Oxytocin
Oxytocin is a neuropeptide that is important for prosocial behavior and improves empathy, emotions, trust and cooperation, while, simultaneously, decreasing aggression and apathy. Aversive behaviors are notable in a subtype of FTD, behavioral variant (bvFTD), as well as AD and other dementias, and can pose an immense hardship on caregivers, as well as impacting self-care, and personal relationships.  
The  hypothalamic -pituitary-adrenal (HPA) axis, part of the neuroendocrine system involved in basal homeostasis, diurnal circadian rhythms and stress responses, may contribute to the development of AD \cite{Watermeyer_2021}. Oxytocin is produced in the hypothalamic bilateral supraoptic (SON), paraventricular (PVN), and accessory nuclei, primarily in magnocellular neurons \cite{Grinevich2020}. In addition, these oxytocin-producing neurons extend into the pituitary, amygdala, nucleus accumbens and medial prefrontal cortex, regions likewise affected in neurodegenerative diseases  \cite{Diodati2012}.  Oxytocin is released either systemically (via the pituitary gland) or into the CNS. However, while TDP-43 pathological inclusions were not identified in the SON and PVN  in either LBD, AD, or FTLD \cite{Diodati2012}, the brain regions in which oxytocinergic project into (pituitary, amygdala, nucleus accumbens and medial prefrontal cortex),  were not investigated in this study and, as these regions are important for TDP-43 pathology, such as the amygdala \cite{Makkinejad2019},  it is conceivable that there are altered levels of oxytocin in these brain regions in neurodegenerative conditions.  In support, elderly nursing home residents, with a varying degrees of dementia as determined by clinical and cognitive performance tests, but without a diagnosis of AD or FTLD, TDP-43 inclusions were identified in the amygdala ( 43.7% , stage 1), hippocampus or entorhinal cortex (40%, stage 2) and  temporal and frontal cortices (16.3%, stage 3)\cite{Nag_2017}
Twenty-three patients diagnosed with probable bvFTD were enrolled in a double bind, placebo controlled trial of intranasal oxytocin (0,  24, 48, or 72 IU)  (NCT01386333),  administered twice weekly for 1 week and followed via telephone assessments after 1 week washout period \cite{Finger2015}.  The authors found that all three doses of oxytocin were well tolerated and a significant improvement was observed, in a dose-related manner, on the FBI Apathy subscale, with the greatest improvement obtained at 72 IU. However, the study was limited by the small number of participants and short duration of follow-up time, and, additionally, in follow up studies determining the potential modulation of TDP-43 by oxytocin would be very interesting.
 
Modulation of TDP-43 phosphorylation
preclinical IGS-2.7 benzothiazole-based CK-1δ inhibitor  
The TDP-43 protein is susceptible to a variety of post-translational modifications which include hyperphosphorylation at the serine 409/serine 410 site, ubiquitination and cleavage into  C-terminal TDP-43 fragments (CTFs) by caspases or calpain at miscellaneous amino acids residues \cite{Wobst_2017}. These alteration culminate in the depletion of nuclear TDP-43 and its translocation into the cytoplasm where TDP-43 aggregates tend to form at the glycine rich prion-like domain (PrLD) of the protein \cite{Wobst_2017} 
The phosphorylation of TDP-43,  which occurs widely in brain inclusions of ALS and FTD/FTLD-TDP patients,  may represent a targetable modification. Indeed several protein kinases that induce phosphorylation of TDP-43 have been identified, with protein casein kinase-1 (CK-1) in particular being shown to phosphorylate the protein at 29 different sites in vivo, 18 of which are within the C-terminal glycine-rich region involved in aberrant cytosolic compartmentalization and aggregation \cite{Liachko_2013}.  CK-1-dependent phosphorylation of TDP-43 is induced during cellular stresses and the inhibition of CK-1 may have therapeutic value in neurodegenerative disorders \cite{Gu2020}. In virtually all TDP-43 proteinopathies, serine 409 and serine 410 sites are phosphorylated,  triggering TDP-43 monomers to oligomerize a process that can become irreversible which triggers aggregate formation and cellular degeneration \cite{Neumann_2009}
In ALS the upper and lower motor neurons in the CNS and spinal cord degenerate and die and TDP-43 plays a major role in both sALS and fALS. In a preclinical study , the hyperphosphorylation of TDP-43 was targeted with IGS-2.7 in TDP-43 (A315T) transgenic mice and human lymphoblasts derived from sALS patients.  In mice, IGS-2.7 delayed weight loss,  increased motor neurons survival in lumbar anterior horn, decreased inflammation as shown by a decrease in astrocyte and microglia immunoreactivity using GFAP and Iba-1 staining, respectively and decreased the level of TDP-43 phosphorylation in TDP-43 transgenic mice to that of wildtype animals \cite{Martínez-González2020}. In the human sALS lymphocytes, treatment for 24 hours with 5 µM of IGS-2.7 decreased phospho-TDP-43 as well as its cytosolic mislocalization. These results suggest that  IGS-2.7  has neuroprotective activity which may have translational importance should future clinical trials be conducted on ALS  or other patients with neurodegenerative diseases. 
    
 Immune Modulation and TDP-43
Tocilizumab (ClinicalTrials.gov Identifier: NCT0246996
Tocilizumab is a monoclonal antibody which is anti-inflammatory and acts as a competitive inhibitor of  interleukin-6 (IL-6), and it prevents IL-6 from binding to its receptor (IL-6R). This prevents the pro-inflammatory IL-6 from signaling to mediators which in turn trigger inflammation through B and T cells \cite{Khalid2017}.  Inflammation is known to play a role in motor neuron diseases such as ALS. In a randomized phase II, double-blind, multicenter, placebo-controlled trial of Tocilizumab (also known as Actemr) in ALS subjects (TCZALS-001 clinicaltrials.gov  NCT02469896 ), tocilizumab was tested for efficacy in ALS patients from the ages of 18-75 in a study that included both genders. The trial did not exclude patients that were receiving a stable dose of riluzole, those not taking riluzole, or women of child-bearing age, thus having broader implications. Primary endpoints were the Rates of All-cause Mortality, safety and tolerability.   Secondary endpoints were efficacy as determined by the mean change in ALSFRS-R total score, Rate of Decline in Slow Vital Capacity (SVC),  change in  Peripheral Blood Mononuclear Cells  and cytokine levels.  Patients (n=14, treatment group, n=8 placebo) received 8mg/kg of IV tocilizumab every 4 weeks for 3 months via IV infusion.  At this time, both the treatment and placebo group had no difference patients lost to death, while rate of decline in ALSFRS-R did not have a significant p-value and Rate of Decline in Slow Vital Capacity (SVC) and fold change in cytokine markers was indicated as superiority that is not specified. The results are not yet published and TDP-43 was not measured biomarker in this study.