Mitochondrial DNA G13708A variation and multiple sclerosis: Is there an association?

BACKGROUND: Multiple sclerosis (MS) is considered a pathogenetic enigma. Recently, efforts to implicate genetics in human susceptibility to MS have identified an important role of mitochondrial DNA (mtDNA). G13708A is a common mtDNA variation associated with MS in specific populations. This study tested the hypothesis that the mtDNA G13708A variation is associated with MS in an Iranian population. MATERIALS AND METHODS: Blood samples were collected from 100 MS patients and 100 unrelated healthy controls. DNA was extracted using a salting-out method, followed by polymerase chain reaction (PCR) amplification. For assessment of restriction fragment length polymorphism (RFLP), PCR products were restricted by restriction enzyme Mva I. Thereafter, the restriction products were assessed by means of an ultraviolet (UV) transilluminator following electrophoresis with 3% agarose gel. Accuracy of the genotyping procedure was assessed by direct sequencing. RESULTS: The mtDNA G13708A variation was found in 17 cases (17%) and 19 controls (19%) (P=0.7, OR: 0.8, 95% CI: 0.3-1.9). CONCLUSION: The findings of the present study fail to support the hypothesis that the G13708A mtDNA variation is associated with MS in the selected Iranian population.

Behavioural effects of high fat diet in a mutant mouse model for the schizophrenia risk gene neuregulin 1.

Schizophrenia patients are often obese or overweight and poor dietary choices appear to be a factor in this phenomenon. Poor diet has been found to have complex consequences for the mental state of patients. Thus, this study investigated whether an unhealthy diet [i.e. high fat diet (HFD)] impacts on the behaviour of a genetic mouse model for the schizophrenia risk gene neuregulin 1 (i.e. transmembrane domain Nrg1 mutant mice: Nrg1 HET). Female Nrg1 HET and wild-type-like littermates (WT) were fed with either HFD or a control chow diet. The mice were tested for baseline (e.g. anxiety) and schizophrenia-relevant behaviours after 7 weeks of diet exposure. HFD increased body weight and impaired glucose tolerance in all mice. Only Nrg1 females on HFD displayed a hyper-locomotive phenotype as locomotion-suppressive effects of HFD were only evident in WT mice. HFD also induced an anxiety-like response and increased freezing in the context and the cued version of the fear conditioning task. Importantly, CHOW-fed Nrg1 females displayed impaired social recognition memory, which was absent in HFD-fed mutants. Sensorimotor gating deficits of Nrg1 females were not affected by diet. In summary, HFD had complex effects on the behavioural phenotype of test mice and attenuated particular cognitive deficits of Nrg1 mutant females. This topic requires further investigations thereby also considering other dietary factors of relevance for schizophrenia as well as interactive effects of diet with medication and sex.

Delayed response task performance as a function of age in cynomolgus monkeys (Macaca fascicularis).

We compared delayed response task performance in young, middle-aged, and old cynomolgus monkeys using three memory tests that have been used with non-human primates. Eighteen cynomolgus monkeys--6 young (4-9 years), 6 middle-aged (10-19 years), and 6 old (above 20 years)--were tested. In general, the old monkeys scored significantly worse than did the animals in the two other age groups. Longer delays between stimulus presentation and response increased the performance differences between the old and younger monkeys. The old monkeys in particular showed signs of impaired visuo-spatial memory and deteriorated memory consolidation and executive functioning. These results add to the body of evidence supporting the utility of Macaca fascicularis in studies of cognition and as a potential translational model for age-associated memory impairment/dementia-related disorders.

Cortical plasticity after cochlear implantation.

The most dramatic progress in the restoration of hearing takes place in the first months after cochlear implantation. To map the brain activity underlying this process, we used positron emission tomography at three time points: within 14 days, three months, and six months after switch-on. Fifteen recently implanted adult implant recipients listened to running speech or speech-like noise in four sequential PET sessions at each milestone. CI listeners with postlingual hearing loss showed differential activation of left superior temporal gyrus during speech and speech-like stimuli, unlike CI listeners with prelingual hearing loss. Furthermore, Broca's area was activated as an effect of time, but only in CI listeners with postlingual hearing loss. The study demonstrates that adaptation to the cochlear implant is highly related to the history of hearing loss. Speech processing in patients whose hearing loss occurred after the acquisition of language involves brain areas associated with speech comprehension, which is not the case for patients whose hearing loss occurred before the acquisition of language. Finally, the findings confirm the key role of Broca's area in restoration of speech perception, but only in individuals in whom Broca's area has been active prior to the loss of hearing.

Dopaminergic and clinical correlates of pathological gambling in Parkinson's disease: a case report.

Dopaminergic medication for motor symptoms in Parkinson's disease (PD) recently has been linked with impulse control disorders, including pathological gambling (PG), which affects up to 8% of patients. PG often is considered a behavioral addiction associated with disinhibition, risky decision-making, and altered striatal dopaminergic neurotransmission. Using [(11)C]raclopride with positron emission tomography, we assessed dopaminergic neurotransmission during Iowa Gambling Task performance. Here we present data from a single patient with PD and concomitant PG. We noted a marked decrease in [(11)C]raclopride binding in the left ventral striatum upon gambling, indicating a gambling-induced dopamine release. The results imply that PG in PD is associated with a high dose of dopaminergic medication, pronounced motor symptomatology, young age at disease onset, high propensity for sensation seeking, and risky decision-making. Overall, the findings are consistent with the hypothesis of medication-related PG in PD and underscore the importance of taking clinical variables, such as age and personality, into account when patients with PD are medicated, to reduce the risk of PG.

Low dopamine D5 receptor density in hippocampus in an animal model of attention-deficit/hyperactivity disorder (ADHD).

A state of low dopaminergic activity has been implicated in attention-deficit/hyperactivity disorder (ADHD). The clinical symptoms of ADHD include inattention, impulsivity and hyperactivity, as well as impaired learning; dopaminergic modulation of the functions in the hippocampus is important to both learning and memory. To determine dopamine receptor (DR) density in a well-established animal model for ADHD, we quantified the dopamine D5 receptors in the hippocampus in the spontaneously hypertensive rat. We used immunofluorescence microscopy and immunogold electron microscopy to quantify the dopamine D5 receptor density on CA1 pyramidal cell somas and dendrites and dendritic spines in the stratum radiatum and stratum oriens. The density of the dopamine D5 receptors was significantly lower in the cytoplasm of pyramidal cell somas in the spontaneously hypertensive rat compared to the control, indicating a reduced reservoir for insertion of receptors into the plasma membrane. DRs are important for long-term potentiation and long-term depression, hence the deficit may contribute to the learning difficulties in individuals with the diagnosis of ADHD.

Correlations between serum levels of beta amyloid, cerebrospinal levels of tau and phospho tau, and delayed response tasks in young and aged cynomolgus monkeys (Macaca fascicularis).

BACKGROUND: In an attempt to explore cynomolgus monkeys as an animal model for Alzheimer's disease, the present study focused on the Alzheimer's biomarkers beta amyloid 1-42 (Aß42 ) in serum, and total tau (t-tau) and phosphorylated tau (p-tau) levels in cerebrospinal fluid. METHODS: We measured biomarker levels in Young and Aged cynomolgus monkeys and correlated these with performance on three delayed response tasks. RESULTS: The Aß42 concentration of the Aged monkeys was significantly lower than in the Young subjects, while the t-tau and p-tau did not significantly differ between the groups. The Young subjects performed significantly better than the Aged individuals on the memory tests. Only Aß42 levels were significantly correlated with performance in the three delayed response tasks. CONCLUSIONS: Circulating Aß42 levels were lower in Aged monkeys and were correlated with inferior performance on delayed response tasks in Aged animals; therefore, both measures may be useful in establishing cynomolgus monkeys as models for studies of AD.

Exenatide alters myocardial glucose transport and uptake depending on insulin resistance and increases myocardial blood flow in patients with type 2 diabetes.

CONTEXT: Glucagon-like peptide-1 (GLP-1) and GLP-1 receptor agonists provide beneficial cardiovascular effects by protecting against ischemia and reperfusion injury. Type 2 diabetes mellitus patients have reduced glycolysis in the heart. OBJECTIVE: We hypothesized that cardioprotection by GLP-1 is achieved through increased glucose availability and utilization and aimed to assess the effect of exenatide, a synthetic GLP-1 receptor agonist, on myocardial glucose uptake (MGU), myocardial glucose transport, and myocardial blood flow (MBF). DESIGN AND METHODS: We conducted a randomized, double-blinded, placebo-controlled crossover study in eight male, insulin-naive, type 2 diabetes mellitus patients without coronary artery disease. Positron emission tomography was used to determine the effect of exenatide on MGU and MBF during a pituitary-pancreatic hyperglycemic clamp with (18)F-fluorodeoxyglucose and (13)N-ammonia as tracers. RESULTS: Overall, exenatide did not alter MGU. However, regression analysis revealed that exenatide altered initial clearance of glucose over the membrane of cardiomyocytes and MGU, depending on the level of insulin resistance (P = 0.017 and 0.010, respectively). Exenatide increased MBF from 0.73 ± 0.094 to 0.85 ± 0.091 ml/g · min (P = 0.0056). Except for an increase in C-peptide levels, no differences in circulating hormones or metabolites were found. CONCLUSIONS: The action of exenatide as an activator or inhibitor of the glucose transport and glucose uptake in cardiomyocytes is dependent on baseline activity of glucose transport and insulin resistance. Exenatide increases MBF without changing MGU.

Dopamine release in ventral striatum of pathological gamblers losing money.

OBJECTIVE: To investigate dopaminergic neurotransmission in relation to monetary reward and punishment in pathological gambling. Pathological gamblers (PG) often continue gambling despite losses, known as 'chasing one's losses'. We therefore hypothesized that losing money would be associated with increased dopamine release in the ventral striatum of PG compared with healthy controls (HC). METHOD: We used Positron Emission Tomography (PET) with [(11)C]raclopride to measure dopamine release in the ventral striatum of 16 PG and 15 HC playing the Iowa Gambling Task (IGT). RESULTS: PG who lost money had significantly increased dopamine release in the left ventral striatum compared with HC. PG and HC who won money did not differ in dopamine release. CONCLUSION: Our findings suggest a dopaminergic basis of monetary losses in pathological gambling, which might explain loss-chasing behavior. The findings may have implications for the understanding of dopamine dysfunctions and impaired decision-making in pathological gambling and substance-related addictions.

Reduced muscle activation during exercise related to brain oxygenation and metabolism in humans.

Maximal exercise may be limited by central fatigue defined as an inability of the central nervous system to fully recruit the involved muscles. This study evaluated whether a reduction in the cerebral oxygen-to-carbohydrate index (OCI) and in the cerebral mitochondrial oxygen tension relate to the ability to generate a maximal voluntary contraction and to the transcranial magnetic stimulated force generation. To determine the role of a reduced OCI and in central fatigue, 16 males performed low intensity, maximal intensity and hypoxic cycling exercise. Exercise fatigue was evaluated by ratings of perceived exertion (RPE), arm maximal voluntary force (MVC), and voluntary activation of elbow flexor muscles assessed with transcranial magnetic stimulation. Low intensity exercise did not produce any indication of central fatigue or marked cerebral metabolic deviations. Exercise in hypoxia (0.10) reduced cerebral oxygen delivery 25% and decreased 11+/-4 mmHg (P<0.001) together with OCI (6.2+/-0.7 to 4.8+/-0.5, P<0.001). RPE increased while MVC and voluntary activation were reduced (P<0.05). During maximal exercise declined 8+/-4 mmHg (P<0.05) and OCI to 3.8+/-0.5 (P<0.001). RPE was 18.5, and MVC and voluntary activation were reduced (P<0.05). We observed no signs of muscular fatigue in the elbow flexors and all control MVCs were similar to resting values. Exhaustive exercise provoked cerebral deoxygenation, metabolic changes and indices of fatigue similar to those observed during exercise in hypoxia indicating that reduced cerebral oxygenation may play a role in the development of central fatigue and may be an exercise capacity limiting factor.

Cerebral oxygenation is reduced during hyperthermic exercise in humans.

AIM: Cerebral mitochondrial oxygen tension (P(mito)O(2)) is elevated during moderate exercise, while it is reduced when exercise becomes strenuous, reflecting an elevated cerebral metabolic rate for oxygen (CMRO(2)) combined with hyperventilation-induced attenuation of cerebral blood flow (CBF). Heat stress challenges exercise capacity as expressed by increased rating of perceived exertion (RPE). METHODS: This study evaluated the effect of heat stress during exercise on P(mito)O(2) calculated based on a Kety-Schmidt-determined CBF and the arterial-to-jugular venous oxygen differences in eight males [27 +/- 6 years (mean +/- SD) and maximal oxygen uptake (VO(2max)) 63 +/- 6 mL kg(-1) min(-1)]. RESULTS: The CBF, CMRO(2) and P(mito)O(2) remained stable during 1 h of moderate cycling (170 +/- 11 W, approximately 50% of VO(2max), RPE 9-12) in normothermia (core temperature of 37.8 +/- 0.4 degrees C). In contrast, when hyperthermia was provoked by dressing the subjects in watertight clothing during exercise (core temperature 39.5 +/- 0.2 degrees C), P(mito)O(2) declined by 4.8 +/- 3.8 mmHg (P < 0.05 compared to normothermia) because CMRO(2) increased by 8 +/- 7% at the same time as CBF was reduced by 15 +/- 13% (P < 0.05). During exercise with heat stress, RPE increased to 19 (19-20; P < 0.05); the RPE correlated inversely with P(mito)O(2) (r(2) = 0.42, P < 0.05). CONCLUSION: These data indicate that strenuous exercise in the heat lowers cerebral P(mito)O(2), and that exercise capacity in this condition may be dependent on maintained cerebral oxygenation.

Regional cerebral glucose metabolism during sevoflurane anaesthesia in healthy subjects studied with positron emission tomography.

BACKGROUND: The precise mechanism by which sevoflurane exerts its effects in the human brain remains unknown. In the present study, we quantified the effects of sevoflurane on regional cerebral glucose metabolism (rGMR) in the human brain measured with positron emission tomography. METHODS: Eight volunteers underwent two dynamic 18F-fluorodeoxyglucose positron emission tomography (PET) scans. One scan assessed conscious-baseline metabolism and the other scan assessed metabolism during 1 minimum alveolar concentration (MAC) sevoflurane anaesthesia. Cardiovascular and respiratory parameters were monitored and bispectral index responses were registered. Statistical parametric maps and conventional regions of interest analysis were used to determine rGMR differences. RESULTS: All subjects were unconsciousness at 1.0 MAC sevoflurane. Cardiovascular and respiratory parameters were constant over time. In the awake state, rGMR ranged from 0.24 to 0.35 mumol/g/min in the selected regions. Compared with the conscious state, total GMR decreased 56% in sevoflurane anaesthesia. In white and grey matter, GMR was averaged 42% and 58% of normal, respectively. Sevoflurane reduced the absolute rGMR in all selected areas by 48-71% of the baseline (P< or = 0.01), with the most significant reductions in the lingual gyrus (71%), occipital lobe in general (68%) and thalamus (63%). No increases in rGMR were observed. CONCLUSIONS: Sevoflurane caused a global whole-brain metabolic reduction of GMR in all regions of the human brain, with the most marked metabolic suppression in the lingual gyrus, thalamus and occipital lobe.

A deformation-based morphometry study of patients with early-stage Parkinson's disease.

BACKGROUND AND PURPOSE: Previous volumetric magnetic resonance imaging (MRI) studies of Parkinson's disease (PD) utilized primarily voxel-based morphometry (VBM), and investigated mostly patients with moderate- to late-stage disease. We now use deformation-based morphometry (DBM), a method purported to be more sensitive than VBM, to test for atrophy in patients with early-stage PD. METHODS: T1-weighted MRI images from 24 early-stage PD patients and 26 age-matched normal control subjects were compared using DBM. Two separate studies were conducted, where two minimally-biased nonlinear intensity-average were created; one for all subjects and another for just the PD patients. The DBM technique creates an average population-based MRI-average in an iterative hierarchical fashion. The nonlinear transformations estimated to match each subject to the MRI-average were then analysed. RESULTS: The DBM comparison between patients and controls revealed significant contraction in the left cerebellum, and non-significant trends towards frontal, temporal and cingulate sulcal expansions with frontal and temporal white matter contractions. Within the patient group, the unified PD rating scores were highly correlated with local expansions in or near sulci bordering on frontal and temporal cortex. CONCLUSION: Our results suggest that DBM could be a sensitive method for detecting morphological changes in early-stage PD.

Improvement of brain tissue oxygenation by inhalation of carbogen.

Hyperoxic therapy for cerebral ischemia is suspected to reduce cerebral blood flow (CBF), due to the vasoconstrictive effect of oxygen on cerebral arterioles. We hypothesized that vasodilation predominates when 5% CO(2) is added to the inhaled oxygen (carbogen). Therefore, we used positron emission tomography (PET) to measure CBF and cerebral metabolic rate of oxygen (CMRO(2)) during inhalation of test gases (O(2), CO(2), carbogen and atmospheric air) in 10 healthy volunteers. Arterial blood gases were recorded during administration of each gas. The data were analyzed with volume-of-interest and voxel-based statistical methods. Inhalation of CO(2) or carbogen significantly increased global CBF, whereas pure oxygen decreased global CBF. The CMRO(2) generally remained unchanged, except in white matter during oxygen inhalation relative to condition of atmospheric air inhalation. The volume-of-interest results were confirmed by statistical cluster analysis. Oxygen and carbogen were equally potent in increasing oxygen saturation of arterial blood (Sa(O2)). The present data demonstrate that inhalation of carbogen increases both CBF and Sa(O2) in healthy adults. In conclusion we speculate that carbogen inhalation is sufficient for optimal oxygenation of healthy brain tissue, whereas carbogen induces concomitant increases of CBF and Sa(O2).

TMS of the occipital cortex induces tactile sensations in the fingers of blind Braille readers.

Various non-visual inputs produce cross-modal responses in the visual cortex of early blind subjects. In order to determine the qualitative experience associated with these occipital activations, we systematically stimulated the entire occipital cortex using single pulse transcranial magnetic stimulation (TMS) in early blind subjects and in blindfolded seeing controls. Whereas blindfolded seeing controls reported only phosphenes following occipital cortex stimulation, some of the blind subjects reported tactile sensations in the fingers that were somatotopically organized onto the visual cortex. The number of cortical sites inducing tactile sensations appeared to be related to the number of hours of Braille reading per day, Braille reading speed and dexterity. These data, taken in conjunction with previous anatomical, behavioural and functional imaging results, suggest the presence of a polysynaptic cortical pathway between the somatosensory cortex and the visual cortex in early blind subjects. These results also add new evidence that the activity of the occipital lobe in the blind takes its qualitative expression from the character of its new input source, therefore supporting the cortical deference hypothesis.

Serotonin 5HT1A receptor availability and pathological crying after stroke.

OBJECTIVES: Post-stroke depression and pathological crying (PC) implicate an imbalance of serotonergic neurotransmission. We claim that PC follows serotonin depletion that raises the binding potential (p(B)) of the 5-HT(1A) receptor antagonist [carbonyl-(11)C]WAY-100635, which is reversible by selective serotonin re-uptake inhibitor (SSRI) treatment. MATERIALS AND METHODS: We PET scanned patients with acute stroke and PC and age-matched control subjects. Maps of receptor availability were generated from the images of eight cortical regions and raphe nuclei. RESULTS: The maps showed highest binding in limbic areas and raphe nuclei, while binding in basal ganglia and cerebellum was negligible. Baseline binding potentials of patients were lower than that of control subjects (3.7 +/- 0.6 vs 4.2 +/- 0.2). Treatment with SSRI markedly reduced free receptor sites, whereas placebo administration led to a global increase. DISCUSSION: The study is the first suggestion of changes of serotonergic neurotransmission in the early phase of stroke and the modulation of these changes with SSRI treatment.

Dynamic changes in corticospinal tracts after stroke detected by fibretracking.

BACKGROUND AND AIMS: The integrity of motor pathways and functional connectivity patterns are important in assessing plastic changes related to successful recovery, to obtain prognostic information and to monitor future therapeutic strategies of stroke patients. We tested the following hypotheses: (1) that changes in axonal integrity along the corticospinal tract after stroke can be detected as a reduction in fractional anisotropy; and (2) that sustained low fractional anisotropy is indicative of axonal loss and therefore is correlated with poor motor outcome, as measured by specific neurological motor scores. METHODS: We developed a segmentation tool based on magnetic resonance diffusion tensor imaging in conjunction with three dimensional fibretracking for longitudinal studies of the corticospinal tract, and used specific neurological motor scores to test the hypotheses in five stroke patients within the first week and 30 and 90 days after the stroke. RESULTS: Reduction in fractional anisotropy within the first weeks after stroke reflected a decline in axonal integrity, leading to Wallerian degeneration, and demonstrated a correlation between the temporal evolution of fractional anisotropy and motor function in patients with poor motor outcome. CONCLUSION: The study demonstrated the feasibility of fibretracking as a segmentation tool for mapping distal parts of the corticospinal motor pathways and showed that fractional anisotropy in the segmented corticospinal tract is a sensitive measure of structural changes after stroke.

A volumetric screening procedure for the Göttingen minipig brain.

A screening procedure was developed to provide quantitative estimates of structural parameters, regional volumes and neuron number, in a neurotoxicologic study of the Göttingen minipig brain. The study material consisted of normal controls and brains collected from young minipigs which had been exposed in utero to the mitotic inhibitor methylazoxymethanol acetate (MAM). Based on stereological principles and systematic sampling techniques, volumetric data from pre-selected regions of the pig brain was obtained using Cavalieri's principles and point-counting. Secondarily, estimates of total hemispheric neocortical cell numbers were obtained from pre-selected groups to test the potential effect of MAM on neuron number. No significant differences were observed in volume of the pre-selected regions of MAM intoxicated pigs nor in estimates of total neocortical neuron number.