Accumulation of phosphorylated α-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy

We immunohistochemically examined the brain and peripheral sympathetic ganglia from eight patients with multiple system atrophy (MSA), using an antibody specific for phosphorylated -synuclein (anti-PSer129). Phosphorylated -synuclein was deposited in five cellular locations: oligodendroglial cytoplasm and nucleus, and neuronal cytoplasm, processes and nucleus. Many neuronal cytoplasmic inclusions (NCIs) were found in the pontine and inferior olivary nuclei and, to a lesser extent, in the substantia nigra, locus ceruleus, and neocortical and hippocampal neurons. NCIs were also found in the sympathetic ganglia in two out of the eight cases. Moreover, anti-PSer129 immunohistochemistry revealed extensive neuropil pathology; swollen neurites were abundant in the pontine nucleus, delicate neurites were observed in the deeper layers of the cerebral cortex and thalamus, and neuropil threads and dot-like structures were distributed in the basal ganglia and brainstem. Diffuse neuronal cytoplasmic staining (pre-NCI) was frequently found in the pontine and inferior olivary nuclei. Thus, the widespread accumulation of phosphorylated -synuclein in both glial and neuronal cells is a pathological feature in patients suffering from MSA.     

A tale of two factors: What determines the rate of progression in Huntington's disease? A longitudinal MRI study

Over the past several years, increased attention has been devoted to understanding regionally selective brain changes that occur in Huntington's disease and their relationships to phenotypic variability. Clinical progression is also heterogeneous, and although CAG repeat length influences age of onset, its role, if any, in progression has been less clear. We evaluated progression in Huntington's disease using a novel longitudinal magnetic resonance imaging analysis. Our hypothesis was that the rate of brain atrophy is influenced by the age of onset of Huntington's disease. We scanned 22 patients with Huntington's disease at approximately 1‐year intervals; individuals were divided into 1 of 3 groups, determined by the relative age of onset. We found significant differences in the rates of atrophy of cortex, white matter, and subcortical structures; patients who developed symptoms earlier demonstrated the most rapid rates of atrophy compared with those who developed symptoms during middle age or more advanced age. Rates of cortical atrophy were topologically variable, with the most rapid changes occurring in sensorimotor, posterior frontal, and portions of the parietal cortex. There were no significant differences in the rates of atrophy in basal ganglia structures. Although both CAG repeat length and age influenced the rate of change in some regions, there was no significant correlation in many regions. Rates of regional brain atrophy seem to be influenced by the age of onset of Huntington's disease symptoms and are only partially explained by CAG repeat length. These findings suggest that other genetic, epigenetic, and environmental factors play important roles in neurodegeneration in Huntington's disease. © 2011 Movement Disorder Society     

Role of the cannabinoid system in the transit of beta-amyloid across the blood–brain barrier

Emerging evidence suggests beta-amyloid (Aβ) deposition in the Alzheimer's disease (AD) brain is the result of impaired clearance, due in part to diminished Aβ transport across the blood–brain barrier (BBB). Recently, modulation of the cannabinoid system was shown to reduce Aβ brain levels and improve cognitive behavior in AD animal models. The purpose of the current studies was to investigate the role of the cannabinoid system in the clearance of Aβ across the BBB. Using in vitro and in vivo models of BBB clearance, Aβ transit across the BBB was examined in the presence of cannabinoid receptor agonists and inhibitors. In addition, expression levels of the Aβ transport protein, lipoprotein receptor-related protein1 (LRP1), were determined in the brain and plasma of mice following cannabinoid treatment. Cannabinoid receptor agonism or inhibition of endocannabinoid-degrading enzymes significantly enhanced Aβ clearance across the BBB (2-fold). Moreover, cannabinoid receptor inhibition negated the stimulatory influence of cannabinoid treatment on Aβ BBB clearance. Additionally, LRP1 levels in the brain and plasma were elevated following cannabinoid treatment (1.5-fold), providing rationale for the observed increase in Aβ transit from the brain to the periphery. The current studies demonstrate, for the first time, a role for the cannabinoid system in the transit of Aβ across the BBB. These findings provide insight into the mechanism by which cannabinoid treatment reduces Aβ burden in the AD brain and offer additional evidence on the utility of this pathway as a treatment for AD.     

Striatal blood–brain barrier permeability in Parkinson's disease

In vivo studies have shown that blood–brain barrier (BBB) dysfunction is involved in the course of Parkinson''s disease (PD). However, these have lacked either anatomic definition or the ability to recognize minute changes in BBB integrity. Here, using histologic markers of serum protein, iron, and erythrocyte extravasation, we have shown significantly increased permeability of the BBB in the postcommissural putamen of PD patients. The dense innervation of the striatum by PD-affected regions allows for exploitation of this permeability for therapeutic goals. These results are also discussed in the context of the retrograde trans-synaptic hypothesis of PD spread.     

Immunologic privilege in the central nervous system and the blood–brain barrier

The brain is in many ways an immunologically and pharmacologically privileged site. The blood–brain barrier (BBB) of the cerebrovascular endothelium and its participation in the complex structure of the neurovascular unit (NVU) restrict access of immune cells and immune mediators to the central nervous system (CNS). In pathologic conditions, very well-organized immunologic responses can develop within the CNS, raising important questions about the real nature and the intrinsic and extrinsic regulation of this immune privilege. We assess the interactions of immune cells and immune mediators with the BBB and NVU in neurologic disease, cerebrovascular disease, and intracerebral tumors. The goals of this review are to outline key scientific advances and the status of the science central to both the neuroinflammation and CNS barriers fields, and highlight the opportunities and priorities in advancing brain barriers research in the context of the larger immunology and neuroscience disciplines. This review article was developed from reports presented at the 2011 Annual Blood-Brain Barrier Consortium Meeting.     

Decreased blood–brain barrier P-glycoprotein function in the progression of Parkinson’s disease,PSP and MSA

Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.     

Assessment of the blood–brain barrier in CNS drug discovery

A wide variety of models have been developed over the years to predict blood–brain barrier (BBB) penetration, most of them have focussed on predicting total concentrations of drug and then expressing this as a brain:blood (or plasma) ratio. This approach is somewhat flawed and fails to address the critical issue of understanding the relationship between access of free drug to the requisite site of action. In this short review, we highlight the need for an integrated approach and whilst blood–brain barrier permeability is an important determinant in achieving efficacious CNS drug concentrations it should not be viewed or measured in isolation. Optimal CNS penetration is achieved through the correct balance of permeability, a low potential for active efflux and the appropriate physicochemical properties that allow for drug partitioning and distribution into brain tissue. Such an approach should enhance and accelerate our understanding and ability to predict CNS efficacy in terms of free drug concentrations and the rate at which they are achieved.     

Structure and function of the blood–brain barrier

Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the blood–brain barrier (BBB), blood–CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood–CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB.     

Do cognitive patterns of brain magnetic activity correlate with hippocampal atrophy in Alzheimer's disease?

BACKGROUND: Many reports support the clinical validity of volumetric MRI measurements in Alzheimer's disease. OBJECTIVE: To integrate functional brain imaging data derived from magnetoencephalography (MEG) and volumetric data in patients with Alzheimer's disease and in age matched controls. METHODS: MEG data were obtained in the context of a probe-letter memory task. Volumetric measurements were obtained for lateral and mesial temporal lobe regions. RESULTS: As expected, Alzheimer's disease patients showed greater hippocampal atrophy than controls bilaterally. MEG derived indices of the degree of activation in left parietal and temporal lobe areas, occurring after 400 ms from stimulus onset, correlated significantly with the relative volume of lateral and mesial temporal regions. In addition, the size of the right hippocampus accounted for a significant portion of the variance in cognitive scores independently of brain activity measures. CONCLUSIONS: These data support the view that there is a relation between hippocampal atrophy and the degree of neurophysiological activity in the left temporal lobe.     

The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy

Summary. α-Synuclein, a synaptic protein of unknown function, is a major component of Lewy bodies and may play a role in the pathophysiological process of Parkinson’s disease (PD). In this study, we measured the plasma α-synuclein levels in 105 patients with PD, 38 patients with multiple system atrophy (MSA), and 51 age-matched controls. The α-synuclein level was significantly elevated in patients with PD (79.9 ± 4.0 pg/ml, p < 0.001) and in those with MSA (78.1 ± 3.5 pg/ml, p = 0.019) compared with the level in controls (76.1 ± 3.9 pg/ml). The α-synuclein level was higher in patients with PD than in those with MSA (79.9 ± 4.0 vs 78.1 ± 3.5, p = 0.016). Our study demonstrated that the α-synuclein level in plasma is elevated in patients with PD and MSA.     

Changes in the permeability of blood brain barrier and endothelial cell damage after cerebral ischemia

INTRODUCTION The relationship between the permeability of blood-brain barrier (BBB) and endothelial cells is very complex. In order to expound the effect of endothelial cells and its change mechanism in the change of permeability of BBB after cerebral isc…     

Reduced bowel sounds in Parkinson’s disease and multiple system atrophy patients

Digital auscultation of bowel sounds was performed in newly diagnosed, drug-naïve patients with Parkinson’s disease (PD) (n = 10), multiple system atrophy (MSA) (n = 12), progressive supranuclear palsy/corticobasal degeneration (PSP/CBD) (n = 7), and control subjects (n = 18). The number of bowel sounds per minute and the integrated time of bowel sounds were significantly lower in PD and MSA patients than in control subjects. Reduced bowel sounds may herald compromised gastrointestinal motility in patients with PD and MSA.     

Diagnostic progression to schizophrenia in 35,255 patients with obsessive–compulsive disorder: a longitudinal follow-up study

Evidence suggests a continuity between obsessive–compulsive disorder (OCD) and schizophrenia. However, the factors that may predict diagnostic progression from OCD to schizophrenia remain unclear. A total of 35,255 adolescents and adults with OCD (ICD-9-CM code: 300.3) were enrolled between 2001 and 2010 and followed up at the end of 2011 for the identification of de novo schizophrenia (ICD-9-CM code: 295). The Kaplan–Meier method was used to estimate incidence rates, and the Cox regression was used to determine the significance of candidate predictors. At the end of the 11-year follow-up period, the crude cumulative progression rate from OCD to schizophrenia was 6%, and the estimated progression rate totaled 7.80%. Male sex (hazard ratio: 1.23), obesity (1.77), autism spectrum disorder (1.69), bipolar disorder (1.69), posttraumatic stress disorder (1.65), cluster A personality disorder (2.50), and a family history of schizophrenia (2.57) also were related to an elevated likelihood of subsequent progression to schizophrenia in patients with OCD. Further study is necessary to elucidate the exact pathomechanisms underlying diagnostic progression to schizophrenia in patients with OCD.

     

Understanding the mechanisms underlying the disruption of the blood–brain barrier in parasitic infections

Parasites have a significant impact on the neurological, cognitive, and mental well-being of humans, with a global population of over 1 billion individuals affected. The pathogenesis of central nervous system (CNS) injury in parasitic diseases remains limited, and prevention and control of parasitic CNS infections remain significant areas of research. Parasites, encompassing both unicellular and multicellular organisms, have intricate life cycles and possess the ability to infect a diverse range of hosts, including the human population. Parasitic illnesses that impact the central and peripheral nervous systems are a significant contributor to morbidity and mortality in low- to middle-income nations. The precise pathways through which neurotropic parasites infiltrate the CNS by crossing the blood–brain barrier (BBB) and cause neurological harm remain incompletely understood. Investigating brain infections caused by parasites is closely linked to studying neuroinflammation and cerebral impairment. The exact molecular and cellular mechanisms involved in this process remain incomplete, but understanding the exact mechanisms could provide insight into their pathogenesis and potentially reveal novel therapeutic targets. This review paper explores the underlying mechanisms involved in the development of neurological disorders caused by parasites, including parasite-derived elements, host immune responses, and modifications in tight junctions (TJs) proteins.     

α-Synuclein-immunoreactive structure formation is enhanced in sympathetic ganglia of patients with multiple system atrophy

We immunohistochemically examined the sympathetic ganglia (SG) and brains of 26 patients with multiple system atrophy (MSA), 19 age-matched controls, and 25 patients with amyotrophic lateral sclerosis (ALS). -Synuclein-immunoreactive structures were found in the neuronal cytoplasm and processes of the SG in 11 of the 26 MSA cases (42.3%) and 1 of the 25 ALS cases (4%), but not in the 19 controls. No -synuclein-immunoreactive structures were found in Schwann cells or the neuronal nucleus. Mean disease duration of MSA cases with -synuclein-immunoreactive structures was significantly longer than that of MSA cases without -synuclein-immunoreactive structures. -Synuclein-immunoreactive structures in 4 cases proved to be Lewy bodies (LB) based on hematoxylin-eosin staining. A few LB were also found in the brains of 3 of these 4 cases. In the other 7 MSA cases, diffuse or focal neuronal cytoplasmic aggregates and swollen neurites were detected with -synuclein immunostaining, but not with hematoxylin-eosin staining. However, a few LB-like structures with ring-like staining were observed in those aggregates, which suggested those aggregates had progressed to form LB. Immunoelectron microscopically, those aggregates were composed of filaments and granular materials which closely resembled the ultrastructural features of LB. We inferred that -synuclein aggregates found in the SG in our study evidenced LB-related pathologies. MSA, a type of synucleinopathy, is characterized by glial cytoplasmic inclusions in oligodendrocytes, but also frequently develops LB pathology in the late stage, especially in the SG.