Changes in the solubility and phosphorylation of ��-synuclein over the course of Parkinson��s disease

Lewy bodies are made from insoluble, phosphorylated α-synuclein, but the earliest changes that precipitate such pathology still remain conjecture. In this study, we quantify and identify relationships between the levels of the main pathologic form of phosphorylated α-synuclein over the course of Parkinson's disease in regions affected early through to end-stage disease. Brain tissue samples from 33 cases at different disease stages and 13 controls were collected through the Australian Network of Brain Banks. 500 mg of frozen putamen (affected preclinically) and frontal cortex (affected late) was homogenized, fractionated and α-synuclein levels evaluated using specific antibodies (syn-1, BD Transduction Laboratories; S129P phospho-α-synuclein, Elan Pharmaceuticals) and quantitative western blotting. Statistical analyses assessed the relationship between the different forms of α-synuclein, compared levels between groups, and determined any changes over the disease course. Soluble S129P was detected in controls with higher levels in putamen compared with frontal cortex. In contrast, insoluble α-synuclein occurred in Parkinson's disease with a significant increase in soluble and lipid-associated S129P, and a decrease in soluble frontal α-synuclein over the disease course. Increasing soluble S129P in the putamen correlated with increasing S129P in other fractions and regions. These data show that soluble non-phosphorylated α-synuclein decreases over the course of Parkinson's disease, becoming increasingly phosphorylated and insoluble. The finding that S129P α-synuclein normally occurs in vulnerable brain regions, and in Parkinson's disease has the strongest relationships to the pathogenic forms of α-synuclein in other brain regions, suggests a propagating role for putamenal phospho-α-synuclein in disease pathogenesis.     

A test of the role of two prefrontal/ subcortical networks in the ��sequencing�� of non-motor, visuo-spatial information

There are a number of prefrontal/sub-cortical networks in the brain (e.g., cerebellar-thalamic-prefrontal or basal ganglia/supplementary motor cortex circuits) that despite having a clear role in motor function have been shown to be involved in non-motor tasks. In this project we test for the involvement of these networks in a dimensional judgment task that utilizes visual perceptual, visual spatial processing and requires the ordering of dimensional (height) information. Unlike previous studies examining non-motor sequencing, we directly compare both non-motor and motor versions of our dimensional judgment task. In addition, we examine activation uniquely associated with correct task responses. The findings provide evidence for the role of cortical not subcortical structures in the sequencing of visuo-spatial material apart from any motor output requirements. Our results suggest that the inferior parietal cortex (BA 7, 40) and medial frontal regions (BA 6, 8, 9 including the SMA) are instrumental to the task. Based on these results, we propose a prefrontal/parietal network plays a role in the implementation of a comparator mechanism that makes accurate comparisons along the dimension of interest, holds the information in working memory, and then (regardless of whether the information is correct or incorrect) generates a tag or abstract code that assigns the information a place in an ordered sequence. Most important, the information involved can be visual/symbolic and non-motor (not just motor) in nature.     

Microsurgical decompression of the median nerves for treating diabetic peripheral neuropathy in the upper limbs： A 21-month follow-up

BACKGROUND： Peripheral nerve injured by abnormal glucose metabolism is compressed, which is an important etiological factor of diabetic peripheral neuropathy （DPN）. Microsurgical decompression of peripheral nerve maybe effectively releases the symptoms of DPN. OBJECTIVE： To investigate the curative effects of microsurgical decompression of median nerves for treatment of DPN in upper limbs. DESIGN： Case-follow up observation. SETTING： Department of Orthopaedics, Department of Neurosurgery, China-Japan Friendship Hospital, Ministry of Health. PARTICIPANTS： Twelve patients with DPN in upper limbs （19 hands） who received treatment in the Department of Orthopaedics, Department of Neurosurgery, China-Japan Friendship Hospital, Ministry of Public Health between March 2004 and July 2006 were involved in this experiment. The involved patients, 5 male and 7 female, were aged 44 to 77 years, with DPN course of 6 months to 16 years. They all met 1999 WHO diabetic diagnosis criteria. Both two hands had symptom in 7 patients, and only one hand had symptom in 5 patients. Informed consents of detected items were obtained from all the patients, who also received 21 months of follow-up treatment. METHODS： （1）Operation was carried out under the anesthetic status of brachial plexus. Under an operating microscope, transverse carpal ligament was exposed. Subsequently, transverse carpal ligament, forearm superficial fascia and palmar aponeurosis were fully liberated, and then part of them was cut off. Connective tissue around median nerve, superficial flexor muscle of fingers, radial flexor, palmaris longus and other flexor tendons were completely loosened. Finally, epineurium was opened with microinstrument for neurolysis. After tourniquet was loosened, and bipolar coagulator was used to stop bleeding, and the incision was closed. （2） In postoperative 21 months, the subjective symptom, two-point discrimination （The smallest distance of two normal points was 3 to 6 mm）, nerve conduction velocity and action potential amplitude （short abductor muscle of thumb end Lat 〈 4.5 ms; Motor nerve conduction velocity of forearm 〉 50 m/s）, etc. of all the patients were followed up. MAIN OUTCOME MEASURES＂ The objective evaluation and long-term follow up of curative effect of microsurgical decompression of median nerves for treatment of DPN in upper limbs. RESULTS： Twelve patients with DPN in upper limbs participated in the final analysis. （1） After operation, numbness and pain symptom releasing 100% were found in 19 hands of 12 patients with DPN. During follow up, numbness and recrudescent pain symptom were found in one hand （5%, 1/19）. （2）Postoperatively, index finger two point discrimination in 15 （94%, 15/16） hands recovered to normal. （3） nerve conduction velocity and action potential amplitude improved completely. （4） Two hands （2/19, 10% ）had poor healing at incision, and they late healed at postoperative 1 and 1.5 months, respectively. CONCLUSION： Long-term follow-up results show that microsurgical decompression is an effective method to treat DPN in upper limbs.     

��Willpower�� over the life span: decomposing self-regulation

In the 1960s, Mischel and colleagues developed a simple ‘marshmallow test’ to measure preschoolers’ ability to delay gratification. In numerous follow-up studies over 40 years, this ‘test’ proved to have surprisingly significant predictive validity for consequential social, cognitive and mental health outcomes over the life course. In this article, we review key findings from the longitudinal work and from earlier delay-of-gratification experiments examining the cognitive appraisal and attention control strategies that underlie this ability. Further, we outline a set of hypotheses that emerge from the intersection of these findings with research on ‘cognitive control’ mechanisms and their neural bases. We discuss implications of these hypotheses for decomposing the phenomena of ‘willpower’ and the lifelong individual differences in self-regulatory ability that were identified in the earlier research and that are currently being pursued.     

Concurrent Measurement of ��Real-World�� Stress and Arousal in Individuals With Psychosis: Assessing the Feasibility and Validity of a Novel Methodology

Background: Psychosis has been repeatedly suggested to be affected by increases in stress and arousal. However, there is a dearth of evidence supporting the temporal link between stress, arousal, and psychosis during “real-world” functioning. This paucity of evidence may stem from limitations of current research methodologies. Our aim is to the test the feasibility and validity of a novel methodology designed to measure concurrent stress and arousal in individuals with psychosis during “real-world” daily functioning. Method: Twenty patients with psychosis completed a 36-hour ambulatory assessment of stress and arousal. We used experience sampling method with palm computers to assess stress (10 times per day, 10 AM → 10 PM) along with concurrent ambulatory measurement of cardiac autonomic regulation using a Holter monitor. The clocks of the palm computer and Holter monitor were synchronized, allowing the temporal linking of the stress and arousal data. We used power spectral analysis to determine the parasympathetic contributions to autonomic regulation and sympathovagal balance during 5 minutes before and after each experience sample. Results: Patients completed 79% of the experience samples (75% with a valid concurrent arousal data). Momentary increases in stress had inverse correlation with concurrent parasympathetic activity (ρ = −.27, P < .0001) and positive correlation with sympathovagal balance (ρ = .19, P = .0008). Stress and heart rate were not significantly related (ρ = −.05, P = .3875). Conclusion: The findings support the feasibility and validity of our methodology in individuals with psychosis. The methodology offers a novel way to study in high time resolution the concurrent, “real-world” interactions between stress, arousal, and psychosis. The authors discuss the methodology''s potential applications and future research directions.     

Cubital tunnel syndrome--simple nerve decompression or decompression with subcutaneous anterior transposition?

The purpose of this prospective, randomised and controlled study was to evaluate which kind of operative technique for treatment of cubital tunnel syndrome is favourable: subcutaneous anterior transposition or nerve decompression without transposition. This study included 66 patients suffering from pain and/either neurological deficits with clinically and electrographically proven cubital tunnel syndrome. 32 patients underwent nerve decompression without transposition, whereas 34 underwent subcutaneous transposition of the nerve. Follow-up examinations evaluating pain, motor and sensory deficits as well as motor nerve conduction velocities were performed three, nine and 24 months postoperatively. Irrespectively of operative procedures (simple decompression vs. subcutaneous anterior transposition) there were no significant differences between the outcomes of the two groups at either postoperative follow-up examination (p > 0.05).     

��Better the devil you know��: a preliminary study of the differential modulating effects of reputation on reward processing for boys with and without externalizing behavior problems

Very little is known about the neurobiological correlates of reward processing during social decision-making in the developing brain and whether prior social and moral information (reputations) modulates reward responses in youth as has been demonstrated in adults. Moreover, although externalizing behavior problems in youth are associated with deficits in reward processing and social cognition, a real-life social interaction paradigm using functional neuroimaging (fMRI) has not yet been applied to probe reward processing in such youth. Functional neuroimaging was used to examine the neural correlates of reward-related decision-making during a trust task in two samples of age-matched 11 to 16-year-old boys: with (n?=?10) and without (n?=?10) externalizing behavior problems. The task required subjects to decide whether to share or keep monetary rewards from partners they themselves identified during a real-life peer sociometric procedure as interpersonally aggressive or kind (vs. neutral). Results supported the notion that prior social and moral information (reputations) modulated reward responses in the adolescent brain. Moreover, boys with externalizing problems showed differential activation in the bilateral insula during the decision phase of the game as well as the caudate and anterior insula during the outcome phase of the game. Similar activation in adolescents in response to reward related stimuli as found in adults suggests some developmental continuity in corticostriatal circuits. Group differences are interpreted with caution given the small group sizes in the current study. Notwithstanding this limitation, the study provides preliminary evidence for anomalous reward responses in boys with externalizing behavior problems, thereby providing a possible biological correlate of well-established social-cognitive and reward-related theories of externalizing behavior disorders.     

The Comparative Morphometric Study of the Posterior Cranial Fossa : What Is Effective Approaches to the Treatment of Chiari Malformation Type 1?

Objective

The objective of this study was to investigate changes in the posterior cranial fossa in patients with symptomatic Chiari malformation type I (CMI) compared to a control group.

Methods

We retrospectively reviewed clinical and radiological data from 12 symptomatic patients with CMI and 24 healthy control subjects. The structures of the brain and skull base were investigated using magnetic resonance imaging.

Results

The length of the clivus had significantly decreased in the CMI group than in the control group (p=0.000). The angle between the clivus and the McRae line (p<0.024), as the angle between the supraocciput and the McRae line (p<0.021), and the angle between the tentorium and a line connecting the internal occipital protuberance to the opisthion (p<0.009) were significantly larger in the CMI group than in the control group. The mean vertical length of the cerebellar hemisphere (p<0.003) and the mean length of the coronal and sagittal superoinferior aspects of the cerebellum (p<0.05) were longer in the CMI group than in the control group, while the mean length of the axial anteroposterior aspect of the cerebellum (p<0.001) was significantly shorter in the CMI group relative to control subjects.

Conclusion

We elucidate the transformation of the posterior cranial fossa into the narrow funnel shape. The sufficient cephalocaudal extension of the craniectomy of the posterior cranial fossa has more decompression effect than other type extension of the craniectomy in CMI patients.     

Complications of microvascular decompression in hemifaciai spasm treatment：Retrospective analysis of 156 cases

BACKGROUND： Microvascular decompression has become a well-accepted, safe method in the treatment of hemifacial spasms. However, postoperative complications exist and influence the prognosis of the disease. OBJECTIVE： This study aimed to analyze, by case review, the characteristics and regularity of microvascular decompression complications in the treatment of hemifacial spasm. DESIGN： Retrospective analysis. SETTING： Beijing General Group Hospital of the Chinese People＇s Armed Police Forces. PARTICIPANTS： A total of 156 patients with hemifacial spasm were admitted to the Department of Neurosurgery, Beijing General Group Hospital of the Chinese People＇s Armed Police Forces from June 2004 to June 2006 and recruited for this study. The patients, 57 males and 99 females, averaged 46 years of age （range 17-68-years old）. All suffered from facial innervated muscular paroxysmal and recurrent contraction, which could not be controlled by consciousness. Electromyogram demonstrated waves of fibrillation and fasciculation. Prior to admission, all patients had received other treatments. Written informed consents for treatment were obtained from all patients. This protocol was approved by the Hospital＇s Ethics Committee. METHODS： After anesthesia, a cranial bone pore was drilled below the connection of the lateral sinus and sigmoid sinus. Dura mater was dissected at the ＂⊥＂ shape and held in the air. Under microscopy, the flocculus cerebelli was lifted slightly up for convenient observation of the cerebellopontine angle. The mucous membrane was sharply separated. Corresponding vessels were identified at the root of the facial nerves and subsequently liberated and disassociated from the root exit zone. Suitably sized Teflon cotton was placed between the corresponding vessels and brain stem. MAIN OUTCOME MEASURES： Complications of microvascular decompression. RESULTS： All 156 patients participated in the final analysis. （1） Postoperatively, 66 （42%） patients presented with obvious headach     

Classification of hydrocephalus: critical analysis of classification categories and advantages of ��Multi-categorical Hydrocephalus Classification�� (Mc HC)

Objective  

Hydrocephalus is a complex pathophysiology with disturbed cerebrospinal fluid (CSF) circulation. There are numerous numbers of classification trials published focusing on various criteria, such as associated anomalies/underlying lesions, CSF circulation/intracranial pressure patterns, clinical features, and other categories. However, no definitive classification exists comprehensively to cover the variety of these aspects. The new classification of hydrocephalus, “Multi-categorical Hydrocephalus Classification” (Mc HC), was invented and developed to cover the entire aspects of hydrocephalus with all considerable classification items and categories.     

The fate of syringomyelia after surgical treatment of syringomyelia–Chiari I complex

Neurological Sciences -     

Chiari畸形研究进展

Chiari畸形是一种病理改变复杂的先天发育异常性疾病,以小脑扁桃体下疝至枕大孔平面以下为特征,常伴有脊髓积水.家族性Chiari畸形的研究提示其致病原因可能与某些基因的突变相关;后颅窝形态学研究证实其发病机制可能为后颅窝骨性发育不良,导致后颅窝拥挤所致;治疗方法多样,后颅窝减压术是目前治疗Chiari畸形最主要的术式.对于合并颅底凹陷的复杂Chiari畸形,可行经口齿状突切除、后外侧入路枕大孔减压加齿状突切除术及后颅窝减压加枕颈植骨融合术等.     

Trafficking of glucose, lactate, and amyloid-�� from the inferior colliculus through perivascular routes

Metabolic brain imaging is widely used to evaluate brain function and disease, and quantitative assays require local retention of compounds used to register changes in cellular activity. As labeled metabolites of [1- and 6-¹⁴C]glucose are rapidly released in large quantities during brain activation, this study evaluated release of metabolites and proteins through perivascular fluid flow, a pathway that carries solutes from brain to peripheral lymphatic drainage sites. Assays with [3,4-¹⁴C]glucose ruled out local oxidation of glucose-derived lactate as a major contributor of label loss. Brief infusion of [1-¹⁴C]glucose and -[¹⁴C]lactate into the inferior colliculus of conscious rats during acoustic stimulation labeled the meninges, consistent with perivascular clearance of [¹⁴C]metabolites from interstitial fluid. Microinfusion of Evans blue albumin and amyloid-β₁₋₄₀ (Aβ) caused perivascular labeling in the inferior colliculus, labeled the surrounding meninges, and Aβ-labeled-specific blood vessels in the caudate and olfactory bulb and was deposited in cervical lymph nodes. Efflux of extracellular glucose, lactate, and Aβ into perivascular fluid pathways is a normal route for clearance of material from the inferior colliculus that contributes to underestimates of brain energetics. Convergence of ‘watershed'' drainage to common pathways may facilitate perivascular amyloid plaque formation and pathway obstruction in Alzheimer''s disease.     

The Neuropathology of Late-Onset Friedreich��s Ataxia

Friedreich’s ataxia (FRDA) affects very young persons. In a large series, the mean ages of onset and death were 11 and 38 years, respectively. The clinical spectrum of FRDA has expanded after genetic confirmation of the mutation became a routine laboratory test. The main cause of death in juvenile-onset FRDA is cardiomyopathy whereas patients with late-onset are more likely to succumb to neurological disability or an intercurrent illness. Many patients with early onset now survive for 20 years or longer. This study made a systematic comparison of the neuropathology in 14 patients with juvenile onset and long survival, and five patients with late onset and long survival. Mean ages of onset (± standard deviation) were 10 ± 5 and 28 ± 13 years, respectively. Disease durations were 33 ± 11 and 47 ± 11 years, respectively. Cross-sectional areas of the thoracic spinal cord were greatly reduced from the normal state but did not differ between the two groups. Similarly, the neurons of dorsal root ganglia were significantly reduced in size in both juvenile- and late-onset cases of FRDA. The dentate nucleus showed severe loss of neurons as well as modification and destruction of corticonuclear terminals in all FRDA patients. Delayed atrophy of the dentate nucleus is the likely cause of the ataxic phenotype of FRDA in late-onset cases, but the reason for the delay is unknown. Frataxin levels in the dentate nucleus of two patients with late onset were similar to those of seven patients with juvenile onset.     

Oxidative stress increases phosphorylation of I��B kinase-�� by enhancing NF-��B-inducing kinase after transient focal cerebral ischemia

The IκB kinase (IKK) complex is a central component in the classic activation of the nuclear factor-κB (NF-κB) pathway. It has been reported to function in physiologic responses, including cell death and inflammation. We have shown that IKK is regulated by oxidative status after transient focal cerebral ischemia (tFCI) in mice. However, the mechanism by which oxidative stress influences IKKs after tFCI is largely unknown. Nuclear accumulation and phosphorylation of IKKα (pIKKα) were observed 1 h after 30 mins of tFCI in mice. In copper/zinc-superoxide dismutase knockout mice, levels of NF-κB-inducing kinase (NIK) (an upstream kinase of IKKα), pIKKα, and phosphorylation of histone H3 (pH3) on Ser10 were increased after tFCI and were higher than in wild-type mice. Immunohistochemistry showed nuclear accumulation and pIKKα in mouse brain endothelial cells after tFCI. Nuclear factor-κB-inducing kinase was increased, and it enhanced pH3 by inducing pIKKα after oxygen–glucose deprivation (OGD) in mouse brain endothelial cells. Both NIK and pH3 interactions with IKKα were confirmed by coimmunoprecipitation. Treatment with IKKα small interfering RNA significantly reduced cell death after OGD. These results suggest that augmentation of NIK, IKKα, and pH3 in response to oxidative stress is involved in cell death after cerebral ischemia (or stroke).     

Chemical priming for spinal cord injury: a review of the literature part II��potential therapeutics

Introduction  

Spinal cord injury is a complex cascade of reactions secondary to the initial mechanical trauma that puts into action the innate properties of the injured cells, the circulatory, inflammatory, and chemical status around them, into a non-permissive and destructive environment for neuronal function and regeneration. Priming means putting a cell, in a state of “arousal” towards better function. Priming can be mechanical as trauma is known to enhance activity in cells.