bvFTD: behavioral variant frontotemporal dementia
C9orf72: chromosome 9 open reading frame 72
FTD: frontotemporal dementia
Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative condition characterized by prominent behavioral changes and executive impairment (Rascovsky et al, 2011). The three main genes associated with FTD are microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72). The C9orf72 hexanucleotide repeat expansion is the most common cause of familial FTD and FTD-amyotrophic lateral sclerosis (Cooper-Knock et al, 2014). Behavioral variant FTD shares a constellation of clinical features with primary psychiatric disorders such as disinhibition, apathy, and perseverative/compulsive behaviors. Social cognition impairment, including alteration in interpersonal functioning and social interactions, is also a common thread between these disorders. This clinical overlap leads to misdiagnoses in up to 50% of patients presenting with atypical psychiatric conditions or frontal lobe syndrome (Krudop et al, 2017). The differential diagnosis is especially challenging in C9orf72 repeat expansion carriers, who may initially exhibit psychotic symptoms (Galimberti et al, 2013; Shinagawa et al, 2014). Such findings revive the debate about the overlap between schizophrenia and FTD (Harciarek et al, 2013) and raise the question of whether C9orf72 repeat expansion may be involved in neuropsychiatric syndromes beyond the spectrum of neurodegenerative disease.
A 61-year-old woman was referred to our memory clinic for behavioral changes and progressive cognitive decline over the past 3 years. During her life, she had obtained an undergraduate college degree and had worked as a secretary at a university. At 36 years of age, she started developing delusions and auditory hallucinations (eg, she described being pursued by “bad angels” and reported that her husband and the devil communicated with her telepathically). She also exhibited social withdrawal and lack of self-awareness. At this time, the patient was diagnosed with paranoid schizophrenia. Since then, she has been hospitalized in the psychiatric department several times. Subsequently, her psychotic symptoms remained relatively stable, but she was unable to return to work. The patient also experienced severe adverse reactions to antipsychotic medication, which is consistent with neuroleptic malignant syndrome.
At age 55, the patient presented with an exacerbation of psychotic symptoms. The police had to intervene after she began regularly standing in front of a house she was convinced she had inherited. She gradually became highly disorganized and passive, and she no longer initiated activity, which impacted her activities of daily living considerably and necessitated nursing home placement. In addition, the patient started to display new perseverative behaviors such as wiping her saliva for hours and playing with her wheelchair brakes (following a leg fracture). For her psychiatric symptoms, she was on clozapine, risperidone, and divalproex. She was referred by her psychiatrist to our memory clinic for unusual disease course, and we were asked to evaluate whether her condition was an atypical exacerbation of schizophrenic symptoms or an atypical neurodegenerative disorder. Her family history revealed that she had been adopted in childhood because her biological mother suffered from psychiatric disorders. Her son was also known to have been diagnosed with schizophrenia.
On first examination, at the age of 61, the patient was apathetic and exhibited echolalia and motor stereotypies. She scored 20 on the Mini-Mental State Examination (Folstein et al, 1975) and 14 on the Montreal Cognitive Assessment (Nasreddine et al, 2005). Her cognitive performance was remarkable for executive dysfunction, including attention and working memory deficits, decreased phonemic fluency, and altered abstract thinking, as well as visuoconstructional dyspraxia. Her basic neurologic examination was unremarkable, and her laboratory workup was within normal limits.
The patient’s brain MRI showed mild bilateral frontal and temporal cortical atrophy (Figure 1A), and her 18F-fluorodeoxyglucose PET revealed predominantly left hypometabolism in the frontopolar, orbitofrontal, and medial frontal regions and the anterior temporal cortex (Figure 1B). Her electromyogram was normal. Genetic analysis revealed C9orf72 hexanucleotide repeat expansion with more than 80 G4C2 repeats.
Based on consensual diagnostic criteria (Rascovsky et al, 2011), we made a diagnosis of bvFTD with definite frontotemporal lobar degeneration pathology (ie, presence of a known pathogenic mutation, C9orf72 hexanucleotide repeat expansion).
All patient information, test results, and history described here were collected through evaluation at our memory clinic and from the patient’s medical record. Informed consent for publication was obtained from the patient’s caregiver. The patient’s son was not available for genetic testing.
This case illustrates the overlap between schizophrenia and bvFTD and raises the issue of whether C9orf72 mutation can be involved in the occurrence of both conditions. Recently, C9orf72 repeat expansion carriers have been reported to show a high frequency of psychotic symptoms (up to 38% of cases) (Snowden et al, 2012), which often emerge several years before the onset of hallmark features of dementia (Arighi et al, 2012; Ducharme et al, 2017). In most reports of C9orf72 repeat expansion carriers, psychiatric symptoms appeared at the same time, or preceded by a few years, typical symptoms of bvFTD (Block et al, 2016), and were often described as late-onset psychosis (Galimberti et al, 2013). Our patient, however, presented with schizophrenia more than 20 years before the progressive behavioral-cognitive decline that led to the diagnosis of bvFTD.
The C9orf72 hexanucleotide repeat expansion has previously been identified as a rare but possible cause of schizophrenia spectrum disorders (Galimberti et al, 2014). In a previous study, the C9orf72 repeat expansion was detected in only 0.67% of patients with schizophrenia or schizoaffective disorders (Galimberti et al, 2014). However, it has recently been found that relatives of C9orf72 repeat expansion carriers have a significantly higher risk of developing schizophrenia than relatives of noncarriers (Devenney et al, 2018).
Although data are scarce, psychotic symptoms in C9orf72 repeat expansion carriers have been suggested to be phenomenologically close to the symptoms of schizophrenia. In addition, somatic delusions and body image distortion have been suggested to be potential key features of the C9orf72 mutation (Ducharme et al, 2017; Snowden et al, 2012). Some anecdotal cases of adverse reactions to antipsychotics have also been reported (Ducharme et al, 2017). Neuropsychiatric symptoms in C9orf72 repeat expansion carriers have been previously suggested to arise from an aberrant body or self-schema processing (Downey et al, 2014). Although the mechanisms underpinning the C9orf72-related phenotypes remain elusive, the cortico-thalamo-cerebellar network has been suggested to be a possible substrate (Devenney et al, 2018).
The hypothesis of an insular dysfunction in C9orf72 repeat expansion carriers could also be worth exploring. The insula, as a key hub in the salience network, has been shown to be involved in both schizophrenia and genetic FTD (Palaniyappan and Liddle, 2012; Rohrer et al, 2015). A recent study has also demonstrated a correlation between neuropsychiatric symptoms in C9orf72 repeat expansion carriers and gray matter atrophy in several frontal and cerebellar areas (Sellami et al, 2018); this study suggested that the clinical overlap between FTD and primary psychiatric conditions might be mediated by common alterations and intrinsic vulnerability of large-scale networks such as the salience network. Another study suggested that the alteration of the cortico-thalamo-cerebellar network might be a signature of C9orf72 hexanucleotide repeat expansion (Marshall et al, 2016). The hypothesis of C9orf72-related neurodevelopmental abnormalities or early functional synaptic and neurotransmitter changes, preceding neurodegeneration, could be one explanation of the time gap between schizophreniform manifestations and typical features of bvFTD.
In summary, this report described a distinct C9orf72-associated phenotype revealed by schizophrenia with severe neuroleptic sensitivity that preceded bvFTD by 20 years. This case suggests that early emergence of schizophrenia manifestations might reflect prodromal and slowly progressive neurodegeneration or neurodevelopmental and neurobiological effects of C9orf72 hexanucleotide repeat expansion (Lee et al, 2017).
We suggest that analysis of C9orf72 hexanucleotide repeat expansion be considered in some specific cases of schizophrenia spectrum disorders (eg, a family history of bvFTD and/or amyotrophic lateral sclerosis; schizophrenia cases showing atypical cognitive-behavioral changes, even after a long disease course; or unusual response to antipsychotic medication). Further studies are needed to identify the distinctive clinical features of the schizophrenia phenotype associated with C9orf72 hexanucleotide repeat expansion and establish specific indications for this genetic testing in patients with schizophrenia.
Arighi A, Fumagalli GG, Jacini F, et al. 2012. Early onset behavioral variant frontotemporal dementia
due to the C9ORF72
hexanucleotide repeat expansion: psychiatric clinical presentations. J Alzheimers Dis. 31:447–452.
Block NR, Sha SJ, Karydas AM, et al. 2016. Frontotemporal dementia
and psychiatric illness: emerging clinical and biological links in gene carriers. Am J Geriatr Psychiatry. 24:107–116.
Cooper-Knock J, Shaw PJ, Kirby J. 2014. The widening spectrum of C9ORF72
-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype. Acta Neuropathol. 127:333–345.
Devenney EM, Ahmed RM, Halliday G, et al. 2018. Psychiatric disorders in C9orf72
kindreds: study of 1414 family members. Neurology. 91:e1498–e1507. doi:10.1212/WNL.0000000000006344
Downey LE, Fletcher PD, Golden HL, et al. 2014. Altered body schema processing in frontotemporal dementia
mutations. J Neurol Neurosurg Psychiatry. 85:1016–1023.
Ducharme S, Bajestan S, Dickerson BC, et al. 2017. Psychiatric presentations of C9orf72
mutation: what are the diagnostic implications for clinicians? J Neuropsychiatry Clin Neurosci. 29:195–205.
Folstein MF, Folstein SE, McHugh PR. 1975. Mini-Mental State. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 12:189–198.
Galimberti D, Fenoglio C, Serpente M, et al. 2013. Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72
hexanucleotide repeat expansion: late-onset psychotic clinical presentation. Biol Psychiatry. 74:384–391.
Galimberti D, Reif A, Dell’osso B, et al. 2014. C9ORF72
hexanucleotide repeat expansion is a rare cause of schizophrenia
. Neurobiol Aging. 35:1214 e7–1214 e10.
Harciarek M, Malaspina D, Sun T, et al. 2013. Schizophrenia
and frontotemporal dementia
: shared causation? Int Rev Psychiatry. 25:168–177.
Krudop WA, Dols A, Kerssens CJ, et al. 2017. The pitfall of behavioral variant frontotemporal dementia
mimics despite multidisciplinary application of the FTDC criteria. J Alzheimers Dis. 60:959–975.
Lee SE, Sias AC, Mandelli ML, et al. 2017. Network degeneration and dysfunction in presymptomatic C9ORF72
expansion carriers. Neuroimage Clin. 14:286–297.
Marshall CR, Bocchetta M, Rohrer JD, et al. 2016. C9orf72
mutations and the puzzle of cerebro-cerebellar network degeneration. Brain. 139:e44. doi:10.1093/brain/aww103
Nasreddine ZS, Phillips NA, Bédirian V, et al. 2005. The Montreal Cognitive Assessment MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 53:695–699. doi:10.1111/j.1532-5415.2005.53221.x
Palaniyappan L, Liddle PF. 2012. Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction. J Psychiatry Neurosci. 37:17–27.
Rascovsky K, Hodges JR, Knopman D, et al. 2011. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia
. Brain. 134:2456–2477.
Rohrer JD, Nicholas JM, Cash DM, et al. 2015. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia
in the Genetic Frontotemporal dementia
Initiative (GENFI) study: a cross-sectional analysis. The Lancet Neurology. 14:253–262.
Sellami L, Bocchetta M, Masellis M, et al. 2018. Distinct neuroanatomical correlates of neuropsychiatric symptoms in the three main forms of genetic frontotemporal dementia
in the GENFI cohort. J Alzheimers Dis. 65:147–163.
Shinagawa S, Nakajima S, Plitman E, et al. 2014. Psychosis in frontotemporal dementia
. J Alzheimers Dis. 42:485–499.
Snowden JS, Rollinson S, Thompson JC, et al. 2012. Distinct clinical and pathological characteristics of frontotemporal dementia
associated with C9ORF72
mutations. Brain. 135:693–708.