Deficits in Mitochondrial Spare Respiratory Capacity Contribute to the Neuropsychological Changes of Alzheimer's Disease

Overview

Journal J Pers Med

Date 2020 May 6

PMID 32365522

Citations 16

Authors

Simon M Bell

Matteo De Marco

Katy Barnes

Pamela J Shaw

Laura Ferraiuolo

Daniel J Blackburn

Heather Mortiboys

Annalena Venneri

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is diagnosed using neuropsychological testing, supported by amyloid and tau biomarkers and neuroimaging abnormalities. The cause of neuropsychological changes is not clear since they do not correlate with biomarkers. This study investigated if changes in cellular metabolism in AD correlate with neuropsychological changes. Fibroblasts were taken from 10 AD patients and 10 controls. Metabolic assessment included measuring total cellular ATP, extracellular lactate, mitochondrial membrane potential (MMP), mitochondrial respiration and glycolytic function. All participants were assessed with neuropsychological testing and brain structural MRI. AD patients had significantly lower scores in delayed and immediate recall, semantic memory, phonemic fluency and Mini Mental State Examination (MMSE). AD patients also had significantly smaller left hippocampal, left parietal, right parietal and anterior medial prefrontal cortical grey matter volumes. Fibroblast MMP, mitochondrial spare respiratory capacity (MSRC), glycolytic reserve, and extracellular lactate were found to be lower in AD patients. MSRC/MMP correlated significantly with semantic memory, immediate and delayed episodic recall. Correlations between MSRC and delayed episodic recall remained significant after controlling for age, education and brain reserve. Grey matter volumes did not correlate with MRSC/MMP. AD fibroblast metabolic assessment may represent an emergent disease biomarker of AD.

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References

Folstein M, Folstein S, McHugh P . "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3):189-98. DOI: 10.1016/0022-3956(75)90026-6. View

Ewers M, Brendel M, Rizk-Jackson A, Rominger A, Bartenstein P, Schuff N . Reduced FDG-PET brain metabolism and executive function predict clinical progression in elderly healthy subjects. Neuroimage Clin. 2013; 4:45-52. PMC: 3841292. DOI: 10.1016/j.nicl.2013.10.018. View

Mortiboys H, Johansen K, Aasly J, Bandmann O . Mitochondrial impairment in patients with Parkinson disease with the G2019S mutation in LRRK2. Neurology. 2010; 75(22):2017-20. DOI: 10.1212/WNL.0b013e3181ff9685. View

Sriskanthadevan S, Jeyaraju D, Chung T, Prabha S, Xu W, Skrtic M . AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress. Blood. 2015; 125(13):2120-30. PMC: 4375109. DOI: 10.1182/blood-2014-08-594408. View

Mosconi L . Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging. 2005; 32(4):486-510. DOI: 10.1007/s00259-005-1762-7. View

Harada C, Love M, Triebel K . Normal cognitive aging. Clin Geriatr Med. 2013; 29(4):737-52. PMC: 4015335. DOI: 10.1016/j.cger.2013.07.002. View

Yao J, Irwin R, Zhao L, Nilsen J, Hamilton R, Brinton R . Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2009; 106(34):14670-5. PMC: 2732886. DOI: 10.1073/pnas.0903563106. View

Boller B, Mellah S, Ducharme-Laliberte G, Belleville S . Relationships between years of education, regional grey matter volumes, and working memory-related brain activity in healthy older adults. Brain Imaging Behav. 2016; 11(2):304-317. DOI: 10.1007/s11682-016-9621-7. View

Liang W, Reiman E, Valla J, Dunckley T, Beach T, Grover A . Alzheimer's disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A. 2008; 105(11):4441-6. PMC: 2393743. DOI: 10.1073/pnas.0709259105. View

10.

Haroutunian V, Schnaider-Beeri M, Schmeidler J, Wysocki M, Purohit D, Perl D . Role of the neuropathology of Alzheimer disease in dementia in the oldest-old. Arch Neurol. 2008; 65(9):1211-7. PMC: 3071251. DOI: 10.1001/archneur.65.9.1211. View

11.

Maynard S, Hejl A, Dinh T, Keijzers G, Hansen A, Desler C . Defective mitochondrial respiration, altered dNTP pools and reduced AP endonuclease 1 activity in peripheral blood mononuclear cells of Alzheimer's disease patients. Aging (Albany NY). 2015; 7(10):793-815. PMC: 4637207. DOI: 10.18632/aging.100810. View

12.

Stern Y . Cognitive reserve: implications for assessment and intervention. Folia Phoniatr Logop. 2013; 65(2):49-54. PMC: 3970779. DOI: 10.1159/000353443. View

13.

Cardoso M, Leung K, Modat M, Keihaninejad S, Cash D, Barnes J . STEPS: Similarity and Truth Estimation for Propagated Segmentations and its application to hippocampal segmentation and brain parcelation. Med Image Anal. 2013; 17(6):671-84. DOI: 10.1016/j.media.2013.02.006. View

14.

Ramanoel S, Hoyau E, Kauffmann L, Renard F, Pichat C, Boudiaf N . Gray Matter Volume and Cognitive Performance During Normal Aging. A Voxel-Based Morphometry Study. Front Aging Neurosci. 2018; 10:235. PMC: 6085481. DOI: 10.3389/fnagi.2018.00235. View

15.

Braak H, Braak E . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991; 82(4):239-59. DOI: 10.1007/BF00308809. View

16.

Martin-Maestro P, Gargini R, Garcia E, Perry G, Avila J, Garcia-Escudero V . Slower Dynamics and Aged Mitochondria in Sporadic Alzheimer's Disease. Oxid Med Cell Longev. 2017; 2017:9302761. PMC: 5672147. DOI: 10.1155/2017/9302761. View

17.

Baik S, Kang S, Lee W, Choi H, Chung S, Kim J . A Breakdown in Metabolic Reprogramming Causes Microglia Dysfunction in Alzheimer's Disease. Cell Metab. 2019; 30(3):493-507.e6. DOI: 10.1016/j.cmet.2019.06.005. View

18.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

19.

Sonntag K, Ryu W, Amirault K, Healy R, Siegel A, McPhie D . Late-onset Alzheimer's disease is associated with inherent changes in bioenergetics profiles. Sci Rep. 2017; 7(1):14038. PMC: 5656579. DOI: 10.1038/s41598-017-14420-x. View

20.

Scahill R, Schott J, Stevens J, Rossor M, Fox N . Mapping the evolution of regional atrophy in Alzheimer's disease: unbiased analysis of fluid-registered serial MRI. Proc Natl Acad Sci U S A. 2002; 99(7):4703-7. PMC: 123711. DOI: 10.1073/pnas.052587399. View