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

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. Capitalizing on multimodal imaging: Analysis of animal models and postmortem material from patients suggests that mitochondrial impairments and cellular stress play a role in the pathophysiology of Alzheimer's disease (AD). However, more longitudinal in vivo measurements in patients are needed. Here, Venkatamaran et al. analyzed PET and MRI data from patients with AD and showed increased ER stress response and indication of mitochondrial and synaptic dysfunction at early disease stages. Longitudinal analysis showed that brain volume loss and mitochondrial density were particularly susceptible to disease progression. The results suggest that multimodal, longitudinal imaging studies are necessary for complete disease characterization and could be of value in the clinical setting for diagnosis and clinical trial evaluation. [ABSTRACT FROM AUTHOR]