Aberrant corticospinal tract characteristics in prodromal PD: A diffusion tensor imaging study.

Introduction: Parkinson's disease (PD) is typically diagnosed when motor symptoms first occur. However, PD-related non-motor symptoms may appear several years before diagnosis. REM sleep behaviour disorder (RBD) and olfactory deficits (hyposmia) are risk factors, but they are not specific for predicting progression towards PD. Other PD-related markers, for example brain imaging markers, may help to identify preclinical PD in hyposmic RBD patients. Studies have reported abnormal structural characteristics in the corticospinal tract (CST) of PD patients, but it is unclear whether hyposmic RBD patients have similar abnormalities that may help to predict PD in these individuals. This study examined whether CST abnormalities may be a potential marker of PD risk by using diffusion tensor imaging (DTI) measures. Methods: Twenty hyposmic RBD patients, 31 PD patients, and 29 healthy controls (HCs) were studied. DTI data were collected on a 1.5 T MRI scanner and CST characteristics (FA, MD, AD, and RD) were evaluated using probabilistic tractography (with seed regions in the bilateral primary motor cortex and mediolateral cerebral peduncles). Olfactory function was assessed with the University of Pennsylvania Smell Identification Test (UPSIT). Results: Hyposmic RBD patients showed significantly higher mean diffusivity (MD) values of the right CST compared to HCs but did not differ from PD patients. PD patients showed a trend of higher MD values compared to HCs. Conclusions: Altered diffusivity in the CST seems to be associated with RBD. The combination of RBD, hyposmia, and CST alterations may be related to later development of PD with comorbid RBD.

Olfactory Function and Diffusion Tensor Imaging as Markers of Mild Cognitive Impairment in Early Stages of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder that is typified by motor signs and symptoms but can also lead to significant cognitive impairment and dementia Parkinson's Disease Dementia (PDD). While dementia is considered a nonmotor feature of PD that typically occurs later, individuals with PD may experience mild cognitive impairment (PD-MCI) earlier in the disease course. Olfactory deficit (OD) is considered another nonmotor symptom of PD and often presents even before the motor signs and diagnosis of PD. We examined potential links among cognitive impairment, olfactory functioning, and white matter integrity of olfactory brain regions in persons with early-stage PD. Cognitive tests were used to establish groups with PD-MCI and with normal cognition (PD-NC). Olfactory functioning was examined using the University of Pennsylvania Smell Identification Test (UPSIT) while the white matter integrity of the anterior olfactory structures (AOS) was examined using magnetic resonance imaging (MRI) diffusion tensor imaging (DTI) analysis. Those with PD-MCI demonstrated poorer olfactory functioning and abnormalities based on all DTI parameters in the AOS, relative to PD-NC individuals. OD and microstructural changes in the AOS of individuals with PD may serve as additional biological markers of PD-MCI.

Lateralized microstructural changes in early-stage Parkinson's disease in anterior olfactory structures, but not in substantia nigra.

Parkinson's disease (PD) is a progressive neurological disorder characterized by motor symptoms as well as severe deficits in olfactory function and microstructural changes in olfactory brain regions. Because of the evidence of asymmetric neuropathological features in early-stage PD, we examined whether lateralized microstructural changes occur in olfactory brain regions and the substantia nigra in a group of early-stage PD patients. Using diffusion tensor imaging (DTI) and the University of Pennsylvania Smell Identification Test (UPSIT), we assessed 24 early-stage PD patients (Hoehn and Yahr stage 1 or 2) and 26 healthy controls (HC). We used DTI and a region of interest (ROI) approach to study the microstructure of the left and right anterior olfactory structures (AOS; comprising the olfactory bulbs and anterior end of the olfactory tracts) and the substantia nigra (SN). PD patients had reduced UPSIT scores relative to HC and showed increased mean diffusivity (MD) in the SN, with no lateralized differences. Significant group differences in fractional anisotropy (FA) and MD were seen in the AOS, but these differences were restricted to the right side and were not associated with the primary side of motor symptoms amongst PD patients. No associations were observed between lateralized motor impairment and lateralized microstructural changes in AOS. Impaired olfaction and microstructural changes in AOS are useful for early identification of PD but asymmetries in AOS microstructure seem unrelated to the laterality of PD motor symptoms.

Diffusion tensor imaging and olfactory identification testing in early-stage Parkinson's disease.

Evidence from imaging, clinical studies, and pathology suggests that Parkinson's disease is preceded by a prodromal stage that predates clinical diagnosis by several years but there is no established method for detecting this stage. Olfactory impairment, which is common in Parkinson's disease and often predates clinical diagnosis, may be a useful biomarker for early Parkinson's. Evidence is emerging that diffusion imaging parameters might be altered in olfactory tract and substantia nigra in the early stages of clinical Parkinson's disease, possibly reflecting pathological changes. However, no study has examined olfaction and diffusion imaging in olfactory tract and substantia nigra in the same group of patients. The present study compared newly diagnosed Parkinson's disease patients with a matched control group using both olfactory testing and diffusion tensor imaging of the substantia nigra and anterior olfactory structures. Fourteen patients with stage 1-2 Hoehn & Yahr Parkinson's disease were matched to a control group by age and sex. All subjects then completed the University of Pennsylvania Smell Identification Test, as well as a series of MRI scans designed to examine diffusion characteristics of the olfactory tract and the substantia nigra. Olfactory testing revealed significant impairment in the patient group. Diffusion tensor imaging revealed significant group differences in both the substantia nigra and anterior olfactory region, with fractional anisotropy of the olfactory region clearly distinguishing the Parkinson's subjects from controls. This study suggests that there may be value in combining behavioral (olfaction) and MRI testing to identify early Parkinson's disease. Since loss of olfaction often precedes the motor symptoms in Parkinson's disease, the important question raised is "will the combination of olfactory testing and MRI (DTI) testing identify pre-motor Parkinson's disease?"

Mechanisms of dressing apraxia: a case study.

OBJECTIVE: To investigate the neural mechanisms that differentiate dressing apraxia from other forms of apraxia such as ideomotor apraxia. Hypotheses examined included (1) that dressing is more sensitive to alternations in body schema, (2) that dressing is a demanding bimanual task, and (3) that clothing represents a particularly complex spatial problem. BACKGROUND: A focal degenerative condition can specifically target a function such as dressing, allowing a unique approach to its study. METHOD: A case study of the cognitive impairments of a 75-year-old man who presented with progressive dressing difficulties in the absence of neglect or motor disturbances. RESULTS: Neuropsychologic testing indicated possible executive function deficits as well as visuospatial and visuocontructional deficits, but intact praxic skills, verbal abilities, and visual recognition skills. In addition, testing revealed no evidence of Balint's or impairments in body schema. CONCLUSION: Overall, the test results suggested that visuospatial dysfunction is the underlying deficit in dressing apraxia. The present case study confirmed the independence of praxic functioning from spatial ability and conversely, the dependence of dressing on spatial ability.

Hymenolepis diminuta: catalysis of transmembrane proton translocation by mitochondrial NADPH-->NAD transhydrogenase.

The mitochondrial, inner-membrane-associated, reversible NADPH-->NAD transhydrogenase of adult Hymenolepis diminuta physiologically couples matrix-localized, NADP-specific "malic" enzyme with NADH-dependent anaerobic electron transport. Employing submitochondrial particles (SMP) as the source of enzyme activity and both spectrophotometric and fluorometric assessments, the present study made evident that in its catalysis of transhydrogenation between NADPH and NAD, the cestode enzyme engages in the concomitant transmembrane translocation of protons. As assessed spectrophotometrically, the catalysis of NADPH-dependent NAD reduction by H. diminuta SMP was stimulated significantly by carbonyl cyanide 3-chlorophenylhydrazone (CCCP), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), as well as by the protonophoric anthelmintic, niclosamide. In addition, N,N'-dicyclohexylcarbodiimide (DCCD) markedly diminished SMP-catalyzed hydride ion transfer between NADPH and NAD. The catalysis by SMP of concomitant, transhydrogenase-mediated proton translocation was evaluated more directly via fluorometric assays using 8-anilino-1-napthalenesulfonic acid (ANS) as the probe. These latter evaluations revealed a transhydrogenase-dependent enhancement of ANS fluorescence in accord with an intravesicular accumulation of protons. ANS fluorescence was quenched rapidly when the assay system was supplemented with CCCP, FCCP, or niclosamide. Consistent with the helminth transhydrogenase acting as a proton pump, transhydrogenase-mediated enhanced fluorescence also was inhibited by DCCD. Considered collectively, these data indicated, apparently for the first time for any invertebrate system, that the transhydrogenase, in catalyzing the NADPH-->NAD reaction, acts in the translocation of protons from the matrix to the intermembrane space mitochondrial compartment.

Right-hemisphere dysfunction in Asperger's syndrome.

Asperger's syndrome has many clinical features in common with acquired right-hemisphere dysfunction and has been postulated to result from a developmental abnormality of the right hemisphere. However, right-hemisphere abnormality has not previously been documented on neuroanatomic or functional imaging in patients with Asperger's syndrome. We report three patients with Asperger's syndrome found to have abnormal right-hemisphere function on single photon emission computed tomographic (SPECT) imaging. The subjects were two males and one female, ranging from 12 to 16 years of age. All were diagnosed on the basis of the presence of the complete constellation of clinical features previously outlined. All patients were investigated with computed tomographic (CT) scanning, magnetic resonance imaging (MRI), and SPECT scanning. In one subject, CT and MRI revealed enlargement of the right lateral ventricle, reflecting a mild degree of right hemispheric atrophy. CT and MRI studies on the other two subjects were normal. SPECT scanning demonstrated right hemispheric abnormalities in each subject: right temporal hypoperfusion with a central area of increased perfusion along with frontal polar hyperperfusion in one; diffusely decreased right hemispheric uptake in the second; and decreased frontal and occipital uptake in the third. Cerebellar abnormalities were also present: a smaller right hemisphere with increased uptake in the first; decreased uptake in the vermis and right hemisphere in the second; and decreased vermal uptake in the third. These findings support the hypothesis that the neurobiologic basis of Asperger's syndrome is a developmental abnormality of the right cerebral hemisphere.

Situation specificity in attention-seeking problem behavior. A case study.

Previous research on attention-seeking problem behavior has focused on individuals who misbehaved under general conditions of low adult attention. In general, no detailed analyses were conducted to determine whether different situations involving low levels of adult attention (such as familiar vs. unfamiliar adults, setting events, or the presence or absence of peers) exacerbated or attenuated problem behavior. The current case study demonstrates that, for one adolescent, all situations involving low levels of adult attention were not equally discriminative for problem behavior. Two functional analyses concerning different situations involving low levels of adult attention were conducted. The first analysis consisted of systematically manipulating antecedent and consequence conditions related to adult attention and task demands. This analysis indicated that low levels of adult attention evoked problem behavior. The second analysis involved two different conditions presenting low levels of adult attention. In one, the adult spoke to another child; in the second, the adult spoke to another adult. This second analysis revealed that, when the adult spoke to another adult, problem behavior resulted. However, when the adult spoke to another child, problem behavior did not occur. On the basis of these functional analyses, a positive intervention was designed to reduce problem behavior. Theoretical implications related to functional analysis are discussed, and applied issues concerning functionally based treatment selection are explored.

Reliability and validity of the Diabetes Family Behavior Scale (DFBS).

The Diabetes Family Behavior Scale (DFBS) was designed to measure diabetes-specific family support. The purposes of this study were to refine the scale and to assess reliability and criterion validity in terms of relationship to metabolic control. The DFBS was administered to 321 children and adolescents with insulin-dependent diabetes mellitus (IDDM). Blood was drawn for determination of glycosylated hemoglobin (HbA1c). Based on an item-analysis procedure, the DFBS was revised to include 47 items with two subscales, one to reflect guidance-control and one to reflect warmth-caring. Acceptable internal consistency was found for the DFBS total score (.86), and for the guidance-control (.81) and warmth-caring (.79) subscales. There was a statistically significant relationship in the expected direction between DFBS total score and HbA1c (r = -.12, P < .03), and between the guidance-control subscale and HbA1c (r = -.17, P < .002).

Energy-linked mitochondrial pyridine nucleotide transhydrogenase of adult Hymenolepis diminuta.

Employing "phosphorylating" submitochondrial particles as the source of pyridine nucleotide transhydrogenase, the occurrence of an energy-linked NADH----NADP+ transhydrogenation in the adult cestode Hymenolepis diminuta was demonstrated. The isolated particles displayed rotenone-sensitive NADH utilization and the reversible transhydrogenase, with the NADPH----NAD+ transhydrogenation being more prominent. Although not inhibiting the NADPH----NAD+ reaction, rotenone, but not oligomycin, inhibited the catalysis of NADH----NADP+ transhydrogenation. In the presence of rotenone, Mg2+ plus ATP stimulated by more than 3-fold NADH----NADP+ transhydrogenation. This stimulation was ATP specific and was abolished by EDTA or oligomycin. Succinate was essentially without effect on the NADH----NADP+ reaction. These data demonstrate the occurrence of an energy-linked transhydrogenation between NADH and NADP+ with energization resulting from either electron transport-dependent NADH oxidation or ATP utilization via the phosphorylating mechanism in accord with the preparation of "phosphorylating" particles. This is the first demonstration of an energy-linked transhydrogenation in the parasitic helminths and apparently in the invertebrates generally.

Family development and the use of diabetes groups: experience with a model approach.

Health professionals commonly recognize the need to educate the child or adolescent with diabetes in developmentally appropriate ways and to include the family in this process. Identification of family life cycle stages and tasks is useful in developing continued opportunities for support and education of these families. A variety of group experiences were used to promote family development in the following stages: child-bearing; preschool; school-age; and teenage. Recommendations are made for implementing groups to provide support and education for the family of a child or adolescent with diabetes.

GABA transport in Saccharomyces cerevisiae.

Gamma-aminobutyrate (GABA) accumulation in growing cultures of Saccharomyces cerevisiae was shown to occur by means of an active transport system that is inhibited by proton ionophores, azide, fluoride and arsenate ions. Transport occurred maximally at pH 5.0 and exhibited apparent Km values of 12 microM and 0.1 mM. Accumulated GABA did not efflux upon treatment with proton ionophores and exchanged with extracellular material only very slowly. However, release was complete upon treatment with nystatin. These observations raise the possibility that a major portion of intracellular GABA is sequestered in the vacuole. The response of GABA uptake to growth on various nitrogen sources suggested that uptake may be subject to several types of regulation.

Biochemical and morphological studies on the percutaneous uptake of [14C] ethylenediamine in the rat.

Male Wistar rats were exposed to aqueous [14C]ethylenediamine (EDA) solutions (10, 25, or 50%) percutaneously over a 7 x 7 cm area on the back with occlusion for 24 h. For each rat dosed, three types of studies were conducted: (1) plasma kinetics, (2) material balance, and (3) histological evaluation, including autoradiography of the skin sample from the dosing area. Adequate kinetic measurements were obtained only from animals treated with 25 and 50% EDA, but not from the 10% treatment group, due to analytical limitations. The uptake of [14C]EDA percutaneously by the rat was relatively slow in comparison with uptake following peroral or endotracheal administration. The absorption of EDA by the animals was estimated to be greater than 61, 55, and 12%, respectively, for the 50, 25, and 10% treatment groups. A large portion (11-32%) of the dose was left on/in the dosing area. Urinary excretion was the predominant route for the disposition of EDA. The recovery of the administered dose was low (70-83%), possibly due to volatilization of EDA from the skin during dosing and holding. Histologic examination of skin sections (dosing areas) revealed a normal, intact epidermis in rats dosed with 10% EDA, but full-thickness epidermal necrosis in rats dosed with 25% or 50% EDA solutions. The damage of the epidermis apparently enhanced the penetration of EDA. Autoradiographic preparations revealed a concentration of the [14C]EDA radiolabel over the keratin layer and hair shafts.

Localization of cytochrome C oxidase and cytochrome C peroxidase in mitochondria of Hymenolepis diminuta (Cestoda).

The intramitochondrial localization of cytochrome c oxidase and cytochrome c peroxidase in adult Hymenolepis diminuta was investigated. Mitochondria were fractionated into inner membrane, outer membrane, intermembrane space and matrix and the efficacy of fractionation was monitored employing marker enzymes. Cytochrome c oxidase was associated with the mitochondrial inner membrane. Whereas 55% of the cytochrome c peroxidase activity was in the matrix, 32% of the activity was in the intermembrane space fraction. Based upon the distribution of marker enzymes, a dual compartmentalization of cytochrome c peroxidase is apparent in H. diminuta mitochondria.

The effects of ethylene oxide (EO) exposure on tissue glutathione levels in rats and mice.

Male Fischer 344 rats and male Swiss-Webster mice were exposed to different atmospheric concentrations of ethylene oxide (EO) for 4 hours. In mice sacrificed immediately after exposure to 100, 450 or 900 ppm EO, there was a concentration related decrease in the GSH levels of all tissues examined. Similar findings were obtained in rats immediately after exposure to 100, 600 or 1200 ppm EO except that blood GSH levels were not affected at any exposure concentration. In both species, lung and liver GSH levels were depressed at all exposure concentrations. Twenty-four hours after exposure to 1200 ppm EO, the GSH concentrations of rat bone marrow and testis had not returned to control levels. Only blood GSH levels remained depressed in mice 48 hours after exposure to 900 ppm EO. The results indicate a marked species difference between rats and mice regarding the effects of EO exposure on blood GSH levels which may have important toxicological implications.

Intramitochondrial localization of fumarate reductase, NADPH----NAD transhydrogenase, 'malic' enzyme and fumarase in adult Hymenolepis diminuta.

The intramitochondrial localization of the fumarate reductase, NADPH----NAD transhydrogenase, 'malic' enzyme and fumarase was determined in adult Hymenolepis diminuta. The distribution of marker enzymes for the inner membrane, matrix, intermembrane space and outer membrane of H. diminuta mitochondria simulated that of the corresponding ascarid and mammalian organelles. The electron transport-coupled fumarate reductase and the NADPH----NAD transhydrogenase were components of the inner membrane whereas the 'malic' enzyme and fumarase were in the matrix soluble compartment. Assessments of NADH utilization, malate-dependent NADP reduction and NADPH----NAD transhydrogenation by presumedly intact and disrupted mitochondria supported the localization data. The findings presented indicate that in H. diminuta mitochondria (a) NADPH and fumarate are accumulated within the matrix compartment; (b) transhydrogenation between NADPH and NAD is an event associated with the matrix side of the inner membrane; and (c) electron transport-dependent NADH oxidation and fumarate reduction occur at sites on the matrix side of the inner membrane.

Age-dependent pharmacokinetic changes of ethylenediamine in Fischer 344 rats parallel to a two-year chronic toxicity study.

As part of a 2-year chronic toxicity study, the pharmacokinetics of ethylenediamine (EDA) was studied in Fischer 344 rats of both sexes at day zero (naive animals), 6 months (controls and high level animals), and 18 months (controls and high level animals). The rats, which were randomized along with the rest of the animals on the toxicity study, were taken for pharmacokinetic experiments at the specified time. A single per os (po) dose of 50 mg [14C]EDA X 2HCl/kg was given to each rat and the plasma kinetics was followed for a 24-hr period. Five pharmacokinetic parameters (absorption rate constant, terminal half-life, area under the curve, volume of distribution, and 14CO2 production rate constant) were compared with respect to age, sex, and chronic dosing. There were no apparent age-, sex-, and/or chronic dosing-related differences in absorption rate constant and terminal half-life. However, age-related changes in area under the curve (AUC) were evident. The older rats had higher values (generally two- to threefold) for AUC than the younger rats. This age-related difference in AUC is closely associated with the volumes of distribution (Vd) of the animals of varying ages. On the basis of liters per kilogram, the Vd's of the older rats are approximately one-fourth to one-half of those for the younger (zero day) rats. The 14CO2 production rate constant was derived from the rate of formation of 14CO2 as a result of [14C]EDA X 2HCl dosing. The comparison of this constant under the various experimental conditions suggests sex-related differences.(ABSTRACT TRUNCATED AT 250 WORDS)