Association between ACTN3 (R577X), ACE (I/D), BDKRB2 (-9/+9), and AGT (M268T) polymorphisms and performance phenotypes in Brazilian swimmers.

BACKGROUND: The influence of genetic polymorphisms on athletic performance has been widely explored. This study investigated the interactions between the polymorphisms ACTN3 (R577X), ACE (I/D), BDKRB2 (-9/+9), and AGT (M/T) and their association with endurance and strength phenotypes in Brazilian swimmers. METHODS: 123 athletes (aged 20-30 years) and 718 controls participated in the study. The athletes were divided into elite and sub-elite (N = 19 and 104, respectively) and strength and endurance experts (N = 98 and 25, respectively). Hardy-Weinberg equilibrium was observed in all groups. RESULTS: Considering the ACE polymorphism, it was observed a higher frequency of the DD genotype than expected in the strength experts of the elite group, whereas the strength experts sub-elite athletes had a higher frequency of the ID genotype (χ2 = 8.17; p = 0.01). Subjects with XX genotypes of ACTN3 are more likely to belong to the athlete group when compared to the control group (OR = 1.79, p = 0.04). The DD homozygotes of the ACE are more likely to belong to the elite group with strength phenotypes than the group of sub-elite (OR = 7.96, p = 0.01) and elite strength experts compared to elite endurance (OR = 18.0, p = 0.03). However, no significant differences were observed in the allelic distribution of the polymorphisms evaluated when comparing Elite, sub-elite athletes and controls. CONCLUSION: ACE and ACTN3 allele frequencies should be considered with regard to performance influencing factors in Brazilian swimmers.

Differential associations of clinical features with cerebrospinal fluid biomarkers in dementia with Lewy bodies and Alzheimer's disease.

AIM: To explore associations of cerebrospinal fluid biomarkers of neurodegeneration and amyloidosis with caregiver burden, cognition and functionality in dementia with Lewy bodies (DLB) paired with late-onset Alzheimer's disease (AD) and healthy older people. METHODS: Consecutive outpatients with DLB were matched with outpatients with AD according to sex, cognitive scores and dementia stage, and with cognitively healthy controls according to age and sex to investigate associations of cerebrospinal fluid amyloid-ß (Aß42,Aß40,Aß38), tau, phospho-tau Thr181, ubiquitin, α-synuclein and neurofilament light with caregiver burden, functionality, reverse digit span, a clock drawing test, Mini-Mental State Examination (MMSE) and Severe MMSE, adjusted for sex, age, education, dementia duration and APOE-ε4 alleles. RESULTS: Overall, 27 patients with DLB (78.98 ± 9.0 years-old; eleven APOE-ε4 +) were paired with 27 patients with AD (81.50 ± 5.8 years-old; twelve APOE-ε4 +) and 27 controls (78.98 ± 8.7 years-old; four APOE-ε4 +); two-thirds were women. In AD, Aß42/Aß38 and Aß42 were lower, while tau/Aß42 and phospho-tau Thr181/Aß42 were higher; α-synuclein/Aß42 was lower in DLB and higher in AD. The following corrected associations remained significant: in DLB, instrumental functionality was inversely associated with tau/phospho-tau Thr181 and tau/Aß42, and reverse digit span associated with α-synuclein; in AD, instrumental functionality was inversely associated with neurofilament light, clock drawing test scores inversely associated with phospho-tau Thr181/Aß42 and α-synuclein/Aß42, and Severe MMSE inversely associated with tau/Aß42 and tau/phospho-tau Thr181. CONCLUSIONS: Cerebrospinal fluid phospho-tau Thr181 in DLB was similar to AD, but not Aß42. In associations with test scores, biomarker ratios were superior to isolated biomarkers, while worse functionality was associated with axonal degeneration only in AD.

Effect of the ACTN-3 gene polymorphism on functional fitness and executive function of elderly.

During aging, physical integrity and cognitive abilities, especially executive function, become compromised, directly influencing the quality of life of the elderly. One good strategy to ensure healthy aging is the practice of physical exercise. Activities to improve aerobic capacity and muscle strength are extremely important in old age. However, some genetic factors can interfere both positively and negatively with these gains. In this context, the polymorphism rs1815739 (R577X) of the α-actinin 3 gene (ACTN-3) is commonly studied and related to muscle phenotype. Thus, the present study aimed to investigate the effect of the ACTN-3 gene polymorphism on the functional fitness (measured by the Senior Fit test) and cognitive capacity (evaluated by the Stroop test) of the elderly (n = 347), both men and women. We did not find the effect of genotype on functional fitness, but we did observed a positive effect of the ACTN-3 gene polymorphism on executive function. The presence of the X allele of the ACTN3 gene in the elderly was related to a better performance in the Stroop test (shorter answer time). Our results showed that ACTN-3 gene polymorphism affects the executive function of the elderly but not their functional fitness.

The Effect of Association between Fat Mass and Obesity-associated Gene Polymorphism (rs9939609) on the Body Composition of Older People: A Systematic Review.

BACKGROUND: The aging population is growing faster than any other age group worldwide. Associated with aging, the prevalence of overweight and obesity is a potential risk factor for the development and aggravation of numerous pathologies. A genetic factor often associated with obesity is the fat mass and obesity-associated (FTO) (rs9939609) gene polymorphism, which has been extensively investigated in children, young, and adults. However, few studies have been carried out on the older population. This review aimed to verify the influence of the FTO (rs9939609) gene polymorphism on the body composition of the older population. METHODS: We conducted a systematic review and meta-analysis on PubMed, Scielo, and LILACS databases. Statistical analysis for meta-analysis was performed using mean values of Body Mass Index (BMI) and standard deviations. RESULTS: The results did not show significant differences between FTO genotypes and BMI values (-0.32, 95% CI -0.45 to -0.19, I2 = 0%, p = 0.52). However, 59% of the studies identified some influence on body composition, obesity, or comorbidities. CONCLUSION: Few publications verify FTO polymorphism effects on specific groups of the older population, suggesting a reduction in the influence of this gene on the BMI with advancing age. However, we believe that more controlled studies in older populations should be performed.

APOE ε4 Carrier Status as Mediator of Effects of Psychotropic Drugs on Clinical Changes in Patients With Alzheimer's Disease.

OBJECTIVE: Neuropsychiatric syndromes have been associated with memory dysfunction and risk of and earlier onset of dementia, but how psychotropic drugs affect clinical changes in Alzheimer's disease is not entirely clear. This study aimed to assess the prospective effects of psychotropic drugs on cognitive and functional changes in Alzheimer's disease according to APOE ε4 carrier status. METHODS: The study included consecutive outpatients with late-onset Alzheimer's disease (N=193) and examined score variations at 1 year on the following tests: Clinical Dementia Rating sum of boxes, Mini-Mental State Examination, Severe Mini-Mental State Examination (SMMSE), Brazilian version of the Zarit Caregiver Burden Interview, Index of Independence in Activities of Daily Living, and Lawton's Instrumental Activities of Daily Living Scale. Analyses of score variations accounted for the use of psychotropic drugs or the number of different medications in use, as well as APOE ε4 carrier status, with significance at p<0.05. RESULTS: For APOE ε4 noncarriers (N=90), cholinesterase inhibitors were beneficial regarding caregiver burden (p=0.030) and basic functionality (p=0.046), memantine was harmful regarding SMMSE score changes (p=0.032), second-generation antipsychotics had nonsignificant harmful effects on SMMSE score changes (p=0.070), and antiepileptic therapy (p=0.001) and the number of different medications in use (p=0.006) were harmful in terms of basic functionality. APOE ε4 carriers (N=103) did not experience any effects of isolated psychotropic drugs on clinical changes, including antidepressants. CONCLUSIONS: Results support the harmful prospective effects of second-generation antipsychotics and antiepileptic drugs on cognitive and functional changes in Alzheimer's disease, particularly for APOE ε4 noncarriers, whereas antidepressants may be safer options for behavioral enhancement.

Associations of Neuropsychiatric Features with Cerebrospinal Fluid Biomarkers of Amyloidogenesis and Neurodegeneration in Dementia with Lewy Bodies Compared with Alzheimer's Disease and Cognitively Healthy People.

BACKGROUND: Behavioral features may reflect proteinopathies predicting pathophysiology in neurodegenerative diseases. OBJECTIVE: We aimed to investigate associations of cerebrospinal fluid biomarkers of amyloidogenesis and neurodegeneration with neuropsychiatric features in dementia with Lewy bodies (DLB) compared with late-onset Alzheimer's disease (AD) and cognitively healthy people. METHODS: Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive scores, and with cognitively healthy controls according to sex and age to investigate associations of cerebrospinal fluid amyloid-ß (Aß)42, Aß40, Aß38, total tau, phospho-tau Thr181, α-synuclein, ubiquitin, and neurofilament light with neuropsychiatric features according to APOEɛ4 carrier status. RESULTS: Overall, 27 patients with DLB (78.48±9.0 years old, eleven APOEɛ4 carriers) were paired with 27 patients with AD (81.00±5.8 years old, twelve APOEɛ4 carriers) and 27 controls (78.48±8.7 years old, four APOEɛ4 carriers); two thirds were women. Behavioral burden was more intense in DLB. Biomarker ratios reflecting amyloidogenesis and neurodegeneration in DLB were more similar to those in AD when patients carried APOEɛ4 alleles. After corrections for false discovery rates, the following associations remained significant: in DLB, dysphoria was associated with tauopathy and indirect measures of amyloidogenesis, while in AD, agitation, and night-time behavior disturbances were associated with tauopathy, and delusions were associated with tauopathy and indirect measures of amyloidogenesis. CONCLUSION: Biomarker ratios were superior to Aß and tau biomarkers predicting neuropsychiatric symptoms when associations with isolated biomarkers were not significant. At the end, APOEɛ4 carrier status influenced amyloidogenesis and tau pathology in DLB and in AD, and axonal degeneration only in DLB.

Behavioural effects of the ACE insertion/deletion polymorphism in Alzheimer's disease depend upon stratification according to APOE-ϵ4 carrier status.

Introduction: The inherited risk of late-onset Alzheimer's disease (AD) is genetically determined. We aimed to examine associations of genetic variants of APOE and ACE with age at AD onset and with neuropsychiatric symptoms according to each dementia stage.Methods: Consecutive outpatients with AD were assessed for demographic features, Clinical Dementia Rating scores, and the 10-item Neuropsychiatric Inventory, and genotyped for rs7412 and rs429358 (APOE haplotypes, Real-Time Polymerase Chain Reactions), and the ACE insertion/deletion polymorphism (Polymerase Chain Reactions). Combined genetic variants of APOE and ACE were associated with age at dementia onset, and with neuropsychiatric symptoms in each dementia stage (adjusted for sex and age at dementia onset).Results: Over two-thirds of the 238 patients were women, whereas the mean age at dementia onset was 73.82 ± 6.2 years-old. APOE-ϵ4/ϵ4 carriers had earlier dementia onset (p<.001). The ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p=.37) but was not associated with age at dementia onset, regardless of APOE-ϵ4 carrier status. The only results that survived corrections for false discovery rates were higher scores of dysphoria for APOE-ϵ4 carriers (n=122) who also carried ACE deletion/deletion (p=.031). No results survived corrections for false discovery rates for APOE-ϵ4 non-carriers (n=116).Conclusions: Though only the APOE-ϵ4/ϵ4 haplotype affected AD onset, effects of the ACE insertion/deletion polymorphism over behavioural features might differ according to APOE-ϵ4 carrier status in genetic associations.

Polymorphism of the bradykinin type 2 receptor gene modulates blood pressure profile and microvascular function in prepubescent children.

Previous reports reveal that +9/-9 polymorphism of the bradykinin B2 receptor (BDKRB2) is suggestive of cardiometabolic diseases. The aim of this study was to examine the impact of BDKRB2 + 9/-9 polymorphism genotypes on the blood pressure parameters and microvascular function in prepubescent children. We screened for BDKRB2 + 9/-9 polymorphism in the DNA of 145 children (86 boys and 59 girls), and its association with body composition, blood pressure levels, biochemical parameters, and endothelial function was determined. No significant association of the BDKRB2 genotypes with gender (P=0.377), race (P=0.949) or family history of cardiovascular disease (CVD) (P=0.858) was observed. Moreover, we did not identify any interaction between BDKRB2 genotypes with a phenotype of obesity (P=0.144). Children carrying the +9/+9 genotype exhibited a significant linear trend with higher levels of systolic blood pressure and pulse pressure (P<0.001). Moreover, the presence of +9 allele resulted in a decrease of reactive hyperemia index, showing a decreasing linear trend from -9/-9 to +9/+9, wherein this parameter of endothelial function was the lowest in the +9/+9 children, intermediate in the +9/-9 children, and the highest in the -9/-9 children (P<0.001). There was a significant inverse correlation between reactive hyperemia index and systolic blood pressure (r= - 0.348, P< 0.001) and pulse pressure (r= - 0.399, P< 0.001). Our findings indicate that the +9/+9 BDKRB2 genotype was associated with high blood pressure and microvascular dysfunction in prepubescent Brazilian children.

Pharmacogenetic analyses of variations of measures of cardiovascular risk in Alzheimer's dementia.

Background & objectives: Neurodegeneration affects blood pressure variations, while renal function and cerebral perfusion are impaired by vascular risk factors. This study was aimed to estimate variations of measures of cardiovascular risk in Alzheimer's dementia by pharmacogenetic analyses of the effects of angiotensin-converting enzyme (ACE) inhibitors and statins. Methods: Consecutive patients were prospectively followed to study variations of creatinine clearance and blood pressure for one year, estimated by correlating the effects of ACE inhibitors with the ACE Alu I/D polymorphism and genotypes or haplotypes of rs1800764 or rs4291, and the effects of statins with LDLR (low-density lipoprotein receptor) genotypes or haplotypes of rs11669576 (exon 8) or rs5930 (exon 10), or genotypes of rs2695121 (liver X receptor ß gene). Variations of the coronary heart disease (CHD) risk according to these cardiovascular measures were also explored. Results: All polymorphisms of the 193 patients were in Hardy-Weinberg equilibrium. Genetic determinants of cardiovascular effects affected the individual variability of the response to ACE inhibitors and statins. ACE inhibitors, but not statins, reduced blood pressure for all patients. ACE inhibitors protected carriers of alleles that supposedly decrease serum ACE levels (rs1800764-T, rs4291-A, Alu II) regarding creatinine clearance variations (P <0.005), but carriers of Alu DD (P <0.02), rs1800764-C (P <0.05), or rs4291-AT (P <0.04) showed better blood pressure lowering effects. The presence of rs2695121-T (P=0.007) or rs5930-A (P=0.039) was associated with systolic blood pressure lowering, whereas rs5930-AA was protective against decrease in creatinine clearance (P=0.019). Statins lowered creatinine clearance for carriers of rs2695121-CT (P=0.026). Interpretation & conclusions: Pharmacological response of blood pressure and creatinine clearance to ACE inhibitors and statins may be genetically mediated.

Lifetime Risk Factors for Functional and Cognitive Outcomes in Patients with Alzheimer's Disease.

Lifetime risk factors for cognitive and functional decline in Alzheimer's disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration.

High serum levels of proinflammatory markers during epileptogenesis. Can omega-3 fatty acid administration reduce this process?

During the epileptogenic process, several events may occur, such as an important activation of the immune system in the central nervous system. The response to seizure activity results in an inflammation in the brain as well as in the periphery. Moreover, CRP and cytokines may be able to interact with numerous ligands in response to cardiac injury caused by sympathetic stimulation in ictal and postictal states. Based on this, we measured the serum levels of C-reactive protein (CRP) and cytokines during acute, silent, and chronic phases of rats submitted to the pilocarpine model of epilepsy. We have also analyzed the effect of a chronic treatment of these rats with omega-3 fatty acid in CRP and cytokine levels, during an epileptic focus generation. C-reactive protein and cytokines such as IL-1ß, IL-6, and TNF-α presented high concentration in the blood of rats, even well after the occurrence of SE. We found reduced levels of CRP and all proinflammatory cytokines in the blood of animals with chronic seizures, treated with omega-3, when compared with those treated with vehicle solution. Taken together, our results strongly suggest that the omega-3 is an effective treatment to prevent SUDEP occurrence due to its capability to act as an anti-inflammatory compound, reducing the systemic inflammatory parameters altered by seizures.

Novel GAA mutations in patients with Pompe disease.

Pompe disease is an autosomal recessive disorder linked to GAA gene that leads to a multi-system intralysosomal accumulation of glycogen. Mutation identification in the GAA gene can be very important for early diagnosis, correlation between genotype-phenotype and therapeutic intervention. For this purpose, peripheral blood from 57 individuals susceptible to Pompe disease was collected and all exons of GAA gene were amplified; the sequences and the mutations were analyzed in silico to predict possible impact on the structure and function of the human protein. In this study, 46 individuals presented 33 alterations in the GAA gene sequence, among which five (c.547-67C>G, c.547-39T>G, p.R437H, p.L641V and p.L705P) have not been previously described in the literature. The alterations in the coding region included 15 missense mutations, three nonsense mutations and one deletion. One insertion and other 13 single base changes were found in the non-coding region. The mutation p.G611D was found in homozygosis in a one-year-old child, who presented low levels of GAA activity, hypotonia and hypertrophic cardiomyopathy. Two patients presented the new mutation p.L705P in association with c.-32-13T>G. They had low levels of GAA activity and developed late onset Pompe disease. In our study, we observed alterations in the GAA gene originating from Asians, African-Americans and Caucasians, highlighting the high heterogeneity of the Brazilian population. Considering that Pompe disease studies are not very common in Brazil, this study will help to better understand the potential pathogenic role of each change in the GAA gene. Furthermore, a precise and early molecular analysis improves genetic counseling besides allowing for a more efficient treatment in potential candidates.