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Despite treatment, cognitive and motor deficits are common in individuals with inherited urea cycle disorders. However, the extent to which the deficits involve specific cognitive or sensorimotor domains is unknown. Furthermore, little is known about the neurochemical basis of cognitive impairment in these disorders. This paper reviews studies of cognitive and motor dysfunction in urea cycle disorders, and discusses potential venues for investigation of the underlying neural basis that may elucidate these defects. Such methods of investigation may serve as a model for studying the relationship between genes, biochemical markers, brain function, and behavior in other metabolic diseases.
Mol Genet Metab 2004 Apr
PMID:Cognitive outcome in urea cycle disorders. 1505 Sep 75

Great interest is now devoted to elderly people with memory or other cognitive complaints who are not demented. The determination of this impairment from normality is difficult, because memory performance may decline slowly along the lifetime of the individual. On the other hand, the identification of dementia depends on the criteria used for dementia (DSM-IV or ICD-10). Furthermore, cognitive deterioration of the elderly appears to be heterogenous and may forerun not only Alzheimer's disease but also other forms of dementia. By applying a set of criteria for frontotemporal mild cognitive impairment, it was possible to identify, retrospectively, a series of patients with behavioral, affective, or speech symptoms suggestive of frontotemporal dysfunction and deficits in frontal lobe-dependent neuropsychological tests, but who have maintained activities of daily living and are not demented. These patients appear to have a high probability of progressing subsequently to dementia of the frontotemporal type. Several potential neuroprotective compounds are now being subjected to clinical trials. Should they be effective in delaying the progression to dementia, the need to detect and treat elderly people with cognitive impairment will become very important.
J Mol Neurosci 2004
PMID:Mild cognitive impairment: focus on diagnosis. 1512 99

The glucocorticoid component of the stress response has been the subject of intense scientific scrutiny because of the wide ranging pathological consequences resulting from excess glucocorticoid exposure, including mood and anxiety disorders, and cognitive impairment. Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic adrenomedullary system, which are regulated by neuronal pathways, including the inhibitory GABAergic (gamma-aminobutyric acid) system. Approximately 60% of the variance in glucocorticod levels may be attributable to genetic individual differences. In the present study, 56 healthy subjects underwent genotyping to determine the influence of the T1521C single nucleotide polymorphism (SNP) in the GABA(A)alpha6 receptor subunit gene (GABRA6) on the hormonal and autonomic responses to psychological stress induced by the Trier Social Stress Test (TSST). Adrenocorticotropin (ACTH), cortisol, diastolic blood pressure, and mean blood pressure responses to the TSST were significantly greater in subjects homozygous for the T allele or heterozygous compared to subjects homozygous for the C allele. Behavioral data was collected employing the Revised NEO Personality Inventory (NEO PI-R); subjects homozygous for the C allele scored significantly lower on the Extraversion factor compared to subjects homozygous for the T allele or heterozygous. These results suggest that the T1521C polymorphism in the GABRA6 gene is associated with specific personality characteristics as well as a marked attenuation in hormonal and blood pressure responses to psychological stress.
Mol Psychiatry 2004 Nov
PMID:GABRA6 gene polymorphism and an attenuated stress response. 1519 99

The NeuroTrax Mindstreams computerized cognitive assessment system was designed for widespread clinical and research use in detecting mild cognitive impairment (MCI). However, the capability of Mindstreams tests to discriminate the elderly with MCI from those who are cognitively healthy has yet to be evaluated. Moreover, the comparability between these tests and traditional neuropsychological tests in detecting MCI has not been examined. A two-center study was designed to assess the discriminant validity of tests in the Mindstreams Mild Impairment Battery. Participants were 30 individuals diagnosed with MCI, 29 with mild Alzheimer's disease (AD), and 39 healthy elderly. Testing was with the Mindstreams battery and traditional neuropsychological tests. Receiver operating characteristic (ROC) analysis was used to examine the ability of Mindstreams and traditional measures to discriminate those with MCI from cognitively healthy elderly. Between-group comparisons were made (Mann-Whitney U test) between MCI and healthy elderly and between MCI and mild AD groups. Mindstreams outcome parameters across multiple cognitive domains significantly discriminated between MCI and healthy elders with considerable effect sizes (p < 0.05). Measures of memory, executive function, visual spatial skills, and verbal fluency discriminated best, and discriminability was at least comparable to that of traditional neuropsychological tests in these domains. Mindstreams tests are effective in detecting MCI, providing a comprehensive profile of cognitive function. Further, the enhanced precision and ease of use of these computerized tests make the NeuroTrax system a valuable clinical tool in the identification of elders at high risk for dementia.
J Mol Neurosci 2004
PMID:Validity of the Mindstreams computerized cognitive battery for mild cognitive impairment. 1531 47

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory deficit, cognitive impairment, and personality changes accompanied by specific structural abnormalities in the brain. Deposition of amyloid-beta (Abeta) peptide into senile plaques is a consistent feature of the brains of patients affected by AD. Studies with both animal and cellular models of AD have shown that cholesterol homeostasis and distribution regulate Abeta generation. We have provided genetic, biochemical, and metabolic evidence that implicates intracellular cholesterol distribution, rather than total cholesterol levels, in the regulation of Abeta generation. This minireview focuses on the role of acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) in Abeta generation. In genetically mutant cell lines that overproduce cholesterol but cannot synthesize cholesteryl esters (CEs) because of deficient ACAT activity, Abeta production is almost completely inhibited. Acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) inhibitors, currently being developed for the treatment and prevention of atherosclerosis, reduce CE levels and Abeta generation by up to 50% in cell culture models of AD. Future mechanistic and transgenic animal studies are needed to evaluate the potential use of ACAT inhibitors in the therapeutic treatment or prevention of AD.
J Mol Neurosci 2004
PMID:Role of acyl-coenzyme a: cholesterol acyltransferase activity in the processing of the amyloid precursor protein. 1531 56

Magnetic resonance imaging (MRI) has opened a new window to the brain. Measuring hippocampal volume with MRI has provided important information about several neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. Smaller hippocampal volumes have been reported in epilepsy, Alzheimer's disease, dementia, mild cognitive impairment, the aged, traumatic brain injury, cardiac arrest, Parkinson's disease, Huntington's disease, Cushing's disease, herpes simplex encephalitis, Turner's syndrome, Down's syndrome, survivors of low birth weight, schizophrenia, major depression, posttraumatic stress disorder, chronic alcoholism, borderline personality disorder, obsessive-compulsive disorder, and antisocial personality disorder. Significantly larger hippocampal volumes have been correlated with autism and children with fragile X syndrome. Preservation of hippocampal volume has been reported in congenital hyperplasia, children with fetal alcohol syndrome, anorexia nervosa, attention-deficit and hyperactivity disorder, bipolar disorder, and panic disorder. Possible mechanisms of hippocampal volume loss in neuropsychiatric disorders are discussed.
Mol Psychiatry 2005 Feb
PMID:MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders. 1535 39

The tremor rat is a spontaneous epilepsy model with a seizure phenotype caused by a deletion in the aspartoacylase (ASPA) gene. The absence of ASPA expression in these animals results in undetectable levels of enzyme activity and the accumulation of the substrate N-acetyl-aspartate (NAA) in brain, leading to generalized myelin vacuolation and severe motor and cognitive impairment. In support of human gene therapy for CD, recombinant adeno-associated viral vector (AAV-2) expressing ASPA was stereotactically delivered to the tremor rat brain and effects on the mutant phenotype were measured. AAV-ASPA gene transfer resulted in elevated aspartoacylase bioactivity compared to untreated mutant animals and elicited a significant decrease in the pathologically elevated whole-brain NAA levels. Assessment of motor function via quantitative rotorod testing demonstrated that rats injected with AAV-ASPA significantly improved on tests of balance and coordinated locomotion compared to animals receiving control vectors. This study provides evidence that AAV-2-mediated aspartoacylase gene transfer to the brain improves biochemical and behavioral deficits in tremor rat mutants (tm/tm) and supports the rationale of human gene transfer for Canavan disease.
Brain Res Mol Brain Res 2005 Apr 27
PMID:Effects of AAV-2-mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease. 1585 74

Sex-specific incidence rates for Alzheimer's disease (AD) are higher in women than men. Many fundamental researches and some clinical investigations have reported therapeutic and preventive effects of estrogens on AD. But WHIMS [S.A. Shumaker, C. Legault, S.R. Rapp, L. Thal, R.B. Wallace, J.K. Ockene, S.L. Hendrix, B.N. Jones IIIrd, A.R. Assaf, R.D. Jackson, J.M. Kotchen, S. Wabertheil-Smoller, J. Wactawsk-Wende, WHIMS investigators, Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The women's health initiative memory study: a randomized controlled trial, JAMA 289 (2003) 2651-2662], which used daily continuous hormone replacement therapy (HRT), reported that the hazard ratio of the HRT for probable dementia was 2.05. Effect of progestins, and continuous (not cyclically) HRT, even only with estrogen should be reconsidered. In our clinical study, conjugated equine estrogen (CEE) alone showed good changes of psychiatric tests for AD on the 3rd week, but addition of medroxyprogesterone acetate (MPA) or norethindrone since 4th week suppressed these tests. Using human umbilical vein epithelial cell (HUVEC), levonorgestrel (LNG), norethindrone acetate (NETA), MPA increased intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-secretin but dienogest (DNG) showed no effect. In vitro flow system, estradiol (E2), suppressed adhesion of white cell, but LNG, NETA, MPA increased the adhesions. DNG showed less effect. Non-feminizing estrogen J 861, which has delta8,9 double bond and straight in its structure and has less effect on sexual organs. J 861 has shown ameliorative effects on central nervous system (CNS) (increasing of cholineacetyltransferase immunoreactive cells in substantia innominata (SI), etc.) like E2. More investigations about progestins and estrogens and AD should be done.
J Steroid Biochem Mol Biol 2005 Feb
PMID:Progestins and estrogens and Alzheimer's disease. 1586 Feb 74

Chronic cerebral hypoperfusion causes cognitive impairment, but the underlying molecular mechanism is not well understood. We used permanent occlusion of bilateral common carotid arteries (2-VO) to induce chronic cerebral hypoperfusion in male Wistar rats. Cognitive impairment and the expression patterns of MAP-2, GAP-43, and synaptophysin were examined. We found that both learning capacity and memory were gradually impaired in the rats with chronic cerebral hypoperfusion concomitant with increased duration of 2-VO treatment. Four weeks of 2-VO treatment resulted in down-regulation of synaptophysin expression at the protein levels, and a further decrease was observed at 10-20 weeks, although mRNA levels remained the same. Ten weeks of 2-VO treatment lead to down-regulation of MAP-2 expression at both the mRNA and protein levels with a further decrease at 20 weeks. Interestingly, GAP-43 mRNA was significantly up-regulated by 2-VO treatment, although the protein levels were not altered. Therefore, the cognitive impairment caused by chronic cerebral hypoperfusion may be partially explained by reduced expression of synaptophysin and MAP-2 at the protein level. The reduction in MAP-2 expression may be attributed to the inhibition of transcription, while the reduction in synaptophysin expression might be due to the inhibition of translation. Up-regulation of GAP-43 mRNA in the rat hippocampus with 2-VO treatment suggests that a compensatory mechanism may antagonize ischemic challenges.
Brain Res Mol Brain Res 2005 Sep 13
PMID:Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment. 1596 96

Dysfunction of the serotonergic pathway disrupts normal cognitive functioning and is believed to be the underlying basis for a variety of psychiatric disorders. Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals. We have investigated these two polymorphisms for association with both the level of cognitive abilities and their decline with age using a cohort consisting of over 750 elderly nondemented individuals with a follow-up of up to 15 years. We found that volunteers homozygous for the VNTR2 12 allele had a faster rate of decline for all cognitive tests. This reached significance for both tests of fluid intelligence (novel problem solving) (AH1 P=0.002, AH2 P=0.014), the test of semantic memory (P=0.010) and general cognitive ability (P=0.006). No association was observed between the HTTLPR polymorphism and the rate of cognitive decline when analysed either independently or in combination with the VNTR2 polymorphism based on their influence on expression in vitro. No associations were observed between the two polymorphisms and the baseline level of cognitive abilities. This is only the second gene that has been reported to regulate the rate of cognitive decline in nondemented individuals and may be a target for the treatment of cognitive impairment in the elderly.
Mol Psychiatry 2005 Dec
PMID:Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population. 1610 87


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