Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s disease
| Autor: | Ashwin V. Venkataraman, Ayla Mansur, Gaia Rizzo, Courtney Bishop, Yvonne Lewis, Ece Kocagoncu, Anne Lingford-Hughes, Mickael Huiban, Jan Passchier, James B. Rowe, Hideo Tsukada, David J. Brooks, Laurent Martarello, Robert A. Comley, Laigao Chen, Adam J. Schwarz, Richard Hargreaves, Roger N. Gunn, Eugenii A. Rabiner, Paul M. Matthews |
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| Přispěvatelé: | National Institute for Health Research, UK DRI Ltd |
| Rok vydání: | 2022 |
| Předmět: |
IN-VIVO EVALUATION
Science & Technology Brain Cell Biology General Medicine Research & Experimental Medicine 06 Biological Sciences Magnetic Resonance Imaging ATROPHY Mitochondria POSITRON-EMISSION-TOMOGRAPHY Medicine Research & Experimental Alzheimer Disease Cerebrovascular Circulation Positron-Emission Tomography SIGMA(1) Humans OXIDATIVE STRESS LIGAND Life Sciences & Biomedicine RECEPTOR-BINDING SA4503 Biomarkers 11 Medical and Health Sciences AMYLOID DEPOSITION |
| Zdroj: | Venkataraman, A V, Mansur, A, Rizzo, G, Bishop, C, Lewis, Y, Kocagoncu, E, Lingford-Hughes, A, Huiban, M, Passchier, J, Rowe, J B, Tsukada, H, Brooks, D J, Martarello, L, Comley, R A, Chen, L, Schwarz, A J, Hargreaves, R, Gunn, R N, Rabiner, E A & Matthews, P M 2022, ' Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease ', Science Translational Medicine, vol. 14, no. 658, eabk1051 . https://doi.org/10.1126/scitranslmed.abk1051 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.abk1051 |
| Popis: | Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [ 11 C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [ 18 F]BCPP-EF, and the presynaptic vesicular protein SV2A with [ 11 C]UCB-J in 12 patients with early AD and in 16 cognitively normal controls. We integrated these molecular measures with assessments of regional brain volumes and cerebral blood flow (CBF) measured with magnetic resonance imaging arterial spin labeling. Eight patients with AD were followed longitudinally to estimate the rate of change of the physiological and structural pathology markers with disease progression. The patients showed widespread increases in S1R (≤ 27%) and regional reduction in MC1 (≥ −28%) and SV2A (≥ −25%) radioligand binding, brain volume (≥ −23%), and CBF (≥ −26%). [ 18 F]BCPP-EF PET MC1 binding (≥ −12%) and brain volumes (≥ −5%) showed progressive reductions over 12 to 18 months, suggesting that they both could be used as pharmacodynamic indicators in early-stage therapeutics trials. Associations of reduced MC1 and SV2A and increased S1R radioligand binding with reduced cognitive performance in AD, although exploratory, suggested a loss of metabolic functional reserve with disease. Our study thus provides in vivo evidence for widespread, clinically relevant cellular stress and bioenergetic abnormalities in early AD. |
| Databáze: | OpenAIRE |
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