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1.
JAMA Neurol ; 2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33683313

RESUMO

Importance: Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control. Objective: To evaluate the association of intensive blood pressure control on AD-related brain biomarkers. Design, Setting, and Participants: This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020. Interventions: Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317). Main Outcomes and Measures: Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle. Results: Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy. Conclusions and Relevance: Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

3.
J Int Neuropsychol Soc ; : 1-10, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33563358

RESUMO

OBJECTIVES: It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults. METHODS: Lipids were measured at baseline (1985-1986; age: 18-30 years) and at serial examinations conducted over 25 years. Time-averaged cumulative LDL-C was calculated using the area under the curve for 3,328 participants with ≥3 LDL-C measurements and a cognitive function assessment. Cognitive function was assessed at the Year 25 examination with the Digit Symbol Substitution Test [DSST], Rey Auditory Visual Learning Test [RAVLT], and Stroop Test. A brain magnetic resonance imaging (MRI) sub-study (N = 707) was also completed at Year 25 to assess abnormal white matter tissue volume (AWMV) and gray matter cerebral blood flow volume (GM-CBFV) as secondary outcomes. RESULTS: There were 15.6%, 32.9%, 28.9%, and 22.6% participants with time-averaged cumulative LDL-C <100 mg/dL, 101-129 mg/dL, 130-159 mg/dL, and ≥160 mg/dL, respectively. Standardized differences in all cognitive function test scores ranged from 0.16 SD lower to 0.09 SD higher across time-averaged LDL-C categories in comparison to those with LDL-C < 100 mg/dL. After covariate adjustment, participants with higher versus lower time-averaged LDL-C had a lower RAVLT score (p-trend = 0.02) but no differences were present for DSST, Stroop Test, AWMV, or GM-CBFV. CONCLUSION: Cumulative LDL-C was associated with small differences in memory, as assessed by RAVLT scores, but not other cognitive or brain MRI measures over 25 years of follow-up.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33231259

RESUMO

CONTEXT: Glycogen storage diseases are rare. Increased glycogen in the liver results in increased attenuation. OBJECTIVE: Investigate the association and function of a noncoding region associated with liver attenuation but not histologic nonalcoholic fatty liver disease. DESIGN: Genetics of Obesity-associated Liver Disease Consortium. SETTING: Population-based Main Outcome: Computed tomography measured liver attenuation. RESULTS: Carriers of rs4841132-A (frequency 2-19%) do not show increased hepatic steatosis; they have increased liver attenuation indicative of increased glycogen deposition. rs4841132 falls in a noncoding RNA LOC157273 ~190kb upstream of PPP1R3B. We demonstrate that rs4841132-A increases PPP1R3B through a cis genetic effect. Using CRISPR/Cas9 we engineered a 105bp deletion including rs4841132-A in human hepatocarcinoma cells which increases PPP1R3B, decreases LOC157273 and increases glycogen perfectly mirroring the human disease. Overexpression of PPP1R3B or knockdown of LOC157273 increased glycogen but did not result in decreased LOC157273 or increased PPP1R3B, respectively, suggesting that the effects may not all occur via affecting RNA levels. Based on EHR data, rs4841132-A associates with all components of the metabolic syndrome (MetS). However, rs4841132-A associated with decreased low-density lipoprotein (LDL) cholesterol and risk for myocardial infarction (MI). A metabolic signature for rs4841132-A includes increased glycine, lactate, triglycerides and decreased acetoacetate and beta-hydroxybutyrate. CONCLUSIONS: These results show that rs4841132-A promotes a hepatic glycogen storage disease by increasing PPP1R3B and decreasing LOC157273. rs4841132-A promotes glycogen accumulation and development of MetS but lowers LDL cholesterol and risk for MI. These results suggest that elevated hepatic glycogen is one cause of MetS that does not invariably promote MI.

5.
PLoS One ; 15(11): e0230035, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33186364

RESUMO

BACKGROUND: Genome-wide association studies have identified multiple genomic loci associated with coronary artery disease, but most are common variants in non-coding regions that provide limited information on causal genes and etiology of the disease. To overcome the limited scope that common variants provide, we focused our investigation on low-frequency and rare sequence variations primarily residing in coding regions of the genome. METHODS AND RESULTS: Using samples of individuals of European ancestry from ten cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, both cross-sectional and prospective analyses were conducted to examine associations between genetic variants and myocardial infarction (MI), coronary heart disease (CHD), and all-cause mortality following these events. For prevalent events, a total of 27,349 participants of European ancestry, including 1831 prevalent MI cases and 2518 prevalent CHD cases were used. For incident cases, a total of 55,736 participants of European ancestry were included (3,031 incident MI cases and 5,425 incident CHD cases). There were 1,860 all-cause deaths among the 3,751 MI and CHD cases from six cohorts that contributed to the analysis of all-cause mortality. Single variant and gene-based analyses were performed separately in each cohort and then meta-analyzed for each outcome. A low-frequency intronic variant (rs988583) in PLCL1 was significantly associated with prevalent MI (OR = 1.80, 95% confidence interval: 1.43, 2.27; P = 7.12 × 10-7). We conducted gene-based burden tests for genes with a cumulative minor allele count (cMAC) ≥ 5 and variants with minor allele frequency (MAF) < 5%. TMPRSS5 and LDLRAD1 were significantly associated with prevalent MI and CHD, respectively, and RC3H2 and ANGPTL4 were significantly associated with incident MI and CHD, respectively. No loci were significantly associated with all-cause mortality following a MI or CHD event. CONCLUSION: This study identified one known locus (ANGPTL4) and four new loci (PLCL1, RC3H2, TMPRSS5, and LDLRAD1) associated with cardiovascular disease risk that warrant further investigation.

6.
PLoS One ; 15(9): e0239548, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32956388

RESUMO

OBJECTIVE: Investigate whether socioeconomic status (SES) was related to brain volume in aging related regions, and if so, determine whether this relationship was mediated by lifestyle factors that are known to associate with risk of dementia in a population-based sample of community dwelling middle-aged adults. METHODS: We studied 645 (41% black) participants (mean age 55.3±3.5) from the Coronary Artery Risk Development in Young Adults (CARDIA) study who underwent brain magnetic resonance imaging. SES was operationalized as a composite measure of annual income and years of education. Gray matter volume was estimated within the insular cortex, thalamus, cingulate, frontal, inferior parietal, and lateral temporal cortex. These regions are vulnerable to age-related atrophy captured by the Spatial Pattern of Atrophy for Recognition of Brain Aging (SPARE-BA) index. Lifestyle factors of interest included physical activity, cognitive activity (e.g. book/newspaper reading), smoking status, alcohol consumption, and diet. Multivariable linear regressions tested the association between SES and brain volume. Sobel mediation analyses determined if this association was mediated by lifestyle factors. All models were age, sex, and race adjusted. RESULTS: Higher SES was positively associated with brain volume (ß = .109 SE = .039; p < .01) and smoking status significantly mediated this relationship (z = 2.57). With respect to brain volume, smoking accounted for 27% of the variance (ß = -.179 SE = .065; p < .01) that was previously attributed to SES. CONCLUSION: Targeting smoking cessation could be an efficacious means to reduce the health disparity of low SES on brain volume and may decrease vulnerability for dementia.


Assuntos
Encéfalo/anatomia & histologia , Fumar , Classe Social , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Consumo de Bebidas Alcoólicas/epidemiologia , Atrofia , Pressão Sanguínea , Índice de Massa Corporal , Encéfalo/patologia , Cognição , Estudos Transversais , Dieta , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Atividades de Lazer , Estilo de Vida , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Inquéritos e Questionários
7.
Brain Behav Immun ; 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32966872

RESUMO

OBJECTIVE: Elevated inflammation is associated with worse late-life cognitive functioning and brain health. Our goal was to examine the relationship between inflammation trajectories and white matter integrity in midlife. METHODS: Participants were 508 adults from the Coronary Artery Risk Development in Young Adults Study (CARDIA; 51% female). Latent class analysis was used to identify inflammation trajectories based on repeated measures of the inflammatory marker C-reactive protein (CRP) over the 18 years before brain magnetic resonance imaging (MRI). Outcomes were brain MRI measures of total and region-specific white matter volume and integrity at a mean age of 50.6 ± 3.4 years. Linear regression was used to examine if inflammation trajectories were associated with brain MRI outcomes, adjusting for potential confounds in all models and for disease and health behaviors in follow-up models. RESULTS: Lower-stable (38%), moderate-increasing (7%), and consistently-higher (54%), trajectories emerged. Compared to the lower-stable group, the moderate-increasing group showed lower white matter volume (ß = -0.18, 95% CI -0.29, -0.06) and worse white matter integrity as indexed by lower fractional anisotropy (FA; ß = -0.37, 95% CI -0.70, -0.04) and higher mean diffusivity (ß = 0.44, 95% CI 0.11, 0.78) in the whole brain. The consistently-higher group showed lower whole-brain FA (ß = -0.20, -0.38, -0.03). In exploratory analyses, the moderate-increasing group showed lower white matter volume, lower FA and higher MD in the frontal, temporal, and parietal lobes compared to the lower-stable group. The consistently-higher group showed lower white matter volume in the parietal lobe and lower FA in the frontal, temporal, and parietal lobes, but similar MD, compared to the lower-stable group. Findings for the moderate-increasing, but not the consistently-higher, group were robust to adjustment for disease and lifestyle factors. CONCLUSION: Increasing or high inflammation trajectories from early to mid adulthood are associated with worse brain health, as indexed by lower white matter volume and/or worse white matter integrity.

8.
Neurology ; 95(17): e2389-e2397, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-32878993

RESUMO

OBJECTIVE: To test the hypothesis that end-stage renal disease (ESRD) risk exposure during young adulthood is related to worse cognitive performance in midlife. METHODS: We included 2,604 participants from the population-based Coronary Artery Risk Development in Young Adults (CARDIA) Study (mean age 35 years, 54% women, 45% Black). Estimated glomerular filtration rate and albumin-to-creatinine ratio were measured every 5 years at year (Y) 10 through Y30. At each visit, moderate/high risk of ESRD according to the Kidney Disease: Improving Global Outcomes guidelines (estimated glomerular filtration rate <60 mL/min/1.73 m2 or albumin-to-creatinine ratio >30 mg/g) was defined, totaled over examinations, and categorized into 0 episodes, 1 episode, and >1 episodes of ESRD risk. At Y30, participants underwent global and multidomain cognitive assessment. We used analysis of covariance to assess the association of ESRD risk categories with cognitive function, controlling for cardiovascular risk factors. RESULTS: Over the course of 20 years, 427 participants (16% of the study population) had ≥1 episodes of ESRD risk exposure. Individuals with more risk episodes had lower composite cognitive function (p < 0.001), psychomotor speed (p < 0.001), and executive function (p = 0.007). All these associations were independent of sociodemographic status and cardiovascular risk factors. CONCLUSIONS: In this population-based longitudinal study, we show that episodes of decline in kidney function over the young-adulthood course are associated with worse cognitive performance at midlife. Preserving kidney function in young age needs to be investigated as a potential strategy to preserve cognitive function in midlife.


Assuntos
Cognição , Disfunção Cognitiva/psicologia , Falência Renal Crônica/psicologia , Adulto , Albuminas/análise , Doenças Cardiovasculares/epidemiologia , Creatinina/sangue , Função Executiva , Feminino , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Tempo de Reação , Fatores de Risco , Adulto Jovem
9.
Alzheimers Dement ; 2020 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-32920988

RESUMO

INTRODUCTION: Relationships between brain atrophy patterns of typical aging and Alzheimer's disease (AD), white matter disease, cognition, and AD neuropathology were investigated via machine learning in a large harmonized magnetic resonance imaging database (11 studies; 10,216 subjects). METHODS: Three brain signatures were calculated: Brain-age, AD-like neurodegeneration, and white matter hyperintensities (WMHs). Brain Charts measured and displayed the relationships of these signatures to cognition and molecular biomarkers of AD. RESULTS: WMHs were associated with advanced brain aging, AD-like atrophy, poorer cognition, and AD neuropathology in mild cognitive impairment (MCI)/AD and cognitively normal (CN) subjects. High WMH volume was associated with brain aging and cognitive decline occurring in an ≈10-year period in CN subjects. WMHs were associated with doubling the likelihood of amyloid beta (Aß) positivity after age 65. Brain aging, AD-like atrophy, and WMHs were better predictors of cognition than chronological age in MCI/AD. DISCUSSION: A Brain Chart quantifying brain-aging trajectories was established, enabling the systematic evaluation of individuals' brain-aging patterns relative to this large consortium.

10.
BMC Med Genomics ; 13(1): 121, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847530

RESUMO

BACKGROUND: Whether high blood pressure has a causal effect on cognitive function as early as middle age is unclear. We investigated whether high blood pressure (BP) causally impairs cognitive function at midlife using Mendelian Randomization (MR). METHODS: We applied a two-sample MR approach to investigate the causal relationship between BP and midlife cognitive performance measured by the Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and Stroop Interference test. We used a total of 109 genetic polymorphisms with established associations with BP as instrumental variables and estimated gene-cognitive function association in 1369 middle-aged adults (Mean age (SD): 50.8 (3.3), 54.0% women) from the CARDIA study. RESULTS: A 10 mmHg increment in genetically-predicted systolic, diastolic, or pulse pressure was associated with a 4.9 to 7.7-point lower DSST score (P = 0.002, SBP; P = 0.005, DBP and P = 0.008, PP), while a 10 mmHg increment in genetically-predicted SBP was associated with a 0.7 point lower RAVLT and a 2.3 point higher Stroop (P = 0.046 and 0.011, respectively). CONCLUSIONS: This MR analysis shows that high BP, especially SBP, is causally associated with poorer processing speed, verbal memory, and executive function during midlife. These findings emphasize the need for further investigation of the role and mechanisms of BP dysregulation on cognitive health in middle age and perhaps, more broadly, across the lifespan.

11.
Alzheimers Dement ; 16(7): 1078-1094, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32627328

RESUMO

Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer's disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline-from at-risk asymptomatic states to early symptomatic stages-in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.

12.
Transl Psychiatry ; 10(1): 245, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699239

RESUMO

Cognitive function such as reasoning, attention, memory, and language is strongly correlated with brain aging. Compared to non-Hispanic whites, Hispanics/Latinos have a higher risk of cognitive impairment and dementia. The genetic determinants of cognitive function have not been widely explored in this diverse and admixed population. We conducted a genome-wide association analysis of cognitive function in up to 7600 middle aged and older Hispanics/Latinos (mean = 55 years) from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL). Four cognitive measures were examined: the Brief Spanish English Verbal Learning Test (B-SEVLT), the Word Fluency Test (WFT), the Digit Symbol Substitution Test (DSST), the Six-Item Screener (SIS). Four novel loci were identified: one for B-SEVLT at 4p14, two for WFT at 3p14.1 and 6p21.32, and one for DSST at 10p13. These loci implicate genes highly expressed in brain and previously connected to neurological diseases (UBE2K, FRMD4B, the HLA gene complex). By applying tissue-specific gene expression prediction models to our genotype data, additional genes highly expressed in brain showed suggestive associations with cognitive measures possibly indicating novel biological mechanisms, including IFT122 in the hippocampus for SIS, SNX31 in the basal ganglia for B-SEVLT, RPS6KB2 in the frontal cortex for WFT, and CSPG5 in the hypothalamus for DSST. These findings provide new information about the genetic determinants of cognitive function in this unique population. In addition, we derived a measure of general cognitive function based on these cognitive tests and generated genome-wide association summary results, providing a resource to the research community for comparison, replication, and meta-analysis in future genetic studies in Hispanics/Latinos.

13.
medRxiv ; 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32511473

RESUMO

Importance: Recent reports have shown that hypertension is the most common comorbidity associated with mortality in the current coronavirus disease 2019 (COVID-19). This has been related to the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) as animal studies indicate that these medications increase levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2. This has prompted clinicians to recommend discontinuing ACEIs and ARBs. Objective: To examine the effect of ACEIs or ARBs treatment on serum levels of ACE2 and other key enzymes in the renin-angiotensin system (RAS). Design Setting and Participants: A single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75±6 years) stratified by ACEIs (N = 699) or ARBs (N = 753) treatment. Main Outcomes and Measures: The AGES-RS study population was stratified by ACEIs and ARBs medication use and compared for age, body mass index (BMI) (kg/m2), hypertension and type 2 diabetes (T2D) as well as serum levels of renin, ACE and ACE2. Results: While renin and ACE levels were significantly raised in serum of individuals on ACEIs or ARBs treatments, the ACE2 levels remained unaffected. Conclusions and Relevance: Treatment with ACEIs or ARBs does not raise ACE2 levels in serum. Therefore, the present study does not support the proposed discontinuation of these medications among patients affected with COVID-19.

14.
medRxiv ; 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32511628

RESUMO

AIMS: Severity of outcome in COVID-19 is disproportionately higher among the obese, males, smokers, those suffering from hypertension, kidney disease, coronary heart disease (CHD) and/or type 2 diabetes (T2D). We examined if serum levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2, were altered in these high-risk groups. METHODS: Associations of serum ACE2 levels to hypertension, T2D, obesity, CHD, smokers and males in a single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS) of the elderly (mean age 75+/-6 years). RESULTS: Smokers, males, and individuals with T2D or obesity have altered serum levels of ACE2 that may influence productive infection of SARS-CoV-2 in these high-risk groups. CONCLUSION: ACE2 levels are upregulated in some patient groups with comorbidities linked to COVID-19 and as such may have an emerging role as a circulating biomarker for severity of outcome in COVID-19.

15.
Brain ; 143(7): 2312-2324, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32591831

RESUMO

Deep learning has emerged as a powerful approach to constructing imaging signatures of normal brain ageing as well as of various neuropathological processes associated with brain diseases. In particular, MRI-derived brain age has been used as a comprehensive biomarker of brain health that can identify both advanced and resilient ageing individuals via deviations from typical brain ageing. Imaging signatures of various brain diseases, including schizophrenia and Alzheimer's disease, have also been identified using machine learning. Prior efforts to derive these indices have been hampered by the need for sophisticated and not easily reproducible processing steps, by insufficiently powered or diversified samples from which typical brain ageing trajectories were derived, and by limited reproducibility across populations and MRI scanners. Herein, we develop and test a sophisticated deep brain network (DeepBrainNet) using a large (n = 11 729) set of MRI scans from a highly diversified cohort spanning different studies, scanners, ages and geographic locations around the world. Tests using both cross-validation and a separate replication cohort of 2739 individuals indicate that DeepBrainNet obtains robust brain-age estimates from these diverse datasets without the need for specialized image data preparation and processing. Furthermore, we show evidence that moderately fit brain ageing models may provide brain age estimates that are most discriminant of individuals with pathologies. This is not unexpected as tightly-fitting brain age models naturally produce brain-age estimates that offer little information beyond age, and loosely fitting models may contain a lot of noise. Our results offer some experimental evidence against commonly pursued tightly-fitting models. We show that the moderately fitting brain age models obtain significantly higher differentiation compared to tightly-fitting models in two of the four disease groups tested. Critically, we demonstrate that leveraging DeepBrainNet, along with transfer learning, allows us to construct more accurate classifiers of several brain diseases, compared to directly training classifiers on patient versus healthy control datasets or using common imaging databases such as ImageNet. We, therefore, derive a domain-specific deep network likely to reduce the need for application-specific adaptation and tuning of generic deep learning networks. We made the DeepBrainNet model freely available to the community for MRI-based evaluation of brain health in the general population and over the lifespan.

16.
Parkinsonism Relat Disord ; 75: 85-90, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32505084

RESUMO

INTRODUCTION: Mild parkinsonian signs (MPS) are associated with morbidity. Identification of MPS progression markers may be vital for preventive management, yet has not been pursued. This study aimed to ascertain clinical/neuroimaging features predictive of MPS progression. METHODS: 205 participants in the Health ABC Study were included. MPS was defined using published guidelines. MPS progression was evaluated by determining UPDRS-III change between baseline and follow-up ≥2 years later. Standard brain MRI and DTI were obtained at baseline. Correlation coefficients between demographics, vascular risk factors, imaging markers, and UPDRS-III change were adjusted for follow-up time. Linear regression was used to adjust for possible confounders in the relationship between imaging markers and MPS progression. RESULTS: 30% of participants had baseline MPS. Demographics and risk factors did not differ significantly between participants with MPS (MPS+) and without MPS (MPS-). Mean follow-up time was 3.8±0.8 years. Older age, male gender, diabetes were associated with faster rate of UPDRS-III change in MPS- but not MPS+ participants. Among MPS- participants, the only imaging marker associated with faster UPDRS-III progression was higher gray matter mean diffusivity (MD), widespread in various cortico-subcortical bihemispheric regions, independent of age, gender, diabetes. No imaging features were associated with UPDRS-III change among MPS+ participants. CONCLUSIONS: Lower gray matter integrity predicted MPS progression in those who did not have baseline MPS. Microstructural imaging may capture early changes related to MPS development, prior to macrostructural change. Any future management promoting gray matter preservation may inhibit MPS development.

17.
Diabetes Care ; 43(8): 1781-1787, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32527799

RESUMO

OBJECTIVE: Type 2 diabetes has been associated with depression. However, the underlying pathophysiological mechanisms remain unknown. Cerebral small vessel disease, a consequence of diabetes, may lead to depression. Therefore, we evaluated whether cerebral small vessel disease mediates the association between type 2 diabetes and higher depressive symptoms. RESEARCH DESIGN AND METHODS: We used longitudinal data from the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, with examinations from 2002 to 2006 and 5 years later. Type 2 diabetes was defined as self-reported history of type 2 diabetes, use of blood glucose-lowering drugs, or fasting blood glucose level ≥7.0 mmol/L. Cerebral small vessel disease load was quantified in a composite score based on MRI-defined presence of high white matter hyperintensity volume, low total brain parenchyma volume, and subcortical infarcts, cerebral microbleeds, and large perivascular spaces. The 5-year change in the 15-item Geriatric Depression Scale score (GDS-15) was measured between baseline and follow-up. RESULTS: Included were 2,135 individuals without dementia and baseline depression (baseline age 74.5 [SD 4.6] years, 1,245 women [58.3%], and 197 [9.2%] with diabetes). The GDS-15 score increased 0.4 (SD 1.6) points over time. Baseline diabetes was associated with a greater increase in the GDS-15 score (ß = 0.337; 95% CI 0.094; 0.579), adjusted for age, sex, education, and cardiovascular risk factors. Baseline cerebral small vessel disease and change of cerebral small vessel disease statistically significantly mediated a part of this association. CONCLUSIONS: Type 2 diabetes is associated with a greater increase in depressive symptoms score over 5 years, and cerebral small vessel disease partly explains this association.

18.
PLoS One ; 15(5): e0230815, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379818

RESUMO

Smoking is a potentially causal behavioral risk factor for type 2 diabetes (T2D), but not all smokers develop T2D. It is unknown whether genetic factors partially explain this variation. We performed genome-environment-wide interaction studies to identify loci exhibiting potential interaction with baseline smoking status (ever vs. never) on incident T2D and fasting glucose (FG). Analyses were performed in participants of European (EA) and African ancestry (AA) separately. Discovery analyses were conducted using genotype data from the 50,000-single-nucleotide polymorphism (SNP) ITMAT-Broad-CARe (IBC) array in 5 cohorts from from the Candidate Gene Association Resource Consortium (n = 23,189). Replication was performed in up to 16 studies from the Cohorts for Heart Aging Research in Genomic Epidemiology Consortium (n = 74,584). In meta-analysis of discovery and replication estimates, 5 SNPs met at least one criterion for potential interaction with smoking on incident T2D at p<1x10-7 (adjusted for multiple hypothesis-testing with the IBC array). Two SNPs had significant joint effects in the overall model and significant main effects only in one smoking stratum: rs140637 (FBN1) in AA individuals had a significant main effect only among smokers, and rs1444261 (closest gene C2orf63) in EA individuals had a significant main effect only among nonsmokers. Three additional SNPs were identified as having potential interaction by exhibiting a significant main effects only in smokers: rs1801232 (CUBN) in AA individuals, rs12243326 (TCF7L2) in EA individuals, and rs4132670 (TCF7L2) in EA individuals. No SNP met significance for potential interaction with smoking on baseline FG. The identification of these loci provides evidence for genetic interactions with smoking exposure that may explain some of the heterogeneity in the association between smoking and T2D.


Assuntos
Glicemia/análise , Fumar Cigarros/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Genótipo , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Fumar Cigarros/etnologia , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Viabilidade , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Risco
20.
Hypertension ; 75(5): 1289-1295, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32223376

RESUMO

High blood pressure (BP) negatively affects brain structure and function. Hypertension is associated with white matter hyperintensities, cognitive and mobility impairment in late-life. However, the impact of BP exposure from young adulthood on brain structure and function in mid-life is unclear. Identifying early brain structural changes associated with BP exposure, before clinical onset of cognitive dysfunction and mobility impairment, is essential for understanding mechanisms and developing interventions. We examined the effect of cumulative BP exposure from young adulthood on brain structure in a substudy of 144 (61 female) individuals from the CARDIA (Coronary Artery Risk Development in Young Adults) study. At year 30 (Y30, ninth visit), participants (56±4 years old) completed brain magnetic resonance imaging and gait measures (pace, rhythm, and postural control). Cumulative systolic and diastolic BP (cumulative systolic blood pressure, cDBP) over 9 visits were calculated, multiplying mean values between 2 consecutive visits by years between visits. Surface-based analysis of basal ganglia and thalamus was achieved using FreeSurfer-initiated Large Deformation Diffeomorphic Metric Mapping. Morphometric changes were regressed onto cumulative BP to localize regions of shape variation. Y30 white matter hyperintensity volumes were small and positively correlated with cumulative BP but not gait. Negative morphometric associations with cumulative systolic blood pressure were seen in the caudate, putamen, nucleus accumbens, pallidum, and thalamus. A concave right medial putamen shape mediated the relationship between cumulative systolic blood pressure and stride width. Basal ganglia and thalamic morphometric changes, rather than volumes, may be earlier manifestation of gray matter structural signatures of BP exposure that impact midlife gait.

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