Clinical phenotypes in autopsy-confirmed Pick disease

Clinical phenotypes in autopsy-confirmed Pick disease O. Piguet, PhD G.M. Halliday, PhD W.G.J. Reid, PhD B. Casey, PhD R. Carman, MPhil Y. Huang, PhD J.H. Xuereb, MD J.R. Hodges, FRCP J.J. Kril, PhD Address correspondence and reprint requests to Dr. Olivier Piguet, Neuroscience Research Australia, Barker St., Randwick, NSW 2031, Australia o.piguet@neura.edu.au ABSTRACT Background: Neuropathology of frontotemporal lobar degeneration is variable and relationship between the pathology and the clinical presentation remains uncertain. Abnormal deposits of hyperphosphorylated and ubiquitinated tau protein are present in 30% of cases, which include the classic presentation of Pick disease with argyrophilic, intraneuronal inclusions known as Pick bodies. This study aimed to improve sensitivity of clinicopathologic relations in cases with neuropathologically confirmed Pick disease and to identify clinical symptoms and signs predictive of disease progression. Methods: This was a retrospective analysis of 21 cases with a pathologic diagnosis of Pick disease and sufficient clinical information to establish early presenting clinical features from 2 specialist centers, representing 70% of all cases of Pick disease identified between 1998 and 2007 in these centers. Results: At presentation, 13/21 cases (62%) were clinically diagnosed with behavioral variant frontotemporal dementia (bvftd) and 8/21 (38%) with language variant frontotemporal dementia (lvftd) including 2 with mixed syndromes. Patients with bvftd died on average 5 years earlier than those with lvftd (7 years vs 12 years after disease onset). Pathologically, fewer Pick bodies were present in the frontal and inferior temporal cortices of bvftd than lvftd cases. In contrast, both groups showed decreased neuronal density in the dentate gyrus with increasing disease duration. Conclusions: The pathologic course of the disease in FTLD cases with Pick bodies is not uniform and disease duration can be estimated based on early clinical features. These findings have relevance as treatment options, which are likely to be pathology specific, are developed. Neurology 2011;76:253 259 GLOSSARY bvftd behavioral variant frontotemporal dementia; FTLD frontotemporal lobar degeneration; FUS fused in sarcoma; lvftd language variant frontotemporal dementia; PNFA progressive nonfluent aphasia; SemD semantic dementia; TDP TAR DNA binding protein 43. Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative brain disease that encompasses 3 clinical subtypes: behavioral variant frontotemporal dementia (bvftd), semantic dementia (SemD), and progressive nonfluent aphasia (PNFA). 1 All FTLD cases exhibit neuronal loss and gliosis in the frontal or temporal cortices; however, the neuropathology is variable. About 30% of cases exhibit abnormal deposits of hyperphosphorylated and ubiquitinated tau. 2,3 These abnormalities include the classic Pick disease characterized by argyrophilic, intraneuronal Pick bodies and enlarged neurons (Pick cells). About 50% of cases show abnormal deposits of hyperphosphorylated and ubiquitinated TAR DNA binding protein 43 (TDP). Most remaining cases contain abnormal deposits of ubiquitinated fused in sarcoma (FUS) protein, a nuclear ribonucleoprotein. 4 From Neuroscience Research Australia (O.P., G.M.H., W.G.J.R., Y.H., J.R.H.), Sydney; The University of New South Wales (O.P., G.M.H., Y.H., J.R.H.), Sydney; Department of Psychology (B.C.), Concord Repatriation and General Hospital, Sydney; Disciplines of Pathology (R.C., J.J.K.) and Medicine (J.J.K.), Sydney Medical School, The University of Sydney, Sydney, Australia; and Department of Pathology (J.H.X.), University of Cambridge, Cambridge, UK. Study funding: Supported by the National Health and Medical Research Council of Australia (570850). Disclosure: Author disclosures are provided at the end of the article. Copyright 2011 by AAN Enterprises, Inc. 253

The relationship between the clinical presentations of FTD and the pathology remains uncertain, particularly for patients with bvftd, who may have tau, TDP, or FUS pathology. 5 The clinical presentation associated with any single pathologic entity of the FTLD spectrum is also not uniform. Tau pathology cases tend to be most commonly associated with bvftd, although some show language FTD or present with motor symptoms. 5,6 The lack of concordance between clinical presentation and neuropathologic substrate is important in the context of the future development of therapeutic disease-modifying agents which will be pathology specific. The aim of this study was to examine cases of FTLD with neuropathologically confirmed Pick disease to ascertain their presenting clinical features. The purpose was twofold: first, to improve sensitivity of clinicopathologic relations; second, to identify clinical symptoms and signs predictive of disease progression. METHODS Review of the Sydney and Cambridge Brain Banks identified 30 cases with a pathologic diagnosis of Pick disease among the nearly 250 FTLD cases collected by these programs between 1992 and 2008. Sufficient clinical information to establish a clinical profile was available for 21 of the 30 cases identified (70%). Ten cases (5 men) were from a prospective Brain Donor Program in Sydney, Australia, and 11 cases (6 men) were from the Cambridge Memory and Early Onset Dementia Clinic, Cambridge, UK. We conducted a retrospective analysis of the clinical files and examined all existing medical notes, cognitive test results, as well as patient and informant questionnaires. From this investigation, we obtained the following information for all cases: age at disease onset, disease duration, delay between disease onset and first presentation to the clinic, and age at death. Disease onset was estimated based on carers reports of initial changes. All cases were examined by experienced clinicians. Clinical symptoms and signs and behavioral and cognitive changes at initial presentation were extracted from the files as well as the clinical diagnosis established at the time of presentation. Presence or absence of each core and supporting feature for a clinical diagnosis of FTD (behavioral or language presentation) was established based on existing information. 1 Presence and severity of cognitive deficits at initial presentation were determined from available cognitive test scores and clinical investigations. These were grouped according to the following cognitive domains: attention/concentration, memory, expressive language, receptive language, visuoconstructive abilities, working memory, and executive functions. For the postmortem investigations, the brains were collected, weighed, and immersion fixed in 15% buffered formalin for 2 weeks. Neuropathologic examination was performed to confirm the diagnosis of Pick disease and exclude other diagnoses according to standardized criteria. 7 Briefly, the presence of Pick bodies in the dentate gyrus, hippocampus, and/or cerebral cortex was determined using tau (AT8, Thermo Scientific, Rockford IL; 1:1,000) immunohistochemistry. 8 For this study, fixed tissue blocks were taken from the superior frontal (Brodmann area 8) and inferior temporal (Brodmann area 20) cortices and hippocampus, embedded in paraffin, cut at 10 m, and successive serial sections stained immunohistochemically with ubiquitin (Z0458, DAKO, Denmark; 1:200) and tau (AT8, Thermo Scientific, Rockford IL; 1:1,000) and counterstained with 0.5% cresyl violet, as previously described. 9 The density of Pick bodies and neurons was determined in the dentate gyrus and CA1 region of the hippocampus and in the frontal and temporal cortices using a previously described method. 10 Briefly, a graticule eyepiece measuring 500 m 500 mat200 magnification was used to count the number of neurons containing Pick bodies and the number of nucleolated neurons in 2 strips of cortex perpendicular to the pial surface, and 2 nonoverlapping fields in the dentate gyrus and CA1 region, using standard inclusion and exclusion criteria. The density was calculated by dividing the sum of the counts by the sum of the area. Standard protocol approvals, registrations, and patient consents. This research study was approved by the Universities of Sydney and New South Wales Human Research Ethics Committees and the Addenbrooke s Hospital Local Research Ethics Committee. This study also complies with the statement on human experimentation issued by the National Health and Medical Research Council of Australia. RESULTS Mean disease onset was in the early 60s but was highly variable (table 1). Duration between symptom onset and death was about 9 years on average but was also variable. In 6 individuals, disease duration was 12 years or longer. Disease duration was not significantly related to the age at disease onset. There was no family history of dementia in any of the cases. None of the demographic variables varied significantly between the Sydney and Cambridge samples. At the time of presentation, 13 patients were diagnosed clinically with bvftd and 8 with lvftd. Among these, 4 cases received a clinical diagnosis of PNFA, 3 were diagnosed with SemD (one was also diagnosed with probable AD), and one patient with global aphasic features was diagnosed with FTD, not specified further, or atypical AD. When examining clinical characteristics according to clinical diagnosis, age at onset did not differ between groups. Delay between disease onset and initial presentation to the clinic was shorter in bvftd (2.4 years) compared with lvftd (3.6 years) but did not reach statistical significance (table 1). Disease duration, however, was longer in lvftd than in bvftd cases, confirmed by Kaplan-Meyer survival analysis (p 0.007) (figure). Prevalence of clinical diagnostic criteria. bvftd. At presentation, 11 cases exhibited at least 4 of the 5 core features necessary for a diagnosis of bvftd (i.e., insidious onset, decline in social interpersonal con- 254 Neurology 76 January 18, 2011

Table 1 Figure Demographic characteristics in 21 cases with neuropathologically confirmed Pick disease a Total sample (n 21) bvftd (n 13) lvftd (n 8) Mean SD Range Mean SD Range Mean SD Range Sex, F/M 10/11 5/8 5/3 Onset age, y 60 6.5 42 70 59 7.5 42 69 62 4 58 70 Presentation age, y 63 7 45 73 62 8 45 72 66 4 60 73 Time to presentation, y 2.9 2.0 1 5 b 2.4 1.3 1 5 3.6 2.8 1 5 b Disease duration, y 9.1 4.3 2 16 7.1 2.8 2 12 12.2 4.5 c 6 16 Age at death, y 69 7 62 79 66 7 49 74 74.5 4 65 79 Abbreviations: bvftd behavioral variant frontotemporal dementia; lvftd languagevariant frontotemporal dementia. a No significant differences are present between Sydney and Cambridge cases for any of the variables. b One case with 10 years between onset and presentation. c Difference between lvftd and bvftd ( p 0.015). duct, impaired regulation of personal conduct, emotional blunting, loss of insight). The 2 remaining cases showed preserved emotional response and insight into their condition early in the disease process. Presence of features supportive of the diagnosis of bvftd was variable. The most common features were executive dysfunction (10; 77%), rigidity (8; 61%), distractibility (7; 54%), and mental perseveration (7; 54%). Other supportive features were found in fewer than 5 cases. Importantly, 6 cases (46%) exhibited significant memory deficits as a presenting feature. Survival curve in cases of Pick disease clinically diagnosed as behavioral variant frontotemporal dementia (bvftd) and language variant frontotemporal dementia (lvftd) Disease duration was longer in lvftd cases compared with bvftd cases (p 0.007). lvftd. All 3 SemD cases showed insidious onset and impaired naming and confrontation. Semantic paraphasias and prosopagnosia were reported in 2 cases and empty speech in one. Of the supportive features, change in empathy was most common (all cases). The 4 PNFA cases exhibited nonfluent spontaneous speech. They also showed impaired singleword repetition with phonologic errors and distortions but appeared to have preserved comprehension of simple commands. No disturbance in social skills was reported in this group. One case showed a severe visuoconstructive impairment, being able to copy only simple designs (e.g., cross, square). Cognitive profile. Neuropsychological instruments varied between sites and evolved over the course of data collection. As such, test results were transformed into percentile scores (based on published normative data for age- and education-matched healthy controls), to allow comparison across tests and across participants for each cognitive domain. In some cases, formal neuropsychological examination was not available. In these instances, performance in each cognitive domain was rated as preserved or impaired (mild, moderate, severe) based on information from the clinical file. bvftd. Executive dysfunction was present in all bvftd cases with available data (table 2). The second cognitive domain most commonly affected was memory, with 6 cases exhibiting impaired performance on testing and another case showing a memory deficit specific for visuospatial information. One-third of cases displayed significant deficits on language or visuoconstructive tasks. lvftd. At presentation, one lvftd case (global 1, table 2) had severe expressive and receptive language deficits that prevented formal cognitive assessment. Seen 4 years after disease onset, this person could occasionally follow simple commands but was only capable of unreliable yes/no responses to questions. Among the other cases, naming and comprehension deficits were most common, with relative preservation of the other cognitive domains. One case had impaired episodic memory and 2 cases showed reduced executive function. Working memory and attention/concentration were generally preserved in these patients although these domains were not consistently examined. Neuropathology. Data were missing for the superior frontal cortex for 3 cases and in the inferior temporal cortex for 2 cases (one case with missing data in both regions) due to unavailability of tissue block or insufficient tissue to perform counting. The bvftd group had fewer Pick bodies in the superior frontal (p 0.031) and inferior temporal (p 0.049) cor- Neurology 76 January 18, 2011 255

Table 2 Cognitive profiles in 21 cases with neuropathologically confirmed Pick disease a Case Disease duration, y Delay to presentation, y Memory Language: Expression Language: Comprehension Visuoconstructive Executive WM Attention bvftd 1 2 1 Preserved N/A Preserved Preserved N/A bvftd 2 4 2 1 1 N/A 1 1 1 50 75 bvftd 3 5 2 N/A N/A N/A N/A bvftd 4 5 3 1 N/A 1 10 1 N/A N/A N/A bvftd 5 7 5 1 1 10 16 25 50 1 75 90 25 50 bvftd 6 7 2 1 1 10 16 50 75 10 25 50 75 50 bvftd 7 7 3 1 10 25 50 N/A 1 N/A N/A N/A bvftd 8 7 2 25 50 25 50 Preserved 16 25 1 10 N/A N/A bvftd 9 8 5 25 50 1 N/A 25 50 1 10 1 1 10 bvftd 10 9 2 1 1 N/A 1 1 1 10 25 50 bvftd 11 10 1 16 25 16 25 N/A 16 25 1 N/A N/A bvftd 12 10 2 1 25 75 10 16 25 50 1 1 10 75 90 bvftd 13 12 2 Verbal: 25 50; visuospatial: 1 N/A Preserved 25 50 25 50 50 75 25 50 SemD 1 6 2 Preserved 25 50 N/A 50 75 75 90 SemD 2 16 3 1 25 50 25 50 75 90 N/A SemD 3 16 10 25 75 10 16 75 90 10 25 N/A N/A PNFA 1 6 2 N/A N/A PNFA 2 9 3 Preserved N/A N/A PNFA 3 15 2 Preserved N/A N/A N/A PNFA 4 16 4 Preserved N/A N/A N/A N/A Global 1 14 4 N/A N/A N/A N/A N/A Abbreviations: Mild impairment; moderate impairment; severe impairment; bvftd behavioral variant frontotemporal dementia; lvftd language-variant frontotemporal dementia; N/A information not available in the file; PNFA progressive nonfluent aphasia; SemD semantic dementia; WM working memory. a Scores are percentiles. tices compared to the lvftd group, even after taking into account the longer disease duration of the lvftd group (table 3). None of the other Pick body or neuronal density measures were different between the groups before or after covarying for disease duration, although neuronal density declined in the dentate gyrus with increasing disease duration independent of clinical group (p 0.003). No differences in hippocampal Pick body or neuronal densities were observed between cases with and without memory deficits. To determine the relationship among pathologic variables, including disease duration, principal component analysis was performed for each clinical group. Only factors with eigenvalues 1 which explained 15% of the variance were included. Variables with loadings 0.70 were considered significantly related to each other. In the bvftd group, 2 factors accounted for 66% of the variance (44%, 22%) (table 4). The first factor comprised the 4 Pick body density measures and the second factor disease duration and neuronal loss in the dentate gyrus and CA1 regions. In the lvftd group, 2 factors accounted for 78% of the variance (54%, 24%) (table 4). The first factor included neuronal loss in the dentate gyrus, as expected from above, and decreasing Pick body density in all temporal lobe regions, with disease duration also loading on this factor. The second factor included neuronal loss in other temporal lobe regions. These data show that in bvftd, the severity of Pick bodies in frontal and temporal regions are related, independently of disease duration. In contrast, in lvftd, neuronal loss in the temporal cortex and CA1 region are related, independently of disease duration. DISCUSSION This study details the early clinical presentation of 21 autopsy-confirmed cases of Pick disease. This series, which represents two-thirds of all Pick disease cases collected over 16 years by 2 large brain bank programs, was identified from nearly 250 FTLD cases. It demonstrates that Pick disease is rare, accounting for only 1 in 5 tau-positive cases. This study reveals a number of findings which have clinical implications for the management of 256 Neurology 76 January 18, 2011

Table 3 Superior frontal cortex Pick body and neuronal densities in neuropathologically confirmed Pick disease cases according to clinical diagnosis a bvftd (n 13) lvftd (n 8) Mean SD Range Mean SD Range Pick bodies 15 18 0 48 42 22 17 75 Neurons 128 42 67 203 110 25 75 148 Inferior temporal cortex Pick bodies 15 21 0 47 39 23 21 85 Neurons 118 43 67 204 135 76 86 285 Dentate gyrus Pick bodies 436 456 0 1,073 633 571 80 1,560 Neurons 2,052 613 953 3,093 1,474 640 733 2,653 CA1 Pick bodies 38 41 0 94 55 47 4 120 Neurons 131 82 18 284 152 105 36 336 Abbreviations: bvftd behavioral variant frontotemporal dementia; lvftd languagevariant frontotemporal dementia. a Density is n/mm 2. FTLD. The clinical features present at initial presentation are associated with clearly different outcomes: patients with bvftd die on average 5 years earlier than those with clinical features consistent with lvftd (7 years vs 12 years after disease onset). In other words, early clinical profiles are indicative of different disease course in cases with the same neuropathology. Various estimates of survival have been reported in lvftd: either being the longest compared with other subtypes of FTD 11 or shorter disease duration in patients with FTD presenting with language disturbance compared to those who do not. 12 This study reports a difference in survival in clinical groups with the same underlying pathology. A previous study, which compared survival in taupositive and tau-negative cases, reported a disease duration in their tau-positive cases that was similar to that of our bvftd cases (7 years). 13 From our findings, we would predict that their FTD group did not contain cases with early language features. In addition, in that study, the sample was not limited to cases with Pick disease but also comprised cases with other tau-positive pathologies, such as corticobasal degeneration, progressive supranuclear palsy, and argyrophilic grain disease. 13 Longer survival has also been reported in Pick disease cases compared with cases with other tau pathology. 5 Interestingly, a recent report on 100 cases of SemD 14 showed a mean disease duration similar to that reported here for the cases with language presentation (13.8 and 12.2 years, respectively). In that study, disease duration in the cases with postmortem confirmation did not differ across pathologic subtypes (tau-positive, TDPpositive, and AD pathologies). In the lvftd group, an unexpected finding was the relatively large number of cases presenting with SemD 3 and one case with global aphasia, compared to those with PNFA. Previous series have reported that presence Table 4 Summary of exploratory factor analyses for the bvftd and lvftd groups Factor loadings bvftd Factor loadings lvftd Pick bodies Disease load Disease load Temporal lobe neuronal loss Dentate G: Pick bodies 0.96 a 0.02 Dentate G: Neuronal loss 0.98 a 0.08 CA1: Pick bodies 0.94 a 0.09 Dentate G: Pick bodies 0.91 a 0.24 Inferior temporal G: Pick bodies Superior frontal G: Pick bodies 0.94 a 0.17 CA1: Pick bodies 0.87 a 0.08 0.92 a 0.12 Inferior temporal G: Pick bodies 0.85 a 0.35 Disease duration 0.3 0.86 a Disease duration 0.77 a 0.11 CA1: Neuronal loss 0.31 0.75 a Inferior temporal G: Neuronal loss 0.27 0.87 a Dentate G: Neuronal loss 0.2 0.72 a CA1: Neuronal loss 0.35 0.78 a Superior frontal G: Neuronal loss Inferior temporal G: Neuronal loss 0.05 0.33 Superior frontal G: Pick bodies 0.63 0.57 0.44 0.1 Superior frontal G: Neuronal loss 0.63 0.53 Eigenvalues 3.98 1.97 Eigenvalues 4.87 2.18 % of variance 44 22 % of variance 54 24 Abbreviations: bvftd behavioral variant frontotemporal dementia; G gyrus; lvftd language-variant frontotemporal dementia. a Factor loadings over 0.70. Neurology 76 January 18, 2011 257

of SemD tends to predict TDP pathology whereas PNFA tends to predict tau pathology. 5,6,15 Clinicopathologic concordance, however, is not perfect, as shown by the recently published review of a large cohort of SemD cases, 14 and we note that it is possible that the association between PNFA and tau pathology may reflect tau-positive pathology without Pick bodies as described, for instance, as atypical progressive supranuclear palsy. 16 In the present study, neuronal loss in the temporal lobe was characteristic of lvftd cases, consistent with previous studies showing that more severe degeneration in this region occurs in all cases of SemD. 17,18 Results from the factor analysis, however, are exploratory and need to be interpreted cautiously: as many pathologic variables were assessed in only a limited number of cases in our study, this finding will need to be confirmed in a larger cohort of cases. The cognitive profiles in this sample provide further insight into the early clinical presentation in FTLD. Memory complaints and memory deficits documented on formal cognitive testing were common. These deficits were most prominent in the bvftd group, where 7 out of 13 obtained scores well below normal limits. In addition, one case had a severe memory deficit for visuospatial but not verbal material, and another had moderate memory impairment as reported in the clinical notes. Among the lvftd cases, only one experienced significant memory changes. The cause of the episodic memory deficit remains unclear, although hippocampal atrophy has been reported in FTD. 19 In this study, cases with and without memory deficits did not differ with respect to severity of hippocampal pathology in the CA1 region or dentate gyrus. Memory disturbance, however, can also be observed following disturbance in an integrated network that not only comprises the medial temporal lobe region (hippocampus and adjacent cortex) but also includes the mamillary bodies, dorsomedial thalamus, and posterior medial cingulate cortex. 20 Whether the amount of pathology in the extrahippocampal regions of this network differed in the cases with and without memory deficits is not known as these brain regions were not examined in our study. Impaired memory in bvftd has previously been reported. 5,21,22 However, these findings further support the view that a genuine disturbance of episodic memory (i.e., not secondary to faulty retrieval processes) is a possible feature in the initial profile of bvftd and suggest that the presence of memory deficits should not be seen as an exclusion criterion. 23 The prevalence of episodic memory disturbance among Pick disease cases in this study (53%) contrasts with that reported elsewhere recently (7%). 18 In that study, clinical diagnosis was based on the standard criteria, 1 in which memory disturbance represents an exclusion criterion. In addition, it is possible that differences in the types of memory investigations undertaken in the 2 studies may explain the discrepancy in prevalence of memory deficits. The pervasive nature of executive dysfunction in these pathologically confirmed cases provides further evidence that this cognitive deficit is common in bvftd. Although its presence has been thought to be variable, deficits in executive function may have been masked in previous studies by the inclusion of cases presenting with clinical features suggestive of bvftd but who fail to progress to frank dementia over many years (so-called phenocopy or nonprogressive cases). 24 Neuropathologic differences between the clinical subgroups were also present, especially when considering the difference in disease duration, a variable influencing degeneration over time. Our analysis suggests that each clinical group was characterized by a different pathology: neuronal loss in temporal lobe regions occurred in lvftd whereas Pick body deposition characterized bvftd. Importantly, the severity of these pathologies was not related to disease duration. Interestingly, although the density of Pick bodies was lower in bvftd compared with lvftd (table 3), the density of Pick bodies reduced with increased disease duration in the lvftd group. While the contribution of pathologies other than Pick bodies and neuronal loss, or involvement of regions other than those examined, cannot be excluded, these data suggest that neurons that contain Pick bodies are likely targets of neurodegeneration early in bvftd. In lvftd, however, these neurons appear to be affected later in the disease course. Confirmation of these findings in larger cohorts is required. Interestingly, no difference in the severity of pathology was found between cases with and without memory deficit or memory complaint in the 2 regions known to participate in episodic memory function. Because of the retrospective nature of the study, memory integrity was rated only dichotomously and was, arguably, not sensitive enough to detect possible associations between pathology and cognition. The combination of behavioral changes, episodic memory deficits, and executive dysfunction early in the disease process associates with more rapid Pick body related degeneration and a poorer prognosis than language deficits. Importantly, this study confirms that fluent language presentations in FTD are not incompatible with underlying Pick disease, and that temporal lobe neuronal loss underpins these clinical features. In particular, Pick body pathology in lvftd is dependent on disease duration, causing 258 Neurology 76 January 18, 2011

neurodegeneration only late in the disease. These findings have relevance as in vivo disease biomarkers (e.g., blood or CSF) are being developed. As such, accurate diagnosis of time-dependent pathologies will ensure optimal pathology-specific therapeutic interventions. AUTHOR CONTRIBUTIONS Statistical analysis was conducted by Dr. O. Piguet and Dr. G.M. Halliday. ACKNOWLEDGMENT Tissues were obtained from the Cambridge Brain Bank, which is supported by the NIHR Cambridge Biomedical Research Centre, and the Sydney Brain Bank, which is supported by the National Health and Medical Research Council of Australia, the University of New South Wales, and Neuroscience Research Australia. DISCLOSURE Dr. Piguet receives research support from the NHMRC and the Australian Research Council. Dr. Halliday has received funding for travel and speaker honoraria from Elan Corporation; serves on the editorial boards of Brain, Acta Neuropathologica, Journal of Neural Transmission, and Movement Disorders; may accrue revenue on a patent(s) re: Genetic test that predicts the progression of Parkinson s disease; receives publishing royalties for Atlas of the Developing Mouse Brain (Elsevier, 2006) and The Human Nervous System, 2nd ed. (Elsevier, 1990); receives research support from NHMRC, the Australian Research Council, Parkinson s NSW; and holds stock/stock options in Cochlear and NIB Holdings. Dr. Reid, Dr. Casey, and Ms. Carman report no disclosures. Dr. Huang may accrue revenue on patent(s) re: Biomarkers for Parkinson s disease; and receives research support from NHMRC. Dr. Xuereb reports no disclosures. Dr. Hodges serves on the Editorial Boards of Aphasiology, Cognitive Neuropsychiatry, and Cognitive Neuropsychology; receives publishing royalties for Cognitive Assessment for Clinicians (Oxford University Press, 2007) and Frontotemporal Dementia Syndromes (Cambridge University Press, 2007); and receives research support from the Australian Research Council. Dr. Kril receives publishing royalties for the recorded lecture series Neuropathology of Dementia (Henry Stewart Publishing, 2007); and receives research support from NHMRC. Received June 14, 2010. Accepted in final form September 20, 2010. REFERENCES 1. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546 1554. 2. Munoz DG, Dickson DW, Bergeron C, Mackenzie IR, Delacourte A, Zhukareva V. The neuropathology and biochemistry of frontotemporal dementia. Ann Neurol 2003; 54(suppl 5):S24 S28. 3. Josephs KA, Holton JL, Rossor MN, et al. 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