The Diagnostic Patterns of Referring Physicians and Hospital Expert Psychiatrists Regarding Particular Frontotemporal Lobar Degeneration Clinical and Neuropathological Subtypes

Abstract

Background:

It is important to make accurate clinical diagnosis of frontotemporal lobar degeneration (FTLD), which in turn, leads to future therapic approaches. The FTLD cases are frequently inaccurately identified, but the frequency of this misidentification according to the underlying pathological subtypes is still unclear.

Objective:

We aimed to quantify the accuracy of behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) diagnoses by both the patients’ referring physicians and hospital expert psychiatrists, and we investigated whether the physicians’ and psychiatrists’ diagnostic patterns are associated with a specific neuropathology.

Methods:

We retrospectively analyzed the cases of a series of Japanese patients with pathologically diagnosed FTLD (n = 55): the bvFTD group (n = 47) consisted of patients with FTLD-tau (n = 20), FTLD-TDP (TAR DNA-binding protein of 43-kDA) (n = 19), and FTLD-FUS (fused in sarcoma) (n = 8). The svPPA patients (n = 8) all had FTLD-TDP.

Results:

Only 31% of the patients’ referring physicians mentioned FTD syndrome. The referring psychiatrists and neurologists showed similar diagnostic accuracy. High diagnostic accuracy was observed for the TDP pathology group (mainly svPPA patients). The FTLD-FUS patients were more likely to be diagnosed as having a psychiatric disorder by referring physicians. The hospital expert psychiatrists’ accuracy for identifying FTLD-tau pathology was low.

Conclusion:

The results of our analyses revealed a specific diagnostic pattern associated with particular FTLD pathological subtypes, which will help to improve non-specialists’ diagnostic ability.

Keywords

Frontotemporal dementia frontotemporal lobar degeneration hospital expert psychiatrist misdiagnosis referring physician semantic variant

INTRODUCTION

Frontotemporal dementia (FTD) refers to a group of dementia syndromes that result in progressive declines in behavior and/or language and are linked to underlying frontotemporal lobar degeneration (FTLD) pathology [1]. The incidence and prevalence of FTD may be similar to those of Alzheimer’s disease (AD) among young-onset patients [2]. FTD has three major clinical phenotypes: behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent/agrammatic primary progressive aphasia (nfvPPA) [1, 3]. Occasionally, FTD patients develop motor neuron disease (FTD-MND).

FTLD has three major pathological subtypes, based on the protein composition of the neuronal and glial inclusions: Tau (FTLD-Tau), TAR DNA-binding protein of 43-kDA (TDP-43, or FTLD-TDP), and fused in sarcoma (FTLD-FUS) [4]. In FTD, the clinical subtypes and the patterns of atrophy are associated with the protein-accumulation patterns to some extent; most cases of svPPA are associated with TDP-43 type C, and most cases of FTD-MND are associated with TDP-43 type B. In contrast, bvFTD is not strongly correlated with any particular pathological type.

An accurate diagnosis of FTD is important because these conditions affect patients’ lives in differing ways, and each diagnosis has profound implications for the patients, their families, and their communities [5]. The clinical diagnosis of FTD remains challenging because of the limited accuracy of neuroimaging in the early stages of disease and the absence of molecular biomarkers; the clinical diagnosis thus relies predominantly on the clinical assessment. For example, the clinical diagnosis of bvFTD relies on behavioral features, including behavioral disinhibition, apathy/loss of interest, loss of sympathy or empathy, compulsive stereotypic behavior, and dietary changes. Similarly, the clinical diagnosis of svPPA is based on language features, such as the progressive loss of word comprehension and object knowledge. The accurate identification of patients with these various phenotypes is difficult for clinicians, including primary care physicians, general psychiatrists, and general neurologists, as well as psychiatrists [6]. Diagnosing FTD is not easy even for experienced psychiatrists who are not familiar with young-onset dementia disorders. As a result, FTD is often mistaken for AD or other conditions including psychiatric disorders [7, 8]. There are already report on referring physician’s diagnostic accuracy against the consensus diagnosis criteria [6]; however, there are no reports focus on their pathological background. It is increasingly important for non-specialists to make accurate clinical diagnosis, which in turn, resulting in the specialists to treating and caring patients and their families appropriately. Furthermore, because disease-modifying therapies now target specific molecular subtypes of FTLD, specialist will be able to detect the specific underlying pathology using molecular biomarkers in the near future. However, it is not yet clear how frequently FTLD is inaccurately identified based on the underlying pathological subtype.

We thus conducted the present study to: 1) determine the pathological diagnoses in a consecutive series of Japanese patients with clinico-pathological FTD at a psychiatric hospital, 2) quantify the accuracy of bvFTD and svPPA diagnoses made by both the patients’ referring physicians and psychiatrists who work at the psychiatric hospital as dementia experts (i.e., hospital expert psychiatrists), and 3) determine whether each diagnostic pattern is associated with a specific neuropathology. We retrospectively investigated the diagnoses of a series of 79 patients with pathologically diagnosed FTLD. We suppose that the identification of an inaccurate diagnostic pattern associated with particular accumulated proteins will help improve our diagnostic ability and in turn, contribute to future disease-modifying therapies for FTLD.

METHODS

Patients

Seventy-nine Japanese patients with FTLD were registered in the autopsy-confirmed archives of the Dementia Research Project, Tokyo Metropolitan Institute of Medical Sciences. The demographic features of our cohort are in line with those of previous studies of pathologically confirmed FTLD [9, 10]. First, we excluded pathologically unclassifiable cases (n = 5). Clinically, all patients were seen by psychiatric specialists. We defined ‘hospital expert psychiatrist’ as a psychiatrist who was working at a psychiatric hospital as a certified dementia and geriatric psychiatry specialist. All patients underwent physical and neurological examinations. Most patients underwent brain imaging together with the usual battery of screening blood tests. Patients were assessed with battery of neuropsychological and neuropsychiatric tests. Patients with a history of significant head trauma and alcoholism were excluded. Patients with nfvPPA (n = 2) were excluded because the numbers of these patients were too low to enable meaningful comparisons with other groups. Also, patients with FTLD without presenting prominent behavioral features such as corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) were excluded.

This procedure to determine final clinical syndrome was conducted by another expert with reviewing chart who is blinded to the neuropathology. Cases lacking the patient’s detailed clinical records that would enable the identification of the referring physicians’ diagnostic patterns were also excluded. The cases of a final total of 55 patients were included; they comprised two clinical groups: bvFTD (n = 47) and svPPA (n = 8). All patients fulfilled the consensus criteria for bvFTD or svPPA consensus criteria [1, 3]. Patients with neuropathological FTLD-MND (n = 8) who were clinically diagnosed as having bvFTD based on prominent behavioral symptoms were included. All cases were sporadic and included no family history of neurodegenerative disease. We classified the cases of bvFTD and svPPA into neuropathological subtypes based on the accumulated abnormal proteins [11]. We retrospectively investigated each patient’s referring physician’s information, the referral diagnosis, and the hospital expert psychiatrist’s diagnosis.

Statistical analyses

This was a retrospective observational study using a database, and not an interventional study. We compared the clinical/pathological groups for demographic differences and the referring physician’s information, referral diagnosis, and hospital expert psychiatrist’s diagnosis. Data analyses were performed using SPSS statistics ver. 27 software (IBM). The statistical significance of differences among three groups was assessed by a one-way analysis of variance (ANOVA) with the Kruskal-Wallis test for non-parametric variables, and with the χ²-test with post hoc Fisher’s exact test for nominal variables. Probability (p)-values < 0.05 were accepted as significant.

Ethics approval and consent to participate

All patients (or in one case in which the patient had died, the next of kin) provided written consent for autopsy and postmortem analyses for research purposes. Adequate consideration was given to protecting patient anonymity, and approval for our research using databases was obtained from the ethics committee of the Dementia Research Project, Tokyo Metropolitan Institute of Medical Sciences, and Tokyo Metropolitan Matsuzawa Hospital. This study was performed in accordance with the ethical standards outlined in the 1964 Declaration of Helsinki and its later amendments.

RESULTS

Demographic data

Neuropathologically, the bvFTD group consisted of patients with FTLD-tau (n = 20), FTLD-TDP (n = 19), and FTLD-FUS (n = 8). FTLD-tau patients include Pick’s disease pathology (n = 16), corticobasal degeneration (CBD) (n = 3), and PSP (n = 1). All eight of the patients in the svPPA group had FTLD-TDP. The pathological diagnoses for all patients in the bvFTD and svPPA groups are depicted in Fig. 1. The extracted demographic characteristics of the study population, stratified by neuropathological diagnosis are summarized in Table 1. The age at onset in the FTLD-FUS group was 45.0±11.8 years, which is significantly younger than the onset ages in the other pathology groups. In the FTLD-FUS group, the age at consultation and clinical diagnosis was 48.0±13.0 years and the age at death was 52.8±12.6 years; these were also significantly younger compared to the other pathology groups. The patients in the svPPA group tended to be older at death (67.5±5.5 years) and to have a longer disease duration (11.4±3.8 years) than the other groups.

Fig. 1

Pathological diagnoses for all patients of bvFTD and svPPA. Total cases, n = 51. Abbreviations are explained in the footnote of Table 1.

Table 1

Demographic characteristics of the study population, stratified by neuropathological diagnosis

Final clinical syndrome:	bvFTD (n = 47)			svPPA (n = 8)
Pathological diagnosis:	FTLD-tau,	FTLD-TDP,	FTLD-FUS,	FTLD-TDP,
	PiD: n = 16	Type A: n = 4	BIBD: n = 6	Type C: n = 8
	CBD: n = 3	Type B: n = 11	NIFID: n = 1
	PSP: n = 1	Type C: n = 4	aFTLD-U: n = 1
Female, n (%)	12 (60.0)	9 (47.4)	4 (50.0)	3 (37.5)
Age at onset, y	56.4±10.0	54.7±9.0	45.0±11.8^*	55.9±4.9
Age at consultation &clinical diagnosis	60.2±9.8	58.0±8.4	48.0±13.0^*	61.1±4.2
Age at death	64.7±9.4	60.3±8.8	52.8±12.6^*	67.5±5.5
All disease duration, y	8.4±5.7	5.9±5.7	8.2±3.1	11.4±3.8

Values are mean±SD. ^*p < 0.05. aFTLD-U, atypical FTLD with ubiquitin-positive inclusions; BIBD, basophilic inclusion body disease; bvFTD, behavioral variant frontotemporal dementia; CBD, corticobasal degeneration; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; FTLD-FUS, FTLD- fused in sarcoma; FTLD-TDP, FTLD-TAR DNA-binding protein of 43-kDA; NIFID, neuronal intermediate filament inclusion disease; PiD, Pick’s disease; PSP, progressive supranuclear palsy; svPPA, semantic variant primary progressive aphasia.

Description of referral physicians and hospital specialists’ diagnoses

The results of our analysis of the referring physicians’ specialties demonstrated that the majority of the patients’ referrals came from psychiatrists (49.1%) (n = 27), followed by neurologists (30.9%) (n = 17), general physicians and other specialist physicians (9.1%) (n = 5), with 10.9% coming from sources in which the referring physician’s specialty could not be determined clearly (n = 6).

The patients’ referral diagnoses were categorized as mentioning: 1) FTD (21.8%), 2) AD (18.2%), 3) vascular dementia (5.5%), 4) dementia alone without specific disease or syndromes (9.1%), 5) aphasia or aphasic syndrome not mentioning FTD (5.5%), 6) other neurological disease (3.6%), 7) psychiatric disorders including depression, bipolar disorder, and schizophrenia (23.6%), 8) specific symptoms such as merely “memory disturbance” (3.6%), and 9) an unspecific referral reason (9.1%).

The terminology for the diagnosis of FTD syndromes has varied over the past few decades, and we thus used care when reading the patients’ charts and referral notes in order to discriminate among the various terms used by both referring physicians and hospital specialists, to determine the intended meaning. When we included the referral diagnoses that mentioned FTD to some degree or to aphasia or aphasic syndrome and other neurological diseases, the analysis revealed that the frequency with which referring physicians identified in some way that the patient had an FTD syndrome was 30.9%. The psychiatrists and neurologists achieved similar accuracy (29.6% and 23.5%), whereas the other physicians and physicians whose specialty could not be determined had very low accuracy (0%).

The hospital expert psychiatrists’ diagnoses of the patients were categorized as mentioning: 1) FTD (both bvFTD and svPPA) (67.3%), 2) FTD-MND (12.7%), 3) AD (3.6%), 4) vascular dementia (1.8%), 5) psychiatric disorder (1.8%), and 6) dementia not otherwise specified (12.7%). The rate of the hospital expert psychiatrists can make accurate diagnosis that their patient had an FTD syndrome (here including bvFTD, svPPA, and FTD-MND) was 80.0%.

Diagnostic accuracy according to neuropathological subtype

The diagnostic accuracy values according to the neuropathological subtypes among the referring physicians and the hospital expert psychiatrists are depicted in Fig. 2. In the bvFTD-Tau, bvFTD-TDP, and bvFTD-FUS groups, the hospital expert psychiatrists had significantly higher diagnostic accuracy compared to the referring physicians (p < 0.05). In the svPPA-TDP group, the hospital expert psychiatrists showed 100% diagnostic accuracy. The referring physicians tended to show high accuracy for diagnosing svPPA-TDP (p = 0.20). The hospital expert psychiatrists tended to have low accuracy for diagnosing bvFTD-Tau (p = 0.27).

Fig. 2

Diagnostic accuracy according to neuropathological groups among the referring physicians and hospital expert psychiatrists.

The referring physicians’ diagnoses according to neuropathological diagnosis

Figure 3 illustrates the referring physicians’ diagnoses according to the neuropathological diagnosis. Among 20 bvFTD with Tau pathology patients, 15.0% (n = 3) were diagnosed as FTD, 20.0% (n = 4) were diagnosed as AD, 25.0% (n = 5) were diagnosed as psychiatric disorder. Among 19 bvFTD with TDP pathology patients, 21.1% (n = 4) were diagnosed as FTD, 21.1% (n = 4) were diagnosed as AD, 26.3% (n = 5) were diagnosed as psychiatric disorder. Among 8 bvFTD patients with FUS pathology,12.5% (n = 1) were diagnosed as FTD, 0% (n = 0) were diagnosed as AD, and 37.5% (n = 3) were diagnosed as psychiatric disorder. Among 8 svPPA with TDP pathology patient, 50.0% (n = 4) were diagnosed as FTD, 25% (n = 2) were diagnosed as AD, 0% (n = 0) were diagnosed as psychiatric disorder.

Fig. 3

Referring physicians’ diagnoses according to neuropathological groups.

These referring physicians were more likely to diagnose the bvFTD patients with FUS pathology as “psychiatric” or “unspecified,” and there was no diagnosis of AD by a referring physician. On the other hand, these referring physicians were more likely to diagnose the bvFTD patients with Tau pathology as having dementia without a mention of the subtype. The svPPA patients were more likely to receive a referral diagnosis that mentioned FTD, whereas the patients with bvFTD with TDP pathology received a variety of referral diagnoses.

DISCUSSION

Summary of results

Our retrospective analyses revealed that only 31% of the referring physicians mentioned FTD syndrome (including aphasic syndrome and other neurological disease), and that 24% of them mentioned psychiatric disorders. The referring psychiatrists and referring neurologists were observed to have similar diagnostic accuracy. High diagnostic accuracy was demonstrated for the svPPA patients with TDP pathology, and the FUS patients were more likely to be diagnosed as having a psychiatric disorder; in addition, they had shorter durations prior to expert consultation. Hospital expert psychiatrists achieved 80% diagnosis accuracy with a reference to neuropathology, but the accuracy for the Tau pathology group was relatively low. Among both the referring physicians and hospital expert psychiatrists, lower diagnostic accuracy was observed for bvFTD compared to svPPA.

General discussion

Efforts have been made to educate the public about FTD and related disorders, as these were nearly unrecognized until ∼20 years ago. Our study’s first author reported a relatively large number of false-positive cases of bvFTD diagnosed by community-based clinicians in the United States, and that 60% of the patients assigned a single diagnosis of bvFTD by community clinicians did not have bvFTD according to specialists [6]. Our present findings in Japan show that only 30% of referring physicians mentioned FTD syndrome among pathologically proven FTLD cases. Of course, there are many differences between these two countries; for example, the data in the U.S. are based on clinical cases examined at ‘FTD centers,’ whereas our results obtained in Japan are based on pathologically confirmed cases from psychiatric hospital. Especially prior to referral to the hospital, diagnosis may have been affected by psychiatric symptoms, which make it difficult to distinguish diagnostically symptoms. Nevertheless, it is possible that the awareness of FTD among community-based clinicians Japan is lagging behind that in the U.S and we need further education for the health care professionals.

The results of the present retrospective analyses demonstrated that FTD was easily mistaken for a psychiatric disorder (24%) or AD (18%) by referring physicians. This is similar to the reports describing a high rate of psychiatric diagnosis among FTD patients [7 , 12–15]. One of those reports indicated that patients with FTD were significantly more likely than patients with other neurodegenerative diseases to receive a psychiatric diagnosis from a non-specialist [7].

A paper based on a systematic literature review concerning the diagnosis of FTD and its differential diagnoses with primary psychiatric disorders was recently published to provide consensus recommendations on the clinical assessment [8]. According to those authors, nearly 50% of patients with FTD receive a prior psychiatric diagnosis, and the average diagnostic delay is up to 5–6 years from symptom onset. The paper’s recommendations include performing social cognition tests, 3D-T1 brain MRI, ¹⁸F-fluorodeoxyglucose PET, examining the potential role of serum or cerebrospinal fluid (CSF) neurofilament light chain, and screening for C9orf72 mutation. However, these are difficult to conduct in the primary care setting. Our hospital expert psychiatrists made clinical diagnosis, which have enough correlation with formal diagnostic criteria, and as a result, achieved relatively high diagnostic accuracy (80%) with a reference to neuropathology. We believe our result here will encourage non-specialists to refer patients for a specialized diagnostic consultation.

Neuropathological/symptom specific discussion

Our patient series included FTLD-Tau cases (36%), FTLD-TDP cases (49%), and FTLD-FUS cases (15%). Among bvFTD cases, FTLD-Tau was 43%, FTLD-TDP was 40%, and FTLD-FUS was 17%. There is a previous report from cohort in the U.S. showing that 34% FTLD-tau, 61% FTLD-TDP, and 8% FTLD-FUS among bvFTD cases [16]. Comparing with their result, Our Japanese cohort include less FTLD-TDP cases and more FTLD-FUS subjects. However, that their data is based on neurology unit and our data is based on psychiatric hospital. Considering this difference, our pathological data thus appear to be reliable to some degree. There are several other brain archives in Japan that include subjects with FTLD, and most of the subjects were diagnosed in a neurology unit, including subjects clinically diagnosed with amyotrophic lateral sclerosis, PSP syndrome, or CBS. Our Institute center is one of the few centers based on a psychiatric hospital (Tokyo Metropolitan Institute of Medical Science and Tokyo Metropolitan Matsuzawa Hospital) [10 , 18]. This may be one of the reasons why our consecutive Japanese FTD clinico-pathological series showed relatively high frequencies of FTLD-FUS and FTLD-Tau (3R) cases compared to the data from another brain bank dataset in Japan [19]. We do not have correct data whether most FTD cases in Japan are seen by neurologists or psychiatrists, and this finding cannot be applied to all cases in the community.

For each of the pathological subtypes described in this study, the diagnostic accuracy rate of the hospital expert psychiatrists was higher than that of the referring physicians. In our 2020 investigation, we observed that subjects with FTLD-Tau were more likely to have unspecified early symptoms such as physical complaints, reticence, and dizziness before the appearance of behavioral symptoms compared to other pathological groups [9]. These unspecified early symptoms may have affected the diagnostic accuracy among the hospital expert psychiatrists in the present analyses. It is necessary to improve the ability to accurately identify FTD even among expert hospital psychiatrists, especially for patients with FTLD-Tau, as they have many unspecified symptoms and may be difficult to diagnose. This study also revealed that the patients with FTLD-FUS were more likely to be diagnosed with a psychiatric disorder by referring physicians rather than dementing disorders; this may be because they have significantly younger ages at onset compared to other pathology groups. However, they also have younger ages at death, which indicates rapid disease progression as a neurodegenerative disease. This may lead to the relatively higher diagnostic accuracy among hospital expert psychiatrists, and to early clinical diagnoses. However, it is possible that a certain number of patients with FTLD-FUS are admitted to psychiatric hospitals and have not been correctly diagnosed. We need to be more careful about this possibility.

Most cases of FTD-MND are eventually correctly diagnosed by hospital expert psychiatrists clinically in Japan. This may be because FTD-MND is well known among Japanese psychiatrists as Mitsuyama disease, presenting both frontal symptoms and motor neuron symptoms [20]. The diagnosis of svPPA may be easier to make (at least in “FTD as a group”) by both referring physicians and hospital expert psychiatrists, because the patients with svPPA have characteristic aphasic symptoms such as loss of the ability to perceive the meanings of words, as well as behavioral symptoms. The relatively longer disease duration of this group may also affect the relatively high diagnostic accuracy for svPPA. In this research, we intended to separate bvFTD-TDP group and svPPA-TDP group, because our hospital specialist’s clinical diagnosis of bvFTD and svPPA can be compared with the pathological diagnoses.

Study limitations

Limitations of this study include the small sample size (n = 55) and associated referral/sampling bias, and we cannot generalizable our result fully. We could not obtain adequate numbers of patients such as nfvPPA, PSP syndrome, or CBS for comparison, since our cohort was drawn from patients admitted to a psychiatric hospital. However, on the contrary, we could obtain valuable data from those who showed prominent behavioral changes. In addition, this was a retrospective study based on referral documentation, and thus there was necessarily some uncertainty around the referral diagnoses. Another source of ambiguity in this study came from the shifting clinical-feature definitions and terminology used for the FTD syndromes. Another limitation is that the time gap between referral doctors and hospital specialist’s clinical diagnosis. They do not make diagnoses at the same time and hospital specialists may obtain more information to make diagnosis as the disease progressed, they may be able to evaluate more developed syndromes.

Conclusion

This is the first study to explore the diagnostic pattern among both referring physicians and hospital expert psychiatrists regarding Japanese patients with FTLD that was pathologically confirmed at a psychiatric hospital. Our results suggest that 1) we need more education about FTD among non-specialists and 2) need to create a good relationship between non-specialists and specialists in order non-specialists can easily refer patients for a specialized diagnostic consultation in cases in which they suspect FTD. We believe that our present findings will help improve the accuracy of diagnosing FTD. The specific diagnostic pattern associated with particular accumulated proteins revealed herein could also contribute to future disease-modifying therapies for FTLD.

Footnotes

ACKNOWLEDGMENTS

We thank Dr. Kenichi Oshima and Dr. Kazuhiro Niizato (Tokyo Metropolitan Matsuzawa Hospital) for their clinical assistance, and we thank the patients and their families for the time and effort they dedicated to our research.

Authors’ disclosures available online ().

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