Neurodegeneration and Neuroinflammation in Parkinson's Disease: a Self-Sustained Loop.

PURPOSE OF REVIEW: Neuroinflammation plays a significant role in Parkinson's disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps of the neurodegenerative process and justify the growing interest in anti-inflammatory agents as potential disease-modifying treatments in PD. The discovery of inherited gene mutations in PD has allowed researchers to develop cellular and animal models to study the mechanisms of the underlying biology, but the original cause of neuroinflammation in PD is still debated to date. RECENT FINDINGS: Cell autonomous alterations in neuronal cells, including mitochondrial damage and protein aggregation, could play a role, but recent findings also highlighted the importance of intercellular communication at both local and systemic level. This has given rise to debate about the role of non-neuronal cells in PD and reignited intense research into the gut-brain axis and other non-neuronal interactions in the development of the disease. Whatever the original trigger of neuroinflammation in PD, what appears quite clear is that the aberrant activation of glial cells and other components of the immune system creates a vicious circle in which neurodegeneration and neuroinflammation nourish each other. In this review, we will provide an up-to-date summary of the main cellular alterations underlying neuroinflammation in PD, including those induced by environmental factors (e.g. the gut microbiome) and those related to the genetic background of affected patients. Starting from the lesson provided by familial forms of PD, we will discuss pathophysiological mechanisms linked to inflammation that could also play a role in idiopathic forms. Finally, we will comment on the potential clinical translatability of immunobiomarkers identified in PD patient cohorts and provide an update on current therapeutic strategies aimed at overcoming or preventing inflammation in PD.

Glucocerebrosidase mutations in a Serbian Parkinson's disease population.

BACKGROUND AND PURPOSE: To screen for glucocerebrosidase (GBA) mutations in a Serbian Parkinson's disease (PD) population. METHODS: Glucocerebrosidase exons 8-11 harbouring the most common mutations were sequenced in 360 patients with PD and 348 controls from Serbia. Haplotype analysis was performed for the N370S mutation and compared with German and Ashkenazi Jewish carriers. RESULTS: Glucocerebrosidase mutations were significantly more frequent in patients with PD (21/360; 5.8%) vs. controls (5/348; 1.4%; OR = 4.25; CI, 1.58-11.40; P = 0.0041). Two patients with PD carried homozygous or compound heterozygous mutations in GBA. The N370S mutation accounted for about half of the mutated alleles in patients (10/23) but was absent amongst controls. Three novel variants were detected including two non-synonymous variants (D380V, N392S) in the patient group and one synonymous change (V459V) in a control. Carriers of the D409H mutation were also sequenced for H255Q, and all were found to carry the [D409H; H255Q] double-mutant allele. Genotyping suggested a common haplotype for all N370S carriers. CONCLUSION: Glucocerebrosidase mutations represent a PD risk factor in the Serbian population.

Differential effects of PINK1 nonsense and missense mutations on mitochondrial function and morphology.

Mutations of the PINK1 gene are a cause of autosomal recessive Parkinson's disease (PD). PINK1 encodes a mitochondrial kinase of unknown function which is widely expressed in both neuronal and non-neuronal cells. We have studied fibroblast cultures from four family members harbouring the homozygous p.Q456X mutation in PINK1, three of their wild-type relatives, one individual with the homozygous p.V170G mutation and five independent controls. Results showed bioenergetic abnormalities involving decreased activities of complexes I and IV along with increased activities of complexes II and III in the missense p.V170G mutant. There were increased basal levels of mitochondrial superoxide dismutase in these cells and an exaggerated increase of reduced glutathione in response to paraquat-induced free radical formation. Furthermore, swollen and enlarged mitochondria were observed in this sample. In the p.Q456X nonsense mutants, the respiratory chain enzymes were unaffected, but ATP levels were significantly decreased. These results confirm that mutations of PINK1 cause abnormal mitochondrial morphology, bioenergetic function and oxidative metabolism in human tissues but suggest that the biochemical consequences may vary between mutations.

Myoclonus-dystonia: significance of large SGCE deletions.

Myoclonus-dystonia (M-D) is an autosomal-dominant movement disorder caused by mutations in SGCE. We investigated the frequency and type of SGCE mutations with emphasis on gene dosage alterations and explored the associated phenotypes. We tested 35 M-D index patients by multiplex ligation-dependent probe amplification (MLPA) and genomic sequencing. Mutations were found in 26% (9/35) of the cases, all but three with definite M-D. Two heterozygous deletions of the entire SGCE gene and flanking DNA and a heterozygous deletion of exon 2 only were detected, accounting for 33% (3/9) of the mutations found. Both large deletions contained COL1A2 and were additionally associated with joint problems. Further, we discovered one novel small deletion (c.771_772delAT, p.C258X) and four recurrent point mutations (c.289C>T, p.R97X; c.304C>T, p.R102X; c.709C>T, p.R237X; c.1114C>T, p.R372X). A Medline search identified 22 articles on SGCE mutational screening. Sixty-four unrelated M-D patients were described with 41 different mutations. No genotype-phenotype association was found, except in patients with deletions encompassing additional genes. In conclusion, a rigorous clinical preselection of patients and careful accounting for non-motor signs should precede mutational tests. Gene dosage studies should be included in routine SGCE genetic testing.

Absence of compensatory platelet activation in patients with severe haemophilia, but evidence for a platelet collagen-activation defect.

Severe haemophilia is a serious, haemorrhagic disorder of the plasmatic coagulation system. In this study we investigated, whether 'compensatory' activation of the platelet coagulation system occurs in this situation. Platelet function was investigated with aggregation, adhesion and flow cytometric assays. In addition, we performed clot and platelet plug formation tests and determined endogenous thrombin potentials in patients with severe haemophilia A or B; results were compared to those of healthy controls. Platelet aggregation in response to stimulation with ADP, ristocetin and epinephrine was similar in patients and controls; aggregation in response to collagen was reduced significantly in haemophiliacs. Flow cytometric analysis of P-selectin (CD 62P) and CD 63, of the conformationally changed GP IIb/IIIa with PAC 1 and of thrombospondin bound to CD 36 (GP IV) was performed at baseline and post stimulation. Baseline expression of all markers was similar in haemophiliacs and controls. After stimulation of the platelet thrombin receptors with the thrombin receptor activating peptide (TRAP) 6, the surface expression of all markers increased significantly; again, the expression was similar in haemophiliacs and controls. With thrombelastography and PFA 100 analysis, clot formation under low shear and platelet plug formation under high shear is measured. Both test results revealed a significantly reduced clot and platelet plug formation capacity in severe haemophiliacs. Our results did not reveal signs of enhanced platelet preactivation in haemophiliacs, indicating that baseline platelet reactivity in severe haemophilia remains in a neutral state, despite the severely haemorrhagic condition. As expected, both thrombin and clot formation capacities were impaired significantly in severe haemophilia. The reduced response to collagen-based platelet stimulation tests is indicative of a concomitant platelet function defect. This defect probably contributes to the intensity of bleeding events in patients with severe haemophilia.

Paradoxical hyperfibrinolysis is associated with a more intensely haemorrhagic phenotype in severe congenital haemophilia.

To elucidate potential causes for differing bleeding phenotypes of haemophilic patients of identical degree of coagulation factor deficiency, we investigated 21 male patients with severe haemophilia. Median annual coagulation factor demand and the extent of haemophilic arthropathy were used to discriminate between intensely and less intensely haemorrhagic phenotypes. Haemophiliacs with a median annual coagulation factor demand of 800 IU per kg bodyweight or more and with three or more joints affected by haemophilic arthropathy represented the intensely haemorrhagic phenotype group; all other patients comprised the less intense group. The discriminator values represent the respective medians of the overall group. The results of activated partial thromboplastin time, endogenous thrombin potential, pro- and anticoagulant factor analysis did not differ between the two groups. Median tissue-type plasminogen activator concentration (TPA) was elevated significantly in haemophiliacs with an intensely haemorrhagic phenotype, as was the activity of the thrombin-activatable fibrinolysis inhibitor. Median activity of the plasminogen activator inhibitor 1 (PAI 1) and the concentration of TPA-PAI 1 complexes were increased to approximately double those in nonsevere haemophiliacs. Coexistent congenital thrombophilia was found significantly more often in the less intensely haemorrhagic group. Thus, increased stimulation of the fibrinolytic system was associated with a more intensely haemorrhagic phenotype in our patients. We hypothesize that ineffective haemophilic haemostasis in response to trauma evokes a protracted stimulation of the entire haemostatic system, including costimulation of fibrinolysis. The absence of coexistent congenital thrombophilia predisposes to excess stimulation of fibrinolysis, which cannot be downregulated effectively due to the dysfunctional intrinsic pathway. The association of a more intensely haemorrhagic phenotype with a paradoxical hyperstimulation of the fibrinolytic system resembles a vicious circle, where bleeding seems to cause predisposition to more bleeding.

Responses to auditory stimuli in macaque lateral intraparietal area. I. Effects of training.

The lateral intraparietal area (LIP) of macaques has been considered unresponsive to auditory stimulation. Recent reports, however, indicate that neurons in this area respond to auditory stimuli in the context of an auditory-saccade task. Is this difference in auditory responsiveness of LIP due to auditory-saccade training? To address this issue, LIP responses in two monkeys were recorded at two different times: before and after auditory-saccade training. Before auditory-saccade training, the animals had never been trained on any auditory task, but had been trained on visual tasks. In both sets of experiments, activity of LIP neurons was recorded while auditory and visual stimuli were presented and the animals were fixating. Before training, 172 LIP neurons were recorded. Among these, the number of cells responding to auditory stimuli did not reach significance, whereas about one-half of the cells responded to visual stimuli. An information theory analysis confirmed that no information about auditory stimulus location was available in LIP neurons in the experiments before training. After training, activity from 160 cells was recorded. These experiments showed that 12% of cells in area LIP responded to auditory stimuli, whereas the proportion of cells responding to visual stimuli remained about the same as before training. The information theory analysis confirmed that, after training, information about auditory stimulus location was available in LIP neurons. Auditory-saccade training therefore generated responsiveness to auditory stimuli de novo in LIP neurons. Thus some LIP cells become active for auditory stimuli in a passive fixation task, once the animals have learned that these stimuli are important for oculomotor behavior.

Responses to auditory stimuli in macaque lateral intraparietal area. II. Behavioral modulation.

The lateral intraparietal area (LIP), a region of posterior parietal cortex, was once thought to be unresponsive to auditory stimulation. However, recent reports have indicated that neurons in area LIP respond to auditory stimuli during an auditory-saccade task. To what extent are auditory responses in area LIP dependent on the performance of an auditory-saccade task? To address this question, recordings were made from 160 LIP neurons in two monkeys while the animals performed auditory and visual memory-saccade and fixation tasks. Responses to auditory stimuli were significantly stronger during the memory-saccade task than during the fixation task, whereas responses to visual stimuli were not. Moreover, neurons responsive to auditory stimuli tended also to be visually responsive and to exhibit delay or saccade activity in the memory-saccade task. These results indicate that, in general, auditory responses in area LIP are modulated by behavioral context, are associated with visual responses, and are predictive of delay or saccade activity. Responses to auditory stimuli in area LIP may therefore be best interpreted as supramodal responses, and similar in nature to the delay activity, rather than as modality-specific sensory responses. The apparent link between auditory activity and oculomotor behavior suggests that the behavioral modulation of responses to auditory stimuli in area LIP reflects the selection of auditory stimuli as targets for eye movements.

Motion after-effect due to binocular sum of adaptation to linear motion.

The motion after-effect (MAE) can be elicited by adapting observers to global motion of randomly distributed dots before they view a display containing dots moving in random directions, but no global motion. Experiments by others have shown that if the adaptation stimulus contains two directions of motion, the MAE points opposite to the vector sum of the adapting directions. The present study investigated whether such vector addition in the MAE could also occur if the two directions of motion were presented to separate eyes. Observers were adapted to different, but not opposite, directions of motion in the two eyes. Either the left eye, the right eye, or both eyes were tested. Observers reported the direction of perceived motion during the test. When they saw the test stimulus with both eyes, observers reported seeing motion in the direction opposite that of the vector sum of the adaptation directions. In the monocular test conditions observers reported MAE directions opposite to the corresponding monocular adaptation directions. In a second experiment we verified that subjects had interocular transfer of the MAE. Together these results are consistent with a model in which (1) addition of adaptation directions occurs at a binocular site; (2) directional adaptation occurs at a monocular site; and (3) monocular adaptation is able to change the threshold for obtaining an MAE at the binocular site, thus acting like binocular adaptation in interocular transfer of the MAE.

Fast pathway ablation in patients with common atrioventricular nodal reentrant tachycardia and prolonged PR interval during sinus rhythm.

AIMS: This study aimed to clarify the safety and efficacy of selective fast pathway ablation in patients with atrioventricular nodal reentrant tachycardia and a prolonged PR interval during sinus rhythm. Such patients have been reported to have an increased incidence of complete atrioventricular block. METHODS AND RESULTS: In this study, the earliest retrograde atrial activation during atrioventricular nodal reentrant tachycardia and right ventricular stimulation was localized. Fast pathway ablation was then performed in five patients with the common form of atrioventricular nodal reentrant tachycardia and a prolonged PR interval. Three of the five patients had almost incessant atrioventricular nodal reentrant tachycardia. Radiofrequency catheter ablation induced a complete ventriculo-atrial block during right ventricular stimulation in four patients and a marked prolongation of ventriculo-atrial conduction during right ventricular stimulation in one. Non-inducibility of common atrioventricular nodal reentrant tachycardia with and without isoproterenol was achieved in all five patients. The PR interval increased from 254 +/- 53 ms to 276 +/- 48 ms and the atrio-His interval from 172 +/- 46 ms to 192 +/- 45 ms. Second- or third-degree atrioventricular block did not occur during the ablation procedure. During the followup of 19 +/- 20 months none of the patients developed symptoms suggestive of atrioventricular nodal reentrant tachycardia or evidence of second- or third-degree atrioventricular block. CONCLUSION: These data suggest that atrioventricular node (retrograde) fast pathway ablation can apparently be safely performed in patients with common atrioventricular nodal reentrant tachycardia and a prolonged PR interval during sinus rhythm.

Self-organization of binocular disparity tuning by reciprocal corticogeniculate interactions.

This article develops a neural model of how sharp disparity tuning can arise through experience-dependent development of cortical complex cells. This learning process clarifies how complex cells can binocularly match left and right eye image features with the same contrast polarity, yet also pool signals with opposite contrast polarities. Antagonistic rebounds between LGN ON and OFF cells and cortical simple cells sensitive to opposite contrast polarities enable anticorrelated simple cells to learn to activate a shared set of complex cells. Feedback from binocularly tuned cortical cells to monocular LGN cells is proposed to carry out a matching process that dynamically stabilizes the learning process. This feedback represents a type of matching process that is elaborated at higher visual processing areas into a volitionally controllable type of attention. We show stable learning when both of these properties hold. Learning adjusts the initially coarsely tuned disparity preference to match the disparities present in the environment, and the tuning width decreases to yield high disparity selectivity, which enables the model to quickly detect image disparities. Learning is impaired in the absence of either antagonistic rebounds or corticogeniculate feedback. The model also helps to explain psychophysical and neurobiological data about adult 3-D vision.

The combined transvenous implantation of cardioverter defibrillators and permanent pacemakers.

We developed criteria for implantation and programming of permanent endocardial pacemakers in patients with a nonthoracotomy ICD system. These criteria were prospectively used in 10 patients who recieved an ICD prior to (n = 5) or following (n = 5) implantation of a dual chamber (n = 6) or ventricular (n = 4) pacemaker with a unipolar (n = 4) or bipolar (n = 6) lead configuration. All patients were tested for interactions or malfunctions. Undersensing of ventricular fibrillation by the atrial sense amplifier and inadequate atrial pacing occurred in one patient with a unipolar dual chamber system programmed to AAIR but didn't impair ICD sensing. Transient or permanent loss of capture or sensing of the pacemaker was not observed after ICD shocks with the output programmed to double pulse width and voltage of stimulation threshold and the sensitivity to 50% of the detected R wave. One episode of transient reprogramming occurred without clinical consequences. One unipolar ventricular pacemaker lead had to be exchanged against a bipolar lead because of oversensing of the pacing artifact by the ICD. There was no failure of an ICD to detect ventricular arrhythmias due to inadequate pacemaker activity. During a follow-up period of 21 +/- 11 months, a total of 78 ventricular arrhythmias were effectively treated in six patients. Thus, a combined use of transvenous ICD and pacemaker is possible despite the close vicinity of pacing and defibrillations leads. Optimized programming different to the common settings is required. As interactions occurred only in unipolar pacemaker leads bipolar systems should be used in these patients.

[Stored electrograms to differenciate between adequate and inadequate ICD therapy]. / Bedeutung der Speicherelektrogramme zur Differenzierung adäquater und inadäquater ICD-Therapien.

The introduction of implantable cardioverter defibrillators in 1980 by Mirowski et al, offered a new therapeutic device for the treatment of ventrikular tachyarrhythmias. In the beginning it was only possible to evaluate arrhythmic events by analysis of the therapy-counter in combination with clinical symptoms. Even rapid ventricular tachyarrhythmias may not produce significant symptoms prior to ICD shock in more than 50% of patients. On the other hand the ICD device will initiate inappropriate therapy due to sensing error and non sustained tachyarrhythmias in 20-40% of patients. Third generation ICD devices provide sophisticated diagnostic information by stored electrograms. Intracardiac electrograms are recorded by the bipolar tip electrode of the sensing lead, located in the right ventricel (near field) or by the electrodes used for energy delivery (far field). These ECG recordings provide valuable information to evaluate the type of arrhythmia, trigger mechanisms and therapeutic efficacy. The arrhythmia leading to device therapy is judged by cycle length and stability and morphology of the intracardiac signal. A correct arrhythmia classification using electrogram analysis is possible in 92-98% of arrhythmias. Evaluation is limited in 5-10% of patients with bundle branch block or aberand conduction. Inappropriate ICD therapy is caused by atrial fibrillation in more than 50% and by supraventricular tachycardia or sinus tachycardia in about 20%. Sensing of artefacts can be attributed to lead failure in about 17%. The distinction between appropriate and inappropriate therapeutic intervention by the ICD allows the prevention of unnecessary shock delivery and early diagnosis of lead failure. The development of dual chamber systems with enhanced storage capacity and improved algorithms for detection of arrhythmias may further decrease the incidence of inappropriate ICD therapies.

Cortical synchronization and perceptual framing.

How does the brain group together different parts of an object into a coherent visual object representation? Different parts of an object may be processed by the brain at different rates and may thus become desynchronized. Perceptual framing is a process that resynchronizes cortical activities corresponding to the same retinal object. A neural network model is presented that is able to rapidly resynchronize desynchronized neural activities. The model provides a link between perceptual and brain data. Model properties quantitatively simulate perceptual framing data, including psychophysical data about temporal order judgments and the reduction of threshold contrast as a function of stimulus length. Such a model has earlier been used to explain data about illusory contour formation, texture segregation, shape-from-shading, 3-D vision, and cortical receptive fields. The model hereby shows how many data may be understood as manifestations of a cortical grouping process that can rapidly resynchronize image parts that belong together in visual object representations. The model exhibits better synchronization in the presence of noise than without noise, a type of stochastic resonance, and synchronizes robustly when cells that represent different stimulus orientations compete. These properties arise when fast long-range cooperation and slow short-range competition interact via nonlinear feedback interactions with cells that obey shunting equations.

Orthogonal motion after-effect illusion predicted by a model of cortical motion processing.

The motion after-effect occurs after prolonged viewing of motion; a subsequent stationary scene is perceived as moving in the opposite direction. This illusion is thought to arise because motion is represented by the differential activities of populations of cortical neurons tuned to opposite directions; fatigue in one population leads to an imbalance that favours the opposite direction once the stimulus ceases. Following adaptation to multiple directions of motion, the after-effect is unidirectional, indicating that motion signals are integrated across all directions. Yet humans can perceive several directions of motion simultaneously. The question therefore arises as to how the visual system can perform both sharp segregation and global integration of motion signals. Here we show in computer simulations that this can occur if excitatory interactions between different directions are sharply tuned while inhibitory interactions are broadly tuned. Our model predicts that adaptation to simultaneous motion in opposite directions will lead to an orthogonal motion after-effect. This prediction was confirmed in psychophysical experiments. Thus, broadly tuned inhibitory interactions are likely to be important in the integration and segregation of motion signals. These interactions may occur in the cortical area MT, which contains motion-sensitive neurons with properties similar to those required by our model.

Damage to the skin by repetitive washing.

Damage to the skin following the repeated use of 2 different wash solutions was investigated. Stratum corneum capacitative resistance, stratum corneum lipids, transepidermal water loss, skin surface pH, laser Doppler flow and skin reddening were determined. All skin function parameters already showed a marked change after a single wash (e.g., the median of TEWL values increased by more than 0.5 g/m2 h). Repetitive washing for 1 week led to a further deterioration of TEWL and corneometry values (e.g., TEWL increased for about 2.9 g/m2 h after repetitive washing with sodium lauryl sulfate). The rate of skin function regeneration after repetitive washing was unaltered compared to regeneration after a single wash. The surfactants used showed quantitatively differing effects on corneometry, TEWL and laser Doppler flow (e.g., after repetitive washing with Geliderm, the median of TEWL values increased only up to 1.55 g/m2 h). However, damage arising from repetitive washing could not be completely prevented by the selection of a mild surfactant. Skin function regeneration showed no difference with the 2 surfactants used.