Treatments - Frontotemporal Dementia

A review of current, as well as treatments currently under investigation
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Common therapeutic methods in the treatment of Frontotemporal Dementia include antidepressant medications, such as serotonin reuptake inhibitors (SSRI), and Neuroleptics [1] . Cholinesterase inhibitors initially were shown to improve behaviour symptoms, however over time these drugs worsen the symptoms of FTD [2]. Current treatments seek to address the behavioural side effects that, along with impaired memory and language abilities, are the result of frontotemporal lobar degeneration. These behaviour side effects are varied across the three subtypes of FTD. The first and most common, the behavioural variant of FTD (bvFTD) is accountable for 50% of FTD cases. The symptoms of bvFTD include disinhibition, lack of empathy, apathy and social and emotional changes [1] .The other subgroups are progressive non-fluent aphasia ( PNFA ), and semantic dementia (SD) which are both characterized by gradual deterioration of language. There are currently no FDA-approved medications specifically indicated for the treatment of Frontotemporal Dementia (FTD). Further, there are no treatments that combat the pathology of the disease rather than the symptoms that arise from these pathologies.

1. Current Treatments

Behavioral Variant Frontotemporal Dementia (bvFTD) is the most common form of frontotemporal dementia, and is categorized by 6 characteristic cognitive and behavioral symptoms. The International behavioral variant FTD consortium (FTDC) defines this core symptoms as the following: early apathy, behavioral disinhibition, perseverative or compulsive behaviors, and loss of sympathy or empathy, as well as, hyperorality, diet changes, and a dysexectuive neuropsychological profile [3]. Apathy, a lack of motivation to pursue previously pleasurable activities due to inertia, or a difficulty in continuing current activities without prompting, is often confused as a symptom of major depressive disorder ( MDD ). Further, behavioural disinhibition is a hallmark symptom of bvFTD. Individuals can act impulsively, engage in criminal activity, or display heightened aggression or innapropriate sexual behaviour [3] . These outbursts can be stressful to caretakers, as well as potentially cause legal problems for the individual with bvFTD. Psychiatric medications are prescribed to individuals with bvFTD in order to manage behavioural symptoms, as well as improve quality of life for the caregiviers. Huey and his team employed a meta-analysis to gauge the effectiveness of antidepressant medications in treating FTD, and neurotransmitter deficencies across a variety of studies, including uncontrolled and open label studies. They found that while the acetylcholine system was not affected, the serotonin and dopamine systems were impaired in patients with FTD [4]. Due to bvFTD's similarity of symptoms with major depressive disorder, as well as serotonin deficencies, antidepressant medications such as SSRI's are widely prescribed to treat the behavioral symptoms associated with FTD and bvFTD [3].


1.1 Why do current treatments work to treat behavioral symptoms

Voxel based analysis of Positron Emmision Tomography scanning of tagged 5-HT2A receptors show notable differences between healthy controls and FTD patients. Individuals with FTD had statistically significant reductions of these serotonin receptors in the orbitofrontal cortex, frontal medial cortex, and cingulate cortex [5]. Similar reductions of 5-HT2A receptors in the dorsolateral cortex are observed in individuals with MDD. Due to similar symptomology in ftd and mdd, we can conclude that serotinergic abnormalities in the aforementioned orbitofrontal, frontal medial, and cingulate cortices May be responsbile for the charateristic and similar behavioural and cognitive abnormalities in FTD and MDD . SSRI were found to be affective in treating disinhibition, apathy, carbohydrate cravings, and compulsive behaviors in open label-studies [4]. However, Deakin et al. employed a double blind, placebo controlled study of SSRI efficacy and found that after 6 weeks there was a slight increase of cognitive symptoms, and no improvement in behavioral symptoms [6] . This suggests that the effectiveness of SSRI medications in treating behavioural symptoms of FTD may be the result of the placebo effect.

What is the Placebo effect
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1.2 Why do current treatments not halt the progression of the disease

Current pharmacological interventions are effective in treating many of the behavioral symptoms of FTD in open label studies, but show no evidence of neuroprotecting [3]. Frontotemporal dementia is the result of degeneration of the frontal, insular, and temporal brain regions. More specifically bvFTD degneration begins in the orbitofrontal cortex, anterior cingulate and insular cortices. As the disease progresses, atrophy continues laterally and dorsally in the frontal lobes [7]. These atrophies lead patients with bvFTD to suffer behavioral changes as well cognitive symptoms such as frontal executive dysfunction [8]. Therefore an effective pharmacological treatment should combat atrophy in the frontal temporal areas targeted in FTD. Although SSRI's address the loss of serotonergic receptors in the orbitofrontal cortex, frontal medial cortex, and cingulate cortex there is more to the pathology of FTD than a lack of this monoamine [5]. There is no evidence that SSRI’s have any effect on the atrophies characteristic to FTD, therefore they are not effective at halting the progression of the disease.

2. Types of FTD

The neuropathology responsible for FTD is heterogeneous, however each of these pathologies led to frontotemporal lobar degeneration (FTLD). FTLD refers to selective neurodegeneration of the frontal and temporal lobes as well as atypical aggregations of certain protien in neurons as well as glia. In order to treat the pathology of FTD the factors that cause FTLD must be understood [9]. There are currently three neuropathologic subtypes of FTLD. These groupings are based on the molecular abnormality, linked to associated genes, which are thought to cause the degeneration. Most FTLDs are the result of the first two categories: FTLD-tau or FTLD-TDP, however approximately 15% of cases are the result of uncommon FTLD subtypes. The remaining categories are within the FTLD-FUS category and all share Fused in sarcoma (FUS) accumulations. These categories are aFTLD-U, BIBD and NIFID, but will be considered part of one group due to central FUS pathology, and association with the FUS gene . The vast majority of FTLD cases can be classified as FTLD-tua, FTLD-TDP or FTLD-FUS, each class shares common pathologic proteins, and similar disease mechanisms [9].

Figure A: Nomenclature for the classes of FTD as proposed by Mackenzie et. Al.
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[9]


2.1 FTLD - tau

FTLD-tau, comprises approximately 40% of FTLD cases and is characterized by tau cellular inclusion bodies [9] [10]. These inclusion bodies are made of ubiquanated and hyperphosphorylated microtubule-associated binding protein Tau, or MAPT [10]. MAPT gene mutations, on the 17th chromosome, have been associated with early onset FTD, as well as with the behavioral variant FTD. There are a variety of pathogenic MAPT mutations, however for the most part they are clustered around the 9th through 13th exon. This region has been identified as a microtubule binding region, therefore mutations affect Tau's ability to stabilize microtubules [11]. Mutations of tau can also lead to inappropriate phosphorylation of the tau protein, which interferes with microtubule stabilization. Finally, some mutations of MAPT increase the amount of free tau protein found in the cytoplasm, which encourages tau aggregation. In 2011, Astrid Sydow and her team published a paper investigating the effects of mutated tau proteins on learning and memory, hallmark symptoms of dementia. Specifically, this paper investigates the FTDP-17 mutation ΔK280 in pro-aggregate and anti-aggregate formations. The proaggregate mutant has mutation ΔK280 which promotes the formation of β-structure and the aggregation of Tau. The antiaggregate form contains the ΔK280 mutation as well as two additional mutations which prevent β-structure formation. Pathologies of tau including hyperphosphorylation, synaptic loss, neuronal degeneration, and co-assembly of human and mouse Tau was observed in the pro-aggregate form of the mutation. These pathologies lead to impaired learning and LTP in the pro-aggregate mice. LTP and memory, but not neuronal loss, was recovered through the suppression of the pro-aggregate mutation, indicating that the proaggregant ΔK280 may have induced other cell events that may have acted to poison the normal mouse Tau [12].

Figure B: Learning vs Time chart of mice with pro and anti aggregate form mutations

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[12]

This chart shows that mice with anti-aggregate on and off, control mice, as well as pro-aggregate off mice all show normal abilities to learn. The pro-aggregate on mouse has impaired ability to learn.


2.2 FTLD - TDP

FTLD-TDP makes up more than 50% of FTLD cases and is characterized by inclusions, which are negative for tau proteins, but positive for Ubiquitin [13]. This ubiquitinated protein was identified as TAR DNA binding protein 43 (TDP-43) [14]. TDP-43 is, normally located inside the cell nucleus, however in its mutated state it is implicated in most cases of FTLD with upiquitin positive, tau negative inclusions. [16]. Tdp-43 is also involved in most cases of spontaneous amyotrophic lateral sclerosis (ALS)[13]. Furthermore TDP-43 positive inclusions are found in 25-50% of Alzheimer’s Disease (AD) cases, further supporting its link to neurodegeneration [15]. In a recent study, Igaz et al observed the role of abnormal TDP-43 aggregates in the brain and spinal chord and how they may contribute to ALS and FTLD. They did this by creating a hTDP-43-ΔNLS transgenic mice with a faulty nuclear localization signal (NLS). High expressors with high levels of exogenous hTDP-43 experienced gradual loss of neurons in the Dentate gyrus of the hippocampus and neocortex after one month of life. Low expressors showed no detectable neuronal loss at 3 - 4 months, therefore implicating cytoplasmic TDP-43 with neuron death [16]

2.2a PRGN and FTLD - TDP

The Progranulin gene is located on the 17th chromosome and codes for progranulin, a growth factor associated with the resolution of inflammation, as well as wound healing [10]. Heterozygous mutation of the GRN gene leads to disease states due to haploinnsufficeny [10]. Individuals with mutations of GRN display FTLD-TDP pathology in the form of intranuclear inclusions of TDP-43, suggesting the GRN gene is linked to FTD [17]. In 2006 Cruts et al, investigated the relationship between FTD with upiquitin inclusions (FTDU) and the regions surrounding the MAPT gene on the 17th chromosome. They demonstrated through the analysis of FTD patients in Belgium, that FTDU-17 , later known as FTLD – TDP, is caused by mutation in the GRN or PGRN gene [18].


2.3 FTLD - FUS

The final category, FTLD-FUS, includes the remaining 5-10% of FTLD cases. This class is composed of a collection of subtypes that contain inclusions that are tau and TDP negative but ubiquitin positive. These accumulations, found within neurons and glia tag positive for fused in sarcoma (FUS) protein. The FUS gene is on the 16th chromosome and codes the FUS protein ususally responsible for binding to DNA and RNA to regulate DNA repair, transcription, and cell localization in addition to RNA splicing [10]. Interestingly, most FTLD-FUS cases are caused by a spontaneous, yet still unknown, mutation [9].

3. Drugs in development

In 90-95% of FTLD cases abhorrent tau, TDP-43, and TDP-43 related proteins can be held responsible. Therefore, in 2011 a conference called ‘FTD, the Next Therapeutic Frontier’ was held in attempts to accelerate the development of novel treatment for FTD. The conference chose two critical protein families in which to focus their efforts [10]. These families were: Tau and PGRN.


3.1 Target Molecule: Tau

Tau proteins were chosen due to its relevance in the pathology of FTD as well as AD. As demonstrated by Sydow, the main disease mechanisms of Tau are aggregation, and loss of microtubule stabilization through mutation or hyperphosphylation [12].

3.1a GSK Inhibitor

The phosphorylation of tau has been linked to the destabilization of microtubules thus causing disease states such as FTD. There is evidence that glycogen synthase kinase 3-beta (GSK3) is responsible for the phosphorylation of tau therefore making it an excellent target for the prevention of tauopathies in AD and FTD [19]. GSK inhibitors therefore should prevent the phosphorylation of tau and work to treat FTD. Lithium and NP12 are currently being explored as GSK inhibitors for the treatment of corticobasal degeneration (CBD) and progressive supranucleur palsy (PSP) respectively. CBD and PSP, and [[|ALS are a related group of diseases to FTD [10].

3.1b Microtubule Stabilizer

Microtubules are essential for the movement of organelle as well as proteins and vesicles within a cell, however tauopathies in AD , ALS and other neurodegenerative diseases disrupt this process. Davunetide is a very small protein, derived from activity dependent neuroprotective protein (ADNP) and has demonstrated neuroprotective activity. Davenetide, also available as AL-108 ,a nasal spray, protects microtubule stability from exogenous damage [20]. Davunetide is currently being investigated as a treatment for PSP, a disease closely related to FTD [10].

3.1c Inhibits Aggregation

Sydow et al, demonstrated that tau aggregations lead to decreased learning and memory, as well as possibly poisoning neighboring healthy tau proteins to lead to neurone death [12]. Methylene Blue has been reported to inhibit tau aggregations in vivo as well as in vitro. Methylene blue decreased the total amount of tau aggregates, tagged by AT8 in the diagram below, as well as decreased the ratio of AT8 to total tau. Larger doses of methylene blue (MB) further decrease total AT8 therefore indicating a reciprocal relationship between MB and tau aggregation [21]

Figure D: Tau aggregates tagged with AT8 vs. amount of methylene blue used in treatment
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[21]

This image demonstrates that a 1mg/kg/day application of methylene blue is more effective than a smaller dose, or treatment with water, in reduced tau aggregations.


3.2 Target Molecule: PRGN

GRN and PRGN mutations have been linked to TDP-43 pathology, as well as to tau negative- ubiquitin positive inclusion pathologies in the FTD – TDP spectrum [17] [18]. Particularly, GRN mutations are a major cause of FTLD with ubiquitin inclusion bodies [22]. Furthermore, mutations of GRN follow a haploinsufficeny model, by which a heterozygous mutant would experience disease state [10]. Finally, due to recent evidence that increasing levels of the protein progranulin, a anti inflammatory growth factor, is beneficial to neuron health treatments that increase levels of progranulin for the treatment of a variety of diseases [22]. Current potential therapeutic targets for progranulin include compounds that : increase PGRN expression, and increase PGRN levels

3.2a Increase PGRN expression

One method to increase levels of progranulin protein is to increase the translation and transcription of the gene. One method of achieving this would be to increase the ability of translational machinery to access the GRN gene. Suberoylanilide hydroxamic acid (SAHA), is a FDA- approved histone acetylase inhibitor which has been shown to increase GRN mRNA and progranulin levels in a dose dependent manner. Therefore, SAHA is currently being investigated as a target for the treatment of FTD and other neurodegenerative diseases [23].

3.2b Increase PGRN levels

In 2011, Capel et al demonstrated that a more alkalized intracellular space led to upregulation of progranulin. Although the mechanism behind this relationship is undetermined alkalizing compounds are being considered as a treatment for diseases, such as FTLD [24]. Compounds such as Bepridil, Amoidarone, and Chloroquine are FDA- approved alkalizing compounds currently under investigation for their ability to increase progranulin levels [22].

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