J Neurol DOI 10.1007/s00415-014-7474-9
ORIGINAL COMMUNICATION
Heritability in frontotemporal dementia: more missing pieces? Kieren Po • Felicity V. C. Leslie • Natalie Gracia • Lauren Bartley • John B. J. Kwok • Glenda M. Halliday John R. Hodges • James R. Burrell
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Received: 22 July 2014 / Revised: 13 August 2014 / Accepted: 14 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Frontotemporal dementia (FTD) is reportedly highly heritable, even though a recognized genetic cause is often absent. To explain this contradiction, we explored the ‘‘strength’’ of family history in FTD, Alzheimer’s disease (AD), and controls. Clinical syndromes associated with heritability of FTD and AD were also examined. FTD and AD patients were recruited from an FTD-specific research clinic, and patients were further sub-classified into FTD or AD phenotypes. The strength of family history was graded using the Goldman score (GS), and GS of 1–3 was regarded as a ‘‘strong’’ family history. A subset of FTD patients underwent screening for the main genetic causes of FTD. In total, 307 participants were included (122 FTD, 98 AD, and 87 controls). Although reported positive family history did not differ between groups, a strong family history was more common in FTD (FTD 17.2 %, AD 5.1 %, controls
2.3 %, P \ 0.001). The bvFTD and FTD-ALS groups drove heritability, but 12.2 % of atypical AD patients also had a strong family history. A pathogenic mutation was identified in 16 FTD patients (10 C9ORF72 repeat expansion, 5 GRN, 1 MAPT), but more than half of FTD patients with a strong family history had no mutation detected. FTD is a highly heritable disease, even more than AD, and patients with bvFTD and FTD-ALS drive this heritability. Atypical AD also appears to be more heritable than typical AD. These results suggest that further genetic influences await discovery in FTD. Keywords Frontotemporal dementia Alzheimer’s disease Genetics Progranulin Tau C9ORF72 repeat expansion Modified Goldman score
Introduction Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7474-9) contains supplementary material, which is available to authorized users. K. Po J. B. J. Kwok G. M. Halliday J. R. Hodges J. R. Burrell Concord Repatriation General Hospital, Sydney, Australia K. Po Sydney Medical School, University of Sydney, Sydney, Australia F. V. C. Leslie N. Gracia L. Bartley J. B. J. Kwok G. M. Halliday J. R. Hodges J. R. Burrell (&) Neuroscience Research Australia, Barker St., Randwick, Sydney, NSW 2031, Australia e-mail: [email protected] J. B. J. Kwok G. M. Halliday J. R. Hodges J. R. Burrell University of New South Wales, Sydney, Australia
With the application of genome-wide association studies to neurodegenerative diseases [1–3], a new era of discovery beckons, where polygenic-environment interactions are examined anew to explain the development of apparently sporadic diseases. An increased awareness of heritability in diseases such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD) may provide important clues to underlying pathological mechanisms and suggest potential therapeutic targets. Developing a deeper understanding of heritability in FTD and AD is, therefore, critical. The complex issue of heritability in neurodegenerative disease is well demonstrated in FTD. Studies often refer to FTD as highly heritable, with reports of a positive family history in as many as 60 % of cases [4–9], even though a genetic cause may be demonstrated in \20 % [10]. The reasons for this apparent disconnect are unclear, but may
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reflect differing concepts of ‘‘positive’’ family history. For example, a family history of amyotrophic lateral sclerosis (ALS) may not have been considered relevant previously, but is now recognized as an important clue to the possibility of the C9ORF72 repeat expansion [11, 12]. Whether a family history of AD, late-onset dementia, psychiatric illness, or other neurodegenerative disease suggests a genetic cause of FTD remains unknown. The apparent ‘‘strength’’ of the family history may also be important. For example, a family history of a single grandparent with late-onset dementia may carry less significance than a family history of multiple first-degree relatives with FTD. The Goldman score (GS) was developed to grade the ‘‘strength’’ of family history, and to distinguish autosomal dominant from less obvious patterns of inheritance [5]. The GS takes into account the number of affected relatives and the proximity of their relationship to the patient. When examined using the GS, the degree of heritability may differ across the range of FTD phenotypes. For example, one previous study demonstrated that behavioral variant frontotemporal dementia (bvFTD) and the non-fluent/agrammatic variant of primary progressive aphasia (nfv-PPA) appeared to be more heritable than the semantic variant of primary progressive aphasia (sv-PPA) [7]. Little is known about the heritability of atypical AD phenotypes, such as the logopenic variant of primary progressive aphasia (lv-PPA), posterior cortical atrophy, and corticobasal syndrome. Atypical AD phenotypes may develop symptoms at an earlier age than typical AD [13], which could suggest a genetic contribution to their development. The present study explored several hypotheses; firstly, that the degree of heritability of neurodegenerative disease, measured using the GS, is greater in FTD than in AD or control subjects. Secondly, that this degree of heritability differs according to the clinical phenotype of FTD. Thirdly, that the heritability of neurodegenerative diseases is greater in atypical AD than in typical AD.
Methods Participants Patients with a diagnosis of FTD or AD (typical and atypical phenotypes) were recruited from Frontier, an FTD research clinic based at Neuroscience Research Australia. The diagnosis of FTD or AD was made after detailed clinical and neuropsychological assessments, routine blood tests (e.g., vitamin B12 level, syphilis serology, thyroid function tests, autoimmune screen), and magnetic resonance imaging of the brain. A proportion of FTD and AD patients underwent Pittsburgh compound type B positron
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emission tomography (PiB-PET) to detect amyloid deposition, but patients were diagnosed according to clinical criteria, rather than according to the results of PiB-PET imaging. Patients were excluded if they had a psychiatric diagnosis, vascular dementia, chronic alcoholism, an alternate neurodegenerative disease, or where the diagnosis was uncertain. A database was used to recruit age- and gender-matched control subjects. All control subjects had no history of neurodegenerative disease, or other neurological disorders, and performed normally on neuropsychological assessment. Institutional ethics approval was obtained prior to assessment and all participants, or next of kin where necessary, provided written informed consent. Diagnosis and sub-classification of frontotemporal dementia Patients with FTD were further classified into the recognized clinical phenotypes, depending on the mode of presentation, clinical features, neuropsychological profile, and results of neuroimaging. Specifically, patients were diagnosed with behavioral variant FTD (bvFTD), if they presented with insidious onset of behavioral disturbance, characterized by loss of insight, decline in interpersonal skills and/or disinhibition [14]. The diagnosis of nfv-PPA was made in the presence of non-fluent speech with apraxia of speech and/or agrammatism [15]. Patients with sv-PPA were presented with fluent speech, anomia, impaired word and object knowledge, and surface dyslexia [15]. Patients were diagnosed with frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS) if typical features of ALS accompanied cognitive and behavioral disturbance typical of FTD [16]. Diagnosis and sub-classification of Alzheimer’s disease Patients with typical and atypical presentations of AD were included in the study. All patients diagnosed with typical AD met the NINCDS-ADRDA clinical criteria for diagnosis [17]. Patients with lv-PPA [15] and posterior cortical atrophy, both clinical phenotypes highly predictive of underlying AD pathology, as well as those with PiB-PET positive corticobasal syndrome, were included in the study as atypical AD patients. Patients with posterior cortical atrophy presented with impaired visual processing, which manifest as misidentifications, simultanagnosia (inability to appreciate all components of a complex visual scene), optic ataxia, and ocular apraxia. Patients with corticobasal syndrome presented with asymmetric motor dysfunction characterized by limb apraxia, parkinsonism, dystonia, alien limb phenomenon, and occasionally myoclonus [18]. Given that corticobasal syndrome is pathologically heterogeneous, only those patients with evidence of amyloid
J Neurol Table 1 Demographics of FTD, AD, and control participants FTD
AD
Control
P value
Number of patients
122
98
87
Age at assessment (years ± SD)
66.9 ± 8.8
67.7 ± 8.2
70.4 ± 7.4
\0.05a,b
Male gender (%)
73 (59.8 %)
50 (51 %)
39 (44.8 %)
NS
Years of education (mean ± SD)
11.7 ± 3.2
12.5 ± 3.5
13.1 ± 3.0
\0.05a
Symptoms duration (years ± SD)
6.2 ± 3
6 ± 2.4
N/A
NS
PiB imaging (%)
33 (27 %)
41 (41.8 %)
N/A
\0.05
PiB positive (%)
3 (9.1 %)
40 (97.6 %)
N/A
\0.001
Patients with FTD and AD were significantly younger than controls, and FTD patients had less formal education than the other groups. Groups were matched for gender and symptom duration. Almost all AD patients that underwent PiB imaging were PiB positive, compared to a minority of FTD patients a
FTD vs. control P \ 0.05
b
AD vs. control P \ 0.05
deposition on PiB-PET were included [19]. Corticobasal syndrome patients without evidence of amyloid deposition on PiB-PET imaging were excluded from the study.
performed. However, some patients were recruited before the discovery of the C9ORF72 repeat expansion; such patients were tested for GRN and/or MAPT mutations before being tested for the C9ORF72 repeat expansion.
Grading of family history Statistical analysis A family history of neurodegenerative disease was probed using patients, carers, and other family members as informants. Specifically, a family history of FTD, ALS, Parkinson’s disease, AD, or unspecified late-onset dementia was sought and recorded for each participant. The strength of family history was graded prospectively using standardized criteria—the modified GS—as described by Rohrer et al. [7]. A modified GS of 1 denotes an autosomal dominant inheritance pattern (at least three affected individuals across two generations with one affected firstdegree relative). A modified GS of 2 indicates a familial cluster of at least three affected relatives, without an autosomal dominant inheritance pattern. A single affected first-degree family member with dementia onset prior to 65 years of age is denoted by a modified GS of 3, whereas a single affected first-degree family member with dementia onset aged 65 years or older is denoted by a score of 3.5. Finally, a modified GS of 4 is reserved for an individual with no known, or unknown, family history of neurodegenerative disease. In the present study, a strong family history was defined as a GS of 1–3. Genetic screening for common genes causing FTD was performed in a subset of patients as described previously [20, 21]. Specifically, all patients with a strong family history of FTD or ALS underwent testing for the pathological C9ORF72 intronic repeat expansion. If the C9ORF72 repeat expansion was identified, no further testing was performed. If there was a high suspicion of an inherited cause of FTD, but the C9ORF72 repeat expansion was not identified, further testing for mutations of the GRN and MAPT genes was
Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS, IBM Corp, version 21.0). Group comparisons of continuous variables were analyzed using analysis of variance (ANOVA) when normally distributed or the Kruskal–Wallis test when nonnormally distributed. Pairwise comparisons were performed using the independent samples t test when continuous variables were normally distributed and the Mann– Whitney test when non-normally distributed. Categorical data were analyzed using the Chi square test. A P \ 0.05 was considered significant.
Results Patient demographics and clinical features In total, 307 patients were included in the study; 122 with FTD, 98 with AD and 87 control subjects (Table 1). The mean age differed between FTD (66.9 ± 8.8 years), AD (67.7 ± 8.2 years), and control groups (70.4 ± 7.4 years, P \ 0.05), and pairwise comparisons revealed that the FTD and AD groups were significantly younger than the control group. In addition, FTD (11.7 ± 3.2 years) patients had fewer years of formal education than the control group (P \ 0.05). Gender and symptom duration did not differ between groups. Altogether, 74 (33.6 %) FTD and AD patients underwent PiB-PET imaging. Of the AD patients, 41 (41.8 %) underwent PiB-PET imaging. Although
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J Neurol Table 2 Cognitive screening in FTD, AD, and control groups FTD
AD
Control
P value
Attention/orientation
15.1 ± 3.5
14.1 ± 3.8
17.8 ± 0.4
\0.001a,b,c
Memory
15.6 ± 7.3
13.9 ± 6.4
24.3 ± 1.7
\0.001a,b,c
Fluency
4.2 ± 3.4
6.3 ± 3.5
11.8 ± 1.6
\0.001a,b,c
Language
16.8 ± 6.3
19.3 ± 5.7
25 ± 1.1
\0.001a,b,c
Visuospatial
13.7 ± 2.6
11.5 ± 4.4
15.5 ± 0.9
\0.001a,b,c
ACE-R subscores
ACE-R total
65.3 ± 19.2
65 ± 18.8
94.4 ± 3.4
\0.001a,b
MMSE total
23.4 ± 5.7
22 ± 5.8
29.2 ± 0.8
\0.001a,b,c
Patients with FTD and AD were cognitively impaired compared to controls, but the pattern of deficits differed between the two disease groups. Patients with FTD demonstrated more impairment on verbal fluency and language ACE-R subtasks, whereas AD patients performed worse on the attention, memory, and visuospatial ACE-R subtasks. NB ACE-R = Addenbrooke’s Cognitive Examination-Revised. All data presented as mean ± SD a b c
FTD vs. control P \ 0.05 AD vs. control P \ 0.05 FTD vs. AD P \ 0.05
Table 3 Modified Goldman scores by primary diagnosis Goldman score
FTD
AD
Control
1
1 (0.8 %)
1 (1 %)
0 (0)
2
4 (3.3 %)
1 (1 %)
0 (0)
3
16 (13.1 %)
3 (3.1 %)
2 (2.3 %)
3.5
27 (22.1 %)
37 (37.8 %)
23 (27.3 %)
4
74 (60.7 %)
56 (57.1 %)
62 (70.5 %)
Any family history
48 (39.3 %)
42 (42.9 %)
25 (28.7 %)
Strong family history (GS \ or = 3)
21 (17.2 %)
5 (5.1 %)
2 (2.3 %)
P value
NS \0.001a,b
When considered as ‘‘present’’ or ‘‘absent’’, there was no significant difference in the rate of positive family history between the FTD, AD, and control groups. However, FTD patients had a significantly higher rate of ‘‘strong’’ family history compared to the other groups a
FTD vs. control P \ 0.05
b
FTD vs. AD P \ 0.05
diagnosed on clinical grounds, 40 (97.6 %) AD patients who underwent PiB-PET imaging were demonstrated to have evidence of amyloid binding, supporting the accuracy of the clinical diagnosis of AD. In comparison, only three (9.1 %) patients diagnosed clinically with FTD demonstrated increased amyloid binding (P \ 0.001). Demographic details of disease subgroups are presented in Supplementary Table 1.
Cognitive performance across the range of FTD (bvFTD, nfv-PPA, sv-PPA, FTD-ALS) and AD (typical, atypical) phenotypes is presented in Supplementary Table 2. In general, FTD patients performed poorly on the fluency subtask, but patients with sv-PPA also performed particularly poorly on the language subtask. Compared to typical AD patients, atypical AD patients demonstrated reduced ACE-R total (P \ 0.05), and performed worse on fluency, language, and visuospatial subtasks.
Cognitive profile of FTD, AD, and control groups Goldman score in FTD, AD, and controls The cognitive profile of FTD and AD patient groups is presented in Table 2. In short, both groups demonstrated cognitive impairment on the ACE-R, but the pattern of cognitive dysfunction differed. Specifically, FTD patients performed worse on the fluency and language subtasks (P \ 0.05), whereas AD patients performed worse on the attention, memory, and visuospatial subtasks (P \ 0.05).
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Overall, 48 (39.3 %) FTD patients had some family history of neurodegenerative disease, but this was not significantly different to AD patients, of which 42 (42.9 %) had a family history, or controls of which 25 (28.7 %) individuals had a family history (Table 3). Nonetheless, the proportion of patients with a strong family history (GS 1–3, see
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indicated by a GS of 1–3, compared to only 2 (2.3 %) controls (both P \ 0.001). There was no significant increase in the proportion of nfv-PPA and sv-PPA patients with a strong family history compared to controls. In addition, 5 (12.2 %) atypical AD patients had a strong family history (GS of 1–3), which was significantly (P \ 0.05) increased compared to controls. The proportion of typical AD patients with a strong family history was not significantly greater than controls. When the total AD cohort (both typical AD and atypical AD) was split into young- and late-onset groups, there was no difference in the mean GS, or in the proportion of AD patients with a strong family history. Genetic mutation screening in FTD
Fig. 1 Goldman score across disease groups and disease phenotypes. a The percentage of patients with a Goldman score of 1–3 was significantly increased in the FTD group compared to the Alzheimer’s disease and control groups. b The increased heritability of FTD was driven by the bvFTD and FTD-ALS groups, but the atypical AD also had an increased proportion of patients with and Goldman score of 1–3. FTD frontotemporal dementia, AD Alzheimer’s disease, bvFTD behavioral variant frontotemporal dementia, nfv-PPA Non-fluent variant of primary progressive aphasia, sv-PPA semantic variant of primary progressive aphasia
‘‘Methods’’) did differ between the groups (P \ 0.001). Specifically, 21 (17.2 %) FTD patients had a strong family history compared to only 2 (2.3 %) control subjects (P \ 0.001). Overall, five (5.1 %) AD patients had a GS of 1–3 was, but this proportion was not significantly different from the control group. Goldman score in FTD and AD subtypes The proportion of patients with a strong family history differed significantly (P \ 0.001) across the disease subtypes, driven by the bvFTD, FTD-ALS, and atypical AD groups (Fig. 1b). For example, 13 (34.2 %) bvFTD and 5 (21.7 %) FTD-ALS patients had a strong family history, as
Overall, 43 (35.2 %) of the FTD cohort underwent genetic testing for the C9ORF72 repeat expansion. If this mutation was detected no further genetic testing was planned, although in practice almost all C9ORF72 repeat expansionpositive cases had already been tested for GRN mutations. Specifically, of the ten FTD patients with the C9ORF72 repeat expansion, all but one patient was tested for GRN and none were found to carry this additional pathogenic mutation. Testing for MAPT and GRN was performed in C9ORF72-negative patients (36 patients or 29.5 % of the FTD cohort). In total, 16 FTD patients were found to carry pathogenic mutation; 10 (8.2 %) carried a C9ORF72 repeat expansion, 5 (4.1 %) carried GRN mutations, and 1 (0.8 %) patient carried a MAPT mutation. All the C9ORF72 cases presented with either bvFTD or FTD-ALS. Four of six bvFTD cases with the C9ORF72 repeat expansion had a strong family history, whereas two of four FTD-ALS cases carrying the C9ORF72 repeat expansion had a strong family history. The GRN mutation was associated with bvFTD (four cases, all but one had a strong family history) and nfv-PPA (one case). The single MAPT case presented with bvFTD. All FTD patients with a strong family history (GS of 1–3) underwent genetic testing. Of these patients, less than half (10 patients or 47.6 %) had a detectable pathogenic mutation. The C9ORF72 repeat expansion was detected in 6 (28.6 %) patients, while 3 (14.3 %) had a mutation of GRN and 1 (4.8 %) a mutation of MAPT. All patients without a detectable pathogenic mutation underwent testing for C9ORF72, GRN, and MAPT. A pathogenic mutation was infrequent in patients without a strong family history. Overall, 22 (21.8 %) patients with a GS of 3.5 or 4 underwent genetic testing and only six were found to carry a pathogenic mutation. Specifically, 4 (4 %) patients were found to carry the C9ORF72 repeat expansion and 2 (2 %) were found to carry the GRN mutation.
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Discussion The present study has demonstrated that FTD is a highly heritable disease, even more so than AD, and that patients with bvFTD and FTD-ALS drive this apparent heritability. Furthermore, more than half of FTD patients with a strong family history were negative for the main genetic causes of FTD. Separately, patients with atypical AD also demonstrated an increased rate of heritability compared to typical AD patients and controls. Overall, the results of the present study suggest that as yet unknown genetic factors may underlie the increased heritability of FTD, and that genetic factors may also be relevant in the development of atypical AD phenotypes. Previous studies have often declared a high degree of heritability in FTD, but the definition of a ‘‘positive’’ family history has not always been reported consistently, and only a few studies have examined the apparent strength of family history. A major advantage of the present study was the use of the GS to prospectively grade the strength of family history. When considered dichotomously, there was no apparent difference in the proportion of patients with a family history in patients with FTD and AD compared to controls. In contrast, the proportion of FTD patients with a strong family history (defined here as a GS of 1–3) was increased compared to AD and controls, confirming a high degree of heritability in the disease. Only a couple of previous studies have investigated the heritability of FTD by systematically applying the GS [7, 22]. In the study by Rohrer et al. [7], 20.6 % of 225 FTD spectrum patients had a GS of 1–3, and a later study by the same group revealed a GS of 1–3 in 25.3 % of FTD spectrum cases [22], similar to the results of the present study (17.2 %). Nonetheless, the degree of heritability was almost entirely driven by the bvFTD group in the previous study (48 % had a GS of 1–3) [7], whereas both the bvFTD (34.2 %) and FTD-ALS (21.7 %) groups demonstrated an increased degree of heritability in the present study. The reasons for this apparent discord are uncertain, but may reflect the referral pattern of our clinic, which has a close relationship to a well-established ALS clinic. In fact, only ten FTD-ALS patients were included in the initial study by Rohrer et al., whereas the present study included 23 FTDALS patients. The GS is the best-established and cited grading system of family history in FTD, although another system has been proposed recently [23]. In this alternative grading system, developed by Wood et al. [23], family history was graded as ‘‘High’’, ‘‘Medium’’, ‘‘Low’’, ‘‘Apparent sporadic’’ or ‘‘Unknown significance’’, according to the number of firstand second-degree relatives affected by FTD, ALS, Parkinson’s disease or dementia not otherwise specified. Almost two-thirds (64.1 %) of patients with a ‘‘High’’
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degree of heritability were found to carry pathogenic mutations, and 72.3 % of mutation carriers were classified as having either ‘‘High’’ or ‘‘Medium’’ heritability. The authors argue that, unlike the GS, their classification system was designed for clinical use [23]. By comparison, almost half (47.6 %) of FTD patients with a strong family history in the present study had a detectable pathogenic mutation, whereas 62.5 % of mutation carriers had a strong family history according to the GS, suggesting that the GS is useful clinically. Interestingly, despite the increased heritability of FTD in the present study, more than half of patients with a strong family history tested negative for all three of the most frequent FTD mutations (i.e., C9ORF72 repeat expansion, GRN, and MAPT). Similarly, approximately 40 % of patients with ‘‘High’’ heritability in the study by Wood et al. were negative for these three mutations. Screening for the Fused In Sarcoma (FUS), ChromatinModifying Protein 2b (CHMP2B), TAR DNA-Binding Protein (TARDBP), and Sequestosome 1 (SQSTM1) [24, 25] was not performed in the present study, but these mutations are rare causes of FTD [26], and unrecognized mutations of these genes are unlikely to explain the majority of cases in which a more common mutation was not identified. This finding is similar to other large published cohorts [26] and suggests that as yet undetermined genetic factors underlie some of the heritability of FTD observed in the present cohort. Consistent with previous reports, the C9ORF72 repeat expansion was the most common genetic cause of FTD in the present study, followed by GRN. Overall, 8.2 % of FTD patients carried the C9ORF72 repeat expansion, with the rate of detection increasing to 28.6 % in patients with a strong family history. It is also possible that some of our apparently sporadic FTD cases carry the C9ORF72 repeat expansion. As has been reported previously, patients with the C9ORF72 repeat expansion presented with either bvFTD or FTD-ALS [27–29]. Five (4.1 %) of the total FTD cohort had a documented GRN mutation, which is similar to previous reported frequencies of 4.8–10.7 % [7, 30–32]. Similarly, 5.6 % of FTD patients in the present study had a documented MAPT mutation, which is in line with previous reports of 8.0–8.9 % [7, 32]. Very little is currently known about the heritability of atypical AD syndromes. One factor that has been postulated to influence the development of an atypical AD phenotype is the presence or absence of the APOE e4 allele [33]. In addition, rare cases of atypical AD have been described in patients who carry the APP or PSEN 1 mutation [34–36]. In the present study, 12.2 % of atypical AD patients had a strong family history, suggesting that genetic factors may underlie phenotypic variability in the disease.
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The present study has several limitations. Firstly, the diagnosis of FTD and AD was made on clinical, rather than pathological grounds. Reassuringly, in those patients who underwent PiB-PET imaging, the vast majority classified as AD had positive scans, and most FTD patients had negative scans. Three FTD patients had positive PiB-PET scans suggesting either overlapping clinical features or possibly dual pathology. A further limitation was that genetic testing was not performed uniformly across the disease groups. Once the C9ORF72 repeat expansion was identified further testing was not planned, although in practice GRN had already been tested in the majority of C9ORF72 positive cases. As such, the frequency and clinical significance of oligogenic inheritance of FTD (i.e., presence of more than one pathogenic mutation) [37], cannot be fully addressed by our study. On the other hand, a strength of our study is that all FTD patients with a strong family history underwent genetic testing, and patients without a pathogenic mutation were tested for all three common genetic causes. One potential limitation of the GS is that a family history of psychiatric disease is not specifically included. Psychiatric symptoms are common in C9ORF72 repeat expansion-positive cases [21], but GS was developed before the C9ORF72 repeat expansion was discovered; therefore, the significance of a family history of psychiatric disease may not have been fully appreciated. Such family history should be sought when assessing FTD patients. Since AD patients in the present series did not routinely undergo testing for pathogenic mutations, the factors underlying the apparent heritability of atypical AD, specifically APOE e4 status, cannot be examined in any detail. Furthermore, the AD patients included in our study were recruited as disease controls for an FTD research program. Therefore, our results in AD patients may not be representative of AD patients more broadly. Nonetheless, the results suggest that further genetic causes of FTD await discovery, and that atypical expression of AD pathology could be influenced by genetic factors. Acknowledgments This work was supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council of Australia (NHMRC) program Grant (#1037746) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021). We are grateful to the research participants involved with the ForeFront research studies. In addition, JRB is supported by a NHMRC Early Career Fellowship (#1072451) and GMH by a NHMRC Senior Principal Research Fellow (#630434). Genomic DNA was extracted from blood samples by Genetic Repositories Australia, an Enabling Facility supported by NHMRC project Grant #401184, and by Mia McMillan in Professor Halliday’s laboratory. Genetic testing was funded by NHMRC project Grant #510218. We are grateful to Carol Dobson-Stone, Yue Huang and Mia McMillan for assistance with screening for repeat expansions in the C9ORF72 gene.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standard Institutional ethics approval was obtained prior to assessment and all participants, or next of kin where necessary, provided written informed consent.
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ORIGINAL COMMUNICATION
Heritability in frontotemporal dementia: more missing pieces? Kieren Po • Felicity V. C. Leslie • Natalie Gracia • Lauren Bartley • John B. J. Kwok • Glenda M. Halliday John R. Hodges • James R. Burrell
•
Received: 22 July 2014 / Revised: 13 August 2014 / Accepted: 14 August 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Frontotemporal dementia (FTD) is reportedly highly heritable, even though a recognized genetic cause is often absent. To explain this contradiction, we explored the ‘‘strength’’ of family history in FTD, Alzheimer’s disease (AD), and controls. Clinical syndromes associated with heritability of FTD and AD were also examined. FTD and AD patients were recruited from an FTD-specific research clinic, and patients were further sub-classified into FTD or AD phenotypes. The strength of family history was graded using the Goldman score (GS), and GS of 1–3 was regarded as a ‘‘strong’’ family history. A subset of FTD patients underwent screening for the main genetic causes of FTD. In total, 307 participants were included (122 FTD, 98 AD, and 87 controls). Although reported positive family history did not differ between groups, a strong family history was more common in FTD (FTD 17.2 %, AD 5.1 %, controls
2.3 %, P \ 0.001). The bvFTD and FTD-ALS groups drove heritability, but 12.2 % of atypical AD patients also had a strong family history. A pathogenic mutation was identified in 16 FTD patients (10 C9ORF72 repeat expansion, 5 GRN, 1 MAPT), but more than half of FTD patients with a strong family history had no mutation detected. FTD is a highly heritable disease, even more than AD, and patients with bvFTD and FTD-ALS drive this heritability. Atypical AD also appears to be more heritable than typical AD. These results suggest that further genetic influences await discovery in FTD. Keywords Frontotemporal dementia Alzheimer’s disease Genetics Progranulin Tau C9ORF72 repeat expansion Modified Goldman score
Introduction Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7474-9) contains supplementary material, which is available to authorized users. K. Po J. B. J. Kwok G. M. Halliday J. R. Hodges J. R. Burrell Concord Repatriation General Hospital, Sydney, Australia K. Po Sydney Medical School, University of Sydney, Sydney, Australia F. V. C. Leslie N. Gracia L. Bartley J. B. J. Kwok G. M. Halliday J. R. Hodges J. R. Burrell (&) Neuroscience Research Australia, Barker St., Randwick, Sydney, NSW 2031, Australia e-mail: [email protected] J. B. J. Kwok G. M. Halliday J. R. Hodges J. R. Burrell University of New South Wales, Sydney, Australia
With the application of genome-wide association studies to neurodegenerative diseases [1–3], a new era of discovery beckons, where polygenic-environment interactions are examined anew to explain the development of apparently sporadic diseases. An increased awareness of heritability in diseases such as frontotemporal dementia (FTD) and Alzheimer’s disease (AD) may provide important clues to underlying pathological mechanisms and suggest potential therapeutic targets. Developing a deeper understanding of heritability in FTD and AD is, therefore, critical. The complex issue of heritability in neurodegenerative disease is well demonstrated in FTD. Studies often refer to FTD as highly heritable, with reports of a positive family history in as many as 60 % of cases [4–9], even though a genetic cause may be demonstrated in \20 % [10]. The reasons for this apparent disconnect are unclear, but may
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reflect differing concepts of ‘‘positive’’ family history. For example, a family history of amyotrophic lateral sclerosis (ALS) may not have been considered relevant previously, but is now recognized as an important clue to the possibility of the C9ORF72 repeat expansion [11, 12]. Whether a family history of AD, late-onset dementia, psychiatric illness, or other neurodegenerative disease suggests a genetic cause of FTD remains unknown. The apparent ‘‘strength’’ of the family history may also be important. For example, a family history of a single grandparent with late-onset dementia may carry less significance than a family history of multiple first-degree relatives with FTD. The Goldman score (GS) was developed to grade the ‘‘strength’’ of family history, and to distinguish autosomal dominant from less obvious patterns of inheritance [5]. The GS takes into account the number of affected relatives and the proximity of their relationship to the patient. When examined using the GS, the degree of heritability may differ across the range of FTD phenotypes. For example, one previous study demonstrated that behavioral variant frontotemporal dementia (bvFTD) and the non-fluent/agrammatic variant of primary progressive aphasia (nfv-PPA) appeared to be more heritable than the semantic variant of primary progressive aphasia (sv-PPA) [7]. Little is known about the heritability of atypical AD phenotypes, such as the logopenic variant of primary progressive aphasia (lv-PPA), posterior cortical atrophy, and corticobasal syndrome. Atypical AD phenotypes may develop symptoms at an earlier age than typical AD [13], which could suggest a genetic contribution to their development. The present study explored several hypotheses; firstly, that the degree of heritability of neurodegenerative disease, measured using the GS, is greater in FTD than in AD or control subjects. Secondly, that this degree of heritability differs according to the clinical phenotype of FTD. Thirdly, that the heritability of neurodegenerative diseases is greater in atypical AD than in typical AD.
Methods Participants Patients with a diagnosis of FTD or AD (typical and atypical phenotypes) were recruited from Frontier, an FTD research clinic based at Neuroscience Research Australia. The diagnosis of FTD or AD was made after detailed clinical and neuropsychological assessments, routine blood tests (e.g., vitamin B12 level, syphilis serology, thyroid function tests, autoimmune screen), and magnetic resonance imaging of the brain. A proportion of FTD and AD patients underwent Pittsburgh compound type B positron
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emission tomography (PiB-PET) to detect amyloid deposition, but patients were diagnosed according to clinical criteria, rather than according to the results of PiB-PET imaging. Patients were excluded if they had a psychiatric diagnosis, vascular dementia, chronic alcoholism, an alternate neurodegenerative disease, or where the diagnosis was uncertain. A database was used to recruit age- and gender-matched control subjects. All control subjects had no history of neurodegenerative disease, or other neurological disorders, and performed normally on neuropsychological assessment. Institutional ethics approval was obtained prior to assessment and all participants, or next of kin where necessary, provided written informed consent. Diagnosis and sub-classification of frontotemporal dementia Patients with FTD were further classified into the recognized clinical phenotypes, depending on the mode of presentation, clinical features, neuropsychological profile, and results of neuroimaging. Specifically, patients were diagnosed with behavioral variant FTD (bvFTD), if they presented with insidious onset of behavioral disturbance, characterized by loss of insight, decline in interpersonal skills and/or disinhibition [14]. The diagnosis of nfv-PPA was made in the presence of non-fluent speech with apraxia of speech and/or agrammatism [15]. Patients with sv-PPA were presented with fluent speech, anomia, impaired word and object knowledge, and surface dyslexia [15]. Patients were diagnosed with frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS) if typical features of ALS accompanied cognitive and behavioral disturbance typical of FTD [16]. Diagnosis and sub-classification of Alzheimer’s disease Patients with typical and atypical presentations of AD were included in the study. All patients diagnosed with typical AD met the NINCDS-ADRDA clinical criteria for diagnosis [17]. Patients with lv-PPA [15] and posterior cortical atrophy, both clinical phenotypes highly predictive of underlying AD pathology, as well as those with PiB-PET positive corticobasal syndrome, were included in the study as atypical AD patients. Patients with posterior cortical atrophy presented with impaired visual processing, which manifest as misidentifications, simultanagnosia (inability to appreciate all components of a complex visual scene), optic ataxia, and ocular apraxia. Patients with corticobasal syndrome presented with asymmetric motor dysfunction characterized by limb apraxia, parkinsonism, dystonia, alien limb phenomenon, and occasionally myoclonus [18]. Given that corticobasal syndrome is pathologically heterogeneous, only those patients with evidence of amyloid
J Neurol Table 1 Demographics of FTD, AD, and control participants FTD
AD
Control
P value
Number of patients
122
98
87
Age at assessment (years ± SD)
66.9 ± 8.8
67.7 ± 8.2
70.4 ± 7.4
\0.05a,b
Male gender (%)
73 (59.8 %)
50 (51 %)
39 (44.8 %)
NS
Years of education (mean ± SD)
11.7 ± 3.2
12.5 ± 3.5
13.1 ± 3.0
\0.05a
Symptoms duration (years ± SD)
6.2 ± 3
6 ± 2.4
N/A
NS
PiB imaging (%)
33 (27 %)
41 (41.8 %)
N/A
\0.05
PiB positive (%)
3 (9.1 %)
40 (97.6 %)
N/A
\0.001
Patients with FTD and AD were significantly younger than controls, and FTD patients had less formal education than the other groups. Groups were matched for gender and symptom duration. Almost all AD patients that underwent PiB imaging were PiB positive, compared to a minority of FTD patients a
FTD vs. control P \ 0.05
b
AD vs. control P \ 0.05
deposition on PiB-PET were included [19]. Corticobasal syndrome patients without evidence of amyloid deposition on PiB-PET imaging were excluded from the study.
performed. However, some patients were recruited before the discovery of the C9ORF72 repeat expansion; such patients were tested for GRN and/or MAPT mutations before being tested for the C9ORF72 repeat expansion.
Grading of family history Statistical analysis A family history of neurodegenerative disease was probed using patients, carers, and other family members as informants. Specifically, a family history of FTD, ALS, Parkinson’s disease, AD, or unspecified late-onset dementia was sought and recorded for each participant. The strength of family history was graded prospectively using standardized criteria—the modified GS—as described by Rohrer et al. [7]. A modified GS of 1 denotes an autosomal dominant inheritance pattern (at least three affected individuals across two generations with one affected firstdegree relative). A modified GS of 2 indicates a familial cluster of at least three affected relatives, without an autosomal dominant inheritance pattern. A single affected first-degree family member with dementia onset prior to 65 years of age is denoted by a modified GS of 3, whereas a single affected first-degree family member with dementia onset aged 65 years or older is denoted by a score of 3.5. Finally, a modified GS of 4 is reserved for an individual with no known, or unknown, family history of neurodegenerative disease. In the present study, a strong family history was defined as a GS of 1–3. Genetic screening for common genes causing FTD was performed in a subset of patients as described previously [20, 21]. Specifically, all patients with a strong family history of FTD or ALS underwent testing for the pathological C9ORF72 intronic repeat expansion. If the C9ORF72 repeat expansion was identified, no further testing was performed. If there was a high suspicion of an inherited cause of FTD, but the C9ORF72 repeat expansion was not identified, further testing for mutations of the GRN and MAPT genes was
Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS, IBM Corp, version 21.0). Group comparisons of continuous variables were analyzed using analysis of variance (ANOVA) when normally distributed or the Kruskal–Wallis test when nonnormally distributed. Pairwise comparisons were performed using the independent samples t test when continuous variables were normally distributed and the Mann– Whitney test when non-normally distributed. Categorical data were analyzed using the Chi square test. A P \ 0.05 was considered significant.
Results Patient demographics and clinical features In total, 307 patients were included in the study; 122 with FTD, 98 with AD and 87 control subjects (Table 1). The mean age differed between FTD (66.9 ± 8.8 years), AD (67.7 ± 8.2 years), and control groups (70.4 ± 7.4 years, P \ 0.05), and pairwise comparisons revealed that the FTD and AD groups were significantly younger than the control group. In addition, FTD (11.7 ± 3.2 years) patients had fewer years of formal education than the control group (P \ 0.05). Gender and symptom duration did not differ between groups. Altogether, 74 (33.6 %) FTD and AD patients underwent PiB-PET imaging. Of the AD patients, 41 (41.8 %) underwent PiB-PET imaging. Although
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J Neurol Table 2 Cognitive screening in FTD, AD, and control groups FTD
AD
Control
P value
Attention/orientation
15.1 ± 3.5
14.1 ± 3.8
17.8 ± 0.4
\0.001a,b,c
Memory
15.6 ± 7.3
13.9 ± 6.4
24.3 ± 1.7
\0.001a,b,c
Fluency
4.2 ± 3.4
6.3 ± 3.5
11.8 ± 1.6
\0.001a,b,c
Language
16.8 ± 6.3
19.3 ± 5.7
25 ± 1.1
\0.001a,b,c
Visuospatial
13.7 ± 2.6
11.5 ± 4.4
15.5 ± 0.9
\0.001a,b,c
ACE-R subscores
ACE-R total
65.3 ± 19.2
65 ± 18.8
94.4 ± 3.4
\0.001a,b
MMSE total
23.4 ± 5.7
22 ± 5.8
29.2 ± 0.8
\0.001a,b,c
Patients with FTD and AD were cognitively impaired compared to controls, but the pattern of deficits differed between the two disease groups. Patients with FTD demonstrated more impairment on verbal fluency and language ACE-R subtasks, whereas AD patients performed worse on the attention, memory, and visuospatial ACE-R subtasks. NB ACE-R = Addenbrooke’s Cognitive Examination-Revised. All data presented as mean ± SD a b c
FTD vs. control P \ 0.05 AD vs. control P \ 0.05 FTD vs. AD P \ 0.05
Table 3 Modified Goldman scores by primary diagnosis Goldman score
FTD
AD
Control
1
1 (0.8 %)
1 (1 %)
0 (0)
2
4 (3.3 %)
1 (1 %)
0 (0)
3
16 (13.1 %)
3 (3.1 %)
2 (2.3 %)
3.5
27 (22.1 %)
37 (37.8 %)
23 (27.3 %)
4
74 (60.7 %)
56 (57.1 %)
62 (70.5 %)
Any family history
48 (39.3 %)
42 (42.9 %)
25 (28.7 %)
Strong family history (GS \ or = 3)
21 (17.2 %)
5 (5.1 %)
2 (2.3 %)
P value
NS \0.001a,b
When considered as ‘‘present’’ or ‘‘absent’’, there was no significant difference in the rate of positive family history between the FTD, AD, and control groups. However, FTD patients had a significantly higher rate of ‘‘strong’’ family history compared to the other groups a
FTD vs. control P \ 0.05
b
FTD vs. AD P \ 0.05
diagnosed on clinical grounds, 40 (97.6 %) AD patients who underwent PiB-PET imaging were demonstrated to have evidence of amyloid binding, supporting the accuracy of the clinical diagnosis of AD. In comparison, only three (9.1 %) patients diagnosed clinically with FTD demonstrated increased amyloid binding (P \ 0.001). Demographic details of disease subgroups are presented in Supplementary Table 1.
Cognitive performance across the range of FTD (bvFTD, nfv-PPA, sv-PPA, FTD-ALS) and AD (typical, atypical) phenotypes is presented in Supplementary Table 2. In general, FTD patients performed poorly on the fluency subtask, but patients with sv-PPA also performed particularly poorly on the language subtask. Compared to typical AD patients, atypical AD patients demonstrated reduced ACE-R total (P \ 0.05), and performed worse on fluency, language, and visuospatial subtasks.
Cognitive profile of FTD, AD, and control groups Goldman score in FTD, AD, and controls The cognitive profile of FTD and AD patient groups is presented in Table 2. In short, both groups demonstrated cognitive impairment on the ACE-R, but the pattern of cognitive dysfunction differed. Specifically, FTD patients performed worse on the fluency and language subtasks (P \ 0.05), whereas AD patients performed worse on the attention, memory, and visuospatial subtasks (P \ 0.05).
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Overall, 48 (39.3 %) FTD patients had some family history of neurodegenerative disease, but this was not significantly different to AD patients, of which 42 (42.9 %) had a family history, or controls of which 25 (28.7 %) individuals had a family history (Table 3). Nonetheless, the proportion of patients with a strong family history (GS 1–3, see
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indicated by a GS of 1–3, compared to only 2 (2.3 %) controls (both P \ 0.001). There was no significant increase in the proportion of nfv-PPA and sv-PPA patients with a strong family history compared to controls. In addition, 5 (12.2 %) atypical AD patients had a strong family history (GS of 1–3), which was significantly (P \ 0.05) increased compared to controls. The proportion of typical AD patients with a strong family history was not significantly greater than controls. When the total AD cohort (both typical AD and atypical AD) was split into young- and late-onset groups, there was no difference in the mean GS, or in the proportion of AD patients with a strong family history. Genetic mutation screening in FTD
Fig. 1 Goldman score across disease groups and disease phenotypes. a The percentage of patients with a Goldman score of 1–3 was significantly increased in the FTD group compared to the Alzheimer’s disease and control groups. b The increased heritability of FTD was driven by the bvFTD and FTD-ALS groups, but the atypical AD also had an increased proportion of patients with and Goldman score of 1–3. FTD frontotemporal dementia, AD Alzheimer’s disease, bvFTD behavioral variant frontotemporal dementia, nfv-PPA Non-fluent variant of primary progressive aphasia, sv-PPA semantic variant of primary progressive aphasia
‘‘Methods’’) did differ between the groups (P \ 0.001). Specifically, 21 (17.2 %) FTD patients had a strong family history compared to only 2 (2.3 %) control subjects (P \ 0.001). Overall, five (5.1 %) AD patients had a GS of 1–3 was, but this proportion was not significantly different from the control group. Goldman score in FTD and AD subtypes The proportion of patients with a strong family history differed significantly (P \ 0.001) across the disease subtypes, driven by the bvFTD, FTD-ALS, and atypical AD groups (Fig. 1b). For example, 13 (34.2 %) bvFTD and 5 (21.7 %) FTD-ALS patients had a strong family history, as
Overall, 43 (35.2 %) of the FTD cohort underwent genetic testing for the C9ORF72 repeat expansion. If this mutation was detected no further genetic testing was planned, although in practice almost all C9ORF72 repeat expansionpositive cases had already been tested for GRN mutations. Specifically, of the ten FTD patients with the C9ORF72 repeat expansion, all but one patient was tested for GRN and none were found to carry this additional pathogenic mutation. Testing for MAPT and GRN was performed in C9ORF72-negative patients (36 patients or 29.5 % of the FTD cohort). In total, 16 FTD patients were found to carry pathogenic mutation; 10 (8.2 %) carried a C9ORF72 repeat expansion, 5 (4.1 %) carried GRN mutations, and 1 (0.8 %) patient carried a MAPT mutation. All the C9ORF72 cases presented with either bvFTD or FTD-ALS. Four of six bvFTD cases with the C9ORF72 repeat expansion had a strong family history, whereas two of four FTD-ALS cases carrying the C9ORF72 repeat expansion had a strong family history. The GRN mutation was associated with bvFTD (four cases, all but one had a strong family history) and nfv-PPA (one case). The single MAPT case presented with bvFTD. All FTD patients with a strong family history (GS of 1–3) underwent genetic testing. Of these patients, less than half (10 patients or 47.6 %) had a detectable pathogenic mutation. The C9ORF72 repeat expansion was detected in 6 (28.6 %) patients, while 3 (14.3 %) had a mutation of GRN and 1 (4.8 %) a mutation of MAPT. All patients without a detectable pathogenic mutation underwent testing for C9ORF72, GRN, and MAPT. A pathogenic mutation was infrequent in patients without a strong family history. Overall, 22 (21.8 %) patients with a GS of 3.5 or 4 underwent genetic testing and only six were found to carry a pathogenic mutation. Specifically, 4 (4 %) patients were found to carry the C9ORF72 repeat expansion and 2 (2 %) were found to carry the GRN mutation.
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Discussion The present study has demonstrated that FTD is a highly heritable disease, even more so than AD, and that patients with bvFTD and FTD-ALS drive this apparent heritability. Furthermore, more than half of FTD patients with a strong family history were negative for the main genetic causes of FTD. Separately, patients with atypical AD also demonstrated an increased rate of heritability compared to typical AD patients and controls. Overall, the results of the present study suggest that as yet unknown genetic factors may underlie the increased heritability of FTD, and that genetic factors may also be relevant in the development of atypical AD phenotypes. Previous studies have often declared a high degree of heritability in FTD, but the definition of a ‘‘positive’’ family history has not always been reported consistently, and only a few studies have examined the apparent strength of family history. A major advantage of the present study was the use of the GS to prospectively grade the strength of family history. When considered dichotomously, there was no apparent difference in the proportion of patients with a family history in patients with FTD and AD compared to controls. In contrast, the proportion of FTD patients with a strong family history (defined here as a GS of 1–3) was increased compared to AD and controls, confirming a high degree of heritability in the disease. Only a couple of previous studies have investigated the heritability of FTD by systematically applying the GS [7, 22]. In the study by Rohrer et al. [7], 20.6 % of 225 FTD spectrum patients had a GS of 1–3, and a later study by the same group revealed a GS of 1–3 in 25.3 % of FTD spectrum cases [22], similar to the results of the present study (17.2 %). Nonetheless, the degree of heritability was almost entirely driven by the bvFTD group in the previous study (48 % had a GS of 1–3) [7], whereas both the bvFTD (34.2 %) and FTD-ALS (21.7 %) groups demonstrated an increased degree of heritability in the present study. The reasons for this apparent discord are uncertain, but may reflect the referral pattern of our clinic, which has a close relationship to a well-established ALS clinic. In fact, only ten FTD-ALS patients were included in the initial study by Rohrer et al., whereas the present study included 23 FTDALS patients. The GS is the best-established and cited grading system of family history in FTD, although another system has been proposed recently [23]. In this alternative grading system, developed by Wood et al. [23], family history was graded as ‘‘High’’, ‘‘Medium’’, ‘‘Low’’, ‘‘Apparent sporadic’’ or ‘‘Unknown significance’’, according to the number of firstand second-degree relatives affected by FTD, ALS, Parkinson’s disease or dementia not otherwise specified. Almost two-thirds (64.1 %) of patients with a ‘‘High’’
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degree of heritability were found to carry pathogenic mutations, and 72.3 % of mutation carriers were classified as having either ‘‘High’’ or ‘‘Medium’’ heritability. The authors argue that, unlike the GS, their classification system was designed for clinical use [23]. By comparison, almost half (47.6 %) of FTD patients with a strong family history in the present study had a detectable pathogenic mutation, whereas 62.5 % of mutation carriers had a strong family history according to the GS, suggesting that the GS is useful clinically. Interestingly, despite the increased heritability of FTD in the present study, more than half of patients with a strong family history tested negative for all three of the most frequent FTD mutations (i.e., C9ORF72 repeat expansion, GRN, and MAPT). Similarly, approximately 40 % of patients with ‘‘High’’ heritability in the study by Wood et al. were negative for these three mutations. Screening for the Fused In Sarcoma (FUS), ChromatinModifying Protein 2b (CHMP2B), TAR DNA-Binding Protein (TARDBP), and Sequestosome 1 (SQSTM1) [24, 25] was not performed in the present study, but these mutations are rare causes of FTD [26], and unrecognized mutations of these genes are unlikely to explain the majority of cases in which a more common mutation was not identified. This finding is similar to other large published cohorts [26] and suggests that as yet undetermined genetic factors underlie some of the heritability of FTD observed in the present cohort. Consistent with previous reports, the C9ORF72 repeat expansion was the most common genetic cause of FTD in the present study, followed by GRN. Overall, 8.2 % of FTD patients carried the C9ORF72 repeat expansion, with the rate of detection increasing to 28.6 % in patients with a strong family history. It is also possible that some of our apparently sporadic FTD cases carry the C9ORF72 repeat expansion. As has been reported previously, patients with the C9ORF72 repeat expansion presented with either bvFTD or FTD-ALS [27–29]. Five (4.1 %) of the total FTD cohort had a documented GRN mutation, which is similar to previous reported frequencies of 4.8–10.7 % [7, 30–32]. Similarly, 5.6 % of FTD patients in the present study had a documented MAPT mutation, which is in line with previous reports of 8.0–8.9 % [7, 32]. Very little is currently known about the heritability of atypical AD syndromes. One factor that has been postulated to influence the development of an atypical AD phenotype is the presence or absence of the APOE e4 allele [33]. In addition, rare cases of atypical AD have been described in patients who carry the APP or PSEN 1 mutation [34–36]. In the present study, 12.2 % of atypical AD patients had a strong family history, suggesting that genetic factors may underlie phenotypic variability in the disease.
J Neurol
The present study has several limitations. Firstly, the diagnosis of FTD and AD was made on clinical, rather than pathological grounds. Reassuringly, in those patients who underwent PiB-PET imaging, the vast majority classified as AD had positive scans, and most FTD patients had negative scans. Three FTD patients had positive PiB-PET scans suggesting either overlapping clinical features or possibly dual pathology. A further limitation was that genetic testing was not performed uniformly across the disease groups. Once the C9ORF72 repeat expansion was identified further testing was not planned, although in practice GRN had already been tested in the majority of C9ORF72 positive cases. As such, the frequency and clinical significance of oligogenic inheritance of FTD (i.e., presence of more than one pathogenic mutation) [37], cannot be fully addressed by our study. On the other hand, a strength of our study is that all FTD patients with a strong family history underwent genetic testing, and patients without a pathogenic mutation were tested for all three common genetic causes. One potential limitation of the GS is that a family history of psychiatric disease is not specifically included. Psychiatric symptoms are common in C9ORF72 repeat expansion-positive cases [21], but GS was developed before the C9ORF72 repeat expansion was discovered; therefore, the significance of a family history of psychiatric disease may not have been fully appreciated. Such family history should be sought when assessing FTD patients. Since AD patients in the present series did not routinely undergo testing for pathogenic mutations, the factors underlying the apparent heritability of atypical AD, specifically APOE e4 status, cannot be examined in any detail. Furthermore, the AD patients included in our study were recruited as disease controls for an FTD research program. Therefore, our results in AD patients may not be representative of AD patients more broadly. Nonetheless, the results suggest that further genetic causes of FTD await discovery, and that atypical expression of AD pathology could be influenced by genetic factors. Acknowledgments This work was supported by funding to ForeFront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical Research Council of Australia (NHMRC) program Grant (#1037746) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021). We are grateful to the research participants involved with the ForeFront research studies. In addition, JRB is supported by a NHMRC Early Career Fellowship (#1072451) and GMH by a NHMRC Senior Principal Research Fellow (#630434). Genomic DNA was extracted from blood samples by Genetic Repositories Australia, an Enabling Facility supported by NHMRC project Grant #401184, and by Mia McMillan in Professor Halliday’s laboratory. Genetic testing was funded by NHMRC project Grant #510218. We are grateful to Carol Dobson-Stone, Yue Huang and Mia McMillan for assistance with screening for repeat expansions in the C9ORF72 gene.
Conflicts of interest On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical standard Institutional ethics approval was obtained prior to assessment and all participants, or next of kin where necessary, provided written informed consent.
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