Do deficits in Mitochondrial Spare Respiratory Capacity contribute to Neuropsychological changes seen in Alzheimer’s disease? (798)

Objective: To identify if fibroblast metabolic functional abnormalities are linked to neuropsychological/neuroimaging changes seen in sporadic Alzheimer’s disease (AD).

Background: In clinical settings, AD is defined by characteristic deficits in neuropsychological testing supported by amyloid and tau biomarkers and neuroimaging abnormalities. The biological cause of neuropsychological changes is not established. Tau deposition correlates with, but does not fully account for all observed neuropsychological impairments. We have shown mitochondrial spare respiratory capacity (MRSC) is lowered in AD patient fibroblasts. This study investigates if fibroblast mitochondrial functional abnormalities correlate with neuropsychological/neuroimaging changes in AD.

Design/Methods: 10 AD patient and 10 control fibroblast samples were taken. ATP and extracellular lactate were measured using luminescent and fluorescent protocols respectively. Mitochondrial membrane potential (MMP) was measured using tetramethylrhodamine dye. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. Neuropsychological testing and brain structural MRIs were undertaken on all participants. Correlations were performed between MMP, MRSC and neuropsychological/MRI AD markers.

Results: Reductions in delayed (p<0.0001) and immediate recall (p<0.0001), semantic fluency (p<0.0001), phonemic fluency (p=0.0033) and MMSE (p=0.0009) scores were seen in AD patients. After controlling for age, education and brain reserve; left hippocampal (p=0.001), left parietal (p=0.002), right parietal (p=0.001) and anterior medial prefrontal cortical (p=0.017) gray matter volumes were decreased in AD patients. Fibroblast metabolic markers showed a reduction in MMP (p=0.001), MRSC (p<0.0001), glycolytic reserve(p=0.05), and extracellular lactate (p<0.05) in AD patients. MRSC and MMP correlated significantly with immediate recall ([MRSC, p=0.0041], [MMP, p=0.0115]), delayed recall ([MRSC, p=0.0013], [MMP, p=0.0138]) and semantic memory ([MRSC, p=0.0039], [MMP, p=0.009]) tests. The correlations between MRSC and neuropsychological measures remained after controlling for age, education and brain reserve. No correlations were seen between grey matter volumes and fibroblast metabolism.

Conclusions: This study highlights how in-depth metabolic analysis of sporadic AD fibroblasts identifies functional abnormalities that correlate with neuropsychological features distinctive to AD.

Disclosure: Dr. Bell has nothing to disclose. Dr. De Marco has nothing to disclose. Dr. Barnes has nothing to disclose. Dr. Shaw has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultancy for serving on Scientific Advisory Board for Biogen and for speaking, symposium organisation for Cytokinetics. Dr. Shaw has received research support from Research support from Pfizer for investigation of molecular mechanisms of neuronal injury in C9orf72 ALS.. Dr. Ferraiuolo has nothing to disclose. Dr. Blackburn has nothing to disclose. Dr. Mortiboys has nothing to disclose. Dr. Venneri has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck &amp; Co.