Disease progression in bvFTD has been associated with various behavioral changes, from an increase in core features, e.g., decreased socio-emotional abilities and increased multi-dimensional apathy, to specific changes, e.g., increased fat preference and hypersensitivity to loud noises (Midorikawa et al., 2016; Wei et al., 2020; Ahmed et al., 2021; Foster et al., 2022), that correlate with FTD-specific progression measures (FTLD-CDR; FTD-FRS; atrophy rates). Alongside behavior, neuropsychiatric symptoms have been frequently reported, such as depression, anxiety, delusions and hallucinations (Da Silva et al., 2021). For genetic bvFTD, longitudinal cohorts have described mutation-specific behavioral features that seem to be disease phase specified. In early-intermediate phases, MAPT carriers showed increased predominant behavioral symptoms and C9ORF72 carriers showed increased neuropsychiatric symptoms, where after plateauing takes place (Tavares et al., 2020; Benussi et al., 2021b). In late stage on the other hand, C9ORF72 carriers showed decreased reports of depression, whereas GRN carriers showed increased depression and anxiety. Furthermore, behavioral profiles have been associated with age of onset, biological sex and cognitive reserve. Specifically, early onset bvFTD presented with more behavioral symptoms, women showed greater frontotemporal atrophy burden with similar clinical characteristics, and there was a (positive) effect of educational level on rate of change in disinhibition (Linds et al., 2015; Fieldhouse et al., 2021; Illán-Gala et al., 2021a). The concept of behavioral reserve, i.e., behavioral differences in response to a neuropathological burden, was proposed when individuals with less (negative) behavioral symptoms showed a steeper decline in frontotemporal atrophy (Kim et al., 2022). Lastly, it is important to acknowledge the bvFTD phenocopy syndrome (phFTD) as a distinct entity from bvFTD. Apart from clinically mimicking bvFTD while lacking clear etiology, phFTD showed to be non-progressive over an extensive period of time (10+ years) (Devenney et al., 2018).

Simply rating the frequency of behavioral criteria and neuropsychiatric symptoms on a 5-point scale was sufficient to detect progression over time in genetic FTD (1–7 years) (Benussi et al., 2021b). However, most frequently used informant-based questionnaires quantify behavioral change more comprehensively. The Neuropsychiatric Inventory (NPI), developed to evaluate psychopathology in AD (Cummings et al., 1994), generally showed increased scores during follow-up in bvFTD (Linds et al., 2015; Da Silva et al., 2021). While parts of AD-oriented neuropsychiatric scales, such as the NPI and the Columbia University Scale for Psychopathology in Alzheimer’s Disease (CUSPAD), predicted cognitive and functional decline in FTD (2.5 years) (Santacruz Escudero et al., 2019), associations with disease severity were inconsistent (Josephs et al., 2011; Kazui et al., 2016; Ranasinghe et al., 2016) and the evidence as bvFTD-specific progression marker was insufficient. The Frontal Behavioral Inventory (FBI) covers a range of FTD-related functional and behavioral symptoms, resulting in a positive (e.g., impulsivity; hyperorality) and a negative symptom score (e.g., lack of empathy; apathy) (Kertesz et al., 1997). Similar to the FBI, the Cambridge Behavioral Inventory-Revised (CBI-R) assesses frequency of FTD-related symptoms (Nagahama et al., 2006; Wear et al., 2008). Literature showed the FBI and the CBI-R to be sensitive to progression in sporadic and genetic bvFTD (C9ORF72) more consistently than the NPI, over varying follow-up time (1–4 years), despite one study stating comparable decline of FBI and NPI (Marczinski et al., 2004; Boutoleau-Bretonniere et al., 2012; Linds et al., 2015; O’Connor et al., 2016; Floeter et al., 2017; Reus et al., 2018). A range of questionnaires that aim to evaluate single behavioral features, currently lacking limited longitudinal validation, may serve as promising progression markers, such as the Dimensional Apathy Scale (DAS) (Radakovic and Abrahams, 2014), assessing three apathy subtypes in neurodegenerative populations, and the Stereotypy Rating Inventory (SRI) quantifying stereotypic and compulsive behaviors in FTLD (Shigenobu et al., 2002). A cross-sectional study on apathy profiles during disease course of bvFTD, showed an increase of DAS scores, while distinguishing emotional apathy in early (<5 years) and executive apathy in later stages (>5 years), associated with distinct neurobiological substrates (Wei et al., 2020). While one study reported no change of stereotypy over time, the SRI predicted progression of frontotemporal atrophy, institutionalization and death (Reus et al., 2018; Gossink et al., 2019) (Table 1).

During disease progression in bvFTD behavioral symptoms may vary, initial behaviors fade whilst new behaviors appear, showing behavioral trajectories are not linear (Diehl-Schmid et al., 2006). The majority of longitudinal studies (including a clinico-pathological study) supported a crescendo-decrescendo trajectory of behavior in bvFTD, in which progressive and diverse behavioral disturbances were followed by dominating apathy (Chow et al., 2012; O’Connor et al., 2016; Borges et al., 2019; Cosseddu et al., 2019). In detail, positive symptoms (such as disinhibition and perseverations) increased until intermediate phases, whereas negative symptoms (such as apathy and loss of empathy) increased throughout disease course. In addition, increased apathy predicted mortality, as stated in a principal component analysis using the Apathy Evaluation Scale (AES), NPI and CBI sub scores (Lansdall et al., 2019). While one study did not report such behavioral inflection point during follow-up (Linds et al., 2015), the relative reduction of positive symptoms may show improvement of behavioral scores over time (Knopman et al., 2008). Similarly, neuropsychiatric symptoms showed to change over time, with symptoms of depression and anxiety in preclinical and prodromal phases, followed by delusions, hallucinations and euphoria in the symptomatic phase (Laganà et al., 2022).

In current international diagnostic criteria, the cognitive profile of bvFTD is characterized by executive deficits, with relative sparing of memory and visuospatial functioning (Rascovsky et al., 2011). However, memory deficits have been increasingly recognized in bvFTD, at initial presentation and over time (Ramanan et al., 2017). A minority of bvFTD (20%) may present with intact cognition at first visit, and thereafter, cognitive decline is variable (Hornberger et al., 2008; Diehl-Schmid et al., 2011; Devenney et al., 2015). For genetic bvFTD, mutation-specific cognitive profiles and trajectories have been identified: characterized decline of confrontational naming, episodic and semantic memory in MAPT carriers, variable deficits (with frequent executive dysfunction) in GRN carriers, and a global and relatively stable profile (e.g., mildly slowed processing speed) in C9ORF72 carriers (Poos et al., 2020; Barker et al., 2021). Pathology-specific profiles point to impaired visual construction in tau-positive FTLD and confrontation naming in tau-negative FTLD, and linguistic deficits in FTLD-TDP (Grossman et al., 2008; Kawakami et al., 2021). Furthermore, multiple studies identified several protective factors of cognitive reserve, i.e., the resilience against neuropathological burden due to lifetime cognitive experiences. Proxies of cognitive reserve included educational level, occupational attainment, late-life social and leisure lifestyle, and specific occupation activities with social skills and cognitive control, which were associated to frontotemporal abnormalities on multiple imaging modalities, including involvement of areas associated to social functioning (prefrontal, anterior temporal and insula) (Dodich et al., 2018; Maiovis et al., 2018; Massimo et al., 2019; Kinney et al., 2021).

Cognitive screeners are short, widely used and easily administered instruments to assess global cognition. In bvFTD, most frequently used cognitive screeners are the Mini-Mental State Examination [MMSE; (Folstein et al., 1975)], the Frontal Assessment Battery [FAB; (Dubois et al., 2000)] and, originated as extension of the MMSE, the Addenbrook’s Cognitive Examination Revised [ACE-R; (Mioshi et al., 2006)]. These screeners were not developed for bvFTD, and have proven to be effective in diagnosing or differentiating AD, by emphasizing memory and orientation (MMSE), executive functions (FAB) or briefly covering multiple domains (ACE-R). Literature demonstrated declines of MMSE, FAB and ACE-R total scores in bvFTD (Mioshi and Hodges, 2009; Devenney et al., 2015; Schubert et al., 2016; Reus et al., 2018), but a principal component analysis of these measures (reflecting global cognitive status) showed no association with mortality (Lansdall et al., 2019). For MMSE in specific, rates of decline are known to be lacking or modest, and unrelated to frontotemporal changes on multiple neuroimaging modalities (Borroni et al., 2010; Tan et al., 2013; Premi et al., 2016; Leroy et al., 2021). Due to its comprehensive, yet feasible design, the ACE-R is a more valid cognitive progression screener for bvFTD, with marked rates of decline over follow-up (1–5 years) (Mioshi and Hodges, 2009; Devenney et al., 2015; Schubert et al., 2016). Regarding single tests, the letter fluency detected decline over 18 months in genetic bvFTD (mostly C9ORF72), associated to frontotemporal atrophy and FTLD-CDR progression (Floeter et al., 2016, 2017; Agarwal et al., 2019). However, given cognitive heterogeneity, combining multiple test scores into (executive functioning, language and memory) composites is known to increase sensitivity to change and ability to detect annual decline in bvFTD (Knopman et al., 2008). A combination of ACE-R, executive function and IADL showed to differentiate progressive from non-progressive bvFTD (3 years) (Hornberger et al., 2009). Developed as a clinical trial endpoint, the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER), detected executive and behavioral decline over 18 months in presymptomatic genetic FTD, and was associated with brain volume loss and FTLD-CDR (Staffaroni et al., 2019a) (Table 1). Promising digital tools may increase the sensitivity of cognitive assessment, such as semi-structured speech samples that captured decline of fluency and grammaticality (2 years), associated with frontotemporal atrophy (N = 14) (Ash et al., 2019).

Despite cognitive heterogeneity, disease progression in bvFTD has been marked by decline in executive functioning, memory, language and attention (1 to 8 years) (Blair et al., 2007; Wicklund et al., 2007; Smits et al., 2015; Ramanan et al., 2017). The earliest stage was characterized by error insensitivity, slower response time and poor naming, while later stages showed deterioration in a range of executive functions, language and memory, visuo-construction and calculations (Ranasinghe et al., 2016). If impaired at presentation, executive dysfunction was most potent predictor of progression, including grey matter atrophy, institutionalization and mortality (Hornberger et al., 2008; Gossink et al., 2019). Also, language impairment was associated with mortality (Garcin et al., 2009). Studies reported specific patterns of (episodic) memory impairment, with temporal and spatial memory deficits in progressive bvFTD (Irish et al., 2012), and a vulnerability for recent autobiographical memory over time, likely to reflect an encoding deficit rather than retrieval deficit (Irish et al., 2018).

Social cognition deficits are prominent and early features of bvFTD. Social cognition encompasses multiple processes of perceiving, interpreting and regulating social stimuli, including emotion recognition, theory of mind (understanding the cognitive or affective state of others) and social reasoning. Overall, social cognition tests have been well validated for diagnosing bvFTD, but literature on progression is limited. A longitudinal study on emotion recognition, assessed with the Ekman 60-faces test (Aw et al., 2002), reported decline during follow-up (1.5 years), with most rapid decline in bvFTD with marked atrophy (Kumfor et al., 2014). However, other studies did not support this decline, reporting no change or improvement on the Ekman-60-faces over 3 years (Lavenu and Pasquier, 2005; Reus et al., 2018). The addition of different intensities of emotions in the Emotion Recognition Task [ERT; (Kessels et al., 2007)] showed to increase diagnostic sensitivity, even in presymptomatic C9ORF72 carriers (Jiskoot et al., 2021), but longitudinal research is needed. Similarly, first studies on theory of mind (ToM), using different proxies, are inconclusive. One study showed no change of ToM within repeated measures of the Faux Pas test (3 years) (Reus et al., 2018), while performance on Reading the Mind in the Eyes test showed promising associations with disease severity, distinguishing impairment of affective ToM in mild stages from cognitive ToM in severe stages (Torralva et al., 2015). Longitudinal assessment of sarcasm detection, assessed with The Awareness of Social Inference Test [TASIT; (McDonald et al., 2003)], showed a decline in cases with marked atrophy only, indicating it is relatively spared in early stages (Kumfor et al., 2014). Lastly, a cross-sectional study associated distinct social symptoms, as measured by the Social Impairment Rating Scale (SIRS), with three socially relevant (corticolimbic) networks to (Bickart et al., 2014). However, this promising clinician-rated scale requires longitudinal validation. Inconsistent findings in social cognition trajectories highlight current hurdles in the methodology of social cognition assessment, such as possible floor effects due to early impairment and lack of systematic longitudinal multi-level assessment. Novel technologies may improve detection of gradual social cognition decline. Based on the phenomenon of “emotional blunting,” first results on physiological measures (e.g., altered skin conduction or eye gaze) in bvFTD are promising (Joshi et al., 2014; Hutchings et al., 2018; Singleton et al., 2022). Implementation of biometry might capture objective processes related to social functioning (independent of cognitive or cultural factors), highlighting its potential value as (universal) clinical progression marker. Importantly, informant-rated questionnaires on impaired social behavior propose promising markers for progression (Table 1) such as the Revised Self Monitoring Scale (RSMS) and the (modified) Interpersonal Reactivity Index (IRI) (Davis, 1980, 1983; Foster et al., 2022). Socioemotional sensitivity, assessed with the RSMS, showed decline over one year in sporadic and genetic bvFTD, associated to salience network atrophy and caregiver burden (Toller et al., 2020). Yet, correlations between RSMS and social network abnormalities were not supportive, suggesting the true brain-behavior relationship requires further investigation (Toller et al., 2022). Thus far, the IRI, assessing empathetic abilities, was only validated through cross-sectional associations with disease severity (FTLD-CDR) in symptomatic genetic bvFTD, as well as prodromal C9ORF72 carriers (Foster et al., 2022).

In general, structural magnetic resonance imaging (MRI) is able to detect frontotemporal grey matter (GM) atrophy patterns during disease progression of bvFTD, by means of quantitative techniques such as voxel-based morphometry (VBM) and deformation-based morphometry (DBM) (Table 1). Whole brain atrophy and ventricular volume increased in both genetic and sporadic bvFTD, in several one-year follow-up studies and one six-month follow-up (Knopman et al., 2009; Gordon et al., 2010; Lam et al., 2014; Floeter et al., 2016; Sheelakumari et al., 2018; Manera et al., 2019; Gordon et al., 2021). Over varying follow-up (from 6 months to 2.5 years), the increase of GM atrophy was associated with various validated clinical measures of disease progression, such as the CDR, CDR-FTD, MMSE, and, in neuropsychological testing, letter fluency scores (Gordon et al., 2010; Floeter et al., 2016; Staffaroni et al., 2019b; Illán-Gala et al., 2021b). Volumetric studies, with mostly extensive follow-up (2.5–5 years), showed fastest progression rates in the temporal lobe (compared with frontal), whereas distinctive regions such as the primary and sensory cortices remain spared (Seeley et al., 2008; Frings et al., 2012; Staffaroni et al., 2019b; Whitwell et al., 2020). However, since many years regional GM atrophy patterns are known to be heterogeneous in bvFTD, of which a cross-sectional study suggested at least four distinct (data-driven) subtypes (Kril et al., 2005; Ranasinghe et al., 2021). Regarding specific regions-of-interest (ROIs), one longitudinal study found a pattern of increased atrophy primarily in the pallidum, middle temporal gyrus, inferior frontal and middle orbitofrontal gyrus, cingulate gyrus and insula over one year (Anderl-Straub et al., 2021). Other ROI-based studies stated the following regions of importance for longitudinal change: anterior cingulate, paracingulate, medial temporal, medial frontal and insular regions (1 year) (Brambati et al., 2007), the medial and lateral frontal lobes, insula, striatum and bilateral temporo-parietal regions (1 year) (Binney et al., 2017), and early and continuing orbitofrontal, anterior cingulate, temporal and subcortical, primarily striatal, regions (1–4 year) (Landin-Romero et al., 2017). Specific regions have been correlated with decline on clinical measures, such as (left) striatum atrophy and the FTLD-CDR and FBI negative subscale (cross-sectional) (Macfarlane et al., 2015), posterior parietal atrophy and loss of recent autobiographical memory over one year (Irish et al., 2018), and olfactory bulb atrophy (specific to more severe disease stages) and olfactory dysfunction (loss of smell) over 1 year (Carnemolla et al., 2022).

A relatively large amount of studies on diffusion tensor imaging (DTI), visualizing the microstructure of white matter (WM) tracts, concluded sensitive detection of WM changes in an early phase of the disease, over varying follow-up time (0.5 to 2.5 years) (Mahoney et al., 2015; Elahi et al., 2017; Floeter et al., 2018; Kassubek et al., 2018; Staffaroni et al., 2019b). DTI may detect bvFTD pathology before GM atrophy arises, and has been correlated with cognitive decline (cross-sectional ACE-R), contributing to its value as possible early and sensitive progression marker (Chen and Kantarci, 2020) (Table 1). More general, WM tract pathology can be measured by multiple techniques. It’s microtructural integrity can be detected by diffusion-weighted imaging (DWI), of which DTI is a relevant modality as it enables the tracking of WM-fibers (tractography). Macro-structurally, WM pathology can be measured by structural MRI. Progression of WM microstructural disintegrity, as detected by DTI, showed fast rates in early bvFTD (1 year) (Lam et al., 2014). WM volume, as measured with structural MRI, manifested a steeper decline, especially in the temporal lobe, compared to early GM orbitofrontal and insula atrophy (1 year, N = 15) (Frings et al., 2014). WM pathology has been correlated with a decline in executive functioning (1 year) (Yu and Lee, 2019), the presence of a MOPB-risk allele (Massimo et al., 2021) and an increase of WM hyperintensities, both independent of and related to cortical atrophy (cross-sectional) (Huynh et al., 2021). In contrast, one cross-sectional study on a clinically relevant outcome measure (Revised Self-Monitoring Scale), found that GM volumes of the right orbitofrontal cortex, not WM tract pathology (DWI), predicted socioemotional impairment (Toller et al., 2022).

A prospective study on glucose metabolism (fludeoxyglucose-positron emission tomography; FDG-PET) indicated a specific progression pattern over 1.5 years, from decreased glucose uptake in frontal lobe(s), to parietal and temporal lobe(s), to whole frontal lobe hypometabolism (Diehl-Schmid et al., 2007) (Table 1). A genetic study on arterial spin labelling (ASL) in FTD patients, measuring cerebral blood flow (CBF), showed that a specific pattern of frontal, temporal, parietal and subcortical CBF decrease accompanied the clinical conversion from pre-symptomatic to symptomatic stages in MAPT and GRN mutation carriers over 2 years (Dopper et al., 2016). Multiple promising, yet cross-sectional, studies on single photon emission computer tomography (SPECT) reported a decrease in regional CBF in bilateral frontal cortices and right temporal cortices that correlated with several clinical measures, such as the FTLD-CDR, FTD-FRS, and cognitive reserve scales (Borroni et al., 2010; Maiovis et al., 2017, 2018), as well as specific brainstem hypoperfusion that associated with fast clinical progression in bvFTD (Le Ber et al., 2006). Connectivity changes of the salience network (SN), related to the fundamental behavioral and socioemotional deficits in bvFTD, may be measured with functional MRI (fMRI). Although only reported in a small study with limited longitudinal data (8 weeks), specific SN connectivity patterns (e.g., decreased right fronto-dorsal SN) were associated with increased apathy measured with FBI (Day et al., 2013). While lacking longitudinal data, two small yet promising cross-sectional studies on disruption of sensory/auditory information processing, as measured by magnetoencephalography (MEG) analysis of cortical microcircuits, suggested these changes in frontotemporal networks may be a useful biomarker to detect (early) disease progression (2013, N = 12, 2019, N = 44) (Hughes and Rowe, 2013; Shaw et al., 2019).

While studied in limited follow-up or cross-sectional designs, additional PET and MRI-based techniques, focusing on other pathological processes may hold promise as biomarkers of disease progression. First, a small prospective study (N = 10) detected progression of tau-pathology by means of flortaucipir-PET in the frontotemporal region after 1.5 months, and suggested that FTD-specific (tau) tracers could potentially be of superior value (Tsai et al., 2019). Second, a couple of cross-sectional studies detected processes of synaptic loss (11C-UCB-J-PET, N = 11) (Malpetti et al., 2021, 2022), and reduced brain stiffness, which is hypothesized to occur prior to gliosis and cellular damage (magnetic resonance elastography, N = 5) (Huston et al., 2016). Both processes may be associated with early disease progression in bvFTD.

To date, no fluid biomarkers are known that enable specific detection of bvFTD. A first prospective study on a bvFTD specific proteinopathy related to progranulin (PGRN), which is a protective protein altered in GRN mutation carriers which results in pathological TDP-43 accumulation, showed no significant change in CSF or serum PGRN levels at one-year follow-up (Feneberg et al., 2016). Despite apparent variability, PGRN concentrations did decrease in four out of five FTD patients, calling for further large scale investigation. Next to this, CSF amyloid-beta, which is typically decreased in AD, showed to decrease in both genetic and sporadic bvFTD over five year follow-up, and has been associated with higher mortality (Vieira et al., 2019). Cross-sectional studies on other AD-related proteins showed alternations in bvFTD as well, such as plasma tau and the phosphorylated-tau/total-tau ratio (Foiani et al., 2018; Meeter et al., 2018). However, since these protein profiles are not specific to bvFTD, and did not correlate with important progression measures such as whole brain volume, GM atrophy, neurofilament light chain (NfL), or disease duration, they do not have much potential to measure disease progression (Foiani et al., 2018; Meeter et al., 2018).

Currently, the most promising fluid biomarker, measured in both CSF and serum, is neurofilament light chain (NfL), reflecting axonal damage (Table 1). Longitudinal studies, with 9 to 12 months follow-up, concluded levels of CSF or serum NfL increased over time, in both genetic and sporadic bvFTD (Ljubenkov et al., 2018; Gendron et al., 2022). Additionally, serum NfL was found to predict clinical conversion from a prodromal to a symptomatic phase in a genetic bvFTD cohort at one-year follow-up (Benussi et al., 2021a). Increased CSF NfL, in both genetic and sporadic subtypes, has been associated with various progression measures, including CDR, cognition (executive functioning; neuropsychiatry unit cognitive assessment tool), behavioral symptoms (FBI), frontotemporal GM atrophy, WM tract pathophysiology, GABA-ergic deficit, and survival rates (Scherling et al., 2014; Kassubek et al., 2018; Steinacker et al., 2018; Benussi et al., 2020; Spotorno et al., 2020; Walia et al., 2022). Interestingly, when comparing genetic and sporadic subtypes, a large cross-sectional study concluded that serum NfL concentration is higher in genetic bvFTD (Benussi et al., 2022). Another promising, less validated fluid biomarker is soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Also interpreted as a more general response to neuronal injury, first cross-sectional results showed CSF sTREM2 levels increased during neuro-inflammation in familial bvFTD associated with GRN mutations (N = 3) (Woollacott et al., 2018). Contrarily, first cross-sectional results on glial fibrillary acidic protein (GFAP), suggesting to reflect reactive astrogliosis, showed less promising results as suitable progression marker in genetic and sporadic bvFTD, since merely small changes in serum concentration of GFAP were detected (cross-sectional) (Oeckl et al., 2022). The neurotransmitter orexin A, known for regulation of various physiological functions (such as appetite and sleep), has been correlated with obsessive-compulsive (measured by SRI) and extrapyramidal symptoms, that may accompany disease progression (cross-sectional, N = 40) (Roveta et al., 2022). Lastly, specific metabolic changes were found in bvFTD (compared to controls), such as altered metabolites in a wide range of pathways (including amino acids, energy and carbohydrate, cofactor and vitamin, lipid and nucleotide) and increased fat preference, offering a new field to reveal possible physiological progression markers (N = 30, N = 20) (Murley et al., 2020; Ahmed et al., 2021). However, for all suggested fluid biomarkers, e.g., NfL, sTREM2, GFAP, Orexin A as well as metabolic features, longitudinal observations are needed and highly recommended, before they can be evaluated in their potential to track disease progression.