Task-dependent posterior cingulate activation in mild cognitive impairment

Neuroimaging research has demonstrated that the posterior cingulate cortex (PCC) is functionally compromised in individuals diagnosed with amnestic mild cognitive impairment (MCI), a major risk factor for the development of Alzheimer\u27s disease (AD). In functional MRI studies with healthy participants, this same region is active during self-appraisal (requiring retrieval of semantic knowledge about the self) as well as episodic recognition of previously learned information. Administering both types of tasks to people with MCI may reveal important information on the role of the PCC in recollection. This study investigated fMRI activation in the PCC in individuals with MCI and matched controls across two tasks. The first task was a visual episodic recognition task. The second task was an autobiographical self-appraisal task in which subjects rated themselves on a set of trait adjectives. Results of a conjunction analysis revealed the PCC as the sole region commonly active during both tasks in the healthy older adults. Furthermore, additional analysis revealed an interaction in the PCC, indicating a task-dependent response in the MCI group. MCI participants showed PCC activation during self-appraisal, but not episodic retrieval. This result suggests in MCI that the PCC shows functional degradation during episodic retrieval; however, the PCC\u27s role in retrieval and evaluation of highly elaborated information regarding the self is more well-preserved. © 2005 Elsevier Inc. All rights reserved

Anosognosia in mild cognitive impairment: Relationship to activation of cortical midline structures involved in self-appraisal

Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer\u27s disease (AD), is variable. Anosognosia, or unawareness of loss of function, is beginning to be recognized as an important clinical symptom of MCI. However, little is known about the brain substrates underlying this symptom. We hypothesized that MCI participants\u27 activation of cortical midline structures (CMS) during self-appraisal would covary with level of insight into cognitive difficulties (indexed by a discrepancy score between patient and informant ratings of cognitive decline in each MCI participant). To address this hypothesis, we first compared 16 MCI participants and 16 age-matched controls, examining brain regions showing conjoint or differential BOLD response during self-appraisal. Second, we used regression to investigate the relationship between awareness of deficit in MCI and BOLD activity during self-appraisal, controlling for extent of memory impairment. Between-group comparisons indicated that MCI participants show subtly attenuated CMS activity during self-appraisal. Regression analysis revealed a highly significant relationship between BOLD response during self-appraisal and self-awareness of deficit in MCI. This finding highlights the level of anosognosia in MCI as an important predictor of response to self-appraisal in cortical midline structures, brain regions vulnerable to changes in early AD. © 2007 The International Neuropsychological Society

Structural MRI discriminates individuals with Mild Cognitive Impairment from age-matched controls: A combined neuropsychological and voxel based morphometry study

Background: Several previous studies have reported that amnestic mild cognitive impairment (aMCI), a significant risk factor for Alzheimer\u27s disease (AD), is associated with greater atrophy in the medial temporal lobe (MTL) and posterior cingulate gyrus (PCG). Method: In the present study, we examined the cross-sectional accuracy (i.e., the sensitivity and specificity) of voxel-based morphometry (VBM) in discriminating individuals with MCI (n = 15) from healthy age-matched controls (n = 15). In addition, we also sought to determine whether baseline GM volume predicted aMCI patients that converted to AD from those that did not approximately 2 years after the baseline visit. Results: MCI patients were found to display significantly less GM volume in several hypothesized regions including the MTL and PCG relative to the age-matched controls (p \u3c 0.01). Logistic regression analysis and receiver operating characteristic (ROC) curves for GM volume in the anterior MTL and PCG revealed high discriminative accuracy of 87%. By contrast, baseline GM volume in anterior MTL and PCG did not appear to be sensitive to changes in clinical status at the follow-up visit. Conclusion: These results suggest that VBM might be useful at characterizing GM volume reductions associated with the diagnosis of aMCI. © 2006 The Alzheimer\u27s Association

Entorhinal cortex volume is associated with episodic memory related brain activation in normal aging and amnesic mild cognitive impairment

The present study examined the relationship between entorhinal cortex and hippocampal volume with fMRI activation during episodic memory function in elderly controls with no cognitive impairment and individuals with amnesic mild cognitive impairment (aMCI). Both groups displayed limited evidence for a relationship between hippocampal volume and fMRI activation. Smaller right entorhinal cortex volume was correlated with reduced activation in left and right medial frontal cortex (BA 8) during incidental encoding for both aMCI and elderly controls. However, during recognition, smaller left entorhinal cortex volume correlated with reduced activation in right BA 8 for the control group, but greater activation for the aMCI group. There was no significant relationship between entorhinal cortex volume and activation during intentional encoding in either group. The recognition-related dissociation in structure/function relationships in aMCI paralleled our behavioral findings, where individuals with aMCI displayed poorer performance relative to controls during recognition, but not encoding. Taken together, these results suggest that the relationship between entorhinal cortex volume and fMRI activation during episodic memory function is altered in individuals with aMCI.Illinois. Department of Public HealthNational Institute on Aging (Grant P01 AG09466)National Institute on Aging (Grant P30 AG10161)National Institute on Aging (Grant R01 AG017917)National Institute on Aging (Grant T32 AG000257

The effect of body mass index on global brain volume in middle-aged adults: a cross sectional study

BACKGROUND: Obesity causes or exacerbates a host of medical conditions, including cardiovascular, pulmonary, and endocrine diseases. Recently obesity in elderly women was associated with greater risk of dementia, white matter ischemic changes, and greater brain atrophy. The purpose of this study was to determine whether body type affects global brain volume, a marker of atrophy, in middle-aged men and women. METHODS: T1-weighted 3D volumetric magnetic resonance imaging was used to assess global brain volume for 114 individuals 40 to 66 years of age (average = 54.2 years; standard deviation = 6.6 years; 43 men and 71 women). Total cerebrospinal fluid and brain volumes were obtained with an automated tissue segmentation algorithm. A regression model was used to determine the effect of age, body mass index (BMI), and other cardiovascular risk factors on brain volume and cognition. RESULTS: Age and BMI were each associated with decreased brain volume. BMI did not predict cognition in this sample; however elevated diastolic blood pressure was associated with poorer episodic learning performance. CONCLUSION: These findings suggest that middle-aged obese adults may already be experiencing differentially greater brain atrophy, and may potentially be at greater risk for future cognitive decline

Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's Disease: a cross-sectional study

BACKGROUND: The presence of the apolipoprotein E (APOE) ε4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the ε4 allele on hippocampal activation has not been firmly established. METHODS: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD. RESULTS: We found that ε3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to ε3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in ε3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the ε3/3 homozygotes, but not in the ε3/4 heterozygotes. CONCLUSION: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE ε4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline

The hippocampus, timing and trace conditioning of fear-potentiated startle in rats

Includes bibliographical references (pages [101]-117).In Pavlovian delay conditioning, a conditioned stimulus (CS) overlaps and co-terminates with an unconditioned stimulus (US), such as foot shock, whereas in trace conditioning, CS offset occurs before onset of the US. One measure of conditioned fear that has been used to identify the neural substrates associated with learned fear is the fear-potentiated startle (FPS) reflex. Delay fear conditioning studies have revealed a critical role for the amygdala in fear learning and memory, whereas trace conditioning has revealed a critical role for the hippocampus. FPS has only recently been used to examine the neural systems and temporal characteristics involved in trace fear conditioning and the timing of fear expression. These experiments were designed to evaluate the temporal dynamics and neural substrates involved in trace-conditioned FPS. Experiment 1 examined the effects of variables that influence the magnitude of conditioned fear, including (1) the duration of the trace interval, (2) CS modality, and (3) the training to testing interval, on the magnitude and time course of fear expression. Experiment 2 compared the effects of NMDA lesions to the dorsal hippocampus (DH) or ventral hippocampus (VH) on acquisition and expression of trace FPS. The results of experiment I indicated that a light CS, but not a noise CS, resulted in a post-CS enhancement of FPS during the middle of the trace interval. A similar post-CS enhancement of FPS was also seen in subjects tested 1 day after training that was not demonstrated by subjects tested 7 days after training. There was very little evidence for inhibition of delay during the trace interval, and trace conditioning was greater when short trace intervals were used compared to longer trace intervals. In experiment 2, pre-training and post-training lesions of the DH or VH impaired acquisition and expression of trace FPS around the trace interval. In contrast, VH lesions, but not DH lesions, also reduced FPS to the CS. These results support prior studies indicating a role for the hippocampus in trace conditioning, and these results further suggest that the VH has a greater role in trace-conditioned fear compared to the DH.Ph.D. (Doctor of Philosophy

Effects of dorsal versus ventral lesions of the hippocampus on retrograde amnesia for cued and contextual fear

Includes bibliographical references (pages [70]-82)M.A. (Master of Arts