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Dopamine and cognitive functioning: brain imaging findings in Huntington's disease and normal aging.

Recent brain imaging studies in Huntington's disease (HD) and normal aging suggest a relationship between central dopaminergic neurotransmission and cognitive performance. Results demonstrate substantial losses in dopamine (DA) function in both HD and aging. Moreover, HD patients and older adults show deficits across multiple cognitive domains, including episodic memory, speed of processing, and executive functioning. Although few studies are available at present, there is converging evidence that multiple measures of pre- and postsynaptic DA biochemistry are (a) highly interrelated, and (b) strongly associated with the cognitive deficits that accompany HD and aging. There is also emerging evidence that DA neurotransmission influences cognitive performance independent of HD or age. In general, the research reviewed in this article indicates that the nigrostriatal DA system is an important component of a frontostriatal circuitry that is critically involved in cognitive functioning.

Aging↗

A new point-based warping method for enhanced and simplified analysis of functional brain image data.

Comparison of brain imaging data requires the exact matching of data sets from different individuals. Warping methods, used to optimize matching of data sets, can exploit either local gray value distribution or identifiable reference points within the images to be compared. Gray value-based warping, which is more comfortable, cannot be used if gray values include functional information that should be compared between images. A major drawback in the use of point-based warping methods is the lack of methods for efficient and precise definition of reference points (landmarks) within comparable data sets. Here, we present a novel approach to automatically detect sufficient numbers of landmarks, which is based on 3D differential operators. In addition, we have developed a new distance-weighted warping method, which optimizes individual local weighting factors of displacement vectors. The quality of the methods was evaluated using a set of autoradiographs documenting the metabolic activity of gerbil brains after acoustic stimulation. The new warping method was compared with known methods of landmark-based warping, i.e., warping with radial basis functions and with distance-weighted methods. For the data sets presented in this study our new optimized warping method produced an increase in linear cross correlation of 4.44%, an increase in volume overlap index of 1.55%, and a decrease in the registration error of 36.2%. In addition, the detection of functional differences was improved after warping. Therefore, the new method is a powerful tool, which enhances the comparison of complex biological structures and the quantitative evaluation of functional imaging data.

Algorithms↗

[Noninvasive higher-order brain-function imaging by near-infrared spectroscopy].

The simultaneous position encoding method for optical topography was developed. Each channel has dual-wavelength optics to separately determine the changes in oxy-hemoglobin and deoxy-hemoglobin concentrations around their isobestic points at 805 nm. Part of the incident light penetrates the scalp and skull and is reflected from brain tissues including the cerebral cortex. Any change in the light extinction is mainly due to changes in the oxy-hemoglobin and/or the deoxy-hemoglobin concentration during the activation of a functional area linked to a neuronal activity. Unlike conventional functional imaging methodologies, it can be used for behavioral studies because the flexible optical fibers allow a subject to move, and a very light and compact system can be made. Noninvasive dynamic optical topography has a wide variety of applications from basic science to clinical medicine. Several applications, such as the study of the Broca and Wernicke language areas, the assessment of the dominant hemisphere of the brain, epilepsy focus determination, and sleep studies are reported. We also tested a 14-month-old baby with a extremely abnormal brain.

Brain↗

Susceptibility to toxoplasmosis: correlation between macrophage function, brain cyst formation and mortality in rats.

Rats are resistant to Toxoplasma infection, and in contrast to mice do not form cysts in their tissues. Because rats treated with beta adrenergics, corticosteroids or 60cobalt are more susceptible to toxoplasmosis, we conducted experiments to investigate if the impaired resistance of drug-treated rats is related to macrophage function or induction of cystogenic capacity. Our experiments in 0.7 or 1.2 mg/kg-corticosteroid or 12 Gy-60cobalt-treated rats indicated that the decreased survival rate (P < 0.001 to P < 0.0001, compared to infected-untreated or infected-unirradiated animals) was associated with a decrease of both macrophage toxoplasmastatic activity and intracellular killing (P < 0.05 each group), compared to infected-untreated or infected-unirradiated rats. However in 9 Gy-60cobalt-treated animals the decreased survival rate (P < 0.001, compared with control rats) was accompanied only by a decrease of the toxoplasmastatic activity in comparison to macrophages of the control animals. Moreover in these animals, the release of NO2- by these macrophages was poorly detectable (P < 0.05) or completely inhibited (P < 0.01) in comparison with infected-untreated or infected-unirradiated rats. In contrast, in all groups of rats treated with high doses of beta adrenergic, the decreased survival (P < 0.001 to P < 0.0001, compared with untreated rats) was accompanied by values of intracellular killing and intracellular proliferation of Toxoplasma parasites that did not significantly (P = ns each group) differ from macrophages of infected-untreated rats. Furthermore in the high beta adrenergic treated groups only small amounts of NO2- were detectable (P < 0.05) in comparison with control animals. In addition, our data in rats treated with 0.7 or 1.2 mg/kg of corticosteroid or 12 Gy of 60cobalt indicated that the increased mortality was correlated to the presence of a small number of cysts in their brains (P < 0.05; P = ns; P < 0.01 respectively) in comparison to infected-untreated or infected-unirradiated rats. These results suggest that the susceptibility of drug-immunosuppressed rats is not due exclusively to a deficient macrophage function, but is probably also linked to immune mechanisms involved in the process of cystogenesis.

Adrenergic beta-Antagonists↗

Psychometric tests for assessment of brain function after solvent exposure.

Psychometric testing is a key issue in neuropsychological toxicology assessment. Evaluation of methods for assessing general intellectual impairment is necessary as conventional neurology has been shown to be insensitive to the neurotoxic effects of solvents and metals. This study presents an analysis of a psychometric test battery from an investigation of psycho-organic syndrome in a historical cohort of 96 metal degreasers with long-term exposure to solvents, particularly trichloroethylene. The neuropsychological test battery was a combination of Wechsler Adult Intelligence Scale (WAIS), Luria, and tests developed in Scandinavia. Linear regression analysis showed a significant dose-response relation between increasing cumulative solvent exposure and impaired psychometric test performance in 9 out of 15 tests. Multivariate analysis, however, suggests that much of the variance was due to confounding variables, especially age, and to a lesser degree, primary intellectual function and word blindness. After control for confounding factors the strongest association with solvent exposure occurred for the following three tests: acoustic-motor function, Paced Auditory Serial Addition Test (PASAT), and the visual gestalt test.

Brain Diseases↗

Cognitive performance during a simulated climb of Mount Everest: implications for brain function and central adaptive processes under chronic hypoxic stress.

High altitude is characterized by hypoxic environmental conditions and is well known to induce both physiological and psychological disturbances. In the present study, called ”Everest-Comex 97”, the authors investigated the effects of high altitude on the psychosensorimotor and reasoning processes of eight climbers participating in a simulated climb from sea level to 8,848 m over a 31-day period of confinement in a decompression chamber. Tests of visual reaction time, psychomotor ability, and number ordination were used. The climbers’ data were compared with data from a similar laboratory study at sea level in control subjects. Continued testing of the control subjects at sea level clearly led to learning effects and improvement of performance in psychomotor ability and number ordination. In the climbers, similar learning effects occurred up to an altitude of 5,500–6,500 m. With further increases in altitude, the climbers’ psychomotor performance and mental efficiency deteriorated progressively, leading to significant differences in psychomotor ability and mental efficiency between control subjects and climbers (9 and 13% respectively at 8,000 m and 17.5 and 16.5% respectively at 8,848 m). Three days (72 h) after the climbers had returned to sea level, their mental and psychomotor performances were still significantly lower than those of control subjects (by approximately 10%). In contrast, visual reaction time showed no significant changes in either climbers or control subjects. It is suggested that chronic hypoxic stress could alter selectively mental learning processes, i.e. explicit, rather than implicit (stimulus-response learning processes) memory and cortico-limbic rather than basal ganglia-sensorimotor system function.

Adaptation, Physiological↗

Calcitonin binding site distribution in the cat central nervous system: a wider insight of the peptide involvement in brain functions.

Calcitonin (CT) binding site distribution has been studied in the cat CNS. The autoradiographic analyses of [125I]-eelCT (ECT) binding showed high density of silver grains in the mesencephalic PAG, in the raphe nuclei and in the dorsal horns, laminae I, IV, V, and VI, where ECT may act to inhibit nociceptive transmission. Other binding-rich areas included the caudatus, the amygdala, the hypothalamus, the substantia nigra, the locus coeruleus and the formatio reticularis mesencephalica. Medium to low density was seen, amongst other areas in the cortex piriformis, the hippocampus, the medial and intralaminar thalamus and the tractus spino-thalamicus. ECT binding site distribution revealed essentially homologous locations in the cat and rat CNS. At difference, the presence of binding in the piriform cortex and in discrete thalamic nuclei suggests a widespread involvement of ECT in a variety of central functions in addition to what already demonstrated.

Animals↗

Thyroid hormones, brain function and cognition: a brief review.

In addition to their role in cellular metabolic activity, thyroid hormones (THs), also regulate neural development; the central nervous system is particularly dependent on TH for normal maturation and function. Specifically, there appears to be extensive inter-reliance between TH and acetylcholine (Ach), nerve growth factor and hippocampal function. These associations led us to investigate the possible effects of thyroxine (L-T4) on performance of a spatial learning task, where cholinergic activity and hippocampal function are known to be important. Groups of rats (n=20) received saline (controls) or L-T4 at 2.5 or 5mg/kg daily for 4 days as a sub-chronic treatment, or 0, 5 or 10mg/kg doses administered every third day for 28 days prior to testing as a chronic regimen. Rats were assessed in a water maze for their ability to find a submerged or visible platform. Forty minutes prior to water maze testing, half the animals in each group received 1mg/kg scopolamine to elicit a cognitive deficit. Following testing, rats were decapitated, blood samples taken, and the frontal cortex and hippocampus were dissected out for acetylcholinesterase (AChE) assay. The results showed that L-T4 treatment, administered both sub-chronically and chronically, significantly enhanced the ability of rats to learn a spatial memory task, compared with controls. Moreover, both short-term and long-term L-T4 treatment reduced the cognitive-impairing effects of scopolamine. Improvements in performance were shown to occur alongside significantly increased cholinergic activity in frontal cortex and in the hippocampus of treated animals. These findings demonstrate an augmentative effect of L-T4 upon cognitive function, possibly mediated by an enhancement of cholinergic activity. The results support previous findings of a relationship between L-T4 and acetylcholine, and underscore possible mechanisms by which disorders of thyroid function may be associated with cognitive decline.

Animals↗

Prolonged muscular flaccidity after stroke. Morphological and functional brain alterations.

Patients with a motor deficit due to ischaemic stroke usually develop muscular spasticity, but in some cases they may remain with a prolonged muscular flaccidity which impairs their recovery. Little is known about the causes of these two different functional outcomes. We correlated CT/MRI and 99mTc HM-PAO SPECT with clinical findings in 42 patients at a mean time interval of 3 months after stroke. The patients were divided into two cohorts with either flaccid (prolonged muscular flaccidity) or spastic (muscular spasticity) hemiparesis. Although patients with prolonged muscular flaccidity had a greater motor deficit, the mean structural volume of the ischaemic lesion was similar to that of the muscular spasticity cohort. There was a significantly higher prevalence of structural involvement of the lentiform nucleus in prolonged muscular flaccidity cases. Relative perfusion in the lentiform nucleus, thalamus and contralateral cerebellar hemisphere was significantly lower in prolonged muscular flaccidity than in muscular spasticity patients. A subgroup with only subcortical structural lesions also showed significantly lower relative perfusion in the ipsilateral frontal association areas. A primary involvement of the lentiform nucleus by the structural lesion seems to be crucial for the persistence of flaccidity after stroke. However, cerebral blood flow (CBF) changes in other structurally intact regions indicate their additional role. It is likely that both subcortical-cortical loops involved in motor control, i.e. cortex-basal ganglia-thalamus-cortex and cortex-pons-cerebellum-thalamus-cortex, are more widely and more severely affected in patients with prolonged muscular flaccidity.

Adult↗

Motor disturbance and brain functional imaging in Parkinson's disease.

18F-Dopa positron emission tomography (PET) provides a sensitive means of quantitating the loss of nigrostriatal dopaminergic fibres in Parkinson's disease and so can be used to diagnose its presence and to objectively follow the rate of disease progression. It can also be used, in principle, to determine the efficacy of putative neuroprotective agents and has already been extensively used to monitor the viability of striatal transplants of fetal mesencephalic tissue. Loss of dopaminergic projections produces significant changes in the patterns of both resting and activated cortical function. H2(15)O PET activation studies have suggested that the akinesia of Parkinson's disease is associated with failure to activate the supplementary motor and dorsal prefrontal areas, brain regions particularly involved in motor preparation and decision making. Activation of these cortical areas can be restored by administering dopaminergic medication, implanting the striatum with fetal mesencephalic tissue, and by pallidotomy. This article reviews the insight that PET studies have provided into the pathophysiology of Parkinson's disease.

Brain↗