Why neurons lose their spark?

[sbrown]

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

sharon x

[Banned]

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

[Banned]

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!

[Banned]

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

[Terry]

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

[marieline]

Wow Graham, i have been wanting to get those definitions for ever. It is still complex but you make it a lot simpler to read. Keep up with the informative post.

Best wishes
Marieline

[Banned]

In March 2016 it was reported on the BBC that a gentleman in a Polish clinic, who had had his own olfactory stem cells taken and inserted in the rupture of his spinal cord, continued to make good progress. From being quadriplegic, the gentleman had gained partial control of all limbs, continence and sexual function.

The concept of repairing the spinal cord had been dismissed as fantasy in the medical establishment, however following the reports from Poland, a professor from King's College is investigating.

[Lycanthrope]

That's fantastic news. Thanks for posting it Graham. Just shows anything is possible
xx Becky

[Banned]

On Horizon 23.05.16 was a documentary highlighting recent research into dementia. The effects of tau proteins degenerating the way that neurones are nourished was highlighted. The brain has an innate ability to eliminate tau proteins during sleep.

Tau proteins that cause degeneration of neurones also apply to forms of MND. The form of MND is Predominantly Upper Motor Neurone Disease. Signals from the Upper Motor Neurones to the Lower Motor Neurones are attenuated.

[Terry]

That's interesting Graham,

When I stay awake playing on the computer, my body does not perform so well the next day or two.

No idea what Tau Proteins are, maybe I should look.

Love Terry

[SusanMcGee]

Thanks for sharing with us. Very informative sharing .

[Banned]

By God, is Graham still alive and wanting to kick??

[Terry]

Hi Graham;

So pleased to hear from you, I assumed that you were no longer with us.

Have you left the chess site?

How are things?

Love Terry

[Barry52]

Great to hear from you Graham after such a long time absent.

Barry

[Banned]

Hi Terry/Barry,

Good to see both of you are soldiering on and I am saddened to have read of more people wMND struggling. Nothing changes.

I'm ok and working harder than ever, hence no chess, and ready to have fun...