Association of activities of daily living, mobility and balance ability, and symptoms of Parkinson's disease with the masses and amounts of intramuscular non-contractile tissue of the trunk and lower extremity muscles in patients with Parkinson's disease.

PURPOSE: We examined the association of activities of daily living (ADL), mobility and balance ability, and symptoms of Parkinson's disease (PD) with the masses and amounts of intramuscular non-contractile tissue of the trunk and lower extremity muscles in patients with PD. METHODS: The subjects were 11 community-dwelling patients with PD. ADL were assessed using the Functional Independence Measure. Mobility capacity was assessed based on measurement of maximal walking speed and timed up-and-go time, while balance ability was evaluated based on measurement of one-legged stance time. The symptoms of PD were assessed based on measurement of the Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale. Muscle thickness (MT) and echo intensity (EI) of the trunk and lower extremity muscles were also measured using an ultrasound imaging device. RESULTS: Partial correlation analysis revealed an association between reduced ADL and increased EI of the lumbar erector spinae muscle; reduced mobility capacity and increased EI of the rectus abdominis and gluteus minimus muscles; and reduced balance ability and decreased MT of the lumbar erector spinae muscle and increased EI of the lumbar erector spinae, semitendinosus, and tibialis posterior muscles. Partial correlation analysis also showed an association between symptoms of severe PD and decreased MT of the tibialis anterior muscles and increased EI of the lumbar erector spinae, gluteus minimus, and tibialis posterior muscles. CONCLUSION: The properties of the trunk and lower extremity muscles may be critical for ADL, mobility and balance ability, and symptoms of PD in patients with PD.

Association of sagittal spinal alignment in the standing position with the masses and amounts of intramuscular non-contractile tissue of the trunk and lower extremity muscles in patients with Parkinson's disease.

BACKGROUND: We examined the association of sagittal spinal alignment in the standing position with the masses and amounts of intramuscular non-contractile tissue of multiple trunk and lower extremity muscles, such as the hip joint muscles, measured using an ultrasound imaging device in patients with Parkinson's disease (PD). METHODS: The participants were 10 patients with PD. Sagittal spinal alignment (thoracic kyphosis, lumbar lordosis, and sacral anterior inclination angles) in the standing position was measured using a Spinal Mouse. Muscle thicknesses and echo intensities of the trunk and lower extremity muscles, including the hip joint muscles, were also measured in the prone or supine position using an ultrasound imaging device. FINDINGS: Partial correlation analysis with body height and weight as control variables showed that a low lumbar lordosis angle in the standing position was significantly associated with low thicknesses of the trunk extensor muscles (lumbar erector spinae and multifidus). Partial correlation analysis also revealed that a high sacral anterior inclination angle in the standing position was significantly associated with low lumbar multifidus muscle thickness. However, the thicknesses and echo intensities of the trunk flexor and hip joint muscles were not significantly related to thoracic kyphosis, lumbar lordosis, or sacral anterior inclination angles. INTERPRETATION: The results of this study suggested the association between a low lumbar lordosis angle in the standing position and low lumbar erector spinae and multifidus muscle thicknesses and between a high sacral anterior inclination angle in the standing position and low lumbar multifidus muscle thickness in patients with PD.

Comparison of the mass and amount of intramuscular non-contractile tissue of the trunk and lower extremity muscles between patients with Parkinson's disease and community-dwelling older adults.

OBJECTIVE: This study compared the masses and amounts of intramuscular non-contractile tissue of the trunk and lower extremity muscles, sagittal spinal alignment, and mobility and balance ability between patients with Parkinson's disease (PD) and older adults. METHODS: This study included 26 older adults (control [CTR] group) and eight patients with PD (PD group). Muscle thicknesses and echo intensities of the trunk and lower extremity muscles were measured using an ultrasound imaging device. Sagittal spinal alignments in the standing and prone positions were assessed using a Spinal Mouse. Mobility capacity was assessed based on the measurements of usual and maximal walking speeds, timed up-and-go (TUG) time, and five-chair-stand time, while balance ability was assessed based on the measurement of one-legged stance (OLS) time. RESULTS: Our results showed significantly lower gluteus maximus and tibialis anterior muscle thicknesses, higher thickness of the short head of the biceps femoris muscle, and higher echo intensity of the gluteus maximus muscle in the PD group than in the CTR group. Lumbar lordosis angle in the standing position, usual and maximal walking speeds, and OLS time were significantly lower, while the TUG and five-chair-stand times were significantly higher in the PD group than in the CTR group. The other factors did not differ significantly between groups. CONCLUSIONS: Our results revealed lower masses of the gluteus maximus and tibialis anterior muscles, higher mass of the short head of the biceps femoris muscle, and higher amounts of intramuscular non-contractile tissue of the gluteus maximus muscle in patients with PD.

Comparison of the Upper and Lower Extremity and Trunk Muscle Masses between Children with Down Syndrome and Children with Typical Development.

PURPOSE: Comparison of not only the upper and lower extremity but also trunk muscle masses measured by means of an ultrasound imaging device between children with Down syndrome (DS) and children with typical development (TD). METHODS: The study included 35 children with TD (TD group) and 26 children with DS (DS group). The upper and lower extremity and trunk muscle thicknesses were measured using an ultrasound imaging device. RESULTS: The thicknesses of the rectus abdominis, obliquus externus and internus abdominis, rectus femoris, and short head of the biceps femoris muscles were significantly lower in the DS group than in the TD group. The thicknesses of the other upper and lower extremity and trunk muscles did not differ significantly between the groups. CONCLUSIONS: The results of this study demonstrated lower masses of trunk flexor and knee extensor and flexor muscles in children with DS compared to those in children with TD.

Association of mobility capacity with the masses and amounts of intramuscular non-contractile tissue of the trunk and lower extremity muscles in community-dwelling older adults.

We examined the association of mobility capacity with muscle thicknesses and echo intensities of the trunk and lower extremity muscles measured using an ultrasound imaging device in community-dwelling older adults. The participants were 57 community-dwelling older adults. Mobility capacity was assessed based on the measurement of usual and maximal walking speeds and timed up-and-go (TUG) time. Muscle thickness and echo intensity of the trunk and lower extremity muscles were measured using an ultrasound imaging device. Finally, sagittal spinal alignment was assessed based on the measurement of thoracic kyphosis, lumbar lordosis, and sacral anterior inclination angles in the standing position using a Spinal Mouse. Stepwise regression analysis showed that the tibialis anterior muscle thickness, tibialis posterior muscle echo intensity, and body weight were significant and independent factors of usual walking speed, with a coefficient of determination (R2) of 0.25. The thicknesses of the thoracic erector spinae and obliquus externus abdominis muscles were significant and independent factors of maximal walking speed (R2 = 0.26). Moreover, only age was a significant and independent factor for TUG time (R2 = 0.10). The results of this study suggested associations 1) between slow usual walking speed and low tibialis anterior muscle thicknesses and high echo intensity of the tibialis posterior muscle and 2) between slow maximal walking speed and low thoracic erector spinae and obliquus externus abdominis thicknesses in community-dwelling older adults.

Association of sagittal spinal alignment in the sitting position with the trunk and lower extremity muscle masses in children and adults with cerebral palsy: A pilot study.

BACKGROUND: We examined the association of sagittal spinal alignment in the sitting position with the trunk and lower extremity muscle masses in children and adults with cerebral palsy (CP). We also compared muscle masses between children and adults with CP who could and could not sit without the support of their upper extremities. METHODS: The subjects were 34 children and adults with CP. Sagittal spinal alignment in the sitting position, such as thoracic kyphosis, lumbar lordosis, and sacral anterior inclination angles were measured using a Spinal Mouse. The thicknesses of the trunk and lower extremity muscles were measured using an ultrasound imaging device. Furthermore, the subjects were classified into the sitting-possible group (n = 18), who could sit without the support of the upper extremities, or a sitting-impossible group (n = 16), who could not sit without the support of the upper extremities. FINDINGS: Stepwise regression analysis revealed that the lumbar multifidus muscle thickness and body weight were significant and independent factors of the lumbar lordosis angle in the sitting position. The thicknesses of the thoracic erector spinae, gluteus maximus and minimus, long head of the biceps femoris, semitendinosus, and rectus femoris muscles were significantly lower in the sitting-impossible group than those in the sitting-possible group. INTERPRETATION: Decreased lumbar lordosis angle in the sitting position was associated with decreased lumbar multifidus muscle mass in children and adults with CP. Furthermore, not only trunk extensor but also hip joint muscles may contribute to sitting without upper extremity support.

In Vivo Pharmacological Comparison of TAK-071, a Positive Allosteric Modulator of Muscarinic M1 Receptor, and Xanomeline, an Agonist of Muscarinic M1/M4 Receptor, in Rodents.

Activation of the M1 muscarinic acetylcholine receptor (M1R) may be an effective therapeutic approach for Alzheimer's disease (AD), dementia with Lewy bodies, and schizophrenia. Previously, the M1R/M4R agonist xanomeline was shown to improve cognitive function and exert antipsychotic effects in patients with AD and schizophrenia. However, its clinical development was discontinued because of its cholinomimetic side effects. We compared in vivo pharmacological profiles of a novel M1R-selective positive allosteric modulator, TAK-071, and xanomeline in rodents. Xanomeline suppressed both methamphetamine- and MK-801-induced hyperlocomotion in mice, whereas TAK-071 suppressed only MK-801-induced hyperlocomotion. In a previous study, we showed that TAK-071 improved scopolamine-induced cognitive deficits in a rat novel object recognition task (NORT) with 33-fold margins versus cholinergic side effects (diarrhea). Xanomeline also improved scopolamine-induced cognitive impairments in a NORT; however, it had no margin versus cholinergic side effects (e.g., diarrhea, salivation, and hypoactivity) in rats. These side effects were observed even in M1R knockout mice. Evaluation of c-Fos expression as a marker of neural activation revealed that xanomeline increased the number of c-Fos-positive cells in several cortical areas, the hippocampal formation, amygdala, and nucleus accumbens. Other than in the orbital cortex and claustrum, TAK-071 induced similar c-Fos expression patterns. When donepezil was co-administered to increase the levels of acetylcholine, the number of TAK-071-induced c-Fos-positive cells in these brain regions was increased. TAK-071, through induction of similar neural activation as that seen with xanomeline, may produce procognitive and antipsychotic effects with improved cholinergic side effects.

Discovery of Potent, Selective, and Brain-Penetrant 1 H-Pyrazol-5-yl-1 H-pyrrolo[2,3- b]pyridines as Anaplastic Lymphoma Kinase (ALK) Inhibitors.

Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, is predominantly expressed in the brain and implicated in neuronal development and cognition. However, the detailed function of ALK in the central nervous system (CNS) is still unclear. To elucidate the role of ALK in the CNS, it was necessary to discover a potent, selective, and brain-penetrant ALK inhibitor. Scaffold hopping and lead optimization of N-(2,4-difluorobenzyl)-3-(1 H-pyrazol-5-yl)imidazo[1,2- b]pyridazin-6-amine 1 guided by a cocrystal structure of compound 1 bound to ALK resulted in the identification of (6-(1-(5-fluoropyridin-2-yl)ethoxy)-1-(5-methyl-1 H-pyrazol-3-yl)-1 H-pyrrolo[2,3- b]pyridin-3-yl)((2 S)-2-methylmorpholin-4-yl)methanone 13 as a highly potent, selective, and brain-penetrable compound. Intraperitoneal administration of compound 13 significantly decreased the phosphorylated-ALK (p-ALK) levels in the hippocampus and prefrontal cortex in the mouse brain. These results suggest that compound 13 could serve as a useful chemical probe to elucidate the mechanism of ALK-mediated brain functions and the therapeutic potential of ALK inhibition.

Lifelong, central corticotropin-releasing factor (CRF) overexpression is associated with individual differences in cocaine-induced conditioned place preference.

Stress, through corticotropin-releasing factor (CRF), influences all aspects of cocaine addiction. Earlier studies suggest that individual differences in responsivity to stress affect susceptibility to develop addiction. We have previously found that CRF over-expression alters individual differences in behavioural responses to novelty stress in mice. Therefore, we hypothesised that post-natal, long-term over-expression of brain CRF may alter the rewarding effects of cocaine in a manner that is sensitive to individual differences. In this study we specifically investigated cocaine-induced conditioned place preference (CPP) in transgenic mice over-expressing CRF (CRF-OE) and in wild-type (WT) littermates after determining their individual locomotor and emotional responsivity to inescapable novelty. CRF-OE mice showed decreased overall locomotor activity and increased anxiety-like behaviour in response to novelty compared to WT mice. Low behavioural reactivity to novelty (LR) was associated with heightened anxiety-like behaviour in CRF-OE, but not in WT, mice. WT and CRF-OE mice developed CPP equally to both low (5mg/kg) and high (20mg/kg) doses of cocaine. However, LR CRF-OE mice expressed significantly stronger cocaine CPP than transgenic mice with high locomotor response to novelty (HR). In WT mice, on the other hand, stronger CPP induced by 20mg/kg of cocaine was found in the HR animals. Furthermore, there was a strong negative correlation between locomotor reactivity to novelty and CPP in CRF-OE, but not in WT, mice. Collectively, these results suggest that long-term, post-natal CRF over-expression increases the rewarding effects of cocaine in individuals with high emotional response to stress.

The influence of work-related chronic stress on the regulation of emotion and on functional connectivity in the brain.

Despite mounting reports about the negative effects of chronic occupational stress on cognitive and emotional functions, the underlying mechanisms are unknown. Recent findings from structural MRI raise the question whether this condition could be associated with a functional uncoupling of the limbic networks and an impaired modulation of emotional stress. To address this, 40 subjects suffering from burnout symptoms attributed to chronic occupational stress and 70 controls were investigated using resting state functional MRI. The participants' ability to up- regulate, down-regulate, and maintain emotion was evaluated by recording their acoustic startle response while viewing neutral and negatively loaded images. Functional connectivity was calculated from amygdala seed regions, using explorative linear correlation analysis. Stressed subjects were less capable of down-regulating negative emotion, but had normal acoustic startle responses when asked to up-regulate or maintain emotion and when no regulation was required. The functional connectivity between the amygdala and the anterior cingulate cortex correlated with the ability to down-regulate negative emotion. This connectivity was significantly weaker in the burnout group, as was the amygdala connectivity with the dorsolateral prefrontal cortex and the motor cortex, whereas connectivity from the amygdala to the cerebellum and the insular cortex were stronger. In subjects suffering from chronic occupational stress, the functional couplings within the emotion- and stress-processing limbic networks seem to be altered, and associated with a reduced ability to down-regulate the response to emotional stress, providing a biological substrate for a further facilitation of the stress condition.

Traumatic brain injury alters the functional brain network mediating working memory.

PRIMARY OBJECTIVE: Investigation of the impact of traumatic brain injury (TBI) on the functional brain network that mediates working memory function. RESEARCH DESIGN: Functional magnetic resonance imaging (fMRI) during an n-back working memory task in nine chronic-stage patients with TBI and nine age-matched healthy controls. In addition to classical analyses investigating regional activity, the authors examined functional connectivity of the brain regions critical to working memory performance using psychophysiological interaction (PPI) analyses. MAIN OUTCOMES AND RESULTS: Patients with TBI made a greater percentage of errors than controls at high working memory load conditions. The fMRI data showed that the activation of the left inferior parietal gyrus (LIPG) was significantly reduced, whereas the activation of the right inferior frontal gyrus (RIFG) was significantly increased in patients compared with controls. Task performance accuracy was significantly associated with the activation of the LIPG in controls and the activation of the RIFG in patients. PPI analyses on fMRI data further suggested that the functional connectivity between the RIFG and LIPG was compromised in patients. CONCLUSION: The abnormal functional connectivity between LIPG and RIFG may underlie the observed working memory deficits and abnormal brain activation pattern in patients.

Corticotropin-releasing factor (CRF) over-expression down-regulates hippocampal dopamine receptor protein expression and CREB activation in mice.

BACKGROUND: Stress results in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by increased central CRF activity, elevated circulating glucocorticoid levels, impaired glucocorticoid-mediated negative feedback and abnormal hippocampal functions, possibly contributing to the development of behavioral pathologies, such as depression. The hippocampus is critically involved in the control of the HPA axis as well as in explicit memory, contextual aspects of fear, organization of the behavioral response to environmental novelty and in habituation. We have previously shown that mice that over-express CRF in the brain exhibit impaired novelty detection and altered psychophysiological and behavioral habituation, functions linked to dopamine receptor-dependent hippocampal plasticity. OBJECTIVE AND METHODS: Therefore, the aim of the present study was to measure D1 and D2 dopamine receptor expression and related signaling, such as CREB and ERK protein levels and phosphorylation, in the hippocampus and other brain regions of mice with post-natal CRF over-expression (CRF-OE mice). RESULTS: We found a region-specific down-regulation of both D1 and D2 protein expression, without altered CRF receptor protein expression, in the hippocampus in CRF-OE mice. This was accompanied by an impaired phosphorylation of hippocampal CREB, but not ERK1 and ERK2, in the same animals. CONCLUSIONS: These results suggest that post-natal onset CRF over-expression results in an impairment of dopamine signaling in the hippocampus, which may underlie cognitive and motivational aspects of stress-related, CRF-driven mood disorders.

Influence of transgenic corticotropin-releasing factor (CRF) over-expression on social recognition memory in mice.

We examined juvenile social recognition and discrimination in mice with early post-natal onset, transgenic CRF over-expression (CRF-OE) and in their wild-type littermates (WT). CRF-OE mice showed enhanced social investigation during the first encounter, normal short-term and facilitated long-term social recognition memory, compared to WT. These results suggest that chronically elevated brain CRF tone may contribute in better remembering ethologically relevant and emotionally salient stimuli, such as social interaction.

Variety of the molecular conformation in Peptide nanorings and nanotubes.

Possible molecular conformations in peptide nanorings and nanotubes were theoretically investigated by a mathematical conformation analysis as well as ab initio Hartree-Fock calculations. The mathematical analysis predicts not only the conventional nanorings having an extended-type (E-type) backbone (trans zigzag) but also the novel ones having bound-type (B-type) backbones with a smaller internal diameter. Ab initio calculations for the amino acid substitution reveal that all 20 encoded residues can form both types of the above nanorings as a local minimum. However, the energetically stable type is determined in accordance with the kind of the replaced side chains. Moreover, the present work theoretically reveals that both types of nanorings stack to form nanotubes through inter-ring hydrogen bonds, i.e., larger E-type nanotubes and smaller B-type nanotubes. Electronically, the HOMO and LUMO states of the nanoring and nanotube backbones are formed by the in-plane pi state. The replacement by the appropriate residues is furthermore predicted to intrude additional levels in the energy gap and to form the frontier states localized at the side chains.