Received: 24 October 2022 Revised: 15 May 2023 Accepted: 1 June 2023

DOI: 10.1002/alz.13363

REVIEW ARTICLE

Frontotemporal dementia: Past, present, and future

Hulya Ulugut1,2 Yolande A. L. Pijnenburg1

1
Alzheimer Center Amsterdam, Department
of Neurology, Amsterdam Neuroscience, Vrije Abstract
Universiteit Amsterdam, Amsterdam UMC,
INTRODUCTION: The history of frontotemporal dementia (FTD) is both old and
Amsterdam, The Netherlands
2 new. This study explores its historical roots, dating back to the 19th century, while
Memory and Aging Center, Department of
Neurology, University of California, San recognizes it as a distinct neurological entity only a few decades ago.
Francisco, California, USA
METHODS: This qualitative study and literature review provides an overview of FTD’s
Correspondence historical background, birth, evolution, and future directions.
Hulya Ulugut, Alzheimer Center Amsterdam, RESULTS: Recognition of FTD was hindered by rigid perceptions of dementia, the
Amsterdam UMC, De Boelelaan 1118, 1081
HZ Amsterdam, The Netherlands and Memory division between neurology and psychiatry, reliance on IQ-based assessment, limited
and Aging Center, University of California, San neuroimaging capabilities, and lack of pathological proof. Overcoming these bar-
Francisco, 1651 4th St Suite 212, San
Francisco, CA 94158, USA. riers involved revisiting early pioneers’ approaches, focusing on focal impairment,
Email: [email protected] establishing non-Alzheimer’s disease cohorts, fostering collaboration, and developing

Funding information
diagnostic criteria. Current gaps include the need for biology-oriented psychiatry edu-
Alzheimer’s Association grant, Grant/Award cation, biological biomarkers, and culturally sensitive, objective clinical instruments
Number: AACSF-22-849085
predicting underlying pathology.
DISCUSSION: Independent multidisciplinary centers are essential. The future of
FTD lies in disease-modifying therapies, presenting new opportunities for healthcare
professionals and researchers.

KEYWORDS
behavioral sciences, dementia, dementia of the frontal type, frontal lobe dementia, frontotempo-
ral dementia, history, neuropsychiatry, pick’s disease and frontotemporal lobar degeneration

1 INTRODUCTION (behavioral problems predominant), progressive nonfluent aphasia

(PNFA), and semantic dementia.1 In 2011, consensus clinical diagnos-
Frontotemporal dementia (FTD) is a clinical disorder associated with tic criteria were revised, and FTD was classified as behavioral variant
neurodegeneration of the cortex of the frontal and temporal lobes, FTD (bvFTD),2 whereas semantic dementia and PNFA were classified
often in conjunction with the degeneration of subcortical brain under the umbrella of primary progressive aphasia (PPA), including
areas.1–4 This illness presents with a spectrum of social, behavioral, the semantic variant (svPPA), the nonfluent variant (nfvPPA), and
language, psychiatric, and motor problems. Although the name of logopenic variant (lvPPA), even though the latter has most often under-
the disorder emphasizes its major anatomical involvement, the wide lying Alzheimer’s pathology.3 Both sets of diagnostic criteria have been
spectrum of clinical presentations complicates recognition. Over time, widely used worldwide. In both sporadic and familial forms of FTD,
scientists have tried to elucidate the hallmarks of the disorder and distinct histopathological substrates have been identified.5,6
phenotype the characteristic presentations. Clinical diagnostic criteria The term FTD is relatively new, and significant work was per-
published in 1998 classified FTD into three prototypic syndromes: FTD formed following the publication of research diagnostic criteria for

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
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© 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Alzheimer’s Dement. 2023;19:5253–5263. wileyonlinelibrary.com/journal/alz 5253

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5254 ULUGUT and PIJNENBURG

FTD in 1994. Since then, a dramatic increase in research activities

and publications has expanded our knowledge in this field. The first RESEARCH IN CONTEXT
FTD gene was discovered in 1998, when mutations in microtubule-
1. Systematic review: This study provides an analytical
associated protein tau (MAPT) were shown to cause familial FTD
review of the evolution of the concept of frontotempo-
with Parkinsonism linked to chromosome 17q21 (FTDP-17).7 In 2006,
ral dementia (FTD), behavioral neurology research, and
mutations in the neighboring progranulin (GRN) gene were discovered,
education based on the published literature as well as the
explaining the genetic linkage to the same chromosome.8,9 Soon after,
personal experiences of four leading experts in the FTD
transactive response DNA-binding protein 43 (TDP-43) was identi-
field: Professor Marsel Mesulam, Professor Julie Snow-
fied as the main causative of the tau-negative neuronal inclusions10
den, Professor David Neary, and Professor Bruce Miller.
seen in both GRN-mutation carriers as well as non-familial FTD.
FTD is a disorder that initially was poorly recognized and
In 2011, hexanucleotide repeat expansions in chromosome 9 open
considered a quirk of Viking origin; it is now accepted
reading frame 72 (C9orf72) gene, which would be identified as the
worldwide as a major cause of early-onset dementia.
most common genetic cause of FTD, were linked to FTD and motor
2. Interpretation: The main result of this study is that col-
neuron disease (MND).11,12 In a few decades, several rare genes
laboration/interaction is the key factor to facilitate FTD
and proteinopathies were identified,5,13 and international consortia
research, and multidisciplinary independent centers are
facilitated tremendous progress in the unveiling of the molecular char-
crucial. Current gaps in the field are the lack of multi-
acteristics of FTD.14 Gradually, the measurement of CSF and blood
cultural data, biological biomarkers, tools to objectively
biomarkers has attracted great interest and yielded many promis-
assess and quantitate behavioral problems, and restric-
ing results including greater emphasis on neurofilament light chain
tions of positron emission tomography (PET) imaging in
(NfL), TDP-43, plasma tau, phosphorylated tau (p-tau), glial fibrillary
distinguishing tau pathology.
acidic protein (GFAP), and progranulin. These discoveries are having
3. Future directions: The future interests of the FTD field
an impact on clinical practice.15,16 Working groups and international
lie in developing disease-modifying therapies that would
networks such as GENFI (in Europe) and ALLFTD (North America)
create new opportunities and new topics for healthcare
established large cohorts to study cross-sectional and longitudinal
professionals and researchers working on FTD.
features of sporadic and genetic FTD, furthering biomarker and trial
efforts for FTD. Other efforts are under way in Australia, South
America, Asia, and Africa (Table 1).17 More than 250 clinical trials
are active (https://clinicaltrials.gov/ct2/results?cond=frontotemporal+
dementia&term=&cntry=&state=&city=&dist=) aimed at curing this 2 METHODS
devastating disorder.
In the last 40 years, FTD research has advanced substantially, as First, we conducted a review of the literature using the following
outlined in other review articles focusing on the history and updates keywords: “neuropsychiatry,” “behavioral sciences,” “history,” “social
of FTD. Still, many of those articles are missing facts about the cur- psychiatry,” “mental tests,” “dementia,” “frontotemporal dementia,”
rent challenges in clinical practice, research, behavioral neurology “frontal lobe dementia,” “dementia of the frontal type,” “pick’s dis-
education, potential solutions, and comprehensive future directions. ease,” “progressive aphasia,” and “frontotemporal lobar degeneration”
Importantly, most narratives regarding the history of FTD start with using MEDLINE (PubMed) covering the literature until January 2022
Picks’ case report in 189218 and continue with Mesulam’s progressive (Supplementary material; Search strategy and PRISMA flow chart).
aphasia (1982),19 Snowden’s and Hodges’ semantic dementia (1989, We intentionally selected old terminologies to capture early literature.
1992),20,21 and Neary and Snowden’s diagnostic criteria (1998)4 and Articles were included if (i) full text was available and (ii) the language
arrive at current diagnostic criteria published in 2011 by Rascovsky was English, Dutch, or Turkish. Secondly, we used qualitative research
et al.2 and Gorno Tempini et al.3 However, one of the great mysteries methodologies22 to discuss challenges, potential solutions, and future
in FTD is what happened between Pick and the contemporary behav- directions in behavioral neurology education and FTD research. Four
ioral neurologists that would explain the 100 years of silence. This is leading experts were invited to a video call, and the content was
important because uncovering the key factors in the journey of ground- summarized in box tables. The details of the methodology, full inter-
breaking discoveries may help derive lessons from the past to better views, and short highlight clips can be found in the Supplementary
shape the future. materials. The experts who contributed to the discussion are Profes-
In this article, we aim to place current behavioral neurology research sor M. Marsel Mesulam, who provided the first characterization of
in FTD in the context of its history and future. With this aim, we progressive aphasia19,23 and the director of the Mesulam Center for
reviewed the literature of the history of behavioral neurology research Cognitive Neurology and Alzheimer’s disease, Professors David Neary
in FTD targeting the early 19th century until 1994, when FTD was and Julie Snowden, founders of the Manchester FTD cohort, which is
first recognized. Moreover, to better understand the current status and the first largest non-Alzheimer’s disease cohort in the world,6 and the
future directions in the field, we interrogated four international leaders first neuroscientists to suggest the term “semantic dementia,”9 and
on their visions on the status quo and future of the FTD concept. lastly Professor Bruce L. Miller, who conducted seminal work that has
 15525279, 2023, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13363 by Cochrane Colombia, Wiley Online Library on [05/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ULUGUT and PIJNENBURG 5255

TA B L E 1 International networks, working groups, and multicenter cohorts.

Organization Reference
Genetic Frontotemporal Dementia Initiative (GENFI) https://www.genfi.org/
Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) https://www.allftd.org/
Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) https://www.allftd.org/
Dominantly Inherited Non-Alzheimer Dementias (DINAD) https://www.forefrontresearch.org/dinad/
Diagnostic and Prognostic Precision medicine for behavioral variant Frontotemporal https://www.neurodegenerationresearch.eu/wp-
Dementia (DIPPA-FTD) content/uploads/2020/06/PROJECT-DIPPA-FTD.pdf
Multi-Partner Consortium to Expand Dementia Research in Latin America (ReDLaT) https://www.gbhi.org/projects/multi-partner-
consortium-expand-dementia-research-latin-
america-redlat
Latin American and Caribbean Consortium on Dementia (LAC-CD) http://lac-cd.org/
Clinical research center for dementia of South Korea (CREDOS-FTD) https://pubmed.ncbi.nlm.nih.gov/25589724/
LEAF-FTD in Korea https://boxerlab.ucsf.edu/study/fpi
New Zealand Genetic FTD (FTDGenZ) https://journal.nzma.org.nz/journal-articles/diagnosing-
pre-clinical-dementia-the-nz-genetic-
frontotemporal-dementia-study-ftdgenz
South East Asia FTD Consortium https://boxerlab.ucsf.edu/study/fpi
African dementia cohorts https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/
alz.12432
Frontotemporal Dementia Prevention Initiative (FPI) https://www.genfi.org.uk/fpi.html
Tau Consortium https://tauconsortium.org
Bluefield Project https://www.bluefieldproject.org/
Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) FTD https://enigma.ini.usc.edu/ongoing/enigma-ftd/
Four Repeat Tauopathy Neuroimaging Initiative (4RT-NI) https://iadrp.nia.nih.gov/project/four-repeat-tauopathy-
neuroimaging-initiative-4
Alzheimer’s Association International Society to Advance Alzheimer’s Research and https://action.alz.org/PersonifyEbusiness/Default.aspx?
Treatment (ISTAART) FTD Professional Interest Area (PIA) TabID=1519
Neuropsychiatric International Consortium FTD (NIC-FTD) https://www.alzheimercentrum.nl/wetenschap/lopend-
onderzoek/nic-ftd/
International right temporal variant FTD working group https://www.medscape.com/viewarticle/955742
International Network for Cross-Linguistic Research on Brain Health (INCLUDE) https://include-network.com/
Global Brain Health Institute (GBHI)-FTD https://www.gbhi.org/news-
publications/frontotemporal-dementia

increased the awareness and understanding of FTD. Currently, he is the Pinel and Esquirol, emphasized the organic etiology of mental disor-
founder and director of the UCSF Memory and Aging Center. ders, and Antoine Laurent Bayle (1799–1858) claimed that demen-
tia and mental disorders were both aspects of the same disease,24
whereas Paul Broca (1861) identified the brain region responsible
3 RESULTS for the motor structure of language.26 In Germany, in 1845, Wilhelm
Griesinger wrote his revolutionary book Psychische Krankheiten sind
3.1 Literature review Erkrankungen des Gehirns (Mental Illnesses Are Diseases of the Brain).24
Following his work, German-Austrian psychiatrist, neuropathologist,
The 19th century was a golden age in the history of neuropsychiatry. At and anatomist Theodor Meynert classified the behavioral onset dis-
that time, the disciplines were broad, and neurologists, psychiatrists, orders under the term of “clinical disorders of the forebrain.”27
surgeons, anatomists, and pathologists worked together, where often Meynert’s contribution should be emphasized because, beyond his
one person had multidisciplinary expertise. The traditional approach personal achievement, his legendary pupils changed the direction of
was localization using autopsy techniques to identify the origins of behavioral neurology. One of his famous students, Carl Wernicke,
mental illnesses.24 With the influence of the French Revolution, France established the neuroanatomical localization of receptive aphasia,27
became the heart of science and art, which influenced science across whereas another student, Sigmund Freud, challenged the main author-
Europe.25 In France, Étienne-Jean Georget (1795–1828), a disciple of ities by asserting that their manner of understanding aphasias was no
 15525279, 2023, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13363 by Cochrane Colombia, Wiley Online Library on [05/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
5256 ULUGUT and PIJNENBURG

longer tenable.28 Freud separated himself from his peers and he estab- tic response from his colleague, Emil Kraepelin, who promptly included
lished a new technique, psychoanalysis, which is a clinical method for “Alzheimer’s disease” in the 3rd edition of his text Psychiatrie in 1910.39
treating psychopathology through dialogue between a patient and a Thus, Alzheimer’s name would be linked forever with one of the most
psychoanalyst.29 Although Freud’s fame spread throughout Europe, he common and feared diseases, although in the same year, Oskar Fis-
was influenced by another famous personage, Jean-Martin Charcot. cher published the clinicopathological features of 12 cases of senile
Charcot’s hospital in Paris, Salpêtrière Hospital, was a meeting point dementia, in which he provided the first description of the neuritic
that hosted many great scientists, including Charles Bouchard, Joseph plaque.32 The role of Emil Kraepelin in Alzheimer’s fame might be
Babinski, Gilles de la Tourette, Pierre Janet, Joseph Jules Dejerine, and important because Kraepelin was one of the most influential psychia-
Sigmund Freud.30 In this scientific milieu, one group (Freud and his fol- trists considered as the founder of modern psychiatry.39 He introduced
lowers) dug into childhood traumas to find the etiologies of psychiatric a new system for classifying mental disorders (including dementia)
disorders, whereas another group was studying the organic etiologies and hypothesized that the main origin of psychiatric disorders was
underlying mental disorders. These two different approaches had an also neurobiological malfunction.29 Moreover, he popularized the term
influence across the world and triggered the split between neurology “dementia praecox” (schizophrenia) and characterized this as a pro-
and psychiatry. gressive neurodegenerative disease that resulted in irreversible loss of
Although the Paris-Berlin-Vienna triangle was leading behavioral cognitive functions.39 Another important name who visited this cen-
neurology research, another capital, Prague, was highly influential ter was Austrian psychiatrist and neurologist Constantin von Economo,
based on the contributions of Arnold Pick. After undergoing training who characterized the Von Economo cells, originally described by Betz,
in Vienna (under the supervision of Meynert) and Berlin (under the which are currently assumed to be the target of FTD.40
supervision of Westphal), Pick returned to Prague to head the Prague In the following decades of the 1900s, research in behavioral neu-
neuropathological school with his colleague Oskar Fischer (the sec- rology continued. An assistant of Wernicke, Hugo Liepmann, started
ond neuropathological school at the time; the other was in Munich, a debate on the nature of conceptual knowledge and suggested that
where Alois Alzheimer worked).31 In this school, Fischer reported neu- “meaning” was more than knowing a given object; it is also related to
ritic plaques in 12 cases of senile dementia,32 and Pick published the relationship of one object to another, with respect to both time
several articles focusing on apraxia, agnosia, memory, consciousness, and space,41 which might be retrospectively interpreted as the basis
and psychosis as well as aphasia.31 In 1891, the term “dementia prae- of semantics.42 Furthermore, Rosenfeld presented a case with naming
cox,” which today is known as schizophrenia, was first used by Pick.33 problems, word comprehension deficit, fluent speech, and preoccupa-
In 1892, he published his famous case report who presented with tions, as well as with left temporal pole predominant atrophy,43 where,
behavioral and language problems and asymmetric left temporal lobe based on current knowledge, we can conclude that his case was a
atrophy and would retrospectively be classified as svPPA based on semantic dementia case.42 Another student, Karl Kleist, published his
current diagnostic criteria.3 After his report, Dejerine and Serieux famous brain map that displayed the function of each brain area.44
(1897)30 described a case of sensory aphasia with bilateral anterior Conversely, another pupil, Kurt Goldstein, was an antilocalizationist
temporal atrophy. Pick went on to report four additional cases with influenced by Gestalt psychology who conceived a holistic approach to
temporal lobe atrophy and language disturbances, and in 1906 he the brain in which he postulated that function in a damaged area could
described a patient with disinhibition and mixed apraxia who had be compensated through the capacity of other areas.45–47
severe bilateral frontal and left-sided parietal atrophy, with more mod- World War II left a scar on the history of science and changed the
erate atrophy of the left temporal lobe.31 Eventually, he proposed a destiny of neuropsychiatry. Many scientists living in Germany were
concept to distinguish two forms of linguistic disorders: frontal and incarcerated or forced to emigrate. Among those who met a tragic
temporal variants.31 fate in this period was Oskar Fischer, who deserved major credit for
In another important scientific hub, Munich, in 1911, Alois the description of what is now known as AD. Many of the expelled
Alzheimer outlined the histological characteristics of silver staining scientist-physicians that immigrated to North America eventually
argyrophilic cytoplasmic inclusions within neurons.34 In the 1920s, the played prominent roles in shaping the development of modern neu-
research on Alzheimer’s and Pick’s results were expanded and “Pick’s roscience and clinical research in neuropsychiatric disorders.24,29,48
atrophy,” “Pick’s body,” and eventually “Pick’s disease” were identified Here, must be mentioned the name of one of those scholars: Profes-
by Pick’s pupils: Gans, Onari, Spatz, and Schneider.35–37 sor Alfred (Fred) Quadfasel. Quadfasel’s impact was not limited to his
Even though Alois Alzheimer defined the histological features of scientific work, he influenced his famous pupil Norman Geschwind’s
Pick’s disease, these unique inclusions were attributed to Pick,24 how- work on aphasiology and neuropsychology and encouraged Geschwind
ever, another case, Auguste D., would make Alzheimer quite famous, to study classical texts of neurology from the nineteenth and early
even more than Pick.38 Although the neuropsychiatric features of twentieth century, revealing that many crucial findings in behavioral
Alzheimer’s disease (AD) were neglected for decades, Auguste D. neurology had already been reported decades earlier yet had been
was admitted to Alzheimer’s center for paranoia, progressive sleep forgotten by the medical community.49
disturbance, aggression, and confusion, as well as memory deficit.38 In the meantime, the rest of the field was facing an intellectual polar-
Alzheimer noted distinctive plaques and neurofibrillary tangles in her ization due to the post-Freudian effect. Several scientists fell under the
brain histology.38 This case excited little interest despite an enthusias- influence of psychoanalysis, and inevitably psychiatry’s roots within
 15525279, 2023, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13363 by Cochrane Colombia, Wiley Online Library on [05/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ULUGUT and PIJNENBURG 5257

neurobiology were abandoned50 ; furthermore, the division between seminal articles/books/theses emphasizing positive family history in
neurology and psychiatry became explicit.24 In 1948, the American Pick’s disease, the relationship with MND, and the clinical and his-
Academy of Neurology published the “pure” neurological issues, and tological differences between AD and Pick’s disease. Furthermore,
separate neurology departments were established throughout the Switzerland-based scientists Constantinidis, Richard, and Tissot pro-
United States.24 Then, in 1965, the Residency Review Committee posed a new neuropathological classification of Pick’s disease into
for Psychiatry and Neurology, an accrediting body separate from the three types (A, B, and C), depending on the presence or absence of
American Board of Psychiatry and Neurology, eliminated psychiatric Pick’s bodies and ballooned neurons; this system was widely used
training as a mandatory experience for neurologists.50 After this sep- until being replaced by the recent classification of FTLD.60 In this
aration, neurologists focused on those brain disorders with cognitive era, the epochal work of the Lund group, especially Lars Gustafson,
and behavioral abnormalities that also presented with somatic signs David Ingvar, and Arne Brun, must be mentioned because they started
such as stroke, multiple sclerosis, and Parkinson’s disease, for exam- to collect patients with non-Alzheimer type frontal lobe degenera-
ple, whereas psychiatrists focused on those disorders of mood and tion and published their 20-year follow-up results. This revolutionary
thought associated with no or only minor physical signs found in the cohort revealed the clinical picture,61 regional cerebral blood flow
neurological examination.24,50 This oversimplified approach closed the abnormalities,62,63 white matter changes,64 and pathological fea-
doors of cognitive and behavioral neurology to neurologists. By the tures of the syndrome.65,66 In parallel, in Manchester, Neary and
1970s, neurologists had found a new bridge between cognitive sci- Snowden were also collecting dementia patients with non-AD. They
ence and neurology, and vascular etiology was the accepted cause of described the dementia of the frontal type,67 its single photon emission
senility.50 Following this connection, researchers revisited their old tomography characteristics,68 and its relationship with motor neuron
topic, “dementia”; Alzheimer’s neuropathology became more popular, disorder.69 Additionally, they proposed the term “semantic demen-
and a major shift occurred in the field.51 Despite the split between neu- tia,” which corresponds to Warrington’s “semantic memory,”70 and
rology and psychiatry and Alzheimer’s research dominance, a group of suggested that the temporal regions would be the principal site of
scientists who would become formative figures in behavioral neurology pathology in semantic dementia.20 They subsequently highlighted the
and architects of much of the current knowledge structure of neurobe- link between FTD and PPA.71,72
havioral syndromes in the United States continued the early pioneers’ In addition, around the world, interest in developing cogni-
work in Boston as part of the Geschwind école.49 Norman Geschwind, tive/neuropsychological tests to assess different cognitive domains
a founder of behavioral neurology in the United States, translated and assisted in the recognition of selective cognitive deficits in neurode-
reinterpreted key papers by European pioneers in neuropsychiatry generative disorders. Modern cognitive tests originated with the work
written during the previous 100 years, including Karl Wernicke, Paul of James McKeen Cattell, who coined the term “mental tests,”73 and
Fleschig, Hugo Liepmann, Arnold Pick, Jules Dejerine, and Theodore followed Francis Galton’s development of physical and psychological
Meynert. His writing reframed concepts regarding language, praxis, tests.74 However, Alfred Binet, who invented the first practical IQ test,
disconnection, and personality and launched efforts to study the neu- influenced the field strongly, and cognitive assessment became mostly
roanatomical and physiological basis for cortical and subcortical brain “intelligence” centered.75 Although the intelligence-based assess-
disorders. Geschwind brought together an imaginative group of neu- ment generalized cognitive impairment as a global impairment in all
rologists, neuropsychologists, pathologists, and linguists that changed domains, previous clinical observations in patients with focal brain
the way epilepsy, dementia, and many other neuropsychiatric disor- lesions spurred an interest in assessing various cognitive domains
ders were understood and studied.52 The first and second generations separately. In the early 1920s, Charcot’s pupil Piere Marie proposed
of the Geschwind école brought the principles of behavioral neurol- to assess spoken and written language in a systematic way.76 His test
ogy to the study of dementia in the United States and were critical for battery included speech comprehension, production, object recogni-
understanding FTD and the PPAs. In 1967, Frank Benson reported two tion, object naming, repetition, spelling, gesturing, color identification,
clusters of aphasia located in the anterior and posterior parts of the understanding the value of money, giving directions to well-known city
fissure of Rolando.53 In 1981, Jeffrey Cummings collaborated with Pro- landmarks, reading, writing, and singing.76–78 In 1941, Kurt Goldstein
fessor Duchen, and they reported the clinical and pathological findings and his colleagues developed an influential set of constructional and
of five cases of Pick disease that exhibited prominent behavioral and sorting tests, such as cubes, color sorting, object sorting, color form
language problems and had severe anterior temporal atrophy.54 Later, sorting, and stick tests, focusing on abstract thinking and problem
in 1985, Cummings identified the aphasia profile in AD,42 and another solving.79 British psychologist Donald Broadbent (1958) described dif-
student, Bruce Miller, described the clinical, neuropsychological, and ferences between automatic and controlled processes that created a
SPECT characteristics of frontal lobe degeneration in 1991.55 Around basis for research on attention and executive functioning.80 However,
that time, Marsel Mesulam described patients with nonfluent and flu- an important foundation for understanding the functions of the frontal
ent aphasia without Alzheimer’s pathology in 198219 and he proposed lobe can be found in the works of Russian psychologist Alexander Luria
the term PPA.23 (1960s), who influenced several United States- and Europe-based
A series of European researchers also reexamined Pick’s disease. scientists.81–84 Luria gave the first extensive description of frontal
Sjögren et al. (1952) in Sweden,56 van Mansvelt (1954)57 and Schenk lobe syndromes in soldiers with focal brain lesions during the war
(1959)58 in the Netherlands, and Escourolle (1958) in France59 wrote and emphasized the role of the frontal lobe in the control of behavior,
 15525279, 2023, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13363 by Cochrane Colombia, Wiley Online Library on [05/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
5258 ULUGUT and PIJNENBURG

programming, regulation, and verification of activity.81–84 In 1972, have prompted new questions, and currently the field faces ongoing
Tulving revealed the distinction between semantic (general knowl- and emerging problems. Box 2 provides an overview of the gaps, rec-
edge) and episodic memory (memory of events) by describing semantic ommendations, and future directions (also visit Supplementary videos
memory as a system that processes, stores, and retrieves information 1–12).
about the meaning of words, concepts, and facts and the relationship
between them.85 In 1975, in London, Elisabeth Warrington identified
semantic impairment as a separate cognitive deficit. Moreover, in 4 CONCLUSION
her article, she put forth a hierarchically organized modality-specific
semantic memory system that played a pivotal role in explaining the This article aimed to conceptualize the past, present, and future of FTD
semantic system and the syndrome later called “semantic dementia.”70 to better understand where we came from and where we are headed.
Over the years, topics, names, techniques, and places have changed, but
neuroscientists have always tried to understand how the brain works.
3.2 Expert opinion From a historical point of view, it is interesting to see that quite sem-
inal work had already been done by 19th-century scientists despite the
Although those scientific advances contributed to the recognition of lack of current technology. Those scientists coined the canonical terms
FTD, several challenges blocked the identification of the syndrome and their localizations such as aphasia, apraxia, alexia, and agraphia,
(Box 1, also visit Supplementary videos 1–12). as well as the features of behavioral disturbances; they also paved
Despite the barriers, different groups were publishing the distinct the way to neuropsychiatry. However, somehow a prolonged period
profiles of their patients, developing novel tests to better identify focal of silence set in, but the previous fruitful atmosphere was able to be
cognitive impairment, applying new neuroimaging techniques to their recreated by the new generation of FTD researchers more than 100
practices, and establishing clinical cohorts and biobanks. Their work years later. Although World War II negatively affected scientific activ-
created a huge awareness. Many clinicians approached them shar- ity and Freud’s influence caused the paths of neurology and psychiatry
ing their experiences with their patients and referring their patients to diverge, the key factor might have been the loss of a multidisciplinary
for a second opinion. However, importantly, collaboration played a approach. As we reported in the literature review section, back in the
key role in worldwide awareness. The Lund and Manchester groups day, either researchers had more than one specialty or they worked
joined forces and published the famous Lund and Manchester cri- with people who had come from different backgrounds. The centers
teria for FTD in 1994.1 The first initiative for global collaboration led by famous researchers, such as Thedor Meynert, Alois Alzheimer,
came from Sweden. In 1986, the Lund dementia research group orga- and Jean Martin Charcot, functioned as a scientific hub that edu-
nized an international conference on FTD as a satellite symposium cated several pioneers who had different approaches and ideas. This
of the 10th International Congress of Neuropathology.86 This confer- freedom enabled the synergistic interaction of varying perspectives:
ence played a bridge role, and its overwhelming impression was the localizationist theory, antilocalization ideas, and even psychoanalysis.
need for further promotion of research interaction among researchers However, modern medical education has been formed by disciplines or
active in this field.86 The awaited second International Conference departments such as neurology, psychiatry, and pathology. Inevitably,
on FTD took place in Lund in 1992, with contributions from research clinicians have followed the trajectory that starts with medical school,
centers in England, the United States, France, Japan, Denmark, Swe- followed by residency in a department, which served to widen the
den, and other countries.86 Benson’s progressive frontal dysfunction,87 divide between neurology and psychiatry. FTD was ignored by both
Miller’s progressive right frontotemporal degeneration,88 Knopman’s disciplines since neurologists did not know how to assess behavior
dementia lacking distinctive histology,89 Neary, Snowden, and Mann’s and psychiatry was not biologically oriented. However, the pioneers of
clinical-pathological correlates of frontotemporal lobar atrophy,90 and the field noticed the gap in the field and re-initiated the tradition of
Mitsuyama’s presenile dementia with MND91 were some of the high- interdisciplinary collaboration. More importantly, the independent and
lights of the conference. These eminent studies showed that FTD was a collaborative work of those centers catalyzed the recognition of FTD,
separate entity and developing new diagnostic criteria for FTD became and in a very short period of time, our knowledge about neurodegener-
a necessity. Inevitably, in 1998, the first consensus diagnostic criteria ation has increased. Furthermore, beyond the reunion of neurologists,
for FTD were published by this international team.4 neuropsychologists, psychiatrists, and basic scientists, they opened
The collaboration in research continued, and the annual frequency new doors for philosophers and social scientists; indeed, FTD cre-
of publications accelerated dramatically. The Lund initiative led to the ated a new way of thinking about human behavior and prompted the
formation of the International Society for Frontotemporal Dementias big question of where the boundary lies where one crosses over into
(ISFTD), which aims to unite FTD researchers around the world and abnormality. Additionally, this new era initiated a new way of cogni-
organize biennial FTD conferences. In subsequent years, numerous tive assessment and encouraged psychologists to assess all cognitive
prominent names provided incredible contributions that reshaped the domains by novel tests, unlike the classic, oversimplified IQ-based
current status of the syndrome, and we read on a daily basis of new neuropsychological assessments.
studies that increase our belief in curative treatments of this devas- Current gaps in the field are the lack of multicultural data, biolog-
tating disorder. On the other hand, as expected, all scientific findings ical biomarkers, tools to objectively assess and quantitate behavioral
 15525279, 2023, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13363 by Cochrane Colombia, Wiley Online Library on [05/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ULUGUT and PIJNENBURG 5259

Box 1. Challenges before the recognition of FTD (based on experts’ opinions)

Real-life examples

A rigid “We encountered resistance to the idea of a separate dementia type. . . ” The accepted view in the 1980s was that there were
perception just two causes of dementia: AD and vascular dementia, and neurodegenerative diseases that led to dementia were also
of supposed to cause problems with memory, not behavioral change. Moreover, if you had aphasia, it had to be related to a
dementia in focal lesion such as a stroke, gunshots, or something else. However, our patients were not following any of those rules.
the field These patients would come with slowly progressive aphasia, a problem that looked neurodegenerative but without a
memory problem, stroke, or tumor. Those patients would have gone to a lot of doctors without getting a diagnosis. Some
of them would be referred to a psychiatrist claiming that these symptoms are stress related. Or neurologists would say: it
is stroke, but we cannot see it! They would even be referred to ENT specialists who looked for vocal cord lesions. At that
time, the field didn’t understand the difference between syndrome and disease. There was tremendous controversy
about whether it is a separate disease or just AD. Even with pathological proof distinct from AD, we were dealing with
skepticism stating that “frontal” type dementia might be a rare disorder seen only in the north of England and Sweden and
linked to Viking genes because the largest cohorts were in Lund and Manchester. There was also the view that dementia
was untreatable, so defining new subtypes was pointless.
With the benefit of hindsight, it is easy to assume a smooth, linear trajectory in the development of knowledge of FTD. Yet
our own experience is of a more abrupt, stepwise development linked to a paradigm shift, for example, “seeing” that
neurodegenerative disease is not global.
An IQ based “We needed an assessment protocol, designed to tease out distinct areas of cognition systematically. . . ” The major challenge at
cognitive the time was the prevailing view of dementia suggesting that dementia constituted a global impairment of intellectual
assessment functions that could be identified by an IQ test. However, traditional methodologies were overlooking patients with focal
neurodegeneration. Our first semantic dementia patient, subsequently pathologically confirmed, is a great example. The
patient’s problems were framed in terms of memory. The patient complained, “I can’t remember things,” yet close analysis
showed the memory disorder to be one of semantic memory: difficulty remembering words and people and what things
were for. It highlighted the limitations of cognitive assessment that relies solely on overall test scores since such scores
potentially mask different reasons for task failure. The emphasis on IQ testing hindered recognition and acceptance of
distinct profiles of dementia, and unfortunately, psychologists were very skeptical about a new approach to assess
different cognitive domains.
The split “The split hindered the recognition of FTD. . . ” because neurologists have paid little attention to cognition and behavior,
between whereas psychiatrists have had little training in neurological examination and neuroimaging.
neurology The distinction between specialties is likely to lead to referral biases as well. Even if they see the same patient,
and psychiatrists tend to report depression, mania, or hypochondriasis while neurologists emphasize aphasia, executive
psychiatry dysfunction, or semantic problems. On the other hand, the positive effects might be related to practical clinical
management. Neurologists would not want to take care of psychosis, neurosis, or schizophrenia, and probably
psychiatrists would not want to treat neuropathology. Second, neurologists take care of the acute treatment of dementia,
whereas psychiatrists can provide long-term support. Additionally, the behavioral features of FTD do not fit standard
psychiatric classifications. Perhaps it is an advantage if neurologists do not force unusual behavioral features into
preexisting psychiatric categories.
Technical “The lack of high-resolution neuroimaging and pathological proof were the most important problems. . . ” Pathologically, we were
limitations able to show that it was not AD – no plaques, no tangles, just a loss of cells, and there were some cases with tau pathology,
with ballooned cells and inclusion bodies consistent with traditional pathological descriptions of Pick’s disease; however,
the majority did not fit the description. In Manchester, we developed single photon emission computed tomography
(SPECT). Our early images were grainy with poor resolution, yet they distinguished predominant posterior hypoperfusion
in AD and anterior changes in our presumed FTD patients. And a couple of years later, in the United States, we were able
to have a PET scan that showed asymmetric hypometabolism, and over the years autopsies started to come in, and we had
a better idea of the heterogeneity. Therefore, our experiences led us to establish brain banks that helped us to better
understand the underpinnings of neurodegeneration.

problems, and limitations of PET imaging in distinguishing tau pathol- recruit dedicated scientists focusing on the same goal are crucial
ogy. Additionally, the current department-based system is not optimal for taking the field in new directions, and for this collaboration is
for improving behavioral neurology education or developing new tech- needed. Since the future of the syndrome will be more biologically
nologies to identify biomarkers. Therefore, independent centers that oriented, new-generation neuroscientists and behavioral neurologists
 15525279, 2023, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13363 by Cochrane Colombia, Wiley Online Library on [05/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
5260 ULUGUT and PIJNENBURG

Box 2. Current gaps, recommendations, and future directions (based on experts’ opinions)

Limitations in ∙ Current behavioral neurology education/research is based on patients with neurodegenerative diseases. The
current classic background in anatomical neurocircuitries, such as that derived from animal studies that are crucial for
behavioral understanding anatomy and mechanisms, is lacking.
neurology ∙ Training in cognitive neurology is patchy or absent in most training programs throughout the world and not
education and systematic.
research ∙ There are limited data on FTD in middle-/low-income countries or underrepresented populations in
high-income countries.
∙ Current clinical terminologies for behavioral problems need greater precision. Available clinical tools provide
little scope for objectively quantifying and deciphering umbrella terms such as “disinhibition,” “apathy,” and
“psychosis,” for example, and monitoring the initial characteristics and progression of behavioral problems.
∙ Current controversies in the field are bvFTD phenocopy syndrome, mixed or atypical presentations of patients
with PPA, and the clinical manifestations of right anterior temporal lobe atrophy.
∙ Considering atypical/heterogeneous clinical presentations, better clinicopathological correlation techniques
are warranted to predict the underlying molecular pathology at early stages.
∙ A revision of the latest diagnostic criteria that have been immensely useful in shaping FTD research and the
clinical landscape is needed, ideally via the collection of multicultural data and an international consensus.
∙ Tau-PET has limited value for distinguishing FTD, although new PET ligands for FTD are being developed.
∙ Developing biological diagnostic biomarkers and dynamic neurophysiological and autonomic markers is an
urgent need in FTD research.
Potential solutions ∙ A multidisciplinary approach is crucial to ensure the integration of various aspects of the condition: cognitive,
to facilitate and behavioral, physical, and social. In particular, recent basic neuroscience advances in social cognition should be
better adapted to FTD clinical practice and research. Specialized centers will be necessary to bring different sciences
conceptualize together for more accurate diagnosis of FTD. Training in neurology or psychiatry alone is not sufficient for the
current diagnosis of FTD. This physical proximity enables clinicians and computer and basic scientists to work together
behavioral to create a real interdisciplinary system concretely, not abstractly.
neurology educa- ∙ These specialized centers need freedom. They need to control the space, funding, and administrative decisions.
tion/research ∙ There is some improvement now in that there is greater overlap and communication among disciplines.
Cognitive/behavioral neurology became a recognized branch of neurology, and neuropsychiatry became a
recognized branch of psychiatry.
∙ The recommendation for young clinicians and researchers would be to visit the specialized centers to receive a
high-quality education.
Future directions ∙ The complexity of neurodegenerative disorders, in particular FTD, will require specialized training in the
clinical, imaging molecular, and treatment possibilities for these conditions. For example, advice that would be
suitable to give someone with a TDP 43-related aphasic syndrome would not be appropriate for someone
presenting with a behavioral disorder. Therefore, two levels need to be addressed separately: (i) the clinical
syndrome and (ii) the underlying disease.
∙ In the near future, it will likely be possible to perform genetic profiling on all patients, regardless of their family
history. This will become important when therapies emerge.
∙ The future of the field will be diagnostic biological biomarkers and disease-modifying treatments. This is a
realistic and achievable goal.
∙ Note that everything we discover will grow more complex. How do we integrate this and work with patients,
their families, and the greater society? Therefore, healthcare professionals who work with FTD patients will
have tremendous responsibilities and roles beyond diagnosing patients and providing medication.

must be aware of the complexity of neurodegenerative disorders and Some limitations about our methodology should be noted. First, we
the heterogeneity of individual patient management. interviewed only four leading experts considering their critical contri-
One of the messages of this article is that limitations have always bution to the recognition of FTD as well as their experiences in the
been and will always be present. Once our colleagues had to face era of unwritten history. However, other researchers would provide
technical limitations, such as a lack of access to neuroimaging and more extensive information. Second, several articles in Japanese, Rus-
pathology, they fought against the rigid idea of one type of demen- sian, Italian, French, and especially German were not available in the
tia; current discussions focus on developing diagnostic biomarkers and search databases. Since we could not retrieve many of the original doc-
disease-modifying agents. uments, we obtained the information mostly from translated articles,
 15525279, 2023, 11, Downloaded from https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.13363 by Cochrane Colombia, Wiley Online Library on [05/05/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
ULUGUT and PIJNENBURG 5261

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ACKNOWLEDGMENTS 14. Moore KM, Nicholas J, Grossman M, et al. Age at symptom onset and
We are most thankful to Professor M. Marsel Mesulam, Professor Julie death and disease duration in genetic frontotemporal dementia: an
international retrospective cohort study. Lancet Neurol. 2020;19:145-
Snowden, Professor David Neary, and Professor Bruce L. Miller for
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their invaluable contributions and generosity. Every session with them 15. Karantali E, Kazis D, Chatzikonstantinou S, Petridis F, Mavroudis I. The
was a great lesson, inspiration, and experience. We truly appreciate role of neurofilament light chain in frontotemporal dementia: a meta-
them for their guidance and for sharing their personal experiences analysis. Aging Clin Exp Res. 2021;33:869-881. doi:10.1007/s40520-
020-01554-8
and visions. Hulya Ulugut received an Alzheimer’s Association Clini-
16. Ntymenou S, Tsantzali I, Kalamatianos T, et al. Blood biomarkers
cian Scientist grant, and this work was supported by an Alzheimer’s in frontotemporal dementia: review and meta-analysis. Brain Sci.
Association grant (AACSF-22-849085). 2021;11:244. doi:10.3390/brainsci11020244
17. Rohrer JD, Boxer AL. The frontotemporal dementia prevention ini-
CONFLICT OF INTEREST STATEMENT tiative: linking together genetic frontotemporal dementia cohort
studies. Adv Exp Med Biol. 2021;1281:113-121. doi:10.1007/978-3-
The authors declare no conflicts of interest. Author disclosures are
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