Clinical Approach to the Differential Diagnosis Between Behavioral Variant Frontotemporal Dementia and Primary Psychiatric Disorders

Major depressive disorder and bvFTD share common symptoms, including lack of interest, decreased motivation, low energy, and impaired concentration. Diagnostic confusion can occur between bvFTD and severe major depression that is causing impaired cognitive processing. However, sustained depressed mood, which is a hallmark of depression, is usually not present in bvFTD. Other symptoms of major depression rarely seen in bvFTD include guilty ruminations, feelings of worthlessness, and suicidal thoughts. Patients with bvFTD sometimes report mood changes (e.g., inability to feel normally), but their descriptions tend to be shallow (15).

Major depression can also present with diminished interest or pleasure (anhedonia) without pervasive sadness, which can be difficult to distinguish from apathy. Apathy is a deficit in motivation, manifested by a reduction in self-initiated or environment-responsive goal-directed behaviors, cognitive activity, and emotional responsiveness. A core distinction is that apathy is not experienced as distressing or accompanied by dysphoria.

Geriatric major depression can be challenging, as elderly patients tend to have less subjective sadness, more cognitive symptoms, and less insight (16). Strategies to distinguish depression-related cognitive impairment from bvFTD include a structured clinical history (17), social cognition batteries (18), and neuroimaging studies (see the Clinical Approach section).

In bipolar depression there is a higher prevalence of atypical features, including hypersomnia and hyperphagia, symptoms that may be observed in bvFTD. In addition, bvFTD and mania share symptoms such as disinhibition, irritability, distractibility, risk taking, impaired social judgment, and excessive involvement in pleasurable activities with potentially harmful consequences (19).

Although patients with bvFTD can be inappropriately jocular (20), euphoric mania is accompanied by a qualitatively distinct elevated and expansive mood, with a sense of grandiosity and invulnerability that is uncommon in bvFTD. In addition, in mania irritability is combined with increased energy and decreased need for sleep, a clinical feature not seen in bvFTD.

Most importantly, bvFTD involves an inexorable deterioration of cognitive and behavioral functions, while bipolar disorder is usually an episodic syndrome with waxing and waning symptoms. Severe cases of bipolar disorder can evolve toward a chronic state, but cognitive impairment is not as profound or progressive (21).

Stereotyped and compulsive/ritualistic behaviors due to bvFTD range from simple stereotypies (e.g., rubbing) to more elaborate rituals mimicking compulsions of OCD (e.g., checking, washing) (22). Compulsions can be the initial manifestation of bvFTD (23).

Compulsive/ritualistic behaviors can be phenotypically identical in bvFTD and OCD, but there are key distinguishing factors. In OCD, the patients engage in repetitive rituals as a response to obsessions to reduce distress or to “prevent” an adverse outcome. Although the behavior in bvFTD appears seemingly driven by a specific worry, patients usually deny or are unable to describe obsessions (15). It remains unclear whether there are no obsessions, or whether the loss of neuronal function causes an inability to consciously identify obsessions. Importantly, rituals in bvFTD are not typically accompanied by apparent anxiety, which is a core feature of OCD. Most people suffering from OCD have insight that their compulsions are excessive and do not logically prevent dreaded consequences, although some hold on to this possibility. Patients with FTD usually exhibit an almost complete absence of insight.

Hoarding can be a prominent feature of bvFTD (24), but it can also manifest as an idiopathic OCD-related disorder. Idiopathic hoarding tends to start in early life and get worse over the years, while in bvFTD it usually follows the onset of cognitive decline. In some cases hoarding may have been present before the onset of bvFTD symptoms and subsequently intensified. Patients with idiopathic hoarding usually accumulate objects with some theoretical value (e.g., paperwork) and endorse weak rationalization about the potential need for future use. In bvFTD, hoarded items can be unsanitary (e.g., rotten food), and hoarding is attributable to impaired decision making rather than anxiety (25).

Negative symptoms of schizophrenia strikingly overlap with the predominantly apathetic variant of bvFTD. Moreover, schizophrenia is associated with mild cognitive deficits in attention, working memory, executive function, declarative memory, and processing speed, which can mimic early deficits of bvFTD (26). The two diseases also share similar social cognitive deficits (27) and limited insight.

The clinical distinction is informed by the presence of positive psychotic symptoms, which are relatively rare in FTD (28), and longitudinal history. Schizophrenia usually starts with a prodrome beginning in the late teens to mid-30s, followed by episodic exacerbations and a variable level of residual deficits. Onset of symptoms before age 30–35 is supportive of a primary psychotic disorder; onset of bvFTD before age 30–35 is unusual although possible (29). Most importantly, the course of primary psychotic disorder with periodic exacerbations intertwined with more stable phases is incompatible with bvFTD, which follows a course of progressive neurodegeneration without remission of deficits.

Differentiating bvFTD from late-onset schizophrenia (i.e., after age 40) can be more challenging. Late-onset schizophrenia presents with variable combinations of symptoms, including hallucinations (auditory and sometimes other types) and systematized delusions, typically with a lesser degree of negative and cognitive symptoms than is seen in younger patients. Clinical presentations with prominent positive psychotic symptoms unaccompanied by apathy and/or cognitive decline are more likely to be caused by a primary psychotic disorder. One notable exception is the strikingly higher prevalence of psychosis as the initial presentation of bvFTD secondary to C9ORF72 mutations (30, 31) (see the Psychiatric Disorders as a Prodrome of bvFTD section below).

Catatonic syndromes and bvFTD share symptoms, including stereotypies, echophenomena, decreased verbal output, and negativism (32). When amenable to cognitive examination, patients with catatonia often show frontal network types of dysfunction such as perseveration and environmental dependency. These syndromes are not mutually exclusive, as catatonia can be a manifestation of bvFTD (33).

The diagnosis of catatonia is based on DSM-5 criteria, and it can be supported by a “lorazepam challenge.” Rapid improvement of cognitive and behavioral symptoms after the administration of a short-acting benzodiazepine (or ECT) strongly suggests catatonia. Of note, there have been anecdotal reports of persisting cognitive deficits after remission of a catatonic episode (32, 34), which could potentially mimic bvFTD.

Deficits in communication and interpersonal interactions are the core features of autism spectrum disorder (ASD). Similar acquired social cognition deficits are produced by bvFTD, suggesting some degree of shared neuroanatomical circuits (27). Obtaining a collateral developmental history is crucial to differentiate bvFTD from ASD given that symptoms of the latter must be present during early development.

It can occasionally be challenging to determine whether distractibility, inattentiveness, and organization deficits are due to long-standing adult attention deficit hyperactivity disorder (ADHD) or to a neurodegenerative process. As with ASD, the key is to elicit a history of similar or more severe ADHD symptoms in childhood. Clinical improvement with psychostimulants is expected to be much more significant in ADHD than in bvFTD (35). While distractibility due to early-stage bvFTD can overlap with symptoms of ADHD, over time the progression of bvFTD will inexorably lead to symptoms that cannot be explained by ADHD, such as loss of empathy or apathy.

Early symptoms of bvFTD involve subtle changes in personality and values (36). Relatives often perceive the initial phase as a psychosocial crisis, which can lead to major life changes (e.g., divorce) or legal repercussions (37). In practice, clinicians need to determine whether unusual behaviors reported by relatives should be considered a symptom of an illness or within the realm of normative experience. Indeed, patients with bvFTD often rationalize pathological behaviors as being a normal reaction to events or blame relatives for overreacting.

The best strategy, in our experience, is to develop a general sense of premorbid personality by questioning the patient and the family. Reported behaviors can then be analyzed as a function of how much they deviate from the patient’s own norms. A particular action might be deemed worrisome in one individual but normal in others. For example, impulsively investing a significant sum of money in a risky venture might be a symptom of disinhibition in someone with a conscientious temperament, but not in a risk-taking entrepreneur. Conversely, patients with bvFTD can exhibit an unusual calmness or ease (38) that can be normal in certain individuals, but pathological in previously dynamic or anxious individuals. If the patient has a psychotherapist, it can be useful to discuss the reported symptoms with the therapist. Longitudinal observations in therapy can provide valuable information that can favor (e.g., inability to engage with therapist) or lead away (e.g., capacity for introspection) from a diagnosis of bvFTD.

While it is often difficult to determine whether or not an isolated behavior is pathological, patients with bvFTD will, over time, exhibit multiple unusual behaviors across symptomatic domains (e.g., impulse control, lack of empathy, and so on). Therefore, even if each individual symptom is subtle, bvFTD should be suspected when a patient exhibits multiple types of abnormal behaviors along the lines of bvFTD diagnostic criteria. Of note, with increased public awareness, we have also encountered situations in which families have erroneously interpreted interpersonal conflicts as being symptoms of bvFTD.

Diagnosing bvFTD in patients with preexisting personality disorders can be challenging (39, 40). The key diagnostic clue for all personality disorders is their longitudinal nature, with symptoms of maladaptive traits present since early adulthood. Borderline personality disorder and bvFTD can both present with impulsivity, impaired judgment, and anger outbursts. The fear of abandonment, high degree of self-concerns, self-harm, and unstable sense of self differentiate borderline personality disorder from bvFTD. Narcissistic personalities and bvFTD can both have selfishness, disregard for others, and lack of empathy. However, it is not typical for patients with bvFTD to have an excessive sense of self-grandiosity. Patients with bvFTD can exhibit acquired antisocial behaviors, but they usually consist of impulsive actions resulting from disinhibition rather than instrumental aggression (41).

A subgroup of patients who meet criteria for possible bvFTD do not show clear deterioration over time (42). These “bvFTD phenocopies” are predominantly men and are less impaired in executive functions, social cognition, and activities of daily living. They do not show supportive features of FTD on neuroimaging (42). Their lifespan is normal, and in many such individuals autopsy has not shown frontotemporal lobar degeneration. While some of these individuals have very slowly progressive forms of bvFTD secondary to C9ORF72 (43), it is generally assumed that many of them do not have bvFTD (42). Some authors have suggested that this phenotype could be a late deterioration of unidentified ASD (Asperger’s syndrome) (42, 44). This seems unlikely given the long-standing nature of deficits in ASD. Atypical residual mood disorders, low-grade psychotic disorders, and catatonic syndromes are diagnostic alternatives, but there is much uncertainty as to the nature of this disorder.

Primary psychiatric disorders are often diagnosed in the few years preceding a diagnosis of bvFTD (3). While this is in part related to missing the bvFTD diagnosis because of complex symptomatic overlap (45), recent studies (especially related to the C9ORF72 mutation) have highlighted the possibility of bone fide primary psychiatric disorders representing the initial (or prodromal) stage of bvFTD. Among patients with C9ORF72 mutations, a relatively high proportion have late-onset positive psychotic symptoms as the initial presentation (30, 31). Various other neuropsychiatric presentations have been reported, including mania/bipolar disorder (46, 47) and “depressive pseudodementia” (48). However, C9ORF72 mutations are rare (<1%) in cohorts of patients with a clinical diagnosis of schizophrenia (49, 50) or bipolar disorder (46, 51). Based on these findings, patients presenting with late-onset psychiatric disorders should have a careful clinical assessment for bvFTD symptoms and a detailed family history to identify autosomal-dominant disease inheritance patterns.

Specialized evaluation for neurodegenerative diseases should be pursued aggressively when a patient presents with progressive cognitive impairment in parallel with the new onset of a neuropsychiatric syndrome (55, 56). The first step is to disentangle cognitive weaknesses that can be satisfactorily explained by an acute mental illness from those that cannot. During acute episodes of depression, mania, psychosis, or delirium, attentional disturbances often severely interfere with cognitive performance for a temporary period (57). Persistent and especially progressive executive dysfunction despite improvement in psychiatric symptoms raises the index of suspicion for bvFTD. It is important to keep in mind that severe chronic mental illnesses are associated with multidomain cognitive deficits even between acute exacerbations, but with limited progression over time (26). Deficits due to schizophrenia have been documented prior to the first psychotic episode and can involve multiple cognitive domains, including attention, working memory, verbal learning, verbal memory, and executive functions (performance across testing on average 0.5–2 standard deviations below the mean of age- and education-matched controls) (26, 58). In bipolar disorder, there can be mild and generally stable weaknesses in attention, working memory, lexical fluency, and verbal learning and memory (21, 59).

Patients suffering from major depressive episodes and anxiety disorders often express subjective memory concerns. These are usually secondary to primary deficits in attention and working memory, which can have a negative impact on other cognitive domains (e.g., executive functions) and lead to inefficient encoding and retrieval of information (57). Cognitive symptoms are expected to improve in parallel with mood with treatment (60). High antipsychotic dosages and polypharmacy can contribute to cognitive impairment (26, 59); if possible, clinicians should attempt to reduce use of antipsychotics, mood stabilizers, benzodiazepines, and any medication with anticholinergic effects.

In the initial stages of bvFTD, the magnitude of cognitive weaknesses can be similar to symptoms observed in primary psychiatric disorders, including major depression (61). The relative specificity of deficits in executive function and language and their progressive nature are characteristics that can help distinguish cognitive impairments in bvFTD from those of severe and persistent mental illnesses (61). Performance on standard screening tests can be within normal limits in early bvFTD (62), and a referral for more in-depth neuropsychological testing is often helpful to identify subtle deficits. Deficits in social cognition are among the earliest impairments in bvFTD and are not captured adequately by standard cognitive tests. Social cognition refers to a cluster of cognitive skills that are required for interpersonal interactions, such as theory of mind, self-knowledge, and perception of others (27). Social cognition batteries, including tests such as identification of interpersonal faux-pas and facial emotion recognition, have been shown to be potentially more sensitive than standard neuropsychological testing for the early diagnosis of bvFTD and to distinguish bvFTD from mood disorders (18, 62).

Neuroimaging plays a crucial role in the diagnosis of bvFTD. The degree of certainty increases from possible to probable if either frontal or anterior temporal atrophy is identified in CT or MRI studies, or if a pattern of frontal or temporal lobe abnormality is identified in positron emission tomography (PET) or single-photon emission computed tomography (SPECT) (1) (Figure 2). Positive neuroimaging biomarkers increase the diagnostic specificity from 82% to 95% (63).

Brain imaging should be obtained for the evaluation of any late-onset psychiatric syndrome for which bvFTD is in the differential diagnosis. Structural imaging with CT or MRI is a reasonable first examination, ideally including coronal and sagittal images if available. MRI offers the advantage of more accurate definition of boundaries between CSF and brain parenchyma, thus permitting more sensitive evaluation for patterns of atrophy. Since neuroimaging findings in early FTD can be subtle, a specialist with expertise in the imaging of neurodegenerative disorders should review the examination, ideally in close collaboration with the treating physicians. If the initial brain MRI is unremarkable, obtaining a [¹⁸F]fluorodeoxyglucose (FDG)-PET (or perfusion SPECT if FDG-PET is not available) is an appropriate next step. A principal advantage of FDG-PET relative to structural imaging is increased sensitivity that may allow diagnosis at an earlier stage (64). Normal imaging results argue against bvFTD but do not entirely exclude the diagnosis, especially in the early phases. Of note, schizophrenia and bipolar disorder have been statistically associated with cortical thinning compared with healthy subjects (52, 65), but this finding is usually very subtle and is not a reliable diagnostic feature at the individual level. Similarly, structural and functional abnormalities that have been identified in specific networks in major depression (66) and OCD (67) are based on small differences detected by group statistics and are not reliable diagnostic indicators in individual patients. Although MRI and PET findings are generally expected to be within normal limits, some patients with primary psychiatric disorders, including bipolar disorder and major depression, may exhibit frontal hypometabolism on FDG scans (68); thus, a radiologic finding of isolated frontal hypometabolism should be considered within the clinical context and may not necessarily indicate bvFTD.

Genetic testing for MAPT, GRN, and C9ORF72 should be considered when a patient with bvFTD symptoms has a family history positive for at least one first-degree relative with early-onset dementia (13, 14). As previously mentioned, C9ORF72 testing should be considered in late-onset psychosis or mania if there is at least one first-degree relative with FTD or ALS (30, 31, 47). A referral for genetic counseling prior to testing is recommended.

No reliable diagnostic CSF biomarker pattern has yet emerged for bvFTD. CSF analysis can be helpful when Alzheimer’s disease is also a possible diagnosis, in appropriately selected cases given the invasive nature of the test. There are numerous other, relatively rare neurological disorders that should be considered when symptoms are atypical for bvFTD or are rapidly progressive, and the diagnostic evaluation of many of these conditions should include CSF analysis (56). EEG findings are usually normal in early bvFTD, and EEG is generally not useful in distinguishing bvFTD from primary psychiatric disorders.