Poster 13: Early Diagnosis of Mitochondrial Dysfunction in Huntington's Disease In Vivo (original) (raw)

Neurotherapeutics, 2009

Abstract

ABSTRACT Mitochondria are central to normal cell function, and their dysfunction underlies a wide variety of diseases, such as diabetes (insulin resistance), aging, and both cardiovascular and neurodegenerative diseases. Herein we show new approaches and results that help to identify the mitochondrial changes unique to Huntington's disease that occur well before the onset of symptoms. New optical and magnetic resonance spectroscopic techniques provide for non-invasive, in vivo diagnosis of mitochondrial dysfunction in muscle without the need for a surgical biopsy. These methods reveal changes in mitochondria a decade or more prior to the onset of symptoms. We have found a significant decrease in mitochondrial efficiency in presymptomatic subjects (n = 4, mean age 38 years) versus control subjects (n = 11, mean age 38 years). A continued decrease is evident in symptomatic individuals (n = 3, mean age 53 years), but not yet statistically significant relative to the presymptomatic individuals. Accompanying this loss of mitochondrial efficiency is a corresponding increase in the contribution of non-mitochondrial ATP synthesis from 8% to 23% in the HD individuals. Thus, we have found a substantial reorganization of cellular metabolism in subjects presymptomatic for HD, and this reorganization of cellular energetics continues in the symptomatic individuals. These changes are compared to other disease states to identify the biomarkers reflective of mitochondrial changes that are unique to Huntington's disease. For example, the trade-off between mitochondrial inefficiency and increased glycolysis with stable [ATP] are unique to presymptomatic HD. Identification of biomarkers of HD well before the onset of symptoms provides the opportunity to test interventions that may reverse these dysfunctions and forestall irreversible mitochondrial changes. Thus, innovative noninvasive methods provide new insight into the early cellular changes in HD and provide the opportunity for intervention that may stall the onset of symptoms.

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