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%).

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.

Frontal lobe dysfunction following infarction of the left-sided medial thalamus.

We treated a 62-year-old woman who developed a dramatic change in personality and behavior following a discrete left-sided medial thalamic infarction involving the dorsomedial nucleus. Neuropsychological testing demonstrated severe impairment of complex executive behaviors that are usually associated with frontal lobe function. Electroencephalography and single-photon emission computed tomography strongly implicated dysfunction of the ipsilateral frontal lobe. This case further supports a functional and physiologic thalamofrontal linkage as part of a broader cerebral network modulating complex human behavior.

Broca's aphasia following damage to Wernicke's area. For or against traditional aphasiology?

Classic aphasiology has been challenged by studies that have employed cranial computed tomography to test predicted anatomic-behavioral correlations. We treated a patient who developed a classic Broca's aphasia but whose computed tomographic scan revealed damage to Wernicke's area, thus seeming to contradict the principles of traditional aphasiology. However, subsequent information obtained by magnetic resonance imaging, intracarotid amobarbital (Amytal) testing, and electrophysiologic studies, including cortical stimulation, demonstrated that the brain-behavior correlations in this patient can be understood in terms of the formulations of traditional aphasiology.

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.

Regional magnetic resonance imaging lesion burden and cognitive function in multiple sclerosis: a longitudinal study.

OBJECTIVE: To investigate the relationship between magnetic resonance imaging regional lesion burden and cognitive performance in multiple sclerosis (MS) over a 4-year follow-up period. DESIGN: Twenty-eight patients with MS underwent magnetic resonance imaging and took the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis at baseline, 1-year, and 4-year follow-up. An automated 3-dimensional lesion detection method was used to identify MS lesions within anatomical regions on proton density T2-weighted images. The relationship between magnetic resonance imaging regional lesion volumes and the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis results was examined using regression analyses. RESULTS: At all time points, frontal lesion volume represented the greatest proportion of total lesion volume, and the percentage of white matter classified as lesion was also highest in frontal and parietal regions. On neuropsychological testing, when compared with age- and educational level-matched control subjects, patients with MS showed significant impairment on tests of sustained attention, processing speed, and verbal memory (P<.001). Performance on these measures was negatively correlated with MS lesion volume in frontal and parietal regions at baseline, 1-year, and 4-year follow-up (R = -0.55 to -0.73, P<.001). CONCLUSIONS: Multiple sclerosis lesions show a propensity for frontal and parietal white matter. Lesion burden in these areas was strongly associated with performance on tasks requiring sustained complex attention and working verbal memory. This relationship was consistent over a 4-year period, suggesting that disruption of frontoparietal subcortical networks may underlie the pattern of neuropsychological impairment seen in many patients with MS.

Donepezil therapy in clinical practice: a randomized crossover study.

OBJECTIVE: To determine the efficacy of donepezil hydrochloride for the treatment of Alzheimer disease in patients drawn from clinical practice. DESIGN: Two-center, randomized, placebo-controlled, double-masked crossover study. SETTING: Memory disorders units at Massachusetts General and Brigham and Women's hospitals, Boston. PATIENTS: Sixty individuals (30 men and 30 women; mean +/- SD age, 75.0+/-9.5 years) with probable Alzheimer disease and scores of 20 or less on the information-memory-concentration subscale of the Blessed Dementia Scale. INTERVENTIONS: Placebo wash-in, followed in randomized sequence by (1) donepezil hydrochloride therapy, 5 mg/d, for 6 weeks, followed by placebo washout for 6 weeks and (2) placebo treatment for 6 weeks. PRIMARY OUTCOME MEASURE: Change in Alzheimer's Disease Assessment Scale cognitive subscale scores from the beginning to the end of the two 6-week treatment periods. RESULTS: Among patients completing treatment and testing for both periods (n = 48), subscale scores improved (mean +/- SEM) 2.17+/-0.98 points (95% confidence interval, 0.20-4.10 points) during donepezil therapy relative to placebo therapy (P = .04). Scores returned toward baseline within 3 weeks of drug washout. There was no associated change in caregiver-rated global impression (donepezil vs placebo: proportion improved, 0.24 vs 0.22; proportion worsened, 0.27 vs 0.35; P = .34) or on specific tests of explicit memory or verbal fluency. Contrary to studies with tacrine, the presence of the apolipoprotein E epsilon4 allele did not predict donepezil treatment failure. Most common adverse events related to donepezil therapy were nausea (5 patients), diarrhea (3 patients), and agitation (3 patients). Serious events possibly related to drug use were seizure, pancreatitis, and syncope (1 patient each). CONCLUSION: This independent confirmation of data from phase 3 trials suggests that donepezil therapy modestly improves cognition in patients with Alzheimer disease who are encountered in clinical practice.

Lyme polyradiculoneuropathy presenting as increasing abdominal girth.

We describe a patient with documented Lyme disease whose major complaint was increasing abdominal distention. Electrophysiologic studies demonstrated denervation of the lower thoracic paraspinal muscles and the rectus abdominis. Expanding abdominal girth can be an unusual manifestation of the polyradiculoneuropathy associated with Lyme disease.

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.

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.

When false recognition is unopposed by true recognition: gist-based memory distortion in Alzheimer's disease.

The authors examined false recognition of semantic associates in patients with probable Alzheimer's disease (AD), older adults, and young adults using a paradigm that provided rates of false recognition after single and multiple exposures to word lists. Using corrected false recognition scores to control for unrelated false alarms, the authors found that (a) the level of false recognition after a single list exposure was lower in AD patients than in controls; (b) across 5 trials, false recognition increased in AD patients, decreased in young adults, and showed a fluctuating pattern in older adults; and (c) all groups showed an increase in true recognition over the 5 trials. Analyses suggested that AD patients built up semantic gist across trials, whereas both control groups were able to use increased item-specific recollection and more conservative response criteria to suppress gist-based false alarms.

Perceptual false recognition in Alzheimer's disease.

Previous research has found that patients with probable Alzheimer's disease (AD) show lower levels of false recognition of semantic associates than do healthy older adults. To investigate whether this finding is attributable to semantic impairments in patients with AD, the authors examined false recognition of perceptually related novel objects with little semantic content in patients with AD and healthy older adults. By using corrected recognition scores to control for unrelated false alarms, it was found that patients with AD showed lower levels of both true and false recognition of novel objects than did older adults. These results suggest that the previous difference in false recognition of semantic associates observed between patients with AD and older adults is not entirely attributable to semantic memory deficits in patients with AD but may also involve poorly developed gist information in these patients.

Psychiatric and behavioral problems.

In an emergency setting, many neurologic conditions present with psychiatric and behavioral symptoms. These symptoms may either be the first manifestation of the neurologic illness or a later occurrence in the progression of the disease. It is important for clinicians evaluating patients with psychiatric symptoms to identify the signs indicating associated neurologic illness and to have strategies for managing the acute, potentially dangerous, neuropsychiatric manifestations of the disease. This article addresses emergency evaluation and management of depression, anxiety, psychosis, mania, suicide attempts, neuroleptic malignant syndrome and other hypermetabolic and amnestic syndromes, somatoform disorders, aggression, and legal issues, such as capacity to accept or refuse treatment.

Age-related differences in enhancement and suppression of neural activity underlying selective attention in matched young and old adults.

Selective attention reflects the top-down control of sensory processing that is mediated by enhancement or inhibition of neural activity. ERPs were used to investigate age-related differences in neural activity in an experiment examining selective attention to color under Attend and Ignore conditions, as well as under a Neutral condition in which color was task-irrelevant. We sought to determine whether differences in neural activity between old and young adult subjects were due to differences in age rather than executive capacity. Old subjects were matched to two groups of young subjects on the basis of neuropsychological test performance: one using age-appropriate norms and the other using test scores not adjusted for age. We found that old and young subject groups did not differ in the overall modulation of selective attention between Attend and Ignore conditions, as indexed by the size of the anterior Selection Positivity. However, in contrast to either young adult group, old subjects did not exhibit reduced neural activity under the Ignore relative to Neutral condition, but showed enhanced activity under the Attend condition. The onset and peak of the Selection Positivity occurred later for old than young subjects. In summary, older adults execute selective attention less efficiently than matched younger subjects, with slowed processing and failed suppression under Ignore. Increased enhancement under Attend may serve as a compensatory mechanism.

The plight of caring for young patients with frontotemporal dementia.

We present the case of a 39-year-old patient with frontotemporal dementia. This case depicts the complexities in the process leading to the diagnosis, treatment, and placement of young patients presenting with severe psychiatric symptoms as the first signs of an underlying neurological disease. Obstacles in the health care system and residential placement process that hinder the optimal and timely care of such difficult cases are discussed. Practical solutions are offered that center upon better awareness and education and the provision of additional resources. These interventions are likely to provide a positive return on investment for the medical system and could be used as strong levers for new health policies relevant to younger patients with neurological illness.