A Review of Functional Neuroimaging in People with Down Syndrome with and without Dementia

<b><i>Background:</i></b> Individuals with Down syndrome (DS) are at high risk of dementia which is difficult to diagnose in DS. Neuroimaging has been identified as a potential tool to aid diagnosis by detecting changes in brain function. We carried out a review comparing functional neuroimaging in DS individuals with and without dementia. <b><i>Summary:</i></b> A literature search was conducted using PubMed to identify relevant studies. In DS subjects with dementia, fluorodeoxyglucose-positron emission tomography (PET) studies showed glucose hypometabolism particularly in the parietal and/or temporal regions whilst magnetic resonance spectroscopy studies showed increased myoinositol and decreased N-acetylaspartate. Ligand-based PET studies revealed significant Pittsburgh compound B binding in DS subjects over the age of 40, particularly if they had dementia. <b><i>Key Messages:</i></b> Neuroimaging may aid the early detection of dementia in DS; however, further longitudinal studies are required.

Ketone Supplementation: Meeting the Needs of the Brain in an Energy Crisis

Diverse neurological disorders are associated with a deficit in brain energy metabolism, often characterized by acute or chronic glucose hypometabolism. Ketones serve as the brain's only significant alternative fuel and can even become the primary fuel in conditions of limited glucose availability. Thus, dietary supplementation with exogenous ketones represents a promising novel therapeutic strategy to help meet the energetic needs of the brain in an energy crisis. Preliminary evidence suggests ketosis induced by exogenous ketones may attenuate damage or improve cognitive and motor performance in neurological conditions such as seizure disorders, mild cognitive impairment, Alzheimer's disease, and neurotrauma.

Ketones – Potential to Achieve Brain Energy Rescue and Sustain Cognitive Health during Aging

Alzheimer’s disease (AD) is the most common major neurocognitive disorder of aging. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive ‘brain energy gap’. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition – mild cognitive impairment (MCI) - to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during aging. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimizing the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.

Aβ initiates brain hypometabolism, network dysfunction and behavioral abnormalities via NOX2-induced oxidative stress in mice

A predominant trigger and driver of sporadic Alzheimer’s disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences have remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind Aβ1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients both ex- and in-vivo to show that Aβ1-42 induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.

Brain Glucose Transporters: Role in Pathogenesis and Potential Targets for the Treatment of Alzheimer’s Disease

The most common cause of dementia, especially in elderly people, is Alzheimer’s disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer’s disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.

Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology

GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model.