Our preliminary studies suggest there is intra-individual homogeneity within both early and chronic MS lesions with respect to pathologic measures of inflammation, dominant immune effector mechanisms of active demyelination, and extent of tissue injury and repair. Evidence of intra- individual pathological homogeneity may reflect genetic variation in loci controlling lesion formation. We propose to collect and pathologically phenotype a large sample of MS lesions in order to examine both the complex relationships between inflammation, demyelination, remyelination, and axonal injury in both early and chronic MS lesions, as well as investigate the relationship of demographic and clinical variables with these pathologic outcomes. In addition, we will assess the degree of intra-individual homogeneity for these well defined specific histo- and immunopathological outcomes in order to validate our preliminary observations of intra-individual homogeneity, and more accurately establish the number of cases within each of the respective pathological phenotypes available for future genetic study.
We aim to establish a reliable and statistically robust MS Tissue-DNA Databank which will use pathology as a novel intermediate outcome for future genetic-association studies The proposed studies will yield a tremendous resource of patient material having both detailed and quantitative pathologic analyses and DNA, and will provide the framework for an efficient and cost-effective transition from discovery of chromosomal regions or candidate genes of interest in genome-wide linkage, population-association and tissue microarray studies, to detailed clinical-pathologic analysis in order to determine pathogenic relevance. By stratifying patients based on specific pathological features, we will increase the likelihood of identifying potential genetic contributions common to each category. Furthermore, there are pragmatic reasons for supporting additional research into MS pathology and genetics. A more fundamental understanding of the variable pathological and genetic factors involved in MS lesion evolution will not only provide additional pathogenetic insights into MS, but will lead to improved determination of long term prognoses, as well as impact the selection of current, and design of future, treatment approaches tailored to the patient. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049577-02
Application #
7232273
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2006-05-15
Project End
2009-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$323,343
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Tobin, W Oliver; Costanzi, Chiara; Guo, Yong et al. (2017) Clinical-radiological-pathological spectrum of central nervous system-idiopathic inflammatory demyelinating disease in the elderly. Mult Scler 23:1204-1213
Tobin, W O; Popescu, B F; Lowe, V et al. (2016) Multiple sclerosis masquerading as Alzheimer-type dementia: Clinical, radiological and pathological findings. Mult Scler 22:698-704
Paz Soldán, M Mateo; Novotna, Martina; Abou Zeid, Nuhad et al. (2015) Relapses and disability accumulation in progressive multiple sclerosis. Neurology 84:81-8
Pfeifenbring, Sabine; Bunyan, Reem F; Metz, Imke et al. (2015) Extensive acute axonal damage in pediatric multiple sclerosis lesions. Ann Neurol 77:655-67
Frischer, Josa M; Weigand, Stephen D; Guo, Yong et al. (2015) Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol 78:710-21
Popescu, Bogdan F G; Guo, Yong; Jentoft, Mark E et al. (2015) Diagnostic utility of aquaporin-4 in the analysis of active demyelinating lesions. Neurology 84:148-58
Flanagan, Eoin P; Weinshenker, Brian G; Krecke, Karl N et al. (2015) Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders. JAMA Neurol 72:81-7
Wilson, Michael R; Shanbhag, Niraj M; Reid, Michael J et al. (2015) Diagnosing Balamuthia mandrillaris Encephalitis With Metagenomic Deep Sequencing. Ann Neurol 78:722-30
Clardy, Stacey L; Lucchinetti, Claudia F; Krecke, Karl N et al. (2014) Hydrocephalus in neuromyelitis optica. Neurology 82:1841-3
Metz, Imke; Weigand, Stephen D; Popescu, Bogdan F G et al. (2014) Pathologic heterogeneity persists in early active multiple sclerosis lesions. Ann Neurol 75:728-38

Showing the most recent 10 out of 34 publications