A potential noninvasive neurobiological test for Alzheimer's disease.

Currently Alzheimer's disease, which affects more than 20 million people worldwide, can only be definitely diagnosed by histological examination of brain tissue obtained at autopsy or biopsy. There is a great need for an early, noninvasive, sensitive, and easily administered diagnostic test of Alzheimer's disease. Here it is reported that patients diagnosed with probable Alzheimer's disease by standard clinical criteria exhibited a marked hypersensitivity in their pupil dilation response to a cholinergic antagonist, tropicamide, placed in their eyes. It was possible to distinguish 18 of 19 individuals (95%) either clinically diagnosed with Alzheimer's disease or classified as suspect Alzheimer's individuals by neuropsychological screening from 30 of 32 normal elderly controls (94%).

ApoE allelic variability influences pupil response to cholinergic challenge and cognitive impairment.

Exaggerated pupil response to dilute tropicamide has been suggested as an early biological marker for Alzheimer's disease. The current study links apolipoprotein E (ApoE) allelic variability to the magnitude of pupil response in a sample of community-dwelling elderly without a diagnosis of Alzheimer's disease or dementia. Possession of an epsilon 4 allele influences both the likelihood of exhibiting an exaggerated pupil response above a predetermined cut-off (13% above baseline diameter) and the absolute overall magnitude of the response. Allelic variability was also shown to correlate with cognitive impairments in memory and attention. The data in this study further elucidate the nature of the biological bond between an exaggerated pupil response and the pathology of Alzheimer's disease. ApoE allelic variability is probably linked to pupil response through its influence on tau hyperphosphorylation. The early Alzheimer's pathology seen in the Edinger-Westphal area of cranial nerve III, a major centre for pupil control, is primarily tau-based with significant cell loss in this nucleus leading to central denervation hypersensitivity even in elderly who are clinically silent but who have early pathology.

Selective cell loss in Edinger-Westphal in asymptomatic elders and Alzheimer's patients.

Exaggerated pupillary response to a low concentration of cholinergic antagonists has been suggested as an early marker for Alzheimer's Disease (AD). To examine the anatomic basis of this phenomenon, we determined possible neuropathological changes in the Edinger-Westphal (EW) nucleus, a midbrain neural center with a significant functional role in the control of pupil size. Stereologically determined neuronal numbers within the EW were counted in individuals with pathologically confirmed AD, control cases with no AD-type pathology, and subjects with AD pathology not meeting diagnostic criteria for AD. The EW of AD patients displayed a marked and striking neuronal loss when compared with controls. In contrast, the number of neurons in the somatic portion of the nucleus of the third cranial nerve (NCNIII) remained intact. The EW in brains from clinically normal individuals with evidence of early AD-type pathology also displayed a significant and selective loss of neurons. The magnitude of EW neuronal loss in the latter group was smaller than that observed in AD. These findings suggest that pupillary hypersensitivity in AD may be caused by abnormalities in the EW. Neuronal loss and pathology within the EW in a subpopulation of clinically silent controls with pathologic findings consistent with early-stage AD constitutes a possible explanation for the reported exaggerated pupil response in some normal elderly subjects.

Impairment of spatially directed attention in patients with probable Alzheimer's disease as measured by eye movements.

OBJECTIVE: To investigate changes in spatially directed attention in patients with a diagnosis of probable Alzheimer's disease (AD). BACKGROUND: Impaired attention in patients with probable AD has not been the subject of extensive research. Yet recent reports suggest that attentional deficits may be an important early feature of the disease in a subset of patients. SETTING: University hospital center studying dementia and aging. SUBJECTS: Ten mild to moderately impaired patients diagnosed as having probable AD, by National Institute of Neurologic and Communicative Diseases and Stroke criteria, and 11 healthy age- and education-matched controls. MEASURES: Eye movements were recorded as subjects participated in two experiments designed to measure spatially directed attention. Subjects were instructed to (1) attend to and fixate a target appearing randomly to the right or left of a central marker and (2) direct attention to and fixate a target appearing randomly in one of four peripheral locations. RESULTS: Patients with probable AD exhibited fewer accurate trials and longer saccade latencies in both tasks. As a group, patients performed worse in the second task that placed increased demands on attention. However, the performance of patients in this second experiment varied. Four patients performed significantly worse than all other patients, while three patients performed as well as controls. Errors in the second task were reviewed to identify specific types of attentional deficits. Six empirically derived error patterns were classified into one of two major categories: perseveration and impersistence. Seven of 10 patients made greater than 50% errors of perseveration, and three of 10 made greater than 50% errors of impersistence. CONCLUSIONS: Impairment of attention may be an early feature of AD and a prominent clinical characteristic of some patients. The differences observed in error types made by patients may reflect the varied distribution of neuropathologic changes affecting structures that mediate aspects of attention. The architecture of eye movements can be used as a physiologic measure that should provide useful information for the diagnosis and clinicopathologic subtyping of patients with AD.

The impact of aging on curiosity as measured by exploratory eye movements.

OBJECTIVE: To investigate changes in novelty-seeking behavior (curiosity) associated with normal aging. BACKGROUND: Recently, we demonstrated that patients with a diagnosis of probable Alzheimer's disease display diminished novelty-seeking behavior as measured by exploratory eye movements. Nondemented, elderly individuals are often depicted in clinical descriptions as exhibiting diminished curiosity and increased disengagement from their surroundings. However, this behavior has not been systematically investigated as a function of normal aging. SETTING: University hospital center studying aging and dementia. SUBJECTS: Fourteen active, healthy elderly subjects (mean age, 72 years) and 16 middle-aged subjects (mean age, 42 years) matched for education and estimated IQ. MEASURES: Exploratory eye movements were recorded in response to visual stimuli that varied in novelty, complexity, and incongruity. RESULTS: Both older and middle-aged subjects (1) spent significantly more time exploring the more irregular or incongruous of two simultaneously presented stimuli, (2) spent increasingly less time looking at a repeating visual stimulus paired with a stimulus that changed with each trial, and (3) exhibited the same degree of overall exploration of a visual scene and devoted an approximately equal amount of attention to an unexpected element within it. As a group, older subjects spent slightly less time than middle-aged subjects examining incongruous stimuli. However, 71% (10/14) of older subjects performed within 1 SD of the mean of middle-aged subjects and 21% (3/14) performed as well as the top 50% (8/16) of middle-aged controls. CONCLUSIONS: The drive for curiosity, as measured by exploratory eye movements, can be well preserved in older individuals. Further research is needed to determine if the integrity of this drive can serve as a marker of "successful aging" and to identify which physiological and psychological factors influence its preservation through the life cycle.

Diminished curiosity in patients with probable Alzheimer's disease as measured by exploratory eye movements.

Clinical accounts of Alzheimer's disease (AD) suggest that some patients exhibit markedly diminished curiosity and initiative early in the course of their illness. Such behavioral changes are extremely difficult to measure experimentally. We studied one aspect of curiosity by measuring exploratory eye movements in response to provocative visual stimuli in 12 patients with probable AD and 10 matched controls. Subjects viewed slides, each of which contained an incongruous or irregular figure paired with a congruous or regular one. Unlike controls, who spent significantly more time viewing the incongruous stimuli, AD patients distributed their viewing time equally and spent significantly less time than controls looking at the novel stimuli. Additionally, when presented with picture slides containing an unexpected element, AD patients exhibited diminished visual exploration overall and decreased attention to the incongruous part. Further analyses suggest that the results cannot be adequately explained by a general decline in cognition or by problems with ocular motility or directing visual attention. We conclude that AD patients exhibit diminished curiosity which can be measured by the study of exploratory eye movements.

Pathophysiology underlying diminished attention to novel events in patients with early AD.

BACKGROUND: Patients with mild to moderate AD often are apathetic and fail to attend to novel aspects of their environment. OBJECTIVE: To investigate the mechanisms underlying these changes by studying the novelty P3 response that measures shifts of attention toward novel events. METHODS: While event-related potentials were recorded, mildly impaired AD patients and matched normal controls (NC) viewed line drawings that included a repetitive background stimulus, an infrequent target stimulus, and infrequent novel stimuli. Subjects controlled how long they viewed each stimulus by pressing a button. This served as a measure of their allocation of attention. They also responded to targets by depressing a foot pedal. Patients did not differ from NC in age, education, estimated IQ, or mood but were judged by informants to be more apathetic. RESULTS: P3 amplitude to novel stimuli was significantly smaller for AD patients than NC. However, P3 amplitude to target stimuli did not differ between groups. For NC, P3 response to novel stimuli was much larger than to background stimuli. In contrast, for patients with AD, there was no difference in P3 response to novel vs background stimuli. Although NC spent more time looking at novel than background stimuli, patients with AD distributed their viewing time evenly. Remarkably, for patients with AD, the amplitude of the novelty P3 response powerfully predicted how long they would spend looking at novel stimuli (R2 = 0.52) and inversely correlated with apathy severity. CONCLUSIONS: The decreased attention to novel events exhibited by patients with AD cannot be explained by a nonspecific reduction in their attentional abilities. The novelty P3 response is markedly diminished in mild AD, at a time when the target P3 response is preserved. The disruption of the novelty P3 response predicts diminished attention to novel stimuli and is associated with the apathy exhibited by patients with AD.

Selective age-related loss of calbindin-D28k from basal forebrain cholinergic neurons in the common marmoset (Callithrix jacchus).

A significant number of the cholinergic neurons in the basal forebrain of the primate, but not the rodent brain contain the calcium binding protein calbindin-D28k (CB). Previous experiments in our laboratory have demonstrated a substantial age-related loss of CB from the human basal forebrain cholinergic neurons (BFCN). The present study investigated the possible age-related loss of CB from the BFCN in a non-human primate species, the common marmoset (Callithrix jacchus). Quantitative analysis of matching sections as well as unbiased stereological determination of neuronal number were used in 16 adult marmosets ranging in age between 2 and 15 years. No significant changes were observed in the number of choline acetyltransferase-positive BFCN when a group of young animals (< or =4 years) was compared with a 6-8-year-old group and a 9-15-year-old group. Similarly, no age-related changes were observed in Nissl-stained magnocellular basal forebrain (putatively cholinergic) neurons. In contrast, the BFCN of the two older groups of animals displayed a significant loss of CB. The age-related loss of CB occurred in all sectors of the BFCN, but was greatest in the anterior sector of this cell group. The CB loss was neurochemically specific since the BFCN in the older groups of animals continued to express other markers such as high and low affinity neurotrophin receptors. The age-related loss of CB from the marmoset BFCN was also regionally selective as CB positive neurons in other structures, such as the cerebral cortex and the striatum displayed no apparent age-related changes. These results indicate that the marmoset BFCN display a significant and selective age-related loss of CB reminiscent of that observed in the human. Therefore, the common marmoset represents an appropriate animal model in which the consequences of BFCN CB loss can be investigated in depth. Loss of CB from the aged BFCN is likely to reduce the capacity of these neurons to buffer intracellular calcium and to leave them vulnerable to insults which can result in increased calcium levels. The vulnerability of the CB-negative BFCN in the aged marmoset to various insults which disturb calcium homeostasis remains to be investigated.

Deficient antisaccades in the social-emotional processing disorder.

We investigated whether adolescents and adults with the developmental social-emotional processing disorder (SEPD) exhibit deficits in visual attention, as measured by eye movements, when compared with dyslexic and normal control subjects. On the antisaccade task, subjects with SEPD made more errors than either control group and were the only group to show a decrease in performance accuracy compared with prosaccade. This deficit in inhibiting reflexive shifts of attention and gaze suggests that individuals with SEPD have dysfunction of the prefrontal component of the right hemisphere dominant network for spatially directed attention.

Regulation of attention to novel stimuli by frontal lobes: an event-related potential study.

This study examined the relationship between orienting responses to novel events and subsequent exploratory behavior. The N2-P3 electrophysiologic component of the orienting response was found to be larger for novel than repetitive background stimuli. Across subjects, the amplitude of this N2-P3 response in frontal regions strongly predicted the proportional increase in the duration of viewing directed toward novel compared to background stimuli. Within subjects, larger N2-P3 amplitudes in response to novel stimuli were associated with longer viewing durations on those stimuli. These results suggest that the N2-P3 component of the orienting response reflects the activity of a neural system involving frontal networks that dynamically regulates the subsequent allocation of attentional resources to novel stimuli.

Mechanisms underlying diminished novelty-seeking behavior in patients with probable Alzheimer's disease.

OBJECTIVE: To better understand apathy and disengagement in patients with Alzheimer's disease (AD), the authors investigated possible behavioral mechanisms underlying diminished novelty-seeking activity in patients with probable AD. BACKGROUND: Apathy and disengagement have been shown to be the most common behavioral changes associated with AD. METHOD: Patients and age-matched normal controls had their eye movements recorded while pairs of line drawings pitting an incongruous figure against a congruous figure were shown on a screen for 12 seconds. Characteristics of a subset of AD patients who were indifferent to novel visual stimuli as measured by exploratory eye movements were compared to those of a subset of AD patients who were attracted to novel stimuli to a degree similar to that of normal controls. RESULTS: The indifferent patients were judged by informants, who completed a personality questionnaire, to exhibit a greater degree of apathy. The two AD groups did not differ in overall dementia severity or performance on a Saccade-to-Target Task that required shifts of attention and gaze. In a separate task, the indifferent patients were able to accurately identify the more novel stimuli in 97.5% of trials. Normal control subjects exhibited a strong bias toward processing novel stimuli, directing a higher proportion of their first fixations and dwell time to the incongruous stimuli whether the analysis was run for 3, 6, or 12 seconds of viewing. Indifferent patients did not direct their initial fixation toward novel stimuli and distributed their looking time evenly between incongruous and congruous stimuli throughout all measured intervals. CONCLUSIONS: The results suggest that the indifference to novelty observed in some patients with probable AD cannot simply be attributed to global cognitive decline, more elementary attentional deficits, more rapid habituation of response to novel stimuli, or an inability to discriminate upon demand between stimuli of varying degrees of novelty. It is more likely that their behavior reflects a disruption, by AD pathology, of neural systems that modulate behavioral engagement and maintain attentional bias toward novel events in the environment.

Focal pathology in the Edinger-Westphal nucleus explains pupillary hypersensitivity in Alzheimer's disease.

Patients who suffer from Alzheimer's disease (AD) and a sub-population of community-dwelling elders show an exaggerated pupillary reaction to dilute tropicamide, a cholinergic antagonist. This finding may serve as an early diagnostic marker of AD. Here we report a likely pathological basis for this hypersensitive pupillary response. Our observations indicate that the Edinger-Westphal nucleus (EW), a known center for the control of pupillary function, is a selective target of Alzheimer pathology early in the course of the disease. In all AD cases examined, the EW contained plaques and tangles. In contrast, the adjacent somatic portion of the oculomotor complex was virtually spared of pathology. Early pathology in the EW is likely to initiate a cascade of events that may give rise to pupillary hypersensitivity.

An electrophysiological index of stimulus unfamiliarity.

This study investigated the functional significance of the N2 response to novel stimuli. In one condition, background, target, and deviant stimuli were simple geometric figures. In a second condition, all stimulus types were unfamiliar/unusual figures. In a third condition, background and target stimuli were unusual figures and deviant stimuli were simple shapes. Unusual figures, whether they were deviant, target, or background stimuli, evoked larger N2 responses than their simple, familiar counterparts. N2 elicited by an unusual background stimulus was larger than that evoked by simple, deviant stimuli, a pattern opposite that exhibited by the subsequent P3. Deviance from immediate context had limited influence over N2 amplitude. The results suggest that novelty N2 and novelty P3 reflect the processing of different aspects of "novel" visual stimuli. The novelty P3 is particularly sensitive to deviation from immediate context. In contrast, the novelty N2 is sensitive to deviation from long-term context that renders a stimulus unfamiliar and difficult to encode.

Frontal and parietal components of a cerebral network mediating voluntary attention to novel events.

Despite the important role that attending to novel events plays in human behavior, there is limited information about the neuroanatomical underpinnings of this vital activity. This study investigated the relative contributions of the frontal and posterior parietal lobes to the differential processing of novel and target stimuli under an experimental condition in which subjects actively directed attention to novel events. Event-related potentials were recorded from well-matched frontal patients, parietal patients, and non-brain-injured subjects who controlled their viewing duration (by button press) of line drawings that included a frequent, repetitive background stimulus, an infrequent target stimulus, and infrequent, novel visual stimuli. Subjects also responded to target stimuli by pressing a foot pedal. Damage to the frontal cortex resulted in a much greater disruption of response to novel stimuli than to designated targets. Frontal patients exhibited a widely distributed, profound reduction of the novelty P3 response and a marked diminution of the viewing duration of novel events. In contrast, damage to posterior parietal lobes was associated with a substantial reduction of both target P3 and novelty P3 amplitude; however, there was less disruption of the processing of novel than of target stimuli. We conclude that two nodes of the neuroanatomical network for responding to and processing novelty are the prefrontal and posterior parietal regions, which participate in the voluntary allocation of attention to novel events. Injury to this network is indexed by reduced novelty P3 amplitude, which is tightly associated with diminished attention to novel stimuli. The prefrontal cortex may serve as the central node in determining the allocation of attentional resources to novel events, whereas the posterior parietal lobe may provide the neural substrate for the dynamic process of updating one's internal model of the environment to take into account a novel event.

The central role of the prefrontal cortex in directing attention to novel events.

The physiological basis for the striking decrease of attention to novel events following frontal lobe injury is poorly understood. In this study, event-related potentials (ERPs) were recorded from patients with frontal lobe damage and matched subjects, who controlled the duration of viewing of background, novel and target stimuli. Frontal lobe patients did not differ from normal controls in terms of age, education, estimated IQ or mood. However, they were judged to be more apathetic as measured by self-report and informants' ratings. Patients with frontal lobe damage exhibited markedly reduced amplitude of the novelty P3 response and the duration of viewing of novel stimuli. In contrast, injury to the frontal lobes had a limited impact on P3 amplitude and behavioural responses (viewing duration and reaction time) to target stimuli. A strong correlation was found between measures of apathy and both attenuated P3 amplitude and viewing duration in response to novel but not target stimuli. Differences in amplitude of the novelty P3 response explained a large portion of the variance associated with duration of viewing of novel stimuli. After controlling for the influence of P3 amplitude, there was no association between frontal lobe injury and reduced viewing of novel stimuli. The results of this study suggest that frontal lobe damage leads to diminished visual attention to novel events through its disruption of neural processes underlying the novelty P3 response. These processes appear to regulate the allocation of attentional resources and early exploratory behaviours, and are not limited to immediate orienting responses. Damage to the frontal lobes may prevent the generation of a signal which indicates that a novel event in the environment requires additional attention due to its potential behavioural significance. The disruption of these processes is likely to contribute to the apathy observed in patients after injury to the frontal lobes.

The influence of stimulus deviance on electrophysiologic and behavioral responses to novel events.

This study investigated the role of stimulus deviance in determining electrophysiologic and behavioral responses to "novelty." Stimulus deviance was defined in terms of differences either from the immediately preceding context or from long-term experience. Subjects participated in a visual event-related potential (ERP) experiment, in which they controlled the duration of stimulus viewing with a button press, which served as a measure of exploratory behavior. Each of the three experimental conditions included a frequent repetitive background stimulus and infrequent stimuli that deviated from the background stimulus. In one condition, both background and deviant stimuli were simple, easily recognizable geometric figures. In another condition, both background and deviant stimuli were unusual/unfamiliar figures, and in a third condition, the background stimulus was a highly unusual figure, and the deviant stimuli were simple, geometric shapes. Deviant stimuli elicited larger N2-P3 amplitudes and longer viewing durations than the repetitive background stimulus, even when the deviant stimuli were simple, familiar shapes and the background stimulus was a highly unusual figure. Compared to simple, familiar deviant stimuli, unusual deviant stimuli elicited larger N2-P3 amplitudes and longer viewing times. Within subjects, the deviant stimuli that evoked the largest N2-P3 responses also elicited the longest viewing durations. We conclude that deviance from both immediate context and long-term prior experience contribute to the response to novelty, with the combination generating the largest N2-P3 amplitude and the most sustained attention. The amplitude of the N2-P3 may reflect how much "uncertainty" is evoked by a novel visual stimulus and signal the need for further exploration and cognitive processing.

Disruption of attention to novel events after frontal lobe injury in humans.

OBJECTIVE: To investigate whether frontal lobe damage in humans disrupts the natural tendency to preferentially attend to novel visual events in the environment. METHODS: Nine patients with chronic infarctions in the dorsolateral prefrontal cortex (DLPFC) and 23 matched normal controls participated in a study in which subjects viewed repetitive background stimuli, infrequent target stimuli, and novel visual stimuli (for example, fragmented or "impossible" objects). Subjects controlled viewing duration by a button press that led to the onset of the next stimulus. They also responded to targets by pressing a foot pedal. The amount of time spent looking at the different kinds of stimuli, and the target detection accuracy and speed served as dependent variables. RESULTS: Overall, normal controls spent significantly more time than frontal lobe patients looking at novel stimuli. Analysis of responses across blocks showed that initially frontal lobe patients behaved like normal controls by directing more attention to novel than background stimuli. However, they quickly began to distribute their viewing time evenly between novel and background stimuli, a pattern that was strikingly different from normal controls. By contrast, there were no differences between frontal lobe patients and normal controls for viewing duration devoted to background and target stimuli, target detection accuracy, or reaction time to targets. Frontal lobe patients did not differ from normal controls in terms of age, education, estimated IQ, or mood, but were more apathetic as measured by self report and informants' judgments. Attenuated responses to novel stimuli significantly correlated with degree of apathy. CONCLUSIONS: This study demonstrates that DLPFC injury selectively impairs the natural tendency to seek stimulation from novel and unusual stimuli. These data provide the first quantitative behavioural demonstration that the human frontal lobes play a critical part in directing and sustaining attention to novel events. The impairment of novelty seeking behaviour may contribute to the characteristic apathy found in patients with frontal lobe injury.