Consequences of folate deficiency – treated by immunomodulators (Infliximab, IVIG, Propes and Inflamafertin) and the relevance of mutations in MTHFR, MTR, and MTRR genes in identifying those at risk. Plus the effect of rTMS and tDCS on milder autism

 

Today’s post returns to folate deficiency, but before that a quick mention of magnetic/electrical brain stimulation therapies for autism without impaired cognition.

I encountered a new term IC-ASD. It stands for intellectually capable autism spectrum disorder. Most people with autism these days seem to have IC-ASD. Some struggle and some do not.

 

The effects of rTMS and tDCS on repetitive/stereotypical behaviors,cognitive/executive functions in intellectually capable children and young adults with autism spectrum disorder: A systematic review and meta-analysis of randomized controlled trials

 

Objective

This study aims to evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on repetitive/stereotypical behaviors and cognitive/executive functions in children and young adults with intellectually capable autism spectrum disorder (IC-ASD).

Methods

Literature searches across PubMed, Web of Science, Cochrane Library, Embase, and Scopus were performed to identify randomized controlled trials (RCTs) evaluating the efficacy of rTMS and tDCS in children and young adults with IC-ASD. The search encompassed articles published up to April 25, 2025. The standardized mean difference (SMD) with 95 % confidence intervals (CI) was calculated and pooled. Sensitivity and subgroup analyses were conducted to assess potential sources of heterogeneity and refine the robustness of the findings.

Results

This meta-analysis included 18 RCTs involving 813 participants. Compared with sham interventions, tDCS demonstrated significant improvements in social communication, repetitive and stereotypical behaviors, cognitive and executive functions among individuals with IC-ASD (e.g., Social Responsiveness Scale: SMD = –0.48; 95 % CI: –0.75 to –0.22; p < 0.01). Similarly, rTMS improved social communication, repetitive and abnormal behaviors (Social Responsiveness Scale: SMD = –0.21; 95 % CI: –0.42 to –0.00; p < 0.05; Repetitive Behavior Scale-Revised: SMD = –0.62; 95 % CI: –1.17 to –0.07; p = 0.04; Aberrant Behavior Checklist: SMD = –0.53; 95 % CI: –0.79 to –0.26; p < 0.01). No significant heterogeneity was observed across studies.

Conclusion

tDCS and rTMS may enhance cognitive and executive functions and reduce repetitive behaviors in children and young adults with IC-ASD. However, these findings require careful interpretation due to the limited high-quality studies and variability in treatment protocols. Future research should prioritize the development of standardized protocols to address inconsistencies in stimulation parameters (including frequency, intensity, and duration) and core outcome sets. Additionally, larger-scale, rigorously blinded multi-center RCTs are necessary to accurately evaluate the clinical efficacy and applicability of these neuromodulation techniques in these populations.

 

rTMS and tDCS look like interesting non-pharmaceutical options for those with milder types of autism. How well they work in those with lower cognitive function is not addressed.

 

Back to Folate Deficiency

Stephen recently highlighted a Chinese study that looked at the relevance of mutations in the genes MTHFR, MTR, and MTRR to try and identify those most at risk of folate deficiency.

I also highlight research into treating some of the downstream consequences that occur when folate metabolism is impaired. The lack of folate disrupts the immune system causing anomalies such as low NK cells, low NKT cells, high TNF-alpha.

Immunodeficiency (Low NK and NKT cells): The deficiency in these crucial innate immune cells means the body's ability to fight off infections (particularly opportunistic ones) and perform immune surveillance (e.g., against abnormal cells) is compromised. This immunosuppression is a direct consequence of the impaired cell proliferation due to the folate cycle defect.

Systemic Inflammation (High TNF-alpha): Despite the low numbers of certain immune cells, there can be an overproduction of pro-inflammatory cytokines like TNF-alpha. This leads to chronic systemic inflammation. This phenomenon is often referred to as hypercytokinemia.

Beyond TNF-alpha, you might expect a possible overproduction of:

• Interleukin-1 beta (IL-1β): This is a potent pro-inflammatory cytokine involved in various immune responses and neuroinflammation.
• Interleukin-6 (IL-6): Another major pro-inflammatory cytokine that plays a role in systemic inflammation and can affect brain development and function.
• Interferon-gamma (IFN-γ): This is a key cytokine in Th1 immune responses and is also pro-inflammatory.

 

The recent Chinese study concludes that high-dose folinic acid appears to be a promising intervention for children with autism. Its efficacy is notably associated with specific folate metabolism gene polymorphisms. The researchers suggest that high-dose folinic acid may help to improve neurodevelopmental outcomes by alleviating the folate metabolism abnormalities caused by single or combined mutations in these genes.

This research indicates that providing a metabolically active form of folate (folinic acid, calcium folinate, leucovorin etc) can be a direct approach to address the underlying metabolic challenges in a subset of people with autism who have specific genetic predispositions related to folate metabolism. Children with MTHFR A1298C or MTRR A66G mutations showed greater improvements in various developmental domains compared to those with the standard versions.

The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group.

No significant adverse effects were observed during the intervention period.

 

How does this fit in with US research into brain folate deficiency in autism

US researchers consider an autoimmune mechanism where the body produces antibodies that specifically target the Folate Receptor Alpha (FRα). FRα is a crucial protein responsible for transporting folate across the blood-brain barrier (and into other cells).

When these antibodies bind to FRα, they block or interfere with the normal transport of folate into the cells, particularly into the brain. This results in Cerebral Folate Deficiency (CFD), where folate levels in the cerebrospinal fluid are low, despite potentially normal folate levels in the blood.

US research indicates that FRAAs are prevalent in a significant percentage of children with ASD (up to 70% in some studies) and are associated with specific physiological and behavioral characteristics.

Treatment with folinic acid/ leucovorin has been shown to be effective in many children with autism who are positive for FRAAs, improving symptoms like communication, irritability, and stereotypical behaviors. It is believed that high doses of folinic acid can overcome the transport blockade caused by the antibodies

The US and Chinese research avenues complement each other by identifying different, but potentially converging, pathways that lead to folate dysfunction in autism, both of which demonstrate the therapeutic potential of folinic acid.

Here is the Chinese paper: 

Safety and Efficacy of High-Dose Folinic Acid in Children with Autism: The Impact of Folate Metabolism Gene Polymorphisms

Background/Objectives: Research on the safety and efficacy of high-dose folinic acid in Chinese children with autism spectrum disorder (ASD) is limited, and the impact of folate metabolism gene polymorphisms on its efficacy remains unclear. This trial aimed to evaluate the safety and efficacy of high-dose folinic acid intervention in Chinese children with ASD and explore the association between folate metabolism gene polymorphisms and efficacy. Methods: A 12-week randomized clinical trial was conducted, including 80 eligible children with ASD, randomly assigned to an intervention group (n = 50) or a control group (n = 30). The intervention group was administered folinic acid (2 mg/kg/day, max 50 mg/day) in two divided doses. Efficacy was measured using the Psycho-Educational Profile, Third Edition (PEP-3) at baseline and 12 weeks by two trained professionals blind to the group assignments. Methylenetetrahydrofolate reductase (MTHFR C677T, MTHFR A1298C), methionine synthase (MTR A2756G), and methionine synthase reductase (MTRR A66G) were genotyped by the gold standard methods in the intervention group. Results: 49 participants in the intervention group and 27 in the control group completed this trial. Both groups showed improvements from baseline to 12 weeks across most outcome measures. The intervention group demonstrated significantly greater improvements in social reciprocity compared to the control group. Children with MTHFR A1298C or MTRR A66G mutations demonstrated greater improvements in various developmental domains than wild type. Folinic acid may be more effective in certain genotype combinations, such as MTHFR C677T and A1298C. No significant adverse effects were observed during the intervention. Conclusions: High-dose folinic acid may be a promising intervention for children with ASD, and its efficacy is associated with folate metabolism gene polymorphisms. High-dose folinic acid intervention may promote better neurodevelopmental outcomes by alleviating folate metabolism abnormalities caused by single or combined mutations in folate metabolism genes.

 

Treating the downstream consequences of low brain folate

Today’s next papers highlight Infliximab, IVIG, Propes, and Inflamafertin as immunomodulatory therapies that target the downstream consequences of folate deficiency; they do not address or improve the underlying lack of folate.

Folate Deficiency in the Brain: This means there is an inherent problem in the body's ability to process or utilize folate, even if dietary intake is sufficient. It is often due to mutations in genes encoding enzymes of the folate cycle (like MTHFR) or transporters. This leads to issues with DNA synthesis, cell proliferation, and methylation, impacting various systems, including the immune system.

 

Infliximab

Infliximab is a TNF-alpha inhibitor. It blocks the activity of TNF-alpha, a key pro-inflammatory cytokine.

It does not put more folate into the system or fix how folate is metabolized. It is like putting out a fire (inflammation) that was started because of a broken electrical wire (folate deficiency's impact on immunity).

 

IVIG (Intravenous Immunoglobulin)

IVIG is a broad-acting immunomodulatory therapy composed of pooled antibodies from thousands of healthy donors. Its mechanisms are complex and include neutralizing autoantibodies, blocking Fc receptors, modulating cytokine production, affecting T and B cell function, and influencing complement activation.

IVIG aims to rebalance a dysregulated immune system, reduce inflammation, and sometimes provide passive immunity. It is like resetting an overactive or misdirected immune alarm system. The effect may not last.

 

Propes

Propes contains alpha- and beta-defensins and has a "pronounced immunoactivating and lymphoproliferative effect." It directly stimulates the growth and activity of immune cells like NK and NKT cells. It directly addresses the numbers and activity of NK and NKT cells that are deficient due to the folate cycle problem. It makes the existing cells (or promotes the creation of new ones) work better, despite the underlying folate issue.

 

Inflamafertin

This drug, containing alarmines and adrenomedulin of placental origin, has "pronounced anti-inflammatory and immunomodulatory effects mediated by the induction of interleukin 10 synthesis." Its role is to temper the immune activation  and ensure a more balanced, anti-inflammatory environment.

 

In summary

These therapies are all symptomatic or compensatory treatments for the consequences of genetic folate deficiency on the immune system and the body. They address the resulting immunodeficiency, inflammation, and associated clinical symptoms (like behavioral issues or opportunistic infections).

 

They do not:

• Add more folate to the body (like folic acid or L-methylfolate supplementation would).
• Correct the genetic defect that causes the folate cycle deficiency.
• Improve the body's intrinsic ability to metabolize folate.

Genetic deficiency in the folate cycle disrupts fundamental cellular processes required for the normal development, proliferation, and function of NK and NKT cells, leading to their deficiency in affected children. This deficiency, in turn, contributes to the complex immune dysregulation often seen in autism.

 

Key Findings on NK Cells:

• Initial Deficiency: A significant number of children in the study group (53 patients) had an initial deficiency of NK cells.
• Response to Immunotherapy:
• During the 3-month course of Propes and Inflamafertin, the average number of NK cells in the blood almost doubled.
• NK cell counts reached the lower limit of normal in 74% (39 out of 53) of the patients with a deficiency.
• There was a strong statistical link between the immunotherapy and NK cell normalization.
• Sustainability: A notable finding was that the NK cell numbers returned to almost their initial level within 2 months after the immunotherapy was stopped. This suggests that the effect on NK cells might be temporary and dependent on continuous treatment.

 

Key Findings on NKT Cells:

• Initial Deficiency: A larger proportion of children in the study group (87 patients) had an initial deficiency of NKT cells.
• Response to Immunotherapy:
• The average number of NKT cells in the blood increased by half during the 3-month immunotherapy course.
• NKT cell counts were normalized in 89% (78 out of 87) of the patients with a deficiency.
• There was an even stronger statistical link between the immunotherapy and NKT cell normalization compared to NK cells.
• Sustainability: Importantly, the NKT cell numbers continued to grow for an additional 2 months after the discontinuation of the immunotropic drugs. This suggests a more sustained and potentially longer-lasting effect on NKT cells.

Overall Conclusions from the Study:

• Combination immunotherapy with Propes and Inflamafertin is presented as an effective treatment strategy for the immunodeficiency (specifically NK and NKT cell deficiency) found in children with ASD linked to genetic folate deficiency.
• Both biological drugs were able to normalize the reduced numbers of NK and NKT cells during the 3-month treatment period.
• The study highlights that the effect on NKT cells was more frequent, stronger, and more lasting compared to the effect on NK lymphocytes.

 

The research papers:

EFFICACY OF INFLIXIMAB IN AUTISM SPECTRUM DISORDERS IN CHILDREN ASSOCIATED WITH GENETIC DEFICIENCY OF THE FOLATE CYCLE

 The notion of systemic inflammation in autism spectrum disorders in children has been established. A recent meta-analysis of randomized controlled trials published in 2019, which included a systematic review of 25 case-control studies, suggests an association between genetic deficiency of the folate cycle and autism spectrum disorders in children [18]. This evidence is consistent with an earlier meta-analysis of randomized controlled trials from 2013, which included data from 8 studies [17]. The encephalopathy that develops in children with genetic deficiency of the folate cycle and manifests as autism spectrum disorders is associated with oxidative stress. The reason for the latter can be seen in the suppression of the immune system with the development of a special form of immunodeficiency, which is based on the deficiency of natural killers, natural killer T lymphocytes and CD8 +  cytotoxic T cells [11]. Immunodeficiency mediates all three known mechanisms of brain damage in children with genetic deficiency of the folate cycle, namely the development of opportunistic infections [2, 15], autoimmune reactions against neuronal antigens [3, 6] and manifestations of systemic inflammation, which is based on the phenomenon of hypercytokinemia [13, 20]. Children with autism spectrum disorders have been shown to have overproduction of several proinflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta, and interleukin-6

In SG, there was a pronounced positive dynamics in the direction of hyperactivity, hyperexcitability and stereotyped behavior, but no significant effect was noted on the stability of eye contact and the development of expressive-receptive language, while in CG some positive changes were achieved specifically in terms of expressive language and the level of eye contact, which indicates different points of action of infliximab and specialized educational programs (Table 11.1). The psychotropic effect obtained with infliximab differs from that of intravenous immunoglobulin, which has also demonstrated clinical efficacy in ASD associated with GDFC [10, 12]. The changes induced by infliximab are more pronounced and develop in a shorter time frame, but they are significantly narrower in terms of the spectrum of positive psychotropic effects compared to high-dose immunoglobulin therapy, which has a total modifying effect on the psyche of such children.

Materials and methods. This prospective controlled single-center non-randomized clinical study included 225 children diagnosed with autism spectrum disorders associated with genetic deficiency of the folate cycle. The diagnosis of autism spectrum disorders was made by psychiatrists from regional hospitals or specialized departments according to DSM–IV–TR (Diagnostic and Statistical Manual of mental disorders) and ICD–10 criteria. Children were recruited into the study group (SG) in 2019–2020. These were patients from different regions of Ukraine aged 2 to 9 years, in whom elevated serum TNF-alpha concentrations were observed. As is known, the phenotype of genetic deficiency of the folate cycle includes 5 main syndromes: autism spectrum disorders, intestinal syndrome (persistent enteritis/colitis) [7], PANDAS [4, 9], epileptic syndrome [5] and signs of pyramidal tract damage.

 

Conclusions. Infliximab leads to significant improvements in hyperactivity and hyperexcitability, as well as stereotypic behavior in children with autism spectrum disorders associated with genetic deficiency of the folate cycle. Responders to immunotherapy are 76 % of patients with this pathology, which is twice as high as with standard therapy. However, there is no effect of infliximab on such manifestations of autism as the level of eye contact and language development. Psychotropic effects of infliximab immunotherapy are closely related to the normalization of previously elevated serum TNF-alpha concentrations and are probably due to the elimination of the pathological activating effect of this pro-inflammatory cytokine on CNS neurons. In parallel, there is an improvement in other clinical syndromes of genetic deficiency of the folate cycle in children with autism spectrum disorders – intestinal pathology, epileptic syndrome, and PANDAS, in the pathogenesis of which, as is known, TNF-alpha and the systemic and intracerebral inflammation induced by this cytokine are involved. However, under the influence of immunotherapy, there is no change in the dynamics of motor deficit in children with symptoms of pyramidal tract damage. Further clinical studies in this direction with a larger number of participants and randomization are necessary to obtain more convincing data.

Efficacy of combined immunotherapy with Propes and Inflamafertin in selective deficiency of NK and NKT cells in children with autism spectrum disorders associated with genetic deficiency of the folate cycle

 Objectives. The results of previous small clinical trials indicate the potential benefit of combination immunotherapy with Propes and Inflamafertin to compensate for NK and NKT cell deficiency due to genetic deficiency of the folate cycle in children with autism spectrum disorders. The purpose of the research was to study the effectiveness of combined immunotherapy with Propes and Inflamafertin in NK and NKT cell deficiency in children with autism spectrum disorders associated with genetic deficiency of the folate cycle. Material and methods. This single-center, prospective, controlled, nonrandomized clinical trial included 96 children aged 2 to 10 years with autism spectrum disorders associated with a genetic folate deficiency (study group, SG). Children of SG received Propes at a dose of 2 ml IM every other day for 3 consecutive months (45 injections), and Inflamafertin at a dose of 2 ml IM every other day for 3 months in a row, alternating with Propes (45 injections). The control group (CG) consisted of 32 children of similar age and gender distribution who suffered from autism spectrum disorders associated with genetic deficiency of the folate cycle, but who did not receive immunotherapy. Outcomes. The number of NK cells reached the lower limit of normal in 39 out of 53 patients (74% of cases), with the resulting deficiency of these lymphocytes, and the average number of NK cells in the blood in SG almost doubling during the 3-month course of immunotherapy (р ˂ 0.05; Z ˂ Z0.05). However, it returned to almost initial level in the 2 months following the discontinuation of immunotherapeutic agents (р˃0.05; Z˃Z0.05). The number of NKT cells was normalized in 78 out of 87 patients (89% of cases) with an initial deficiency of these cells, and the average number of NKT cells in the blood in the DG increased during the course of immunotherapy by half (р ˂ 0.05; Z ˂ Z0.05) and continued to grow for the next 2 months after the discontinuation of immunotropic drugs (р ˂ 0.05; Z ˂ Z0.05). There was a link between immunotherapy and normalization of NK - (χ2 = 18.016; OR = 13.929; 95%CI = 3.498-55.468) and NKT-cells (χ2 = 60.65; OR = 46.800; 95%CI = 14.415-151.937) in the blood with a strong association between these processes (criterion φ = 0.504 and 0.715 respectively; С = 0.450 and 0.581 respectively). Conclusions. Combination immunotherapy with Propes and Inflamafertin is an effective strategy for the treatment of immunodeficiency caused by genetic deficiency of the folate cycle in children with autism spectrum disorders.

 

The results obtained in this controlled non-randomized clinical trial indicate that combination immunotherapy with Propes and Inflamafertin is an effective treatment strategy for immunodeficiency caused by genetic folate deficiency in children with autism spectrum disorders. These biological immunotropic drugs are able to normalize the previously reduced number of NK and NKT cells in the blood in this category of patients during a 3-month course of immunotherapy, with a more frequent, stronger and more lasting effect on NKT cells compared to NK lymphocytes.

  

Conclusion

Folinic acid supplementation is an effective therapy for many people with autism. There are many anomalies that appear, for example those people who test positive for the folate transporter antibodies but a lumbar punction then finds normal levels of folate in the brain.  Many people report agitation or aggression when children take calcium folinate at high doses, but this does not seem to get noted in clinical trials. Nonetheless it looks like everyone with autism should at least make a trial.

Note that you should always add a vitamin B12 supplement when giving high dose calcium folinate. This is because more B12 will be required by the biological processes ongoing in the brain and deficiency will cause side effects.

Many people who respond well to calcium folinate end up needing some kind of immunotherapy on top. IVIG is extremely expensive and quite a bother if you need to take it forever. Some of the therapies from the two papers today also involve a very large number of injections, so are not really practical.  The less intrusive immunotherapies look more practical but are not cheap.

I think that rTMS and tDCS will be attractive to those seeking non-pharmaceutical options that have a scientific basis. The same applies to low level laser therapy, also known as photobiomodulation therapy.

Applying insights from novel Alzheimer’s treatments to autism – mast cell stabilizers, brain cholesterol reduction, menthol, and vitamin D

 

Treating autism has many parallels with treating other complex neurological conditions like dementia or MS. You need to treat multiple individual features of the disease and then you will the greatest effect, this is called polytherapy.

·        Mast cell activation is a common feature in both autism and Alzheimer’s.

·        Neuroinflammation is a fundamental part of autism and Alzheimer’s. It looks like both menthol and vitamin D may have a role to play.

·        Impaired cholesterol metabolism in the brain is a key feature of Alzheimer’s and occurs in some autism. It can be either too much, or too little. 

An interesting new idea in Alzheimer’s research is to use a potent mast cell stabilizer called Masitinib. It is interesting because this drug has already been commercialized to treat pets.

 

Masivet UK (Kinavet US) Cancer Treatment Tablets for Dogs

 

There is great deal in this blog about mast cells and autism.

Many readers give their child cromolyn sodium, which is an excellent mast cell stabilizer, but it poorly crosses the blood brain barrier. While cromolyn sodium is effective for conditions where mast cell activity is predominantly peripheral, its limited CNS action makes it less suitable for addressing neuroimmune dysregulation in autism, or other brain-related conditions.

Ketotifen is another mast cell stabilizer and it does cross the blood brain barrier better. It has also been widely used in autism. It is cheap in some countries but expensive in others.

One known feature of mast cell activation is an impaired blood brain barrier (BBB), so some of these drugs may be more effective than expected.

Studies suggest that masitinib can cross the BBB, particularly in conditions where the BBB is disrupted (inflammation, neurodegenerative diseases, or neuroimmune disorders).

Masitinib works by inhibiting tyrosine kinases  involved in mast cell activation and degranulation. By reducing mast cell activity, it may help to mitigate neuroinflammatory processes implicated in conditions like autism, Alzheimer's disease, and indeed multiple sclerosis (MS).

For those that want an up to date summary of mast cell activation in autism there is an excellent new paper.

 

The role of mast cells (MCs) in Autism Spectrum Disorder

 

Highlights

·        Increased MC activity may be linked to the development of ASD.

·        MC mediators influence neuroinflammatory pathways that are altered in ASD.

·        MCs can interact with other immune and neuronal cells contributing to ASD symptoms.

·        The role of MC in gut permeability and microbiota dysbiosis may also underly gastrointestinal comorbidities in ASD.

·        Targeting MC activity offers promising therapeutic avenues in treatment of ASD.

 

ASD represents a multifaceted condition influenced by genetic, environmental, and immune-related factors. MCs have emerged as pivotal players in the immune processes associated with ASD, impacting neuroinflammation, autoimmunity and gastrointestinal health. They interact with other immune cells, release mediators that influence neurological processes, and help maintain the integrity of the blood-brain and gut barriers. Evidence of alterations in these processes in ASD patients, supported by extensive data from relevant animal models, has highlighted disruptions in these processes among individuals with ASD, underscoring the critical role of MCs in ASD pathology.

Current ASD treatments primarily aim at managing symptoms rather than addressing underlying mechanisms. However, targeting MC activity may represent a promising innovative approach for intervention. The development of novel MC inhibitors could significantly enhance our understanding of ASD pathobiology while potentially offering therapeutic benefits for a defined subset of individuals with ASD, improving their symptoms and quality of life.

 

Alzheimer’s research is very well funded and so we already have results from the use of Masitinib in humans.

 

Masitinib for mild-to-moderate Alzheimer’s disease: results from a randomized, placebo-controlled, phase 3, clinical trial

Abstract

Background

Masitinib is an orally administered tyrosine kinase inhibitor that targets activated cells of the neuroimmune system (mast cells and microglia). Study AB09004 evaluated masitinib as an adjunct to cholinesterase inhibitor and/or memantine in patients with mild-to-moderate dementia due to probable Alzheimer’s disease (AD).

Methods

Study AB09004 was a randomized, double-blind, two parallel-group (four-arm), placebo-controlled trial. Patients aged ≥50 years, with clinical diagnosis of mild-to-moderate probable AD and a Mini-Mental State Examination (MMSE) score of 12–25 were randomized (1:1) to receive masitinib 4.5 mg/kg/day (administered orally as two intakes) or placebo. A second, independent parallel group (distinct for statistical analysis and control arm), randomized patients (2:1) to masitinib at an initial dose of 4.5 mg/kg/day for 12 weeks that was then titrated to 6.0 mg/kg/day, or equivalent placebo. Multiple primary outcomes (each tested at a significance level of 2.5%) were least-squares mean change from baseline to week 24 in the Alzheimer’s Disease Assessment Scale - cognitive subscale (ADAS-cog), or the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL). Safety for each masitinib dose level was compared against a pooled placebo population.

Results

Masitinib (4.5 mg/kg/day) (n=182) showed significant benefit over placebo (n=176) according to the primary endpoint of ADAS-cog, −1.46 (95% CI [−2.46, −0.45]) (representing an overall improvement in cognition) versus 0.69 (95% CI [−0.36, 1.75]) (representing increased cognitive deterioration), respectively, with a significant between-group difference of −2.15 (97.5% CI [−3.48, −0.81]); p<0.001. For the ADCS-ADL primary endpoint, the between-group difference was 1.82 (97.5% CI [−0.15, 3.79]); p=0.038 (i.e., 1.01 (95% CI [−0.48, 2.50]) (representing an overall functional improvement) versus −0.81 (95% CI [−2.36, 0.74]) (representing increased functional deterioration), respectively). Safety was consistent with masitinib’s known profile (maculo-papular rash, neutropenia, hypoalbuminemia). Efficacy results from the independent parallel group of titrated masitinib 6.0 mg/kg/day versus placebo (n=186 and 91 patients, respectively) were inconclusive and no new safety signal was observed.

Conclusions

Masitinib (4.5 mg/kg/day) may benefit people with mild-to-moderate AD. A confirmatory study has been initiated to substantiate these data.

 

Not surprisingly there is a similar study in MS.

 

Efficacy and Safety of Masitinib in Progressive Forms of Multiple Sclerosis

Discussion

Masitinib (4.5 mg/kg/d) can benefit people with PPMS and nSPMS. A confirmatory phase 3 study will be initiated to substantiate these data.

 

Masitinib has already been patented to treat ALS the motor neuron disease.

 

Masitinib  for autism?

I think the people who respond to cromolyn sodium, but feel it lacks potency would be the ones who might benefit.

You either consult Prof Theoharides, or the local vet (It’s a doggy medication).

 

 

Low dose Efavirenz to activate CYP46A1 to reduce brain cholesterol 

Our reader Katya did raise the idea, a few months ago, of low dose Efavirenz to lower cholesterol in the brain.

Elevated cholesterol in the brain is a feature of some specific variants of autism.

Elevated brain cholesterol is a contributing factor in many cases of Alzheimer's, but it is not a universal feature. It depends which version of the APOE gene the person carries.

The brain has a lot of cholesterol in it and all of it was produced there.

The brain cannot rely on peripheral cholesterol transport due to the blood-brain barrier. The enzyme CYP46A1 ensures local cholesterol balance in the brain, by facilitating clearance of excess cholesterol to maintain healthy neuronal and synaptic functions.

Proper cholesterol metabolism, facilitated by CYP46A1, supports synaptic remodeling, plasticity, and repair, which are critical for cognitive function.

Dysregulated cholesterol levels in the brain can impair synapse function, and CYP46A1 helps prevent these disruptions.

Efavirenz is a drug used in the treatment of HIV. Interestingly, at subtherapeutic doses, it has been shown to activate CYP46A1 and so increase cholesterol clearance from the brain.

 

CYP46A1 activation by low-dose efavirenz enhances brain cholesterol metabolism in subjects with early Alzheimer’s disease

Background

Efavirenz is an anti-HIV drug, and cytochrome P450 46A1 (CYP46A1) is a CNS-specific enzyme that metabolizes cholesterol to 24-hydroxycholesterol (24HC). We have previously shown that allosteric CYP46A1 activation by low-dose efavirenz in a transgenic mouse model of Alzheimer’s disease (AD) enhanced both cholesterol elimination and turnover in the brain and improved animal performance in memory tests. Here, we sought to determine whether CYP46A1 could be similarly activated by a low-dose efavirenz in human subjects. 

Methods

This pilot study enrolled 5 subjects with early AD. Participants were randomized to placebo (n = 1) or two daily efavirenz doses (50 mg and 200 mg, n = 2 for each) for 20 weeks and evaluated for safety and CYP46A1 target engagement (plasma 24HC levels). A longitudinal mixed model was used to ascertain the statistical significance of target engagement. We also measured 24HC in CSF and conducted a unique stable isotope labeling kinetics (SILK) study with deuterated water to directly measure CYP46A1 activity changes in the brain.

Results

In subjects receiving efavirenz, there was a statistically significant within-group increase (P ≤ 0.001) in the levels of plasma 24HC from baseline. The levels of 24HC in the CSF of subjects on the 200-mg dose of efavirenz were also increased. Target engagement was further supported by the labeling kinetics of 24HC by deuterated water in the SILK study. There were no serious adverse effects in any subjects.

Conclusions

Our findings suggest efavirenz target engagement in human subjects with early AD. This supports the pursuit of a larger trial for further determination and confirmation of the efavirenz dose that exerts maximal enzyme activation, as well as evaluation of this drug’s effects on AD biomarkers and clinical symptomatology.

 

It looks like 50mg a day of efavirenz is an effective option to reduce levels of cholesterol in the brain. Interestingly it is not effective in people already taking a high dose of atorvastatin. This should not be a surprise since atorvastatin will have already lowered cholesterol in the brain.

So to lower cholesterol in the brain you could use the 50mg of efavirenz, or if that was not possible then 40mg of atorvastatin  would be an option. The trial showed using both drugs together was pointless.

  

First patient completes new trial to test Alzheimer’s medication

13 March 2025

The existing HIV medication Efavirenz may potentially also be effective for Alzheimer’s patients, Vrije Universiteit Amsterdam neuroscientist Rik van der Kant and Amsterdam UMC neurologist Jort Vijverberg discovered. This fall, a clinical trial has begun at Amsterdam UMC, and the first patient has just completed the trial.

Participants are still being recruited. The research is led by Rik van der Kant and Jort Vijverberg (Amsterdam UMC - Alzheimer Center Amsterdam). Van der Kant has been researching new drugs for Alzheimer’s disease for years, using groundbreaking technology that allows him to test hundreds of potential medications simultaneously. 

Promising step  
“I discovered that cholesterol buildup in brain cells of Alzheimer’s patients directly leads to an accumulation of the toxic proteins Tau and Amyloid,” Van der Kant explains. “Efavirenz turned out to be suitable for reversing this buildup. It's very special and unique to be able to do all of this ourselves, within the walls of Amsterdam UMC." Vijverberg is also hopeful. “We are very curious to see how this medication will work in Alzheimer's patients. Of course, we still have to see the results, but I consider it a promising step in the right direction.” 

 

The Alzheimer’s APOE story

Apolipoprotein E (APOE) plays a critical role in lipid transport and cholesterol homeostasis in the brain. It facilitates the redistribution of cholesterol and other lipids between cells for membrane repair, synaptogenesis, and other neuronal functions.

In the brain, APOE interacts with specific receptors, such as the low-density lipoprotein receptor (LDLR), to regulate cholesterol and amyloid-beta (Aβ) clearance.

APOE Variants:

There are three major alleles of the APOE gene: ε2, ε3, and ε4, which encode the respective protein isoforms.

APOE ε2: Rare and protective against AD.

APOE ε3: The most common variant with neutral risk for AD.

APOE ε4: A strong genetic risk factor for AD.

 

APOE ε4's Impact on Cholesterol and Aβ

Reduced Cholesterol Transport: APOE ε4 is less efficient in binding and redistributing cholesterol compared to APOE ε3 or ε2. This inefficiency can lead to local cholesterol dysregulation in the brain, particularly in neurons and astrocytes.

APOE ε4 is less effective in promoting Aβ clearance via receptor-mediated pathways (e.g., LDLR, LRP1).

The isoform is associated with an increased tendency of Aβ peptides to aggregate, contributing to plaque formation. 

Cholesterol Accumulation and AD Pathogenesis:

Elevated cholesterol levels in neuronal membranes can favour the activity of β- and γ-secretases, enzymes involved in Aβ production.

The inefficient lipid transport by APOE ε4 exacerbates cholesterol accumulation in affected brain regions, creating a feedback loop that promotes amyloidogenic processing.

 

 

Vitamin D in Alzheimer’s and Maternal Immune Activation Autism

Vitamin D’s role in Alzheimer’s disease has been widely studied, with growing evidence suggesting it may influence risk and progression, but it is not a cure or primary treatment.

Vitamin D appears to have a supportive role in brain health, potentially lowering the risk or slowing progression of Alzheimer’s disease by reducing inflammation, aiding amyloid clearance, and protecting neurons. However, vitamin D alone is not a standalone treatment for AD. Ensuring adequate vitamin D status is a simple, low-risk strategy that could contribute positively as part of a broader approach to brain health and dementia prevention.

In Japan researchers have recently found that they can prevent autism caused by maternal immune activation simply by giving a vitamin D supplement during pregnancy. This was in a mouse model, but what about its use as yet another method to prevent/reduce some human autism?

 

Supplementing with Vitamin D during Pregnancy Reduces Inflammation and Prevents Autism-Related Behaviors in Offspring Caused by Maternal Immune Activation 

Autism spectrum disorder (ASD), a neurodevelopmental disorder of unknown etiology with limited treatment options, has emerged as a significant public health concern. Studies have demonstrated that prenatal vitamin D deficiency is a risk factor for ASD development in offspring; however, the underlying mechanism remains unclear. In this project, vitamin D was administered orally to pregnant mice with/without the subsequent administration of polyriboinosinic polyribocytidylic acid (Poly(I:C)), which induced the maternal immune activation (MIA). Our results showed that vitamin D supplementation during pregnancy alleviated MIA-induced ASD-like behaviors in offspring. Moreover, vitamin D supplementation reduced the MIA-induced elevation of interleukin-6 (IL-6) and IL-17a levels in both the maternal ileum and fetal brains. It also suppressed signal transducer and activator of transcription 3 (Stat3) activation and the elevated expression of serum amyloid A1 and A2 (SAA1/2) in the ileum of MIA-affected pregnant mice. This study revealed that vitamin D may reduce the expression of IL-17a by inhibiting the IL-6/Stat3/SAA signaling pathway, thereby improving ASD-like behavior in offspring mice, and provide a new theoretical support for the prevention and treatment of ASD by scientific dietary interventions and nutritional supplement during pregnancy.

 

 

 

Menthol for Alzheimer’s and some Autism? 

I recall one reader, I think is was Natasa in London, mentioned that menthol should be a helpful autism therapy for some people. I see today that Nestle even holds an old patent on its use for autism.

The surprise is that just inhaling the smell of menthol has an anti-inflammatory effect in the mouse model of Alzheimer’s. 

 

Surprise Link Between Menthol And Alzheimer's Found in Mice

In recent years, scientists discovered something strange: When mice with Alzheimer's disease inhale menthol, their cognitive abilities improve.

It seems the chemical compound can stop some of the damage done to the brain that's usually associated with the disease.

In particular, researchers noticed a reduction in the interleukin-1-beta (IL-1β) protein, which helps to regulate the body's inflammatory response – a response that can offer natural protection but one that leads to harm when it's not controlled properly.

The team behind the study, published in April 2023, says it shows the potential for particular smells to be used as therapies for Alzheimer's. If we can figure out which odors cause which brain and immune system responses, we can harness them to improve health.

"The results suggest that odors and immune modulators may play an important role in the prevention and treatment of Alzheimer's and other diseases related to the central nervous system." 

 

Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells

 

 

 

 

Patent - Treatment or prevention of autism disorders using menthol, linalool and/or icilin

Current Assignee: Societe des Produits Nestle SA

 

Compositions for treatment or prevention of autism disorders are provided, and the compositions contain a therapeutically effective amount of a compound selected from the group consisting of Menthol, Linalool, Icilin and combinations thereof. Methods for treatment or prevention of autism disorders are also provided, and the methods include administering such compositions.

 

Menthol has shown promising effects in modulating inflammatory pathways, including those involving IL-1β and the NLRP3 inflammasome.

Menthol and IL-1β

• Menthol inhibits the production and release of pro-inflammatory cytokines, including IL-1β, which is a key mediator in various inflammatory conditions.
• Menthol primarily acts through transient receptor potential melastatin 8 (TRPM8) channels. Activation of TRPM8 can indirectly reduce inflammation by modulating neural and immune pathways.

Menthol and the NLRP3 Inflammasome

• Studies indicate that menthol may inhibit the activation of the NLRP3 inflammasome, a multiprotein complex responsible for IL-1β maturation and release.
• Menthol's ability to suppress oxidative stress and calcium influx, both of which are critical for NLRP3 activation, contributes to its anti-inflammatory effects.
• These properties make menthol a potential therapeutic candidate for diseases where the NLRP3 inflammasome plays a role, such as neurodegenerative diseases, autoimmune conditions, and metabolic disorders.

 

Conclusion

It looks like keeping an eye on research across a broad range of neurological conditions is a wise idea, if you want to treat autism.