Border-associated macrophages mediate the neuroinflammatory response in an alpha-synuclein model of Parkinson disease.

Dopaminergic cell loss due to the accumulation of α-syn is a core feature of the pathogenesis of Parkinson disease. Neuroinflammation specifically induced by α-synuclein has been shown to exacerbate neurodegeneration, yet the role of central nervous system (CNS) resident macrophages in this process remains unclear. We found that a specific subset of CNS resident macrophages, border-associated macrophages (BAMs), play an essential role in mediating α-synuclein related neuroinflammation due to their unique role as the antigen presenting cells necessary to initiate a CD4 T cell response whereas the loss of MHCII antigen presentation on microglia had no effect on neuroinflammation. Furthermore, α-synuclein expression led to an expansion in border-associated macrophage numbers and a unique damage-associated activation state. Through a combinatorial approach of single-cell RNA sequencing and depletion experiments, we found that border-associated macrophages played an essential role in immune cell recruitment, infiltration, and antigen presentation. Furthermore, border-associated macrophages were identified in post-mortem PD brain in close proximity to T cells. These results point to a role for border-associated macrophages in mediating the pathogenesis of Parkinson disease through their role in the orchestration of the α-synuclein-mediated neuroinflammatory response.

Connectomic Basis for Tremor Control in Stereotactic Radiosurgical Thalamotomy.

BACKGROUND AND PURPOSE: Given the increased use of stereotactic radiosurgical thalamotomy and other ablative therapies for tremor, new biomarkers are needed to improve outcomes. Using resting-state fMRI and MR tractography, we hypothesized that a "connectome fingerprint" can predict tremor outcomes and potentially serve as a targeting biomarker for stereotactic radiosurgical thalamotomy. MATERIALS AND METHODS: We evaluated 27 patients who underwent unilateral stereotactic radiosurgical thalamotomy for essential tremor or tremor-predominant Parkinson disease. Percentage postoperative improvement in the contralateral limb Fahn-Tolosa-Marin Clinical Tremor Rating Scale (TRS) was the primary end point. Connectome-style resting-state fMRI and MR tractography were performed before stereotactic radiosurgery. Using the final lesion volume as a seed, "connectivity fingerprints" representing ideal connectivity maps were generated as whole-brain R-maps using a voxelwise nonparametric Spearman correlation. A leave-one-out cross-validation was performed using the generated R-maps. RESULTS: The mean improvement in the contralateral tremor score was 55.1% (SD, 38.9%) at a mean follow-up of 10.0 (SD, 5.0) months. Structural connectivity correlated with contralateral TRS improvement (r = 0.52; P = .006) and explained 27.0% of the variance in outcome. Functional connectivity correlated with contralateral TRS improvement (r = 0.50; P = .008) and explained 25.0% of the variance in outcome. Nodes most correlated with tremor improvement corresponded to areas of known network dysfunction in tremor, including the cerebello-thalamo-cortical pathway and the primary and extrastriate visual cortices. CONCLUSIONS: Stereotactic radiosurgical targets with a distinct connectivity profile predict improvement in tremor after treatment. Such connectomic fingerprints show promise for developing patient-specific biomarkers to guide therapy with stereotactic radiosurgical thalamotomy.

Enhanced recovery after surgical repair of incisional hernias.

AIM: Enhanced recovery programmes (ERPs) were developed to improve the patient's post-operative comfort and reduce post-operative morbidity after several types of major surgery including the incisional hernia repair. The aim of this review was to describe the features of ERPs in the setting for incisional hernia repair. METHODS: The literature review was conducted until March 2019, but retrieved very few papers (n = 4) on this topic. All studies were retrospective. RESULTS: Setting and comorbidities of incisional hernia patients are of such importance in many cases that prehabilitation (including tobacco use cessation, management of obesity, diabetes or malnutrition) should play a greater role compared with other specialties. The other peri-operative measures are similar to other specialties but their implementation was very heterogeneous in the published studies. CONCLUSIONS: Like in other surgeries, ERPs were feasible and probably efficient to improve the post-operative course of incisional hernia patients. But the level of evidence remains low.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy.

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

An individualized coaching program for patients with acute ischemic stroke: Feasibility study.

OBJECTIVES: An individualized stroke care program was developed to match patients' education with their needs regarding stroke knowledge, secondary prevention and rehabilitation. Our purpose was to assess feasibility of in-hospital and post-discharge, personalized stroke coaching service. METHODS: Acute ischemic stroke patients enrolled in ASTRAL-B stroke registry (Sint-Lucashospital, Bruges Belgium) with: (a) hospitalization between 12/2014-12/2015, (b) hospital-to-home discharge, and (c) without cognitive decline, were selected. The stroke coach contacted patients individually twice during hospitalization (2×20min) and post-discharge via phone calls using the standardized WSO Post-Strokechecklist. Risk factor management, review of therapy and clinical evolution were discussed. Participants were contacted at 2 weeks, followed by repeat calls if necessary and ambulatory with the vascular neurologist at 1, 3, 6 and 12 months. RESULTS: Of all 255 patients meeting the inclusion criteria, 152 (59.7%) received individualized education during hospitalization by the stroke coach. Median age of our population was 74 years and median NIHSS 5. Majority of patients had at least two cardiovascular risk factors. Patients were not coached because of palliative care/decease (10%), unfavorable life expectancy (2%), dementia (8.5%) and lack of time due to short hospitalization (22%). A quarter of all patients were contacted at least once by phone, 12% were contacted at least twice after discharge. At three months, low stroke recurrence (5%) and mortality rates (4%) were identified, probably linked to improved adherence. CONCLUSIONS: We demonstrated feasibility of an individualized coaching service executed by well-trained stroke nurse. Future research will focus on developing an online portal delivering post-discharge services to patients and caregivers.

Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia.

Dystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestation of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia.

A full-brain, bootstrapped analysis of diffusion tensor imaging robustly differentiates Parkinson disease from healthy controls.

There is a compelling need for early, accurate diagnosis of Parkinson's disease (PD). Various magnetic resonance imaging modalities are being explored as an adjunct to diagnosis. A significant challenge in using MR imaging for diagnosis is developing appropriate algorithms for extracting diagnostically relevant information from brain images. In previous work, we have demonstrated that individual subject variability can have a substantial effect on identifying and determining the borders of regions of analysis, and that this variability may impact on prediction accuracy. In this paper we evaluate a new statistical algorithm to determine if we can improve accuracy of prediction using a subjects left-out validation of a DTI analysis. Twenty subjects with PD and 22 healthy controls were imaged to evaluate if a full brain diffusion tensor imaging-fractional anisotropy (DTI-FA) map might be capable of segregating PD from controls. In this paper, we present a new statistical algorithm based on bootstrapping. We compare the capacity of this algorithm to classify the identity of subjects left out of the analysis with the accuracy of other statistical techniques, including standard cluster-thresholding. The bootstrapped analysis approach was able to correctly discriminate the 20 subjects with PD from the 22 healthy controls (area under the receiver operator curve or AUROC 0.90); however the sensitivity and specificity of standard cluster-thresholding techniques at various voxel-specific thresholds were less effective (AUROC 0.72-0.75). Based on these results sufficient information to generate diagnostically relevant statistical maps may already be collected by current MRI scanners. We present one statistical technique that might be used to extract diagnostically relevant information from a full brain analysis.

Relapsing visceral leishmaniasis in a HIV-1 infected patient with advanced disease.

Leishmaniasis, an intracellular protozoal infection in which tissue macrophages are targeted, is transmitted by female sandfly bite and occurs in 98 countries. Visceral leishmaniasis (VL) is the clinical form of leishmaniasis most frequently associated with HIV, especially in Europe. Both diseases have a synergistic detrimental effect on the cellular immune response. Treatment of VL in patients with underlying HIV-infection is associated with lower cure rates, higher rates of drug toxicity, higher relapse rates and greater mortality than treatment of VL in immunocompetent patients. We report the case of a HIV-1 infected patient with advanced disease who presented VL with multiple relapses. This case highlights the difficulties of treating VL in patients with HIV co-infection.

Differential neuroprotective effects of 14-3-3 proteins in models of Parkinson's disease.

14-3-3 proteins are important negative regulators of cell death pathways. Recent studies have revealed alterations in 14-3-3s in Parkinson's disease (PD) and the ability of 14-3-3s to interact with alpha-synuclein (α-syn), a protein central to PD pathophysiology. In a transgenic α-syn mouse model, we found reduced expression of 14-3-3θ, ε, and γ. These same isoforms prevent α-syn inclusion formation in an H4 neuroglioma cell model. Using dopaminergic cell lines stably overexpressing each 14-3-3 isoform, we found that overexpression of 14-3-3θ, ε, or γ led to resistance to both rotenone and 1-methyl-4-phenylpyridinium (MPP(+)), while other isoforms were not protective against both toxins. Inhibition of a single protective isoform, 14-3-3θ, by shRNA did not increase vulnerability to neurotoxic injury, but toxicity was enhanced by broad-based inhibition of 14-3-3 action with the peptide inhibitor difopein. Using a transgenic C. elegans model of PD, we confirmed the ability of both human 14-3-3θ and a C. elegans 14-3-3 homolog (ftt-2) to protect dopaminergic neurons from α-syn toxicity. Collectively, these data show a strong neuroprotective effect of enhanced 14-3-3 expression - particularly of the 14-3-3θ, ε, and γ isoforms - in multiple cellular and animal models of PD, and point to the potential value of these proteins in the development of neuroprotective therapies for human PD.

Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia.

Early-onset torsion dystonia (DYT1) is an autosomal dominant disease caused by a deletion in the gene encoding the protein torsinA. Recently, a transgenic mouse model of DYT1 has been described, expressing either the human wild-type torsinA (hWT) or mutant torsinA (hMT). We recorded the activity of striatal cholinergic interneurons of hWT, hMT, and control mice. In slice preparations, no significant differences were observed in resting membrane potential (RMP), firing activity, action potential duration or Ih current. Quinpirole, a D2-like dopamine receptor agonist, did not produce detectable effects on RMP of cholinergic interneurons in control mice and hWT mice, but in the hMT mice caused membrane depolarization and an increase in the firing rate. D2 receptor activation inhibits N-type high-voltage-activated calcium currents. We found that, in isolated interneurons from hMT mice, the quinpirole-mediated inhibition of N-type currents was significantly larger than in hWT and controls. Moreover, the N-type component was significantly over-represented in hMT mice. The altered sensitivity of N-type channels in hMT mice could account for the paradoxical excitatory effect of D2 stimulation. Our data support the existence of an imbalance between striatal dopaminergic and cholinergic signaling in DYT1 dystonia.

Huntingtin inclusions do not down-regulate specific genes in the R6/2 Huntington's disease mouse.

Transcriptional dysregulation is a central pathogenic mechanism in Huntington's disease (HD); HD and transgenic mouse models of HD demonstrate down-regulation of specific genes at the level of mRNA expression. Furthermore, neuronal intranuclear inclusions (NIIs) have been identified in the brains of R6/2 mice and HD patients. One possibility is that NIIs contribute to transcriptional dysregulation by sequestering transcription factors. We therefore assessed the relationship between NIIs and transcriptional dysregulation in the R6/2 mouse, using double-label in situ hybridization combined with immunohistochemistry, and laser capture microdissection combined with quantitative real-time PCR. There was no difference in transcript levels of specific genes between NII-positive and NII-negative neurons. These results demonstrate that NIIs do not cause decreases in D2, PPE and PSS mRNA levels in R6/2 striatum and therefore are not involved in the down-regulation of these specific genes in this HD model. In addition, these observations argue against the notion that NIIs protect against transcriptional dysregulation in HD.

Absence of alpha-synuclein mRNA expression in normal and multiple system atrophy oligodendroglia.

alpha-Synuclein is a major constituent of glial cytoplasmic inclusions (GCIs), which are pathognomic for multiple system atrophy (MSA). We have previously demonstrated that in normal human brain, alpha-synuclein mRNA has a restricted pattern of neuronal expression and no apparent glial expression. The current study used double-label in situ hybridization to determine if alpha-synuclein mRNA is expressed by oligodendroglia of MSA cases. Analysis of MSA brain tissue revealed depletion of regional signal for this transcript in many brain areas due to extensive neurodegeneration. Cellular analysis of oligodendroglia in crus cerebri, a GCI-rich region ventral to substantia nigra, revealed an absence of alpha-synuclein mRNA signal in control and MSA cases. However, an abundance of this transcript was detected in melanin-containing neurons of substantia nigra. Therefore, oligodendroglia do not express alpha-synuclein mRNA in control and MSA cases suggesting that involvement of alpha-synuclein in GCI pathology of MSA is due to its ectopic presence in oligodendroglia.

Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease.

The development of dyskinesias and other motor complications greatly limits the use of levodopa therapy in Parkinson's disease (PD). Studies in rodent models of PD suggest that an important mechanism underlying the development of levodopa-related motor complications is alterations in striatal NMDA receptor function. We examined striatal NMDA receptors in the MPTP-lesioned primate model of PD. Quantitative immunoblotting was used to determine the subcellular abundance of NR1, NR2A and NR2B subunits in striata from unlesioned, MPTP-lesioned (parkinsonian) and MPTP-lesioned, levodopa-treated (dyskinetic) macaques. In parkinsonian macaques, NR1 and NR2B subunits in synaptosomal membranes were decreased to 66 +/- 11% and 51.2 +/- 5% of unlesioned levels respectively, while the abundance of NR2A was unaltered. Levodopa treatment eliciting dyskinesia normalized NR1 and NR2B and increased NR2A subunits to 150 +/- 12% of unlesioned levels. No alterations in receptor subunit tyrosine phosphorylation were detected. These results demonstrate that altered synaptic abundance of NMDA receptors with relative enhancement in the abundance of NR2A occurs in primate as well as rodent models of parkinsonism, and that in the macaque model, NR2A subunit abundance is further increased in dyskinesia. These data support the view that alterations in striatal NMDA receptor systems are responsible for adaptive and maladaptive responses to dopamine depletion and replacement in parkinsonism, and highlight the value of subtype selective NMDA antagonists as novel therapeutic approaches for PD.

Tyrosine phosphorylation of the metabotropic glutamate receptor mGluR5 in striatal neurons.

Protein phosphorylation, controlled by the coordinated actions of phosphatases and kinases, is an important regulatory mechanism in synaptic transmission and other neurophysiological processes. Ionotropic glutamate receptors are known targets of phosphorylation on serine, threonine and tyrosine residues, with functional consequences for cell excitability, plasticity and toxicity. While phosphorylation of metabotropic glutamate receptors (mGluRs) also impacts critical cellular processes, there has been no evidence for direct tyrosine phosphorylation of mGluRs. In the present study, anti-phosphotyrosine and specific mGluR antibodies were used to detect tyrosine-phosphorylated mGluRs in rat brain. In particular, we found that mGluR5 is an abundant phosphotyrosine protein in vivo as well as in primary striatal neurons and tissue slices in vitro. The protein phosphatase inhibitor pervanadate robustly increased the amount of tyrosine-phosphorylated mGluR5, suggesting the receptor is subject to an endogenous, active cycle of phosphorylation and dephosphorylation. Furthermore, NMDA treatment also increased the amount of tyrosine-phosphorylated mGluR5, suggesting these endogenous phosphorylation regulatory mechanisms can be used to mediate crosstalk between synaptic glutamate receptors. While mGluR5-stimulated phosphoinositide hydrolysis appears to be unaltered by pervanadate treatment, tyrosine phosphorylation of mGluR5 may be important in trafficking, anchoring, or signaling of the receptor through G protein-independent pathways.

Dopamine transmission in DYT1 dystonia: a biochemical and autoradiographical study.

Indices of dopamine transmission were measured in the postmortem striatum of DYT1 dystonia brains. A significant increase in the striatal 3,4-dihydroxyphenylacetic acid/dopamine ratio was found. Quantitative autoradiography revealed no differences in the density of dopamine transporter or vesicular monoamine transporter-2 binding; however, there was a trend toward a reduction in D(1) receptor and D(2) receptor binding. One brain with DYT1 parkinsonism was similarly evaluated and marked reductions in striatal dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid content as well as the density of binding of all four dopaminergic ligands were measured.

Dystonia and its disorders.

Dystonia is a movement disorder characterized by sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The term dystonia does not signify a single disease, but instead describes a symptom and sign that may be part of many disorders with a variety of causes. Dystonia may be classified by age of onset, distribution of symptoms, or by etiology. An increasing number of genetic forms of dystonia have been recognized and the findings have advanced knowledge of underlying neural mechanisms of pathogenesis. Options for treatment of dystonia include pharmacological therapy, botulinum toxin injection, or neurosurgical procedures.

Gene expression profiling in the post-mortem human brain--no cause for dismay.

Global expression profiling techniques such as microarray technology promise to revolutionize biology. Soon it will be possible to investigate alterations at the transcript level of the entire human genome. There is great hope that these techniques will at last shed light on the pathological processes involved in complex neuropsychiatric disorders such as schizophrenia. These scientific advances in turn have re-kindled a great interest and demand for post-mortem brain tissue. Good quality post-mortem tissue undoubtedly is the fundamental prerequisite to investigate complex brain disorders with molecular profiling techniques. In this review we show that post-mortem brain tissue can yield good quality mRNA and intact protein antigens which allow the successful application of traditional molecular biology methods as well as novel profiling techniques. We also consider the use of laser-capture microdissection on post-mortem tissue. This recently developed technique allows the experimenter to explore the molecular basis of cellular function at the single cell level. The combination of laser-capture microdissection with high throughput profiling techniques offers opportunities to obtain precise genetic fingerprints of individual neurons allowing comparisons of normal and pathological states.

Dopamine D1 receptor-dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane.

Recent work has shown substantial alterations in NMDA receptor subunit expression, assembly, and phosphorylation in the dopamine-depleted striatum of a rodent 6-hydroxydopamine model of Parkinson's disease. These modifications are hypothesized to result from the trafficking of NMDA receptors between subcellular compartments. Here we show that in rat striatal tissues the NR2A and NR2B subunits in the synaptosomal membrane, and not those in the light membrane and synaptic vesicle-enriched compartments, are tyrosine phosphorylated. The dopamine D1 receptor agonist SKF-82958 produces (1) an increase in NR1, NR2A, and NR2B proteins in the synaptosomal membrane fraction; (2) a decrease in NR1, NR2A, and NR2B proteins in the light membrane and synaptic vesicle-enriched fractions; and (3) an increase in the tyrosine phosphorylation of NR2A and NR2B in the synaptosomal membrane compartment. The protein phosphatase inhibitor pervanadate reproduces the alterations in subcellular distribution and phosphorylation, whereas the effects of the dopamine D1 receptor agonist are blocked by genistein, a protein tyrosine kinase inhibitor. Dopamine D1 receptor agonist treatment does not change the subcellular distribution of the AMPA receptor subunits GluR1 or GluR2/3 in the striatum and has no effect on cortical or cerebellar NMDA receptor subunits. These data reveal a rapid dopamine D1 receptor- and tyrosine kinase-dependent trafficking of striatal NMDA receptors between intracellular and postsynaptic sites. The subcellular trafficking of striatal NMDA receptors may play a significant role both in the pathogenesis of Parkinson's disease and in the development of adverse effects of chronic dopaminergic therapy in parkinsonian patients.