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| Type of Article | | Clinical Trial Editorial Letter Meta-Analysis Practice Guideline Randomized Controlled Trial Review Addresses Bibliography Biography Case Reports Classical Article Clinical Conference Clinical Trial, Phase I Clinical Trial, Phase II Clinical Trial, Phase III Clinical Trial, Phase IV Comment Comparative Study Consensus Development Conference Consensus Development Conference, NIH Controlled Clinical Trial Corrected and Republished Article Dictionary Directory Duplicate Publication English Abstract Evaluation Studies Festschrift Government Publications Guideline Historical Article Interview In Vitro Journal Article Lectures Legal Cases Legislation Multicenter Study News Newspaper Article Overall Patient Education Handout Periodical Index Published Erratum Retracted Publication Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. Retraction of Publication Scientific Integrity Review Support of Research Technical Report Twin Study Validation Studies Not a Primary Study or Review Unknown Primary Study Case Series Case Control Cohort Study Observational Study Qualitative Research CBA or ITS Registry Double Blind Controlled before after study Quasi-randomized trial Simple before after study Cluster-RCT Non-Randomized Study Report Book Book chapter Dissertation Conference procedings Secondary Research Not RCT
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Maija Pihlajamäki,Kristina M DePeau,Deborah Blacker,Reisa A Sperling OBJECTIVES: Neural networks supporting encoding of new information are affected early in the course of Alzheimer disease (AD). Functional magnetic resonance imaging (fMRI) studies in AD have reported decreased medial temporal lobe (MTL) activation when comparing novel versus repeated stimuli. It is... ( view more ), however, unclear whether this finding is related to a failure of normal suppression of MTL activity to repeated stimuli in AD. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Twenty-nine healthy older subjects comprising a comparison group (OC) and 15 mild AD patients underwent fMRI during an associative memory paradigm in an academic medical center. The task consisted of blocks of Novel and Repeated face-name pairs and visual Fixation. To reveal neural correlates of processing repeatedly presented stimuli, Repeated blocks were contrasted to Fixation. RESULTS: AD patients demonstrated greater activation during Repeated stimuli in the MTL and in prefrontal and superior parietal cortices, compared with OC. In contrast, OC showed greater parietal task-induced deactivation than AD. Increased MTL activity during Repeated was correlated with more impaired parietal deactivation and poorer performance of the postscan recognition memory test of encoding the face-name pairs. CONCLUSION: Reduction of MTL activity to repeated stimuli, which become highly familiarized to healthy OC, was impaired in AD. This abnormal increased MTL activation was related to disrupted parietal deactivation and to poor recognition memory performance. These preliminary results suggest that the typical episodic memory impairment seen in mild AD may manifest as a failure of normal repetition suppression and loss of "beneficial" deactivation in the MTL-parietal memory networks. ( view less ) Saul L Miller,Kim Celone,Kristina DePeau,Eli Diamond,Bradford C Dickerson,Dorene Rentz,Maija Pihlajamäki,Reisa A Sperling 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 demo... ( view more )nstrated 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. ( view less ) Bradford C Dickerson,Reisa A Sperling,Bradley T Hyman,Marilyn S Albert,Deborah Blacker OBJECTIVE: To determine whether clinical assessment methods that grade the severity of impairments within the spectrum of mild cognitive impairment (MCI) can predict clinical course, particularly among very mildly impaired individuals who do not meet formal MCI criteria as implemented in clinical t... ( view more )rials. DESIGN: Cohort. SETTING: Community volunteers. PARTICIPANTS: From a longitudinal study of normal (Clinical Dementia Rating [CDR] = 0; n = 77) and mildly impaired (CDR = 0.5; n = 167) participants with 5 or more annual clinical assessments, baseline level of cognitive impairment in daily life was graded using CDR sum of boxes (CDR-SB) and level of cognitive performance impairment was graded using neuropsychological test scores. MAIN OUTCOME MEASURES: Five-year outcome measures included (1) probable Alzheimer disease (AD) diagnosis and (2) clinical "decline" (CDR-SB increase > or = 1.0). Logistic regression models were used to assess the ability of baseline measures to predict outcomes in the full sample and separately in the subjects who did not meet formal MCI criteria as implemented in a multicenter clinical trial (n = 125; "very mild cognitive impairment" [vMCI]). RESULTS: The presence of both higher CDR-SB and lower verbal memory and executive function at baseline predicted greater likelihood of probable AD and decline. Five-year rates of probable AD and decline in vMCI (20%, AD; 49%, decline) were intermediate between normal participants (0%, AD; 28%, decline) and participants with MCI (41%, AD; 62%, decline). Within vMCI, likelihood of probable AD was predicted by higher CDR-SB and lower executive function. CONCLUSIONS: Even in very mildly impaired individuals who do not meet strict MCI criteria as implemented in clinical trials, the degree of cognitive impairment in daily life and performance on neuropsychological testing predict likelihood of an AD diagnosis within 5 years. The clinical determination of relative severity of impairment along the spectrum of MCI may be valuable for trials of putative disease-modifying compounds, particularly as target populations are broadened to include less impaired individuals. ( view less ) Dorene M Rentz,Terri J Huh,Lisa M Sardinha,Erin K Moran,John A Becker,Kirk R Daffner,Reisa A Sperling,Keith A Johnson Cognitive reserve among highly intelligent older individuals makes detection of early Alzheimer's disease (AD) difficult. We tested the hypothesis that mild memory impairment determined by IQ-adjusted norms is associated with single photon emission computed tomography (SPECT) perfusion abnormality ... ( view more )at baseline and predictive of future decline. Twenty-three subjects with a Clinical Dementia Rating (CDR) score of 0, were reclassified after scores were adjusted for IQ into two groups, 10 as having mild memory impairments for ability (IQ-MI) and 13 as memory-normal (IQ-MN). Subjects underwent cognitive and functional assessments at baseline and annual follow-up for 3 years. Perfusion SPECT was acquired at baseline. At follow-up, the IQ-MI subjects demonstrated decline in memory, visuospatial processing, and phonemic fluency, and 6 of 10 had progressed to a CDR of 0.5, while the IQ-MN subjects did not show decline. The IQ-MI group had significantly lower perfusion than the IQ-MN group in parietal/precuneus, temporal, and opercular frontal regions. In contrast, higher perfusion was observed in IQ-MI compared with IQ-MN in the left medial frontal and rostral anterior cingulate regions. IQ-adjusted memory impairment in individuals with high cognitive reserve is associated with baseline SPECT abnormality in a pattern consistent with prodromal AD and predicts subsequent cognitive and functional decline. ( view less ) Reisa Sperling Functional magnetic resonance imaging (fMRI) is a noninvasive neuroimaging technique that can be used to study the neural correlates of complex cognitive processes, and the alterations in these processes that occur in the course of normal aging or superimposed neurodegenerative disease. Our studies... ( view more ) have focused on the neural substrates of successful associative encoding, particularly of face-name associations. We have found that the specific regions of the hippocampus and prefrontal cortices are critical for successful memory in both young and healthy older subjects. Our fMRI studies, as well as those of several other groups, have consistently demonstrated that, compared to cognitively intact older subjects, patients with clinical Alzheimer's disease (AD) have decreased fMRI activation in the hippocampus and related structures within the medial temporal lobe during the encoding of new memories. More recently, fMRI studies of subjects at risk for AD, by virtue of their genetics or evidence of mild cognitive impairment (MCI), have yielded variable results. Some of these studies, including our own, suggest that there may be a phase of paradoxically increased activation early in the course of prodromal AD. Further studies to validate fMRI in these populations are needed, particularly longitudinal studies to investigate the pattern of alterations in functional activity over the course of prodromal AD and the relationship to AD pathology. ( view less ) Elizabeth F Chua,Daniel L Schacter,Erin Rand-Giovannetti,Reisa A Sperling It has been well established that the hippocampal formation plays a critical role in the formation of memories. However, functional specialization within the hippocampus remains controversial. Using functional magnetic resonance imaging (fMRI) during a face-name associative encoding task, followed ... ( view more )by a postscan recognition test for face memory and face-name pair memory, we investigated the roles of anterior and posterior hippocampal regions in successful encoding of associations and items. Whole-brain and region of interest (ROI) analyses revealed that the anterior hippocampal formation showed increased activation for subsequently remembered face-name associations compared with pairs that were forgotten. In contrast, the posterior hippocampal formation showed activation above baseline during attempted encoding of face-name pairs, but no evidence of differential activation based on subsequent memory. Furthermore, exploratory whole-brain analyses revealed that a parahippocampal region, most likely corresponding to perirhinal cortex, showed subsequent memory effects for faces. These data provide evidence for functional specialization within the hippocampal formation based on the associative nature of the stimuli and subsequent memory. ( view less ) David C Alsop,Michael A Fearing,Keith Johnson,Reisa Sperling,Tamara G Fong,Sharon K Inouye Understanding of delirium pathogenesis remains limited despite improved diagnosis, and elucidation of risk factors and prognosis. Major advances in neuroimaging offer the possibility of probing the mechanisms and networks involved in delirium and hence improving understanding of this often devastat... ( view more )ing syndrome. This review describes the current literature of imaging studies in delirium and related conditions, introduces some of the newer capabilities of neuroimaging with magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, and discusses how these techniques may be applied to the study of delirium. Despite considerable challenges in patient recruitment, study design, intersubject variability, and scanner and contrast agent availability, imaging offers great potential for the identification and clarification of pathogenic mechanisms of delirium and its long-term sequelae. ( view less ) Dorene M Rentz,Lisa M Sardinha,Terri J Huh,Meghan M Searl,Kirk R Daffner,Reisa A SperlingThis study presents normative data of commonly used neuropsychological tests administered to 75 individuals with high levels of intelligence (estimated IQ > or = 120). Participants were living independently in the community with ages ranging from 44 to 86. To avoid including individuals with an inc... ( view more )ipient dementia, we selected subjects who scored within the normal range on all cognitive tests for at least a two-year period. The norms are presented in table format to help clinicians easily identify a typical cognitive performance in highly intelligent individuals and to provide a useful guide for detecting abnormal cognitive decline in individuals at risk for progressive dementia. ( view less ) Kim A Celone,Vince D Calhoun,Bradford C Dickerson,Alireza Atri,Elizabeth F Chua,Saul L Miller,Kristina DePeau,Doreen M Rentz,Dennis J Selkoe,Deborah Blacker,Marilyn S Albert,Reisa A Sperling Memory function is likely subserved by multiple distributed neural networks, which are disrupted by the pathophysiological process of Alzheimer's disease (AD). In this study, we used multivariate analytic techniques to investigate memory-related functional magnetic resonance imaging (fMRI) activity... ( view more ) 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. ( view less ) Erin Rand-Giovannetti,Elizabeth F Chua,Amy E Driscoll,Daniel L Schacter,Marilyn S Albert,Reisa A Sperling Episodic memory function is known to decline in the course of normal aging; however, compensatory techniques can improve performance significantly in older persons. We investigated the effects of the memory enhancing technique of repetition encoding on brain activation using event-related functiona... ( view more )l magnetic resonance imaging (fMRI). Twelve healthy older adults without cognitive impairment were studied with fMRI during repetitive encoding of face-name pairs. During the first encoding trials of face-name pairs that were subsequently remembered correctly, activation of the hippocampus and multiple neocortical regions, including prefrontal, parietal and fusiform cortices, was observed. The second and third encoding trials resulted in continued activation in neocortical regions, but no task-related response within the hippocampus. Functional imaging of successful memory processes thus permits us to detect regionally specific responses in the aging brain. Our findings suggest that hippocampal function is preserved in normal aging and that repetition-based memory enhancing techniques may engage primarily neocortical attentional networks. ( view less ) Bradford C Dickerson,Reisa A Sperling The pathophysiologic process leading to neurodegeneration in Alzheimer's disease (AD) is thought to begin long before clinical symptoms develop. Existing therapeutics for AD improve symptoms, but increasing efforts are being directed toward the development of therapies to impede the pathologic prog... ( view more )ression of the disease. Although these medications must ultimately demonstrate efficacy in slowing clinical decline, there is a critical need for biomarkers that will indicate whether a candidate disease-modifying therapeutic agent is actually altering the underlying degenerative process. A number of in vivo neuroimaging techniques, which can reliably and noninvasively assess aspects of neuroanatomy, chemistry, physiology, and pathology, hold promise as biomarkers. These neuroimaging measures appear to relate closely to neuropathological and clinical data, such as rate of cognitive decline and risk of future decline. As this work has matured, it has become clear that neuroimaging measures may serve a variety of potential roles in clinical trials of candidate neurotherapeutic agents for AD, depending in part on the question of interest and phase of drug development. In this article, we review data related to the range of neuroimaging biomarkers of Alzheimer's disease and consider potential applications of these techniques to clinical trials, particularly with respect to the monitoring of disease progression in trials of disease-modifying therapies. ( view less ) Elizabeth F Chua,Erin Rand-Giovannetti,Daniel L Schacter,Marilyn S Albert,Reisa A Sperling Successful memory typically implies both objective accuracy and subjective confidence, but there are instances when confidence and accuracy diverge. This dissociation suggests that there may be distinct neural patterns of activation related to confidence and accuracy. We used event-related function... ( view more )al magnetic resonance imaging to study the encoding of novel face--name associations, assessed with a postscan memory test that included objective measures of accuracy and subjective measures of confidence. We showed specific neural activity in the left inferior prefrontal cortex associated with trials when subjects expressed high confidence that they had chosen the correct name for the face and made a correct identification. Moreover, we found that this region was also associated with imparting high confidence when subjects chose the incorrect name. However, medial temporal lobe regions showed activity only for high-confidence correct trials. Many functional magnetic resonance imaging studies have shown that the medial temporal lobe and left prefrontal regions are particularly important for the successful formation of memories by using a combination of subjective and objective measures. Our findings suggest that these regions may be differentially involved in the objective and subjective components of memory and that the origins of confidence-accuracy dissociations may be related to incomplete activation of the neural pattern seen in successful encoding. These findings may also aid understanding of eyewitness misidentifications and memory distortions. ( view less ) Bradford C Dickerson,David H Salat,Julianna F Bates,Monika Atiya,Ronald J Killiany,Douglas N Greve,Anders M Dale,Chantal E Stern,Deborah Blacker,Marilyn S Albert,Reisa A Sperling Functional magnetic resonance imaging (fMRI) was used to study memory-associated activation of medial temporal lobe (MTL) regions in 32 nondemented elderly individuals with mild cognitive impairment (MCI). Subjects performed a visual encoding task during fMRI scanning and were tested for recognitio... ( view more )n of stimuli afterward. MTL regions of interest were identified from each individual's structural MRI, and activation was quantified within each region. Greater extent of activation within the hippocampal formation and parahippocampal gyrus (PHG) was correlated with better memory performance. There was, however, a paradoxical relationship between extent of activation and clinical status at both baseline and follow-up evaluations. Subjects with greater clinical impairment, based on the Clinical Dementia Rating Sum of Boxes, recruited a larger extent of the right PHG during encoding, even after accounting for atrophy. Moreover, those who subsequently declined over the 2.5 years of clinical follow-up (44% of the subjects) activated a significantly greater extent of the right PHG during encoding, despite equivalent memory performance. We hypothesize that increased activation in MTL regions reflects a compensatory response to accumulating AD pathology and may serve as a marker for impending clinical decline. ( view less ) Reisa Sperling,Elizabeth Chua,Andrew Cocchiarella,Erin Rand-Giovannetti,Russell Poldrack,Daniel L Schacter,Marilyn Albert The ability to form associations between previously unrelated items of information, such as names and faces, is an essential aspect of episodic memory function. The neural substrate that determines success vs. failure in learning these associations remains to be elucidated. Using event-related func... ( view more )tional MRI during the encoding of novel face-name associations, we found that successfully remembered face-name pairs showed significantly greater activation in the anterior hippocampal formation bilaterally and left inferior prefrontal cortex, compared to pairs that were forgotten. Functional connectivity analyses revealed significant correlated activity between the right and left hippocampus and neocortical regions during successful, but not attempted, encoding. These findings suggest that anterior regions of the hippocampal formation, in particular, are crucial for successful associative encoding and that the degree of coordination between hippocampal and neocortical activity may predict the likelihood of subsequent memory. ( view less ) Alon Monsonego,Victor Zota,Arnon Karni,Jeffery I Krieger,Amit Bar-Or,Gal Bitan,Andrew E Budson,Reisa Sperling,Dennis J Selkoe,Howard L Weiner Alzheimer disease (AD) is characterized by the progressive deposition of the 42-residue amyloid beta protein (Abeta) in brain regions serving memory and cognition. In animal models of AD, immunization with Abeta results in the clearance of Abeta deposits from the brain. However, a trial of vaccinat... ( view more )ion with synthetic human Abeta1-42 in AD resulted in the development of meningoencephalitis in some patients. We measured cellular immune responses to Abeta in middle-aged and elderly healthy subjects and in patients with AD. A significantly higher proportion of healthy elderly subjects and patients with AD had strong Abeta-reactive T cell responses than occurred in middle-aged adults. The immunodominant Abeta epitopes in humans resided in amino acids 16-33. Epitope mapping enabled the identification of MHC/T cell receptor (TCR) contact residues. The occurrence of intrinsic T cell reactivity to the self-antigen Abeta in humans has implications for the design of Abeta vaccines, may itself be linked to AD susceptibility and course, and appears to be associated with the aging process. ( view less ) Reisa Sperling,Douglas Greve,Anders Dale,Ronald Killiany,Jennifer Holmes,H Diana Rosas,Andrew Cocchiarella,Paul Firth,Bruce Rosen,Stephen Lake,Nicholas Lange,Carol Routledge,Marilyn Albert To examine alterations in brain activation associated with pharmacologically induced memory impairment, we used functional MRI (fMRI) to study the effects of lorazepam and scopolamine on a face-name associative encoding paradigm. Ten healthy young subjects were scanned on four occasions, 2 weeks ap... ( view more )art; they were administered i.v. saline during two placebo-scanning sessions and then alternately administered i.v. lorazepam (1 mg) or scopolamine (0.4 mg) in a double-blind, randomized, cross-over design. Both the extent and magnitude of activation within anatomic regions of interest (ROIs) were examined to determine the reproducibility of activation in the placebo sessions and the regional specificity of the pharmacologic effects. Activation within all ROIs was consistent across the two placebo scans during the encoding of novel face-name pairs (compared with visual fixation). With the administration of either lorazepam or scopolamine, significant decreases were observed in both the extent and magnitude of activation within the hippocampal, fusiform, and inferior prefrontal ROIs, but no significant alterations in activation in the striate cortex were found. Both medications impaired performance on postscan memory measures, and significant correlations between memory performance and extent of activation were found in hippocampal and fusiform ROIs. These findings suggest that pharmacologic effects can be detected with fMRI by using a reproducible experimental paradigm and that medications that impair memory also diminish activation in specific brain regions thought to subserve complex memory processes. ( view less ) David P Salmon,Jeffrey L Cummings,Shelia Jin,Mary Sano,Reisa A Sperling,Edward Zamrini,Ronald C Petersen,Steven D Edland,Leon J Thal,Steven H Ferris,Alzheimer's Disease Cooperative Study  The validity and reliability of clinic-based and telephone-based versions of a 4 word delayed recall test were evaluated in nondemented elderly individuals (n=644) participating in a simulated primary prevention clinical trial. There was no significant difference in the average scores achieved by p... ( view more )articipants tested in clinic (mean=3.40) or by telephone (mean=3.47) and the 2 groups had similar distributions of scores. Delayed recall scores were significantly, but weakly, correlated with scores on a rigorous verbal memory task, were lower in participants in Clinical Dementia Rating stage 0.5 than in those in Clinical Dementia Rating stage 0, and were lower in those with subjective memory complaints than in those without complaints. There was only fair correspondence between scores achieved at initial testing and 3 months later for both versions of the test. There were no differences in the average scores achieved by men or women, those older (age 80 to 93) or younger (age 75 to 79) than age 80, or those with white or nonwhite ethnicity. Participants with low education scored significantly lower than those with high education. Results suggest that clinic-based and telephone-based versions of the Four Word Delayed Recall Test are valid and reliable and can be used to screen for possible memory deficits in elderly individuals. However, the psychometric properties of the test are relatively weak and do not support the general use of the test for clinical and research purposes if the use of a more rigorous memory test with a wider range of possible scores is feasible. ( view less ) Andrew E Budson,Kalina J Michalska,Dorene M Rentz,Claire C Joubert,Kirk R Daffner,Daniel L Schacter,Reisa A SperlingWe report the first use of a false recognition memory test in a clinical trial of patients with Alzheimer's disease (AD). Tests of false recognition allow measurement of two components of memory: the specific details of a prior encounter with a particular item (item-specific recollection) and the g... ( view more )eneral meaning, idea, or gist conveyed by a collection of items (gist memory). We used a false recognition paradigm with categorized pictures to study the effects of an experimental medication in patients with AD. Because medications to treat AD may preferentially improve gist memory or item-specific recollection, use of this type of paradigm may improve sensitivity for detection of drug effects more than standard memory tests. ( view less ) Sperling, Reisa A., Guttmann, Charles R. G., Hohol, Marika J., Warfield, Simon K., Jakab, Marianna, Parente, Marco, Diamond, Eli L., Daffner, Kirk R., Olek, Michael J., - Orav, E. John, Kikinis, Ron, Jolesz, Ferenc A., and Weiner, Howard L. - Examined the relationship between imaging regional lesion burden as shown by magnetic resonance imaging (MRI) and cognitive performance in 28 patients (mean age 39.3 yrs) with multiple sclerosis (MS). Ss underwent MRI and took the Brief, Repeatable Battery of Neuropsychological Tests in Multiple ... ( view more )Sclerosis at baseline, 1-yr, and 4-yr follow-up. Frontal lesion volume represented the greatest proportion of total lesion volume, and the percentage of white matter classified as lesion was also highest in frontal and parietal regions. Ss showed significant impairment compared with controls on tests of sustained attention, processing speed, and verbal memory. Performance on these measures correlated negatively with MS lesion volume in frontal and parietal regions. (PsycINFO Database Record (c) 2005 APA, all rights reserved) ( view less )
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