Year: 2016
Type: article
Abstract: This scientific commentary refers to ‘Dynamic relationships between age, amyloid-β deposition, and glucose metabolism link to the regional vulnerability to Alzheimer’s disease’, by Oh et al. (doi:10.1093/brain/aww108). One of the neuropathological hallmarks of Alzheimer’s disease is the widespread accumulation in cerebral cortex of extracellular plaques containing amyloid-β, which is reported to begin 10–20 years before dementia onset (Bateman et al., 2012; Buchhave et al., 2012). The mechanisms behind accumulation of amyloid-β in non-familial Alzheimer’s disease remain poorly understood, and the relationship between amyloid-β pathology and subsequent neuronal dysfunction and degeneration needs to be better determined. It is not known why certain brain regions are affected more than others by amyloid-β pathology and neurodegeneration, and whether these events might be related to the neuronal activity of the regions concerned. In this issue of Brain, Oh and co-workers elegantly show that certain cortical regions that are characterized by high levels of energy consumption in young adulthood are more prone to amyloid-β-containing plaques in later life (Oh et al., 2016). Further, they provide evidence that brain regions exhibiting constant energy consumption across the life span degenerate to a greater degree during the dementia stages of Alzheimer’s disease. PET can be used to measure regional energy consumption, via the tracer 18F-fluorodeoxyglucose (FDG), and to detect regional levels of amyloid-β-containing plaques, via tracers such as 11C-PiB that bind to fibrillar forms of amyloid-β (Klunk et al., 2004). Oh et al. have combined these imaging modalities in a cross-sectional study of cohorts at different ages and with varying levels of amyloid deposition in order to obtain insights into the relationship between brain metabolic activity at particular ages and the development of regional Alzheimer’s disease pathogenesis. The results reveal a possible connection between the activity of brain regions when young and subsequent amyloid deposition and Alzheimer’s disease-related glucose hypometabolism. Overall, Oh et al. report a general anatomical correlation between high resting metabolic glucose utilization in healthy young adults and the development of amyloid plaque pathology later in life. However, when more selective regions of interest are compared, a more complex picture emerges, where some areas that show low metabolic activity when young (e.g. anterior cingulate cortex) are particularly prone to amyloid pathology, while other areas showing high metabolic activity when young (e.g. primary visual cortex) develop less amyloid pathology with age. It has been suggested that amyloid-β pathology is more closely associated with elevated aerobic glycolysis in young brains than with increased total glucose utilization (Vlassenko et al., 2010), which might explain these seemingly discrepant results when using 18F-FDG PET alone. A hypothesis has emerged over the past decade suggesting a relationship between high metabolic demand and the development of Alzheimer’s disease, based on the fact that cortical hubs associated with multimodal integration have high resting state activity. This, combined with experimental cell and animal work showing that neural activity leads to increased amyloid-β generation and secretion, led to the idea that a gradual build-up of amyloid-β might occur in active areas in Alzheimer’s disease with age (Cirrito et al., 2005; Bero et al., 2011). Further, in patients with acute brain injury, levels of amyloid-β in brain interstitial fluid increase with improved neurological status, indicating that neuronal activity regulates extracellular amyloid-β concentration (Brody et al., 2008). However, such a linear mechanistic hypothesis linking activity and amyloid-β pathology in Alzheimer’s disease is not easy to prove and not all experimental data are supportive (Tampellini et al., 2010). Oh and collaborators also provide new data showing that some brain areas with little age-related hypometabolism show hypometabolism in full-blown Alzheimer’s disease. This is particularly evident in brain regions such as the precuneus that also exhibit hypermetabolism at early preclinical stages of amyloid deposition. Here one can certainly speculate that it is the hyperactivity induced by amyloid-β accumulation that then makes these brain regions more vulnerable to neurodegeneration. Hyperactivity has been seen early in experimental animal models of Alzheimer’s disease (Palop and Mucke, 2010), as well as in some human imaging studies featuring cases with preclinical Alzheimer’s disease, such as the current study. However, it remains unclear whether such increased activity is a direct effect of abnormal amyloid-β metabolism or a compensatory response to brain injury induced by amyloid-β. Recent animal work suggests that hyperactivity might be a primary neuronal dysfunction mediated by early amyloid-β pathology, and that it is soluble oligomeric amyloid-β, and not fibrillar amyloid-β, that induces this condition (Busche et al., 2012). This highlights the need for new PET imaging methods that can detect oligomeric amyloid-β, and not only fibrillar amyloid-β as is the case for current PET tracers. Such tracers are under development (Sehlin et al., 2016). In addition, several PET tracers are now available that can detect tau aggregates (Dani et al., 2016), and it will be exciting to see future longitudinal studies untangling the temporal and spatial relationships between neuronal activity, amyloid-β accumulation and tau tangle formation. Glossary: Amyloid plaque: Amyloid-β peptides aggregate into insoluble β-sheet amyloid fibrils to form plaques, a neuropathological hallmark of Alzheimer’s disease 11C-Pittsburgh compound B (PiB): A radiotracer originally derived from thioflavin T that can be imaged using PET to reveal the abundance of insoluble β-sheet amyloid fibrils. 18F-fluorodeoxyglucose: A marker of cellular uptake of glucose that can be imaged using PET to reflect regional tissue metabolism.
Source: Brain
DOI: 10.1093/brain/aww146
Authors: Oskar Hansson, Gunnar Gouras
Institutions: Lund University, Skåne University Hospital
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2488095492