2012; Mahoney et al., 2012; Snowden et al., 2012), and will be discussed in the following section. Thus, overall findings argue favor of an underlying bvFTD phenotype, with possible bvFTD/ALS. However, since C9ORF72 can also present as the PNFA phenotype, albeit much less frequently (DeJesus-Hernandez et al., 2011; Renton et al., 2011; Hsiung et al., 2012), the following three sections will examine the patterns of cortical thinning in the context of all three variants.  4.1.1 bvFTD neuroanatomical features  Cortical atrophy of the right temporoinsular region is consistent with neuroimaging studies of C9ORF72 (Boeve et al., 2012; Mahoney et al., 2012; Sha et al., 2012; Whitwell et al., 2012; Whitwell et al., 2013) and regional atrophy of the right anterior and posterior dorsal insula is consistent with early bvFTD (Seeley et al., 2006; Seeley et al., 2008). Early disruption of the right frontoinsula and anterior cingulate cortex (ACC) is suggested to initiate dysfunction of the salience network causing early bvFTD symptoms of apathy and disinhibition (Seeley et al., 2006; Kim et al., 2012). The current findings indicate that insular atrophy precedes ACC atrophy, and since the current group is presymptomatic, these findings suggest that either a) both insular and ACC involvement is required for sufficient salience network dysfunction to induce behavioral changes or b) insular involvement must reach a threshold of atrophy to 	   49	  induce behavioural changes. A longitudinal follow-up of the C9ORF72 group that examines the relationship between progressive insular atrophy and the onset of symptoms of apathy and disinhibition in the C9ORF72 group would aid in further understanding the significant early atrophy in this region. The anterior insula has also been linked to emotion recognition, particularly of feelings of disgust (Adolphs, 2001; Calder et al., 2001), which may be connected to the emotional processing deficits common to bvFTD (Miller, 2014). Therefore, tracking of progressive atrophy with the onset of emotional recognition symptoms may also be of interest. Should progressive insular atrophy correlate with the onset of the above symptoms, this would point to the right insula as a possible marker of eventual bvFTD symptomology in presymptomatic C9ORF72 carriers. Right temporal lobe atrophy in the C9ORF72 carriers is also consistent with findings in affected C9ORF72 subjects (Mahoney et al., 2012; Whitwell et al., 2012). Visual inspection of the affected temporal regions reported with strong confidence (the middle and superior temporal gyri) revealed an anterior-greater-than-posterior distribution of atrophy. Right anterior temporal lobe atrophy in FTD has been associated with impaired perception of emotion (Rosen et al., 2002b; Rosen et al., 2006) and a loss in empathy (Rankin et al., 2006). These symptoms also correlated with atrophy in the right orbitofrontal cortex (Rankin et al., 2006), an area identified in our study with weak to moderate confidence (Table 2). Since the C9ORF72 carrier group did not perform significantly worse on any clinical scores or present with any of the above behavioural symptoms, these results further support the theory of structural changes occur prior to functional impairment in C9ORF72. As with the insular cortex, a longitudinal follow-up of 	   50	  the relationship between progressive atrophy of the right anterior temporal lobe and the onset of impaired perception of emotion and/or loss in empathy will aid in understanding of the implications of presymptomatic cortical thinning, and may point to another neuroanatomical marker of eventual bvFTD symptomology in presymptomatic C9ORF72. Similar to the right hemisphere, cortical thinning of the left hemisphere in the C9ORF72 mutation carriers is reflective of neuroanatomical patterns in affected bvFTD subjects (Mahoney et al., 2012; Whitewell et al., 2012). The significant and diffuse involvement of the left superior frontal gyrus across all analyses indicates that this region may be of importance in disease progression. In particular, the relationship between the progression of atrophy and the onset of apathy, as the dorsomedial PFC has been strongly correlated with symptoms of apathy in early bvFTD (Miller 2014, Rosen et al., 2005).  Significant atrophy of the left middle and inferior temporal gyri is consistent with another study of bvFTD that found compulsive behaviours correlated with atrophy in these regions (Perry et al., 2012). The trend toward significant thinning in dorsolateral PFC in the C9ORF72 carriers (Figure 7) highlights this area as an additional region of interest for longitudinal follow-up. Since the in dorsolateral PFC processes executive functions such as planning, inhibition and working memory (Possin et al., 2009), the moderate cortical thinning of this region suggests that the onset of executive dysfunction may occur after symptoms indicated by the more significantly affected behavioural regions. If longitudinal follow-up were to find that symptoms of compulsive behaviour (left temporal) and apathy (dorsomedial PFC) occurred prior executive dysfunction (dorsomedial PFC), this would further indicate the usefulness of 	   51	  cortical thickness measures in the prediction of symptom onset in the C9ORF72 mutation. As with the discussion of the right hemisphere patterns, the left-side patterns allow for speculation of underlying phenotypes and predictions of symptomology, but longitudinal follow-up after phenotype confirmation will be necessary fully appreciate the implications of the regional cortical thinning.  4.1.2 Language variant neuroanatomical features  The regions reported with the strongest confidence, particularly the right temporoinsular area, argue in favor of an underlying bvFTD phenotype within the C9ORF72 carrier group, however, it remains possible that the observed left hemisphere regions of cortical thinning are driven, in part, by a language variant. Atrophy in the left superior frontal gyrus, superior temporal sulcus and superior temporal gyrus are highly consistent with the findings from a study of PNFA subjects (Rohrer et al., 2009b). However, the earliest symptoms of PNFA involve apraxia of speech and agrammatism (Gorno-Tempini et al., 2004), and are associated with atrophy of the left insula (Ogar et al., 2007) and left inferior frontal lobe (Amici et al., 2007), respectively, neither of which are regions significantly affected in the carrier group. It is possible that atrophy of the superior and posterior temporal lobe precedes left-frontoinsular atrophy in PNFA, but again, longitudinal follow-up is necessary to confirm. Cortical thinning of the inferior temporal gyrus and fusiform gyrus is more consistent with SD (Rohrer et al., 2009b), however, this variant is rarely seen in affected C9ORF7 carriers (Renton et al., 2011; DeJesus-Hernandez et al., 2011), making it less likely to be the cause of atrophy.   	   52	  4.1.3 Motor neuroanatomical features  Upwards of 27% of C9ORF72 mutation carriers have been reported to present with FTD/ALS (DeJesus-Hernandez et al., 2011). Furthermore, C9ORF72 bvFTD and FTD/ALS patients have been shown to exhibit similar patterns of atrophy (Sha et al., 2012). Therefore, the previously described bvFTD-like patterns of thinning (4.1.1) in the C9ORF72 carrier group along with the observed motor regions affected leads to the speculation of an underlying bvFTD/ALS phenotype within the carrier group. The specific regions involved include the pre-central and supplementary motor regions of the left hemisphere. On visual inspection of the pre-central gyrus, focal dorsal atrophy is apparent, which is a pattern observed in sporadic ALS patients (Agosta et al., 2012). Clinically, thinning of primary motor cortex in ALS patients has been associated with greater upper motor neuron burden (Mezzapesa et al., 2013), therefore, monitoring for upper motor neuron symptoms, particularly of the trunk and extremities due to the focal dorsal atrophy, may further indicate an underlying bvFTD/ALS phenotype. If longitudinal follow-up were to confirm these speculations, the dorsal premotor cortex may prove to be an important region in predicting an FTD/ALS phenotype in C9ORF72 mutation carriers. Furthermore, since the carrier group performed normally on tests of ALS-like symptoms (Table 2), if longitudinal follow-up were to confirm the presence of an FTD/ALS phenotype within the carrier group, these findings would indicate that cortical thinning occurs prior to functional impairment in the C9ORF72 FTD/ALS phenotype.     	   53	  4.2 Cortical thinning in affected C9ORF72 mutation carriers The analyses of the C9ORF72 affected group are limited by a small sample size (n = 3) making the results are much less conclusive, however, they provide valuable insight into possible regions for longitudinal follow-up in the presymptomatic group. The overall pattern of widespread anterior to posterior atrophy of the affected group (Figure 10), when compared to the non-carrier controls, is consistent with the literature (Mahoney et al., 2012; Whitewell et al., 2012). When compared to the presymptomatic carriers (Figure 8), the most significant and diffuse thinning in the affected group occurred in the right operculum, insula and dorsolateral PFC, which are regions consistent with the groups’ phenotypes (bvFTD and FTD/ALS) and genotype (Sha et al., 2012; Whitwell et al., 2012). The inclusion of FTD/ALS subjects in the affected group, in conjunction with the speculation of an FTD/ALS phenotype in the presymptomatic group, draws attention to the motor regions. The dorsal pre-central gyrus, a region significantly affected in the carrier group, exhibited no between group differences when compared to affected carriers (Figure 7). However, the affected carrier group exhibited bilateral thinning of the ventral pre-central gyrus (right>left), which is consistent with the groups’ worse performance on the ALS Bulbar Scale. These observations, along with the speculation of an underlying FTD/ALS phenotype in the presymptomatic group, suggest a possible dorsal to ventral progression of FTD/ALS motor region atrophy. However, this speculation is greatly limited by the small sample size, but provides an interesting area of follow-up after clinical diagnosis of those in the presymptomatic group.  	   54	  4.3 Between group analyses of the GRN groups  The current literature suggests that the negative findings of cortical thinning in the GRN carrier group may be due to later onset of grey matter atrophy. However, the results may also be explained by variable left-right asymmetrical thinning in the carrier group, which is characteristic of affected GRN mutation carriers (Whitwell, 2009; Rohrer et al., 2010). If both PNFA and bvFTD (behavioural dominant) phenotypes were present in the carrier group the analyses may not reach significance, as these phenotypes often present with left-dominant and right-dominate patterns of cortical atrophy, respectively (Rohrer et al., 2010). However, the cognitive domain scores indicate a decline in executive and language domains, both of which typically present with left-side dominant patterns of atrophy in GRN mutation carriers (Miller, 2014). Although the underlying phenotypes may have influenced the findings, the affected cognitive domains suggest that variable left-right asymmetry is less likely to be the cause for the negative findings. Thus, the current work speculates that subtle cognitive decline occurs prior to cortical atrophy, which may be characteristic of GRN mutation carriers. The neuropsychological profile of reduced performance on domains of executive function and working memory with a trend towards reduced language and visuospatial skills in the GRN mutation carriers suggests the possibility of both bvFTD (executive-dominant) and language phenotypes within the carrier group. When considering the neuroanatomical localization of these domains, the findings indicate primarily frontal (executive and working memory) with possible temporal (language) and parietal (visuospatial) lobe involvement. Although visuospatial impairment is not typically present in early bvFTD (Rascovsky et al., 2011), the findings indicate possible parietal 	   55	  lobe abnormalities. Studies of GRN mutation carriers have indicated that early hypoperfusion (Le Ber et al., 2008) and cortical atrophy (Whitwell et al., 2007a) of the parietal lobe may be reliable marker in differentiating GRN mutation carriers from non-carrier FTD subjects. A follow-up study of the GRN carrier group baseline DTI, PET and/or MRI (white matter volume) may provide insight into the structural origins of this GRN-specific marker. More broadly, follow-up analyses of baseline PET and DTI scans could clarify the underlying cause of the subtle cognitive domain changes in the GRN mutation carrier group. Prior studies report widespread white matter atrophy (Borroni et al., 2012; Dopper et al., 2013) and hypometabolism (Jacova et al., 2013) in presymptomatic GRN mutation carriers, leading to the theory that the observed subtle cognitive changes may have been triggered by white matter and/or metabolic abnormalities.   4.4 Between group analysis of the GRN and C9ORF72 carrier groups  Although the two carrier groups did not differ significantly in any cortical regions, visual inspection of the cortical differences exhibited more regions of C9ORF72 cortical thinning. In particular, a trend towards C9ORF72 thinning in the caudal superior frontal gyrus and anterior paracentral lobule (supplementary motor region) are observed, which again may be indicative of an FTD/ALS phenotype in the C9ORF72 carrier group.   4.5 Molecular mechanisms  The results of this thesis, in combination with the limited literature on presymptomatic GRN carriers, suggest that GRN and C9ORF72 progress towards FTD 	   56	  along different mechanisms. In the presymptomatic phase, GRN appears to affect white matter, while C9ORF72 causes grey matter/neuronal loss. While the mechanism of action by which the progranulin and C9ORF72 proteins lead to neuronal death remains unknown, some speculations can be made based on findings and observations at the cellular level.  4.5.1 GRN deficiency and white matter abnormalities  In the CNS, progranulin is primarily expressed by mature neurons and microglia and plays an important role as a growth factor and in anti-inflammatory responses (Ahmed et al., 2010; Petkau et al., 2010). However, the mechanism by which reduced levels of progranulin causes neuronal loss and FTD remains unclear. Studies to date have found that progranulin is involved in neuronal processes including increasing synaptic density, dendritic arborization and neurite outgrowth (Tapia et al., 2011; Gass et al., 2012). Increasing evidence also indicates upregulation of GRN expression in microglia in response to acute and chronic injury to the CNS, including neurodegenerative diseases such as FTD, suggesting that progranulin plays role in regulating the neuroinflammatory response (Mackenzie et al., 2006; Zhu et al., 2002; Cenik et al., 2012). Progranulin secretion by activated microglia is thought to be neuroprotective during the neuroinflammatory response, consequently, reduced levels of progranulin may cause an over exaggerated inflammatory response leading to neuronal damage (Toh et al., 2011). GRN knockout studies support this theory by showing that neuronal damage can results from prolonged activation of microglia that produce excess levels of pro-inflammatory cytokines (Martens et al., 2012; Suh et al., 	   57	  2012). In a study of post-mortem GRN mutation carriers, the areas most severely affected exhibited an in increase in the number and activation level of microglia, as well as increased GRN mRNA levels, but without a corresponding increase in progranulin protein levels (Chen-Plotkin et al., 2010). Activated microglia were suggested to have signaled the increase in GRN mRNA expression. However, the low levels of progranulin protein suggest a diminished anti-inflammatory response in the GRN carriers, possibility leading to an overactive microglia-mediated neuroinflammatory process causing neuronal damage. The same study found that non-GRN carriers with FTD-TDP exhibited no increase in microglia activity in affected regions, indicating that unregulated microglia may be a pathogenic feature of GRN (Chen-Plotkin et al., 2010). Lastly, a PET study of genetically unclassified FTD subjects found pronounced microglia activation prior to significant cortical atrophy (Cagnin et al., 2004), suggesting that microglia-mediated injury does not directly cause neuronal loss. While the role of progranulin in the neuroinflammatory response of GRN mutation carriers remains to be fully elucidated, it is evident that an important relationship exists between microglia activation and progranulin levels. An underlying neuroinflammatory mechanism regulated by progranulin would indicate that progranulin deficient individuals might exhibit a chronic neuroinflammatory response, which can lead to neuronal damage. This theory, in combination with prior studies indicating presymptomatic GRN white matter abnormalities, suggests chronic neuroinflammation as a possible mechanism causing gliosis and axonal injury early in GRN disease progression. While this idea is speculative, it demonstrates how an appreciation for the chronology of structural 	   58	  changes in the brain may aid in understanding some of the early underlying causes of neuronal abnormalities.     4.5.2 C9ORF72 molecular mechanisms of neuronal loss  Contrary to the GRN findings, the cortical thinning in the presymptomatic C9ORF72 carrier group argues in favor of grey matter/neuronal involvement as an early disease mechanism. However, the functions of the C9ORF72 protein remain unknown, making it more difficult to speculate on the early cause of atrophy. Disease mechanism including C9ORF72 loss-of-function (Ciura et al., 2013; Gijselink et al., 2012) and toxic gain of function caused by accumulation of toxic nuclear RNA foci (DeJesus-Hernandez et al., 2011) have been suggested as C9ORF72 neurodegenerative mechanisms. The C9ORF72 repeat expansion mutation has been shown to form intranuclear RNA foci that initiate apoptotic cell death in a length dependent manner, further supporting the theory that RNA toxicity contributes to neurodegeneration (Lee et al., 2013). Although much more evidence is required, the toxic gain-of-function mechanism would fit with the current study findings of early neuronal loss in C9ORF72 mutation carriers. Compared to the to GRN mutation effect, the damaging effect of C9ORF72 appear to be more specific to the neuronal cell body, and possibly leads to earlier neuronal loss as demonstrated by the cortical thinning in C9ORF72 versus GRN mutation carriers.  4.6 Limitations Although this thesis is limited by small sample sizes, the fact that the groups studied are presymptomatic GRN and C9ORF72 mutation carriers strengthens the 	   59	  paper, as this is a rare and difficult population to recruit. The primary limitation in appreciating the results of this thesis is the yet-unaffected clinical phenotypes. As such, the discussions of these findings remain largely speculative and are based on similar patterns described in the literature of affected mutation carriers. Despite this challenge, the results add significantly to the current literature and provide numerous reasons and rationale for longitudinal follow-up within the clinic.   4.7 Future directions In order to fully appreciate the patterns of atrophy and cognitive changes reported in this thesis, longitudinal follow-up of the various groups will be required. The following three studies are recommended as follow-up to the current thesis: I) A secondary analysis of the GRN carrier group examining the volume and integrity of white matter tracts and the relationship to the early cognitive domain changes observed in the current thesis. II) A retrospective GRN analysis, after phenotype confirmation, to clarify whether cognitive domain changes do in fact precede cortical thinning, or if the unremarkable cortical thickness differences can be attributed to variable left-right asymmetry within the carrier group. III) A retrospective analysis, after phenotype confirmation, in the C90ORF72 carriers to examine phenotypic patterns and rates of atrophy in combination with the onset of early clinical symptoms.    	   60	  4.8 Conclusions  The results from this thesis provide the first evidence of presymptomatic cortical thinning in C9ORF72 mutation carriers prior to cognitive and/or motor decline. Furthermore, the current findings contribute to the literature on presymptomatic GRN mutation carriers by suggesting that cortical grey matter thinning is preceded by subtle cognitive decline. 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