Visual attention deficits in Alzheimer's disease: simple versus conjoined feature search.

The authors investigated selective attention in patients with Alzheimer's disease (AD), using a well-known visual search procedure. In simple feature search, the deficit observed in AD patients represented a baseline shift in the median hit reaction time (RT). On the conjoined feature search task, the median hit RT for AD patients increased disproportionately with increasing array size, indicating an additional cognitive impairment on this task. Of particular importance, the cognitive deficit observed in conjunction search was more profound than that predicted on the basis of previous reports of global cognitive slowing in AD. There was some evidence that the performance of AD patients improved more than the performance of controls over the duration of the experimental test session. Patients also had more difficulty in detecting targets on the right side of hemispace and in more peripheral locations.     

Neural basis for verb processing in Alzheimer's disease: an fMRI study

Patients with probable Alzheimer's disease (AD) have difficulty understanding verbs. To investigate the neural basis for this deficit, the authors used functional magnetic resonance imaging to examine patterns of neural activation during verb processing in 11 AD patients compared with 16 healthy seniors. Subjects judged the pleasantness of verbs, including MOTION verbs and COGNITION verbs. Healthy seniors and AD patients both activated posterolateral temporal and inferior frontal regions during judgments of verbs. These activations were relatively reduced and somewhat changed in their anatomic distribution in AD patients compared with healthy seniors, particularly for the subcategory of MOTION verbs, but AD patients showed minimal activation in association with COGNITION verbs. These findings imply that poor performance with verbs in AD is due in part to altered activation of the large-scale neural network that supports verb processing.     

Sustained attention in mild Alzheimer's disease

The vigilance decrement in perceptual sensitivity was examined in 10 patients with mild Alzheimer's disease (AD) and 20 age-matched controls. A visual high-event rate digit-discrimination task lasting 7.2 min. (six 1.2 min blocks) was presented at different levels of stimulus degradation. Previous studies have shown that sensitivity decrements (d') over time at high-stimulus degradation result from demands on effortful processing. For all degradation levels, the overall level of vigilance (d') was lower in AD patients than in controls. All participants showed sensitivity decrement over blocks, with greater decrement at higher degradation levels. AD patients exhibited greater sensitivity decrement over time at the highest degradation level they all could perform relative to control participants. There were no concomitant changes in either response bias (C) or response times. The results indicate that mild AD patients have overall lower levels of vigilance under conditions that require both automatic and effortful processing. Mild AD patients also exhibit a deficit in the maintenance of vigilance over time under effortful processing conditions. Although the sample of AD patients was small, results further suggest that both possible and probable AD patients had greater sensitivity decrement over time at the highest degradation level than did control participants, but only probable AD patients had lower overall levels of vigilance. In the possible AD patients as a group, the decrement in vigilance occurred in the absence of concurrent deficits on standard attentional tasks, such as the Stroop and Trail Making tests, suggesting that deficits in vigilance over time may appear earlier than deficits in selective attention.     

Everyday memory deficits in very mild Alzheimer's disease

Memory complaints of patients sometimes are not verified via standard cognitive testing. Acquisition of information in everyday life requires memorization in complex three-dimensional environments. The authors mimicked this with a photorealistic virtual environment (VE). Memory for verbal material and spatial scenery was tested in healthy controls (HC) and patients with mild Alzheimer's disease (AD); mini-mental state evaluation (MMSE) 25.7 ± 1.8 (mean ± standard deviation). The number of memorized items increased to 90% in both classical list learning and for items memorized in VE in HC. In contrast, only 40% of items were recalled in list learning and 20% in VE in AD patients. Unlike the gender difference favoring female HC on list learning, performance was alike for both genders in VE. We conclude that verbal learning abilities in healthy elderly subjects are alike in standard settings and under virtual reality conditions. In AD patients memory deficits that are relevant to everyday life yet not detectable with list learning are unmasked in virtual reality. In future, this may aid objective appraisal of interventions with regard to their everyday relevance.     

Resting state fMRI in Alzheimer's disease: beyond the default mode network

Using resting state (RS) functional magnetic resonance imaging (fMRI), the connectivity patterns of the default mode (DMN), frontoparietal, executive, and salience networks were explored in 13 Alzheimer's disease (AD) patients, 12 amnestic mild cognitive impairment (aMCI) patients, and 13 healthy controls. Compared with controls and aMCI, AD was associated with opposing connectivity effects in the DMN (decreased) and frontal networks (enhanced). The only RS abnormality found in aMCI patients compared with controls was a precuneus connectivity reduction in the DMN. RS fMRI group differences were only partly related to gray matter atrophy. In AD patients, the mean executive network connectivity was positively associated with frontal-executive and language neuropsychological scores. These results suggest that AD is associated with an alteration of large-scale functional brain networks, which extends well beyond the DMN. In AD, the limited resources of the DMN may be paralleled, in an attempt to maintain cognitive efficiency, by an increased prefrontal connectivity. A medial parietal RS fMRI signal change seems to be present since the early phase of AD.     

Selective attention impairments in Alzheimer's disease: evidence for dissociable components

Tasks emphasizing 3 different aspects of selective attention-inhibition, visuospatial selective attention, and decision making-were administered to subjects with mild Alzheimer's disease (AD) and to healthy elderly control (HEC) subjects to determine which components of selective attention were impaired in AD subjects and whether selective attention could be dissociated into different components. The tasks were administered with easy versus hard levels of difficulty to assess proportional slowing as the key variable across tasks. The results indicated that the inhibitory and visual search tasks showed greater proportional slowing in subjects with AD than in HEC subjects, and that the task involving inhibition was significantly more affected in subjects with AD. Furthermore, there were no significant intertask correlations, and the results cannot be explained simply in terms of generalized cognitive slowing. These results provide evidence that inhibition is the most strikingly affected aspect of selective attention that is observed to be impaired in early stages of AD.     

Episodic memory deficits in Alzheimer's disease: a behaviorally anchored scale.

This research represents an investigation into a behaviorally anchored scale for assessment of episodic memory. The Episodic Memory Scale (EMS) was theoretically derived and developed for use in a professional office environment. Performances of patients diagnosed with dementia of the Alzheimer's Type (N = 17) were significantly worse (p <.002) on the EMS than a comparison group (N = 17) of patients with cognitive dysfunction not associated with Alzheimer's disease. The EMS was positively and significantly correlated with other measures of episodic memory and less so with a measure of semantic memory. The extent to which episodic and semantic memory deficits relate to caregiver functional assessment ratings was explored. Findings are discussed with respect to ecological validity of the EMS and implications for reality monitoring ability. Utility of measuring episodic memory processes for purposes of neuropsychological assessment and caregiver decision-making are also discussed.     

Resting-state fMRI changes in Alzheimer's disease and mild cognitive impairment

Regional functional connectivity (FC) of 39 patients with Alzheimer's disease (AD), 23 patients with mild cognitive impairment (MCI), and 43 healthy elderly controls was studied using resting-state functional magnetic resonance imaging (rs-fMRI). After a mean follow-up of 2.8 ± 1.9 years, 7 MCI patients converted to AD, while 14 patients remained cognitively stable. Resting-state functional magnetic resonance imaging scans were analyzed using independent component analysis (ICA), followed by a "dual-regression" technique to create and compare subject-specific maps of each independent spatiotemporal component, correcting for age, sex, and gray matter atrophy. AD patients displayed lower FC within the default-mode network (DMN) in the precuneus and posterior cingulate cortex compared with controls, independent of cortical atrophy. Regional FC values of MCI patients were numerically in between AD patients and controls, but only the difference between AD and stable MCI patients was statistically significant. Correlation with cognitive dysfunction demonstrated the clinical relevance of FC changes within the DMN. In conclusion, clinically relevant decreased FC within the DMN was observed in AD.     

Neurotransmitter deficits in behavioural and psychological symptoms of Alzheimer's disease

Behavioural and psychological symptoms of dementia (BPSD) occur in 50-90% of Alzheimer's disease (AD) patients. Imbalance of different neurotransmitters (acetylcholine, dopamine, noradrenaline and serotonin), involvement of specific brain regions responsible for emotional activities (parahippocampal gyrus, dorsal raphe and locus coeruleus) and cortical hypometabolism have been proposed as neurobiological substrate of BPSD. Compared to with respect to the neurochemical component, the cholinergic dysfunction seems to play a major role in contributing to BPSD occurrence. This view is also supported by the findings of recent trials with cholinesterase inhibitors, showing that these drugs are effective in controlling and/or improving BPSD, independent on effects on cognitive dysfunction. On the site of psychotropic drugs, atypical or novel antipsychotics represent the reference drugs for treating BPSD, whereas classic antipsychotic drugs for their profile and the potential side effects should be avoided.     

Heterogeneity of semantic and visuospatial deficits in early Alzheimer's disease

Staging of visuospatial and semantic deficits in patients with dementia of the Alzheimer type (DAT) was examined. The authors hypothesized that semantic ability would be more impaired in these patients, reflecting predominant temporal pathology early in the disease. However, in the 1st study (n = 26), 3 patients (11.5%) had marked visual but no semantic impairment. This finding was extended in a 2nd study with a 2nd patient sample (n = 21) and more specific tasks. Two patients (9.5%) again had visual but no semantic impairment. These studies confirm that, in patients with DAT presenting with relatively focal deficits, visual deficits sometimes occur before semantic problems. The findings are discussed with regard to the cognitive demands and neuroanatomical underpinning of the tests used and point to the necessity of using cognitively specific tests to enable accurate analysis of deficits in the context of the neuroanatomical basis of impairment.     

Specificity of inhibitory deficits in normal aging and Alzheimer's disease

Deficits of suppression abilities are frequently observed in normal aging and Alzheimer's disease. However, few studies have explored these deficits in the two populations simultaneously using a large battery of tasks. The aim of the present study was to explore if the pattern of performance presented by elderly subjects and AD patients is in agreement with theoretical frameworks [Wilson, S.P., Harnishfeger, K.K., 1998. The development of efficient inhibition: Evidence from directed forgetting tasks. Dev. Rev. 18, 86-123; see also Nigg J.T., 2000. On inhibition/disinhibition in developmental psychopathology: views from cognitive and personality psychology and a working inhibition taxonomy. Psychol. Bull. 126, 220-246], distinguishing between the concepts of inhibition (a voluntary suppression of irrelevant information) and interference (an automatic suppression process occurring prior to conscious awareness). The results obtained demonstrated that (1) there is an alteration of the inhibitory process in normal elderly subjects; (2) inhibitory and interference resolution processes are quantitately less efficient in AD, since these patients present a correct performance only for information which leaves weak traces in memory.     

Involuntary attention impairment in early Parkinson's disease: an event-related potential study

Dopaminergic nigro-striatal depletion interferes with the detection of novel stimuli. This suggests that Parkinson's disease (PD) may generate from the initial stages a failure in involuntary attention (IA), which can be studied through the distraction potential, composed by the mismatch negativity (MMN), the P3a and the reorientation negativity (RON). This study analyzed IA using event-related potentials (ERPs) in patients with early PD with and without dopaminergic replacement therapy. Twenty-five medicated, and 17 non-medicated patients with early PD were studied, as well as 20 healthy control subjects. All subjects performed an auditory distraction task while a digital EEG was being recorded. The distraction potential was obtained by averaging methodology. Each wave was analyzed with a Repeated Measures ANOVA test. The MMN was obtained in all subjects and no significant differences in mean amplitude were found among the groups. There was a main effect of group for the amplitude of P3a (F(2,59) = 4.8, p = 0.01, ? = 0.411), with a significant lower amplitude in the medicated group compared to the control group (MD = −1.03, p = 0.003). RON also showed a main effect of group (F(2,59) = 4.8, p = 0.01, ? = 0.467), with significantly lower amplitudes in non-medicated patients with respect to both the control and medicated groups (MD = 1.19, p = 0.01, MD = 1.27, p = 0.005, respectively). There were no significant differences in the latencies of any of the waves among the groups. The main finding of this study was the reduction in the IA in early PD. Reorientation of attention (RON) showed a dopaminergic modulation in these patients. These results represent the basis for future in depth studies on the involvement of IA in executive impairments in PD.     

Response-monitoring dysfunction in aging and Alzheimer's disease: an event-related potential study

Executive control is a broad-reaching function that includes response monitoring and is likely implemented in the frontal lobes. Age- and dementia-related changes in response-monitoring were assessed during a Picture-Name Verification Task, using response-synchronized event-related potential (ERP) markers of response monitoring: the centrally oriented error-related negativity (ERN); the smaller and more frontally-oriented correct-response negativity (CRN); and the positivity associated with errors (Pe), a marker of error awareness. These were recorded from 10 younger and 10 older healthy controls, as well as 12 Alzheimer's disease (AD) patients. Although the older and younger controls showed equivalent accuracy, error awareness (Pe), and relative ERN>CRN amplitude, aging was associated with slower behavioral responses and decreased ERN amplitude. Although dementia was associated with decreased accuracy, decreased ERN, and a loss of relative ERN>CRN amplitude, error awareness (Pe) remained somewhat intact in AD patients. In AD patients, CRN amplitude was affected by item certainty (assessed a week earlier), being larger to items that were idiosyncratically difficult for patients to name.     

Abnormal function of the brain system supporting motivated attention in medicated patients with schizophrenia: an fMRI study

BACKGROUND: Patients with schizophrenia have an impaired ability to generate activity that is appropriate to current circumstances and goals. METHOD: We report a study using functional magnetic resonance imaging (fMRI) to examine cerebral activity during a three-tone auditory oddball target detection task in a sample of 28 patients with schizophrenia and 28 healthy controls. RESULTS: The patients exhibited significantly less activation in response to target stimuli relative to baseline in an extensive set of sites in association neocortex, paralimbic cortex, limbic structures and subcortical nuclei, yet demonstrated a normal level of activation in the sensorimotor cortex. Comparison of activity elicited by rare target stimuli with that elicited by equally rare novel stimuli makes it possible to distinguish cerebral activity associated with attention to behaviourally salient stimuli from activity associated with attending to other attention-capturing stimuli. This comparison revealed that the patients with schizophrenia also exhibited a deficit in activation of basal forebrain areas that mediate motivation during the processing of behaviourally salient stimuli, including the amygdala, ventral striatum, orbital frontal cortex and rostral anterior cingulate cortex. CONCLUSION: Patients with schizophrenia have a deficit in function of the brain system concerned with mediating motivation, in addition to a more general deficit in the cerebral response to attention-captivating stimuli.     

Increased fMRI signal with age in familial Alzheimer's disease mutation carriers

Although many Alzheimer's disease (AD) patients have a family history of the disease, it is rarely inherited in a predictable way. Functional magnetic resonance imaging (fMRI) studies of nondemented adults carrying familial AD mutations provide an opportunity to prospectively identify brain differences associated with early AD-related changes. We compared fMRI activity of 18 nondemented autosomal dominant AD mutation carriers with fMRI activity in eight of their noncarrier relatives as they performed a novelty encoding task in which they viewed novel and repeated images. Because age of disease onset is relatively consistent within families, we also correlated fMRI activity with subjects' distance from the median age of diagnosis for their family. Mutation carriers did not show significantly different voxelwise fMRI activity from noncarriers as a group. However, as they approached their family age of disease diagnosis, only mutation carriers showed increased fMRI activity in the fusiform and middle temporal gyri. This suggests that during novelty encoding, increased fMRI activity in the temporal lobe may relate to incipient AD processes.     

A cancellation test: its reliability in assessing attentional deficits in Alzheimer's disease.

The aim of the study is to provide (i) a standardized procedure for a Cancellation Test of Digits, designed to assess in the visual modality selective attention deficits in patients with Alzheimer's disease, and (ii) a detailed analysis of how patients cope with it. Age-, education-, and sex-adjusted normative scores earned by 352 healthy controls are set forth, as well as data yielded by the Digit Cancellation Test in 74 Alzheimer patients, in 26 patients with a CT-assessed frontal lobe lesion and in a group of 24 healthy subjects urged to perform the task with a shortened time-constraint. Findings include discriminant power of Alzheimer patients versus healthy controls, sensitivity to cognitive evolution of the dementing process and analysis of errors. Attention data failed to supply psychometric support for the posterior-to-anterior algorithm of progressive cortical encroachment of Alzheimer's disease suggested by PET-findings. Emphasis is put on methodological aspects of neuropsychological research on Alzheimer patients and on the analysis of processing components of the tests employed. Results are discussed in the light of the relationships between psychometric assessments and related functions, and underlying neuronal degeneration.     

Pineal calcification in Alzheimer's disease: an in vivo study using computed tomography

Melatonin has been postulated to have diverse properties, acting as an antioxidant, a neuroprotector, or a stabilizer within the circadian timing system, and is thus thought to be involved in the aging process and Alzheimer's disease (AD). We used computed tomography to determine the degree of pineal calcification (DOC), an intra-individual melatonin deficit marker, as well as the size of uncalcified pineal tissue, in 279 consecutive memory clinic outpatients (AD: 155; other dementia: 25; mild cognitive impairment: 33; depression: 66) and 37 age-matched controls. The size of uncalcified pineal tissue in patients with AD (mean 0.15 cm(2) [S.D. 0.24]) was significantly smaller than in patients with other types of dementia (0.26 [0.34]; P=0.038), with depression (0.28 [0.34]; P=0.005), or in controls (0.25 [0.31]; P=0.027). Additionally, the DOC in patients with AD (mean 76.2% [S.D. 26.6]) was significantly higher than in patients with other types of dementia (63.7 [34.7]; P=0.042), with depression (60.5 [33.8]; P=0.001), or in controls (64.5 [30.6]; P=0.021). These two findings may reflect two different aspects of melatonin in AD. On the one hand, the absolute amount of melatonin excretion capability, as indicated by uncalcified pineal volume, refers to the antioxidant properties of melatonin. On the other hand, the relative reduction in melatonin production capability in the individual, as indicated by DOC, refers to the circadian properties of melatonin.     

Observing social gestures: an fMRI study

We investigated the effects of social content of gestures on brain activation patterns. We used a 3 × 3 × 3 factorial design in an event-related functional magnetic resonance imaging experiment with participants observing gestures varied by type (fascist salute, wave, or arm lift), number of images shown at a time, and face frequency. We sought to determine whether increasing the social content of the gesture spreads activation from traditional sensorimotor regions engaged in mirror neuron activity to prefrontal regions concerned with social behavior. Results indicate that viewing a highly provocative gesture (fascist salute) compared to a less provocative but still socially meaningful gesture (wave) reveals activation in prefrontal and limbic areas. In addition, as expected there was more inferior frontal gyrus activation when participants observed a greater number of gesturing actors. Additionally, the psychological characteristics of shame and defeat affected activation in the inferior parietal lobe, which is part of the mirror neuron system, for the fascist salute compared to the wave contrast. We conclude that observing social gestures activates social- and emotion-processing areas of the brain, and the activation varies depending on the observer’s psychological characteristics.