Ketone Ester Effects on Biomarkers of Brain Metabolism and Cognitive Performance in Cognitively Intact Adults ≥ 55 Years Old. A Study Protocol for a Double-Blinded Randomized Controlled Clinical Trial.

BACKGROUND: Ketone bodies have been proposed as an "energy rescue" for the Alzheimer's disease (AD) brain, which underutilizes glucose. Prior research has shown that oral ketone monoester (KME) safely induces robust ketosis in humans and has demonstrated cognitive-enhancing and pathology-reducing properties in animal models of AD. However, human evidence that KME may enhance brain ketone metabolism, improve cognitive performance and engage AD pathogenic cascades is scarce. OBJECTIVES: To investigate the effects of ketone monoester (KME) on brain metabolism, cognitive performance and AD pathogenic cascades in cognitively normal older adults with metabolic syndrome and therefore at higher risk for AD. DESIGN: Double-blinded randomized placebo-controlled clinical trial. SETTING: Clinical Unit of the National Institute on Aging, Baltimore, US. PARTICIPANTS: Fifty cognitively intact adults ≥ 55 years old, with metabolic syndrome. INTERVENTION: Drinks containing 25 g of KME or isocaloric placebo consumed three times daily for 28 days. OUTCOMES: Primary: concentration of beta-hydroxybutyrate (BHB) in precuneus measured with Magnetic Resonance Spectroscopy (MRS). Exploratory: plasma and urine BHB, multiple brain and muscle metabolites detected with MRS, cognition assessed with the PACC and NIH toolbox, biomarkers of AD and metabolic mediators in plasma extracellular vesicles, and stool microbiome. DISCUSSION: This is the first study to investigate the AD-biomarker and cognitive effects of KME in humans. Ketone monoester is safe, tolerable, induces robust ketosis, and animal studies indicate that it can modify AD pathology. By conducting a study of KME in a population at risk for AD, we hope to bridge the existing gap between pre-clinical evidence and the potential for brain-metabolic, pro-cognitive, and anti-Alzheimer's effects in humans.

FTD and ALS: a tale of two diseases.

The first reports of disorders that in terms of cognitive and behavioral symptoms resemble frontotemporal dementia (FTD) and in terms of motor symptoms resemble amyotrophic lateral sclerosis (ALS) bring us back to the second half of the 1800s. Over the last 150 years, and especially in the last two decades, there has been growing evidence that FTD signs can be seen in patients primarily diagnosed with ALS, implying clinical overlap among these two disorders. In the last decade pathological investigations and genetic screening have contributed tremendously in elucidating the pathology and genetic variability associated with FTD and ALS. To the most important recentdiscoveries belong TAR DNA binding protein [TARDBP or TDP-43] and the fused in sarcoma gene [FUS] and their implication in these disorders.FTD and ALS are the focus of this review which aims to 1. summarize clinical features by describing the diagnostic criteria and specific symptomatology, 2. describe the morphological aspects and related pathology, 3. describe the genetic factors associated with the diseases and 4. summarize the current status of clinical trials and treatment options. A better understanding of the clinical, pathological and genetic features characterizing FTD and ALS will shed light into overlaps among these two disorders and the underpinning mechanisms that contribute to the onset and development. Nevertheless, advancements in the knowledge of the biology of these two disorders will help developing novel and, hopefully, more effective diagnostic and treatment options.

High rates of antibiotic resistance among normal fecal flora Escherichia coli isolates in children from Greece.

OBJECTIVE: To study the distribution of antibiotic resistant Escherichia coli in the fecal flora of healthy children in Greece. METHODS: Rectal swabs were collected from 181 children, not suffering from infections and not undergoing antibiotic treatment, aged 6 months to 6 years, outpatients of a pediatric hospital, and plated on McConkey agar with ampicillin or trimethoprim. Isolated resistant colonies were identified to the species level and E. coli strains were studied further by molecular methods. RESULTS: Forty-four per cent of the children carried resistant E. coli, and in 20% resistance was transferable. Forty-seven per cent of the children with no history of antibiotic consumption during the last year were found to carry resistant strains in their feces, and transferable R plasmids were present in 23% of them. Forty per cent of the strains and 30% of the transconjugants were multiresistant. Although plasmids of various molecular weights and restriction endonuclease digest patterns were identified, six 60-MDa and four 80-MDa plasmids, originating from epidemiologically unrelated children, were found to be similar. CONCLUSION: Normal flora E. coli in Greece seems to constitute an important reservoir of resistance genes. Eradication of resistance from a population that comes into frequent contact with antibiotics seems to be difficult.