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.     

��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.     

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.     

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.     

CD3 in Lewy pathology: does the abnormal recall of neurodevelopmental processes underlie Parkinson��s disease

CD3ζ is a subunit of the CD3 molecule that, until recently, appeared restricted to T cells and natural killer cells. However, experimental studies have demonstrated a role of CD3ζ in dendritic outgrowth in the visual system as well as in synaptic plasticity. Given the increasing evidence for uncharacteristic recapitulation of neurodevelopmental processes in neurodegenerative diseases, in this study, we evaluated brains from subjects with Parkinson's disease and Lewy body dementia for evidence of aberrant CD3 expression. Our data shows marked CD3ζ in association with the α-synuclein containing pathological lesions, i.e., Lewy bodies and Lewy neurites, in the brains of subjects with Parkinson's disease and Lewy body dementia. This finding raises the novel concept of CD3 dysregulation in these disorders as a pathogenic factor and also furthers the increasing evidence that the recall of aberrant neurodevelopmental processes underlies the pathogenesis of neurodegenerative diseases.     

Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer��s disease: a proof of concept study

The current drug treatment for Alzheimer's disease (AD) is only partially and temporary effective. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current inducing modulation in cortical excitability. In addition, cognitive training (COG) may improve cognitive functions in AD. Our aim was to treat AD patients combining high-frequency repetitive TMS interlaced with COG (rTMS-COG). Eight patients with probable AD, treated for more than 2 months with cholinesterase inhibitors, were subjected to daily rTMS-COG sessions (5/week) for 6 weeks, followed by maintenance sessions (2/week) for an additional 3 months. Six brain regions, located individually by MRI, were stimulated. COG tasks were developed to fit these regions. Primary objectives were average improvement of Alzheimer Disease Assessment Scale-Cognitive (ADAS-cog) and Clinical Global Impression of Change (CGIC) (after 6 weeks and 4.5 months, compared to baseline). Secondary objectives were average improvement of MMSE, ADAS-ADL, Hamilton Depression Scale (HAMILTON) and Neuropsychiatric Inventory (NPI). One patient abandoned the study after 2 months (severe urinary sepsis). ADAS-cog (average) improved by approximately 4 points after both 6 weeks and 4.5 months of treatment (P < 0.01 and P < 0.05) and CGIC by 1.0 and 1.6 points, respectively. MMSE, ADAS-ADL and HAMILTON improved, but without statistical significance. NPI did not change. No side effects were recorded. In this study, rTMS-COG (provided by Neuronix Ltd., Yokneam, Israel) seems a promising effective and safe modality for AD treatment, possibly as good as cholinesterase inhibitors. A European double blind study is underway.     

Activation of PKC isoform ��I at the blood�Cbrain barrier rapidly decreases P-glycoprotein activity and enhances drug delivery to the brain

P-glycoprotein is an ATP (adenosine triphosphate)-driven drug efflux transporter that is highly expressed at the blood–brain barrier (BBB) and is a major obstacle to the pharmacotherapy of central nervous system diseases, including brain tumors, neuro-AIDS, and epilepsy. Previous studies have shown that P-glycoprotein transport activity in rat brain capillaries is rapidly reduced by the proinflammatory cytokine, tumor necrosis factor-α (TNF-α) acting through protein kinase C (PKC)-dependent signaling. In this study, we used isolated rat brain capillaries to show that the TNF-α-induced reduction of P-glycoprotein activity was prevented by a PKCβ_I/II inhibitor, {"type":"entrez-nucleotide","attrs":{"text":"LY333531","term_id":"1257370768","term_text":"LY333531"}}LY333531, and mimicked by a PKCβ_I/II activator, 12-deoxyphorbol-13-phenylacetate-20-acetate (dPPA). Western blotting of brain capillary extracts with phospho-specific antibodies showed that dPPA activated PKCβ_I, but not PKCβ_II. Moreover, in intact rats, intracarotid infusion of dPPA potently increased brain accumulation of the P-glycoprotein substrate, [³H]-verapamil without compromising tight junction integrity. Thus, PKCβ_I activation selectively reduced P-glycoprotein activity both in vitro and in vivo. Targeting PKCβ_I at the BBB may prove to be an effective strategy for enhancing the delivery of small molecule therapeutics to the brain.     

Chemical priming for spinal cord injury: a review of the literature. Part I��factors involved

Introduction  

There are significant differences between the propensity of neural regeneration between the central and peripheral nervous systems.     

Mortality in mechanically ventilated patients of Guillain Barr�� Syndrome

Background:

The mortality of patients with Guillain Barré syndrome (GBS) has varied widely with rates between 1-18%. Death results from pneumonia, sepsis, adult respiratory distress syndrome (ARDS) and less frequently due to autonomic dysfunction or pulmonary embolism. There are only few studies which have used a large sample and have in detail analyzed the circumstances relating to death and the prognostic factors for the same in a cohort, including only mechanically ventilated patients.

Objective:

The objective of our study was to analyze the circumstances and factors related to mortality in mechanically ventilated patients of GBS.

Materials and Methods:

Case records of patients of GBS, satisfying National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria, and requiring mechanical ventilation from 1984 to 2007, were analyzed.

Results:

A total of 273 GBS patients were managed with ventilatory support (190 men and 83 women) during the period. Besides symmetrical paralysis in all patients, bulbar palsy was present in 186 (68.1%), sensory involvement in 88 (32.2%) and symptomatic autonomic dysfunction in 72 (26.4%) patients. The mortality was 12.1%. The factors determining mortality were elderly age group (P=0.03), autonomic dysfunction (P=0.03), pulmonary complications (P=0.001), hypokalemia (P=0.001) and bleeding (P=0.001) from any site. Logistic regression analysis showed the risk of mortality was 4.69 times more when pneumonia was present, 2.44 times more when hypokalemia was present, and 3.14 times more when dysautonomia was present. The odds ratio for age was 0.97 indicating that a higher age was associated with a higher risk of mortality.

Conclusions:

Ventilator associated pulmonary complications, bleeding and hypokalemia especially in elderly patients require optimal surveillance and aggressive therapy at the earliest for reducing the mortality in this group of GBS patients.     

What is the role of the cerebellum in the pathophysiology of dystonia?

Journal of Neurology -     

Why ��Willusionism�� Leads to ��Bad Results��: Comments on Baumeister, Crescioni, and Alquist

Drawing on results discussed in the target article by Baumeister et al. (1), I argue that the claim that the modern mind sciences are discovering that free will is an illusion (“willusionism”) is ambiguous and depends on how ordinary people understand free will. When interpreted in ways that the evidence does not justify, the willusionist claim can lead to ‘bad results.’ That is, telling people that free will is an illusion leads people to cheat more, help less, and behave more aggressively, but these responses may be based on people’s interpreting willusionist claims to mean that they lack the powers of rational choice and self-control.