Imperial College London
Portrait Picture

ProfessorAnneLingford-Hughes

Faculty of Medicine, Department of Brain Sciences

Chair in Addiction Biology
 
 
 
//

Contact

 

+44 (0)20 7594 8682anne.lingford-hughes Website

 
 
//

Location

 

Commonwealth BuildingHammersmith Campus

//

Summary

 

Publications

Citation

BibTex format

@article{Venkataraman:2022:10.1126/scitranslmed.abk1051,
author = {Venkataraman, A and Mansur, A and Rizzo, G and Bishop, C and Lewis, Y and Kocagoncu, E and Lingford-Hughes, A and Huiban, M and Passchier, J and Rowe, J and Tsukada, H and Brooks, D and Martarello, L and Comley, R and Chen, L and Schwarz, A and Hargreaves, R and Gunn, R and Rabiner, E and Matthews, P},
doi = {10.1126/scitranslmed.abk1051},
journal = {Science Translational Medicine},
pages = {1--11},
title = {Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s Disease},
url = {http://dx.doi.org/10.1126/scitranslmed.abk1051},
volume = {14},
year = {2022}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
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 PET, the mitochondrial complex I (MC1) with [18F]BCPP-EF and the pre-synaptic 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 (MRI) arterial spin labelling. 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 12-18 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.
AU  - Venkataraman,A
AU  - Mansur,A
AU  - Rizzo,G
AU  - Bishop,C
AU  - Lewis,Y
AU  - Kocagoncu,E
AU  - Lingford-Hughes,A
AU  - Huiban,M
AU  - Passchier,J
AU  - Rowe,J
AU  - Tsukada,H
AU  - Brooks,D
AU  - Martarello,L
AU  - Comley,R
AU  - Chen,L
AU  - Schwarz,A
AU  - Hargreaves,R
AU  - Gunn,R
AU  - Rabiner,E
AU  - Matthews,P
DO  - 10.1126/scitranslmed.abk1051
EP  - 11
PY  - 2022///
SN  - 1946-6234
SP  - 1
TI  - Widespread cell stress and mitochondrial dysfunction occur in patients with early Alzheimer’s Disease
T2  - Science Translational Medicine
UR  - http://dx.doi.org/10.1126/scitranslmed.abk1051
UR  - http://hdl.handle.net/10044/1/98921
VL  - 14
ER  -
Download