Cognitive Neurometabolism Laboratory

Barrow Neurological Institute
of St. Joseph's Hospital and Medical Center
Phoenix, Arizona

Curriculum vitae

Biographical sketch

The focus of the Cognitive Neurometabolism Laboratory is brain energy metabolism, particularly the causes and effects of mitochondrial energy metabolism deficiencies in Alzheimer's disease (AD) and other neurodegenerative conditions. Several key mitochondrial enzymes involved in energy production, free radical production, and other functions are in some way deficient in Alzheimer's disease, including Kreb's cycle enzymes and enzyme complexes of the electron transport chain. 

Electron transport chain Complex IV (cytochrome c oxidase) has been heavily studied, and our laboratory recently found that Complex IV is deficient in platelets from patients with amnestic mild cognitive impairment (MCI), many of whom have an early stage of Alzheimer's disease. We also discovered that Complex III was deficient in patients with Alzheimer's disease, adding to the list of bioenergetic problems in this devastating disorder. Platelets appear to show much of the same pathophysiology as neurons in Alzheimer's disease, perhaps due to the long-lived nature of the megakaryocytes from which they derive, providing us with a window to such dysfunction in living patients and persons who are at-risk.

The laboratory is dedicated to identifying the order of events in early Alzheimer's disease, especially the relationship between the traditional pathology of Alzheimer's disease and mitochondrial function. Our studies encompass all levels of analysis, from the neuroanatomical, systems-level distribution of energy metabolism enzymes across the brains of animal models of disease and postmortem human tissue to cellular analyses of both neurons and glia and to studies of isolated mitochondria. 

We have published several reports on the pattern of regional neurometabolism in emerging transgenic models of Alzheimer's disease, including the "PDAPP" mouse and the doubly-transgenic PS1+APP mouse model, using fluoro-deoxyglucose autoradiography to map glucose uptake across the brain. These mice exhibit a most severe neurometabolic decline in the retrosplenial or posterior cingulate cortex, similar in fashion to the most severe regional decline in patients with Alzheimer's disease, as seen on positron emission tomography (PET). We are beginning to test select interventions in a transgenic mouse model to assess our ability to prevent or reverse these metabolic alterations.

We are also working to create individualized models of disease-associated mitochondrial dysfunction by transferring mitochondria isolated from our subjects into neutral cell lines depleted of their own mitochondrial DNA. These so-called "cybrid" cell lines have been shown to replicate many aspects of Alzheimer's disease pathophysiology and will provide a model for testing our hypotheses regarding the order of events in early Alzheimer's disease, and for testing potential mitochondrially targeted interventions.

The Cognitive Neurometabolism Laboratory was founded in July 2003 with continuing support from the Arizona Alzheimer's Disease Consortium and the Barrow Neurological Foundation. Support has also been provided by the Barrow Women's Board, Arizona State University, and the Harrington Research Center. 

Dr. Valla holds adjunct positions in the Harrington Department of Bioengineering at Arizona State University and in the Neurogenomics Division of the Translational Genomics Research Institute (TGen).  The laboratory proudly participates in several student scientific enrichment programs, including the Howard Hughes Medical Institute (HHMI)-funded School of Life Sciences Undergraduate Research (SOLUR) program and other departmental undergraduate research programs at Arizona State University, and the High School Scientific Enrichment Program at Barrow Neurological Institute.

Selected References

Valla, J., L.E. Schneider, F. Gonzalez-Lima, E.M. Reiman. Nonprogressive transgene-related callosal and hippocampal changes in PDAPP mice. Neuroreport 17, 829-832, 2006.

Valla, J., L.E. Schneider, E.M. Reiman. Age and transgene-related changes in regional cerebral metabolism in PSAPP mice. Brain Research 1116, 194-200, 2006.

Coon KD, Valla J, Szelinger S, Schneider LE, Niedzielko TL, Brown KM, Pearson JV, Halperin R, Dunckley T, Stafford P, Papassotiropoulos A, Caselli RJ, Reiman EM,  Stephan DA. Quantitation of heteroplasmy of mtDNA sequence variants identified in a population of Alzheimer's disease patients and controls by array-based resequencing. Mitochondrion 6, 194-210, 2006.

Valla, J., L. Schneider, T. Niedzielko, K.D. Coon, R. Caselli, M.N. Sabbagh, G.L. Ahern, L. Baxter, G. Alexander, D.G. Walker, E.M. Reiman. Impaired platelet mitochondrial activity in Alzheimer's disease and mild cognitive impairment. Mitochondrion 6, 323-330, 2006.

Lin, L., K. Chen, J. Valla, J. He, E.M. Reiman, J.-P. Galons, B. Hauss-Wegrzyniak, G.E. Alexander. MRI template and atlas toolbox for the C57BL/6J mouse brain. Proceedings of the 2nd International IEEE EMBS Conference on Neural Engineering,  6-8, 2005.

Liang, Z., J. Valla, S. Sefidvash-Hockley, J. Rogers, and R. Li. Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer's disease patients, Journal of Neurochemistry 80, 807-814, 2002.

Valla, J., K. Chen, J.D. Berndt, F. Gonzalez-Lima, S.R. Cherry, D. Games, and E.M. Reiman. Effects of image resolution on autoradiographic measurements of posterior cingulate activity in PDAPP mice: Implications for functional brain imaging studies of transgenic mouse models of Alzheimer's disease, NeuroImage 16, 1-6, 2002.

Gonzalez-Lima, F., J.D. Berndt, J. Valla, D. Games, and E.M. Reiman. Reduced corpus callosum, fornix and hippocampus in PDAPP transgenic mouse model of Alzheimer's disease. NeuroReport 12, 2375-2379, 2001.

Valla, J., J.D. Berndt, and F. Gonzalez-Lima. Energy hypometabolism in posterior cingulate cortex of Alzheimer's patients: superficial laminar cytochrome oxidase associated with disease duration. Journal of Neuroscience 21, 4923-4930, 2001.

Valla, J., J.L. Humm, T. Schallert, and F. Gonzalez-Lima. Metabolic activation of the subependymal zone after cortical injury. NeuroReport 10, 1-4, 1999.

Gonzalez-Lima, F., J. Valla, and A. Cada. Brain cytochrome oxidase activity and how it relates to the pathophysiology of memory and Alzheimer's disease. In T. Ozben (Ed.),  Free Radicals, Oxidative Stress and Antioxidants: Pathological and Physiological Significance. NATO ASI Series A Vol. 296, New York:  Plenum Press, 1998, pp. 205-227.

Gonzalez-Lima, F.,  J. Valla and L. Jorandby. Cytochrome oxidase inhibition in Alzheimer's disease. In Gonzalez-Lima, F. (Ed.) Cytochrome Oxidase in Neuronal Metabolism and Alzheimer's Disease. Plenum, New York, 1998, pp. 171-201.

Gonzalez-Lima, F., J. Valla and S. Matos-Collazo. Quantitative cytochemistry of cytochrome oxidase and cellular morphometry of the human inferior colliculus in control and Alzheimer's patients. Brain Research 752, 117-126, 1997.

Valla, J., F. Gonzalez-Lima, E.M. Reiman. Gene dose-related changes in regional cerebral metabolism in PDAPP transgenic mice. Submitted.

Research Faculty | Home