Research
Original Investigation
Frontotemporal Dementia Associated With the C9ORF72 Mutation A Unique Clinical Profile Emma Devenney, MRCP; Michael Hornberger, PhD; Muireann Irish, PhD; Eneida Mioshi, PhD; James Burrell, PhD; Rachel Tan, PhD; Matthew C. Kiernan, FRACP; John R. Hodges, FRCP
IMPORTANCE While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear. OBJECTIVES To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)–FTD cohort. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD–amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained. MAIN OUTCOMES AND MEASURES Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale. RESULTS In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD. CONCLUSIONS AND RELEVANCE The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.
JAMA Neurol. 2014;71(3):331-339. doi:10.1001/jamaneurol.2013.6002 Published online January 20, 2014.
Author Affiliations: Prince of Wales Clinical School, University of New South Wales, Sydney, Australia (Devenney); Neuroscience Research Australia, Sydney, Australia (Devenney, Hornberger, Irish, Mioshi, Burrell, Tan, Kiernan, Hodges); School of Medical Sciences, University of New South Wales, Sydney, Australia (Hornberger, Mioshi, Burrell, Tan, Hodges); School of Psychology, University of New South Wales, Sydney, Australia (Irish); Brain and Mind Research Institute, University of Sydney, Sydney, Australia (Kiernan). Corresponding Author: Emma Devenney, MRCP, Neuroscience Research Australia, Randwick, Sydney, New South Wales, 2031, Australia ([email protected]).
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Research Original Investigation
Frontotemporal Dementia and C9ORF72 Mutation
T
he C9ORF72 mutation accounts for approximately onethird of cases of familial frontotemporal dementia (FTD) and familial amyotrophic lateral sclerosis (ALS).1-7 Notably, it is also positive in a percentage (4%-21%) of patients with apparently sporadic disease.1,3-5,7-9 Given the relatively high rate of mutations in apparently sporadic cases, it is important to delineate the clinical profile of C9ORF72 carriers. Across the clinical spectrum of FTD, the predominant phenotype associated with the C9ORF72 mutation is behavioralvariant (bv) FTD, often occurring with features of ALS,2,4,7,10-13 although primary progressive aphasia has been reported to varying degrees.4,7 Additional features that characterize C9ORF72 carriers have been suggested by previous studies and include family history of ALS, parkinsonism, psychosis at presentation, a distinctive neuroanatomical signature with posterior and subcortical atrophy, and the typical frontal and temporal atrophy of FTD.2,4,7,10-14 However, these results have not always been consistent across studies, and with these inconsistencies come diagnostic challenges. As such, our study aimed to establish the frequency of the C9ORF72 mutation in a well-defined cohort of patients with FTD and to clarify the clinical, behavioral, neuropsychological, and imaging profile of patients with bvFTD who harbor this mutation by comparing mutation carriers with noncarriers. In contrast to previous studies, which often included historical data from numerous sources, our study has the advantage of prospectively collected comprehensive data during a 5-year period (2008-2012 inclusive) using standardized instruments. As such, this study seeks to provide a coherent description of the clinical phenotype of patients with bvFTD who have the C9ORF72 mutation.
score of 3.5, 1 relative with unspecified or late-onset dementia; and score of 4, no family history of FTD, ALS, or dementia. All patients completed a detailed family history questionnaire that asked about neurological and psychiatric illnesses in first-degree relatives. In a second phase, we compared demographic, clinical, behavioral, neuropsychological, and imaging data in C9ORF72 carriers with bvFTD, noncarriers, and a healthy control group selected from a volunteer panel at FRONTIER who were matched case by case for age, sex, and education history. The bvFTD comparison group comprised those who had previously tested negative for other available genetic mutations and subsequently tested negative for the C9ORF72 mutation. Global cognitive function at first presentation was measured using Addenbrooke’s Cognitive Examination–Revised.19 Disease staging was assessed with the FTD Functional Rating Scale.20
Genetic Analysis Blood sampling for genetic analysis was collected after informed consent was obtained. Genomic DNA was extracted from peripheral blood lymphocytes or frozen brain tissue according to standard procedures. Proband DNA was screened for the hexanucleotide repeat expansion in C9ORF72 by repeatprimed polymerase chain reaction based on the protocol of Renton et al.1 Samples were scored as expansion positive if they harbored more than 30 repeats. The C9ORF72 hexanucleotide repeat nonexpansion alleles were detected by polymerase chain reaction amplification and capillary electrophoresis.
Clinical and Behavioral Features
Methods Participants To establish the frequency of the C9ORF72 mutation, we adopted an inclusive approach and screened consecutive patients in whom a diagnosis of bvFTD was considered as well as those with a clinical diagnosis of bvFTD, semantic dementia (semantic-variant primary progressive aphasia), nonfluentvariant primary progressive aphasia, FTD-ALS, and corticobasal syndrome as per current diagnostic guidelines.15-17 Each patient was assessed at FRONTIER, the Frontotemporal Dementia Research Group, at Neuroscience Research Australia, between January 1, 2008, and December 31, 2012. Ethical approval for this study was obtained from the ethics committees of the South Eastern Sydney and Illawarra Area Health Service and the University of New South Wales. Participants, or their person responsible, provided written informed consent in accordance with the Declaration of Helsinki. Participants did not receive a stipend. A detailed family history was obtained and the Goldman Scale score was calculated.18 A score of 1 indicates at least 3 family members with FTD and/or ALS over 2 generations with 1 person being a first-degree relative of the other; score of 2, 3 or more family members with dementia and/or ALS but do not meet criteria for a score of 1; score of 3, at least 1 family member with confirmed FTD and/or ALS or early-onset dementia; 332
All patients were assessed by an experienced behavioral neurologist (J.R.H.). Core behavioral symptoms of FTD were systematically explored during the carer interview and recorded on a standardized inventory based on the Cambridge Behavioural Inventory21 as present or absent. Features on neurological examination of ALS, aphasia, parkinsonism, apraxia, ataxia, and eye movement abnormalities were documented. A longitudinal approach was favored for the analysis of the clinical data as it was crucial to establish whether these features developed as the disease progressed.
Neuropsychological Assessments The copy component of the Rey-Osterrieth Complex Figure Test22 and the Visual Object and Space Perception Battery assessed visuospatial abilities.23 The Rey Auditory Verbal Learning Test24 and the recall component of the Rey-Osterrieth Complex Figure Test22 assessed episodic memory. Tests of executive function included the Hayling Test,25 the FAS Verbal Fluency test,26and the Trail Making Test.27 Semantic and phonological processing was assessed using the Sydney Language Battery.28 The Test for Reception of Grammar, version 2,29 assessed syntactic comprehension.
Neuroimaging Patients underwent a 3T T1- and T2-weighted magnetic resonance imaging (MRI) scan. When the MRI findings were not typical for bvFTD, fludeoxyglucose F 18 positron emission to-
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Frontotemporal Dementia and C9ORF72 Mutation
Original Investigation Research
Figure 1. Frequency of C9ORF72 Mutation Positivity in a Frontotemporal Dementia Cohort 114 Patients included
14 Mutation positive
Phenotype
Family history
4/23 (17%) FTD-MND
10/29 (34%) bvFTD
3/10 (30%) GS score ≥3.5
7/10 (70%) GS score ≤3.0
1/4 (25%) GS score ≥3.5
0/20 PPA-nf
0/35 PPA-sv
0/7 CBS
3/4 (75%) GS score ≤3.0
The flowchart demonstrates the frequency of C9ORF72 mutation positivity in a frontotemporal dementia cohort. Patients with frontotemporal dementia are categorized according to subtype, and mutation-positive patients are further categorized by Goldman Scale (GS) score. Twenty-eight additional patients were screened but deemed not suitable for inclusion in the study, so they were
excluded. bvFTD indicates behavioral-variant frontotemporal dementia; CBS, corticobasal syndrome; FTD-MND, frontotemporal dementia with motor neuron disease; PPA-nf, nonfluent-variant primary progressive aphasia; and PPA-sv, semantic-variant primary progressive aphasia.
mography (FDG-PET) was performed. Previously validated MRI visual rating scales based on coronal T1 images were used for 5 areas: orbitofrontal cortex, anterior cingulate, temporal lobe, insula, and basal ganglia.30,31 This method was extended to include precuneus and cerebellar regions. Areas of atrophy were rated on a Likert scale by a rater (E.D.) blinded to the diagnosis after appropriate training on an independent data set. Interrater reliability was assessed using intraclass correlation coefficient and was found to be very high (Cronbach α = 0.9). The scale ranged from 0 (no atrophy) to 4 (severe atrophy) for all of the areas except the cerebellum, which was rated on a 4-point Likert scale.
patients with a Goldman Scale score of 3.0 or lower, 7 (54%) were mutation positive; of those with a Goldman Scale score of 3.5 or higher, 3 (19%) were mutation positive. Of 23 patients with FTD-ALS, 4 (17%) expressed the C9ORF72 mutation. Of these 23 patients, 6 (26%) had a Goldman Scale score of 3.0 or lower, while 17 (74%) had a Goldman Scale score of 3.5 or higher. Of patients with a Goldman Score of 3.0 or lower, 3 (50%) harbored the mutation; of those with a Goldman Scale score of 3.5 or higher, 1 (6%) was mutation positive. To put this another way and as illustrated in Figure 1, 70% of mutation carriers with bvFTD and 75% of mutation carriers with FTD-ALS had a Goldman Scale score of 3.0 or lower.
Statistical Analysis
Clinical and Behavioral Features
Data were analyzed using SPSS version 20.0 statistical software (SPSS Inc). Kolmogorov-Smirnov tests determined whether variables were normally distributed. Parametric variables were compared across the groups via independent t tests. Nonparametric data were analyzed using Mann-Whitney U tests, and categorical data were compared with χ2 tests. For MRI data, P < .01 was regarded as statistically significant, which allowed for multiple comparisons.
A comparison of the 10 C9ORF72 mutation carriers with bvFTD and 19 matched noncarriers revealed no significant difference between the groups across age at disease onset, disease duration at presentation, sex, education history, Addenbrooke’s Cognitive Examination–Revised score at onset, or disease severity on the FTD Functional Rating Scale score at onset (Table 1). The behavioral and imaging features of the C9ORF72 mutation carriers were compared against the International Consensus Diagnostic Criteria for bvFTD.15 In this comparison, 4 mutation carriers (40%) did not meet diagnostic criteria for possible bvFTD (Table 2). In 1 instance, this was due to lack of a sufficient number of core features; in the other cases, the presence of exclusion features was a factor, most notably strong indicators of psychiatric disease in 1 case, prominent episodic memory impairment and visuospatial deficits in 1 case, and the likelihood of autoimmune or prion disease in another. Of the cases in which imaging was possible (8 cases [80%]), it was striking that only 3 (38%) of these fulfilled criteria for probable bvFTD. This was due almost entirely to the absence of typical imaging changes on MRI or FDG-PET. Typically abnormal MRI findings with unequivocal frontal or temporal atrophy were found in only 1 patient with the C9ORF72
Results Frequency of C9ORF72 Mutations In total, 114 subjects were included in this study and screened for the C9ORF72 mutation. These included patients with FTD (n = 84), FTD-ALS (n = 23), and corticobasal syndrome (n = 7). The mutation was found in 14 patients (12%): 10 with bvFTD and 4 with FTD-ALS (Figure 1). In the overall bvFTD cohort of 29 patients, 10 cases (34%) were mutation positive. Of the 29 patients with bvFTD, 13 (45%) had a Goldman Scale score of 3.0 or lower (indicating a strong family history), while 16 (55%) had a Goldman Scale score of 3.5 or higher (indicating a weak or absent family history). Of jamaneurology.com
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Table 1. Baseline Demographic Characteristics of Patients With Behavioral-Variant Frontotemporal Dementia, Comparing C9ORF72 Mutation Carriers, Noncarriers, and Controls Carriers (n = 10)
Characteristic Age at onset, mean (SD), y Duration of symptoms at presentation, mean (SD), y Education history, mean (SD), y
Noncarriers (n = 19)
Controls (n = 35)
54.1 (9.4)
57.2 (7.8)
4.7 (3.5)
2.6 (1.4)
NA NA
10.6 (1.6)
11.3 (3.2)
11.8 (2.3) Abbreviations: ACE-R, Addenbrooke’s Cognitive Examination–Revised; FTDFRS, Frontotemporal Dementia Functional Rating Scale; NA, not applicable.
Sex, No. Male
6
13
Female
4
6
17 18
ACE-R score, mean (SD)a
75.7 (8.4)
67.3 (22.1)
94.2 (3.1)
FTDFRS Rasch score, mean (SD)a
−0.8 (1.8)
−1.1 (1.5)
NA
a
P < .001 for carriers vs controls and for noncarriers vs controls.
Table 2. Characteristics of C9ORF72 Mutation Carriers Compared With the International Consensus Diagnostic Criteria for Behavioral-Variant Frontotemporal Dementia bvFTD Neurodegenerative, Appropriate Progression
Behavioral Features, No.
Exclusion Featuresb
Possible bvFTD
Functional Declinec
Typical MRI
Typical PET
Probable bvFTD
1
+
4/6
−
+
+
+
NA
+
2
+
4/6
−
+
+
−
+
+
3
+
6/6
−
+
+
−
+
+
4
+
3/6
−
+
+
−
−
−
5
+
5/5
−
+
+
NA
NA
NA
6
+
6/6
−
+
+
NA
NA
NA
7
−
4/4
+d
−
+
−
NA
−
8
−
2/6
−
−
−
−
−
−
9
+
5/6
+e
−
+
−
+
−
10
+
3/6
+d
−
+
−
−
−
Patient No.
Abbreviations: bvFTD, behavioral-variant frontotemporal dementia; MRI, magnetic resonance imaging; NA, not assessed; PET, positron emission tomography; +, present; −, absent. a
Most cases failed to meet criteria for probable bvFTD.
b
Exlusion criteria for bvFTD were according to the International Consensus Diagnostic Criteria. Criteria A and B must be answered negatively for any bvFTD diagnosis; criterion C can be positive for possible bvFTD but must be negative for probable bvFTD. The exclusion criteria were as follows: criterion A, pattern of deficit is better accounted for by other neurodegenerative disease or medical disorder; criterion B, behavioral disturbance is better accounted for by a psychiatric diagnosis; and criterion C, biomarkers are
mutation. Imaging with FDG-PET was undertaken in 6 patients who had normal findings on MRI, and it showed a pattern typical of bvFTD in 3 cases. Patients harboring the C9ORF72 mutation were more likely to have a family member with ALS than nonmutation carriers (6 vs 0, respectively; P = .001). Psychiatric illness in family members was also significantly more common in mutation carriers than in nonmutation carriers (4 vs 1, respectively; P = .02). Psychiatric illnesses comprised schizophrenia in 1 family member, significant depression in 2, and suicide in another. Psychotic symptoms were more common in patients with the mutation (n = 4) than in those without, a finding that remained consistent for delusions (P = .02) and hallucinations (P = .02). By contrast, apathy in the very early stage of disease was more common in C9ORF72 noncarriers (n = 9) compared with mutation carriers (n = 1) (P = .002). As the illness progressed, apathy in the mutation carriers increased; at pre334
Probablea
Possible
strongly indicative of Alzheimer disease or other neurodegenerative process. c
Impaired activities of daily living.
d
Patients met exclusion criterion A. In patient 7, autoimmune or prion disease was initially thought to be most likely owing to rapidity of onset and normal imaging findings. In patient 10, prominent memory and visuospatial dysfunction made Alzheimer disease the most likely diagnosis.
e
Patient met exclusion criterion B. Late-onset psychiatric illness was the primary consideration in this case because of severe delusions, hallucinations, and mood disorder.
sentation, there was no significant difference between the groups (P = .63). Disease progression in general was slow in 5 carriers; 1 patient exhibited symptoms for 10 years prior to presentation. The C9ORF72 mutation carriers had a higher likelihood of developing parkinsonism throughout their illness than noncarriers (P = .02). There were no significant differences in groups at presentation for the following features: aphasia (P = .48), parkinsonism (P = .67), apraxia (P = .65), or eye movement abnormalities (P > .99). Ataxia was not present in either C9ORF72 carriers or noncarriers at presentation. No C9ORF72 mutation–positive patients with pure bvFTD had developed ALS at follow-up.
Neuropsychological Assessments Performance on memory, executive, and language tests failed to discriminate between C9ORF72 mutation carriers and non-
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Frontotemporal Dementia and C9ORF72 Mutation
carriers, with both groups showing comparable performance. The C9ORF72 mutation carriers scored significantly more poorly than the noncarriers on the Rey-Osterrieth Complex Figure Test copy subscale (P = .03), but the Visual Object and Space Perception Battery did not discriminate between the groups.
Neuroimaging Patterns of Gray Matter Atrophy Two patients were unable to undergo MRI or FDG-PET. The visual rating scores revealed variability across the groups with significant differences in each of the 7 areas assessed (Figure 2). Compared with controls, there was a trend toward more significant atrophy of the precuneus in the C9ORF72 mutation carriers (P = .02). By contrast, the C9ORF72 noncarriers had more atrophy than controls in each of the 7 areas (all P < .01). Notably, the C9ORF72 carriers showed an absence of significant atrophy of the orbitofrontal cortex, anterior cingulate, insula, and temporal pole, regions all typically involved in bvFTD. A comparison of the 2 bvFTD groups confirmed no significant difference in the precuneus region between C9ORF72 carriers and noncarriers. Significant differences were found in the orbitofrontal cortex (P = .001), anterior temporal lobe (P = .001), insula (P = .001), and anterior cingulate (P < .001), with noncarriers showing greater atrophy across these regions. Illustrative examples of MRI scans from C9ORF72 carriers and noncarriers are shown in Figure 3. Patterns of Regional Hypometabolism Imaging with FDG-PET was performed in 6 mutation carriers and showed an unequivocal pattern of hypometabolism in the frontal and/or temporal regions, as seen in typical bvFTD, in 3 cases. In 1 of these typical cases, hypometabolism was also present in the parietal region. In contrast, 1 atypical case revealed abnormal perfusion globally, including the parietal region, thalamus, and cerebellum. The second atypical case showed mild hypometabolism in the temporal and parietal regions, while the findings in the third were equivocal.
Discussion This study has highlighted a constellation of characteristics that may be used to identify patients with bvFTD who have the C9ORF72 mutation. Initial indications include a high rate of psychosis in mutation carriers combined with an increased frequency of ALS in family members. The clinical course was frequently atypical with slow disease progression in one-half of patients and lack of brain atrophy on MRI in the majority, potentially leading to misdiagnosis. Our results also suggest that 2 novel clues to the presence of the mutation are lack of apathy early in the disease course and psychiatric illness in family members. A high frequency of the C9ORF72 mutation in patients with familial bvFTD and familial FTD-ALS was identified in this study and corroborated previous reports.1,2,4,32 By contrast, the frequency rate in apparent sporadic bvFTD was considerably higher than previously reported.7 This high frequency in apjamaneurology.com
Original Investigation Research
parently sporadic disease raises the question of whether genetic mutations in sporadic cases are due to expansion instability in patients without family history or simply represent low penetrance. On a practical level, the presence of the mutation in sporadic disease has significant implications for genetic counseling, highlighting the need to establish clear markers of carrier status. Most of our mutation carriers with bvFTD had a family history of ALS in a first-degree relative, often in conjunction with an increased frequency of psychiatric illness in family members, suggesting that the phenotype might extend beyond FTD and ALS to psychiatric disease. A recent study reported a high prevalence of mental health disorders in first-degree relatives of patients with ALS who harbored the C9ORF72 mutation.33 More recently, additional evidence for an expansion in genotype-phenotype correlation has emerged, with reports of the C9ORF72 mutation in other common diseases such as Alzheimer disease, Huntington disease–like syndromes, and forms of parkinsonism.34,35 The prominence of psychotic symptoms may not be unexpected given that earlier studies have linked this feature to FTD-ALS.36,37 Inthisstudy,delusionsweremorefrequentlypresent than hallucinations and were mainly persecutory, negative, and paranoid, often involving the health or relationships of the patient. In 1 case, previously reported in the literature, the patient with the C9ORF72 mutation exhibited bizarre and complex delusions and hallucinations similar to those described by other groups.38 This was an extreme case in our cohort; in most instances, the delusions and hallucinations were more prosaic. The high frequency of psychosis contrasts with a low frequency of apathy in mutation carriers. This dissociation has not been previously described in C9ORF72 mutation carriers. Hence, the neural substrates underlying this remain unexplored. Most C9ORF72 mutation carriers in this study lacked the typical imaging features associated with bvFTD. Comparison of C9ORF72 mutation carriers with controls showed a trend toward greater precuneus atrophy in the former group with other regions lacking significant atrophy. Other studies have highlighted differences in the degree of precuneus atrophy, in which precuneus atrophy accurately discriminated between C9ORF72 mutation and sporadic FTD.14,39 At a clinical level, an apparently normal MRI lacking overt frontal or temporal atrophy does not exclude a diagnosis of bvFTD related to the C9ORF72 mutation. A study of 2 mutation carriers has linked bvFTD phenocopy syndrome with the C9ORF72 mutation.40 The most reliable features that distinguish true bvFTD cases from phenocopy cases are frontal and/or temporal atrophy on imaging, deterioration in activities of daily living, poor performance on global cognitive tests, and impairment on executive tasks.20,30,41-44 Considering our cohort of C9ORF72 mutation carriers in this context, most had functional decline in activities of daily living, all scored below the cutoff level on Addenbrooke’s Cognitive Examination–Revised, and at a group level they were impaired on tests of executive function. In brief, while this cohort of C9ORF72 mutation carriers has imaging findings similar to those of phenocopy cases, it is evident that JAMA Neurology March 2014 Volume 71, Number 3
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Figure 2. Cortical Atrophy Ratings in C9ORF72 Mutation Carriers, Noncarriers, and Controls A Orbitofrontal cortex
B
Anterior cingulate 4
3
Cortical Atrophy Score
Cortical Atrophy Score
4
2
1
0 Carriers
Controls
3
2
1
0
Noncarriers
Controls
C9ORF72 Status C
Cortical Atrophy Score
Cortical Atrophy Score
4
3
2
1
0
3
2
1
0 Controls
Carriers
Noncarriers
Controls
C9ORF72 Status
Carriers
Noncarriers
C9ORF72 Status F
Basal ganglia 4
Precuneus 4
Cortical Atrophy Score
Cortical Atrophy Score
Sporadic
D Insula
Anterior temporal lobe 4
E
Carriers
C9ORF72 Status
3
2
1
0
3
2
1
0 Controls
Carriers
Noncarriers
Controls
C9ORF72 Status
Carriers
Sporadic
C9ORF72 Status
Cortical Atrophy Score
G Cerebellum 4
3
2
1
0 Controls
Carriers
Noncarriers
C9ORF72 Status
distinguishing features that differentiate them from the phenocopy syndrome are present. Taken together, our findings suggest that C9ORF72 mutation carriers represent a distinct group not typical of patients with bvFTD. This finding is exemplified by the failure of most 336
Box plots (whiskers indicate minimum and maximum scores) demonstrate atrophy ratings for C9ORF72 mutation carriers, noncarriers, and controls. A magnetic resonance imaging visual rating scale assessed 7 cortical regions: the orbitofrontal cortex (A), anterior cingulate (B), anterior temporal lobe (C), insula (D), basal ganglia (E), precuneus (F), and cerebellum (G). There was a statistical trend for more precuneus atrophy in the C9ORF72 mutation carriers compared with controls (P = .02). For all other regions, no statistical differences were found between C9ORF72 mutation carriers and controls. The horizontal lines represent the median (ie, 50% of the data are greater than this value). The top and bottom lines of the box represent the 75th and 25th percentiles, respectively. In some cases, the median is the same value as the 25th or 75th percentile and therefore is not shown.
to satisfy the International Consensus Diagnostic Criteria for bvFTD for probable, and in almost half of cases even possible, bvFTD. Given the complexity of accurate diagnosis in this cohort coupled with the high frequency of this mutation in sporadic disease, it seems paramount that the key characteristics
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Original Investigation Research
Figure 3. Variable Patterns of Cortical Atrophy in C9ORF72 Mutation Carriers and Noncarriers Slice 1
Slice 2
Slice 3
A
B
C
D
Coronal T1-weighted images are shown at the orbitofrontal cortex (slice 1), the anterior temporal lobe (slice 2), and the precuneus and cerebellum (slice 3). These illustrative examples demonstrate the variability in cortical atrophy between C9ORF72 mutation carriers (A and B) and noncarriers (C and D).
of C9ORF72 mutation carriers identified in this study are used as a complement to current diagnostic criteria. Our study has clear limitations that temper the conclusions that can be drawn. Recruitment through specialist centers may introduce bias, future prospective studies would benefit from larger sample sizes, and replication of our findings in a population-based cohort would be desirable. Larger studies should include patients with other neurodegenerative and psychiatric disorders in addition to FTD. Consequently, the non-FTD phenotype of the C9ORF72 mutation may be uncovered. Collection of detailed jamaneurology.com
family history data with particular emphasis on psychiatric disease would be an interesting addition to future studies. The imaging findings clearly need to be replicated with quantification of the FDG-PET abnormalities.
Conclusions We have confirmed several characteristic features of C9ORF72 mutation carriers. We have also identified a number of novel JAMA Neurology March 2014 Volume 71, Number 3
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Frontotemporal Dementia and C9ORF72 Mutation
features in this group, including links with a family history of psychiatric illness and lack of apathy early in the disease course. These results have important clinical implications. First, this mutation is prevalent in sporadic FTD cases, raising challenging issues for physicians in the selection of patients for genetic testing. Second, a significant number of mutation carriers do not satisfy current diagnostic criteria for bvFTD, mainly
ARTICLE INFORMATION Accepted for Publication: November 27, 2013. Published Online: January 20, 2014. doi:10.1001/jamaneurol.2013.6002. Author Contributions: Dr Devenney had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition of data: Burrell, Hodges. Analysis and interpretation of data: Devenney, Hornberger, Irish, Mioshi. Drafting of the manuscript: Devenney, Irish, Tan, Kiernan, Hodges. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Devenney. Study supervision: Kiernan, Hodges. Conflict of Interest Disclosures: Dr Hodges receives publishing royalties for Cognitive Assessment for Clinicians (Oxford University Press, 2007) and Frontotemporal Dementia Syndromes (Cambridge University Press, 2007). No other disclosures were reported. Funding/Support: Dr Devenney was supported by a grant from the Motor Neurone Disease Association. Drs Devenney, Tan, Kiernan, and Hodges were supported by grant 1037746 from the National Health and Medical Research Council of Australia. Dr Hornberger was supported by Research Fellowship DP110104202 from the Australian Research Council. Dr Irish was supported by Discovery Early Career Research Award DE130100463 from the Australian Research Council. Dr Mioshi was supported by Early Career Fellowship 1016399 from the National Health and Medical Research Council of Australia. Drs Mioshi, Burrell, and Tan were supported by the Motor Neurone Disease Research Institute of Australia. Dr Tan was supported by the Mick Rodger Benalla MND Research Grant. Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: John Kwok, PhD, and Carol Dobson Stone, Neuroscience Research Australia and School of Medical Sciences, University of New South Wales, Sydney, Australia, carried out the genetic analysis on blood samples from participants in this study. They did not receive compensation for their contributions. REFERENCES 1. Renton AE, Majounie E, Waite A, et al; ITALSGEN Consortium. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257-268.
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owing to lack of cortical atrophy on visual inspection. With this in mind, we propose that clinicians should consider this mutation in patients with bvFTD in the presence of the key markers identified in this study and, in particular, psychosis. Atypical MRI findings should raise suspicion of the C9ORF72 syndrome, and clinicians are advised to check for precuneus atrophy.
2. Hsiung GY, DeJesus-Hernandez M, Feldman HH, et al. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain. 2012;135(pt 3):709-722. 3. Majounie E, Renton AE, Mok K, et al; Chromosome 9-ALS/FTD Consortium; French Research Network on FTLD/FTLD/ALS; ITALSGEN Consortium. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012;11(4):323-330. 4. Simón-Sánchez J, Dopper EG, Cohn-Hokke PE, et al. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain. 2012;135(pt 3):723-735. 5. Byrne S, Elamin M, Bede P, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 2012;11(3):232-240. 6. Chiò A, Borghero G, Restagno G, et al; ITALSGEN consortium. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain. 2012;135(pt 3):784-793. 7. Boeve BF, Boylan KB, Graff-Radford NR, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain. 2012;135(pt 3):765-783. 8. Van Langenhove T, van der Zee J, Gijselinck I, et al. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. JAMA Neurol. 2013;70(3):365-373. 9. Mahoney CJ, Downey LE, Ridgway GR, et al. Longitudinal neuroimaging and neuropsychological profiles of frontotemporal dementia with C9ORF72 expansions. Alzheimers Res Ther. 2012;4(5):41. 10. Snowden JS, Rollinson S, Thompson JC, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain. 2012;135(pt 3):693-708. 11. Mahoney CJ, Beck J, Rohrer JD, et al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain. 2012;135(pt 3):736-750. 12. Sha SJ, Takada LT, Rankin KP, et al. Frontotemporal dementia due to C9ORF72 mutations: clinical and imaging features. Neurology. 2012;79(10):1002-1011. 13. Irwin DJ, McMillan CT, Brettschneider J, et al. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and
amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2013;84(2):163-169. 14. Whitwell JL, Weigand SD, Boeve BF, et al. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain. 2012;135(pt 3):794-806. 15. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134(pt 9):2456-2477. 16. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011;76(11):1006-1014. 17. Mathew R, Bak TH, Hodges JR. Diagnostic criteria for corticobasal syndrome: a comparative study. J Neurol Neurosurg Psychiatry. 2012;83(4):405-410. 18. Goldman JS, Farmer JM, Wood EM, et al. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology. 2005;65(11):1817-1819. 19. Mioshi E, Dawson K, Mitchell J, Arnold R, Hodges JR. The Addenbrooke’s Cognitive Examination–Revised (ACE-R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry. 2006;21(11):1078-1085. 20. Mioshi E, Hsieh S, Savage S, Hornberger M, Hodges JR. Clinical staging and disease progression in frontotemporal dementia. Neurology. 2010;74(20):1591-1597. 21. Wedderburn C, Wear H, Brown J, et al. The utility of the Cambridge Behavioural Inventory in neurodegenerative disease. J Neurol Neurosurg Psychiatry. 2008;79(5):500-503. 22. Meyers J, Meyers K. The Meyers Scoring System for the Rey Complex Figure and the Recognition Trial: Professional Manual. Odessa, FL: Psychological Assessment Resources; 1995. 23. Warrington EK, James M. The Visual Object and Space Perception Battery. Bury St Edmunds, England: Thames Valley Test Co; 1991. 24. Schmidt M. Rey Auditory Verbal Learning Test: A Handbook. Los Angeles, CA: Western Psychological Services; 1996. 25. Burgess PW, Shallice T. Response suppression, initiation and strategy use following frontal lobe lesions. Neuropsychologia. 1996;34(4):263-272. 26. Spreen O, Strauss E. A Compendium of Neuropsychological Tests: Administration, Norms, and Commentary. New York, NY: Oxford University Press; 1998. 27. Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage. Percept Mot Skills. 1958;8(3):271-276. doi:10.2466 /pms.1958.8.3.271. 28. Savage S, Hsieh S, Leslie F, Foxe D, Piguet O, Hodges JR. Distinguishing subtypes in primary progressive aphasia: application of the Sydney
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Original Investigation Research
Language Battery. Dement Geriatr Cogn Disord. 2013;35(3-4):208-218.
[published online July 9, 2013]. Ann Neurol. doi:10.1002/ana.23969.
and without C9ORF72 expansions. Neuroimage Clin. 2013;2:836-843.
29. Bishop DV. Test for Reception of Grammar: TROG-2 Version 2. London, England: Pearson Education; 2003.
34. Beck J, Poulter M, Hensman D, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet. 2013;92(3):345-353.
40. Khan BK, Yokoyama JS, Takada LT, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. J Neurol Neurosurg Psychiatry. 2012;83(4):358-364.
35. Lesage S, Le Ber I, Condroyer C, et al; French Parkinson’s Disease Genetics Study Group. C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain. 2013;136(pt 2):385-391.
41. Davies RR, Kipps CM, Mitchell J, Kril JJ, Halliday GM, Hodges JR. Progression in frontotemporal dementia: identifying a benign behavioral variant by magnetic resonance imaging. Arch Neurol. 2006;63(11):1627-1631.
30. Kipps CM, Davies RR, Mitchell J, Kril JJ, Halliday GM, Hodges JR. Clinical significance of lobar atrophy in frontotemporal dementia: application of an MRI visual rating scale. Dement Geriatr Cogn Disord. 2007;23(5):334-342. 31. Davies RR, Scahill VL, Graham A, Williams GB, Graham KS, Hodges JR. Development of an MRI rating scale for multiple brain regions: comparison with volumetrics and with voxel-based morphometry. Neuroradiology. 2009;51(8): 491-503. 32. Dobson-Stone C, Hallupp M, Bartley L, et al. C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts. Neurology. 2012;79(10):995-1001. 33. Byrne S, Heverin M, Elamin M, et al. Aggregation of neurologic and neuropsychiatric disease in amyotrophic lateral sclerosis kindreds: a population-based case-control cohort study of familial and sporadic amyotrophic lateral sclerosis
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36. Lillo P, Garcin B, Hornberger M, Bak TH, Hodges JR. Neurobehavioral features in frontotemporal dementia with amyotrophic lateral sclerosis. Arch Neurol. 2010;67(7):826-830. 37. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942-955.
42. Hornberger M, Shelley BP, Kipps CM, Piguet O, Hodges JR. Can progressive and non-progressive behavioural variant frontotemporal dementia be distinguished at presentation? J Neurol Neurosurg Psychiatry. 2009;80(6):591-593.
38. Loy CT, Kril JJ, Trollor JN, et al. The case of a 48 year-old woman with bizarre and complex delusions. Nat Rev Neurol. 2010;6(3):175-179.
43. Hornberger M, Piguet O, Kipps C, Hodges JR. Executive function in progressive and nonprogressive behavioral variant frontotemporal dementia. Neurology. 2008;71(19):1481-1488.
39. Irish M, Devenney E, Wong S, et al. Neural substrates of episodic memory dysfunction in behavioural variant frontotemporal dementia with
44. Mioshi E, Hodges JR. Rate of change of functional abilities in frontotemporal dementia. Dement Geriatr Cogn Disord. 2009;28(5):419-426.
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Original Investigation
Frontotemporal Dementia Associated With the C9ORF72 Mutation A Unique Clinical Profile Emma Devenney, MRCP; Michael Hornberger, PhD; Muireann Irish, PhD; Eneida Mioshi, PhD; James Burrell, PhD; Rachel Tan, PhD; Matthew C. Kiernan, FRACP; John R. Hodges, FRCP
IMPORTANCE While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear. OBJECTIVES To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)–FTD cohort. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD–amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained. MAIN OUTCOMES AND MEASURES Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale. RESULTS In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD. CONCLUSIONS AND RELEVANCE The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.
JAMA Neurol. 2014;71(3):331-339. doi:10.1001/jamaneurol.2013.6002 Published online January 20, 2014.
Author Affiliations: Prince of Wales Clinical School, University of New South Wales, Sydney, Australia (Devenney); Neuroscience Research Australia, Sydney, Australia (Devenney, Hornberger, Irish, Mioshi, Burrell, Tan, Kiernan, Hodges); School of Medical Sciences, University of New South Wales, Sydney, Australia (Hornberger, Mioshi, Burrell, Tan, Hodges); School of Psychology, University of New South Wales, Sydney, Australia (Irish); Brain and Mind Research Institute, University of Sydney, Sydney, Australia (Kiernan). Corresponding Author: Emma Devenney, MRCP, Neuroscience Research Australia, Randwick, Sydney, New South Wales, 2031, Australia ([email protected]).
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Research Original Investigation
Frontotemporal Dementia and C9ORF72 Mutation
T
he C9ORF72 mutation accounts for approximately onethird of cases of familial frontotemporal dementia (FTD) and familial amyotrophic lateral sclerosis (ALS).1-7 Notably, it is also positive in a percentage (4%-21%) of patients with apparently sporadic disease.1,3-5,7-9 Given the relatively high rate of mutations in apparently sporadic cases, it is important to delineate the clinical profile of C9ORF72 carriers. Across the clinical spectrum of FTD, the predominant phenotype associated with the C9ORF72 mutation is behavioralvariant (bv) FTD, often occurring with features of ALS,2,4,7,10-13 although primary progressive aphasia has been reported to varying degrees.4,7 Additional features that characterize C9ORF72 carriers have been suggested by previous studies and include family history of ALS, parkinsonism, psychosis at presentation, a distinctive neuroanatomical signature with posterior and subcortical atrophy, and the typical frontal and temporal atrophy of FTD.2,4,7,10-14 However, these results have not always been consistent across studies, and with these inconsistencies come diagnostic challenges. As such, our study aimed to establish the frequency of the C9ORF72 mutation in a well-defined cohort of patients with FTD and to clarify the clinical, behavioral, neuropsychological, and imaging profile of patients with bvFTD who harbor this mutation by comparing mutation carriers with noncarriers. In contrast to previous studies, which often included historical data from numerous sources, our study has the advantage of prospectively collected comprehensive data during a 5-year period (2008-2012 inclusive) using standardized instruments. As such, this study seeks to provide a coherent description of the clinical phenotype of patients with bvFTD who have the C9ORF72 mutation.
score of 3.5, 1 relative with unspecified or late-onset dementia; and score of 4, no family history of FTD, ALS, or dementia. All patients completed a detailed family history questionnaire that asked about neurological and psychiatric illnesses in first-degree relatives. In a second phase, we compared demographic, clinical, behavioral, neuropsychological, and imaging data in C9ORF72 carriers with bvFTD, noncarriers, and a healthy control group selected from a volunteer panel at FRONTIER who were matched case by case for age, sex, and education history. The bvFTD comparison group comprised those who had previously tested negative for other available genetic mutations and subsequently tested negative for the C9ORF72 mutation. Global cognitive function at first presentation was measured using Addenbrooke’s Cognitive Examination–Revised.19 Disease staging was assessed with the FTD Functional Rating Scale.20
Genetic Analysis Blood sampling for genetic analysis was collected after informed consent was obtained. Genomic DNA was extracted from peripheral blood lymphocytes or frozen brain tissue according to standard procedures. Proband DNA was screened for the hexanucleotide repeat expansion in C9ORF72 by repeatprimed polymerase chain reaction based on the protocol of Renton et al.1 Samples were scored as expansion positive if they harbored more than 30 repeats. The C9ORF72 hexanucleotide repeat nonexpansion alleles were detected by polymerase chain reaction amplification and capillary electrophoresis.
Clinical and Behavioral Features
Methods Participants To establish the frequency of the C9ORF72 mutation, we adopted an inclusive approach and screened consecutive patients in whom a diagnosis of bvFTD was considered as well as those with a clinical diagnosis of bvFTD, semantic dementia (semantic-variant primary progressive aphasia), nonfluentvariant primary progressive aphasia, FTD-ALS, and corticobasal syndrome as per current diagnostic guidelines.15-17 Each patient was assessed at FRONTIER, the Frontotemporal Dementia Research Group, at Neuroscience Research Australia, between January 1, 2008, and December 31, 2012. Ethical approval for this study was obtained from the ethics committees of the South Eastern Sydney and Illawarra Area Health Service and the University of New South Wales. Participants, or their person responsible, provided written informed consent in accordance with the Declaration of Helsinki. Participants did not receive a stipend. A detailed family history was obtained and the Goldman Scale score was calculated.18 A score of 1 indicates at least 3 family members with FTD and/or ALS over 2 generations with 1 person being a first-degree relative of the other; score of 2, 3 or more family members with dementia and/or ALS but do not meet criteria for a score of 1; score of 3, at least 1 family member with confirmed FTD and/or ALS or early-onset dementia; 332
All patients were assessed by an experienced behavioral neurologist (J.R.H.). Core behavioral symptoms of FTD were systematically explored during the carer interview and recorded on a standardized inventory based on the Cambridge Behavioural Inventory21 as present or absent. Features on neurological examination of ALS, aphasia, parkinsonism, apraxia, ataxia, and eye movement abnormalities were documented. A longitudinal approach was favored for the analysis of the clinical data as it was crucial to establish whether these features developed as the disease progressed.
Neuropsychological Assessments The copy component of the Rey-Osterrieth Complex Figure Test22 and the Visual Object and Space Perception Battery assessed visuospatial abilities.23 The Rey Auditory Verbal Learning Test24 and the recall component of the Rey-Osterrieth Complex Figure Test22 assessed episodic memory. Tests of executive function included the Hayling Test,25 the FAS Verbal Fluency test,26and the Trail Making Test.27 Semantic and phonological processing was assessed using the Sydney Language Battery.28 The Test for Reception of Grammar, version 2,29 assessed syntactic comprehension.
Neuroimaging Patients underwent a 3T T1- and T2-weighted magnetic resonance imaging (MRI) scan. When the MRI findings were not typical for bvFTD, fludeoxyglucose F 18 positron emission to-
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Frontotemporal Dementia and C9ORF72 Mutation
Original Investigation Research
Figure 1. Frequency of C9ORF72 Mutation Positivity in a Frontotemporal Dementia Cohort 114 Patients included
14 Mutation positive
Phenotype
Family history
4/23 (17%) FTD-MND
10/29 (34%) bvFTD
3/10 (30%) GS score ≥3.5
7/10 (70%) GS score ≤3.0
1/4 (25%) GS score ≥3.5
0/20 PPA-nf
0/35 PPA-sv
0/7 CBS
3/4 (75%) GS score ≤3.0
The flowchart demonstrates the frequency of C9ORF72 mutation positivity in a frontotemporal dementia cohort. Patients with frontotemporal dementia are categorized according to subtype, and mutation-positive patients are further categorized by Goldman Scale (GS) score. Twenty-eight additional patients were screened but deemed not suitable for inclusion in the study, so they were
excluded. bvFTD indicates behavioral-variant frontotemporal dementia; CBS, corticobasal syndrome; FTD-MND, frontotemporal dementia with motor neuron disease; PPA-nf, nonfluent-variant primary progressive aphasia; and PPA-sv, semantic-variant primary progressive aphasia.
mography (FDG-PET) was performed. Previously validated MRI visual rating scales based on coronal T1 images were used for 5 areas: orbitofrontal cortex, anterior cingulate, temporal lobe, insula, and basal ganglia.30,31 This method was extended to include precuneus and cerebellar regions. Areas of atrophy were rated on a Likert scale by a rater (E.D.) blinded to the diagnosis after appropriate training on an independent data set. Interrater reliability was assessed using intraclass correlation coefficient and was found to be very high (Cronbach α = 0.9). The scale ranged from 0 (no atrophy) to 4 (severe atrophy) for all of the areas except the cerebellum, which was rated on a 4-point Likert scale.
patients with a Goldman Scale score of 3.0 or lower, 7 (54%) were mutation positive; of those with a Goldman Scale score of 3.5 or higher, 3 (19%) were mutation positive. Of 23 patients with FTD-ALS, 4 (17%) expressed the C9ORF72 mutation. Of these 23 patients, 6 (26%) had a Goldman Scale score of 3.0 or lower, while 17 (74%) had a Goldman Scale score of 3.5 or higher. Of patients with a Goldman Score of 3.0 or lower, 3 (50%) harbored the mutation; of those with a Goldman Scale score of 3.5 or higher, 1 (6%) was mutation positive. To put this another way and as illustrated in Figure 1, 70% of mutation carriers with bvFTD and 75% of mutation carriers with FTD-ALS had a Goldman Scale score of 3.0 or lower.
Statistical Analysis
Clinical and Behavioral Features
Data were analyzed using SPSS version 20.0 statistical software (SPSS Inc). Kolmogorov-Smirnov tests determined whether variables were normally distributed. Parametric variables were compared across the groups via independent t tests. Nonparametric data were analyzed using Mann-Whitney U tests, and categorical data were compared with χ2 tests. For MRI data, P < .01 was regarded as statistically significant, which allowed for multiple comparisons.
A comparison of the 10 C9ORF72 mutation carriers with bvFTD and 19 matched noncarriers revealed no significant difference between the groups across age at disease onset, disease duration at presentation, sex, education history, Addenbrooke’s Cognitive Examination–Revised score at onset, or disease severity on the FTD Functional Rating Scale score at onset (Table 1). The behavioral and imaging features of the C9ORF72 mutation carriers were compared against the International Consensus Diagnostic Criteria for bvFTD.15 In this comparison, 4 mutation carriers (40%) did not meet diagnostic criteria for possible bvFTD (Table 2). In 1 instance, this was due to lack of a sufficient number of core features; in the other cases, the presence of exclusion features was a factor, most notably strong indicators of psychiatric disease in 1 case, prominent episodic memory impairment and visuospatial deficits in 1 case, and the likelihood of autoimmune or prion disease in another. Of the cases in which imaging was possible (8 cases [80%]), it was striking that only 3 (38%) of these fulfilled criteria for probable bvFTD. This was due almost entirely to the absence of typical imaging changes on MRI or FDG-PET. Typically abnormal MRI findings with unequivocal frontal or temporal atrophy were found in only 1 patient with the C9ORF72
Results Frequency of C9ORF72 Mutations In total, 114 subjects were included in this study and screened for the C9ORF72 mutation. These included patients with FTD (n = 84), FTD-ALS (n = 23), and corticobasal syndrome (n = 7). The mutation was found in 14 patients (12%): 10 with bvFTD and 4 with FTD-ALS (Figure 1). In the overall bvFTD cohort of 29 patients, 10 cases (34%) were mutation positive. Of the 29 patients with bvFTD, 13 (45%) had a Goldman Scale score of 3.0 or lower (indicating a strong family history), while 16 (55%) had a Goldman Scale score of 3.5 or higher (indicating a weak or absent family history). Of jamaneurology.com
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Research Original Investigation
Frontotemporal Dementia and C9ORF72 Mutation
Table 1. Baseline Demographic Characteristics of Patients With Behavioral-Variant Frontotemporal Dementia, Comparing C9ORF72 Mutation Carriers, Noncarriers, and Controls Carriers (n = 10)
Characteristic Age at onset, mean (SD), y Duration of symptoms at presentation, mean (SD), y Education history, mean (SD), y
Noncarriers (n = 19)
Controls (n = 35)
54.1 (9.4)
57.2 (7.8)
4.7 (3.5)
2.6 (1.4)
NA NA
10.6 (1.6)
11.3 (3.2)
11.8 (2.3) Abbreviations: ACE-R, Addenbrooke’s Cognitive Examination–Revised; FTDFRS, Frontotemporal Dementia Functional Rating Scale; NA, not applicable.
Sex, No. Male
6
13
Female
4
6
17 18
ACE-R score, mean (SD)a
75.7 (8.4)
67.3 (22.1)
94.2 (3.1)
FTDFRS Rasch score, mean (SD)a
−0.8 (1.8)
−1.1 (1.5)
NA
a
P < .001 for carriers vs controls and for noncarriers vs controls.
Table 2. Characteristics of C9ORF72 Mutation Carriers Compared With the International Consensus Diagnostic Criteria for Behavioral-Variant Frontotemporal Dementia bvFTD Neurodegenerative, Appropriate Progression
Behavioral Features, No.
Exclusion Featuresb
Possible bvFTD
Functional Declinec
Typical MRI
Typical PET
Probable bvFTD
1
+
4/6
−
+
+
+
NA
+
2
+
4/6
−
+
+
−
+
+
3
+
6/6
−
+
+
−
+
+
4
+
3/6
−
+
+
−
−
−
5
+
5/5
−
+
+
NA
NA
NA
6
+
6/6
−
+
+
NA
NA
NA
7
−
4/4
+d
−
+
−
NA
−
8
−
2/6
−
−
−
−
−
−
9
+
5/6
+e
−
+
−
+
−
10
+
3/6
+d
−
+
−
−
−
Patient No.
Abbreviations: bvFTD, behavioral-variant frontotemporal dementia; MRI, magnetic resonance imaging; NA, not assessed; PET, positron emission tomography; +, present; −, absent. a
Most cases failed to meet criteria for probable bvFTD.
b
Exlusion criteria for bvFTD were according to the International Consensus Diagnostic Criteria. Criteria A and B must be answered negatively for any bvFTD diagnosis; criterion C can be positive for possible bvFTD but must be negative for probable bvFTD. The exclusion criteria were as follows: criterion A, pattern of deficit is better accounted for by other neurodegenerative disease or medical disorder; criterion B, behavioral disturbance is better accounted for by a psychiatric diagnosis; and criterion C, biomarkers are
mutation. Imaging with FDG-PET was undertaken in 6 patients who had normal findings on MRI, and it showed a pattern typical of bvFTD in 3 cases. Patients harboring the C9ORF72 mutation were more likely to have a family member with ALS than nonmutation carriers (6 vs 0, respectively; P = .001). Psychiatric illness in family members was also significantly more common in mutation carriers than in nonmutation carriers (4 vs 1, respectively; P = .02). Psychiatric illnesses comprised schizophrenia in 1 family member, significant depression in 2, and suicide in another. Psychotic symptoms were more common in patients with the mutation (n = 4) than in those without, a finding that remained consistent for delusions (P = .02) and hallucinations (P = .02). By contrast, apathy in the very early stage of disease was more common in C9ORF72 noncarriers (n = 9) compared with mutation carriers (n = 1) (P = .002). As the illness progressed, apathy in the mutation carriers increased; at pre334
Probablea
Possible
strongly indicative of Alzheimer disease or other neurodegenerative process. c
Impaired activities of daily living.
d
Patients met exclusion criterion A. In patient 7, autoimmune or prion disease was initially thought to be most likely owing to rapidity of onset and normal imaging findings. In patient 10, prominent memory and visuospatial dysfunction made Alzheimer disease the most likely diagnosis.
e
Patient met exclusion criterion B. Late-onset psychiatric illness was the primary consideration in this case because of severe delusions, hallucinations, and mood disorder.
sentation, there was no significant difference between the groups (P = .63). Disease progression in general was slow in 5 carriers; 1 patient exhibited symptoms for 10 years prior to presentation. The C9ORF72 mutation carriers had a higher likelihood of developing parkinsonism throughout their illness than noncarriers (P = .02). There were no significant differences in groups at presentation for the following features: aphasia (P = .48), parkinsonism (P = .67), apraxia (P = .65), or eye movement abnormalities (P > .99). Ataxia was not present in either C9ORF72 carriers or noncarriers at presentation. No C9ORF72 mutation–positive patients with pure bvFTD had developed ALS at follow-up.
Neuropsychological Assessments Performance on memory, executive, and language tests failed to discriminate between C9ORF72 mutation carriers and non-
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Frontotemporal Dementia and C9ORF72 Mutation
carriers, with both groups showing comparable performance. The C9ORF72 mutation carriers scored significantly more poorly than the noncarriers on the Rey-Osterrieth Complex Figure Test copy subscale (P = .03), but the Visual Object and Space Perception Battery did not discriminate between the groups.
Neuroimaging Patterns of Gray Matter Atrophy Two patients were unable to undergo MRI or FDG-PET. The visual rating scores revealed variability across the groups with significant differences in each of the 7 areas assessed (Figure 2). Compared with controls, there was a trend toward more significant atrophy of the precuneus in the C9ORF72 mutation carriers (P = .02). By contrast, the C9ORF72 noncarriers had more atrophy than controls in each of the 7 areas (all P < .01). Notably, the C9ORF72 carriers showed an absence of significant atrophy of the orbitofrontal cortex, anterior cingulate, insula, and temporal pole, regions all typically involved in bvFTD. A comparison of the 2 bvFTD groups confirmed no significant difference in the precuneus region between C9ORF72 carriers and noncarriers. Significant differences were found in the orbitofrontal cortex (P = .001), anterior temporal lobe (P = .001), insula (P = .001), and anterior cingulate (P < .001), with noncarriers showing greater atrophy across these regions. Illustrative examples of MRI scans from C9ORF72 carriers and noncarriers are shown in Figure 3. Patterns of Regional Hypometabolism Imaging with FDG-PET was performed in 6 mutation carriers and showed an unequivocal pattern of hypometabolism in the frontal and/or temporal regions, as seen in typical bvFTD, in 3 cases. In 1 of these typical cases, hypometabolism was also present in the parietal region. In contrast, 1 atypical case revealed abnormal perfusion globally, including the parietal region, thalamus, and cerebellum. The second atypical case showed mild hypometabolism in the temporal and parietal regions, while the findings in the third were equivocal.
Discussion This study has highlighted a constellation of characteristics that may be used to identify patients with bvFTD who have the C9ORF72 mutation. Initial indications include a high rate of psychosis in mutation carriers combined with an increased frequency of ALS in family members. The clinical course was frequently atypical with slow disease progression in one-half of patients and lack of brain atrophy on MRI in the majority, potentially leading to misdiagnosis. Our results also suggest that 2 novel clues to the presence of the mutation are lack of apathy early in the disease course and psychiatric illness in family members. A high frequency of the C9ORF72 mutation in patients with familial bvFTD and familial FTD-ALS was identified in this study and corroborated previous reports.1,2,4,32 By contrast, the frequency rate in apparent sporadic bvFTD was considerably higher than previously reported.7 This high frequency in apjamaneurology.com
Original Investigation Research
parently sporadic disease raises the question of whether genetic mutations in sporadic cases are due to expansion instability in patients without family history or simply represent low penetrance. On a practical level, the presence of the mutation in sporadic disease has significant implications for genetic counseling, highlighting the need to establish clear markers of carrier status. Most of our mutation carriers with bvFTD had a family history of ALS in a first-degree relative, often in conjunction with an increased frequency of psychiatric illness in family members, suggesting that the phenotype might extend beyond FTD and ALS to psychiatric disease. A recent study reported a high prevalence of mental health disorders in first-degree relatives of patients with ALS who harbored the C9ORF72 mutation.33 More recently, additional evidence for an expansion in genotype-phenotype correlation has emerged, with reports of the C9ORF72 mutation in other common diseases such as Alzheimer disease, Huntington disease–like syndromes, and forms of parkinsonism.34,35 The prominence of psychotic symptoms may not be unexpected given that earlier studies have linked this feature to FTD-ALS.36,37 Inthisstudy,delusionsweremorefrequentlypresent than hallucinations and were mainly persecutory, negative, and paranoid, often involving the health or relationships of the patient. In 1 case, previously reported in the literature, the patient with the C9ORF72 mutation exhibited bizarre and complex delusions and hallucinations similar to those described by other groups.38 This was an extreme case in our cohort; in most instances, the delusions and hallucinations were more prosaic. The high frequency of psychosis contrasts with a low frequency of apathy in mutation carriers. This dissociation has not been previously described in C9ORF72 mutation carriers. Hence, the neural substrates underlying this remain unexplored. Most C9ORF72 mutation carriers in this study lacked the typical imaging features associated with bvFTD. Comparison of C9ORF72 mutation carriers with controls showed a trend toward greater precuneus atrophy in the former group with other regions lacking significant atrophy. Other studies have highlighted differences in the degree of precuneus atrophy, in which precuneus atrophy accurately discriminated between C9ORF72 mutation and sporadic FTD.14,39 At a clinical level, an apparently normal MRI lacking overt frontal or temporal atrophy does not exclude a diagnosis of bvFTD related to the C9ORF72 mutation. A study of 2 mutation carriers has linked bvFTD phenocopy syndrome with the C9ORF72 mutation.40 The most reliable features that distinguish true bvFTD cases from phenocopy cases are frontal and/or temporal atrophy on imaging, deterioration in activities of daily living, poor performance on global cognitive tests, and impairment on executive tasks.20,30,41-44 Considering our cohort of C9ORF72 mutation carriers in this context, most had functional decline in activities of daily living, all scored below the cutoff level on Addenbrooke’s Cognitive Examination–Revised, and at a group level they were impaired on tests of executive function. In brief, while this cohort of C9ORF72 mutation carriers has imaging findings similar to those of phenocopy cases, it is evident that JAMA Neurology March 2014 Volume 71, Number 3
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Figure 2. Cortical Atrophy Ratings in C9ORF72 Mutation Carriers, Noncarriers, and Controls A Orbitofrontal cortex
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distinguishing features that differentiate them from the phenocopy syndrome are present. Taken together, our findings suggest that C9ORF72 mutation carriers represent a distinct group not typical of patients with bvFTD. This finding is exemplified by the failure of most 336
Box plots (whiskers indicate minimum and maximum scores) demonstrate atrophy ratings for C9ORF72 mutation carriers, noncarriers, and controls. A magnetic resonance imaging visual rating scale assessed 7 cortical regions: the orbitofrontal cortex (A), anterior cingulate (B), anterior temporal lobe (C), insula (D), basal ganglia (E), precuneus (F), and cerebellum (G). There was a statistical trend for more precuneus atrophy in the C9ORF72 mutation carriers compared with controls (P = .02). For all other regions, no statistical differences were found between C9ORF72 mutation carriers and controls. The horizontal lines represent the median (ie, 50% of the data are greater than this value). The top and bottom lines of the box represent the 75th and 25th percentiles, respectively. In some cases, the median is the same value as the 25th or 75th percentile and therefore is not shown.
to satisfy the International Consensus Diagnostic Criteria for bvFTD for probable, and in almost half of cases even possible, bvFTD. Given the complexity of accurate diagnosis in this cohort coupled with the high frequency of this mutation in sporadic disease, it seems paramount that the key characteristics
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Original Investigation Research
Figure 3. Variable Patterns of Cortical Atrophy in C9ORF72 Mutation Carriers and Noncarriers Slice 1
Slice 2
Slice 3
A
B
C
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Coronal T1-weighted images are shown at the orbitofrontal cortex (slice 1), the anterior temporal lobe (slice 2), and the precuneus and cerebellum (slice 3). These illustrative examples demonstrate the variability in cortical atrophy between C9ORF72 mutation carriers (A and B) and noncarriers (C and D).
of C9ORF72 mutation carriers identified in this study are used as a complement to current diagnostic criteria. Our study has clear limitations that temper the conclusions that can be drawn. Recruitment through specialist centers may introduce bias, future prospective studies would benefit from larger sample sizes, and replication of our findings in a population-based cohort would be desirable. Larger studies should include patients with other neurodegenerative and psychiatric disorders in addition to FTD. Consequently, the non-FTD phenotype of the C9ORF72 mutation may be uncovered. Collection of detailed jamaneurology.com
family history data with particular emphasis on psychiatric disease would be an interesting addition to future studies. The imaging findings clearly need to be replicated with quantification of the FDG-PET abnormalities.
Conclusions We have confirmed several characteristic features of C9ORF72 mutation carriers. We have also identified a number of novel JAMA Neurology March 2014 Volume 71, Number 3
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features in this group, including links with a family history of psychiatric illness and lack of apathy early in the disease course. These results have important clinical implications. First, this mutation is prevalent in sporadic FTD cases, raising challenging issues for physicians in the selection of patients for genetic testing. Second, a significant number of mutation carriers do not satisfy current diagnostic criteria for bvFTD, mainly
ARTICLE INFORMATION Accepted for Publication: November 27, 2013. Published Online: January 20, 2014. doi:10.1001/jamaneurol.2013.6002. Author Contributions: Dr Devenney had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: All authors. Acquisition of data: Burrell, Hodges. Analysis and interpretation of data: Devenney, Hornberger, Irish, Mioshi. Drafting of the manuscript: Devenney, Irish, Tan, Kiernan, Hodges. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Devenney. Study supervision: Kiernan, Hodges. Conflict of Interest Disclosures: Dr Hodges receives publishing royalties for Cognitive Assessment for Clinicians (Oxford University Press, 2007) and Frontotemporal Dementia Syndromes (Cambridge University Press, 2007). No other disclosures were reported. Funding/Support: Dr Devenney was supported by a grant from the Motor Neurone Disease Association. Drs Devenney, Tan, Kiernan, and Hodges were supported by grant 1037746 from the National Health and Medical Research Council of Australia. Dr Hornberger was supported by Research Fellowship DP110104202 from the Australian Research Council. Dr Irish was supported by Discovery Early Career Research Award DE130100463 from the Australian Research Council. Dr Mioshi was supported by Early Career Fellowship 1016399 from the National Health and Medical Research Council of Australia. Drs Mioshi, Burrell, and Tan were supported by the Motor Neurone Disease Research Institute of Australia. Dr Tan was supported by the Mick Rodger Benalla MND Research Grant. Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: John Kwok, PhD, and Carol Dobson Stone, Neuroscience Research Australia and School of Medical Sciences, University of New South Wales, Sydney, Australia, carried out the genetic analysis on blood samples from participants in this study. They did not receive compensation for their contributions. REFERENCES 1. Renton AE, Majounie E, Waite A, et al; ITALSGEN Consortium. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257-268.
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owing to lack of cortical atrophy on visual inspection. With this in mind, we propose that clinicians should consider this mutation in patients with bvFTD in the presence of the key markers identified in this study and, in particular, psychosis. Atypical MRI findings should raise suspicion of the C9ORF72 syndrome, and clinicians are advised to check for precuneus atrophy.
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