Neuropsychiatric features of C9orf72-associated behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease
© BioMed Central Ltd 2012
Published: 3 October 2012
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© BioMed Central Ltd 2012
Published: 3 October 2012
Earlier reports of chromosome 9p-linked frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS) kindreds observed psychosis as a prominent feature in some patients. Since the discovery of chromosome 9 open reading frame 72 (C9orf72) hexanucleotide expansions as a cause of FTD and ALS, research groups and consortia around the world have reported their respective observations of the clinical features associated with this mutation. We reviewed the recent literature on C9orf72-associated FTD and ALS with focus on the neuropsychiatric features associated with this mutation, as well as the experience at University of California, San Francisco. The results and methodologies varied greatly across studies, making comparison of results challenging. Four reports found that psychotic features (particularly delusions) were frequent among mutation carriers, particularly when present early during the disease course, suggesting that this symptom category may be a marker for the mutation. Disinhibition and apathy were the most commonly reported early behavioral symptoms, but these may not be helpful in distinguishing carriers and noncarriers because of the symptoms' frequency in sporadic behavioral variant FTD. Other neuropsychiatric features were reported in different frequencies across studies, suggesting either a similar behavioral phenotype in carriers and noncarriers or reflecting the heterogeneity in clinical presentation of behavioral variant FTD due to C9orf72 expansions. Further studies with larger cohorts will be necessary to determine the neuropsychiatric presentation associated with this mutation.
Only recently has the overlap between psychiatry and neurology been more thoroughly explored. Among all neurodegenerative disorders, frontotemporal dementia (FTD) particularly distinguishes itself because behavioral changes are the hallmark of this group of disorders. Approximately 50% of patients with behavioral variant FTD (bvFTD) receive a psychiatric diagnosis (most frequently major depressive disorder, schizophrenia, and bipolar disorder) prior to correct diagnosis . Understanding the manner in which bvFTD may present as a neuropsychiatric syndrome is paramount to avoid erroneous diagnoses and provide the best treatment for patients.
A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) [GenBank:JN681271] was recently discovered to probably be the most frequent genetic cause of bvFTD, FTD with motor neuron disease (FTD-MND) and amyotrophic lateral sclerosis (ALS) [2, 3]. The mean age at onset of symptoms has been reported to be approximately 56 years [4–6], ranging from the fourth to the ninth decade [5, 7]. bvFTD, FTD-MND and ALS are the most commonly observed phenotypes, but nonfluent variant primary progressive aphasia, Alzheimer's disease, parkinsonism, corticobasal syndrome, and ataxia have also been reported, albeit infrequently [4, 6, 8–10]. Although the majority of patients with C9orf72 expansions have a positive family history of FTD and/or MND , approximately 6% of sporadic cases of bvFTD are also due to this mutation .
Earlier reports of chromosome 9p-linked families described patients with psychotic features (hallucinations or delusions) [12–15], suggesting that these symptoms could be markers of this mutation. The first studies to describe the phenotype associated with C9orf72 expansions at a group level therefore sought to characterize the neuropsychiatric features associated with this mutation.
In this review, we will consider the neuropsychiatric features associated with bvFTD (with or without MND) due to mutations in C9orf72, based on the literature published since September 2011, presenting available data from cohorts of mutation carriers.
We reviewed papers published and/or listed on PubMed prior to 1 May 2012, using the search term 'C9orf72'. We included in this review studies on cohorts of C9orf72 mutation carriers that presented data on neuropsychiatric symptoms of any kind. Case reports, reviews and/or editorials were excluded. We gathered information on whether the behavioral features were present early in the disease course (early behavioral features) or anytime during the course of disease. Symptoms reported as 'first (neuropsychiatric) symptoms' , 'at initial referral'  or at 'first assessment' , in the setting of 'initial clinical presentation' , or occurring within the first year of disease  were considered early behavioral features. Symptoms reported without mention of timing [7, 18], in the 'last assessment' , or in the 'final year'  were considered present during the disease course.
Neuropsychiatric features reported in C9orf72 expansion carriers
Snowden and colleagues 
Mahoney and colleagues 
Hsiung and colleagues 
Boeve and colleagues 
Chio and colleagues 
Simón-Sanchez and colleagues 
Byrne and colleagues 
Phenotype of carriersb
19 bvFTD, 1 SD/FTD, 3 PNFA
12 bvFTD, 1 PNFA
6 FTD-MND, 1 PPA-MND
166 ALS (± FTD)
RCR and NPI
FSBS and RCRe
63 → 76%
40 → 70%
49 → 63%
30 → 47%
Loss of sympathy/empathy
~12 → ~18%
50% repet., 50% comp.
18% repet., 54% comp.
~25 → 50% obsessive
27 → 50% rigidity/persev.
1.5% acute OCD
~39 → 52%
0 → ~12%
~6 → ~12%
Lack of insight
Twenty-two manuscripts were initially identified. Of those articles, four were reviews, three were case reports and two were editorials, and all nine studies were therefore excluded. Five papers were excluded because behavioral features were not reported. One study reported psychiatric symptoms in seven (of 20) mutation carriers . Psychiatric symptoms in that paper included depression, delusions, hallucinations and paranoia, and were considered 'not uncommon' among carriers with ALS and frontotemporal lobar degeneration with MND. Because no further analysis or description was conducted, the paper was excluded from this review.
As a result, seven papers were included [4, 6, 7, 16, 17, 20, 21]. We also included a paper with the results from our center . The diagnostic make-up and methodology for behavioral symptom assessment are presented in Table 1. Only one study analyzed bvFTD and FTD-MND separately (Table 1) .
Seven studies reported psychotic features among C9orf72 expansion carriers. Delusions were reported in 0 to 45% of patients and hallucinations in 0 to 50% (Table 1). An important point to note is that only two studies compared the frequency of psychosis among carriers with FTD against a group of noncarriers [4, 5].
Prominent psychotic symptoms were observed in carriers as early manifestations by Snowden and colleagues . They reported these symptoms in 12/32 patients (38%) with C9orf72 expansion (contrasting with <4% among noncarriers, which was a statistically significant difference), leading to initial diagnoses of 'delusional psychosis, somatoform psychosis, or paranoid schizophrenia'. At the time of referral, 16/32 patients had developed delusions, which were somatic in nature (that is, altered temperature perception, preoccupation with bowel movements, leg pain, and so forth) in eight of those patients. The authors also observed that none of the patients with delusions had a prior history of psychiatric conditions, which differed from those without the mutation. Hallucinations were reported in six carriers (19%) at the time of referral.
Psychotic symptoms were also frequent in our group . Delusions were more frequently reported as the first neuropsychiatric symptoms among bvFTD patients with the C9orf72 mutation (21%) than among sporadic non-carriers (0%). In FTD-MND, however, carriers and noncarriers had similar frequencies of delusions as first symptoms (18% and 11%, respectively). Delusions were usually of paranoid type, and frequently involved the patients' spouses, such as claiming the partner was cheating or tricking the patient. The type of delusion in our cohort did not seem to differentiate carriers and noncarriers, and somatic delusions such as those reported by Snowden and colleagues were not observed among carriers in our cohort. Visual hallucinations were not reported as early neuropsychiatric symptoms in C9orf71-associated disease and, at first evaluation, were infrequent (Table 1). There were no auditory hallucinations. Interestingly, using the Neuropsychiatric Inventory  at first evaluation, the difference in delusions between carriers and noncarriers was no longer present, suggesting that, in this cohort, delusions could be specific to C9orf72 mutations only if reported as first symptoms rather than at first evaluation.
Boeve and colleagues reported delusions in 45% and hallucinations in 50% of 20 carriers with bvFTD, FTD-MND, and ALS, but those symptoms were not further detailed . In their cohort, delusions and hallucinations were present in two out of three patients with FTD-MND.
Carriers with ALS were also noted to have psychotic symptoms. In a cohort of familial ALS (with or without FTD), Chio and colleagues reported three probands with prominent delusions and/or hallucinations (in the context of FTD-MND), stating that psychotic symptoms were more common among carriers than noncarriers with familial ALS . However, ALS patients with C9orf72 expansions were also more likely to develop cognitive impairment (that is, FTD) than carriers of other ALS-causing mutations (such as FUS, TARDBP, SOD1 and unknown genes), making it less clear whether psychosis was associated with the mutation or was only associated with the presence of cognitive impairment.
In contrast, three studies found lower numbers of carriers with psychotic symptoms. Although Simón-Sanchez and colleagues noted hallucinations (visual or auditory), this occurred only in two out of 42 mutation carriers and none had delusions . Mahoney and colleagues reported delusions and hallucinations in only approximately 10% of patients with C9orf72 expansions . Delusions were late manifestations of disease, and were not observed in the initial assessment in any carrier, whereas hallucinations were reported in about one-half of patients at the first assessment. Hsiung and colleagues reported one bvFTD mutation carrier out of 30 that presented with delusions, who was initially diagnosed with psychosis/schizophrenia .
Apathy and disinhibition were common early neuropsy-chiatric symptoms in many cohorts (Table 1) [5, 17, 24]. Although these symptoms are hallmarks of bvFTD and are included in the diagnostic criteria (disinhibition, apathy/inertia, loss of sympathy and/or empathy, per-severative or compulsive behavior, and eating behavior changes) , other symptoms, such as depression or anxiety, were also found to be frequent among carriers in some studies. The most frequent symptoms were highly variable across studies. For example, Mahoney and colleagues found that anxiety (33%) and disinhibition (13%) were the most commonly reported initial behavioral changes . Hsiung and colleagues observed that carriers developed, in the first year of disease, disinhibition (40%), apathy (30%), rigidity/perseveration (27%) and depression (13%) . Simón-Sanchez and colleagues found in the 34 carriers diagnosed with bvFTD that the initial clinical presentation was apathy in 53%, disinhibition in 32%, and obsessive-compulsive behavior in 15% . Obsessive-compulsive disorder was also reported in one carrier from the study by Chio and colleagues .
Only one study compared the first neuropsychiatric features of carriers and noncarriers with bvFTD and FTD-MND separately , and statistically significant differences were not found. In C9orf72-associated bvFTD, apathy (50%), obsession (28.5%) and delusions (21%) were the most common first neuropsychiatric symptoms. Aggression, depression and irritability were reported in 14.2% of cases. Carriers with FTD-MND presented disinhibition (36.3%), rash/careless actions (27.2%), apathy (18.1%) and delusions (18.1%).
As expected, the most frequently reported behavioral symptoms in cohorts with C9orf72 mutations are those also used in the FTD research diagnostic criteria . Across all studies that reported neuropsychiatric symptoms in patients carrying this mutation, apathy and disinhibition were again the most frequently observed (Table 1), but frequencies varied considerably across studies. Using the Frontal Systems Behavioral Scale [19, 26, 27], Byrne and colleagues found higher apathy scores in carriers than in noncarriers (but disinhibition scores were not different) . In the study by Sha and colleagues, however, neither the apathy or disinhibition subscores from the Neuropsychiatric Inventory were significantly different . In Table 1 the frequencies are reported during the course of disease and/or at last assessment in mutation carriers.
In the study by Snowden and colleagues, repetitive/stereotypic behaviors were commonly characterized by complex routines, sometimes associated with obsessive symptoms, while simple motor behaviors were infrequent [4, 6].
Regarding eating behaviors, Snowden and colleagues found that mutation carriers in their cohort had less dietary changes than noncarriers . This was mostly due to decreased preference for sweet foods rather than changes in food intake. We found a similar pattern in our cohort, as mutation carriers with bvFTD had milder eating behaviors than noncarriers as noted on the Neuropsychiatric Inventory at first evaluation in our cohort . In contrast, Boeve and colleagues reported appetite/eating behavior changes in all mutation carriers from whom information was available . Altered eating behaviors are common in bvFTD, and have been associated with pathology for frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP) , so no conclusions regarding C9orf72 and these behaviors can be reached at this point.
We reviewed the neuropsychiatric features observed in the recently discovered C9orf72 mutation and found seven studies from major FTD and/or ALS groups or consortia that included these features. The number of carriers in the available studies was relatively small and most studies did not systematically compare behavioral symptoms in mutation carriers with noncarriers, thus limiting the conclusions on whether there are distinguishing features specific to the mutation. In addition, direct comparison across studies is difficult due to significant variation in results, data collection methodology, and means of reporting data.
Psychosis was often reported in studies as an early neuropsychiatric feature in C9orf72-associated bvFTD. In fact, both studies that compared this behavioral feature among expansion carriers with a group of non-carriers found that psychosis was more frequent among carriers. However, this finding was not consistent across groups and there was a broad range of frequencies of psychotic symptoms among carriers. Most studies were retrospective chart reviews, which could explain the variation across studies in part, as some neuropsychiatric features might be underestimated. In addition, the cohorts were relatively small (all cohorts had less than 67 carriers), which could substantiate this variability. Studies with larger cohorts to determine more reliably the frequency of psychosis are needed. Molecular and pathological characteristics of the cohorts could also be different, leading to different experiences across groups. The number of hexanucleotide repeats, which is not currently quantifiable , could be a source of phenotypical heterogeneity. The neuropathological findings associated with this mutation are also heterogeneous. While ubiquitin/p62-positive inclusions in the cerebellar granule cell layer appear to be specific of this mutation, they are found in most, but not all, cases [6, 7, 17]. The distribution of TDP-43 pathology may be consistent with FTLD-TDP types A or B, or may show mixed features of both types [6, 7, 17]. Different frequencies of TDP pathology types could explain the disparity in findings: FTD-MND and its underlying pathological finding, FTLD-TDP type B, have also been linked to psychotic features [19, 26]. In the cohort characterized by our group, only carriers diagnosed with bvFTD had a higher frequency of delusions, without a statistically significant difference between carriers and noncarriers with FTD-MND . Conversely, Snowden and colleagues reported delusions in only one noncarrier with the FTD-MND phenotype , suggesting that this symptom type was associated with the mutation rather than with pathology.
The neuroanatomical basis of delusions in FTD is yet to be clearly characterized , and additional analyses of C9orf72 may further develop this knowledge. Thalamic and cerebellar atrophy have been reported in mutation carriers [5, 6], and Mahoney and colleagues hypothesized that thalamic and cerebellar projections could be related to the neuropsychiatric features associated with this mutation, including hallucinations and/or delusions .
One should note that although psychosis is considered rare in bvFTD , it is not specific to this mutation and has been also reported with a higher frequency in patients diagnosed with the FTD-MND phenotype and those with atypical frontotemporal lobar degeneration with FUS pathology. Lillo and colleagues found that delusions were present in 50% of patients diagnosed with FTD-MND (not tested for C9orf72 expansion), which was significantly more frequent than in patients with bvFTD without MND (19%) . They observed a variety of delusions, including somatic and persecutory delusions. The frequency of hallucinations was not different between groups, however. Urwin and colleagues reported that 36% of patients presenting a subtype of FTLD with FUS pathology, termed atypical FTLD-U, had hallucinations or delusions . The age at onset of symptoms in this group was younger than observed in bvFTD due to C9orf72 expansions. Psychosis has also been reported in patients with bvFTD carrying other mutations, although no studies have shown higher frequencies of psychotic symptoms among carriers of other FTD-causing mutations when compared with a group of non-carriers. Le Ber and colleagues reported hallucinations in 25% of progranulin gene GRN mutation carriers  (although other groups did not find similarly high frequencies of this symptom ). Johnson and colleagues reported psychotic features in one patient with a valosin-containing protein gene VCP mutation . Psychosis has only infrequently been reported in families with microtubule-associated protein tau gene MAPT mutations [35, 36].
Apathy and disinhibition were also frequently seen in mutation carriers. However, these symptoms are also common in sporadic bvFTD and are unlikely to distinguish carriers from noncarriers. Other behavioral features were variably reported during the course of disease (Table 1) without a discernible pattern that can be attributed to the C9orf72 expansions at this point. For example, eating behavior changes were suggested to be less common among carriers in two studies [4, 5], but in another study were observed in 100% of carriers . The lack of substantial differences by genotype could indicate that overall the neuropsychiatric presentation associated with the mutation is similar to sporadic patients. This lack of difference could also reflect the heterogeneity seen in the clinical presentation of C9orf72 expansion carriers with bvFTD (with or without MND), leading to varying results in different groups (particularly considering the size of the samples reported in each study). Some patients, for example, may develop subtle behavioral changes years or decades before being diagnosed with dementia , a feature that may not be captured in group-based studies.
Although imaging is not the focus of this review, it is noteworthy that a fraction of patients with FTD due to C9orf72 mutations may have minimal atrophy on neuroimaging [7, 38], which is another aspect of the heterogeneity associated with this mutation. Interestingly, among five patients with bvFTD who presented with psychotic symptoms, Velakoulis and colleagues reported minimal macroscopic atrophy in two (one patient with FTD-MND pathology, and the other patient with FTD and MND-type inclusions on autopsy) . Atrophy on neuroimaging is sometimes used in clinical practice as a way to distinguish neurodegenerative conditions from those considered primarily psychiatric, so patients with this mutation who present with prominent neuropsychiatric symptoms and have little to no changes on neuroimaging may be particularly prone to being misdiagnosed .
In summary, delusions and hallucinations might be markers of C9orf72-associated disease, but studies with larger cohorts are needed to further substantiate this armation. The overall neuropsychiatric presentation of this mutation appears to be similar to sporadic disease in regard to typical bvFTD symptoms, but its presentation is heterogeneous and a subset of mutation carriers may be at higher risk of being misdiagnosed with primary psychiatric conditions.
amyotrophic lateral sclerosis
behavioral variant frontotemporal dementia
chromosome 9 open reading frame 72
frontotemporal lobar degeneration with TDP-43 positive inclusions
motor neuron disease
Data shown in this manuscript include information collected through research funded by the Larry L. Hillblom Foundation, the Consortium for Frontotemporal Dementia Research, the John Douglas French Alzheimer's Foundation, the Tau Consortium, NIH grants P50AG023501, P01AG019724 and P50 AG1657303, the State of California, and the Alzheimer's Disease Research Center of California grant 03-7527.