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.     

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.     

Revisiting Arieti's ��Listening Attitude�� and Hallucinated Voices

Silvano Arieti proposed that auditory/verbal hallucinations (AVHs) are triggered by momentary states of heightened auditory attention that he identified as a “listening attitude.” Studies and clinical observations by our group support this view. Patients enrolled in our repetitive transcranial magnetic stimulation trials, if experiencing a significant curtailment of these hallucinations, often report an episodic sense that their voices are still occurring even if they no longer can be heard, suggesting episodic states of heightened auditory expectancy. Moreover, a functional magnetic resonance study reported by our group detected activation in the left insula prior to hallucination events. This finding is suggestive of activation in the same region detected in healthy subjects during “auditory search” in response to ambiguous sounds when anticipating meaningful speech. AVHs often are experienced with a deep emotional salience and may occur in the context of dramatic social isolation that together could reinforce heightened auditory expectancy. These findings and clinical observations suggest that Arieti''s original formulation deserves further study.     

Failure of repetition suppression and memory encoding in aging and Alzheimer��s disease

The suppression of neural activity in the medial temporal lobe (MTL) has been suggested as a marker of successful recognition of familiarity in healthy subjects, but to be impaired in patients with Alzheimer’s disease (AD). In this study, we investigated whether the ability to suppress MTL activity during repeated exposure to face-name pairs was related to the ability to successfully encode novel associations in 90 individuals ranging from healthy young and older subjects to mildly impaired elderly and AD patients. Activity in the anterior MTL during Repeated stimuli was inversely related to performance in post-scan associative recognition for the Novel face-name pairs. In a subset (n = 60) of subjects undergoing more detailed neuropsychological testing, greater MTL Repeated activity was correlated with worse word-list delayed recall performance. Failure of response suppression to familiar information may be a sensitive marker of MTL dysfunction and memory impairment in aging and prodromal AD.     

Early atrophy of pallidum and accumbens nucleus in Huntington��s disease

In Huntington's disease (HD) atrophy of the caudate nucleus and putamen has been described many years before clinical manifestation. Volume changes of the pallidum, thalamus, brainstem, accumbens nucleus, hippocampus, and amygdala are less well investigated, or reported with contradicting results. The aim of our study is to provide a more precise view of the specific atrophy of the subcortical grey matter structures in different stages of Huntington's disease, and secondly to investigate how this influences the clinical manifestations. All TRACK-HD subjects underwent standardised T1-weighted 3T MRI scans encompassing 123 manifest HD (stage 1, n = 77; stage 2, n = 46), 120 premanifest HD (close to onset n = 58, far from onset n = 62) and 123 controls. Using FMRIB's FIRST and SIENAX tools the accumbens nucleus, amygdala, brainstem, caudate nucleus, hippocampus, pallidum, putamen, thalamus and whole brain volume were extracted. Results showed that volumes of the caudate nucleus and putamen were reduced in premanifest HD far from predicted onset (>10.8 years). Atrophy of accumbens nucleus and pallidum was apparent in premanifest HD in the close to onset group (0-10.8 years). All other structures were affected to some degree in the manifest group, although brainstem, thalamus and amygdala were relatively spared. The accumbens nucleus, putamen, pallidum and hippocampus had a strong significant correlation with functional and motor scores. We conclude that volume changes may be a sensitive and reliable measure for early disease detection and in this way serve as a biomarker for Huntington's disease. Besides the caudate nucleus and putamen, the pallidum and the accumbens nucleus show great potential in this respect.     

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.     

The effects of aging and Alzheimer��s disease on associative recognition memory

We investigated the effects of aging and Alzheimer's disease (AD) on item and associative recognition memory. Three groups of participants (younger adults, elderly adults, and AD patients) studied photographs of common objects that were located on either the left or the right side of a black computer screen inside either a red or a blue square. In a subsequent old/new recognition memory test, the participants were presented with four kinds of stimuli: "intact" stimuli, which were presented as they were during the study phase; "location-altered" stimuli, which were presented in a different location; "color-altered" stimuli, which were presented with a different surrounding color; and "new" stimuli, which consisted of photographs that had not been presented during the study phase. Compared with younger adults, the older adults showed equivalent performance in simple item recognition but worse performance in discriminating location-altered and color-altered stimuli. Compared with older adults, the AD patients showed equivalent performance in discriminating color-altered stimuli but worse performance in simple item recognition and the discrimination of location-altered stimuli. We speculate that distinct structural and functional changes in specific brain regions that are caused by aging and AD are responsible for the different patterns of memory impairment.     

Reciprocal Induction Between ��-Synuclein and ��-Amyloid in Adult Rat Neurons

In spite of definite roles for ??-amyloid (A??) in familial Alzheimer??s disease (AD), the cause of sporadic AD remains unknown. Amyloid senile plaques and Lewy body pathology frequently coexist in neocortical and hippocampal regions of AD and Parkinson??s diseases. However, the relationship between A?? and ??-synuclein (??-Syn), the principle components in the pathological structures, in neuronal toxicity and the mechanisms of their interaction are not well studied. As A?? and ??-Syn accumulate in aging patients, the biological functions and toxicity of these polypeptides in the aging brain may be different from those in young brain. We examined the neurotoxicity influences of A??1-42 or ??-Syn on mature neurons and the effects of A??1-42 or ??-Syn on the production of endogenous ??-Syn or A??1-40 reciprocally using a model of culture enriched with primary neurons from the hippocampus of adult rats. Treatment of neurons with high concentrations of A??1-42 or ??-Syn caused significant apoptosis of neurons. Following A??1-42 treatment at sub apoptotic concentrations, both intra- and extra-cellular ??-Syn levels were significantly increased. Reciprocally, the non-toxic levels of ??-Syn treatment also increased intra- and extra-cellular A??1-40 levels. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, suppressed ??-Syn-induced A??1-40 elevation, as well as A??1-42-induced ??-Syn elevation. Thus, high concentrations of A??1-42 and ??-Syn exert toxic effects on mature neurons; however, non-toxic concentration treatment of these polypeptides induced the production of each other reciprocally with possible involvement of PI3K pathway.     

Physical and functional cooperation of neural cell adhesion molecule and ��1-integrin in neurite outgrowth induction

Neural cell adhesion molecule (NCAM) and ??1-integrin are both involved in cell differentiation, with changes in the expression of these two molecules correlating with changes in the malignancy of tumor cells. There is a known functional correlation between NCAM and ??1-integrin in adhesion and also neurite outgrowth in tumor cells. In the present study, we used immunostaining and immunoprecipitation studies to demonstrate that isoform 120 of NCAM associates physically as well as functionally with ??1-integrin in the induction of neurite outgrowth in SH-SY5Y-human neuroblastoma cells. The interaction between these two molecules is mandatory for neurite outgrowth. NCAM blockage completely inhibits the effects of ??1-integrin on neurite outgrowth. These findings further our understanding of the interactions between NCAMs and integrins in malignancy.     

Prenatal exposure to ��2-adrenergic receptor agonists and risk of autism spectrum disorders

This study aims to investigate the association between prenatal exposure to terbutaline and other β2 adrenergic receptor (B2AR) agonists and autism spectrum disorders (ASDs). The methodology used is a case–control study among children born from 1995 to 1999 at Kaiser Permanente Northern California hospitals. Cases (n = 291) were children with an ASD diagnosis; controls (n = 284) were children without ASDs, randomly sampled and frequency-matched to cases on sex, birth year, and delivery hospital. Exposure to B2AR agonists during 30 days prior to conception and each trimester of pregnancy was ascertained from prenatal medical records and health plan databases. The frequency of exposure to any B2AR agonist during pregnancy was similar for mothers of children with ASD and mothers of controls (18.9% vs. 14.8%, P = 0.19). Exposure to B2AR agonists other than terbutaline was not associated with an increased risk for ASDs. However, terbutaline exposure for >2 days during the third trimester was associated with more than a fourfold increased risk for ASDs independent of indication although the limited sample size resulted in an imprecise and nonsignificant effect estimate (OR_adj = 4.4; 95% confidence interval, 0.8–24.6). This analysis does not offer evidence linking B2AR exposure in pregnancy with autism risk. However, exposure to terbutaline during the third trimester for >2 days may be associated with an increased risk of autism. Should this result be confirmed in larger samples, it would point to late pregnancy as an etiologic window of interest in autism risk factor research.     

Alzheimer��s disease is not ��brain aging��: neuropathological, genetic, and epidemiological human studies

Human studies are reviewed concerning whether "aging"-related mechanisms contribute to Alzheimer's disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human "accelerated aging" diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical "dementia" and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an "aging-linked" disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging.     

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.     

Clinical features and prognosis with Guillain-Barr�� syndrome

Background:

Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy commonly characterized by rapidly progressive, symmetric weakness and areflexia.

Materials and Methods:

We retrospectively assessed the clinical manifestations, results of electrodiagnostic tests, functional status and prognosis of 36 children diagnosed with GBS.

Results:

Based on clinical and electrophysiological findings, the patients were classified as having acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (n = 25), acute motor axonal neuropathy (AMAN) (n = 10) and acute motor-sensory axonal neuropathy (AMSAN) (n = 1). Twenty (55.5%) patients were males and 16 (44.5%) patients were females. The mean age of the 36 patients was 68.1 ± 45.01 months (range, 6–180 months). Five (13.8%) patients were younger than 2 years. The most common initial symptoms were limb weakness, which was documented in 34 (94.4%) patients. In our study, 18 patients (51.4%) showed albuminocytological dissociation (raised protein concentration without pleocytosis) on cerebrospinal fluid (CSF) examination. Three patients (8.3%) required mechanical ventilation therapy during hospitalization. Unfortunately, three (8.3%) patients died; one patient had AIDP and two patients had axonal involvement (one case was AMAN and another case was AMSAN). When we compared the cases of residual sequel/dead and cases of complete recovery for neural involvement type including AIDP, AMAN and AMSAN, we did not find a statistically significant difference between the groups (P > 0.05).

Conclusion:

Our findings showed that cases of GBS was not uncommon in children younger than 2 years of age, and CSF protein level might be found high in the first week of the disease in about one half of the patients, with a higher rate of morbidity and mortality in patients with axonal involvement than in those with AIDP.     

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.     

��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.     

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.