Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease

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

doi:10.1126/scitranslmed.abk1051

Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease

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

Research output: Contribution to journal › Article › peer-review

75 Citations (Scopus)

Abstract

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 [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic vesicular protein SV2A with [11C]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%). [18F]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.

Original language	English
Article number	eabk1051
Pages (from-to)	eabk1051
Journal	Science Translational Medicine
Volume	14
Issue number	658
DOIs	https://doi.org/10.1126/scitranslmed.abk1051
Publication status	Published - 17 Aug 2022

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10.1126/scitranslmed.abk1051

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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, 14(658), eabk1051. Article eabk1051. https://doi.org/10.1126/scitranslmed.abk1051

@article{1254aa19c831488cbd50fb789b9c7160,

title = "Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease",

abstract = "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 [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic vesicular protein SV2A with [11C]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\%). [18F]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.",

author = "Venkataraman, \{Ashwin V.\} and Ayla Mansur and Gaia Rizzo and Courtney Bishop and Yvonne Lewis and Ece Kocagoncu and Anne Lingford-Hughes and Mickael Huiban and Jan Passchier and Rowe, \{James B.\} and Hideo Tsukada and Brooks, \{David J.\} and Laurent Martarello and Comley, \{Robert A.\} and Laigao Chen and Schwarz, \{Adam J.\} and Richard Hargreaves and Gunn, \{Roger N.\} and Rabiner, \{Eugenii A.\} and Matthews, \{Paul M.\}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved.",

year = "2022",

month = aug,

day = "17",

doi = "10.1126/scitranslmed.abk1051",

language = "English",

volume = "14",

pages = "eabk1051",

journal = "Science Translational Medicine",

issn = "1946-6234",

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Venkataraman, AV, Mansur, A, Rizzo, G, Bishop, C, Lewis, Y, Kocagoncu, E, Lingford-Hughes, A, Huiban, M, Passchier, J, Rowe, JB, Tsukada, H, Brooks, DJ, Martarello, L, Comley, RA, Chen, L, Schwarz, AJ, Hargreaves, R, Gunn, RN, Rabiner, EA & Matthews, PM 2022, 'Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease', Science Translational Medicine, vol. 14, no. 658, eabk1051, pp. eabk1051. https://doi.org/10.1126/scitranslmed.abk1051

TY - JOUR

T1 - Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease

AU - Venkataraman, Ashwin V.

AU - Mansur, Ayla

AU - Rizzo, Gaia

AU - Bishop, Courtney

AU - Lewis, Yvonne

AU - Kocagoncu, Ece

AU - Lingford-Hughes, Anne

AU - Huiban, Mickael

AU - Passchier, Jan

AU - Rowe, James B.

AU - Tsukada, Hideo

AU - Brooks, David J.

AU - Martarello, Laurent

AU - Comley, Robert A.

AU - Chen, Laigao

AU - Schwarz, Adam J.

AU - Hargreaves, Richard

AU - Gunn, Roger N.

AU - Rabiner, Eugenii A.

AU - Matthews, Paul M.

PY - 2022/8/17

Y1 - 2022/8/17

N2 - 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 [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic vesicular protein SV2A with [11C]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%). [18F]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.

AB - 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 [11C]SA4503 positron emission tomography (PET), the mitochondrial complex I (MC1) with [18F]BCPP-EF, and the presynaptic vesicular protein SV2A with [11C]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%). [18F]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.

UR - https://www.scopus.com/pages/publications/85136080626

U2 - 10.1126/scitranslmed.abk1051

DO - 10.1126/scitranslmed.abk1051

M3 - Article

C2 - 35976998

AN - SCOPUS:85136080626

SN - 1946-6234

VL - 14

SP - eabk1051

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 658

M1 - eabk1051

ER -

Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer's disease

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Widespread cell stress and mitochondrial dysfunction in early Alzheimers Disease

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