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Showing posts with label HBOT. Show all posts
Showing posts with label HBOT. Show all posts

Thursday 7 March 2019

A Case Study Treating Adult Hypoxia with Clemastine - a potential treatment to promote myelin recovery in premature infants


I did think we had finished with Clemastine for a while, but a researcher reader of this blog sent me a very interesting recent case study about a man with brain damage caused by hypoxia (lack of oxygen) and we have the MRI brain scans showing how that damage was reversed by this OTC antihistamine. Hypoxia is often caused by carbon monoxide poisoning or in childbirth, if things get tangled up.


The researchers go on to suggest Clemastine treatment to promote myelin recovery in premature infants. In this case the graphics in the paper relate to mice, not humans, but are really impressive.
This means that what is called Ataxic Cerebral Palsy, which is caused by a lack of oxygen during birth might now have a treatment.
Some children with autism, including some discussed in the comments in this blog, appear to have suffered hypoxia during birth. This caused damage which resulted in symptoms of autism.  You would expect that damage to show up on the “right sort of MRI” in the same way as the adult male, below. Some of these children are reported by parents to respond to hyperbaric oxygen, even though it is carried out years after the hypoxia.

Findings in human DPHL case treated with clemastine. Axial FLAIR (fluid attenuated inversion recovery) at 1 (A), 2 (B), 6 (C), and 12 (D) months after injury in a human case of DPHL, showing MRI white matter abnormalities on FLAIR and diffusion weighted images, subtle at 1 month and striking at 2 months, parallel to patient’s worsening clinical course; white matter signal changes showed a periventricular/ deep white matter distribution with involvement of the corpus callosum (particularly splenium), with sparing of U-fibres. The patient was started on clemastine treatment at 2 months. At 6 months, MRI abnormalities in the white matter were partially normalized, showing fuzzy signal changes, unchanged at 12 months follow-up.

What I found interesting was the time delay, it was two months after the hypoxia that the man’s symptoms became really severe, but rather than being game over, the white patches in the month 2 MRI gradually fade away, after clemastine treatment started.
In my posts on autism and myelin, I pointed out that the problem appears to be re-myelination, which is the repair and maintenance of existing myelin. In autism you could consider it as “Friday afternoon myelination”, when the oligodendrocytes are thinking more about the weekend than your axons. In the man in the case study he already had plenty of myelin prior to his hypoxia, but the hypoxia affected his capacity to re-myelinate his axons.
The progressive cognitive decline with profound short-term memory loss, impaired executive function, and paucity of speech, psychomotor retardation, urinary incontinence and gait impairment was reversed.  The patient was seen in follow-up 5 months after his hypoxic event. His cognitive function had markedly improved and he was able to return to work.  All thanks to OTC clemastine and I think he should thank someone for reading the Multiple Sclerosis research on clemastine.
The researchers then looked in detail at a mouse model of hypoxia and among other things, Myelin Basic Protein (MBP).


suggesting a rescue of MBP expression defects by clemastine during chronic hypoxia
Daily treatment with oral clemastine during hypoxia leads to significant (3-fold) increases in MBP in the cerebellar foliae compared to untreated hypoxic littermates
We found that oral administration of clemastine in murine neonatal hypoxia leads to significant increases in the numbers of differentiating OPCs expressing the markers proteolipid protein (Plp) and myelin associated glycoprotein (Mag) mRNA in corpus callosum and striatum compared to untreated hypoxic littermates




Clemastine promotes myelin protein expression in neonatal hypoxia.(A) MBP protein expression in the (A) forebrain, (C) striatum white matter of postnatal Day 10 (P10) normoxic mice (‘Normoxia’), versus those exposed to neonatal hypoxia (‘Hypoxia’), versus hypoxic littermates treated with clemastine (‘Hypoxia + Clemastine’) 

Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia. We report a case of an adult patient who developed the rare condition DPHL and made a nearly complete recovery in the setting of treatment with clemastine, a widely available antihistamine that in preclinical models promotes oligodendrocyte precursor cell differentiation. This suggested possible therapeutic benefit in the more clinically prevalent hypoxic injury of newborns, and we demonstrate in murine neonatal hypoxic injury that clemastine dramatically promotes oligodendrocyte precursor cell differentiation, myelination, and improves functional recovery. We show that its effect in hypoxia is oligodendroglial specific via an effect on the M1 muscarinic receptor on oligodendrocyte precursor cells. We propose clemastine as a potential therapy for hypoxic brain injuries associated with white matter injury and oligodendrocyte precursor cell maturation arrest. 


Conclusion

The days of cheap clemastine in North America are probably numbered.



Monday 2 November 2015

Brain Hypoperfusion in Autism & Cocoa



Today’s post is simpler than many earlier ones and is actionable.

A known feature of many neurological conditions like Alzheimer’s and dementia is reduced blood flow to certain parts of the brain.  In the medical jargon this is called hypoperfusion.

This reduced blood flow is also present in autism and is measurable by MRI.

We encountered epicatechin in early posts on cocoa flavanols.  It would seem that one of epicatechin’s many effects is to increase cerebral blood flow. 

Two chocolate companies, Mars (Cocoavia) in the US and Barry Callebaut (ACTICOA) in France, have developed high flavanol cocoa.  10 g of their cocoa contains about 1 g of flavanols and produces cognitive benefits; even a quarter of this dose gives the cardiovascular benefits.  Mars, in particular, are funding a great deal of research and have committed to a five year project with Harvard.  The high flavanol products are available today.


Brain Perfusion Anomalies in Autism

While most research focuses on Alzheimer’s and other types of cognitive impairment and memory loss, there are studies on brain perfusion in autism.



  
Autism is a severe developmental disorder, the biological mechanisms of which remain unknown. Hence we conducted this study to assess the cerebral perfusion in 10 children with autism and mental retardation. Five age matched normal children served as controls. These cases were evaluated by single photon emission computed tomography (SPECT) using Tc-99m HMPAO, followed by segmental quantitative evaluation. Generalized hypoperfusion of brain was observed in all 10 cases as compared to controls. Frontal and prefrontal regions revealed maximum hypoperfusion. Subcortical areas also indicated hypoperfusion. We conclude that children with autism have varying levels of perfusion abnormities in brain causing neurophysiologic dysfunction that presents with cognitive and neuropsychological defects.
  
Significant hypoperfusion was observed at cortical and subcortical areas of brain in autistic subjects, suggesting that the structural abnormalities
of these brain areas may result in reduced cortical activity, thus causing dysfunction of these brain areas, and eventually producing some of the
emotional and behavioral disorders usually described in autistic subjects. These SPECT findings may help to explain several behavioral features of autism, such as impulsive and aggressive behaviours (to self and others), motor disinhibition (such as stereotypic and manneristic movements and echophenomena), and deficits in planning, sequencing and attention.


Abnormal regional cerebral blood flow in childhood autism


Neuroimaging studies of autism have shown abnormalities in the limbic system and cerebellar circuits and additional sites. These findings are not, however, specific or consistent enough to build up a coherent theory of the origin and nature of the brain abnormality in autistic patients. Twenty-three children with infantile autism and 26 non-autistic controls matched for IQ and age were examined using brain-perfusion single photon emission computed tomography with technetium-99m ethyl cysteinate dimer. In autistic subjects, we assessed the relationship between regional cerebral blood flow (rCBF) and symptom profiles. Images were anatomically normalized, and voxel-by-voxel analyses were performed. Decreases in rCBF in autistic patients compared with the control group were identified in the bilateral insula, superior temporal gyri and left prefrontal cortices. Analysis of the correlations between syndrome scores and rCBF revealed that each syndrome was associated with a specific pattern of perfusion in the limbic system and the medial prefrontal cortex. The results confirmed the associations of (i) impairments in communication and social interaction that are thought to be related to deficits in the theory of mind (ToM) with altered perfusion in the medial prefrontal cortex and anterior cingulate gyrus, and (ii) the obsessive desire for sameness with altered perfusion in the right medial temporal lobe. The perfusion abnormalities seem to be related to the cognitive dysfunction observed in autism, such as deficits in ToM, abnormal responses to sensory stimuli, and the obsessive desire for sameness. The perfusion patterns suggest possible locations of abnormalities of brain function underlying abnormal behaviour patterns in autistic individuals.


Cerebral Hypoperfusion and HBOT?

One therapy proposed to treat Cerebral Hypoperfusion in autism is hyperbaric oxygen therapy (HBOT).  Some proponents go as far as to link specific areas of the brain to specific autistic features as below.







The mainstream view, among those using HBOT for other conditions, is that it would not help stimulate increased blood flow in autistic brains.  But there are proponents of the therapy like Rossignol.




You may have realized that the science exists to test, once and for all, whether HBOT can improve cerebral blood flow in autism.  It just takes two visits to an MRI.




I did see a report about a US neurologist who showed via MRI that the cerebral blood flow of his autistic patient improved using HBOT and he tried to use this to get access to the further HBOT on insurance.



Hypoperfusion in Alzheimer’s, Dementia  and Cognitive Impairment

Reduced cerebral blood flow is a marker of incipient dementia.  I expect one day this might even be used to trigger preventative therapy.

Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study.

Abstract

Cerebral blood flow (CBF) velocity is decreased in patients with Alzheimer's disease. It is being debated whether this reflects diminished demand because of advanced neurodegeneration or that cerebral hypoperfusion contributes to dementia. We examined the relation of CBF velocity as measured with transcranial Doppler with dementia and markers of incipient dementia (ie, cognitive decline and hippocampal and amygdalar atrophy on magnetic resonance imaging) in 1,730 participants of the Rotterdam Study aged 55 years and older. Cognitive decline in the 6.5 years preceding CBF velocity measurement was assessed with repeated Mini-Mental State Examinations in nondemented subjects (n = 1,716). Hippocampal and amygdalar volumes were assessed in a subset of 170 nondemented subjects. Subjects with greater CBF velocity were less likely to have dementia. Furthermore, in nondemented subjects, greater CBF velocity was related to significantly less cognitive decline over the preceding period (odds ratio per standard deviation increase in mean CBF 0.74 [95% confidence interval, 0.58-0.98]) and larger hippocampal and amygdalar volumes. A low CBF is associated with dementia, but also with markers of incipient dementia. Although we cannot exclude that this is caused by preclinical neurodegeneration leading to hypoperfusion, it does suggest that cerebral hypoperfusion precedes and possibly contributes to onset of clinical dementia.


Vascular dementia

Vascular dementia is the second-most-common form of dementia after Alzheimer's disease.  It is a much simpler condition, it is dementia caused by problems in the supply of blood to the brain, typically by a series of minor strokes.

The incidence peaks between the fourth and the seventh decades of life and 80% will have a history of hypertension. Patients develop progressive cognitive, motor and behavioural signs and symptoms.

Blood pressure rises with aging and the risk of becoming hypertensive in later life is considerable

It would seem that you could treat hypertension and vascular dementia with the same preventative therapy.  See the clinical trial on treating vascular aging with Cocoa, later in this post.






It has also been suggested that endothelial dysfunction and vascular inflammation may also contribute to increased peripheral resistance and vascular damage in hypertension. 

In essence you want to control peripheral resistance and before it is too late.  It really is a case of “a stitch in time saves nine”.

The research done in to peripheral resistance / vascular stiffness can be re-purposed to help us treat brain hypoperfusion.  In autism we may have Brain Hypoperfusion, but without high blood pressure (hypertension).




Increased vascular stiffness, endothelial dysfunction, and isolated systolic hypertension are hallmarks of vascular aging. Regular cocoa flavanol (CF) intake can improve vascular function in healthy young and elderly at-risk individuals. However, the mechanisms underlying CF bioactivity remain largely unknown. We investigated the effects of CF intake on cardiovascular function in healthy young and elderly individuals without history, signs, or symptoms of cardiovascular disease by applying particular focus on functional endpoints relevant to cardiovascular aging. In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 22 young (<35 years) and 20 elderly (5080 year) healthy, male non-smokers consumed either a CF-containing drink (450 mg CF) or nutrientmatched, CF-free control drink bi-daily for 14 days.
The primary endpoint was endothelial function as measured by flow-mediated vasodilation (FMD). Secondary endpoints included cardiac output, vascular
stiffness, conductance of conduit and resistance arteries, and perfusion in the microcirculation. Following 2 weeks of CF intake, FMD improved in young (6.1±0.7 vs. 7.6±0.7 %, p<0.001) and elderly (4.9 ± 0.6 vs. 6.3 ± 0.9 %, p < 0.001).
Secondary outcomes demonstrated in both groups that CF intake decreased pulse wave velocity and lowered total peripheral resistance, and increased arteriolar and microvascular vasodilator capacity, red cell deformability, and diastolic blood pressure, while cardiac output remained affected. In the elderly, baseline systolic blood pressure was elevated, driven by an arterial-stiffness-related augmentation.
CF intake decreased aortic augmentation index (9 %) and thus systolic blood pressure (7 mmHg;



Cocoa Flavanols

I did write an earlier post about the various benefits of Cocoa Flavanols. 


  
Here is a very good review paper:-



Norman Hollenberg, at Harvard, has been an advocate of high flavanol cocoa for decades.  Here is one of his papers.





Using functional MRI, the following study measures the effect on brain blood flow, before and after taking a high flavanol cooca drink









There is now good evidence that the acute benefits for cognitive function and blood flow exerted by cocoa flavanol consumption peak approximately 90120 min postconsumption (Schroeter et al. 2006; Francis et al. 2006; Scholey et al. 2010; Field et al. 2011); however, it is presently unclear whether separate chronic mechanisms exists following cumulative consumption over several weeks and months, or indeed whether chronic consumption enhances the effectiveness of acute mechanisms in a cumulative fashion. Despite several plausible mechanisms for increased neuronal activity (as described above), it remains to be seen whether a single cocoa flavanol dose-induced increase in CBF is associated with concomitant benefits in cognitive performance in the immediate postprandial period. More broadly, recent reviews of acute interventions and epidemiological surveys provide good evidence that flavonoids and their subclasses are beneficial for cognitive function


In conclusion, the present findings support the hypothesis that flavanol-rich cocoa beverages are associated with increased CBF within a 2-h post-prandial time frame. More specifically, increased brain perfusion following the HF drink relative to the LF drink was observed in the anterior cingulate cortex and a region in the left parietal lobe. These data add to the substantial body of literature demonstrating that flavanol consumption is beneficial for peripheral and cerebral vascular function and thus for maintaining, protecting and enhancing cardiovascular health.



Does High Flavanol Cocoa have an effect in Autism?

This is probably the question you have been asking yourself.

I did acquire some ACTICOA, high flavanol cocoa some time ago.  I was wondering how I was going to administer enough of it to make a trial.  In the trials on improving memory in older adults 10g a day was needed.

While adding it to milk seems an obvious choice, Hollenberg suggests that the milk may neutralize the flavanols.  This is true with black tea; once you add milk you lose its healthy antioxidant properties.

In the end I choose to add 5ml to the breakfast broccoli powder and water concoction and mix with a frappe mixer.  Monty, aged 12 with ASD, was the ever willing test subject.

Two and a half hours later there was unprompted laughter and smiling.  This is repeated each time I give the ACTICOA  cocoa.

According to the literature, the peak level of epicatechin occurs 2 to 3 hours after consuming cocoa.

Then I tried a regular raw cocoa powder at the same dose; no laughter.

So I conclude that ACTICOA is indeed different to regular non-alkalized cocoa powder.  The more common alkalized cocoa has virtually no flavanols at all, and this is what is used to make most chocolate and is sold in supermarkets as "cocoa".

There are potentially other sources of epicatechin, but you really want a reliable standardized product.  If you live in the US/Canada this is easy; you can buy the Cocoavia product from Mars.  It is not cheap if you want 1g of flavanols a day.


The literature does suggest that there is a cumulative effect of taking epicatechin and Hollenberg has documented that regular consumption of unprocessed cocoa (rich in flavanols) is associated with numerous health benefits, particularly related to blood flow (strokes, heart attacks, endothelial dysfunction, cholesterol etc.)

Since Mars are now funding considerable research into the health benefits of these flavanols, I did think of suggesting they look at autism.

They could take a group of people with autism, measure their IQ and then score their autism using one of the standard scales.  Then off to the MRI to measure blood flow and velocity in different parts of the brain.

Give half of the test subjects a daily high flavanol drink and the other half a low flavanol drink.  After three months, repeat the IQ test, autism test and measure blood flow again via MRI.

I suspect that reduced blood flow/hypoperfusion would be more present in those with lower IQ and that they might show improved IQ at the end of the trial.  I suspect that in terms of autism, most would show an improvement on the high flavanol treatment.

I would like to think that after three months, blood flow/velocity would have increased.

You could then repeat on people with Down Syndrome and more general MR/ID.