OPTIMIZED DOSAGE OF DIAMINOPHENOTHIAZINES IN POPULATIONS

Abstract

The present invention relates to novel dosage regimens for leucomethylthioninium compounds that maximize the proportion of subjects in whom the MT concentration will exceed the concentrations at which therapeutic efficacy for the treatment of neurodegenerative disorders such as Alzheimer's disease and frontotemporal dementia can be achieved, while maintaining a desirable clinical profile. Dosage units containing LMT and other compositions are also provided.

Description

OPTIMIZED DOSAGE OF DIAMINOPHENOTHIAZINES IN POPULATIONS Field of Invention The present invention relates in general to optimized dosage regimens of diaminophenothiazines in the treatment or prophylaxis of neurodegenerative disorders, particularly within populations of individuals who have different pharmacokinetic responses. Background of the Invention Aberrant protein aggregation is believed to be the proximate cause of numerous disease states, which can manifest as neurodegeneration, clinical dementia, and other pathological symptoms. In general, aberrant protein aggregation is that which originates from an induced conformational polymerization interaction, that is, one in which a conformational change of the protein, or in a fragment of it, gives rise to the bonding and tempered aggregation of additional protein molecules (precursors) in a self-propagating manner. Once nucleation begins, an aggregation cascade can occur involving the induced conformational polymerization of additional protein molecules, leading to the formation of toxic product fragments in aggregates which are QCQ«nn / C7n7 / e / YiAi substantially resistant to further proteolysis. For example, certain dementia conditions can be characterized by a progressive accumulation of intracellular and / or extracellular deposits of proteinaceous structures such as β-amyloid plaques and neurofibrillary tangles (NFTs) in the brains of affected patients. The appearance of these lesions is strongly correlated with pathological neurofibrillary degeneration and brain atrophy, as well as with cognitive impairment (see, for example, Mukaetova-Ladinska et al., 2000). Current approved treatments for Alzheimer's disease include acetylcholinesterase inhibitors (AChEIs) and the N-methyl-D-aspartate receptor antagonist memantine. These are symptomatic and do not address the underlying disease pathology. Therapies targeting amyloid pathology have thus far shown no success in late-stage clinical trials (Geerts et al., 2013; Mullane and Williams, 2013). According to a recent Lancet Committee on Neurology report, an effective treatment for AD is perhaps the greatest unmet medical need facing modern medicine (Wnblad et al., 2016), not least because the global economic cost of dementia is estimated by QCQ«nn / C7n7 / e / YiAi be $818 billion dollars, or 0.65% of global gross domestic product (Alzheimer's Disease International, 2015). NFTs (the pathology discovered by Alois Neurofibrillary tangles (PHFs) in Alzheimer's disease (Alzheimer, 1907) are composed of paired helical filaments (PHFs), predominantly made up of a 12-kDa repeat domain fragment of microtubule-associated tau protein (Wischik et al., 1985; Wischik et al., 1988a,b). Numerous studies have confirmed a quantitative link between the spread of neurofibrillary tangle pathology and the amount of tau aggregated with both the extent of clinical dementia and functional molecular imaging deficits in Alzheimer's disease (Arriagada et al., 1992; Brier et al., 2016; Giannakopoulos et al., 2003; Josephs et al., 2003; Maruyama et al., 2013). Since pathological aggregation of tau protein begins at least 20 years prior to any clinical manifestations (Braak and del Tredici, 2013), targeting this pathology offers a rational procedure for both treatment and prevention of AD and related tau aggregation disorders (Huang and Mucke, 2012; Wischik et al., 2014; Wischik et al., 2010). The tau fragment, originally identified as an intrinsic structural constituent of the PHF core, has prion-like proteins in vitro that capture normal tau protein with very high affinity (Lai et al., 2016) and convert it into a proteolytically stable replica (Wischik et al., 1996; Harrington et al., 2015) in a self-propagating and autocatalytic process. Tau phosphorylation inhibits its aggregation (Lai et al., 2016) and is indistinct in driving the cascade (Mukaetova-Ladinska et al., 2000; Schneider et al., 1999). Wischik et al., 1995). Direct inhibition of tau aggregation represents a plausible target for therapeutic intervention. Methylthioninium (MT) acts as a tau aggregation inhibitor (TAI) in vitro (Wischik et al., 1996; Harrington et al., 2015), dissolves PHFs from Alzheimer's disease brain tissue (Wischik et al., 1996), and reduces tau pathology and associated behavioral deficits in transgenic mouse tau models at brain concentrations consistent with human oral dosing (Melis et al., 2015; Baddeley et al., 2015). MT has also been shown to inhibit other disease-associated protein aggregation (see, for example, document W02007 / 110629 and references thereto). MT is a redox molecule, and depending on the environmental conditions (e.g., pH, oxygen, reducing agents), it exists in equilibrium between a reduced form [leucomethylthioninium (LMT)] and an oxidized form (MT+). Document WO96 / 30766 describes such compounds QCQ«nn / C7n7 / e / YiAi containing MT for use in the treatment and prophylaxis of various diseases, including AD and Lewy body disease. An example compound is methylthioninium chloride (MTC), commonly known as methylene blue, which is the chloride salt of the oxidized form of methylthioninium (MT), i.e., MT+. QCQ«nn / C7n7 / e / YiAi Document WO96 / 30766 describes, in the case of oral administration, a daily dosage of approximately 50 g to approximately 700 mg, preferably approximately 150 mg to approximately 300 mg, divided into preferably 1-3 unit doses. Document WC2007 / 110630 describes certain specific diaminophenothiazine compounds related to MTC, including (so-called) ETC, DEMTC, DMETC, DEETC, MTZ, ETZ, MTI, MTILHI, ETI, ETLHI, MTN, and ETN, which are useful as drugs, for example, in the treatment of Alzheimer's disease and other diseases such as frontotemporal dementia (FTD). Document WC2007 / 110630 describes dosage units comprising 20 to 300 mg of the 3,76-diaminophenothiazine (DAPTZ) compound described therein, for example, 30 to 200 mg, e.g., 30 mg, 60 mg, 100 mg, 150 mg, 200 mg. An appropriate dose of the DAPTZ compound is suggested to be in the range of approximately 100 ng to approximately 25 mg (more typically approximately 1 pg to approximately 10 mg) per kilogram of the subject's body weight per day, e.g., 100 mg three times daily, 150 mg twice daily, 200 mg twice daily. A dosage of 50 mg three or four times daily is also discussed. A preliminary pharmacokinetic model for methylene blue, based on established urinary excretion data studies in humans, dogs, and rats, was proposed by Disanto and Wagner, J Pharm Sci 1972, 61:1086-1090 and 1972, 61:1090-1094 and Moody et al., Biol Psych 1989, 26:847858. Peter et al. (2000) Eur J Clin Pharmacol 56: 247250 provides a model which integrates blood level data, which contradicts the previous data from Disanto and Wagner regarding the terminal elimination half-life. May et al. (Am J Physiol Cell Physiol, 2004, Vol. 286, pp. C1390-C1398) showed that human erythrocytes sequentially reduce and absorb MTC; that is, MTC itself is not absorbed by the cells but is preferentially reduced from MT that crosses the cell membrane. They also showed that the rate of absorption is enzyme-dependent and that both oxidized and reduced MT are concentrated in the cells (the reduced MT equilibrates again once inside the cell to the oxidized MT form). Based on these and other discussions, it is believed that orally administered MTC and similar drugs are absorbed in the intestine and enter the bloodstream, while unabsorbed drug percolates descend into the alimentary canal, specifically the distal intestine. A significant undesirable side effect is the effect of unabsorbed drug in the distal intestine, for example, sensitization of the distal intestine and / or antimicrobial effects of the unabsorbed drug on the flora in the distal intestine, both of which can lead to diarrhea. MTC was clinically tested in a phase 2 study (Wischik et al., 2015). Although the minimum safe and effective dose was identified as 138 mg / day, a higher dose of 218 mg / day has limited efficacy due to absorption limitations, most likely due to the need for MT+ to be reduced to the leuco-MT (LMT) form to allow efficient absorption by passive diffusion. QCQ«nn / C7n7 / e / YiAi Document W02009 / 044127 describes the results of a phase 2 clinical trial, which indicates that MTC has two systemic pharmacological actions: cognitive effects and hematological effects, but that these actions were separable. Specifically, the cognitive effects did not show a monotonic dose-response relationship, while the hematological effects did. It is proposed that two distinct species were responsible for the two types of pharmacological activity: MTC absorbed as the uncharged LMT form is responsible for the beneficial cognitive activity, and MTC absorbed as an oxidized dimeric species is responsible for hemoglobin oxidation. Document W02009 / 044127 describes how dosage forms could be used to maximize the bioavailability of the therapeutically active (cognitively effective) species when dosing with leuco-DAPTZ or oxidized compounds. Since it is the reduced form of MT that is absorbed by cells, administering a reduced form to patients has been proposed. This could also reduce dependence on the rate-limiting stage of enzyme reduction. MTC, a phenothiazine-5-ium salt, can be considered to be an oxidized form relative to the corresponding 1 OH-phenothiazine compound, N,N,N',N' QCQ«nn / C7n7 / e / YiAi tetramethi1-1 OH-phenothiazine-3,7-diamine, which can be considered as being a reduced form: reduced form oxidized form (MTC) The reduced form (or leuco form) is known to be unstable and can be easily and quickly oxidized to give the corresponding oxidized form. Document W002 / 055720 describes the use of reduced forms of certain diaminophenothiazines for the treatment of protein aggregation diseases, primarily tauopathies. Based on the in vitro activity of the reduced forms of diaminophenothiazines therein, a suggested daily dosage of 3.2–3.5 mg / kg is also described, along with dosages of 20 mg tds, 50 mg tds, or 100 mg tds, combined with a ratio of 2x mg of ascorbic acid in such a manner as to achieve more than 90% reduction prior to ingestion. Document W02007 / 110627 describes certain 3,7-diamino-1-OH-phenothiazinium salts, effective as drugs or prodrugs for the treatment of diseases including Alzheimer's disease and other conditions such as frontotemporal dementia (FTD). These compounds are also in the reduced or lenco form when considered with respect to Traditional Chinese Medicine (TCM). These leucothiazinium compounds are referred to as LMTX salts and include the following salts: 1 1 <D φ \ / z x—z ω z / \ <l><D 1_____________________________________________________________________________________1 HCI HCI di(clorhidrato) de N,N,N'N'-tetramet¡l-10Hfenotiaz¡n-3,7-d¡am¡nio, (LMT.2HCI) 1 1 Φ 0) S S \ / z x—z ω z / \ Φ <1> SS 1______________________________________________________________________________________1 HBr HBr di(bromide) de Ν,Ν,Ν',Ν'-tetramethyl-lOHfenotiaz¡n-3,7-d¡amin¡o, (LMT.2HBr) 1 1 φ Φ z ω z—xz / \ φ o 1______________________________________________________________________________________1 Hl Hl di(yodhihydrate) de Ν,Ν,Ν',Ν'-tetramethyl-1OHfenothiaz¡n-3,7-d¡amin¡o, (LMT.2HI) The document W02012 / 107706 describe other sales de LMTX has superior properties to the LMTX sales listed above, which include leuco-methylthioninium bis(hidromethanesulfonate) (LMTM): H 1 JL / NS NC Me ' μ Me Π 1 1 MeSC^p MeSC^ bis(hidromethanesulfonate) de / ½ / ½ / v; / V'-tetra metí 1-10 Hphenothiazin-3,7diaminio. LMT.2MsOH / LMTM QCQ«nn / C7n7 / e / YiAi Specifically, LMTM retains TAI activity in vitro and in vivo (Harrington et al., 2015; Melis et al., 2015), has superior pharmaceutical properties in terms of solubility and pKa, and is not subject to the absorption limitations of the MT+ form (Baddeley et al., 2015). Documents W02007 / 110627 and W02012 / 107706 describe dosage units comprising 20 to 300 mg of the DAPTZ compounds described therein, for example, 30 to 200 mg, e.g., 30 mg, 60 mg, 100 mg, 150 mg, 200 mg. An appropriate dose of the DAPTZ compound is suggested to be in the range of approximately 100 ng to approximately 25 mg (more typically approximately 1 pg to approximately 10 mg) per kilogram of the subject's body weight per day, e.g., 100 mg, 3 times daily, 150 mg, 2 times daily, 200 mg, 2 times daily. Document WO2018 / 019823 describes new regimens for the treatment of neurodegenerative disorders using compounds containing methylthioninium (MT). Briefly, these regimens identified two key factors. The first was related to the dosage of MT compounds, and the second was their interaction with symptomatic treatments based on the modulation of acetylcholinesterase levels. In the analysis described in document WO2018 / 019823, low doses of MT compounds (e.g., 4 mg twice daily) showed therapeutic benefits when monotherapy was compared to complement. Efficacy profiles were similar in mild and moderate subjects for most of the measured outcomes. Furthermore, the treatment benefit in AD (according to the trial criteria) was restricted to patients taking LMTM as monotherapy. Conversely, the decline seen at corresponding dosages in patients taking LMTM in combination with treatments labeled as AD (acetylcholinesterase inhibitors [AChE1] and / or memantine), who were the majority, is indistinguishable in all parameters from those seen in the control arm. The potential for LMT compounds to be active at low doses, and the apparent lack of a dose response, are discussed in WO2018 / 019823. It is hypothesized that there may be a critical threshold for activity at the tau aggregation inhibitor target, and that the effect of higher doses may plateau or even become negative at brain concentrations above 1 mM (Melis, 2015). Based on these analyses, and given that lower doses (4 mg twice daily) have a better overall clinical profile than the high dose (100 mg twice daily), WO2018 / 019823 presents treatment methods for neurodegenerative disorders of protein aggregation involving the oral administration of MT-containing compounds, where such administration provides a total of between 0.5 and 20 mg of MT to the subject per day, optionally as a single dose or divided into two or more doses. Other publications that use low dose or low dosage in relation to compounds containing MT are described in document WO2018 / 019823. For example: Telch, Michael J., et al. Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia. American Journal of Psychiatry 171.10 (2014): 1091-1098: This publication addresses the use of low-dose methylene blue on fear extinction and contextual memory retention following fear extinction training. The paper reports that methylene blue is a diaminophenothiazine drug that, at low doses (0.5-4 mg / kg), has neurometabolic-enhancing properties. The dosage used in the publication was 260 mg / day for adult participants, corresponding to a dose of 4 mg / kg. Gonzalez-Lima F and Auchter A (2015) Protection against neurodegeneration with low-dose methylene blue and near-infrared light. Front. Cell. Neurosci. 9:179. doi: 10.3389 / fncel.2015.00179: This publication discusses the cellular mechanism of neurodegeneration through the neuroprotective effects of low doses of methylene blue and near-infrared light. It refers to previous work, citing 0.5–4 mg / kg of methylene blue as safe and effective. Alda, Martin, et al. Methylene blue treatment for residual symptoms of bipolar disorder: randomised crossover study. The British Journal of Psychiatry (2016): doi: 10.1192 / bjp.bp.1 15.173930: This publication describes the use of a low dose of 15 mg of methylene blue as a placebo in a 6-month trial. The active dose was 195 mg. In this case, the dose was divided into three daily doses. Rodríguez, Pavel, et al. Multimodal Randomized Functional MR Imaging of the Effects of Methylene Blue in the Human Brain. Radiology (2016): 152893: This publication also refers to the known side effects and pharmacokinetics of low-dose methylene blue (0.5–4.0 mg / kg), which are contrasted with the effects of doses greater than 10 mg / kg. The dosages used in the publication were 280 mg / day for adult participants, approximating a dose of 4 mg / kg. QCQ«nn / C7n7 / e / YiAi Naylor et al. (1986) A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. Biol. Psychiatry 21:915-920 and Naylor et al. (1987) A controlled trial of methylene blue in severe depressive psychosis. Biol. Psychiatry 22:657-659: these studies used 1 mg / day of methylene blue, nominally as a placebo, against a treatment of 300 mg / day of methylene blue. However, in the latter paper, the authors propose that the placebo dosage may act as an antidepressant. As discussed above, due to their activity with respect to tau aggregation and TDP-43 aggregation, MT-based compounds have been suggested for the treatment of FTD (see W02007 / 110630; W02007 / 110627; W02009 / 044127; WO2012 / 107706, all described above). Document WO2018 / 041739 describes the results of a phase 3 clinical trial investigating the treatment of frontotemporal dementia disease (FTD) using LMTM. The results indicate that even a relatively low dose of the compound MT (which was used in the trial as a control) can show benefit in FTD, compared to the cognitive decline seen in historical controls. Besides Unexpectedly, the results of QCQ«nn / C7n7 / e / YiAi indicate strong interaction effects when MT is co-mediated with AD treatments that modify synaptic neurotransmission in the brain. Significant cognitive benefits appeared in FTD patients taking MT in combination with such AD treatments (e.g., acetylcholinesterase inhibitors and / or memantine) compared to MT alone. Document WO2018 / 041739 further describes how MT compounds can be combined with acetylcholinesterase inhibitors and / or memantine without apparent incompatibility. The insights provided in documents WO2018 / 019823 and WO2018 / 041739 provide an important contribution to the technique in relation to the minimum dosage of MT compounds to achieve cognitive benefit in subjects suffering from, or at risk of, neurodegenerative disorders such as AD and FDT. However, it is well known that there is inter-individual variability among subjects with respect to how a given drug dosage will result in the drug concentration in the subject's body fluids. It is advantageous that any dosage regimen applied to such subject populations can, to the extent possible, take this variability into account in order to ensure maximum therapeutic benefit for all subjects, without the need for rigid regimens. QCQ«nn / C7n7 / e / YiAi customized, and while nevertheless maintaining a desirable clinical profile. Brief Description of the Figures Figure 1. Schematic of the simplified population PK model for MT. Figure 2a and 2b. Histogram of Bayesian post-hoc estimates of steady-state precursor MT Cmax in AD patients from Studies 005 and 015 who received LMTM 4 ng BID or c. 200 mg / dla. Figures 3a and 3b. ADAS-cog switching over 65 weeks to combined doses of 8 mg / day as mono- or adjunctive therapy in AD subjects from Studies 005 and 015 in accordance with the estimated steady-state Cmax. Note that the lower p-value in 'stratum Acmem' is due to a large number of subjects receiving LMTM as adjunctive therapy. Figures 4a-4c. Analysis of AD subjects showing reduced brain atrophy and ventricular expansion in the high Cmax group as both monotherapy and adjunctive therapy. Figure 5. Estimated proportion of AD subjects in the high Cmax group according to dose. The Y-axis shows the % above the threshold. 4 mg BID is 50%, reflecting the original median split of the Cmax groups. QCQ«nn / C7n7 / e / YiAi high and low at this dosage. Figures 6a and 6b. Distribution of estimated Cmax values ​​for 8 and 200 mg / day in bvFTD trial subjects. Figure 7. Difference in the decline in the ACE-R scale according to the Cmax group in patients with bvFTD receiving LMTM 8 mg / day as monotherapy for the treatment of bvFTD. Figure 8. Difference in the decline on the ACE-R scale according to the Cmax group in bvFTD patients receiving LMTM 200 mg / day as monotherapy for the treatment of bvFTD Figure 9. Difference in decline on the FAQ scale of compliance with the Cmax group in bvFTD patients receiving LMTM 8 mq / day as monotherapy. Figure 10. Difference in decline on the FAQ scale of compliance with the Cmax group in bvFTD patients receiving LMTM 8 mg / day or 200 mg / day as monotherapy. Figures lla-llc. Difference in WBV, FTV and LW according to the Cmax group in patients with bvFTD receiving LMTM 8 mg / day as monotherapy. Figure 12. Sigmoid Emax analysis for ADAS-cogn decline at week 65 with model covariates to population mean values ​​and 90% startup confidence intervals using Cmax,EE on day 1 for low-dose AD patients from studies TRx-237-005 and TRx-237-015. Figures 13a-13d. Response ratio of QCQ«nn / C7n7 / e / YiAi concentration for volumetric MRI and clinical endpoints for CTláx,ss clusters of AD patients receiving LMTM at a dose of 8 mg / day Figures 14a-14d. Comparison of volumetric MRI and primary clinical endpoints for all patients with AD: categorized by Cmax,ss above (high exposure) or below (low exposure) the precursor MT threshold of 0.373 ng / mL. Figure 15. Expected percentage of patients with AD above the critical therapeutic threshold for Cplus,ss (0.393 ng / ml) and Cprom,ss (0.223 ng / ml) according to daily (qd) and twice daily (bid) dosing regimens. Figures 16a-16d. Comparison of primary clinical and MRI endpoint in AD patients receiving LMTM, 8 mg / day: categorized by Cmax,ss above (high exposure) or below (low exposure) the precursor MT threshold of 0.373 ng / ml and AChEI and / or memantine use status. Figure 17. Pharmacokinetic-pharmacodynamic response on the ADAS-cog scale during 65 weeks in AD patients taking LMTM at a dose of 8 mg / day and categorized by co-medication status with treatments labeled as AD. Figures 18a-18e. Concentration response relationships for ACE-R, FAQ, FTV, LW, and WBV in patients QCQ«nn / C7n7 / e / YiAi with bvFTD. Figures 19a-19e. Estimated change from baseline over time in MRI neuroimaging and clinical endpoints in bvFTD patients taking 8 mg / day categorized by plasma levels above or below the Cmax,ss threshold of 0.34 6 ng / ml. Figure 20. Fitting of expanded Hill equation with change in whole brain volume over 52 weeks for patients with bvFTD. Detailed Description of the Invention The present inventors have devised a novel pharmacokinetic (PK) model for dosing MT compounds in patient populations. This versatile model was derived from a Phase 1 study in elderly volunteers and is described in the Examples section below. The new population PK model was then used to estimate the Cmax of precursor MT in patients who received LMTM in the two phase 3 AD studies described in document WO2018 / 019823 (Studies 005 and 015, for the treatment of patients with mild or mild-to-moderate AD, respectively). Once the Cmax was estimated in each of the subjects, a distribution of Cmax estimates for each of the treated populations could be derived. As expected, there was substantial variability in MT Cmax values ​​across the population for the given low dosage. Analysis of this distribution confirmed the findings in WO2018 / 019823 that low dosages (4 mg MT twice daily) were effective (as measured, for example, by the reduced decline in the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog)). It was further confirmed that monotherapy provides a substantial benefit by this criterion compared with adjunctive therapy with AChEls and / or memantine (with the mean benefit between monotherapy and adjunctive therapy being ~4 ADAS-cog units over 65 weeks) (see Figure 3a). However, unexpectedly, given the published literature describing a lack of recognizable dose response, the novel analysis showed a concentration response within the low-dose treated population. This can be demonstrated for patients receiving 8 mg / day using a sigmoid analysis of Emax for ADAS-cogn decline over 65 weeks in patients combined with Studies 015 and 005 (Figure 12). Based on a population median Cmax threshold split, the group of individuals with high estimated Cmax showed an improvement of approximately ~2 to 3 ADAS-cog units compared to the group of individuals with low estimated Cmax (see Figure 3a). However, based on splitting patients according to the 0.373 ng / ml threshold, which encompasses the 35% of patients with the lowest values, the treatment difference in patients receiving the 8 mg / day dose is -3.4 ADAS-cog units (see Figures 14a-14d). These perceptions suggest that it is advantageous to adopt a dosing regimen which maximizes both the proportion of subjects in whom the MT concentration will exceed the average Cmax or CProm, and also maximizes the expected therapeutic efficacy of LMTM if taken alone or in combination with (or at least preceded by) symptomatic treatments, while nevertheless maintaining a relatively low dose so as to maintain a desirable clinical profile in relation to being well tolerated with minimal side effects. The total biphasic concentration response for LMTM shown in Figure 17 supports the proposition that the median dose which achieves all these objectives is at least 20 mg / day, and doses in the range 20-40 mg / day, or 20-60 mg / day, could be expected to maximize therapeutic benefit, although good efficacy, particularly in AD patients not pre-treated with symptomatic treatments, can still be seen at dosages of 100 mg or more. The new population PK model was additionally used to estimate the Cmax of precursor MT in patients who received different dosages of LMTM bid in the phase 3 clinical trial investigating the bvFTD treatment described in document WO2018 / 041739. These results confirm the concentration-response relationship for low-dose monotherapy to clinical benefit, measured by change over 52 weeks on the cognitive scale (ACE-R) and the functional scale (FAQ), similar to that seen in AD. A similar concentration-response relationship exists for MRI measurements of brain atrophy progression (frontotemporal volume, lateral ventricular volume, whole brain volume). This is shown in Figures 18a–18e. As can be seen by comparing the plots of the corresponding expanded Hill equation for AD and bvFTD (Figs. 17 and 20), the biphasic nature of the concentration-response relationship is more evident in bvFTD. This implies that the optimal dosing range for achieving maximum treatment benefit in bvFTD is somewhat narrower, i.e., 20–40 mg / day, or preferably less, 20–60 mg / day. As preferably noted in document WQ2018 / 041739, there is an additional benefit of combination with symptomatic treatments, which may be seen particularly in patients with plasma levels below the population average for Cmá:·:,.=·.=·. In light of the results described herein, it can be seen that there are at least two distinct benefits to using the minimum dose of compound MT that maximizes the treatment effect. First, certain rare adverse events or side effects associated with MT occur in a dose-related manner. Therefore, avoiding higher doses that are otherwise necessary is clearly possible in order to maintain an optimal clinical profile. Second, there is evidence of an inverse dose-response relationship for certain therapeutic criteria at high doses; thus, the benefit may actually be attenuated at high doses. Overall, these novel findings indicate that there is a benefit in using slightly higher low-dose LMT treatments than those previously assumed, and further indicate that LMT treatments can, in some contexts, be advantageously used as adjuncts to symptomatic treatments, which increase the versatility of MT-based therapeutic regimens. Further analysis by the inventors indicates that the above dosage of 20mg of MT (e.g., administered as LMTM) will achieve a Cmax above the median derived threshold value in 90 to 100% of subjects (see Figure 5), with the precise percentage being dependent on the number of split doses being employed. With regard to AD treatments, such treatments could preferably be a monotherapy, or at least introduced either prior to, or after the cessation of currently available AD treatments. QCQ«nn / C7n7 / e / YiAi memantine. However, importantly, and as explained above, the analysis described herein indicates that even when MT treatments are used as adjunctive therapy, they can be beneficial (of ~2 units of ADAS-cog, or more) in dosing to achieve a Cmax above the threshold value, compared to a low Cmax value. Thus, in one aspect, a therapeutic treatment method for a neurodegenerative disorder, for example a neurodegenerative disorder (e.g., protein aggregation), in a subject is described, wherein the method comprises orally administering to such subject a compound containing methylthioninium (MT), wherein such administration provides a total daily dose of between 20.5 and 40, 20.5 and 50, 20.5 and 60, 20.5 and 70, 20.5 and 80, or 20.5 and 99 or 100 mg of MT to the subject per day, optionally divided into 2 or more doses, wherein the MT-containing compound is a salt of The total daily MT dose can be between 20.5 and 60ng. The total daily dose may be approximately 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24 mg up to approximately any of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mg The total daily dose may be approximately 20.5, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg. An example dosage is 20.5 or 21 to 40mg. An additional example dosage is 22 to 35 mg. An additional example dosage is 23 to 30 mg. The present invention relates to administering MT in the reduced form (LMT). The total daily dose of the compound can be administered as a divided dose twice a day or three times a day. As explained below, when administering the MT dose divided into a larger number of doses / day, it may be desirable to use a smaller total amount within the mentioned interval, compared to a single daily dosage, or a smaller number of doses per day. As explained herein, in some modalities, particularly with regard to the treatment of AD, the treatment will be monotherapy, or at least will exclude co-medication with AChEs and memantine. In some modalities, subjects are selected who have not QCQ«nn / C7n7 / e / YiAi have not had or have recent prior treatment in which AChEls or memantine or other symptomatic treatments, but such treatment is optionally initiated or restarted after the start of treatment with LMT. Thus, as explained herein, in other modalities the treatment will be complementary therapy, for example, co-medication with AChE and / or memantine. In this way, patients who have already received AChE and / or memantine may benefit from receiving these MT compound dosages, while patients receiving these MT compound dosages may benefit from AChE and / or memantine. In some modalities, the treatment is part of a treatment regimen which includes: (i) administering orally to such subject the compound containing MT for an initial period of time, wherein such administration provides a total daily dose of between 1 and 10 mg of MT to the subject per day, optionally 8 mg per day, optionally divided into 2 or more doses; (ii) administering orally to such subject the compound containing MT for an immediately subsequent period of time, wherein such administration provides a total daily dose of between 20.5 and 40 mg, 20.5 and 60, 20.5 and 80 or 20.5 and 100 mg of MT to the subject per day, optionally approximately 21 to 40, 50, or 60 mg per day, QCQ«nn / C7n7 / e / YiAi optionally divided into 2 or more doses; (iii) optionally combine the treatment in (ii) with the administration of a neurotransmission modifying compound which is a modifier of the activity of acetylcholine or glutamate neurotransmitters, such as an AChEI and / or memantine. These different phases of the regime will typically follow one another immediately. Also provided herein are prophylactic treatment methods for neurodegenerative disorders of protein aggregation. These aspects and modalities will be described in more detail: Methylthioninium portion QCQ«nn / C7n7 / e / YiAi IUPAC Structure H N3,N3,N7,N7-tetramethyl-10Hphenothiazine-3,7-diamine Composition Formula Weight: 285.41(1) Exact Mass: 285.1299683(1) Formula: C16HigN3S Composition: C 67.33% H 6.71% N 14.72% S 11.23% Synonym leucomethylthioninium (LMT) The compound containing MTs used in the present invention contains a portion of MT as the active ingredient in a reduced form (called LMT). The LMT portion per se described above is not stable. Therefore, it is administered as an LMT compound—for example, LMT salts. Compounds containing LMT will generally be stabilized, for example, by the presence of one or more protic acids, for example, two protic acids. The MT content of such salts can be easily calculated by those skilled in the art based on the molecular weight of the compound and the molecular weight of the MT portion. Examples of such calculations are provided herein. LMT Compounds Preferably it is an LMTX compound of the type described in documents W02007 / 110627 or W02012 / 107706. Thus, the compound can be selected from compounds of the following formula, or hydrates or solvates thereof: Each of HnA and HnB (where present) are protic acids which can be the same or different. Protic acid means a proton (H+) donor in aqueous solution. Within the protic acid group, A₀B⁻ is therefore a conjugate base. Protic acids thus have a pH of less than 7 in water (i.e., the hydronium ion concentration is greater than 10⁻⁷ moles per liter). In one form, the salt is a mixed salt that has the following formula, where HA and HB are different nono-protic acids: H 1 Me. 1 JL ^Me 1 1 Me Me HA HB when: P= 1 q= 1 n = 1 (1 + 1) x 1 = 2 However, preferably the salt is not a blended salt, and has the following formula: where each of HnX is a protic acid, such as di-protic acid and mono-protic acid. In one form, salt has the following properties: QCQ«nn / C7n7 / e / YiAi formula, where H2A is a di-protic acid. H 1 1 1 Me Me H2A when: P= 1 q = 0 n = 2 (1 + 0) x 2 = 2 Preferably, the salt has the following formula, which is a bis monoprotic acid: H 1 Μβ'ΝΑΑ3ΧΑΝ-Μθ 1 1 Me Me 2(HA) when: p = 2 q = 0 n = 1 (2 + 0) x 1 = 2 Examples of protic acids that may be present in the LMTX compounds used herein include: Inorganic acids: hydrohalic acids (e.g., HC1, HBr), nitric acid (HNO3), sulfuric acid (H2SO4). Organic acids: carbonic acid (H2CO3), acetic acid (CH3COOH), methanesulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, p-toluenesulfonic acid. The preferred acids are monoprotic acid, and the salt is a bis(monoprotic) salt. A preferred MT compound is LMTM: QCQ«nn / C7n7 / e / YiAi 1 HI jls, S NC Me H Me Π ' 1 MeSC^ Mesáp LMT.2MSOH (LMTM) 477.6 (1-67) Weight Factors The anhydrous salt has a molecular weight of approximately 477.6. Based on a molecular weight of 285.1 for the LMT core, the weight factor for using this MT compound in the invention is 1.67. By weight factor means the relative weight of the compound containing pure MT versus the weight of the MT containing it. Other weight factors can be calculated, for example, MT compounds of the present, and the corresponding dosage intervals can be calculated from these. Therefore, the invention covers a total daily dose of approximately 34 to 67, 34 to 100, 34 to 134, or 34 to about 167 mg / day of LMTM. Other example LMTX compounds are as follows. Molecular weight (anhydrous) and weight factor are also shown: 2 H 1 Me >® 629.9 (2.20) 4 H 1 ^X^N^^X Me®Xx JL JL >Jx® Me XN S Me γ, μ Me Π 1 1 so? 2 or LMT.2BSA 601.8 (2.11) 5 H 1 Mex®J^ JL JL<íX®xMe O s nC Me Y, H Me Π 1 1 L © - Θ / x .so, o3s 3 LMT.EDSA 475.6 (1-66) 6 H 1 Me ®x-Lx JL JL ^X® Me Me xH Me Π 1 1 o / \ / -x O o3s so3 LMT.PDSA 489.6 (1-72) QCQ«nn / C7n^ / e / Y 7 H 1 qn sn; Me Y, H Me HO or L so.. so. or LMT.NDSA 573.7 (2.01) The dosages described herein with respect to TM thus apply mutatis mutandis to these MT-containing compounds, as adjusted for their molecular weight. Accumulation factors As those skilled in the technique for a given daily dosage will appreciate, more frequent dosing may lead to greater accumulation of a drug. Therefore, in certain embodiments of the claimed invention, the total daily dose amount of compound MT may be relatively lower when dosed more frequently (e.g., twice a day [bid] or three times a day [tid]), or higher when dosed once a day [qd]. Treatment and prophylaxis The term treatment, as used herein in the context of treating a condition, generally pertains to the treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, e.g., inhibition of the progression of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, regression of the condition, relief of the condition, and cure of the condition. The term therapeutically effective amount, as used herein, refers to such quantity of a compound of the invention, or a material, composition, or dosage comprising such compound, which is effective in producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen. The present inventors have demonstrated that a therapeutically effective amount of a compound MT with respect to the diseases of the invention may be much lower than what is currently understood in the art. The invention also encompasses treatment as a prophylactic measure. Accordingly, the invention also provides a method of prophylaxis against a neurodegenerative disorder (e.g., protein aggregation) in a subject, wherein the method comprises orally administering to such a patient a compound containing MT, wherein such administration provides a total of between 20 or 21 and 40 mg, 20.5 and 60, 20.5 and 80, or 20.5 and 99 or 100 mg of MT to the subject per day, optionally divided into two or more doses, as described above. The term prophylactically effective quantity as used herein, pertains to such quantity of a compound of the invention, or a material, composition or dosage comprising such compound, which is effective in producing some desired prophylactic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen. Prophylaxis in the context of this description should not be understood as implying complete success, that is, complete protection or complete prevention. Preferably, prophylaxis in this context refers to a measure administered prior to the detection of a symptomatic condition with the aim of preserving health and helping to delay, mitigate, or prevent that particular condition. Combination and monotherapy treatments The term treatment includes combination treatments and therapies, in which two or more Treatments or therapies for the same neurodegenerative disorder are combined, for example, sequentially or simultaneously. These may be disease-modifying or symptomatic treatments. The specific combination could be at the specialist's discretion. In combination therapies, the agents (i.e., a MT compound as described herein, plus or plus other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dosing regimens and via different routes. For example, when administered sequentially, the agents may be administered at closely spaced intervals (e.g., over a period of 5–10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart, if required); the precise dosing regimen is commensurate with the properties of the therapeutic agent(s). An example of a combination treatment of the invention (for AD) could be an agent which is a compound containing MT at the specified dosage in combination with an agent which is an inhibitor of the processing of the amyloid precursor protein to beta-amyloid (e.g., an inhibitor of the processing of QCQ«nn / C7n7 / e / YiAi amyloid precursor protein that leads to enhanced beta-amyloid generation). The invention also allows the co-administration of either or both of: an acetylcholinesterase inhibitor of an N-methyl-D-aspartate receptor antagonist. As described herein, with regard to combination therapies, the invention provides methods for improving the therapeutic effectiveness of a first compound, which is a MT compound, at a dose described herein for the treatment of a neurodegenerative disorder in a subject. The method comprises administering to the subject a second compound, wherein the second compound directly modifies synaptic neurotransmission in the subject's brain (e.g., an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist). The invention further provides a first compound, which is a MT compound at a dose described herein, in a method of treating a neurodegenerative disorder in a subject in a treatment regimen wherein the treatment further comprises a second compound, wherein the second compound directly modifies synaptic neurotransmission in the subject's brain. QCQ«nn / C7n7 / e / YiAi The invention further provides for the use of a compound which directly modifies synaptic neurotransmission in the brain of a subject to enhance the therapeutic effectiveness of a MT compound at a dose described herein in the treatment of a neurodegenerative disorder in the subject. The invention further provides a MT compound at a dose described herein and a compound which directly modifies synaptic neurotransmission in the brain for use in combination methods of the invention. The invention further provides a compound which directly modifies synaptic neurotransmission in the subject's brain for use in a method for enhancing the therapeutic effectiveness of a MT compound at a dose described herein in the treatment of a neurodegenerative disorder in a subject. The invention further provides for the use of a first compound, which is a MT compound at a dose described herein, in combination with a second compound, wherein the second compound directly modifies synaptic neurotransmission in the subject's brain, in the manufacture of a drug for the treatment of a neurodegenerative disorder. The invention further provides for the use of an MT compound at a dosage described herein in the manufacture of a medicament for use in the treatment of QCQ«nn / C7n7 / e / YiAi a neurodegenerative disorder syndrome in a subject, wherein the treatment further comprises the use of a second compound, wherein the second compound directly modifies synaptic neurotransmission in the subject's brain. The invention further provides for the use of a compound that directly modifies synaptic neurotransmission in the brain, in the manufacture of a medicament for use in the treatment of a neurodegenerative disorder in a subject, wherein the treatment further comprises the use of a MT compound at a dose described herein and the compound that directly modifies synaptic neurotransmission in the subject's brain. In other modalities, the treatment is a monotherapy, which is said to mean that the MT-containing compound is not used in combination (within the meaning discussed above) with another active agent to treat the same neurodegenerative protein aggregation disorder in the subject. Treatment duration For the treatment of the neurodegenerative disorder described herein, a treatment regimen based on low-dose MT compounds will preferably be extended over a sustained period. The specific duration may be at the discretion of the specialist. For example, the duration of treatment may be: At least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or more. At least 2, 3, 4, 5 years, or more. Between 6 and 12 months. Between 1 and 5 years old. For prophylaxis, treatment can be continuous. In all cases, the overall duration of treatment will be subject to consultation and review by the specialist. Desired endpoints The methods (treatment regimens) described herein can be used to achieve a specific therapeutic or prophylactic outcome. Such a specific outcome can be quantified according to a scale relevant to the neurodegenerative disorder. Such scales can, for example, measure changes in cognitive, functional, or physical criteria relevant to the disorder. The examples herein illustrate appropriate scales by which the effect of a dosage regimen can be confirmed, compared to placebo or another reference point (e.g., different dosage regimens). These include the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog) used in relation to AD, and the Addenbrooke's Cognitive Examination-Revised (ACE-R). QCQ«nn / C7n7 / e / YiAi used in relation to bvFTD. QCQ«nn / C7n7 / e / YiAi Thus, by way of non-limiting example, in a modality where the treatment is an AD treatment, it achieves (or is achieving) a reduction in cognitive decline in the subject, which is optionally a reduction of at least 1, 2, 2.5, 3, 4, 5 or 6-points in the decline on the 11-point cognitive subscale Alzheimer's Disease Assessment Scale (ADAS-cog) over a period of 65 weeks compared to a corresponding control or control population not being treated in accordance with the invention. In one modality, the treatment is a bfFTD treatment which achieves (or is achieving): (i) a reduction in cognitive decline in the subject, which is optionally a reduction of at least 1, 2, 3, 4, 5, 6, 7 or 8-point decline on the revised Addenbrooke Cognitive Examination (ACE-R) scale during a period of 52 weeks; or (ii) a reduction in functional decline in the subject, which is optionally a reduction of at least 1, 2, 3, 4, 5, or 6-point decline on the Functional Activities Questionnaire (FAQ) during a period of 52 weeks, in which case compared to a corresponding control or control population not being treated in accordance with the invention. Pharmaceutical dosage forms The MT compound of the invention, or pharmaceutical composition comprising it, is administered orally to a subject / patient. Typically, in the practice of the invention, the compound will be administered as a composition comprising the compound and a pharmaceutically acceptable carrier or diluent. In some embodiments, the composition is a pharmaceutical composition (e.g., formulation, preparation, drug) comprising a compound as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. The term pharmaceutically acceptable, as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, to the best of sound medical judgment, suitable for use in contact with the tissues of the subject concerned (e.g., human) without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, etc., must also be acceptable in the sense of being compatible with the other ingredients of the formulation. In some embodiments, the composition is a pharmaceutical composition comprising at least one compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, coloring agents, flavoring agents, and sweetening agents. In some forms, the composition also includes other active agents, for example, other therapeutic or prophylactic agents. Suitable carriers, diluents, excipients, etc., can be found in standard pharmaceutical texts. See, for example, Handbook of Pharmaceutical Additives, 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 20th edition, pub. Lippincott, Williams & Wilkins, 2000; and Handbook of Pharmaceutical Excipients, 2nd Edition, 1994. One aspect of the present invention pertains to a dosage unit (for example, a pharmaceutical tablet or capsule) comprising a MT compound as described herein (for example, obtained by, or obtainable by, a method as described herein; which QCQ«nn / C7n7 / e / YiAi has a purity as described herein; etc.), and a pharmaceutically acceptable carrier, diluent, or excipient. Compound MT, although present in a relatively low quantity, is the active agent of the dosage unit, which is purported to have a therapeutic or prophylactic effect with respect to a neurodegenerative protein aggregation disorder. Preferably, the other ingredients in the dosage unit will typically be inactive, for example, carriers, diluents, or excipients. Thus, preferably, there will be no other active ingredients in the dosage unit, nor any other agent proposed to have a therapeutic or prophylactic effect with respect to a disorder for which the dosage unit is intended to be used. In some forms, the dosage unit is a tablet. In some forms, the dosage unit is a capsule. In some forms, these capsules are gelatin capsules. In some forms, such capsules are HPMC (hydroxypropyl methylcellulose) capsules. The appropriate amount of MT in the composition QCQ«nn / C7n7 / e / YiAi will depend on how frequently it is taken by the subject per day. An example dosage unit may contain 8 to 32mg of MT. An additional example dosage unit may contain 8 to 16 mg of MT. In some forms, the quantity is approximately 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 mg MT. Using the weight factors described or explained herein, a person skilled in the art may select appropriate amounts of a compound containing MT for use in oral formulations. As explained above, the MT weight factor for LMTM is 1.67. Since it is convenient to use unit or simple fractional amounts of active ingredients, non-limiting example dosage units of LMTM may include 13.4, 15, 16.7 mg etc. In one modality, a unit-dose pharmaceutical composition is provided which comprises approximately 34, 67, or 100 mg of LMTM. Nutraceutical Compositions The compositions containing MT used in the invention may be present in a composition QCQ«nn / C7n7 / e / YiAi nutraceutical containing an appropriate dose of MT compound, as described herein, in combination with one or more nutrients in an editable form (e.g. an oral dosage form). The novel nutraceutical compositions of the invention can be used as food and beverage supplements and as pharmaceutical compositions. These nutraceutical compositions, containing the dosage of compound MT described herein, constitute another aspect of the invention per se. Nutrients, as used herein, refers to the components of nutraceutical compositions that serve a biochemical and / or physiological function in the human or animal body. Nutrients include substances such as vitamins, minerals, trace elements, micronutrients, antioxidants, and the like, as well as other bioactive materials, such as enzymes, or compounds biosynthetically produced by human or animal enzymes; as well as herbs and herbal extracts; fatty acids, amino acids, and their derivatives. Edible form denotes a composition that can be ingested directly or converted into an ingestible form, such as by dissolving it in water. Alternatively QCQ«nn / C7n7 / e / YiAi The nutraceutical composition may be in the form of a food or beverage, such as a defined portion of a food product (in which the term includes both food and beverage) supplemented with the defined dosage of the MT compound. These food products will typically comprise one or more of a fat, a protein, or a carbohydrate. The term nutraceutical as used herein denotes utility in both the nutritional and pharmaceutical fields of application, and the description herein that refers to pharmaceutical dosage forms applies mutatis mutandis to nutraceutical compositions. Oral dosage forms particularly suitable for nutraceutical compositions are well known in the art and are described in more detail elsewhere herein. They include powders, capsules, pills, tablets, caplets, gel capsules, and defined portions of edible food products. Liquid forms include solutions or suspensions. General examples of dosage forms and nutraceutical forms are provided, for example, in WO2010 / 078659. Some examples of useful nutrients in the compositions of the present invention are as follows. Any combination of these nutrients is contemplated by the present invention: Vitamins Vitamin B supplementation (folic acid [folate, vitamin B12, vitamin B2, vitamin B6]) has been reported to reduce atrophy of specific brain regions that are a key component of the Alzheimer's disease process and are associated with cognitive decline. This is particularly true for older subjects with high homocysteine ​​levels (Douaud, Gwenaelle, et al. Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proceedings of the National Academy of Sciences 110.23 (2013): 9523-9528). see also Quadri, Pierluigi, et al. Homocysteine, folate, and vitamin B12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. The American journal of clinical nutrition 80.1 (2004): 114-122; Rosenberg IH, Miller JW. Nutritional factors in physical and cognitive functions of elderly people. The American Journal of Clinical Nutrition. 1992 Jun 1; 55(6):1237S1243S. ). It has been suggested that, along with other antioxidants (see below), vitamin C may be useful in protecting neural tissue, as well as potentially reducing β-amyloid generation and acetylcholinesterase activity and preventing endothelial dysfunction. QCQ«nn / C7n7 / e / YiAi regulating nitric oxide (see for example, Heo JH, Hyon-Lee, Lee KM. The possible role of antioxidant vitamin C in Alzheimer's disease treatment and prevention. American Journal of Alzheimer's Disease & Other Dementias. 2013 Mar; 28(2): 120-5). It has also been suggested that vitamin E supplementation may have a role to play in the treatment of AD (see, for example, Mangialasche, Franceses, et al. Serum levels of vitamin E forms and risk of cognitive impairment in a Finnish cohort of older adults. Experimental Gerontology 48.12 (2013): 1428-1435). Antioxidant micronutrients Micronutrients or antioxidants, such as polyphenols, have been reported to have benefits in relation to the protection or treatment of age-related diseases, including neurodegenerative diseases, particularly cognitive impairment and AD. The micronutrients and / or antioxidants that can be used in the nutraceutical compositions described herein include flavonoids shown in the Table below (reproduced from Mecocci, Patrizia, et al. Nutraceuticals in cognitive impairment and Alzheimer's disease. Frontiers in Pharmacology 5: 147 (2014)): Chemical subgroups of flavonoids and sources QCQ«nn / C7nz / e / YiAi Relative food sources: Groups FLAVANOLS Molecules Catechin, epicatechin, epigallocatechin, epigallocatechin gallate (EGCG) Kaempferol, Food source Cocoa and chocolate, green tea, grapes Onions, apples, green tea, FLAVONOLS FLAVONES ISOFLAVONES quercetin Luteolin, apigenin Daidzein, genistein Hesperetin, capers, leek, broccoli Celery, parsley, rosemary Soy Citrus fruits, FLAVANONES naringenin tomatoes Berry fruits, wine ANTHOCYANIDINS Pelargonidin, cyanidin, malvidin red Other micronutrients that have potential utility in relation to the protection or treatment of age-related diseases, as described by Mecocci et al., include: • Non-flavonoid polyphenols: resveratrol and curcumin, • Carotenoids: lycopene, lutein, zeacanthin, β-cryptoxanthin, α-carotene, and the most prominent carotenoid, β-carotene, • Crocin (the main chemical compound identified in saffron), • Diterpenes: for example, carnosic and rosamyrinic acids are two of the most important antioxidant compounds in rosemary. Herbs and plant extracts In addition to the plants described or cross-referenced above regarding micronutrients and antioxidants, other plant and herbal extracts are reported to have benefits in CNS disorders—see Kumar, Vikas. Potential medicinal plants for CNS disorders: an overview. Phytotherapy Research 20.12 (2006): 1023–1035. These include Ginkgo biloba, Hypericum perforatum (St. John's wort), Piper methysticum Forst. (Piperaceae family, also called kava kava), Valeriana officinalis L. (Valerian), Bacopa monniera (which in India is locally known as Brahmi or Jalanimba), and Convolvulos pluricaulis (also known as Shankhpushpi or shankapushpi). Oils and fats It has been reported that the polyunsaturated omega-3 fatty acid (PUFA), for example, may be a promising tool for preventing age-related brain decline. Sources of PUFAs such as docosahexaenoic acid (DHA, 22:6) and eicosapentenoic acid (EPA, 20:5) include fish oils (Denis, I., et al. Omega-3 fatty acids and brain resistance to ageing and stress: body of evidence and possible mechanisms. Ageing Research Reviews 12.2 (2013). 579-594.) Subjects, patients and patient groups The teachings of the invention can be applied to a subject / patient which is an animal, a mammal, a placental mammal, a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a lizard (e.g., a rabbit), a bird (e.g., a bird), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a porcine (e.g., a pig), an ovine (e.g., a sheep), a bovine (e.g., a cow), a primate, an ape (e.g., a monkey or ape), a monkey (e.g., a marmoset, a gibbon), a monotreme (e.g., a platypus), an ape (e.g., a gorilla, a chimpanzee, an orangutan, a gibbon), or a human. In preferred modalities, the subject / patient is a human who has been diagnosed with having one of the cognitive or CNS disorders described herein, or (for prophylactic treatment) assessed for being susceptible to one of the neurodegenerative protein aggregation disorders (e.g., CNS or cognitive disorders) described herein - e.g., based on genetic or family or other data. QCQ«nn / C7n7 / e / YiAi The patient may be an adult human, and the population-based dosages described herein are promising on such a basis (typical weight 50 to 70 kg). If desired, corresponding dosages may be used for subjects falling outside this range by using a subject weight factor; thus, the subject's weight is divided by 60 kg to provide the multiplicative factor for such an individual subject. Thus, for example, for AD diagnosis and severity assessment, the initial selection of a patient may involve any or more of: rigorous evaluation by an experienced specialist; exclusion of non-AD diagnosis to the extent possible by complementary laboratory and other investigations; objective assessment of the level of cognitive function using a neuropathologically validated battery. The diagnosis of AD and other disorders described herein can be made by specialists using methods well known to those experts in the technique. As explained herein, appropriately dosed MT compounds can demonstrate benefit (e.g., with respect to a lower rate of decline as measured by ADAS-Cog) even in subjects or patient populations being treated for AD using an acetylcholinesterase inhibitor or an antagonist of the QCQ«nn / C7n7 / e / YiAi N-methyl-D-aspartate receptor. Examples of acetylcholinesterase inhibitors include Donepezil (Aricept™), Rivastigmine (Exelon™), and Galantamine (Reminyl™). An example of an NMDA receptor antagonist is Memantine (Ebixa™, Namenda™). Examples of the total daily dosage of this neurotransmission-modifying compound are as follows: Donepezil: 5 to 23 mg; Rivastigmine: 3 to 12 mg; Galantamine: 4 to 24 mg; Memantine: 5 to 20 mg. Thus, in one embodiment of the present invention, a method of treatment (or prophylaxis) of AD in a subject is provided, wherein the method comprises orally administering to such subject a compound containing methylthioninium (MT) in the dosage described herein, wherein such treatment further comprises the administration of either or both of an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist. In other modalities, the subject or group of patients with AD may be completely native to these other treatments, and has not historically received one or both of an acetylcholinesterase inhibitor or an antagonist of the QCQ«nn / C7n7 / e / YiAi N-methyl-D-aspartate receptor. Alternatively, the subject or group of patients with AD may have historically received one or both of them, but has ceased such medication for at least 1, 2, 3, 4, 5, 6, 7 days, or 2, 3, 4, 5, 6, 7, 8, 12, or 16 weeks, or more preferably at least 1, 2, 3, 4, 5, or 6 months etc., prior to treatment with a MT compound in accordance with the present invention. Any aspect of the present invention may include the active step of selecting the subject or group of patients with AD in accordance with this criterion, or selecting a subject or group of patients with AD who is or are receiving treatment with either or both of an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist, and discontinuing such treatment (instructing the subject or group of patients to discontinue treatment) prior to treatment with a MT compound in accordance with the present invention. Such treatment may be optionally initiated or restarted after starting treatment with the MT compound. Labels, instructions, and parts kits The unit dosage compositions described herein (e.g., a compound containing low-dose MT plus optionally other ingredients, or more generally MT compositions for QCQ«nn / C7n7 / e / YiAi treatment in AD) , may be provided in a labeled package along with instructions for use. In one form, the package is a bottle, as is well known in pharmaceutical technology. A typical bottle may be made of pharmaceutical-grade HDPE (High-Density Polyethylene) with a child-resistant HDPE snap closure and contain silica gel desiccant, which is available in sachets or cans. The bottle itself may include a label and be packaged in a cardboard container with instructions for use and, optionally, an additional copy of the label. In one embodiment, the package or packages are blister packs (preferably ones with an aluminum cavity and foil lining), which are thus substantially impermeable to moisture. In this case, the package may be packed in a cardboard container with instructions for use and labeling on the container. Such labeling or instructions may provide information regarding the neurodegenerative protein aggregation disorders (e.g., CNS or cognitive disorder) for which the medication is intended. Where the medication is indicated for AD, such labeling or instructions may provide information instructing the user that the compositions should not be used in conjunction with any of: an inhibitor of QCQ«nn / C7n7 / e / YiAi acetylcholinesterase or an N-methylD-aspartate receptor antagonist. Such label or instructions may provide information regarding the maximum permitted daily dosage of the compositions as described herein - for example based on a daily, bid, or t.i.d. basis. Such label or instructions may provide information regarding the suggested duration of treatment, as described herein. Reversal and / or Inhibition of protein aggregation One aspect of the invention is the use of a MT compound or composition as described herein to regulate (e.g., to reverse and / or inhibit) the aggregation of a protein, for example, the aggregation of a protein associated with a neurodegenerative disease and / or clinical dementia. The aggregation will be associated with a disease state as discussed below. Similarly, one aspect of the invention pertains to a method for regulating (for example, reversing and / or inhibiting) the aggregation of a protein in the brain of a mammal, wherein the aggregation is associated with a disease state as described herein, the treatment comprising the step of administering to such mammal QCQ«nn / C7n7 / e / YiAi in need of such treatment, a prophylactically or therapeutically effective amount of a compound or composition of MT or as described herein, which is an inhibitor of such aggregation. Disease conditions treatable by the present invention are discussed in more detail below. Treatment Methods Another aspect of the present invention, as explained above, pertains to a treatment method comprising administering to a patient in need of treatment a prophylactically or therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition. Use in Therapy Methods Another aspect of the present invention pertains to a compound or composition as described herein, for use in a method of treatment (for example, of a disease condition) of the human or animal body by therapy. Use in the Manufacture of Medicines Another aspect of the present invention pertains to the use of a compound or composition of MT, or as described herein, in the manufacture of a medicament for use in the treatment (e.g., of a disease condition). QCQ«nn / C7n7 / e / YiAi In some forms, the drug is a composition, for example, a low-dose unit-dose composition as described herein. Neurodegenerative disorders of protein aggregation The findings described herein have implications for the dosing of MT compounds in various diseases. In particular, adopting a dosing regimen that maximizes the proportion of subjects in whom the MT concentration will exceed the Cmax threshold, while maintaining a relatively low dose to preserve a desirable clinical profile, could be applied in the treatment or prophylaxis of several protein aggregation diseases in which MT has been described as effective. Thus, in some modalities, the disease condition is a protein aggregation disease, and, for example, the treatment is with an amount of a compound or compound as described herein, sufficient to inhibit the aggregation of the protein associated with such a disease condition. The following table lists several protein aggregation associated with the disease and the corresponding protein aggregation neurodegenerative disease. The use of the dosage regimens of the invention with respect to these proteins or diseases is covered by the present invention. Protein Disease Aggregation domain and / or mutations Fibrill subunit size (kDa) Reference prion protein Prion diseases sporadic and inherited forms 27 Prusiner (1998) (CJD, nvCJD, Fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, Kuru) PrP-27-30; many mutations. 27 Prusiner (1998) Fibrillogenic domains: 113-120, 178-191, 202218. Gasset et al. (1992) Tau protein Alzheimer's disease, syndrome 10-12 Wischik et al. (1988) Down syndrome, FTDP-17, CBD, post-encephalitic parkinsonism, Pick's disease, parkinsonism with Guam dementia complex. Sporadic and inherited forms. Truncated tau (tubulin-binding domain) 297-391. 10-12 Wischik et al. (1988) Tau mutations in FTDP17. Hutton et al. (1998) Many mutations in presenilin proteins. Czech et al. (2000) β-amyloid protein. Alzheimer's disease, sporadic forms and 4 Glenner & Wong, (1984) QCQ«nn / C7n7 / e / YiAi Inherited Down syndrome 5 β-amyloid protein; 142 (3). 4 Glenner & Wong, (1984) Mutations in APP in rare families. Goate et al. (1991) 10 Huntington's disease N-terminal protein with expanded glutamine repeats. DiFíglia et al. (1997) 40 Ataxin spinocerebellar ataxias Proteins with expanded glutamine repeats. Paulson et al. (1999) 15 Atrophin dentadoluisian atrophy Proteins with expanded glutamine repeats. Paulson et al. (1999) 20 Adrenocortical tubular atrophy (DRPLA) Proteins with expanded glutamine repeats. Paulson et al. (1999) Neuroserpine Familial Encephalopathy with Neuronal Inclusion Bodies (FENIB) Neuroserpine; S49P, S52R. 57 Davis et al. (1999) α-Synuclein Parkinson's disease, Lewy body dementia, multiple system atrophy Sporadic and inherited forms 19 Spillantini et al. (1998) also PCT / GB2007 / 001105 A53T, A30P in rare autosomal dominant PD families. Polymeropoulos et al. (1997) TDP-43 FTLD-TDP Severe TDP-43 mutations 10-43 Mackenzie et al. (2010) Amyotrophic lateral sclerosis Severe TDP-43 mutations 10-43 Mackenzie et al. (2010) Cystatin C Angiopathy Cystatin C 12-13 Abrahamson QCQ«nn / C7n7 / e / YiAi Hereditary cerebral (Icelandic) minus 10 residues; L68Q. et al. (1992) Superoxide dismutase 1 Amyotrophic lateral sclerosis SOD1 mutations. 16 Shibata et al. (1996) QCQ«nn / C7n7 / e / YiAi As described in documents WO 02 / 055720, WG2007 / 110630, and WO2007 / 110627, diaminophenothiazines are useful in inhibiting such protein aggregation diseases. Thus it will be appreciated that, except where the context otherwise requires, the description of modalities with respect to tau protein or tau-like proteins (e.g., MAP2; see below) should be taken as applying equally to the other proteins discussed herein (e.g., TDP-43, β-amyloid, synuclein, prion, etc.) or other proteins which can initiate or undergo similar pathological aggregation by virtue of a conformational change in a domain critical for aggregation propagation, or which imparts proteolytic stability to the aggregate thus formed (see, e.g., the article by Wischik et al. in Neurobiology of Alzheimer's Disease, 2nd Edition, 2000, Eds. Dawbarn, D. and Alien, SJ, The Molecular and Cellular Neurobiology Series, Bios Scientific Publishers, Oxford). All of such proteins may be referred to herein as aggregation disease proteins. Similarly, where tau-tau aggregation, or similar, is mentioned herein, this can also be considered applicable to other protein aggregation, such as β-amylorde aggregation, prion aggregation, synuclein aggregation, and so on. The same applies to tau proteolytic degradation, etc. Preferred Target Proteins for Aggregation Disease Preferred embodiments of the invention are based on the tau protein. The term tau protein, as used herein, generally refers to any protein of the tau family. Tau proteins are characterized as being among a large number of protein families that co-purify with microtubules during repeated cycles of assembly and disassembly (see, for example, Shelanski et al., 1973, Proc. Nati. Acad. Sci. USA, Vol. 70, pp. 765-768), and are known as microtubule-associated proteins (MAPs). Members of the tau family share the common characteristics of having a characteristic N-terminal segment, sequences of approximately 50 amino acids inserted into the N-terminal segment, which are QCQ«nn / C7n7 / e / YiAi regulated development in the brain, a characteristic serial repeat region consisting of 3 or 4 serial repeats of 31-32 amino acids, and a C-terminal tail. MAP2 is the predominant microtubule-associated protein in the somatodendritic compartment (see, for example, Matus, A., in Microtubules [Hyams and Lloyd, Eds.] pp. 155-166, John Wiley and Sons, New York, USA). MAP2 isotherms are nearly identical to tau protein in the serial repeat region, but differ substantially in both the sequence and extent of the N-terminal domain (see, for example, Kindler and Garner, 1994, Mol. Brain Res., Vol. 26, pp. 218-224). However, aggregation in the serial repeat region is not selective for the tau repeat domain. Thus, any discussion herein concerning tau protein or tau-tau aggregation must also be considered in relation to tau-MAP2 aggregation, MAP2-MAP2 aggregation, and so on. In some forms, the protein is a tau protein. In some forms, the protein is a synuclein, for example, α- or β-synuclein. In some forms, the protein is TDP-43. TAR DNA-binding protein 43 (TDP-43) is QCQ«nn / C7n7 / e / YiAi is a 414-amino-acid protein encoded by TARDBP on chromosome lp36.2. The protein is highly conserved, widely expressed, and predominantly localized in the nucleus but can intercalate between the nucleus and cytoplasm (Mackenzie et al., 2010). It is involved in transcription and splicing regulation and may have roles in other processes, such as microRNA processing, apoptosis, cell division, messenger RNA stabilization, regulation of neuronal plasticity, and maintenance of dendritic integrity. Furthermore, since 2006, a substantial body of evidence has accumulated supporting the toxic gain of TDP-43 hypothesis of function in amyotrophic lateral sclerosis (ALS). TDP-43 is an inherently aggregating pronic protein and the aggregates formed in vitro are ultrastructurally similar to the TDP-43 deposits seen in neuronal degeneration in ALS patients (Johnson et al 2009).Johnson et al. (2008) showed that when TDP-43 is overexpressed in a yeast model, only the aggregated form is toxic. Several in vitro studies have also shown that C-terminal fragments of TDP-43 are more likely to form insoluble cytoplasmic aggregates than full-length TDP-43, becoming ubiquitinated and toxic to cells (Arai et al. 2010; Igaz et al. 2009; Nonaka et al. 2009; Zhang et al. 2009). However. Nonaka et al. (2009) suggest that these cytoplasmic aggregates bind to the endogenous full-length protein, depleting it from the nucleus. Zhang et al. (2009) found retention of normal nuclear expression, suggesting a purely toxic effect of the aggregates. Yang et al. (2010) described the trapping of full-length TDP-43 within aggregates of C- and N-terminal TDP-43 fragments in cultured NSC34 motor neurons. Neurite growth, altered as a result of the presence of such truncated fragments, could be rescued by overexpression of the full-length protein. Although the role of neurite growth in vivo has not been established, this model could support the suggestion made by Nonaka et al. for an aggregation role of TDP-43 in the pathogenesis of ALS. The expression of mutant TDP-43 in cell cultures has already been repeatedly reported to result in increased generation of C-terminal fragments, with even greater cytoplasmic aggregation and toxic effects than the wild-type protein (Kabashi et al 2008; Sreedharan et al 2008; Johnson et al 2009; Nonaka et al 2009; Arai et al 2010; Barmarda et al 2010; Kabashi et al 2010). Where the protein is a tau protein, in some embodiments of the present invention, a method is provided for inhibiting the production of aggregated protein aggregates (e.g., in the form of helical filaments) QCQ«nn / C7n7 / e / YiAi paired (PHFs), optionally in neurofibrillary tangles (NFTs) in the brain of a mammal, the treatment is as described above. Preferred indications - Protein aggregation disease In one embodiment, the present invention is used for the treatment of Alzheimer's disease (AD) - for example, mild, moderate, or severe AD. Notably, it is not only Alzheimer's disease (AD) in which the tau protein (and its aberrant function or processing) may play a role. The pathogenesis of neurodegenerative disorders such as Pick's disease and progressive supranuclear palsy (PSP) appears to correlate with an accumulation of pathologically truncated tau aggregates in the dentate gyrus and stellate pyramidal cells of the neocortex, respectively. Other dementias include frontotemporal dementia (FTD); FTD with chromosome 17-linked parkinsonism (FTDP-17); disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC); pallidopontonigral degeneration (PPND); Guam-ALS syndrome; and pallidonigro-Louisian degeneration (PNLD). corticobasal degeneration (CBD) and others (see, for example, the article by Wischik et al. in Neurobiology of Alzheimer's Disease, 2nd Edition, 2000, Eds. Dawbarn, D. and Alien, SJ, The Molecular and Cellular Neurobiology QCQ«nn / C7n7 / e / YiAi Series, Bies Scientific Publishers, Oxford; especially Table 5.1). All these diseases, which are characterized mainly or partially by abnormal tau aggregation, are referred to herein as tauopathies. Thus, in some forms, the condition of the disease is tauopathy. In some forms, the disease condition is a neurodegenerative taupopathy. In some modalities, the disease condition is selected from Alzheimer's disease (AD), Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), FTD with chromosome 17-linked parkinsonism (FTDP 17), frontotemporal lobar degeneration syndromes (FTLD); disinhibition-dementia-parkinsonism-amyotrophy complexes (DDPAC), pallidopontonigral degeneration (PPND), Guam-ALS syndrome, paleo-Louisian degeneration (PNLD), corticobasal degeneration (CBD), argyrophilic granule dementia (AgD), dementia pugilistica (DP) or chronic traumatic encephalopathy (GTE), Down syndrome (DS), Lewy body dementia (DLB), subacute sclerosing panencephalitis (SSPE), MCI, Niemann-Pick disease, type C (NPC), Sanfilippo syndrome type B (mucopolysaccharidosis III B), or myotonic dystrophies (DM), DM1 or DM2, or chronic traumatic encephalopathy (GTE). In some forms, the disease condition QCQ«nn / C7nz / e / YiAi is a lysosomal storage disorder with tau pathology. NPC is caused by mutations in the NPd gene, which affects cholesterol metabolism (Love et al., 1995), and Sanfilippo syndrome type B is caused by a mutation in the NAGLU gene, in which there is lysosomal accumulation of heparin sulfate (Ohmi et al., 2009). In these lysosomal storage disorders, tau pathology is observed, and its treatment can slow disease progression. Other lysosomal storage disorders are also characterized by tau accumulation. The use of phenothiazine diammonium salts in the treatment of Parkinson's disease and MCI is described in more detail in documents PCT / GB2007 / 001105 and PCT / GB2008 / 002066. In some forms, the disease condition is Parkinson's disease, MCI, or Alzheimer's disease. In some forms, the disease condition is Huntington's disease, or another polyglutamine disorder such as spinal bulbar muscular atrophy (or Kennedy's disease), and dentalorubropallidal-Louisian atrophy and various types of spinocerebellar ataxias. In some forms, the disease condition is an FTLD syndrome (which may be, for example, a TDP-43 tauopathy or proteinopathy, see below). In some forms, the disease condition is ESP or ALS. TDP-43 proteinopathies include amyotrophic lateral sclerosis (ALS; ALS-TDP) and frontotemporal lobar degeneration (FTLD-TDP). The role of TDP-43 in neurodegeneration in ALS and other neurodegenerative disorders has been reviewed in several recent publications (Chen-Plotkin et al 2010; Gendron et al 2010; Geser et al 2010; Mackenzie et al 2010). ALS is a neurodegenerative disease characterized by progressive paralysis and muscle wasting resulting from the degeneration of both upper and lower motor neurons in the primary motor cortex, brainstem, and spinal cord. It is sometimes referred to as motor neuron disease (MND), but other diseases besides ALS affect either upper or lower motor neurons. A definitive diagnosis requires signs of both upper and lower motor neuron involvement in the bulbar, arm, and leg musculature, with clear evidence of clinical progression that cannot be explained by any other disease process (Wijesekera and Leigh 2009). Although most cases are ALS-TDP, there are other cases where the pathological protein differs from TDP-43. SOD1 misfolding is the pathological protein in ubiquitin-positive inclusions in ALS with mutations of SOD1 (see Setharaman et al., 2009) and in very small subseries (approximately 3–4%) of familial ALS, due to mutations in FUS (focused on sarcoma protein), the pathological ubiquitinated protein is FUS (Vanee et al., 2009; Blair et al., 2010). FUS, like TDP-43, appears to be important in the nuclear-cytoplasmic shuttle, although the ways in which the altered nuclear import of FUS occurs remain unclear. A new molecular classification of ALS, adapted from Mackenzie et al. (2010), reflects the distinct underlying pathological mechanisms in the different subtypes (see Table below). New Molecular Classification of ALS (modified from Mackenzie et al., 2010). In most cases, TDP-43 is the pathological ubiquitinated protein found in ALS. Positive ubiquitin inclusions in ALS Ubiquitinated disease protein TDP-43 FUS SOD1 Clinicopathological subtype ALS-TDP ALS-FUS ALS-SPD1 Associated genotype TARDBP FUS SOD1 Frequency of ALS cases Common Rare Rare Amyotrophic lateral sclerosis has been recognized as a nosological entity for almost a century and a half and is recognized in ICD-10 and is classified as a subtype of MND in ICD 10, codeG12.2. Reliable clinical diagnoses are available for ALS, which differ little from Charcot's original description, and the neuropathological criteria, reflecting the underlying molecular pathology, have also been agreed upon. While ALS is pathologically classified into three subgroups—ALS-TDP, ALS-SOD1, and ALS-FUS—the latter two conditions are rare. The largest study to date showed that all sporadic ALS cases had TDP-43 pathology (Mackenzie et al., 2007). Only about 5% of ALS is familial (Byrne et al., 2010), and SOD1 mutations, the most common mutations found in familial ALS, account for 12–23% of cases (Andersen et al., 2006). SOD1 may also be implicated in 2–7% of cases of familial ALS. FUS mutations appear to be fairly common, accounting for only about 3–4% of cases of familial ALS (Blair et al., 2010). Thus, it can be reliably predicted that a clinical case of familial ALS will have TDP-43-based pathology. Similarly, this can be reliably predicted in FALS due to mutations in TDP-43, which accounts for approximately 4% of cases (Mackenzie et al 2010).ALS with mutations in: VCP, represents 1-2% of FALS (Johnson et al 2010), ANG (Seilhean et al 2009), and CHMP2B (Cox et al 2010) have also been reported as being associated with TDP-43 positive pathology. Although SOD1, FUS and ΆΤΧΝ2 mutations have not been found to be associated with them. QCQ«nn / C7n7 / e / YiAi positive aggregates to TDP-43, however, TDP-43 has been reported to be involved in pathological processes that putatively originate from these mutations (Higashr et al 2010; Ling et al 2010; Elden et al 2010). Therefore, it is established that TDP-43 has an important, and potentially central, role in the pathogenesis of the vast majority of ALS cases and may be implicated in the pathogenesis of a significant proportion of FALS cases. ALS is now widely considered to be a TDP-43 proteinopathy (Neumann et al., 2009), and numerous in vitro and in vivo studies support the hypothesis that toxic gain of function due to TDP-43 aggregation is responsible for at least some of the neurotoxicities in the disease. FTLD syndromes are insidious, relentlessly progressive neurodegenerative conditions with a peak onset in late middle age. There is often a positive family history of similar disorders in a first-degree relative. The behavioral variant of FTD is characterized by a prominent early change in social and interpersonal functioning, often accompanied by repetitive behaviors and changes in eating patterns. In semantic dementia, word-finding difficulties are prominent, due to otherwise fluent speech, with QCQ«nn / C7n7 / e / YiAi degraded object knowledge and impaired single-word comprehension on cognitive assessment. Progressive nonfluent aphasia presents with a combination of motor speech problems and grammatical deficits. The core clinical diagnostic features for these three FTLD syndromes are shown in the table below and the full criteria in Neary et al (1998). QCQ«nn / C7n7 / e / YiAi Clinical Profile and Diagnostic Characteristics FTLD Syndromes Center FTLD Syndrome - Clinical Profile Core Diagnostic Features Frontotemporal Dementia Change in character and disordered social behavior are the dominant features initially and throughout the course of the disease. Instrumental functions of perception, spatial skills, praxis, and memory are intact or relatively well preserved. 1. Insidious onset and gradual progression 2. Early decline in social interpersonal behavior 3. Early deterioration in personal behavior regulation 4. Early emotional blunting 5. Early loss of perception Semantic Dementia Semantic disturbance (altered understanding of word meaning and / or object identity) is the dominant feature A) Insidious onset and gradual progression B) Language disturbance characterized by 1. Progressive, empty, effluent speech Initially and throughout the course of the disease. Other aspects of cognition, including autobiographical memory, are intact or relatively well preserved. 2. Loss of word meaning manifested by naming and impaired comprehension 3. Semantic paraphasias and / or 4. Perceptual disturbance characterized by 1. Prosopagnosia: impaired recognition of the identity of familiar faces and / or 2. Associative agnosia: impaired recognition of the identity of the object C) Preserved perceptual matching and reproduction of drawings D) Preserved single-word repetition E) Preserved ability to read loudly and write to dictate orthographically regular words Non-Effluent Progressive Aphasia Expressive language disturbance is the dominant feature initially and throughout the course of the disease. Other aspects of cognition are intact or relatively well preserved.A) Insidious onset and gradual progress B) Non-effluent spontaneous speech with at least one of the following: agrammatism, phonemic paraphasias, or anomia. QCQ«nn / C7n7 / e / YiAi The discovery that TDP-43-positive inclusions characterize ALS and FTLD-TDP (Neumann et al., 2006) was quickly followed by the identification of missense mutations in the TARDBP gene in both sporadic and familial cases of ALS (Gitcho et al., 2008; Sreedharan et al., 2008). To date, 38 different TARDBP mutations have been reported in 79 genealogically unrelated families worldwide (Mackenzie et al., 2010). TARDBP mutations account for approximately 4% of all families and approximately 1.5% of sporadic ALS cases. As of December 2010, mutations in thirteen genes associated with sporadic and familial ALS have been identified. A link between ALS and five other chromosome sites has been demonstrated, but many specific mutations remain unidentified. TDP-43 proteinopathy MT has a mode of action which directs and can reduce the aggregation of TDP-43 protein in cells, which is a pathological feature of the vast majority of familial and sporadic ALS and is also characteristic of FTLD-P. Furthermore, laboratory data show that methylthioninium inhibits the formation of TDP-43 aggregates in QCQ«nn / C7n7 / e / YiAi SH-SY5Y cells. After treatment with 0.05 mM MT, the number of TDP-43 aggregates was reduced by 50%. These findings were confirmed by immunostaining analysis (Yamashita et al 2009). The compounds and compositions of the invention may therefore be useful for the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Huntington's disease and polyglutamine disorders MT can reduce polyglutamine protein aggregation in cells, a pathological feature of Huntington's disease. Huntington's disease is caused by an expansion of translated CAG repeats located at the N-terminal end of huntingtin. Wild-type chromosomes contain 6–34 repeats, while in Huntington's disease, chromosomes contain 36–121 repeats. The age of onset of the disease is inversely correlated with the length of the CAG tracts encoding polyglutamine repeats within the protein. Laboratory data show that methylthioninium inhibits the formation of aggregates of a huntingtin derivative containing a 102-residue polyglutamine stretch in zebrafish (van Bebber et al. 2010). MT, when tested at 0, 10, and 100 mM, prevents the formation of QCQ«nn / C7n7 / e / YiAi such aggregates in zebrafish in a dose-dependent manner. The compounds and compositions of the invention may therefore be useful in the treatment of Huntington's disease and other polyglutamine disorders such as spinal bulbar muscular atrophy (or Kennedy's disease), and dentalorubropallidal-Louisian atrophy and various spinocerebellar ataxias (Orr & Zoghbi, 2007). Mitochondrial Diseases.es and Lafora Disease The most frequently affected organ in mitochondrial disorders, particularly respiratory chain diseases (RCDs), besides skeletal muscle, is the central nervous system (CNS). CNS manifestations of RCDs include stroke-like episodes, epilepsy, migraine, ataxia, spasticity, movement disorders, psychiatric disorders, cognitive decline, or even dementia (mitochondrial dementia). To date, mitochondrial dementia has been reported in MELAS, MERRF, LHON, CPEO, KSS, MNGIE, NARP, Leigh syndrome, and Alpers-Huttenlocher disease (Finsterer, 2009). There are four complexes in the mitochondrial respiratory chain, involving a series of electron transfers. Abnormal function of any of these complexes can result in mitochondrial diseases secondary to an abnormal electron transport chain and subsequent abnormal mitochondrial respiration.Complex III of the mitochondrial respiration chain acts to transfer electrons to cytochrome c. The compounds and compositions of the invention can also be used to treat mitochondrial diseases associated with impaired and / or altered function of Complex III of the respiratory chain. The compounds have the ability to act as an effective electron carrier and / or transfer agent, since the thioninium portion has a low redox conversion potential between the oxidized and reduced forms. In cases of impaired and / or impaired Complex III function leading to mitochondrial diseases, the compounds of the invention are also capable of performing the electron transport and transfer function of Complex III due to the ability of the thioninium portion to intercalate between the oxidized and reduced forms, thereby acting as an electron carrier in place of the suboptimally functioning Complex III, transferring electrons to cytochrome c. The compounds and compositions of the invention also have the ability to generate an active thioninium portion that has the ability to divert amino acid / misfolded protein monomers / oligomers away from the accumulation of Hsp70 ADP-associated protein and / or refolding pathways, and preferably rechannel these abnormally folded protein monomers / oligomers to the pathway that leads directly to the Hsp70 ΆΤΡ-dependent ubiquitin-proteasome system (UPS), a pathway which removes these misfolded protein / amino acid monomers / oligomers by the direct route (Jinwal et al. 2009). Lafora disease (LD) is a juvenile-onset autosomal recessive fatal epilepsy associated with the gradual accumulation of insoluble, poorly branched glycogen called polyglucosan in many tissues. In the brain, polyglucosan bodies, or Lafora bodies, form on neurons. Inhibition of Hsp70 ATPase by MT (Jinwal et al. 2009) can upregulate the removal of misfolded proteins. Lafora disease is primarily due to a defect in the lysosomal ubiquitin-proteasomal system (UPS) caused by a mutation in either the Laforin or Malin genes, both located on chromosome 6, resulting in inclusions that can accelerate the aggregation of misfolded tau protein.Secondary mitochondrial damage from the altered USP can further result in suppressed mitochondrial activity and an altered electron transport chain, leading to additional lipofuscin and initiating the seizures that are characteristic of Lafora disease. The MT portion can disaggregate existing tau aggregates, reduce further tau accumulation, and improve lysosomal efficiency by inhibiting Hsp70 ATPase. MT can lead to a reduction in tau tangles by improving the removal of tau monomers / oligomers by the ubiquitin proteasomal system through its inhibitory action on Hsp70 ATPase. Thus, the compounds and compositions of the present invention may be useful in the treatment of Lafora disease. Mixtures of oxidized and reduced MT compounds The LMT-containing compounds used in the present invention may include oxidized compounds (MT+) as impurities during synthesis, and may also oxidize (e.g., self-oxidize) after synthesis to give the corresponding oxidized forms. Thus, it is probable, if not inevitable, that compositions comprising the compounds of the present invention will contain, as an impurity, at least some of the corresponding oxidized compounds. For example, an LMT salt may include up to 15%, e.g., 10 to 15% of an MT+ salt. When mixed MT compounds are used, the MT dosage can be easily calculated using the molecular weight factors of the compounds present. QCQ«nn / C7n7 / e / YiAi Salts and Solvates Although the compounds containing MTs described herein are the same salts, they may also be provided in the form of a mixed salt (i.e., the compound of the invention in combination with another salt). Such mixed salts are proposed to be encompassed by the term "and pharmaceutically acceptable salts thereof." Unless otherwise specified, a reference to a particular compound also includes salts thereof. The compounds of the invention may also be provided in the form of a solvate or hydrate. The term solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of the compound) and solvent. If the solvent is water, the solvate may conveniently be referred to as a hydrate, e.g., a monohydrate, dihydrate, trihydrate, pentahydrate, etc. Unless otherwise specified, any reference to a compound also includes the solvate and any of its hydrate forms. Naturally, the solvates or hydrates of salts of the compounds are also covered by the present invention. A number of patents and publications are cited herein in order to describe more fully the QCQ«nn / C7n7 / e / YiAi invention and the prior art to which the invention belongs. Each of these references is incorporated herein by reference in its entirety in the present description, to the same extent as if each individual reference were specifically and individually indicated to be incorporated by reference. Throughout this description, which includes the claims that follow, unless the context otherwise requires, the word comprise, and variations such as comprise and that comprise, shall be understood to imply the inclusion of a declared whole or stage or group of members or stages, but not the exclusion of any other member or stage or group of members or stages. It should be noted that, as used in the description and accompanying claims, the singular forms a, one, and the include plural referents unless the context clearly dictates otherwise. Thus, for example, the reference to a pharmaceutical carrier includes mixtures of two or more such carriers, and the like. Intervals are often expressed here as being from approximately one particular value, and / or to approximately another particular value. When such an interval is expressed, another modality includes being from one particular value and / or to the other particular value. Similarly, when the QCQ«nn / C7nz / e / YiAi values ​​are expressed as approximations, by the use of the antecedent approximately, it will be understood that the particular value forms another modality. Any of the subheadings herein are included for convenience only, and are not being constructed as limitations of the description in any way. The invention will now be further described with reference to the following non-limiting Figures and Examples. Other embodiments of the invention will be revealed to those skilled in the art of reading these. The description of all references cited herein, insofar as they may be used by those skilled in the art to carry out the invention, are thus specifically incorporated herein by cross-reference. Examples Example 1 - provision of the compound containing MT Methods for the chemical synthesis of compounds containing MT that are known in the art are described herein. For example: Synthesis of compounds 1 to 7 can be carried out in accordance with the methods described in document W02012 / 107706, or methods analogous to those. QCQ«nn / C7n7 / e / YiAi Synthesis of compound 8 can be carried out in accordance with the methods described in WO2007 / 110627, or a method analogous to those. Example 2 - Provision of symptomatic AD treatments Symptomatic AD treatments include those that directly modify synaptic neurotransmission in the brain and are commercially available as acetylcholinase inhibitors (AChEIs) or NMDA receptor antagonists. Examples of ACheEIs include tracrin (Cognex™, First Horizon), donepezil (Aricept™, formely Reminil™, Ortho-McNeil). Memantines available as Ebixa™ or Namenda™, for example from Forest. Example 3 - a new population PK model for MT In an initial model (not shown), the arrangement of all MT portions (precursor MT, desmethyl MT, and LMT conjugate) was simultaneously characterized by a multi-compartment model. The arrangement of precursor MT after PO administration was adequately described by a two-compartment model with binding originating in plasma and tissue compartments, and delayed absorption originating through two transit compartments. This model has a fixed Ve. There is a tendency for the absorption rate to decrease with increasing dose, which is incorporated into the model using The dose-dependent absorption rate constant (Ka) was QCQ«nn / C7n7 / e / YiAi. Apparent oral clearance (CL / F) of precursor MT was related to renal function, such that a small portion of the variability in precursor CL was described by normalized creatinine clearance (CLCRN). A minor fraction of precursor MT was metabolized to desmethyl MT, and the disposition of desmethyl MT was described by a two-compartment model with linear elimination. Precursor MT was also converted to glucuronide-MLT, and its disposition was described by a one-compartment model with linear elimination. Notably, a fraction of conjugated LMT underwent enterohepatic recycling (EHR), which was physiologically mimicked by a gallbladder compartment with a pulsatile pattern of bile secretion. The model described above was applied to data from a single- or multiple-dose phase 1 study in older subjects (Study 036) to assess the model's ability to predict the steady-state pharmacokinetics (PK) of precursor metamizole (MT). The model was successfully fitted to data obtained from subjects who received either 4 mg twice daily (BID) or 10 mg once daily (QD) of lactose-free metamizole (LMTM) in Study 036. This PK model was later developed and simplified to a two-compartment model adjusted for precursor MT concentrations only. A schematic of this simplified population PK model for MT is provided in Figure 1. This model has a fixed Ve, QCQ«nn / C7n7 / e / YiAi but the dose-dependent Ka was removed. This model was derived from Study 036 described above. The post-PO administration disposition of LMTM was adequately described by a two-compartment model with delayed absorption occurring through two transit compartments. The apparent oral clearance (CL / F) of precursor MT was related to renal function such that a small portion of the variability in precursor CL is described by normalized creatine clearance (CLCRN). The model was successfully fitted to data obtained from subjects who received either 4 mg BID or 10 mg QD of LMTM in study 036. The simplified model provides a similar fit to the more sophisticated model, but allows co-modeling of all Study 036 data. Overall, excellent fits to individual subject data were obtained, suggesting that the model provides an adequate description of the precursor MT PK after LMTM administration. Example 4 - estimation of MT precursor Cmax in patients who received 4 mg BID in phase 3 AD studies (studies 005 and 015). The trial design for phase 3 AD studies 005 and 015 is described in examples 4 and 3, respectively, of WO2018 / 019823; these examples also discuss the results. The description of those examples is specifically incorporated herein by reference. Briefly, these phase 3 trials compared high doses of LMTM (150–250 mg / day) with a low dose (8 mg / day) proposed as a potential urine discoloration mask (Gauthier 2016; Wilcock 2018). These trials showed potential utility for LMTM, particularly as monotherapy, in delayed disease progression in imaging and brain endpoints, and that the high doses did not confer any greater potential benefit than the 8 mg / day dose. The population PK model was then used to estimate Cmax of precursor TM in patients who received 4 mg or high doses (c. 200 mg / day) in these phase 3 studies. This Bayesian process involves setting the population mean and interindividual variability parameters to the estimates from fitting the population PK model to the steady-state data from study 036 and allowing the program to select a series of parameters, giving those prior Bayesians, which best predict the day 1 precursor MT concentrations in each individual. The distribution of resulting Cmax estimates is provided in Figures 2a and 2b. The ~200 mg / day group QCQ«nn / C7n7 / e / YiAi represents subjects with combined high doses from study 015 (150 and 250 mg / day) and study 005 (200 mg / day). In these figures, the vertical black lines indicate the mean for each distribution, which can be used to divide patients into low and high Cmax groups. Example 5 - Assessment of different effects of 8 mg / day combined doses as mono- or adjunctive therapy from studies 005 and 015 in high and low steady-state Cmax groups Using a Repeated Measurement procedure of Mixed Effect Model (MMRM), ADAS-cog switching over 65 weeks for mono- or adjunctive 8 mg / day therapy from studies 005 and 015 was calculated for the high Cmax and low Cmax groups, in each case divided into those receiving LMTM as monotherapy, or in combination (adjunctive) with symptomatic treatments (AChEIs and / or memantine). The results are shown in Figures 3a and 3b, which display the same data. Patients using symptomatic treatments are labeled Achmem. Figure 3a emphasizes the findings in WO2018 / 19823 that symptomatic treatments interfere with the effect of LMTM treatment. The mean difference between monotherapy and adjunctive therapy can be observed to be ~4 ADAS-cog units. As highlighted in Figure 3b, inexplicably, the analysis of this low dose (8 mg / day) also showed a difference between high and low Cmax groups for monotherapy of ~2.4 ADAS-cog units, and a difference between high and low Cmax groups for complement groups of ~2.7 ADAS-cog units, i.e., the same concentration-dependent difference as seen for monotherapy and complement treatment. In further analysis, Figures 4a–4c show that the high Cmax group had less temporal lobe and whole-brain atrophy, and less expansion of both ventricles, with both monotherapy and complement therapy. As expected, there was less atrophy in the monotherapy group than in the complement therapy group. It has been noted that statistically significant differences were achieved only in the complement therapy group, which had a substantially large number of subjects. The corresponding analysis of the combined dose group (average of 200 mg / day) does not show a corresponding different treatment effect between the high and low Cmax groups, whether as monotherapy or adjunct (data not shown). Example 6 - Safe and adverse events: benefits using minimum effective dose of LMT compounds Controlled, double-blind, phase three studies of LMTM have been completed (each in subjects QCQ«nn / C7n7 / e / YiAi with medium and medium to moderate AD and one subject with bvFTD). The results of the AD studies have been published (Gauthier et al., 2016; Wilcock et al., 2018). In these three studies, 1897 subjects received at least one dose of LMTM (Safety population [Five additional subjects with AD, who participated in one TRx-237-005 study site, received a dose of study drug were excluded from all analyses due to GCP violations]. 1679 subjects with AD and 218 subjects with bvFTD). Of these, 860 subjects received the control (LMTM 8 mg / day, 750 with AD and 110 with bvFTD) and 1037 subjects received at least one dose of LMTM at the higher doses of 150 to 250 mg / day (929 with AD and 108 with bvFTD). The mean ages of the study participants were 71 years (ranging to 89 years) for subjects with AD and 63 years (ranging to 79 years) for subjects with bvFTD. Overall, there was comparable representation by sex (55% female), with more AD subjects being female (58%) and more bvFTD subjects being male (63%). The majority of subjects were white (88% of AD and 91% of bvFTD). Approximately 17% of the AD subjects received LMTM as monotherapy (as reported in the report of QCQ«nn / C7nz / e / YiAi case of concomitant medication more than by stratification [overall, 87% of subjects received AChEI and / or memantine based on stratified randomization]), with the remainder receiving concomitant AChEI and / or memantine. Furthermore, the majority of subjects with bvFTD received LMTM as monotherapy (79%). Psychiatric disorders / symptoms are common, with depression reported by 23% of subjects overall and anxiety by 12%. Concomitant use of antidepressants and antipsychotics was more common in subjects with bvFTD (50% and 22%, respectively) compared to AD (36% and 10%, respectively). The most common treatment-emergent adverse events (TEAEs) considered at least possibly associated with LMTM given at a dose of 8 mg / day are GI (primarily diarrhea and nausea), genitourinary (primarily pollakiuria and urinary incontinence), hematologic (anemia, folate decrease, and folate deficiency), and nervous system-related (primarily fatigue, dizziness, headache, agitation, and insomnia). Other common events are considered to represent events expected in these patient populations over a duration of 12 to 18 days. QCQ«nn / C7n7 / e / Yi me se s. At the higher LMTM doses studied, 150 to 250 mg / day, there is a dose-related increase in the incidence of adverse events related to anemia (decreased hemoglobin in addition to anemia, decreased folate, and folate deficiency), gastrointestinal events (including vomiting and the possibility of associated weight loss, diarrhea, and nausea), and genitourinary events (including dysuria, urinary urgency, and apparent urinary tract infections, in addition to pollakiuria and urinary incontinence). The lack of a dose-response in systemic and nervous / psychiatric events (other than anxiety) suggests that these are associated with the subject's underlying condition and are unrelated to the treatment. The incidence of the most common adverse events (AEs) is summarized by dose in the following table from EX. 1. This includes AEs occurring at an incidence of >2.0% in either subjects randomized to 8 mg / day of LMTM or higher doses (150 to 250 mg / day). The subset of AEs that are severe in intensity are also included. As can be seen, few events occur at severe intensities with respect to dose. QCQ«nn / C7n7 / e / YiAi Table EX 1: Incidence of Treatment-Emergent Adverse Events in >2.0% of Subjects per Dose: 8 mg / day of LMTM vs. Higher Doses (Double-Blind, Phase 3 LMTM Combined Safety Population) MedDRA System Organ Class / Preferred Term 8 mg / day of LMTM (N=860) High Dose (150-250 mg / day) (N=1037) all n (%) Severe Intensity n (%) all n (%) Severe Intensity n (%) No. (%) of subjects reporting at least one of AEDs 720 (83.7%) 86 (10.0%) 902 (87.0%) 126 (12.2%) Blood and Lymphatic System Disorders Anemia 19 (2.2%) 1 (0.1%) 59 (5.7%) 0 Cardiac Disorders Atrial Fibrillation 17 (2.0%) 3 (0.3%) 10 (1.0%) 2 (0.2%) Gastrointestinal Disorders Abdominal Pain 16 (1.9%) 1 (0.1%) 30 (2.9%) 1 (0.1%) Upper abdominal pain 10 (1.2%) 1 (0.1%) 21 (2.0%) 0 Constipation 23 (2.7%) 2 (0.2%) 24 (2.3%) 1 (0.1%) Diarrhea 109 (12.7%) 5 (0.6%) 278 (26.8%) 14 (1.4%) Nausea 39 (4.5%) 1 (0.1%) 86 (8.3%) 1 (0.1%) Vomiting 20 (2.3%) 0 80 (7.7%) 3 (0.3%) General disorders and administration site conditions Fatigue 26 (3.0%) 0 38 (3.7%) 1 (0.1%) Peripheral edema 19 (2.2%) 0 20 (1.9%) 0 Infections and Infestations Bronchitis 27 (3.1%) 0 19(1.8%) 0 Nasopharyngitis 40 (4.7%) 0 43 (4.1%) 0 upper respiratory tract infection 35 (4.1%) 0 34 (3.3%) 0 urinary tract infection 76 (8.8%) 1 (0.1%) 116 (11.2%) 3 (0.3%) Injuries, poisonings and procedural complications Contusion 24 (2.8%) 0 15 (1.4%) 0 decrease 90 (10.5%) 4 (0.5%) 78 (7.5%) 7 (0.7%) Laceration 17 (2.0%) 0 14 (1.4%) 1 (0.1%) Investigations blood creatinine increased phosphokinase 18 (2.1%) 0 31 (3.0%) 0 decrease blood folate 45 (5.2%) 0 76 (7.3%) 0. Decreased renal creatinine clearance 20 (2.3%) 0 26 (2.5%) 0 Decreased hemoglobin 6 (0.7%) 0 34 (3.3%) 0 Decreased vitamin B12 23 (2.7%) 0 21 (2.0%) 0 Weight loss 18 (2.1%) 0 39 (3.8%) 0 Metabolism and Nutrition Disorders Loss of appetite 13 (1.5%) 0 39 (3.8%) 1 (0.1%) Dehydration 17 (2.0%) 4 (0.5%) 18 (1.7%) 2 (0.2%) QCQ«nn / C7n7 / e / YiAi MedDRA System Organ Class / Preferred Term 8 mg / day of LMTM (N=860) High Dose (150-250 mg / day) (N=1037) All n (%) Severe Severity n (%) All n (%) Severe Severity n (%) Folate Deficiency 17 (2.0%) 0 45 (4.3%) 0 Musculoskeletal and Connective Tissue Disorders Arthralgia 28 (3.3%) 0 31 (3.0%) 1 (0.1%) Back Pain 31 (3.6%) 1 (0.1%) 44 (4.2%) 2 (0.2%) Extremity Pain 19 (2.2%) 1 (0.1%) 17 (1.6%) 0 Nervous System Disorders Cerebral Microhemorrhage 24 (2.8%) 0 16 (1.5%) 0 Dizziness 49 (5.7%) 3 (0.3%) 64 (6.2%) 2 (0.2%) Headache 55 (6.4%) 1 (0.1%) 61 (5.9%) 3 (0.3%) Syncope 26 (3.0%) 1 (0.1%) 28 (2.7%) 5 (0.5%) Tremors 20 (2.3%) 0 13 (1.3%) 0 Psychiatric disorders Agitation 46 (5.3%) 1 (0.1%) 61 (5.9%) 7 (0.7%) Anxiety 52 (6.0%) 0 39 (3.8%) 2 (0.2%) Confusional state 22 (2.6%) 2 (0.2%) 45 (4.3%) 2 (0.2%) Depression 41 (4.8%) 0 37 (3.6%) 2 (0.2%) Hallucination 13 (1.5%) 0 21 (2.0%) 4 (0.4%) Insomnia 29 (3.4%) 0 32 (3.1%) 0 Suicidal ideation 27 (3.1%) 2 (0.2%) 30 (2.9%) 0 Renal and urinary disorders Dysuria 6 (0.7%) 0 75 (7.2%) 1 (0.1%) Urinary urgency 11 (1.3%) 0 35 (3.4%) 0 Pollakiuria 19 (2.2%) 0 71 (6.8%) 2 (0.2%) Urinary incontinence 34 (4.0%) 0 63 (6.1%) 1 (0.1%) Respiratory, thoracic and mediastinal disorders Cough 37 (4.3%) 0 42 (4.1%) 0 Skin and cutaneous tissue disorders Rash 21 (2.4%) 0 30 (2.9%) 0 Vascular disorders Hypertension 20 (2.3%) 0 22 (2.1%) 1 (0.1%). The TEAEs were further analyzed using MedDRA (Medical Dictionary for Regulatory Activities) related groupings, preferred terms for better estimating the incidence of potentially adverse events related to treatment. The incidence of all groups for subjects categorized by dose (8 mg / day) versus high dose (150 to 250 mg / day) is shown in Table EX 2 below. Table EX2: Incidence of Treatment-Emergent Adverse Events pooled with 8 mg / day of MLTM versus high doses (Combined Safety Population with QCQ«nn / C7n7 / e / YiAi LMTM, double-blind, Phase 3) Grouping Term TauRx 8 mg / day of LMTM (N=860) n (%) High Dose (150-250 mg / day) (N=1037) n (%) Effective symptoms / anxiety 60 (7.0%) 55 (5.3%) Anemia 111 (12.9%) 219 (21.1%) Behavioral symptoms 114 (13.3%) 118 (11.4%) Falls and related terms 188 (21.9%) 202 (19.5%) Liver function impairment 13 (1.5%) 34 (3.3%) Hypersensitivity 42 (4.9%) 63 (6.1%) Ischemic events, including myocardial infarction 20 (2.3%) 35 (3.4%) Psychotic symptoms 28 (3.3%) 34 (3.3%) Renal function impairment 29 (3.4%) 42 (4.1%) Renal and urinary disorders (including 135 (15.7%) 326 (31.4%) Sleep disorders 41 (4.8%) 48 (4.6%) Targeted gastrointestinal events 183 (21.3%) 401 (38.7%) The clustering that occurs in >10.0% of subjects treated with 8 mg / day of LMTM includes calving and related terms (22%), GI events (21%), renal and urinary disorders including infections (16%), symptoms of 100 behaviors and terms indicative of anemia (each grouping in 13%). There is a dose-related trend for an increased incidence of all of these (other falls and behavioral symptoms). For the less common clusters, there is also evidence of a dose-related trend for liver function impairment. The fact that several TEAEs appear to be dose-related clearly indicates a desire to use a minimum effective dose of MT. Example 7 - effect of Cmax on treatment effects using other scales Based on the available data, the Cmax effect was not observed when assessing the temporal lobe FDG-PET decrease. For this measurement, it appears that the high dose of LMTM (200 mg / day combined) currently attenuated benefit seen otherwise for LMTM monotherapy, despite some remaining monotherapy benefit (results not shown). Based on the available data, the effect of Cmax is not observed when evaluating outcome measurements: decrease in Study Activities of Alzheimer's Disease Cooperative for Daily Living (ADCSADL). 101 Example 8 - provides an optimized dosing regimen in AD subject populations In summary, a PK model was developed using closely sampled phase 1 study databases. From this steady-state Cmax per subject, it was estimated and used to divide patients taking 8 mg / day into low (below mean) and high (above mean) Cmax groups. Unexpectedly, the high and low Cmax groups differed in cognitive decline (as assessed using ADAS-cog) by -2.5 units, with this effect observed in both the monotherapy and adjunctive treatment groups. Interestingly, there is evidence of a dose-response relationship for FDGPET at high doses. Thus, the response to treatment is determined by two factors: 1. Monotherapy and adjunctive treatment status 2. Plasma concentration, which can vary in subject populations even for a given dose. For both groups (monotherapy and adjunctive therapy), there is therefore a benefit in dosing at a level sufficient to maximize the proportion of subjects in the high Cmax group (while also avoiding high doses, which have a less desirable clinical profile). Figure 5 estimates the proportion of subjects expected to be in the high Cmax group according to the dose. By way of illustration: At 4 mg twice daily, 50% of subjects had an earlier Cmax threshold, with a predicted treatment effect relative to placebo of ~5 units of ADAS-cog for 65 weeks. Using at least 16 mg twice daily (bid), a dosing regimen greater than 4 mg twice daily is desirable. However, there is little benefit in excess of around 20 mg twice daily (40 mg total), since it is estimated that the vast majority of treated subjects may be in the Cmax irrespective group if the dose is divided. There are at least two distinct reasons for wanting to use the minimum concentration that maximizes the beneficial cognitive treatment effect. First, TEAEs, more notable GI events, and renal and urinary disorders, including infections and hemolytic anemia, occur in a dose-related manner. Therefore, avoiding higher doses is clearly desirable to maintain an optimal clinical profile. Second, there is evidence of an inverse dose-response relationship for FDG-PET at high doses; that is, the benefit may actually be attenuated at high doses. These new findings definitely indicate that there is QCQ«nn / C7n7 / e / YiAi 103 benefit using low-dose LMT treatments that have been previously assumed, and further indicates that LMT treatments can be used as adjunctive to symptomatic treatments (although with less effect than for monotherapy). Example 9 - providing an optimized dosing regimen in populations undergoing bvFTD The trial design for the phase 3 LMTM trial in behavioral variant frontotemporal dementia (bvFTD) is described in Examples 3 to 10 of WO2018 / 041739; these examples also discuss the results. The descriptions in these examples are specifically incorporated herein by reference. The document WO2018 / 041739 concludes that there is less cognitive decline (as measured using ACER) observed at 4 mg twice daily and 100 mg twice daily than can be expected from historical studies. This can be expected if both the 4 mg twice daily (control arm) and 100 mg twice daily (active arm) arm demonstrate efficacy. Furthermore, the status and severity of AD co-medication were found to be significant covariates. Taking these covariates into account, significant benefits of ACE-R in patients taking mementin were observed compared to LMTM alone. Directional support benefits were also found in FAQ, MMSE, and time volume. The PK population model described above is 104 was used to estimate Cmax in MT patients in the bvFTD study. As in the AD trials described above, the mean value at each dose was taken as a threshold to divide patients into high Cmax and low Cmax groups. Figures 6a and 6b show the distribution of Cmax values ​​in bvFTD. The vertical black line indicates the division of the lower mean from the higher Cmax groups. Figure 7 shows the difference in the decline in the revised Addenbrooke's Cognitive Examination-Revised (ACE-R) scale according to the Cmax group in bv FTD patients receiving 8 mg / day of LMTM as monotherapy. The decline in Cmax in the low-dose group was found to be -13.3 ± 1.8 (which is comparable to Kipps et al., (2008) = -15.3 ± 1.4). However, the decline in Cmax in the high-dose group was much smaller (-6.1 ± 1.9). All efficacy analyses are based on a MMRM procedure. The difference between the high Cmax groups at 32 weeks was 4.2 ± 2.0 (p= 0.0389) and at 52 weeks 7.3 ± 2.6 (p= 0.0059). As illustrated in Figure 8, there was a very significant difference between the high / low groups in Cmax at 8 mg / day. At 200 mg / day, this appeared to be an inverse dose response. Figure 9 shows the difference in decrease in QCQ«nn / C7n7 / e / YiAi 105 The Functional Activities Questionnaire (FAQ) scale was measured in accordance with the Cmax group in bvFTD patients receiving 8 mg / day of LMTM as monotherapy. Again, the decrease was less than in the high Cmax group on this scale (decrease in the low group in Cmax at 52 weeks: 8.3 ± 0.9; decrease in the high group in Cmax at 52 weeks: 2.9 + 0.9; difference at 32 weeks: -3.6 ± 1.2 (p= 0.0022); difference at 52 weeks: -5.4 ±1.3 (p < 0.001). Figure 10 illustrates that the benefit of FAQ is observed for a high Cmax at 8 mg / day and is greatly reduced at 200 mg / day. Furthermore, there is a dose-response effect such that the overall benefit is reduced by 200 mg / day. Figures lla-llc show the corresponding changes in whole brain volume (WBV), temporal atrophy, and lateral ventricular volume (LW) in bvTFD patients. For BWV, in figure lia the decrease in the low group in Cmax at 52 weeks was -24.5 ± 2.6 (cm3). The decrease in the high group in Cmax at 52 weeks was -15.3 ± 2.5. The difference at 52 weeks was 9.2 ± 3.5 (p = 0.0089). Figure 11b shows the difference in the progression of frontotemporal atrophy according to the Cmax group in bvFTD patients who received 8 mg / day of LMTM as monotherapy (low group decrease in Cmax at 52 weeks; -2.3 ± 0.2 (cm3) ; high group decrease in Cmax at 52 weeks; QCQ«nn / C7n7 / e / YiAi 106 -1.7 ± 0.2, difference at 52 weeks: 0.6 ± 0.3 (p = 0.0247). Figure 11c shows the difference in ventricular expansion according to the Cmax group in patients receiving 8 mg / day of LMTM as monotherapy (low group increase in Cmax at 52 weeks; 8.3 ± 0.8 (cm3) ; high group increase in Cmax at 52 weeks; 5.0 ± 0.8; difference at 52 weeks: -3.3 ± 1.1 (p = 0.0027)). Interestingly, in ACE-R, there is again an inverse dose response for high doses, 200 mg / day. As concluded in document WO2018 / 04739, this further analysis confirmed the additional benefit of combining treatment with symptomatic therapies, with triple therapy (MT, acetylcholinesterase inhibitors) potentially offering benefits. For combination therapy, the benefit of excess Cmax (relative to ACE-R and FAQ) cannot be confirmed, as it takes into account smaller groups and therefore large error bars in the estimates (data not shown). Furthermore, the same data indicate that the addition of symptomatic therapies covers the deterioration at high doses (inverse dose response), at least in relation to these scales (data not shown). The significant volumetric MRI benefits for Cmax are best observed as adjunctive therapy (data not shown). These results confirm the concentration-response relationship for monotherapy of 8 mg / day for the QCQ«nn / C7n7 / e / YiAi 107 Cognitive function in bvFTD was similar to that seen in AD. There was also a concentration-response relationship for 8 mg / day monotherapy on the functional FAQ scale in bvFTD and an inverse dose-response relationship for high-dose monotherapy (i.e., 200 mg / day) was worse than that for 8 mg / day). Absolutely, a low dose administered in a regimen that ensures a high Cmax (e.g., -20 mg / day (10 mg bid)) appears to be an optimal monotherapy treatment for bvFTD. However, as previously noted, and in contrast to AD, there is an additional benefit of combining it with symptomatic treatments, which may be particularly noticeable in the low Cmax group. In view of these factors, a regimen can be initiated with LMTX monotherapy at 8 mg / day and then increased to ~20 mg / day, with the possibility of adding symptomatic AD treatments in bvFTD as the disease progresses. Example 10 - further analysis in relation to the optimized dosing regimen in populations subjected to AD A more informative procedure which allows statistical analysis to be conducted is for categorized patients receiving LMTM at a dose of 8 mg / day at the Cmax,EE bases using a threshold that defines the limit QCQ«nn / C7nz / e / YiAi 108 upper of the lower 35% of patients, corresponding to the 35% of patients with plasma levels below the validated limit of quantification (0.2 - 10 ng / ml; N = 208) following the first dose on day 1. That the threshold was < 0.373 ng / mL. The remaining 65% were categorized into three Cmax,ss groups of comparable size (N = 128 per group) to allow better visualization of the concentration-response relationship. Higher doses were grouped according to dose (N = 187–329 per group). Estimates based on the plasma model for these groups, as well as for the higher doses, are shown in Table EX3 below. QCQ«nn / C7n7 / e / YiAi Table EX3: Modeled precursor MT in plasma Cmax,s for all patients with plasma data available from studies TRx-237-015 and TRx-237-005 in accordance with either plasma Cmax,ss subgroups (LMTM, 8 mg / day) or dose (LMTM, 150-250 mg / day): Dose groups n(%) Cmax,ss (ng / mL) Mean (SD) Range 8 mg / day - Group 1 208 (35%) 0.334 (0.0251) 0.257-0.373 8 mg / day - Group 2 127 (21%) 0.393 (0.0125) 0.373-0.414 8 mg / day - Group 3 129 (22%) 0.449 (0.0189) 0.415-0.478 8 mg / day - Group 4 128 (22%) 0.565 (0.0810) 0.479-0.812 150 mg / day 188 (100%) 7.820 (1.787) 5 . 099-18.611 200 mg / day 329 (100%) 10.126 (2.374) 6.557-21.291 250 mg / day 187 (100%) 12.573 (2.460) 8 . 833-21.188 Standard error and least squared mean estimates for change in ADAS-cogu, ADCS-ADL23, LW and WBV show 109 clear concentration response as a clustering function Cmax,SE in patients receiving LMTM at a dose of 8 mg / day (figs. 13a-13d). There is a general tendency to be higher but at exposure levels associated with doses in the 150-250 mg / day range, implying the existence of a biphasic dose response. Example 11 - Analysis based on Cmax threshold, critical therapeutic ss of 0.393 ng / ml in relation to the optimized dosing regimen in populations subjected to AD. Based on the division of patients according to the 0.373 ng / ml threshold, the difference in treatment in patients who received the 8 mg / day dose is -3.4 ADAS-cog units (see Table EX4 below, compare example 8 concerning the mean division showing approximately -2 to 3 ADAS-cog units): Table EX4 QCQ«nn / C7n7 / e / YiAi A. All; 5 patients divided by Cmax.ss 0.373 ng / ml B. Patients who received LMTM, 8 mg / day, divided by cmax.ss 0.373 ng / mL. Difference of±SEM Cl p value Nlow Nhigh Difference of ± SEM Cl p value Nlow Nalto ADAS - cog -2.99 ± 0.67 -4.32 - 1.67 <0.0001 193 969 -3.41 ± 0.76 -4.89 - 1.92 <0.0001 193 373 ADCS -ADL 0.54 ± 0.94 -1.30-2.38 0.5634 192 967 1.22 ±1.01 -0.77-3.21 0.2283 192 373 LVV (cm3) -1.52 ±0.34 -2.18- 0.83 <0.0001 184 863 -1.78 ± 0.38 -2.53 - - 1.03 <0.0001 184 335 WBV (cm3) 3.55 ± 1.06 1.48-5.62 0.0008 180 859 4.39 ±1.18 2.07-6.71 0.0002 180 332 110 The corresponding longitudinal trajectories over 65 weeks in accordance with Cmáz,ssa below or above the threshold value of 0.373 ng / mL are shown in Figures 14a-14d. Since only 65% ​​of patients receiving 8 mg / day had plasma concentrations above the threshold required for significant treatment benefit, it is desirable to determine the minimum dose at which 100% of patients can be expected to have plasma levels within the therapeutic range. Given the population variability observed in the large available dataset, it is possible to estimate the expected percentage of patients above the critical therapeutic threshold for Cmax,s (0.393 ng / ml) and Cmax,EE (0.223 ng / ml) according to once-daily (QD) and twice-daily (BID) dosing regimens. As can be seen in Figure 15, using either criterion and dosing regimen, LMTM needs to be given at a dose of at least 16 mg / day for 100% of patients to have plasma levels within the therapeutic range. Example 12 - Incorporation of the discriminator between monotherapy and compensatory therapy An additional consideration is whether patients are dosed with LMTM alone or in combination with AD-enhanced therapies (AChEIs and / or memantine). Patients receiving the 8 mg / day dose were also examined 111 compliance with the co-medication status with these drugs. As can be seen in Table EX 5 below, the difference between patients who have steady-state plasma levels above and below the threshold of 0.373 ng / ml reached statistical significance if LMTM is taken as monotherapy or as compensatory therapy at cognitive atrophy (ADAS-cog) and brain (LW and WBV) endpoints. Table EX5. Comparison of AD patients who received LMTM 8 mg / day, with Cmax above and below the precursor MT threshold of 0.373 ng / ml: Categorized in accordance with AChEI and / or memantine use states at the reference value QCQ«nn / C7n^ / e / YiAi LMTM, 8 mg / day, as monotherapy LMTM, 8 mg / day, as compensatory therapy Cl difference ±SEM p value Nlow Nhigh Difference ± SEM Cl p value Nlow Nalto ADAS- cogn -2.60 ±1.16-4.88- 0.33 0.0251 33 67 -3.52 ± 0.78 -5.05- 2.00 0.0001 160 306 ADCS ADL23 0.46 ± 1.47 -2.43- 3.34 0.7552 32 67 1.32 ± 1.04 -0.71 3.36 0.2016 160 306 LW (cm3) -1.46 + 0.45 _2 33— 0.58 0.0011 33 61 -1.35 ± 0.37 -2.08- 0.62 0.0003 151 274 WBV (cm3) 2.76 ± 1.66 -0.49- 6.01 0.0966 32 61 4.69 ± 1.21 2.32- 7.06 0.0001 148 271 The corresponding longitudinal trajectories over 65 weeks are illustrated below by ADAS-gogu, ADCS-ADL23, LW and WBV in Figures 16a-16d. Example 13 - ADAS-cogll analysis decreases against plasma concentration Further analysis of ADAS-cog decreases over A 112-week study was conducted using a modified form of the Hill equation (Wagner, 1968) to estimate the minimum and maximum plasma concentrations for the expected treatment response over 65 weeks. The Hill equation was applied under the assumption of non-cooperation, and a general zero was imposed, with the no-effect level taken as 11 units at a Cmax.ss concentration of 0.29 ng / mL based on visual inspection of the data. The use of different cutoff values ​​did not significantly change the results. In addition, a linear term was added to allow trends occurring at high concentrations to be included in the model using data for doses in the range of 150 to 250 mg / day. The extended Hill equation was applied to the data as follows: change in parameter = Einin - (Emax * ([C] - 0.29)) / (EC50 + ([C] - 0.29)) + (A * ([C] - 0.29)) where Einin is the imposed zero value, Emax is the maximum treatment effect assumed in the standard Hill equation, EC50 is the Cmax.ss at which the treatment effect is 50% of the maximum assumed in the standard Hill equation, and A is an additional linear term estimated by the model to account for a potential biphasic response. Cmax.ss was also expressed as the estimated mean equivalent dose using a relationship obtained by fitting a linear model to mean plasma concentrations at doses of 8, 150, 200 113 and 250 mg / day: estimated dose (mg / day) = 0.045*Cmax,ss + 0.016 As can be seen in Fig. 17, there is a general biphasic concentration-response for LMTM taken alone or in combination with symptomatic treatments. The dose range in which the treatment response is estimated to be maximal is 20 to 60 mg / day. Compared with monotherapy, the estimated maximum treatment response is reduced by approximately 4 ADAScog units when LMTM is combined with symptomatic treatments. An additional effect is to shift the Cmax.ss concentration required for the maximum half-treatment response to the right, from 0.32 ± 0.01 ng / mL to 0.40 ± 0.05 ng / mL. It will become evident that the effects of plasma concentration and co-medication status are additive. This allows for a general estimation of treatment benefit by comparing patients receiving the 8 mg / day dose as monotherapy who have plasma levels above the 0.373 ng / mL threshold with patients receiving the same dose in combination with symptomatic treatments who have plasma levels below this threshold. As can be seen in Fig. 17, the latter group comes closer to the approximation of the minimum measurable treatment response. This analysis shows that the treatment effect for the 8 mg / day dose as QCQ«nn / C7n7 / e / Y 114 monotherapy in patients with therapeutic plasma levels of the drug is -7.53 (C1 -9.93 - -5.13, p <0.0001) ADAS-cogn units, with corresponding treatment effects for ADCS-ADL??, LW and WBV (Table EX6 below): Table EX6: Comparison of LMTM as an adjunct versus monotherapy and between the Cn,á:·: low adjunct and Cmá-;high monotherapy. Comparison of LMTM, 8 mg / day, in monotherapy low Cmax complement of Cmax versus high Cmax QCQ«nn / C7n7 / e / YiAi Difference ± SEM Cl p value complemc ntO Nlow ✓ Nalto.mono ADAS- -7.53 ±1.22 -9.93-5.13 < 0.0001 160 67 cogn ADCS- 6.14± 1.64 2.93-9.34 0.0002 160 67 ADL23 LVV (cm3) -3.15 ±0.62 -4.37-1.93 < 0.0001 151 61 WBV (cm3) 11.54 ±1.87 7.88-15.21 < 0.0001 148 61 Example 14 - Implications of findings related to monotherapy versus complementary therapy in relation to dosing regimens. As can be seen from the above, there is a reduction in the maximum effect of LMTM when combined with symptomatic treatments. However, it should be noted that this relates to a context in which patients have received LMTM in the context of chronic pretreatment with symptomatic drugs. The mechanism for this has been elucidated in a series of experiments in a well-characterized transgenic tau mouse model. If these animals are In 115 patients previously treated chronically with a cholinesterase inhibitor (rivastigmine), almost all of the neurobiological effects observed when LMTM was administered alone were reduced or completely eliminated, leading to the elimination of LMTM's beneficial effect on spatial learning memory. Pretreatment with memantine also eliminated the effect on spatial learning memory (results not shown). The mechanism appears to be a generalized homeostatic negative regulation affecting many synaptic and neurotransmitter systems in the brain, counteracting the activating effects of symptomatic drugs. Therefore, the effects induced by LMTM are subject to dynamic negative regulation if the brain is already under chronic stimulation from prior symptomatic treatments. Example 15 - further analysis in relation to the provision of an optimized dosing regimen in FTP subject populations The cutoff value that defined the upper limit of the lowest 35% group (corresponding to the percentage of patients with plasma levels below the validated limit of quantification on day 1) was 0.346 ng / mi for the bvFTD population. Regarding the EA (see example 10), the rest QCQ«nn / C7nz / e / YiAi 116 with day 1 plasma levels within the validated quantification range at the 8 mg / day dose were distributed into 3 groups that had approximately the same number (22% each; see Table EX7 below). Table EX7: MT Cmax,ss plasma modeling precursor for LMTM groups Dose Groups Cmax.ss (ng / mL) n (%) Mean (SD) Range 8 mg / day 8 mg / day - Group 1 32 (35%) 0.321 (0.0198) 0.281-0.346 8 mg / day - Group 2 20 (22%) 0.355 (0.0082) 0.346-0.372 8 mg / day - Group 3 19 (21%) 0.387 (0.0121) 0.373-0.409 8 mg / day - Group 4 20 (22%) 0.470 (0.0537) 0.413-0.583 200 mg / day 81 9.040 (1.6259) 6.800-14.235 A similar concentration-response relationship exists for MRI measures of brain atrophy progression (frontotemporal volume, lateral ventricular volume, total brain volume). This is shown in Figs. 18a-18e. Alternative efficacy analyses were performed in which the group of patients with minimal systemic exposure to the drug was used as a placebo substitute. These are shown in Table EX8 below and illustrated in Figs. 19a-19e. Example 16 - Analysis of change in results against plasma concentration As can be seen in Figures 18a-18e above, the effects of the treatment were worse with the high dose 117 out of 200 mg / day in all outcomes, implying a biphasic concentration-response relationship in bvFTD. Regarding the effect (EA), an extended Hill equation was applied under the assumption of non-cooperation, and general zero values ​​were imposed, where the no-effect level was taken as -12 ACE-R units, 8 FAQ units, or -30 cm³ for total brain volume. The maximum concentration (Cmax.ss) was 0.29 ng / ml, as determined by visual inspection of the data. The use of different cutoff values ​​did not significantly change the results. Furthermore, a linear term was added to allow trends occurring at high concentrations to be included in the model, using the mean decrease that occurs with the 200 mg / day dose. 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Claims

1. A compound containing methylthioninium (MT) for use in the therapeutic or prophylactic treatment of a neurodegenerative disorder in a human subject, such treatment providing a total daily oral dose of between 20.5 and 60 mg of MT to the subject per day, optionally divided into 2 or more doses, wherein the MT-containing compound is an LMTX compound of the following formula: P(HA) q(HB) wherein each of HnA and HnB (where present) are protic acids which may be the same or different, and wherein p=102; q=00; n=102; (p+q) xn = 2, and wherein the disorder is selected from: (i) a synucleinopathy, which is optionally selected from Parkinson's disease, dementia with 140 Lewy bodies and multiple system atrophy; or (ii) an FTLD syndrome;or (iii) a polyglutamine disorder, which is optionally selected from Huntington's disease, spinal bulbar muscular atrophy, dentanorubropallidoluysian atrophy, or spinocerebellar ataxias; or (iv) hereditary cerebral angiopathy, amyotrophic lateral sclerosis, familial encephalopathy with neuronal inclusion bodies, or Lafora disease, and wherein therapeutic treatment is not combined with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist.

2. A compound for use according to claim 1, wherein the disorder is an FTLD syndrome that is (i) a TAR DNA-binding protein 43 (TDP-43) proteinopathy and / or (ii) is FTLD with tau pathology or FTLD with TDP-43 pathology and / or (iii) is selected from behavioral-variant frontotemporal dementia (bvFTD), primary progressive aphasia, and semantic dementia.

3. A compound for use according to claim 1, wherein the disorder is a polyglutamine disorder, which is optionally selected from Huntington's disease, spinal bulbar muscular atrophy, dentanorubropallidoluysian atrophy, or spinocerebellar ataxias. QCQ«nn / C7n7 / e / YiAi 141 4. A compound for use according to claim 1, wherein the disorder is a synuclemopathy, which is optionally selected from Parkinson's disease, Lewy body dementia, and multiple system atrophy.

5. A compound for use according to claim 1, wherein the disorder is hereditary cerebral angiopathy, amyotrophic lateral sclerosis, familial encephalopathy with neuronal inclusion bodies, or Lafora disease.

6. A compound for use according to claim 2, wherein the FTLD syndrome is behavioral-variant frontotemporal dementia (bvFTD), optionally wherein the total daily dose is between 20.5 and 40 mg of MT to the subject per day, optionally divided into 2 or more doses.

7. A compound for use according to any of claims 1 to 6, wherein the MT-containing compound has the following formula, wherein HA and HB are different monoprotic acids: QCQ«nn / C7n7 / e / YiAi II Me Me 8. A compound for use according to any of claims 1-6, wherein the MT-containing compound has the following formula: QCQ«nn / C7n7 / e / YiAi P(HX) wherein each of HnX is a protic acid.

9. A compound for use according to any of claims 1 to 6, wherein the MT-containing compound has the following formula and H2A is a diprotic acid: HA 10. A compound for use according to claim 8, wherein the compound containing MT has the following formula and is a bis monoprotic acid: 2(HA) 11. A compound for use in accordance with any one of claims 1 to 10, wherein the or each protic acid is an inorganic acid.

12. A compound for use according to claim 11, wherein each protic acid is a hydrohalic acid.

13. A compound for use in accordance with any one of claims 1 to 10, wherein the or each protic acid is an organic acid.

14. A compound for use according to claim 11 or 13, wherein the or each protic acid is selected from H2CO3; CH3COOH; methanesulfonic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, p-toluenesulfonic acid.

15. A compound for use according to any one of claims 1 to 6, wherein the compound containing MT is LMTM:

16. A compound for use according to any one of claims 1 to 6, wherein the compound containing MT is selected from the list consisting of: 144 QCQ«nn / C7n^ / e / YiAi 145 17. A compound containing methylthioninium (MT) for use in the therapeutic or prophylactic treatment of a neurodegenerative disorder in a human subject, such treatment providing a total daily oral dose of between 20.5 and 60 mg of MT to the subject per day, optionally divided into 2 or more doses, wherein the MT-containing compound is LMTM; and wherein the disorder is mild cognitive impairment.

18. A compound for use according to claim 17, wherein the therapeutic treatment is not combined with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist.

19. A compound for use according to claim 17, wherein the therapeutic treatment is combined with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist.

20. A compound for use according to claim 19, wherein the acetylcholinesterase inhibitor is selected from the list consisting of donepezil; rivastigmine; and galantamine and / or the N-methyl-D-aspartate (NMDA) receptor antagonist is memantine.

21. A compound for use according to any of claims 17 to 20, wherein the treatment is a combination treatment of a first agent being the compound containing MT in the specified dosage in combination with a second agent being an inhibitor of the processing of amyloid precursor protein to beta-amyloid.

22. A compound for use according to any of claims 17 to 21, wherein the treatment achieves or is intended to achieve a reduction in cognitive decline in the subject, which is optionally a reduction of at least 1, 2, 2.5, 3, 4, 5 or 6-point decline on the 11-point Alzheimer's Disease Assessment Scale (ADAS-cog) cognitive subscale over a period of 65 weeks.

23. A compound for use according to any of claims 17 to 22, wherein the treatment is part of a treatment regimen comprising: (i) treating the subject with the MT-containing compound for an initial period of time, wherein the administration provides a total daily dose of between 1 and 10 mg of MT to the subject per day, optionally 8 mg per day, optionally divided into 2 or more doses; (ii) treating the subject with the MT-containing compound for an additional period of time, wherein the administration provides a total daily dose of between 20.5 and 40, 20.5 and 60, 20.5 and 80 or 20.5 and 100 mg of MT to the subject per day, optionally divided into 2 or more doses.

24. A compound for use in accordance with any of claims 1 to 23, wherein the subject is a human who has been diagnosed with the neurodegenerative disorder, or wherein the method comprises making the diagnoses.

25. A compound for use in accordance with any of claims 1 to 23, wherein the subject is a human who has been assessed as susceptible to, or at risk of, the disorder, optionally based on family or genetic or other data.

26. A compound for use according to any of claims 1 to 25, wherein the total daily dosage of MT is 21 to 40 mg; 21 to 32 mg; or 24 to 32 mg.

27. A compound for use according to any of claims 1 to 26, wherein the total daily dose is approximately 20.5, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg.

28. A compound for use in accordance with QCQ«nn / C7n7 / e / Yi 148 any of claims 1 to 27, wherein the total daily dose of the compound containing MT is administered once a day, or as a divided dose twice a day or three times a day.

29. A compound for use according to any one of claims 1 to 18, wherein the subject: (a) has not historically received treatment with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist, or (b) has historically received treatment with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist, but has discontinued such treatment at least 1, 2, 3, 4, 5, 6, 7 days, or 2, 3, 4, 5, 6, 7, 8 weeks prior to treatment with the MT-containing compound, or (c) is selected as someone who is receiving treatment with an acetylcholinesterase inhibitor or an N-methyl-D-aspartate receptor antagonist, wherein the treatment is discontinued prior to treatment with the MT-containing compound.