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Thread: Why neurons lose their spark?

  1. #11
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    Epigenetics reported on Horizon 10 Jul 2013. This branch of genetics has developed just over last two years, enabled by sophisticated computer technology.

    At the moment the embryo divides in the womb at the genesis of identical twins, each twin has its own copy of the same DNA from which to develop. Identical twins' genetic profiles were analysed in later life and it was found that certain genes were being expressed/turned on in one twin while not in the other. This process appears sporadic.

    When the gene mutates in adolesence or prior to the act of procreation, the gene mutation will pass on to following generations. However it may be subsequent generations later when the gene mutation expresses itself.

    In an average lifespan, between 10 and 50 gene mutations may occur.

    Radio-active element decay radiation, solar radiation and many ingested chemicals cause gene mutation.

    The human genome is particularly unstable and contrasts starkly with the genome of insects that are extremely stable. For example, the dragonfly's genome has remained largely unchanged for 400,000,000 years.

    At the human bottleneck of the Lake Toba supervolcano, 72,000 years ago when the human population of earth was less than 10,000, it is highly unlikely MND existed.

    MND gene mutations are known to be in a single generation, persisted for several generations or run for millenia. The C9orf72 gene mutation is only present in white Europeans. Many of the SOD1 gene mutations are only found in white North Americans while North Indians majorly succumb to slow progression MND variants.
    Last edited by Graham; 7th July 2014 at 01:09.

  2. #12
    Forum Member Laila's Avatar
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    Thanks Graham for the info. I think MND is a gene thing. Interesting that they find sporadic gene changes/switches on , so I guess there isn't any specific cause, just a random change in gene function?

    Link to BBC news story on gene therapy , it mentions,a neuro degenerative disease and gene therapy towards the end of the article.


    http://www.bbc.co.uk/news/health-23269778

    Carol
    Last edited by Laila; 12th July 2013 at 10:26. Reason: Added link to news article

  3. #13
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    Our DNA contains the coding for the biological machine. The coding is very basic and is denoted by only four molecules on the DNA ladder, A' T, C and G. A always pairs with T and C always pairs with G on the DNA ladder. The DNA coils on itself in the first instance and then histones assist the coils to further coil on themselves. The process of coiling further continues until the complete chromosome is formed.

    Technology fitting of the 22nd century demonstrated that individual pieces of the DNA denoted by the letters, A, T, C and G can now be editted with absolute precision using Crispr and SAS9 technology described as 'jaw-dropping' by seasoned professors. This technology supersedes virus techniques of editing DNA.

    The tool for elliminating MND from DNA now exists, but is banned in the UK on ethical grounds, designer babies n all that.

    A BBC article was aired in April 2014 describing precision editing of the yeast genome for uses in making bread.
    Last edited by Graham; 19th October 2014 at 22:10.

  4. #14
    Forum Member marieline's Avatar
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    It is such a pleasure to visit your post Graham, your knowledge is remarkable and i am quite impressed. Thanks for the refreshers.

    I make sure to not over - indulge in the red wine in future. But 1 beer always make me feel fantastic.

    I personally find paracetamol to be the best pain killer out there. 500mg usually see me through the day when i badly need it.

    Best wishes
    Marieline

  5. #15
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    TREATMENTS IN CLINICAL TRIAL

    Stem Cell Treatments

    BrainStorm - - - - - - - - - Phase 2A. - - - Autologous(self) bone marrow derived stem cells
    FDA Fast Track
    Neuralstem - - - - - - - - - In progress - - - Spinal cord derived neural stem cells
    TCA Cellular Therapy - - In progress - - - Autologous(self) bone marrow derived stem cells


    Other Treatments

    Basiliximab - - - - - - - - Safe
    Dexpramipexole - - - - - FAILED
    GM604 - - - - - - - - - - - - Phase 2A. - - - - - FDA Fast Track, Orphan Drug Status
    KNS-760704 - - - - - - - - Safe
    Lithium - - - - - - - - - - - - FAILED
    NP001 - - - - - - - - - - - - Safe
    SB-509 - - - - - - - - - - - - Safe
    Talampanel - - - - - - - - - Safe
    Thalidomide - - - - - - - - FAILED
    Tirasemtiv - - - - - - - - - - FAILED

    22
    Last edited by Graham; 11th November 2014 at 21:13.

  6. #16
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    thankyou graham this has been most useful think i will get tested for the gene .

    sharon x

  7. #17
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    NOTES ON PLS

    AN OVERVIEW

    Primary Lateral Scelorsis, PLS, is the name given to MND affecting the Upper Motor Neurones, UMNs.

    The UMNs nucleus reside in the motor cortex that locates towards the rear of the frontal lobe. This translates to more or less the top of the brain. Distinct regions of the brain control distinct muscle groups of the body. A diagram showing which areas of the motor cortex that control particular muscle group/appendages is given on the build-uk site. The nucleii of the UMNs reside in the brain's grey matter.

    The UMNs are controlled by the cerebral cortex to perform the high functions, for example, writing, walking, chewing. Interfacing the UMNs and cerebral cortex are neurones that control combinations of motor neurones that perform the complex tasks. A case was documented where a gentleman's arm would always move to open a door as the door came within range of the arm despite him not wanting to move through the door. This demonstrated how the motor neurone interface functions with control inputs from the eyes only initiating movement in this example. The cerebral control input was lost.

    There are over 600 muscle groups in the human body.

    The skull case may be removed and electrical stimulation of distinct parts of the motor cortex will illicit movement in the various muscle groups, for example causing a hand to grasp or a face to smile.

    The anatomy of motor neurones is well documented on wikipedia. The salient features are a nucleus with projections/tails from off the neucleus that connect to other neurones or direct to a muscle. The projections to the muscles or LMNs are up to 1 metre long and 1/10 the diameter of a human hair. The projections organise into groups (tracts) that are the white matter of the brain.

    Motor neurones do not have programmed regeneration cycle (apoptosis) within the body''s lifespan. Motor neurones take 15 years to fully mature.

    A type of glial (support) cell named oligodendrocyte supports the motor neurone by encasing the motor neurone projections in myelin. Myelin insulates the motor neurone projections both physically and electrically. Oligodendrocytes also support the mono-carboxylate transport 1 (MCT-1) system that nourish the neurone.

    Another type of glial cell is the astrocyte. These cells act as the resident immune system and patrol the motor neurones by touching the motor neurones. Chemical messages are sensed by the astrocyte to determine the health of the motor neurone. When the astrocytes senses the motor neurone is stressed, immune responses are generated including inflammation, anti-body and nerve growth responses.

    There are two methods of intra neurone communication, chemical and electrical. Different neurone cell types use different chemicals for signalling.

    The UMNs of the motor cortex project into the central region of the brain that is called the basal ganglia region. There are two distinct projections from the UMNs named the cortico-spinal tract and the cortico-bulbar tract. The cortico-spinal tract contains the UMNs' projections that control the limbs and trunk muscles. The cortico-bulbar tract contains the UMNs' projections that control the tongue, pallette, lips, throat, epyglotis (food flap), larynx muscles.

    The basal ganglia is the closed-loop control system of the human machine that collates feedback from the muscle groups, by means of the peripheral nervous system, to define the exact muscle movement demand from the UMNs of the motor cortex.

    There are Lower Motor Neurones, LMNs making the voluntary control decisions for muscles in the basal ganglia (mid brain) such as coughing, sneezing, breathing, pain reflexes, blinking, bowel and stomach movement, throat regurgitation, saliva production, yawning, hiccups.

    The UMNs and LMNs interact where they both have need to exert control over the same muscle group, for example, the eyelids. The LMNs control the blink, UMNs control sleep and shut-eye movements.

    UPPER MOTOR NEURON DISEASES

    Pure PLS

    This version of MND is rare, affecting only 2% of people with MND. A definative diagnosis of pure PLS takes a minimum of four years. The reason why it takes so long for a diagnosis of pure PLS is because it takes a minimum of four years for atypical symptoms NOT to appear.

    A mild dementia is typically associated with pure PLS.

    Riluzole not effective.
    Predominantly UMN ALS

    This version of MND is characterised by symptoms typical of PLS in the early stages of the disease, then symptoms of ALS as the disease progresses. It is commonly called PLS turning to ALS.

    Limb onset is typical. Slowness of movement, spasticity (stiffness) and some weakness of muscle strength will be noticed. Briskness of reflexes will become apparent. Walking gait will change as specific muscle groups weaken and often foot-drop is an early indicator of leg involvement. Over years muscle weakness will spread throughout much of the body, but what distinguishes this disease from pure PLS is that muscles will waste during the progression of the disease.
    Emotional lability will often develop in the early stages of the disease.The physical emotional responses will become more exaggerated, resulting in quickening to cry and laugh.
    Severe fatigue will develop as the disease progresses.
    Dementia is not a factor in this version of MND.
    Bulbar symptoms will develop. Speech will start to slur initially as muscle control slows. Eating and swallowing becomes a slow process and coughing when eating will become necessary to clear food that has penetrated and is interfering with the epiglottis. Coughing remains strong as the LMNs remain functional. The development of the bulbar symptoms typically takes years.
    The essential LMN functions remain unaffected. Breathing will continue to operate for many years and maybe decades.

    MRI scans reveal high signal change in the cortico-spinal tracts and cortico-bulbar tracts. As the disease progresses the degeneration of the neurone projections will travel down the spinal cord, impacting the LMNs. Lumbar Puncture results will offer oligoclonal bands suggesting demyelination, however not the classical bands associated with multiple sclerosis. Nerve conduction studies reveal slowing of signal conduction through the neurone projections. Anti-bodies will be present in the Lumbar Puncture sample during the early phase of the disease.

    It is reasonable to assume that the oligodendrocytes are the root cause of this version of MND. All the symptoms of demyelination of the UMNs are present backed up by clinical tests consistent with demyelination.

    The potential treatments could be:
    Stem cell treatment for remyeliination of the neurones (see Multiple Sclerosis websites)
    BrainStorm neurotrophic factor treatment.
    Neuralstem neurone replacement treatment.

    Riluzole not effective.

    References:
    Oligodendrocytes, Wikipedia
    Last edited by Graham; 24th December 2014 at 20:08.

  8. #18
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    NOTES ON NEUROTROPHIC FACTORS

    Neurotrophic factors are involved in controlling the growth and regrowth of cells of the body's nervous system. They are a subset of body's growth factors that control how the body develops with time, from the fertilised egg in the womb until death. Neurotrophic factors control how cells divide and how cells differentiate into new types of cells.

    Growth factors, but not neurotrophic growth factors, are used widely in farming to accelerate muscle growth for meat production. Some steroids are growth factors and are used by humans for body building.

    Neurotrophic factors are a good bet in the quest for a treatment for MND. Indeed, BrainStorm Cell Therapeutics Inc. have ongoing trials that are based on neurotrophic factors.

    Neurotrophic factors are proteins that modify the behaviour of other cell-building proteins within the central nervous system. One such neurotrophic factor was found to influence/activate over 400 other proteins. This is the magic of life itself and is intensely complicated. Having said that, there are fundamental mechanisms and once these mechanisms are understood, progress is made.

    Neurotrophic factors groups include:

    BDF - blood differentiation factors
    BDNF - Brain derived neurotrophic factors
    GDNF - Glial derived neurotrophic factors
    MNTF - Motor neurotrophic factors
    OGF - Olfactory growth factors
    VEGF - Vascular endothelial growth factors

    BDF - blood differentiation factors
    BDF is found in the circulating blood. BDF manages cellular function and repair in the vascular (artery) fed system. BDF levels in our blood fall away as we age.
    Trials done in mice show replacing the blood supply of old mice with that of young mice blood had rejuvenating effect for the old mice with respect to organ repair. Trials now underway in humans.

    BDNF- Brain derived neurotrophic factors


    GDNF - Glial derived neurotrophic factors


    MNTF - Motor neurotrophic factors


    OGF - Olfactory growth factors
    Olfactory growth factors replace the nerves that sense odour in the nasal cavity. OGF remain active throughout life as the nerves that sense odour are in constant need of replenishment. OGF have been used with some success to bridge spinal cord grafts.


    VEGF - Vascular endothelial growth factors
    VEGF is found in the central nervous system. VEGF manages cellular function and repair within the brain and spinal cord and specifically has effect on motor neurones. BrainStorm uses a cocktail of growth factors including VEGF.
    Trials conducted in rats injected with rat VEGF showed MND being significantly delayed. Even rats injected with human VEGF showed resilience to MND. Current human trials conducted by BrainStorm are demonstrating efficacy

    BrainStorm's stem cell therapy directly places a combination of BDNF, GDNF and VEGF into the intrathecal space (the space encapsulating the brain and spinal cord). Excellent!
    Last edited by Graham; 10th November 2014 at 19:36.

  9. #19
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    NOTES ON BIOMARKERS

    MND is a term given to diseases of the nervous system. There are many mechanisms of failure leading to a variety of symptoms that can be difficult to pinpoint in the early stages of disease. It would be of great benefit to conduct tests that accurately predict the underlying condition so that intervention may start as early as possible.

    In the case of MND, 50% of neurones are already compromised when first symptoms begin appearing. For bulbar MND the damage is even more grievous before symptoms first appear. There is a dual pathway for signals to the mouth muscles and both pathways need to be compromised for symptoms to be apparent. Therefore biomarkers have the ability to detect disease even before symptoms appear.

    Biomarkers give impartial evidence of the progression of disease. And may be used to evidence the efficacy of therapies that reverse MND.

    Known Biomarkers

    C9ORF72 Extrapalase
    The manufacture of faulty protein from the faulty gene presents itself in the Cerebrospinal Fluid.

    CD14+/CD16-
    Inflammation biomarkers.

    Compliment c3 CSF
    Efficacy biomarker

    Cystatin C CSF
    Efficacy biomarker

    pNFH CSF
    A prognostic biomarker.

    SOD1 Plasma
    Efficacy biomarker.
    TDP-43 Plasma
    Efficacy biomarker. Excess TDP-43 presents itself in the Cerebospinal Fluid.

    Total TAU Plasma
    Efficacy biomarker
    Last edited by Graham; 11th November 2014 at 21:25.

  10. #20
    Forum Member Terry's Avatar
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    Thanks for this thread Graham;

    I just read your 16th April post again and it makes so much sense, I was diagnosed with PLS and a bit of ALS and the Predominantly UMN ALS does meet most of my symptoms.

    Regards Terry

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