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1.  One-pot synthesis of cinnamylideneacetophenones and their in vitro cytotoxicity in breast cancer cells 
A series of cinnamylideneacetophenones were synthesized via a modified Claisen-Schmidt condensation reaction and evaluated for cytotoxicity against breast cancer cells using the Alamar Blue™assay. Derivatives 17 and 18 bearing a 2-nitro group on the B ring, exhibited sub-micromolar cytotoxicity in MCF-7 cells (IC50 = 71 and 1.9 nM) respectively. Derivative 17 also displayed sub-micromolar (IC50 = 780 nM) cytotoxicity in MDA-MB-468 cells. Additionally, 17 and 18 displayed significantly less cytotoxicity than the chemotherapeutic doxorubicin in non-tumorigenic MCF-10A cells. This study provides evidence supporting the continued development of nitro-substituted cinnamylideneacetophenones as small molecules to treat breast cancer.
PMCID: PMC4145842  PMID: 24957352
breast cancer; estrogen receptor; chalcone derivatives; leinamycin; cytotoxicity
2.  Neural correlates of conceptual object priming in young and older adults: An event-related fMRI study 
Neurobiology of aging  2012;34(4):1254-1264.
In this event-related fMRI study, we investigated age-related differences in brain activity associated with conceptual repetition priming in young and older adults. Participants performed a speeded “living/non-living” classification task with three repetitions of familiar objects. Both young and older adults showed a similar magnitude of behavioral priming to repeated objects and evidencing repetition-related activation reductions in fusiform gyrus, superior occipital, middle and inferior temporal cortex, as well as inferior frontal and insula regions. The neural priming effect in young adults was extensive and continued through both the second and third stimulus repetitions, whereas neural priming in older adults was markedly attenuated and reached floor at the second repetition. In young adults, greater neural priming in multiple brain regions correlated with greater behavioral facilitation whereas in older adults, only activation reduction in the left inferior frontal correlated with faster behavioral responses. These findings provide evidence for altered neural priming in older adults despite preserved behavioral priming, and suggest the possibility that age-invariant behavioral priming is observed as a result of more sustained neural processing of stimuli in older adults which may be a form of compensatory neural activity.
PMCID: PMC4028122  PMID: 23102512
Aging; fMRI; repetition priming; priming; implicit memory; recognition
3.  Changes in Brain Function Occur Years before the Onset of Cognitive Impairment 
The Journal of Neuroscience  2013;33(46):18008-18014.
To develop targeted intervention strategies for the treatment of Alzheimer's disease, we first need to identify early markers of brain changes that occur before the onset of cognitive impairment. Here, we examine changes in resting-state brain function in humans from the Baltimore Longitudinal Study of Aging. We compared longitudinal changes in regional cerebral blood flow (rCBF), assessed by 15O-water PET, over a mean 7 year period between participants who eventually developed cognitive impairment (n = 22) and those who remained cognitively normal (n = 99). Annual PET assessments began an average of 11 years before the onset of cognitive impairment in the subsequently impaired group, so all participants were cognitively normal during the scanning interval. A voxel-based mixed model analysis was used to compare groups with and without subsequent impairment. Participants with subsequent impairment showed significantly greater longitudinal rCBF increases in orbitofrontal, medial frontal, and anterior cingulate regions, and greater longitudinal decreases in parietal, temporal, and thalamic regions compared with those who maintained cognitive health. These changes were linear in nature and were not influenced by longitudinal changes in regional tissue volume. Although all participants were cognitively normal during the scanning interval, most of the accelerated rCBF changes seen in the subsequently impaired group occurred within regions thought to be critical for the maintenance of cognitive function. These changes also occurred within regions that show early accumulation of pathology in Alzheimer's disease, suggesting that there may be a connection between early pathologic change and early changes in brain function.
PMCID: PMC3828456  PMID: 24227712
4.  Frontal Function and Executive Processing in Older Adults: Process and Region Specific Age-Related Longitudinal Functional Changes 
NeuroImage  2012;69:43-50.
Longitudinal studies on aging brain function have shown declines in frontal activity as opposed to the over-recruitment shown in cross-sectional studies. Such mixed findings suggest that age-related changes in frontal activity may be process- and region-specific, having varied associations across different frontal regions involved in distinct cognitive processes, rather than generalized across the frontal cortex. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined individual differences through cross-sectional associations at baseline evaluation and longitudinal changes in regional cerebral blood flow (rCBF) in relation to different executive abilities in cognitively normal older adults. We found that, at baseline, greater rCBF in middle frontal regions correlated with better performance in abstraction and chunking, but greater rCBF in the insula and a distinct middle frontal region correlated with poorer inhibition and discrimination, respectively. In addition, increases in frontal rCBF over time were associated with longitudinal declines in abstraction, chunking, inhibition, discrimination, switching, and manipulation. These findings indicate process- and region-specific, rather than uniform, age-related changes in frontal brain-behavior associations, and also suggest that longitudinally high-levels of frontal engagement reflect declining rather than stable cognition.
PMCID: PMC3557589  PMID: 23266746
Aging; Longitudinal; Cross-Sectional; Brain Function; Executive Processing
5.  Culture-related differences in default network activity during visuo-spatial judgments 
Studies on culture-related differences in cognition have shown that Westerners attend more to object-related information, whereas East Asians attend more to contextual information. Neural correlates of these different culture-related visual processing styles have been reported in the ventral-visual and fronto-parietal regions. We conducted an fMRI study of East Asians and Westerners on a visuospatial judgment task that involved relative, contextual judgments, which are typically more challenging for Westerners. Participants judged the relative distances between a dot and a line in visual stimuli during task blocks and alternated finger presses during control blocks. Behaviorally, East Asians responded faster than Westerners, reflecting greater ease of the task for East Asians. In response to the greater task difficulty, Westerners showed greater neural engagement compared to East Asians in frontal, parietal, and occipital areas. Moreover, Westerners also showed greater suppression of the default network—a brain network that is suppressed under condition of high cognitive challenge. This study demonstrates for the first time that cultural differences in visual attention during a cognitive task are manifested both by differences in activation in fronto-parietal regions as well as suppression in default regions.
PMCID: PMC3575716  PMID: 22114080
culture; default network; fMRI; visuo-spatial processing
6.  Imaging-Based Biomarkers of Cognitive Performance in Older Adults Constructed via High-Dimensional Pattern Regression Applied to MRI and PET 
PLoS ONE  2013;8(12):e85460.
In this study, we used high-dimensional pattern regression methods based on structural (gray and white matter; GM and WM) and functional (positron emission tomography of regional cerebral blood flow; PET) brain data to identify cross-sectional imaging biomarkers of cognitive performance in cognitively normal older adults from the Baltimore Longitudinal Study of Aging (BLSA). We focused on specific components of executive and memory domains known to decline with aging, including manipulation, semantic retrieval, long-term memory (LTM), and short-term memory (STM). For each imaging modality, brain regions associated with each cognitive domain were generated by adaptive regional clustering. A relevance vector machine was adopted to model the nonlinear continuous relationship between brain regions and cognitive performance, with cross-validation to select the most informative brain regions (using recursive feature elimination) as imaging biomarkers and optimize model parameters. Predicted cognitive scores using our regression algorithm based on the resulting brain regions correlated well with actual performance. Also, regression models obtained using combined GM, WM, and PET imaging modalities outperformed models based on single modalities. Imaging biomarkers related to memory performance included the orbito-frontal and medial temporal cortical regions with LTM showing stronger correlation with the temporal lobe than STM. Brain regions predicting executive performance included orbito-frontal, and occipito-temporal areas. The PET modality had higher contribution to most cognitive domains except manipulation, which had higher WM contribution from the superior longitudinal fasciculus and the genu of the corpus callosum. These findings based on machine-learning methods demonstrate the importance of combining structural and functional imaging data in understanding complex cognitive mechanisms and also their potential usage as biomarkers that predict cognitive status.
PMCID: PMC3877379  PMID: 24392010
7.  Differential Trajectories of Age-Related Changes in Components of Executive and Memory Processes 
Psychology and aging  2011;27(3):707-719.
Several studies have demonstrated age-related declines in general executive function and memory. In this study, we examined cross-sectional and longitudinal age effects in more specific cognitive processes that constitute executive function and memory. We postulated that, whereas some components of executive and memory functions would show age differences and longitudinal declines, other specific abilities would be maintained or even improve with repeated testing. In a sample of individuals ≥55 years old from the Baltimore Longitudinal Study of Aging, we found longitudinal declines in inhibition, manipulation, semantic retrieval, phonological retrieval, switching, and long-term memory over a maximum of 14 years follow-up. In contrast, abstraction, capacity, chunking, discrimination, and short-term memory were maintained or even improved longitudinally, probably due in part to repeated testing. Moreover, whereas several different abilities were correlated across participants’ cross-sectional performance, longitudinal changes in performance showed more heterogeneous trajectories. Finally, compared with cross-sectional performance, longitudinal trajectories showed better distinction between participants with and those without later cognitive impairment. These results show that longitudinal cognitive aging of executive and memory functions is not a uniform process but a heterogeneous one and suggest that certain executive and memory functions remain stable despite age-related declines in other component processes.
PMCID: PMC3439590  PMID: 22201331
aging; executive function; memory; longitudinal; cross-sectional
8.  Sustained happiness? Lack of repetition suppression in right-ventral visual cortex for happy faces 
Emotional stimuli have been shown to preferentially engage initial attention but their sustained effects on neural processing remain largely unknown. The present study evaluated whether emotional faces engage sustained neural processing by examining the attenuation of neural repetition suppression to repeated emotional faces. Repetition suppression of neural function refers to the general reduction of neural activity when processing a repeated stimulus. Preferential processing of emotional face stimuli, however, should elicit sustained neural processing such that repetition suppression to repeated emotional faces is attenuated relative to faces with no emotional content. We measured the reduction of functional magnetic resonance imaging signals associated with immediate repetition of neutral, angry and happy faces. Whereas neutral faces elicited the greatest suppression in ventral visual cortex, followed by angry faces, repetition suppression was the most attenuated for happy faces. Indeed, happy faces showed almost no repetition suppression in part of the right-inferior occipital and fusiform gyri, which play an important role in face-identity processing. Our findings suggest that happy faces are associated with sustained visual encoding of face identity and thereby assist in the formation of more elaborate representations of the faces, congruent with findings in the behavioral literature.
PMCID: PMC3150853  PMID: 20584720
emotion; faces; repetition suppression; sustained processing; ventral visual cortex
9.  Cerebrospinal Fluid Aβ and Tau Level Fluctuation in an Older Clinical Cohort 
Archives of Neurology  2012;69(2):246-250.
To determine whether cerebrospinal fluid (CSF) biomarkers for Alzheimer disease fluctuate significantly over time in a cohort of older, mildly symptomatic individuals.
Biomarker validation in a clinical cohort.
University hospital inpatient unit.
Ten patients admitted for CSF drainage for diagnostic purposes.
Main Outcome Measures
The CSF levels of Aβ1–40, Aβ1–42, tau, and phosphorylated tau on threonine 181 (p-tau181) were measured every 6 hours for 24 or 36 hours.
The mean coefficient of variation values for each biomarker assessed in our 10 patients were 5.5% (95% CI, 3.8%–10.0%) for Aβ1–42, 12.2% (9.0%–24.2%) for Aβ1–40, 8.2% (5.7%–15.1%) for total tau, and 11.9% (8.5%–23.0%) for p-tau181. These values are only slightly higher than the variability in the assay. In addition, no significant circadian fluctuation in any Alzheimer disease biomarker was observed given the limitations of our sampling frequency.
In a cohort of elderly patients, little fluctuation in the levels of important Alzheimer disease biomarkers in lumbar CSF is seen as a function of time.
PMCID: PMC3310240  PMID: 22332192
10.  Brain Structure in Young and Old East Asians and Westerners: Comparisons of Structural Volume and Cortical Thickness 
Journal of Cognitive Neuroscience  2010;23(5):1065-1079.
There is an emergent literature suggesting that East Asians and Westerners differ in cognitive processes because of cultural biases to process information holistically (East Asians) or analytically (Westerners). To evaluate the possibility that such differences are accompanied by differences in brain structure, we conducted a large comparative study on cognitively matched young and old adults from two cultural/ethnic groups—Chinese Singaporeans and non-Asian Americans—that involved a total of 140 persons. Young predominantly White American adults were found to have higher cortical thickness in frontal, parietal, and medial-temporal polymodal association areas in both hemispheres. These findings were replicated using voxel-based morphometry applied to the same data set. Differences in cortical thickness observed between young volunteers were not significant in older subjects as a whole. However, group differences were evident when high-performing old were compared. Although the observed differences in gray matter may be rooted in strategic differences in cognition arising from ethnic/cultural differences, alternative explanations involving genetic heritage and environmental factors are also considered.
PMCID: PMC3361742  PMID: 20433238
11.  Neuroplasticity and cognitive aging: The scaffolding theory of aging and cognition 
A recent proposal called the Scaffolding Theory of Cognitive Aging (STAC) postulates that functional changes with aging are part of a lifespan process of compensatory cognitive scaffolding that is an attempt to alleviate the cognitive declines associated with aging. Indeed, behavioral studies have shown that aging is associated with both decline as well as preservation of selective cognitive abilities. Similarly, neuroimaging studies have revealed selective changes in the aging brain that reflect neural decline as well as compensatory neural recruitment. While aging is associated with reductions in cortical thickness, white-matter integrity, dopaminergic activity, and functional engagement in posterior brain regions such as the hippocampus and occipital areas, there are compensatory increases in frontal functional engagement that correlate with better behavioral performance in older adults. In this review, we discuss these age-related behavioral and brain findings that support the STAC model of cognitive scaffolding and additionally integrate the findings on neuroplasticity as a compensatory response in the aging brain. As such, we also examine the impact of external experiences in facilitating neuroplasticity in older adults. Finally, having laid the foundation for STAC, we briefly describe a proposed intervention trial (The Synapse Program) designed to evaluate the behavioral and neural impact of engagement in lifestyle activities that facilitates successful cognitive scaffolding using a controlled experiment where older adult participants are randomly assigned to different conditions of engagement.
PMCID: PMC3355626  PMID: 19847066
12.  Both left and right posterior parietal activations contribute to compensatory processes in normal aging 
Neuropsychologia  2011;50(1):55-66.
Older adults often exhibit greater brain activation in prefrontal cortex compared to younger adults, and there is some evidence that this increased activation compensates for age-related neural degradation that would otherwise adversely affect cognitive performance. Less is known about aging and compensatory recruitment in the parietal cortex. In this event-related functional magnetic resonance imaging study, we presented healthy young and old participants with two Stroop-like tasks (number magnitude and physical size). In young, the number magnitude task activated right parietal cortex and the physical size task activated left parietal cortex. In older adults, we observed contralateral parietal recruitment that depended on the task: in the number magnitude task older participants recruited left posterior parietal cortex (in addition to the right parietal activity observed in young) while in the physical size task they recruited right (in addition to left) posterior parietal cortex. In both cases, the additional parietal activity was associated with better performance suggesting that it played a compensatory role. Older adults also recruited left prefrontal cortex during both tasks and this common activation was also associated with better performance. The results provide evidence for task-specific compensatory recruitment in parietal cortex as well as task-independent compensatory recruitment in prefrontal cortex in normal aging.
PMCID: PMC3355662  PMID: 22063904
Age-related compensation; Event-related fMRI; Interference resolution; Posterior parietal cortex; Prefrontal cortex
13.  Culture differences in neural processing of faces and houses in the ventral visual cortex 
Behavioral and eye-tracking studies on cultural differences have found that while Westerners have a bias for analytic processing and attend more to face features, East Asians are more holistic and attend more to contextual scenes. In this neuroimaging study, we hypothesized that these culturally different visual processing styles would be associated with cultural differences in the selective activity of the fusiform regions for faces, and the parahippocampal and lingual regions for contextual stimuli. East Asians and Westerners passively viewed face and house stimuli during an functional magnetic resonance imaging experiment. As expected, we observed more selectivity for faces in Westerners in the left fusiform face area (FFA) reflecting a more analytic processing style. Additionally, Westerners showed bilateral activity to faces in the FFA whereas East Asians showed more right lateralization. In contrast, no cultural differences were detected in the parahippocampal place area (PPA), although there was a trend for East Asians to show greater house selectivity than Westerners in the lingual landmark area, consistent with more holistic processing in East Asians. These findings demonstrate group biases in Westerners and East Asians that operate on perceptual processing in the brain and are consistent with previous eye-tracking data that show cultural biases to faces.
PMCID: PMC2894673  PMID: 20558408
ventral-visual; selectivity; culture; faces; houses
14.  Cultural differences in the lateral occipital complex while viewing incongruent scenes 
Converging behavioral and neuroimaging evidence indicates that culture influences the processing of complex visual scenes. Whereas Westerners focus on central objects and tend to ignore context, East Asians process scenes more holistically, attending to the context in which objects are embedded. We investigated cultural differences in contextual processing by manipulating the congruence of visual scenes presented in an fMR-adaptation paradigm. We hypothesized that East Asians would show greater adaptation to incongruent scenes, consistent with their tendency to process contextual relationships more extensively than Westerners. Sixteen Americans and 16 native Chinese were scanned while viewing sets of pictures consisting of a focal object superimposed upon a background scene. In half of the pictures objects were paired with congruent backgrounds, and in the other half objects were paired with incongruent backgrounds. We found that within both the right and left lateral occipital complexes, Chinese participants showed significantly greater adaptation to incongruent scenes than to congruent scenes relative to American participants. These results suggest that Chinese were more sensitive to contextual incongruity than were Americans and that they reacted to incongruent object/background pairings by focusing greater attention on the object.
PMCID: PMC2894688  PMID: 20083532
culture; scene perception; context; incongruence; lateral occipital cortex
15.  Reduced Neural Selectivity Increases fMRI Adaptation with Age during Face Discrimination 
NeuroImage  2010;51(1):336-344.
Ventral-visual activity in older adults has been characterized by dedifferentiation, or reduced distinctiveness, of responses to different categories of visual stimuli such as faces and houses, that typically elicit highly specialized responses in the fusiform and parahippocampal brain regions respectively in young adults (Park et al., 2004). In the present study, we demonstrate that age-related neural dedifferentiation applies to within-category stimuli (different types of faces) as well, such that older adults process less distinctive representations for individual faces than young adults. We performed a functional magnetic resonance imaging adaptation experiment while young and older participants made same-different judgments to serially presented face-pairs that were Identical, Moderate in similarity through morphing, or Different. As expected, older adults showed adaptation in the fusiform face area (FFA), during the Identical as well as the Moderate conditions relative to the Different condition. Young adults showed adaptation during the Identical condition, but minimal adaptation to the Moderate condition. These results indicate that older adults’ FFA treated the morphed faces as Identical faces, reflecting decreased fidelity of neural representation of faces with age.
PMCID: PMC2847054  PMID: 20139012
Aging; Dedifferentiation; Faces; Fusiform Area; Adaptation
16.  Functional Dedifferentiation and Altered Connectivity in Older Adults: Neural Accounts of Cognitive Aging 
Aging and disease  2011;2(1):30-48.
Aging is associated with myriad changes in behavioral performance and brain structure and function. Given this complex interplay of brain and behavior, two streams of findings are reviewed here that show that aging is generally associated with dedifferentiated neural processes, and also changes in functional connectivity. This article considers an integrated view of how such age-related dedifferentiation of neural function and changes in functional connectivity are related, highlighting some recent findings on differences in small-world architecture in the functional connectivity of young and older adults. These findings suggest that both neural connectivity and the organization of these connections are important determinants of processing efficiency with aging that may be the underlying mechanisms for dedifferentiation. Thus, the evaluation of the neurocognitive effects of aging on functional connectivity provides an alternative framework that captures the behavioral and brain changes that are observed in cognitive aging.
PMCID: PMC3066008  PMID: 21461180
Aging; Dedifferentiation; Connectivity; Functional; Structural; Behavioral; Neuromodulation; Imaging
17.  Culture Modulates Eye-Movements to Visual Novelty 
PLoS ONE  2009;4(12):e8238.
When viewing complex scenes, East Asians attend more to contexts whereas Westerners attend more to objects, reflecting cultural differences in holistic and analytic visual processing styles respectively. This eye-tracking study investigated more specific mechanisms and the robustness of these cultural biases in visual processing when salient changes in the objects and backgrounds occur in complex pictures.
Methodology/Principal Findings
Chinese Singaporean (East Asian) and Caucasian US (Western) participants passively viewed pictures containing selectively changing objects and background scenes that strongly captured participants' attention in a data-driven manner. We found that although participants from both groups responded to object changes in the pictures, there was still evidence for cultural divergence in eye-movements. The number of object fixations in the US participants was more affected by object change than in the Singapore participants. Additionally, despite the picture manipulations, US participants consistently maintained longer durations for both object and background fixations, with eye-movements that generally remained within the focal objects. In contrast, Singapore participants had shorter fixation durations with eye-movements that alternated more between objects and backgrounds.
The results demonstrate a robust cultural bias in visual processing even when external stimuli draw attention in an opposite manner to the cultural bias. These findings also extend previous studies by revealing more specific, but consistent, effects of culture on the different aspects of visual attention as measured by fixation duration, number of fixations, and saccades between objects and backgrounds.
PMCID: PMC2790339  PMID: 20016829
18.  Investigation and validation of intersite fMRI studies using the same imaging hardware 
To provide a between site comparison of functional MRI (fMRI) signal reproducibility in two laboratories equipped with identical imaging hardware and software. Many studies have looked at within subject reliability and more recent efforts have begun to calibrate responses across sites, magnetic field strengths, and software. By comparing identical imaging hardware and software, we provide a benchmark for future multi-site comparisons.
Materials and Methods
We evaluated system compatibility based on noise and stability properties of phantom scans and contrast estimates from repeated runs of a blocked motor and visual task on the same four subjects at both sites.
ANOVA and ROI analysis confirmed that site did not play a significant role in explaining variance in our large fMRI data set. Effect size analysis shows that between-subject differences account for nearly ten times more variance than site effects.
We show that quantitative comparisons of contrast estimates derived from cognitive experiments can reliably be compared across two sites. This allows us to establish an effective platform for comparing group differences between two sites using fMRI when group effects are potentially confounded with site, as in the study of neurocultural differences between countries or multi-center clinical trials.
PMCID: PMC2785504  PMID: 18581342
functional MRI; reproducibility; intersite comparisons; effect size; cultural neuroscience
19.  Contextual Interference in Recognition Memory with Age 
NeuroImage  2007;35(3):1338-1347.
Previous behavioral research suggests that although elderly adults' memory benefits from supportive context, misleading or irrelevant contexts produce greater interference. In the present study, we use event-related fMRI to investigate age differences when processing contextual information to make recognition judgments. Twenty-one young and 20 elderly incidentally encoded pictures of objects presented in meaningful contexts, and completed a memory test for the objects presented in identical or novel contexts. Elderly committed more false alarms than young when novel objects were presented in familiar, but task-irrelevant, contexts. Elderly showed reduced engagement of bilateral dorsolateral prefrontal cortex and anterior cingulate relative to young, reflecting disruption of a cognitive control network for processing context with age. Disruption occurred for both high and low performing elderly, suggesting that cognitive control deficits are pervasive with age. Despite showing disruption of the cognitive control network, high performing elderly recruited additional middle and medial frontal regions that were not recruited by either low-performing elderly or young adults. This suggests that high-performing elderly may compensate for disruption of the cognitive control network by recruiting additional frontal resources to overcome cognitive control deficits that affect recognition memory.
PMCID: PMC1865530  PMID: 17355910
Aging; Cognitive control; Context; Long-term Memory; Prefrontal Cortex
20.  Functional Dedifferentiation and Altered Connectivity in Older Adults: Neural Accounts of Cognitive Aging 
Aging and Disease  2011;2(1):30-48.
Aging is associated with myriad changes in behavioral performance and brain structure and function. Given this complex interplay of brain and behavior, two streams of findings are reviewed here that show that aging is generally associated with dedifferentiated neural processes, and also changes in functional connectivity. This article considers an integrated view of how such age-related dedifferentiation of neural function and changes in functional connectivity are related, highlighting some recent findings on differences in small-world architecture in the functional connectivity of young and older adults. These findings suggest that both neural connectivity and the organization of these connections are important determinants of processing efficiency with aging that may be the underlying mechanisms for dedifferentiation. Thus, the evaluation of the neurocognitive effects of aging on functional connectivity provides an alternative framework that captures the behavioral and brain changes that are observed in cognitive aging.
PMCID: PMC3066008  PMID: 21461180
Aging; Dedifferentiation; Connectivity; Functional; Structural; Behavioral; Neuromodulation; Imaging

Results 1-20 (20)