[Conductor71]

I know that melanin and vitamin D have something to do with it all...they are now finding that loss of melanin may be an accurate marker for charting decline. Rather sobering but beats the paper and pencil system we have now.

Mov Disord. 2011 Apr 12. doi: 10.1002/mds.23722. [Epub ahead of print]
T1-Weighted MRI shows stage-dependent substantia nigra signal loss in Parkinson's disease.

Schwarz ST, Rittman T, Gontu V, Morgan PS, Bajaj N, Auer DP.

Radiological & Imaging Sciences, University of Nottingham, Nottingham, United Kingdom.
Abstract

Depigmentation of the substantia nigra is a conspicuous pathological feature of Parkinson's disease and related to a loss of neuromelanin. Similar to melanin, neuromelanin has paramagnetic properties resulting in signal increase on specific T1-weighted magnetic resonance imaging. The aim of this study was to assess signal changes in the substantia nigra in patients with Parkinson's disease using an optimized neuromelanin-sensitive T1 scan. Ten patients with Parkinson's disease and 12 matched controls underwent high-resolution T1-weighted magnetic resonance imaging with magnetization transfer effect at 3T. The size and signal intensity of the substantia nigra pars compacta were determined as the number of pixels with signal intensity higher than background signal intensity + 3 standard deviations and regional contrast ratio. Patients were subclassified as early stage (n = 6) and late stage (n = 4) using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr Parkinson's disease staging scale. The T1 hyperintense area in the substantia nigra was substantially smaller in patients compared with controls (-60%, P < .01), and contrast was reduced (-3%, P < .05). Size reduction was even more pronounced in more advanced disease (-78%) than in early-stage disease (-47%). We present preliminary findings using a modified T1-weighted magnetic resonance imaging technique showing stage-dependent substantia nigra signal reduction in Parkinson's disease as a putative marker of neuromelanin loss. Our data suggest that reduction in the size of neuromelanin-rich substantia nigra correlates well with postmortem observations of dopaminergic neuron loss. Further validation of our results could potentially lead to development of a new biomarker of disease progression in Parkinson's disease. © 2011 Movement Disorder Society.
Copyright © 2011 Movement Disorder Society.

[paula_w]

My grandmother had pervasive loss of skin pigmentation and my first cousin [our mothers were sisters and daughters of this grandmother) has no pigmentation at all. She is completely white. She is 68. I have little blotches but nothing too large,yet it is there. This is something that should be looked into seriously because it all started in the 80s and i noticed it during my second pregnancy.

I think i have every biomarker mentioned that you don't have to test for, Hopefully, the upcoming NIH eval will fill in some blanks.

[Conductor71]

Originally Posted by paula_w

I think i have every biomarker mentioned that you don't have to test for, Hopefully, the upcoming NIH eval will fill in some blanks.

Paula,

I don't have any of the biggie biomarkers like REM disorder, olfactory loss, or constipation. In fact, these tests would have made absolutely no difference in my initial diagnosis of Essential Tremor. Such a big deal is made of them and it gives me pause cause some of us are still gonna slip through the tracks.

They have a cerebral-spinal fluid measure for the protein in clinical trial right now, so now that they seem pretty sure we all have aggregate alpha-synuclein maybe they'll start using for diagnostics.

Oh, and this an interesting find. It seems to support the prion theory that alpha-syn is the bad guy in the depletion of dopa and neuromelanin. I wonder if it is responsible for the hit our other neurotransmitters take?


Residual substantia nigra neuromelanin in Parkinson's disease is cross-linked to alpha-synuclein.

Fasano M, Giraudo S, Coha S, Bergamasco B, Lopiano L.

Department of Structural and Functional Biology, University of Insubria, Via Jean H. Dunant 3, I-21100 Varese, Italy. mauro.fasano@uninsubria.it
Abstract

The pigmentation of substantia nigra pars compacta dopaminergic neurons is due to the presence of neuromelanin, an irregular macromolecular pigment belonging to the family of melanins. Depletion of neuromelanin in Parkinson's disease is typically indicated by loss of brown color in this area. Unlike that from controls, the pigment extracted from substantia nigra of parkinsonian patients seems to be mainly composed by highly cross-linked, protease-resistant proteic material and the neuromelanin macromolecule appears to be a minor presence. In the present paper we describe the isolation by SDS-PAGE of this proteic component after cleavage of the melanin backbone under solubilizing conditions. A single band is observed, which has been identified as alpha-synuclein by western blotting. As expected, the same process performed on a control specimen did not show occurrence of any major proteic component. Nevertheless, extraction from a 91 years old control with Lewy bodies displayed minor alpha-synuclein immunoreactive aggregates, whereas inclusion of free alpha-synuclein was not observed at all. Results reported here support the view that alpha-synuclein accumulates within substantia nigra neurons and is entrapped in pigment granules during neuromelanin biosynthesis, i.e. before the melanin depletion characteristic of Parkinson's disease starts.

[paula_w]

Peptides. 2009 Nov;30(11):2031-9. Epub 2009 Jun 11.
Melanin-concentrating hormone producing neurons: Activities and modulations.

Guyon A, Conductier G, Rovere C, Enfissi A, Nahon JL.
Institut de Pharmacologie Moléculaire et Cellulaire, Univrsité de Nice-Sophia Antipolis, Centre National de la Recherche Scientifique, Valbonne, France. alice.guyon@ipmc.cnrs.fr
Abstract

Regulation of energy homeostasis in animals involves adaptation of energy intake to its loss, through a perfect regulation of feeding behavior and energy storage/expenditure. Factors from the periphery modulate brain activity in order to adjust food intake as needed. Particularly, "first order" neurons from arcuate nucleus are able to detect modifications in homeostatic parameters and to transmit information to "second order" neurons, partly located in the lateral hypothalamic area. These "second order" neurons have widespread projections throughout the brain and their proper activation leads them to a coordinated response associated to an adapted behavior. Among these neurons, melanin-concentrating hormone (MCH) expressing neurons play an integrative role of the various factors arising from periphery, first order neurons and extra-hypothalamic arousal systems neurons and modulate regulation of feeding, drinking and seeking behaviors. As regulation of MCH release is correlated to regulation of MCH neuronal activity, we focused this review on the electrophysiological properties of MCH neurons from the lateral hypothalamic area. We first reviewed the knowledge on the endogenous electrical properties of MCH neurons identified according to various criteria which are described. Then, we dealt with the modulations of the electrical activity of MCH neurons by different factors such as glucose, glutamate and GABA, peptides and hormones regulating feeding and transmitters of extra-hypothalamic arousal systems. Finally, we described the current knowledge on the modulation of MCH neuronal activity by cytokines and chemokines. Because of such regulation, MCH neurons are some of the best candidate to account for infection-induced anorexia, but also obesity.

PMID: 19524001 [PubMed - indexed for MEDLINE]

--------------

Int Rev Cytol. 2002;213:233-77.
Cell and molecular cell biology of melanin-concentrating hormone.

Griffond B, Baker BI.
Laboratoire d'Histologie, Faculté de Médecine, Place St-Jacques, Besançon, France.
Abstract

Recent advances in the study of melanin-concentrating hormone (MCH) have depended largely on molecular biological techniques. In mammals, which have attracted the most attention, novel findings concern (i) the MCH gene, which can yield several peptides by either posttranslational cleavage or alternative splicing, as well as bidirectional transcription; (ii) the identification of two G protein-coupled MCH receptors in the brain and peripheral tissues; and (iii) the evidence for subpopulations of MCH neurons in the central nervous system, characterized by their chemical phenotypes, connections, and individual physiological responses to different physiological paradigms. The involvement of central MCH in various functions, including feeding, reproduction, stress, and behavior patterns, is reviewed. The stage during evolution at which MCH may have acquired hypophysiotrophic and hormonal functions in lower vertebrates is considered in light of morphological data. Evidence that MCH also has peripheral paracrine/autocrine effects in mammals is provided.

PMID: 11837894 [PubMed - indexed for MEDLINE]

==============
removed last one because it was over my head.- more than usual that is.

[lindylanka]

Laura,
I have extensive depigmentation that has happened relatively quickly, in just over four years I have lost around 60%, though my face is largely spared at this point in time. My grandmother who also had PD had this, family say this was inherited from her mother's side, she had no sisters. No males in the family have this, and there is no other female to female lineage. I am unable know whether my mother would have developed this, she died aged 41. I found Paula's info on this very interesting, because of this female link. There is a study somewhere done in 1971, do not remember author, that links the two.... and seem to remember that there was atypical presentation. conventional thinking is that it is auto-immune w/apoptosis, like pd ??, but interesting thing is that when pigment loss is like this, generalised, one side depigments and then the other mirrors it. Analogy of PD, perhaps? Also interesting is that sometimes areas spontaneously re-pigment......... even years later, even though melanin producing cells supposedly have self-destructed......

[Muireann]

I also have extensive de-pigmentation. Vitiligo is the name of it. It started in my twenties after the birth of my second child, presumably when auto immunity turned on with a bang post-pregnancy.

At the time of dx with PD it had spread rapidly in that year. It is very much correlated with B12 deficiency. I associate it more with B12 deficiency than PD. But I think B12 deficiency is bad for PD as it makes you handle stress poorly which, in turn, produces adrenaline. From there, my understanding is that adrenaline increases acetylcholine production [which tenses up muscles] and concomitantly this places extra demand on the body to produce dopamine to relax those muscles and keep them in perfect tension. If you had less stress you might never become aware of your impoverished dopa producing capacity. Sub-clinical PD if you like.

No history of PD in my family, but lots of Vitiligo - three generations.

[lindylanka]

And very topical for me, as I have just today been diagnosed with pernicious anaemia.......


“Birds of a Feather Flock Together”: Type 1A Diabetes and Other Autoimmune Disease States

1. Russell D. White, MD and
2. George D. Harris, MD, MS


Polyglandular autoimmune (PGA) syndromes are constellations of multiple endocrine gland insufficiencies. Three types are now recognized.2,3

Type I PGA is rare and presents in childhood. It is associated with candidiasis, hypoparathyroidism, and adrenal failure and is a rare disorder, having sporadic autosomal recessive inheritance.

Type III PGA is the co-occurrence of autoimmune thyroid disease with two other autoimmune disorders, including type 1A diabetes, pernicious anemia, or a nonendocrine, organ-specific, autoimmune disorder such as alopecia or vitiligo. Because it does not involve the adrenal cortex, Addison's disease is absent.

Type II PGA is the most common and is defined as primary adrenal insufficiency (Addison's disease) with either autoimmune thyroid disease (Hashimoto's thyroiditis) or type 1A diabetes occurring in the same individual. Primary hypogonadism, Graves' disease, myasthenia gravis, pernicious anemia, Parkinson's disease, vitiligo, and celiac disease may also be observed in this syndrome. PGA II occurs primarily in adulthood, usually around the 3rd and 4th decades of life, and is associated with HLA-DR3 and/or HLA-DR4 haplotypes. Its pattern of inheritance is autosomal dominant with variable expressivity.3,4

The pathophysiology of PGA II is thought to include an initial genetic susceptibility of the individual, allowing exposure to an autoimmune trigger (environmental or intrinsic factor), which initiates immunological change in specific proteins. These proteins mimic the molecular structure of a self-antigen and start the active production of organ-specific autoantibodies as well as the occurrence of autoimmune activity in the respective organ. This process leads to progressive glandular destruction. Unfortunately, the individual is asymptomatic during this process. Not until extensive organ damage has occurred does overt clinical disease ensue, as autoantibodies react to target tissue-specific antigens.2,3

As mentioned above, type 1A diabetes is an autoimmune disease characterized by β-cell destruction and subsequent insulin deficiency. Approximately 85-90% of people with type 1 diabetes test positive for autoantibodies and are deemed to have type 1A. The remaining individuals test negative for autoantibodies and are classified as having idiopathic type 1 diabetes, sometimes called type 1B diabetes.1 Many type 1A diabetic patients have a personal or family history of other autoimmune diseases, such as Hashimoto's thyroiditis, Addison's disease, pernicious anemia, or vitiligo.5

The insidious autoimmune process of type 1A diabetes begins long before clinical symptoms occur and a diagnosis is confirmed (Figure 1). More than 90% destruction of the components of the β-cells within the islets of Langerhans occurs before the onset of clinical symptoms. Autoantibodies that have been associated with type 1A diabetes and serve as markers of this process are listed in Table 1.

[Conductor71]

Primary hypogonadism, Graves' disease, myasthenia gravis, pernicious anemia, Parkinson's disease, vitiligo, and celiac disease may also be observed in this syndrome.

Most interesting to me that PD falls right in the thick of all these auto-immune disorders...really what is is it going to take to establish PD as a auto-immune condition.

Wow, Linda. Can you get any sort of genetic test or test for polyglandular syndrome?

Laura

[lindylanka]

Laura, I have not been able to find anything that constitutes a test for PAS, it is more made on the aggregation of several auto-immune conditions, usually with something like thyroid or diabetes as the primary one, though there does not seem to be a pattern or order in which these conditions develop. Or not as far as the things I could find would lead you to believe.

I also have somewhat elevated thyroid something or another that they are going to look at again in 6 months. Hmmm.

Looking into B12 deficiency is fascinating as it has neurological implications.
But also because of something in the gut that gets damaged, apparently auto-immune ....... leading to a loss of something called intrinsic factor....

Also because it can be underdiagnosed or missed for a long time, by which time neurological damage has occurred........ Another condition they have had treatments for for 60 years........

[olsen]

J Neurochem. 2008 Aug;106(4):1866-75. Epub 2008 Jul 4.
Neuromelanin can protect against iron-mediated oxidative damage in system modeling iron overload of brain aging and Parkinson's disease.
Zecca L, Casella L, Albertini A, Bellei C, Zucca FA, Engelen M, Zadlo A, Szewczyk G, Zareba M, Sarna T.
Source
Institute of Biomedical Technologies - Italian National Research Council, Milano, Italy. luigi.zecca@itb.cnr.it
Abstract
In Parkinson's disease (PD), dopamine neurons containing neuromelanin selectively degenerate. Neuromelanin binds iron and accumulates in aging. Iron accumulates in reactive form during aging, PD, and is involved in neurodegeneration. It is not clear how the interaction of neuromelanin and iron can be protective or toxic by modulating redox processes. Here, we investigated the interaction of neuromelanin from human substantia nigra with iron in the presence of ascorbic acid, dopamine, and hydrogen peroxide. We observed that neuromelanin blocks hydroxyl radical production by Fenton's reaction, in a dose-dependent manner. Neuromelanin also inhibited the iron-mediated oxidation of ascorbic acid, thus sparing this major antioxidant molecule in brain. The protective effect of neuromelanin on ascorbate oxidation occurs even in conditions of iron overload into neuromelanin. The blockade of iron into a stable iron-neuromelanin complex prevents dopamine oxidation, inhibiting the formation of neurotoxic dopamine quinones. The above processes occur intraneuronally in aging and PD, thus showing that neuromelanin is neuroprotective. The iron-neuromelanin complex is completely decomposed by hydrogen peroxide and its degradation rate increases with the amount of iron bound to neuromelanin. This occurs in PD when extraneuronal iron-neuromelanin is phagocytosed by microglia and iron-neuromelanin degradation releases reactive/toxic iron.

PMID: 18624918 [PubMed - indexed for MEDLINE]