Introduction

Behavioural frontotemporal dementia (bvFTD) is a heterogeneous neurodegenerative disorder (Balasa et al., 2015; Ledger & Banks, 2013). It is the most common subtype of frontotemporal dementia (FTD) predominately occurring in people under the age of 65, and it remains one of the most difficult phenomena to diagnose (Balasa et al., 2015; Cerami et al., 2016; Erzurumluoglu Gokalp et al., 2021; Gambogi et al., 2019; Henry et al., 2014; Perry et al., 2017; Samra et al., 2022). Clinicopathology has been able to give a deeper insight into the disease progression of bvFTD by correlating the clinical, neurobiological and neuropathological changes that led to death (Mendez et al., 2013; Perry et al., 2017). Some pathology that has come to the fore shows bvFTD evolving to supra-nuclear gaze palsy leading to progressive supranuclear palsy (PSP); and bvFTD progressing to profound semantic loss, and anterior temporal atrophy, which predicts frontotemporal lobar degeneration-transactive response protein (FTLD-TDP) (Perry et al., 2017). To gain an insight of bvFTD this literature review will look at the research into differential diagnosis, disease progression, the influence of age, neuropathology, neurobiology, and genetics and how a diagnosis of bvFTD can impact support and therapeutic approaches.

International consensus criteria for behavioural variant FTD (FTDC)

BvFTD is primarily known as a frontotemporal executive disorder. However, severe executive dysfunction does not apply to everyone diagnosed with bvFTD, because of varying underlying pathology and overlapping neurological disorders (Ledger et al., 2013; Perry et al., 2017; Rascovsky et al., 2011). BvFTD is a difficult disease to correctly diagnose which led to the development of the international bvFTD criteria consortium (FTDC) (Rascovsky et al., 2011). History of behaviour, or cognition deterioration, is the first required criterion, followed by the second criteria of possible bvFTD, where three of six persistent, or recurrent behavioural, or cognitive symptoms, must be present, for example: early apathy, behavioural disinhibition or hyperorality (Rascovsky et al., 2011). The third criteria required for probable bvFTD must include three symptoms, such as: possible bvFTD criteria, evidence of functional decline and imaging results displaying either frontal and/or anterior atrophy or hypofusion (Rascovsky et al., 2011). The fourth criteria must include either possible or probable bvFTD and have frontotemporal lobar dementia (FTLD) pathology, such as histopathological or pathogenic mutation evidence (Rascovsky et al., 2011). The fifth criterion excludes psychiatric disorders and other non-associated medical or nervous disorders, whereas Alzheimer’s disease biomarkers may only be included with possible bvFTD (Rascovsky et al., 2011). Although the international FTDC have been essential in the difficult diagnosis of bvFTD, because of the lack of evidenced biomarkers at the time, prospective bvFTD diagnosis was made adhering to the international clinical criteria (Rascovsky et al., 2011).

Diagnosis and differentiation

Clinical guidelines for early and accurate diagnosis of bvFTD are essential for ensuring initial and ongoing disease management and support for people living with bvFTD and their caregivers (Rascovsky et al., 2011). The challenging differential diagnosis of bvFTD from primary psychiatric disorders (PPD) led to the establishment of the Neuropsychiatric International Consortium for Frontotemporal Dementia (NIC-FTD) to assist clinicians in utilising best practice diagnostic skills to diagnose bvFTD (Ducharme et al., 2020). However, other dementias also have frontal lobe damage, hence more diagnostic imaging is warranted, such as fluorodeoxyglucose-positron emission tomography (FDG-PET) and histopathological investigation (Barker et al., 2022; Cerami et al., 2016; Malpetti et al., 2019). With the availability of FDG-PET, there is more scope to differentiate bvFTD from other neurodegenerative diseases because of the capture of specific neural and synaptic functioning which impact bvFTD (Malpetti et al, 2019). Another first study provided evidence of the presence of two functional metabolic connectivity networks in a large bvFTD sample size, giving insight into the variability of bvFTD neural pathways (Malpetti et al, 2019). The misdiagnosis of bvFTD as a primary psychiatric disorder, such as major depression, may leave an average of five to six years of delayed diagnosis for an estimated 50 per cent of people living with bvFTD, therefore recommendations that distinguish the two are essential (Ducharme et al., 2020; Gambogi et al., 2019). Other contributing factors that can confuse diagnosis is the occurrence of parkinsonism and motor neuron disease with bvFTD (Erzurumluoglu Gokalp et al., 2021). Another challenge for diagnosticians is differentiating bvFTD from long-term severe psychiatric disorders, because often there is minimal cognitive impairment in early bvFTD (Gambogi et al., 2019).

Although language and speech deficits are screened during bvFTD assessment, to date there is no evidence of definitive phonological impairment bvFTD research, which could contribute to a core bvFTD diagnostic symptom (Geraudie et al., 2021). It is worth noting that speech deficits in bvFTD has had minimal mention in literature, which is possibly why the first systematic review was done to examine what neurobiological, neuropathological and possibly genetic influences that may affect speech in bvFTD (Geraudie et al., 2021). Language deficits have been observed in early bvFTD and apparently, pre-symptomatic changes have been noted, which makes it an important symptom that would be best to include as a definite diagnostic feature along with the importance of hyperorality (Geraudie et al., 2021; Rascovsky et al., 2011). Because of the heterogeneity of bvFTD and of the research that shows more impairment of somatic and motor speech function in bvFTD than AD, then these differences may contribute to a clearer differentiation of not only bvFTD and AD, but possibly other neurodegenerative conditions (Geraudie et al., 2021).

Clinicians need to be continually aware of the possible overlapping of bvFTD and primary psychiatric disorders (PPDs), because of the potential of delayed diagnosis and disease management, and support, for either condition when there is a misdiagnosis (Rascovsky et al., 2011; Ulugut et al., 2023). However, the overlapping of neurodegeneration in bvFTD and primary psychiatric disorders (PPDs) in neuroanatomical investigation suggested that there may be shared neuropathology and genetic makeup causing similar conditions (Ulugut et al., 2023).

To ensure correct diagnosis, it is necessary to note the difference between bvFTD-AD pathology, where there is usually initial memory impairment, compared to bvFTD, where memory is initially intact, but behaviour changes (Ulugut et al., 2023).

Genetic risk factors

The genetic factors involved show an estimated 20 per cent chance of an autosomal-dominant genetic mutation, with the most common being hexanucleotide repeat expansions near the chromosome 9 open reading frame gene (C9orf72), progranulin (GRN) and microtubule-associated protein tau (MAPT) (Ducharme et al., 2020). Research suggests anxiety and depression symptoms are due mainly to the mutation changes in C9orf72, however these symptoms are also identified where there is not a genetic influence (Samara et al., 2023). Genetic studies have advanced more in studying bvFTD and family history of bvFTD has been observed, for example, Valosin-containing protein (VCP) (Erzurumluoglu Gokalp et al., 2021).

Neurobiology and pathology

Although clinicopathology of bvFTD has given a better understanding of disease pathology and progression, because postmortem examination may be undertaken across several settings, there may be a variation of results if there was not standard assessment used (Perry et al., 2017). Grey matter of the prefrontal, anterior temporal, anterior cingulate, anterior insula, striatum, and thalamus have been established in early onset bvFTD affecting socio-executive functions, yet white matter requires further investigation even though degenerative changes were noted in the anterior cingulum, fornix, and corpus callosum (Chu et al.,2023).

Apathy and disinhibition have been shown through imaging to result from the orbital frontal gyrus (Chu et al., 2023). Transactive response protein DNA binding protein (TDP-C) pathology showed atrophy in the anterior lobe of people with bvFTD, which was demonstrated in their dysfunctional social-emotional behaviour (Perry et al., 2017).

Cerebral network pathways for speech and language need to be considered in differential diagnosis of bvFTD, because it seems that research has overlooked the importance of dysfunction of speech and language skills, which may be a valuable contributing diagnostic symptom (Geraudie et al., 2021; Rascovsky et al., 2011). Another area that has been suggested as having limited evidence-based research is the inclusion of white matter (WM) and grey matter (GM) proteinopathies and its associated impact on bvFTD (Giannini et al., 2021; Giannini et al., 2023).

Clinicopathological studies have shown that FTLD-Tau and FTLD-TDP have been present in relatively equal amounts at autopsy and lean more to a bvFTD diagnosis (Giannini et al., 2021). This does not always mean there is a clear-cut diagnosis of bvFTD, because the overlapping clinical language symptoms of primary progressive aphasia (PPA) and bvFTD are similar, and autopsy clarification is not always available (Giannini et al., 2021). However, the systematic review of autopsy results showed there was WM pathology and degeneration in bvFTD and primary progressive aphasia (Giannini et al., 2021). Another pathology contributing to bvFTD is the fused in sarcoma (FUS) protein, which has been identified as a cause of bvFTD, even though there was a low prevalence of FUS (Lee et al., 2012).

Disease progression

One of the diagnostic misleading factors of bvFTD in the early stages is that often there is minimum memory loss, but very noticeable impairments in executive function, such as judgement, changed behaviour, personality change, and varying emotions (Dinand et al., 2015).

The international consensus criteria gave a guideline for bvFTD progression from possible to what is considered definitive, such as observed behavioural and cognition and executive function deterioration (Erzurumluoglu Gokalp et al., 2021; Rascovsky et al., 2011). Although there are behavioural and socio-emotional changes in the early stage of bvFTD, sometimes there may also be language and speech deterioration without the person living with bvFTD being aware of the changes, which affect activities of daily living (Geraudie et al., 2021).

The international consensus criteria for bvFTD referred to stereotypy of speech as one of the symptoms that could contribute to probable bvFTD, but was not a required symptom inclusion in the criteria (Rascovsky et al., 2011). Stereotypy of speech is when the person living with bvFTD repeatedly uses single words or phrases that are either grammatically incorrect or are incomprehensible (Rascovsky et al., 2011).

Currently, the known degenerative pattern of bvFTD begins with atrophy in the frontal cortex and anterior temporal lobes and may progress sporadically to either the right or left temporo-limbic regions (Cerami et al, 2016; Geraudie et al., 2021; Mendez et al., 2013; Perry et al., 2017; Rascovsky et al., 2011). Where the TDP-C pathology is involved, then atrophy is identified predominately in the right anterior temporal lobe (Perry et al., 2017). Another concept that develops in bvFTD is the unawareness of the inability to empathise with another person’s feelings and needs, often referred to as theory of mind (ToM), which is one of the six possible bvFTD symptoms (Henry et al., 2014; Rascovsky et al., 2011).

Not everyone diagnosed with bvFTD deteriorates at the same rate or pattern. For example, the slow and progressive bvFTD-SP phenotype, where there is no evident brain atrophy, but may stop and stay at a mild or moderate stage (Khan et al., 2012). One study suggested that because of the family history of dementia and subsequent slow progression of two subject’s dementia that there may have been a mutation of C9ORF72 (Khan et al., 2012).

Impact on people living with bvFTD, families and community

Currently, there is no evidence-based intervention or cure known for bvFTD. The condition has sometimes been misdiagnosed as depression, or another primary psychiatric disorder, which delays proactive support and management of bvFTD (Dinand et al, 2015). Having a diminished life expectancy from an estimated 8.2 to 8.7 years from disease onset and one to six years after diagnosis, further negatively impacts the person living with bvFTD and families (Dinand et al., 2015; Erzurumluoglu Gokalp et al., 2021; Giannini et al., 2023). What makes managing a family member with bvFTD stressful is often the person living with bvFTD believes that there is nothing wrong with them and does not realise how their behaviour affects themselves and others, which further increases the burden on family caregivers (Dinand et al, 2015). Caregivers and professionals would benefit from education about the progressive degenerative nature of bvFTD as well as carer support to enable them to better manage the care of people living with bvFTD (Dinand et al, 2015; Fieldhouse et al., 2022). There are other practical and clinical recommendations from a caregiver’s perspective, including using a person-centred approach, improving symptomatic treatments, and improving bvFTD diagnosis and early clinical intervention studies (Fieldhouse et al., 2022). The socio-economic burden for families, communities and public health care exacerbates when bvFTD diagnosis and much needed supportive care is needed (Fieldhouse et al., 2022; Galvin et al., 2017).

Looking to the future

Postmortem neurobiological examination of bvFTD has been able to more clearly correlate the pathological and clinical progression of bvFTD, which may contribute to an earlier antemortem diagnosis, disease management and supportive therapeutic approaches (Giannini et al., 2021; Mendez et al., 2013; Perry et al., 2017). Overall, most of the literature referred to the diagnostic criteria of the international consensus criteria for behavioural variant FTD (FTDC) as well as Neuropsychiatric International Consortium for Frontotemporal Dementia (NIC-FTD) (Balasa et al., 2015; Barker et al., 2022; Cerami et al., 2016; Ducharme et al., 2020; Erzurumluoglu Gokalp et al., 2021; Gambogi, et al., 2019; Henry et al., 2014; Khan et al., 2012; Perry et al., 2017; Rascovsky et al., 2011; Samra et al., 2022). To achieve better definitive diagnosis of bvFTD, specific education about the heterogeneity of bvFTD and the overlapping of psychiatric symptoms, such as apathy, may help decrease the incidence of bvFTD misdiagnosis as a major depressive disorder or a bipolar disorder (Samara et al, 2023).

More focused bvFTD research, early intervention and diagnostic education for behavioural neurology and neuropsychiatry clinicians in decreasing diagnostic confusion between bvFTD and primary psychiatric disorders is essential for earlier diagnosis and disease management for the people living with bvFTD and family caregiver support (Ducharme et al., 2020; Fieldhouse et al., 2022; Rascovsky et al., 2011).

References

Balasa, M., Gelpi, E., Martín, I., Antonell, A., Rey, M. J., Grau‐Rivera, O., Molinuevo, J. L., Sánchez‐Valle, R., & Lladó, A. (2015). Diagnostic accuracy of behavioral variant frontotemporal dementia consortium criteria (FTDC) in a clinicopathological cohort. Neuropathology and Applied Neurobiology, 41(7), 882-892. https://doi.org/10.1111/nan.12194

Barker, M. S., Gottesman, R. T., Manoochehri, M., Chapman, S., Appleby, B. S., Brushaber, D., Devick, K. L., Dickerson, B. C., Domoto-Reilly, K., Fields, J. A., Forsberg, L. K., Galasko, D. R., Ghoshal, N., Goldman, J., Graff-Radford, N. R., Grossman, M., Heuer, H. W., Hsiung, G.-Y., Knopman, D. S., & Kornak, J. (2022). Proposed research criteria for prodromal behavioural variant frontotemporal dementia. Brain, 145(3), 1079–1097. https://doi.org/10.1093/brain/awab365

Cerami, C., Dodich, A., Lettieri, G., Iannaccone, S., Magnani, G., Marcone, A., Gianolli, L., Cappa, S. F., & Perani, D. (2016). Different FDG-PET metabolic patterns at single-subject level in the behavioral variant of fronto-temporal dementia. Cortex, 83, 101-112. https://doi.org/10.1016/j.cortex.2016.07.008

Chu, M., Jiang, D., Liu, L., Nie, B., Rosa-Neto, P., Chen, K., & Wu, L. (2023). Clinical relevance of disrupted topological organization of anatomical connectivity in behavioral variant frontotemporal dementia. Neurobiology of Aging, 124, 29–38. https://doi.org/10.1016/j.neurobiolaging.2023.01.004

Dinand, C., Nover, S. U., Holle, D., Zischka, M., & Halek, M. (2015). What is known about the subjective needs of people with behavioural variant frontotemporal dementia? A scoping review. Health & Social Care in the Community, 24(4), 375-385. https://doi.org/10.1111/hsc.12225

Ducharme, S., Dols, A., Laforce, R., Devenney, E., Kumfor, F., van den Stock, J., Dallaire-Théroux, C., Seelaar, H., Gossink, F., Vijverberg, E., Huey, E., Vandenbulcke, M., Masellis, M., Trieu, C., Onyike, C., Caramelli, P., de Souza, L. C., Santillo, A., Waldö, M. L., & Landin-Romero, R. (2020). Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders. Brain, 143(6), 1632–1650. https://doi.org/10.1093/brain/awaa018

Erzurumluoglu Gokalp, E., Ozbabalik Adapinar, D., & Artan, S. (2021). Genetics of frontotemporal dementia. Factors Affecting Neurological Aging, 3–16. https://doi.org/10.1016/b978-0-12-817990-1.00001-9
‌

Fieldhouse, J. L. P., van Dijk, G., Gillissen, F., van Engelen, M. E., de Boer, S. C. M., Dols, A., van der Waal, H., Regeer, B. J., Vijverberg, E. G. B., & Pijnenburg, Y. A. L. (2022). A caregiver’s perspective on clinically relevant symptoms in behavioural variant frontotemporal dementia: Tools for disease management and trial design. Psychogeriatrics, 23(1), 11–22. https://doi.org/10.1111/psyg.12898

Galvin, J. E., Howard, D. H., Denny, S. S., Dickinson, S., & Tatton, N. (2017). The social and economic burden of frontotemporal degeneration. Neurology, 89(20), 2049–2056. https://doi.org/10.1212/wnl.0000000000004614

Gambogi, L. B., Guimarães, H. C., De Souza, L. C., & Caramelli, P. (2019). Behavioral variant frontotemporal dementia in patients with previous severe mental illness: A systematic and critical review. Arquivos de Neuro-Psiquiatria, 77, 654–668. https://doi.org/10.1590/0004-282X20190107

Geraudie, A., Battista, P., García, A. M., Allen, I. E., Miller, Z. A., Gorno-Tempini, M. L., & Montembeault, M. (2021). Speech and language impairments in behavioral variant frontotemporal dementia: A systematic review. Neuroscience & Biobehavioral Reviews, 131, 1076–1095. https://doi.org/10.1016/j.neubiorev.2021.10.015

Giannini, L., Peterson, C., Ohm, D. T., Xie, S. X., McMillan, C. T., Katya Raskovsky, Massimo, L., Suh, E., Deerlin, V., Wolk, D. A., Trojanowski, J. Q., Lee, E. B., Grossman, M., & Irwin, D. J. (2021a). Frontotemporal lobar degeneration proteinopathies have disparate microscopic patterns of white and grey matter pathology. Acta Neuropathologica Communications, 9(1). https://doi.org/10.1186/s40478-021-01129-2

Giannini, L., Mol, M. O., Rajicic, A., Renee van Buuren, Sarkar, L., Sanaz Arezoumandan, Ohm, D. T., Irwin, D. J., Annemieke Rozemüller, John, & Harro Seelaar. (2023). Presymptomatic and early pathological features of MAPT-associated frontotemporal lobar degeneration. Acta Neuropathologica Communications, 11(1). https://doi.org/10.1186/s40478-023-01588-9

Henry, J. D., Phillips, L. H., & von Hippel, C. (2014). A meta-analytic review of theory of mind difficulties in behavioural-variant frontotemporal dementia. Neuropsychologia, 56, 53–62. https://doi.org/10.1016/j.neuropsychologia.2013.12.024

Khan, B. K., Yokoyama, J. S., Takada, L. T., Sha, S. J., Rutherford, N. J., Fong, J. C., Karydas, A. M., Wu, T., Ketelle, R. S., Baker, M. C., Hernandez, M., Coppola, G., Geschwind, D. H., Rademakers, R., Lee, S. E., Rosen, H. J., Rabinovici, G. D., Seeley, W. W., Rankin, K. P., … Miller, B. L. (2012). Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion. Journal of Neurology, Neurosurgery & Psychiatry, 83(4), 358-364. https://doi.org/10.1136/jnnp-2011-301883

Lee, S. E., Seeley, W. W., Pardis Poorzand, Rademakers, R., Karydas, A., Stanley, C. M., Miller, B. L., & Rankin, K. P. (2012). Clinical characterization of bvFTD due to FUS neuropathology. Neurocase, 18(4), 305–317. https://doi.org/10.1080/13554794.2011.604637

Léger, G. C., & Banks, S. J. (2013). Neuropsychiatric symptom profile differs based on pathology in patients with clinically diagnosed behavioral variant Frontotemporal dementia. Dementia and Geriatric Cognitive Disorders, 37(1-2), 104-112. https://doi.org/10.1159/000354368

Lima-Silva, T., Bahia, V., Nitrini, R., & Yassuda, M. (2013). Functional status in behavioral variant frontotemporal dementia: A systematic review. BioMed Research International, 2013, 1–7. https://doi.org/10.1155/2013/837120

Malpetti, M., Carli, G., Sala, A., Cerami, C., Marcone, A., Iannaccone, S., Magnani, G., & Perani, D. (2019). Variant-specific vulnerability in metabolic connectivity and resting-state networks in behavioural variant of frontotemporal dementia. Cortex, 120, 483–497. https://doi.org/10.1016/j.cortex.2019.07.018

Mendez, M. F., Joshi, A., Tassniyom, K., Teng, E., & Shapira, J. S. (2013). Clinicopathologic differences among patients with behavioral variant frontotemporal dementia. Neurology, 80(6), 561–568. https://doi.org/10.1212/wnl.0b013e3182815547

Perry, D. C., Brown, J. A., Possin, K. L., Datta, S., Trujillo, A., Radke, A., Karydas, A., Kornak, J., Sias, A. C., Rabinovici, G. D., Gorno-Tempini, M. L., Boxer, A. L., De May, M., Rankin, K. P., Sturm, V. E., Lee, S. E., Matthews, B. R., Kao, A. W., Vossel, K. A., & Tartaglia, M. C. (2017). Clinicopathological correlations in behavioural variant frontotemporal dementia. Brain, 140(12), 3329–3345. https://doi.org/10.1093/brain/awx254

Rascovsky, K., Hodges, J. R., Knopman, D., Mendez, M. F., Kramer, J. H., Neuhaus, J., van Swieten, J. C., Seelaar, H., Dopper, E. G. P., Onyike, C. U., Hillis, A. E., Josephs, K. A., Boeve, B. F., Kertesz, A., Seeley, W. W., Rankin, K. P., Johnson, J. K., Gorno-Tempini, M.-L., Rosen, H., & Prioleau-Latham, C. E. (2011). Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain, 134(9), 2456–2477. https://doi.org/10.1093/brain/awr179

Samra, K., Macdougall, A., Peakman, G., Bouzigues, A., Bocchetta, M., Cash, D. M., Greaves, C. V., Convery, R. S., Swieten, J. C. van, Jiskoot, L. C., Seelaar, H., Moreno, F., Sánchez-Valle, R., Laforce, R., Graff, C., Masellis, M., Tartaglia, M. C., Rowe, J. B., Borroni, B., & Finger, E. (2023). Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales. Journal of Neurology, Neurosurgery & Psychiatry. https://doi.org/10.1136/jnnp-2022-330152

Ulugut, H., Trieu, C., Groot, C., van’t Hooft, Tijms, B., Scheltens, P., Ossenkoppele, R., Barkhof, F., van den Heuvel, O., & Pijnenburg, A. (2023). Overlap of neuroanatomical involvement in frontotemporal dementia and primary psychiatric disorders: A meta-analysis. Biological Psychiatry, 93(9), 820–828. https://doi.org/10.1016/j.biopsych.2022.05.028