New Approaches to the Treatment of Frontotemporal Dementia

Abstract

Frontotemporal dementia (FTD) comprises a diverse group of clinical neurodegenerative syndromes characterized by progressive 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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13311-023-01380-6.

Introduction

Frontotemporal dementia (FTD) comprises a diverse and heterogeneous neurodegenerative syndrome involving the frontal and anterior temporal lobes. It typically presents 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 patients under 65 years of age, FTD should be considered in all early-age-of-onset dementias [2]. Additionally, approximately 25% of all FTD cases occur in people above the age of 65 years. Estimates of prevalence of FTD range from 15 to 22/100,000, though this is likely an underestimate given diagnostic challenges [3].

Despite significant clinical burden, FTD remains a disease without disease-modifying treatments. This paper will review the clinical syndromes, genetics, neuropathology, and the current state of treatment and clinical management of FTD. Active clinical trials, advancements in understanding of the genetics and pathogenesis of FTD, and promising future directions for the field are discussed.

Clinical Syndromes

Frontotemporal dementia is an umbrella term for three clinical syndromes: behavioral variant FTD (bvFTD) and two forms of primary progressive aphasia (PPA)—semantic variant PPA (svPPA) and non-fluent variant PPA (nfvPPA). Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and frontotemporal dementia-motor neuron disease (FTD-MND) or FTD-amyotrophic lateral sclerosis (FTD-ALS) often present with FTD clinical syndromes that have overlapping neuropathology. The term frontotemporal lobar degeneration (FTLD) refers to the heterogeneous group of neuropathologic diagnoses underlying FTD clinical syndromes.

Behavioral variant FTD is characterized by early and progressive behavior and personality changes including disinhibition, apathy, loss of sympathy and empathy for others, perseverative or compulsive behavior, hyperorality and dietary changes, and deficits of executive function with relative sparing of visuospatial abilities [4]. Pathology is close to evenly divided between the tau or TAR DNA-binding protein 43 (TDP-43) subtypes [5]. In approximately 5% of cases, abnormal aggregates of the fused-in-sarcoma (FUS) protein are present.

Semantic variant PPA presents with anomia and impaired single-word comprehension if the left temporal lobe is more severely damaged, and prominent emotional and behavioral dysfunction including irritability, loss of empathy, libido changes, and inability to interpret social cues if right temporal lobe damage predominates [6]. Approximately 7% of patients with left svPPA develop new artistic abilities early in the course of their illness [7–9]. Most cases of svPPA show underlying TDP-43 pathology, although Pick’s disease pathology and FTD-MND changes are also seen.

Non-fluent variant PPA presents with effortful non-fluent speech, apraxia of speech, and agrammatism [6]. Other deficits may emerge with disease progression, including executive dysfunction and motor features similar to those seen in PSP or CBS [10, 11]. In those patients, the underlying pathology is often congruent with those clinical syndromes showing PSP or corticobasal degeneration (see below).

Progressive supranuclear palsy (PSP) is characterized by axial dystonia and rigidity, bradykinesia, supranuclear gaze palsy, and falls [12]. Neuropsychiatric syndromes are common and patients with PSP pathology often present as a bvFTD or nfvPPA syndrome. Nearly all people with this clinical phenotype show a 4R tauopathy consistent with PSP.

Corticobasal syndrome (CBS) is a clinical entity characterized by progressive asymmetric cognitive syndrome with executive loss, parkinsonism, myoclonus, apraxia, dystonia, and sometimes in the later stages, alien limb syndrome [12]. Clinicopathologic studies have found that CBS is a neuropathologically heterogenous syndrome with a range of underlying pathology including corticobasal degeneration (CBD)—a 4R tauopathy within the FTLD spectrum—as well as Alzheimer’s disease (AD) [12].

Finally, there is syndromic and genetic overlap with bvFTD and motor neuron disease or ALS, with FTD, MND, and FTD-MND (also commonly referred to as FTD-ALS) [13]. Nearly all patients with FTD-MND show TDP-43 neuropathology.

Genetics

Approximately 20% of FTD cases are genetic and 40% of patients with FTD have a family history of dementia or neuropsychiatric illness [14–16]. Of the FTLD spectrum disorders, FTD-ALS is the most heritable while svPPA is the least genetic.

More than twenty genetic mutations have been discovered to cause FTD spectrum disorders, but the three most common genetic mutations are discussed below.

C9orf72

The most common cause of familial FTD and ALS is a genetic mutation with a hexanucleotide repeat expansion GGGGCC in the non-coding region of the chromosome 9 open reading frame 72 (C9orf72) gene. This mutation accounts for 13–26% of familial FTD cases [14, 15, 17–19]. It is inherited in an autosomal dominant fashion which exhibits increased penetrance with age (near 100% by age 80) and possible anticipation phenomenon (earlier age of onset and greater severity in subsequent generations) [20]. The most common clinical presentation of C9orf72 forms of FTD is bvFTD, ALS, and FTD-ALS. CBS, nfvPPA, and svPPA occur less frequently. It commonly presents with psychiatric symptoms including hallucinations, delusions, and obsessive compulsive or psychotic features [15, 16]. Age of onset is 20–91, though typically between 50 and 64 [20]. Survival is variable, ranging from 1 to 22 years with a worse prognosis in ALS patients (on average 1.8 years) [16, 20]. C9orf72 forms of FTD are most associated with TDP-43 type B pathology, though TDP-43 type A and type U, while less common, do occur. On neuroimaging, patients tend to exhibit mild and symmetric dorsal frontal, temporal, parietal, cerebellar, and dorsomedial thalamic atrophy [20]. The pathogenesis of C9orf72 repeat expansion is not fully understood, but proposed mechanisms include toxic gain of function, alteration of RNA expression, and haploinsufficiency [21].

GRN

Progranulin is a highly conserved protein that serves as a growth factor and plays a role in the regulation of cell growth and survival, inflammation, and microglial and lysosomal function in the central nervous system [22]. Progranulin is encoded by the progranulin gene (GRN) on chromosome 17. Homozygous GRN mutations lead to absence of progranulin and neuronal ceroid lipofuscinosis, a lysosomal storage disorder characterized by young-onset neurodegeneration [22]. Heterozygous GRN mutations lead to progranulin deficiency and constitute about 8% of genetic forms of FTD [15]. GRN mutations are inherited in an autosomal dominant 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 nfvPPA, CBS, svPPA, or an atypical parkinsonism phenotype all occur [24, 25]. Symptom onset tends to be in the 50s–80s, with a mean of about 65 years [23]. Survival on average is 3–12 years [23]. GRN mutations lead to accumulation of TDP-43 type A in the brain. On neuroimaging, patients commonly have asymmetric atrophy of the dorsal frontoparietal regions [15, 24].

MAPT

Tau is a multifunctional protein encoded by the microtubule-associated protein tau (MAPT) gene on chromosome 17 that interacts with microtubules to stabilize the neuronal cytoskeleton and plays a role in axonal transport [26]. Tau is predominantly expressed in six isoforms via alternative mRNA splicing [27]. In tauopathies, hyperphosphorylation of tau protein disrupts cell function, leading to deposition of aggregates of neurotoxic hyperphosphorylated tau [26]. Genetic mutations in MAPT lead to an imbalance of 3R/4R tau isoforms and comprise 17–32% of cases of bvFTD with a positive family history [15]. MAPT mutations are inherited in an autosomal dominant fashion with a high degree of penetrance [28]. Clinical presentation is variable and may span the range of FTD phenotypes: bvFTD, svPPA, nfvPPA, CBS, PSP, or AD-like presentation [12]. Patients often have a psychiatric prodrome and psychotic features. Age of onset ranges from the 20s to 80s, with a mean around 49–50 [28]. Different mutations in MAPT can be associated with either 3R or 4R tau pathology and vary as to their ages at onset. On neuroimaging, patients with MAPT mutations tend to have symmetric anterior temporal lobe and basal ganglia atrophy [15].

Rarer genetic causes of FTD include mutations in FUS, 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 pathological 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 neuropathologic entities of FTLD are discussed below. For a more comprehensive 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 mutations [16]. Other clinical syndromes associated with TDP-43 include bvFTD, CBS, and nfvPPA [16].

FTLD-Tau

Accumulation of hyperphosphorylated tau can cause neurodegenerative diseases known as tauopathies, which include FTLD and AD [27]. Accumulation of hyperphosphorylated 3R tau filaments known as “Pick bodies” is seen in 20% of FTLD cases [14, 16]. Clinical syndromes associated with 3R tauopathies include bvFTD, CBS, nfvPPA, and svPPA. With classical Pick’s disease neuropathology, neuroimaging may show “knife-edge” cortical atrophy (Fig. 1) [14, 33]. Accumulation of hyperphosphorylated 4R tau inclusions is seen in CBD, PSP, globular glial tauopathy, and argyrophilic grain disease, with a subset of those with 4R tauopathies presenting with FTD clinical syndromes [12, 33]. For example, approximately 50% of the nfvPPA patients seen at the University of California San Francisco Memory and Aging Center show CBD neuropathology and 85% have an underlying tauopathy [34].

Fig. 1.

Brain axial T1-weighted MRI from a patient with bvFTD. Arrow depicts frontal lobe “knife-edge” atrophy. MRI magnetic resonance imaging, bvFTD behavioral variant frontotemporal dementia

FTLD-FUS

The fused-in-sarcoma (FUS) protein binds to DNA and RNA and regulates expression of more than 100 proteins [35]. Cytoplasmic aggregations of FUS protein can cause FTD or FTD-MND, typically with very early onset in the third to fifth decades (20–40) [16]. Patients with FTLD-FUS often have compulsive behavior, prominent psychotic symptoms, and hyperorality [14].

Treatment

There are currently no FDA-approved pharmacotherapies for FTD. Treatment and management of FTD involve a combination of pharmacological and non-pharmacological strategies.

Pharmacotherapy

A pharmaceutical approach to FTD largely entails the use of non-disease-modifying, off-label pharmacotherapy targeting particular behaviors and symptoms. Clinicians should first rule out other causes of behavioral disturbances including infection, electrolyte disturbance, drug intoxication, structural brain lesions, normal pressure hydrocephalus, and sagging brain syndrome before initiating medication therapy. Consideration of risks and benefits of pharmacotherapy should first include an evaluation of whether given symptoms are particularly bothersome or potentially harmful to the patient first, but also to the caregivers and other people who interact with the patient. Patients and caregivers should be counseled that the goal of pharmacotherapy is typically the amelioration or reduction in frequency or severity of symptoms and that complete resolution of an issue may not be feasible. Pharmacotherapy is best paired with environmental and behavioral adjustments, when possible, as discussed below.

Alzheimer’s Disease Medications

In FTD, there is no benefit for the pharmacotherapies found useful for Alzheimer’s disease. Cholinesterase inhibitors, one of the primary classes of medications used in the treatment of AD which include donepezil, rivastigmine, and galantamine, have been studied in FTD and show no effect on cognitive performance but can actually worsen neuropsychiatric symptoms [15, 36]. One small study demonstrated an improvement in patient behavior and caregiver reports of burden after donepezil was discontinued in patients with FTD who were previously given a diagnosis of AD [37]. Donepezil can worsen both gait and dysphagia in PSP [38]. The NMDA receptor inhibitor memantine had no benefit on either cognition or behavior in FTD patients and was associated with worsening of neuropsychiatric symptoms in some patients [39, 40]. The NMDA-receptor antagonist amantadine may improve gait and freezing in some patients with PSP but adverse events include visual hallucinations and delirium [41].

Selective Serotonin Reuptake Inhibitors (SSRIs)

The class of medications with the largest supportive body of evidence in FTD is the SSRIs. Several clinical trials of SSRIs (citalopram, fluoxetine, sertraline, paroxetine) and a recent meta-analysis found improvements in behavioral symptoms of FTD including disinhibition, irritability, agitation, hyperorality, and less consistently, apathy [16, 42]. SSRIs may also reduce pseudobulbar affect [41]. In general, escitalopram and citalopram are first choice medications for neuropsychiatric symptoms in FTD given their high tolerability and lower degree of anticholinergic side effects (e.g., dry mouth, blurred vision, constipation, urinary retention) [43, 44]. Prescribers should begin with the lowest possible dose and monitor for 4–6 weeks for symptomatic improvement and side effects before titrating upward.

Atypical Antipsychotics

Patients with FTD are susceptible to adverse reactions to antipsychotic medications, especially their extrapyramidal side effects [45]. The FDA has issued a black box warning on all antipsychotics in the elderly and in patients with dementia due to their increased mortality risk. However, atypical antipsychotics including quetiapine, olanzapine, risperidone, and aripiprazole improve psychiatric and behavioral symptoms in some patients with FTD [46]. Therefore, physicians and families must consider the potential risks and benefits of antipsychotics for an individual patient. For patients with severe behavioral symptoms including delusions and agitation, the use of second-generation antipsychotics may be considered. Quetiapine demonstrates the most favorable side effect profile with regard to parkinsonism [47].

Pharmacotherapy Targeting Motor Symptoms

Patients with PSP and CBD show atypical parkinsonian symptoms, with predominant rigidity and infrequent tremor. Unlike patients with Parkinson’s disease (PD), patients with FTD-related parkinsonism tend not to be responsive to dopamine replacement therapy including carbidopa-levodopa [46]. Still, some patients experience transient and usually mild motoric improvement, so physicians can consider a trial of dopamine replacement therapy in patients with functional impairments due to tremor, bradykinesia, or rigidity [12, 41]. Side effects to monitor include nausea, hypotension, and psychosis.

In patients with ALS, the FDA has approved riluzole, edaravone, and Relyvrio (combination of sodium phenylbutyrate and taurursodiol) as disease-modifying treatments [48, 49]. Riluzole was not found to affect rates of functional decline or survival in patients with PSP [50].

Pharmacotherapy Targeting Pseudobulbar Affect

Pseudobulbar affect (PBA), characterized by sudden bouts of uncontrollable crying or laughter, is frequently seen in FTD-MND and PSP [51]. Several medications can help reduce the severity and frequency of pseudobulbar affect. Dextromethorphan-quinidine sulfate (brand name Nuedexta^®) is the first FDA-approved medication specifically targeting PBA [51]. Antidepressants including SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) are also used as off-label treatment for PBA and may additionally help with concurrent behavior and neuropsychiatric symptoms. Tricyclic antidepressants have also shown efficacy in treating PBA but should be used with caution in patients with FTD spectrum disorders given significant anticholinergic side effects.

Antiepileptic Medications

There is limited evidence suggesting a role for antiepileptic medications in FTD. Mood stabilizers such as carbamazepine and valproic acid have been used in the management of mania in bipolar disorder, which has symptomatic overlap with bvFTD including impulsivity and irritability [46]. There are limited studies suggesting the utility of mood stabilizers in FTD, and there are only a few case reports that document improved behavior and agitation [52–54]. There have been case reports of the use of topiramate in reducing hyperorality in FTD patients [55, 56]. As antiepileptic medications have significant side effects including gastrointestinal upset, electrolyte imbalance, kidney stones, and possible adverse drug reactions, the risks and benefits must be carefully considered. Currently, there is not enough quality evidence to recommend the use of antiepileptic medications in FTD.

Medications to Avoid in FTD

In general, patients should avoid or use with caution medications with strong cognitive side effects, including benzodiazepines, antihistamines, and tricyclic antidepressants [41]. Activating medications such as methylphenidate and dexamphetamine have mixed reports in the literature but should be used with great caution, if at all [57]. Adverse effects such as increased behavioral disturbances and hallucinations have been noted in patients with PD taking dexamphetamine [46]. There have been small studies in FTD patients demonstrating improved apathy and disinhibition, though no large placebo-controlled studies have been performed [58]. Dopamine agonists and the NMDA-receptor antagonist amantadine do not improve symptoms in PSP [41].

Non-pharmacological Approaches to the Treatment of FTD

Lifestyle Modifications

Regular physical exercise and cognitive activity in epidemiologic studies are associated with reduced cognitive decline with age and with improved outcomes in several neurodegenerative diseases including AD, PD, and vascular dementia. A recent study found physical and cognitive exercise to be inversely related to disease severity and rate of annual clinical decline in familial FTD [59]. In addition to improving cardiovascular health, aerobic exercise can increase strength and balance and reduce falls [41].

Other lifestyle modifications that are associated with better outcomes in dementia include eating a balanced diet and limiting alcohol intake although studies of FTD populations are lacking. Dietary changes may pose a challenge to some patients with FTD as changes in appetite and physical activity are often major features of the disease. Therefore, it may or may not be a realistic goal for an individual patient.

Speech Therapy

Speech therapy can be effective in patients with PPA or other FTLD spectrum disorders who have apraxia of speech, dysarthria, or hypophonia [60]. It is particularly effective if the speech therapist is trained in neurodegenerative aphasias. Sessions may be conducted effectively in person or via telehealth [61]. Speech therapy in PPA may include elements of script training, the development of strategies for improving communication, training on non-verbal communication, and the use of augmentative or alternate modes of communication (AAC) including communication books or assistive technology. Patients with svPPA can often learn approximately 25 words that they need for day-to-day communication. Speech therapists can also provide resources for cognitive rehabilitation including organization strategies for executive dysfunction [62]. Patients with dysphagia should undergo a swallowing evaluation.

Physical and Occupational Therapy

Many patients with motor symptoms may benefit from physical therapy to work on strength, gait, range of motion, and balance training [63]. Occupational therapists can assess patients’ cognitive and physical status and provide strategies and interventions to maximize function—for example, the use of step-by-step “activity templates” or visual aids for patients with apraxia or executive dysfunction. Occupational therapy can also perform home safety evaluations to prevent falls and provide assistive devices for activities of daily living [41].

Peer Support Groups

Patients with FTD spectrum disorders may experience increased isolation and depression [64]. Patients may benefit from peer support groups, to connect with others with shared experiences and share coping strategies. In particular, patients may find use in support groups designed for patients with younger onset dementia or PPA [65]. Research on the impact of support groups in bvFTD is limited, but patients with PPA have reported improved quality of life, confidence, hope, and practical coping strategies from peer support and education programs [66].

Caregiver Support and Education

Caregivers of patients with FTD demonstrate high rates of burden and distress [67]. Efforts to improve caregiver support, education, coping skills, and strategies for redirecting or minimizing unwanted behaviors have all shown success in reducing caregiver stress [68]. Organizations such as the Association for Frontotemporal Degeneration and CurePSP offer information-rich resources and peer support groups for caregivers and families. Caregivers may benefit from respite care, short-term caregiving services, or enrolling patients in longer-duration day care programs.

Other Considerations

The American Academy of Neurology recommends early integration of palliative care in patients with progressive neurodegenerative disease including ALS and FTD spectrum disorders, with particular attention paid to eliciting patient preferences before disease progression precludes capacity and effective communication [69]. Referral to palliative care demonstrates improved quality of life in PSP and ALS [41, 70]. Therefore, planning ahead with advanced care directives and assigning a designated power of attorney are recommended early in the disease course whenever possible [41]. Patients with motor neuron disease should be connected with ALS centers for multidisciplinary care.

As FTD commonly affects patients of working age, many families undergo significant financial stress. Patients may qualify for Social Security disability benefits. Patients are at increased risk for financial victimization or exorbitant spending. Laws regarding reporting of dementia diagnosis to the Department of Motor Vehicles differ by state, but patients with frontotemporal dementia have difficulty driving safely. They should, at the very least, have regular driving assessment. Deficits in executive function, impulse control, and judgment, as well as motor and gaze abnormalities in FTD spectrum disorders, can all impair safety while driving.

Patients with FTD may require supervision given impaired judgment, a lack of typical responses to pain stimuli, and risk of inadvertent self-harm related to compulsive behaviors [71]. For example, patients may have repetitive pacing or roaming behavior to the point of developing blisters. Patients may need to be monitored while eating to minimize choking, as they may eat quickly, overfill their mouths to the point of choking, attempt to consume non-food items, or risk burning their mouth on hot food given disrupted pain responses.

Another safety consideration is the removal of firearms from the home.

Active Trials and Future Directions

Frontotemporal dementia encompasses a wide spectrum of diverse clinical presentations and underlying pathology, posing a challenge to therapeutic development. Recent advancements in the understanding of the genetics, pathophysiology, neuropathology, and neuroimmunology of the frontotemporal dementia spectrum of disorders have expanded possibilities for disease-modifying and symptom-targeted precision medicine treatments.

Pharmacotherapy and Gene Therapy Approaches

Autosomal Dominant FTD-Targeted Approaches

The autosomal dominant forms of FTD represent an area of blossoming research in drug development utilizing gene therapy techniques and the use of antisense oligonucleotides (ASOs) or other small molecules. One advantage of studying genetic populations is that early intervention is possible. Similarly, the therapies are known to be directed towards the specific cause for FTD.

Several studies have targeted progranulin replacement in patients with GRN mutations. Prior trials using nimodipine and histone deacetylase inhibitors did not successfully raise progranulin concentrations [72, 73]. Newer techniques in development for GRN mutations include the use of adeno-associated viral vector therapies (active trials include NCT04747431 and NCT04408625), recombinant progranulin protein replacement, antibody delivery of progranulin to the brain (active trials include NCT05262023), and the use of monoclonal antibodies targeting sortilin, a protein involved in progranulin degradation, to investigate the effect of increased progranulin concentration on patients with GRN mutations (active trials include NCT03987295 and NCT04374136) [21, 74–77]. Several different candidate ASOs have been developed to try to suppress the aberrant RNA transcript expansion seen in C9orf72 mutation carriers with active trials for ALS and FTD patients (NCT04931862) [21].

Tau-Targeted Approaches

Clinical trials targeting tau protein have utilized different strategies to reduce accumulation of hyperphosphorylated tau, including using gene therapy techniques to alter MAPT expression, increasing tau degradation and clearance, inhibiting tau post-translational modifications including phosphorylation and acetylation, preventing tau aggregation, and stabilizing tau microtubules [78–87].

ASOs have been developed to selectively reduce or modulate MAPT expression in the brain and potentially target alternative splicing to correct 3R or 4R isoform imbalances and prevent accumulation of toxic tau aggregates. In mice and non-human primate models, ASOs decrease tau mRNA and protein in the brain, spinal cord, and cerebrospinal fluid (CSF) [88]. Anti-tau ASOs are currently being studied in patients with PSP (NCT04539041) and AD (NCT05399888).

Monoclonal antibodies and anti-tau vaccines have been developed to increase tau degradation and clearance through both passive and active immunizations. Several recent trials have used different candidate anti-tau monoclonal antibodies, including gosuranemab and tilavonemab, which bind to the N terminus of tau protein. Progression of tau pathology was slowed in mouse models, but efficacy was not shown in human trials of PSP, CBD, and nfvPPA despite dose-dependent accumulation of the drug in serum and CSF [81, 89]. Newer candidate anti-tau monoclonal antibodies in active trials of PSP include bepranemab which binds to the central region of tau (NCT04658199). An anti-tau active vaccine is currently being studied in a clinical trial of nfvPPA patients, but results are pending (NCT03174886).

Several candidate drugs and trials have explored altering post-translational modification of tau, including kinase inhibitors, sodium selenate, and lithium (NCT00703677, NCT02862210) to prevent tau phosphorylation and salsalate to inhibit tau acetylation [85, 90]. To date, none have shown clinical efficacy on measures of disease progression. A trial using a rho kinase inhibitor in PSP and CBS patients is underway (NCT04734379).

Other tau-targeting strategies have involved the use of agents to inhibit tau aggregation including methylene blue derivatives, but clinical trials in AD and bvFTD patients were negative (NCT02245568, NCT01689233, NCT01689246, NCT01626378).

Lastly, several trials have utilized the strategy of stabilizing tau microtubules. Davunetide demonstrated no clinical efficacy, and an abeotaxane led to worsening of falls and clinical dementia rating scale measures [86, 91].

While none of the tau-targeting trials have yielded positive results in human subjects to date, tau-targeted therapy still remains a promising area of development. With continued preclinical investigations and clinical trials, we expand our understanding of the role of tau in the pathogenesis of FTD and improve both drug delivery to the central nervous system and binding of drug targets.

Symptomatic Pharmacotherapy

Several trials have focused on symptomatic therapy, including promising preliminary results from a recent study of the use of intranasal oxytocin to augment neural activity in brain regions associated with emotional processing and empathy in FTD [92]. Another active Phase 2 trial is using intranasal oxytocin to target apathy in FTD (NCT03260920) [93].

Neuroinflammation in FTD

There is a growing body of research demonstrating an immune and inflammatory response in FTD, suggesting a possible pathogenic role of immune dysfunction [94]. Patients with svPPA and GRN mutation carriers have been shown to have increased prevalence of autoimmune disease [95]. FTD spectrum disorders have shown increased levels of inflammatory cytokines in CSF compared to controls [94]. Genome-wide association studies have shown enrichment in gene loci associated with inflammation as well as both the innate and adaptive immune systems [96]. Progranulin deficiency has been shown to lead to defects in microglial lysosomes, with mouse models showing subsequent upregulation of the complement system and synaptic pruning in the thalamus [97]. This accelerated cell death in progranulin-deficient mice was seen to be attenuated by deletion of the complement protein C1qa, suggesting a possible future role for complement-targeted therapies in the treatment of FTD caused by GRN mutations.

Progranulin deficiency leads to accumulation of gangliosides, glycosphingolipids that contain sialic acid, in human and murine brains [98]. Ganglioside degradation normally occurs in the lysosome, facilitated in part by bis(monoacylglycerol)phosphate (BMP), a regulatory lipid [22]. It is hypothesized that in progranulin deficiency, low BMP impairs ganglioside catabolism, leading to gangliosidosis which may impair other lysosomal functions and subsequently lead to the accumulation of TDP-43 [98]. Gangliosidosis may also trigger a hyper-activated neuroimmune microglia response [98]. The mechanism by which progranulin deficiency leads to low BMP levels is yet to be determined. In addition to TDP-43 targeted therapies, future studies may target BMP or ganglioside levels in patients with progranulin mutations. Additionally, the role of the lysosome and gangliosidosis warrants continued investigation in FTD more broadly.

Neuroinflammation-Targeted Clinical Trials

Several trials under investigation are targeting different mechanisms of neuroinflammation. One trial in patients with svPPA is using verdiperstat, an irreversible inhibitor of myeloperoxidase, with the aim of reducing oxidative stress and pathologic activation of microglia leading to cell death (NCT05184569). Verdiperstat has previously been studied in multiple system atrophy and ALS and demonstrated safety but not efficacy on measures of disease progression (NCT03952806, NCT04436510, NCT02388295). Another approach using a derivative of a nucleoside analog reverse transcriptase inhibitor originally developed for HIV is currently under investigation. This involves a Phase 2a trial of patients with ALS or FTD with a C9orf72 mutation with the aim of preventing the neuroinflammatory response triggered by TDP-43 inclusion accumulation (NCT04993755).

Lastly, preclinical laboratory studies are actively investigating whether the recent advancements in pharmacotherapy for ALS could have a role in the treatment of FTD. Edaravone, a free radical scavenger, reduced tau phosphorylation and neuroinflammation in a mouse model of FTD [99].

Non-pharmacological Clinical Trials

For PPA, an active area of investigation involves the use of transcranial direct current stimulation (tDCS), a non-invasive method of applying electrical current to stimulate particular brain regions, with initial results suggesting moderate enhancement in language outcomes [100, 101]. Various studies have adapted tDCS protocols to examine effects on language abilities in patients with PPA, with and without concurrent speech and language therapy [102, 103]. There are several studies of this type currently active (including NCT05615922, NCT04486586, NCT05368350, and NCT04566731). Other studies are using comparable design with transcranial magnetic stimulation (TMS) in patients with PPA (recently completed trials include NCT03728582 and NCT03406429) [104].

Using a similar paradigm, the use of transcranial stimulation in other FTD syndromes is actively under investigation. One study in patients with FTD found tDCS led to improvement of clinical scores and behavioral symptoms [105]. Another active trial is using transcranial alternating current stimulation (tACS) in a cohort of bvFTD patients (NCT04425148).

While there are currently no disease-modifying treatments available for FTD, the rapid expansion of knowledge in pathogenesis, genetics, neuropathology, and neuroimmunology across the main variants of FTD and the advances in gene therapies have opened up exciting possibilities for breakthrough advances in this family of disorders. We are on the cusp of a new era of treatment and management for frontotemporal dementia spectrum disorders.

Supplementary Information

Below is the link to the electronic supplementary material.

Funding

This study was supported by NIH/NIA P30AG062422 and P01AG019724 (BM) and the Rainwater Charitable Foundation.