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Showing posts with label Dementia. Show all posts
Showing posts with label Dementia. Show all posts

Wednesday, 6 November 2019

Metformin to raise Cognition in Fragile X and some other Autisms?




I started to write this post a long time ago, when Agnieszka first highlighted an interview with Dr Hagerman from UC Davis.  Hagerman is experimenting in using Metformin to treat Fragile-X.

Having again be reminded about Metformin, I realized that I never finished my post on this subject. With some extras about autophagy and a nice graphic courtesy of Ling’s excellent paper, here it is. 

Metformin has already been covered in 5 previous posts.


One interesting point is that the researchers at UC Davis are using the measurement of IQ as one of the outcome measures in their trial of Metformin.  I have been suggesting the French Bumetanide researchers do this for a long time.

It is my opinion that simple medical interventions can have a profound impact on the IQ of some people with severe autism. I mean raising IQ not by 5-10 points as at UC Davis, but by 20-50 points.  IQ can be measured using standardized tools and is far less subjective than any autism rating scale.

The big-time potential IQ enhancers we have seen in this blog include: -

·        Bumetanide/Azosemide
·        Statins (Atorvastatin, Lovastatin, Simvastatin, but they are not equivalent and the effect has nothing to do with lowering cholesterol)
·        Micro-dose Clonazepam
·        Clemastine
·        It seems DMF, in n=2 trial

The good news is that these drugs are all off-patent cheap generics (except DMF), as is metformin.  No need for drugs costing $50,000 a year.

For those that do not know, metformin is the first line medication for type-2 diabetes. It was introduced as a medication in France in 1957 and the United States in 1995.  In many countries Metformin is extremely cheap, with 30 x 500 mg tablets costing about $2 or Eur 2. In the US it costs about $10 for generic, so not expensive. 

There are sound reasons why Metformin could increase IQ in someone with autism or Fragile-X. In the case of idiopathic autism is there a likely biomarker to identify a likely responder? One has not yet been identified.

Clearly Metformin will not work for all people with autism and MR/ID, but even if it only works for 10% that would be great.

Are all parents going to notice an increase in IQ of 5-10 points?  You might think so, but I doubt it.  I would hope therapists, teachers and assistants would notice.

I think basic mental maths is the best way to notice improved cognitive function in people with IQ less than 70.  You can easily establish a baseline and then you can notice/measure improvements.

Improved cognitive function does not just help with maths, it helps with learning basic skills like tying shoe laces, brushing teeth and later shaving.  This does also involve many other types of skill.





In the study, researchers from the UC Davis Medical Investigation of Neurodevelopmental Disorders Institute in California tested the long-term effects of metformin, delivered at 1,000 milligrams (mg) twice a day, for one year in two male patients, 25 and 30 years old. Genetic analysis confirmed that both patients had mutations in the FMR1 gene, confirming their fragile X syndrome diagnoses.

The younger patient had autism and was also diagnosed with generalized anxiety disorder. First prescribed metformin at 22, he is currently taking 500 mg of metformin twice a day and 10 mg per day of simvastatin — used to lower the level of cholesterol in the blood.
The second patient was also diagnosed with anxiety and exhibited socially nervous behaviors, including panic attacks. He had severe limitations in language use, and communicated in short sentences and by mumbling. He had been on an extended-release formulation of metformin, taking 1,000 mg once a day for one year.

Both patients showed significant cognitive and behavioral improvements. After one year of treatment with metformin, test results revealed an increase in the patients’ IQ scores, from 53 to 57 in the younger patient and from 50 to 58 in the second patient.

Verbal and nonverbal IQ — the ability to analyze information and solve problems using visual or hands-on reasoning — were also improved in both patients. Non-verbal IQ increased from 50 to 52 in the younger patient and from 47 to 51 in the other. Verbal IQ went from 61 to 66 in the first patient, and from 58 to 68 in the second.

                                                              

Researcher Randi Hagerman is a big proponent of metformin — a diabetes drug that helps people manage their weight. In fact, Hagerman takes the drug herself as a preventive measure against cancer.
Metformin has also unexpectedly shown promise for improving cognition in people with fragile X syndrome, a leading genetic cause of autism characterized by severe intellectual disability.

A study published in 2017 linked impaired insulin signalling in the brain to cognitive and social deficits in a fruit fly model of fragile X, and the flies improved on metformin. A second paper that year showed that metformin reverses abnormalities in a mouse model of the syndrome, including the number of branches the mice’s neurons form. It also improved seizures and hyperactivity in the mice — issues we also see in people with fragile X.
I began prescribing metformin to people with fragile X syndrome to help curb overeating. Many of the people I treat are overweight because of this habit — it’s one of the symptoms of a subtype of fragile X called the Prader-Willi phenotype, not to be confused with Prader-Willi syndrome.
I was surprised when the families of these individuals told me they could talk better and carry out conversations, where they couldn’t before. That really gave us impetus to conduct a controlled clinical trial.
It’s not a cure-all, but we do see some positive changes. It doesn’t resolve intellectual disability, but we have seen IQ improvements of up to 10 points in two boys who have been treated with metformin. We are very excited about that.

Individuals on metformin tend to start eating less, and often lose weight as a result. I could kick myself, because metformin has been approved to treat obesity for many years, but I never thought to use it in fragile X syndrome. Oftentimes children with fragile X syndrome have so many problems that you aren’t thinking about obesity as the top priority.
We’ve also seen a gradual effect on language, which we can detect after two to three months. Sometimes there are improvements in other behaviors too; I’ve seen mood-stabilizing effects. Many people with fragile X syndrome have issues with aggression, and it’s possible these could be moderated with metformin too. 

Individuals with fragile X syndrome (FXS) have both behavioral and medical comorbidities and the latter include obesity in approximately 30% and the Prader‐Willi Phenotype (PWP) characterized by severe hyperphagia and morbid obesity in less than 10%. Metformin is a drug used in individuals with type 2 diabetes, obesity or impaired glucose tolerance and it has a strong safety profile in children and adults. Recently published studies in the Drosophila model and the knock out mouse model of FXS treated with metformin demonstrate the rescue of multiple phenotypes of FXS.

Materials and Methods

We present 7 cases of individuals with FXS who have been treated with metformin clinically. One case with type 2 diabetes, 3 cases with the PWP, 2 adults with obesity and/or behavioral problems and, a young child with FXS. These individuals were clinically treated with metformin and monitored for behavioral changes with the Aberrant Behavior Checklist and metabolic changes with a fasting glucose and HgbA1c.

Results

We found consistent improvements in irritability, social responsiveness, hyperactivity, and social avoidance, in addition to comments from the family regarding improvements in language and conversational skills. No significant side‐effects were noted and most patients with obesity lost weight.

Conclusion

We recommend a controlled trial of metformin in those with FXS. Metformin appears to be an effective treatment of obesity including those with the PWP in FXS. Our study suggests that metformin may also be a targeted treatment for improving behavior and language in children and adults with FXS.

Recruiting: Clinical Trial of Metformin for Fragile X Syndrome


While a growing number of families are trying metformin and reporting mixed results, metformin has not yet been systematically studied in patients with Fragile X syndrome. This open-label trial is designed to better understand the safety and efficacy of this medicine on behavior and cognition, and to find the best dosages for children and adults.

20 children and adults with Fragile X syndrome will take metformin 250mg twice a day for the first week, followed by metformin 500mg twice a day for the next 8 weeks.
The study will measure changes in the total score on the Aberrant Behavior Checklist-Community (ABC-C) after 9 weeks of metformin treatment. The ABC-C is a 58-item behavior scale which is filled out by a caregiver. In addition, Transcranial Magnetic Stimulation (TMS) will be used to look for changes in cortical excitability and Electroencephalography (EEG) will assess levels of synaptic plasticity.
Participants in this study must be Canadian residents and be able to travel to the University of Sherbrooke in Quebec, Canada, for several visits. If you are interested in metformin but this trial is not convenient, there are two alternatives. FRAXA is funding a new trial of metformin in New Jersey, and Dr. Randi Hagerman is currently recruiting for metformin trial at the University of California at Davis MIND Institute.



Metformin has emerged as a candidate drug for the targeted treatment of FXS based on animal studies showing rescue of multiple phenotypes in the FXS model. Metformin may contribute to normalizing signalling pathways in FXS in the central nervous system, which may include activities of mTOR and PI3K, both of which have shown to be pathogenically overactive in FXS. In addition, metformin inhibits phosphodiesterase, which would lead to correction of cAMP levels, and MMP9 production, which is also elevated in FXS. Looking at the potential signalling pathways, metformin appears to be a good candidate for targeting several of the intracellular functions in neurons disrupted in FXS and, therefore, has potential to rescue several types of symptoms in individuals with FXS. The researchers have utilized metformin in the clinical treatment of over 20 individuals with FXS between the ages of 4 and 58 years and have found the medication to be well tolerated and to provide benefits not only in lowering weight gain and normalizing appetite but also in language and behavior. In this controlled trial, the researchers hope to further assess metformin's safety and benefits in the areas of language and cognition, eating and weight loss, and overall behavior.


mTOR and P13K

Hagerman highlights Metformin’s effects on mTOR and P13K pathways.

This is a highly complex subject and the graphic below from an early post shows how interconnected everything is.  If mTOR is not working correctly you can expect many things not to work as nature intended.

Numerous things can cause an imbalance in mTOR and so there are numerous ways to re-balance it.

Not surprisingly much of this pathway plays a role in many types of cancer.

Hagerman herself is taking Metformin to reduce her chances of developing cancer. I think that is a good choice, particularly if you are overweight.  My anticancer choice, not being overweight, is Atorvastatin which targets inhibition of PI3K signalling through Akt and increases PTEN.

Hagerman is 70 years old and I think many cancers actual initiate years before they are large enough to get noticed and to be effective any preventative therapy needs to be started before that initiation has occurred. Hopefully she started her Metformin long ago. 

Given that 50% of people are likely to develop one cancer or another, I am with Dr Hagerman on the value of prevention, rather than treatment/cure.







The Wrong Statin for Fragile-X?

In the first article highlighted in this post, there is a case history of a man with FX being treated by a Statin, it looks to me that he has the wrong prescription (Simvastatin). Perhaps Dr Hagerman should read this old post from this blog:-


Choose your Statin with Care in FXS, NF1 and idiopathic Autism







   Simvastatin does not reduce ERK1/2 or mTORC1 activation in the Fmr1-/y hippocampus.
So  ? = Does NOT inhibit

The key is to reduce Ras. In the above graphic it questions does Simvastatin inhibit RAS and Rheb.
                                                                                                     

For anyone really interested, the following graphic from a previous post shows the fragile X mental retardation protein, FMRP.  Lack of FMRP goes on increase neuroligins (NLFNS) this then creates an excitatory/inhibitory imbalance which cause mental retardation and features of autism.





This all suggests that the 25 year-old young man with Fragile X treated at UC Davis (case study above) should switch from Simvastatin to Lovastatin.




Metformin and Autophagy

I also think Dr Hagerman is less likely to get dementia now that she is talking metformin.  If she takes vigorous exercise at least once a week, I think that is also going to keep her grey cells ticking over nicely. Like Dr Ben Ari, Hr Hagerman is working way past normal retirement.  If you love your job, then why not?  As with many things, in the case of neurons, “use them or lose them”.

Autophagy in Dementias


Dementias are a varied group of disorders typically associated with memory loss, impaired judgment and/or language and by symptoms affecting other cognitive and social abilities to a degree that interferes with daily functioning. Alzheimer’s disease (AD) is the most common cause of a progressive dementia, followed by dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia (VaD) and HIV associated neurocognitive disorders (HAND).
The pathogenesis of this group of disorders has been linked to the abnormal accumulation of proteins in the brains of affected individuals, which in turn has been related to deficits in protein clearance. Autophagy is a key cellular protein clearance pathway with proteolytic cleavage and degradation via the ubiquitin-proteasome pathway representing another important clearance mechanism. Alterations in the levels of autophagy and the proteins associated with the autophagocytic pathway have been reported in various types of dementias. This review will examine recent literature across these disorders and highlight a common theme of altered autophagy across the spectrum of the dementias.

Below is an excellent graphic from a paper highlighted by Ling. Note metformin, above AMPK.


Autophagy Activator Drugs: A New Opportunity in Neuroprotection from Misfolded Protein Toxicity









I would highlight the presence of IP3R, the calcium channel proposed by Gargus as being a nexus in autism, for where multiple types of autism meet up, to do damage.

Verapamil, in Monty’s Polypill, increases autophagy independently of mTOR in a complicated mechanism  involving IP3R and likley calpain.  It is proposed as a therapy for Huntington’s Disease via this mechanism. At the lower right of the chart below we see calpain, a group of calcium dependent enzymes, not well understood.  ROS can activate calpains via L-type calcium channels.





I would not worry about the details.  The take home point is that if you have autism, dementia or many other neurological conditions, you might well benefit from increasing autophagy.  There are very many ways to do this.      
                                                           
Conclusion

Fortunately, I am not a doctor.  I do recall when my doctor father was out visiting his sick patients at their homes, he did have not only his medical bag, but also some useful gadgets always kept in his car, that might come in handy.

The autism equivalent is the personalized Polypill therapy for daily use and the autism toolbox to delve into to treat flare-ups in autism as and when they arise.

I do think some people should have metformin in their daily Polypill therapy.

I think we can safely call Fragile-X a type of autism, so we already know it works for at least some autism.  Metformin is a very safe old drug, with minimal side effects and it is cheap.  It ticks all the boxes for a potential autism therapy.  Will it work for your case?  I can tell you with certainty that it does not work for everyone.

Metformin has been trialled to treat people with obesity and autism, since it can reduce appetite.

Metformin forTreatment of Overweight Induced by Atypical Antipsychotic Medication in YoungPeople With Autism Spectrum Disorder: A Randomized Clinical Trial.


INTERVENTIONS:

Metformin or matching placebo titrated up to 500 mg twice daily for children aged 6 to 9 years and 850 mg twice daily for those 10 to 17 years.

MAIN OUTCOMES AND MEASURES:

The primary outcome measure was change in body mass index (BMI) z score during 16 weeks of treatment. Secondary outcomes included changes in additional body composition and metabolic variables. Safety, tolerability, and efficacy analyses all used a modified intent-to-treat sample comprising all participants who received at least 1 dose of medication.

RESULTS:

Of the 61 randomized participants, 60 participants initiated treatment (45 [75%] male; mean [SD] age, 12.8 [2.7] years). Metformin reduced BMI z scores from baseline to week 16 significantly more than placebo (difference in 16-week change scores vs placebo, -0.10 [95% CI, -0.16 to -0.04]; P = .003). Statistically significant improvements were also noted in secondary body composition measures (raw BMI, -0.95 [95% CI, -1.46 to -0.45] and raw weight, -2.73 [95% CI, -4.04 to -1.43]) but not in metabolic variables. Overall, metformin was well tolerated. Five participants in the metformin group discontinued treatment owing to adverse events (agitation, 4; sedation, 1). Participants receiving metformin vs placebo experienced gastrointestinal adverse events during a significantly higher percentage of treatment days (25.1% vs 6.8%; P = .005).

CONCLUSIONS AND RELEVANCE:

Metformin may be effective in decreasing weight gain associated with atypical antipsychotic use and is well tolerated by children and adolescents with ASD.

My guess is that a minority will be responders, the benefit will manifest itself in different ways and so it will be a useful part of polytherapy for some people, but it will not be a silver bullet.  Other than via an IQ test, I think the benefit will be hard to measure, even when it is very evident. 

In the end there will be a clever way to predict who will respond to which therapy.  Today’s post actually replaces one that will look into genetic testing and DEGs (differentially expressed genes). Most likely testing for DEGs will be the best predictor of what drugs work for whom.

Intelligent, cautious trial and error using safe drugs is an alternative strategy.  It is available today; it is cheap and it does work.

I have not tried Metformin yet, in recent years I have had most success with my own ideas. I have some of Dr Frye's calcium folinate sitting at home waiting for a trial.  Both Metformin and calcium folinate should be trialled.  The other obvious thing to trial is that Japanese PDE4 inhibitor Ibudilast (Ketas).  Thanks to Rene we now know you can acquire this is via any international pharmacy in Germany, with a prescription. It also reappeared on the website of a Japanese online pharmacy. The Western PDE4 inhibitors, like Daxas/Roflumilast are not selective enough and so are emetic (they make you want to vomit). Low dose Roflumilast has been patented as a cognitive enhancer, but you may need to have a bucket with you at all times.




     






Tuesday, 4 June 2019

Meningeal Lymphatics in Autism - at least two possibly relevant dysfunctions




  
I am always surprised how popular some posts with complicated titles are on this blog. Meningeal lymphatics in Bart Simpson speak would be “brain plumbing”.  Today we discover that:-

·        Immune cells can enter the brain by climbing up the brain’s plumbing pipes, entering originally via lymph nodes outside the brain

·        Those same plumbing pipes get blocked and waste is not free flowing out of the brain. The blockage may be at a brain-draining lymph node.

Today’s post follows up some research that I think Tyler highlighted a long time ago, about the recent discovery that the brain has its own lymphatic system.





                       
Human Lymphatic System before 2015              Human Lymphatic System after 2015




In a stunning discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist. That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer's disease to multiple sclerosis.

Structural and functional features of central nervous system lymphatic vessels


Editorial Summary

A lymphatic system for the brain

The central nervous system is under constant immune surveillance, but the exit route for immune cells has been unclear as the brain was thought to lack a classical lymphatic drainage system. Jonathan Kipnis and colleagues now show that the brain does indeed possess functional lymphatic vessels, located in the meninges, and that these vessels are able to carry both fluid and immune cells from the cerebrospinal fluid. The presence of a classical lymphatic system in the central nervous system suggests that current thinking on brain tolerance and the immune privilege of the brain should be revisited. Malfunction of the meningeal lymphatic vessels could be a root cause of a variety of neuroimmunological disorders. 

  

Knowledge has moved on a bit further since 2015 and hence today’s post, but the research is focused on MS and Alzheimer’s rather than autism.

The lymphatic system carries a clear fluid call lymph.

The lymphatic system has multiple interrelated functions

·         It is responsible for the removal of interstitial fluid from tissues
·         It absorbs and transports fatty acids and fats as chyle from the digestive system
·         It transports white blood cells to and from the lymph nodes into the bones
·         The lymph transports antigen-presenting cells, such as dendritic cells, to the lymph nodes where an immune response is stimulated.

The discovery in 2015 - A lymphatic system for the brain

The central nervous system is under constant immune surveillance, but the exit route for immune cells has been unclear as the brain was thought to lack a classical lymphatic drainage system.

Jonathan Kipnis discovered that the brain does indeed possess functional lymphatic vessels, located in the meninges, and that these vessels are able to carry both fluid and immune cells from the cerebrospinal fluid. The presence of a classical lymphatic system in the central nervous system suggests that current thinking on brain tolerance and the immune privilege of the brain should be revisited. Malfunction of the meningeal lymphatic vessels could be a root cause of a variety of neuroimmunological disorders.






When a tissue is infected by a pathogen, like a virus, bacteria, or parasite, bits and pieces of the offending pathogen end up in the lymph. These pieces, along with immune cells from the infected tissue, reach the lymph node, and the cells in the lymph node then react to coordinate a specific immune response to the pathogen. Thus, the system not only allows for recirculation of bodily fluid, but it also provides a means for the immune system to sift through material from around the body in order to scan for infection. Without lymphatics, fluid would build up in body tissues, and there would be no way to alert the adaptive immune system to invading pathogens.


Alzheimer's, Autism, MS and Beyond

The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer's disease. "In Alzheimer's, there are accumulations of big protein chunks in the brain," Kipnis said. "We think they may be accumulating in the brain because they're not being efficiently removed by these vessels." He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there's an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist

It is now suggested that several organs may be sites at which CNS-specific T cells become ‘licensed’ to acquire an appropriate migratory profile that will allow them to infiltrate the CNS.

What that means is an immune dysfunction far away from the brain and its blood brain barrier defences can send its messengers up the brain’s drain pipes and directly into the brain.

By closing the drain pipes you can prevent serious brain inflammation like that found in Multiple Sclerosis.

 Kipnis’ idea is to target major neurological disorders through therapeutic manipulation of peripheral structures, such as lymphatic vessels.  In other words, you block the inflammatory signals from entering the brain.

The research has now shown that this is indeed achievable in the mouse model of multiple sclerosis.

The problem with blocking the flow through the pipes is that you need them to be free flowing to avoid dementia and cognitive decline.  The Alzheimer’s research suggests that opening up the pipes wide to clear away accumulated junk in the brain might well stave off the disease.

The solution might involve some complex plumbing adjustment.

For old people it might be key to modify the lymphatic system inside the brain, so as to open those blocked pipes.  It may be that in some autism a variant of this problem also exists.  There is a section on this later in the post, with some case histories.
For people with MS and inflammatory-type autism it might be the case of closing the pipes at a clever location in the lymphatic system outside the brain to stop inflammatory messengers entering the lymph system and heading up into the brain. 

While autism research is rarely class-leading, MS research and Alzheimer’s research attracts plenty of smart scientists and research dollars.  This means that you may want to keep an eye on research in those two diseases.

Now we look at the research:

  • Multiple Sclerosis
  • Alzheimer’s
  • Autism


Multiple Sclerosis

Great strides are being made in MS research and some of the off-label therapies like Ibudilast, referred to in this autism blog, are showing promise in clinical trials.

Brain-draining lymph nodes exist outside the brain and you can actually measure how much CSF is flowing out of the brain.  In older brains the flow rate is much less, as if the drains have got clogged up. 

Brain-draining lymph nodes also allow inflammatory messengers to enter the central nervous system (CNS) that was supposed to be kept safe behind the blood brain barrier.

Brain's lymphatic vessels as new avenue to treat multiple sclerosis

Vessels carry mysterious message from brain that causes MS, research suggests

                          
Lymphatic vessels that clean the brain of harmful material play a crucial role in the development and progression of multiple sclerosis, new research from the University of Virginia School of Medicine suggests. The vessels appear to carry previously unknown messages from the brain to the immune system that ultimately trigger the disease symptoms. Blocking those messages may offer doctors a new way to treat a potentially devastating condition that affects more than 2 million people.
The discovery comes from the lab of UVA researchers who identified the lymphatic vessels surrounding the brain, vessels that textbooks long insisted did not exist. In an exciting follow-up, the researchers have determined that the vessels play an important role in not only multiple sclerosis but, most likely, many other neuroinflammatory diseases and in dangerous brain infections.
"Our data suggests that there is a signal coming from the brain to the lymph nodes that tells immune cells to get back into the brain, causing the [multiple sclerosis] pathology," said researcher Antoine Louveau, PhD, of UVA's Department of Neuroscience and its Center for Brain Immunology and Glia (BIG). "This is an important proof of principle that exploring the role of these vessels in different neurological disorders, including multiple sclerosis, is worth it."
Stopping Multiple Sclerosis
The researchers at UVA, led by Jonathan Kipnis, PhD, were able to impede the development of multiple sclerosis in mice by targeting the lymphatic vessels surrounding the brain. They used multiple strategies to block the lymphatics or destroy them with a precision laser. All led to the same outcome: a decrease in the number of destructive immune cells capable of causing paralysis.
"The idea was to prevent more widespread damage to the nervous system," said researcher Jasmin Herz. "If communication of brain inflammation through lymphatic vessels is the root cause of multiple sclerosis, therapies targeting these vessels could be clinically important."
The message from the brain that appears to drive multiple sclerosis remains poorly understood. The researchers can tell the message is being sent, and they can tell what it is instructing the immune system to do, but they don't yet know what mechanism the brain is using to send it. "I think the next step in this specific research is to identify what that signal is. Is it a cellular signal, is it a molecular signal?" Louveau said. "And then to try to target that signal specifically."
The researchers noted that removing the vessels did not stop multiple sclerosis entirely. That suggests there are likely other factors at play -- and much more for scientists to explore.

An Important Proof of Principle
UVA's new research offers important insight into the function and role of the lymphatic vessels that connect the brain to the immune system. In most aspects, they work exactly as scientists would expect -- just like other lymphatic vessels in the body.
"Meningeal lymphatic vessels are quite small compared to other lymphatics in the body, and we and others wondered if this might limit the amount and size of cargo they can pass through," Herz said. "During inflammation, they did not change in size or complexity much, but what was really exciting to discover [was that] they allowed whole immune cells to traffic through them, and we found the molecular cues for that."
the lab's recent research also highlights the complexity doctors face when trying to But manipulate the vessels to benefit human health. For example, blocking the vessels had a benefit in the multiple sclerosis model, but the lab has also shown that the vessels' healthy function is vital to staving off Alzheimer's disease and preventing the cognitive decline that comes with age.
That means that it's unlikely that stopping MS could be as simple as blocking the flow inside the vessels. It also suggests that there is probably no one treatment approach that will work for every neurological disorder. But the emerging importance of the vessels offers doctors an exciting new avenue for tackling neurological diseases.
"These findings on the role of brain-draining lymphatic vessels in MS, together with our recent work on their role in Alzheimer's disease, demonstrate that the brain and the immune system are closely interacting. When these interactions go out of control, pathologies emerge," said Kipnis, chairman of UVA's Department of Neuroscience and director of the BIG Center. "The idea that we could target major neurological disorders through therapeutic manipulation of peripheral structures, such as lymphatic vessels, is beyond exciting. Through our collaboration with PureTech Health, we hope to bring these laboratory findings to improve patients' lives one day."
Kipnis recently signed a deal with biopharmaceutical company PureTech Health to explore the potential clinical applications of his discoveries.


CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature


Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfil two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.

Discussion

Here we show that meningeal lymphatic vessels sample macromolecules and immune cells from the CSF and serve as an important conduit for CNS drainage. We also describe structural features of spinal cord meningeal lymphatics. We expand on our understanding of immune-cell trafficking via the meningeal lymphatic vessels to the draining lymph nodes, which is primarily dependent on CCR7. Using a pharmacological method that we adopted to specifically ablate meningeal (or nasal) lymphatic vessels, we demonstrated that the nasal route drains directly into the sCLNs, while the meningeal lymphatic route drains into both the dCLNs and sCLNs. RNAseq analysis of LECs from mouse meninges, diaphragm, and skin revealed that the meningeal lymphatic vessels exhibited a unique transcriptional profile, which, under local inflammatory conditions, might underlie the distinct behavior of meningeal lymphatics. Attenuation of EAE was obtained after surgical and pharmacological blockade of lymphatic function, suggesting that drainage contributed to the activation of encephalitogenic T cells in the lymph nodes. Supporting this notion, reduction of meningeal lymphatic drainage reduced interactions of 2D2 T cells with local antigen-presenting cells. RNA-seq of activated 2D2 T cells isolated from dCLNs showed that T cells from mice lacking lymphatic drainage acquired a different phenotype from that of controls. These findings warrant further research to identify the cellular (and/or molecular) mediators draining from the CNS and driving T cell encephalitogenicity. Meningeal lymphatic vessels are embedded within the dura. This raises an obvious question: how can macromolecules and immune cells drain from the CSF into meningeal lymphatic vessels, given that the arachnoid mater is supposedly impermeable to CSF45? We noticed, however, that certain spots along the meningeal lymphatics could be seen to take up the tracer from the CSF almost immediately after its injection, whereas tracer uptake along remaining parts of the vessels was slower. Subsequent experiments revealed certain spots along the meningeal lymphatics where the vessel structure was more complex and ramified and where extensions were exposed to the CSF. The structure of these lymphatic sprouts is reminiscent of peripheral-tissue lymphatic buttons, which serve as entry gates into the lymphatic vasculature. Further experiments using electron microscopy technique will be necessary to demonstrate that the meningeal lymphatic vessels are physically crossing the arachnoid mater. Previous reports have implicated the cribriform plate as a major player in the passage of immune cells from the CNS to its draining lymph nodes. Furthermore, a recent study has challenged the potential contribution of the meningeal lymphatics in the drainage of CSF into the CLNs6 . Here using live-imaging, our data (supported by others46) clearly demonstrates the uptake by meningeal lymphatics of tracers injected into the CSF. Our observations, however, do not exclude alternative routes as previously suggested. In the present study, we injected exogenous cells into the cisterna magna and also observed cells in the nasal mucosa and associated lymphatics. However, we could not detect any T cells on the nasal side of the cribriform plate under physiological conditions. Moreover, we labeled endogenous meningeal T cells using laser photoconversion but could not detect any labeled cells in the nasal mucosa. It is possible that if photoconversion of meningeal T cells was complete, some crossing of the cribriform plate by meningeal T cells could have been observed. Furthermore, the speed of injection (and, hence, change in intracranial pressure) appears to be a major factor in facilitating crossing of the cribriform plate by CNS immune cells. Our results thus suggest that the cribriform plate in all probability does not represent a major physiological immunerelevant exit route. This structure has been shown, however, to play an important role in the regulation of CSF homeostasis, since its surgical blockade results in an immediate and constant increase in CSF pressure47. Our results also show that chronic neuroinflammation is accompanied by expansion of the lymphatic vasculature localized around the cribriform plate (as opposed to brain and spinal cord meningeal lymphatics), suggesting that the nasal region might have a more important function at later stages of disease development. Several organs (such as lungs48, for example) have been suggested as sites at which CNS-specific T cells become ‘licensed’ to acquire an appropriate migratory profile that will allow them to infiltrate the CNS. Our data suggest that dCLNs could be another site for T cell licensing or reactivation. Dendritic cells migrating from different tissues have been shown to uniquely influence T cell activation and migration49, and MOG-loaded dendritic cells reportedly activate T cells in the CLNs before their migration into the CNS50. In the context of EAE (both induced and spontaneous), excision of the brain-draining lymph nodes has been shown to delay or attenuate disease development38–40. In spontaneous models, limitation of the drainage of MOG into the dCLNs, thereby preventing activation of MOG-specific T cells, is a likely mechanism. A similar scenario might apply when meningeal lymphatics are ablated. It is important to note that meningeal lymphatic ablation only attenuates and ameliorates EAE but does not completely stop it, suggesting that other routes are involved. Although no side effects were found when using the Visudyne approach, future development of targeted techniques will allow researchers to discern the role of anatomically distinct lymphatics in EAE. Overall, the work described here provides the first characterization, to our knowledge, of the meningeal lymphatic system in the context of brain immunity and neuroinflammation and opens the way to a better understanding of brain immune surveillance and the generation of CNS-directed immune responses. These results might help to uncover the etiology of the immune imbalance typical of neuroinflammatory disorders, with promising implications for therapy

  
                           

Dementia including Alzheimer’s

Brain discovery could block aging's terrible toll on the mind

Faulty brain plumbing to blame in Alzheimer's, age-related memory loss -- and can be fixed


Aging vessels connecting the brain and the immune system play critical roles in both Alzheimer's disease and the decline in cognitive ability that comes with time, new research reveals. By improving the function of the lymphatic vessels, scientists have dramatically enhanced aged mice's ability to learn and improved their memories. The work may provide doctors an entirely new path to treat or prevent Alzheimer's disease, age-related memory loss and other diseases. 
Kipnis and his colleagues were able to use a compound to improve the flow of waste from the brain to the lymph nodes in the neck of aged mice. The vessels became larger and drained better, and that had a direct effect on the mice's ability to learn and remember. "Here is the first time that we can actually enhance cognitive ability in an old mouse by targeting this lymphatic vasculature around the brain," Kipnis said. "By itself, it's super, super exciting, but then we said, 'Wait a second, if that's the case, what's happening in Alzheimer's?'"
The researchers determined that obstructing the vessels in mice worsens the accumulation of harmful amyloid plaques in the brain that are associated with Alzheimer's. This may help explain the buildup of such plaques in people, the cause of which is not well understood. "In human Alzheimer's disease, 98 percent of cases are not familial, so it's really a matter of what is affected by aging that gives rise to this disease," said researcher Sandro Da Mesquita, PhD. "As we did in mice, it will be interesting to try and figure out what specific changes are happening in the old [brain] lymphatics in humans so we can develop specific approaches to treat age-related sickness."
Kipnis noted that impairing the vessels in mice had a fascinating consequence: "What was really interesting is that with the worsening pathology, it actually looks very similar to what we see in human samples in terms of all this aggregation of amyloid protein in the brain and meninges," he said. "By impairing lymphatic function, we made the mouse model more similar to human pathology."

Treating -- or Preventing -- Alzheimer's
The researchers now will work to develop a drug to improve the performance of the lymphatic vessels in people. (Kipnis just inked a deal with biopharmaceutical company PureTech Health to explore the potential clinical applications of his discoveries.) Da Mesquita also noted that it would be important to develop a method to determine how well the meningeal lymphatic vasculature is working in people.
The researchers believe that the best way to treat Alzheimer's might be to combine vasculature repair with other approaches. Improving the flow through the meningeal lymphatic vessels might even overcome some of the obstacles that have doomed previously promising treatments, moving them from the trash heap to the clinic, they said.
It may be, though, that the new discovery offers a way to stave off the onset of Alzheimer's to the point that treatments are unnecessary -- to delay it beyond the length of the current human lifespan.
"It may be very difficult to reverse Alzheimer's, but maybe we would be able to maintain a very high functionality of this lymphatic vasculature to delay its onset to a very old age," Kipnis said. "I honestly believe, down the road, we can see real results."


Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice


Cerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions 


Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease




Autism

While Kipnis is busy developing a drug to improve the lymphatic drainage from the aging brain, some people believe they can achieve something similar via massage.

I have no idea if this really is possible, but this is the idea being practised on children with autism in Italy.

So, because this is after all an autism blog, let’s see what the Italian have been up to.





In this study we report the results of a protocol for improving brain lymphatic flow in autism through lymphatic drainage massage, a technique successfully used in a variety of conditions where intracranial lymphatic circulation is hampered by obstacles at the level of deep cervical nodes. At the end of May 2018, the Biomedical Centre for Autism Research and Treatment started implementing a protocol of manual lymphatic drainage of the deep cervical nodes on autistic subjects. By October 2018, several scores of patients had been treated with this protocol. In this report, we describe the cases of three autistic patients for whom manual lymphatic massage was remarkably effective. To our knowledge, this is the first report of lymphatic drainage massage at the level of the deep cervical nodes in autism. Symptomatic improvement was robust and we attribute these results to the effects of the massage on the intracranial lymph or sometimes referred to as the glymphatic circulation with improvement of brain lymphatic drainage believed leading to a decrease of neuroinflammation. In addition to stimulating lymphatic drainage, we postulate that the protocol may serve also as vagus nerve stimulation. The protocol also targets the larynx in a manner similar as described for laryngeal manual therapy for the treatment of dysphonia, and this factor may be contributing to the overall improvement of symptoms, with particular reference to speech. Based on the cases described in this report and on our ongoing research, we are convinced that this type of inexpensive, harmless and easy-to-implement approach of manual lymphatic drainage can be beneficial to autistic patients and represents a new and promising treatment. We expect that the described protocol will play a central role in future treatments for autism, both alone and in combination with other therapies such as behavioral therapies or nutritional interventions.

Case Reports

Patient 1:

Male, 2 years and 9 months old at the time of implementing the manual lymphatic drainage protocol. The patients showed first signs of autism at 20 months of age when he lost the few words he had learned, lost eye contact, stopped responding when called, and began bizarre behaviors - motor stereotypies - that included flapping. Subsequently, this patient developed crises of anger and violent tantrums, in particular when contradicted. The patient did not show significant bio-humoral alterations with the exception of slightly elevated platelet count and IgE. The patient had frequent bowel movements with very soft and hypocholic feces. Three days after implementation of the manual lymphatic drainage protocol, the patient spontaneously begun speaking a few words and eating without the need of assistance, properly using the tableware. Bowel movement were reduced to two movements per day with well-formed feces. The patient begun showing curiosity toward new foods and flapping progressively disappeared. In the following two months, he significantly increased the complexity of his vocabulary and the ability to appropriately follow complex instructions. Stereotypies disappeared and ability of learning during behavioral therapies significantly improved.

Patient 2:

Female, 9 years old at the time of implementing the manual lymphatic drainage protocol, with confirmed diagnosis of early-onset autism and recurrent allergic asthma requiring desloratadine treatment. The most prominent autism symptoms were motor stereotypies, speech limited to very simple sentences, and significant delay in learning. Immediately after implementation of the manual lymphatic drainage, a slight, temporary, enlargement of latero-cervical nodes lasting for a few days was noted, possibly due to mobilization of lymph. Evident improvement of autistic symptoms consisted in spontaneous, faster and easier learning at school with increased alertness and focus. Ability in performing coordinated fine movements significantly increased and the patient began to write; this in turn resulted in increased self-esteem. Motor stereotypies significantly decreased and personal autonomy significantly increased.

Patient 3:

Male, 6 years and 6 months old at the time of implementing the manual lymphatic drainage protocol. The patients showed first signs of autism at 15 months of age when he stopped developing speech, lost eye contact, stopped responding when called and refrained from social interactions. A diagnosis of atypical autism with hyperactivity and attention deficit was proposed at the age of 5. The child had chronic allergic rhinitis and sinusitis with persistent nasal congestion that caused open mouth breathing. The patient was very selective in his eating habits and only ate a few types of fried foods. Following implementation of the manual lymphatic drainage protocol, chronic nasal congestion was rapidly resolved, and nose breathing was reestablished. Eating habits were significantly improved and the patient began eating a variety of healthier foods. The patient also showed improvement in socialization; began to look at other children, trying to imitate their actions. Also, significant improvements in speech were observed with the patient speaking more complex sentences with better pronunciation.



Conclusion

I think it is very likely that something in today’s post is indeed very relevant to much autism.

Now we know not to blame only the vagus nerve for transmitting inflammatory signals from the body to the brain.

Hopefully the researchers will eventually pursue their original idea from 2015 that the study of meningeal lymphatics might lead to autism therapies.

We are of course at liberty to learn from the Alzheimer’s and MS research and develop our own therapies.