Shy-Drager/MSA Support Group


 

 

   Multiple System Atrophy News

 

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December 2001

Table of Contents

1. Shy-Drager/MSA Support Group Annual Patient/Family Conference Postponed
2. Shy-Drager/MSA Support Group Non-Profit Status Confirmed
3. North American MSA Study Group Submits Proposal to NIH
4. Protein Protects Against Degeneration of Neurons in Fruit Flies
5. A Review of Online Articles on MSA/Shy-Drager
6. NIH Funded Studies of Multiple System Atrophy (2001)

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1. Shy-Drager/MSA Support Group Annual Patient/Family Conference Postponed by Pam Bower

The events of September 11, 2001 had far reaching effects and our group was no exception. This year the annual Shy-Drager/MSA patient/family conference was scheduled to be held the weekend of September 14th at the Boston Logan Hilton Hotel. The uncertainty surrounding the September 11th events resulted in the necessity of postponing this event. Plans are being made by Don Summers to reschedule this conference for the spring of 2002. Please watch the Shy-Drager/MSA Support Group website http://www.shy-drager.com for any announcements regarding this event.

Announcements will also be made on the ShyDrager Yahoo mailing list at http://groups.yahoo.com/group/shydrager

Note that you can subscribe there and set your email delivery option to "Special Announcements Only" or "No Mail Web/Only" Write me if you need help setting one of these two options: pbower@accesscable.net

I'll also attempt to get the word out to those on my personal database.

If you've never attended the annual conference and would like an idea of what goes on there please see this review of the Cleveland conference held in September 2000. http://www.shy-drager.com/sds_msa_cleveland_2000.htm

This conference is organized and fully funded by the Shy-Drager/MSA Support Group.

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2. Shy-Drager/MSA Support Group Non-Profit Status Confirmed (Item Contributed by Don Summers)

August 7, 2001

Hi Everyone,

I received the papers from the IRS yesterday confirming our Non Profit Status. Anyone requesting to see a copy may make their request by direct e-mail to me and I'll fax or mail a copy to them.

Please help to spread the word that all donations to the SDS/MSA Support Group are fully tax deductible! With the help of everyone on the list, we can truly make this support group successful in fulfilling our mission

statement:
"To Educate And Support"
Don Summers, President
Shy-Drager/MSA Support Group
2004 Howard Lane
Austin, TX
USA 78728
Website:
http://www.shy-drager.com
Email: Don.Summers@shy-drager.com
Toll Free Information Line: 1-866-SDS-4999
Fax: 512-251-3315

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3. North American MSA Study Group Submits Proposal to NIH

(Item Contributed by John Moller)

A unique proposal for the first comprehensive study of Multiple System Atrophy has now been submitted to the NIH's National Institute of Neurological Disorders and Stroke for funding consideration. The proposal was submitted by a collaborative research team which calls itself the North American MSA Study Group. If approved, the proposed work is scheduled to begin in the summer of 2002.

Following is the abstract of this proposal.

Multiple system atrophy (MSA) is a progressive, degenerative neurological disorder, which is characterized clinically by the combination of varying degrees of parkinsonism, autonomic dysfunction and impaired cerebellar function. The cardinal pathological feature of MSA is the presence of glial cytoplasmic inclusions (GCIs) in oligodendrocytes. Significant recent developments in the nascent research of MSA have been the development of consensus criteria for the clinical diagnosis of MSA and the discovery that a major component of GCIs is alpha-synuclein. Research in MSA has been hampered by the fact that MSA, though not rare, is not common enough for a single center to study a sufficient number of subjects and, until now, an absence of insights into molecules involved in the disorder.

The focuses of the proposed work are to study pathogenic factors for MSA, particularly the role that alpha-synuclein plays, and to evaluate and refine clinical and laboratory assessments used to diagnose and follow the course of the illness. A central component of our effort will be recruitment and semiannual, standardized evaluation of a cohort of 150 clinically probable MSA subjects and evaluation of 300 control subjects. The clinical evaluations will be carried out at seven sites and overseen by Core A (Administrative and Clinical, led by Dr. Cliff Shults, Univ. of California, San Diego) and Core B (Data, led by Dr. Ron Thomas, Univ. of California, San Diego). These groups of MSA and control subjects will be the basis for studies of environmental risk factors (Project 1, led by Dr. Caroline Tanner, Parkinson's Institute and Dr. Walter Kukull, University of

Washington) and the development of a brain bank by Core C (Neuropathology, led by Dr. John Trojanowski, Univ. of Pennsylvania) and a DNA Repository by Core D (Genetics, led by Dr. Laurie Ozelius, Albert Einstein College of Medicine). All of the cores will be informative for all of the projects by clarifying the MSA phenotype, pathology and possible genotypic determinants thereof. A subgroup of the MSA subjects will be involved in studies of autonomic function in MSA (Project 4, led by Dr. Phillip Low, Mayo Clinic). Projects 2 and 3 will study the biology of alpha-synuclein in MSA. Project 2 (led by Dr. Virginia Lee, Univ. of Pennsylvania) will characterize the composition and structure of GCIs and alpha-synuclein in brains from MSA subjects acquired in Core C. Project 3 (led by Drs. Cliff Shults and Eliezer Masliah, Univ. of California, San Diego) will utilize an oligodendrocytic cell line and transgenic mice that overexpress alpha-synuclein to study factors, including potential factors identified in Projects 1 and 2, that affect accumulation, aggregation and toxicity of alpha-synuclein in oligodendrocytes. The proposed program project is the first comprehensive study of MSA.

The MSA patients will be evaluated and followed by members of our group at seven medical centers. These investigators and centers are:

Cliff Shults, M.D., Univ. of California, San Diego;
Caroline Tanner, M.D., Ph.D., Parkinson's Institute;
Matt Stern, M.D., Univ. of Pennsylvania;
Phillip Low, M.D., Mayo Clinic;
Sid Gilman, M.D., Univ. of Michigan;
Stephen Reich, M.D., Johns Hopkins Univ.; and
Fred Marshall, M.D., Univ. of Rochester.
The Scientific Advisory Committee is chaired by Dr. Sid Gilman of the Univ. of Michigan.

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4. Protein Protects Against Degeneration of Neurons in Fruit Flies (Item Contributed by Carol Langer)

NOTE to Readers: Alpha-synucluein (a-synuclein) is also believed to contribute to cell death in Multiple System Atrophy

See: http://www.hhmi.org/news/bonini.html

December 21, 2001- Researchers have genetically manipulated fruit flies so that the flies produce a human protein that protects against the degeneration of neurons similar to those affected in Parkinson's disease.

The protective protein, called a chaperone, suppresses the toxicity of a-synuclein, a protein associated with Parkinson's disease in humans. Progressive loss of dopaminergic neurons produces the neurological symptoms of Parkinson's disease. Chaperone proteins normally aid in proper folding of proteins and are involved in protecting against cellular stresses.

The findings were reported in the December 21, 2001, issue of Science by Howard Hughes Medical Institute investigator Nancy M. Bonini and colleagues at the University of Pennsylvania School of Medicine.

In Parkinson's disease and select other neurodegenerative disorders a-synuclein is a key component of inclusion bodies, known as Lewy bodies, that are characteristic of these diseases. Mutations in a-synuclein have been found in some inherited forms of Parkinson's disease. Working with the fruit fly Drosophila, researchers had previously produced similar pathological effects of dopaminergic neuron loss, by engineering a-synuclein over-production in flies.

In previous studies, Bonini and her colleagues had shown that the Hsp70 chaperone protected against neurotoxicity in a Drosophila model of a neurodegenerative disorder in which pathogenic human proteins with long runs of polyglutamine caused the destruction of neurons.

"We had shown that Hsp70 was a very powerful suppressor of polyglutamine toxicity in Drosophila, so we theorized that a chaperone that interfered with one neurodegenerative disease might interfere with another," said Bonini.

In their experiments, the scientists showed that flies engineered to express the gene for human Hsp70 along with a-synuclein showed survival of dopaminergic neurons that normally degenerated upon expression of a-synuclein alone.

"We observed that the inclusion bodies were still present in the neurons," said Bonini. "But the toxicity of a-synuclein was greatly diminished. This told us that the presence of the Hsp70 was reducing the toxicity of the a-synuclein, despite the continued presence of inclusions."

The researchers showed that by experimentally interfering with a Drosophila counterpart of human Hsp70, they enhanced the toxicity of a-synuclein, suggesting a critical role for chaperones in the dopaminergic neurons. Moreover, loss of chaperone activity caused some loss of dopaminergic neurons in the flies in the absence of a-synuclein. This loss of neurons was similar to the damage caused by a-synuclein alone.

The neuroprotective effect of Hsp70 might stem from the chaperone's ability to correct an abnormal and toxic conformation of a-synuclein and render it non-toxic. Alternatively, a-synuclein's toxicity might arise from its ability to bind to Hsp70 and prevent it from doing its normal job. Augmenting levels of Hsp70, as the scientists did in their experiments, might correct that deficit and overcome the toxic effect of loss of chaperone function.

In addition to their studies in flies, the scientists explored whether Hsp70 might be found in Lewy body inclusions in the brain tissue of humans who had Parkinson's disease. "When we examined brain tissue from Parkinson's patients, as well as patients with other diseases associated with abnormal a-synuclein aggregation, we could see staining for Hsp70 and for another chaperone, Hsp40," said Bonini. "This finding makes us hopeful that the protective effect of chaperones we found in flies might also be applicable to humans."

Bonini said she hopes that her findings will encourage more research on the role of chaperones in mammalian models of disease. "If Hsp70's role of protecting against a-synuclein toxicity is confirmed in mammals, an important step would be to pursue drugs that upregulate the stress response that produces these chaperones, and determine whether they will protect neurons," she said.

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5. A Review of Online Articles on MSA/Shy-Drager

by Pam Bower

Many of these articles are suitable to be printed off to share with doctors and other medical professionals as well as to share with family members. I've attempted to categorize them below.

I. Concise and not too techical (intended for non-medical audience):

a. Multiple System Atrophy Information:
A lay Guide for Patients and their Carers
http://glaxocentre.merseyside.org/msainfo.html
(3 Pages Printed)

b. Multisystem Atrophy
http://neurologychannel.com/msa
(3 Pages Printed)
NOTE: You have to click on the left of the page to see all the parts of this article.

c. MSA Booklet http://www.clinical-services.med.umn.edu/movement-disorders/msa.htm
(5 Pages Printed) (This is written from the perspective of what can be done for MSA patients in helping their symptoms.)

d. Parkinson's Report - Multiple System Atrophy
1998 article co-authored by Dr. David Robertson and others at Vanderbilt University
http://www.parkinson.org/atrophy.htm
(5 Pages Printed) (This is my favourite article written on MSA. I always recommend this one.)

e. Shy-Drager Syndrome
by Carol A Turkington
http://www.ahealthyme.com/article/gale/100084049
(4 Pages Printed) I really like this one in that it describes the autonomic symptoms well but it only mentions the name Shy-Drager Syndrome and leaves out the other important terminology: Multiple System Atrophy, Sporadic Olivopontocerebellar Atrophy and Striatonigral Degeneration.

f: Sporadic Cerebellar Degeneration
March 2001 presentation by Dr. Sid Gilman
http://www.ataxia.org/generations/2001summer/gilman.html
See also http://accesswave.ca/~pbower/msa_gilman.htm
(7 Pages Printed) (This is especially useful for understanding the balance problems in MSA - especially pages 4 through 7):

g. NINDS Shy-Drager Syndrome Information Page http://www.ninds.nih.gov/health_and_medical/disorders/shydrger_doc.htm
(2 Pages Printed) (Maybe a bit too concise, it leaves out alot and it's very cold. Not really recommended as a first read for the newly diagnosed.)

h. MSA Information by the National Dysautonomia Research Foundation
http://www.ndrf.org/MSA.htm
(3 Pages Printed) (Good general description that describes the terminology well but it doesn't offer much to patients in what can help them deal with their symptoms.)

i. Multiple System Atrophy Information
June 2000 information published by Worldwide Education and Awareness for Movement Disorders ( WE MOVE), New York
http://www.wemove.org/msa.html
(2 Pages Printed) (This seems fairly well done but it has a serious flaw at the very end. It points people to the Online Mendelian Inheritance in Man website. This points you to some very old research on what at the time they believed was a hereditary form of MSA. I asked some researchers to clarify this for me several years ago and they said that the disorder being referred to in that study actually turned out to be Spinocerebellar Ataxia type I (SCA1). There are still no known hereditary forms of MSA.)

j. Multiple System Atrophy
Information from the Parkinson Institute
http://www.parkinsonsinstitute.org/movement_disorders/multiple_system.html
(1 Page Printed) (Very concise!)

k. What is Shy-Drager Syndrome/Multiple System Atrophy?
http://www.shy-drager.com/sdssg.htm
(3 Pages Printed)

II. Articles aimed more at medical professionals but loaded with good information if you're interested in more technical articles.

a. Multiple System Atrophy
June 2001 article by H U Rehman
http://www.ahealthyme.com/article/bellhowell/100998411
(6 Pages Printed)

b. Keynote Lecture on Multiple System Atrophy
by P. L. Lantos
http://brainpathology.upmc.edu/vol7/0704/KL52.HTM
(7 Pages Printed)

c. Update: Multiple System Atrophy
May 1999 article by Laurie Swan and Jerome Dupont
published in "Physical Therapy"
http://www.ptjournal.org/May99/Toc.cfm
NOTE: You must click on "FULL TEXT! Multiple System Atrophy" near the bottom of the page to view this article. This is excellent in describing what can be done for MSA patients via physical therapy.
(10 Pages Printed)

d. Multiple System Atrophy
by Horatio Kaufman
http://www.mssm.edu/neurology/autodis/disorders/msa/msapaper.pdf
Note you need Adobe Acrobat Reader to view this file.
(9 Pages Printed)

e. Multiple System Atrophy: Information for medical students and neurology residents
2001 article by Dr.Timothy Hain, Northwestern University Medical School, Chicago, IL
http://www.neuro.nwu.edu/meded/MOVEMENT/msa.html
(3 Pages Printed)

III. Not concise but very thorough.

a. Multiple System Atrophy (written in October 2001) http://emedicine.com/NEURO/topic671.htm
(30 Pages Printed)

b. Parkinson Plus Syndromes (Includes MSA - written in September 2001) http://emedicine.com/NEURO/topic596.htm
(14 Pages Printed)

c. Differential Diagnosis of Parkinson's Disease and the Parkinsonism Plus Disorders
1995 article by Drs. Mark Stacy & Joseph Jankovic, Baylor College, Texas
http://www.parkinsons-information-exchange-network-online.com/archive/091.html
Not as up to date as the two above but still an excellent article that discusses the differences between MSA and similar disorders.
(20 Pages Printed)

IV. These sites, created by our online support group members, offer a unique perspective on the illness:

a. Multi System Atrophy and My Story
by Tim Foley from Trumbull, Connecticut, USA
http://msainfo.tripod.com/

b. The World Wide Wombat Multiple System Atrophy Web Site
by: John Cummings aka the World Wide Wombat from Melbourne, Australia
http://members.optushome.com.au/wwwombat/

c. Charmayne's MSA/Shy-Drager Pages http://freepages.health.rootsweb.com/~charmayn/index.html

d. Jeff's ShyDrager Page http://garlic.corwin-millman.com/shy-drager/

e. Darlene Turner's Shy-Drager Tribute Page http://members.tripod.com/darleneturner_1/index_m.htm

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6. NIH Funded Studies of Multiple System Atrophy (2001)

See: https://www-commons.cit.nih.gov/crisp/

Grant Number: 5P50NS032352-07
PI Name: LOW, PHILLIP A.
PI Title: PROFESSOR
Project Title: AUTONOMIC DISORDERS PROGRAM PROJECT

Abstract: Autonomic dysfunction including orthostatic hypertension (OH) is a major health problem, causing significant morbidity and mortality. Its pathophysiology remains poorly understood and hence its management lacks a solid scientific base. The PPG focuses on the pathophysiology and treatment of autonomic failure.

Project 1 (Low) incorporates a novel strategy of cholinesterase inhibition in the treatment of OH, an approach that promises to improve OH without supine hypertension. A second blinded treatment trial will evaluate if sodium chloride will expand plasma volume and if urinary sodium excretion is a suitable surrogate measure of plasma volume status. A series of studies, including the use of microneurography to measure sympathetic impuls3es, will evaluate the pathophysiology of postural tachycardia syndrome (POTS). A novel approach of amplitude modulation of the EEG in POTS shows a selective reduction of a frequency band of 0.02-0.05 Hz; this component is of particular interest since it may have a brainstem origin. The venous capacitance bed will be evaluated (Projects) to determine if there is excessive transcapillary efflux and changes in compliance in POTS and the effects of aging. The relative importance of the mesenteric, systematic and cerebrovascular circulations in OH will be evaluated.

Project(Benarroch) will expand its studies on the neurochemical organization of autonomic control regions of the medulla in multiple system atrophy (MSA) and the parkinsonian syndromes. These include quantitative evaluates of new cellular groups (nucleus ambiguus, nuclease retroambiguus) and new receptors (including angiotensin II) that are likely to provide insights into the pathophysiology of autonomic failure in MSA.

Project (Joyner) will undertake a detailed evaluation of the effects of denervation (mild in POTS and severe in neurogenic OH) and aging on the venous capacity and compliance.

Project (Brimijoin) will focus on the response of the pre-ganglionic neuron to denervation and will study the mechanism of spinal intermediolateral column cell loss, using he model of immune-mediated pre-ganglionic autonomic neuropathy. The roles of apoptosis, excitotoxicity, growth factors, and aging will be evaluated and related to MSA.

Thesaurus Terms:
autonomic disorder, postural hypotension

Institution: MAYO CLINIC ROCHESTER
200 1ST ST SW
ROCHESTER, MN 55905
Fiscal Year: 2001
Department:
Project Start: 01-JAN-1995
Project End: 31-AUG-2005
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: NSD

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Grant Number: 5P01AG009215-12
PI Name: TROJANOWSKI, JOHN Q.
PI Title: LABORATORY MEDICINE
Project Title: MOLECULAR SUBSTRATES OF AGING AND NEURON DEATH

Abstract: Mechanisms of brain dysfunction and death due to neurodegenerative diseases of the central nervous system (CNS) are poorly understood, but the emergence of profound cognitive and/or motor impairments in these heterogenous diseases is a manifestation of the progressive and massive degeneration of selectively vulnerable populations of neurons that distinguishes neurodegenerative diseases from normal aging. Additionally, intracellular filamentous inclusions are neuropathological hallmarks of many neurodegenerative diseases despite their heterogeneity. For example, abnormal alpha-synuclein filaments aggregate to form Lewy bodies (Lbs) in neurons and they are signature lesions of Parkinson's disease (PD), dementia with Lbs (DLB) and an Alzheimer's disease (AD) subtype known as the LB variant of AD (LBVAD), while multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) composed of alpha-synuclein filaments aggregate to form Lewy bodies (Lbs) in neurons and they are signature lesions of Parkinson's disease (PD), dementia with Lbs (DLB) and an Alzheimer's disease (AD) subtype known as the LB variant of AD (LBVAD), while multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) composed of alpha-synuclein filaments. Although these inclusions often were regarded as epiphenomena unrelated to mechanisms of brain degeneration, this view has undergone dramatic revisions after the discoveries that: mutations in the alpha- synuclein cause familial PD in rare kindreds, alpha-synuclein is a major component of Lbs and GCIs, and wild type, as well as mutant alpha- synuclein form filaments in vitro similar to those in Lbs and GCIs. Moreover, the pressure or abundant alpha-synuclein from filaments in vitro similar to those in Lbs and GCIs. Moreover, the presence of abundant alpha-synuclein Lbs in the most common variant of sporadic AD (i.e., LBVAD), >60% of familial AD brains and >50% of Down's syndrome brains with AD provides an opportunity to elucidate mechanisms of the enigmatic, but frequent overlap of AD and PD. Finally, we also have shown that beta- and gamma-synucleins accumulate in dystrophic overlap of AD and PD. Finally, we also have shown that beta- and gamma-synucleins accumulate in dystrophic hippocampal processes in PD and DLB. Thus, we hypothesize that accumulations of synuclein filaments or aggregates play a mechanistic role in neurodegenerative diseases characterized by abundant synuclein pathology, and this Program Project grant describes four complementary Projects to test this hypothesis with the support of an Administrative,. Clinical, and Neuropathology Core. The Projects are highly synergistic and pursue research conducted on disease brains with authentic human synuclein pathology (Project 1), as well as on mechanisms of synuclein pathologies using in vitro (Project 2), transgenic fly (Project 3) and transgenic mouse (Project 4) models. This Program Project will provide new insights into mechanisms of synuclein pathologies and their role in brain degeneration, which are likely to accelerate efforts to improve the diagnosis and therapy of these and other neurodegenerative disorders characterized by filamentous brain lesions.

Thesaurus Terms:
Alzheimer's disease, Lewy body, Parkinson's disease, aging, alpha synuclein, histopathology, molecular pathology, neural degeneration

Institution: UNIVERSITY OF PENNSYLVANIA
PHILADELPHIA, KPA 19104-6380
PHILADELPHIA, PA 19104
Fiscal Year: 2001
Department: PATHOLOGY AND LAB MEDICINE
Project Start: 01-AUG-1990
Project End: 30-APR-2005
ICD: NATIONAL INSTITUTE ON AGING
IRG: ZAG1

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Grant Number: 5M01RR000585-301051
PI Name: BHARUCHA, ADIL E.
PI Title:
Project Title: PYRIDOSTIGMINE FOR CONSTIPATION IN PATIENTS W/ AN AUTONOMIC NEUROPATHY

Abstract: Patients with an autonomic neuropathy frequently have severe constipation unresponsive to our current therapeutic armementarium. We recently demonstrated that i.v. neostigmine increases colonic contractility and transit in healthy volunteers; neostigmine also increased colonic tone and improved symptoms in one patient with autonomic neuropathy and intractable constipation. Pyridostigmine is an acetylcholinesterase inhibitor with higher bioavailability than neostigmine. Hypotheses- 1) In patients with slow transit constipation due to an autonomic neuropathy resulting from diabetes, pure autonomic failure, an immune-mediated process or multiple system atrophy, the acetylcholinesterase inhibitor pyridostigmine is safe, well tolerated, will improve colonic transit and satisfaction with bowel habits, 2) The effect of intravenous neostigmine on colonic tone during a motility study will predict treatment success with pyridostigmine. Aims - To assess the safety, tolerability, effect on symptoms, colonic transit and satisfaction with bowel movements of pyridostigmine in patients with constipation due to an autonomic neuropathy, and to determine if neostigmine's effects on the colonic pressure-volume relationship during a motility study predict the therapeutic response to pyridostigmine. Methods - Open-label, phase II pilot study of an escalating dose of pyridostigmine (60 mg t.i.d. to 180 mg t.i.d) in 10 patients with an autonomic neuropathy and constipation. A two-week run-in single-blind placebo phase will be followed by a 6-week single-blind treatment phase. Standard clinical assessments and a radionuclide whole-gut transit study will be performed at the beginning and end of the study. The effect of i.v. neostigmine on colonic tone and compliance will be assessed prior to the therapeutic trial. Primary endpoints are the effect of pyridostigmine on colonic transit and patient reported satisfaction with bowel movements during the last 2 weeks of the treatment period. Secondary endpoints are derived from the Rome Criteria for constipation (number of stools/week, stool consistency, frequency of straining and incomplete evacuation) and the proximal colonic emptying rate. A total of 10 patients in this pilot study should provide sufficient information to estimate the response magnitude and variability of the quantitative primary response variable, colonic transit. Significance - A successful therapeutic response in >6/10 patients in this pilot study will lead to an placebo-controlled study of pyridostigmine in a similar patient population and perhaps other patient groups with constipation due to an autonomic neuropathy.

Thesaurus Terms:
autonomic nervous system, constipation, gastrointestinal disorder chemotherapy, human therapy evaluation, nervous system disorder, pyridostigmine clinical trial phase I, clinical trial phase II /III /IV, gastrointestinal motility /pressure, neostigmine clinical research, human subject

Institution: MAYO CLINIC ROCHESTER
200 1ST ST SW
ROCHESTER, MN 55905
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL CENTER FOR RESEARCH RESOURCES
IRG:

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Grant Number: 5R01NS038220-03
PI Name: CARTER, BRUCE D.
PI Title: ASSISTANT PROFESSOR

Project Title: MECHANISMS NEUROTROPHIN SIGNALING THROUGH P75 RECEPTOR

Abstract: DESCRIPTION (Adapted from applicant's abstract): During the normal development of the mammalian nervous system nearly half of the neurons undergo apoptosis as part of a natural pruning process. Dysfunctional apoptosis has been associated with a variety of neurological diseases such as Alzheimer's, Huntington's and Parkinson's diseases, ALS and multiple system atrophy. The critical balance between necessary cell death and maintenance of essential neurons is controlled by the neurotrophins. Their effects are mediated through binding to a family of tyrosine kinase receptors, the Trks, and a 75-kD receptor, p75. It has been shown that the Trks activate canonical growth factor receptor signaling pathways. In contrast, the function of p75 remains largely unexplored. Recent evidence suggests that ligand binding to p75 in specific cell types can activate the transcription factor NFkappaB and induce apoptosis through a mechanism involving jun kinase. The activation of programmed cell death by classical trophic factors is somewhat surprising, especially given the widespread expression of both p75 and the neurotrophins throughout the nervous system. Clearly, the activation of apoptosis must be highly regulated such that it only occurs in specific contexts. The overall goal of this research proposal is to understand the molecular mechanisms by which the neurotrophins regulate neuronal survival, in particular, signaling through the p75 receptor. Currently there are no known receptor-associated proteins that transduce p75's signal. This proposal describes a novel zinc finger protein, NRIF, isolated using the yeast two hybrid system, which binds to the cytoplasmic domain of p75 in a ligand-dependent manner. This proposal will test the hypothesis that neurotrophin binding to p75 activates a signal transduction pathway that promotes both cell survival and programmed cell death mediated in part by the novel p75 interactor NRIF. To test this hypothesis the following specific aims are proposed: (1) Define the domains of NRIF and p75 responsible for their interaction; (2) Determine the molecular components of p75 signaling; (3) Assess the mechanisms by which p75 regulates cell survival. Understanding neurotrophin signaling mechanisms will provide insight into how these essential factors regulate the development of the vertebrate nervous system and could suggest novel strategies for therapeutic intervention in neurological disorders.

Thesaurus Terms:
biological signal transduction, growth factor receptor, neurotrophic factor, programmed cell death, protein structure /function, protein tyrosine kinase, receptor binding binding protein, developmental neurobiology, neuroregulation, protein protein interaction

Institution: VANDERBILT UNIVERSITY
NASHVILLE, TN 37240
Fiscal Year: 2001
Department: BIOCHEMISTRY
Project Start: 03-DEC-1998
Project End: 30-NOV-2001
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: ZRG1

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Grant Number: 2P01NS015655-21A1
PI Name: FREY, KIRK A.
PI Title: PROFESSOR OF RADIOLOGY AND NEUROLOGY
Project Title: PET Study of Biochemistry and Metabolism of the CNS

Abstract: This Program Project focuses on in vivo neurochemistry of human neurological disorders, emphasizing subcortical structures and their interactions in neurodegenerative and idiopathic functional disorders of movement. Studies in the proposal combine neurochemical phenotypes with functional measures, the latter including motor performance, blood flow activation, neurotransmitter release, ans aspects of sleep physiology. The Program consists of 4 Scientific Projects and 3 Cores. Project by Kilbourn, "New Radiotracers for Neurological PET", will introduce a novel functional approach to assessment of GABAA receptors through allosteric ligands of the chloride ionophore. GABAergic projects are critical components of striatal output and other extrapyrimidal sites. Assessment of GABAA function will complement glucose metabolism studies that may preferentially reflect excitatory glutamatergic pathways. Project by Frey, "Striatal Dopamine and Motor Performance in Aging and Parkinson's Disease" will determine functional motor correlates of nigrostriatal dopaminergic losses in aging and Parkinson's disease and will assess their reversal by acute dopaminergic challenge. Project by Gilman, "Neurochemical and Sleep Disorders in Multiple System Atrophy", will assess the relationships between disrupted sleep in extrapyrimidal neurodegeneration and brain stem cholinergic projections. Project by Albin, "Dopamine Synaptic Mechanisms in Tourette Syndrome", will assess striatal dopaminergic projects and their function from a multi-faceted approach, including measures of their density, their capacity for dopamine re-uptake, their capacity for dopamine release, and an assessment of ambient synaptic dopamine occupancy of D2-type dopamine receptors. Cyclotron/Radiochemistry, Tomography and Data Analysis, and Administrative Core functions support each Project. Overall , the disorders under study in this Program are of unknown pathogenesis and have only symptomatic therapies. The proposed studies will lead to enhanced insight into extrapyrimidal neurochemistry and will address important aspects of dysfunction and disability in these disorders. Novel and improved therapies and new pathophysiological mechanisms and insight may ultimately result.

Thesaurus Terms:
central nervous system, nervous system disorder, neurochemistry, positron emission tomography bioimaging /biomedical imaging, human subject

Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR
ANN ARBOR, MI 48109
Fiscal Year: 2001
Department: INTERNAL MEDICINE
Project Start: 01-DEC-1979
Project End: 31-JUL-2006
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: NSD

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Grant Number: 1Z01NS002979-03
PI Name: GOLDSTEIN, DAVID S.
PI Title:
Project Title: Clinical Neurocardiology: Catecholamine Systems In Stress

Abstract: We conducted patient-oriented clinical research in neurocardiology. Studies focused on elucidating pathophysiologic mechanisms and developing novel diagnostic and therapeutic approaches for disorders involving altered regulation of catecholamine systems. These conditions result from dysfunction of the autonomic nervous system (dysautonomia) or abnormally decreased or increased production of the catecholamines, norepinephrine (NE), epinephrine (EPI), or dopamine (DA). Patients with autonomic failure in the setting of Parkinson's disease all had cardiac sympathetic denervation, detected by 6-[18F]fluorodopamine positron-emission tomographic scanning. In contrast, patients with multiple system atrophy, which can be difficult to distinguish clinically from Parkinson's disease, all had evidence for intact cardiac sympathetic nerve terminals. Even in the absence of autonomic failure, most patients with Parkinson's disease had evidence for localized or diffuse loss of cardiac sympathetic nerve terminals. Cardiac sympathetic denervation in Parkinson's was found to be independent of levodopa treatment and can arise from mutation of the gene encoding alpha-synuclein. In the diagnostic evaluation of pheochromocytoma, a clinically important tumor that produces catecholamines, plasma levels of metanephrines, metabolites of NE and EPI made in the tumor, provided a uniquely and virtually perfectly sensitive screening test. In patients with chronic orthostatic intolerance, a pattern of increased adrenomedullary hormonal system activity and inhibition of sympathetic nervous system activity ("sympathoadrenal imbalance") was found to precede tilt-induced and spontaneously occurring neurocardiogenic syncope. 6-[18F]Fluorodopamine positron-emission tomographic scanning successfully localized the tumor even in difficult cases. A combined neurogenetic and neurochemical approach holds great promise for understanding how particular mutations in familial diseases associated with increased production of NE (pheochromocytoma) or decreased production of NE (Menkes disease) relate to particular neurochemical and clinical manifestations.

Thesaurus Terms:
Parkinson's disease, autonomic disorder, dopamine, epinephrine, heart disorder, norepinephrine, pheochromocytoma, stress autonomic nervous system, denervation, peripheral nervous system disorder, postural hypotension, sympathetic nervous system clinical research, human subject, positron emission tomography

Institution:
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: CNCS

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Grant Number: 5P50NS032352-070005
PI Name: BENARROCH, EDUARDO E.
PI Title: PROFESSOR
Project Title: NEURONAL DEPLETION IN THE VENTROLATERAL MEDULLA AND CARDIORESPIRATORY FAILURE

Abstract: Multiple system atrophy (MSA) is characterized by severe autonomic failure and life-threatening respiratory manifestations. We have shown that there is a marked depletion of catecholaminergic (tyrosine hydroxylase, TH, positive) neurons in the rostral and caudal ventrolateral medulla (VLM) in patients with MSA. The objective of this project is to test the hypothesis that other neurochemically defined neuronal groups in the VLM, implicated in sympathetic, cardiovagal and respiratory control, are also affected in patients with MSA. We will perform quantitative analysis of VLM neuronal populations reactive for TH, NADPH diaphorase, acetylcholinesterase, choline-acetyltransferase (CAT), angiotensin II type I (AT1R) and mu opioid receptors (MOR) in medullae obtained at postmortem from patients evaluated at the Mayo Clinic for autonomic failure, and possible MSA, as compared to age- and sex- matched controls and patients with other forms of parkinsonism. The three specific aims are: (1) to determine whether loss of AT1R neurons in the VLM correlates with the presence of orthostatic hypotension; (2) to determine whether loss of CAT neurons in the nucleus ambiguus correlates with cardiovagal failure; and (3) to determiner whether MSA patients with respiratory dysfunction have loss of NADPH- and MOR- reactive neurons in the VLM. We plan to study approximately 5-7 cases/year, including (1) 2-4 cases with no history of neurologic disease (controls); (2) 1-3 cases with clinical and autonomic laboratory diagnosis of MSA; (3) 1-3 cases with Parkinson's disease; and (4) 1-2 cases with other forms of parkinsonism. These studies will provide insight into the medullary circuits involved in human cardiorespiratory control and the pathophysiology of MSA.

Thesaurus Terms:
autonomic disorder, brain disorder, heart failure, medulla oblongata, postural hypotension, respiratory insufficiency /failure NAD(P)H dehydrogenase, Parkinson's disease, angiotensin II, angiotensin receptor, atrophy, choline acetyltransferase, glial fibrillary acidic protein, opioid receptor, sleep apnea clinical research, human subject, human tissue, postmortem

Institution: MAYO CLINIC ROCHESTER
200 1ST ST SW
ROCHESTER, MN 55905
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: NSD

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Grant Number: 2P01NS015655-21A10015
PI Name: GILMAN, SID
PI Title: DIRECTOR, MICHIGAN ALZHEIMER'S DISEASE C
Project Title: NEUROCHEMICAL /SLEEP DISORDERS /MULTIPLE SYSTEM ATROPHY

Abstract: This project will explore the neurochemical basis of rapid eye movement sleep (REM) behavior disorder (RBD) in multiple atrophy (MSA), including cases with predominantly cerebellar (MSA-C) and with predominantly parkinsonian features (MSA-P), The unifying concept is that RBD results from the direct results of decreased pedunculopontine (PPN) and a laterodorsal tegmental (LTD) cholinergic innervation of the brainstem reticular formation and thalamus and, to a lesser extent, from the indirect effects of decreased nigrostriatal monoaminergic innervation. Three specific hypotheses will be tested: (1) PPN/LTD cholinergic innervation is decreased in MSA-P and MSA-C patients as compared with normal control subjects. The decreased monoaminergic innervation is greater in MSA-P than in MSA-C patients (2) MSA-C and MSA-P patients with RBD have greater deficits of PPN/LTD cholinergic innervation than MSA-C and MSA-P patients, respectively, without RBD. MSA-C and MSA-P patients with RBD have no difference in nigrostriatal monoaminergic innervation as compared to MSA-C and MSA-P patients, respectively, without RBD. (3) In MSA-P and MSA-C patients who have RBD, the intensity of REM sleep abnormalities is negatively correlated with the degree of PPN/LTD cholinergic, and non correlated with the degree of nigrostriatal monoaminergic innervation. To test these hypotheses, nocturnal, laboratory-based polysomnography will be performed in normal controls and in patients who meet current diagnostic criteria for MSA-C and MSA-P, with similar ages and genders between groups. RBD will be quantified with measurements of the percentage of REM sleep that shows phasic EMG bursts. Positron emission tomography with (+)-[11C]dihydrotetrabenazine will be used to measure the density of striatal monoaminergic terminals and single photon emission computed tomography with (-)-5- [123i]iodobenzovesamicol will be used to measure the density of striatal monoaminergic terminals and single photon emission computer tomography with (-)-5-[123I)iodobenzovesamicol will be used to measure the density of thalamic cholinergic terminals. The data analysis will include comparisons of ligand binding across patient groups and normal controls, comparisons of RBD across subject groups, and correlations of ligand binding with RBD.

Thesaurus Terms:
Parkinson's disease, REM sleep, acetylcholine, atrophy, autonomic disorder, behavior disorder, cerebellar ataxia /dyskinesia, dopamine, innervation, neurochemistry, sleep disorder corpus striatum, neuron, substantia nigra, synapse, tegmentum behavioral /social science research tag, electromyography, patient oriented research, polysomnography, positron emission tomography, single photon emission computed tomography

Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR
ANN ARBOR, MI 48109
Fiscal Year: 2001
Department:
Project Start: 01-DEC-1979
Project End: 31-JUL-2006
ICD: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG: NSD

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Grant Number: 5P01HD038760-020001
PI Name: GARNER, CRAIG C.
PI Title: PROFESSOR
Project Title: Presynaptic cytomatrix proteins and synaptogenesis

Abstract: Synapses of the mammalian CNS are highly specialized cellular junctions designed for rapid and regulated signaling between nerve cells and their targets. Abnormal synaptogenesis and synaptic reorganization in the developing CNS has been strongly correlated with developmental disorders such as fragile X, epilepsy, schizophrenia and mental retardation. Our ability to understand how different genetic and environmental insults cause cognitive dysfunction and mental retardation requires a better understanding of the cellular mechanisms that lead to the proper assembly and function of CNS synapses. This requires a molecular description of the constituents of synaptic junctions and the mechanisms used by neurons to correctly sort traffic and localized each component. Our studies of CNS synapses have led to the identification and characterization of numerous synaptic junctional proteins. One of the most recently identified, Bassoon, is a novel component of the presynaptic cytoskeletal matrix assembled at the active zone. Based on its structure on its structure and distribution, we hypothesize that it is involved in the assembly and function of CNS synapses. With regard to mental retardation and cognitive dysfunction, our analysis of the Bassoon gene and its transcripts have revealed the presence of a CAG expansion similar to these found Huntingtin, Ataxins and the Fragile X mental retardation Moreover, Basson expression is selectively enhance in a neurodegenerative disorder, multiple system atrophy. To gain insights into the role played by Bassoon in the presynaptic cytoskeletal matrix, we proposed to examine the mechanisms directing that transport and assembly of Bassoon at CNS synapses In addition we propose to assess the function of Bassoon in presynaptic nerve terminals by analyzing loss of function mutations in the mouse Bassoon gene Bsn on the structure, assembly, and function of CNS synapses in the developing mouse brain.

Thesaurus Terms:
nerve /myelin protein, neuronal transport, protein localization, protein structure function, synaptogenesis gene expression, molecular assembly /self assembly, protein transport embryo /fetus cell culture, laboratory mouse, laboratory rat, tissue /cell culture

Institution: UNIVERSITY OF ALABAMA AT BIRMINGHAM
UAB STATION
BIRMINGHAM, AL 35294
Fiscal Year: 2001
Department:
Project Start:
Project End:
ICD: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
IRG: CHHD