RARE DISEASE
Behavioral variant of frontotemporal dementia
Behavioral variant of frontotemporal dementia
Behavioral variant of frontotemporal dementia
Synonyms: bv-FTD
Synonyms: bv-FTD
Synonyms: bv-FTD
Drug discovery
3
drugs
With orphan designations
Overview
Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disorder marked by progressive personality changes, social disinhibition, apathy, loss of empathy, and executive dysfunction due to frontal/temporal lobe atrophy [1][4][6]. Pathology involves tau, TDP-43, or FUS protein aggregates [1][20]. Diagnosis relies on behavioral criteria, neuroimaging, and exclusion of biomarkers for Alzheimer’s disease [1][4]. Symptoms typically emerge between 45-65 years but can occur earlier or later [2][4][7].
Burden
Therapies
Pharmacologic: SSRIs (e.g., citalopram) for disinhibition/compulsions; cautious use of antipsychotics (e.g., quetiapine) for severe agitation [3][8][13].
Non-pharmacologic: Structured routines, caregiver education, occupational/speech therapy, and palliative care planning [3][9][14].
Avoid cholinesterase inhibitors/memantine (ineffective or harmful) [13][20].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
257 drug discovery papers about Behavioral variant of frontotemporal dementia, with 5 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
257 drug discovery papers about Behavioral variant of frontotemporal dementia, with 5 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-29 | Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD.
Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72-associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.
2026-07-16 | Survival estimates and their predictors in genetic frontotemporal dementia: an international, retrospective, cohort study.
What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation. In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method. Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6·94 years (95% CI 6·59-7·80) from symptom onset. The median survival estimate for patients with GRN mutations was 6·63 years (6·08-7·98), for patients with a C9orf72 expansion was 7·04 years (6·45-8·77), and for patients with MAPT mutations was 8·56 years (7·06-13·50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level. Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed. Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.
2026-06-29 | Associations of local white matter geometry with network efficiency, macrostructural abnormalities, and clinical severity in behavioural variant frontotemporal dementia.
Behavioural variant frontotemporal dementia (bvFTD), marked by profound changes in behaviour and personality, is the most common subtype of frontotemporal dementia, driven by neurodegeneration in frontotemporal regions. This neurodegeneration pattern is partially shaped by white matter abnormalities arising from the spread of protein aggregates along axonal pathways. While prior studies mainly focused on diffusion tensor imaging metrics such as fractional anisotropy and mean diffusivity, the alteration in local white matter geometry remains largely unexplored. Using a novel Director Field Analysis (DFA) method, 51 patients with bvFTD and 51 healthy controls were studied to examine alterations in the local geometry of white matter fibres in bvFTD, and their associations with macrostructural morphology, global network parameters, and clinical manifestations. Unlike the unidirectional decrease in fractional anisotropy and increase in mean diffusivity, we identified significant bidirectional alterations in white matter local geometry, characterized by increased geometric distortion in the forceps minor and dorsal cingulum and decreased distortion in widespread frontotemporal association tracts, including the inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus, frontal aslant tract, and arcuate fasciculus. Patients with bvFTD also showed reduced cerebral white and grey matter volumes (both P < 0.0026), enlarged lateral ventricles and choroid plexus (both P < 0.0001), decreased global network efficiency (P = 0.0010), and increased local efficiency (P = 0.0014). Importantly, decreased white matter geometric distortion across affected tracts was strongly associated with greater clinical severity, as reflected by higher Clinical Dementia Rating scores (r = -0.68, P < 0.0001). Mediation analyses further demonstrated that white matter geometric distortion significantly mediated the effects of macrostructural atrophy and reduced global network efficiency on clinical severity. Furthermore, neuroimaging-transcriptional association analysis on the group differences in nodal efficiency of the white matter networks identified several biological processes/pathways critical for the formation and propagation of TAR-DNA-binding protein 43/microtubule-associated protein tau pathologies along axonal pathways, as well as processes related to cellular homeostasis and oligodendrocyte-related pathways that may exacerbate these proteinopathies. Our findings advance understanding of the neural bases of the functional impairments in bvFTD and suggest potential mechanistic pathways for developing novel treatment strategies.
2026-06-17 | Diagnosis and management of frontotemporal dementia: a narrative review.
Frontotemporal dementia (FTD) is an umbrella term that encompasses a group of clinically heterogeneous neurodegenerative disorders. It is biologically referred to as Frontotemporal lobar degeneration (FTLD) and is characterized by progressive degeneration of frontal and/or temporal lobes. FTD poses substantial diagnostic and therapeutic challenges due to its heterogeneous clinical presentations, limited biomarker specificity, and overlap with other neurodegenerative and psychiatric diseases. This review synthesizes updated knowledge on the clinical phenotypes of FTD, their prognostic elements, and the underlying genetic and molecular mechanisms. Advances in diagnostic strategies are discussed, including structural and functional neuroimaging, fluid biomarkers, and genetic testing, together with emerging digital and AI-assisted tools that may enhance diagnostic precision. Evidence-based management approaches are examined, alongside the role of multidisciplinary care and caregiver support. Promising therapeutic strategies, including gene-targeted interventions, antisense oligonucleotides, progranulin restoration strategies, immunotherapies, and neuromodulation techniques, are discussed considering recent clinical and preclinical developments. Despite the absence of approved disease-modifying therapies, rapid progress in biomarker development, patient stratification, and personalized approaches offers encouraging prospects for more effective interventions across the FTD spectrum. PubMed/MEDLINE was searched for peer-reviewed articles on FTD diagnosis and management; reference lists of key articles were screened to identify additional sources.
2026-06-09 | Obsessive-compulsive Symptomatology and Caudate Tau Burden in Autopsy-confirmed FTLD-tau (P9-13.003)
To examine the relationship between obsessive-compulsive symptoms and caudate tau pathology in behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) due to frontotemporal lobar degeneration with tau pathology (FTLD-tau).
2026-07-29 | Single-cell transcriptomic atlas of frontoinsular cortex reveals molecular correlates of selective neuronal vulnerability in FTD.
Frontotemporal dementia (FTD) is characterized by selective neuronal vulnerability, yet the features that predispose specific neuron types to degeneration remain unclear. We performed single-nucleus RNA sequencing of frontoinsular cortex, a region affected early in behavioral variant FTD, across individuals with C9orf72-associated and sporadic FTD-MND spectrum disease. By enriching for large projection neurons, we resolved molecular subtypes of layer 5 extratelencephalic neurons, including von Economo neurons, and identified selective depletion of specific layer 2/3 and layer 5 neuron subtypes, convergent across genotypes. Despite selective neuronal loss, disease-associated transcriptional changes were convergent across excitatory neuron populations, suggesting that they reflect upstream pathophysiology or shared responses to local neurodegeneration. By relating neighborhood-level depletion in disease to gene expression in controls, we found that baseline cellular respiration and ATP synthesis predict neuronal vulnerability in disease. These findings define molecular correlates of selective neuronal vulnerability in FTD and provide a framework linking cell type and state to neurodegeneration.
2026-07-16 | Survival estimates and their predictors in genetic frontotemporal dementia: an international, retrospective, cohort study.
What drives the heterogeneity of survival estimates in genetic frontotemporal dementia is unknown. We sought to understand the natural history and predictors of disease trajectory, which are crucial not only for effective care but also for the design of therapeutic clinical trials and efficacy evaluation. In this international, cohort study, we used the Kaplan-Meier method to retrospectively assess survival estimates in patients enrolled in the GENFI cohort, which included 32 research sites located in Belgium, Canada, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, and the UK, and comprised participants carrying a causal C9orf72 expansion or a causal mutation in GRN or MAPT genes. Survival was calculated as the time from symptom onset to time of death or censoring date; median survival estimate for all patients was the primary endpoint. Cox proportional hazards models were used to identify predictors of survival, which were subsequently externally validated in an independent cohort. We further designed a structural equation model to assess the relationships between predictors, applying a least absolute shrinkage and selection operator method. Of 278 participants of the GENFI cohort included in this study, 160 (58%) were men and 118 (42%) were women. 162 died during follow-up (58%) and 116 were still alive (42%) on June 1, 2024, the chosen censoring date. 138 participants carried a C9orf72 expansion, 94 carried a GRN mutation, and 46 a MAPT mutation. 179 participants were diagnosed with behavioural variant frontotemporal dementia, 46 with primary progressive aphasia, and 31 with frontotemporal dementia-amyotrophic lateral sclerosis. 22 participants had other diagnoses. The median survival estimate for all patients with genetic frontotemporal dementia was 6·94 years (95% CI 6·59-7·80) from symptom onset. The median survival estimate for patients with GRN mutations was 6·63 years (6·08-7·98), for patients with a C9orf72 expansion was 7·04 years (6·45-8·77), and for patients with MAPT mutations was 8·56 years (7·06-13·50). Older age at onset, shorter disease duration from onset to enrolment in the GENFI study, clinical presentation (ie, frontotemporal dementia-amyotrophic lateral sclerosis), domain of first symptom (ie, motor or language onset), and geographical area of residency (ie, central and southern Europe) were associated with poorer prognosis. Genetic group did not directly affect survival estimates; rather its effect was mediated by age at onset and clinical phenotype. We computed a genetic frontotemporal dementia survival risk index, which can be used at an individual patient level. Our results highlight that motor impairment in addition to cognitive and behavioural symptoms should be considered when estimating prognosis in genetic frontotemporal dementia. Individual risk scores might be of help for patient stratification in future therapeutic trials, although refinement and prospective validation are now needed. Italian Ministry of Health (Ricerca Corrente), Fondation Philippe Chatrier, and Fondation Vaincre Alzheimer.
2026-06-29 | Associations of local white matter geometry with network efficiency, macrostructural abnormalities, and clinical severity in behavioural variant frontotemporal dementia.
Behavioural variant frontotemporal dementia (bvFTD), marked by profound changes in behaviour and personality, is the most common subtype of frontotemporal dementia, driven by neurodegeneration in frontotemporal regions. This neurodegeneration pattern is partially shaped by white matter abnormalities arising from the spread of protein aggregates along axonal pathways. While prior studies mainly focused on diffusion tensor imaging metrics such as fractional anisotropy and mean diffusivity, the alteration in local white matter geometry remains largely unexplored. Using a novel Director Field Analysis (DFA) method, 51 patients with bvFTD and 51 healthy controls were studied to examine alterations in the local geometry of white matter fibres in bvFTD, and their associations with macrostructural morphology, global network parameters, and clinical manifestations. Unlike the unidirectional decrease in fractional anisotropy and increase in mean diffusivity, we identified significant bidirectional alterations in white matter local geometry, characterized by increased geometric distortion in the forceps minor and dorsal cingulum and decreased distortion in widespread frontotemporal association tracts, including the inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus, frontal aslant tract, and arcuate fasciculus. Patients with bvFTD also showed reduced cerebral white and grey matter volumes (both P < 0.0026), enlarged lateral ventricles and choroid plexus (both P < 0.0001), decreased global network efficiency (P = 0.0010), and increased local efficiency (P = 0.0014). Importantly, decreased white matter geometric distortion across affected tracts was strongly associated with greater clinical severity, as reflected by higher Clinical Dementia Rating scores (r = -0.68, P < 0.0001). Mediation analyses further demonstrated that white matter geometric distortion significantly mediated the effects of macrostructural atrophy and reduced global network efficiency on clinical severity. Furthermore, neuroimaging-transcriptional association analysis on the group differences in nodal efficiency of the white matter networks identified several biological processes/pathways critical for the formation and propagation of TAR-DNA-binding protein 43/microtubule-associated protein tau pathologies along axonal pathways, as well as processes related to cellular homeostasis and oligodendrocyte-related pathways that may exacerbate these proteinopathies. Our findings advance understanding of the neural bases of the functional impairments in bvFTD and suggest potential mechanistic pathways for developing novel treatment strategies.
2026-06-17 | Diagnosis and management of frontotemporal dementia: a narrative review.
Frontotemporal dementia (FTD) is an umbrella term that encompasses a group of clinically heterogeneous neurodegenerative disorders. It is biologically referred to as Frontotemporal lobar degeneration (FTLD) and is characterized by progressive degeneration of frontal and/or temporal lobes. FTD poses substantial diagnostic and therapeutic challenges due to its heterogeneous clinical presentations, limited biomarker specificity, and overlap with other neurodegenerative and psychiatric diseases. This review synthesizes updated knowledge on the clinical phenotypes of FTD, their prognostic elements, and the underlying genetic and molecular mechanisms. Advances in diagnostic strategies are discussed, including structural and functional neuroimaging, fluid biomarkers, and genetic testing, together with emerging digital and AI-assisted tools that may enhance diagnostic precision. Evidence-based management approaches are examined, alongside the role of multidisciplinary care and caregiver support. Promising therapeutic strategies, including gene-targeted interventions, antisense oligonucleotides, progranulin restoration strategies, immunotherapies, and neuromodulation techniques, are discussed considering recent clinical and preclinical developments. Despite the absence of approved disease-modifying therapies, rapid progress in biomarker development, patient stratification, and personalized approaches offers encouraging prospects for more effective interventions across the FTD spectrum. PubMed/MEDLINE was searched for peer-reviewed articles on FTD diagnosis and management; reference lists of key articles were screened to identify additional sources.
2026-06-09 | Obsessive-compulsive Symptomatology and Caudate Tau Burden in Autopsy-confirmed FTLD-tau (P9-13.003)
To examine the relationship between obsessive-compulsive symptoms and caudate tau pathology in behavioral variant frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA) due to frontotemporal lobar degeneration with tau pathology (FTLD-tau).
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for Behavioral variant of frontotemporal dementia.
3 orphan drug designations for Behavioral variant of frontotemporal dementia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
2ʹ-O-(2-methoxyethyl) antisense oligonucleotide targeting microtubule-associated protein tau pre-mRNA | oligonucleotides | EMA | 2018-07-31 | — | Biogen Netherlands B.V. |
Tolfenamic acid | small molecules | EMA | 2016-02-17 | — | RV Developpement |
Methylthioninium | small molecules | EMA | 2010-11-26 | — | Pharma Gateway AB |
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