The Pitfall of Behavioral Variant Frontotemporal Dementia Mimics Despite Multidisciplinary Application of the FTDC Criteria

Abstract

Background:

The behavioral variant of frontotemporal dementia (bvFTD) has a broad differential diagnosis including other neurological and psychiatric disorders. Psychiatric misdiagnoses occur in up to 50% of bvFTD patients. Numbers on misdiagnosis of bvFTD in psychiatric disorders are lacking.

Objective:

The aim of our study was to investigate the frequency and characteristics of bvFTD misdiagnoses in psychiatric disorders and other neurologic disorders.

Methods:

Thirty-five patients with a (possible or probable) bvFTD diagnosis made by specialized memory clinic neurologists were included. Change in diagnosis after consulting a psychiatrist at baseline was recorded as well as change in diagnosis after two years of multidisciplinary neuropsychiatric follow-up. Differences in cognitive and behavioral profiles were investigated per diagnostic group after follow-up (bvFTD, psychiatry, other neurologic disorders). Clinical profiles are described in detail.

Results:

In 17 patients (48.5%), the bvFTD baseline diagnosis changed: Two at baseline after psychiatric consultation, and 15 after two years of multidisciplinary follow-up. Eleven (64.5%) of these 17 patients (31.5% of total) were reclassified with a psychiatric diagnosis. We found no differences for cognitive baseline profiles between patients with bvFTD versus psychiatric diagnoses.

Conclusion:

In almost half of cases, the initial bvFTD diagnosis was changed after follow-up, most often into a psychiatric disorder. A multidisciplinary neuropsychiatric approach in the diagnostic process of bvFTD results in the identification of treatable disorders. Our findings illustrate a limited specificity of the [¹⁸F]FDG-PET-scan and the bvFTD criteria in a neuropsychiatric cohort, especially combined with certain clinical symptoms, like disinhibition, apathy, or loss of empathy.

Keywords

Behavioral variant FTD differential diagnosis frontotemporal dementia psychiatry

INTRODUCTION

Behavioral variant frontotemporal dementia (bvFTD) is characterized by a frontal lobe syndrome, resulting in profound behavioral and character changes, caused by a neurodegenerative disease [1, 2]. However, many diseases of neurologic as well as psychiatric origin may show a similar frontal lobe syndrome as seen in bvFTD [3 –7]. Fortunately, recent research has made great progress in improving diagnostic biomarkers for the main neurodegenerative differential diagnoses [Alzheimer’s disease (AD), dementia with Lewy Bodies (DLB), and vascular dementia (VaD)], discriminating them more easily from bvFTD [8 –12]. Nowadays, the main clinical dilemma is formed by the psychiatric differential diagnosis of bvFTD [6 , 14]. Differentiating between early bvFTD and primary psychiatric disorders is challenging due to the lack of a disease-specific biomarker, the absence of insight on the patients, and the fact that bvFTD may present with psychiatric symptoms, fitting psychotic, compulsive, or mood disorders [14]. Typical features like apathy, loss of initiative, and economy of speech are seen in bvFTD as well as in negative symptoms in schizophrenia or mood disorders [15 –23]. Similarly, in bipolar disorder, anxiety disorders, obsessive-compulsive disorder, autism, or tic syndromes, other behavioral disturbances like stereotypical or compulsive language and behavior or disinhibition occur as seen in bvFTD [24 –27]. Especially in the bvFTD subgroup with a C9orf72 mutation, psychiatric symptoms are often the presenting feature and a disease duration up to 20 y has been described, complicating differentiation from primary psychiatric causes [6 , 29]. In consequence, up to 50% of bvFTD patients initially receives a psychiatric misdiagnosis [13]. Not much is known about misdiagnosis the other way around: bvFTD misdiagnosis in psychiatric disorders. With the publication of the Frontotemporal Dementia Consortium (FTDC) criteria, sensitivity has clearly improved, but specificity for bvFTD within a patient group with early manifestation of frontal lobe symptomatology, including psychiatric disorders, might be limited [30, 31]. The number and characteristics of psychiatric patients fitting a bvFTD diagnosis according to the FTDC criteria has not been prospectively examined before. Since bvFTD is progressive and will eventually lead to death, whereas psychiatric disorders are treatable, every approach adding to the correct discrimination between the two is of paramount importance [14, 32]. Our aim was to prospectively investigate the number of bvFTD misdiagnoses in other diagnoses, including primary psychiatric disorders, when applying the FTDC criteria in a memory clinic setting. Secondly, our aim was to examine whether the baseline characteristics differed between the patient group with a stable bvFTD diagnosis over time and the groups in which diagnosis was changed towards either a psychiatric diagnosis or a neurologic disorder. Especially characterizing the subgroup of patients with a psychiatric disorder mimicking bvFTD is of interest, since these patients are at risk for serious treatmentdelay.

METHODS

Participants

Study subjects were participants of the LOF-study (Late Onset Frontal lobe syndrome study, inclusion between April 2011 and June 2013, follow-up until 2015), an observational prospective follow-up study including 137 subjects aged 45–75 y, of which the study design and baseline characteristics were published previously [7, 33].

In summary, the subjects were selected from the neurology memory clinic and the old age psychiatry department between 2011 and 2013 when new behavioral disturbances (inappropriateness, disinhibition, loss of decorum, apathy, inertia, loss of empathy, loss of sympathy, compulsive behavior, inflexibility) were mentioned by a reliable informant as the main complaint and a Frontal Behavior Inventory (FBI) score of 11 or higher and/or a Stereotype Rating Inventory (SRI) of 10 or higher and the patient was aged between 45 and 75 years. The detailed information is given in the earlier publication [33].

The LOF study was designed to investigate which factors contribute to an early and accurate bvFTD diagnosis in a neuropsychiatric cohort. This present study focused on the subgroup with a baseline bvFTD diagnosis and therefore potential bvFTD misdiagnosis as may be revealed after follow-up. For the present study subjects were drawn from the LOF-study when they: 1) had been referred to the memory clinic of the Alzheimer center (VU University Medical Center), 2) were diagnosed with possible or probable bvFTD by a specialized neurologist after a standardized assessment, and 3) a follow-up diagnosis after two years was available. Patients who died during follow-up were only included when no doubt remained about the underlying disease at the time of death.

Diagnostic assessment

All patients underwent standardized clinical assessment, consisting of behavioral and cognitive medical history, neurological exam, Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Montgomery-Asberg Depression Rating Scale (MADRS), Positive And Negative Symptom Scale (PANSS), and a neuropsychological test battery [33]. Informant-based behavioral screening instruments were used to assess behavioral disturbances: the FBI which is split in a positive (disinhibition) and a negative subscale (apathy and inertia) and the SRI.

All patients underwent an MRI-scan of the brain, visually assessed by a neuroradiologist using the appropriate scales [34 –36]. In case of normal MRI findings or doubt on the interpretation of the abnormalities being explanatory for the behavioral changes, an [¹⁸F]FDG-PET-scan was made and assessed by a nuclear physician. CSF was obtained with a lumbar puncture, performed according to standard medical procedure in the lateral position in the L3-L4, L4-L5 or L5-S1 intervertebral space by a 25-gauge needle and syringe. Reasons for not obtaining CSF included technical difficulties, use of oral anticoagulants, and patient refusal.

After clinical assessment, a specialized neurologist (Y.P., N.P., P.S.) determined the most likely baseline diagnosis, taking into account results from neuropsychological assessment, neuroimaging, and CSF. A specialized psychiatrist (A.D, C.K., M.S.) also determined the most likely diagnosis at baseline, independent of the neurologist, taking into account all the available test results. In a subsequently held multidisciplinary meeting the neurologist could revise the diagnosis into the most likely baseline diagnosis after consulting the psychiatrist. Diagnoses were based upon the total workup described above and the NIA-AA guidelines for Alzheimer’s disease, the NINDS-AIREN-criteria for vascular dementia, the international consensus diagnostic criteria for dementia with Lewy bodies, the DSM-IV for psychiatric disorders and the FTDC criteria for bvFTD [10 , 37].

This preliminary multidisciplinary diagnosis with the highest evidential ground possible at baseline was used as a clinical diagnosis in order to treat and guide the patient and caregivers. Patients were regularly followed in a clinical multidisciplinarysetting.

After two years of follow-up the clinical diagnosis was re-evaluated based on the clinical course, repeated MRI and repeated neuropsychological examination. For each patient, a multidisciplinary meeting was held in which all available factors were carefully weighed by the specialized neurologist and psychiatrist. This final diagnosis after two years of follow-up was used as a gold standard.

For analysis, the patients were grouped into ‘bvFTD’, ‘psychiatry’, and ‘other neurological disorders’ based on their multidisciplinary follow-up diagnosis. In order to characterize the subjects in more detail, a subdivision in possible and probable bvFTD was made. In case of a positive family history for dementia, patients were referred for clinical genetic counseling and optional genetic screening for MAPT, GRN, PSEN1, and APP genes. Taking into account the clinical overlap in C9orf72 cases and psychiatric disorders, C9orf72 genotyping was performed in all cases as part of this study [6 , 29].

Medical ethical/informed consent

This study followed the Declaration of Helsinki on medical protocol and ethics and has been approved by the Medical Ethical Committee of the VU University Medical Center Amsterdam, the Netherlands. All subjects gave written informed consent for the use of their clinical data for research purposes.

Statistical analysis

Statistical analyses were performed using the IBM SPSS Statistics for Windows, version 22. Demographic baseline characteristics were compared between diagnostic patient groups [bvFTD diagnosis, psychiatric diagnosis, or other neurological diagnoses (OND)]. Dichotomous variables were compared using the Pearson’s χ ² test. Non-parametric tests were used to investigate relationships between the diagnostic groups and the clinical scales (FBI, SRI, MMSE, and FAB) because of the small sample size (Kruskal-Wallis). For significant findings, post hoc analyses were performed using Mann-Whitney U test with Bonferroni correction for multiple comparison. Pearson Chi-square test was used to investigate groups differences in gender. Results were considered to be statistically significant if p < 0.05 unless otherwise indicated.

RESULTS

A total of 35 patients met the inclusion criteria of receiving a possible bvFTD (n = 5) or a probable bvFTD (n = 30) diagnosis by the memory clinic neurologist at baseline and had follow-up information available. In 17 (48.5%) of the 35 patients, the bvFTD baseline diagnosis was changed. In two patients, the diagnosis was changed at baseline after psychiatric consultation, and, in 15 patients, diagnosis was changed after two years of multidisciplinary follow-up by the neurologist and psychiatrist (Table 1). Eleven patients (64.5% of the patients with a changed diagnosis, 31.5% of the total) eventually received a psychiatric diagnosis, of which mood disorders were the most common. Six patients (17%) received other neurologic diagnoses (OND), most commonly other neurodegenerative disorders, half of which were considered to be part of the FTD-spectrum, like semantic dementia. The remaining 18 patients had a probable bvFTD diagnosis after two years based on the FTDC consensus criteria [30]. In all 5 cases with an initial possible bvFTD diagnosis made by the neurologist at baseline, the diagnosis changed towards a psychiatric diagnosis. In 6 of the initial probable bvFTD cases (16.7% of the total of 30 initial probable bvFTD cases) the diagnosis was changed toward a psychiatric diagnosis.

Table 1

Diagnosis after consultation psychiatrist at baseline and after two years multidisciplinary follow-up

Patients diagnosed with bvFTD by	bvFTD	Psychiatric	OND
neurologist at baseline, n = 35		diagnosis
Baseline diagnosis neurologist and	33 (94.5%)	2 (5.5%)	0 (0%)
psychiatrist (% of total group)
Follow-up diagnosis neurologist and	18 (51.5%)	11 (31.5%)	6 (17%)
psychiatrist (% of total group)

bvFTD, behavioral variant frontotemporal dementia; OND, other neurologic disease.

No significant differences were found for age of onset (Kruskal-Wallis: H(2) = 0.49, p = 0.78), sex Pearson’s χ ² (2) = 3.97, p = 0.14) and education (H(2) = 0.01, p = 0.99) between the three final diagnostic groups (stable bvFTD: ‘FTD’, changed to psychiatry: ‘psychiatry’ and changed to other neurologic disorders: ‘OND’) after multidisciplinary follow-up (Table 2).

Table 2

Demographics for diagnostic groups

	bvFTD	Psychiatry	OND	p-value
	(n = 18)	(n = 11)	(n = 6)
Age of onset (y) median (IQR)	59 (54–66)	60 (46–62)	56 (55–62)	0.78^a
Sex (males (% within diagnosis))	10 (55.5%)	10 (91%)	4 (66.5%)	0.14^b
Education (y) median (IQR)	11 (10–14)	11 (10–15)	11 (10–15)	0.99^a

bvFTD, behavioral variant frontotemporal dementia; OND, other neurologic disease; IQR, interquartile range, 25th–75th percentile. ^aKruskal-Wallis, ^bPearson’s χ ².

Group differences between the three diagnostic groups after follow-up (bvFTD, psychiatric diagnoses, and OND) were examined for the baseline results of the cognitive screening instruments and informant-based behavioral questionnaires. Results are depicted in Fig. 1. No significant differences were found for the MMSE (Kruskal-Wallis: H(2) = 0.42, p = 0.81), FAB (Kruskal-Wallis: H(2) = 3.55, p = 0.17), positive subscale of the FBI (Kruskal-Wallis: H(2) = 2.20, p = 0.33) and the negative subscale of the FBI (Kruskal-Wallis: H(2) = 0.23, p = 0.89) (Fig. 1).

Fig.1

Box and whisker plots for MMSE, FAB, FBI, and SRI for diagnostic groups. Significant differences are marked with an asterisk (*). FTD, frontotemporal dementia; OND, other neurologic disorder; MMSE, Mini-Mental State Examination; FAB, Frontal Assessment Battery; FBI, Frontal Behavioral Inventory; SRI, Stereotypy Rating Inventory.

For the SRI, a significant group difference was found (Kruskal-Wallis: H(2) = 6.96, p = 0.03) (Fig. 1). Post hoc analyses (with a Bonferroni corrected significance level of p < 0.02) showed a significantly higher score on the SRI in bvFTD patients compared to OND patients (Mann-Whitney U(1) = 17.50, p = 0.01). The other diagnostic groups did not differ significantly (FTD versus psychiatry: p = 0.17, psychiatry versus OND: p = 0.12) (Fig. 1).

Table 3 shows the clinical descriptive characteristics of the patients and the clinical disease courses during follow-up. In most cases the clinical course of the disease and the evolution of symptoms combined with the presence or absence of neuroimaging progression, was very relevant for the final follow-up diagnosis. The patients in which the diagnosis was changed from bvFTD into a psychiatric diagnosis, complained about impaired memory function most frequently at baseline (n = 7) or had no complaint at all (n = 6), while their spouse or informant complained about more behavioral issues, especially disinhibition, inappropriate behavior, inertia, apathy, and loss of empathy (Table 3). Part of these patients did not officially fulfill the criteria for a major psychiatric diagnosis. For instance, in these patients newly developed subthreshold mood disorders combined with impaired coping strategies due to personality disorder traits or severe relational disputes were found. Although some improvement was seen on the cognitive and behavioral screening instruments, in many of these patients the scores fluctuated or remained stable (two patients refused part of the follow-up assessment). The patients in which a probable bvFTD diagnosis was maintained almost all showed clear clinical progression within two years, including severe behavioral problems, the development of motor neuron disease in three cases, nursing home admission in four cases, prosopagnosia in one case and aphasia or semantic deficits in six cases (Table 3). Almost half of the bvFTD patients were unable to complete the follow-up assessment due to serious disease progression. In one patient, a progranulin mutation was found. Screening the cohort for C9orf72 status showed a repeat expansion in one subject with a psychiatric diagnosis (Table 3, case number 6). No C9orf72 abnormalities were found in all other 34 cases. More details on clinical reasoning and neuroimaging findings on an individual patient level are given in Table 3.

Table 3

Characteristics subjects with final diagnosis

					FBI	FBI	SRI	SRI	MMSE	MMSE	FAB	FAB		Clinical course T0-T2.
Patient	Age	Sex	Diagnosis T2	D	T0	T2	T0	T2	T0	T2	T0	T2	Imaging	Bold symptoms: main complaint of informant
1	46	M	major depression^*	5	20	12	23	6	27	29	16	16	T0 MRI: n.a.	Hypochondriac delusions and somatic complaints e.c.i., disinhibition, obsessive behavior. Anxiety and depression became more and more apparent during FU; almost full recovery after ECT, besides some mild remaining anxiety complaints and some lack of initiative.
													T0 FDG: fitting FTD
													T2 MRI: no progression
2	58	F	major depression^*	3	42	m	26	m	24	m	14	m	T0: MRI: n.a.	Social withdrawal, severe emotional indifference, loss of empathy, apathy, anhedonia, restlessness, and eating rituals. Admission old age psychiatry ward for diagnostic observation: symptoms due to anxiety and depression and anorexia nervosa (both late onset). So far no effects of medication and ECT.
													T0 FDG: fitting FTD
													T2: m (refusal due to anxiety)
3	56	M	bipolar disorder^*	3	19	20	2	1	28	30	17	17	T0 MRI: n.a.	Disinhibition, euphoria, and social inappropriate behavior. Loss of sympathy. Patient complained of memory impairment. Conclusion: symptoms due to bipolar disorder. Mood stabilized after treatment during FU, other frontal behavioral symptoms stayed apparent (stable).
													T0 FDG: n.a.
													T2 MRI: no progression, n.a.
4	66	M	exacerbation personality disorder^*	1	32	37	12	7	27	24	11	15	T0 MRI: n.a.	Irritability, emotional indifference, mental rigidity, and somatic complaints (e.c.i.). Due to combination of cluster C personality disorder and mild depressive symptoms. No progression. Treatment started recently; mental flexibility improved with medication.
													T0 FDG: fitting FTD
													T2 MRI: no progression, n.a
5	62	M	minor depression, impulse control disorder^*	4	27	22	1	3	27	26	16	16	T0 MRI: n.a.	Irritability and aggression, disinhibition, loss of empathy and initiative. Due to minor depression with impulse control problems; may be partly induced by sleep deprivation due to obstructive sleep apnea syndrome. No clinical progression over time during FU.
													T0 FDG: n.a.
													T2 MRI: no progression, n.a
6	46	M	schizoaffective disorder^*	4	14	10	7	2	24	24	14	14	T0 MRI: non-specific features possibly fitting neurodegeneration	Loss of initiative, loss of empathy, depression, psychotic features, and cognitive impairments during FU. Patient had no complaints. Clinical improvement during two years of FU and treatment according to informant and clinician. C9orf72 repeat expansion found at screening, but taking into account the clinical profile, disease course and age of the patient the this did not change the diagnosis, although more doubt remains and longer FU is indicated.
													T0 FDG: fitting FTD
													T2 MRI: no progression, n.a
7	59	M	exacerbation personality disorder, relational problems^*	1	47	44	2	6	22	29	12	17	T0 MRI: n.a.	Increasing discrepancy between clinical observations (improved insight in behavior and less irritability during FU) and information given by spouse (increasingly severe behavioral disturbances, aggression, obsessive behavior) in a patient with cluster C personality disorder.
													T0 FDG: fitting AD ^**
													T2 MRI: no progression, n.a
8	44	M	exacerbation personality disorder^*	7	36	30	24	0	28	21	12	14	T0 MRI: n.a.	Increasing discrepancy between clinical observation (stable or subtle improvement of irritability and jocularity) and information given by spouse (increasingly severe behavioral disturbances, loud inappropriate and childish behavior, hyperorality) in a patient with cluster B personality disorder. Patient only complained of memory impairment.
													T0 FDG: n.a.
													T2 MRI: no progression, n.a
9	60	M	minor depression and relational problems^*	1	41	m	10	m	27	m	10	m	T0 MRI: n.a.	Loss of empathy, aggression, apathy, and hyperorality; during FU increasing insight in own behavior and relational dispute became apparent. Patient increasingly expressed depressive symptoms. Mild improvement after pharmacological treatment.
													T0 FDG: fitting FTD
													T2 MRI: m (refused)
10	62	M	severe relational problems /marital dispute^*	1	11	19	1	11	29	30	14	17	T0 MRI: non-specific neurodegenerative features	Emotional indifference, loss of decorum, and mild cognitive impairments (executive). Stable course and some minor improvement of cognitive test results. Patient complained of memory impairment.
													T0 FDG: fitting FTD
													T2 MRI: slight progression non-specific neurodegenerative features
11	61	M	severe relational problems / marital dispute^*	2	21	0∧	10	0∧	25	27	18	18	T0 MRI: n.a.	Apparent loss of initiative, loss of empathy, disinhibition, and rude behavior. During FU, this seemed to be mostly based on severe marital dispute. Clear improvement of mood and behavior after divorce. Patient had no complaints. ^∧The T2 FBI and SRI are with a different informant (daughter) after divorce (T0 with spouse at the time).
													T0 FDG: n.a.
													T2 MRI: no progression, n.a.
12	60	M	semantic dementia^†	4	23	20	8	4	29	m	17	m	T0 MRI: n.a.	Emotional indifference and irritability. Patient only complained of impaired memory function. During FU progressive semantic impairments. Disease insight and awareness declined during FU.
													T0 FDG: fitting FTD
													T2 MRI: some progression global atrophy
13	67	F	semantic dementia^†	2	13	10	0	0	23	m	11	m	T0 MRI: non-specific neurodegeneration	Subtle loss of initiative, apathy, and minor fluency problems at inclusion. Patient had no complaints. During FU, word finding difficulties and increasing deficiency of semantic knowledge; behavioral problems less pronounced.
													T0 FDG: fitting FTD
													T2 MRI: m
14	56	M	cortical basal syndrome^†	3	26	34	9	0	28	25	15	10	T0 MRI: n.a.	Inflexibility, inappropriate laughter, and jocularity. Patient had no complaints, except fatigue. During FU patient developed compulsive behavior, bradykinesia, and apraxia.
													T0 FDG: fitting FTD
													T2 MRI: mild progression of right sided diffuse atrophy
15	53	F	postanoxic encephalopathy^†	3	36	38	11	19	20	m	15	m	T0 MRI: n.a.	Cognitive impairments, apathy, hyperorality, and perseveration. Patient had no complaints. No progression during FU, in retrospect probably postanoxic damage during surgery; patient did develop some depressive symptoms during FU which responded well to medication.
													T0 FDG: fitting FTD
													T2 MRI: some mesiofrontal atrophy, fitting normal aging
16	56	M	multiple sclerosis^†	1	25	13	0	7	28	m	14	m	T0 MRI: fitting leucodystrophy or multiple sclerosis	Emotional indifference, irritability, and bradyphrenia. Increasing mistakes in administration and at work. Patient had no complaints except some mild memory complaints. Clinical progression during FU.
													T0 FDG: fitting FTD or PSP
													T2 MRI: no progression
17	56	M	Parkinson’s disease dementia^†	10	15	35	0	6	29	26	15	15	T0 MRI: fitting FTD	Disinhibition, hyperorality, inappropriate behavior, and mental inflexibility. Patient complained of impaired memory function. Slight tremor of the right hand. During FU clear hypokinetic rigid syndrome, followed by increasing cognitive disorders.
													T2 MRI: m
18	58	F	bvFTD	3	11	25	0	1	26	15	16	4	T0 MRI:	Loss of initiative and memory impairment. Clinical behavioral progression during FU with stereotypical and compulsive shopping behavior. Referral to clinical genetics followed: progranulin-mutation was found.
													T0 PET: fitting FTD and/or AD
													T2 MRI: Severe progression of (right sided) frontal atrophy
19	69	F	bvFTD	5	30	34	26	21	24	29	18	18	T0 MRI: fitting (right > left) FTD	Disinhibition, hyperorality and impulsive/dangerous behavior. Patient had no complaints. Clinical behavioral progression with aggression, compulsive behavior, and increased religious interest. During FU economy of speech and semantic deficits, nursing home admission followed.
													T2 MRI: Progression of atrophy fitting FTD
20	71	M	bvFTD	2	25	43	11	20	26	0	0	0	T0 MRI: fitting FTD and /or AD	Disinhibition, obsessive behavior, and loss of empathy. During FU clear clinical behavioral progression was seen, combined with a progressive aphasia, semantic deficits, and mild parkinsonism.
													T0 PET: fitting FTD
													T2 MRI: m
21	69	M	bvFTD	6	29	34	44	10	29	25	14	13	T0 MRI: endstage frontotemporal atrophy	Stereotypical and obsessive behavior, increased religious interests, inappropriate behavior, and mental rigidity. Patient had no complaints. Clear clinical behavioral progression during FU progressive semantic impairment.
													T2 MRI: endstage frontotemporal atrophy
22	68	F	bvFTD	8	13	21	11	16	27	15	27	15	T0 MRI: fitting AD ^**	Slowly progressive irritability, obsessive shopping behavior. Patient has slight memory complaints. During FU, severe disinhibition and other forms of clinical behavioral progression with memory impairment.
													T2 MRI: progression of non-specific atrophy
23	57	M	bvFTD	7	35	31	21	16	30	21	13	14	T0 MRI: fitting FTD and/or AD^**	Social withdrawal, mental rigidity, diminished self-care, and echolalia. Clear clinical progression during FU with palilalia and eventually day-care at nursing home facility was organized.
													T0 PET: fitting FTD
													T2 MRI: Progression of atrophy
24	66	M	bvFTD	4	13	19	4	9	28	m	16	m	T0 MRI: fitting FTD	Irritability, aggression, and prosopagnosia. Clinical behavioral progression with memory impairment and increasing loss of empathy.
													T2 MRI: m
25	68	M	bvFTD	2	26	m	16	m	30	m	15	m	T0 MRI: fitting FTD	Loss of empathy, loss of initiative, obsessive behavior and anxiety. Clinical behavioral progression with severe aphasia, repetitive behavior, and nursing home admission during FU.
													T0 PET: fitting FTD
													T2 MRI: m
26	55	F	bvFTD	1	25	m	2	m	24	m	8	m	T0 MRI: fitting FTD	Economy of speech, echopraxia, and stereotypical behavior. Patient had complaints of memory impairment. Clinical behavioral progression during FU, as well as severe aphasia. Patient developed MND /ALS. Deceased during FU.
													T2 MRI: m
27	58	M	bvFTD	2	26	m	26	m	22	m	16	m	T0 MRI: non-specific neurodegenerative features	Stereotypical and compulsive behavior, disinhibited when with strangers, apathy at home. Patient has no complaints. Clinical behavioral progression during FU, as well as severe aphasia. Patient developed MND /ALS. Deceased during FU.
													T0 PET: fitting FTD
													T2 MRI: Progression of atrophy
28	56	M	bvFTD	4	9	12	19	6	28	29	17	18	T0 MRI: fitting FTD or AD ^**	Loss of empathy, social withdrawal, and mild stereotypical behavior. Clinical behavioral progression, and patient developed prosopagnosia and increasing motor tics.
													T2 MRI: no progression
29	71	F	bvFTD	3	37	56	37	27	22	m	18	m	T0 MRI: fitting FTD	Loss of empathy, irritability, emotional bluntness, and subtle motortics. Clinical behavioral progression during FU, with severe stereotypical motor behavior, obsessive behavior, and perseveration. Admission in nursing home followed.
													T2 MRI: Progression of atrophy
30	60	F	bvFTD	11	28	m	17	m	29	m	17	m	T0 MRI: fitting FTD	Hypochondria, compulsive behavior, loss of empathy and loss of interest in others. Clinical behavioral progression with aggression and hyperorality, aprosodia, economy of speech, and language impairments leading to complete aphasia during FU.
													T2 MRI: m
31	54	F	bvFTD	2	22	m	3	m	28	m	18	m	T0 MRI: fitting FTD	Loss of empathy, egocentric behavior, and emotional bluntness. Clinical behavioral progression during FU with disinhibited and compulsive behavior. Patient developed MND/ALS. Deceased during FU.
													T2 MRI: m
32	66	M	bvFTD	3	35	m	15	m	28	m	15	m	T0 MRI: n.a.	Mental rigidity, loss of empathy, and hyperorality. Patient complained of memory impairment. Clinical behavioral progression during FU with echolalia and eventually aphasia. Patient developed MND/ALS during FU.
													T0 PET: fitting FTD
													T2 MRI: m
33	63	F	bvFTD	4	50	m	24	m	24	m	17	m	T0 MRI: fitting FTD	Loss of empathy, loss of interest, and stereotypical motor behavior. Patients complained of memory impairment. Clinical behavioral progression with severe apathy, disinhibition, and mental rigidity. Admission in nursing home during FU.
													T2 MRI: m
34	70	M	bvFTD	4	37	34	14	42	28	18	12	0	T0 MRI: fitting FTD	Loss of interest, irritability, and hoarding with shop lifting. Patient had no complaints. Clinical behavioral progression with aggression, mental rigidity, and semantic impairment. Admission in nursing home followed during FU.
													T2 MRI: m
35	52	F	bvFTD	4	12	m	6	m	21	m	18	m	T0 MRI: fitting FTD	Emotional bluntness and apathy. Patient expressed somatic complaints. Clinical behavioral progression with disinhibition and prosopagnosia during FU. Admission in nursing home followed during FU.
													T2 MRI: m

Age, age of onset in years; M, male; F, female; D, disease duration in years; Informant, spouse, child, or other close and reliable informant; m, missing; FBI T0, total score Frontal Behavioral Inventory at baseline; FBI T2, total score Frontal Behavioral Inventory two years follow-up; SRI T0, total score Stereotypy Rating Inventory at baseline; SRI T2, total score Stereotypy Rating Inventory after two years of follow-up; FU, follow-up; n.a., no abnormalities; ECT, electroconvulsion therapy; MND/ALS, motor neuron disease/amyotrophic lateral sclerosis. The imaging findings in italic resulted in the change from possible into probable bvFTD. Main complaint according to patient / closest informant are bold. ^*psychiatric diagnosis. ^†other neurological diagnosis (OND). ^**these imaging findings fitting Alzheimer’s disease (among other disorders) were combined with CSF results including an amyloid-beta >1000 ng/L, considered a non-Alzheimer profile, before a bvFTD diagnosis was made.

DISCUSSION

Almost half of the bvFTD diagnoses made by the specialized memory clinic neurologist with the use of the FTDC criteria at baseline were changed, either after psychiatric consultation or after multidisciplinary neuropsychiatric follow-up. The most striking finding in this study is the number of bvFTD baseline misdiagnoses in actual psychiatric patients, since these patients have a curable or at least treatable disease. Especially a possible bvFTD diagnosis should be applied with caution and followed up carefully, since in our cohort all possible bvFTD baseline diagnoses were withdrawn during follow-up. Although also a proportion of probable bvFTD cases showed to suffer from psychiatric disorders instead of bvFTD during follow-up, these probable cases seem to be less at risk for misdiagnosis. We found six patients with other neurological disorders responsible for the behavioral disturbances initially labeled as bvFTD. Since the majority of these subjects had other neurodegenerative disorders, these findings have less clinical impact because these patients are receiving proper and adequate memory clinic care from baseline on, even though their diagnosis changed during follow-up when applying the appropriate guidelines. Especially the subgroup of patients with a follow-up diagnosis of semantic dementia or corticobasal syndrome should not necessarily be classified as an initial misdiagnosis, since they are considered to be part of the same neurodegenerative spectrum and can exhibit various symptoms of different diagnostic groups during natural disease course, even though official diagnostic guidelines group them separately. However, patients with a psychiatric disorder would have missed adequate referral and treatment and their prognosis might have been worsened by diagnostic delay, had they not been clinically followed by a psychiatrist.

The recently developed FTDC criteria signify a great step forward, incorporating neuroimaging to determine the level of diagnostic certainty and increasing sensitivity for bvFTD diagnosis [30, 38]. The need for cautious use of these new criteria with an increased sensitivity but also less restrictive exclusion features, especially in the psychiatric differential diagnosis, has been stressed by others as well [31, 39]. Nonetheless, it is stated that a bvFTD diagnosis cannot be made in the presence of an explanatory psychiatric condition. The definition of ‘dementia’ as given in the DSM-IV does not capture the clinical FTD syndrome [15]. The DSM-5 criteria for ‘cognitive disorders’ have been adapted in order to include neurodegenerative disorders not presenting with memory decline as a first symptom, making them more fitting for bvFTD [16]. Still, the clinician must decide if the cognitive deficits are not primarily attributable to another mental disorder in which case no neurocognitive disorder may be diagnosed. Vice versa, before diagnosing a psychotic or mood disorder according to the DSM, one must exclude the possibility the symptoms may be caused by an organic or neurodegenerative disorder. This illustrates clearly that in clinical practice, in the absence of definitive biomarkers, the diagnostic dilemma “bvFTD or psychiatry” is not solved by simply applying the different sets of clinical consensus criteria. The sensitivity and specificity of the FTDC criteria in a study containing the total LOF-cohort were 85% and 27% for possible bvFTD and 85% and 82% for probable bvFTD, respectively [31]. The subgroup of patients driving this limited specificity for possible bvFTD is described in this study in clinical detail.

The sensitivity of neuroimaging for bvFTD is about 50–63.5% for MRI and about 81–90% for [¹⁸F]FDG-PET within a memory clinic cohort [40 –43]. However, neuroimaging may reveal frontal atrophy or hypofrontality in psychiatric patients as well, compromising the specificity of these investigations [18 , 44–47]. This is emphasized by the considerable group of subjects in our cohort with initially a probable bvFTD diagnosis, based on clinical features and MRI or [¹⁸F]FDG-PET findings, in which the diagnosis was changed into a psychiatric disorder. The diagnostic change after follow-up was based upon clinical findings, increasingly suggesting a psychiatric origin of the complaints, as well as upon the absence of progression of neuroimaging abnormalities. So, although neuroimaging is very valuable in a bvFTD diagnosis, the evaluation of further disease progression and imaging progression over time remains important. Diagnostic quality of imaging for bvFTD within the total LOF-cohort has been prospectively studied in more detail showing a sensitivity of 70% and a specificity of 93% for MRI and a sensitivity of 90% and a specificity of 68% for [¹⁸F]FDG-PET [48]. Notably, in all our patients with an initial probable bvFTD diagnosis that was changed into a psychiatric diagnosis, the MRI findings were rated as normal and not suggestive of FTD and the [¹⁸F]FDG-PET was rated as abnormal, as is illustrated by the detailed description of the subjects in the present study. The imaging results in these subjects are explanatory for the relatively low specificity of [¹⁸F]FDG-PET for bvFTD. In future, research confirmation of these findings, preferably with considerable follow-up or neuropathological confirmation, would be veryvaluable.

Part of our cohort shows clinical similarities with patients labeled as the ‘benign bvFTD-phenocopy syndrome’ by others [49]. This phenocopy syndrome concerns patients in whom clinical characteristics indistinguishable from possible bvFTD are found, but no functional decline nor neuroimaging abnormalities have been found. More evidence starts to emerge that atypical psychiatric disorders might be causing this so-called phenocopy syndrome and that psychiatric consultation might reveal treatable disorders, not always fitting the definition of a major psychiatric disease [14, 50]. Interestingly, part of our cohort with a psychiatric diagnosis did not officially fulfill the criteria for a major psychiatric diagnosis when strictly applied [50]. The subgroup of our cohort in which the diagnosis changed from possible bvFTD into a psychiatric disorder might fulfill this phenocopy syndrome definition. Nonetheless, our study shows a significant group of patients that do not fulfill the phenocopy description, since they do show hypometabolism on [¹⁸F]FDG-PET. A subgroup, initially considered a probable bvFTD group, also had its diagnosis changed into a typical or atypical psychiatric disorder after follow-up and are therefore not expected to show any more progress over time. This suggests that carefully screening patients psychiatrically is indicated in a larger group of subjects, and not just in those fulfilling the ‘phenocopy’ definition. More prospective research is needed to further characterize this group in which screening is beneficial.

In our cohort, no measured baseline characteristics differentiated between the three diagnostic groups.

The most misleading clinical features of psychiatric patients that had been misdiagnosed with bvFTD were disinhibition, apathy or inertia, loss of sympathy and/or loss of empathy. These clinical symptoms, as reported by the informant, seemed to be non-specific for bvFTD when compared to psychiatric patients. Especially, when these symptoms are reported and frontal and/ or temporal hypometabolism on the [¹⁸F]FDG-PET is seen, patients seem to be at risk for a bvFTD-misdiagnosis.

For clinical practice is it important to note that not only the informant based behavioral screening instruments, but also the widely-used baseline MMSE and FAB did not differentiate between bvFTD and psychiatric disorders. Although in this study the numbers are small and no definite conclusions can therefore be drawn from the statistical analyses, these findings are in line with earlier findings: neuropsychological tests may help to identify mild to moderate bvFTD cases, but early bvFTD usually shows intact cognitive functions and the most often displayed executive dysfunction is also frequently seen in psychiatric disorders [20, 51]. It must be noted that the examined cohort is part of a larger cohort focusing on early recognition of bvFTD [33]. Therefore, all diagnoses were made in early staged disorders and the correct diagnosis may therefore be more difficult to discern from the differential diagnosis compared to more advanced cases.

Since we failed to identify clinically distinguishing features in the cognitive and behavioral screening, we would suggest consulting a psychiatrist in all bvFTD cases in the early diagnostic phase and during follow-up. We would recommend to do so in all possible and all probable bvFTD cases, although the number of possible bvFTD cases switching to a psychiatric diagnosis is expected to be greater than the number of probable bvFTD cases.

Even though no statistically significant differences between the main diagnostic groups were found for sex, an interestingly higher number of subjects in whom diagnosis was changed from bvFTD towards a psychiatric diagnosis were male (10 out of 11). Also in previous research on the bvFTD phenocopy syndrome, male gender predominated [49]. Further research should clarify if indeed males are more prone to be misdiagnosed as bvFTD in psychiatric disorders. This would be an interesting topic to study, as in women the opposite seems to hold: women showed to receive a psychiatric misdiagnosis in actual bvFTD more often compared to men [13]. The one case that revealed a C9orf72 repeat expansion illustrates another diagnostic dilemma. Considering the clinical profile, the patients age (46) and the improvement of the behavior during follow-up, the psychiatric diagnosis was maintained. However, the penetrance of a C9orf72 repeat expansion increases with age. So, the possibility of the symptoms being the first presenting features of a bvFTD due to the C9orf72 repeat expansion should be considered during further follow-up.

To our knowledge, this is the first prospective multidisciplinary study to investigate bvFTD misdiagnosis in primary psychiatric disorders. Our results are of great clinical relevance and strongly suggest incorporating a multidisciplinary approach when it comes to bvFTD early diagnosis and critically reviewing the diagnosis over time. Our data illustrate that the clinical profiles and in some cases the neuroimaging findings of the psychiatric patients in which a bvFTD misdiagnosis was made vividly mimic a bvFTD profile, considering the complaints mentioned by patients and their relatives. It strengthens our study that we blinded both the neurologist and the psychiatrist in the diagnostic process for each other’s interpretations and results.

This study has several limitations. Our study was performed in a tertiary center. Therefore, our results cannot easily be extrapolated to a general population. Possibly, the number of misdiagnoses in our cohort is an underestimation of that in a general memory clinic due to the expertise available. On the other hand, it may be that more complex cases are referred to a tertiary center in the first place. Secondly, the study design shows that a consulting psychiatrist during follow-up is essential for identifying both bvFTD misdiagnoses and psychiatric diagnoses. Nonetheless, since the bvFTD differential diagnosis is complex and primary psychiatric disorders have no diagnostic gold standard and often have an atypical phenotype in the older population we strongly advise the multidisciplinary approach used in this study for future clinical practice. Especially in male patients, in patients with multiple psychiatric of psychological disorder traits and in patients merely fulfilling possible bvFTD, the FTCD criteria must be applied with caution and alternative diagnoses should be considered again during follow-up.

Furthermore, the numbers in our study are small and the used gold standard of two years follow-up is too short for a proportion of patients. It is hard to come by large numbers of suspected bvFTD subjects for prospective research, but we strongly recommend future repetition of the study in a larger cohort with longer follow-up, ideally with a full genetic screening or neuropathological confirmation to increase diagnostic certainty.

Our study results stress that not only the already known risk of making a psychiatric misdiagnosis in case of bvFTD is a pitfall to recognize [13], but also a bvFTD misdiagnosis in case of a psychiatric disorder could be an increasingly common scenario due to improved knowledge of bvFTD, especially in cases exhibiting disinhibition, apathy or inertia, loss of sympathy and/or loss of empathy. Our findings suggest a limited specificity of the [¹⁸F]FDG-PET-scan and of the FTDC criteria. Further research on the factors discriminating bvFTD from psychiatric disorders is needed.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/17-0608r1).

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