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Aims: To examine awareness of memory abilities by groups (healthy control, suspected dementia/mild cognitive impairment, MCI, and diagnosed dementia/MCI), and to describe group differences in the relationship between awareness and cognitive performance in a community sample. Methods: In a cross-sectional design, 183 subjects were evaluated in a community setting and categorized into 3 groups based on their cognitive performance and reported medical history. Awareness of memory abilities was quantified using a published anosognosia ratio (AR) comparing the estimated to the objective memory performance by subjects. Each group was further categorized into ‘overestimators’, ‘accurate estimators’, and ‘underestimators’ based on their AR scores. Results: The suspected and diagnosed dementia/MCI groups had significantly higher AR scores than the controls. The suspected group also had a significantly larger proportion (96.2%) of overestimators than the diagnosed (73.3%) and control groups (26.1%). Impaired awareness in overestimators of the suspected and diagnosed groups was correlated with deficits in executive function, language or global cognition. Conclusion: Impaired awareness of memory abilities was prevalent in community-dwelling older adults with suspected and diagnosed dementia or MCI. Those with suspected dementia or MCI were more likely to overestimate their memory abilities than their diagnosed counterparts, suggesting that limited awareness of deficits may hinder utilization of dementia diagnostic services.

Background: a small number of reports exist on the cognitive effects of soy isoflavones, the findings from which are mixed. Isoflavone efficacy is dependent upon conversion of glycosides contained in soy foods and supplements to the biologically active aglycons. Of particular interest is the production of the metabolite, equol, which is dependent upon intestinal microflora and an integrous digestive system, both being altered by age and age-associated conditions. Unfortunately, few studies enrolled adults over the age of 70, and none included older men. Objective: we examined safety, feasibility and cognitive efficacy of soy isoflavone administration in older nondemented men and women (age 62‐89 years). Design and Methods: in this randomised, placebo-controlled, double-blind pilot study, subjects ingested either 100 mg/day soy isoflavones (glycoside weight) or matching placebo tablets for 6 months. Results:active and placebo-treated subjects exhibited a comparable side-effect profile. Plasma levels of genistein and daidzein (P < 0.001), but not equol, increased with isoflavone administration. While similar at baseline, the two groups differed across 6 months of treatment on 8 of 11 cognitive tests administered. Isoflavone-treated subjects improved on tests of visual-spatial memory (P < 0.01) and construction (P = 0.01), verbal fluency (P < 0.01) and speeded dexterity (P = 0.04). Placebo-treated participants were faster than isoflavone-treated subjects on two tests of executive function (P < 0.05). Conclusions: these data suggest that administration of 100 mg/day of isoflavones was well tolerated. Plasma genistein and daidzein levels, but not equol, increased with isoflavone administration. Finally, data support the potential cognitive effects of soy isoflavones in older adults.

First-degree family history (FH) of sporadic Alzheimer's disease and the apolipoprotein E epsilon4 allele (APOE4) are risk factors for Alzheimer's disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal individuals. The group effects on this recognition task were tested with a 2 x 2 ANCOVA factorial design (+FH/-FH and +APOE4/-APOE4). There were significant APOE4 and FH effects in the left dorsal posterior cingulate cortex and precuneus, where decreased risk resulted in greater activity during recollection. Recognition performance was positively correlated with BOLD signal in the left posterior hippocampus, parahippocampal-retrosplenial gyrus and left superior frontal cortex regardless of risk factors. To examine condition-specific group effects, both the PV and NV faces were tested further in separate 2 x 2 ANCOVAs. Both models revealed an APOE effect, with the -APOE4 group showing stronger signal than the +APOE4 group in anterior cingulate cortices, while a FH effect was found in the dorsal cuneus and medial frontal cortices with the -FH group showing stronger signal than the +FH group. Finally, interactions between APOE4 and FH effects were found bilaterally in the fusiform gyrus. These results suggest that risk factors and cognitive performance each influence brain activity during recognition. The findings lend further support to the idea that functional brain changes may begin far in advance of symptomatic Alzheimer's disease.

Given the predicted increase in prevalence of Alzheimer's disease (AD) in the coming decades, early detection and intervention in persons with the predementia condition known as mild cognitive impairment (MCI) is of paramount importance. Recent years have seen remarkable advances in the application of neuroimaging and other biomarkers to the study of MCI. This article reviews the most recent developments in the use of magnetic resonance imaging (MRI) to characterize brain changes and to prognosticate clinical outcomes of patients with MCI. The review begins with description of methods and findings in structural MRI research, delineating findings regarding both gross atrophy and microstructural brain changes in MCI. Second, we describe the most recent findings regarding brain function in MCI, enumerating findings from functional MRI and brain perfusion studies. Third, we will make recommendations regarding the current clinical use of MRI in identification of MCI. As a conclusion, we will look to the future of neuroimaging as a tool in early AD detection.

Voxel-based morphometry (VBM) was used to examine the relationship between gray matter (GM) volume and performance on two commonly used clinical neuropsychological measures of frontal lobe or executive function, the Trail Making Test part B (TrailsB) and the Controlled Oral Word Association Test (COWAT) in 221 cognitively healthy adults between the ages of 18 and 84. We hypothesized that these measures would be associated with GM volume in the dorsolateral frontal lobes. Voxel-based multiple regression was used to correlate cognitive function with modulated GM probability maps while controlling for age, education, gender, and total intracranial volume. A relationship with TrailsB was found in bilateral lateral inferior frontal gyri and left basal ganglia. A relationship with COWAT was found in the left lateral inferior and middle frontal gyri. Lesion studies have long implicated the importance of these regions for executive function. The present results confirm and extend those prior findings to healthy adults.

Background: Several previous studies have reported that amnestic mild cognitive impairment (aMCI), a significant risk factor for Alzheimer's 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 < 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's Association.

First-degree family history of sporadic Alzheimer disease (AD) and the apolipoprotein E ε4 (APOE4) are risk factors for developing AD. Although the role of APOE4 in AD pathogenesis has been well studied, family history remains a rarely studied and poorly understood risk factor. Both putatively cause early brain changes before symptomatic disease, but the relative contribution of each to brain function is unknown. We examined 68 middle-aged participants with a parent diagnosed with AD[family history (-FH)] and 64 age- and education matched controls without a first-degree family history of any dementia [no family history (+FH)]. All underwent cognitive testing, APOE genotyping, and a functional magnetic resonance imaging encoding task that required discrimination of novel items from previously learned items. A 2 x 2 factorial ANOVA (presence/absence of parental family history and presence/absence of the APOE4) was used to detect group effects. A greater response to novel items was detected in the mesial temporal lobe and fusiform gyrus bilaterally among persons without a first-degree family history of AD. In hippocampal areas, the -FH + ε4 group exhibited the greatest signal change, and the +FH + ε4 group exhibited the least. These findings indicate that FH of AD is an important predictor of hippocampal activation during encoding and that FH may modulate the effect of APOE4 in these middle-aged adults, suggesting that an as yet unspecified factor embodied in first-degree family history of AD is influencing the expression of APOE4 on brain function. Copyright © 2006 Society for Neuroscience.

Declarative memory impairment is a common long-term sequela of severe closed head injury (CHI). Although veridical memory performance following severe CHI has received attention in the literature, little is known about false memory production in this population. Within the present study, both long-term survivors of severe CHI and matched control participants studied and were tested on six 12-items word lists from the Deese Roediger McDermott (DRM) paradigm. Word lists from the DRM are composed of words that are strongly semantically associated to a non-presented word (i.e., the critical lure). Prior studies have shown that healthy young adults show a high level of false recall and recognition memory for the critical lures, and it was hypothesized individuals with severe CHI would show heightened susceptibility to false memory compared to control participants due to difficulty with monitoring of memory. It was further hypothesized that severe CHI participants would show high confidence in their false memories. Consistent with hypotheses, results indicated that although severe CHI participants remembered fewer actual list items, they made more semantically related intrusion errors (recall) and false-positive responses (recognition) than the control participants. Severe CHI participants also showed greater confidence in their false memories than did control participants. The results are interpreted in the context of theoretical accounts of false memory, and possible structural and functional brain changes that might account for the Severe CHI group's memory performance are discussed.

Cognitive decline in children with seizure disorders is due to several factors, one being the choice of anticonvulsant and total anticonvulsant exposure. This paper reviews research investigating cognitive effects associated with “older” anticonvulsant medications (i.e., phenobarbital, phenytoin, carbamazepine, and valproate) prescribed as monotherapy. A number of cognitive difficulties such as intellectual decline, mild memory loss, visual-motor impairment, and psychomotor slowing have been associated with these medications. Each study included in this review is assessed in terms of the appropriateness of study design and ability of the reader to draw clear conclusions about the cognitive effects associated with the anticonvulsant under investigation. The review also includes a synopsis of the myriad of methodological difficulties that plague this body of literature. Conclusions that can be drawn from the existing literature are delineated, and future directions for research are suggested.

It is tentatively estimated that 25% of people with early Alzheimer's disease (AD) show impaired awareness of disease-related changes in their own cognition. Research examining both normative self-awareness and altered awareness resulting from brain disease or injury points to the central role of the medial prefrontal cortex (MPFC) in generating accurate self-appraisals. The current project builds on this work - examining changes in MPFC functional connectivity that correspond to impaired self-appraisal accuracy early in the AD time course. Our behavioral focus was self-appraisal accuracy for everyday memory function, and this was measured using the Memory Function Scale of the Memory Awareness Rating Scale - an instrument psychometrically validated for this purpose. Using regression analysis of data from people with healthy memory (n=12) and people with impaired memory due to amnestic mild cognitive impairment or early AD (n=12), we tested the hypothesis that altered MPFC functional connectivity - particularly with other cortical midline structures and dorsolateral prefrontal cortex - explains variation in memory self-appraisal accuracy. We spatially constrained (i.e., explicitly masked) our regression analyses to those regions that work in conjunction with the MPFC to evoke self-appraisals in a normative group. This empirically derived explicit mask was generated from the result of a psychophysiological interaction analysis of fMRI self-appraisal task data in a separate, large group of cognitively healthy individuals. Results of our primary analysis (i.e., the regression of memory self-appraisal accuracy on MPFC functional connectivity) were generally consistent with our hypothesis: people who were less accurate in making memory self-appraisals showed attenuated functional connectivity between the MPFC seed region and proximal areas within the MPFC (including subgenual anterior cingulate cortex), bilateral dorsolateral prefrontal cortex, bilateral caudate, and left posterior hippocampus. Contrary to our expectations, MPFC functional connectivity with the posterior cingulate was not significantly related to accuracy of memory self-appraisals. Results reported here corroborate findings of variable memory self-appraisal accuracy during the earliest emergence of AD symptoms and reveal alterations in MPFC functional connectivity that correspond to impaired memory self-appraisal.

Functional MRI (fMRI) allows one to study task-related regional responses and task-dependent connectivity analysis using psychophysiological interaction (PPI) methods. The latter affords the additional opportunity to understand how brain regions interact in a task-dependent manner. The current implementation of PPI in Statistical Parametric Mapping (SPM8) is configured primarily to assess connectivity differences between two task conditions, when in practice fMRI tasks frequently employ more than two conditions. Here we evaluate how a generalized form of context-dependent PPI (gPPI; http://www.nitrc.org/projects/gppi), which is configured to automatically accommodate more than two task conditions in the same PPI model by spanning the entire experimental space, compares to the standard implementation in SPM8. These comparisons are made using both simulations and an empirical dataset. In the simulated dataset, we compare the interaction beta estimates to their expected values and model fit using the Akaike information criterion (AIC). We found that interaction beta estimates in gPPI were robust to different simulated data models, were not different from the expected beta value, and had better model fits than when using standard PPI (sPPI) methods. In the empirical dataset, we compare the model fit of the gPPI approach to sPPI. We found that the gPPI approach improved model fit compared to sPPI. There were several regions that became non-significant with gPPI. These regions all showed significantly better model fits with gPPI. Also, there were several regions where task-dependent connectivity was only detected using gPPI methods, also with improved model fit. Regions that were detected with all methods had more similar model fits. These results suggest that gPPI may have greater sensitivity and specificity than standard implementation in SPM. This notion is tempered slightly as there is no gold standard; however, data simulations with a known outcome support our conclusions about gPPI. In sum, the generalized form of context-dependent PPI approach has increased flexibility of statistical modeling, and potentially improves model fit, specificity to true negative findings, and sensitivity to true positive findings.

reflect specific cleavage sites in proteins and, due to their smaller size, will pass the BBB. Importantly, these smaller protein fragments include more information than their intact counterparts, namely that the proteins are degraded by specific enzymes, a cardinal feature of the brain damage in AD. Methods: Tau was cleaved with BACE1, ADAM10 and caspase 3, and fragments were identified by Mass spectrometry. 10 different fragments of tau was selected for monoclonal antibody development, and one assay measuring tau degradation mediated by the protease ADAM10 using an ELISA assay (NB191) was developed. 33 paired CSF and serum samples from patients with severe ADwere investigated. Brains fromwild-type (wt) and Tg4510 transgenic mice known to develop some aspects of Alzheimer’s disease were extracted. Results: The NB191 antibody recognized the cleavage site generated by ADAM10 with an IC50 of 12.5ng/mL, but not an elongated sequence with one more amino acid (see figure). Technically robust and measurable levels of the tau neoepitope in human Alzheimer’s disease patient sera and CSF samples with averages of 21ng/ml and 2ng/ mL respectively were obtained. Finally, we compared the levels of NB191 in CSF to the levels in serum and found a correlation of R 1⁄4 0.45, borderline significant. Brain extracts from Tg4510 mice had 10-fold elevated levels of the tau neoepitope when compared to wildtype controls (p

Background Brain alterations in structure and function have been identified in people with risk factors for sporadic type Alzheimer's disease (AD), suggesting that alterations can be detected decades before AD diagnosis. Although the effect of apolipoprotein E ( APOE ) ɛ4 on the brain is well-studied, less is known about the effect of family history of AD. We examined the main effects of family history and APOE ɛ4 on brain integrity, in addition to assessing possible additive effects of these two risk factors. Methods Diffusion tensor imaging was performed in 136 middle-aged asymptomatic participants stratified on family history and APOE ɛ4. Mean diffusivity and fractional anisotropy (FA) were entered in factorial analyses to test the effect of AD risk on microstructural brain integrity. We performed a post hoc analysis of the three principal diffusivities (λ1, λ2, λ3) to provide potential additional insight on underlying tissue differences. Results Parental family history of AD was associated with lower FA in regions of the brain known to be affected by AD, including cingulum, corpus callosum, tapetum, uncinate fasciculus, hippocampus, and adjacent white matter. Contrary to previous reports, there was no main effect of APOE ɛ4; however, there was an additive effect of family history and APOE ɛ4 in which family history–positive participants who were also APOE ɛ4 carriers had the lowest FA compared with the other groups. Conclusions The data indicate that unknown risk factors contained in family history are associated with changes in microstructural brain integrity in areas of the brain known to be affected by AD. Importantly, the results provide further evidence that AD pathology might be detected before cognitive changes, perhaps decades before disease onset.

Structural brain change and concomitant cognitive decline are the seemingly unavoidable escorts of aging. Despite accumulating studies detailing the effects of age on the brain and cognition, the relationship between white matter features and cognitive function in aging have only recently received attention and remain incompletely understood. White matter microstructure can be measured with diffusion tensor imaging (DTI), but whether DTI can provide unique information on brain aging that is not explained by white matter volume is not known. In the current study, the relationship between white matter microstructure, age, and neuropsychological function was assessed using DTI in a statistical framework that employed white matter volume as a voxel-wise covariate in a sample of 120 healthy adults across a broad age range (18-83). Memory function and executive function were modestly correlated with the DTI measures while processing speed showed the greatest extent of correlation. The results suggest that age-related white matter alterations underlie age-related declines in cognitive function. Mean diffusivity and fractional anisotropy in several white matter brain regions exhibited a nonlinear relationship with age, while white matter volume showed a primarily linear relationship with age. The complex relationships between cognition, white matter microstructure, and white matter volume still require further investigation.

Factors contributing to increased risk for Alzheimer's disease (AD) include age, sex, genes, and family history of AD. Several risk factors for AD are endogenous; however, accumulating evidence implicates modifiable risk factors in the pathogenesis of AD. Although the continued task of identifying new genes will be critical to learning more about the disease, several research findings suggest that potentially alterable environmental factors influence genetic contributions, providing targets for disease prevention and treatment. Here, we review midlife risk factors for AD, and address the potential for therapeutic intervention in midlife.

Background: Memory formation and retrieval is a dynamic process that employs a network of brain regions. Here we aim to investigate the neural correlates of memory formation in healthy middle-aged individuals using an event-related fMRI paradigm. Methods: Participants were asked to remember forty simple line drawings of objects that were presented and repeated three times in a pseudo-random order while collecting fMRI data. Two conceptual approaches were used to analyze the fMRI images. First, we used a traditional approach with parametric modulation based on repetition to investigate which regions showed attenuation in the BOLD response over repetitions. In the second approach, we examined how the hippocampus interacts with other brain regions across repetitions. Using an in-house variant of psychophysiological interactions (PPI) to investigate context-dependent connectivity, we were able to identify regions where connectivity with the left and right hippocampus did not change over repetition (repetition-invariant connectivity [RI]) and regions that changed with repetition (repetitiondependent connectivity [RD]). Results: The first approach revealed numerous regions exhibiting an adaptation response including the fusiform gyrus, parahippocampal gyrus, hippocampus, amygdala, ventral occipital lobes, and lateral frontal lobes. The second approach provides a dynamic picture of memory representation in the network over time. Early memory representation, at least for visual stimuli, appears dependent upon synchronous activation of the hippocampus, occipital lobes, and frontal regions; whereas representation during later encoding requires less connectivity between hippocampus and visual processing areas [RD], but continues to evoke similar connectivity with frontal regions [RI]. Conclusions: Importantly, these findings demonstrate a need to consider the effects of repetition on the BOLD signal in any memory paradigm. In addition to informing our understanding of normal memory function in terms of functional brain networks, we believe these methods will be critical to investigating memory change in aging and disease. Specifically, our in-house variant of PPI allows investigators to identify which connections, involved in a cognitive process, might be altered between groups. In the future, we aim at investigating the impact of risk-factors for Alzheimer’s disease on the alteration of these memory systems.

ments were obtained. An ANCOVA was performed for each of the NP tests and SNI variables, using group membership as fixed factors, and age, sex and years of education as covariates. Only variables with a significant group effect in the ANCOVA (13 NP tests and 33 SNI variables) were used. A canonical correlation analysis was then performed between those NP and SNI variables. Results: We found that the first five of the canonical-variate-pairs (CVP) were statistically significant. The contribution of each of the NP and SNI variables to the canonical correlation depended on the canonical-dimension of each CVP, as follows. The first CVP related to language and attention with bilateral involvement of SNI; the second CVP had a stronger relation to language with elements of memory and attention, and involved mostly left hemispheric SNI; the third CVP related to more global deficits and bilateral SNI contribution; the fourth CVP related mostly to memory with bilateral SNI involvement; finally, the fifth CVP related mostly to attention with left hemispheric SNI involvement. Conclusions: These results reveal how information in the SNI relates to specific aspects of cognitive deficit.

Hypercholesterolemia in midlife increases the risk of subsequent cognitive decline, neurovascular disease, and Alzheimer's disease (AD), and statin use is associated with reduced prevalence of these outcomes. While statins improve vasoreactivity in peripheral arteries and large cerebral arteries, little is known about the effects of statins on cerebral hemodynamic responses and cognition in healthy asymptomatic adults. At the final visit of a 4-month randomized, controlled, double-blind study comparing atorvastatin 40 mg daily to placebo, 16 asymptomatic middle-aged adults (15 had useable data) underwent blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI), arterial spin labeling (ASL) quantitative cerebral blood flow (qCBF), dynamic susceptibility contrast (DSC) and structural imagings of the brain. Using a memory recognition task requiring discrimination of previously viewed (PV) and novel (NV) human faces, fMRI was used to elicit activation from brain regions known to be vulnerable to changes associated with AD. The BOLD signal amplitude (PV > NV) and latency to each stimulus were tested on a voxel basis between the atorvastatin (n=8) and placebo (n=7) groups. Persons randomized to atorvastatin not only showed significantly greater BOLD amplitude in the right angular gyrus, left superior parietal lobule, right middle temporal and superior sulcus than the placebo group, but also decreased hemodynamic response latencies in the right middle frontal gyrus, left precentral gyrus, left cuneus and right posterior middle frontal gyrus. However, neither the resting cerebral blood flow (CBF) measured with ASL nor the mean transit time (MTT) of cerebral perfusion calculated from DSC showed differences in these regions in either group. The drug related BOLD differences during memory recognition suggest that atorvastatin may have improved cerebral small vessel vasoreactivity, possibly through an effect on endothelial function. Furthermore, these results suggest that the effect of atorvastatin on the task-induced BOLD signal may not be a simple consequence of baseline flow change.

Traumatic brain injury (TBI) is associated with brain volume loss, but there is little information on the regional gray matter (GM) and white matter (WM) changes that contribute to overall loss. Since axonal injury is a common occurrence in TBI, imaging methods that are sensitive to WM damage such as diffusion-tensor imaging (DTI) may be useful for characterizing microstructural brain injury contributing to regional WM loss in TBI. High-resolution T1-weighted imaging and DTI were used to evaluate regional changes in TBI patients compared to matched controls. Patients received neuropsychological testing and were imaged approximately 2 months and 12.7 months post-injury. Paradoxically, neuropsychological function improved from Visit 1 to Visit 2, while voxel-based analyses of fractional anisotropy (FA), and mean diffusivity (MD) from the DTI images, and voxel-based analyses of the GM and WM probability maps from the T1-weighted images, mainly revealed significantly greater deleterious GM and WM change over time in patients compared to controls. Cross-sectional comparisons of the DTI measures indicated that patients have decreased FA and increased MD compared to controls over large regions of the brain. TBI affected virtually all of the major fiber bundles in the brain including the corpus callosum, cingulum, the superior and inferior longitudinal fascicules, the uncinate fasciculus, and brain stem fiber tracts. The results indicate that both GM and WM degeneration are significant contributors to brain volume loss in the months following brain injury, and also suggest that DTI measures may be more useful than high-resolution anatomical images in assessment of group differences.

Context Asymptomatic middle-aged adult children of patients with Alzheimer disease (AD) recently were found to exhibit functional magnetic resonance imaging (fMRI) deficits in the mesial temporal lobe during an encoding task. Whether this effect will be observed on other fMRI tasks is yet unknown. This study examines the neural substrates of self-appraisal (SA) in persons at risk for AD. Accurate appraisal of deficits is a problem for many patients with AD, and prior fMRI studies of healthy young adults indicate that brain areas vulnerable to AD such as the anterior mesial temporal lobe and posterior cingulate are involved during SA tasks. Objective To determine whether parental family history of AD (hereafter referred to as FH) or presence of the e 4 allele of the apolipoprotein E gene ( APOE4 ) exerts independent effects on brain function during SA. Design Cross-sectional factorial design in which APOE4 status (present vs absent) was one factor and FH was the other. All participants received cognitive testing, genotyping, and an fMRI task that required subjective SA decisions regarding trait adjective words in comparison with semantic decisions about the same words. Setting An academic medical center with a research-dedicated 3.0-T MR imaging facility. Participants Cognitively normal middle-aged adults (n = 110), 51 with an FH and 59 without an FH. Main Outcome Measure Blood oxygen–dependent contrast measured using T2*-weighted echo-planar imaging. Results Parental family history of AD and APOE4 status interacted in the posterior cingulate and left superior and medial frontal regions. There were main effects of FH (FH negative > FH positive) in the left hippocampus and ventral posterior cingulate. There were no main effects of APOE genotype. Conclusions Our results suggest that FH may affect brain function during subjective SA in regions commonly affected by AD. Although the participants in this study were asymptomatic and middle-aged, the findings suggest that there may be subtle alterations in brain function attributable to AD risk factors.

This exploratory and retrospective analysis compared fMRI and cognitive data from nine HT-naïve women to data from women exposed to either opposed CEE (N=10) or opposed estradiol (N=4). These preliminary data suggested that exposure to either form of HT was associated with healthier fMRI response; however, CEE-exposed women exhibited poorer memory performance than either HT-naïve or estradiol-exposed subjects. These preliminary findings emphasize the urgency to characterize differential neural effects of various HTs.

This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD. © 2005 Elsevier Inc. All rights reserved.

Awareness of cognitive dysfunction shown by individuals with Mild Cognitive Impairment (MCI), a condition conferring risk for Alzheimer's 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' 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.

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.

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’s disease (AD). In functional magnetic resonance imaging (fMRI) 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 recently-learned information. Administering both types of tasks to people with MCI may reveal important information regarding the role of the PCC in recollection. This study investigated fMRI activation in the PCC in individuals with MCI and age, gender, and education-matched controls across two tasks. The first task was a visual episodic recognition task in which participants indicated whether pictures had or had not been presented during a study session. 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 during episodic retrieval. These results suggest in MCI that the PCC shows functional degradation during episodic retrieval of visual information learned in the laboratory. In contrast, the PCC’s role in retrieval and evaluation of highly-elaborated information regarding the self is more well-preserved.

Heightened distractibility following severe closed head injury (sCHI) may result from a deficit in selective attention. The integrity of inhibitory processes involved in selective attention was assessed through use of a negative priming paradigm, allowing dissociation of inhibitory and episodic retrieval processes. In this task, inhibitory processes are elicited under intact stimulus conditions, whereas episodic retrieval is elicited when target stimuli are degraded. Despite inconsistent evidence of inhibitory deficits following sCHI in the literature, long-term survivors of sCHI showed no negative priming under intact stimulus conditions, providing evidence of compromised inhibitory processing. The sCHI participants' demonstration of negative priming when target stimuli were degraded provides evidence that automatic retrieval processes are intact following sCHI, results that are consistent with prior findings.

The Wada test has historically been the conventional procedure for determining language lateralization before neurosurgery. However, functional magnetic resonance imaging (fMRI) offers a less invasive alternative to the Wada procedure. Research indicates that the two techniques used together may provide comparable, and sometimes complementary, information that results in improved prediction of postsurgical language ability. We present a case in which use of fMRI in conjunction with Wada testing provided complementary information about language lateralization before neurosurgical resection of a mesial temporal subependymoma for seizure control in a patient with schizencephaly.

Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel-wise image analysis methods were used to test whether baseline CSF Aβ(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter.

Depressive symptoms occurring late in life are an important risk factor for Alzheimer’s disease (AD). The latest research finds that onset of depressive symptoms in late life may herald the development of AD, not only for amnestic Mild Cognitive Impairment (aMCI) patients, but also for cognitively-normal older adults. Neuroimaging of brain structure, blood flow, and glucose metabolism indicates that depressive symptoms in late life are accompanied by structural and functional changes in limbic brain regions vulnerable to AD. The present cross-sectional study was guided by the hypothesis that compared to their non-depressed counterparts, older adults with mild to moderate depressive symptoms have less volume in limbic structures vulnerable to changes in AD—specifically, cortical midline structures such as anterior cingulate and posterior cingulate cortex as well as mesial temporal regions such as bilateral hippocampi and amygdalae. Consistent with our hypothesis, results of a voxel-based morphometry analysis revealed smaller retrosplenial, posterior cingulate, and precuneus gray matter volumes in depressed individuals relative to healthy controls. Right lateral parietal cortex—another region vulnerable to change in AD—was also smaller in the group with depressive symptoms. Contrary to our hypothesis, no volumetric differences were found in the anterior cingulate cortex or mesial temporal lobe. Results of this study show a relationship between geriatric depressive symptoms and brain volume in regions vulnerable to AD. Follow-up of participants over time will tell if brain changes detected here predict development of AD.