Genetics

The genetic landscape of FTD has been gradually expanding. At least 30% of FTD patients have a causative genetic mutation, with the C9orf72 hexanucleotide repeat expansion, GRN mutations, and MAPT mutations being the most common.^{Reference Onyike and Diehl-Schmid58,Reference Greaves and Rohrer59} In addition, mutations in VCP, CHMP2B, TIA1, TBK1, TARDBP, OPTN, and UBQLN2 are reported in small number of families all over the world.^{Reference Raggi, Bartoletti-Stella, Parchi and Capellari52,Reference Greaves and Rohrer59} Among the rarer genetic mutations, UBQLN2 has been associated with psychosis in a recent case report.^{Reference Raggi, Bartoletti-Stella, Parchi and Capellari52}

C9orf72

A hexanucleotide repeat expansion in the C9orf72 gene, discovered in 2011, is the most frequent genetic cause of FTD and ALS in North America and Europe.^{Reference Balendra and Isaacs60} This repeat expansion may cause pathogenic effects through multiple mechanisms, including toxic gain-of-function and loss-of-function. According to the putative gain-of-function mechanism, C9orf72 hexanucleotide repeats undergo transcription into repeat RNAs which sequestrate RNA binding proteins and are translated into dipeptide repeats, which form neuronal inclusions.^{Reference Ducharme, Bajestan, Dickerson and Voon7,Reference Balendra and Isaacs60} According to the putative loss-of-function mechanism, expansion of the hexanucleotide repeat in the promoter region of the C9orf72 gene leads to lower protein levels of C9orf72, which impairs autophagy and lysosomal function.^{Reference Balendra and Isaacs60}

Our literature review revealed 29 articles that reported psychosis in association with the C9orf72 mutation. Out of a total of 557 subjects with the C9orf72 hexanucleotide repeat expansion, 175 subjects (31.4%) developed psychotic symptoms, making it the most common genetic mutation reported in association with psychosis and FTD. Compared to the total number of FTD patients with a confirmed genetic mutation with clinical psychosis we found in the literature (N = 204), C9orf72 mutation carriers constituted the majority (86%), confirming the previously reported assertion that psychosis in the context of a family history of FTD is suggestive of C9orf72 mutation.^{Reference Snowden, Rollinson and Thompson28} A small study reported that a 10-base pair deletion adjacent to the C9orf72 expansion may be protective against the development of psychosis.^{Reference Snowden, Harris and Adams44}

Patients with the C9orf72 hexanucleotide repeat expansion demonstrate wildly different ages of onset and clinical presentations, including bvFTD, FTD-ALS, or ALS alone. The clinical characteristics of C9orf72 carriers are summarized in Table 2. The mean age of onset of symptoms in C9orf72 mutation carriers with psychosis was 55.7 years (Table 2). In addition to behavioral features of FTD, 27.0% of patients developed ALS and 23.6% of patients developed Parkinsonism. Among C9orf72 mutation carriers, delusions were the most common psychotic feature. Patients reported bizarre delusions, hallucinations, or both.

Table 2: Clinical characteristics of FTD patients with a genetic mutation and psychosis

Although most patients with psychosis developed cognitive and behavioral features suggestive of bvFTD, cognitive impairment may trail the onset of psychotic symptoms in C9orf72 mutation carriers.^{Reference Sommerlad, Lee, Warren and Price38} Patients with longstanding psychosis prior to the diagnosis of bvFTD have also been described.^{Reference Sellami, St-Onge, Poulin and Laforce3,Reference Kertesz, Ang and Jesso32} In these situations, neuroimaging and genetic testing for the C9orf72 mutation led to the final diagnosis. As patients with the C9orf72 mutation may present with predominantly psychotic features, investigators examined cohorts of patients with a psychiatric diagnosis for the mutation. Screening of two cohorts of patients with schizophrenia and psychosis for C9orf72 mutation did not reveal any mutation carriers, suggesting this is not a common cause of psychosis in the general population.^{Reference Huey, Nagy and Rodriguez-Murillo61} However, family members of C9orf72 carriers are at increased risk of developing schizophrenia or psychosis^{Reference Devenney, Ahmed, Halliday, Piguet, Kiernan and Hodges62}, suggesting some pathogenic role of the C9orf72 mutation in the development of psychosis in sporadic schizophrenia.

GRN

GRN encodes the progranulin protein, which is widely distributed throughout the body and has diverse functions, including neuronal differentiation and anti-inflammatory actions.^{Reference Hsiung, Feldman, Pagon, Adam, Ardinger and et al.63} The GRN mutation was discovered as an etiology of autosomal dominant FTD in 2006.^{Reference Baker, Mackenzie and Pickering-Brown64} Since then several pathogenic mutations have been described, which possibly cause neurodegeneration through a loss-of-function mechanism. Heterozygous mutations in GRN lead to haploinsufficiency and loss of functional progranulin protein.

Our literature search identified seven articles that reported psychotic symptoms associated with GRN mutations, which reported a combined prevalence of psychosis of 15.0% among GRN mutation carriers (N = 153). GRN mutations may be associated with bvFTD, a PPA syndrome, or a mixed phenotype.^{Reference Greaves and Rohrer59} The clinical characteristics of GRN carriers with psychosis are summarized in Table 2. The average age of onset of symptoms in GRN mutation carriers in our literature survey was 59.1 years. Visual hallucinations were the most common psychotic feature in GRN mutation carriers. In addition, cognitive deficits in the form of aphasia, apraxia and acalculia, and motor symptoms of Parkinsonism were present. Analysis of the Genetic FTD Initiative (GENFI) cohort revealed a 4% prevalence of hallucinations and a 5% prevalence of delusions among GRN mutation carriers (N = 75).^{Reference Sellami, Bocchetta and Masellis49} Several mutations in the GRN gene were reported in patients with psychosis, including deletions (c.753–754del TG) and missense (c.1A > G) mutations. Le Ber et al reported a higher incidence of visual hallucinations among GRN mutation carriers.^{Reference Le Ber, Camuzat and Hannequin11} They also reported a unique patient who was diagnosed with schizophrenia due to lack of cognitive impairment. Momeni et al also reported a family with the GRN mutation (c.675–676del CA) with history of early-onset psychosis, which was diagnosed as schizophrenia.^{Reference Momeni, DeTucci and Straub16} A genetic study of families with schizophrenia revealed a significant linkage with the genetic locus 17q21, which contains the GRN gene.^{Reference Escamilla, Hare and Dassori65}

MAPT

The MAPT gene encodes isoforms of the tau protein, which is involved in microtubule stabilization in neurons. MAPT was the first gene associated with the development of FTD, described by Hutton et al in 1998.^{Reference Hutton, Lendon and Rizzu66} Since then several mutations in the MAPT gene have been described, which cause FTD through different mechanisms, including an altered 3R/4R tau ratio and abnormal tau phosphorylation.^{Reference Deleon and Miller67}

Our literature survey revealed six articles that reported psychosis in association with MAPT mutations. MAPT mutation carriers may present with clinical features of FTD, PPA, or an atypical Parkinsonian syndrome, such as corticobasal syndrome.^{Reference Greaves and Rohrer59} The articles reported 6 patients with psychotic symptoms out of a total of 65 patients with MAPT mutations (9.2%). The average age of onset of symptoms in patients with psychosis was 36.5 years, though the accuracy of this result is limited by small numbers. In MAPT mutation carriers, delusions were the prevalent psychotic feature, whereas frank hallucinations were rare.^{Reference Naasan, Shdo and Rodriguez56} Notably, the age of onset of MAPT mutation carriers with psychosis was younger than C9orf72 or GRN mutation carriers, which has also been observed in previous publications.^{Reference Gasca-Salas, Masellis and Khoo68,Reference Moore, Nicholas and Grossman69} Khan et al described a patient with longstanding psychosis prior to diagnosis of FTD.^{Reference Khan, Woolley and Chao24} A comparative study reported a lower frequency of psychotic features in MAPT mutation carriers (zero percent) compared to GRN (24% delusions and 6% hallucinations) and C9orf72 (50% delusions and 21% hallucinations) mutation carriers.^{Reference Snowden, Adams and Harris41} Thirty-three percent of MAPT mutation carriers demonstrated Parkinsonism on neurologic examination.^{Reference Snowden, Harris and Adams44}

Pathology

The pathological cause of clinical FTD is frontotemporal lobar degeneration (FTLD) named after the pattern of brain atrophy identified on macroscopic examination of the brain. FTLD is subclassified based on the type of abnormal protein inclusions observed on histological examination. There are three main types of proteins that accumulate abnormally in FTLD: transactive response DNA-binding protein 43 kDa (TDP-43; FTLD-TDP), tau (FTLD-tau), and the FET family of RNA-binding proteins (FTLD-FET).^{Reference Neumann and Mackenzie70} C9orf72 and GRN mutations are associated with FTLD-TDP pathology, while MAPT mutations are associated with FTLD-tau pathology. The prevalence of psychosis is different for each pathological class; however, overall 22.7% of cases were found to have psychosis in this review. A single study was found that compared sporadic and genetic cases within pathological classes: it showed that patients with FTLD-TDP type B pathology with and without delusions had a similar percentage that tested positive for the C9orf72 hexanucleotide repeat expansion.^{Reference Naasan, Shdo and Rodriguez56} This suggests that delusions were not necessarily predictive of the presence of this mutation.

FTLD-TDP

TDP-43 is a widely expressed RNA-binding protein that is predominantly localized in the nucleus of a cell. TDP-43 regulates metabolism of a wide variety of RNA species, which in turn regulate neuronal development and synaptic functions. Fifty percent of FTD patients demonstrate abnormal TDP-43 inclusions in the brain (FTLD-TDP).^{Reference Deleon and Miller67} Abnormal TDP-43 undergoes posttranslational modifications including phosphorylation and ubiquitination. The normal nuclear staining pattern of TDP-43 is also lost in FTD.

We retrieved 10 articles that reported psychosis in the context of FTLD-TDP pathology from the literature search. The studies reported a combined 223 patients with FTLD-TDP, including single case reports. Overall, 25.3% of patients with FTLD-TDP pathology were reported to have developed psychosis, most of these data taken from any point in the disease course. Among 61 patients with FTLD-TDP pathology and the C9orf72 mutation, 12 patients (19.7%) developed psychosis.^{Reference Dobson-Stone, Hallupp and Bartley21,Reference Hsiung, DeJesus-Hernandez and Feldman23,Reference Mahoney, Beck and Rohrer25,Reference Landqvist Waldo, Gustafson and Nilsson33} Among 51 patients with FTLD-TDP pathology without the C9orf72 mutation, 21 patients (41.2%) developed psychosis. In psychotic patients with FTLD-TDP pathology, delusions were slightly more common than hallucinations. A wide variety of delusions were reported, including delusion of pregnancy and bizarre somatoform delusions. Two studies reported a high prevalence of hallucinations in the range of 40–50%.^{Reference Boeve, Boylan and Graff-Radford20,Reference Naasan, Shdo and Rodriguez56} However, multiple studies specifically recruited patients with the C9orf72 mutation^{Reference Pearson, Williams and Majounie18,Reference Dobson-Stone, Hallupp and Bartley21,Reference Hsiung, DeJesus-Hernandez and Feldman23,Reference Mahoney, Beck and Rohrer25,Reference Snowden, Rollinson and Thompson28} , including one of these two studies. Therefore, the studies, which described patients with the C9orf72 mutation, may have influenced the prevalence of psychosis in patients with FTLD-TDP pathology. Furthermore, several studies looked at psychosis at any stage of the disease course, so it could be that they have captured psychosis in late-stage disease, a feature of many neurodegenerative disorders.

Pathologically, the literature does not reveal a clear difference in general histological findings between patients with and without psychosis. Almost all studies reported degeneration of the frontotemporal cortex and variable involvement of the hippocampus, particularly the CA1 subsector.

FTLD-TDP pathology is heterogeneous in its cortical distribution and morphology of inclusions and has been further organized into several pathological subtypes named A to D.^{Reference Neumann and Mackenzie70} We examined the reported prevalence among these subtypes in patients with psychosis. As some articles did not mention the subtypes specifically, VHR reviewed the pathological description and assigned subtypes according to the current classification. Within FTLD-TDP, subtype B (N = 21) was the most common subtype associated with psychosis in FTD patients, compared to four cases associated with subtype A (N = 4) and one case each with subtypes C and D.

FTLD-Tau

Approximately 40% of patients with FTD demonstrate abnormal tau pathology (FTLD-tau).^{Reference Neumann and Mackenzie70} Tau is a phosphoprotein that promotes microtubule polymerization and stabilization of microtubules. Different isoforms of tau exist based on splicing of exon 10 of the tau-encoding MAPT gene. The isoforms are labeled 3R or 4R depending on the number of repeats of a 32 amino acid conserved sequence. FTLD-tau is a clinically and pathologically heterogenous group and comprises both 3R tauopathies (e.g., Pick’s disease) and 4R tauopathies (e.g., corticobasal degeneration and progressive supranuclear palsy).

Nine articles described psychosis in association with FTLD-tau pathology in 227 patients, and in total, 16.4% with tau pathology developed psychosis. The average age of disease onset was 59.8 years. Most of the patients with psychosis were from a single study.^{Reference Naasan, Shdo and Rodriguez56} In this study, hallucinations were slightly more common than delusions, and over 50% of those with psychosis had both delusions and hallucinations. Delusions were less common when compared to patients with FTLD-TDP pathology. In addition, some of the patients with visual hallucinations had concomitant Lewy Body pathology, which may have been a contributing factor.^{Reference Naasan, Shdo and Rodriguez56} This was supported by logistic regression analysis in another study, demonstrating an increased risk of delusions and hallucinations in patients with any concomitant Alzheimer or Lewy Body pathology.^{Reference Devanand, Lee, Huey and Goldberg57}

Pick’s disease is characterized by argyrophilic, tau-immunoreactive pathological inclusions called Pick bodies, which are predominantly composed of 3R tau.^{Reference Mackenzie and Neumann71} In this review, 5 articles reported 12 patients with psychosis associated with Pick’s disease, or 17.9% of cases. The mean age of onset of symptoms in psychotic patients with Pick’s disease was 56.3 years. A mixture of delusions and hallucinations were reported in these 12 patients, with the largest study reporting a slightly higher number with delusions than hallucinations, and a small proportion with both.^{Reference Naasan, Shdo and Rodriguez56} Hallucinations were often auditory.^{Reference Waddington, Youssef, Farrell and Toland9,Reference Irwin, Brettschneider and McMillan43}

FTLD-FUS

In some patients with tau- and TDP-43-negative FTLD pathology, Fused in Sarcoma (FUS) was discovered to be the constituent of pathological inclusions.^{Reference Urwin, Josephs and Rohrer17} FUS is a member of the FET family of RNA-binding proteins, which also include EWS RNA binding protein 1 (EWSR1) and TAF15.^{Reference Neumann and Mackenzie70} FUS pathology is also observed in familial ALS, which is a result of mutations in the FUS gene. In contrast, FTD associated with FUS pathology is almost always sporadic.^{Reference Mann and Snowden72} FUS is involved in several steps of RNA metabolism, which include RNA granule formation, nucleo-cytoplasmic transport, and protein translation. FUS has a low-complexity domain that can form polymers and transition from soluble to insoluble states. This is a putative mechanism for neurodegeneration in FUS pathology.

Patients with FTLD-FUS pathology had a high overall prevalence of psychosis in our literature survey, though the proportion varied in individual studies likely due to small numbers. We retrieved five articles that reported psychosis in the context of FUS pathology.^{Reference Urwin, Josephs and Rohrer17,Reference Rohrer, Lashley and Holton19,Reference Landqvist Waldo, Gustafson, Passant and Englund39,Reference Kawakami, Arai, Shinagawa, Niizato, Oshima and Ikeda53,Reference Devanand, Lee, Huey and Goldberg57} The prevalence of psychosis was 30% among 40 patients reported in the retrieved articles. Patients with FTLD-FUS pathology had an earlier age of onset compared to sporadic bvFTD, which holds true for patients who develop psychosis as well. Although the ages of onset for all the patients were not available, one study reported three patients with FTLD-FUS and psychosis with an average age of onset 32.7 years.^{Reference Landqvist Waldo, Gustafson, Passant and Englund39} It was also noted that patients with FTLD-FUS are more likely to receive a psychiatric diagnosis initially due to their early age of onset.