Kim A. Celone

Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer's Disease: An Independent Component Analysis

Memory function is likely subserved by multiple distributed neural networks, which are disrupted by the pathophysiological process of Alzheimers disease (AD). In this study, we used multivariate analytic techniques to investigate memory-related functional magnetic resonance imaging (fMRI) activity in 52 individuals across the continuum of normal aging, mild cognitive impairment (MCI), and mild AD. Independent component analyses revealed specific memory-related networks that activated or deactivated during an associative memory paradigm. Across all subjects, hippocampal activation and parietal deactivation demonstrated a strong reciprocal relationship. Furthermore, we found evidence of a nonlinear trajectory of fMRI activation across the continuum of impairment. Less impaired MCI subjects showed paradoxical hyperactivation in the hippocampus compared with controls, whereas more impaired MCI subjects demonstrated significant hypoactivation, similar to the levels observed in the mild AD subjects. We found a remarkably parallel curve in the pattern of memory-related deactivation in medial and lateral parietal regions with greater deactivation in less-impaired MCI and loss of deactivation in more impaired MCI and mild AD subjects. Interestingly, the failure of deactivation in these regions was also associated with increased positive activity in a neocortical attentional network in MCI and AD. Our findings suggest that loss of functional integrity of the hippocampal-based memory systems is directly related to alterations of neural activity in parietal regions seen over the course of MCI and AD. These data may also provide functional evidence of the interaction between neocortical and medial temporal lobe pathology in early AD.

Age-related memory impairment associated with loss of parietal deactivation but preserved hippocampal activation

The neural underpinnings of age-related memory impairment remain to be fully elucidated. Using a subsequent memory face–name functional MRI (fMRI) paradigm, young and old adults showed a similar magnitude and extent of hippocampal activation during successful associative encoding. Young adults demonstrated greater deactivation (task-induced decrease in BOLD signal) in medial parietal regions during successful compared with failed encoding, whereas old adults as a group did not demonstrate a differential pattern of deactivation between trial types. The failure of deactivation was particularly evident in old adults who performed poorly on the memory task. These low-performing old adults demonstrated greater hippocampal and prefrontal activation to achieve successful encoding trials, possibly as a compensatory response. Findings suggest that successful encoding requires the coordination of neural activity in hippocampal, prefrontal, and parietal regions, and that age-related memory impairment may be primarily related to a loss of deactivation in medial parietal regions.

Hippocampal Hyperactivation in Presymptomatic Familial Alzheimer's Disease

The examination of individuals who carry fully penetrant genetic alterations that result in familial Alzheimers disease (FAD) provides a unique model for studying the early presymptomatic disease stages. In AD, deficits in episodic and associative memory have been linked to structural and functional changes within the hippocampal system. This study used functional MRI (fMRI) to examine hippocampal function in a group of healthy, young, cognitively‐intact presymptomatic individuals (average age 33.7 years) who carry the E280A presenilin‐1 (PS1) genetic mutation for FAD. These PS1 subjects will go on to develop the first symptoms of the disease around the age of 45 years. Our objective was to examine hippocampal function years before the onset of clinical symptoms.

Working memory for social cues recruits orbitofrontal cortex and amygdala: A functional magnetic resonance imaging study of delayed matching to sample for emotional expressions

During everyday interactions, we continuously monitor and maintain information about different individuals and their changing emotions in memory. Yet to date, working memory (WM) studies have primarily focused on mechanisms for maintaining face identity, but not emotional expression, and studies investigating the neural basis of emotion have focused on transient activity, not delay related activity. The goal of this functional magnetic resonance imaging study was to investigate WM for two critical social cues: identity and emotion. Subjects performed a delayed match-to-sample task that required them to match either the emotional expression or the identity of a face after a 10 s delay. Neuroanatomically, our predictions focused on the orbitofrontal cortex (OFC) and the amygdala, as these regions have previously been implicated in emotional processing and long-term memory, and studies have demonstrated sustained OFC and medial temporal lobe activity during visual WM. Consistent with previous studies, transient activity during the sample period representing emotion and identity was found in the superior temporal sulcus and inferior occipital cortex, respectively. Sustained delay-period activity was evident in OFC, amygdala, and hippocampus, for both emotion and identity trials. These results suggest that, although initial processing of emotion and identity is accomplished in anatomically segregated temporal and occipital regions, sustained delay related memory for these two critical features is held by the OFC, amygdala and hippocampus. These regions share rich connections, and have been shown previously to be necessary for binding features together in long-term memory. Our results suggest a role for these regions in active maintenance as well.

Relationship of fMRI activation to clinical trial memory measures in Alzheimer disease

Background: Functional MRI (fMRI) has shown promise as a tool to characterize altered brain function in Alzheimer disease (AD) and for use in proof of concept clinical trials. FMRI studies of subjects with AD have demonstrated altered hippocampal and neocortical activation while encoding novel stimuli compared to older controls. However, the relationship between fMRI activation and performance on standardized clinical trial memory measures has not been fully investigated. Objective: To determine whether patterns of activation during an associative-memory fMRI paradigm correlate with performance on memory measures used in AD clinical trials. Methods: Twenty-nine subjects with AD underwent neuropsychological testing, including the AD Assessment Scale (ADAS-Cog), and an associative-encoding fMRI paradigm. Scores were entered as regressors in SPM2 analyses of the differential fMRI activation to novel-vs-repeated (NvR) stimuli. To account for cerebral atrophy, native-space structure-function analyses were performed with subjects’ high-resolution structural images. Results: Performance on the ADAS-Cog verbal memory component, and the ADAS-Cog total score, correlated with NvR activation in left superior temporal (p = 0.0003; r = −0.51) and left prefrontal (p = 0.00001; r = −0.63) cortices. In a subgroup with more extensive neuropsychological testing (n = 14), performance on the Free and Cued Selective Reminding Test was correlated with activation in these same regions. fMRI activation remained correlated with performance even when accounting for atrophy. Conclusions: The relationship between functional MRI (fMRI) activation and standardized memory measures supports the potential use of fMRI to investigate regional mechanisms of treatment response in clinical trials of novel therapies for Alzheimer disease. GLOSSARY: AD = Alzheimer disease; ADAS-Cog = AD Assessment Scale; EPI = echoplanar imaging sequence; FA = flip angle; FCSRT = Free and Cued Selective Reminding Test; FLAME = FMRIB’s Local Analysis of Mixed Effects; fMRI = Functional MRI; FOV = field of view; GLM = general linear model; HRF = hemodynamic response function; LFG = left fusiform gyrus; LPFC = left prefrontal cortex; LSTG = left superior temporal gyrus; MMSE = Mini-Mental State Examination; MTL = medial temporal lobe; NvR = novel-vs-repeated; ROI = region of interest; TE = echo time; TR = repetition time.

Event-related potential markers of brain changes in preclinical familial Alzheimer disease

Objectives: Event-related potentials (ERPs) can reflect differences in brain electrophysiology underlying cognitive functions in brain disorders such as dementia and mild cognitive impairment. To identify individuals at risk for Alzheimer disease (AD) we used high-density ERPs to examine brain physiology in young presymptomatic individuals (average age 34.2 years) who carry the E280A mutation in the presenilin-1 (PSEN1) gene and will go on to develop AD around the age of 45. Methods: Twenty-one subjects from a Colombian population with familial AD participated: 10 presymptomatic subjects positive for the PSEN1 mutation (carriers) and 11 siblings without the mutation (controls). Subjects performed a visual recognition memory test while 128-channel ERPs were recorded. Results: Despite identical behavioral performance, PSEN1 mutation carriers showed less positivity in frontal regions and more positivity in occipital regions, compared to controls. These differences were more pronounced during the 200–300 msec period. Discriminant analysis at this time interval showed promising sensitivity (72.7%) and specificity (81.8%) of the ERP measures to predict the presence of AD pathology. Conclusions: Presymptomatic PSEN1 mutation carriers show changes in brain physiology that can be detected by high-density ERPs. The relative differences observed showing greater frontal positivity in controls and greater occipital positivity in carriers indicates that control subjects may use frontally mediated processes to distinguish between studied and unstudied visual items, whereas carriers appear to rely more upon perceptual details of the items to distinguish between them. These findings also demonstrate the potential usefulness of ERP brain correlates as preclinical markers of AD.

An fMRI investigation of the fronto-striatal learning system in women who exhibit eating disorder behaviors

In the present study, we sought to examine whether the fronto-striatal learning system, which has been implicated in bulimia nervosa, would demonstrate altered BOLD activity during probabilistic category learning in women who met subthreshold criteria for bulimia nervosa (Sub-BN). Sub-BN, which falls within the clinical category of Eating Disorder Not Otherwise Specified (EDNOS), is comprised of individuals who demonstrate recurrent binge eating, efforts to minimize their caloric intake and caloric retention, and elevated levels of concern about shape, weight, and/or eating, but just fail to meet the diagnostic threshold for bulimia nervosa (BN). fMRI data were collected from eighteen women with subthreshold-BN (Sub-BN) and nineteen healthy control women group-matched for age, education and body mass index (MC) during the weather prediction task. Sub-BN participants demonstrated increased caudate nucleus and dorsolateral prefrontal cortex (DLPFC) activation during the learning of probabilistic categories. Though the two subject groups did not differ in behavioral performance, over the course of learning, Sub-BN participants showed a dynamic pattern of brain activity differences when compared to matched control participants. Regions implicated in episodic memory, including the medial temporal lobe (MTL), retrosplenial cortex, middle frontal gyrus, and anterior and posterior cingulate cortex showed decreased activity in the Sub-BN participants compared to MCs during early learning which was followed by increased involvement of the DLPFC during later learning. These findings demonstrate that women with Sub-BN demonstrate differences in fronto-striatal learning system activity, as well as a distinct functional pattern between fronto-striatal and MTL learning systems during the course of implicit probabilistic category learning.

A neuroimaging perspective on the use of functional magnetic resonance imaging (fmri) in educational and legal systems

The goal of this commentary is to offer the perspective of neuroimaging researchers to the issues raised by Fenton and colleagues (2009) in their target article. We focus on two issues raised by the authors: 1) the link between functional magnetic resonance imaging (fMRI) signal and behavior, and 2) the power of fMRI group-level inference and the relative inefficiency of interpretation of fMRI at the level of the individual. In addition, we also discuss how fMRI researchers are fostering a sense of accountability and responsibility through accurate reporting practices and participation in the peer-review processes and by becoming active in public education, public policy, and the review of mainstream media reports of fMRI findings. Fenton and colleagues (2009) communicate concerns regarding potential uses of neuroimaging methods to inform educational and legal practices. These concerns reflect a genuine attempt to look ahead and safeguard society through policy and education. As neuroscientists, the goal of this commentary is to provide the larger community, including educators, members of the law enforcement and judicial system, policy makers, and journalists and the media with a neuroimaging perspective on the role of fMRI in society. fMRI technology provides a non-invasive method for investigating and understanding the relationship between behavior and cognition and the anatomical structure and physiological functioning of the brain. Critically, it is important to understand that fMRI was developed as a research tool, not as a clinical diagnostic method. Most people will at some point during their lives undergo a clinical MRI scan for diagnostic purposes. For example, your physician may want to examine the structural integrity of your knee, shoulder, hip, or spine. fMRI differs from these structural MRIs as it tracks changes in blood flow and oxygenation, known as the blood oxygen level-dependent (BOLD) signal. Changes in BOLD signal can be measured when subjects are performing different cognitive tasks, such as reading, listening to a story or music, learning a list of words, or viewing pictures. fMRI

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who progressed to AD after follow-up period (CDR 1; 11 patients; 7 women, 4 men) and second group consisted of patients who had stable symptoms of MCI (CDR 0.5; 8 patients; 3 women, 5 men). The relationship between hippocampal volume z-score and the risk of developing AD over a two-year period of observation adjusted for age and sex interaction in logistic regression model was Rsquare 0.65; p 0.045 for left hippocampus and Rsquare 0.56; p 0.055 for right hippocampus. Conclusions: Initial hippocampal volume may influence the dynamics of cognitive decline in MCI patients over a two-year period of observation. The difference of effect between sides suggests higher sensitivity of left hippocampal volume as a predictive marker of AD. However lack of normative values of hippocampal volume mean and SD for elderly population limits calculated z-score to studied population.