Antiphospholipid Antibodies Bind ATP: A putative Mechanism for the Pathogenesis of Neuronal Dysfunction

Antiphospholipid antibodies (aPL) generated in experimental animals cross-react with ATP. We therefore examined the possibility that aPL IgG from human subjects bind to ATP by affinity column and an enzyme linked immunosorbent assay (ELISA). Sera with high levels of aPL IgG were collected from 12 patients with the antiphospholipid syndrome (APS). IgG fractions from 10 of 12 APS patients contained aPL that could be affinity-bound to an ATP column and completely eluted with NaCl 0.5 M. A significant (>50%) inhibition of aPL IgG binding by ATP 5 mM was found in the majority. Similar inhibition was obtained with ADP but not with AMP or cAMP. All the affinity purified anti-ATP antibodies also bound β2-glycoprotein-I (β2-GPI, also known as apolipoprotein H) suggesting that, similar to most pathogenic aPL, their binding depends on this serum cofactor. We further investigated this possibility and found that the binding of β2-GPI to the ATP column was similar to that of aPL IgG in that most was reversed by NaCl 0.5 M. Furthermore, addition of β2-GPI to aPL IgG significantly increased the amount of aPL binding to an ATP column. We conclude that aPL IgG bind ATP, probably through β2-GPI. This binding could interfere with the normal extracellular function of ATP and similar neurotransmitters

Towards a pathway definition of Parkinson’s disease: a complex disorder with links to cancer, diabetes and inflammation

We have previously established a first whole genome transcriptomic profile of sporadic Parkinson’s disease (PD). After extensive brain tissue-based validation combined with cycles of iterative data analysis and by focusing on the most comparable cases of the cohort, we have refined our analysis and established a list of 892 highly dysregulated priority genes that are considered to form the core of the diseased Parkinsonian metabolic network. The substantia nigra pathways, now under scrutiny, contain more than 100 genes whose association with PD is known from the literature. Of those, more than 40 genes belong to the highly significantly dysregulated group identified in our dataset. Apart from the complete list of 892 priority genes, we present pathways revealing PD ‘hub’ as well as ‘peripheral’ network genes. The latter include Lewy body components or interact with known PD genes. Biological associations of PD with cancer, diabetes and inflammation are discussed and interactions of the priority genes with several drugs are provided. Our study illustrates the value of rigorous clinico-pathological correlation when analysing high-throughput data to make optimal use of the histopathological phenome, or morphonome which currently serves as the key diagnostic reference for most human diseases. The need for systematic human tissue banking, following the highest possible professional and ethical standard to enable sustainability, becomes evident

Effect of terminal accuracy requirements on temporal gaze-hand coordination during fast discrete and reciprocal pointings

Background\ud \ud Rapid discrete goal-directed movements are characterized by a well known coordination pattern between the gaze and the hand displacements. The gaze always starts prior to the hand movement and reaches the target before hand velocity peak. Surprisingly, the effect of the target size on the temporal gaze-hand coordination has not been directly investigated. Moreover, goal-directed movements are often produced in a reciprocal rather than in a discrete manner. The objectives of this work were to assess the effect of the target size on temporal gaze-hand coordination during fast 1) discrete and 2) reciprocal pointings.\ud \ud Methods\ud \ud Subjects performed fast discrete (experiment 1) and reciprocal (experiment 2) pointings with an amplitude of 50 cm and four target diameters (7.6, 3.8, 1.9 and 0.95 cm) leading to indexes of difficulty (ID = log2[2A/D]) of 3.7, 4.7, 5.7 and 6.7 bits. Gaze and hand displacements were synchronously recorded. Temporal gaze-hand coordination parameters were compared between experiments (discrete and reciprocal pointings) and IDs using analyses of variance (ANOVAs).\ud \ud Results\ud \ud Data showed that the magnitude of the gaze-hand lead pattern was much higher for discrete than for reciprocal pointings. Moreover, while it was constant for discrete pointings, it decreased systematically with an increasing ID for reciprocal pointings because of the longer duration of gaze anchoring on target.\ud \ud Conclusion \ud \ud Overall, the temporal gaze-hand coordination analysis revealed that even for high IDs, fast reciprocal pointings could not be considered as a concatenation of discrete units. Moreover, our data clearly illustrate the smooth adaptation of temporal gaze-hand coordination to terminal accuracy requirements during fast reciprocal pointings. It will be interesting for further researches to investigate if the methodology used in the experiment 2 allows assessing the effect of sensori-motor deficits on gaze-hand coordination

Altered Perceptual Sensitivity to Kinematic Invariants in Parkinson's Disease

Ample evidence exists for coupling between action and perception in neurologically healthy individuals, yet the precise nature of the internal representations shared between these domains remains unclear. One experimentally derived view is that the invariant properties and constraints characterizing movement generation are also manifested during motion perception. One prominent motor invariant is the “two-third power law,” describing the strong relation between the kinematics of motion and the geometrical features of the path followed by the hand during planar drawing movements. The two-thirds power law not only characterizes various movement generation tasks but also seems to constrain visual perception of motion. The present study aimed to assess whether motor invariants, such as the two thirds power law also constrain motion perception in patients with Parkinson's disease (PD). Patients with PD and age-matched controls were asked to observe the movement of a light spot rotating on an elliptical path and to modify its velocity until it appeared to move most uniformly. As in previous reports controls tended to choose those movements close to obeying the two-thirds power law as most uniform. Patients with PD displayed a more variable behavior, choosing on average, movements closer but not equal to a constant velocity. Our results thus demonstrate impairments in how the two-thirds power law constrains motion perception in patients with PD, where this relationship between velocity and curvature appears to be preserved but scaled down. Recent hypotheses on the role of the basal ganglia in motor timing may explain these irregularities. Alternatively, these impairments in perception of movement may reflect similar deficits in motor production

mTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1

Leucine rich repeat kinase 2 is a complex enzyme with both kinase and GTPase activities, closely linked to the pathogenesis of several human disorders including Parkinson’s disease, Crohn’s disease, leprosy and cancer. LRRK2 has been implicated in numerous cellular processes; however its physiological function remains unclear. Recent reports suggest that LRRK2 can act to regulate the cellular catabolic process of macroautophagy, although the precise mechanism whereby this occurs has not been identi ed. To investigate the signalling events through which LRRK2 acts to in uence macroautophagy, the mammalian target of rapamycin (mTOR)/Unc-51-like kinase 1 (ULK1) and Beclin-1/phosphatidylinositol 3-kinase (PI3K) pathways were evaluated in astrocytic cell models in the presence and absence of LRRK2 kinase inhibitors. Chemical inhibition of LRRK2 kinase activity resulted in the stimulation of macroautophagy in a non-canonical fashion, independent of mTOR and ULK1, but dependent upon the activation of Beclin 1-containing class III PI3-kinase

A questionnaire-based (UM-PDHQ) study of hallucinations in Parkinson's disease

Background: Hallucinations occur in 20-40% of PD patients and have been associated with unfavorable clinical outcomes (i.e., nursing home placement, increased mortality). Hallucinations, like other non-motor features of PD, are not well recognized in routine primary/secondary clinical practice. So far, there has been no instrument for uniform characterization of hallucinations in PD. To this end, we developed the University of Miami Parkinson's disease Hallucinations Questionnaire (UM-PDHQ) that allows comprehensive assessment of hallucinations in clinical or research settings.Methods: The UM-PDHQ is composed of 6 quantitative and 14 qualitative items. For our study PD patients of all ages and in all stages of the disease were recruited over an 18-month period. The UPDRS, MMSE, and Beck Depression and Anxiety Inventories were used for comparisons.Results and Discussion: Seventy consecutive PD patients were included in the analyses. Thirty-one (44.3%) were classified as hallucinators and 39 as non-hallucinators. No significant group differences were observed in terms of demographics, disease characteristics, stage, education, depressive/anxiety scores or cognitive functioning (MMSE) between hallucinators and non-hallucinators. Single mode hallucinations were reported in 20/31 (visual/14, auditory/4, olfactory/2) whereas multiple modalities were reported in 11/31 patients. The most common hallucinatory experience was a whole person followed by small animals, insects and reptiles.Conclusion: Using the UM-PDHQ, we were able to define the key characteristics of hallucinations in PD in our cohort. Future directions include the validation of the quantitative part of the questionnaire than will serve as a rating scale for severity of hallucinations

In Vivo Evaluation of Retinal Neurodegeneration in Patients with Multiple Sclerosis

To evaluate macular morphology in the eyes of patients with multiple sclerosis (MS) with or without optic neuritis (ON) in previous history.Optical coherence tomography (OCT) examination was performed in thirty-nine patients with MS and in thirty-three healthy subjects. The raw macular OCT data were processed using OCTRIMA software. The circumpapillary retinal nerve fiber layer (RNFL) thickness and the weighted mean thickness of the total retina and 6 intraretinal layers were obtained for each eye. The eyes of MS patients were divided into a group of 39 ON-affected eyes, and into a group of 34 eyes with no history of ON for the statistical analyses. Receiver operating characteristic (ROC) curves were constructed to determine which parameter can discriminate best between the non-affected group and controls.The circumpapillary RNFL thickness was significantly decreased in the non-affected eyes compared to controls group only in the temporal quadrant (p = 0.001) while it was decreased in the affected eyes of the MS patients in all quadrants compared to the non-affected eyes (p<0.05 in each comparison). The thickness of the total retina, RNFL, ganglion cell layer and inner plexiform layer complex (GCL+IPL) and ganglion cell complex (GCC, comprising the RNFL and GCL+IPL) in the macula was significantly decreased in the non-affected eyes compared to controls (p<0.05 for each comparison) and in the ON-affected eyes compared to the non-affected eyes (p<0.001 for each comparison). The largest area under the ROC curve (0.892) was obtained for the weighted mean thickness of the GCC. The EDSS score showed the strongest correlation with the GCL+IPL and GCC thickness (p = 0.007, r = 0.43 for both variables).Thinning of the inner retinal layers is present in eyes of MS patients regardless of previous ON. Macular OCT image segmentation might provide a better insight into the pathology of neuronal loss and could therefore play an important role in the diagnosis and follow-up of patients with MS