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Odors can be powerful stimulants. It is well-established that odors provide strong cues for recall of locations, people and events. The effects of specific scents on other cognitive functions are less well-established. We hypothesized that scents with different odor qualities will have a different effect on attention. To assess attention, we used Inter-Subject Correlation of the EEG because this metric is strongly modulated by attentional engagement with natural audiovisual stimuli. We predicted that scents known to be "energizing" would increase Inter-Subject Correlation during watching of videos as compared to "calming" scents. In a first experiment, we confirmed this for eucalyptol and linalool while participants watched animated autobiographical narratives. The result was replicated in a second experiment, but did not generalize to limonene, also considered an "energizing" odorant. In a third, double-blind experiment, we tested a battery of scents including single molecules, as well as mixtures, as participants watched various short video clips. We found a varying effect of odor on Inter-Subject Correlation across the various scents. This study provides a basis for reliably and reproducibly assessing effects of odors on brain activity. Future research is needed to further explore the effect of scent-based up-modulation in engagement on learning and memory performance. Educators, product developers and fragrance brands might also benefit from such objective neurophysiological measures.

Introduced is a general framework for performing group level analyses of fMRI data using any basis set of two functions (i.e. the canonical hemodynamic response function and its first derivative) to model the hemodynamic response to neural activity. The approach allows for flexible implementation of physiologically based restrictions on the results. Information from both basis functions is used at the group level and the limitations avoid physiologically ambiguous or implausible results. This allows for investigation of specific BOLD activity such as hemodynamic responses peaking within a specified temporal range (i.e. 4 to 5 seconds). The general nature of the presented approach allows for applications using basis sets specifically designed to investigate various physiologic phenomena, i.e. age-related variability in post-stimulus undershoot, hemodynamic responses measured with cerebral blood flow imaging or subject specific basis sets. An example using data from a group of healthy young participants demonstrates the methods and the specific steps to study post-stimulus variability are discussed. The approach is completely implemented within the general linear model and requires minimal programmatic calculations.

Objective To assess combined antidepressant and cognitive enhancer treatment in elderly patients presenting with depression plus cognitive impairment. Methods Twenty-three elderly (>50 years old) depressed, cognitively impaired (DEP-CI) patients participated in a pilot study. We evaluated whether, after 8 weeks of open antidepressant treatment, donepezil HCl (Aricept) would afford added cognitive benefit compared to placebo in a randomized 12-week trial. A subsample continued in an 8-month extension phase of open treatment with donepezil. Neuropsychological testing (NPT) was performed and antidepressant response monitored at baseline and the 8, 20, and 52-week time points. Results At 8-weeks, the antidepressant response rate was 61% (14/23). Improvement in SRT immediate recall (SRT-IR; e.g. episodic verbal memory) was observed in responders compared to non-responders. During the 12-week, placebo-controlled, donepezil add-on trial, patients on donepezil showed further improvement in SRT-IR versus patients on placebo. In the open extension phase, patients who continued open donepezil treatment (n = 6) maintained improvement in memory and tended to show an advantage over patients who never received donepezil and were evaluated at the 52-week time point (n = 6). There were no observed significant donepezil effects on non-memory cognitive domains. Conclusion These preliminary findings suggest that addition of a cholinesterase inhibitor (AChEI) following antidepressant medication treatment in elderly Dep-CI patients may improve cognition, and support the need for a confirmatory, larger randomized placebo-controlled trial. Copyright © 2007 John Wiley & Sons, Ltd.

Recent neuroimaging studies have converged to show that odorant-induced responses to prolonged stimulation in primary olfactory cortex (POC) are characterized by a rapidly habituating time course. Different statistical approaches have effectively modeled this time course. One approach explicitly modeled rapid habituation using an exponentially decaying reference waveform that decreased to baseline levels within 30 to 40 s. A second approach modeled an early transient response by simply shortening the odorant 'ON' period to be less than the actual stimulation period (i.e., 9 of 40 s). The goal of the current study was to validate, compare, and optimize these methodological approaches by applying them to an olfactory fMRI block-design dataset from 10 healthy young subjects presented with odorants for 12 s (ON), alternating with 30 s of clear air (OFF). Both approaches significantly improved sensitivity to odorant-induced signal changes in POC relative to a square-wave model based on the actual stimulation period. Our findings further demonstrate that the 'optimal' model fit to the data was achieved by shortening the odorant 'ON' period to approximately 6 s. These results suggest that sensitivity to odorant-induced POC activity in block-design experiments can be optimized by modeling an early phasic response followed by a precipitous rather than specific exponential decrease to baseline levels. Notably, whole brain voxel-wise analyses further established that modeling rapid habituation in this way is not only sensitive, but also highly specific to odorant-induced activation in a well-established network of olfactory-related brain areas.

International audience; Over the past several decades a growing amount of research has focused on the possibility of transiently reducing left neglect signs in right brain-damaged patients by using vestibular and/or visuo-proprioceptive stimulations. Here we review seminal papers dealing with these visuo-vestibulo-proprioceptive stimulations in normal controls, right brain-damaged (RBD) patients, and animals. We discuss these data in terms of clinical implications but also with regards to theoretical frameworks commonly used to explain the unilateral neglect syndrome. We undermine the effect of these stimulations on the position of the egocentric reference and extend the notion that the positive effects of these stimulation techniques may stem from a reorientation of attention towards the neglected side of space or from a recalibration of sensori-motor correlations. We conclude this review with discussing the possible interaction between experimental rehabilitation, models of neglect and basic spatial cognition research.

Temporoparietal and posterior cingulate metabolism deficits characterize patients with Alzheimer's disease (AD). A H(2)(15)O resting PET scan covariance pattern, derived by using multivariate techniques, was previously shown to discriminate 17 mild AD patients from 16 healthy controls. This AD covariance pattern revealed hypoperfusion in bilateral inferior parietal lobule and cingulate; and left middle frontal, inferior frontal, precentral, and supramarginal gyri. The AD pattern also revealed hyperperfusion in bilateral insula, lingual gyri, and cuneus; left fusiform and superior occipital gyri; and right parahippocampal gyrus and pulvinar. In an independent sample of 23 outpatients with mild cognitive impairment (MCI) followed at 6-month intervals, the AD pattern score was evaluated as a predictor of cognitive decline. In this MCI sample, an H2(15)O resting PET scan was carried out at baseline. Mean duration of follow-up was 48.8 (SD 15.5) months, during which time six of 23 MCI patients converted to AD. In generalized estimating equations (GEE) analyses, controlling for age, sex, education, and baseline neuropsychological scores, increased AD pattern score was associated with greater decline in each neuropsychological test score over time (Mini Mental State Exam, Selective Reminding Test delayed recall, Animal Naming, WAIS-R digit symbol; Ps

Prosodic expression is an important channel of emotional communication and can be assessed through computerized acoustical analysis. Fundamental Frequency (F0) is the most commonly studied acoustic measure and considered the best index of perceived pitch. In this study, we examined two factors that can influence prosodic expression, sex and emotion type, A special feature is the use of a neutral expression as a control measure. We also described procedures for eliciting posed prosodic expression via an experimental task from the New York Emotion Battery. Subjects were healthy men ( n=10) and women ( n=9), matched for. age ( M = 29.2 yr.) and education ( M= 15.6 yr). Subjects were asked to intone neutral-content sentences with happy, sad, and neutral prosody. F0 mean and standard deviation were measured using the Computerized Speech Lab program. Initial findings indicated that women produced significantly higher F0 values than did men and that happy sentences were produced with significantly higher F0 values than were sad sentences. When semitone conversions were applied and neutral prosody was subtracted out, differences remained for emotion type but not for sex. Findings are discussed in terms of implications for the assessment and treatment of prosody in clinical populations.

The current study examined the effects of age and gender on emotional and nonemotional expression using an experimental word list generation (WLG) task (also referred to in the literature as verbal fluency) from the New York Emotion Battery (Borod, Welkowitz,Obler, 1992). Subjects were 28 young ( M = 29.6 years), 28 middle-aged (M = 49.8 years), and 28 older (M = 69.9 years) healthy adults. The WLG task consists of 8 emotional (E; 3 positive and 5 negative) and 8 nonemotional (NE) categories. We developed and present here a detailed word error-type analysis that was used to evaluate the lexical output. In this study, both quantitative (amount of output and error-types) and qualitative (accuracy and intensity) analyses were used. While subjects produced more nonemotional than emotional words and more positive than negative words, the amount of error-free output and the number of errors did not change with age. An age group by error-type interaction indicated that older adults, especially men, produced more repetition errors than younger adults. The error-free output was subsequently rated for accuracy and emotional intensity. The rating data revealed that older women's overall lexical output was less accurate than that produced by younger women. Also, negative emotional words were more accurate and intense than positive emotional words. The procedures described here have implications for research assessing word list generation and emotional expression in clinical populations.

The current protocol can be used to examine selective attention. It has been used to acquire behavioral performance data in neurologically healthy normal control subjects and schizophrenic patients. A modified version, also described here, has been used to acquire functional neuroimaging data in normal subjects using positron emission tomography. Subject response accuracy and reaction times are recorded while subjects detect visual stimuli in either hemifield (left vs. right of a fixation point) or along the vertical meridian (above or below fixation). The lateralized presentation of stimuli permits the study of hemispheric specialization for selective attentional processes. Attentional load is manipulated by presenting larger-sized target stimuli alone (i.e., the letter ‘O’) or smaller-sized target stimuli surrounded by flanking letters. This protocol report includes a description of subject exclusion criteria, procedural details, relevant experimental conditions and variables, suggestions for data analysis, expected results, and a discussion of the protocol’s significance for attentional research along with suggestions for future research.

This study was designed to address the issue of whether there is a general processor for the perception of emotion or whether there are separate processors. We examined the relationships among three channels of emotional communication in 100 healthy right-handed adult males and females. The channels were facial, prosodic/intonational, and lexical/verbal; both identification and discrimination tasks of emotional perception were utilised. Statistical analyses controlled for nonemotional perceptual factors and subject characteristics (i.e. demographic and general cognitive). For identification, multiple significant correlations were found among the channels. For discrimination, fewer correlations were significant. Overall, these results provide support for the notion of a general processor for emotional perceptual identification in normal adult subjects.

SUMMARY Objective—To compare state and trait anxiety in mild cognitive impairment (MCI) patients and matched control subjects, and to assess the impact of these variables in predicting conversion to Alzheimer’s disease. Methods—One hundred and forty-eight patients with MCI, broadly defined, were assessed and followed systematically. Baseline predictors for follow-up conversion to AD (entire sample: 39/148 converted to Alzheimer’s disease (AD)) included the Spielberger State-Trait Anxiety Inventory (STAI). Results—At baseline evaluation, MCI patients had higher levels of state and trait anxiety than controls, with no differences between future AD converters (n = 39) and non-converters. In agestratified Cox proportional hazards model analyses, STAI State was not a significant predictor of conversion to AD (STAI State ≤30 vs. > 30 risk ratio, 1.68; 95% CI, 0.75, 3.77; p = 0.21), but higher Trait scores indicated a lower risk of conversion when STAI State, education, the Folstein MiniMental State Examination and HAM-D (depression score) were also included in the model (STAI Trait ≤30 vs. > 30 risk ratio, 0.36; 95% CI, 0.16, 0.82; p = 0.015). Conclusions—In contrast to two other recent studies that showed anxiety predicted cognitive decline or conversion to AD, in this clinic-based sample, state anxiety was not a significant predictor. However, higher Trait anxiety predicted a lower risk of future conversion to AD. Further research with systematic long-term follow-up in larger samples is needed to clarify the role of state and trait anxiety in predicting MCI conversion to AD.

Jason Steffener, Matthias Tabert, Christian Habeck, Gregory Pelton, Yaakov Stern, Davangere Devanand, Taub Institute for Research in Alzheimer’s Disease and the Aging Brain and Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA; Division of Geriatric Psychiatry, Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. Contact e-mail: js2746@columbia.edu

Background The utility of combining early markers to predict conversion from mild cognitive impairment (MCI) to Alzheimer's Disease (AD) remains uncertain. Methods Included in the study were 148 outpatients with MCI, broadly defined, followed at 6-month intervals. Hypothesized baseline predictors for follow-up conversion to AD (entire sample: 39/148 converters) were cognitive test performance, informant report of functional impairment, apolipoprotein E genotype, olfactory identification deficit, and magnetic resonance imaging (MRI) hippocampal and entorhinal cortex volumes. Results In the 3-year follow-up patient sample (33/126 converters), five of eight hypothesized predictors were selected by backward and stepwise logistic regression: Pfeffer Functional Activities Questionnaire (FAQ; informant report of functioning), University of Pennsylvania Smell Identification Test (UPSIT; olfactory identification), Selective Reminding Test (SRT) immediate recall (verbal memory), MRI hippocampal volume, and MRI entorhinal cortex volume. For 10% false positives (90% specificity), this five-predictor combination showed 85.2% sensitivity, combining age and Mini-Mental State Examination (MMSE) showed 39.4% sensitivity; combining age, MMSE, and the three clinical predictors (SRT immediate recall, FAQ, and UPSIT) showed 81.3% sensitivity. Area under ROC curve was greater for the five-predictor combination (.948) than age plus MMSE (.821; p = .0009) and remained high in subsamples with MMSE ≥ 27/30 and amnestic MCI. Conclusions The five-predictor combination strongly predicted conversion to AD and was markedly superior to combining age and MMSE. Combining the clinically administered measures also led to strong predictive accuracy. If independently replicated, the findings have potential utility for early detection of AD.

Mild Parkinsonian signs (MPS, impaired gait, rigidity, bradykinesia, rest tremor) are commonly found during the clinical examination of older people and may be a precursor to Parkinson's disease (PD) or Alzheimer's disease (AD). Marked deficits in olfaction occur in PD and AD. The objective of this study was to determine whether University of Pennsylvania Smell Test (UPSIT) scores were lower in nondemented community-dwelling elderly with versus without MPS. Nondemented persons age >or=65 years without PD in Washington Heights-Inwood, NY were evaluated with an abbreviated motor Unified PD Rating Scale and a 40-item UPSIT. Lower UPSIT and higher transformed UPSIT score (square root [UPSIT - 41]) indicated greater olfactory dysfunction. One-hundred-seventy-seven (16.4%) of 1,078 participants had MPS. Mean UPSIT scores (MPS vs. without MPS) were 24.3 +/- 7.1 versus 26.4 +/- 6.8, P < 0.001. In a logistic regression analysis adjusting for age and education, transformed UPSIT score was associated with MPS (OR 1.25, 95% CI 1.04-1.52, P = 0.02). In an adjusted logistic regression analysis, participants with higher transformed UPSIT scores (based on a median split) were 1.55 times more likely to have MPS than were those with lower scores (P = 0.01). Within transformed UPSIT score quartiles, the odds of having MPS were 1.0 (reference), 1.35, 2.02, and 2.20 (P < 0.05). The association with transformed UPSIT scores was similar across MPS subtypes (axial dysfunction, rigidity, tremor).MPS were associated with a mild reduction in olfactory function. These observations further support the view of MPS as a marker of emerging degenerative brain pathologies.

To evaluate the utility of MRI hippocampal and entorhinal cortex atrophy in predicting conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD).Baseline brain MRI was performed in 139 patients with MCI, broadly defined, and 63 healthy controls followed for an average of 5 years (range 1 to 9 years).Hippocampal and entorhinal cortex volumes were each largest in controls, intermediate in MCI nonconverters, and smallest in MCI converters to AD (37 of 139 patients converted to AD). In separate Cox proportional hazards models, covarying for intracranial volume, smaller hippocampal volume (risk ratio [RR] 3.62, 95% CI 1.93 to 6.80, p0.0001), and entorhinal cortex volume (RR 2.43, 95% CI 1.56 to 3.79, p0.0001) each predicted time to conversion to AD. Similar results were obtained for hippocampal and entorhinal cortex volume in patients with MCI with Mini-Mental State Examination (MMSE) scoresor = 27 out of 30 (21% converted to AD) and in the subset of patients with amnestic MCI (35% converted to AD). In the total patient sample, when both hippocampal and entorhinal volume were entered into an age-stratified Cox model with sex, MMSE, education, and intracranial volume, smaller hippocampal volume (RR 2.21, 95% CI 1.14 to 4.29, p0.02) and entorhinal cortex volume (RR 2.48, 95% CI 1.54 to 3.97, p0.0002) predicted time to conversion to AD. Similar results were obtained in a Cox model that also included Selective Reminding Test (SRT) delayed recall and Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit Symbol as predictors. Based on logistic regression models in the 3-year follow-up sample, for a fixed specificity of 80%, the sensitivities for MCI conversion to AD were as follows: age 43.3%, MMSE 43.3%, age + MMSE 63.7%, age + MMSE + SRT delayed recall + WAIS-R Digit Symbol 80.6% (79.6% correctly classified), hippocampus + entorhinal cortex 66.7%, age + MMSE + hippocampus + entorhinal cortex 76.7% (85% correctly classified), age + MMSE + SRT delayed recall + WAIS-R Digit Symbol + hippocampus + entorhinal cortex 83.3% (86.8% correctly classified).Smaller hippocampal and entorhinal cortex volumes each contribute to the prediction of conversion to Alzheimer disease. Age and cognitive variables also contribute to prediction, and the added value of hippocampal and entorhinal cortex volumes is small. Nonetheless, combining these MRI volumes with age and cognitive measures leads to high levels of predictive accuracy that may have potential clinical application.

Prosody or speech melody subserves linguistic (e.g., question intonation) and emotional functions in speech communication. Findings from lesion studies and imaging experiments suggest that, depending on function or acoustic stimulus structure, prosodic speech components are differentially processed in the right and left hemispheres. This direct current (DC) potential study investigated the linguistic processing of digitally manipulated pitch contours of sentences that carried an emotional or neutral intonation. Discrimination of linguistic prosody was better for neutral stimuli as compared to happily as well as fearfully spoken sentences. Brain activation was increased during the processing of happy sentences as compared to neutral utterances. Neither neutral nor emotional stimuli evoked lateralized processing in the left or right hemisphere, indicating bilateral mechanisms of linguistic processing for pitch direction. Acoustic stimulus analysis suggested that prosodic components related to emotional intonation, such as pitch variability, interfered with linguistic processing of pitch course direction.

Olfactory dysfunction is present in patients diagnosed with Alzheimer’s disease or idiopathic Parkinson’s disease and can differentiate each of these disorders from related disorders with similar clinical presentations. The pathologic hallmarks of each disease are present in brain regions involved in processing olfactory input. Both the olfactory functional deficits and the corroborating pathologic lesions are present in asymptomatic subjects with increased risk of developing these diseases. Preclinical detection of neurodegenerative diseases is necessary to control their devastating effects on individuals and societies. We address whether olfactory dysfunction can be used to assess risk for developing Alzheimer’s disease or Parkinson’s disease in asymptomatic individuals. We argue that further characterization and a deeper understanding of olfactory deficits in these neurodegenerative diseases at the molecular, cellular, and systems levels will augment our acumen for preclinical detection and elucidate pathogenic mechanisms to guide the development of new therapeutic modalities.

Context: The likelihood of conversion to Alzheimer disease (AD) in mild cognitive impairment (MCI) and the “optimal” early markers of conversion need to be established. Objectives: To evaluate conversion rates to AD in subtypes of MCI and to identify neuropsychological measures most predictive of the time to conversion. Design: Patients were followed up semiannually and controls annually. Subtypes of MCI were determined by using demographically adjusted regression norms on neuropsychological tests. Survival analysis was used to identify the most predictive neuropsychological measures. Setting: Memory disorders clinic. Participants: One hundred forty-eight patients reporting memory problems and 63 group-matched controls. Main Outcome Measure: A consensus diagnosis of probable AD. Results: At baseline, 108 patients met criteria for amnestic MCI: 87 had memory plus other cognitive domain deficits and 21 had pure memory deficits. The mean duration of follow-up for the 148 patients was 46.6 ±2 4.6 months. In 3 years, 32 (50.0%) of 64 amnestic-“plus” and 2 (10.0%) of 20 “pure” amnestic patients converted to AD (P=.001). In 148 patients, o f5ap rioripredictors, the percent savings from immediate to delayed recall on the Selective Reminding Test and the Wechsler Adult Intelligence Scale–Revised Digit Symbol Test were the strongest predictors of time to conversion. From the entire neuropsychological test battery, a stepwise selection procedure retained 2 measures in the final model: total immediate recall on the Selective Reminding Test (odds ratio per 1-point decrease, 1.10; 95% confidence interval, 1.051.14; P.0001) and Digit Symbol Test coding (odds ratio, 1.06; 95% confidence interval, 1.01-1.11;P=.01). The combined predictive accuracy of these 2 measures for conversion by 3 years was 86%. Conclusions: Mild cognitively impaired patients with memory plus other cognitive domain deficits, rather than those with pure amnestic MCI, constituted the highrisk group. Deficits in verbal memory and psychomotor speed/executive function abilities strongly predicted conversion to AD.

University of Pennsylvania Smell Identification Test data from control subjects (n = 63), patients with mild cognitive impairment (n = 147), and patients with Alzheimer's disease (n = 100) were analyzed to derive an optimal subset of items related to risk for Alzheimer's disease (ie, healthy through mild cognitive impairment to early and moderate disease stages). The derived 10-item scale performed comparably with the University of Pennsylvania Smell Identification Test in classifying subjects, and it strongly predicted conversion to Alzheimer's disease on follow-up evaluation in patients with mild cognitive impairment. Independent replication is needed to validate these findings.

Background In cognitively impaired patients without dementia, the utility of apolipoprotein E ( APOE ) genotyping is unclear. Objective To evaluate the predictive utility of the APOE e4 genotype for conversion to probable Alzheimer disease (AD). Design Naturalistic, longitudinal study. Setting Memory disorders outpatient clinic. Patients A total of 136 patients with memory complaints were determined to have mild cognitive impairment and were evaluated every 6 months. Fifty-seven age- and sex-matched healthy controls were evaluated annually. Main Outcome Measures Primary outcome measures included conversion to AD. Secondary outcome measures included change over time in Mini-Mental State Examination (MMSE) score and Selective Reminding Test (SRT) delayed recall score. Results The APOE e4 allele was present in 25% of patients and 21% of healthy controls. During a mean ± SD follow-up of 35.2 ± 24.3 months, 35 of 136 patients converted to AD. APOE e4 carrier status did not differ between converters (31%) and nonconverters to AD (23%, P = .3) and did not affect the time trend in MMSE or SRT scores in the entire sample. Four of 5 APOE e4 homozygotes converted to AD compared with 7 of 29 heterozygotes ( P = .02). In a Cox proportional hazards model stratified by age quartiles, after controlling for sex, education, MMSE score, and SRT delayed recall score, APOE e4 increased the risk of AD in patients 70 to 85 years old (n = 57; risk ratio, 2.77; 95% confidence interval, 1.1-7.3; P = .03) but not in patients 55 to 69 years old (n = 79; P = .7). Conclusions APOE e4 carrier status was associated with conversion to AD in older outpatients after controlling for known demographic and clinical risk factors, and APOE e4 homozygosity was associated with increased risk of conversion to AD. However, APOE e4 carrier status by itself did not predict cognitive decline or conversion to AD, indicating that APOE genotyping in patients with mild cognitive impairment may have limited clinical applicability for prediction of outcome.

Objective Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects. Methods Using H215O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-epsilon4 carriers and 6 epsilon4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the "activation" difference (TD-SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the epsilon4 allele) as the independent variable. Results Compared with non-carriers, epsilon4 carriers exhibited significantly decreased TD-SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because epsilon4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition. Conclusion Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the epsilon4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.

Although multivariate analytic techniques might identify diagnostic patterns that are not captured by univariate methods, they have rarely been used to study the neural correlates of Alzheimer's disease (AD) or cognitive impairment. Nonquantitative H2(15)O PET scans were acquired during rest in 17 probable AD subjects selected for mild severity [mean-modified Mini Mental Status Examination (mMMS) 46/57; SD 5.1], 16 control subjects (mMMS 54; SD 2.5) and 23 subjects with minimal to mild cognitive impairment but no dementia (mMMS 53; SD 2.8). Expert clinical reading had low success in discriminating AD and controls. There were no significant mean flow differences among groups in traditional univariate SPM Noxel-wise analyses or region of interest (ROI) analyses. A covariance pattern was identified whose mean expression was significantly higher in the AD as compared to controls (P = 0.03; sensitivity 76-94%; specificity 63-81%). Sites of increased concomitant flow included insula, cuneus, pulvinar, lingual, fusiform, superior occipital and parahippocampal gyri, whereas decreased concomitant flow was found in cingulate, inferior parietal lobule, middle and inferior frontal, supramarginal and precentral gyri. The covariance analysis-derived pattern was then prospectively applied to the cognitively impaired subjects: as compared to subjects with Clinical Dementia Rating (CDR) = 0, subjects with CDR = 0.5 had significantly higher mean covariance pattern expression (P = 0.009). Expression of this pattern correlated inversely with Selective Reminding Test total recall (r = -0.401, P = 0.002), delayed recall (r = -0.351, P = 0.008) and mMMS scores (r = -0.401, P = 0.002) in all three groups combined. We conclude that patients with AD may differentially express resting cerebral blood flow covariance patterns even at very early disease stages. Significant alterations in expression of resting flow covariance patterns occur even for subjects with cognitive impairment. Expression of covariance patterns correlates with cognitive and functional performance measures, holding promise for meaningful associations with underlying biopathological processes.

When two visual events appear consecutively in the same spatial location, our response to the second event is slower than to the first. This inhibition for repeated events may reflect a bias toward sampling novel locations, a bias useful for exploring visual space. It has been shown that the left hemisphere is more specialized in selective attentional processes than the right one. The aim of the present experiment was to test if this hemispheric specialization for selective attention may also affect the inhibition for repeated events. For this purpose, we asked 11 normal subjects to perform an identity-based discrimination task in which the target to be detected could appear alone or surrounded by flanking letters, in the left or in the right visual field. Results show that inhibition for repeated events is present only when selective attention is required and when the task is performed in the right specialized visual field.

Objective: To evaluate the predictive utility of self-reported and informant-reported functional deficits in patients with mild cognitive impairment (MCI) for the follow-up diagnosis of probable AD. Methods: The Pfeffer Functional Activities Questionnaire (FAQ) and Lawton Instrumental Activities of Daily Living (IADL) Scale were administered at baseline. Patients were followed at 6-month intervals, and matched normal control subjects (NC) were followed annually. Results: Self-reported deficits were higher for patients with MCI than for NC. At baseline, self- and informant-reported functional deficits were significantly greater for patients who converted to AD on follow-up evaluation than for patients who did not convert, even after controlling for age, education, and modified Mini-Mental State Examination scores. While converters showed significantly more informant- than self-reported deficits at baseline, nonconverters showed the reverse pattern. Survival analyses further revealed that informant-reported deficits (but not self-reported deficits) and a discrepancy score indicating greater informant- than self-reported functional deficits significantly predicted the development of AD. The discrepancy index showed high specificity and sensitivity for progression to AD within 2 years. Conclusions: These findings indicate that in patients with MCI, the patient’s lack of awareness of functional deficits identified by informants strongly predicts a future diagnosis of AD. If replicated, these findings suggest that clinicians evaluating MCI patients should obtain both self-reports and informant reports of functional deficits to help in prediction of long-term outcome.

This study used fMRI to examine the response of the amygdala in the evaluation and short-term recognition memory of unpleasant vs. neutral words in nine right-handed healthy adult women. To establish specificity of the amygdala response, we examined the fMRI BOLD signal in one control region (visual cortex). Alternating blocks of unpleasant and neutral trials were presented. During the emotional decision task, subjects viewed sets of three unpleasant or three neutral words while selecting the most unpleasant or neutral word, respectively. During the memory task, subjects identified words that were presented during the emotional decision task (0.50 probability). Images were detrended, filtered, and coregistered to standard brain coordinates. The Talairach coordinates for the center of the amygdala were chosen before analysis. The BOLD signal at this location in the right hemisphere revealed a greater amplitude signal for the unpleasant relative to the neutral words during the emotional decision but not the memory task, confirmed by Time Course x Word Condition ANOVAs. These results are consistent with the memory modulatory view of amygdala function, which suggests that the amygdala facilitates long-term, but not short-term, memory consolidation of emotionally significant material. The control area showed only an effect for Time Course for both the emotional decision and memory tasks, indicating the specificity of the amygdala response to the evaluation of unpleasant words. Moreover, the right-sided amygdala activation during the unpleasant word condition was strongly correlated with the BOLD response in the occipital cortex. These findings corroborate those by other researchers that the amygdala can modulate early processing of visual information in the occipital cortex. Finally, an increase in subject's state anxiety (evaluated by questionnaire) while in the scanner correlated with amygdala activation under some conditions.