Oral and intestinal dysbiosis in Parkinson's disease.

The suspicion of an origin of Parkinson's disease (PD) at the periphery of the body and the involvement of environmental risk factors in the pathogenesis of PD have directed the attention of the scientific community towards the microbiota. The microbiota represents all the microorganisms residing both in and on a host. It plays an essential role in the physiological functioning of the host. In this article, we review the dysbiosis repeatedly demonstrated in PD and how it influences PD symptoms. Dysbiosis is associated with both motor and non-motor PD symptoms. In animal models, dysbiosis only promotes symptoms in individuals genetically susceptible to Parkinson's disease, suggesting that dysbiosis is a risk factor but not a cause of Parkinson's disease. We also review how dysbiosis contributes to the pathophysiology of PD. Dysbiosis induces numerous and complex metabolic changes, resulting in increased intestinal permeability, local and systemic inflammation, production of bacterial amyloid proteins that promote α-synuclein aggregation, as well as a decrease in short-chain fatty acid-producing bacteria that have anti-inflammatory and neuroprotective potential. In addition, we review how dysbiosis decreases the efficacy of dopaminergic treatments. We then discuss the interest of dysbiosis analysis as a biomarker of Parkinson's disease. Finally, we give an overview of how interventions modulating the gut microbiota such as dietary interventions, pro-biotics, intestinal decontamination and fecal microbiota transplantation could influence the course of PD.

Evaluation of electrode position in deep brain stimulation by image fusion (MRI and CT).

INTRODUCTION: Imaging has an essential role in the evaluation of correct positioning of electrodes implanted for deep brain stimulation (DBS). Although MRI offers superior anatomic visualization of target sites, there are safety concerns in patients with implanted material; imaging guidelines are inconsistent and vary. The fusion of postoperative CT with preoperative MRI images can be an alternative for the assessment of electrode positioning. The purpose of this study was to assess the accuracy of measurements realized on fused images (acquired without a stereotactic frame) using a manufacturer-provided software. METHODS: Data from 23 Parkinson's disease patients who underwent bilateral electrode placement for subthalamic nucleus (STN) DBS were acquired. Preoperative high-resolution T2-weighted sequences at 3 T, and postoperative CT series were fused using a commercially available software. Electrode tip position was measured on the obtained images in three directions (in relation to the midline, the AC-PC line and an AC-PC line orthogonal, respectively) and assessed in relation to measures realized on postoperative 3D T1 images acquired at 1.5 T. RESULTS: Mean differences between measures carried out on fused images and on postoperative MRI lay between 0.17 and 0.97 mm. CONCLUSION: Fusion of CT and MRI images provides a safe and fast technique for postoperative assessment of electrode position in DBS.

Differentiation between Parkinson disease and other forms of Parkinsonism using support vector machine analysis of susceptibility-weighted imaging (SWI): initial results.

OBJECTIVES: To diagnose Parkinson disease (PD) at the individual level using pattern recognition of brain susceptibility-weighted imaging (SWI). METHODS: We analysed brain SWI in 36 consecutive patients with Parkinsonism suggestive of PD who had (1) SWI at 3 T, (2) brain (123)I-ioflupane SPECT and (3) extensive neurological testing including follow-up (16 PD, 67.4 ± 6.2 years, 11 female; 20 OTHER, a heterogeneous group of atypical Parkinsonism syndromes 65.2 ± 12.5 years, 6 female). Analysis included group-level comparison of SWI values and individual-level support vector machine (SVM) analysis. RESULTS: At the group level, simple visual analysis yielded no differences between groups. However, the group-level analyses demonstrated increased SWI in the bilateral thalamus and left substantia nigra in PD patients versus other Parkinsonism. The inverse comparison yielded no supra-threshold clusters. At the individual level, SVM correctly classified PD patients with an accuracy above 86 %. CONCLUSIONS: SVM pattern recognition of SWI data provides accurate discrimination of PD among patients with various forms of Parkinsonism at an individual level, despite the absence of visually detectable alterations. This pilot study warrants further confirmation in a larger cohort of PD patients and with different MR machines and MR parameters.

Diagnosis of and treatment for symptomatic carotid stenosis: an updated review.

Carotid stenoses of ≥50% account for about 15-20% of strokes. Their degree may be moderate (50-69%) or severe (70-99%). Current diagnostic methods include ultrasound, MR- or CT-angiography. Stenosis severity, irregular plaque surface, and presence of microembolic signals detected by transcranial Doppler predict the early recurrence risk, which may be as high as 20%. Initial therapy comprises antiplatelets and statins. Benefit of revascularization is greater in men, in older patients, and in severe stenosis; patients with moderate stenoses may also profit particularly if the plaque has an irregular aspect. An intervention should be performed within <2 weeks. In large randomized studies comparing endarterectomy and stenting, endovascular therapy was associated with a higher risk of periprocedural stroke, yet in some studies, with a lower risk of myocardial infarction and of cranial neuropathy. These trials support endarterectomy as the first choice treatment. Risk factors for each of the two therapies have been indentified: coronary artery disease, neck radiation, contralateral laryngeal nerve palsy for endarterectomy, and, elderly patients (>70 years), arch vessel tortuosity and plaques with low echogenicity on ultrasound for carotid stenting. Lastly, in direct comparisons, a contralateral occlusion increases the risk of periprocedural complications in both types of treatment.

Coiled coils: a highly versatile protein folding motif.

The alpha-helical coiled coil is one of the principal subunit oligomerization motifs in proteins. Its most characteristic feature is a heptad repeat pattern of primarily apolar residues that constitute the oligomer interface. Despite its simplicity, it is a highly versatile folding motif: coiled-coil-containing proteins exhibit a broad range of different functions related to the specific 'design' of their coiled-coil domains. The architecture of a particular coiled-coil domain determines its oligomerization state, rigidity and ability to function as a molecular recognition system. Much progress has been made towards understanding the factors that determine coiled-coil formation and stability. Here we discuss this highly versatile protein folding and oligomerization motif with regard to its structural architecture and how this is related to its biological functions.

Restless legs syndrome: an early manifestation of Huntington's disease?

BACKGROUND: Far from being uniform, Huntington's disease (HD)'s phenotype encompasses a large variety of motor and non-motor symptoms which occur in various combinations in individual patients. AIM: To describe an unusual association between restless legs syndrome (RLS) and HD. METHODS AND RESULTS: We report a patient with an atypical presentation of genetically demonstrated HD, who developed typical RLS a few years prior to and during the course of HD. Common causes of RLS were excluded and the polysomnography confirmed frequent and severe periodic limb movements during sleep and while awake. CONCLUSIONS: We propose RLS as an uncommon but early feature of HD in some patients, and suggest adding HD to the already long list of RLS secondary to neurodegenerative conditions.

Naloxone-responsive acute dystonia and parkinsonism following general anaesthesia.

Various movement disorders such as dystonia may acutely develop during or at emergence from general anaesthesia in patients with or without pre-existing Parkinson disease. These movements are triggered by a variety of drugs including propofol, sevoflurane, anti-emetics, antipsychotics and opioids. The postulated mechanism involves an imbalance between dopaminergic and cholinergic neurotransmitters in the basal ganglia. We report an acute, severe and generalised dystonic reaction in an otherwise healthy woman at emergence from general anaesthesia, dramatically reversed by the administration of naloxone, pointing to a potential role of the fentanyl and morphine that the patient had received. Recent literature on the mechanisms of abnormal movements induced by opioids are discussed. The severity of the reaction with usual doses of opioids, in a patient with no prior history of parkinsonism, led to further investigation that demonstrated the possibility of an enhanced susceptibility to opioids, involving a genetically determined abnormal function of glycoproteine-P and catechol-O-methyltransferase.

[Autoantibodies in neurological diseases: clinical implications]. / Autoanticorps en neurologie: implications cliniques.

Autoantibodies are defined as antibodies directed against self antigens, i.e., against a normal antigenic endogenous tissue constituent. They can be the immediate cause of the neurological syndrome or be detected as an epiphenomenon of the pathogenic process. Autoantibodies are often considered useful biomarkers for the improvement of diagnostic accuracy, for the staging of disease progression or for the follow up of a biological response to a therapeutic intervention. The purpose of this article is to review the autoantibodies that are available to investigate immune-mediated neurological conditions. The detection of some of these autoantibodies may help the clinician to establish a definite diagnosis which may further facilitate the therapeutic decision.

Long-term outcome of 50 consecutive Parkinson's disease patients treated with subthalamic deep brain stimulation.

OBJECTIVE: To describe the long-term outcome in 50 consecutive advanced Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS). METHOD: Assessments were carried out at baseline, 6 months, 2 years, and 5 years postoperatively. RESULTS: Compared to baseline scores without medication, we found a highly significant improvement of UPDRS III with stimulation, maintained at 5 years (p<0.001). This improvement, however, tended to diminish over time. Dyskinesia and off periods were also improved (p<0.0001 for both). Seventeen patients died during follow-up, who tended to be older at surgery (p<0.01). CONCLUSIONS: STN-DBS is an effective treatment for advanced PD patients, and the beneficial effect is maintained at 5 years. However, worsening occurs over time due to disease progression.

Sub-acute delayed failure of subthalamic DBS in Parkinson's disease: the role of micro-lesion effect.

OBJECTIVE: To study delayed failure after subthalamic nucleus (STN) deep brain stimulation in Parkinson's disease (PD) patients. METHODS: Out of 56 consecutive bilaterally STN-implanted PD patients, we selected subjects who, after initial clinical improvement (1 month after surgery), lost benefit (delayed failure, DF). RESULTS: Five patients developed sub-acutely severe gait disorders (DF). In 4/5 DF patients, a micro-lesion effect, defined as improvement without stimulation, was observed; immediate post-operative MRI demonstrated electrode located above or behind to the STN. CONCLUSIONS: Patients presenting micro-lesion effect should be carefully monitored, as this phenomenon can mask electrodes misplacement and evolution in DF.

[Impulse control disorders and Parkinson's disease]. / Troubles du contrôte des impulsions et maladie de Parkinson.

A variety of behavioral disorders occurring abruptly in patients with Parkinson's disease (PD) has been recently published and attracted considerable attention in the press. Taking the form of pathological gambling, compulsive shopping, addiction to Internet and to other recreational activities, hypersexuality or bulimia, impulse control disorders (ICD) related to PD are probably more frequent than previously appreciated and may have consequences as spectacular as disastrous for the involved patients. ICD are currently viewed as particular adverse reactions to antiparkinsonian medications, notably to dopamine agonists, and, accordingly, tend to improve or disappear when PD therapy is appropriately adjusted.

[Hysteria: an historical entity, a psychiatric condition or a neurological disease?]. / L'hystérie: une entité historique, un trouble psychiatrique ou une maladie neurologique?

It has been suggested that hysteria had waned and was an old-fashioned, stigmatizing and false concept, reflecting the incapacity of the medical community to establish a diagnosis in certain situations. Nowadays, however, those disturbances, now referred to as conversion or dissociative disorders, still remain a frequent and incapacitating condition that every clinician faces. These past decades, several studies have tried to better describe their clinical presentation and their neurobiological mechanisms, with the help of the development of new neuroimaging techniques. If the neurobiological correlates are now better understood, efficient treatments are still lacking and only a multidisciplinary (general practitioners, neurologists and psychiatrists) and individually-tailored therapy might be beneficial to the patients.

Levodopa-induced ocular dyskinesia in Parkinson's disease.

Levodopa (LD)-induced dyskinesia (LID), one of the most common motor complications in advanced Parkinson's disease (PD), involve mostly the limbs, trunk and head, but unusual locations have been reported including respiratory muscles, the face and the eyes. The aim of this study was to further investigate the frequency and characteristics of LD-related abnormal involuntary eye movements (AIEMs) in PD. Thirty-two patients with advanced PD and various motor complications were evaluated and videotaped in an ON and OFF state. We found AIEMs in five patients (16%) which were present exclusively during the ON state and which completely disappeared when OFF. They consisted of repeated, stereotyped upward and/or sideways gaze deviation movements, sometimes phasic, brief and jerky, sometimes tonic and sustained for several seconds. The main direction of gaze deviation was toward the side more affected by parkinsonism. AIEMs typically paralleled limb and trunk LID and were modulated by the same facilitation and inhibitory maneuvers. We concluded that AIEMs are not uncommon in advanced PD and represent a particular topography of LID, hence the term 'ocular dyskinesia' to designate these AIEMs that seem to have a specific pattern in PD as compared with other forms of parkinsonism.

Is cerebral autoregulation impaired in Parkinson's disease? A transcranial Doppler study.

Orthostatic hypotension (OH) is one of the many autonomic disturbances observed in Parkinson's disease (PD). It has been debated whether an additional impairment of cerebral autoregulation (CA) in PD patients may exacerbate the consequences of OH upon brain perfusion. We assessed CA in PD patients and the potential influence of dopaminergic agents. CA was determined by means of transcranial Doppler (TCD) monitoring of the middle cerebral artery (MCA) at rest and during a thigh cuff release test inducing a systemic blood pressure (BP) drop. Fourteen patients were investigated when taking their usual dopaminergic medication and after drug discontinuation for 12 h. A control group was composed of 11 age-matched subjects (CS). In comparison with PD patients, CS presented a significantly higher increase of the mean cerebral blood flow velocities in the MCA after the BP drop. Mean velocities were increased above the initial values in all CS, whereas a flattened curve was observed in PD patients. No significant differences could be further observed between the PD patients regarding the BP, the cerebrovascular resistance, the heart rate and the pulsatility index. These results provide evidence of an impaired cerebral autoregulation in PD patients which appears independent of dopaminergic treatment.

Classification of self-assembling protein nanoparticle architectures for applications in vaccine design.

We introduce here a mathematical procedure for the structural classification of a specific class of self-assembling protein nanoparticles (SAPNs) that are used as a platform for repetitive antigen display systems. These SAPNs have distinctive geometries as a consequence of the fact that their peptide building blocks are formed from two linked coiled coils that are designed to assemble into trimeric and pentameric clusters. This allows a mathematical description of particle architectures in terms of bipartite (3,5)-regular graphs. Exploiting the relation with fullerene graphs, we provide a complete atlas of SAPN morphologies. The classification enables a detailed understanding of the spectrum of possible particle geometries that can arise in the self-assembly process. Moreover, it provides a toolkit for a systematic exploitation of SAPNs in bioengineering in the context of vaccine design, predicting the density of B-cell epitopes on the SAPN surface, which is critical for a strong humoral immune response.

Changes of the cortex proteome and Apolipoprotein E in transgenic mouse models of Alzheimer's Disease.

Transgenic mice carrying human Amyloid Precursor Protein mutations present amyloid plaque deposition in the brain upon aging. In this study, we characterized the changes of cortex proteome and endogenous Apolipoprotein E in these mice. Differential analysis of two-dimensional electrophoresis images revealed spots altered upon aging, transgene addition and plaque deposition. Alpha-synuclein and cytochrome oxidase polypeptide Va were up-regulated in transgenic mice. Upon aging, expression of ATP synthase alpha, alpha enolase, UMP-CMP kinase, and dihydropyrimidinase like-2 protein was modified. These proteins and their modification probably play a role in the amyloid aggregate formation in these mice.

The coiled-coil trigger site of the rod domain of cortexillin I unveils a distinct network of interhelical and intrahelical salt bridges.

BACKGROUND: The parallel two-stranded alpha-helical coiled coil is the most frequently encountered subunit-oligomerization motif in proteins. The simplicity and regularity of this motif have made it an attractive system to explore some of the fundamental principles of protein folding and stability and to test the principles of de novo design. RESULTS: The X-ray crystal structure of the 18-heptad-repeat alpha-helical coiled-coil domain of the actin-bundling protein cortexillin I from Dictyostelium discoideum is a tightly packed parallel two-stranded alpha-helical coiled coil. It harbors a distinct 14-residue sequence motif that is essential for coiled-coil formation, and is a prerequisite for the assembly of cortexillin I. The atomic structure reveals novel types of ionic coiled-coil interactions. In particular, the structure shows that a characteristic interhelical and intrahelical salt-bridge pattern, in combination with the hydrophobic interactions occurring at the dimer interface, is the key structural feature of its coiled-coil trigger site. CONCLUSIONS: The knowledge gained from the structure could be used in the de novo design of alpha-helical coiled coils for applications such as two-stage drug targeting and delivery systems, and in the design of coiled coils as templates for combinatorial helical libraries in drug discovery and as synthetic carrier molecules.

[Neuronal death and growth factors: new therapeutic approaches in Parkinson's disease]. / Dégénérescence, régénérescence: un espoir thérapeu- tique pour la maladie de Parkinson.

Neurodegenerative disorders represent a major and growing cause of morbidity and mortality in our populations, and a therapeutic challenge for the years to come. This paper reviews the mechanisms implicated in neuronal death, focusing on the model of Parkinson's disease. Available data are critically presented, and oriented in a therapeutic perspective. Neuroprotective strategies are mentioned, along with stem cell transplantation, growth factor production and gene therapy.

[Pathogenic mechanisms of neurodegenerative diseases: amyotrophic lateral sclerosis]. / Mécanismes pathogéniques des maladies neurodégénératives: l'exemple de la sclérose latérale amyotrophique.

Since its description by Charcot in 1869, the mechanism underlying the characteristic selective degeneration and death of motor neurons in amyotrophic lateral sclerosis (ALS) has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics have now identified two genes, SODI and ALS2 as primary causes of the disease and has implicated others as potential contributors. These insights have enabled development of model systems to test hypotheses of disease mechanism and potential therapies. Along with errors in the handling of synaptic glutamate and the potential excitotoxic response that it provokes, these model systems underscore the involvement of non-neuronal cells in disease progression and provide new therapeutic strategies.