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Showing posts with label Alzheimer's. Show all posts
Showing posts with label Alzheimer's. Show all posts

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.






Monday, 6 May 2019

Mushrooms and Cognitive Function - Something healthy in the English Breakfast!




Breakfast overlooking the river Thames


















The more typical English Breakfast


If you happen to stay at a very nice hotel in London, the best meal to have is breakfast and after that comes tea.  The other meals are unlikely to feature much memorable English food.

Whether it is the five-star Savoy, overlooking the river Thames, or the Travelodge by the station, mushrooms will be on the menu. 

The movers and shakers actually get up early and have their power meetings over breakfast at the Savoy. This is not so expensive and a good way to experience British cuisine, served in a much more spacious environment than most restaurants.  Scotland contributes its porridge and black pudding, kippers might be on offer, but there will be mushrooms, a regular part of even the humblest hotel’s English breakfast.


Eating mushrooms more than twice a week could prevent memory and language problems occurring in the over-60s, research from Singapore suggests.
A unique antioxidant present in mushrooms could have a protective effect on the brain, the study found.
The more mushrooms people ate, the better they performed in tests of thinking and processing. The researchers point to the fact that mushrooms are one of the richest dietary sources of ergothioneine - an antioxidant and anti-inflammatory which humans are unable to make on their own.
Mushrooms also contain other important nutrients and minerals such as vitamin D, selenium and spermidine, which protect neurons from damage. 



We examined the cross-sectional association between mushroom intake and mild cognitive impairment (MCI) using data from 663 participants aged 60 and above from the Diet and Healthy Aging (DaHA) study in Singapore. Compared with participants who consumed mushrooms less than once per week, participants who consumed mushrooms >2 portions per week had reduced odds of having MCI (odds ratio = 0.43, 95% CI 0.23–0.78, p = 0.006) and this association was independent of age, gender, education, cigarette smoking, alcohol consumption, hypertension, diabetes, heart disease, stroke, physical activities, and social activities. Our cross-sectional data support the potential role of mushrooms and their bioactive compounds in delaying neurodegeneration.




Fig. 1. Functional dependence of mild cognitive impairment on mushroom consumption (treated as continuous variable): the solid curve is estimated via the smoothing spline approach. Adjusted for age, gender, education, cigarette smoking, alcohol consumption, hypertension, diabetes, heart diseases, stroke, physical activities, social activities.

Using data from the Diet and Healthy Aging Study in Singapore, we found that mushroom consumption was associated with reduced odds of having MCI. The reduction was significant for participants who consumed greater than 2 portions of mushrooms per week

The observed correlation between mushrooms and reduced odds of MCI in our study sample is biologically plausible. Certain components in mushrooms, such as hericenones, erinacines, scabronines and dictyophorines may promote the synthesis of nerve growth factors. Bioactive compounds in mushrooms may also protect brain from neurodegeneration by inhibiting production of amyloid- and phosphorylated tau, and acetylcholinesterase. Mushrooms are also one of the richest dietary sources of ergothioneine (ET). ET, a thione-derivative of histidine is an unique putative antioxidant and cytoprotective compound. While humans are unable to synthesize ET, it can be readily absorbed from diet (main source is mushrooms) and actively accumulated in the body and the brain via a specific transporter, OCTN1. Our recent study in elderly Singaporeans revealed that plasma levels of ET in participants with MCI were significantly lower than age-matched healthy individuals, leading us to believe that a deficiency in ET may be a risk factor for neurodegeneration, and increase ET intake through mushroom consumption might possibly promote cognitive health.

In summary, using community-based data in Singapore, we found that mushroom consumption was associated with reduced odds of MCI. Based on current evidence, we propose that mushroom consumption could be a potential preventive measure to slow cognitive decline and neurodegeneration in aging.


Conclusions

Studying all possible forms of cognitive impairment is interesting if you want to understand autism. 

Mushroom would appear to have a similar scale of potential benefit in MCI (mild cognitive impairment) to cocoa flavanols, which have been commercialized as a therapy by Mars. 

We did see previously how one specific type of mushroom (Lion’s Mane) has a particular effect of raising levels of NGF (nerve growth factor).  Oyster mushrooms produce Lovastatin.

Mushroom contain spermidine and so will improve autophagy, the intracellular garbage collection service that is impaired in many neurological conditions.

Eat mushrooms.





Thursday, 28 February 2019

Who lives in Libya? And Raising the level of BHB in your blood.



Today’s post is mainly about some “home-research” that was sent to me by a company that sold me C8 oil (caprylic acid MCT oil).
It is not peer-reviewed research, but it is a well thought out home experiment measuring the level of the ketone BHB in the blood of two healthy young adults testing a range of commercially available products. It is important to note that BHB was measured in blood and not urine, which is a big plus for the experiment.

Dr D’Agostino’s starting dose
First, a recap of where we started a few months ago in this blog.
One of the leading ketone researchers is Dr D’Agostino and his suggested starting dose on ketone supplements is 10 ml of Ketoforce and 10ml of C8/caprylic acid.
We saw in earlier posts that the amount of BHB produced by taking C8 is highly dependent on whether it is taken with food. Taken on an empty stomach resulted in more BHB in the bloodstream.
10 ml of KetoForce contains 4g of BHB along with 500mg of sodium and 500mg of potassium.

BHB salts and BHB esters
Until recently BHB supplements were all salts, so the BHB was combined with sodium, potassium, calcium or magnesium.
Taking large amounts of sodium, calcium, potassium or magnesium will likely disturb the electrolytes in your body and may cause you problems.
Ketone esters are composed of a ketone molecule like BHB bound to a ketone precursor using an ester bond (butanediol or glycerol).
Ketone esters are commercially available, but very expensive.  They are currently used by athletes and the US military.
The first commercial product was developed based on the work of researchers at Oxford University in the UK, but the resulting product cannot legally be sold in the UK. HVMN, a company in the US, are currently selling it as a supplement for athletes. I wonder if it has been declared a banned substance by sports doping agencies.
Some of the research:-

Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson’s disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with (R)-3-hydroxybutyl (R)-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [31P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.






The Military as Early Adopters
For centuries military forces have sought to gain a competitive advantage using drugs, so it is not surprising that the current US military are interested in ways to increase physical endurance.

Survival rations for downed airmen, or just reducing the weight of food rations for Special Forces, would be obvious applications for BHB esters.
In modern times it was the Germans who made the greatest military use of drugs with their Pervitin tablets that enabled their soldiers and airmen to fight for days without sleep. Pervitin turned out to be Methamphetamine. Such drugs are used today by irregular forces.
Extensive use was made of drugs to counter altitude sickness in Afghanistan, first by the Russians and later by the Americans. Diamox/Acetazolamide is the Western drug and this same drug has application in some channelopathies and some types of autism.
Drugs that improve exercise endurance, and so are likely banned for use in sport, are potentially interesting for people with mitochondrial disease, vascular abnormalities and even glucose transporter dysfunctions. In short if you have restricted ATP production in your brain, anything that can overcome whatever the route problem is, should improve brain function. Alzheimer’s disease is a good example where apparently quite different reasons result in reduced power output within the brain. 
I thought it was encouraging to see that military funding is being used to develop medical therapies for PTSD and suicide prevention. The latter was the application for the hormone TRH, which I suggested as a possible autism treatment, since it affects a chain reaction of important hormones affecting mood.

The n=2 home trials of BHB-raising supplements

You can read the full report by clicking the link below


I have extracted some interesting highlights.

·      HVMN and KE4 are very expensive ketone esters (red and green lines)

·      C8 MCT oil is the product that I currently use (20ml a day) (purple line)

·      Keto Max and KETOCANA are ketone salts (blue and orange lines)































 Recall an earlier graphic of "the ketone zone" so you can put BHB levels into context.





Summary: The Takeaways

·       We confirmed that ketone supplements increase ketones: All of the ketone supplements tested resulted in an increase in ketones for a temporary time period.

·       Rapid 3-Hour Windows: Ketone esters and ketone salts rapidly increase ketones within 30 minutes. The effects last for a ~3 hour period.

·       Slow 5-Hour Window: C8 MCT oil increases ketones more slowly. However, the ketone increase lasts for a more prolonged period of ~5 hours (see C8 MCT Oil research review covering this).

·       What Does this Say About When to Use Which Supplement? This is a complex question that requires further investigation into the different applications. However, we have three hypotheses to start with based on these results.

1.     For higher ketone boosting needs: If you are looking to boost ketones into the therapeutic range of 2-4mmol, it is more cost effective to take KetoCaNa (Ketone Salts). But a more gut tolerable option would be a Ketone Ester – at a greater price. Both are able to boost ketones enough to meet this target.

2.     For lower ketone boosting needs: If you are looking for less than a 1 mmol boost in ketones, the most cost effective and convenient (longer duration) approach is via C8 MCT oil. This may be most relevant to A) People not on ketogenic diets who want some of the ‘satiation benefits’ of ketosis, and B) People on ketogenic diets who already have raised ketones and only want a small additional boost (e.g. you’re at 1 or 2 mmol, and want to increase to 2 or 3 mmol respectively).

3.     For the highest ketone boosting needs: Should you want a greater increase in ketones for any reason Ketone Esters are the best option (this article explores where and why this may be interesting)


My conclusions
The effect of C8 is slightly different to Ketone salts like Ketoforce and I think D’Agostino’s advice to combine them is wise.

A dose of 20ml of C8 appears a good upper limit, since its effect at producing BHB gradually fades. Better to make sure it is taken without food to maximize the effect. Even though it is the cheapest supplement there appears to be no point taking larger doses like 50ml.
Ketone salts are definitely limited by their composition of sodium, potassium, calcium or magnesium. I think high doses are extremely unwise. D’Agostino’s 10 ml of Ketoforce seems safe.
Ketone esters are very expensive, but do actually provide a genuine energy-boosting level of BHB, which will also trigger all the other suggested effects of BHB (summarized in the old post below), quite possible at increased levels.


So I suppose the ideal autism research study would be to use KetoneAid KE4 or the HVMN BHB Ester, as used by the US military.

I expect the BHB Ester would have a big effect on someone with Alzheimer’s disease. They have a problem with the glucose transporter at the blood brain barrier and with reduced insulin sensitivity. The large amount of BHB from the ester supplement would provide an alternative fuel for the mitochondria, which are not producing enough ATP from glucose to power the brain.
We saw that Nestle is investing in MCT as a nutraceutical for Alzheimer’s. Today’s home research suggests that high doses of MCT are not going to be effective at raising BHB levels in the blood to a very significant level. BHB esters look much more promising.

This would be an expensive Alzheimer’s therapy, but still much cheaper than relocating to a care home. 

I did check and there actually is a case history; it is a physician wife treating her own husband who has early onset Alzheimer's. She read the research and translated it into a novel therapy for him. Nice work! This would of course be frowned upon in most countries as treating hubby like a guinea pig and doctors are not meant to treat family members, but to me it looks like the most caring thing she could do.  The good thing is that she published the result. Mainstream doctors treating their own children with autism, or even sometimes others, rarely seek to publish/share their results, so helping to maintain the convenient false perception that all autism treatments are just quackery (some are, while some clearly are not).
  • After six to eight weeks of taking 28.7g of the KME thrice daily, he began to exhibit improvement in memory retrieval, spontaneously discussing events that occurred up to a week earlier. He was again able to perform more complex tasks, such as vacuuming, washing dishes by hand, and yard work.
  • Plasma βHB levels were measured occasionally to assess KME-plasma βHB dose-response relationships (Fig. 2). Noticeable improvements in performance (conversation, interaction) were observed at higher, post-dose βHB levels, compared to pre-dose values.

  • In treatment of TP’s long-standing AD dementia, KME-produced repeated diurnal elevations of circulating βHB levels were clearly effective, during the 20-month study, in improving behavior, and cognitive and daily-activity performance. The physician-caregiver noted that performance seemed to track plasma ketone concentrations, with conversation and interaction declining as levels fell toward baseline. From requiring almost constant supervision, TP became much more self-sufficient on KME

The question in autism is what level of BHB do you need to maximize the effect and how long does this spike in blood BHB produce its beneficial effect. Do you need a constant level for 24 hours (I think not)? Do you need one BHB elevation/spike a day? Does a second daily dose have any benefit?
The BHB ester would be a good research tool, since it should not disturb electrolyte levels.


Who does live in Libya?
Anecdotal evidence has always got to be taken with a large pinch of salt, but if all you are doing is an N=1 trial that is often all you have got.

From more than half a year of experimenting with the combination BHB salts and C8 oil, the effect is clear. It causes an increase in relevant speech, directly related to current activities. You could call this unprompted commenting.
Monty will now answer the phone at home, rather than just hanging up to stop the annoying ringing noise, or having an ultra-trivial conversation. He will have a functional conversation in either of his two languages. This was particularly noted by his Grandmother as an improvement.

The good thing is the increased conversation fades when BHB/C8 is paused and returns when re-started.
Along the way we have discovered that not all BHB salts are equal. The Ketoforce liquid is the best, because it has most effect and does not disturb electrolytes, as Primaforce BHB powder appeared to, not by much, but enough to have an impact.

Using a mixture of C8 + C10 oil, produced a negative effect (aggression) after a few weeks. So while C10 may have a unique effect on mitochondria, beneficial to some, it was not tolerated.
10ml of Ketoforce and 20ml of C8 a day means one bottle of Ketoforce and one litre of C8 lasts 50 days.

The beneficial effect is not on the magnitude of bumetanide. The Ketoforce/C8 therapy costs 15 times more than bumetanide, but I think that really just means that generic bumetanide is extremely cheap.
Adding the small 0.5mg dose of Clemastine in the evening does seem to have an incremental effect after a few weeks.

It does appear to manifest itself again in improved speech. Now the comments are not related to current activities, but also past events and making connections.
“Colin has a moustache, like Poirot”
Colin is a friend of mine who Monty last saw a few months ago. He does have a moustache and so does Hercule Poirot.
The strangest recent “conversation” started with:-

“Who lives in Libya?    Do Indians live in Libya?” asked Monty
“No, Indians do not live in Libya, Arabs live in Libya”, I replied.
“Indians live in London” he countered
            “Yes, some Indians do live in London, but a lot more live in India”
“Who lives in Israel?” he asked    (We did recently visit Jerusalem)
            “Jewish people and Arabs live in Israel”, I replied
            “Who lives in France?” I asked
“Leopoldine” (a former classmate from school) he answered
            “Who lives in Italy?” and so it continued.

This is not the sort of “conversation” you normally have with Monty. This was the longest ever "conversation".
You would not expect him to recall that London has a large population of Asian descent. He lives far away.

Is this the cumulative effect of BHB/C8, or an emerging benefit of a quarter dose of an OTC hay fever drug?

Clemastine, taken in the evening, has had no negative side effects and is not expensive. $10 buys 60 pills that will last 4 months. Daniel Kerlinsky, the enlightened US psychiatrist we encountered in a post a while back, was keen to point out that it takes months for low dose Clemastine to show its effect (myelin, microglia or both).
In our case BHB/C8 looks like it is heading towards being included in the PolyPill. The only side effect is feeling thirsty, which is manageable. I am surprised to be considering adding what is a Californian diet therapy to my son’s autism therapy. Incidentally he has not lost any weight, he continues to gain it.

The jury is still out on Clemastine. Due to the onset of its potential benefit being very slow, it is not so easy to make a withdrawal trial (stopping a therapy, seeing if the believed effect is lost and then restarting to see if that effect returns). I will wait to see the feedback of other readers of this blog.