ABSTRACT
A homozygous mutation of the CNTNAP2 gene has been associated with a syndrome of focal epilepsy, mental retardation, language regression and other neuropsychiatric problems in children of the Old Order Amish community. Here we report genomic rearrangements resulting in haploinsufficiency of the CNTNAP2 gene in association with epilepsy and schizophrenia. Genomic deletions of varying sizes affecting the CNTNAP2 gene were identified in three non-related Caucasian patients. In contrast, we did not observe any dosage variation for this gene in 512 healthy controls. Moreover, this genomic region has not been identified as showing large-scale copy number variation. Our data thus confirm an association of CNTNAP2 to epilepsy outside the Old Order Amish population and suggest that dosage alteration of this gene may lead to a complex phenotype of schizophrenia, epilepsy and cognitive impairment.
Subject(s)
Epilepsy/genetics , Gene Dosage/genetics , Genetic Predisposition to Disease , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Polymorphism, Single Nucleotide , Schizophrenia/genetics , Adult , Chromosomes, Human, Pair 7 , Female , Humans , In Situ Hybridization, Fluorescence/methods , Male , Middle Aged , Sequence AnalysisABSTRACT
OBJECTIVE: Follow-up studies of cognitive functions of poor-outcome (long-term institutionalized) elderly patients with schizophrenia have demonstrated deterioration over time, while stable cognitive functions over time have been reported for younger, better-outcome schizophrenic patients. This study examined whether cognitive changes in elderly schizophrenic patients with a history of long-term institutional stay extended to institutionalized younger patients. The rate of decline was compared to changes associated with Alzheimer's disease. METHOD: Patients with schizophrenia (N=107) age 20-80 years were followed over 6 years and assessed with the Clinical Dementia Rating and the Mini-Mental State Examination. The schizophrenic subjects age 50 and older were compared to 136 healthy comparison subjects and 118 Alzheimer's disease patients age 50 and older who were assessed over a similar follow-up period. RESULTS: There was a significant age group effect on the magnitude of cognitive decline for the schizophrenic subjects, with older subjects experiencing greater levels of decline over the follow-up. Neither the healthy individuals nor the Alzheimer's disease patients demonstrated similar age-related differences in the magnitude of cognitive change over the follow-up, with healthy comparison subjects showing no change and Alzheimer's disease patients manifesting decline regardless of age at the initiation of the follow-up. CONCLUSIONS: Institutionalized schizophrenic patients demonstrated an age-related pattern of cognitive change different from that observed for Alzheimer's disease patients and healthy individuals. The cognitive and functional status of these schizophrenic patients was fairly stable until late life, suggesting that cognitive change may not be occurring in younger patients over an interval as long as 6 years.
Subject(s)
Aging/psychology , Alzheimer Disease/diagnosis , Cognition Disorders/diagnosis , Schizophrenia/diagnosis , Adult , Age Factors , Aged , Alzheimer Disease/psychology , Cognition Disorders/epidemiology , Cognition Disorders/psychology , Diagnosis, Differential , Educational Status , Female , Follow-Up Studies , Geriatric Assessment , Humans , Institutionalization , Male , Middle Aged , Psychiatric Status Rating Scales/statistics & numerical data , Risk Factors , Schizophrenic Psychology , Severity of Illness IndexABSTRACT
Cognitive dysfunction has been described as a hallmark feature of schizophrenia since the first descriptions of the illness. Kraepelin described a number of features of the disorder that he thought reflected impairments in cognition and attention. He also speculated that cognitive impairments were mediated by neurobiologic dysfunction, specifically impairments in the functions of the frontal lobe. Since Kraepelin's time, there have been many changes in the general conceptions of schizophrenia, including ideas regarding the status and importance of cognitive impairment in the illness. Due to increased sophistication of neuropsychologic assessment and neuroimaging techniques, cognitive impairment has again has risen to the forefront of importance in terms of theories regarding the etiology and treatment of schizophrenia.
Subject(s)
Cognition Disorders/etiology , Schizophrenia/complications , Attention , Cognition Disorders/diagnosis , Cognition Disorders/physiopathology , Frontal Lobe/physiopathology , Humans , Neuropsychological Tests , Schizophrenia/physiopathologyABSTRACT
Norepinephrine plays a significant role in the working memory functions of the prefrontal cortex by its actions at alpha-2a noradrenergic receptors. Guanfacine has demonstrated efficacy in reversing working memory deficits in non-human primate. In the present study the effect of guanfacine adjunctive treatment to neuroleptics on the cognitive performance of schizophrenic patients was investigated in a four week, placebo-controlled, double-blind, parallel design trial. The primary analyses revealed no significant differences between guanfacine and placebo treatment; however, exploratory non-parametric statistics revealed some significant and some trend differences between guanfacine and placebo on spatial working memory test performance and CPT reaction time in those subjects treated with atypical neuroleptics.
Subject(s)
Adrenergic alpha-Agonists/therapeutic use , Cognition Disorders/drug therapy , Cognition Disorders/etiology , Guanfacine/therapeutic use , Schizophrenia/complications , Schizophrenia/drug therapy , Schizophrenic Psychology , Adult , Antipsychotic Agents/therapeutic use , Double-Blind Method , Female , Humans , Male , Middle Aged , Prefrontal Cortex/physiology , Psychiatric Status Rating Scales , Reaction Time/drug effects , Risperidone/therapeutic useABSTRACT
BACKGROUND: Our study examined the differential performance of cognitive skills in geriatric, cognitively impaired schizophrenic patients (n = 165) with a lengthy course of institutional stay and a poor overall functional outcome. Their relative deficits were compared with a sample of healthy elderly individuals. METHODS: Schizophrenic patients were matched one-to-one with healthy individuals of the same age and education and compared on a number of measures of cognitive functioning. The schizophrenic patients' old-learning performance was also compared with their educational level only. RESULTS: Mini-Mental State Examination (Folstein et al 1975) scores of the patients were in the moderately demented range (M = 20.36), and these patients underperformed healthy control subjects by more than 1 to slightly less than 3 standard deviations on measures of memory, praxis, and verbal skills. Wide Range Achievement Test-Revised word-recognition reading scores were found to be at the 10th-grade level, although the patients on average had completed 11 years of formal education. CONCLUSIONS: These results suggest that even in schizophrenic patients with significant cognitive impairment, reading scores are relatively consistent with educational attainment. These data indicate that poor performance on measures of cognitive functioning in this population does not necessarily occur on measures of old learning.
Subject(s)
Cognition , Reading , Schizophrenia/diagnosis , Schizophrenic Psychology , Aged , Aged, 80 and over , Analysis of Variance , Case-Control Studies , Chronic Disease , Female , Humans , Male , Mental Status Schedule , Psychiatric Status Rating Scales , Schizophrenia/physiopathology , Word Association TestsABSTRACT
The role of noradrenergic neurotransmission in normal cognitive functions has been extensively investigated, however, the involvement of noradrenergic functions in the cognitive impairment associated with schizophrenia and Alzheimer's disease has not been as intensively considered. The limited ability of atypical antipsychotics to treat the cognitive impairment of schizophrenia, and cholinomimetics to treat the cognitive impairment of Alzheimer's disease, may be related to the influence of a multiplicity of neurotransmitter abnormalities including noradrenergic dysfunction, which these treatments do not address. The evidence of noradrenergic dysfunction occurring concomitantly with dopamine dysfunction in schizophrenia and acetylcholine dysfunction in Alzheimer's disease supports therapeutic approaches using noradrenergic drugs in combination with neuroleptics and cholinesterase inhibitors, respectively, to enhance the treatment of cognitive impairment. Given the results of animal and human studies, it appears that alpha-2A agonists may be the optimal choice for this purpose.
Subject(s)
Alzheimer Disease/complications , Cognition Disorders/etiology , Cognition Disorders/physiopathology , Neurotransmitter Agents/metabolism , Schizophrenia/complications , Adrenergic alpha-2 Receptor Agonists , Adrenergic alpha-Agonists/therapeutic use , Alzheimer Disease/drug therapy , Cognition Disorders/drug therapy , Cognition Disorders/metabolism , Drug Therapy, Combination , Humans , Norepinephrine/metabolism , Schizophrenia/drug therapyABSTRACT
The variation in functional outcome in schizophrenia appears to be exaggerated in late life. The cognitive and functional deficits commonly seen in younger schizophrenic patients appear to worsen in some cases in late life, while others patients appear to have a stable course of illness without functional decline, and still other patients have been reported to have essentially no residual symptoms in their later years. Cognitive and functional deficits appear to worsen more significantly in patients with a lifetime course of severe functional deficit. Despite the profound functional and cognitive deficits in these patients, neuropathologic studies have found no evidence of typical causes of severe cognitive impairments. This paper reviews the current findings on cognitive and functional changes in aging in schizophrenia, with a specific focus on patients with a poor lifetime functional outcome.
Subject(s)
Activities of Daily Living/psychology , Alzheimer Disease/diagnosis , Cognition Disorders/diagnosis , Schizophrenic Psychology , Aged , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Brain/pathology , Cognition Disorders/pathology , Cognition Disorders/psychology , Disease Progression , Follow-Up Studies , HumansABSTRACT
There is recognition that the cognitive symptoms of schizophrenia have the most substantial impact on illness outcome. Domains of cognition reported to be significantly affected include serial learning, executive function, vigilance, and distractibility, to name a few. Dopamine activity at D1 receptors mediates many cognitive processes subserved by the prefrontal cortex (PFC), particularly working memory. The number of D1 receptors in the PFC is decreased in schizophrenics and is unaffected by chronic administration of typical neuroleptics. Therefore, medications that increase dopamine in the PFC, such as atypical neuroleptics, or that directly activate the D1 receptor may prove useful in the remediation of prefrontal-dependent cognitive deficits in schizophrenia. Decreased levels of cortical norepinephrine (NE) are associated with impaired learning and working memory in animal models, and can be reversed by drugs that restore NE activity. More specifically, alpha-2 adrenergic receptor agonists have been particularly effective in improving delayed response performance in young monkeys with localized 6-hydroxydopamine lesions in the PFC. Furthermore, human postmortem studies have demonstrated decreased NE in the frontal cortex of demented schizophrenic patients. Therefore, alpha-2 receptor agonists hold promise as drugs to improve cognitive performance on tasks dependent upon PFC function in schizophrenics. Finally, the finding that cortical choline acetyl transferase activity correlates with Clinical Dementia Rating scores in schizophrenic patients and that cholinomimetic drugs enhance cognition in healthy subjects suggests that cholinergic drugs may also treat cognitive symptoms in schizophrenia. Two potential types of cholinomimetics for use in schizophrenics are the acetylcholinesterase inhibitors and M1/M4 muscarinic agonists, both of which increase cortical cholinergic activity.
