Platelet Function Is Associated With Dementia Risk in the Framingham Heart Study
Ramos-Cejudo, Jaime; Johnson, Andrew D; Beiser, Alexa; Seshadri, Sudha; Salinas, Joel; Berger, Jeffrey S; Fillmore, Nathanael R; Do, Nhan; Zheng, Chunlei; Kovbasyuk, Zanetta; Ardekani, Babak A; Nunzio, Pomara; Bubu, Omonigho M; Parekh, Ankit; Convit, Antonio; Betensky, Rebecca A; Wisniewski, Thomas M; Osorio, Ricardo S
Background Vascular function is compromised in Alzheimer disease (AD) years before amyloid and tau pathology are detected and a substantial body of work shows abnormal platelet activation states in patients with AD. The aim of our study was to investigate whether platelet function in middle age is independently associated with future risk of AD. Methods and Results We examined associations of baseline platelet function with incident dementia risk in the community-based FHS (Framingham Heart Study) longitudinal cohorts. The association between platelet function and risk of dementia was evaluated using the cumulative incidence function and inverse probability weighted Cox proportional cause-specific hazards regression models, with adjustment for demographic and clinical covariates. Platelet aggregation response was measured by light transmission aggregometry. The final study sample included 1847 FHS participants (average age, 53.0Â years; 57.5% women). During follow-up (median, 20.5Â years), we observed 154 cases of incident dementia, of which 121 were AD cases. Results from weighted models indicated that platelet aggregation response to adenosine diphosphate 1.0Â Âµmol/L was independently and positively associated with dementia risk, and it was preceded in importance only by age and hypertension. Sensitivity analyses showed associations with the same directionality for participants defined as adenosine diphosphate hyper-responders, as well as the platelet response to 0.1Â Âµmol/L epinephrine. Conclusions Our study shows individuals free of antiplatelet therapy with a higher platelet response are at higher risk of dementia in late life during a 20-year follow-up, reinforcing the role of platelet function in AD risk. This suggests that platelet phenotypes may be associated with the rate of dementia and potentially have prognostic value.
Does obesity-associated insulin resistance affect brain structure and function of adolescents differentially by sex?
Gabay, Andrea; London, Stephanie; Yates, Kathy F; Convit, Antonio
Metabolic abnormalities affect the adolescent brain. For equivalent abnormalities in metabolism young people exhibit deficits in more cognitive domains than adults. We examine sex differences performance for adolescents with obesity/insulin resistance (IR) and evaluated how sex and IR effected frontal lobe structures and executive functioning. 125 adolescents underwent medical, cognitive, and brain-imaging assessments. Participants were categorized as insulin sensitive (IS) (QUICKI â‰¥ 0.350) or IR (QUICKI < 0.350). Degree of IR may affect brain and cognition differentially by sex. Females had positive associations between QUICKI and anterior cingulate cortex (ACC) volume, medial orbito-frontal cortex (OFC) thickness, and scores on the Stroop and Digit Symbol Substitution (DSST) tests. Females with IR tended to have thinner insular cortices. No such associations were found in males. In female adolescents, IR may negatively affect brain structure and function. No such effects were found for males. Although needing more development, hormonal effects and inflammation are potential contributors.
Lower extremity MRI following 10-week supervised exercise intervention in patients with diabetic peripheral neuropathy
Brown, Ryan; Sharafi, Azadeh; Slade, Jill M; Convit, Antonio; Davis, Nathan; Baete, Steven; Milton, Heather; Mroczek, Kenneth J; Kluding, Patricia M; Regatte, Ravinder R; Parasoglou, Prodromos; Rao, Smita
INTRODUCTION/BACKGROUND:The purpose of this study was to characterize using MRI the effects of a 10-week supervised exercise program on lower extremity skeletal muscle composition, nerve microarchitecture, and metabolic function in individuals with diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS/METHODS:) and once following intervention to measure relaxation times (T1, T1Ï, and T2), phosphocreatine recovery, fat fraction, and diffusion parameters. RESULTS:and postintervention MRI metrics were: calf adipose infiltration -2.6%Â±6.4%, GM T1Ï -4.1%Â±7.7%, GM T2 -3.5%Â±6.4%, and gastrocnemius lateral T2 -4.6Â±7.4%. Insignificant changes were observed in gastrocnemius phosphocreatine recovery rate constant (p>0.3) and tibial nerve fractional anisotropy (p>0.6) and apparent diffusion coefficient (p>0.4). CONCLUSIONS:The 10-week supervised exercise intervention program successfully reduced adiposity and altered resting tissue properties in the lower leg in DPN. Gastrocnemius mitochondrial oxidative capacity and tibial nerve microarchitecture changes were not observed, either due to lack of response to therapy or to lack of measurement sensitivity.
The Neutrophil to Lymphocyte Ratio Is Associated With the Risk of Subsequent Dementia in the Framingham Heart Study
Ramos-Cejudo, Jaime; Johnson, Andrew D; Beiser, Alexa; Seshadri, Sudha; Salinas, Joel; Berger, Jeffrey S; Fillmore, Nathanael R; Do, Nhan; Zheng, Chunlei; Kovbasyuk, Zanetta; Ardekani, Babak A; Bubu, Omonigho M; Parekh, Ankit; Convit, Antonio; Betensky, Rebecca A; Wisniewski, Thomas M; Osorio, Ricardo S
Obesity impacts brain metabolism and structure independently of amyloid and tau pathology in healthy elderly
Pegueroles, Jordi; Pané, Adriana; Vilaplana, Eduard; Montal, VÃctor; Bejanin, Alexandre; Videla, Laura; Carmona-Iragui, María; Barroeta, Isabel; Ibarzabal, Ainitze; Casajoana, Anna; Alcolea, Daniel; Valldeneu, Silvia; Altuna, Miren; de Hollanda, Ana; Vidal, Josep; Ortega, Emilio; Osorio, Ricardo; Convit, Antonio; Blesa, Rafael; Lleó, Alberto; Fortea, Juan; Jiménez, Amanda
Aims/hypothesis/UNASSIGNED:Midlife obesity is a risk factor for dementia. We investigated the impact of obesity on brain structure, metabolism, and cerebrospinal fluid (CSF) core Alzheimer's disease (AD) biomarkers in healthy elderly. Methods/UNASSIGNED:We selected controls from ADNI2 with CSF AD biomarkers and/or fluorodeoxyglucose positron emission tomography (FDG-PET) and 3T-MRI. We measured cortical thickness, FDG uptake, and CSF amyloid beta (AÎ²)1-42, p-tau, and t-tau levels. We performed regression analyses between these biomarkers and body mass index (BMI). Results/UNASSIGNED:). Higher BMI was related to less cortical thickness and higher metabolism in brain areas typically not involved in AD (family-wise error [FWE]Â <0.05), but not to AD CSF biomarkers. It is notable that the impact of obesity on brain metabolism and structure was also found in amyloid negative individuals. Conclusions/interpretation/UNASSIGNED:In the cognitively unimpaired elderly, obesity has differential effects on brain metabolism and structure independent of an underlying AD pathophysiology.
Cognitive functions among predominantly minority urban adolescents with metabolic syndrome
Mangone, Alexander; Yates, Kathy F; Sweat, Victoria; Joseph, Adriana; Convit, Antonio
The rise in the rate of adolescent obesity has led to a concurrent rise in the rate of metabolic syndrome (MetS) among young people. In addition to diabetes and cardiovascular disease, MetS has also been linked to cognitive dysfunction. The goal of this study was to assess whether cognitive differences exist between minority urban adolescents carrying excess weight who meet criteria for MetS as compared to their peers without MetS. Two hundred and ninety-six urban adolescents, predominantly Hispanic and carrying excess weight as defined by a BMI above 25 kg/m2, were screened for MetS and divided into MetS and no MetS groups. All participants completed the CNS Vital Signs (CNS-VS) computerized neurocognitive battery that assesses cognitive domains of Memory, Processing Speed, Reaction Time, Executive Function, Complex Attention, and Cognitive Flexibility. The MetS group (29.2%, n = 84) performed significantly lower on 2 of the 7 cognitive domains: Executive Function (EF) and Cognitive Flexibility. Additionally, waist circumference was determined to be a significant predictor of both these domains. These findings suggest EF is negatively impacted in adolescents with MetS, despite there being no statistical differences between MetS groups on most other measured cognitive domains. Due to the interrelated nature of obesity, waist circumference, and MetS, these findings have larger implications for the obesity epidemic as well.
Lifestyle and vascular risk effects on MRI-based biomarkers of Alzheimer's disease: a cross-sectional study of middle-aged adults from the broader New York City area
Mosconi, Lisa; Walters, Michelle; Sterling, Joanna; Quinn, Crystal; McHugh, Pauline; Andrews, Randolph E; Matthews, Dawn C; Ganzer, Christine; Osorio, Ricardo S; Isaacson, Richard S; De Leon, Mony J; Convit, Antonio
OBJECTIVE:To investigate the effects of lifestyle and vascular-related risk factors for Alzheimer's disease (AD) on in vivo MRI-based brain atrophy in asymptomatic young to middle-aged adults. DESIGN:Cross-sectional, observational. SETTING:Broader New York City area. Two research centres affiliated with the Alzheimer's disease Core Center at New York University School of Medicine. PARTICIPANTS:We studied 116 cognitively normal healthy research participants aged 30-60 years, who completed a three-dimensional T1-weighted volumetric MRI and had lifestyle (diet, physical activity and intellectual enrichment), vascular risk (overweight, hypertension, insulin resistance, elevated cholesterol and homocysteine) and cognition (memory, executive function, language) data. Estimates of cortical thickness for entorhinal (EC), posterior cingulate, orbitofrontal, inferior and middle temporal cortex were obtained by use of automated segmentation tools. We applied confirmatory factor analysis and structural equation modelling to evaluate the associations between lifestyle, vascular risk, brain and cognition. RESULTS:â‰¥-0.22, Pâ‰¤0.01). CONCLUSIONS:In cognitively normal middle-aged adults, MeDi and insulin sensitivity explained cortical thickness in key brain regions for AD, and EC thickness predicted memory performance in turn. Intellectual activity and overweight were associated with cognitive performance through different pathways. Our findings support further investigation of lifestyle and vascular risk factor modification against brain ageing and AD. More studies with larger samples are needed to replicate these research findings in more diverse, community-based settings.
Asian Adolescents with Excess Weight are at Higher Risk for Insulin Resistance than Non-Asian Peers
Elsamadony, Ahmed; Yates, Kathy F; Sweat, Victoria; Yau, Po Lai; Mangone, Alex; Joseph, Adriana; Fierman, Arthur; Convit, Antonio
OBJECTIVE: The purpose of this study was to evaluate whether Asian American adolescents have higher metabolic risk from excess weight than non-Asians. METHODS: Seven hundred thirty-three students, aged 14 to 19 years old, completed a school-based health screening. The 427 Asian and 306 non-Asian students were overall equivalent on age, sex, and family income. Height, weight, waist circumference, percent body fat, and blood pressure were measured. Fasting triglycerides, high- and low-density lipoproteins, glucose, and insulin levels were measured. Asian and non-Asians in lean or overweight/obesity groups were contrasted on the five factors that make up the metabolic syndrome. RESULTS: Asian adolescents carrying excess weight had significantly higher insulin resistance (IR), triglyceride levels, and waist-height ratios (W/H), despite a significantly lower overall BMI than corresponding non-Asians. Similarly, Asians had a stronger relationship between W/H and the degree of IR than non-Asian counterparts; 35% and 18% of the variances were explained (R2 = 0.35, R2 = 0.18) respectively, resulting in a significant W/H by racial group interaction (Fchange [1,236] = 11.56, P < 0.01). CONCLUSIONS: Despite lower overall BMI, Asians have higher IR and triglyceride levels from excess weight than their non-Asian counterparts. One-size-fits-all public health policies targeting youth should be reconsidered and attention paid to Asian adolescents, including those with mild degrees of excess weight.
Insulin resistance among obese middle-aged is associated with decreased cerebrovascular reactivity
Frosch, Olivia H; Yau, Po Lai; Osorio, Ricardo S; Rusinek, Henry; Storey, Pippa; Convit, Antonio
OBJECTIVE: To evaluate differences in cerebrovascular reactivity (CVR) to mild hypercapnia in obese/overweight individuals with and without insulin resistance (IR) compared to comparable lean controls. METHODS: A total of 60 cognitively normal participants (20 lean controls and 24 obese/overweight individuals with and 16 without IR) were evaluated using a high spatial resolution arterial spin labeling MRI technique at rest and during mild hypercapnia. We analyzed group differences in CVR in cerebral cortex and ascertained the relationships between CVR, IR, and body mass index (BMI). RESULTS: Obese/overweight participants with and without IR had significantly lower CVR to hypercapnia than lean controls after controlling for age, sex, and the presence of hypertension (F2,53 = 5.578, p = 0.006 eta2p = 0.174). In the obese/overweight participants with IR, there was a significant correlation between higher CVR and a measure of insulin sensitivity, even after accounting for BMI (rp = 0.575, p = 0.004). In contrast, there was no relationship between CVR and BMI when controlling for IR. No such relationships existed for the other 2 groups. CONCLUSIONS: IR is associated with impaired CVR; the relationship appears to be driven by the degree of IR and not by obesity. These rarely reported results suggest that early forms of cerebrovascular dysfunction exist among obese middle-aged individuals with significant IR but without type 2 diabetes mellitus. These functional vascular abnormalities may help explain the associations among IR, diabetes, and dementia, and suggest that interventions aiming to improve IR or CVR may help prevent cognitive decline later in life.
Obese Adolescents Show Reduced Cognitive Processing Speed Compared with Healthy Weight Peers
Sweat, Victoria; Yates, Kathy F; Migliaccio, Renee; Convit, Antonio
BACKGROUND: Childhood obesity and obesity-associated diabetes and metabolic syndrome (MetS) continue to rise. Obesity has been linked to structural and functional brain abnormalities, particularly in the frontal lobe. METHODS: One hundred sixty-two adolescents (aged 19.53 +/- 1.53 years) underwent medical, neurocognitive, and brain magnetic resonance imaging assessments. Participants were either healthy weight (BMI <25.0 kg/m2 or BMI percentile <85%) or obese (BMI >/=30.0 kg/m2 or BMI percentile >/=95%). We evaluated frontal lobe cognitive functions and the size of the corpus callosum (CC). RESULTS: Groups differed on four measures of processing speed contained in four different cognitive tests, but not on executive function. A confirmatory factor analysis verified that the significant processing speed variables loaded on the same factor. We also found differences between the weight groups on the area of the anterior portion of the CC, but not the overall CC. Only the Controlled Oral Word Association Test (COWAT) was significantly correlated with the area of the anterior portion of the CC. In the obese group, 32.4% met criteria for MetS. No differences were found between obese participants with or without MetS and none of the MetS factors contributed consistently to cognitive performance. CONCLUSIONS: Obese adolescents show slower cognitive processing speed while maintaining equivalent performance on executive functioning compared with their healthy weight peers. The group differences in the anterior portion of the CC, responsible for frontal lobe interhemispheric communication, may in part explain our processing speed findings. Future studies should include a longitudinal design and diffusion tensor imaging to examine the integrity of white matter.