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PubMed2001

Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches?

The observations of the loss of cholinergic function in neocortex and hippocampus in Alzheimer's disease (AD) developed the hypothesis that replacement of cholinergic function may be of therapeutic benefit to AD patients. The different approaches proposed or tested included intervention with acetylcholine (ACh) precursors, stimulation of ACh release, use of muscarinic or nicotinic receptor agonists and acetylcholinesterase (AChE) or cholinesterase (ChE) inhibition. Inhibition of endogenous ACh degradation through ChE inhibitors and precursor loading were treatments more largely investigated in clinical trials. Of the numerous compounds in development for the treatment of AD, AChE and ChE inhibitors are the most clinically advanced, although clinical trials conducted to date did not always confirm a significant benefit of these drugs on all symptom domains of AD. The first attempts in the treatment of AD with cholinergic precursors did not confirm a clinical utility of this class of compounds in well controlled clinical trials. However, cholinergic precursors most largely used such as choline and phosphatidylcholine (lecithin) were probably not suitable for enhancing brain levels of ACh. Other phospholipids involved in choline biosynthetic pathways such as CDP-choline, choline alphoscerate and phosphatidylserine clearly enhanced ACh availability or release and provided a modest improvement of cognitive dysfunction in AD, these effects being more pronounced with choline alphoscerate. Although some positive results cannot be generalized due to the small numbers of patients studied, they probably would justify reconsideration of the most promising molecules in larger carefully controlled trials.

Age of Onset↗
PubMed2001

Cognitive dysfunction in patients with amyotrophic lateral sclerosis is associated with spherical or crescent-shaped ubiquitinated intraneuronal inclusions in the parahippocampal gyrus and amygdala, but not in the neostriatum.

Skeins or skein-like inclusions, one of the two types of ubiquitinated intraneuronal inclusions in amyotrophic lateral sclerosis (ALS), in the neostriatum are not specific to the disease, but it has not yet been determined whether the other, spherical or crescent-shaped inclusions (SCI) are pathognomonic. To clarify this and also to investigate whether the distribution of SCI in particular brain regions is associated with clinical parameters, we examined the occurrence of SCI in the brains of 24 patients with ALS and 94 controls. SCI in the neostriatum were specifically detected in 54% of the ALS cases, but not in any of the controls. No apparent phenotypic denominator, such as disease duration or the occurrence of dementia, correlated to the distribution of SCI in the neostriatum in ALS cases. On the other hand, the occurrence of SCI in both the second and third layers of the parahippocampal gyrus and amygdala was significantly correlated to the presence of dementia in ALS cases. SCI were distributed in association with each other among the parahippocampal gyrus, dentate gyrus of the hippocampus and amygdala, but not between the spinal anterior horn and any non-motor-associated brain regions. These findings suggest that these particular brain regions might be significantly involved in the neurodegenerative process associated with ALS. The relationship of SCI to either ALS pathogenesis or cognitive dysfunction depends on the brain regions in which they are distributed, and this indicates that the neurodegenerative processes in ALS proceed differentially in particular motor-associated and nonmotor-associated brain regions.

Aged↗
PubMed1998

Tinnitus Cognitions Questionnaire: Development and Psychometric Properties of a Measure of Dysfunctional Cognitions Associated with Tinnitus.

The development of the Tinnitus Cognitions Questionnaire (TCQ), a scale designed to assess positive and negative cognitions associated with tinnitus, is described. Psychometric analyses of the TCQ are examined, with a total of 189 subjects from three separate samples. The results indicate good test-retest reliability (r = 0.88) and internal consistency (Cronbach's alpha = 0.91). Factor analysis revealed two factors that were interpreted as positive cognitions and negative cognitions. TCQ negative items and positive items were found to be unrelated (r = 0.09). Correlations between the TCQ and other self-report indices of depression, automatic negative thoughts, and tinnitus-specific symptomatology are reported. The TCQ may provide a useful index of the cognitive responses of tinnitus sufferers and may be employed as a measure of change in outcome research on psychological management of tinnitus.

Journal Article↗
PubMedDate not supplied

Clozapine-induced cognitive dysfunction in mice.

The atypical antipsychotic clozapine was examined for its ability to interrupt cognitive functions in mice on passive avoidance paradigm and elevated plus maze. The posttraining intraperitoneal injection of clozapine (0.1-7.5 mg/kg) induced dysfunction in acquisition as well as retrieval, which was reversed by physostigmine (0.05 mg/kg). Clozapine showed dose-related effects on scopolamine-induced cognitive dysfunction, with higher doses having no significant effect and lower doses reversing the dysfunction. These results are explained on the basis of clozapine's effects on central cholinergic receptors.

Animals↗
PubMedDate not supplied

Dietary enrichment counteracts age-associated cognitive dysfunction in canines.

Advanced age is accompanied by cognitive decline indicative of central nervous system dysfunction. One possibly critical causal factor is oxidative stress. Accordingly, we studied the effects of dietary antioxidants and age in a canine model of aging that parallels the key features of cognitive decline and neuropathology in humans. Old and young animals were placed on either a standard control food, or a food enriched with a broad spectrum of antioxidants and mitochondrial enzymatic cofactors. After 6 months of treatment, the animals were tested on four increasingly difficult oddity discrimination learning problems. The old animals learned more slowly than the young, making significantly more errors. However, this age-associated decline was reduced in the animals fed the enriched food, particularly on the more difficult tasks. These results indicate that maintenance on foods fortified with complex mixtures of antioxidants can partially counteract the deleterious effects of aging on cognition.

Aging↗
PubMed1999

Cognitive dysfunction in schizophrenia: a new set of tools for the assessment of cognition and drug effects.

Cognitive impairment in schizophrenia must be seen as a disturbance of cortico-sub-cortical connectivity with a neurotransmitter imbalance in a circuitry system, which connects thalamic input with prefrontal processing and supplementary motor cortex and basal ganglia output. The concept of maze-solving behaviour as a continuous cognitive task evoking a conflict between prefrontal cortex and basal ganglia activity is explained and introduced to distinguish between the effects of D2 blocking agents and substances with a predominant 5HT2A receptor affinity, such as clozapine and risperidone. Complex mazes show a cognitive deficit in untreated schizophrenic patients that are impaired by conventional and improved by atypical antipsychotic substances. Processing speed improves most on clozapine, while parallel processing is best supported by the non-sedative atypical substance risperidone. Maze paradigms are presented.

Antipsychotic Agents↗
PubMed1988

The incidence of cognitive dysfunction in an encopretic population in children.

Cognitive testing was conducted in a clinical population of encopretic patients. Testing included the Weschler Intelligence Scale for Children-Revised (WISC-R), the Wide Range Achievement Test (WRAT) and the Bender Visual-Motor Gestalt Test (BVMGT). Although Full Scale, Verbal and Performance Intelligence Quotients on the WISC-R were not statistically different from general population means, subtests in Arithmetic (p less than 0.001), Digit Span (p less than 0.001) and Coding (p less than 0.05) were. There was also a high incidence of Verbal/Performance discrepancies and statistically significant differences on the WRAT in Spelling (p less than 0.01) and Arithmetic (p less than 0.01). Visual-motor integration was delayed two or more years in 43% of the patients on the BVMGT. These findings are consistent with the diagnosis of specific learning disabilities. An increased frequency of learning disabilities in an encopretic population may represent a subset of patients with a distinct syndrome in this disorder. These findings may point to the central nervous system (CNS) as the common point of pathology for the encopresis and learning disabilities, or reflect a common insult to both the CNS and gastrointestinal tract. Since histories in these patients did not reveal significant pregnancy or neonatal risk factors, this association could be related to genetic or environmental issues. Health professionals should be alert to the possibility of an increased incidence of learning disabilities in their encopretic patients. Further controlled studies are needed to determine if this finding is present in other settings, and if so, to determine the etiology.

Adolescent↗
PubMed1987

Cognitive dysfunction, negative symptoms, and tardive dyskinesia in schizophrenia. Their association in relation to topography of involuntary movements and criterion of their abnormality.

Little is known of factors that, on an individual basis, confer vulnerability to the emergence of involuntary movements (tardive dyskinesia) during long-term neuroleptic treatment. In this study of 88 chronic schizophrenic inpatients, 22 variables (four demographic, 14 medication history, and four features of illness) were compared for any association(s) with the presence, by differing topographies and criteria of abnormality, and severity of involuntary movements. Irrespective of the criterion used, the presence of marked cognitive dysfunction-muteness bore a consistent and highly significant primary association with both the presence and the overall severity of orofacial dyskinesia; no such association was found in relation to the presence of limb-truncal dyskinesia. Flattening of affect was the only other variable consistently associated with the presence of orofacial movements. The reliability and prominence of the association between the presence of orofacial, but not of limb-truncal, movements and cognitive dysfunction-negative symptoms suggest that these varying topographies may not constitute a unitary syndrome. This strong association, not with indexes of neuroleptic exposure but rather with features of the illness for which that treatment was prescribed, suggests some neurologic process, more subtle than may previously have been appreciated, as a vulnerability factor of some importance. In schizophrenia it appears to be intimately related to the disease process.

Adult↗
PubMed2003

Lower endotoxin immunity predicts increased cognitive dysfunction in elderly patients after cardiac surgery.

BACKGROUND AND PURPOSE: Although coronary artery bypass graft surgery (CABG) improves the quality of life and functional capacity for numerous patients, many also exhibit impairment in cognitive function immediately after surgery. Although the etiology of this cognitive decline is multifactorial, the inflammatory response to the primary insult may modulate the extent of dysfunction. Patients with low preoperative levels of anti-endotoxin core antibody (EndoCAb) are more likely to experience adverse outcomes, suggesting that decreased immunity to endotoxin causes a heightened release of inflammatory mediators. We therefore sought to determine the association of decreased EndoCAb and the incidence of postoperative cognitive decline. METHODS: EndoCAb levels were measured before surgery in 460 patients undergoing elective CABG. Cognitive function was measured preoperatively and 6 weeks postoperatively. Multivariable analysis accounted for the effects of age, Parsonnet score, sex, body mass index, baseline cognition, years of education, history of hypertension, bypass time, cross-clamp time, and number of grafts. RESULTS: At 6-week follow-up, 122 patients (36%) showed cognitive decline. Lower preoperative EndoCAb levels were associated with a greater incidence and severity of postoperative cognitive decline. The elderly with decreased endotoxin immunity are particularly susceptible to this decline (relative risk=1.97 for age >64). CONCLUSIONS: Reduced preoperative endotoxin immunity is a predictor of increased postoperative cognitive dysfunction in patients undergoing CABG, particularly in those >60 years old. Interventions that increase IgM EndoCAb levels might improve cognitive function after cardiac surgery.

Adult↗
PubMed2002

Cerebrovascular disease and cognitive dysfunction.

As the general population ages, the progressive cognitive decline that occurs with aging and dementia is having a significant socioeconomic impact on society. Vascular dementia associated with cerebral vascular disease is now the third most common cause of dementia. Recent evidence has revealed a new and significant etiopathogenetic role of cerebrovascular pathology, as well as newly determined risk factors for the development of neurocognitive deficits and other forms of dementia including Alzheimer's disease. In this article, we summarize the experimental and clinical data linking cerebrovascular pathology to neurocognitive decline and dementia.

Animals↗
PubMed2002

[Clinical investigation of cognitive dysfunction by specialists].

The clinical investigation of the cognitively impaired, or demented, patient includes a clinical bedside examination supported by, for instance, structural and functional brain imaging, analyses of biochemical markers, and genetic analyses. Valuable discussions have been held during the last decade between specialists and primary care physicians to define the clinical elements that should be included in bedside examinations carried out by general practitioners. The present paper is focused instead on the bedside investigation performed by the specialist in the field. Emphasis is put on the importance of combined cognitive and neurological assessments to determine symptoms and syndromes that possibly reflect regional pathological changes in the brain. The article also stresses the importance of detecting possible behavioural and psychological signs of dementia, and the importance of collecting information on the premorbid personality of the patient.

Aged↗
PubMed1996

Prevalence of cognitive dysfunction and hypothyroidism in an elderly community population.

Cognitive function was assessed in 801 elderly subjects (aged 65-92 years) using the Mini Mental State Examination (MMSE). The mean (+/- SD) MMSE score in the age group 65-70 years was 27.8 +/- 5.6, and the score declined to 22.3 +/- 7.8 at the age 85-90 (P = 0.001). Abnormal MMSE scores (less than 24) were found in 5.2% of the subjects aged 65-70 and gradually increased with age to 35.5% in the age group of 85-90. Serum thyroid-stimulating hormone (TSH) levels were determined in 751 subjects. Elevated TSH (> 4.5 mIU/l) were detected in 112 people (14%). The prevalence of hypothyroidism was higher in females (18.2%) than in males (9.7%). MMSE scores in 39 patients (14 males and 25 females) with untreated hypothyroidism were compared to the scores of 570 euthyroid elderly controls (235 males and 335 females). The mean +/- SD MMSE scores were 27.0 +/- 2.1 in hypothyroid males vs. 26.0 +/- 4.7 in male controls and 25.0 +/- 7.7 in hypothyroid females vs. 25.0 +/- 6.6 in female controls. The scores in the hypothyroid patients were not significantly different from the controls. Our data suggest that: a) the average cognitive performance declines with age; b) the percentage of subjects with abnormal MMSE scores increases with age, and is higher in females than in males; c) the prevalence of hypothyroidism in the elderly population is 14% and is higher in females (18%) than in males (10%); and d) mild untreated hypothyroidism is not associated with cognitive impairment.

Aged↗
PubMed1992

Treatment of cognitive dysfunctions and behavioral deficits in schizophrenia.

Integrated Psychological Therapy (IPT) is a structured intervention program that prescribes steps to remediate cognitive and behavioral dysfunctions that are characteristic of the psychopathology of schizophrenia. Evaluative studies of IPT indicated that the program improved schizophrenic patients' elementary cognitive processes such as attention, abstraction, and concept formation but that patients' performance was still below the normal range. The clinical utility of IPT will depend on studies that document the hierarchical generalization of improvements from the cognitive to the social and symptomatic levels of functioning.

Antisocial Personality Disorder↗
PubMed2003

Craniotomy for treatment of unruptured aneurysms is not associated with long-term cognitive dysfunction.

BACKGROUND AND PURPOSE: Many studies have reported frequent cognitive deficits associated with subarachnoid hemorrhage (SAH) and aneurysm repair. One study found more severe cognitive deficits after clipping than coiling of aneurysms, raising the possibility that deficits are due to surgery instead of SAH itself. This possibility was directly addressed by evaluating the cognitive effects of surgery without SAH. The goal of this study was to identify changes in cognitive function associated with surgical clipping of unruptured intracerebral aneurysms. METHODS: A consecutive series of 25 patients who underwent surgical clipping of >or=1 unruptured intracerebral aneurysm were tested within 1 week preoperatively and again postoperatively (before hospital discharge and at 3-month follow-up if they had deficits at discharge) on a neuropsychological battery. Different forms of each test were used preoperatively and postoperatively to reduce practice effects. Paired t tests were used to examine differences between preoperative and postoperative test scores across individuals. RESULTS: On most tests, there was no significant change between preoperative and postoperative scores. A significant decline in accuracy before hospital discharge was found only in figure copying (P<0.04) and associative learning (P<0.01), and significant slowing was found on 1 test (P<0.01). Even on these tests, only 3 of 25 patients showed significant deterioration. All but 1 patient returned to baseline by the 3-month follow-up. CONCLUSIONS: We found no evidence of subtle cognitive deficits resulting from aneurysm clipping alone, suggesting that the common impairments after surgery for ruptured aneurysms are due to SAH itself, complications of SAH such as vasospasm or hydrocephalus, or perioperative stroke.

Adult↗