Neurotherapeutics (2023) 20:1055–1065

https://doi.org/10.1007/s13311-023-01380-6

CURRENT PERSPECTIVES

New Approaches to the Treatment of Frontotemporal Dementia

Kyra D. Neylan1 · Bruce L. Miller1

Accepted: 14 April 2023 / Published online: 8 May 2023

© The American Society for Experimental Neurotherapeutics, Inc. 2023

Abstract
Frontotemporal dementia (FTD) comprises a diverse group of clinical neurodegenerative syndromes characterized by progres-
sive changes in behavior, personality, executive function, language, and motor function. Approximately 20% of FTD cases
have a known genetic cause. The three most common genetic mutations causing FTD are discussed. Frontotemporal lobar
degeneration refers to the heterogeneous group of neuropathology underlying FTD clinical syndromes. While there are no
current disease-modifying treatments for FTD, management includes off-label pharmacotherapy and non-pharmacological
approaches to target symptoms. The utility of several different drug classes is discussed. Medications used in the treatment of
Alzheimer’s disease have no benefit in FTD and can worsen neuropsychiatric symptoms. Non-pharmacological approaches
to management include lifestyle modifications, speech-, occupational-, and physical therapy, peer and caregiver support,
and safety considerations. Recent developments in the understanding of the genetics, pathophysiology, neuropathology, and
neuroimmunology underlying FTD clinical syndromes have expanded possibilities for disease-modifying and symptom-
targeted treatments. Different pathogenetic mechanisms are targeted in several active clinical trials, opening up exciting
possibilities for breakthrough advances in treatment and management of FTD spectrum disorders.

Keywords Frontotemporal dementia · Neurodegenerative disease · Treatments · Genetics · Neuropathology

Introduction of the genetics and pathogenesis of FTD, and promising

future directions for the field are discussed.
Frontotemporal dementia (FTD) comprises a diverse and
heterogeneous neurodegenerative syndrome involving the
frontal and anterior temporal lobes. It typically presents Clinical Syndromes
in the sixth decade, but age of onset can range from 21 to
80 years of age [1]. As common as Alzheimer’s disease in Frontotemporal dementia is an umbrella term for three clini-
patients under 65 years of age, FTD should be considered in cal syndromes: behavioral variant FTD (bvFTD) and two
all early-age-of-onset dementias [2]. Additionally, approxi- forms of primary progressive aphasia (PPA)—semantic
mately 25% of all FTD cases occur in people above the age variant PPA (svPPA) and non-fluent variant PPA (nfvPPA).
of 65 years. Estimates of prevalence of FTD range from 15 Progressive supranuclear palsy (PSP), corticobasal syn-
to 22/100,000, though this is likely an underestimate given drome (CBS), and frontotemporal dementia-motor neuron
diagnostic challenges [3]. disease (FTD-MND) or FTD-amyotrophic lateral sclerosis
Despite significant clinical burden, FTD remains a dis- (FTD-ALS) often present with FTD clinical syndromes that
ease without disease-modifying treatments. This paper will have overlapping neuropathology. The term frontotempo-
review the clinical syndromes, genetics, neuropathology, and ral lobar degeneration (FTLD) refers to the heterogeneous
the current state of treatment and clinical management of group of neuropathologic diagnoses underlying FTD clinical
FTD. Active clinical trials, advancements in understanding syndromes.
Behavioral variant FTD is characterized by early and
progressive behavior and personality changes including
* Kyra D. Neylan disinhibition, apathy, loss of sympathy and empathy for
[email protected]
others, perseverative or compulsive behavior, hyperoral-
1
University of California San Francisco Memory and Aging ity and dietary changes, and deficits of executive function
Center, San Francisco, USA

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1056 K. D. Neylan, B. L. Miller

with relative sparing of visuospatial abilities [4]. Pathology More than twenty genetic mutations have been discovered
is close to evenly divided between the tau or TAR DNA- to cause FTD spectrum disorders, but the three most com-
binding protein 43 (TDP-43) subtypes [5]. In approximately mon genetic mutations are discussed below.
5% of cases, abnormal aggregates of the fused-in-sarcoma
(FUS) protein are present. C9orf72 The most common cause of familial FTD and ALS
Semantic variant PPA presents with anomia and impaired is a genetic mutation with a hexanucleotide repeat expan-
single-word comprehension if the left temporal lobe is more sion GGG​GCC​in the non-coding region of the chromosome
severely damaged, and prominent emotional and behavioral 9 open reading frame 72 (C9orf72) gene. This mutation
dysfunction including irritability, loss of empathy, libido accounts for 13–26% of familial FTD cases [14, 15, 17–19].
changes, and inability to interpret social cues if right tem- It is inherited in an autosomal dominant fashion which exhib-
poral lobe damage predominates [6]. Approximately 7% of its increased penetrance with age (near 100% by age 80) and
patients with left svPPA develop new artistic abilities early possible anticipation phenomenon (earlier age of onset and
in the course of their illness [7–9]. Most cases of svPPA greater severity in subsequent generations) [20]. The most
show underlying TDP-43 pathology, although Pick’s disease common clinical presentation of C9orf72 forms of FTD is
pathology and FTD-MND changes are also seen. bvFTD, ALS, and FTD-ALS. CBS, nfvPPA, and svPPA
Non-fluent variant PPA presents with effortful non-fluent occur less frequently. It commonly presents with psychiatric
speech, apraxia of speech, and agrammatism [6]. Other defi- symptoms including hallucinations, delusions, and obsessive
cits may emerge with disease progression, including execu- compulsive or psychotic features [15, 16]. Age of onset is
tive dysfunction and motor features similar to those seen 20–91, though typically between 50 and 64 [20]. Survival is
in PSP or CBS [10, 11]. In those patients, the underlying variable, ranging from 1 to 22 years with a worse prognosis in
pathology is often congruent with those clinical syndromes ALS patients (on average 1.8 years) [16, 20]. C9orf72 forms
showing PSP or corticobasal degeneration (see below). of FTD are most associated with TDP-43 type B pathology,
Progressive supranuclear palsy (PSP) is characterized though TDP-43 type A and type U, while less common, do
by axial dystonia and rigidity, bradykinesia, supranuclear occur. On neuroimaging, patients tend to exhibit mild and
gaze palsy, and falls [12]. Neuropsychiatric syndromes are symmetric dorsal frontal, temporal, parietal, cerebellar, and
common and patients with PSP pathology often present as dorsomedial thalamic atrophy [20]. The pathogenesis of
a bvFTD or nfvPPA syndrome. Nearly all people with this C9orf72 repeat expansion is not fully understood, but pro-
clinical phenotype show a 4R tauopathy consistent with PSP. posed mechanisms include toxic gain of function, alteration
Corticobasal syndrome (CBS) is a clinical entity charac- of RNA expression, and haploinsufficiency [21].
terized by progressive asymmetric cognitive syndrome with
executive loss, parkinsonism, myoclonus, apraxia, dysto- GRN Progranulin is a highly conserved protein that serves
nia, and sometimes in the later stages, alien limb syndrome as a growth factor and plays a role in the regulation of cell
[12]. Clinicopathologic studies have found that CBS is a growth and survival, inflammation, and microglial and lyso-
neuropathologically heterogenous syndrome with a range somal function in the central nervous system [22]. Progranu-
of underlying pathology including corticobasal degenera- lin is encoded by the progranulin gene (GRN) on chromo-
tion (CBD)—a 4R tauopathy within the FTLD spectrum—as some 17. Homozygous GRN mutations lead to absence of
well as Alzheimer’s disease (AD) [12]. progranulin and neuronal ceroid lipofuscinosis, a lysosomal
Finally, there is syndromic and genetic overlap with storage disorder characterized by young-onset neurodegener-
bvFTD and motor neuron disease or ALS, with FTD, MND, ation [22]. Heterozygous GRN mutations lead to progranulin
and FTD-MND (also commonly referred to as FTD-ALS) deficiency and constitute about 8% of genetic forms of FTD
[13]. Nearly all patients with FTD-MND show TDP-43 [15]. GRN mutations are inherited in an autosomal dominant
neuropathology. fashion with more variable penetrance (about 90% by age
75) than MAPT and C9orf72 [23]. Clinically, patients with
GRN most commonly present with a bvFTD phenotype, but
Genetics nfvPPA, CBS, svPPA, or an atypical parkinsonism pheno-
type all occur [24, 25]. Symptom onset tends to be in the
Approximately 20% of FTD cases are genetic and 40% of 50s–80s, with a mean of about 65 years [23]. Survival on
patients with FTD have a family history of dementia or neu- average is 3–12 years [23]. GRN mutations lead to accu-
ropsychiatric illness [14–16]. Of the FTLD spectrum dis- mulation of TDP-43 type A in the brain. On neuroimaging,
orders, FTD-ALS is the most heritable while svPPA is the patients commonly have asymmetric atrophy of the dorsal
least genetic. frontoparietal regions [15, 24].

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New Approaches to the Treatment of Frontotemporal Dementia 1057

MAPT Tau is a multifunctional protein encoded by the FTLD‑Tau Accumulation of hyperphosphorylated tau can
microtubule-associated protein tau (MAPT) gene on chro- cause neurodegenerative diseases known as tauopathies,
mosome 17 that interacts with microtubules to stabilize the which include FTLD and AD [27]. Accumulation of hyper-
neuronal cytoskeleton and plays a role in axonal transport phosphorylated 3R tau filaments known as “Pick bodies”
[26]. Tau is predominantly expressed in six isoforms via is seen in 20% of FTLD cases [14, 16]. Clinical syndromes
alternative mRNA splicing [27]. In tauopathies, hyperphos- associated with 3R tauopathies include bvFTD, CBS,
phorylation of tau protein disrupts cell function, leading to nfvPPA, and svPPA. With classical Pick’s disease neuropa-
deposition of aggregates of neurotoxic hyperphosphorylated thology, neuroimaging may show “knife-edge” cortical atro-
tau [26]. Genetic mutations in MAPT lead to an imbalance phy (Fig. 1) [14, 33]. Accumulation of hyperphosphorylated
of 3R/4R tau isoforms and comprise 17–32% of cases of 4R tau inclusions is seen in CBD, PSP, globular glial tauopa-
bvFTD with a positive family history [15]. MAPT mutations thy, and argyrophilic grain disease, with a subset of those
are inherited in an autosomal dominant fashion with a high with 4R tauopathies presenting with FTD clinical syndromes
degree of penetrance [28]. Clinical presentation is variable [12, 33]. For example, approximately 50% of the nfvPPA
and may span the range of FTD phenotypes: bvFTD, svPPA, patients seen at the University of California San Francisco
nfvPPA, CBS, PSP, or AD-like presentation [12]. Patients Memory and Aging Center show CBD neuropathology and
often have a psychiatric prodrome and psychotic features. 85% have an underlying tauopathy [34].
Age of onset ranges from the 20s to 80s, with a mean around
49–50 [28]. Different mutations in MAPT can be associated FTLD‑FUS The fused-in-sarcoma (FUS) protein binds to
with either 3R or 4R tau pathology and vary as to their ages DNA and RNA and regulates expression of more than 100
at onset. On neuroimaging, patients with MAPT mutations proteins [35]. Cytoplasmic aggregations of FUS protein can
tend to have symmetric anterior temporal lobe and basal cause FTD or FTD-MND, typically with very early onset in
ganglia atrophy [15]. the third to fifth decades (20–40) [16]. Patients with FTLD-
FUS often have compulsive behavior, prominent psychotic
Rarer genetic causes of FTD include mutations in FUS, symptoms, and hyperorality [14].
TARDBP, VCP, and UBQLN2. For a more comprehensive
review, please refer to Deleon and Miller [29].

Neuropathology

FTLD refers to a heterogeneous group of neuropathologies

underlying frontotemporal dementia clinical syndromes,
based on immunohistochemical staining for intracellular
protein aggregates of different proteins. There is large path-
ological overlap underlying the clinical syndromes of the
FTLD spectrum. Mixed neuropathology can occur, although
due to the younger age of onset, it is less common than with
autopsy studies of AD [30]. The most common neuropatho-
logic entities of FTLD are discussed below. For a more com-
prehensive review, please refer to Younes and Miller [16].

FTLD‑TDP TAR DNA-binding protein 43 (TDP-43) is a

nuclear protein. TDP-43 aggregates occur in the cytoplasm
in FTD and MND [23]. There are four subtypes of TDP-43
characterized by morphology and distribution of TDP-43
inclusions [31, 32]. TDP-43 type A is associated with the
GRN mutation. TDP-43 type B is the most common cause
of FTD-MND and is commonly associated with C9orf72
mutations. TDP-43 type C is seen in the majority of cases
of svPPA (~ 83%). TDP-43 type D is seen with VCP gene
Fig. 1  Brain axial T1-weighted MRI from a patient with bvFTD.
mutations [16]. Other clinical syndromes associated with Arrow depicts frontal lobe “knife-edge” atrophy. MRI magnetic reso-
TDP-43 include bvFTD, CBS, and nfvPPA [16]. nance imaging, bvFTD behavioral variant frontotemporal dementia

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1058 K. D. Neylan, B. L. Miller

Treatment SSRIs (citalopram, fluoxetine, sertraline, paroxetine) and

a recent meta-analysis found improvements in behavioral
There are currently no FDA-approved pharmacotherapies symptoms of FTD including disinhibition, irritability, agi-
for FTD. Treatment and management of FTD involve a tation, hyperorality, and less consistently, apathy [16, 42].
combination of pharmacological and non-pharmacological SSRIs may also reduce pseudobulbar affect [41]. In general,
strategies. escitalopram and citalopram are first choice medications for
neuropsychiatric symptoms in FTD given their high toler-
ability and lower degree of anticholinergic side effects (e.g.,
Pharmacotherapy dry mouth, blurred vision, constipation, urinary retention)
[43, 44]. Prescribers should begin with the lowest possible
A pharmaceutical approach to FTD largely entails the use of dose and monitor for 4–6 weeks for symptomatic improve-
non-disease-modifying, off-label pharmacotherapy targeting ment and side effects before titrating upward.
particular behaviors and symptoms. Clinicians should first
rule out other causes of behavioral disturbances including Atypical Antipsychotics
infection, electrolyte disturbance, drug intoxication, struc-
tural brain lesions, normal pressure hydrocephalus, and sag- Patients with FTD are susceptible to adverse reactions to
ging brain syndrome before initiating medication therapy. antipsychotic medications, especially their extrapyramidal
Consideration of risks and benefits of pharmacotherapy side effects [45]. The FDA has issued a black box warning on
should first include an evaluation of whether given symp- all antipsychotics in the elderly and in patients with demen-
toms are particularly bothersome or potentially harmful to the tia due to their increased mortality risk. However, atypical
patient first, but also to the caregivers and other people who antipsychotics including quetiapine, olanzapine, risperidone,
interact with the patient. Patients and caregivers should be and aripiprazole improve psychiatric and behavioral symp-
counseled that the goal of pharmacotherapy is typically the toms in some patients with FTD [46]. Therefore, physicians
amelioration or reduction in frequency or severity of symp- and families must consider the potential risks and benefits
toms and that complete resolution of an issue may not be fea- of antipsychotics for an individual patient. For patients with
sible. Pharmacotherapy is best paired with environmental and severe behavioral symptoms including delusions and agita-
behavioral adjustments, when possible, as discussed below. tion, the use of second-generation antipsychotics may be
considered. Quetiapine demonstrates the most favorable side
Alzheimer’s Disease Medications effect profile with regard to parkinsonism [47].

In FTD, there is no benefit for the pharmacotherapies found Pharmacotherapy Targeting Motor Symptoms
useful for Alzheimer’s disease. Cholinesterase inhibitors,
one of the primary classes of medications used in the treat- Patients with PSP and CBD show atypical parkinsonian symp-
ment of AD which include donepezil, rivastigmine, and toms, with predominant rigidity and infrequent tremor. Unlike
galantamine, have been studied in FTD and show no effect patients with Parkinson’s disease (PD), patients with FTD-
on cognitive performance but can actually worsen neuropsy- related parkinsonism tend not to be responsive to dopamine
chiatric symptoms [15, 36]. One small study demonstrated replacement therapy including carbidopa-levodopa [46]. Still,
an improvement in patient behavior and caregiver reports some patients experience transient and usually mild motoric
of burden after donepezil was discontinued in patients with improvement, so physicians can consider a trial of dopamine
FTD who were previously given a diagnosis of AD [37]. replacement therapy in patients with functional impairments
Donepezil can worsen both gait and dysphagia in PSP [38]. due to tremor, bradykinesia, or rigidity [12, 41]. Side effects to
The NMDA receptor inhibitor memantine had no benefit monitor include nausea, hypotension, and psychosis.
on either cognition or behavior in FTD patients and was In patients with ALS, the FDA has approved riluzole,
associated with worsening of neuropsychiatric symptoms edaravone, and Relyvrio (combination of sodium phenylb-
in some patients [39, 40]. The NMDA-receptor antagonist utyrate and taurursodiol) as disease-modifying treatments
amantadine may improve gait and freezing in some patients [48, 49]. Riluzole was not found to affect rates of functional
with PSP but adverse events include visual hallucinations decline or survival in patients with PSP [50].
and delirium [41].
Pharmacotherapy Targeting Pseudobulbar Affect
Selective Serotonin Reuptake Inhibitors (SSRIs)
Pseudobulbar affect (PBA), characterized by sudden bouts of
The class of medications with the largest supportive body uncontrollable crying or laughter, is frequently seen in FTD-
of evidence in FTD is the SSRIs. Several clinical trials of MND and PSP [51]. Several medications can help reduce the

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New Approaches to the Treatment of Frontotemporal Dementia 1059

severity and frequency of pseudobulbar affect. Dextromethorphan- decline with age and with improved outcomes in several
quinidine sulfate (brand name ­Nuedexta®) is the first FDA- neurodegenerative diseases including AD, PD, and vascu-
approved medication specifically targeting PBA [51]. Antide- lar dementia. A recent study found physical and cognitive
pressants including SSRIs and serotonin-norepinephrine reup- exercise to be inversely related to disease severity and rate
take inhibitors (SNRIs) are also used as off-label treatment for of annual clinical decline in familial FTD [59]. In addition
PBA and may additionally help with concurrent behavior and to improving cardiovascular health, aerobic exercise can
neuropsychiatric symptoms. Tricyclic antidepressants have also increase strength and balance and reduce falls [41].
shown efficacy in treating PBA but should be used with cau- Other lifestyle modifications that are associated with bet-
tion in patients with FTD spectrum disorders given significant ter outcomes in dementia include eating a balanced diet and
anticholinergic side effects. limiting alcohol intake although studies of FTD populations
are lacking. Dietary changes may pose a challenge to some
Antiepileptic Medications patients with FTD as changes in appetite and physical activ-
ity are often major features of the disease. Therefore, it may
There is limited evidence suggesting a role for antiepileptic or may not be a realistic goal for an individual patient.
medications in FTD. Mood stabilizers such as carbamaz-
epine and valproic acid have been used in the management Speech Therapy
of mania in bipolar disorder, which has symptomatic over-
lap with bvFTD including impulsivity and irritability [46]. Speech therapy can be effective in patients with PPA or
There are limited studies suggesting the utility of mood sta- other FTLD spectrum disorders who have apraxia of speech,
bilizers in FTD, and there are only a few case reports that dysarthria, or hypophonia [60]. It is particularly effective
document improved behavior and agitation [52–54]. There if the speech therapist is trained in neurodegenerative apha-
have been case reports of the use of topiramate in reduc- sias. Sessions may be conducted effectively in person or
ing hyperorality in FTD patients [55, 56]. As antiepileptic via telehealth [61]. Speech therapy in PPA may include ele-
medications have significant side effects including gastro- ments of script training, the development of strategies for
intestinal upset, electrolyte imbalance, kidney stones, and improving communication, training on non-verbal commu-
possible adverse drug reactions, the risks and benefits must nication, and the use of augmentative or alternate modes of
be carefully considered. Currently, there is not enough qual- communication (AAC) including communication books or
ity evidence to recommend the use of antiepileptic medica- assistive technology. Patients with svPPA can often learn
tions in FTD. approximately 25 words that they need for day-to-day com-
munication. Speech therapists can also provide resources for
Medications to Avoid in FTD cognitive rehabilitation including organization strategies for
executive dysfunction [62]. Patients with dysphagia should
In general, patients should avoid or use with caution medica- undergo a swallowing evaluation.
tions with strong cognitive side effects, including benzodi-
azepines, antihistamines, and tricyclic antidepressants [41]. Physical and Occupational Therapy
Activating medications such as methylphenidate and dexa-
mphetamine have mixed reports in the literature but should Many patients with motor symptoms may benefit from
be used with great caution, if at all [57]. Adverse effects physical therapy to work on strength, gait, range of motion,
such as increased behavioral disturbances and hallucinations and balance training [63]. Occupational therapists can assess
have been noted in patients with PD taking dexamphetamine patients’ cognitive and physical status and provide strate-
[46]. There have been small studies in FTD patients demon- gies and interventions to maximize function—for example,
strating improved apathy and disinhibition, though no large the use of step-by-step “activity templates” or visual aids
placebo-controlled studies have been performed [58]. Dopa- for patients with apraxia or executive dysfunction. Occupa-
mine agonists and the NMDA-receptor antagonist amanta- tional therapy can also perform home safety evaluations to
dine do not improve symptoms in PSP [41]. prevent falls and provide assistive devices for activities of
daily living [41].
Non‑pharmacological Approaches to the Treatment
of FTD Peer Support Groups

Lifestyle Modifications Patients with FTD spectrum disorders may experience

increased isolation and depression [64]. Patients may ben-
Regular physical exercise and cognitive activity in epi- efit from peer support groups, to connect with others with
demiologic studies are associated with reduced cognitive shared experiences and share coping strategies. In particular,

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1060 K. D. Neylan, B. L. Miller

patients may find use in support groups designed for patients to the point of choking, attempt to consume non-food items,
with younger onset dementia or PPA [65]. Research on the or risk burning their mouth on hot food given disrupted pain
impact of support groups in bvFTD is limited, but patients responses.
with PPA have reported improved quality of life, confidence, Another safety consideration is the removal of firearms
hope, and practical coping strategies from peer support and from the home.
education programs [66].

Caregiver Support and Education Active Trials and Future Directions

Caregivers of patients with FTD demonstrate high rates of Frontotemporal dementia encompasses a wide spectrum of
burden and distress [67]. Efforts to improve caregiver sup- diverse clinical presentations and underlying pathology, pos-
port, education, coping skills, and strategies for redirecting ing a challenge to therapeutic development. Recent advance-
or minimizing unwanted behaviors have all shown success ments in the understanding of the genetics, pathophysiology,
in reducing caregiver stress [68]. Organizations such as the neuropathology, and neuroimmunology of the frontotempo-
Association for Frontotemporal Degeneration and CurePSP ral dementia spectrum of disorders have expanded possibili-
offer information-rich resources and peer support groups for ties for disease-modifying and symptom-targeted precision
caregivers and families. Caregivers may benefit from respite medicine treatments.
care, short-term caregiving services, or enrolling patients in
longer-duration day care programs. Pharmacotherapy and Gene Therapy Approaches

Other Considerations Autosomal Dominant FTD‑Targeted Approaches

The American Academy of Neurology recommends early The autosomal dominant forms of FTD represent an area
integration of palliative care in patients with progressive of blossoming research in drug development utilizing gene
neurodegenerative disease including ALS and FTD spec- therapy techniques and the use of antisense oligonucleotides
trum disorders, with particular attention paid to eliciting (ASOs) or other small molecules. One advantage of study-
patient preferences before disease progression precludes ing genetic populations is that early intervention is possible.
capacity and effective communication [69]. Referral to pal- Similarly, the therapies are known to be directed towards the
liative care demonstrates improved quality of life in PSP specific cause for FTD.
and ALS [41, 70]. Therefore, planning ahead with advanced Several studies have targeted progranulin replacement in
care directives and assigning a designated power of attor- patients with GRN mutations. Prior trials using nimodipine
ney are recommended early in the disease course whenever and histone deacetylase inhibitors did not successfully raise
possible [41]. Patients with motor neuron disease should progranulin concentrations [72, 73]. Newer techniques in
be connected with ALS centers for multidisciplinary care. development for GRN mutations include the use of adeno-
As FTD commonly affects patients of working age, many associated viral vector therapies (active trials include
families undergo significant financial stress. Patients may NCT04747431 and NCT04408625), recombinant progranu-
qualify for Social Security disability benefits. Patients are lin protein replacement, antibody delivery of progranulin to
at increased risk for financial victimization or exorbitant the brain (active trials include NCT05262023), and the use of
spending. Laws regarding reporting of dementia diagno- monoclonal antibodies targeting sortilin, a protein involved in
sis to the Department of Motor Vehicles differ by state, progranulin degradation, to investigate the effect of increased
but patients with frontotemporal dementia have difficulty progranulin concentration on patients with GRN mutations
driving safely. They should, at the very least, have regular (active trials include NCT03987295 and NCT04374136) [21,
driving assessment. Deficits in executive function, impulse 74–77]. Several different candidate ASOs have been devel-
control, and judgment, as well as motor and gaze abnormali- oped to try to suppress the aberrant RNA transcript expan-
ties in FTD spectrum disorders, can all impair safety while sion seen in C9orf72 mutation carriers with active trials for
driving. ALS and FTD patients (NCT04931862) [21].
Patients with FTD may require supervision given
impaired judgment, a lack of typical responses to pain stim-
uli, and risk of inadvertent self-harm related to compulsive Tau‑Targeted Approaches
behaviors [71]. For example, patients may have repetitive
pacing or roaming behavior to the point of developing blis- Clinical trials targeting tau protein have utilized different
ters. Patients may need to be monitored while eating to mini- strategies to reduce accumulation of hyperphosphorylated
mize choking, as they may eat quickly, overfill their mouths tau, including using gene therapy techniques to alter MAPT

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New Approaches to the Treatment of Frontotemporal Dementia 1061

expression, increasing tau degradation and clearance, inhib- Symptomatic Pharmacotherapy

iting tau post-translational modifications including phospho-
rylation and acetylation, preventing tau aggregation, and Several trials have focused on symptomatic therapy, includ-
stabilizing tau microtubules [78–87]. ing promising preliminary results from a recent study of the
ASOs have been developed to selectively reduce or use of intranasal oxytocin to augment neural activity in brain
modulate MAPT expression in the brain and potentially tar- regions associated with emotional processing and empathy
get alternative splicing to correct 3R or 4R isoform imbal- in FTD [92]. Another active Phase 2 trial is using intranasal
ances and prevent accumulation of toxic tau aggregates. oxytocin to target apathy in FTD (NCT03260920) [93].
In mice and non-human primate models, ASOs decrease
tau mRNA and protein in the brain, spinal cord, and cer- Neuroinflammation in FTD
ebrospinal fluid (CSF) [88]. Anti-tau ASOs are currently
being studied in patients with PSP (NCT04539041) and AD There is a growing body of research demonstrating an immune
(NCT05399888). and inflammatory response in FTD, suggesting a possible
Monoclonal antibodies and anti-tau vaccines have been pathogenic role of immune dysfunction [94]. Patients with
developed to increase tau degradation and clearance through svPPA and GRN mutation carriers have been shown to have
both passive and active immunizations. Several recent trials increased prevalence of autoimmune disease [95]. FTD spec-
have used different candidate anti-tau monoclonal antibod- trum disorders have shown increased levels of inflammatory
ies, including gosuranemab and tilavonemab, which bind to cytokines in CSF compared to controls [94]. Genome-wide
the N terminus of tau protein. Progression of tau pathology association studies have shown enrichment in gene loci asso-
was slowed in mouse models, but efficacy was not shown ciated with inflammation as well as both the innate and adap-
in human trials of PSP, CBD, and nfvPPA despite dose- tive immune systems [96]. Progranulin deficiency has been
dependent accumulation of the drug in serum and CSF shown to lead to defects in microglial lysosomes, with mouse
[81, 89]. Newer candidate anti-tau monoclonal antibodies models showing subsequent upregulation of the complement
in active trials of PSP include bepranemab which binds system and synaptic pruning in the thalamus [97]. This accel-
to the central region of tau (NCT04658199). An anti-tau erated cell death in progranulin-deficient mice was seen to
active vaccine is currently being studied in a clinical trial of be attenuated by deletion of the complement protein C1qa,
nfvPPA patients, but results are pending (NCT03174886). suggesting a possible future role for complement-targeted
Several candidate drugs and trials have explored alter- therapies in the treatment of FTD caused by GRN mutations.
ing post-translational modification of tau, including kinase Progranulin deficiency leads to accumulation of gan-
inhibitors, sodium selenate, and lithium (NCT00703677, gliosides, glycosphingolipids that contain sialic acid, in
NCT02862210) to prevent tau phosphorylation and sal- human and murine brains [98]. Ganglioside degradation
salate to inhibit tau acetylation [85, 90]. To date, none have normally occurs in the lysosome, facilitated in part by
shown clinical efficacy on measures of disease progression. bis(monoacylglycerol)phosphate (BMP), a regulatory lipid
A trial using a rho kinase inhibitor in PSP and CBS patients [22]. It is hypothesized that in progranulin deficiency, low
is underway (NCT04734379). BMP impairs ganglioside catabolism, leading to gangli-
Other tau-targeting strategies have involved the use osidosis which may impair other lysosomal functions and
of agents to inhibit tau aggregation including methyl- subsequently lead to the accumulation of TDP-43 [98].
ene blue derivatives, but clinical trials in AD and bvFTD Gangliosidosis may also trigger a hyper-activated neuroim-
patients were negative (NCT02245568, NCT01689233, mune microglia response [98]. The mechanism by which
NCT01689246, NCT01626378). progranulin deficiency leads to low BMP levels is yet to be
Lastly, several trials have utilized the strategy of stabiliz- determined. In addition to TDP-43 targeted therapies, future
ing tau microtubules. Davunetide demonstrated no clinical studies may target BMP or ganglioside levels in patients
efficacy, and an abeotaxane led to worsening of falls and with progranulin mutations. Additionally, the role of the
clinical dementia rating scale measures [86, 91]. lysosome and gangliosidosis warrants continued investiga-
While none of the tau-targeting trials have yielded posi- tion in FTD more broadly.
tive results in human subjects to date, tau-targeted therapy
still remains a promising area of development. With contin- Neuroinflammation‑Targeted Clinical Trials
ued preclinical investigations and clinical trials, we expand
our understanding of the role of tau in the pathogenesis of Several trials under investigation are targeting different
FTD and improve both drug delivery to the central nervous mechanisms of neuroinflammation. One trial in patients
system and binding of drug targets. with svPPA is using verdiperstat, an irreversible inhibitor of

13
1062 K. D. Neylan, B. L. Miller

myeloperoxidase, with the aim of reducing oxidative stress Required Author Forms Disclosure forms provided by the authors are
and pathologic activation of microglia leading to cell death available with the online version of this article.
(NCT05184569). Verdiperstat has previously been stud- Funding This study was supported by NIH/NIA P30AG062422 and
ied in multiple system atrophy and ALS and demonstrated P01AG019724 (BM) and the Rainwater Charitable Foundation.
safety but not efficacy on measures of disease progression
(NCT03952806, NCT04436510, NCT02388295). Another
approach using a derivative of a nucleoside analog reverse References
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101. Nissim NR, Moberg PJ, Hamilton RH. Efficacy of noninvasive Publisher's Note Springer Nature remains neutral with regard to
brain stimulation (tDCS or TMS) paired with language therapy jurisdictional claims in published maps and institutional affiliations.
in the treatment of primary progressive aphasia: an exploratory
meta-analysis. Brain Sci. 2020;10. Springer Nature or its licensor (e.g. a society or other partner) holds
102. McConathey EM, White NC, Gervits F, et al. Baseline performance exclusive rights to this article under a publishing agreement with the
predicts tDCS-mediated improvements in language symptoms in author(s) or other rightsholder(s); author self-archiving of the accepted
primary progressive aphasia. Front Hum Neurosci. 2017;11:347. manuscript version of this article is solely governed by the terms of
103. Gervits F, Ash S, Coslett HB, et al. Transcranial direct current such publishing agreement and applicable law.
stimulation for the treatment of primary progressive aphasia: an
open-label pilot study. Brain Lang. 2016;162:35–41.

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