Article Text

Accuracy of clinical diagnosis of behavioural variant frontotemporal dementia: a protocol for a systematic review and meta-analysis
  1. Daniele Urso1,2,
  2. Stefano Giannoni-Luza3,
  3. Stefania Mondello4,
  4. Giancarlo Logroscino1,5
  1. 1 Center for Neurodegenerative Diseases and the Aging Brain, Department of Clinical Research in Neurology, University of Bari Aldo Moro, Pia Fondazione Cardinale G. Panico, Tricase, Puglia, Italy
  2. 2 Department of Neurosciences, Institute of Psychiatry Psychology and Neuroscience, London, London, UK
  3. 3 Sensory-Motor Lab (SeMoLa), Department of Ophthalmology, Fondation Asile des Aveugles, Lausanne, Vaud, Switzerland
  4. 4 Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Messina, Sicily, Italy
  5. 5 Department of Translational Biomedicine and Neurosciences (DiBraiN), University of Bari, Bari, Italy
  1. Correspondence to Dr Daniele Urso; daniele.urso{at}


Introduction Behavioural variant frontotemporal dementia (bvFTD) characterisation has evolved, but diagnosis remains challenging, relying on clinical diagnostic criteria that have undergone revisions over time. In this systematic review, our aims are to evaluate the accuracy of clinical diagnostic criteria for bvFTD by comparing them against pathological diagnoses and determine potential improvement in performance over the years.

Methods and analysis This systematic review protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines and is registered on PROSPERO. We will search four databases (MEDLINE-PubMed, Web of Science, Embase and LILACS) using tailored search terms on May 1st 2024. Inclusion criteria encompass peer-reviewed articles reporting diagnostic parameters or raw data regarding bvFTD clinical diagnosis based on well-defined criteria. Screening and selection of relevant articles will be independently performed by two reviewers using the Covidence systematic review manager. Discrepancies will be resolved by a third researcher. Pathologic and genetic diagnosis will be the main gold standard, but we will also consider refined diagnoses after a follow-up period. Data will be collected on study design, baseline demographics and sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy. Study quality will be assessed with Quality Assessment of Diagnostic Accuracy Studies-2. If possible, we will conduct a meta-analysis using bivariate random-effect models. Subgroup analyses will consider study settings, gold standards, disease stages and bias.

Ethics and dissemination Ethics approval will not be needed because the data used in this systematic review will be extracted from published studies. Findings will be disseminated through peer-reviewed publications and presentations at relevant scientific conferences, potentially enhancing our understanding of bvFTD clinical diagnosis reliability and guiding future criteria refinements.

PROSPERO registration number CRD42023389063.

  • Systematic Review
  • Meta-Analysis
  • Dementia

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Strengths and limitations of this study

  • This systematic review fills a significant gap by thoroughly evaluating the evidence on the diagnostic performance of clinical criteria for behavioural variant frontotemporal dementia and its evolution over time.

  • In addition to pathological and genetic diagnosis as reference standard, we will include refined diagnosis after follow-up to increase the inclusion rate.

  • A potential limitation may be the small number of eligible studies and their heterogeneity in the design and conduct.


Behavioural variant frontotemporal dementia (bvFTD), often referred to as bvFTD, is a complex neurodegenerative disorder characterised by progressive changes in behaviour, personality and social functioning.1 This condition falls under the broader category of frontotemporal dementia (FTD), which encompasses a spectrum of disorders with distinct clinical and neuropathological profiles and involves proteinopathies associated with frontotemporal network dysfunction.2–5 In the case of bvFTD, individuals affected by this syndrome experience a profound and often early-onset deterioration in their cognitive and emotional faculties—a clinical syndrome characterised by prominent changes in personality or behaviour, including behavioural disinhibition, apathy or inertia, loss of sympathy or empathy, perseverative and stereotyped or compulsive and ritualistic behaviour and hyperorality and dietary changes.6 Once considered rare and more prevalent in the population of individuals with young onset dementia, now the findings of a multinational European study suggest that FTD is more common than previously described and the diagnosis needs to be considered even in the elderly, beyond the age of 70 years.7

Diagnosing FTD clinically poses significant challenges. First, bvFTD is frequently mistaken for primary psychiatric disorders due to overlapping initial symptoms and its characteristic early onset.8 In fact, approximately 50% of bvFTD patients initially receive a psychiatric diagnosis before being correctly diagnosed with bvFTD.8 Furthermore, the widespread familiarity with Alzheimer’s disease dementia often leads patients, caregivers and even clinicians to implicitly associate dementia solely with memory deficits—a characteristic not typically associated with core features of FTD syndromes. Most formal cognitive assessments primarily concentrate on identifying memory impairment, often overlooking assessments related to social cognition and behaviour, which are frequently impaired in individuals with FTD.9 10 This lack of recognition, diagnosis and subsequent treatment can be attributed to the limited number of medical specialists and the insufficient training these specialists have received in identifying bvFTD specifically.

The importance of accurately diagnosing bvFTD cannot be overstated, as it holds far-reaching implications for both patients and healthcare providers.11 In the absence of definitive diagnostic tools, the accuracy of clinical diagnosis plays a critical role in guiding the management of individuals with bvFTD.12 An accurate diagnosis is pivotal for prognosis, treatment planning and patient management,13–15 enabling timely support and interventions that optimise the quality of life for patients and their families while providing invaluable information to family members and caregivers, who often experience disproportionate stress and burden.11 However, bvFTD diagnosis presents an important challenge for clinicians and researchers alike. The behavioural and personality changes that define this condition are often subtle and can overlap with symptoms of other neurodegenerative disorders or even psychiatric conditions.16 17 This diagnostic complexity is compounded by the diverse pathological substrates underlying bvFTD, further hindering a straightforward diagnosis.18 Over the years, diagnostic criteria for bvFTD have undergone revisions, trying to address these challenges and improve diagnostic accuracy (table 1).6 19 20 These changes have aimed to refine and enhance sensitivity, considering the evolving understanding of the syndrome and its clinical presentation. Nonetheless, to date, uncertainty remains in the discriminative accuracy of the clinical criteria and, although numerous primary studies have investigated the diagnostic value, no systematic reviews with meta-analysis have been conducted. Although the sensitivity of diagnostic criteria for bvFTD has been extensively evaluated, less attention has been given to their specificity. This oversight is critical as understanding the specificity is paramount in reducing false-positive diagnoses, thereby ensuring that patients receive accurate and tailored care.

Table 1

. Criteria for bvFTD (modified from Lund-Manchester 1994, Neary et al,1998, Rascovsky et al 2011)

This work-study protocol seeks to comprehensively assess the evidence regarding the value of the diagnostic criteria for bvFTD. Our primary objective is to systematically identify all published primary studies in this domain, rigorously synthesise the results and determine the diagnostic accuracy of clinical diagnostic criteria. We will also investigate the performance over time, seek to define sources of possible heterogeneity and evaluate the methodological quality of the included studies.


This is registered in the PROSPERO International Prospective Register of Systematic Reviews (CDR42023389063). The final manuscript will be written in accordance with the methodological guidelines delineated in the Cochrane Handbook for Systematic Reviews and Meta-Analyses21 and with reporting based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (online supplemental material).22

Supplemental material

Study selection criteria

Type of studies

We will include all observational studies that report any diagnostic parameter or raw information on the clinical diagnosis of bvFTD by well-defined criteria (table 1). We consider the pathologic and genetic diagnosis as the main gold standard, but will also include refined diagnosis after a follow-up period. Included studies must completely or partially include data on sensitivity (proportion of patients with bvFTD correctly diagnosed using clinical criteria), specificity (proportion of patients without bvFTD correctly screened out of the disease by using clinical criteria), positive predictive value (PPV) (proportion of patients with initial diagnosis of bvFTD using clinical criteria who genuinely had the disease), negative predictive value (NPV) (proportion of patients with initial diagnosis of non-bvFTD using clinical criteria who genuinely had not the disease) and diagnostic accuracy (proportion of correct diagnoses). We will exclude abstracts, book chapters and studies that did not specify the diagnostic criteria. The study population consisted of individuals diagnosed with bvFTD. This complex neurodegenerative disorder is characterised by progressive alterations in behaviour, personality and social functioning. Our analysis encompassed studies conducted in diverse settings, ensuring the broadest possible representation of clinical diagnostic practices. For the purpose of this investigation, we designated the pathological diagnosis as the primary reference standard. However, we also considered genetic diagnosis, and diagnoses refined after a follow-up period as alternative reference standard. This approach allowed us to assess the performance of clinical diagnostic criteria against various gold standards. We evaluated clinical diagnostic criteria, including the Lund-Manchester 1994 criteria,20 Neary et al 1998 criteria and the international consensus criteria for behavioural variant FTD proposed by Rascovsky et al in 2011. To ensure a comprehensive analysis, we restricted our study to articles published in English, Spanish, Italian, German, French or Portuguese.

Search strategy and study selection

Four databases, including MEDLINE (PubMed), Web of Science (Clarivate Analytics), Embase (Elsevier) and LILACS (BIREME/PAHO/WHO), will be systematically searched on 1 May 2024. The strategy comprehends a combination of terms mainly as title/abstract and medical subject headings (eg, frontotemporal lobar degeneration, FTD, behavioural variant, diagnostic accuracy, sensitivity, specificity, NPV, PPV, online supplemental table 1). We tailored the terms according to the database. The screening and selection process will be performed by using the Covidence platform (Veritas Health Innovation, Melbourne, Australia). Following the removal of duplicates, two reviewers (DU and SG-L) will independently screen titles and abstracts, followed by full-text review of retained articles. Discrepancies will be resolved by discussing with a third senior reviewer (SM). Reasons for exclusion at full-text stage will be displayed. In addition, we will carefully review the list of references for the included studies to identify any additional articles missed in our search strategy. We will document the study selection process in a PRISMA flow diagram.

Supplemental material

Data extraction and preparation

The same authors (DU and SG-L) selecting the articles will independently collect study data using a standardised and piloted form. The following information will be extracted: title and authors of the study, year of publication, journal, country, study design and funding, sample size, time of recruitment, population setting and patient demographics (ie, age, sex, comorbidities), clinical characteristics (ie, disease duration, imaging findings, genetic variants) reference standard and diagnostic criteria. Besides, relevant outcome data will be extracted (sensitivity, specificity, accuracy, PPV, NPV, true positive values, true negative values) and information regarding the false negatives and positives (quantitatively and qualitatively). Studies reporting accurate outcomes on different diagnostic criteria and/or separating the diagnosis as possible or probable will be included in the meta-analysis with more than one record. In case relevant information is missing or needs to be clarified, authors will be contacted by email. In addition, we will extract information regarding the nature of misdiagnoses, when available, to understand the common patterns of diagnostic errors.

Risk of bias assessment

The risk of bias in all included studies will be assessed through a tailored Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool.23 This tool classifies each study as having a high, unclear, or low risk of bias on four domains: patient’s selection, index test, reference standard and flow and timing. Two authors (DU and SG-L) will independently evaluate the risk of bias for each of the four domains. Disagreements will be resolved by a third researcher.

Statistical analysis and data synthesis

We will provide a narrative summary and a table reporting the main characteristics of the studies included in our review. This summary will encompass various aspects, including study design, sample size, country, year of study, baseline characteristics of the population under investigation, diagnostic indicators assessed and the reference standard used. Our exploratory approach will involve constructing two-by-two tables, calculating sensitivity and specificity with 95% CIs and presenting these results graphically (forest plots and receiver operating characteristic (ROC) space). Furthermore, if meta-analysis is possible, we will use random effects bivariate model accounting for the unexplained heterogeneity between studies to meta-analyse pairs of sensitivity and specificity and estimate a summary point.24 We will proceed with a meta-analysis only if we identify at least three studies that employ the same diagnostic criteria. Descriptive analyses, data processing and statistical analyses will be conducted using RevMan Web and Stata V.18 including the user-written commands metandi.

Assessment of heterogeneity

We will initially assess heterogeneity by visually inspecting forest plots and the ROC plots. We consider the following as the main a priori sources of heterogeneity: diagnostic criteria used for the definition of bvFTD (Lund-Manchester19 or before Neary et al criteria20 and Rascovsky et al 6), reference standard type (pathological, genetic or follow-up), participants’ characteristics (age, disease duration), setting (clinical-based vs community-based) and study design. The bivariate regression model can be extended to include covariates to assess whether the estimation of summary estimates of sensitivity and specificity vary with study‐level covariates. Where possible, we will investigate the effect of each potential source of heterogeneity estimating differences in the value of summary estimates of sensitivity and specificity.

Analysis of sensitivity

We will assess the robustness of our meta-analyses through sensitivity analyses, which involve the exclusion of studies based on various aspects of the QUADAS-2 tool, which assesses the risk of bias. Our primary analysis will encompass all studies, while sensitivity analyses will exclude those with a high risk of bias or significant concerns regarding applicability. We will also use Cook’s distance to identify particularly influential studies and we will check for outliers by creating a scatter plot of the standardised predicted random effects.25 If it is possible, the model will be refitted leaving out any outliers and very influential studies to check the robustness of the results.

Assessment of publication biases

If we identify an adequate number of studies, we will explore the possibility of publication bias using Deek’s funnel plot. However, we will exercise caution in interpreting the results of this analysis due to its limited statistical power and the absence of consensus regarding appropriate methods for detecting publication bias in reviews of diagnostic test accuracy.

Quality of the evidence

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology for diagnostic tests has been established and offers instructions on how to transform accuracy data into a recommendation that considers outcomes important to patients. We intend to implement the GRADE approach26 to assess the quality of the evidence using GRADEpro GDT: GRADEpro Guideline Development Tool (McMaster University and Evidence Prime, 2023).

Patient and public involvement

Patients and the public were not involved in the design of this protocol.

Ethics and dissemination

Approval from an ethics committee is not required since this systematic review will use publicly available data without directly involving human participants. Our findings will be presented at relevant scientific conferences and disseminated through publication in a peer-reviewed journal.


Our study protocol seeks to address these challenges and gaps in the diagnosis of bvFTD. By conducting a systematic review and meta-analysis of the existing literature, we aim to comprehensively evaluate the accuracy of clinical diagnosis criteria in use and assess whether there has been an improvement over time. Our findings will highlight the importance of addressing both specificity and sensitivity to enhance diagnostic accuracy, suggesting a pathway for future research and clinical practice refinement. Ultimately, our study aspires to support improvements in diagnostic practices, enhancing the lives of individuals affected by bvFTD and advancing our understanding of this challenging neurodegenerative disorder.

Ethics statements

Patient consent for publication


Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.


  • DU and SG-L are joint first authors.

  • DU and SG-L contributed equally.

  • Contributors The manuscript protocol was drafted by DU and SG-L and was revised by SM and GL. DU and SG-L defined the concepts and search items. SM will arbitrate in case of disagreement. DU, SG-L, SM and GL planned the data extraction and statistical analysis. All authors reviewed the manuscript and have approved and contributed to the final written manuscript.

  • Funding This work has been supported by the founding of Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione. D.G.R. n. 2117 of 21.11.2018 (CUPB84I18000540002)—C.I.R.E.M.I.C. (Research Center of Excellence for Neurodegenerative Diseases and Brain Aging)—University of Bari ‘Aldo Moro’.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.