GnRH replacement rescues cognition in Down syndrome Manfredi-Lozano, Maria; Leysen, Valerie; Adamo, Michela ...
Science (American Association for the Advancement of Science),
09/2022, Letnik:
377, Številka:
6610
Journal Article
Recenzirano
Odprti dostop
At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological ...symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction-gonadotropin-releasing hormone (GnRH)-and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.
In vertebrate species, fertility is controlled by gonadotropin-releasing hormone (GnRH) neurons. GnRH cells arise outside the central nervous system, in the developing olfactory pit, and migrate ...along olfactory/vomeronasal/terminal nerve axons into the forebrain during embryonic development. Congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome are rare genetic disorders characterized by infertility, and they are associated with defects in GnRH neuron migration and/or altered GnRH secretion and signaling. Here, we documented the expression of the jagged-1/Notch signaling pathway in GnRH neurons and along the GnRH neuron migratory route both in zebrafish embryos and in human fetuses. Genetic knockdown of the zebrafish ortholog of JAG1 (jag1b) resulted in altered GnRH migration and olfactory axonal projections to the olfactory bulbs. Next-generation sequencing was performed in 467 CHH unrelated probands, leading to the identification of heterozygous rare variants in JAG1. Functional in vitro validation of JAG1 mutants revealed that 7 out of the 9 studied variants exhibited reduced protein levels and altered subcellular localization. Together our data provide compelling evidence that Jag1/Notch signaling plays a prominent role in the development of GnRH neurons, and we propose that JAG1 insufficiency may contribute to the pathogenesis of CHH in humans.
We investigated the effects of glucose and diverse breakfasts on glucose increment and ghrelin suppression and cognitive processing of sensory information assessed by frontal P300 evoked potentials. ...In a randomized crossover design, 12 healthy individuals (6M/6F; BMI 22.2 ± 0.4 kg/m2; 27 ± 1.3 years, mean ± SEM) underwent 50 g OGTT (A) and 3 breakfasts (B1: milk and cereals; B2: milk, apple, and chocolate cream-filled sponge cake; B3: milk, apple, bread, and hazelnut chocolate cream) to assess plasma glucose-, insulin-, and ghrelin excursions. An electroencephalography was performed before and 100 min after consumption of each load to measure the latency of frontal P300 evoked potentials as index of cognitive performance. Breakfasts B1 and B2 exhibited significantly lower glycemic and insulinemic responses as compared to A. Breakfast B3 exhibited significantly lower glycemic, but not insulinemic response, as compared to A. Final plasma ghrelin inhibition was more pronounced, albeit not significantly, in all breakfasts with respect to A. P300 latency tended to decrease following each of the three breakfasts, but B3 was the only breakfast capable to elicit a statistically significant reduction in P300 latency with respect to A (p<0.01), suggesting ameliorated cognitive performance. Such amelioration was correlated with the 2-hour final inhibition of plasma ghrelin concentration (r=0.61, p=0.01).
Aim
To test the hypothesis that deep transcranial magnetic stimulation (dTMS) reduces food craving and causes weight loss via neuromodulation.
Materials and methods
This pilot study was designed as a ...randomized, double‐blind, sham‐controlled study. A total of 33 obese people (nine men, 24 women, mean age 48.1 ± 10.6 years, body mass index BMI 36.9 ± 4.7 kg/m2) were randomized and completed the study: 13 participants underwent a 5‐week treatment with high‐frequency (HF) dTMS (18 Hz; HF group), 10 were treated with low‐frequency (LF) dTMS (1 Hz; LF group), and 10 were sham‐treated (sham group). Food craving, and metabolic and neuro‐endocrine variables were evaluated at baseline, after the 5‐week treatment, and at follow‐up visits (1 month, 6 months, 1 year after the end of treatment).
Results
The mixed‐model analysis for repeated measures showed a significant interaction of time and groups for body weight (P = 0.001) and BMI (P = 0.001), with a significant body weight (−7.83 ± 2.28 kg; P = 0.0009) and BMI (−2.83 ± 0.83, P = 0.0009) decrease in the HF versus the sham group. A decreasing trend in food craving in the HF versus the LF and sham groups (P = 0.073) was observed. A significant improvement of metabolic and physical activity variables was found (P < 0.05) in the HF group.
Conclusions
We demonstrated the safety and efficacy of dTMS, in addition to physical exercise and a hypocaloric diet, in reducing body weight for up to 1 year in obese people. We hypothesize that a possible mechanism of HF dTMS treatment is modulation of the dopaminergic pathway and stimulation of physical activity.
Purpose
In obesity, metabolic and voluntary factors regulate appetite, and a dysregulation of the reward pathway was demonstrated in all addiction disorders. Deep transcranial magnetic stimulation ...(dTMS) is already used to modulate cerebral dopamine activation in neuro-psychiatric diseases. We presently assess the acute effect of high frequency (HF) and low frequency (LF) dTMS on the modulation of the main neuropeptides and neurotransmitters involved in the reward pathway in obese subjects.
Methods
This study was designed as a double-blind, sham-controlled, randomized clinical trial. Thirty-three obese patients (9 males, 24 females, age 48.1 ± 10.6, BMI 36.4 ± 4.7) were enrolled in the study. All patients were studied during a single dTMS session and blood aliquots were drawn before and after a single dTMS session. Metabolic and neuro-endocrine parameters were evaluated before and after: (1) 18 Hz dTMS (HF, 13 patients); (2) 1 Hz dTMS (LF, 10 patients); (3) Sham treatment (Sham, 10 patients).
Results
No statistically significant variations in metabolic parameters, systolic and diastolic blood pressure, and heart rate were shown acutely. HF showed a significant increase of β-endorphin compared to other groups (
p
= 0.048); a significant increase of ghrelin in LF (
p
= 0.041) was also demonstrated.
Conclusions
A single session of HF dTMS treatment determines in obese subjects an acute increase of β-endorphin level, indicating an activation of the reward pathway. The present findings constitute proof of principle for a potential application of this methodology in obesity treatment.
Growing evidence highlights the crucial role of gut microbiota in affecting different aspects of obesity. Potential mechanisms for microbial control over eating behavior include microbiota influence ...on reward and satiety pathways, neurotransmitters release, and hypothalamic-pituitary-adrenal (HPA) axis modulation. A methodology proved to be effective in modulating orexigenic/anorexigenic pathways and food-reward system in obesity is the dTMS. Considering its assets, we hypothesized a potential role of dTMS in inducing weight loss in obesity also via microbiota composition modulation. Twenty-two obese subjects (5 M, 17 F; 44.6±2.5 years; BMI 37.5±1.1 kg/m2) were allocated into 3 groups receiving 15 sessions (3 per week for 5 weeks) of high frequency (18 Hz, HF), low frequency (1 Hz, LF) dTMS, or sham stimulation. Fecal samples were collected at baseline and after 5 weeks of treatment. Total bacterial DNA was extracted from fecal samples using the QIAamp DNA Stool Mini Kit (Qiagen, Italy) and analyzed by a metagenomics approach (Ion Personal Genome Machine). After 5 weeks, a weight loss in HF (-3.4±1.0%; p<0.05) was found, associated with a decrease in norepinephrine (-61.5±15.2%; p<0.01). Furthermore, an increase of Faecalibacterium (+153.3% vs. baseline, p<0.05) and Alistipes (+153.4% vs. baseline, p<0.05) genera, and a significant decrease of Lactobacillus (-77.1% vs. baseline, p<0.05) were found in HF. A significant inverse correlation between Phascolarctobacterium variation and BMI reduction (R:-0.728; p<0.05) was found in HF; norepinephrine change significantly correlated with Eubacterium (R:0.857; p<0.05), Parasutterella (R:0.786; p<0.05), and Streptococcus (R:-0.937; p<0.01) variations.
In conclusion, the weight loss, induced by HF dTMS, improves sympathetic activity and gut microbiota composition in obese subjects, mainly promoting bacterial species with anti-inflammatory properties, that are typical of healthy subjects intestinal flora.
Disclosure
A. Ferrulli: None. M. Toscano: None. M. Adamo: None. I. Terruzzi: None. L. Drago: None. L. Luzi: Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Eli Lilly and Company. Research Support; Self; Gelesis. Consultant; Self; McKinsey & Company. Speaker's Bureau; Self; Menarini Group, Merck Sharp & Dohme Corp.. Research Support; Self; Novartis AG. Speaker's Bureau; Self; Novo Nordisk A/S. Research Support; Self; Sunstar Foundation. Speaker's Bureau; Self; Smith & Nephew.
Cocoa helps maintain endothelium-dependent vasodilation; consumption of hazelnuts has been associated with reduced cardiovascular disease risk. This study assesses the effects of hazelnuts and cocoa ...on vascular reactivity and metabolic profile. Sixty-one healthy volunteers, examined in a randomised, controlled, two-week intervention, received one of six breakfast integrations containing either hazelnuts, cocoa, both or none. Consumption of unpeeled hazelnuts improved HDL-cholesterol (+7.3%, p = .01 vs. baseline, p = .02 vs. control). Brachial artery peak systolic velocities (PSV) at rest increased with hazelnut integrations by 43.4% (p = .04 vs. control) and hazelnut-cocoa integrations by 26.4% (p = .01 vs. control). PSV after 3-min cuff occlusion increased by 60.7% (p = .002 vs. control) with a peeled hazelnut snack and by 64.7% with a hazelnut-cocoa integration (p = .04 vs. control). The combination hazelnut-cocoa may act in a synergic and protective way on cardiovascular system.
Following pancreatic islet transplantation (IT), the major barriers to the long-term insulin independence of type 1 diabetic patients are the progressive deterioration of b-cellfunction and the need ...for immunosuppressive therapy. Within this context, we found favorable effects for physical exercise in several studies. In particular, the authors monitored metabolic, autoimmune, and inflammatory profiles of an islet-tran-planted marathon runner (10-year transplanted) during his training and participation in a variety of ultra-enduranc eevents.
Abstract
Aims
To compare demographic characteristics, clinical presentation, and outcomes of patients with and without concomitant cardiac disease, hospitalized for COVID-19 in Brescia, Lombardy, ...Italy.
Methods and results
The study population includes 99 consecutive patients with COVID-19 pneumonia admitted to our hospital between 4 March and 25 March 2020. Fifty-three patients with a history of cardiac disease were compared with 46 without cardiac disease. Among cardiac patients, 40% had a history of heart failure, 36% had atrial fibrillation, and 30% had coronary artery disease. Mean age was 67 ± 12 years, and 80 (81%) patients were males. No differences were found between cardiac and non-cardiac patients except for higher values of serum creatinine, N-terminal probrain natriuretic peptide, and high sensitivity troponin T in cardiac patients. During hospitalization, 26% patients died, 15% developed thrombo-embolic events, 19% had acute respiratory distress syndrome, and 6% had septic shock. Mortality was higher in patients with cardiac disease compared with the others (36% vs. 15%, log-rank P = 0.019; relative risk 2.35; 95% confidence interval 1.08–5.09). The rate of thrombo-embolic events and septic shock during the hospitalization was also higher in cardiac patients (23% vs. 6% and 11% vs. 0%, respectively).
Conclusions
Hospitalized patients with concomitant cardiac disease and COVID-19 have an extremely poor prognosis compared with subjects without a history of cardiac disease, with higher mortality, thrombo-embolic events, and septic shock rates.
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