Imidazoacridin-6-ones as novel inhibitors of the quinone oxidoreductase NQO2.

The purpose of the work was to identify novel inhibitors of the enzyme NQO2. Using computational molecular modelling, a QSAR (R(2)=0.88) was established, relating inhibitory potency with calculated binding affinity. From this, the imidazoacridin-6-one, NSC660841, was identified as the most potent inhibitor of NQO2 yet reported (IC(50)=6 nM).

An association between a polymorphism of the tryptophan hydroxylase gene and aggression in schizophrenia and schizoaffective disorder.

Serotonergic pathways have been implicated in impulsive and aggressive behavior. Polymorphisms in the regulatory region of the serotonin transporter (5-HTT), in intron 7 of the tryptophan hydroxylase (TPH) gene and in the MAOA gene were previously reported to be associated with mood and anxiety disorders, impulsivity and aggression. In this study, we analyzed these polymorphisms in men and women with schizophrenia or schizoaffective disorder (n = 84) who met our criteria for violence (history of two or more assaults on others) or nonviolence (no history of either assaultive or threatening behavior). In males, a modest association between TPH genotype and history of violence (chi-square test = 6.703, degrees of freedom = 2, P = 0.035) was not statistically significant after correction for multiple comparisons (corrected P = 0.21). The TPH L allele was more frequent in violent males (chi-square = 5.323, degrees of freedom = 1, P = 0.021) but this difference also failed to withstand correction (corrected P = 0.126). No significant associations were found for either the 5-HTT or MAOA polymorphisms in males or females. These results tend to support previous reports by New et al. (1996; 1998) of an association between the TPH L allele and impulsive aggression in males with personality disorder, but larger studies are needed.

Suicidal behavior in patients with schizophrenia is related to COMT polymorphism.

A common functional polymorphism that results in a three- to four-fold difference in catechol-O-methyltransferase (COMT) enzyme activity has been related to psychiatric disorders such as ultra-ultra rapid cycling bipolar disorder, drug abuse and alcoholism (Lachman et al., 1996a; Karayiorgou et al., 1997; Vandenbergh et al., 1997; Papolos et al., 1998; Tiihonen et al., 1999). Several studies have also reported associations between the allele encoding the low enzyme activity COMT variant (L allele) and other-directed aggression (Strous et al., 1997; Lachman et al., 1998; Kotler et al., 1999) in schizophrenic and schizoaffective patients. The current study investigated whether the COMT L allele is also associated with suicide attempts in schizophrenic and schizoaffective patients. COMT genotypes were determined and history of suicide attempts was retrospectively investigated in a Finnish sample (n = 94) and a US sample (n = 54). Significant associations were observed between COMT genotype and suicide; specifically, history of violent suicide attempts. The COMT L allele was more frequent in subjects who had attempted suicide by violent means. These associations were significant in males but not females. These findings support a common neurobiological substrate for self- and other-directed aggression, and suggest that catecholaminergic alterations may contribute to these behaviors in schizophrenic and schizoaffective patients.

Psychopathy and violent behavior among patients with schizophrenia or schizoaffective disorder.

OBJECTIVE: Although a strong association between violence and psychopathy has been demonstrated in nonpsychotic forensic populations, the relationship between psychopathy and violence among patients with schizophrenia has not been thoroughly explored. Patients with and without a history of persistent violent behavior were compared for comorbidity of psychopathy and schizophrenia or schizoaffective disorder. METHODS: Violent and nonviolent patients were identified through reviews of hospital charts and records of arrests and convictions. The Psychopathy Checklist: Screening Version was administered to 51 patients, 26 violent patients and 25 matched nonviolent patients. Analysis of variance was used as the principal statistical method for comparing violent and nonviolent groups. RESULTS: Mean psychopathy scores were higher for violent patients than nonviolent patients. Five of the violent patients (19 percent) had scores exceeding the cutoff for psychopathy, and 13 (50 percent) scored in the possible psychopathic range. All of the nonviolent patients scored below the cutoff for possible psychopathy. Higher psychopathy scores were associated with earlier age of onset of illness and more arrests for both violent and nonviolent offenses. CONCLUSIONS: The comorbidity of schizophrenia and psychopathy was found to be higher among violent patients than among nonviolent patients. Violent patients with schizophrenia who score high on measures of psychopathy may have a personality disorder that precedes the emergence of psychotic symptoms, or they may constitute a previously unclassified subtype of schizophrenia, characterized by early symptoms of conduct disorder symptoms and persistent violent behavior.

Ret oncogene activation in papillary thyroid carcinoma: prevalence and implication on the histological parameters.

The Ret proto-oncogene is known to be rearranged in papillary carcinoma of the thyroid. The aim of this study was to investigate the in situ expression of Ret mRNA in thyroid tumors. Formalin-fixed, paraffin-embedded tissue specimens from 45 thyroid lesions were examined by in situ hybridization using manual capillary action technology (MicroProbe Staining System) and a 52-base synthetic biotinylated oligonucleotide probe complementary to the tyrosine-kinase domain of Ret proto-oncogene. The clinicopathological features of these patients with thyroid lesions also were noted. Ret was noted in 17 (43%) of 40 papillary carcinomas. In contrast, none of the three follicular carcinomas, follicular adenoma, nodular hyperplasia, and normal thyroids, showed evidence of Ret mRNA. Our results showed that, in papillary thyroid carcinoma, there is an important role of Ret activation. The Ret staining could be a useful marker for papillary carcinoma.

Association between catechol O-methyltransferase genotype and violence in schizophrenia and schizoaffective disorder.

OBJECTIVE: The authors previously reported a relationship between an allele encoding the low activity variant of catechol O-methyltransferase (COMT) and aggressive behavior in schizophrenic patients. This study replicates and extends these findings by using more direct measures of violent behavior. METHOD: Fifty-five white patients (34 men, 21 women) with DSM-IV diagnoses of schizophrenia or schizoaffective disorder were selected to form two groups (violent and nonviolent) on the basis of history of aggressive behavior. COMT genotypes were determined by restriction fragment length polymorphism analysis. RESULTS: A significant association was found between COMT genotype and history of violent behavior. Sixty-four percent of patients homozygous for the low-activity COMT allele were violent; 80% of patients homozygous for the high-activity allele were nonviolent. CONCLUSIONS: The gene determining the activity of an important regulatory enzyme in catecholamine inactivation is associated with violent behavior in patients with schizophrenia and schizoaffective disorder.

Absence of vascular dementia in an autopsy series from a dementia clinic.

OBJECTIVE: The role of cerebrovascular disease in dementia in older people has been the subject of controversy. This study was undertaken to examine the prevalence of vascular disease in a prospective autopsy series of patients with clinically diagnosed dementia. DESIGN: Structured review of clinical and neuropathological examinations. Clinical diagnoses were assigned in accordance with the recommendations of the NINCDS/ADRDA consensus panel. Neuropathological examinations were performed at an academic neuropathology service using published consensus criteria for the diagnosis of Alzheimer's disease and other forms of dementia. SETTING: A subspecialty, outpatient dementia clinic in a university-affiliated suburban American hospital. PARTICIPANTS: Eighty-seven unselected patients coming to autopsy who had undergone clinical dementia evaluation. RESULTS: Dementia could not be attributed to the effects of cerebrovascular disease alone in any of the 87 patients coming to autopsy. Seventy-six (87%) of the patients were found to have Alzheimer's disease (AD), 44 had AD alone, and 32 had AD in combination with cerebrovascular disease (CVD). All of the patients with signs of CVD at autopsy were also found to have some concomitant neurodegenerative disease. The absence of patients in whom vascular dementia could be diagnosed at neuropathology was not the result of recruitment bias. CONCLUSION: Clinicians should maintain a high index of suspicion of AD or other neurodegenerative process in older patients whose presenting complaint is dementia, even in the presence of well documented cerebrovascular disease.

Incidence of the Fuld WAIS-R profile in traumatic brain injury and Parkinson's disease.

The frequency of occurrence of the Fuld Profile for cholinergic deficiency was investigated in two clinical populations: inpatients who had suffered traumatic brain injury and outpatients who carried a diagnosis of Parkinson's disease. The observed incidence of positive Fuld profiles was not significantly different in the two groups, 14% in the traumatic brain injury group and 24% in the Parkinson's disease group. These findings are consistent with recent reviews of the sensitivity and specificity of the Fuld profile in various clinical and nonclinical populations. The generally low sensitivity of the Fuld profile does not support its usefulness in the differential diagnosis of dementia. However, it may serve as an indicator of cholinergic deficiency, which could be used to select patients who would be likely to respond to cholinomimetic therapies.

The continuum of deep/surface dyslexia.

A right-handed male sustained traumatic brain injury which resulted in anomia, dyslexia and agraphia. The most severe CT (computed tomography)-identified brain damage was located in the right parieto-temporal lobe. In the first months following the injury, the pattern of reading errors was similar to that associated with deep dyslexia. However, nonlexical derivation of phonology from print was not abolished. As the patient's ability to associate letter patterns with sounds improved, oral reading also improved. Although he no longer produced semantic errors in oral reading, he continued to produce oral reading errors that were visually and phonologically related to the targets. Four months after the injury, the error pattern observed in the patient's oral reading was consistent with very mild surface dyslexia. The significance of these observations to dual-deficit models of acquired dyslexia is discussed, as are their implications for rehabilitation.

Failure of CT scan to detect ischemic lesions in patients with dementia.

Although clinical series have described relatively high accuracy in the ability of computed tomographic (CT) scan to detect significant cerebrovascular damage in patients with dementia, a recent neuropathologically controlled study failed to document that relationship. We now present clinical, neuroradiologic (CT), and neuropathologic information on four patients in whom CT scans did not contribute to the diagnosis of multi-infarct dementia or mixed dementia, despite clinical and neuropathologic evidence of infarcts. In one patient, the failure of CT scan to detect ischemic lesions may be attributable to less sensitive neuroradiologic criteria in use at the time of the examination. In the other three, even neuroradiologic review after the pathology was known failed to reveal the infarcts. These observations suggest the advisability of caution in using CT scan as a criterion for the presence or absence of cerebrovascular damage in patients with dementia.

Relationship between cognitive status and behavioral symptoms in Alzheimer's disease and mixed dementia.

OBJECTIVE: To investigate the relationship between cognitive and behavioral impairments in Alzheimer's disease (AD) and to examine whether the addition of cerebrovascular disease modifies that relationship. DESIGN: Correlational analysis. SETTING: An outpatient dementia clinic. PATIENTS: An autopsy-confirmed series of 28 patients with AD and 16 patients with mixed Alzheimer and vascular dementia (MIX). MEASUREMENTS: Neuropsychological and behavioral tests during life: Mini-Mental State (MMS), Blessed Dementia Scale (BDS), Haycox Dementia Behavior Scale (HDBS), and two non-cognitive functional scales derived from the BDS and HDBS. RESULTS: In the AD group, MMS scores correlated significantly with scores on the BDS, HDBS, and two non-cognitive functional scales. In the MIX group, however, no significant relationship was observed between MMS scores and scores on any of the behavioral measures. CONCLUSIONS: These observations suggest that in AD, cognitive and behavioral impairments progress simultaneously. However, with the addition of a vascular component to the dementing process, cognitive and behavioral impairments may progress more independently.

Pentoxifylline in cerebrovascular dementia.

OBJECTIVE: To test the effect of pentoxifylline, a hemorheologic agent used to treat intermittent claudication, on the course of vascular dementia. DESIGN: Randomized, double-blind, placebo-controlled, parallel group trial. SETTING: Outpatient tertiary care center. PATIENTS: 64 patients meeting DSM-III criteria for multi-infarct dementia with modified Hachinski ischemic scores greater than or equal to 6, 38 of whom completed the trial. INTERVENTION: Pentoxifylline (Trental) 400 milligram tablets three times daily vs placebo for 36 weeks. MAIN OUTCOME MEASURE: Alzheimer's Disease Assessment Scale (ADAS). RESULTS: Baseline demographic values and psychometric variables were similar in the placebo and control groups; endpoint statistical analysis was used to allow the use of data from all patients in this clinically high-risk group. For the total group, the slowing of deterioration did not reach statistical significance (by 2-tailed t test), as measured by scores on the total ADAS (P = 0.058) or on the cognitive (ADAS items 1-11; P = 0.064) or non-cognitive subscales (ADAS items 12-21; P = 0.234), although it was significant on the cognitive subscales excluding memory (ADAS items 2-6, 8-10; P = 0.036). For the subgroup of 40 patients who had CT and/or MRI evidence of stroke as well as meeting the other inclusion criteria, treatment with pentoxifylline was associated with significantly slower deterioration, as measured by the total ADAS (P = 0.023) and cognitive subscores (P = 0.020) but not non-cognitive subscores (P = 0.118). For the subgroup of 37 patients who had at least one discrete clinical stroke, treatment with pentoxifylline was associated with significantly less deterioration on the total ADAS (P = 0.002) and both the cognitive (P = 0.001) and non-cognitive (P = 0.017) subscores. CONCLUSION: Treatment with pentoxifylline may slow the progression of dementia in patients who meet DSM-III criteria for "multi-infarct dementia" and who also have clinical and neuroradiological evidence of cerebrovascular disease.

Preventing cognitive decline.

Many studies of age-related cognitive decline have failed to distinguish between usual and successful aging. Although some degree of cognitive impairment is associated with aging, when one looks at average performance, there is great variability among individuals, with many showing little or no deleterious effects of aging on intellectual abilities. Many of the risk factors for dementia and for conditions associated with cognitive impairments can be treated or controlled. Among the preventable causes of cognitive decline are the following: AIDS, Alcohol and drug abuse, Cerebrovascular disease, Exposure to organic solvents or lead, Head trauma, Overmedication, Syphilis. Other conditions that may cause cognitive decline can be controlled or treated: Atherosclerosis, Depression, Diabetes, Emphysema, High blood pressure, Obesity, Sleep disorders, Thyroid dysfunction. In addition, it may be possible to enhance the cognitive performance of even healthy elderly people through changes in diet and lifestyle. Recent data raise the possibility that improved prenatal and perinatal care and greater access to educational opportunities may result in a decreased incidence of dementia in future generations of older adults. Although they are rapidly becoming more numerous, the efficacy of cognitive training programs in preventing or slowing cognitive decline has not yet been demonstrated. Nevertheless, such programs may ameliorate cognitive impairment by reducing the psychiatric disabilities associated with anxiety and depression. The general principle underlying these strategies for limiting cognitive impairment with age is to maximize brain reserve and minimize brain damage.

A trial of thiamine in Alzheimer's disease.

Because a previous short-term study demonstrated a statistically significant, but not clinically important, improvement in cognitive test scores during thiamine treatment in patients with dementia of the Alzheimer's type, a 12-month, double-blind, parallel-group study was conducted to examine whether long-term administration of thiamine at 3 g/d might slow the progression of dementia of the Alzheimer's type. Fifteen subjects were enrolled and 10 completed the 1-year study. Data are available for two additional subjects through the first 9 months of study. No significant differences were found between the placebo and thiamine groups at any point during the study. In both groups, overall means for the Mini-Mental State Examination, verbal learning, and naming scores decreased significantly over the 12-month study period. These results do not support the hypothesis that long-term administration of thiamine at 3 g/d might slow the progression of dementia of the Alzheimer's type.

Delirium: phenomenology and diagnosis--a neurobiologic view.

"Delirium" is a reversible confusional state. It results from widespread but reversible interference with the function of cortical neurons, as documented by diffuse slowing on EEG and decreases in cerebral metabolic rate. Delirium can be due to impairments in neuronal metabolism, in neurotransmission (notably cholinergic), or in input from subcortical structures. Engel and Romano (1959) formulated delirium and dementia as the two poles of a spectrum of "cerebral insufficiency," with delirium resulting from reversible functional impairment and dementia from irreversible anatomic damage. So many disorders can precipitate delirium that the differential diagnosis tests every facet of one's knowledge of medicine. With aging, both normative changes in the brain and the increasing incidence of brain diseases predispose to the development of delirium. The brain damage responsible for a dementia can sensitize to the development of a superimposed delirium.

An analysis of writing in a case of deep dyslexia.

In tests of her ability to produce written and spoken language, this deep dyslexic patient produced semantic, visual, and derivational errors, including functor substitutions, and exhibited part-of-speech and abstractness effects in oral reading, oral and written naming, and writing to dictation, but not in repetition of single words and copying from memory. This patient therefore provides confirmation of the hypothesis presented in Nolan and Caramazza (1982) that the defining symptoms of deep dyslexia will be observed in responses to any task which requires lexical mediation. The patient's written responses in all tasks but direct copying were characterized by spelling errors which included transpositions, omissions, substitutions, and additions of letters. A model of writing is proposed which explains these errors in terms of a disruption of a phoneme-grapheme conversion process which normally functions to prevent decay of information from a Graphemic Buffer.