X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease.

BACKGROUND: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear. OBJECTIVE: The objective of this study was to perform the first X-chromosome-wide association study for PD risk in a Latin American cohort. METHODS: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations. RESULTS: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478-0.77], P = 3.13 × 10-5 replication odds ratio: 0.60 [0.37-0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome-wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations. CONCLUSIONS: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Polymorphisms in cytokine genes influence cognitive and functional performance in a population aged 75 years and above.

OBJECTIVE: To investigate the frequency of the cytokine single nucleotide polymorphisms (SNPs) tumor necrosis factor (TNF)-α -308G > A, tumor growth factor (TGF)-ß1 codon +10C > T, TGF-ß1 codon +25G > C, interleukin (IL)-10 -1082A > G, IL-10 -819C > T, IL-10 -592C > A, IL-6 -174G > C, and IFN-γ +874T > A in a sample of healthy and cognitively impaired elderlies and to verify the probable association between these SNPs and cognitive and functional performance of subjects aged 75 years and above. METHODS: 259 Brazilian subjects were included, comprising 81 with cognitive impairment no dementia (CIND) and 54 demented seniors (together made up the cognitively impaired group, CI) and 124 age-matched and gender-matched cognitively healthy controls (CHS). The genotyping was performed by multiplex polymerase chain reaction. The cognitive performance was evaluated by Mini-Mental State Examination Brief Cognitive Screening Battery. The functional performance was accessed by Functional Activities Questionnaire. RESULTS: The CClower genotype of TGF-ß1 codon +25G > C was frequent in both patient groups. The TThigher genotype of INF-γ +874T > A was less frequent in the dementia group. IL-10 haplotypes of lower expression were more frequent among CIND and demented patients. In CI, individuals with genetic variants that produce higher expression of TGF-ß1, INF-γ, and IL-10 showed better normalized cognitive performance. Additionally, the Alower allele of INF-γ +874T > A was related to worse functional performance in CI, while the Alower allele of TNF-α -308G > A was associated with better cognitive and functional scores in the CIND group. CONCLUSIONS: Our findings suggest a potential role for certain cytokine SNPs in the development of CIND and dementia, which may influence the functional and cognitive performance of these patients. Copyright © 2016 John Wiley & Sons, Ltd.

Cortisol, HDL-c, VLDL-c, and APOE Polymorphisms as Laboratorial Parameters Associated to Cognitive Impairment No Dementia (CIND) and Dementia.

BACKGROUND: Population aging is a global phenomenon whose main consequence is the increase of chronic degenerative diseases, including dementia. The aim of this case-control study was to evaluate the laboratorial parameters lipid profile, cortisol, and apolipoprotein E (APOE) gene genotype, comparing cognitively healthy controls and subjects with cognitive impairment no dementia (CIND) and dementia in a group of elderly people. METHODS: Three hundred and nine individuals enrolled in the Pietà Study (Brazil) were divided into three groups: control (n = 158), CIND (n = 92), and dementia (n = 59). Participants were interviewed, went through examination, and had blood samples taken. RESULTS: Age and APOE showed significant differences among the groups, while sex and lipid profile did not. According to multivariate regression logistic analyses, higher cortisol levels, lower high-density lipoprotein (HDL-c) and very low-density lipoprotein (VLDL-c), presence of ε4 allele of APOE, and aging were associated with CIND and dementia. CONCLUSION: These laboratorial parameters are risk factors associated to CIND and dementia in the elderly people and should be investigated in order to develop strategies to prevent or delay the onset of dementia in the oldest-old populations.

Genetic predisposition to higher production of interleukin-6 through -174 G > C polymorphism predicts global cognitive decline in oldest-old with cognitive impairment no dementia / Predisposição genética à maior produção de interleucina-6 por meio do polimorfismo -174 G > C prediz declínio cognitivo global em idosos muito idosos com comprometimento cognitivo não demência

Interleukin 6 (IL-6) is a pro-inflammatory cytokine upregulated in neurodegenerative contexts. The polymorphism IL-6 -174 G > C influences release levels of this cytokine. We aimed to evaluate the influence of IL-6 -174 G > C on global cognitive score of a group with cognitive impairment no dementia in one year of follow-up.Methods The subjects were categorized in two groups: short-term decline in global cognitive score and those with short-term stability or improvement. IL-6 174 G > C information were compared among these groups.Results We observed that individuals with cognitive impairment no dementia with GGlowergenotype were more frequent among global cognitive score non-decliners while carriers of at least one Chigherallele were more frequent in the group with global cognitive score decliners (p = 0.012; RR = 3.095 IC95%= 1.087-8.812).Conclusion These results suggest that the higher expression of IL-6 gene may be an independent risk factor for cognitive decline among individuals with cognitive impairment no dementia.

Interleucina 6 (IL-6) é uma citocina pró-inflamatória cuja produção acentua-se em contextos neurodegenerativos. O polimorfismo IL-6 -174 G > C influencia os níveis secretados deste mediador inflamatório. Nós objetivamos avaliar a influência de IL-6 -174 G > C sobre o escore cognitivo global de um grupo com comprometimento cognitivo não demência em um ano de seguimento.Métodos Os participantes foram categorizados em dois grupos: com declínio em escore cognitivo global em curto prazo e aqueles com melhora ou estabilidade do escore cognitivo global.Resultados Nós observamos que indivíduos com comprometimento cognitivo não demência carreadores do genótipo GGbaixa foram mais frequentes entre pacientes com escore cognitivo global não declinante, enquanto carreadores de no mínimo um alelo Caltaforam mais frequentes no grupo que apresentou declínio no escore cognitivo global (p = 0,012; RR = 3,095 IC95%= 1,087-8,812).Conclusão Estes resultados sugerem que a alta expressão do gene IL-6 pode ser um fator de risco independente para declínio cognitivo entre pacientes com comprometimento cognitivo não demência.

Genetic predisposition to higher production of interleukin-6 through -174 G > C polymorphism predicts global cognitive decline in oldest-old with cognitive impairment no dementia.

Interleukin 6 (IL-6) is a pro-inflammatory cytokine upregulated in neurodegenerative contexts. The polymorphism IL-6 -174 G > C influences release levels of this cytokine. We aimed to evaluate the influence of IL-6 -174 G > C on global cognitive score of a group with cognitive impairment no dementia in one year of follow-up.Methods The subjects were categorized in two groups: short-term decline in global cognitive score and those with short-term stability or improvement. IL-6 174 G > C information were compared among these groups.Results We observed that individuals with cognitive impairment no dementia with GGlowergenotype were more frequent among global cognitive score non-decliners while carriers of at least one Chigherallele were more frequent in the group with global cognitive score decliners (p = 0.012; RR = 3.095 IC95%= 1.087-8.812).Conclusion These results suggest that the higher expression of IL-6 gene may be an independent risk factor for cognitive decline among individuals with cognitive impairment no dementia.

TGF-ß1 Codon 10 T>C Polymorphism Influences Short-Term Functional and Cognitive Decline in Healthy Oldest-Old Individuals: The Pietà Study.

BACKGROUND: Inflammation and cytokine production are a common finding in aging, which probably exert influence on cognitive and functional abilities in elderly people. Transforming-growth-factor beta 1 (TGF-ß1) is an important multifunctional anti-inflammatory cytokine that displays immunomodulatory activities. OBJECTIVE: This prospective investigation aimed to evaluate the TGF-ß1 codon 10 T>C on functional and cognitive decline in subjects aged 75+ years. METHODS: The Functional Activities Questionnaire evaluated the functional performance and the cognitive assessment was evaluated through brief cognitive tests, consisting of: the Mini-Mental State Examination, animal category fluency test, and picture drawings memory test. All tests were administered twice, with a one-year interval. RESULTS: Carriers of Tlower allele showed significant short-term decline in cognitive and functional performance, while individuals with CChigher genotype of TGF-ß1 codon 10 T>C remained stable or showed improvement. CONCLUSION: Our findings indicate that the lower production of TGF-ß1 could predict a longitudinal functional and cognitive decline in oldest-old individuals.

High cortisol levels are associated with cognitive impairment no-dementia (CIND) and dementia.

BACKGROUND: This study aimed to compare serum cortisol concentrations in cognitively healthy elderly and in subjects with cognitive impairment no dementia (CIND) and dementia, besides to evaluate these concentrations according to apolipoprotein E genotype (APOE). METHODS: Three-hundred and nine elderly enrolled in the Pietà Study (Brazil) were divided in 3 groups: control (n=158), CIND (n=92) and dementia (n=59) and had concentrations of morning serum cortisol measured. Hormone concentrations were measured by chemiluminescence and APOE genotypes were determined by PCR followed by restriction fragment length polymorphism (RFLP). RESULTS: Medians of cortisol concentrations (µg/dl) for the groups were 12.14 (interquartile range - IQR 6.34) for control, 13.65 (IQR 5.88) for CIND and 14.47 (IQR 7.35) for dementia. Significant differences were observed for control vs. CIND (P=0.003), control vs. dementia (P=0.001), but not for CIND vs. dementia (P=0.269). No association was observed between cortisol concentrations and APOE genotype among the groups (P=0.348). CONCLUSIONS: The elevation in cortisol concentrations is associated with dementia, independently of APOE genotypes. Further studies are required to understand if elevation of cortisol is an initial event and how hippocampal damage and the loss of hypothalamus-pituitary-adrenal (HPA) axis inhibition may affect its concentrations.