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.

Developing a Persian Verbal Fluency Test and Comparing the Results Between Healthy Persian Speakers and Persian Speakers Patients With Alzheimer Disease and Mild Cognitive Impairment

Objectives: Phonemic and semantic fluency tasks are used for verbal fluency (VF) evaluation. The present study aimed to select the most appropriate semantic categories and the most frequent phonemes of Persian as items for the VF test. Then, we determine the test results in differentiation between cognitively intact people and those with Mild Cognitive Impairment (MCI) and Alzheimer Disease (AD). Methods: A cross-sectional study was conducted on 120 people (60 cognitively intact, 30 with AD, and 30 with MCI) in two phases. In phase one, linguists determine the most frequent phonemes at the beginning of Persian words and the most frequent semantic categories based on a survey. In phase two, the verbal fluency test was administered to cognitively intact people and those with cognitive impairment (patients with AD and MCI). One-way ANOVA and multiple linear regression were used for statistical analysis. Results: The normal subjects scored significantly higher in all phonemic and semantic fluency tasks than the patients with AD and people with MCI (P<0.05). Regarding the phonemic VF task, the phonemes /sh/, /s/, and then /a/ were better in differentiating the MCI and AD groups from the normal group. Regarding the semantic VF task, the animals’ category was better differentiated the MCI and AD groups from the normal group. Discussion: Comparing frequent phonemes and semantic categories of Persian across three groups of normal, AD, and MCI showed that some phonemes and semantic categories can be more differentiating in the VF task. However, it is a preliminary validation study, and this topic needs more investigation in the future.

Angiotensin Receptor Blockers Upregulate Angiotensin Type 4 Receptor in Brains of Cognitively Intact Individuals

The primary dementia-protective benefits of Angiotensin receptor type 1 (AT1R) blockers (ARBs) are believed to arise from systemic effects on blood pressure. However, there is a brain-specific renin-angiotensin system (b-RAS) that acts mainly through three receptor subtypes: AT1R, AT2R, and AT4R. AT1R promotes inflammation and oxidative stress (OS). AT2R increases nitric oxide. AT4R is essential for dopamine release and mediates memory consolidation. Here, we aimed to investigate the effects of ARBs on b-RAS, OS, inflammation, PHF-tau, and beta-amyloid load. Postmortem frontal-cortex brains of age- and sex-matched cognitively intact (CI) individuals using (n=30) and not using ARBs (n=30) and Alzheimer's disease (AD) patients using (n=30) and not using ARBs (n=30) were studied. Protein levels of receptors were measured by Western blot. Protein carbonyl (PC) and cytokine levels were measured by ELISA. Tangle and amyloid-β scores were used as outcomes. In CI individuals, our data shows that ARB treatment was associated with higher protein levels of AT4R (median(range) 0.69(1.92) vs 0.17(1.18) CI+ARBs vs CI, p=0.02), lower level of OS marker PC (10.60(8.32) vs 11.26(7.44), CI+ARBs vs CI, p=0.03) and lower hippocampal and overall amyloid scores (0(5.45) vs 1.15(4.21) p=0.03, 0.79(12.75) vs 3.41(13.36) p=0.04, CI+ARBs vs CI, respectively). In AD group, ARB treatment was associated with lower AT1R protein levels (0.47(1.15) vs 0.59(1.99), AD+ARBs vs AD, p=0.02). No significant changes were observed in OS, inflammation, or PHF-tau and amyloid load in AD brains treated with ARBs. Our results highlight the impact of ARBs on the brains of cognitively intact and AD older individuals.

CAPABLE Program Improves Disability in Research and Implementation Settings

Interventions to reduce disability are crucial for older adults with disabilities to avert unnecessary hospitalizations or nursing home placements and improve daily life. Developed and tested at one research site, multiple health systems and community based organizations have since implemented CAPABLE. All published or peer reviewed tests of CAPABLE were reviewed (six studies, 11 sites) with a total of 1087 low-income community-dwelling older adults with disabilities. Participants were an average age of 74-79, cognitively intact, and self-reported difficulty with one or more activities of daily living (ADL). These trials were reviewed by extracting the participants’ scores on main outcomes, ADLs and IADLs, and when available, fall efficacy, depression, pain and cost savings. All studies yielded improvements in ADL and IADL limitations, with small to strong effect sizes. Studies with the complete dose of CAPABLE showed more improvement in ADLs and cost savings than the studies that implemented a decreased dose.

White Matter Hyperintensity Distribution Differences in Aging and Neurodegenerative Disease Cohorts

Introduction: White matter hyperintensities (WMHs) are common magnetic resonance imaging (MRI) findings in the aging population in general, as well as in patients with neurodegenerative diseases. They are known to exacerbate the cognitive deficits and worsen the clinical outcomes in the patients. However, it is not well-understood whether there are disease-specific differences in prevalence and distribution of WMHs in different neurodegenerative disorders. Methods: Data included 976 participants with cross-sectional T1-weighted and fluid attenuated inversion recovery (FLAIR) MRIs from the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort of the Canadian Consortium on Neurodegeneration in Aging (CCNA) with eleven distinct diagnostic groups: cognitively intact elderly (CIE), subjective cognitive impairment (SCI), mild cognitive impairment (MCI), vascular MCI (V-MCI), Alzheimers dementia (AD), vascular AD (V-AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), cognitively intact elderly with Parkinsons disease (PD-CIE), cognitively impaired Parkinsons disease (PD-CI), and mixed dementias. WMHs were segmented using a previously validated automated technique. WMH volumes in each lobe and hemisphere were compared against matched CIE individuals, as well as each other, and between men and women. Results: All cognitively impaired diagnostic groups had significantly greater overall WMH volumes than the CIE group. Vascular groups (i.e. V-MCI, V-AD, and mixed dementia) had significantly greater WMH volumes than all other groups, except for FTD, which also had significantly greater WMH volumes than all non-vascular groups. Women tended to have lower WMH burden than men in most groups and regions, controlling for age. The left frontal lobe tended to have a lower WMH burden than the right in all groups. In contrast, the right occipital lobe tended to have greater WMH loads than the left. Conclusions: There were distinct differences in WMH prevalence and distribution across diagnostic groups, sexes, and in terms of asymmetry. WMH burden was significantly greater in all neurodegenerative dementia groups, likely encompassing areas exclusively impacted by neurodegeneration as well as areas related to cerebrovascular disease pathology.

Changes of Brain Functional Connectivity in End-Stage Renal Disease Patients Receiving Peritoneal Dialysis Without Cognitive Decline

Background: Functional connectivity detected by resting-state functional MRI (R-fMRI) helps to discover the subtle changes in brain activities. Patients with end-stage renal disease (ESRD) on hemodialysis (HD) have impaired brain networks. However, the functional changes of brain networks in patients with ESRD undergoing peritoneal dialysis (PD) have not been fully delineated, especially among those with preserved cognitive function. Therefore, it is worth knowing about the brain functional connectivity in patients with PD by using R-fMRI.Methods: This case-control study prospectively enrolled 19 patients with ESRD receiving PD and 24 age- and sex- matched controls. All participants without a history of cognitive decline received mini-mental status examination (MMSE) and brain 3-T R-fMRI. Comprehensive R-fMRI analyses included graph analysis for connectivity and seed-based correlation networks. Independent t-tests were used for comparing the graph parameters and connectivity networks between patients with PD and controls.Results: All subjects were cognitively intact (MMSE &gt; 24). Whole-brain connectivity by graph analysis revealed significant differences between the two groups with decreased global efficiency (Eglob, p &lt; 0.05), increased betweenness centrality (BC) (p &lt; 0.01), and increased characteristic path length (L, p &lt; 0.01) in patients with PD. The functional connections of the default-mode network (DMN), sensorimotor network (SMN), salience network (SN), and hippocampal network (HN) were impaired in patients with PD. Meanwhile, in DMN and SN, elevated connectivity was observed in certain brain regions of patients with PD.Conclusion: Patients with ESRD receiving PD had specific disruptions in functional connectivity. In graph analysis, Eglob, BC, and L showed significant connectivity changes compared to the controls. DMN and SN had the most prominent alterations among the observed networks, with both decreased and increased connectivity regions. Our study confirmed that significant changes in cerebral connections existed in cognitively intact patients with PD.

Locus Coeruleus magnetic resonance imaging in cognitively intact elderly subjects

The locus coeruleus is the main noradrenergic nucleus of the brain and is often affected in neurodegenerative diseases. Recently, magnetic resonance imaging with specific T1-weighted sequences for neuromelanin has been used to evaluate locus coeruleus integrity in patients with these conditions. In some of these studies, abnormalities in locus coeruleus signal have also been found in healthy controls and related to ageing. However, this would be at variance with recent post-mortem studies showing that the nucleus is not affected during normal ageing. The present study aimed at evaluating locus coeruleus features in a well-defined cohort of cognitively healthy subjects who remained cognitively intact on a one-year follow-up. An ad-hoc semiautomatic analysis of locus coeruleus magnetic resonance was applied. Sixty-two cognitively intact subjects aged 60–80 years, without significant comorbidities, underwent 3 T magnetic resonance with specific sequences for locus coeruleus. A semi-automatic tool was used to estimate the number of voxels belonging to locus coeruleus and its intensity was obtained for each subject. Each subject underwent extensive neuropsychological testing at baseline and 12 months after magnetic resonance scan. Based on neuropsychological testing 53 subjects were cognitively normal at baseline and follow up. No significant age-related differences in locus coeruleus parameters were found in this cohort. In line with recent post-mortem studies, our in vivo study confirms that locus coeruleus magnetic resonance features are not statistically significantly affected by age between 60 and 80 years, the age range usually evaluated in studies on neurodegenerative diseases. A significant alteration of locus coeruleus features in a cognitively intact elderly subject might be an early sign of pathology.

Management of preoperative pain in elderly patients with moderate to severe cognitive deficits and hip fracture: a retrospective, monocentric study in an orthogeriatric unit

Background Patients with cognitive deficits are 3 times more likely to suffer a hip fracture than geriatric patients of the same age group without cognitive deficits. The persistence of perioperative pain following hip fracture is a risk factor for the occurrence of delirium, poor functional prognosis, and the development of secondary chronic pain. Patients with cognitive deficits receive 20 to 60% less analgesics than those without cognitive deficits. Our retrospective descriptive monocentric study was performed in an orthogeriatric unit on a cohort of elderly patients hospitalized for hip fracture. The aim of the study was to compare the quantity of strong opioids delivered in a morphine sulfate equivalent daily during the preoperative period after a hip fracture between cognitively intact patients and those with cognitive deficits. Results Our total population of 69 patients had a median age of 90 years old, and 46% of these patients had moderate or severe cognitive deficits. During the preoperative period, the same quantity of strong opioids was administered to both groups of patients (13.1 mg/d versus 10.8 mg/d (p = 0.38)). Patients with moderate to severe cognitive deficits more often experienced delirium during their hospitalization (p < 0.01) and received more psychotropic drugs in the first 3 postoperative days (p = 0.025). Conclusions We reported that with standardized pain management in an orthogeriatric unit, patients aged 75 years and older received the same daily average quantity of strong opioids during the preoperative period regardless of the presence of cognitive deficits.