Journal of the International Neuropsychological Society (2014), 20, 694–703. Copyright © INS. Published by Cambridge University Press, 2014. doi:10.1017/S1355617714000551

Early Neuropsychological Characteristics of Progranulin Mutation Carriers

Bradley J. Hallam,1 Claudia Jacova,1 Ging-Yuek R. Hsiung,1 Dana Wittenberg,1 Pheth Sengdy,1 Phoenix Bouchard-Kerr,1 Penny Slack,1 Rosa Rademakers,2 Matthew Baker,2 Tiffany W. Chow,3 Brian Levine,4 Howard H. Feldman,1 AND Ian R. Mackenzie5 1

Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada Department of Neuroscience, Mayo Clinic, Jacksonville, Florida Department of Medicine, Division of Neurology, University of Toronto, Toronto, Ontario, Canada 4 Rotman Research Institute at Baycrest Health Sciences, Toronto, Ontario, Canada 5 Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada 2 3

(RECEIVED January 23, 2014; FINAL REVISION May 16, 2014; ACCEPTED May 28, 2014; FIRST PUBLISHED ONLINE July 4, 2014)

Abstract Mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal dementia. We used a comprehensive neuropsychological battery to investigate whether early cognitive changes could be detected in GRN mutation carriers before dementia onset. Twenty-four at-risk members from six families with known GRN mutations underwent detailed neuropsychological testing. Group differences were investigated by domains of attention, language, visuospatial function, verbal memory, non-verbal memory, working memory and executive function. There was a trend for mutation carriers (n = 8) to perform more poorly than non-carriers (n = 16) across neuropsychological domains, with significant between group differences for visuospatial function (p < .04; d = 0.92) and working memory function (p < .02; d = 1.10). Measurable cognitive differences exist before the development of frontotemporal dementia in subjects with GRN mutations. The neuropsychological profile of mutation carriers suggests early asymmetric, right hemisphere brain dysfunction that is consistent with recent functional imaging data from our research group and the broader literature. (JINS, 2014, 20, 694–703) Keywords: Ubiquitin positive frontotemporal dementia, Granulin, FTLD with TDP-43 Pathology, Hereditary neurodegenerative disease, Cognitive symptom, Neuropsychology

Stevens et al., 1998). One of the most common causes of familial FTD is mutations of the progranulin gene (GRN) that result in haploinsufficiency, associated with TDP-43 pathology (FTLD-TDP) (Arai et al., 2006; Baker et al., 2006; Benussi et al., 2009; Mackenzie et al., 2006; Neumann et al., 2006; Yu et al., 2010). Previous studies indicate GRN is responsible for 20% of familial FTD (FTD-GRN) with a clear pattern of autosomal dominant inheritance (Gijselinck, Van Broeckhoven, & Cruts, 2008). Although penetrance is high with 90% of mutation carriers manifesting symptoms by age 75 (Cruts et al., 2006; Gass et al., 2006), the phenotypes associated with GRN mutations are remarkably variable, both between families with different GRN mutations and among members of individual families (Baker et al., 2006; Behrens et al., 2007; Bruni et al., 2007; Gass et al., 2006; Hsiung & Feldman, 1993; Josephs et al., 2007; Lopez de Munain et al., 2008; Masellis et al., 2006; Mesulam et al., 2007; Moreno et al., 2009; Mukherjee et al., 2006; Rademakers et al., 2007; Spina et al., 2007). There is a

INTRODUCTION Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive decline in behavior, language, and cognitive function with underlying frontotemporal lobar degeneration (FTLD) (Neary et al., 1998; Rascovsky et al., 2011). Three clinical syndromes occur in FTD: behavioral variant FTD (bvFTD), non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA), and semantic variant of primary progressive aphasia (svPPA) (Gorno-Tempini et al., 2011; Neary et al., 1998; Rascovsky et al., 2011). Approximately 30–50% of FTD cases have a positive family history, often with an autosomal dominant pattern of inheritance (Chow, Miller, Hayashi, & Geschwind, 1999; Mackenzie et al., 2009; McKhann et al., 2001; Rabinovici & Miller, 2010;

Correspondence and reprint requests to: Bradley J. Hallam, GF Strong Rehabilitation Centre, 4255 Laurel Street, Vancouver, British Columbia V5Z 2G9, Canada. E-mail: [email protected] 694

Progranulin mutation carriers broad range in age of onset (48–83 years; mean = 59 ± 7), as well as mean age at death (53–87 years, mean = 65 ± 8) (Gass et al., 2006). The most common clinical diagnoses of FTD-GRN are bvFTD and nfvPPA (Bruni et al., 2007; Chen-Plotkin et al., 2011). Cross-sectional neuropsychological studies of fully symptomatic FTD-GRN subjects have revealed heterogeneous cognitive profiles. Language dysfunction in the form of word-finding difficulties, paraphasic errors, and impaired comprehension (van Swieten & Heutink, 2008) is prominent early in the disease process and affects 20–25% of FTD-GRN patients. Individuals often have deficits in verbal fluency, working memory, problem solving, response inhibition, and mental flexibility (Le Ber et al., 2008; van Swieten & Heutink, 2008). Prominent parietal dysfunction is common, with evidence of corticobasal syndrome, dyspraxia, alien-hand, and dyscalculia (Kelley et al., 2010; van Swieten & Heutink, 2008; Yu et al., 2010). A single longitudinal, neuropsychological case study from Rohrer and colleagues (Rohrer, Warren, Barnes, et al., 2008) documented the progression of an FTD-GRN family member from the asymptomatic phase with progressive atrophy in frontal lobe (word retrieval and fluency), parietal lobe (praxis, speech repetition, and calculation), and orbitofrontal and anterior temporal lobes (facial emotion recognition). Studies of the prodromal neuropsychological changes in asymptomatic GRN mutation carriers are limited. In one crosssectional study (Borroni et al., 2008), presymptomatic GRN mutation carriers and non-carriers from a single family underwent clinical assessments with neuropsychological measures, which did not reveal neuropsychological dysfunction. However, comparisons between mutation carrier and non-carrier groups were not reported, and the neuropsychological battery included many dementia screening measures, likely insensitive to subtle cognitive changes in early disease expression. In another study, the asymptomatic siblings of FTD-GRN patients underwent neuropsychological assessment. Asymptomatic mutation carriers as compared to non-carriers revealed no group differences on one dementia screening measure and four neuropsychological measures (Borroni et al., 2012). However, the neuropsychological battery was not comprehensive and the neuropsychological assessment of asymptomatic siblings was a secondary analysis, not central to the study’s aims. Accordingly, it was likely insensitive to subtle cognitive changes in early disease expression. In another cross-sectional study (Barandiaran et al., 2012), subtle cognitive changes were noted in domains of attention, mental flexibility, and language (confrontation naming) in GRN mutation carriers as compared to non-carriers. The authors argued that their study provided evidence of prodromal cognitive dysfunction preceding dementia. As opposed to dementia screening measures used in most of the previous studies, we administered a comprehensive neuropsychological battery likely to be more sensitive to early cognitive changes in mutation carriers. The present study aims to add to the limited body of literature investigating the earliest cognitive features in a cohort of GRN mutation carriers before the onset of frank dementia. We administered a comprehensive neuropsychological battery

695 to mutation carriers and non-carrier members from the same families. We hypothesized that mutation carriers would have more frequent low scores than non-carriers. We also hypothesized that at least some of the mutation carriers would perform more poorly than non-carriers on domain scores on language, working memory and executive functions. Within the GRN mutation carrier group, we hypothesized that older subjects (closer to the mean age of onset of dementia for their family) would perform more poorly than younger mutation carriers. Given the variable phenotype in FTD-GRN, we also anticipated that neuropsychological symptoms might be heterogeneous among subjects.

METHODS Study Overview The University of British Columbia (UBC) FTD research program is a multidisciplinary, prospective study of familial FTD. The broad goals of the study are to characterize the neurological, neuropsychological, neuropsychiatric, pathological, and molecular genetic features in these families. The present study focuses on the preclinical and early stage of disease, before the onset of dementia, by investigating the neuropsychological profile of mutation carriers from families known to have FTD caused by GRN mutations.

Subjects The 24 subjects were recruited from six different families with autosomal dominant FTD in which a deceased proband was clinically diagnosed with FTD at the UBC Clinic for Alzheimer’s Disease and Related Disorders (Table 1). Furthermore, probands were pathologically confirmed to have FTLD-TDP and subsequent genetic testing identified a pathogenic GRN mutation as the cause of disease in the family. For inclusion in this study, subjects had to (i) have no evidence of dementia on neurological examination, (ii) be considered at-risk for developing disease by having a parent or sibling affected with dementia, and (iii) be able to provide consent to participate in the study (age 19 or older). There was no upper age limit for subjects included in the study. Subjects were excluded from the study if they had evidence of an acquired medical condition affecting cognitive function (e.g., acquired brain injury). The mutation status of the subjects (carrier or non-carrier) was not determined until after enrollment and was not made known to the subjects or the investigators, except to the database manager and statistical analyst. DNA was analyzed for GRN mutations as previously described (Baker et al., 2006). Consensus conferences consisted of a neurologist, neuropsychologist, and research assistant, all blind to subject mutation status. Clinical diagnoses of normal and clinically symptomatic no dementia (CSND) were assigned in a hierarchical manner. CSND was assigned if the neurologist or neuropsychologist identified by clinical impression or on rating scales evidence of behavioral or cognitive symptoms

696 or findings suggestive of FTD not yet impairing everyday function or by severity not yet meeting dementia diagnostic criteria. As previously described, clients with dementia were excluded from the study. First, the neurologist provided a clinical diagnosis based on results from the neurologist’s neurological examination, the research assistant’s cognitive screening, and functional rating forms completed by collateral sources. The neurologist remained blind to neuropsychological assessment results. Next, the neuropsychologist provided a clinical diagnosis based solely on cognitive performance on the standardized neuropsychological battery. A cut-point was established at 1 standard deviation below the mean for cognitive domain performance (e.g., Attention), with subjects performing below the cut point on any single domain being classified as CSND and subjects performing above this cut point for all domains being classified as normal. The final consensus clinical diagnosis was the most clinically symptomatic diagnosis from either the neurologist or neuropsychologist. This study was conducted in accordance with the Helsinki Declaration and was approved by the institutional ethics committee. The subjects provided written consent.

Neuropsychological Assessment Given that the clinical phenotype of FTD-GRN is still not fully known, the neuropsychological battery was designed to be comprehensive, assessing seven cognitive domains including attention, working memory, language, visuospatial function, verbal memory, non-verbal memory and executive function (Table 2). Whereas many dementia screening batteries use a limited number of tests with selective sampling of cognitive domains known to be affected by a particular disease, the current neuropsychological battery was chosen to sample all domains of cognitive function without a priori assumptions regarding the cognitive profile of early neuropsychological characteristics of GRN mutation carriers. The test battery was comprised of well validated and reliable standardized neuropsychological measures used in clinical settings to better inform the generalizability of findings to clinical practice. To the extent possible, large, demographically-corrected normative samples were chosen to minimize ceiling or floor effects, thus increasing the sensitivity of these measures in detecting subtle cognitive changes. Measures were grouped by domain in accordance with current neuropsychological clinical practices (Lezak, Howieson, & Loring, 2004). All tests were administered and scored according to standardized procedures. Individual test scores were converted to Z-scores using demographically corrected normative data from test publisher manuals and published studies (Delis, Kramer, Kaplan, & Ober, 2000; Heaton, Chelune, Talley, Kay, & Curtiss, 1993; Kramer et al., 2003; Mitrushina, Boone, Razani, & D’Elia, 2005; Ruff, Light, Parker, & Levin, 1996; Wechsler, 1997a, 1997b). Domain scores (e.g., attention) were calculated by averaging individual test Z-scores within that domain. Because domains scores represent the average of several individual test scores, analyses were included to determine whether low domain scores

B.J. Hallam et al. indicated convergence of several low test scores or marked impairment on a single test. Inter-rater reliability for complex visuospatial measures was established by having testing clinicians independently score a random sample of five subjects (approximately 20% of sample) for the WMS-III Visual Reproduction subtests (Wechsler, 1997b) and Rey Modified Figure (Kramer et al., 2003). Intra-class correlation coefficients (ICC) for inter-rater reliability were moderate for WMS-III Visual Reproduction Copy (ICC = 0.54), and strong for WMS-III Visual Reproduction I (ICC = 0.89), WMS-III Visual Reproduction (ICC = 0.973), Rey Modified Figure Copy (ICC = 0.77), and Rey Modified Figure Recall (ICC = 0.88) (Kramer et al., 2003; Wechsler, 1997b).

Analyses The Kolmogorov-Smirnov test of normality was conducted for both mutation carrier and non-carrier groups by neuropsychological domain to examine for the presence of outlier scores, defined as scores greater than 1.5 the interquartile range from box plot inspection. Levene’s test was also conducted to assess the equality of variance of neuropsychological data by domain to inform the selection of parametric or non-parametric tests for group comparison. Due to the large number of neuropsychological measures, data analyses were conducted in a hierarchical manner. First, Student’s t tests (or Mann Whitney test) were conducted to compare the mean scores by neuropsychological domain between mutation carriers and non-carriers. Subsequently, Student’s t tests (or Mann Whitney test) were conducted between mutation carriers and non-carriers for individual neuropsychological measures within significant neuropsychological domains. Significance was set at p < .05 for all group comparisons. Cohen’s d values were computed to measure effect sizes of group comparisons. Given that we expected only a subset of the mutation carriers to have early clinical symptoms of disease, it was determined that group analyses might not inform the presence of low cognitive scores in individual subjects. Accordingly, qualitative inspection of individual low score counts (1 standard deviation below the mean) was conducted by domain for individual subjects within groups. The association between age and neuropsychological performance among mutation-carriers was tested using the Spearman product–moment correlation of the ranks. Receiver operating characteristic (ROC) curve was based on the sensitivity and specificity of significant neuropsychological domains and individual neuropsychological measures in identifying cognitive symptoms in the mutation carrier group. All statistical analyses were performed using SPSS package (v 17.0, Chicago, IL).

RESULTS Genetic analysis revealed that eight subjects were carriers of pathogenic GRN mutations and 16 subjects were noncarriers (Table 1). Subjects came from six different families, each with a different GRN mutation. Fifty percent of total

Progranulin mutation carriers

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Table 1. Demographic Information for Carriers and Non-carriers of the GRN mutation GRN mutation carriers (n = 8) Age, mean ± SD Education, mean ± SD Sex Male Female MMSE, mean ± SD Clinical diagnosis, neurological exam only Asymptomatic CSND Clinical diagnosis, neurological exam and neuropsychological data Asymptomatic CSND Family, mean age at onset (range), proband clinical presentation, cDNA nomenclature of the GRN mutation A7, 53 (46–59), FTD/parkinsonism, c.85_88dupGCCT F8, 63 (55–66), bvFTD, c.933 + 1G>A R8, 59 (53–70), bvFTD/parkinsonism, c.90_91insCTGC T2, 50 (50–68), bvFTD, c.1252C>T M3, 62 (54–73), bvFTD/CBS, c.1157G>A K3, 56 (45–64), bvFTD, c.463–1G>A Years to estimated onsetb, mean ± SD (range) ≤10 years >10 years

Non-carriers (n = 16)

47.25 ± 9.79 13.00 ± 2.34

53.31 ± 10.35 12.88 ± 1.96

1 7 29.75 ± 2.31

8 8 28.88 ± 2.31

7 1

13 3

4 4

13 3

1 0 6 1 0 0 − 11.11 ± 9.20 (−24 to 16) 3 5

1 1 6 4 3 1 − 6.26 ± 9.52 (−17 to 8) 11 5

Note. GRN = progranulin; MMSE = Mini Mental State Examination; CSND = clinically symptomatic, no dementia; bvFTD = behavioural variant frontotemporal dementia; CBS = corticobasal syndrome; PSP = progressive supranuclear palsy. a The t test for continuous variables, χ2 test for categorical variables b Years to estimated onset = the difference between the subject’s age and the mean age of onset of frontotemporal dementia in the subject’s family; negative numbers indicate ages younger than mean age at onset, positive numbers ages older than mean age at onset.

subjects (12/24 GRN mutation carriers and non-carriers) and 75% (6/8) of GRN mutation carriers came from a single family (Family R8), in which the clinical phenotype in the proband was bvFTD with parkinsonism (Table 1). Although not statistically significant, mutation carriers were younger than non-carriers (47 ± 10 vs. 53 ± 10 years) and further below the mean age from disease onset for their respective families (11 ± 9 vs. 6 ± 10 years). The mutation carrier group included only one male subject (13%) while there was equal sex distribution of non-carriers. The groups had similar education and Mini-Mental State Examination scores (Folstein, Folstein, McHugh, & Fanjiang, 2001). Clinical classifications from neurologists blind to both genetic status and neuropsychological test data resulted in similar rates of CSND versus normal in both group. Specifically, of mutation carriers, 87% (7/8) were classified as normal (e.g., clinically asymptomatic) and 13% (1/8) as CSND (e.g., evidence of clinical symptoms not significantly impacting daily function). Of non-carriers, 81% were clinically classified as normal and 19% as CSND. When neuropsychological data was combined with neurological examination, an additional 3 mutation carriers were identified as CSND. Specifically, of mutation carriers, 50% (4/8) were classified as CSND and 50% as normal. There was no change in classification of non-carriers. Within the mutation carrier group, four subjects (50%) had low scores (≤1 SD) on at least one neuropsychological

domain. Heterogeneous cognitive profiles were noted for individuals within the mutation carrier group (Figures 1 and 2); subjects 1 & 7 both scored low on tests of non-verbal memory; subject 6 scored low on both attention and visuospatial function, and subject 8 scored low on attention. Within the non-carrier group, two subjects (13%) had low scores on at least one domain (Figure 1); subject 11 scored low on language, verbal memory, and nonverbal memory; and subject 24 scored low on verbal memory. There were no outliers in the non-carrier group. In the mutation carrier group, there was a single subject (subject 6) with an outlier score in the visuospatial domain but the group difference in the visuospatial domain remained significant even when excluding this subject’s visuospatial performance (p < .04). However, it seemed unreasonable to exclude this subject’s neuropsychological performance from analysis given that the subject did not have outlier scores in any other domain. Furthermore, it also seemed unreasonable to exclude impaired scores when the aim of the study was to investigate the presence of cognitive dysfunction in mutation carriers. Rather, the subject’s scores were retained and nonparametric statistical measures (Mann Whitney) were used to examine group differences in the visuospatial domain since equal variance could not be assumed. Tests of normality confirmed normal distribution of test scores in other cognitive domains, and parametric statistical measures

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Fig. 1. Scatter plots of individual neuropsychological domain standard scores (Z-scores) of GRN mutation carriers and non-carriers. GRN = progranulin gene; ATT = Attention; WM = Working Memory; LANG = Language; VSP = Visuospatial; VN = Verbal Memory; NVM = Non-verbal Memory; EXF = Executive Function.

(Student’s t tests) were used to examine all other between group domain scores. Mutation carrier neuropsychological mean scores by domain were within the normal range (±1 SD) (Table 2) with an overall trend for mutation carriers to perform worse than non-carriers on neuropsychological testing. Compared to non-carriers, mutation carriers demonstrated significantly lower domain scores with large effect sizes (d > .08) for working memory (p < .02; d = 1.10) and visuospatial function (p < .04; d = 0.92), and approached significance for

B.J. Hallam et al. the domain of non-verbal memory (p < .07; d = 0.86). When examining performance on individual neuropsychological measures within domains, mutation carriers demonstrated significantly lower scores (p < .05) with large effect sizes on the following measures: WMS-III Spatial Span Backward in the working memory domain (p < .03; d = 1.05); WMS-III Visual Reproduction Copy in the visuospatial domain (p < .006; d = 1.34); and WMS-III Visual Reproduction Immediate Recall (p < .007; d = 1.31) in the non-verbal memory domain (Table 2; Wechsler, 1997b). The Block Design subtest in the Visuospatial Domain approached significance (p = .05; d = 0.89) (Wechsler, 1997a). Mutation carriers did not perform significantly better than non-carriers on any neuropsychological domains or individual measures. Within the mutation carrier group, there was an overall trend for positive correlations between neuropsychological domain performance and age, with significant correlations in the domains of Attention (r = 0.84; p < .01), Working Memory (r = 0.83; p < .05), and Executive Function (r = 0.78; p < .05). The correlations were similar when comparing neuropsychological domain performance with the mean age of onset of disease for one’s family as a variable, instead of age. Accordingly, worse performance was associated with younger age. ROC curve analysis suggested that neuropsychological domain performance and individual neuropsychological test performance were both able to accurately separate mutation carriers from non-carriers (area under the curve >.70). However, due to cut-scores falling within the average range (as opposed to impaired performances), sensitivity and specificity was generally poor (A) with demented patients having heterogeneous clinical and neuropsychological profiles but a high proportion of cases developing corticobasal syndrome as the disease progressed. Accordingly, the presence of parietal dysfunction in a high proportion of cases can be presumed as an evolving expression of disease, even if it was not initially measured by Barandiaran and colleagues. Other factors such as the heterogeneous mutations in our sample, heterogeneous expression of FTD, methodological differences (e.g., measures used, normative data, etc.), and sampling differences might have also contributed to differences in findings between studies. A qualitative inspection of individual mutation carrier neuropsychological performance revealed heterogeneous cognitive profiles, affecting a range of cognitive functions such as attention, visuospatial function, and non-verbal memory. The presence of variable phenotypes within the mutation carrier group aligns with the variability of clinical expression of individual family probands within this study (see Table 1) and well-documented findings of phenotypic variability in fully affected FTD-GRN patients (Baker et al., 2006; Behrens et al., 2007; Bruni et al., 2007; Gass et al., 2006; Hsiung & Feldman, 1993; Josephs et al., 2007; Masellis et al., 2006; Mesulam et al., 2007; Mukherjee et al., 2006; Rademakers et al., 2007; Spina et al., 2007). A surprising finding was that younger mutation carriers performed worse than older mutation carriers. Subjects 6 and 8 (see Graph 2) were the youngest subjects and more than 10 years from the mean age of onset of dementia for the family, but these subjects had the greatest difficulty on neuropsychological testing. This seems counterintuitive, as one would presume that older subjects who are closer to the age of dementia onset would be at greater risk for evidencing mild cognitive impairment. This may simply be a spurious finding due to our small sample size. Alternatively, there is considerable variability in the age of onset of dementia across families (35–87 years; mean = 59 ± 7 years), making it challenging to know at what age any particular individual is likely to begin expressing neurodegenerative symptoms (Bruni et al., 2007). Several limitations of this study need to be acknowledged. First, despite our study being one of the largest samples of neuropsychological function in pre-dementia FTD-GRN subjects, our sample size was relatively small. This did not allow for correction of multiple comparisons. Second, mutation carrier and non-carrier groups were not well matched in size with approximately twice as many non-carriers. The disparity of group sizes is expected owing to the study’s criteria, which excluded mutation carriers who had already converted to dementia, and the fact that no upper age limit was set for non-

Progranulin mutation carriers carriers. There may have also been an ascertainment bias with mutation carriers with early behavioral symptoms (e.g., apathy, social impropriety) being less inclined to volunteer for research. Third, whereas sex was equally represented in the non-carrier group, the mutation carrier group consisted predominantly of women. The reason for unequal sex ratio in mutation carriers is not clear, and inconsistent with studies indicating that FTD affects both sexes equally with no sex difference in mean age of onset (Chow et al., 1999). Finally, findings from our study are specific to the prodromal phase of FTD-GRN and are largely represented by a single family. Accordingly, results may not generalize to other genetic or sporadic forms of FTD. The present study represents the initial characterization of cognitive symptoms in the predementia phase of FTD-GRN. By identifying the neuropsychological changes in early disease expression, we hope to clarify the natural history of the disease, assist in earlier diagnosis and provide much-needed guidance for the timing and efficacy of clinical and therapeutic interventions designed to prevent or slow the progression of this devastating neurodegenerative disease. Future opportunities for research include the integration of these findings with psychobehavioral assessment data to more fully understand the natural disease course of FTD-GRN.

ACKNOWLEDGMENTS This work was supported by the Canadian Institutes of Health Research [operating grants #179009, 74580 to H.F. and I.M.]; the Pacific Alzheimer’s Research Foundation [center grant C06-01 to H.F. and I.M.]; and the National Institutes of Health [grants # R01 NS065782, R01 AG026251 to R.R.]. Dr. Robin Hsiung is supported by a Canadian Institutes of Health Research Clinical Genetics Investigatorship award. Dr. Tiffany Chow is supported by the Women of Baycrest. The authors would like to gratefully acknowledge the contributions of the following testing clinicians and research assistants: Amanda LaMarre, Joanne Ng, Anthony Kupferschmidt, Kate Naus, Penny Slack, Benita Mudge, William Wang and Nadine Richard. Dr. Hsiung discloses that has received funds as a site investigator for a clinical trial sponsored by TauRx, and is a shareholder of Amnax Biomedical. Dr. Howard Feldman discloses that he has been a full-time paid employee of Bristol-Myers Squibb on leave from University of British Columbia (UBC) from 2009 to 2011. He received stocks and stock options in this role from Bristol-Myers Squibb. In 2012, he returned to University of British Columbia, Division of Neurology, Faculty of Medicine. In relationship to this study, he has served as paid consultant to the Bluefield Project on Frontotemporal dementia (2012), and has received travel expenses to serve on an advisory board with Fidelity Biosciences (2012, 2013). He is a co-patent holder of US Serial Number PCT/2007/070008 for Progranulin in the detection and treatment of dementia. In the past 3 years he has provided consulting services to Eli Lilly Pharma, GE Health Care, Biogen Idec and Kyowa Hakko Kirin with payments to UBC.

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