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PubMed2000

Nicotinic systems in central nervous systems disease: degenerative disorders and beyond.

Advances in the understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors has provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realization that such receptors are changed in degenerative neurologic diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Ongoing investigations of the molecular substructure of CNS nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioral, motor, and sensory functioning. Clues from careful studies of human cognition and behavior are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Modulation of these receptors with the ultimate goal of producing therapeutic benefits is the goal of these investigations and drug development. This paper will review studies from our laboratory and others that point to the importance of CNS nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in disease states. In addition, this paper will examine potential clinical applications of nicotine and/or nicotinic agonists in a variety of CNS disorders with particular emphasis on structural brain disease including: movement disorders such as Parkinson's disease and Tourette's syndrome, cognitive/behavioral disorders such as Alzheimer's disease, attention deficit/hyperactivity disorder, and schizophrenia, and other more speculative applications. Important results from early therapeutic studies of nicotine and/or nicotinic agonists in these disease states are presented. For example, recent studies with nicotine and novel nicotinic agonists such as ABT-418 by our group in AD patients suggest that nicotinic stimulation can improve the acquisition and retention of verbal information and decrease errors. Preliminary results from a series of studies examining the acute and subchronic quantitative effects of nicotine on cognitive and motor functioning in Parkinson's disease suggest that acute nicotine administration and stimulation improves some aspects of cognitive and motor performance and may improve the processing speed of more complex tasks. The most likely near-term applications of novel nicotinic agonists in CNS disorders are likely to be in those disorders that are degenerative in nature, e.g. Parkinson's disease and Alzheimer's disease, or other movement disorders such as Tourette's syndrome. The most likely direct therapeutic role for nicotinic agonists is as augmentation therapy in combination with other agents rather than as monotherapy, except early in disease states or as a prophylactic or preventative treatment.

Animals↗

PubMed2004

[BCcogSEP: a French test battery evaluating cognitive functions in multiple sclerosis].

In French language, there is no standardized procedure to assess cognitive function in patients with multiple sclerosis (MS). Such an assessment is however very useful to determine the consequences of the disease on cognitive function, to evaluate the disease progression and the consequences of usual treatments on cognition. This study aimed to develop and validate a French language battery based on "the Brief Repeatable Battery of Neuropsychological tests for Multiple Sclerosis" (BRB-N) often used in other countries. In an initial phase, the battery was composed of the French version of the 5 BRB-N tests to which were added 4 tests assessing immediate and working memory as well as executive function. 52 healthy control subjects (20-50 years) participated in the study. A principal component analysis (PCA) of their data examined the contribution of each test into the battery. 93 other healthy subjects participated in a second phase where analyses of variance were carried out to investigate the effect of the main demographical variables. Finally, the performance of two patient groups (20 with a EDSS score 3) was compared to the healthy controls in order to investigate the ability of our battery to detect cognitive impairment in MS patients. The PCA showed that each test, except one, had a specific contribution to the battery. The final battery (BCcogSEP) was thus comprised of 8 tests. MANOVA and ANOVA showed significant effects of age, sex and educational level on performance. In consequence, a procedure allowing to take into account these factors was developed. The battery was able to detect cognitive impairment in MS patients, even when the disease is not severe. In this case, deficits were observed in tests assessing executive function, information processing speed, immediate and working memory. This short battery with reliable psychometric qualities allows the interpretation of a MS patient's performance considering his/her demographical characteristics and is able to detect cognitive abnormalities even in case of mild physical handicap.

Cognition↗

PubMedDate not supplied

Vision impairment and driving.

Driving is the primary mode of travel in many countries. It facilitates the performance of routine daily activities and is thus integral with the concept of quality of life. Vision is inarguably a fundamental component of safe driving. Drivers with certain eye conditions reduce their driving exposure and restrict their driving to the safest times, yet there is preliminary evidence that some eye conditions increase the risk of crashes. Visual acuity is only weakly related to crash involvement, whereas peripheral vision appears to play a more critical role. Color vision deficiency by itself is not a threat to safe driving. Based on the current literature, it is unclear whether other types of visual sensory impairment have a significant impact on driving safety and performance. Tests of visual attention and processing speed show great promise as methods of identifying high-risk drivers. There is a serious need for well-designed studies in key practical areas, such as the safety of low-vision drivers who use bioptic telescopes, the impact of monocular vision impairment on safety, and the effectiveness of vision rescreening policies after initial licensure. For ophthalmologists to guide patients about driving fitness, valid and reliable assessment tools must be developed and made widely available.

Accidents, Traffic↗

PubMed1997

Is facilitation responsible for the "motion induction" effect.

When a horizontal bar is presented after a single dot is shown at one of its ends, an illusory motion is seen which has been dubbed "motion induction" in the literature. The phenomenon has been attributed to a facilitation process which asymmetrically modulates the inputs to motion detectors, for instance by some sort of changes in processing speed. Computer simulations of motion detector arrays show, however, that this basic effects has to be expected from the properties of simple motion detectors. It has been recently reported that the strength of the illusory motion increases with the subjective salience of the inducing element. New computer simulations demonstrate that this observation can be related to the control of the local gain of motion detector input signals by the feature contrast in a particular region of the stimulus. High-level attentional mechanisms or changes in transmission speed are not required to explain these phenomena. The implications of such local gain-control mechanisms for our understanding of second-order motion perception are discussed.

Attention↗

PubMed1999

Transdermal nicotine: single dose effects on mood, EEG, performance, and event-related potentials.

A 21-mg dose of nicotine was administered transdermally to 16 overnight smoking-deprived smokers in a double-blind, placebo-controlled design. Mood ratings, electroencephalography (EEG), behavioral performance and event-related potential (ERP: P300) indices of attention and information processing speed were assessed before and 4 h after placebo/nicotine treatment. Although nicotine, relative to placebo, failed to alter mood, it increased absolute and relative power indices of EEG arousal, shortened reaction times, and increased P300 amplitudes. The results are discussed in relation to nicotine's actions on cholinergic transmission and its role in smoking behavior.

Administration, Cutaneous↗

PubMed2003

Neuropsychological effects of ethylene dichloride exposure.

Production of 1,2-dichloroethane (EDC) has increased and exposure to it has been reported to produce adverse effects in animals and CNS effects in humans. A group of 221 EDC exposed hazardous clean-up workers incurred chronic exposure to EDC without protective equipment. A clinical history and the following tests were administered: the WHO Adult Environmental Neurobehavioral Test Battery (AENTB), Wechsler Adult Intelligence Scale (WAIS-III), Wechsler Memory Scale (WMS-III); WRAT 3 Reading, Cancellation H, Trail Making, Stroop, Rey Osterreith, Animal Naming, COWAT, TOMM, Rey 15, Lanthony d-15 Color Vision, and Vistech Contrast Sensitivity. Mood and symptoms were assessed with the SCL90-R, BDI, BAI and IES. The clinical neuropsychological evaluation of these workers indicates lower neuropsychological functioning in the domains of processing speed; attention; cognitive flexibility; motor coordination and speed; verbal memory; verbal fluency; and visuo-spatial abilities. These workers also showed disturbed mood and impaired vision. Dose/response relationships between exposure to EDC and test scores are shown.

Adult↗

PubMed1996

Personality: a moderator of the relation between cognitive functioning and depression in adults aged 55-85?

Previous studies found modest associations between cognitive functioning and depressive symptoms in community samples of older adults. Low levels of cognitive functioning are associated with depressive symptoms. The present study investigates whether personality (locus of control and neuroticism) moderates this relation, and whether gender-differences in moderating effects can be established. The study is based on data of the baseline sample of 3107 participants of the Longitudinal Aging Study Amsterdam (LASA), which was age (55-85 years) and sex-stratified. Multiple regression analyses are used to detect moderating effects. The findings show modest effects, indicating that personality is a moderator of the relation between cognitive functioning and depressive symptoms, particularly in women. In women, a relatively strong internal locus of control is protective of becoming depressed when experiencing impairment in general cognitive functioning (MMSE), and impairment in fluid intelligence and information processing speed. In men, a low level of neuroticism is protective of becoming depressed when experiencing memory impairment. If these findings are replicated and extended in future studies, pertinent interventions such as cognitive therapy or memory training may be designed to alleviate depressive symptoms.

Adaptation, Psychological↗

PubMed2002

Changes in cognitive functioning following comprehensive treatment for first episode patients with schizophrenia spectrum disorders.

The course of cognitive functioning over a 1-year period was examined among a community cohort of individuals presenting with first episode schizophrenia spectrum psychosis. Data were obtained for 83 outpatients at entry to an early intervention program and 12 months later on the National Adult Reading Test, Wechsler Adult Intelligence Scales-Third Edition, Wechsler Memory Scales-Third Edition, Paced Auditory Serial Addition Task, Wisconsin Card Sorting Test, Stroop Colour and Word Test, Trail Making Test, Continuous Performance Task and Thurstone Word Fluency Test. Paired sample t-tests indicated significant and positive changes in verbal and non-verbal intelligence, auditory and visual memory, working memory and some aspects of executive functioning. Processing speed also improved though remained an area of relative weakness for this sample. Findings indicated generally average performance at both assessment periods. Neither gender nor duration of untreated psychosis were related to the degree of change in cognitive functioning for this sample. The implications of these findings and the impact of early intervention with this population are discussed.

Adult↗

PubMed2003

The relations between cognition and the independent living skill of shopping in people with schizophrenia.

A great deal of interest has developed regarding the impact of cognitive deficits on the everyday functioning of people with schizophrenia. This study examined the relationships between cognitive functioning and the performance of a specific independent living skill (grocery shopping) in a sample of 73 individuals with schizophrenia or schizoaffective disorder. Cognitive variables included tests of verbal memory, executive functioning, verbal fluency, sustained attention and visual motor skill. Functional outcome was measured with the Test of Grocery Shopping Skills, which is an ecologically based performance measure that requires participants to shop for 10 items within an actual grocery store. Accuracy on the shopping task was significantly associated with fewer perseverative responses on the Wisconsin Card Sorting Test, better verbal memory and faster processing speed. Shopping efficiency (i.e. less redundancy) was associated with better performance on several cognitive tasks, including verbal memory, verbal fluency, sustained attention and executive functioning. Results of this study extend previous research by examining the relation between cognition and the actual performance of daily living skills under natural circumstances.

Activities of Daily Living↗

PubMed2000

Olfactory event-related potentials and aging: normative data.

Unlike the clinical usages of evoked potentials (e.g. brain stem auditory evoked potentials for the assessment of auditory function), normative data for the olfactory event-related potential (OERP) have been unavailable. The principal objective was to establish normative data across the human life span for OERPs with a given set of parameters. Participants were 140 persons from seven age groups (16-19, 20-29, 30-39, 40-49, 50-59, 60-69 and 70-79 years of age), with equal numbers of males and females, screened for nasal health and dementia. The odor stimulus was amyl acetate, presented at nasal temperature in a humidified airstream delivered by an air-dilution olfactometer at a constant flow rate, using a 60-s inter-stimulus interval. OERPs were recorded at Fz, Cz, and Pz electrode sites, amplified and averaged over trials. Amplitudes of the N1/P2 and P3 and latencies of the P2 and P3 were analyzed. Processing speed decreased at a constant rate over decades for the sensory (P2 latency) as well as cognitive (P3 latency) components. Decline in amplitude over decades was also apparent. Normative data will be useful in research on olfactory function and in clinical assessment of olfactory functional status.

Adolescent↗

PubMed2003

Visual dysfunction, neurodegenerative diseases, and aging.

The four most common sight-threatening conditions in older adults in North America are cataract, ARM, glaucoma, and diabetic retinopathy. Even in their moderate stages, these conditions cause visual sensory impairments and reductions in health-related quality of life, including difficulties in daily tasks and psychosocial problems. Many older adults are free from these conditions, yet still experience a variety of visual perceptual problems resulting from aging-related changes in the optics of the eye and degeneration of the visual neural pathways. These problems consist of impairments in visual acuity, contrast sensitivity, color discrimination, temporal sensitivity, motion perception, peripheral visual field sensitivity, and visual processing speed. PD causes a progressive loss of dopaminergic cells predominantly in the retina and possibly in other areas of the visual system. This retinal dopamine deficiency produces selective spatial-temporal abnormalities in retinal ganglion cell function, probably arising from altered receptive field organization in the PD retina. The cortical degeneration characteristics of AD, including neurofibrillary tangles and neuritic plaques, also are present in the visual cortical areas, especially in the visual association areas. The most prominent electrophysiologic change in AD is a delay in the P2 component of the flash VEP. Deficits in higher-order visual abilities typically are compromised in AD, including problems with visual attention, perceiving structure from motion, visual memory, visual learning, reading, and object and face perception. There have been reports of a visual variant of AD in which these types of visual problems are the initial and most prominent signs of the disease. Visual sensory impairments (e.g., contrast sensitivity or achromatopsia) also have been reported but are believed more reflective of cortical disturbances than of AD-associated optic neuropathy.

Age Factors↗

PubMed2003

Cognitive disparity in schizophrenics with and without cocaine dependency.

Although cognition has been investigated in individuals with schizophrenia and in non-schizophrenic cocaine abusers, few studies have focused on cocaine-abusing schizophrenics. Previous studies have shown contradictory results despite the fact that individuals with schizophrenia and cocaine dependence have worse long-term outcomes, and that each disorder separately is associated with neuropsychological impairment. The present study intended to clarify these inconsistencies with a comprehensive neuropsychological battery. Twenty-four cocaine-dependent schizophrenics and 23 non-drug abusing schizophrenics were recruited from the VA. Participants were administered tests focusing on motor skills, processing speed, attention, concentration, and executive functioning. While individuals with schizophrenia and cocaine dependence performed worse on the Grooved Peg Board and the Stroop A, the non-drug abusing schizophrenics performed worse on Trails Part A and B. However, a MANOVA failed to show group differences in overall neuropsychological performance. These findings are similar to the existing literature and suggest that cocaine may compromise motor functioning.

Cocaine-Related Disorders↗

PubMedDate not supplied

The neuropsychology of trichotillomania.

The pathophysiology of trichotillomania (TM) is not well understood. Overlap with obsessive compulsive disorder (OCD) has been proposed, although extant data are inconsistent in this regard. In the neuropsychological domain, some data have supported the proposed TM-OCD overlap. However, the available studies are limited in number, and they typically have sampled a restricted range of performance domains. To examine further neuropsychological functioning in TM, the present study compared performance of 21 patients with TM and 17 normal control (NC) participants on a broad battery of tests assessing intellectual functioning, auditory perception and language, visual perception, somatosensory function, motor ability, memory, concept formation, attention and information processing speed, impulsivity, and cerebral dominance. The TM group demonstrated poorer performance on all measures of divided, but not focused, attention. Correlational data suggested the potentially important role of negative affect in TM. Implications of the data for the conceptualization of TM are discussed.

Adolescent↗

PubMedDate not supplied

Effects of chronic lead exposure on learning and reaction time in a visual discrimination task.

Long-Evans rats exposed chronically to lead (Pb) acetate (0, 75, or 300 ppm) were tested as adults on an automated, three-choice visual discrimination task as part of a larger study designed to elucidate the cognitive effects of developmental Pb exposure. Median adult BPb levels for the groups were <5, 20, and 36 microgram/dl. The pattern of results suggested a linear effect, with increasing lead dose producing progressively slower learning and an increased incidence of "impaired" individuals. This latter measure proved to be slightly more sensitive than the former, suggesting individual differences in susceptibility to Pb neurotoxicity. Additional analyses revealed that the impairing effect of Pb was seen in both the chance and post-chance learning phases, indicating that the deficit was not limited to (but could include) attentional function. Reaction time on incorrect trials was reduced in the 300-ppm group, whereas no Pb effect was seen for correct trials. The present findings suggest that chronic developmental Pb exposure produces an associative deficit as well as a tendency to respond rapidly, but does not affect information-processing speed.

Animals↗

PubMedDate not supplied

Early lead exposure produces lasting changes in sustained attention, response initiation, and reactivity to errors.

The present study tested the hypothesis that early lead (Pb) exposure causes lasting attentional dysfunction. Long-Evans dams were fed Pb-adulterated water during gestation and/or lactation; the offspring were tested as adults. The results of a visual discrimination task revealed no Pb effects on learning rate or information-processing speed. However, lasting effects of the early Pb exposure were seen in the subsequent vigilance tasks, particularly in the final task in which onset of the visual cue and cue duration varied randomly across trials. Exposure during both gestation and lactation impaired response initiation. In addition, animals exposed to Pb during lactation only or lactation+gestation committed significantly more omission errors than controls under two specific conditions: (1) trials in which a delay was imposed prior to cue presentation and (2) trials that followed an incorrect response. The pattern of treatment differences indicated that early Pb exposure produced lasting impairment of sustained attention and increased reactivity to errors. Both effects may contribute to the cognitive impairment, problematic classroom behaviors, and increased delinquency associated with early Pb exposure in children. These findings also demonstrate that the developmental timing of the exposure determines the pattern of effects. Thus, conclusions regarding whether or not a particular cognitive or affective function is impaired or spared by early Pb exposure must be limited to the specific timing and intensity of exposure.

Administration, Oral↗

PubMed2002

Different cognitive functions in relation to falls among older persons. Immediate memory as an independent risk factor for falls.

It is not clear which specific cognitive function is strongest related to falls. To investigate this, not only "general cognitive functioning," but also "nonverbal and abstract reasoning," "information processing speed," and "immediate memory" were related to falls. Furthermore, relevant effect modifiers, confounders, and mediators were identified. This study was performed within the Longitudinal Aging Study Amsterdam (LASA), a multidisciplinary, prospective cohort study. In this study (n = 1437), an interaction between "immediate memory" and age was found. In persons aged 75 years and over, "immediate memory," as measured by the 15 Words Test, showed to be an independent risk factor for falls. Part of this relationship was explained by the mediating effects of activity, mobility, and grip strength. The association between the other cognitive functions and falls was only statistically significant in univariate analysis. We conclude that "immediate memory" is an independent risk factor for recurrent falls in persons aged 75 years and older.

Accidental Falls↗

PubMed2003

An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia.

A pilot study was conducted to examine if donepezil could enhance cognitive function in patients with schizophrenia. Fifteen subjects who were on stable olanzapine treatment were entered into a 6-week open-labeled trial of donepezil. Subjects received baseline and end-of-study P50 and neuropsychological assessments. Donepezil treatment resulted in significant improvement in manual dexterity. There were moderate improvements in verbal recall memory and visual memory and processing speed, with smaller changes in P50 and verbal recognition memory. There was no effect on an attention measure. There were no changes in either positive or negative symptoms. These results suggest that cholinergic tone modulation may enhance selective behavioral functions in patients with schizophrenia, but further study is required to delineate the full extent of the potential benefit of this approach.

Adult↗

PubMed2003

The Maudsley Early-Onset Schizophrenia Study: cognitive function in adolescent-onset schizophrenia.

The neuropsychological correlates of adolescent-onset schizophrenia have been investigated very little to date. We assessed intelligence, memory and executive function in 42 patients with adolescent-onset schizophrenia and 43 healthy control subjects. Cases showed impairments in most cognitive variables. Despite the overall similarity with the quantitative and qualitative performance characteristics of later-onset patients in the literature, their cognitive profile displayed a unique feature: modification of the usual pattern of thinking latencies in the Tower of London Task. After adjusting for potential confounders, no effect of illness duration, symptoms or medication dose on patient performance emerged. However, longer exposure to medication predicted a lower level of performance in aspects of attention, psychomotor processing speed and spatial working memory. Our data are not consistent with worse cognition or progression of neuropsychological impairment in adolescent-onset schizophrenia.

Adolescent↗