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1.  Recognition of Famous Names Predicts Episodic Memory Decline in Cognitively Intact Elders 
Neuropsychology  2013;27(3):333-342.
Semantic memory impairment is common in both Mild Cognitive Impairment (MCI) and early Alzheimer’s disease (AD), and the ability to recognize familiar people is particularly vulnerable. A time-limited temporal gradient (TG) in which well known people from decades earlier are better recalled than those learned recently is also reported in both AD and MCI. In this study, we hypothesized that the TG pattern on a famous name recognition task (FNRT) administered to cognitively intact elders would predict future episodic memory decline, and would also show a significant correlation with hippocampal volume.
78 healthy elders (ages 65-90) with normal cognition and episodic memory at baseline were administered a FNRT. Follow-up episodic memory testing 18 months later produced two groups: Declining (≥ 1 SD reduction in episodic memory) and Stable (< 1 SD).
The Declining group (N=27) recognized fewer recent famous names than the Stable group (N=51), while recognition for remote names was comparable. Baseline MRI volumes for both the left and right hippocampus was significantly smaller in the Declining group than the Stable group. Smaller baseline hippocampal volume was also significantly correlated with poorer performance for recent, but not remote famous names. Logistic regression analyses indicated that baseline TG performance was a significant predictor of group status (Declining versus Stable) independent of chronological age and APOE ε4 inheritance.
Famous name recognition may serve as an early pre-clinical cognitive marker of episodic memory decline in older individuals.
PMCID: PMC3798037  PMID: 23688215
Famous names; episodic memory; hippocampus; semantic memory; temporal gradient
2.  Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease 
We examined the impact of physical activity (PA) on longitudinal change in hippocampal volume in cognitively intact older adults at varying genetic risk for the sporadic form of Alzheimer's disease (AD). Hippocampal volume was measured from structural magnetic resonance imaging (MRI) scans administered at baseline and at an 18-month follow-up in 97 healthy, cognitively intact older adults. Participants were classified as High or Low PA based on a self-report questionnaire of frequency and intensity of exercise. Risk status was defined by the presence or absence of the apolipoprotein E-epsilon 4 (APOE-ε4) allele. Four subgroups were studied: Low Risk/High PA (n = 24), Low Risk/Low PA (n = 34), High Risk/High PA (n = 22), and High Risk/Low PA (n = 17). Over the 18 month follow-up interval, hippocampal volume decreased by 3% in the High Risk/Low PA group, but remained stable in the three remaining groups. No main effects or interactions between genetic risk and PA were observed in control brain regions, including the caudate, amygdala, thalamus, pre-central gyrus, caudal middle frontal gyrus, cortical white matter (WM), and total gray matter (GM). These findings suggest that PA may help to preserve hippocampal volume in individuals at increased genetic risk for AD. The protective effects of PA on hippocampal atrophy were not observed in individuals at low risk for AD. These data suggest that individuals at genetic risk for AD should be targeted for increased levels of PA as a means of reducing atrophy in a brain region critical for the formation of episodic memories.
PMCID: PMC4005962  PMID: 24795624
cognitive aging; Alzheimer's disease; volumetric MRI; association studies in genetics; physical activity; exercise
3.  Motor Variability during Sustained Contractions Increases with Cognitive Demand in Older Adults 
To expose cortical involvement in age-related changes in motor performance, we compared steadiness (force fluctuations) and fatigability of submaximal isometric contractions with the ankle dorsiflexor muscles in older and young adults and with varying levels of cognitive demand imposed. Sixteen young (20.4 ± 2.1 year: 8 men, 9 women) and 17 older adults (68.8 ± 4.4 years: 9 men, 8 women) attended three sessions and performed a 40 s isometric contraction at 5% maximal voluntary contraction (MVC) force followed by an isometric contraction at 30% MVC until task failure. The cognitive demand required during the submaximal contractions in each session differed as follows: (1) high-cognitive demand session where difficult mental math was imposed (counting backward by 13 from a 4-digit number); (2) low-cognitive demand session which involved simple mental math (counting backward by 1); and (3) control session with no mental math. Anxiety was elevated during the high-cognitive demand session compared with other sessions for both age groups but more so for the older adults than young adults (p  < 0.05). Older adults had larger force fluctuations than young adults during: (1) the 5% MVC task as cognitive demand increased (p  = 0.007), and (2) the fatiguing contraction for all sessions (p  = 0.002). Time to task failure did not differ between sessions or age groups (p  > 0.05), but the variability between sessions (standard deviation of three sessions) was greater for older adults than young (2.02 ± 1.05 vs. 1.25 ± 0.51 min, p  < 0.05). Thus, variability in lower limb motor performance for low- and moderate-force isometric tasks increased with age and was exacerbated when cognitive demand was imposed, and may be related to modulation of synergist and antagonist muscles and an altered neural strategy with age originating from central sources. These data have significant implications for cognitively demanding low-force motor tasks that are relevant to functional and ergonomic in an aging workforce.
PMCID: PMC4033244  PMID: 24904410
arousal; ankle dorsiflexor muscles; muscle fatigue; age; motor variability; steadiness; aging; stress
4.  Functional Magnetic Resonance Imaging of Semantic Memory as a Presymptomatic Biomarker of Alzheimer’s Disease Risk 
Biochimica et biophysica acta  2011;1822(3):442-456.
Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer’s disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed.
PMCID: PMC3580153  PMID: 21996618
Apolipoprotein E; Cognitive Activity; Functional Magnetic Resonance Imaging; Hippocampus; Physical Activity; fMRI; semantic memory; person identification; Alzheimer’s disease; cognitive decline; prediction
5.  Physical Activity and Brain Function in Older Adults at Increased Risk for Alzheimer’s Disease 
Brain Sciences  2013;3(1):54-83.
Leisure-time physical activity (PA) and exercise training are known to help maintain cognitive function in healthy older adults. However, relatively little is known about the effects of PA on cognitive function or brain function in those at increased risk for Alzheimer’s disease through the presence of the apolipoproteinE epsilon4 (APOE-ε4) allele, diagnosis of mild cognitive impairment (MCI), or the presence of metabolic disease. Here, we examine the question of whether PA and exercise interventions may differentially impact cognitive trajectory, clinical outcomes, and brain structure and function among individuals at the greatest risk for AD. The literature suggests that the protective effects of PA on risk for future dementia appear to be larger in those at increased genetic risk for AD. Exercise training is also effective at helping to promote stable cognitive function in MCI patients, and greater cardiorespiratory fitness is associated with greater brain volume in early-stage AD patients. In APOE-ε4 allele carriers compared to non-carriers, greater levels of PA may be more effective in reducing amyloid burden and are associated with greater activation of semantic memory-related neural circuits. A greater research emphasis should be placed on randomized clinical trials for exercise, with clinical, behavioral, and neuroimaging outcomes in people at increased risk for AD.
PMCID: PMC4061823  PMID: 24961307
Alzheimer’s disease; cognition; exercise; physical activity; APOE genotype; genetic risk; mild cognitive impairment; memory; MRI; neuroimaging
6.  Comparison of semantic and episodic memory BOLD fMRI activation in predicting cognitive decline in older adults 
Previous studies suggest that task-activated fMRI can predict future cognitive decline among healthy older adults. The present fMRI study examined the relative sensitivity of semantic memory (SM) versus episodic memory (EM) activation tasks for predicting cognitive decline. Seventy-eight cognitively intact elders underwent neuropsychological testing at entry and after an 18-month interval, with participants classified as cognitively “Stable” or “Declining” based on ≥1.0 SD decline in performance. Baseline fMRI scanning involved SM (famous name discrimination) and EM (name recognition) tasks. SM and EM fMRI activation, along with APOE ε4 status, served as predictors of cognitive outcome using a logistic regression analysis. Twenty-seven (34.6%) participants were classified as Declining and 51 (65.4%) as Stable. APOE ε4 status alone significantly predicted cognitive decline (R2 = .106; C index = .642). Addition of SM activation significantly improved prediction accuracy (R2 = .285; C index = .787), whereas the addition of EM did not (R2 = .212; C index = .711). In combination with APOE status, SM task activation predicts future cognitive decline better than EM activation. These results have implications for use of fMRI in prevention clinical trials involving the identification of persons at-risk for age-associated memory loss and Alzheimer’s disease.
PMCID: PMC3584558  PMID: 23199565
magnetic resonance imaging; aging; Apolipoprotein-E; memory loss; mild cognitive impairment; longitudinal study
7.  Lifestyle and Genetic Contributions to Cognitive Decline and Hippocampal Integrity in Healthy Aging 
Current Alzheimer research  2012;9(4):436-446.
Engagement in cognitively stimulating activities (CA) and leisure time physical activity (PA) have been associated with maintaining cognitive performance and reducing the likelihood of cognitive decline in older adults. However, neural mechanisms underlying protective effects of these lifestyle behaviors are largely unknown. In the current study, we investigated the effect of self-reported PA and CA on hippocampal volume and semantic processing activation during a fame discrimination task, as measured by functional magnetic resonance imaging (fMRI). We also examined whether possession of the apolipoprotein E (APOE) ε4 allele could moderate the effect of PA or CA on hippocampal structure or function.
Seventy-eight healthy, cognitively intact older adults underwent baseline neuropsychological assessment, hippocampal volume measurement via manually-traced structural MRI, and task-activated fMRI.
After 18 months, 27 participants declined by one standard deviation or more on follow-up neuropsychological testing. Logistic regression analyses revealed that CA alone or in combination with baseline hippocampal structure or functional activity did not predict the probability of cognitive decline. In contrast, PA interacted with APOE ε4 status such that engagement in PA reduced the risk of cognitive decline in APOE ε4 carriers only. Furthermore, the benefits of PA appeared to diminish with reduced functional activity or volume in the hippocampus.
Our findings suggest that increased leisure time PA is associated with reduced probability of cognitive decline in persons who are at high risk for AD. The beneficial effects of PA in this group may be related to enhancement of the functional and structural integrity of the hippocampus.
PMCID: PMC3584642  PMID: 22272622
Apolipoprotein E; Cognitive Activity; Cognitive Decline; Functional Magnetic Resonance Imaging; Hippocampus; Physical Activity
8.  Does Physical Activity Influence Semantic Memory Activation in Amnestic Mild Cognitive Impairment? 
Psychiatry research  2011;193(1):60-62.
The effect of physical activity (PA) on functional brain activation for semantic memory in amnestic mild cognitive impairment (aMCI) was examined using event-related fMRI during fame discrimination. Greater semantic memory activation occurred in the left caudate of High- versus Low-PA patients (P = 0.03), suggesting PA may enhance memory-related caudate activation in aMCI.
PMCID: PMC3105157  PMID: 21601432
Exercise; Alzheimer’s Disease; Cognition
9.  Interactive Effects of Physical Activity and APOE-ε4 on BOLD Semantic Memory Activation in Healthy Elders 
NeuroImage  2010;54(1):635-644.
Evidence suggests that physical activity (PA) is associated with the maintenance of cognitive function across the lifespan. In contrast, the apolipoproteinE-ε4 (APOE-ε4) allele, a genetic risk factor for Alzheimer’s disease (AD), is associated with impaired cognitive function. The objective of this study was to examine the interactive effects of PA and APOE-ε4 on brain activation during memory processing in older (ages 65–85) cognitively intact adults. A cross-sectional design was used with four groups (n = 17 each): (1) Low Risk/Low PA; (2) Low Risk/High PA; (3) High Risk/Low PA; and (4) High Risk/High PA. PA level was based on self-reported frequency and intensity. AD risk was based on presence or absence of an APOE-ε4 allele. Brain activation was measured using event-related functional magnetic resonance imaging (fMRI) while participants performed a famous name discrimination task. Brain activation subserving semantic memory processing occurred in 15 functional regions of interest. High PA and High Risk were associated with significantly greater semantic memory activation (famous > unfamiliar) in 6 and 3 of the 15 regions, respectively. Significant interactions of PA and Risk were evident in 9 of 15 brain regions, with the High PA/High Risk group demonstrating greater semantic memory activation than the remaining three groups. These findings suggest that PA selectively increases memory-related brain activation in cognitively intact but genetically at-risk elders. Longitudinal studies are required to determine whether increased semantic memory processing in physically active at-risk individuals is protective against future cognitive decline.
PMCID: PMC2962671  PMID: 20691792
Leisure-time physical activity; exercise; Alzheimer’s disease; APOE-epsilon4 allele genetic risk; age-related cognitive decline; fMRI
10.  Common neural systems associated with the recognition of famous faces and names: An event-related fMRI study 
Brain and cognition  2010;72(3):491-498.
Person recognition can be accomplished through several modalities (face, name, voice). Lesion, neurophysiology and neuroimaging studies have been conducted in an attempt to determine the similarities and differences in the neural networks associated with person identity via different modality inputs. The current study used event-related functional-MRI in 17 healthy participants to directly compare activation in response to randomly presented famous and non-famous names and faces (25 stimuli in each of the four categories). Findings indicated distinct areas of activation that differed for faces and names in regions typically associated with pre-semantic perceptual processes. In contrast, overlapping brain regions were activated in areas associated with the retrieval of biographical knowledge and associated social affective features. Specifically, activation for famous faces was primarily right lateralized and famous names were left lateralized. However, for both stimuli, similar areas of bilateral activity were observed in the early phases of perceptual processing. Activation for fame, irrespective of stimulus modality, activated an extensive left hemisphere network, with bilateral activity observed in the hippocampi, posterior cingulate, and middle temporal gyri. Findings are discussed within the framework of recent proposals concerning the neural network of person identification.
PMCID: PMC2935638  PMID: 20167415
11.  Gender Specific Disruptions in Emotion Processing in Younger Adults with Depression 
Depression and anxiety  2009;26(2):182-189.
One of the principal theories regarding the biological basis of Major Depressive Disorder (MDD) implicates a dysregulation of emotion processing circuitry. Gender differences in how emotions are processed and relative experience with emotion processing might help to explain some of the disparities in the prevalence of MDD between women and men. The current study sought to explore how gender and depression status relate to emotion processing.
This study employed a 2 (MDD status) × 2 (gender) factorial design to explore differences in classifications of posed facial emotional expressions (N = 151).
For errors, there was an interaction between gender and depression status. Women with MDD made more errors than did non-depressed women and men with MDD, particularly for fearful and sad stimuli (ps < .02), which they were likely to misinterpret as angry (ps < .04). There was also an interaction of diagnosis and gender for response cost for negative stimuli, with significantly greater interference from negative faces present in women with MDD compared with non-depressed women (p = .01). Men with MDD, conversely, performed similarly to control men (p = .61).
These results provide novel and intriguing evidence that depression in younger adults (< 35 years) differentially disrupts emotion processing in women as compared to men. This interaction could be driven by neurobiological and social learning mechanisms, or interactions between them, and may underlie differences in the prevalence of depression in women and men.
PMCID: PMC3013355  PMID: 18800371
psychiatric disorders; affect perception; sex differences
12.  Prediction of Cognitive Decline in Healthy Older Adults using fMRI 
Few studies have examined the extent to which structural and functional MRI, alone and in combination with genetic biomarkers, can predict future cognitive decline in asymptomatic elders. This prospective study evaluated individual and combined contributions of demographic information, genetic risk, hippocampal volume, and fMRI activation for predicting cognitive decline after an 18-month retest interval. Standardized neuropsychological testing, an fMRI scans semantic memory task (famous name discrimination), and structural MRI (sMRI) were performed on 78 healthy elders (73% female; mean age = 73 years, range = 65 to 88 years). Positive family history of dementia and presence of one or both apolipoprotein E (APOE) ε4 alleles occurred in 51.3% and 33.3% of the sample, respectively. Hippocampal volumes were traced from sMRI scans. At follow-up, all participants underwent a repeat neuropsychological examination. At 18 months, 27 participants (34.6%) declined by at least 1 SD on one of three neuropsychological measures. Using logistic regression, demographic variables (age, years of education, gender) and family history of dementia did not predict future cognitive decline. Greater fMRI activity, absence of an APOE ε4 allele, and larger hippocampal volume were associated with reduced likelihood of cognitive decline. The most effective combination of predictors involved fMRI brain activity and APOE ε4 status. Brain activity measured from task-activated fMRI, in combination with APOE ε4 status, was successful in identifying cognitively intact individuals at greatest risk for developing cognitive decline over a relatively brief time period. These results have implications for enriching prevention clinical trials designed to slow AD progression.
PMCID: PMC2940960  PMID: 20634590
Aging; apolipoprotein E; cognitive decline; fMRI; hippocampal volume; neuroimaging; memory
13.  Semantic Knowledge for Famous Names in Mild Cognitive Impairment 
Person identification represents a unique category of semantic knowledge that is commonly impaired in Alzheimer's Disease (AD), but has received relatively little investigation in patients with Mild Cognitive Impairment (MCI). The current study examined the retrieval of semantic knowledge for famous names from three time epochs (recent, remote, and enduring) in two participant groups; 23 aMCI patients and 23 healthy elderly controls. The aMCI group was less accurate and produced less semantic knowledge than controls for famous names. Names from the enduring period were recognized faster than both recent and remote names in both groups, and remote names were recognized more quickly than recent names. Episodic memory performance was correlated with greater semantic knowledge particularly for recent names. We suggest that the anterograde memory deficits in the aMCI group interferes with learning of recent famous names and as a result produces difficulties with updating and integrating new semantic information with previously stored information. The implications of these findings for characterizing semantic memory deficits in MCI are discussed.
PMCID: PMC2774216  PMID: 19128524
semantic memory; aging; fame recognition; person identity; remote memory; temporal gradient
14.  Comparability of functional MRI response in young and old during inhibition 
Neuroreport  2004;15(1):129-133.
When using fMRI to study age-related cognitive changes, it is important to establish the integrity of the hemodynamic response because, potentially, it can be affected by age and disease. However, there have been few attempts to document such integrity and no attempts using higher cognitive rather than perceptual or motor tasks. We used fMRI with 28 healthy young and older adults on an inhibitory control task. Although older and young adults differed in task performance and activation patterns, they had comparable hemodynamic responses. We conclude that activation during cognitive inhibition, which was predominantly increased in elders, was not due to vascular confounds or specific changes in hemodynamic coupling.
PMCID: PMC2078238  PMID: 15106844
Aging; Cognition; Event-related fMRI; Inhibition; Hemodynamic coupling; Recruitment
15.  An evaluation of distinct volumetric and functional MRI contributions toward understanding age and task performance: A study in the basal ganglia 
Brain research  2007;1135(1):58-68.
Prior work by our group and others has implicated the basal ganglia as important in age-related differences in tasks involving motor response control. The present study used structural and functional MRI approaches to analyze this region of interest (ROI) toward better understanding the contributions of structural and functional MRI measures to understanding age-related and task performance-related cognitive differences. Eleven healthy elders were compared with 11 healthy younger adults while they completed the “go” portion of a complex Go/No-go task. Separate ROI’s in the bilateral caudate (C) and putamen/globus pallidus (PGp) were studied based upon previous findings of age-related functional MRI differences in basal ganglia for this portion of the task. Structural volumes and functional activation (in percent area under the curve during correct responses) were independently extracted for these ROI’s. Results showed that age correlated with ROI volume in bilateral PGp and C, while multiple task performance measures correlated with functional activation in the left PGp. The Go/No-go task measures were also significantly correlated with traditional attention and executive functioning measures. Importantly, fMRI activation and volumes from each ROI were not significantly inter-correlated. These findings suggest that structural and functional MRI make unique contributions to the study of performance changes in aging.
PMCID: PMC2078239  PMID: 17210145
Aging; fMRI; Imaging; Executive functioning; Attention Response execution; Motor skill
16.  Age-related functional recruitment for famous name recognition: An event-related fMRI study 
Neurobiology of aging  2005;27(10):1494-1504.
Recent neuroimaging research shows that older adults exhibit recruitment, or increased activation on various cognitive tasks. The current study evaluated whether a similar pattern also occurs in semantic memory by evaluating age-related differences during recognition of Recent (since the 1990s) and Enduring (1950s to present) famous names. Fifteen healthy older and 15 healthy younger adults performed the name recognition task with a high and comparable degree of accuracy, although older adults had slower reaction time in response to Recent famous names. Event-related functional MRI showed extensive networks of activation in the two groups including posterior cingulate, right hippocampus, temporal lobe and left prefrontal regions. The Recent condition produced more extensive activation than the Enduring condition. Older adults had more extensive and greater magnitude of activation in 15 of 20 regions, particularly for the Recent condition (15 of 15; 7 of 15 also differed for Enduring); young adults did not show greater activation magnitude in any region. There were no group differences for non-famous names, indicating that age differences are task-specific. The results support and extend the existing literature to semantic memory tasks, indicating that older adult brains use functional recruitment to support task performance, even when task performance accuracy is high.
PMCID: PMC2078241  PMID: 16225965
Semantic memory; Event-related fMRI; Functional recruitment; Aging; Posterior cingulate; Frontal lobes; Neuroimaging; Cognition
17.  Temporally Graded Activation of Neocortical Regions in Response to Memories of Different Ages 
Journal of cognitive neuroscience  2007;19(7):1113-1124.
The temporally graded memory impairment seen in many neurobehavioral disorders implies different neuroanatomical pathways and/or cognitive mechanisms involved in storage and retrieval of memories of different ages. A dynamic interaction between medial-temporal and neocortical brain regions has been proposed to account for memory’s greater permanence with time. Despite considerable debate concerning its time-dependent role in memory retrieval, medial-temporal lobe activity has been well studied. However, the relative participation of neocortical regions in recent and remote memory retrieval has received much less attention. Using functional magnetic resonance imaging, we demonstrate robust, temporally graded signal differences in posterior cingulate, right middle frontal, right fusiform, and left middle temporal regions in healthy older adults during famous name identification from two disparate time epochs. Importantly, no neocortical regions demonstrated greater response to older than to recent stimuli. Our results suggest a possible role of these neocortical regions in temporally dating items in memory and in establishing and maintaining memory traces throughout the lifespan. Theoretical implications of these findings for the two dominant models of remote memory functioning (Consolidation Theory and Multiple Trace Theory) are discussed.
PMCID: PMC2078236  PMID: 17583988

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