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Diabetes is associated with cognitive decline, but the underlying mechanisms are complex and their relationship with Alzheimer's Disease biomarkers is not fully understood. We assessed the association of small vessel disease (SVD) and amyloid burden with cognitive functioning in 47 non-demented older adults with type-2 diabetes from the Israel Diabetes and Cognitive Decline Study (mean age 78Y, 64% females). FLAIR-MRI, Vizamyl amyloid-PET, and T1W-MRI quantified white matter hyperintensities as a measure of SVD, amyloid burden, and gray matter (GM) volume, respectively. Mean hemoglobin A1c levels and duration of type-2 diabetes were used as measures of diabetic control. Cholesterol level and blood pressure were used as measures of cardiovascular risk. A broad neuropsychological battery assessed cognition. Linear regression models revealed that both higher SVD and amyloid burden were associated with lower cognitive functioning. Additional adjustments for type-2 diabetes-related characteristics, GM volume, and cardiovascular risk did not alter the results. The association of amyloid with cognition remained unchanged after further adjustment for SVD, and the association of SVD with cognition remained unchanged after further adjustment for amyloid burden. Our findings suggest that SVD and amyloid pathology may independently contribute to lower cognitive functioning in non-demented older adults with type-2 diabetes, supporting a multimodal approach for diagnosing, preventing, and treating cognitive decline in this population.
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Doença de Alzheimer , Doenças de Pequenos Vasos Cerebrais , Transtornos Cognitivos , Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Doenças Vasculares , Feminino , Humanos , Idoso , Masculino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Cognição , Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Transtornos Cognitivos/patologia , Amiloide/metabolismo , Imageamento por Ressonância Magnética , Doenças Vasculares/patologia , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/patologia , Encéfalo/metabolismoRESUMO
Diabetes is associated with cognitive decline, but the underlying mechanisms are complex and their relationship with Alzheimer's Disease biomarkers is not fully understood. We assessed the association of small vessel disease (SVD) and amyloid burden with cognitive functioning in 47 non-demented older adults with type-2 diabetes from the Israel Diabetes and Cognitive Decline Study (mean age 78Y, 64% females). FLAIR-MRI, Vizamyl amyloid-PET, and T1W-MRI quantified white matter hyperintensities as a measure of SVD, amyloid burden, and gray matter (GM) volume, respectively. Mean hemoglobin A1c levels and duration of type-2 diabetes were used as measures of diabetic control. Cholesterol level and blood pressure were used as measures of cardiovascular risk. A broad neuropsychological battery assessed cognition. Linear regression models revealed that both higher SVD and amyloid burden were associated with lower cognitive functioning. Additional adjustments for type-2 diabetes-related characteristics, GM volume, and cardiovascular risk did not alter the results. The association of amyloid with cognition remained unchanged after further adjustment for SVD. Our findings suggest that SVD and amyloid pathology may independently contribute to lower cognitive functioning in non-demented older adults with type-2 diabetes, supporting a multimodal approach for diagnosing, preventing, and treating cognitive decline in this population.
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Objectives: Multiple risk loci for late-onset Alzheimer's disease (LOAD) have been identified. Type 2 diabetes (T2D) is a risk factor for cognitive decline, dementia and Alzheimer's disease (AD). We investigated the association of polygenic risk score (PRS) for LOAD with overall cognitive functioning and longitudinal decline, among older adults with T2D. Methods: The study included 1046 Jewish participants from the Israel Diabetes and Cognitive Decline (IDCD) study, aged ≥ 65 years, diagnosed with T2D, and cognitively normal at baseline. The PRS included variants from 26 LOAD associated loci (at genome-wide significance level), and was calculated with and without APOE. Outcome measures, assessed in 18 months intervals, were global cognition and the specific domains of episodic memory, attention/working memory, executive functions, and language/semantic categorization. Random coefficient models were used for analysis, adjusting for demographic variables, T2D-related characteristics, and cardiovascular factors. Additionally, in a subsample of 202 individuals, we analyzed the association of PRS with the volumes of total gray matter, frontal lobe, hippocampus, amygdala, and white matter hyperintensities. Last, the association of PRS with amyloid beta (Aß) burden was examined in 44 participants who underwent an 18F-flutemetamol PET scan. Results: The PRS was not significantly associated with overall functioning or decline in global cognition or any of the specific cognitive domains. Similarly, following correction for multiple testing, there was no association with Aß burden and other brain imaging phenotypes. Conclusion: Our results suggest that the cumulative effect of LOAD susceptibility loci is not associated with a greater rate of cognitive decline in older adults with T2D, and other pathways may underlie this link.
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Titanium dioxide (TiO2) is a frequently used biomaterial, particularly in orthopedic and dental implants, and it is considered an inert and benign compound. This has resulted in toxicological scrutiny for TiO2 in the past decade, with numerus studies showing potential pathologic downstream effects. Herein we describe case report of a 77-year-old male with subacute CNS dysfunction, secondary to breakdown of a titanium-based carotid stent and leading to blood levels 1000 times higher (3 ppm) than the reported normal. We prospectively collected tissues adjacent to orthopedic implants and found a positive correlation between titanium concentration and time of implant in the body (r = 0.67, p < 0.02). Rats bearing titanium implants or intravascularly treated with TiO2 nanoparticles (TiNP) exhibited memory impairments. A human blood-brain barrier (BBB) in-vitro model exposed to TiNP showed paracellular leakiness, which was corroborated in-vivo with the decrease of key BBB transcripts in isolated blood vessels from hippocampi harvested from TiNP-treated mice. Titanium particles rapidly internalized into brain-like endothelial cells via caveolae-mediated endocytosis and macropinocytosis and induced pro-inflammatory reaction with increased expression of pro-inflammatory genes and proteins. Immune reaction was mediated partially by IL-1R and IL-6. In summary, we show that high levels of titanium accumulate in humans adjacent to orthopedic implants, and our in-vivo and in-vitro studies suggest it may be neurotoxic.
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Nanopartículas , Titânio , Animais , Células Endoteliais , Humanos , Masculino , Camundongos , Estudos Prospectivos , Próteses e Implantes/efeitos adversos , Ratos , Titânio/toxicidadeRESUMO
BACKGROUND: Dietary advanced glycation end-products (AGEs) are linked to cognitive decline. However, clinical trials have not tested the effect of AGEs on cognition in older adults. OBJECTIVE: The aim of the current pilot trial was to examine the feasibility of an intervention to reduce dietary AGEs on cognition and on cerebral blood flow (CBF). METHODS: The design is a pilot randomized controlled trial of dietary AGEs reduction in older adults with type 2 diabetes. Seventy-five participants were randomized to two arms. The control arm received standard of care (SOC) guidelines for good glycemic control; the intervention arm, in addition to SOC guidelines, were instructed to reduce their dietary AGEs intake. Global cognition and CBF were assessed at baseline and after 6 months of intervention. RESULTS: At baseline, we found a reverse association between AGEs and cognitive functioning, possibly reflecting the long-term toxicity of AGEs on the brain. There was a significant improvement in global cognition at 6 months in both the intervention and SOC groups which was more prominent in participants with mild cognitive impairment. We also found that at baseline, higher AGEs were associated with increased CBF in the left inferior parietal cortex; however, 6 months of the AGEs lowering intervention did not affect CBF levels, despite lowering AGEs exposure in blood. CONCLUSION: The current pilot trial focused on the feasibility and methodology of intervening through diet to reduce AGEs in older adults with type 2 diabetes. Our results suggest that participants with mild cognitive impairment may benefit from an intensive dietary intervention.
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Cognição/efeitos dos fármacos , Disfunção Cognitiva/dietoterapia , Diabetes Mellitus Tipo 2/dietoterapia , Ingestão de Alimentos , Produtos Finais de Glicação Avançada/metabolismo , Idoso , Circulação Cerebrovascular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Feminino , Produtos Finais de Glicação Avançada/sangue , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Projetos Piloto , Inquéritos e QuestionáriosRESUMO
Introduction: Advanced glycation end products (AGEs) in diet and serum are positively correlated with chronic conditions such as type 2 diabetes and cognitive decline. Dietary reduction of AGEs was shown to reduce their level in serum and to have a beneficial effect on metabolic biomarkers. However, in part due to limitations of feasibility, clinical trials have not tested its effect on cognition in elderly. The current pilot study examines the feasibility of AGE reduction in elderly with diabetes in terms of recruitment and retention. Methods: The design is a randomized controlled pilot trial of dietary AGEs in elderly with type 2 diabetes (clinicaltrials.gov NCT02739971). Recruitment followed two stages: we first recruited participants with mild cognitive impairment (MCI), and after expanding inclusion criteria, we later recruited cognitively normal participants with subjective memory complaints (SMCs). Participants were randomized to two arms. Participants in the control arm received standard of care (SOC) guidelines for good glycemic control; those in the experimental arm, in addition to SOC guidelines, were instructed to lower their dietary AGE intake, primarily by changing their cooking methods. Participants were closely followed for dietary adherence over 6 months and evaluated before and after the intervention for adherence to the assigned diet, blood tests, cognitive performance, and brain MRI. Results: Seventy-five participants (52 with MCI and 23 cognitively normal with SMCs) were recruited primarily through mass mailing and advertising in social media websites. Seventy participants finished the study, and dropout was similar in both groups (7.5% in control vs. 5.7% in intervention, p = 0.757). The majority (57.5%) of participants in the AGEs-lowering arm showed very high adherence with the dietary guidelines. Discussion: Targeting feasible lifestyle modifications in high-risk populations could prevent substantial cases of cognitive decline. Observational evidence supports that AGEs may contribute to cognitive decline; however, the cognitive effect of reducing AGEs exposure has yet to be evaluated in a randomized controlled trial (RCT). The results of our pilot trial delineate a methodology including effective recruitment strategies, population of choice, and ways to assure high adherence during lifestyle modifications, and significantly advance progress toward a definitive and well-powered future RCT.
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First-degree family history is an established risk factor for Alzheimer's disease (AD). We investigated the association of late-onset AD risk loci with cognitive functioning among 315 offspring of AD patients. Participants were cognitively normal Jewish individuals, aged 40-65 years, from the Israel Registry for Alzheimer's Prevention (IRAP) study. Twenty-two single-nucleotide polymorphisms (SNPs) within these loci and the APOE E4 allele were included in the final analyses, and a polygenic risk score was also calculated. Using linear regression (assuming an additive genetic model), we found a significant association only for SNP rs9473117, located near the CD2-associated protein (CD2AP) gene, with global cognition. Controlling for demographic variables (age, sex, years of education, and ancestry), the late-onset AD risk allele C was associated with lower global cognitive functioning (p = 0.0005), and withstood correction for multiple testing. After adjusting for additional characteristics (APOE E4 status and then also for cardiovascular factors), the results remained essentially unchanged (p = 0.0003 and p = 0.0005, respectively). In secondary analyses examining specific cognitive domains, rs9473117 was similarly associated with episodic memory (p = 0.005), language (p = 0.009), and working memory/attention (p = 0.018) but not with executive functions (p = 0.27). Again, the results were similar after adjusting for APOE E4 status and cardiovascular factors. The polygenic risk score was not associated with global cognitive functioning or with any of the 4 domains. In conclusion, our findings suggest a contribution of the CD2AP locus to cognitive functioning in middle-aged individuals with a parental history of AD. Further validations, including in longitudinal studies, are required.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Envelhecimento/genética , Envelhecimento/psicologia , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Cognição/fisiologia , Proteínas do Citoesqueleto/genética , Estudos de Associação Genética , Loci Gênicos/genética , Anamnese , Polimorfismo de Nucleotídeo Único , Adulto , Fatores Etários , Idoso , Alelos , Apolipoproteína E4/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Herança MultifatorialRESUMO
INTRODUCTION: We examined relationships of body mass index (BMI) with cognition in middle-aged adults at Alzheimer's disease (AD) risk due to parental family history. METHODS: Participants are offspring of AD patients from the Israel Registry of Alzheimer's Prevention (N = 271). Linear regressions assessed associations of BMI and cognition, and whether associations differed by maternal/paternal history. Analyses of covariance examined associations of long-term trajectories of BMI with cognition. RESULTS: Higher BMI was associated with worse language (P = .045). Interactions of BMI with parental history were significant for episodic memory (P = .023), language (p = .027), working memory (P = .006), global cognition (P = .008); associations were stronger among participants with maternal history. Interactions of BMI trajectories with parental history were significant for episodic memory (P = .017), language (P = .013), working memory (P = .001), global cognition (P = .005), with stronger associations for maternal history. DISCUSSION: Higher BMI and overweight/obese trajectories were associated with poorer cognition in adults with maternal history of AD, but not those with paternal history.
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BACKGROUND: Family history of Alzheimer's disease (AD) is associated with increased dementia-risk. OBJECTIVE: The Israel Registry for Alzheimer's Prevention (IRAP) is a prospective longitudinal study of asymptomatic middle-aged offspring of AD patients (family history positive; FH+) and controls (whose parents have aged without dementia; FH-) aimed to unravel the contribution of midlife factors to future cognitive decline and dementia. Here we present the study design, methods, and baseline characteristics. METHODS: Participants are members of the Maccabi Health Services, 40-65 years of age, with exquisitely detailed laboratory, medical diagnoses and medication data available in the Maccabi electronic medical records since 1998. Data collected through IRAP include genetic, sociodemographic, cognitive, brain imaging, lifestyle, and health-related characteristics at baseline and every three years thereafter. RESULTS: Currently IRAP has 483 participants [mean age 54.95 (SDâ=â6.68) and 64.8% (nâ=â313) women], 379 (78.5%) FH+, and 104 (21.5%) FH-. Compared to FH-, FH+ participants were younger (pâ=â0.011), more often males (pâ=â0.003) and with a higher prevalence of the APOE E4 allele carriers (32.9% FH+, 22% FH-; pâ=â0.040). Adjusting for age, sex, and education, FH+ performed worse than FH-in global cognition (pâ=â0.027) and episodic memory (pâ=â0.022). CONCLUSION: Lower cognitive scores and higher rates of the APOE E4 allele carriers among the FH+ group suggest that FH ascertainment is good. The combination of long-term historical health-related data available through Maccabi with the multifactorial information collected through IRAP will potentially enable development of dementia-prevention strategies already in midlife, a critical period in terms of risk factor exposure and initiation of AD-neuropathology.
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Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/epidemiologia , Testes Neuropsicológicos , Sistema de Registros , Projetos de Pesquisa/tendências , Adulto , Idoso , Doença de Alzheimer/psicologia , Estudos Transversais , Feminino , Humanos , Israel/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neuroimagem/tendências , Estudos Prospectivos , Fatores de RiscoRESUMO
INTRODUCTION: High serum concentrations of advanced glycation end-products (AGEs) in older adults and diabetics are associated with an increased risk of cognitive impairment. The aim of this pilot study was to assess the feasibility of long-term adherence to a dietary intervention designed to decrease intake and exposure to circulating AGEs among older adults with type 2 diabetes. METHODS: Herein, 75 participants were randomized to either a standard of care (SOC) control arm or to an intervention arm receiving instruction on reducing dietary AGEs intake. The primary outcome was a change in serum AGEs at the end of the intervention. Secondary and exploratory outcomes included adherence to diet and its association with circulating AGEs. Cognitive function and brain imaging were also assessed but were out of the scope of this article (ClinicalTrials.gov Identifier: NCT02739971). RESULTS: The intervention resulted in a significant change over time in several serum AGEs compared to the SOC guidelines. Very high adherence (above 80%) to the AGE-lowering diet was associated with a greater reduction in serum AGEs levels. There were no significant differences between the two arms in any other metabolic markers. CONCLUSIONS: A long-term dietary intervention to reduce circulating AGEs is feasible in older adults with type 2 diabetes, especially in those who are highly adherent to the AGE-lowering diet.
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Diabetes Mellitus Tipo 2/sangue , Dietoterapia , Ingestão de Alimentos/fisiologia , Produtos Finais de Glicação Avançada/administração & dosagem , Produtos Finais de Glicação Avançada/sangue , Fatores Etários , Idoso , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Estudos de Viabilidade , Feminino , Produtos Finais de Glicação Avançada/efeitos adversos , Humanos , Masculino , Projetos Piloto , Fatores de TempoRESUMO
AIMS/HYPOTHESIS: There are established relationships between adiposity (obesity) and higher dementia risk, faster cognitive decline and associated neural injury. Type 2 diabetes is strongly linked to greater adiposity and has been consistently associated with neural injury and poor cognitive outcomes. However, although obesity is a major cause of type 2 diabetes, there is limited evidence on the association of adiposity with brain atrophy among individuals with type 2 diabetes. METHODS: We examined the association of BMI (a measure of adiposity), and of long-term trajectories of BMI (three empirically identified groups of trajectories-'normal', 'overweight' and 'obese'-using SAS macro PROC TRAJ), with regional brain volume, in a sample of older individuals (aged 64-84) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study (n = 198). RESULTS: Using linear regression, we found that greater BMI was associated with smaller volumes of the inferior frontal gyrus (IFG) (r = -0.25, p = 0.001) and the middle temporal gyrus (r = -0.19; p = 0.010) after adjusting for sociodemographic covariates and total intracranial volume. In addition, there were significant differences between BMI trajectory groups in IFG volume (F = 4.34, p = 0.014), such that a long-term trajectory of obesity was associated with a smaller volume. Additional adjustment for cardiovascular and diabetes-related potential confounders did not substantively alter the results. There were no associations of adiposity with superior frontal gyrus, middle frontal gyrus or total grey matter volumes. CONCLUSIONS/INTERPRETATION: In older adults with type 2 diabetes, long-term adiposity may have a detrimental impact on volume of brain regions relevant to cognitive functioning. Further studies to identify the underlying mechanisms are warranted. Graphical abstract.
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Encéfalo/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Obesidade/fisiopatologia , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Substância Cinzenta/fisiologia , Humanos , Imageamento por Ressonância MagnéticaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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OBJECTIVE: Type 2 diabetes (T2D) is associated with motor impairments and a higher dementia risk. The relationships of motor decline with cognitive decline in T2D older adults has rarely been studied. Using data from the Israel Diabetes and Cognitive Decline study (N = 892), we examined associations of decline in motor function with cognitive decline over a 54-month period. METHODS: Motor function measures were strength (handgrip) and gait speed (time to walk 3 m). Participants completed a neuropsychologic battery of 13 tests transformed into z-scores, summarized into 4 cognitive domains: episodic memory, attention/working memory, executive functions, and language/semantic categorization. The average of the 4 domains' z-scores defined global cognition. Motor and cognitive functions were assessed in 18-months intervals. A random coefficients model delineated longitudinal relationships of cognitive decline with baseline and change from baseline in motor function, adjusting for sociodemographic, cardiovascular, and T2D-related covariates. RESULTS: Slower baseline gait speed levels were significantly associated with more rapid decline in global cognition (P = .004), language/semantic categorization (P = .006) and episodic memory (P = .029). Greater decline over time in gait speed was associated with an accelerated rate of decline in global cognition (P = .050), attention/working memory (P = .047) and language/semantic categorization (P<.001). Baseline strength levels were not associated with cognitive decline but the rate of declining strength was associated with an accelerated decline in executive functions (P = .025) and language/semantic categorization (P = .006). CONCLUSION: In T2D older adults, the rate of decline in motor function, beyond baseline levels, was associated with accelerated cognitive decline, suggesting that cognitive and motor decline share common neuropathologic mechanisms in T2D.
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Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Idoso , Cognição , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Força da Mão , Humanos , IsraelRESUMO
The association between several Single Nucleotide Polymorphisms (SNPs) within the transcription factor 7-like 2 (TCF7L2) gene and Type 2 Diabetes (T2D) as well as additional T2D-related traits is well established. Since alteration in total and regional brain volumes are consistent findings among T2D individuals, we studied the association of four T2D susceptibility SNPS within TCF7L2 (rs7901695, rs7903146, rs11196205, and rs12255372) with volumes of white matter hyperintensities (WMH), gray matter, and regional volumes of amygdala and hippocampus obtained from structural MRI among 191 T2D elderly Jewish individuals. Under recessive genetic model (controlling for age, sex and intracranial volume), we found that for all four SNPs, carriers of two copies of the T2D risk allele (homozygous genotype) had significantly smaller amygdalar volume: rs7901695- CC genotype vs. CT + TT genotypes, p = 0.002; rs7903146-TT vs. TC + CC, p = 0.003; rs11196205- CC vs. CG + GG, p = 0.0003; and rs12255372- TT vs. TG + GG, p = 0.003. Adjusting also for T2D-related covariates, body mass index (BMI), and ancestry did not change the results substantively (rs7901695, p = 0.003; rs7903146, p = 0.005; rs11196205, p = 0.001; and rs12255372, p = 0.005). Conditional analysis demonstrated that only rs11196205 was independently associated with amygdalar volume at a significant level. Separate analysis of left and right amygdala revealed stronger results for left amygdalar volume. Taken together, we report association of TCF7L2 SNPs with amygdalar volume among T2D elderly Jewish patients. Further studies in other populations are required to support these findings and reach more definitive conclusions.
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Tonsila do Cerebelo/patologia , Diabetes Mellitus Tipo 2/genética , Polimorfismo Genético , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Idoso , Diabetes Mellitus Tipo 2/patologia , Feminino , Predisposição Genética para Doença , Humanos , MasculinoAssuntos
Linfócitos B/metabolismo , Predisposição Genética para Doença/genética , Células Germinativas/metabolismo , Janus Quinase 2/genética , Polimorfismo de Nucleotídeo Único/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Criança , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais/genéticaRESUMO
Objectives: Recent large-scale meta-analysis of genome-wide association studies (GWAS) from multiple cohorts, demonstrated the association of the single nucleotide polymorphism (SNP) rs17518584, with processing speed (measured by the Digit Symbol Substitution Test (DSST) or the Letter Digit Substitution Test (LDST)), at GWAS significance level. This SNP is located within the cell adhesion molecule 2 (CADM2) gene. We aimed to validate this finding in our sample of 944 cognitively normal Jewish elderly individuals with type 2 diabetes (T2D), a population which is at risk for cognitive decline and dementia.Methods: Using linear regression, we studied the association of rs17518584 with DSST performance, adjusting for demographic, T2D-related characteristics and cardiovascular factors. In secondary analyses, associations with performance in four cognitive domains (episodic memory, language/semantic categorisation, attention/working memory and executive function) and overall cognition were examined.Results: Controlling for sex, age at cognitive assessment, years of education and ancestry, we found a significant association of rs17518584 with DSST performance (P = 0.013), consistent with the originally reported effect direction. Results remained significant even when the additional covariates (T2D-related and cardiovascular factors) were included in the analysis (P = 0.034). Moreover, this SNP was significantly associated with performance in the cognitive domains of language/semantic categorisation and executive function, as well as overall cognition.Conclusions: Taken together, irrespective of T2D-related characteristics and cardiovascular factors, our findings provide independent support for the association of CADM2 SNP rs17518584 with processing speed (and demonstrate association with additional cognitive phenotypes), among cognitively normal elderly individuals with T2D.
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Moléculas de Adesão Celular/genética , Cognição , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/psicologia , Memória Episódica , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/etiologia , Demência/etiologia , Função Executiva , Feminino , Estudo de Associação Genômica Ampla , Humanos , Israel , Modelos Lineares , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Sistema de RegistrosRESUMO
The association between type 2 diabetes and cognitive dysfunction is well established. Prevention of the development of type 2 diabetes and its complications, as well as cognitive dysfunction and dementia, are leading goals in these fields. Deciphering the causality direction of the interplay between type 2 diabetes and cognitive dysfunction, and understanding the timeline of disease progression, are crucial for developing efficient prevention strategies. The prevailing perception is that type 2 diabetes leads to cognitive dysfunction and dementia. There is substantial evidence showing that accelerated cognitive decline in type 2 diabetes starts in midlife (mean age 40-60 years) and that it may even begin at the prediabetes stage. However, in this issue of Diabetologia, Altschul et al (doi: https://doi.org/10.1007/s00125-018-4645-8 ) show evidence for the reverse causality hypothesis, i.e. that lower cognitive function precedes poor glycaemic control. They found that cognitive function at early adolescence (age 11 years) predicts both HbA1c levels and cognitive function at age 70 years. Moreover, they found that lower cognitive function at age 70 is associated with an increase in HbA1c from age 70 to 79 years. Based on these findings, future studies should explore whether developing prevention strategies that target young adolescents with lower cognitive function will result in prevention of type 2 diabetes, breaking the vicious cycle of type 2 diabetes and cognitive dysfunction.
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Disfunção Cognitiva , Diabetes Mellitus Tipo 2 , Hiperglicemia , Adolescente , Adulto , Idoso , Glicemia , Cognição , Humanos , Pessoa de Meia-IdadeAssuntos
Encéfalo/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Cefaleia/etiologia , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Proteína KRIT1 , Imageamento por Ressonância Magnética , Masculino , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas/genéticaRESUMO
Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Münster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% ± 2% vs 15% ± 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% ± 1% vs 2.0% ± <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% ± 2% vs 81% ± 2%, P < .0001) and overall survival (74% ± 2% vs 89% ± 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 × 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.
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Síndrome de Down/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Síndrome de Down/mortalidade , Síndrome de Down/terapia , Feminino , Seguimentos , Humanos , Lactente , Cariotipagem , Masculino , Análise Multivariada , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Interleukin-7 receptor α (IL7R) is required for normal lymphoid development. Loss-of-function mutations in this gene cause autosomal recessive severe combined immune deficiency. Here, we describe somatic gain-of-function mutations in IL7R in pediatric B and T acute lymphoblastic leukemias. The mutations cause either a serine-to-cysteine substitution at amino acid 185 in the extracellular domain (4 patients) or in-frame insertions and deletions in the transmembrane domain (35 patients). In B cell precursor leukemias, the mutations were associated with the aberrant expression of cytokine receptor-like factor 2 (CRLF2), and the mutant IL-7R proteins formed a functional receptor with CRLF2 for thymic stromal lymphopoietin (TSLP). Biochemical and functional assays reveal that these IL7R mutations are activating mutations conferring cytokine-independent growth of progenitor lymphoid cells. A cysteine, included in all but three of the mutated IL-7R alleles, is essential for the constitutive activation of the receptor. This is the first demonstration of gain-of-function mutations of IL7R. Our current and recent observations of mutations in IL7R and CRLF2, respectively suggest that the addition of cysteine to the juxtamembranous domains is a general mechanism for mutational activation of type I cytokine receptors in leukemia.