Dissertations, Theses, and Capstone Projects

Date of Degree


Document Type


Degree Name





Nancy S. Foldi


Veronica J. Hinton

Committee Members

Jennifer Stewart

Valentina Nikulina

Yian Gu

Subject Categories

Medical Genetics | Neurology | Other Medicine and Health Sciences | Psychology


Neuropsychology, Cognition, MELAS, Genetics, Mitochondrial Disorder, Magnetic Resonance Spectroscopy


Background: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) is a maternally inherited progressive multisystemic disorder. Occurrence of seizure and/or stroke-like episode, as well as classic biomarkers (i.e., cerebral lactic acidosis, depleted N-acetylaspartate (NAA)), have been linked to neuropsychological deficit and trigger the developmental cascade of neurodegeneration affecting posterior prior to anterior brain regions. While a pattern of global deterioration has been reported, systematic examination in a large MELAS cohort has not been conducted.

Objective: First, we examined verbal and visual memory function and its relationship to brain metabolites (lactate, NAA) in individuals with MELAS. Second, we hypothesized that MELAS would perform worse overall and show a selective profile of decline based on localization of seizure/stroke-like episode and increased lactate/decreased NAA, such that posterior-localized visually-mediated functions will show faster decline compared with anterior-localized verbally-mediated functions.

Methods: Cognition was examined over time in 35 MELAS, 78 mt3243A>G carriers, and 28 controls (16-80 years). Composite z-scores were used for global mental status, attention, speed, mental flexibility, reasoning, language, verbal and visual memory, and visual-spatial skills, as well as for visually-mediated and verbally-mediated tasks. MR Spectroscopy (NAA, Lactate), Chi-square, t-tests, Pearson correlations, ANOVA, and Generalized Estimating Equations were run (α=0.05).

Results: When compared to carriers and controls, MELAS patients had: 1) most impaired memory functions (Visual: p=0.0003; Verbal: p=0.02), 2) greater visual than verbal memory impairment, 3) highest brain lactate levels (p

Conclusions: Individuals with MELAS are at increased risk for poor memory, and although both verbal and visual memory are impaired, visual memory is both preferentially affected and more clearly associated with brain metabolite levels. In MELAS, there is an early vulnerability of the posterior brain structures, which results in a distinctive progressive cognitive phenotype with a posterior to anterior hemispheric gradient, such that visual memory is targeted before verbal memory. MELAS show worse cognitive function overall and faster decline in global mental status, speed, and visual-spatial skills. Faster decline in visual, not verbal, tasks supports the notion that a distinct neurodegenerative profile exists affecting posterior brain regions and associated cognitive functions in particular.

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