And the pathway goes to the olfactory area ...interesting!

http://www.nzherald.co.nz/section/1/...ectid=10424284

paula

What do the nose and stomach, the two places where PD first shows up as Lewy Bodies, have in common?
1- they are places where the mucus membranes interface with the external world via inhalation and post-nasal drip
2- they are near major CNS components- the olfactory bulb and the enteric nervous system aka as the "second brain"
3- both components have direct routes to the brain via the olfactory and vagus nerves.
4- both routes bypass the BBB

What else?

Rick,

I am trying to remember, because I haven't found it yet, if there even was a hand out to Langston's talk - Jaye reminded me today that the article was upcoming. But you have just reminded me of some more major components of his talk. He does think it is a CNS disorder, not a movement or brain disorder and that the mucous membranes play a part.

Also, Langston's talk was webcast and will be on the PAN site soon. I recall seeing a picture of an elephant surrounded by specialists, each named. PD was obviously the elephant in the room, and no one specialist dealt with the whole picture.

Do you think that's where patients come in? Redefining indeed.

Paula

This is fascinating. Another article about olfactory system and regeneration:

Review

Spinal Cord (2006) 44, 406–413. doi:10.1038/sj.sc.3101948; published online 6 June 2006
Repair of spinal cord injury: ripples of an incoming tide, or how I spent my first 40 years in research

An Inaugural Lecture given by Geoffrey Raisman, DM, DPhil, FRS on appointment to the Chair of Neural Regeneration and the inception of the Spinal Repair Unit at the Institute of Neurology, University College London

G Raisman1

Abstract

Abstract of the inaugural lecture on appointment to the Chair of Neural Regeneration at University College London January 2006. Record of personal research. Electron microscopic observations led to the concept that the adult brain is capable of forming new synapses after injury, and the search for methods to repair brain and spinal cord injuries. It is proposed that the failure of regeneration after central axotomy is due to protective glial scarring leading to the loss of the aligned astrocytic pathways needed for axon elongation.

Taking advantage of the discovery that the adult olfactory system is capable of continual renewal, cultured olfactory ensheathing cells were transplanted into lesions of the spinal cord and spinal roots.

The transplants re-opened scarred glial pathways, allowed the regeneration of severed nerve fibres, and the restoration of various functions, including paw reaching, climbing, and supraspinal respiratory impulses to the phrenic nerve.

From that article:

Until that time it had been assumed that we are born with a fixed number of nerve cells, and the best that we can do is to try to prevent losing them to alcohol, or to boxing, or to Alzheimer's or Parkinson's diseases. That is still very largely how we understand things. But in the 1960s, Pasquale Graziadei, a former student of JZ at University College London, was working in Florida. He had shown that in one part of the nervous system – and so far in the only one that we know of – nerve cells are continually replaced throughout adult life.17

This is the olfactory system, the part of the nervous system lying in the upper nasal lining and carrying the sense of smell. And this process of continual renewal reflected the persistence of an embryonic property, the property of cell division. So here, in the adult, was a fount of unending youth. And maybe a source of pathway cells? But that's hindsight. We're racing ahead. The idea of transplanting pathway cells from the olfactory system took quite a bit longer, quarter of a century to be precise.

The fibres arising from the newly formed olfactory neurons pass through the skull and terminate in the olfactory bulbs. Moreover, Graziadei et al18 had shown that if an olfactory bulb was removed, the olfactory nerve fibres would continue to grow through the cranial cavity until they reached the next area, the frontal cortex, which they then entered and made connections there. So the olfactory nerve fibres have the property of entering parts of the brain which do not normally receive them. But how do they do it?

Graziadei's observation passed practically unnoticed. It was only some 10 years later, and after his untimely death, that the significance of his work began to percolate into my consciousness. Based on the pathway hypothesis, I had speculated that the ability to grow depended not on the nerve fibres, but on the presence of specialised pathway cells. Finally, in 1985,19 I first described a type of pathway cell, unique in structure and arrangement, and found only in the primary olfactory pathway. This cell is now called the olfactory ensheathing cell.20

Some years later Doucette in Canada described how to obtain olfactory ensheathing cells in tissue culture of samples taken from the adult olfactory system.21 And with this knowledge the stage was set for us to begin to transplant them. In doing this, we were carrying out a transplant not only in space, but – so to speak – in time, from a part of the body which retains embryonic characteristics into a part of the body which has lost them.

The results were beyond our dreams.22 The cells survived transplantation, and they opened up a pathway (Figure 4), which allowed the growth of severed nerve fibres. The transplanted cells formed a bridge conveying the regenerating nerve fibres across the injury (Figure 5). They had repaired the roadway. A bridge had been thrown across the washed out motorway and the cars were driving across it. But most important – they restored function (Figure 6).


**********

I will never forget one early morning, sometime in the dead period between Christmas and New Year, when for some reason I decided to examine the rats at about 0200 hours. On the way to the animal house I remember my breath coming out as steam in the frozen night air. The test was for the rat to retrieve a piece of food I offered it. It was a rat which had a unilateral lesion of the left corticospinal tract at the upper cervical level. Since the time of lesioning, it had never used its left paw for retrieval. The damage was on the left, and the cultured olfactory ensheathing cells had been transplanted into the lesion.

Then I could hardly believe my eyes. The rat put its left paw forward, just tentatively then paused. I was amazed. But I think the rat was equally amazed. For a moment we looked at each other in surprise. Then it went on and took the food. And at that moment I knew the breakthrough had come. It was a moment that occurs once in a lifetime – if you are lucky. Many years followed. Repeat, extend, confirm. We examined three systems in the rat. First the animals recovered the ability to retrieve pieces of food with the forepaw of the operated side. Second they learned to recover the use of the paw for climbing. And third the transplants restored the breathing ability to the diaphragm of the operated side.24

The ability to engineer the re-entry of nerve fibres into the spinal cord is a proof of principle, or rather of principles. These principles are:

1. There exist, in all of our bodies, adult stem cells which can be used to generate reparative tissues. No need to resort to embryonic cells. No need to cross any immune barriers or use any immunosuppressive drugs. The patient can be his or her own donor.
2. Severed nerve fibres can be reconnected in an adult spinal cord.
3. Lost functions can be restored.

In 1974, I moved from the Department of Human Anatomy in Oxford to the National Institute for Medical Research at Mill Hill, where the Medical Research Council supported my research work for many years. This gave me the opportunity to work out the basic methods for transplantation of cultured olfactory ensheathing cells, and to study the reconnection and functional repair in rats. But still I was far from having these dreams applied. It was only in 2005, with the move of the research team to the Institute of Neurology in Queen Square, that we finally had access to the neurosurgeons who were both willing and also had the opportunity to plan for the clinical application of olfactory ensheathing cell transplants.

We already have permission for the first preliminary safety study, which is scheduled for this year, 2006. Our first attempt will be to repair avulsed dorsal roots.25 Success would open the way to evolve techniques for repairing larger ('transverse') spinal cord injuries, as well as brain injuries resulting from some of the most severe types of stroke, those affecting descending motor pathways, and blindness and deafness caused by damage to the fibres of the nerves of vision and hearing.

I hope our team can contribute to some of these. But we need to be realistic. We have not learned how to repair a twelve-lane metalled motorway. If we are lucky we will be able to throw a plank over where a stream crosses a field path. We have not yet invented tarmacadam or reinforced concrete. We do not know how to build cantilevered bridges. There will be many more developments needed for the motorway engineers of the future.

But after all, in the end our success is not that we have done this, but that we have opened a door through a wall that was impenetrable. And repair of injuries is only one aspect of the concept of plasticity. Evolution did not develop plasticity as a potential method for repairing injuries, a method which would lie unachieved and dormant for millions of years until someone thought of transplanting olfactory ensheathing cells. For me, the concept of plasticity opened a much wider significance.

After all, what is the function of the brain? It is not claws and teeth but the brain that is the principal organ of evolution. The battle is to the wily, not to the strong. If we ask what is the function of the brain, the usual answers may be to move the hands, to see, to hear. But these are pretty lowly, mechanical functions, something a robot with a computer might imitate. But look around! Everything we see around us is a creation of the human brain. Nothing is of nature. We made or modified it all, even the sky itself bends to our wills however blind to the consequences. That is the important function of the brain. And it was not the brain of an individual, or of one time, but of an organised society of brains, acting over a long period.

The function of the brain is plasticity, the ability to change, not to respond the same way twice. If it's good, go for more. If it's bad avoid it. Explore, be curious, remember, learn, build, form concepts. And pass them on to future generations. Those are the important functions of the human brain. Those defined our brains. And all of them involve plasticity. The ultimate expression of plasticity is history itself, the ever changing.

This is meant to be an inaugural lecture, but I wonder what I am inaugurating. So large a part for me personally is a valedictory. But all our activities in the end are only an inauguration of what will follow. Research, knowledge, do not belong to anyone. Like the earth itself, they belong to no one. Rather we belong to them. And human evolution is social evolution. The advances come not from a person, but from a team. It is a joy for me to see ideas floated out among our little team, like rose petals in a whirlpool, finally forming a pattern that no single one of us alone could have framed. And so this article uses the word 'I' where it means 'we.' If I pick out Ying Li and Daqing Li, who have given 20 years to this project, and who have changed their homeland to do it, it is not to detract from the many contributors and supporters along the way, who are too numerous and too varied to acknowledge.

This article is not intended to be a review of the wider field of neural regeneration (of which there are many available26), nor to document the work on repair by transplantation of cells. Its purpose is only to record, with the inevitable distortions, omissions, and creations of fallible memory, some of the glimpses of the mysterious countryside seen from the rather cloudy windows of a fast moving train, a personal journey.

http://www.nature.com/sc/journal/v44.../3101948a.html

Stem Cells, Vol. 18, No. 4, 295-300, July 2000

Isolation and Characterization of Neural Stem Cells from the Adult Human Olfactory Bulb
Stefano F. Paganoa, Francesco Impagnatiellob,

We have recently isolated stem cells deriving from the olfactory bulbs of adult patients undergoing particularly invasive neurosurgery. After improving our experimental conditions, we have now obtained neural stem cells according to clonal analysis. The cells can be expanded, established in continuous cell lines and differentiated into the three classical neuronal phenotypes (neurons, astrocytes, and oligodendrocytes). Also, after exposition to leukemia inhibitory factor, we are able to improve the number of neurons, an ideal biological source for transplantation in various neurodegenerative disorders.

**********
DISCUSSION

Pharmacological or neurosurgical therapies are currently used to treat neurological damages in various neurodegenerative disorders (i.e. Parkinson's disease, Alzheimer's disease, Huntington's disease, etc.), but all these strategies are not efficient in preventing or reverting these progressive neurodegenerative processes. Recently, a new approach has been introduced—the cell therapy [20]. This approach is based on the transplantation of appropriate cells, which must not only be well characterized and biologically and immunologically safe, but also sufficiently numerous to ensure adequate post-transplantation survival, tissue regeneration, and an acceptable degree of functional recovery and/or symptomatic improvement.

For the first time we have successfully isolated neural stem cells from the olfactory bulb of adult human subjects. The isolation and characterization of neural stem cells from the human olfactory bulb open up a further interesting therapeutic perspective.

The high regenerative potential of this area suggests that the olfactory bulb is an ideal autologous source for neurodegenerative disease. Under our optimized conditions, the stem cells obtained from the olfactory bulb, like embryonic stem cells, proliferate and are capable of differentiating into the three classical neural phenotypes. We suggest that stem cells deriving from this area can be simply explanted by means of partial bulbectomy in patients (with few damaging effects such as anosmia).

As a result of our many years of experience in manipulating neural stem cells, we are able to expand these cells considerably and, by means of the addition of LIF, ensure their differentiation into neurons [16], the elective biological source for autotransplantation in various neurodegenerative disorders. In particular, the discovery of a large number of immunoreactive tyrosine hydroxylase structures in the olfactory bulbs and peduncles of elderly humans [21] suggests that the olfactory bulb is a hypothetical source for the autotransplantation therapy in Parkinson's disease.

In support of the idea of using olfactory bulb neural stem cells for autologous transplantation in patients with Parkinson's disease, we have recently used an experimental model of Parkinson's disease. Lesions in the nigrostriatal zone were induced by inoculation of 6-hidroxy-dopamine in CD1 mice, and we investigated the ability of these cells to elicit functional recovery after intrastriatal transplantation. These data [22, 23] show that inoculation of these cells induces functional recovery in comparison with control untransplanted mice, and detailed biochemical and immunohistochemical evaluations are currently under way. These are fundamental confirmatory data for the future use of these cells for transplant therapy in patients with Parkinson's disease and other neurodegenerative disorders.

Hi Tina,

But as usual there are the Parkie exceptions. Those with mutations of the Parkin gene, do not have olfactory deficits.

Vicky

This is interesting. Too many dopaminergic cells in the olfactory bulb cause loss of smell....


Movement Disorders

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Volume 19, Issue 6 , Pages 687 - 692

Published Online: 8 Jan 2004

Brief Report
A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease
Evelien Huisman, BSc 1 *, Harry B.M. Uylings, PhD 1 2, Piet V. Hoogland, MD, PhD 1 3

Abstract
Hyposmia is one of the most prevalent symptoms of Parkinson's disease. It may occur even before the motor symptoms start. To determine whether the olfactory dysfunctions, like the motor symptoms, are associated with a loss of dopamine, the number of dopaminergic cells in the olfactory bulb of Parkinson's disease patients was studied using tyrosine hydroxylase immunohistochemistry.

The quantitative analysis reveals that the total number of tyrosine hydroxylase-immunoreactive neurons in the olfactory bulb is twice as high in Parkinson patients compared to age and gender-matched controls. Because dopamine is known to inhibit olfactory transmission in the olfactory glomeruli, we suggest that the increase of dopaminergic neurons in the olfactory bulb is responsible for the hyposmia in Parkinson patients.

The increase of dopamine in the olfactory bulb explains why olfaction does not improve with levodopa therapy.

http://www3.interscience.wiley.com/c...9783/HTMLSTART

Very perturbing. (Hey, there's a PD motto for you!)

What are we to make of this? Lewy Bodies show up there first, but against all common sense the neuronal density is doubled? And I still can't smell? So...
1) Could it be that the extra neurons are some sort of attempt to compensate or something?
2) Whatever it is, is there some way that the effect could be triggered in the SN? Or is it a genetic feature?

I'm never bored. -Rick

When I first read the above article out of NZ, I thought, 'we are evolving. ' Finding these stem cells deep within the brain reminded me of that movie "Journey to the Center of the Earth." Or of those creatures they find at the bottom of the sea.

Maybe the introduction of sinemet to the brain has caused phenomena for which there simply is no comparison or answer because this is a completely new reaction to a completely new substance.

paula