Resting state connectivity within the basal ganglia and gait speed in older adults with cerebral small vessel disease and locomotor risk factors.

BACKGROUND AND AIM: The basal ganglia are critical for planned locomotion, but their role in age-related gait slowing is not well known. Spontaneous regional co-activation of brain activity at rest, known as resting state connectivity, is emerging as a biomarker of functional neural specialization of varying human processes, including gait. We hypothesized that greater connectivity amongst regions of the basal ganglia would be associated with faster gait speed in the elderly. We further investigated whether this association was similar in strength to that of other risk factors for gait slowing, specifically white matter hyperintensities (WMH). METHODS: A cohort of 269 adults (79-90 years, 146 females, 164 White) were assessed for gait speed (m/sec) via stopwatch; brain activation during resting state functional magnetic resonance imaging, WMH, and gray matter volume (GMV) normalized by intracranial volume via 3T neuroimaging; and risk factors of poorer locomotion via clinical exams (body mass index (BMI), muscle strength, vision, musculoskeletal pain, cardiometabolic conditions, depressive symptoms, and cognitive function). To understand whether basal ganglia connectivity shows distinct clusters of connectivity, we conducted a k-means clustering analysis of regional co-activation among the substantia nigra, nucleus accumbens, subthalamic nucleus, putamen, pallidum, and caudate. We conducted two multivariable linear regression models: (1) with gait speed as the dependent variable and connectivity, demographics, WMH, GMV, and locomotor risk factors as independent variables and (2) with basal ganglia connectivity as the dependent variable and demographics, WMH, GMV, and locomotor risk factors as independent variables. RESULTS: We identified two clusters of basal ganglia connectivity: high and low without a distinct spatial distribution allowing us to compute an average connectivity index of the entire basal ganglia regional connectivity (representing a continuous measure). Lower connectivity was associated with slower gait, independent of other locomotor risk factors, including WMH; the coefficient of this association was similar to those of other locomotor risk factors. Lower connectivity was significantly associated with lower BMI and greater WMH. CONCLUSIONS: Lower resting state basal ganglia connectivity is associated with slower gait speed. Its contribution appears comparable to WMH and other locomotor risk factors. Future studies should assess whether promoting higher basal ganglia connectivity in older adults may reduce age-related gait slowing.

Depressive symptoms and cerebral microvascular disease in adults with Type 1 diabetes mellitus.

AIM: To assess the prevalence of, and risk factors for, depressive symptoms, comparing a sample of middle-aged adults with and without juvenile-onset Type 1 diabetes mellitus, and to determine if depressive symptoms were associated with white matter hyperintensity volume among those with Type 1 diabetes. METHODS: Depressive symptoms and white matter hyperintensities were compared between adults (age range 30-65 years) with juvenile-onset Type 1 diabetes (n=130) and adults without Type 1 diabetes (n=133). The association of Type 1 diabetes with depression was computed before and after adjustment for white matter hyperintensities. Among the Type 1 diabetes group, the primary associations of interest were between depressive symptoms (Beck Depression Inventory score ≥10) and white matter hyperintensities (n=71), hyperglycaemia and physical activity. Associations between depressive symptoms and diabetes-related complications, cognitive impairment, smoking and self-reported disability were examined. Analyses were controlled for education, sex, age and antidepressant use. RESULTS: Depressive symptoms were more prevalent among those with vs those without Type 1 diabetes (28% vs 3%; P<0.001). White matter hyperintensities explained 40% of the association of Type 1 diabetes with depressive symptoms, while Type 1 diabetes had a direct effect of 68% on depressive symptoms. Among those with Type 1 diabetes, depressive symptoms were related to white matter hyperintensity volume, a 16-year average HbA1c ≥58 mmol/mol (7.5%), and lower physical activity levels. Associations with other characteristics were not significant. CONCLUSION: These findings suggest a cerebrovascular origin for depressive symptoms in adults with Type 1 diabetes, perhaps triggered by hyperglycaemia. Future longitudinal studies should investigate whether targeting hyperglycaemia and physical inactivity alleviates depressive symptoms, possibly by slowing the development of cerebral microvascular disease, in people with Type 1 diabetes.

Contributions to lateral balance control in ambulatory older adults.

BACKGROUND: In older adults, impaired control of standing balance in the lateral direction is associated with the increased risk of falling. Assessing the factors that contribute to impaired standing balance control may identify areas to address to reduce falls risk. AIM: To investigate the contributions of physiological factors to standing lateral balance control. METHODS: Two hundred twenty-two participants from the Pittsburgh site of the Health, Aging and Body Composition Study had lateral balance control assessed using a clinical sensory integration balance test (standing on level and foam surface with eyes open and closed) and a lateral center of pressure tracking test using visual feedback. The center of pressure was recorded from a force platform. Multiple linear regression models examined contributors of lateral control of balance performance, including concurrently measured tests of lower extremity sensation, knee extensor strength, executive function, and clinical balance tests. Models were adjusted for age, body mass index, and sex. RESULTS: Larger lateral sway during the sensory integration test performed on foam was associated with longer repeated chair stands time. During the lateral center of pressure tracking task, the error in tracking increased at higher frequencies; greater error was associated with worse executive function. The relationship between sway performance and physical and cognitive function differed between women and men. DISCUSSION: Contributors to control of lateral balance were task-dependent. Lateral standing performance on an unstable surface may be more dependent upon general lower extremity strength, whereas visual tracking performance may be more dependent upon cognitive factors. CONCLUSIONS: Lateral balance control in ambulatory older adults is associated with deficits in strength and executive function.

Cognitive Performance Does not Limit Physical Activity Participation in the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P).

OBJECTIVES: We examined whether multiple domains of baseline cognitive performance were associated with prospective physical activity (PA) adherence in the Lifestyle Interventions and Independence for Elders Pilot study (LIFE-P). DESIGN, SETTING, PARTICIPANTS: The LIFE-P study was a single-blind, multicenter, randomized controlled trial of a PA intervention compared to a successful aging educational intervention in sedentary, mobility-limited older adults. INTERVENTION: A 12-month structured, moderate-intensity, multi-modal PA program that included walking, resistance training, and flexibility exercises. For the first 2 months (adoption), 3 center-based exercise sessions (40-60 min) / week were conducted. During the next 4 months (transition), center-based sessions were conducted 2 times / week. The subsequent maintenance phase consisted of optional once-to-twice-per-week center-based sessions and home-based PA. MEASUREMENTS: Tests of executive and global cognitive functioning, working memory and psychomotor speed were administered at baseline. Median test scores were used to dichotomize participants into low or high cognitive performance groups. RESULTS: 52 mobility-limited older adults (age: 76.9 ±5 yrs) were randomized to the PA arm of LIFE-P. Compared to participants with high cognitive performance, participants with low performance had similar PA adherence rates (all P ≥ 0.34). Furthermore, weak and non-significant univariate relationships were elicited between all measures of cognition and overall PA adherence levels (r values ranged: -0.20 to 0.12, P ≥ 0.12). CONCLUSION: These data suggest that cognitive performance does not limit long-term PA adherence in mobility-limited older adults. Additional studies in larger cohorts are warranted to verify these findings.

In Vivo Imaging of Venous Side Cerebral Small-Vessel Disease in Older Adults: An MRI Method at 7T.

BACKGROUND AND PURPOSE: Traditional neuroimaging markers of small-vessel disease focus on late-stage changes. We aimed to adapt a method of venular assessment at 7T for use in older adults. We hypothesized that poorer venular morphologic characteristics would be related to other small-vessel disease neuroimaging markers and a higher prevalence of small-vessel disease-Alzheimer disease risk factors. MATERIALS AND METHODS: Venules were identified in periventricular ROIs on SWI and defined as tortuous or straight. The tortuosity ratio was defined as total tortuous venular length divided by total straight venular length. White matter hyperintensity burden (visually rated from 0 to 3) and the number of microbleeds (0, 1, >1) were determined. Differences in tortuous and straight venular lengths were evaluated. Relationships with demographic variables, allele producing the e4 type of apolipoprotein E (APOE4), growth factors, pulse pressure, physical activity, and Modified Mini-Mental State Examination were assessed via Spearman correlations. RESULTS: Participants had 42% more tortuous venular tissue than straight (median, 1.42; 95% CI, 1.13-1.62). APOE4 presence was associated with a greater tortuosity ratio (ρ = 0.454, P = .001), and these results were robust to adjustment for confounders and multiple comparisons. Associations of the tortuosity ratio with sex and vascular endothelial growth factor did not survive adjustment. Associations of the tortuosity ratio with other variables of interest were not significant. CONCLUSIONS: Morphologic measures of venules at 7T could be useful biomarkers of the early stages of small-vessel disease and Alzheimer disease. Longitudinal studies should examine the impact of apolipoprotein E and vascular endothelial growth factor on the risk of venular damage.

A Bodipy as a luminescent probe for detection of the G protein estrogen receptor (GPER).

We report the rational design, based on docking simulations, and synthesis of the first fluorescent and selective probe of GPER for bioimaging purposes and functional dissecting studies. It has been conceived as a Bodipy derivative and obtained by accessible and direct synthesis. Its optical properties have been measured in different solvents, showing insensitivity to their polarity. Its binding to GPER was achieved by competition assays with [3H]E2 and [5,6-3H] nicotinic acid in ER-negative and GPER-positive SkBr3 breast cancer cells. SkBr3 cells, transfected with a GPER expression vector containing a FLAG tag, were used to confirm that the fluorophore binds to GPER in a specific manner.

Endocrine disruptor agent nonyl phenol exerts an estrogen-like transcriptional activity on estrogen receptor positive breast cancer cells.

Several substances widely dispersed in the environment including hormones, industrial by-products and pollutants exert hormone like activity affecting steroid-responsive physiological systems. These compounds, named endocrine disruptors, are suspected to affect the mammalian reproductive system. However it is still unclear whether these substances are able to elicit estrogen like activity at the low concentrations encountered in the environment. Here we compare the effects of the endocrine disruptor nonylphenol with the effects elicited by 17-ß-estradiol on gene transcription in the human breast cancer cell line MCF7. The correlation of the nonylphenol induced gene expression alterations with a reference profile of estradiol treated cells shows that nonylphenol at a concentration of 100 nM exerts a significant effect on estrogen responsive gene transcription in MCF7 cells. Most of the genes regulated by 17-ß-estradiol respond to the nonylphenol in the same direction though to a much lesser extent. Molecular modeling of the potential interaction of nonylphenol with the estrogen receptor α shows that nonylphenol is likely to bind to the estrogen receptor α.

Exogenous hormonal regulation in breast cancer cells by phytoestrogens and endocrine disruptors.

Observations on the role of ovarian hormones in breast cancer growth, as well as interest in contraception, stimulated research into the biology of estrogens. The identification of the classical receptors ERα and ERß and the transmembrane receptor GPER and the resolution of the structure of the ligand bound to its receptor established the principal molecular mechanisms of estrogen action. The presence of estrogen-like compounds in many plants used in traditional medicine or ingested as food ingredients, phytoestrogens, as well as the estrogenic activities of many industrial pollutants and pesticides, xenoestrogens, have prompted investigations into their role in human health. Phyto- and xenoestrogens bind to the estrogen receptors with a lower affinity than the endogenous estrogens and can compete or substitute the hormone. Xenoestrogens, which accumulate in the body throughout life, are believed to increase breast cancer risk, especially in cases of prenatal and prepuberal exposure whereas the role of phytoestrogens is still a matter of debate. At present, the application of phytoestrogens appears to be limited to the treatment of post-menopausal symptoms in women where the production of endogenous estrogens has ceased. In this review we discuss chemistry, structure and classification, estrogen signaling and the consequences of the interactions of estrogens, phytoestrogens and xenoestrogens with their receptors, the complex interactions of endogenous and exogenous ligands, the evaluation of the health risks related to xenoestrogens, and the perspectives toward the synthesis of potent third generation selective estrogen receptor modulators (SERMs).

Recent advances in the rationale design of GPER ligands.

G-Protein Coupled Receptor (GPCR) superfamily, which comprises approximately 900 members, is the largest family of protein targets with proven therapeutic value. Although at least 500 GPCRs have been identified as therapeutically relevant, only thirteen GPCRs have been structurally characterized in apo-form or in complex with ligands. GPCRs share relatively low sequence similarity making hard the process of homology modelling, nevertheless some successful hits have been determined. Recently, the G-protein-coupled estrogen receptor 1 (GPER, formerly known as GPR30) has attracted increasing interest due to its ability in mediating estrogen signaling in different normal and cancer tissues. In this regard, the identification of selective GPER ligands has provided valuable tools in order to differentiate the specific functions elicited by this novel estrogen receptor respect to those exerted by the classical estrogen receptors (ERs). In this review, we focus on GPER examining "in silico" docking simulations and evaluating the different binding modes of diverse natural and synthetic ligands.

Two novel GPER agonists induce gene expression changes and growth effects in cancer cells.

Although the action of estrogens has been traditionally explained by the binding to and transactivation of the nuclear estrogen receptor (ER)α and ERß, recently the G protein-coupled receptor GPR30/GPER has been involved in the rapid estrogen signaling. We investigated the ability of two original molecules, which were named GPER-L1 and GPERL2, to bind to and activate the GPER transduction pathway in cancer cells. Competition assays, docking simulations, transfection experiments, real-time PCR, immunoblotting, gene silencing technology and growth assays were performed to ascertain the selective action of GPER-L1 and GPER-L2 in activating the GPER-mediated signaling. Both compounds, which did not show any ability to bind to and activate the classical ERs, were able to bind to GPER and to trigger the rapid activation of the GPER/EGFR/ERK transduction pathway which led to the up-regulation of GPER-target genes. Notably, GPER-L1 and GPER-L2 induced the proliferation of SkBr3 breast and Ishikawa endometrial cancer cells at nM concentrations through GPER, hence providing further evidence on their capability to elicit relevant biological responses mediated by GPER. The identification and characterization of these novel compounds as selective GPER agonists represent a valuable tool to further dissect the pharmacology of this novel estrogen receptor and to better differentiate the specific functions elicited by each estrogen receptor subtype in cancer cells.

Structural comparison of the interaction of tubulin with various ligands affecting microtubule dynamics.

Microtubules (MTs), which are highly dynamic assemblies of the protein tubulin, play important and diverse roles in eukaryotic cells. MT dynamics are regulated during the cell cycle by interacting with a large number of endogenous cellular regulators. In addition, many anti-tumour drugs and natural ligands that interact directly with tubulin are able to either stabilise or destabilise MTs and to disrupt the normal dynamics. Herein, we compare the structures of tubulin when complexed with different ligands in order to analyse: (i) various binding-sites of the protein and different positions of ligands within the microtubule (ii) the diverse effect on the microtubule dynamics. The structures and data given are essential for understanding tubulin-ligand interactions and their influence on the regulation of the microtubule system.

Advanced glycation end product level, diabetes, and accelerated cognitive aging.

OBJECTIVE: Several studies report that diabetes increases risk of cognitive impairment; some have hypothesized that advanced glycation end products (AGEs) underlie this association. AGEs are cross-linked products that result from reactions between glucose and proteins. Little is known about the association between peripheral AGE concentration and cognitive aging. METHODS: We prospectively studied 920 elders without dementia, 495 with diabetes and 425 with normal glucose (mean age 74.0 years). Using mixed models, we examined baseline AGE concentration, measured with urine pentosidine and analyzed as tertile, and performance on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and repeatedly over 9 years. Incident cognitive impairment (a decline of >1.0 SD on each test) was analyzed with logistic regression. RESULTS: Older adults with high pentosidine level had worse baseline DSST score (p=0.05) but not different 3MS score (p=0.32). On both tests, there was a more pronounced 9-year decline in those with high and mid pentosidine level compared to those in the lowest tertile (3MS 7.0, 5.4, and 2.5 point decline, p overall <0.001; DSST 5.9, 7.4, and 4.5 point decline, p=0.03). Incident cognitive impairment was higher in those with high or mid pentosidine level than those in the lowest tertile (3MS: 24% vs 17%, odds ratio=1.55; 95% confidence interval 1.07-2.26; DSST: 31% vs 22%, odds ratio=1.62; 95% confidence interval 1.13-2.33). There was no interaction between pentosidine level, diabetes status, and cognitive decline. Multivariate adjustment for age, sex, race, education, hypertension, cardiovascular disease, estimated glomerular filtration rate, and diabetes diminished results somewhat but overall patterns remained similar. CONCLUSION: High peripheral AGE level is associated with greater cognitive decline in older adults with and without diabetes.

Role of the non-receptor tyrosine kinase fes in cancer.

Non receptor protein tyrosine kinases are targets in the treatment of a number of diseases. This review focuses on the role of Fes tyrosine kinase and on the design of inhibitors of this protein. Fes and its homologously related protein Fer are the only two members of a distinct class of non receptor tyrosine kinases and they seem to play a role in cytoskeletal rearrangements and inside-out signaling associated with receptor-ligand, cell-matrix and cell-cell interactions. The knowledge of the three dimensional structure of this protein, in fact, has informed drug design, while at the same time it has helped to shed some light on the molecular mechanism at the basis of kinase activation and functions.

Structure-based approach for the discovery of novel selective estrogen receptor modulators.

In the last twenty years the efforts to design and optimize new drugs have been based on the three dimensional structure of the selected target proteins. In this regard, useful information has been achieved mainly by protein crystallography, which has recently turned from a low into a high-throughput process thanks to the improvement in robot technologies, automation procedure and the use of synchrotron radiation facilities [1-3]. This review examines the impact of Structure Based Drug Design (SBDD) on the discovery of ligands as the selective estrogen receptor modulators (SERMs) of the Estrogen Receptor (ER)α, which is involved in the regulation of several physiological and pathological processes.

Plasma F2-isoprostane level and cognitive function over eight years in non-demented older adults: Findings from the Health ABC Study.

F2-isoprostanes (F2-IsoP) are reportedly increased in dementia patients, and are considered a reliable biomarker of oxidation. However, few studies have examined the predictive value of peripheral F2-IsoP levels in non-demented older adults. This study assesses the association between plasma F2-IsoP and change in cognitive function in non-demented elderly over eight years. Plasma F2-IsoP was measured by gas chromatography-mass spectrometry in a biracial cohort of 726 elderly men and women. Digit Symbol Substitution test and the Modified Mini-Mental State Exam were administered over time. No association was found between F2-IsoP tertile and baseline or change (slope) in cognitive function over eight years. Plasma F2-IsoP is not a valuable biomarker in predicting cognitive change over years in non-demented older adults.

Physical activity predicts gray matter volume in late adulthood: the Cardiovascular Health Study.

OBJECTIVES: Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation. METHODS: In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline. RESULTS: Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold. CONCLUSION: Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.

Executive function, memory, and gait speed decline in well-functioning older adults.

BACKGROUND: In community-dwelling older adults, global cognitive function predicts longitudinal gait speed decline. Few prospective studies have evaluated whether specific executive cognitive deficits in aging may account for gait slowing over time. METHODS: Multiple cognitive tasks were administered at baseline in 909 participants in the Health, Aging, and Body Composition Study Cognitive Vitality Substudy (mean age 75.2 ± 2.8 years, 50.6% women, 48.4% black). Usual gait speed (m/s) over 20 minutes was assessed at baseline and over a 5-year follow-up. RESULTS: Poorer performance in each cognitive task was cross-sectionally associated with slower gait independent of demographic and health characteristics. In longitudinal analyses, each 1 SD poorer performance in global function, verbal memory, and executive function was associated with 0.003-0.004 m/s greater gait speed decline per year (p =.03-.05) after adjustment for baseline gait speed, demographic, and health characteristics. CONCLUSIONS: In this well-functioning cohort, several cognitive tasks were associated with gait speed cross-sectionally and predicted longitudinal gait speed decline. These data are consistent with a shared pathology underlying cognitive and motor declines but do not suggest that specific executive cognitive deficits account for slowing of usual gait in aging.

Predictors of maintaining cognitive function in older adults: the Health ABC study.

BACKGROUND: Although several risk factors for cognitive decline have been identified, much less is known about factors that predict maintenance of cognitive function in advanced age. METHODS: We studied 2,509 well-functioning black and white elders enrolled in a prospective study. Cognitive function was measured using the Modified Mini-Mental State Examination at baseline and years 3, 5, and 8. Random effects models were used to classify participants as cognitive maintainers (cognitive change slope > or = 0), minor decliners (slope < 0 and > 1 SD below mean), or major decliners (slope < or = 1 SD below mean). Logistic regression was used to identify domain-specific factors associated with being a maintainer vs a minor decliner. RESULTS: Over 8 years, 30% of the participants maintained cognitive function, 53% showed minor decline, and 16% had major cognitive decline. In the multivariate model, baseline variables significantly associated with being a maintainer vs a minor decliner were age (odds ratio [OR] = 0.65, 95% confidence interval [CI] 0.55-0.77 per 5 years), white race (OR = 1.72, 95% CI 1.30-2.28), high school education level or greater (OR = 2.75, 95% CI 1.78-4.26), ninth grade literacy level or greater (OR = 4.85, 95% CI 3.00-7.87), weekly moderate/vigorous exercise (OR = 1.31, 95% CI 1.06-1.62), and not smoking (OR = 1.84, 95% CI 1.14-2.97). Variables associated with major cognitive decline compared to minor cognitive decline are reported. CONCLUSION: Elders who maintain cognitive function have a unique profile that differentiates them from those with minor decline. Importantly, some of these factors are modifiable and thus may be implemented in prevention programs to promote successful cognitive aging. Further, factors associated with maintenance may differ from factors associated with major cognitive decline, which may impact prevention vs treatment strategies.

Molecular and functional characterization of eight novel GAA mutations in Italian infants with Pompe disease.

We characterized 29 unrelated patients presenting with the severe form of Pompe disease (Glycogen Storage Disease Type II, acid maltase deficiency) and identified 26 pathogenic mutations divided over 28 different genotypes. Among the eight new mutations, five were exonic point mutations (c.572A>G, c.1124G>T, c.1202A>G, c.1564C>G and c.1796C>A) leading to codon changes (p.Y191C, p.R375L, p.Q401R, p.P522A and p.S599Y); two were intronic point mutations (c.-32-3C>A and c.1636+5G>C) affecting mRNA processing; one was a single base deletion (c.742delC) generating a truncated protein (p.L248PfsX20). A comprehensive evaluation, based on different methodological approaches, confirmed the detrimental effect of the eight mutations on the protein and its function. Structural alterations potentially induced by the five missense mutations were also predicted through visual inspection of the atomic model of the GAA protein, in terms of both function and spatial orientation of specific residues as well as disturbance generated by amino acid substitutions. Although the remarkable heterogeneity of the mutational spectrum in Pompe disease was already known, our data demonstrate and confirm the power of molecular and functional analysis in predicting the natural course of Pompe disease.

PPAR-gamma Pro12Ala genotype and risk of cognitive decline in elders.

BACKGROUND: The Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been associated with decreased risk of diabetes and obesity, both disorders linked to cognitive impairment. We tested whether this polymorphism is associated with cognition. METHODS: Two thousand nine hundred sixty-one participants (mean age, 74.1; 41% Black; 52% women) were administered the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and 4 year follow-up. Test scores were adjusted for age, sex, education, cerebrovascular disease, depression and APOE genotype and additionally for race. We determined the association between Ala allele and development of cognitive decline (3MS decline of > or = 5 points). RESULTS: At baseline, unadjusted scores on both cognitive tests were higher for Ala carriers compared to non-carriers (3MS, 94.2 versus 92.5, p<0.001; DSST, 40.2 versus 34.5, p<0.001). Similarly, follow-up scores were higher for Ala carriers. Multivariable adjustment led to similar results; additional adjustment for race attenuated the baseline 3MS results. After 4 years, 17.5% of Ala carriers developed cognitive decline compared to 25% among non-carriers (unadjusted OR=0.61; 95%CI, 0.46-0.82; adjusted OR=0.75; 95%CI, 0.55-1.02). Further adjustment for metabolic variables including fasting blood glucose and lipid level did not change the results. CONCLUSIONS: The PPAR-gamma Ala12 allele carriers may have less risk of developing cognitive decline.