Exploring the link between GBA1 mutations and Dementia with Lewy bodies, A mini-review.

IMPORTANCE: Dementia with Lewy bodies (DLB) is a neurodegenerative disease linked to abnormal accumulation of phosphorylated α-synuclein. GBA1 is the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), whose mutations are a risk factor of DLB. OBJECTIVE: To report all available data exploring the association between GBA1 mutations and DLB. EVIDENCE REVIEW: All publications focused on GCase and DLB in humans between 2003 and 2022 were identified on PubMed, Cochrane and ClinicalTrials.gov. FINDINGS: 29 studies were included and confirmed the strong association between GBA1 mutations and DLB (Odds Ratio [OR]: 8.28). GBA1 mutation carriers presented a more malignant phenotype, with earlier symptom onset, more severe motor and cognitive dysfunctions, more visual hallucinations and rapid eye movement sleep disorder. GBA1 mutations were associated with "purer" neuropathological DLB. No therapeutic recommendations exist and clinical trials targeting GCase are just starting in DLB patients. CONCLUSIONS AND RELEVANCE: This review reports a link between GBA1 mutations and the DLB phenotype with limited evidence due to the small number of studies.

Cerebrospinal fluid Alzheimer biomarkers can be useful for discriminating dementia with Lewy bodies from Alzheimer's disease at the prodromal stage.

BACKGROUND: Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is not straightforward, especially in the early stages of disease. We compared AD biomarkers (phospho-Tau181, total-Tau, Aß42 and Aß40) in cerebrospinal fluid (CSF) of patients with DLB and AD, focusing especially on the prodromal stage. METHODS: A total of 1221 CSF were collected in different memory centres (ePLM network) in France and analysed retrospectively. Samples were obtained from patients with prodromal DLB (pro-DLB; n=57), DLB dementia (DLB-d; n=154), prodromal AD (pro-AD; n=132) and AD dementia (n=783), and control subjects (CS; n=95). These centres use the same diagnostic procedure and criteria to evaluate the patients. RESULTS: In patients with pro-DLB, CSF Aß42 levels appeared much less disrupted than in patients at the demented stage (DLB-d) (P<0.05 CS>pro-DLB; P<0.001 CS>DLB-d). On average, Aß40 levels in patients with DLB (pro-DLB and DLB-d) were much below those in patients with pro-AD (P<0.001 DLB groups

Cardiovascular Changes After Gastric Bypass Surgery: Involvement of Increased Secretions of Glucagon-Like Peptide-1 and Brain Natriuretic Peptide.

BACKGROUND: Obesity induces cardiovascular alterations, including cardiac hypertrophy, impaired relaxation, and heart rate variability (HRV), which are associated with increased mortality. Gastric bypass surgery (GBP) reduces cardiovascular mortality, but the mechanisms involved are not clearly established. To date, the implication of postsurgical hormonal changes has not been tested. Our aim was to study the relationships between the evolution of cardiovascular functions after GBP and changes in metabolic and hormonal parameters, including glucagon-like peptide-1 (GLP-1) and brain natriuretic peptide (N-terminal pro-brain natriuretic peptide (NT-proBNP)). METHODS: Echocardiographic parameters, 24-h rhythmic Holter recording, plasma concentrations of GLP-1 before and after a test meal, and fasting NT-proBNP were assessed in 34 patients (M/F 2/32, age 36 ± 11 years, BMI 46 ± 6 kg/m(2)), before and 1 year after GBP. RESULTS: After GBP, excess weight loss was 79 ± 20%. Blood pressure (BP), heart rate, and left ventricular mass decreased, while HRV and diastolic function (E/A ratio) improved. Plasma concentrations of NT-proBNP and postprandial (PP) GLP-1 increased. Changes in cardiovascular parameters were related to BMI and insulin sensitivity. Furthermore, the decrease in BP was independently associated with the increase of PP GLP-1 level and HRV was positively associated with NT-proBNP concentration after surgery. CONCLUSIONS: The increase in endogenous GLP-1 observed after GBP was associated with decreased BP but not with improvement of other cardiovascular parameters, whereas the increase in NT-proBNP, within the physiological range, was associated with improved HRV.

Neuronal phenotype dependency of agonist-induced internalization of the 5-HT(1A) serotonin receptor.

Selective serotonin reuptake inhibitors (SSRI) are aimed at increasing brain 5-HT tone; however, this expected effect has a slow onset after starting SSRI treatment because of initial activation of 5-HT(1A) autoreceptor-mediated negative feedback of 5-HT release. After chronic SSRI treatment, 5-HT(1A) autoreceptors desensitize, which allows 5-HT tone elevation. Because 5-HT(1A) receptor (5-HT(1A)R) internalization has been proposed as a possible mechanism underlying 5-HT(1A) autoreceptor desensitization, we examined whether this receptor could internalize under well controlled in vitro conditions in the LLC-CPK1 cell line and in raphe or hippocampal neurons from rat embryos. To this goal, cells were transfected with recombinant lentiviral vectors encoding N-terminal tagged 5-HT(1A)R, and exposed to various pharmacological conditions. Constitutive endocytosis and plasma membrane recycling of tagged-5-HT(1A)R was observed in LLC-PK1 cells as well as in neurons. Acute exposure (for 1 h) to the full 5-HT(1A)R agonists, 5-HT and 5-carboxamido-tryptamine, but not the partial agonist 8-OH-DPAT, triggered internalization of tagged 5-HT(1A)R in serotonergic neurons only. In contrast, sustained exposure (for 24 h) to all agonists induced tagged-5-HT(1A)R endocytosis in raphe serotonergic neurons and a portion of hippocampal neurons, but not LLC-PK1 cells and partial agonist displayed an effect only in serotonergic neurons. In all cases, agonist-induced tagged 5-HT(1A)R endocytosis was prevented by the 5-HT(1A)R antagonist, WAY-100635, which was inactive on its own. These data showed that agonist-induced 5-HT(1A)R internalization does exist in neurons and depends on agonist efficacy and neuronal phenotype. Its differential occurrence in serotonergic neurons supports the idea that 5-HT(1A)R internalization might underlie 5-HT(1A) autoreceptor desensitization under SSRI antidepressant therapy.

Early exposure to ethanol differentially affects ethanol preference at adult age in two inbred mouse strains.

Although the acute effects of ethanol exposure on brain development have been extensively studied, the long term consequences of juvenile ethanol intake on behavior at adult age, regarding especially ethanol consumption, are still poorly known. The aim of this study was to analyze the consequences of ethanol ingestion in juvenile C57BL/6J and DBA/2J mice on ethanol intake and neurobiological regulations at adulthood. Mice were given intragastric ethanol at 4 weeks of age under different protocols and their spontaneous ethanol consumption was assessed in a free choice paradigm at adulthood. Both serotonin 5-HT(1A) and cannabinoid CB1 receptors were investigated using [(35)S]GTP-γ-S binding assay for the juvenile ethanol regimens which modified adult ethanol consumption. In DBA/2J mice, juvenile ethanol ingestion dose-dependently promoted adult spontaneous ethanol consumption. This early ethanol exposure enhanced 5-HT(1A) autoreceptor-mediated [(35)S]GTP-γ-S binding in the dorsal raphe nucleus and reduced CB1 receptor-mediated G protein coupling in both the striatum and the globus pallidus at adult age. In contrast, early ethanol ingestion by C57BL/6J mice transiently lowered spontaneous ethanol consumption and increased G protein coupling of postsynaptic 5-HT(1A) receptors in the hippocampus but had no effect on CB1 receptors at adulthood. These results show that a brief and early exposure to ethanol can induce strain-dependent long-lasting changes in both behavior toward ethanol and key receptors of central 5-HT and CB systems in mice.

Thyroid-stimulating hormone, 5-HTTLPR genotype, and antidepressant response in depressed women.

Basal serum thyroid-stimulating hormone (TSH) levels may predict antidepressant efficacy in patients with major depressive episodes (MDE), but data are inconsistent. As the SS genotype of the 5-HTTLPR polymorphism has been associated with a lower antidepressant efficacy in women with MDE, we aimed at assessing the relationship between normal basal TSH, 5-HTTLPR, and antidepressant efficacy in women. A total of 71 women and 28 men, with normal baseline TSH serum levels, hospitalized for a MDE, were assessed for 5-HTTLPR genotypes and prospectively followed for short-term antidepressant efficacy. Women with SS genotype had higher TSH levels (P=0.002) and a worse antidepressant response (P=0.046) than the women with LL/LS genotype, whereas no significant difference was shown in men. In multivariate analyses, antidepressant response in women was explained by TSH and 5-HTTLPR, but not by other variables. Further research is needed to understand the underlying mechanism explaining interactions between sex, TSH, and serotonergic function.

Does the progesterone receptor genetic polymorphism +331G/A hPR influence the risk of venous thromboembolism among postmenopausal women using hormone therapy? The ESTHER Study.

Hormone therapy (HT) increases venous thromboembolism (VTE) risk among postmenopausal women. Data on the influence of steroids receptors polymorphisms on this association remain scarce. Since progesterone receptor (hPR) is expressed in human veins and specific progestogens increase VTE risk, we investigated the impact of the functional +331G/A hPR polymorphism on the association of VTE with HT. Using the data of the ESTHER study, we showed that ORs for VTE in current users of progesterone or progestins were not significantly different by hPR+331G/A genotype status. hPR polymorphism appears not to have a significant effect on VTE risk related to HT.

5-HTTLPR modulates antidepressant efficacy in depressed women.

BACKGROUND: As compared with the long variant (L), the short variant (S) of the functional polymorphic region of the serotonin transporter gene (5-HTTLPR) has been associated with a lower antidepressant efficacy in major depression, but some replication studies have evidenced contradictory results. Sex differences may explain these contradictory results. METHODS: One hundred and three inpatients (74 women and 29 men) with a major depressive episode were assessed prospectively for antidepressant efficacy after 4 weeks of treatment with selective serotonin reuptake inhibitors (SSRI) and non-SSRI drugs. RESULTS: As compared with LL/LS, the SS genotype of the 5-HTTLPR was associated with a lower antidepressant efficacy in depressed women (79 vs. 50% responders, P = 0.035). This result was shown with both SSRI and non-SSRI antidepressants. The logistic regression performed in women showed that response to treatment was related to genotype (odds ratio=0.15; 95% confidence interval=0.03-0.85; P = 0.03) and not to other variables. No effect of 5-HTTLPR was found in depressed men. CONCLUSION: Despite a low power, this study suggests a significant effect of 5-HTTLPR genotype on antidepressant efficacy in depressed women but not in men, with both SSRI and non-SSRI drugs. Further research is needed to confirm this result and investigate its underlying mechanisms.

Synergism between oral estrogen therapy and cytochrome P450 3A5*1 allele on the risk of venous thromboembolism among postmenopausal women.

CONTEXT: Hormone therapy increases the risk of venous thromboembolism (VTE) among postmenopausal women. This effect may be modulated by the expression of cytochromes P450 3A5 (CYP3A5) and 1A2 (CYP1A2) which are involved in the hepatic metabolism of estrogens. OBJECTIVE: The objective was to investigate the impact of CYP3A5 and CYP1A2 genetic polymorphisms on the association of VTE with hormone therapy. DESIGN: We conducted a case-control study. SETTING: This study was conducted in eight French hospital centers and in the general population. PATIENTS: CYP3A5 and CYP1A2 genotypes were evaluated among 195 cases with a first documented episode of idiopathic VTE and 533 controls matched for center, age, and admission date. OUTCOME MEASURE: The outcome measure was hormone therapy by route of estrogen administration. RESULTS: Overall, oral but not transdermal estrogen increased VTE risk [odds ratio (OR) = 4.5, 95% confidence interval (CI) = 2.6-7.6, and OR = 1.2, 95% CI = 0.8-1.8, respectively]. The allele frequency of CYP3A5*1 was 9 and 10% among cases and controls (OR = 1.0; 95% CI = 0.6-1.5) and that of CYP1A2*1F was 72 and 71% among cases and controls (OR = 1.5; 95% CI = 0.8-2.8). Compared with nonusers, OR for VTE in users of oral estrogen was 3.8 (95% CI = 2.1-6.7) among patients without CYP3A5*1 allele and 30.0 (95% CI = 4.4-202.9) among patients with this allele (test for interaction P = 0.04). By contrast, there was no significant interaction between CYP3A5*1 allele and transdermal estrogen on VTE risk. There is no interaction between CYP1A2 genetic polymorphism and hormone therapy on VTE risk. CONCLUSIONS: Women with CYP3A5*1 allele using oral estrogen can define a subgroup at high VTE risk. Additional data are needed to assess the relevance of this genetic biomarker in the medical management of menopause.