Alpha-lipoic Acid/L-acetyl Carnitine for Progressive Supranuclear Palsy

An Open-label Trial of Alpha-lipoic Acid/L-acetyl Carnitine for Progressive Supranuclear Palsy (PSP): Effect Upon Oxidative Damage and Mitochondrial Biomarkers

Studies have shown that alpha-lipoic acid and L-acetyl carnitine may have some neuroprotective activities and it is hoped that they could be helpful for people with neurodegenerative illnesses such as progressive supranuclear palsy (PSP). The purpose of this study is to find out whether the nutritional supplement alpha-lipoic acid/L-acetyl carnitine is safe and well-tolerated in individuals with PSP when given daily, and whether it affects their well-being, brain scan measurements and blood tests that measure the energy metabolism in cells.

Multiple lines of evidence support mitochondrial dysfunction and oxidative stress playing a role in the pathogenesis of atypical Parkinsonism, including PSP. Such dysfunction may well contribute to the tau pathology that is well-recognized in PSP, thus providing a link between the two processes. This pathway therefore represents an excellent potential target for novel therapeutic intervention in neurodegenerative disorders, and a number of well-tolerated and safe nutritional supplements have been identified that appear to augment mitochondrial function, and improve oxidative stress. Alpha-lipoic acid and L-acetyl carnitine are two nutritional supplements that have received increasing attention as potential neuroprotective interventions in neurodegenerative and other disease states. Alpha-lipoic acid/L-acetyl carnitine had been demonstrated to improve learning in aged beagles over 2 months of administration, and showed a trend to improve cognitive function in a mouse model of Alzheimer's disease (human apoE4 transgene). Moreover, alpha-lipoic acid/L-acetyl carnitine was neuroprotective in a mouse model of Parkinson's disease (rotenone-induced parkinsonism), with effects including decreased oxidative stress, and increased mitochondrial biogenesis. In fibroblasts derived from individuals with Alzheimer's disease, alpha-lipoic acid/L-acetyl carnitine reduced increased levels of oxidative stress. In healthy men exposed to intensive exercise, alpha-lipoic acid provided antioxidant effects systemically (decreased peroxidation). L-acetyl carnitine improved neuroimaging correlates of cerebral blood flow in 30 subjects with dementia. These nutritional supplements have been safe and well-tolerated, and they have been tested in age groups including children, up to the elderly. Alpha-lipoic acid had been successfully administered over an extended period in an open-label trial in Alzheimer's disease. Importantly, it appeared that the effects of alpha-lipoic acid and L-acetyl carnitine when administered together were significantly augmented (100-1000 times), as opposed to when administered separately. This therefore provided a strong rationale to test the two in combination. In addition to monitoring clinical features, we had also chosen to test physiologic effects of alpha-lipoic acid/L-acetyl carnitine in our PSP subjects using two biomarkers that provide measures of mitochondrial function and oxidative stress. This was particularly important, since both supplements may act by multiple mechanisms. 1H MRSI is a technique that provides insight into the metabolism of several endogenous brain compounds, most notably N-acetyl-L-aspartate (NAA), choline-containing compounds (Cho), and creatine and phosphocreatine (Cr). A number of studies of mitochondrial function had firmly established the utility of 1H MRSI in probing potential mitochondrial energy metabolism dysfunction. 31P MRSI provided complementary information to probe in vivo mitochondrial energy metabolism and tissue energetics. In addition, we proposed using markers of oxidative damage (including 8-hydroxydeoxyguanosine) as well as metabolomic analysis to test a composite panel of quantitative measures in plasma. We used an established metabolomic platform that has proven to identify specific combinations of metabolites differing between neurodegenerative disease states (including Parkinson's disease, Huntington's disease) and healthy controls. Our overall aim was to generate an "oxidative biomarker" and "metabolomic read-out" of the peripheral biochemical effects of alpha-lipoic acid/L-acetyl carnitine in PSP.

Progressive supranuclear palsy, alpha-lipoic acid, L-acetyl carnitine, antioxidant, magnetic resonance spectroscopy, neurodegeneration, glutathione

Inclusion Criteria: Diagnosis of probable PSP by NINDS/PSP workshop criteria (see patient folder) Age 40-75 years Able to undergo MRI Absence of significant medical, psychiatric, and other neurological disease Stable intake of supplements and medication Exclusion Criteria: Failure to meet probable PSP diagnosis by NINDS/PSP workshop criteria unable to comply with informed consent process unable to undergo MRI presence of significant medical, psychiatric (incl MDD) or other neurological (incl epilepsy, brain tumor, stroke) disease possibility of pregnancy (negative test required in women of childbearing age)