To investigate whether cerebral metabolic rate of glucose (CMRglu) is altered in normal weight young women with polycystic ovary syndrome (PCOS) who exhibit mild insulin resistance.
Seven women with ...PCOS were compared to eleven healthy female controls of similar age, education and body mass index. Regional brain glucose uptake was quantified using FDG with dynamic positron emission tomography and magnetic resonance imaging, and its potential relationship with insulin resistance assessed using the updated homeostasis model assessment (HOMA2-IR). A battery of cognitive tests was administered to evaluate working memory, attention and executive function.
The PCOS group had 10% higher fasting glucose and 40% higher HOMA2-IR (p ≤ 0.035) compared to the Controls. The PCOS group had 9-14% lower CMRglu in specific regions of the frontal, parietal and temporal cortices (p ≤ 0.018). A significant negative relation was found between the CMRglu and HOMA2-IR mainly in the frontal, parietal and temporal cortices as well as in the hippocampus and the amygdala (p ≤ 0.05). Globally, cognitive performance was normal in both groups but scores on the PASAT test of working memory tended to be low in the PCOS group.
The PCOS group exhibited a pattern of low regional CMRglu that correlated inversely with HOMA2-IR in several brain regions and which resembled the pattern seen in aging and early Alzheimer's disease. These results suggest that a direct association between mild insulin resistance and brain glucose hypometabolism independent of overweight or obesity can exist in young adults in their 20s. Further investigation of the influence of insulin resistance on brain glucose metabolism and cognition in younger and middle-aged adults is warranted.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The brain requires a large amount of energy, mostly derived from the metabolism of glucose, which decreases substantially with age and neurological diseases. While mounting evidence in model ...organisms illustrates the central role of brain nicotinamide adenine dinucleotide (NAD) for maintaining energy homeostasis, similar data are sparse in humans. This study explores the correlations between brain NAD, energy production and membrane phospholipid metabolism by 31-phosphorous magnetic resonance spectroscopy (
P-MRS) across 50 healthy participants including a young (mean age 27.1-year-old) and middle-aged (mean age 56.4-year-old) group. The analysis revealed that brain NAD level and NAD
/NADH redox ratio were positively associated with ATP level and the rate of energy production, respectively. Moreover, a metabolic network linking NAD with membrane phospholipid metabolism, energy production, and aging was identified. An inverted trend between age and NAD level was detected. These results pave the way for the use of
P-MRS as a powerful non-invasive tool to support the development of new therapeutic interventions targeting NAD associated phospho-metabolic pathways in brain aging and neurological diseases.
We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer's disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is ...fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain's main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain's main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal.
Abstract Objective In humans consuming a normal diet, we investigated 1) the capacity of a medium-chain triacylglycerol (MCT) supplement to stimulate and sustain ketonemia, 2)13 C-β-hydroxybutyrate ...and13 C-trioctanoate metabolism, and 3) the theoretical contribution of the degree of ketonemia achieved to brain energy metabolism. Methods Eight healthy adults (26 ± 1 y old) were given an MCT supplement for 4 wk (4 times/d; total of 20 g/d for 1 wk followed by 30 g/d for 3 wk). Ketones, glucose, triacylglycerols, cholesterol, free fatty acids, and insulin were measured over 8 h during two separate metabolic study days before and after MCT supplementation. Using isotope ratio mass spectroscopy,13 C-D-β-hydroxybutyrate and13 C-trioctanoate β-oxidation to13 CO2 was measured over 12 h on the pre- and post-MCT metabolic study days. Results On the post-MCT metabolic study day, plasma ketones (β-hydroxybutyrate plus acetoacetate) peaked at 476 μM, with a mean value throughout the study day of 290 μM. Post-MCT,13 C-trioctanoate β-oxidation was significantly lower 1 to 8 h later but higher 10 to 12 h later. MCT supplementation did not significantly alter13 C-D-β-hydroxybutyrate oxidation. Conclusions This MCT supplementation protocol was mildly and safely ketogenic and had no side effects in healthy humans on their regular diet. This degree of ketonemia is estimated to contribute up to 8% to 9% of brain energy metabolism.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Positron emission tomography using 18F-fluorodeoxyglucose (PET-FDG) is the primary imaging modality used to measure glucose metabolism in the brain (CMRGlu). CMRGlu has been used as a biomarker of ...brain aging and neurodegenerative diseases, but the complexity and invasive nature of PET often limits its use in research. There is therefore great interest in developing non-invasive metrics for estimating brain CMRGlu. We therefore investigated resting state fMRI metrics such as regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF) and regional global connectivity (Closeness) with multiple analytical approaches to determine their relationship to CMRGlu. We investigated this relation in two distinct cognitively healthy populations separated by age (27 young adults and 35 older adults). Overall, we found that both regionally and across participants, ReHo strongly correlated with CMRGlu in healthy young and older adults. Moreover, ReHo demonstrated the same age-related differences as CMRGlu throughout all cortical regions, particularly in the default network and frontal areas.
•PET-FDG accurately represents glucose metabolism (CMRGlu), but remains complex and invasive;•Finding a quantitative relationship between CMRGlu and an fMRI metric has been elusive;•We used a cognitively healthy aging dataset to compare fMRI to CMRGlu in the grey matter;•fMRI local synchrony (ReHo) correlated well to CMRGlu in both young and older groups;•ReHo could be used as a semi-quantitative proxy of CMRGlu and as a biomarker of aging.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract The study hypothesis was that fasting glucose, insulin, fructosamine, C-reactive protein, and interleukin-6 decrease and adiponectin increases with daily flaxseed consumption in overweight ...or obese individuals with pre-diabetes. In this randomized, cross-over study overweight or obese men and postmenopausal women (n = 25) with pre-diabetes consumed 0, 13, or 26 g ground flaxseed for 12 weeks. Glucose, insulin, homeostatic model assessment (HOMA-IR), and normalized percent of α-linolenic fatty acid (ALA) were significantly different by treatment (multiple analysis of variance, P = .036, P = .013, P = .008, P = .024 respectively). Paired t tests showed glucose decreased on the 13 g intervention compared to the 0 g period 13g = −2.10 ± 1.66 mg/L (mean ± SEM), 0 g = 9.22 ± 4.44 mg/L, P = .036. Insulin decreased on the 13 g intervention but not the 26 g ( P = .021) and 0 g ( P = .013) periods (13 g = −2.12 ± 1.00 mU/L, 26 g = 0.67 ± 0.84 mU/L, 0g = 1.20 ± 1.16 mU/L). HOMA-IR decreased on the 13 g period but not on the 26 g ( P = .012) and 0 g ( P = .008) periods (13g = −0.71 ± 0.31, 26g = 0.27 ± 0.24, 0g = 0.51 ± 0.35). The α-linolenic fatty acid decrease for the 0 g period was different than the 13 g ( P = .024) and 26 g ( P = .000) periods (13 g = 0.20 ± 0.04, 26g = 0.35 ± 0.07, 0g = −0.01 ± 0.07). Fructosamine, high sensitivity C-reactive protein, adiponectin, and high-sensitivity interleukin-6 had no significant differences. Flaxseed intake decreased glucose and insulin and improved insulin sensitivity as part of a habitual diet in overweight or obese individuals with pre-diabetes.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract The extent to which the age-related decline in regional brain glucose uptake also applies to other important brain fuels is presently unknown. Ketones are the brain's major alternative fuel ...to glucose, so we developed a dual tracer positron emission tomography protocol to quantify and compare regional cerebral metabolic rates for glucose and the ketone, acetoacetate. Twenty healthy young adults (mean age, 26 years) and 24 healthy older adults (mean age, 74 years) were studied. In comparison with younger adults, older adults had 8 ± 6% (mean ± SD) lower cerebral metabolic rates for glucose in gray matter as a whole ( p = 0.035), specifically in several frontal, temporal, and subcortical regions, as well as in the cingulate and insula ( p ≤ 0.01, false discovery rate correction). The effect of age on cerebral metabolic rates for acetoacetate in gray matter did not reach significance ( p = 0.11). Rate constants (min−1 ) of glucose (Kg) and acetoacetate (Ka) were significantly lower (−11 ± 6%; p = 0.005, and −19 ± 5%; p = 0.006, respectively) in older adults compared with younger adults. There were differential effects of age on Kg and Ka as seen by significant interaction effects in the caudate ( p = 0.030) and post-central gyrus ( p = 0.023). The acetoacetate index, which expresses the scaled residuals of the voxel-wise linear regression of glucose on ketone uptake, identifies regions taking up higher or lower amounts of acetoacetate relative to glucose. The acetoacetate index was higher in the caudate of young adults when compared with older adults ( p ≤ 0.05 false discovery rate correction). This study provides new information about glucose and ketone metabolism in the human brain and a comparison of the extent to which their regional use changes during normal aging.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•Biomarkers of human immunosenescence are discussed.•Longitudinal studies are essential.•Associations of immune markers in older adults with clinical outcome are context-dependent.•There are no ...universal biomarkers of human immunosenescence.•There are common age-associated changes to peripheral immune markers in humans.
There is a great deal of debate on the question of whether or not we know what ageing is (Ref. Cohen et al., 2020). Here, we consider what we believe to be the especially confused and confusing case of the ageing of the human immune system, commonly referred to as “immunosenescence”. But what exactly is meant by this term? It has been used loosely in the literature, resulting in a certain degree of confusion as to its definition and implications. Here, we argue that only those differences in immune parameters between younger and older adults that are associated in some definitive manner with detrimental health outcomes and/or impaired survival prospects should be classed as indicators of immunosenescence in the strictest sense of the word, and that in humans we know remarkably little about their identity. Such biomarkers of immunosenescence may nonetheless indicate beneficial effects in other contexts, consistent with the notion of antagonistic pleiotropy. Identifying what could be true immunosenescence in this respect requires examining: (1) what appears to correlate with age, though generality across human populations is not yet confirmed; (2) what clearly is part of a suite of canonical changes in the immune system that happen with age; (3) which subset of those changes accelerates rather than slows aging; and (4) all changes, potentially population-specific, that accelerate agig. This remains an immense challenge. These questions acquire an added urgency in the current SARS-CoV-2 pandemic, given the clearly greater susceptibility of older adults to COVID-19.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The long-chain ω-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are potential candidates for interventions to delay Alzheimer disease (AD), but evidence from clinical ...studies is mixed. We aimed at determining whether plasma levels of EPA or DHA predict atrophy of medial temporal lobe (MTL) gray matter regions in older subjects.
A total of 281 community dwellers from the Three-City Study, aged 65 years or older, had plasma fatty acid measurements at baseline and underwent MRI examinations at baseline and at 4 years. We studied the association between plasma EPA and DHA and MTL gray matter volume change at 4 years.
Higher plasma EPA, but not DHA, was associated with lower gray matter atrophy of the right hippocampal/parahippocampal area and of the right amygdala (p < 0.05, familywise error corrected). Based on a mean right amygdala volume loss of 6.0 mm(3)/y (0.6%), a 1 SD higher plasma EPA (+0.64% of total plasma fatty acids) at baseline was related to a 1.3 mm(3) smaller gray matter loss per year in the right amygdala. Higher atrophy of the right amygdala was associated with greater 4-year decline in semantic memory performances and more depressive symptoms.
The amygdala, which develops neuropathology in the early stage of AD and is involved in the pathogenesis of depression, may be an important brain structure involved in the association between EPA and cognitive decline and depressive symptoms.
PDF
