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Frontotemporal Dementia - What Are The Therapeutic And Diagnostic Challenges?

Frontotemporal dementia (FTD) is the third most prevalent form of dementia in contemporary culture. It is a serious public health concern.

However, there are presently few medicines designed for FTD in clinical trials.

Investment in tau therapies has historically lagged somewhat because attention has been focused on the proteotoxicity of other aggregated proteins such as amyloid-beta (Aβ) in Alzheimer's disease.

Despite the fact that tau has long been recognized as the primary component of neurofibrillary tangles (NFTs) in FTD, mutations in the microtubule-associated protein tau (MAPT) are responsible for a subset of FTD cases.

Furthermore, the majority of genetic discoveries in FTD have been made relatively recently, and they include genes like progranulin (GRN) and Tar DNA-binding protein (TARDBP), which had little prior neurological literature. Genetic discoveries are frequently a guiding force in neurodegenerative research in the identification of therapeutic targets.

The encoded protein TAR DNA-binding protein of 43 kDa (TDP-43) has been identified as a major component of the ubiquitinated inclusions that characterize approximately half of all FTD cases.

However, only 12 publications on this protein existed prior to this discovery. For instance, mutation of the gene TARDBP is pathogenic in amyotrophic lateral sclerosis (ALS), and only 12 publications on this protein existed before this discovery.

What Is Frontotemporal Dementia?

A set of neurological conditions that predominantly affect the frontal and temporal lobes of the brain are together referred to as frontotemporal dementia. These brain regions are often linked to personality, conduct, and language.

Parts of these lobes decrease in frontotemporal dementia (atrophy). Depending on which section of the brain is injured, different signs and symptoms may appear. Some patients with frontotemporal dementia have major personality changes, being impetuous, emotionally cold, or socially inappropriate, while others lose the capacity to speak clearly.

Frontotemporal dementia might be mistaken for Alzheimer's disease or a mental health issue. However, frontotemporal dementia often strikes younger people more often than Alzheimer's disease does. Frontotemporal dementia may start at any age, but it often starts between the ages of 40 and 65. In between 10% and 20% of instances of dementia, FTD is the underlying cause.

Current Pharmaceutical Intervention In FTD

The reason for their usage is based on their effectiveness in treating other neurodegenerative illnesses or mental problems with comparable behavioral characteristics.

The present trial treatment for FTD is centered on symptom management and does not address causation. Only a few tiny, double-blind, placebo-controlled clinical studies have been conducted.

Some research suggests that serotonin reuptake inhibitors or selective serotonin reuptake inhibitors may generally be helpful for certain individuals, especially those with behavioral disorders. Drugs that target the cholinergic system and antipsychotics seem to be generally unsuccessful.

Furthermore, the greatest clinical research to date revealed no benefit for patients from taking memantine despite its off-label usage to treat FTD. As a result, there is no effective therapy for FTD, and the development of innovative treatments that focus on the underlying reasons is urgently needed.

Clinical FTD And Pathological FTLD

FTD/FTLD Clinical And Pathological Heterogeneity

The clinical term "FTD" refers to a group of symptoms brought on by frontal and temporal lobe degeneration. Even though this condition was once thought to start before the age of 65, most pathologically confirmed patients don't show symptoms until they are older than 65.

In FTD, a number of symptoms that are linked to particular regional atrophy might manifest. Changes in personality and conduct are hallmarks of behavioral-variant frontotemporal dementia (bvFTD), and patients exhibit disinhibition and apathy (lack of interest in obligations) (demonstrating socially inappropriate behavior).

Changes in language function are a feature of two syndromes: semantic dementia (SD) and progressive non-fluent aphasia (PNFA). In contrast to PNFA, where language comprehension is unaffected but speaking is laborious and grammatically incorrect, SD manifests as anomia and poor understanding.

These three variations often coexist, especially as the illness progresses and atrophy spreads further. Corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome, which were first classified as atypical movement diseases but commonly exhibit characteristics of bvFTD or PNFA, are also included within the FTD umbrella.

Similar to this, those who exhibit classic bvFTD/PNFA symptoms at first may also have motor difficulties. bvFTD typically includes a motor dysfunction component, similar to that of motor neuron disease (FTD-MND). This leads to a range of overlapping disorders as the clinical picture of FTD.

Heterogeneity Of FTLD-Tau

The TDP-43 or tau inclusions themselves, which come in a range of subtypes, demonstrate the further intricacy of FTLD. Tau lesions may be further separated into FTLD-tau, which includes diffuse NFT dementia with calcifications, sporadic multisystem tauopathy, Pick's disease, progressive supranuclear palsy, and argyrophilic grains disease (DNTC).

Most FTLD-tau patients are by far characterized by PSP, CBD, and PiD. The cornerstone of the evidence supporting tau's participation in non-familial illness, FTD and Parkinsonism connected to chromosome 17 (FTDP-17t), are caused by mutations in MAPT in addition to these sporadic disorders.

Although the form of the inclusion varies across disorders, each of these pathologies is defined by the emergence of hyperphosphorylated tau that self-aggregates into fibrillar paired helical filaments (PHFs) and subsequently neurofibrillary tangles (NFTs). Exon 10 of MAPT, which codes for one of the four "repeat" sections that serve as microtubule binding domains, is responsible for some of this variability.

With the exception of exon 10, "3R" tau, the deposited tau in PiD is round in shape and cytoplasmic. It is also distinct in that it typically only includes 3 repetitions. The majority of PSP and CBD inclusions are made up of tau that contains exon 10 and all four repeat regions, or "4R" tau.

Heterogeneity Of FTLD-TDP

In 2006, TDP-43 was shown to be a significant contributor to inclusions in instances of FTLD with ubiquitinated aggregates, which account for around 50% of FTLD cases. This discovery gave birth to the term FTLD-TDP.

There are four FTLD-TDP subtypes, each of which has a unique TDP-43 pathological shape and distribution.

Type A is characterized by a propensity for layer 2 of the cortex to contain the majority of aggregated, juxtanuclear, neuronal cytoplasmic inclusions (NCI) and short dystrophic neurites (DN), Type B by fewer NCI and DN that are dispersed more widely throughout the cortex, Type C by long DN in cortical layer 2, and Type D by the appearance of neuronal intranuclear inclusions.

Cytoplasmic aggregation as NCI or DN is the distinguishing feature of sporadic FTLD-TDP as Type D is often identified in uncommon, familial cases with mutations in the valosin-containing protein (VCP) gene.

Additionally, the nuclear TDP-43 expression is lost as a result. TDP-43 is likewise shortened and hyperphosphorylated in FTLD-TDP, resulting in 25 kDa C-terminal fragments that seem to be enriched in inclusions compared to the N-terminus.

As a result, TDP-43 neuropathology manifests as a variety of different entities and clinical subtypes, much as FTLD-tau. Neuropathology does not always reveal the toxicity of TDP-43 and tau in illness, and strong genetic evidence is necessary to support the involvement of both in disease.

Hypothetical Therapeutic Strategies For FTLD-Tau

The development of treatment strategies for FTLD-tau is significantly hampered by the crucial toxicity-related difficulties. Presently, speculative therapy approaches are based on a very complicated toxicity that is not completely understood.

None of the hazardous pathways discussed above has so far emerged as the front-runner in the race to discover new treatments. Therefore, despite the fact that there are several viable therapeutic options, no one candidate stands out as the best option for therapeutic intervention.

According to the gain of function aggregate toxicity model, determining the poisonous species will have a significant impact on future direction. For instance, the harmful effects of big aggregates could be alleviated by the elimination of NFTs using a pharmaceutical "tangle buster" of sorts.

However, if fibrillar or aggregate forms of tau serve as the earliest compensatory mechanisms to sequester more upstream oligomeric forms, then it's possible that eliminating this "toxic sink" might be more detrimental than helpful since it would prevent the toxicity associated with tangles.

In contrast, tiny chemical inhibitors of oligomer or fibrillization production may stop the accumulation of all hazardous species at their source. Phase III studies for bvFTD are beginning using LMTX, a modified version of the aggregation inhibitor methylthionine chloride (methylene blue).

The elimination of pathogenic tau may be accomplished using different treatment approaches that target toxic species in a more targeted manner. Immunotherapy has been shown in a number of cases to suppress tau pathology and enhance phenotypic in transgenic models of tauopathy.

The success of this strategy's use in treating human illness will depend on precisely identifying the species—or epitope of the species—that is harmful. Many epitopes may need to be targeted if there are multiple hazardous species, which is highly conceivable given the variety of alterations that tau goes through.

Therapeutic Strategies For FTLD-TDP

Current knowledge of TDP-43 proteinopathy or even TDP-43 endogenous function is poor, and therefore limits expectations for treatment outcomes. However, restoration of nuclear function and a decrease in the production or an increase in the clearance of aggregates, however, are logical arguments that are possible.

Aiming to limit expression and subsequently aggregation formation, as suggested for tau, is a conceptual non-starter since loss of TDP-43 has major ramifications for cellular integrity. One would speculate that maintaining nuclear function and avoiding cytoplasmic buildup would be advantageous.

It is crucial to simply describe the method by which loss of nuclear function takes place in this circumstance. Targeting aggregated material would logically give relief from both nuclear loss and any direct cytotoxicity if it is supported by cytoplasmic aggregate sequestration. At least dimebon and methylene blue, two drugs that were effective in Phase II clinical trials for AD, are at least capable of lowering TDP-43 aggregation in vitro.

The biology of TDP-43 is probably still too poorly understood for TDP-targeted therapeutics to be a practical short-term objective.

A better understanding of the pathways susceptible to treatment could result from advances in fundamental function knowledge and the creation of more sophisticated research tools, such as patient-specific induced pluripotent stem cells (iPSCs) and animal models recapitulating TDP-43 disease.

Anacardic acid has been shown to potentially modify insoluble TDP-43 species when iPSCs are utilized to assess therapeutic candidates.

An elderly man placing a finger on the side of his head
An elderly man placing a finger on the side of his head

Progranulin As An Unbiased Therapeutic Candidate

The existence of several disease subgroups raises a bigger concern for both tau and TDP-43 focused therapy (for example, CBD, PSP, and PiD in FTLD-tau and type A-D for FTLD-TDP). Because each illness has unique pathophysiology, so too could the processes that cause them to arise.

For each, would a distinct treatment approach be necessary, or are they all supported by the same main mechanism? Similar questions are raised in the realm of cancer, where the best paradigms for treating breast cancer rely on the specific form of cancer that is present.

Therefore, a treatment that has a wider potential use and is independent of the pathophysiology could be more effective. Such a target could be made available by the identification of loss-of-function mutations in progranulin as the root of TDP-43 proteinopathy.

Increasing levels of the possibly neuroprotective progranulin is a theoretically straightforward treatment compared to the difficulty of recognizing toxicity caused by tau and TDP-43. Recently, TNF and sortilin receptors that bind progranulin have recently been discovered, and they represent potential druggable targets.

In fact, iPSCs generated from progranulin mutant carriers restore extracellular progranulin levels to wild-type levels when sortilin-mediated endocytosis is inhibited by small molecules. Additionally, drugs including chloroquine, bepridil, and amiodarone have been shown to stabilize intracellular and subsequently extracellular progranulin by alkalizing intracellular compartments, upregulating progranulin levels via increased transcription (suberoylanilide hydroxamic acid).

Finally, a genome-wide association investigation of GRN mutant carriers revealed protective genetic variations of the transmembrane protein TMEM106b. These variations affect plasma progranulin levels, postpone the age of start or lessen penetrance in GRN mutation carriers, and suggest that TMEM106b or associated pathways are potential therapeutic targets.

Transgenic models of tauopathy/FTLD-tau are an apparent possibility for in vivo testing of these or other potential progranulin treatments for neurodegenerative illnesses other than FTLD-TDP.

People Also Ask

What Are The First Signs Of Frontotemporal Dementia?

Changes in personality and conduct, a gradual loss of speech and language abilities, and sometimes physical signs like tremors or spasms are some of the symptoms that commonly appear between the ages of 40 and 65. FTD often becomes worse with time.

What Is The Main Cause Of Frontotemporal Dementia?

A series of illnesses known as frontotemporal dementia (FTD) or frontotemporal degenerations are brought on by the gradual loss of nerve cells in the frontal or temporal lobes of the brain (the regions behind your ears).

What Age Does Frontotemporal Dementia Start?

FTD is uncommon and tends to manifest earlier in life than other types of dementia. About 60% of FTD patients are between the ages of 45 and 64. Since FTD is progressive, symptoms progressively worsen over time.

What Is A Common Treatment For Frontotemporal Dementia?

Certain antidepressant classes, such as trazodone, may lessen the behavioral issues of frontotemporal dementia. Some people have also found success with selective serotonin reuptake inhibitors (SSRIs), such as citalopram (Celexa), paroxetine (Paxil), or sertraline (Zoloft).

Conclusion

If the results of AD clinical trials in symptomatic individuals can be extrapolated to FTLD, it will be crucial to be able to employ biomarkers to detect certain subtypes of underlying FTLD-TDP or FTLD-tau in early stage illness (whether prodromal or asymptomatic stages).

The intricacy of the condition creates additional complications. The predominant notion at the commencement of investigations concentrating on tau was that elimination of NFTs would result in a therapeutic breakthrough. Years later, the idea appears simplistic, and tauopathies are now considered to be exceedingly complicated diseases with a wide variety of biochemical and structural tau changes that may all, in some way, contribute to the death of neurons via as-yet-unrecognized processes.

Furthermore, both in the creation of harmful tau species and in their impact, such processes could not be a single linear mechanism. It is certain that further research will uncover even more intricacy, and the same is likely to be true with FTLD-TDP.

Although this indicates that our understanding of neurodegenerative pathways is growing, it also reveals that these illnesses are complex and multi-mechanistic, making them challenging for present technology to treat.

In this regard, it's probable that we'll also have to deal with a "technology gap" in addition to the "knowledge gaps" mentioned above. Delivery of a single pharmaceutical compound targeted at a single process or pathway to the entire brain may be oversimplified in comparison to the myriad biochemical changes in tau, TDP-43, and other cellular processes, all of which occur in different cell types at various stages between healthy and degenerating.

It could be necessary to develop innovative technologies or use many different therapy modalities at once. In the meanwhile, caution must be used in choosing therapies since funding for therapeutic intervention studies won't last forever if methods based on speculative pathways consistently fail in clinical trials.

About The Authors

Suleman Shah

Suleman Shah - Suleman Shah is a researcher and freelance writer. As a researcher, he has worked with MNS University of Agriculture, Multan (Pakistan) and Texas A & M University (USA). He regularly writes science articles and blogs for science news website immersse.com and open access publishers OA Publishing London and Scientific Times. He loves to keep himself updated on scientific developments and convert these developments into everyday language to update the readers about the developments in the scientific era. His primary research focus is Plant sciences, and he contributed to this field by publishing his research in scientific journals and presenting his work at many Conferences. Shah graduated from the University of Agriculture Faisalabad (Pakistan) and started his professional carrier with Jaffer Agro Services and later with the Agriculture Department of the Government of Pakistan. His research interest compelled and attracted him to proceed with his carrier in Plant sciences research. So, he started his Ph.D. in Soil Science at MNS University of Agriculture Multan (Pakistan). Later, he started working as a visiting scholar with Texas A&M University (USA). Shah’s experience with big Open Excess publishers like Springers, Frontiers, MDPI, etc., testified to his belief in Open Access as a barrier-removing mechanism between researchers and the readers of their research. Shah believes that Open Access is revolutionizing the publication process and benefitting research in all fields.

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