Force Control Deficits in Individuals with Parkinson’s Disease,Multiple Systems Atrophy,and Progressive Supranuclear Palsy

Objective

This study examined grip force and cognition in Parkinson’s disease (PD), Parkinsonian variant of multiple system atrophy (MSAp), progressive supranuclear palsy (PSP), and healthy controls. PD is characterized by a slower rate of force increase and decrease and the production of abnormally large grip forces. Early-stage PD has difficulty with the rapid contraction and relaxation of hand muscles required for precision gripping. The first goal was to determine which features of grip force are abnormal in MSAp and PSP. The second goal was to determine whether a single variable or a combination of motor and cognitive measures would distinguish patient groups. Since PSP is more cognitively impaired relative to PD and MSAp, we expected that combining motor and cognitive measures would further distinguish PSP from PD and MSAp.

Methods

We studied 44 participants: 12 PD, 12 MSAp, 8 PSP, and 12 controls. Patients were diagnosed by a movement disorders neurologist and were tested off anti-Parkinsonian medication. Participants completed a visually guided grip force task wherein force pulses were produced for 2 s, followed by 1 s of rest. We also conducted four cognitive tests.

Results

PD, MSAp, and PSP were slower at contracting and relaxing force and produced longer pulse durations compared to controls. PSP produced additional force pulses during the task and were more cognitively impaired relative to other groups. A receiver operator characteristic analysis revealed that the combination of number of pulses and Brief Test of Attention (BTA) discriminated PSP from PD, MSAp, and controls with a high degree of sensitivity and specificity.

Conclusions

Slowness in contracting and relaxing force represent general features of PD, MSAp, and PSP, whereas producing additional force pulses was specific to PSP. Combining motor and cognitive measures provides a robust method for characterizing behavioral features of PSP compared to MSAp and PD.     

��1 Integrin Deficiency Results in Multiple Abnormalities of the Knee Joint

The lack of β1 integrins on chondrocytes leads to severe chondrodysplasia associated with high mortality rate around birth. To assess the impact of β1 integrin-mediated cell-matrix interactions on the function of adult knee joints, we conditionally deleted the β1 integrin gene in early limb mesenchyme using the Prx1-cre transgene. Mutant mice developed short limbed dwarfism and had joint defects due to β1 integrin deficiency in articular regions. The articular cartilage (AC) was structurally disorganized, accompanied by accelerated terminal differentiation, altered shape, and disrupted actin cytoskeleton of the chondrocytes. Defects in chondrocyte proliferation, cytokinesis, and survival resulted in hypocellularity. However, no significant differences in cartilage erosion, in the expression of matrix-degrading proteases, or in the exposure of aggrecan and collagen II cleavage neoepitopes were observed between control and mutant AC. We found no evidence for disturbed activation of MAPKs (ERK1/2, p38, and JNK) in vivo. Furthermore, fibronectin fragment-stimulated ERK activation and MMP-13 expression were indistinguishable in control and mutant femoral head explants. The mutant synovium was hyperplastic and frequently underwent chondrogenic differentiation. β1-null synoviocytes showed increased proliferation and phospho-focal adhesion kinase expression. Taken together, deletion of β1 integrins in the limb bud results in multiple abnormalities of the knee joints; however, it does not accelerate AC destruction, perturb cartilage metabolism, or influence intracellular MAPK signaling pathways.Chondrocytes of the articular cartilage (AC)² secrete a unique set of extracellular matrix (ECM) molecules that assemble into interactive associates composed of collagens, proteoglycans (PGs), and non-collagenous glycoproteins (1). The fibrillar collagen meshwork supplies cartilage with its tensile strength, whereas the hydrated glycosaminoglycan (GAG) chains of PGs (mainly aggrecan) generate an osmotic swelling pressure that resists compressive forces. In diarthrodial joints, the molecular composition and the physical properties of the cartilage are principal determinants for the shock-absorbing function of articular surfaces upon mechanical loading. During the development of osteoarthritis (OA), an imbalance between anabolic and catabolic processes increases the proteolysis of PGs and collagens (2, 3), which eventually leads to the mechanical weakening of the AC and culminates in its progressive destruction. Physiological and pathological remodeling of the AC ECM is primarily attributed to the activities of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin-like repeat (ADAMTS) proteases (4, 5) and is controlled by the communication between the cells and their environment.An increasing amount of evidence suggests that interactions between chondrocytes and the ECM through the integrin family of heterodimeric (αβ) transmembrane receptors play a central role in cartilage function (6). Integrins connect the pericellular matrix to cytoskeletal and intracellular signaling complexes and modulate various cellular functions, including survival, proliferation, differentiation, and matrix assembly and metabolism (7, 8). Chondrocytes express several integrin receptors for cartilage matrix ligands, such as α1β1, α2β1, and α10β1 (for collagen II); α5β1, αvβ3, and αvβ5 (for fibronectin); and α6β1 (for laminin) (6, 9). We have previously demonstrated that β1^fl/fl-Col2a1cre⁺ mice, in which the floxed β1 integrin gene (β1^fl/fl) was deleted using the chondrocyte-specific Col2a1cre transgene, display severe chondrodysplasia and a high mortality rate at birth (10). Homozygous mutant mice exhibit multiple growth plate abnormalities during endochondral bone formation, characterized by defects in chondrocyte adhesion, shape, proliferation, cytokinesis, and actin organization. In addition, the cartilage matrix shows a sparse, distorted collagen network. Similar, but milder abnormalities were found in mice lacking the collagen-binding integrin α10β1 or integrin-linked kinase in cartilage (11, 12).Although these works have identified β1 integrins as essential regulators of growth plate development, the role of integrins in joint morphogenesis, adult joint function, and pathology is incompletely understood. In the embryonic mouse limb culture system, administration of β1 and α5 blocking antibodies or RGD peptides induced ectopic joint formation between proliferating and hypertrophic chondrocytes of the growth plate, suggesting that α5β1 integrin controls the decision between cartilage differentiation and joint formation during development (13). In adult joints, increased immunostaining of β1 integrin was reported in osteoarthritic monkey cartilage compared with normal cartilage (14) and in human OA samples at minimally damaged locations compared with areas with more severe lesions (15). In another study, the neoexpression of α2, α4, and β2 integrins was observed in osteoarthritic human femoral head cartilage (16). In vitro experiments have suggested that signaling through the fibronectin (FN) receptor α5β1 integrin is pivotal to prevent cell death of normal and osteoarthritic human articular chondrocytes (17). FN fragments (FN-fs) present in synovial fluid and cartilage of OA patients have been implicated in cartilage breakdown (18–21). Human AC chondrocytes treated with the central, 110–120-kDa cell-binding FN-f but not with intact FN were shown to increase MMP-13 synthesis through the stimulation of α5β1 integrin and the subsequent activation of the proline-rich tyrosine kinase-2 and mitogen-activated protein kinases (MAPKs) ERK-1/2, JNK, and p38 (22, 23). Similarly, an adhesion-blocking antibody against α2β1 integrin induced the phosphorylation of MAPKs in human AC chondrocytes (22). Treatment of cultured rabbit synovial fibroblasts with central FN-fs or activating antibodies against α5β1 integrin elevated MMP-1 and MMP-3 expression (24). Although these experiments suggest that blocking integrin signaling through α2β1/α5β1 in response to degradation fragments may attenuate OA, mice lacking α1β1 integrin are prone to osteoarthritis (25). Knee joints of α1-null mice display precocious PG loss, cartilage erosion associated with increased MMP-2 and MMP-3 expression, and synovial hyperplasia.To further explore the role of β1 integrins in joint biology, here we report the deletion of the floxed β1 integrin gene in embryonic limb bud mesenchymal cells using the Prx1cre transgene (26). β1^fl/fl-Prx1cre⁺ mice were born alive with short limbs due to the lack of β1 integrin heterodimers on chondrocytes. We found that β1 integrin deficiency in knee joints leads to multiple abnormalities of the AC and the synovium, but it is not associated with accelerated AC destruction, perturbed AC metabolism, and MAPK signaling. Our data suggest that β1 integrins are required for the proper structural organization of the AC by anchoring chondrocytes to the ECM, but signaling through β1 integrins is less important for normal cartilage homeostasis.     

Does Pet Arrival Trigger Prosocial Behaviors in Individuals with Autism?

Alteration of social interactions especially prosocial behaviors - an important aspect of development - is one of the characteristics of autistic disorders. Numerous strategies or therapies are used to improve communication skills or at least to reduce social impairments. Animal-assisted therapies are used widely but their relevant benefits have never been scientifically evaluated. In the present study, we evaluated the association between the presence or the arrival of pets in families with an individual with autism and the changes in his or her prosocial behaviors. Of 260 individuals with autism - on the basis of presence or absence of pets - two groups of 12 individuals and two groups of 8 individuals were assigned to: study 1 (pet arrival after age of 5 versus no pet) and study 2 (pet versus no pet), respectively. Evaluation of social impairment was assessed at two time periods using the 36-items ADI-R algorithm and a parental questionnaire about their child-pet relationships. The results showed that 2 of the 36 items changed positively between the age of 4 to 5 (t(0)) and time of assessment (t(1)) in the pet arrival group (study 1): "offering to share" and "offering comfort". Interestingly, these two items reflect prosocial behaviors. There seemed to be no significant changes in any item for the three other groups. The interactions between individuals with autism and their pets were more - qualitatively and quantitatively - reported in the situation of pet arrival than pet presence since birth. These findings open further lines of research on the impact of pet's presence or arrival in families with an individual with autism. Given the potential ability of individuals with autism to develop prosocial behaviors, related studies are needed to better understand the mechanisms involved in the development of such child-pet relationship.     

Factors Influencing Turning and Its Relationship with Falls in Individuals with Parkinson’s Disease

Background

Falls are a major problem for people with Parkinson’s disease (PD). Many studies indicate that more than 50% of people with PD have difficulty in turning that may lead to falls during daily activities. The aims of this study were to identify the relationship between turning performance and falls, and to determine the factors that influence turning performance.

Methods

This study examined 45 patients with idiopathic PD (Hoehn and Yahr stage 1–3) using a battery of tests, including 180° turn time, balance, and muscle strength. The levels of disease severity and freezing of gait were also measured. The number of falls in the past 6 months was recorded.

Results

Sixteen out of forty-five participants experienced falls in the past 6 months. A receiver operating characteristic curve showed that turn time was highly related to falls [more affected side: sensitivity = 0.81, specificity = 0.79, area under the curve (AUC) = 0.83; less affected side: sensitivity = 0.88, specificity = 0.76, AUC = 0.83]. The most important factor influencing turn time was balance ability (both sides: p = 0.000) according to the regression model. Correlations between turn time and dynamic balance were further established with reaction time, movement velocity, endpoint excursion, and maximal excursion of the LOS (limits of stability) test.

Conclusion

The time needed to complete a 180° turn during the SQT (step/quick turn) test is a good index to differentiate fallers from non-fallers in persons with PD. Turn time is most influenced by balance. Furthermore, balance control, especially in an anterior or sideways direction, is important for turning performance.     

The Streptococcal Collagen-binding Protein CNE Specifically Interferes with ��V��3-mediated Cellular Interactions with Triple Helical Collagen

Collagen fibers expose distinct domains allowing for specific interactions with other extracellular matrix proteins and cells. To investigate putative collagen domains that govern integrin α_Vβ₃-mediated cellular interactions with native collagen fibers we took advantage of the streptococcal protein CNE that bound native fibrillar collagens. CNE specifically inhibited α_Vβ₃-dependent cell-mediated collagen gel contraction, PDGF BB-induced and α_Vβ₃-mediated adhesion of cells, and binding of fibronectin to native collagen. Using a Toolkit composed of overlapping, 27-residue triple helical segments of collagen type II, two CNE-binding sites present in peptides II-1 and II-44 were identified. These peptides lack the major binding site for collagen-binding β₁ integrins, defined by the peptide GFOGER. Peptide II-44 corresponds to a region of collagen known to bind collagenases, discoidin domain receptor 2, SPARC (osteonectin), and fibronectin. In addition to binding fibronectin, peptide II-44 but not II-1 inhibited α_Vβ₃-mediated collagen gel contraction and, when immobilized on plastic, supported adhesion of cells. Reduction of fibronectin expression by siRNA reduced PDGF BB-induced α_Vβ₃-mediated contraction. Reconstitution of collagen types I and II gels in the presence of CNE reduced collagen fibril diameters and fibril melting temperatures. Our data indicate that contraction proceeded through an indirect mechanism involving binding of cell-produced fibronectin to the collagen fibers. Furthermore, our data show that cell-mediated collagen gel contraction does not directly depend on the process of fibril formation.