Impaired recognition of facial expressions of emotion in Alzheimer's disease

Recognizing facial emotions is an important aspect of interpersonal communication that may be impaired in Alzheimer's disease (AD). The authors examined facial emotion matching, facial emotion labeling, and same--different emotion differentiation in AD patients, healthy elderly volunteers, and elderly, nondemented psychiatric outpatients. Compared with both control groups, AD patients were significantly impaired on all three measures. AD patients were also impaired on a facial identity matching task. Using facial identity matching scores as a covariate provided evidence suggesting the facial emotion processing deficit may be independent of impairment in nonemotional face processing. AD patients also had selective impairment in labeling facial expressions of sadness. The authors conclude that patients with AD have deficits in recognizing facial emotions, which may be independent of their impairment in recognizing nonemotional features of faces.     

Impaired word recognition in Alzheimer's disease: The role of age of acquisition

Studies of word production in patients with Alzheimer's disease have identified the age of acquisition of words as an important predictor of retention or loss, with early acquired words remaining accessible for longer than later acquired words. If, as proposed by current theories, effects of age of acquisition reflect the involvement of semantic representations in task performance, then some aspects of word recognition in patients with Alzheimer's disease should also be better for early than later acquired words. We employed a version of the lexical decision task which we term the lexical selection task. This required participants to indicate which of four items on a page was a real word (the three ‘foils’ being orthographically plausible nonwords). Twenty-two patients with probable Alzheimer's disease were compared with an equal number of matched controls. The controls made few errors on the test, demonstrating that the controls were cognitively intact, and that the words were familiar to participants of their age and level of education. The Alzheimer patients were impaired overall, and recognized fewer late than early acquired words correctly. Performance of the Alzheimer patients on the lexical selection task correlated significantly with their scores on the mini mental state examination. Word recognition becomes impaired as Alzheimer's disease progresses, at which point effects of age of acquisition can be observed on the accuracy of performance.     

Impaired insight in Alzheimer's disease.

We studied insight into illness in 41 patients with probable Alzheimer's disease. An impaired insight score was developed by measuring discrepancies between patient report and caregiver report on standard instruments of activities of daily living. Insight was more impaired in subjects with greater dementia severity and subjects with paranoid delusions. In a multivariate analysis, the best neuropsychological predictors of impaired insight were the Continuous Performance Test and the Visual Reproduction Test. We speculate that the impaired insight of Alzheimer's disease has two components: confabulation reflecting prefrontal dysfunction and anosognosia reflecting right-hemisphere dysfunction.     

Impaired fear conditioning in Alzheimer's disease

Classical conditioning of the fear response is a basic form of nondeclarative (nonconscious) memory that mediates both normal and pathological responses to aversive stimuli. Because fear conditioning critically depends on the amygdala, a medial temporal lobe structure that frequently undergoes significant pathological changes early in the course of Alzheimer's disease (AD), we hypothesized that fear conditioning would be impaired in patients with mild to moderate AD. We examined simple classical fear conditioning in a group of 10 patients with probable AD and 14 demographically matched, neurologically intact elderly controls. During conditioning, one stimulus (e.g. a green rectangle, the conditioned stimulus (CS+)), was paired with an aversive stimulus (a loud noise, the unconditioned stimulus (US)) using a partial reinforcement conditioning schedule. The opponent color (e.g. red rectangle), the CS-, was never paired with the US. The elderly controls acquired robust fear responses as demonstrated by their differential skin-conductance responses to the CS+ and CS-. In contrast, the AD group showed a marked impairment in conditioning, failing to exhibit significant conditioned fear responses. This failure to acquire conditioned responses could not be attributed to diminished responding by patients, relative to controls, to the aversive US. The results indicate that fear conditioning, an amygdala-dependent form of memory, is impaired in AD. These findings complement previous reports of impairments in declarative emotional memory in AD by demonstrating that a basic form of nondeclarative emotional memory is also impaired in AD.     

Impaired metabolic activation in Alzheimer's disease: a PET study during continuous visual recognition

Regional cerebral metabolic rate of glucose (rCMRGl) was studied in 21 patients with probable Alzheimer's disease (AD) and nine age-matched normal controls by positron emission tomography (PET) of 2(18F)-fluoro-deoxy-D-glucose (FDG) at rest and during stimulation with a continuous visual recognition task. While global metabolism at rest was comparable in both groups, rCMRGl in the temporo-parietal junction area, the mid-temporal and the frontal cortex was typically decreased in the AD patients. The continuous visual recognition task adapted to the individual performance capacity increased the global metabolic rate in the controls by 21 +/- 18%, while in the AD patients the metabolic change (5.7 +/- 11.1%) during activation was significantly weaker (P = 0.023). Due to the tasks chosen the activation of rCMRGl in both groups was most prominent in the visual cortex and the temporo-parietal association areas, although the recognition task additionally involved widespread brain structures with varying rCMRGl. A significant correlation was found between rCMRGl in areas usually severely affected by AD pathology, e.g. the temporo-parietal cortex, and GDS scores, and became stronger during metabolic activation. Neither at rest nor during stimulation was there a relationship between the rCMRGl of structures usually less involved in AD, e.g. the sensorimotor cortex, and the severity of dementia as assessed by the global deterioration scale (GDS). From these results it can be concluded that metabolic rate at rest reflects the extent of morphologic damage, while PET studies during activation indicate the brain's reserve capacity to respond to functional tasks. Since metabolism in AD patients during activation is more severely impaired than at rest, PET studies during functional tests could help in the selection of patients with a potential to benefit from therapeutic intervention.     

Impaired peripheral endothelial microvascular responsiveness in Alzheimer's disease

BACKGROUND: The concept that the neurotoxicity of amyloid beta protein could partly result from vascular effects that may be detected in peripheral microcirculation is new. METHODS: We compared peripheral endothelial vascular responses of patients with early clinically confirmed Alzheimer's disease (AD) to that of people with normal cognition and those with other forms of dementia. Acetylcholine (ACh) was iontophoresed into the skin and the resultant vasodilator response was measured using laser Doppler flowmetery. RESULTS: The ratio of ACh response to saline (ratio E/S) was determined. Mean +/- SEM of ratios E/S were 8.8 +/- 0.9 for controls (n=168), 1.4 +/- 0.1 for AD patients (n=80) and 3.1 +/- 0.5 for other dementia (n=84). Using the optimal cut-off point of E/S ratio of 1.9, an 80% diagnostic sensitivity and specificity for AD have been observed. When the control sample was filtered for those with cardiovascular diseases and with MMSE < 28, this improved the specificity to 90% (n=119). Furthermore, 15 subjects were randomly drawn from a longitudinal healthy ageing study. Five of those subjects met the criteria for mild cognitive impairment (MCI) after eight years of follow up using a battery of cognitive tests. When tested for their E/S ratio in a blind fashion, the skin test successfully identified those subjects. CONCLUSIONS: The results support our hypothesis that endothelial alterations can be detected early in the course of the disease. We suggest that this simple skin test could potentially be applied as diagnostic adjunct in patients with mild cognitive symptoms or those with early clinical evidence of AD.     

Impaired regulation of synaptic actin cytoskeleton in Alzheimer's disease

Representing the most common cause of dementia, Alzheimer's disease (AD) has dramatically impacted the neurological and economic health of our society. AD is a debilitating neurodegenerative disease that produces marked cognitive decline. Much evidence has accumulated over the past decade to suggest soluble oligomers of beta-amyloid (Aβ) have a critical role in mediating AD pathology early in the disease process by perturbing synaptic efficacy. Here we critically review recent research that implicates synapses as key sites of early pathogenesis in AD. Most excitatory synapses in the brain rely on dendritic spines as the sites for excitatory neurotransmission. The structure and function of dendritic spines are dynamically regulated by cellular pathways acting on the actin cytoskeleton. Numerous studies analyzing human postmortem tissue, animal models and cellular paradigms indicate that AD pathology has a deleterious effect on the pathways governing actin cytoskeleton stability. Based on the available evidence, we propose the idea that a contributing factor to synaptic pathology in early AD is an Aβ oligomer-initiated collapse of a "synaptic safety net" in spines, leading to dendritic spine degeneration and synaptic dysfunction. Spine stabilizing pathways may thus represent efficacious therapeutic targets for combating AD pathology.     

Impaired acquisition of a mirror-reading skill in Alzheimer's disease

Several studies using the mirror-reading paradigm have shown that procedural learning and repetition priming may be preserved in the early stages of Alzheimer's disease (AD) (e.g., Deweer et al., 1994). According to the classical interpretation, improved reading time for repeated words is sustained by a repetition priming effect, while procedural learning is demonstrated when this improvement is also observed for new words. Following Masson (1986), the hypothesis tested in the present study was that improved reading of new words could also be due to a repetition priming effect rather than to the acquisition of a mirror-reading skill. Indeed, because the same letters are presented throughout the task, a repetition priming effect for the letters could suffice to explain the improvement in performance. To test this hypothesis, we administered to 30 healthy young and elderly subjects and to 30 AD patients a new mirror-reading task in two phases: an acquisition phase comprising pseudo-words constructed with one part of the alphabet, and a test phase in which both pseudo-words constructed with the same part of the alphabet and pseudo-words constructed with another part of the alphabet were presented. If the new pseudo-words composed with repeated letters were read faster, it would reflect a repetition priming effect; if pseudo-words composed of ‘new’ letters were read faster, it would reflect a procedural learning effect. The results show comparable repetition priming effects in AD patients and in healthy elderly subjects, whereas only healthy subjects showed a procedural learning effect. These results suggest, contrary to previous studies, that the learning of a new perceptual skill may not always be preserved in AD.     

Defining meaningful change in Alzheimer's disease trials: the donepezil experience.

Regulatory guidelines in the US and Europe generally require that a drug specifically indicated for treating Alzheimer's disease (AD) must demonstrate an effect upon the core manifestations of dementia. Progressive cognitive and functional losses are the cardinal features of AD. In the US, current guidelines require that new AD treatments show effectiveness on performance-based measures of cognition and on clinician-rated global assessments. Improvement in function is also emphasized in the European guidelines. The primary instruments that have been used to evaluate changes in cognition and global function in most recent AD trials are the cognitive subscale of the Alzheimer's Disease Assessment Scale and a version of the Clinician's Interview Based Impression of Change, respectively. The results from three pivotal trials investigating the acetylcholinesterase inhibitor, donepezil, are used to demonstrate the way in which these tools are used, how to interpret the data they provide, and to determine their overall value in ascertaining efficacy in clinical practice.     

False item recognition in patients with Alzheimer's disease

Recent evidence suggests that patients with Alzheimer's disease (AD), as compared with normal individuals, exhibit increased false recognition by stimulus repetition in the Deese-Roediger-McDermott (DRM) task or associative recognition memory tasks, probably due to impaired recollection-based monitoring. However, because of possible alternative explanations for the findings of these previous studies, the evidence for impaired recollection-based monitoring in AD patients remains inconclusive. In this study, we employed stimulus repetition in old/new recognition judgments of single-item picture memory without a factor of association between the stimuli and examined whether AD patients showed increased false item recognition as compared with healthy controls. AD patients and healthy controls studied single-item pictures presented either once or three times. They were later asked to make an old/new recognition judgment in response to (a) Same pictures, pictures identical to those seen at encoding, (b) Similar lures, novel pictures similar to but not identical to those seen at encoding, and (c) Dissimilar lures, novel pictures not similar to those seen at encoding. For Same pictures, repeated presentation of stimuli increased the proportion of “old” responses in both groups. For Similar lures, repeated presentation of stimuli increased the rate of “old” responses in AD patients but not in control subjects. The results of the present study clearly demonstrated elevated false recognition by stimulus repetition in single-item recognition in AD patients. The present findings strongly support the view that AD patients are impaired in their ability to use item-specific recollection in order to avoid false recognition.     

Impaired production priming and intact identification priming in Alzheimer's disease.

This study examined the distinction between identification and production processes in repetition priming for 16 patients with Alzheimer's disease (AD) and 16 healthy old control participants (NC). Words were read in three study phases. In three test phases, participants (1) reread studied words, along with unstudied words, in a word-naming task (identification priming); (2) completed 3-letter stems of studied and unstudied words into words in a word-stem completion task (production priming); and (3) answered yes or no to having read studied and unstudied words in a recognition task (explicit memory). Explicit memory and word-stem completion priming were impaired in the AD group compared to the NC group. After correcting for baseline slowing, word-naming priming magnitude did not differ between the groups. The results suggest that the distinction between production and identification processes has promise for explaining the pattern of preservation and failure of repetition priming in AD.     

Impaired acquisition and rapid forgetting of patterned visual stimuli in Alzheimer's disease

Whether or not rate of forgetting is accelerated in Alzheimer's disease (AD) is controversial. This study examined recognition of visual patterns in patients with AD and in controls at 10 min relative to a learning baseline measured after a 10-s delay (delayed recognition ratio, DRR). Comparable baseline performances were attained in the two groups by manipulating stimulus exposure times. Comparisons between 25 AD and 48 age-matched controls demonstrated lower DRR in AD when initial recognition, which was statistically worse in AD, was covariated. DRR was also lower in an analysis of subgroups closely matched on initial performance. The findings suggest that forgetting is accelerated in AD because multiple aspects of memory processing, including storage, are impaired.     

Improved recognition of leukoaraiosis and cognitive impairment in Alzheimer's disease

We identified 85 patients in a longitudinal study of dementia who had uncomplicated Alzheimer's disease and in whom computed tomography of the head and psychometric testing were conducted within a 6-month period following their entry into the study. Thirty-four patients (40%) had leukoaraiosis, which was disproportionately common in female patients (62% vs 15% in male patients). Analysis of covariance demonstrated a relative reduction of scores on the Extended Scale for Dementia in those patients who had leukoaraiosis, after adjusting for the confounding effects of age, sex, educational level, and duration of illness. Leukoaraiosis was also much more common in women, even after adjusting for the possible confounding effects of age, duration of illness, Extended Scale for Dementia score, and hypertension. Multiple regression analysis showed that leukoaraiosis accounted for 11.6% of the variance of the Extended Scale for Dementia scores. Leukoaraiosis, together with duration of illness, accounted for 18.2% of the variance. Leukoaraiosis is associated with a greater degree of cognitive impairment in patients with Alzheimer's disease.     

Normal mere exposure effect with impaired recognition in Alzheimer's disease

We investigated the mere exposure effect and the explicit memory in Alzheimer's disease (AD) patients and elderly control subjects, using unfamiliar faces. During the exposure phase, the subjects estimated the age of briefly flashed faces. The mere exposure effect was examined by presenting pairs of faces (old and new) and asking participants to select the face they liked. The participants were then presented with a forced-choice explicit recognition task. Controls subjects exhibited above-chance preference and recognition scores for old faces. The AD patients also showed the mere exposure effect but no explicit recognition. These results suggest that the processes involved in the mere exposure effect are preserved in AD patients despite their impaired explicit recognition. The results are discussed in terms of Seamon et al.'s (1995) proposal that processes involved in the mere exposure effect are equivalent to those subserving perceptual priming. These processes would depend on extrastriate areas which are relatively preserved in AD patients.     

Impaired semantic knowledge underlies the reduced verbal short-term storage capacity in Alzheimer's disease

A decrease in verbal short-term memory (STM) capacity is consistently observed in patients with Alzheimer's disease (AD). Although this impairment has been mainly attributed to attentional deficits during encoding and maintenance, the progressive deterioration of semantic knowledge in early stages of AD may also be an important determinant of poor STM performance. The aim of this study was to examine the influence of semantic knowledge on verbal short-term memory storage capacity in normal aging and in AD by exploring the impact of word imageability on STM performance. Sixteen patients suffering from mild AD, 16 healthy elderly subjects and 16 young subjects performed an immediate serial recall task using word lists containing high or low imageability words. All participant groups recalled more high imageability words than low imageability words, but the effect of word imageability on verbal STM was greater in AD patients than in both the young and the elderly control groups. More precisely, AD patients showed a marked decrease in STM performance when presented with lists of low imageability words, whereas recall of high imageability words was relatively well preserved. Furthermore, AD patients displayed an abnormal proportion of phonological errors in the low imageability condition. Overall, these results indicate that the support of semantic knowledge on STM performance was impaired for lists of low imageability words in AD patients. More generally, these findings suggest that the deterioration of semantic knowledge is partly responsible for the poor verbal short-term storage capacity observed in AD.     

Impaired capacity for autonoetic reliving during autobiographical event recall in mild Alzheimer's disease

The capacity to mentally travel back in time and relive past events via autonoetic consciousness has been shown to be compromised even in the early stages of Alzheimer's disease (AD). To further understand the unravelling of the recollective experience in pathological ageing, we investigated autobiographical memory (ABM) using the Episodic Autobiographical Memory Interview (EAMI) in thirty middle-aged and thirty healthy elderly controls, and twenty patients with mild AD. Of key interest was the recall of contextual details and the behavioural markers predictive of autonoetic reliving. AD patients exhibited significant difficulties in recalling contextual details across all life epochs on the EAMI manifesting in a negative temporal gradient from the Early Adulthood epoch onwards. Overall there was a low incidence of autonoetic consciousness during ABM recall across all participant groups and life epochs when compared with previous studies. AD patients showed a compromised capacity to mentally relive past memories (AD < healthy elderly < middle-aged controls), across all life epochs on the EAMI. AD patients tended to recall past events as semanticised accounts divested of rich sensory–perceptual imagery. The impoverished capacity to generate egocentric or self-referential imagery resulted in the production of fragmented and depersonalised accounts of formerly evocative events and likely stems from medial temporal and frontal pathology exhibited from early stages of the disease.     

The dissociation between short term retention of meaningful sounds and verbal material

Two patients with a specific deficit of auditory verbal short-term memory were tested on two tasks of short-term retention, one involving verbal material—letters—and the other non-verbal material—meaningful sounds. There was a striking dissociation between performance on the two tasks, only their performance on the verbal tasks being impaired. The results are discussed in the context of the function of this short-term memory system.     

Impaired axonal transport of cortical neurons in Alzheimer's disease is associated with neuropathological changes

Using a novel in vitro post mortem tracing method, we demonstrate a decrease of axonal transport in the temporal cortex neurons as compared to axonal transport in the prefrontal cortex neurons in AD patients, but not in non-demented controls. The decrease of axonal transport is related to the degree of neuropathological changes, as the temporal cortex undergoes more severe neuropathological changes in AD. The present study provides, for the first time, direct evidence of the presence of impaired axonal transport in AD brains.     

Impaired decision-making ability in subjects with Alzheimer's disease and willingness to participate in research

OBJECTIVE: Ethical concerns persist over research participation of decisionally impaired persons, such as those suffering from Alzheimer's disease. Such persons may be poor judges of the burdens and risks of specific research protocols. Since even decisionally incapacitated persons cannot be enrolled in studies against their objection, their preferences convey important ethical information. The authors examined the effects of cognitive and decisional impairment on willingness to participate in research among persons with Alzheimer's disease. METHOD: Cognitive status, decision-making ability, and willingness to participate in four hypothetical research protocols of varying risk/benefit profiles were measured in 34 subjects with mild to mild/moderate Alzheimer's disease and 14 healthy elderly comparison subjects. Univariate and multivariate methods were used to analyze the effects of impairment in cognitive and decision-making abilities on willingness to participate in research. RESULTS: There were no differences in willingness to participate found between the Alzheimer's and the healthy comparison subjects for three of the four hypothetical protocols. In both groups, willingness declined as risk increased. Within the Alzheimer's disease group, the presence of greater decisional impairment tended to predict less willingness to participate in research, even after adjusting for cognitive impairment, gender, and education. CONCLUSIONS: Persons with decisional impairment due to Alzheimer's disease are as a group able to distinguish between research protocols of varying risk/benefit profiles. Because declining decision-making abilities may predict declining willingness to participate in research, informed consent procedures for Alzheimer's disease research should be sensitive to this possibility.