Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2015; 16: 8–15
Constructional apraxia in frontotemporal dementia associated with the C9orf72 mutation: Broadening the clinical and neuropsychological phenotype GIANLUCA FLORIS1, GIUSEPPE BORGHERO1, ANTONINO CANNAS1, FRANCESCA DI STEFANO1, ELISA RUIU1, MARIA R. MURRU2, DANIELA CORONGIU2, STEFANIA CUCCU2, STEFANIA TRANQUILLI2, CLAUDIA SARDU4, MARIA G. MARROSU2, ADRIANO CHIÒ3 & FRANCESCO MARROSU1 1Department
of Neurology, Azienda Universitaria-Ospedaliera of Cagliari and University of Cagliari, Cagliari, Sclerosis Centre Laboratory, University of Cagliari, Cagliari, 3ALS Centre ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, AOU Città della Salute e della Scienza, Torino, and Neuroscience Institute of Torino (NIT), Torino, Italy, and 4Department of Igiene, University of Cagliari, Cagliari, Italy 2Multiple
Abstract In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and nonmutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation. Key words: FTD, C9orf72, visuospatial dysfunction, constructional apraxia
Introduction Recently, two groups found that a large hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9orf72 gene is the most frequent mutation responsible for amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and comorbid FTD-ALS worldwide (1,2). Since then, various epidemiological, clinical, neuropsychological and imaging studies have tried to identify the distinctive features of patients affected by these diseases carrying the C9orf72 mutation (3–10). This mutation has been described to be quite frequent in patients of Sardinian ancestry with both sporadic and familial ALS (11,12). Sardinians have distinctive genetic
characteristics from other Europeans, including mainland Italians (13,14). Despite numerous invasions over the millennia, Sardinia has maintained its own genetic characteristics. The aim of the present study is to compare clinical and neuropsychological features of a Sardinian cohort of FTD patients carrying (C9orf72) and not carrying (C9orf72–) the pathological C9orf72 hexanucleotide repeat. Materials and methods Study participants We evaluated a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging
Correspondence: G. Floris, Department of Neurology, University of Cagliari, Sst 554, 09042, Monserrato, Italy. Fax: 39 07051096497. E-mail: [email protected] (Received 11 April 2014 ; accepted 25 August 2014 ) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.959450
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to the same family). All patients of our FTD database meeting Neary’s criteria for FTD (15) were enrolled. The study was approved by the local research ethics committee under the Declaration of Helsinki guidelines and all subjects gave informed consent for participation. Three patients with logopenic progressive aphasia meeting the GornoTempini et al. criteria (16) were not included in the cohort. Subjects not of Sardinian ancestry from three generations were excluded. Demographic data, family history, clinical features, neuropsychological features and neuroimages were reviewed for every patient. A positive family history was defined as a first-degree relative with FTD and/or ALS (17). We carried out a neurological examination of all patients. Signs of upper or lower motor neuron dysfunction were also evaluated. Comorbid ALS was diagnosed when patients also met the El Escorial revised criteria for ALS (18). Parkinsonism was identified when at least two clinical features between bradykinesia, rigidity, resting tremor and postural instability were present. Appropriate ethics committee approvals were in place for this work.
p-values were obtained using Fisher’s exact test for categorical data and Mann-Whitney U-test for numerical data.
Neuropsychological assessment
Results
Patients underwent an extensive neuropsychological evaluation including tests to assess attention (Attentional Matrices) (19), immediate verbal and visual memory (forward/backward Digit span and Corsi span) (20), long-term verbal memory (Rey’s words) (21), phonemic verbal fluency (22), executive functions (MCST and Stroop Test) (23,24), visuospatial functions (Simple Design Copy) (21), word-picture matching test for nouns and actions (BADA) (25). The MCST is a reduced and modified version of the WCST (26). In the simple design copy test, patients were asked to copy three simple drawings from a model (a star, a cube and a house). Patients with primary progressive aphasia underwent extensive language examination with BADA (24). Behaviour was evaluated with the Neuropsychiatric Inventory (NPI) (27), a questionnaire that is proposed to caregivers. Behaviour and neuropsychiatric features were also evaluated during the clinical assessment and by a direct carer interview. Tests were administered in the same order to all patients and used as suggested by the respective authors. Raw scores obtained from each patient in the various tests were adjusted for a series of variables such as gender, age, and education. The assessment of the normal scores was deduced from comparison with normative values available, developed in the calibration tests on large samples of normal subjects of reference in the Italian population. Neuroimaging data Fifty-five patients underwent a 1.5 T brain magnetic resonance imaging (MRI) and 42 patients
underwent perfusion single photon emission computed tomography (SPECT) with 99Tc-ethylene cystine dimer (ECD) or with 99Tc-HMPAO. Genotyping The hexanucleotide repeat expansion in C9orf72 was searched in all subjects of the cohort. FTD and ALS-associated pathological expansions in C9orf72 have been defined as greater than 30 repeats. In the same cohort of FTD patients we also assessed the presence of the p.A382T missense mutation of the TARDBP gene, as it is particularly frequent in Sardinia in association with sporadic and familial ALS (28). The technique used in our laboratory for the genetic analysis of these mutations in the two genes was previously described (11,29). Statistical analysis
Population description Our cohort included 32 males and 24 females; 30 patients presented with behavioural variant FTD (bvFTD), six with progressive non-fluent aphasia (PNFA), seven with semantic dementia (SD), six with unspecified primary progressive aphasia (PPA) and seven with mixed form of FTD (bvFTD PPA). A familial positive history for FTD and/or ALS was recorded in 19 patients (34%) whereas 37 cases were sporadic. Six patients presented an association of FTD with motor neuron disease; three of them met the El Escorial revised criteria for ALS (18), and three showed an isolated involvement of the upper motor neuron. In the entire cohort nine patients carried the C9orf72 mutation (two patients from the same kindred). The C9orf72 mutation was detected in eight out of 56 (14.2%) index cases and in six out of 19 (31.6%) familial cases. Clinically, seven patients had bvFTD and two a mixed form of FTD. One of the patients with mixed form of FTD was evaluated only clinically because he was presented to our neurological unit when the dementia status was already severe. As, in our C9orf72 cohort, no patients had pure PPA, clinical and neuropsychological characteristics between the groups were compared with the C9orf72– patients with bvFTD and mixed form of FTD. In the same cohort we found also four patients carrying the p.A382T missense mutation of the TARDBP gene; as patients with this mutation were not a matter for this work we do not describe them in the present article.
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Table I. Demographic features of the present FTD cohort in C9orf72 and C9orf72 – with bvFTD and mixed form (bvFTD APP).
Number Age at onset (median, range) M/F Familial Sporadic BvFTD Mixed form (bvFTD APP) MND Parkinsonism Limb apraxia
C9
C9 – (bvFTD and mixed form)
9 58 (51–73) 6/3 7/9 2/9 7/9 2/9 2/9 7/9 1/9
27 67 (48 – 80) 15/12 7/27 20/27 21/27 6/27 2/27 12/27 3/27
In the C9orf72 group we found two patients who were affected by bipolar disorder (BD), one by major recurrent depression and another by postpartum depression. Four of the C9orf72– patients had a clinical history of psychiatric disorders (two had a major depressive episode, one a schizoaffective disorder and the other an anxiety disorder not otherwise specified). Cognitive performances and behavioural characteristics of C9orf72 and C9orf72– patients affected by bvFTD and mixed form were compared. The two groups did not differ in terms of educational level and time from disease onset to neuropsychological and neurobehavioural evaluation. Neuropsychological assessment
Clinical and demographic characteristics (Table I) C9orf72 patients had a younger age of onset (median age 58 vs. 67 years, p 0.01) and higher frequency of positive familial history for FTD/ALS (7/9 (77.8%) vs. 7/27 (25.9%), p 0.01). Motor neuron disease (MND), Parkinsonism and history of psychiatric disorders were more frequently reported in the C9orf72 group, although they did not reach statistical significance (MND p 0.25, Parkinsonism p 0.07, psychiatric disorders p 0.09). Parkinsonism in C9orf72 patients was usually of the rigid-akinetic type, symmetric or slightly asymmetric, with early onset during the disease course. Tremor was absent in all but one patient who presented asymmetric Parkinsonism with PD-like resting tremor at the right upper limb. Dopamine transporter (DAT) scan was performed in five patients in the C9orf72 group and we found in four patients pathological alterations (Figure 1); in particular, two cases showed mild reduced symmetrical uptake at striatal level and two marked asymmetrical reduction. L-Dopa was not administered to these patients. Limb apraxia was assessed by imitation of meaningful and meaningless hand gestures in each hand and determined to be either present or absent. Only 1/9 C9 and 3/27 C9– patients had limb apraxia, without statistical significant differences between groups (p 0.45). None of the patients had ideational apraxia.
In Figure 2 the neuropsychological profiles of C9orf72 and C9orf72– patients are compared. As expected in FTD, all the patients obtained the lowest scores on executive function tests. Neuropsychological tests assessing executive functions, working memory, verbal and visuospatial long-term memory domain failed to discriminate between C9orf72 and C9orf72– patients. The C9orf72 mutation carriers scored significantly worse than the non-carriers on tests assessing constructional apraxia (p 0.02) and on word-picture matching tests for the category nouns (p 0.03). Behavioural evaluation Figure 3 shows comparisons of the scores of the subitems of NPI between the two groups. C9orf72 differed from C9orf72– patients for the higher frequency of delusional psychotic symptoms (p 0.039) and hallucination (p 0.009). No differences were found in apathy, disinhibition, aggressivity, agitation, euphoria, irritability, repetitive behaviour and eating disorders. Discussion In the present study we showed that in our Sardinian cohort of FTD patients there is a high frequency of C9orf72 patients (14.2%); in particular, the
Figure 1. Cerebral dopamine transporter scan showing marked and asymmetric reduction of striatal uptake in a C9orf72 patient with FTD and Parkinsonism.
Constructional apraxia in FTD
Figure 2. Percent of subjects C9orf72 and C9orf72 – with impaired cognitive domains at neuropsychological evaluation. WM: working memory; ATT: attention; EF: executive functions; NN: oral naming nouns; NV: oral naming verbs; VLTM: verbal long-term memory; VSLTM: visuospatial longterm memory; CA: constructional apraxia. In the analysis were included eight C9orf72 patients.
frequency of this mutation was 31.6% in familial form of FTD, whereas the same mutation was rare in sporadic cases (5.4%). A recent report found that in the Italian population the C9orf72 mutation is present in 6% of all the FTD patients and represents 14% of familial cases and 3% of sporadic cases (30). These data highlight the peculiar characteristics of the Sardinian population in which, as we showed, this gene frequency is more relevant than in the rest of Italy in FTD and particularly in familial forms of the disease ( p 0.0168 for FTD and p 0.05 for familial FTD). Several studies suggest that Sardinians have a phylogeny distinct from other Europeans including mainland Italians (13,14). This island has also a uniquely high incidence of several autoimmune and neurological diseases such as multiple sclerosis (31) and ALS (32). Population based studies have shown that in Sardinia 23% of ALS patients have a known family history of ALS, versus 5% in other European ALS populations (33). These data
Figure 3. Prevalence of behavioural symptoms observed at NPI in C9orf72 and C9ORF72 – cases.
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suggest that Sardinia, with its own isolated ethnicity, demonstrates peculiar epidemiological and genetics characteristics. Clinically, we found that C9orf72 patients differed from C9orf72– and presented as distinctive features, younger age of onset, higher frequency of positive familial history for ALS/FTD, higher prevalence of delusional psychotic symptoms and hallucinations. As a point of interest, hallucination was present only in C9orf72 subjects (33%). Neuropsychological assessment showed greater impairment on tests for constructional apraxia and naming nouns disturbances. Aside from patients with FTD-ALS (34,35), psychotic symptoms are rarely reported in FTD. We found that C9orf72 patients presented mystic, bizarre, somatoform and persecutory delusions. Our findings on psychosis are consistent with the literature on clinical features of C9orf72 patients (3–9). C9orf72 subjects had also a tendency to a higher frequency of Parkinsonism, although without reaching statistical significance. Parkinsonism was characterized by rigid-akinetic syndrome, sometimes asymmetric and rarely associated with resting tremor. In our cohort we found tremor PD-like only in one patient. When DAT-SCAN was performed, we found in all but one patient variable degrees of alteration. We did not find Parkinsonism CBS- or PSP-like in patients with the C9orf72 mutation, unlike with some non-mutated patients. Table II summarizes the clinical data of C9orf72 mutated patients. Constructional apraxia was found in a high percentage of C9orf72 patients, while it was rarely observed in the other patients of the cohort (Figure 4). To our knowledge, there is only one recent work in which the authors reported that C9orf72 mutation carriers performed worse than non-carriers on the Rey-Osterrieth Complex figure test copy (36). Usually, visuospatial functions are preserved in FTD patients with few exceptions (15,37). Despite this, in our patients constructional apraxia cannot be attributed to the executive dysfunction that was comparable with the remaining patients in the cohort. Furthermore, constructional apraxia detected with simple design copy is usually not related to executive dysfunction; demographic characteristics (gender, educational level, age at onset of symptoms, duration of illness at neuropsychological evaluation) do not explain the different performances in tests between the groups. Neither motor impairment nor cognitive severity degree could be responsible for the constructional apraxia. Parkinsonism was mild when patients underwent neuropsychological evaluation and, furthermore, among patients in the cohort there was no correlation between Parkinsonism and constructional apraxia. Limb apraxia was present in only one patient C9 and was not related to performances on visuospatial tasks. Discrepancy between the literature on visuospatial impairment in C9orf72 FTD and our data could be related
bvFTD
9
M 54 Psychosis, Disinhibition, Apathy, Irritability
Case 3
Post-partum Depressive episode bvFTD
2
F 73 Psychosis
Case 4
(d): patient died; BD: bipolar disorder; bvFTD: behavioural variant of frontotemporal dementia; PPA: primary progressive aphasia; UMN: upper motor neuron; LMN: lower motor neuron. present; – absent.
bvFTD
bvFTD
BD
Clinical diagnosis Parkinsonism Motor Neuron Disease UMN LMN
3
4 (d)
Duration (years) Familial history FTD ALS Parkinsonism Psyhciatric history
M 64 Psychosis, Disinhibition, Repetitive Behaviours
M 61 Psychosis
Case 2
Gender Age of onset (years) Early symptoms
Case 1
Table II. Clinical data available for C9orf72 mutated patients.
bvFTD PPA
8
M 60 Expressive language disorder
Case 5
bvFTD
Major depression
F 63 Apathy, Irritability, Repetitive behaviours, Executive dysfunction 7
Case 6
bvFTD
3
F 57 Apathy, Executive dysfunction
Case 7
bvFTD PPA
BD
2
M 51 Expressive language disorder
Case 8
bvFTD
13 (d)
M 51 Psychosis
Case 9
12 G. Floris et al.
Constructional apraxia in FTD
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Figure 4. Copy of simple drawings from a model demonstrating marked constructional apraxia in three C9orf72 patients. P1: patient 1; P2: patient 2; P3: patient 3.
to the use of different neuropsychological tools in the assessment of visuospatial functions regarding mostly visuoperceptive abilities. Currently, various studies suggest that C9orf72 patients could present more parietal and occipital cortical involvement than other FTD patients (4,7,9,10). In a recent review on neuroimaging features correlated to C9orf72 expansion, Yokoyama and Rosen (38) found that patients with this mutation could present a relatively diffuse pattern of atrophy, involving frontal and temporal lobe, insula and posterior cortices, which distinguish these patients from others with different mutations and sporadic FTD. Mahoney et al. (6) found that parietal dysfunction of the dominant hemisphere (acalculia, apraxia)
was frequent in these patients. With regard to these reports, it is possible that constructional apraxia in our patients could represent the neuropsychological correlate of right parietal dysfunction and atrophy. As support to this hypothesis we show MRI images of two C9orf72 patients in which is clearly present an involvement of parietal cortices (Figure 5). Processing of nouns and verbs relies on different brain regions (39). ALS-FTD patients are significantly more impaired on verbs naming than nouns naming (39). In our study C9– patients showed this pattern of naming impairment. Interestingly, C9 patients showed the opposite pattern. They were significantly more impaired than C9– patients
Figure 5. T1-weighted MRI images of two patients with C9orf72 mutation and constructional apraxia demonstrating diffuse atrophy with the involvement of the parietal cortices (simple design copy of these two subjects is represented in Figure 4).
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on nouns naming with similar impairment on verbs naming. This neuropsychological pattern could be explained by a possible different regional brain involvement in the two groups, broader in the C9 patients. Sometimes, the presence of psychosis, Parkinsonism and visuospatial dysfunction in patients with FTD C9orf72 brings up problems of differential diagnosis between FTD and Lewy bodies dementia (LBD), as reported by our group and others (40,41). However, the presence of anomia, the high frequency of familiarity for FTD and neuroimaging involving the frontotemporal lobes could help differentiate these two neurodegenerative diseases. Abnormal DAT-SCAN is included within the suggestive features of LBD in current criteria (42). Nevertheless, when DAT-SCAN was performed in the C9orf72 group we found a great number of patients with variable degree of alterations, rendering the exam in the differential diagnosis between FTD and LBD useless.
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Conclusions In our study we show that Sardinian FTD patients have peculiar genetic characteristics and those with C9orf72 mutations have a clinical distinctive phenotype characterized by younger age at onset, high frequency of familiality for ALS/FTD and high prevalence of delusional psychotic symptoms and hallucinations. Furthermore, we found that constructional apraxia was the most prominent feature which differentiates these patients from others in the cohort. We suggest that these clinical and neuropsychological data could help in the differential diagnosis between these patients and others with sporadic and familial FTD or those with other neurodegenerative disorders. Declaration of interest: The authors report no confl icts of interest. The authors alone are responsible for the content and the writing of the paper. References 1. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC Hexanucleotide Repeat in Non-coding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron. 2011;72:245–56. 2. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9orf72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–68. 3. Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, 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;11:232–40. 4. Boeve BF, Boylan KB, Graff-Radford NR, DeJesusHernandez M, Knopman DS, Pedraza O, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral
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Constructional apraxia in frontotemporal dementia associated with the C9orf72 mutation: Broadening the clinical and neuropsychological phenotype GIANLUCA FLORIS1, GIUSEPPE BORGHERO1, ANTONINO CANNAS1, FRANCESCA DI STEFANO1, ELISA RUIU1, MARIA R. MURRU2, DANIELA CORONGIU2, STEFANIA CUCCU2, STEFANIA TRANQUILLI2, CLAUDIA SARDU4, MARIA G. MARROSU2, ADRIANO CHIÒ3 & FRANCESCO MARROSU1 1Department
of Neurology, Azienda Universitaria-Ospedaliera of Cagliari and University of Cagliari, Cagliari, Sclerosis Centre Laboratory, University of Cagliari, Cagliari, 3ALS Centre ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, AOU Città della Salute e della Scienza, Torino, and Neuroscience Institute of Torino (NIT), Torino, Italy, and 4Department of Igiene, University of Cagliari, Cagliari, Italy 2Multiple
Abstract In our study we analysed clinical and neuropsychological data in a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging to the same family), who underwent genetic screening for the C9orf72 mutation. Eight out of 56 patients were found positive for the C9orf72 mutation representing 14% of the entire cohort and 31.6% of the familial cases (6/19). C9orf72 mutated patients differed from the other FTD cases of the cohort for a younger age of onset, higher frequency of familial history for FTD and higher prevalence of delusional psychotic symptoms and hallucinations. In the neuropsychological assessment, C9orf72 mutated patients differed from non-mutated for the high frequency of visuospatial dysfunction regarding constructional apraxia (p 0.02). In conclusion, our study confirms that Sardinian FTD patients have peculiar genetic characteristics and that C9orf72 mutated patients have a distinctive clinical and neuropsychological profile that could help differentiate them from other FTD patients. In our cohort we found that constructional apraxia, rarely reported in FTD, can properly discriminate between C9orf72 mutated and nonmutated patients and contribute to broaden the neuropsychological profile in frontotemporal dementia associated with this mutation. Key words: FTD, C9orf72, visuospatial dysfunction, constructional apraxia
Introduction Recently, two groups found that a large hexanucleotide (GGGGCC) repeat expansion in the first intron of the C9orf72 gene is the most frequent mutation responsible for amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and comorbid FTD-ALS worldwide (1,2). Since then, various epidemiological, clinical, neuropsychological and imaging studies have tried to identify the distinctive features of patients affected by these diseases carrying the C9orf72 mutation (3–10). This mutation has been described to be quite frequent in patients of Sardinian ancestry with both sporadic and familial ALS (11,12). Sardinians have distinctive genetic
characteristics from other Europeans, including mainland Italians (13,14). Despite numerous invasions over the millennia, Sardinia has maintained its own genetic characteristics. The aim of the present study is to compare clinical and neuropsychological features of a Sardinian cohort of FTD patients carrying (C9orf72) and not carrying (C9orf72–) the pathological C9orf72 hexanucleotide repeat. Materials and methods Study participants We evaluated a cohort of 57 Sardinian patients with FTD (55 apparently unrelated and two belonging
Correspondence: G. Floris, Department of Neurology, University of Cagliari, Sst 554, 09042, Monserrato, Italy. Fax: 39 07051096497. E-mail: [email protected] (Received 11 April 2014 ; accepted 25 August 2014 ) ISSN 2167-8421 print/ISSN 2167-9223 online © 2014 Informa Healthcare DOI: 10.3109/21678421.2014.959450
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to the same family). All patients of our FTD database meeting Neary’s criteria for FTD (15) were enrolled. The study was approved by the local research ethics committee under the Declaration of Helsinki guidelines and all subjects gave informed consent for participation. Three patients with logopenic progressive aphasia meeting the GornoTempini et al. criteria (16) were not included in the cohort. Subjects not of Sardinian ancestry from three generations were excluded. Demographic data, family history, clinical features, neuropsychological features and neuroimages were reviewed for every patient. A positive family history was defined as a first-degree relative with FTD and/or ALS (17). We carried out a neurological examination of all patients. Signs of upper or lower motor neuron dysfunction were also evaluated. Comorbid ALS was diagnosed when patients also met the El Escorial revised criteria for ALS (18). Parkinsonism was identified when at least two clinical features between bradykinesia, rigidity, resting tremor and postural instability were present. Appropriate ethics committee approvals were in place for this work.
p-values were obtained using Fisher’s exact test for categorical data and Mann-Whitney U-test for numerical data.
Neuropsychological assessment
Results
Patients underwent an extensive neuropsychological evaluation including tests to assess attention (Attentional Matrices) (19), immediate verbal and visual memory (forward/backward Digit span and Corsi span) (20), long-term verbal memory (Rey’s words) (21), phonemic verbal fluency (22), executive functions (MCST and Stroop Test) (23,24), visuospatial functions (Simple Design Copy) (21), word-picture matching test for nouns and actions (BADA) (25). The MCST is a reduced and modified version of the WCST (26). In the simple design copy test, patients were asked to copy three simple drawings from a model (a star, a cube and a house). Patients with primary progressive aphasia underwent extensive language examination with BADA (24). Behaviour was evaluated with the Neuropsychiatric Inventory (NPI) (27), a questionnaire that is proposed to caregivers. Behaviour and neuropsychiatric features were also evaluated during the clinical assessment and by a direct carer interview. Tests were administered in the same order to all patients and used as suggested by the respective authors. Raw scores obtained from each patient in the various tests were adjusted for a series of variables such as gender, age, and education. The assessment of the normal scores was deduced from comparison with normative values available, developed in the calibration tests on large samples of normal subjects of reference in the Italian population. Neuroimaging data Fifty-five patients underwent a 1.5 T brain magnetic resonance imaging (MRI) and 42 patients
underwent perfusion single photon emission computed tomography (SPECT) with 99Tc-ethylene cystine dimer (ECD) or with 99Tc-HMPAO. Genotyping The hexanucleotide repeat expansion in C9orf72 was searched in all subjects of the cohort. FTD and ALS-associated pathological expansions in C9orf72 have been defined as greater than 30 repeats. In the same cohort of FTD patients we also assessed the presence of the p.A382T missense mutation of the TARDBP gene, as it is particularly frequent in Sardinia in association with sporadic and familial ALS (28). The technique used in our laboratory for the genetic analysis of these mutations in the two genes was previously described (11,29). Statistical analysis
Population description Our cohort included 32 males and 24 females; 30 patients presented with behavioural variant FTD (bvFTD), six with progressive non-fluent aphasia (PNFA), seven with semantic dementia (SD), six with unspecified primary progressive aphasia (PPA) and seven with mixed form of FTD (bvFTD PPA). A familial positive history for FTD and/or ALS was recorded in 19 patients (34%) whereas 37 cases were sporadic. Six patients presented an association of FTD with motor neuron disease; three of them met the El Escorial revised criteria for ALS (18), and three showed an isolated involvement of the upper motor neuron. In the entire cohort nine patients carried the C9orf72 mutation (two patients from the same kindred). The C9orf72 mutation was detected in eight out of 56 (14.2%) index cases and in six out of 19 (31.6%) familial cases. Clinically, seven patients had bvFTD and two a mixed form of FTD. One of the patients with mixed form of FTD was evaluated only clinically because he was presented to our neurological unit when the dementia status was already severe. As, in our C9orf72 cohort, no patients had pure PPA, clinical and neuropsychological characteristics between the groups were compared with the C9orf72– patients with bvFTD and mixed form of FTD. In the same cohort we found also four patients carrying the p.A382T missense mutation of the TARDBP gene; as patients with this mutation were not a matter for this work we do not describe them in the present article.
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Table I. Demographic features of the present FTD cohort in C9orf72 and C9orf72 – with bvFTD and mixed form (bvFTD APP).
Number Age at onset (median, range) M/F Familial Sporadic BvFTD Mixed form (bvFTD APP) MND Parkinsonism Limb apraxia
C9
C9 – (bvFTD and mixed form)
9 58 (51–73) 6/3 7/9 2/9 7/9 2/9 2/9 7/9 1/9
27 67 (48 – 80) 15/12 7/27 20/27 21/27 6/27 2/27 12/27 3/27
In the C9orf72 group we found two patients who were affected by bipolar disorder (BD), one by major recurrent depression and another by postpartum depression. Four of the C9orf72– patients had a clinical history of psychiatric disorders (two had a major depressive episode, one a schizoaffective disorder and the other an anxiety disorder not otherwise specified). Cognitive performances and behavioural characteristics of C9orf72 and C9orf72– patients affected by bvFTD and mixed form were compared. The two groups did not differ in terms of educational level and time from disease onset to neuropsychological and neurobehavioural evaluation. Neuropsychological assessment
Clinical and demographic characteristics (Table I) C9orf72 patients had a younger age of onset (median age 58 vs. 67 years, p 0.01) and higher frequency of positive familial history for FTD/ALS (7/9 (77.8%) vs. 7/27 (25.9%), p 0.01). Motor neuron disease (MND), Parkinsonism and history of psychiatric disorders were more frequently reported in the C9orf72 group, although they did not reach statistical significance (MND p 0.25, Parkinsonism p 0.07, psychiatric disorders p 0.09). Parkinsonism in C9orf72 patients was usually of the rigid-akinetic type, symmetric or slightly asymmetric, with early onset during the disease course. Tremor was absent in all but one patient who presented asymmetric Parkinsonism with PD-like resting tremor at the right upper limb. Dopamine transporter (DAT) scan was performed in five patients in the C9orf72 group and we found in four patients pathological alterations (Figure 1); in particular, two cases showed mild reduced symmetrical uptake at striatal level and two marked asymmetrical reduction. L-Dopa was not administered to these patients. Limb apraxia was assessed by imitation of meaningful and meaningless hand gestures in each hand and determined to be either present or absent. Only 1/9 C9 and 3/27 C9– patients had limb apraxia, without statistical significant differences between groups (p 0.45). None of the patients had ideational apraxia.
In Figure 2 the neuropsychological profiles of C9orf72 and C9orf72– patients are compared. As expected in FTD, all the patients obtained the lowest scores on executive function tests. Neuropsychological tests assessing executive functions, working memory, verbal and visuospatial long-term memory domain failed to discriminate between C9orf72 and C9orf72– patients. The C9orf72 mutation carriers scored significantly worse than the non-carriers on tests assessing constructional apraxia (p 0.02) and on word-picture matching tests for the category nouns (p 0.03). Behavioural evaluation Figure 3 shows comparisons of the scores of the subitems of NPI between the two groups. C9orf72 differed from C9orf72– patients for the higher frequency of delusional psychotic symptoms (p 0.039) and hallucination (p 0.009). No differences were found in apathy, disinhibition, aggressivity, agitation, euphoria, irritability, repetitive behaviour and eating disorders. Discussion In the present study we showed that in our Sardinian cohort of FTD patients there is a high frequency of C9orf72 patients (14.2%); in particular, the
Figure 1. Cerebral dopamine transporter scan showing marked and asymmetric reduction of striatal uptake in a C9orf72 patient with FTD and Parkinsonism.
Constructional apraxia in FTD
Figure 2. Percent of subjects C9orf72 and C9orf72 – with impaired cognitive domains at neuropsychological evaluation. WM: working memory; ATT: attention; EF: executive functions; NN: oral naming nouns; NV: oral naming verbs; VLTM: verbal long-term memory; VSLTM: visuospatial longterm memory; CA: constructional apraxia. In the analysis were included eight C9orf72 patients.
frequency of this mutation was 31.6% in familial form of FTD, whereas the same mutation was rare in sporadic cases (5.4%). A recent report found that in the Italian population the C9orf72 mutation is present in 6% of all the FTD patients and represents 14% of familial cases and 3% of sporadic cases (30). These data highlight the peculiar characteristics of the Sardinian population in which, as we showed, this gene frequency is more relevant than in the rest of Italy in FTD and particularly in familial forms of the disease ( p 0.0168 for FTD and p 0.05 for familial FTD). Several studies suggest that Sardinians have a phylogeny distinct from other Europeans including mainland Italians (13,14). This island has also a uniquely high incidence of several autoimmune and neurological diseases such as multiple sclerosis (31) and ALS (32). Population based studies have shown that in Sardinia 23% of ALS patients have a known family history of ALS, versus 5% in other European ALS populations (33). These data
Figure 3. Prevalence of behavioural symptoms observed at NPI in C9orf72 and C9ORF72 – cases.
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suggest that Sardinia, with its own isolated ethnicity, demonstrates peculiar epidemiological and genetics characteristics. Clinically, we found that C9orf72 patients differed from C9orf72– and presented as distinctive features, younger age of onset, higher frequency of positive familial history for ALS/FTD, higher prevalence of delusional psychotic symptoms and hallucinations. As a point of interest, hallucination was present only in C9orf72 subjects (33%). Neuropsychological assessment showed greater impairment on tests for constructional apraxia and naming nouns disturbances. Aside from patients with FTD-ALS (34,35), psychotic symptoms are rarely reported in FTD. We found that C9orf72 patients presented mystic, bizarre, somatoform and persecutory delusions. Our findings on psychosis are consistent with the literature on clinical features of C9orf72 patients (3–9). C9orf72 subjects had also a tendency to a higher frequency of Parkinsonism, although without reaching statistical significance. Parkinsonism was characterized by rigid-akinetic syndrome, sometimes asymmetric and rarely associated with resting tremor. In our cohort we found tremor PD-like only in one patient. When DAT-SCAN was performed, we found in all but one patient variable degrees of alteration. We did not find Parkinsonism CBS- or PSP-like in patients with the C9orf72 mutation, unlike with some non-mutated patients. Table II summarizes the clinical data of C9orf72 mutated patients. Constructional apraxia was found in a high percentage of C9orf72 patients, while it was rarely observed in the other patients of the cohort (Figure 4). To our knowledge, there is only one recent work in which the authors reported that C9orf72 mutation carriers performed worse than non-carriers on the Rey-Osterrieth Complex figure test copy (36). Usually, visuospatial functions are preserved in FTD patients with few exceptions (15,37). Despite this, in our patients constructional apraxia cannot be attributed to the executive dysfunction that was comparable with the remaining patients in the cohort. Furthermore, constructional apraxia detected with simple design copy is usually not related to executive dysfunction; demographic characteristics (gender, educational level, age at onset of symptoms, duration of illness at neuropsychological evaluation) do not explain the different performances in tests between the groups. Neither motor impairment nor cognitive severity degree could be responsible for the constructional apraxia. Parkinsonism was mild when patients underwent neuropsychological evaluation and, furthermore, among patients in the cohort there was no correlation between Parkinsonism and constructional apraxia. Limb apraxia was present in only one patient C9 and was not related to performances on visuospatial tasks. Discrepancy between the literature on visuospatial impairment in C9orf72 FTD and our data could be related
bvFTD
9
M 54 Psychosis, Disinhibition, Apathy, Irritability
Case 3
Post-partum Depressive episode bvFTD
2
F 73 Psychosis
Case 4
(d): patient died; BD: bipolar disorder; bvFTD: behavioural variant of frontotemporal dementia; PPA: primary progressive aphasia; UMN: upper motor neuron; LMN: lower motor neuron. present; – absent.
bvFTD
bvFTD
BD
Clinical diagnosis Parkinsonism Motor Neuron Disease UMN LMN
3
4 (d)
Duration (years) Familial history FTD ALS Parkinsonism Psyhciatric history
M 64 Psychosis, Disinhibition, Repetitive Behaviours
M 61 Psychosis
Case 2
Gender Age of onset (years) Early symptoms
Case 1
Table II. Clinical data available for C9orf72 mutated patients.
bvFTD PPA
8
M 60 Expressive language disorder
Case 5
bvFTD
Major depression
F 63 Apathy, Irritability, Repetitive behaviours, Executive dysfunction 7
Case 6
bvFTD
3
F 57 Apathy, Executive dysfunction
Case 7
bvFTD PPA
BD
2
M 51 Expressive language disorder
Case 8
bvFTD
13 (d)
M 51 Psychosis
Case 9
12 G. Floris et al.
Constructional apraxia in FTD
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Figure 4. Copy of simple drawings from a model demonstrating marked constructional apraxia in three C9orf72 patients. P1: patient 1; P2: patient 2; P3: patient 3.
to the use of different neuropsychological tools in the assessment of visuospatial functions regarding mostly visuoperceptive abilities. Currently, various studies suggest that C9orf72 patients could present more parietal and occipital cortical involvement than other FTD patients (4,7,9,10). In a recent review on neuroimaging features correlated to C9orf72 expansion, Yokoyama and Rosen (38) found that patients with this mutation could present a relatively diffuse pattern of atrophy, involving frontal and temporal lobe, insula and posterior cortices, which distinguish these patients from others with different mutations and sporadic FTD. Mahoney et al. (6) found that parietal dysfunction of the dominant hemisphere (acalculia, apraxia)
was frequent in these patients. With regard to these reports, it is possible that constructional apraxia in our patients could represent the neuropsychological correlate of right parietal dysfunction and atrophy. As support to this hypothesis we show MRI images of two C9orf72 patients in which is clearly present an involvement of parietal cortices (Figure 5). Processing of nouns and verbs relies on different brain regions (39). ALS-FTD patients are significantly more impaired on verbs naming than nouns naming (39). In our study C9– patients showed this pattern of naming impairment. Interestingly, C9 patients showed the opposite pattern. They were significantly more impaired than C9– patients
Figure 5. T1-weighted MRI images of two patients with C9orf72 mutation and constructional apraxia demonstrating diffuse atrophy with the involvement of the parietal cortices (simple design copy of these two subjects is represented in Figure 4).
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on nouns naming with similar impairment on verbs naming. This neuropsychological pattern could be explained by a possible different regional brain involvement in the two groups, broader in the C9 patients. Sometimes, the presence of psychosis, Parkinsonism and visuospatial dysfunction in patients with FTD C9orf72 brings up problems of differential diagnosis between FTD and Lewy bodies dementia (LBD), as reported by our group and others (40,41). However, the presence of anomia, the high frequency of familiarity for FTD and neuroimaging involving the frontotemporal lobes could help differentiate these two neurodegenerative diseases. Abnormal DAT-SCAN is included within the suggestive features of LBD in current criteria (42). Nevertheless, when DAT-SCAN was performed in the C9orf72 group we found a great number of patients with variable degree of alterations, rendering the exam in the differential diagnosis between FTD and LBD useless.
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Conclusions In our study we show that Sardinian FTD patients have peculiar genetic characteristics and those with C9orf72 mutations have a clinical distinctive phenotype characterized by younger age at onset, high frequency of familiality for ALS/FTD and high prevalence of delusional psychotic symptoms and hallucinations. Furthermore, we found that constructional apraxia was the most prominent feature which differentiates these patients from others in the cohort. We suggest that these clinical and neuropsychological data could help in the differential diagnosis between these patients and others with sporadic and familial FTD or those with other neurodegenerative disorders. Declaration of interest: The authors report no confl icts of interest. The authors alone are responsible for the content and the writing of the paper. References 1. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, et al. Expanded GGGGCC Hexanucleotide Repeat in Non-coding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS. Neuron. 2011;72:245–56. 2. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9orf72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011;72:257–68. 3. Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, 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;11:232–40. 4. Boeve BF, Boylan KB, Graff-Radford NR, DeJesusHernandez M, Knopman DS, Pedraza O, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral
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