Cognition and freezing of gait in Parkinson's disease: A systematic review and meta-analysis.

Freezing of gait (FOG) is a common and disabling symptom in people with Parkinson's Disease (PwPD). Although cognition is thought to be worse in PwPD who freeze, a comprehensive analysis of this relationship will inform future research and clinical care. This systematic review and meta-analysis compared cognition between PwPD who do and do not exhibit FOG across a range of cognitive domains and assessed the impact of disease severity and medication status on this relationship. 145 papers (n = 9010 participants) were included in the analysis, with 144 and 138 articles meeting the criteria to assess moderating effects of disease severity and medication status, respectively. PwPD who freeze exhibited worse cognition than PwPD without FOG across global cognition, executive function/attention, language, memory, and visuospatial domains. Greater disease severity and "ON" levodopa medication status moderated the FOG status-cognition relationship in global cognitive performance but not in other cognitive domains. This meta-analysis confirmed that cognition is worse in PwPD with FOG and highlights the importance of disease severity and medication status in this relationship.

The relationship between plantar sensation and muscle onset during automatic postural responses in people with multiple sclerosis and healthy controls.

BACKGROUND: Plantar sensation is critical for balance control in people with multiple sclerosis (PwMS). While previous research has described its impact on standing balance, the influence of plantar sensation during automatic postural responses (APRs) is not well understood in PwMS. The purpose of this study was to characterize the relationship between plantar sensation and APRs in PwMS and controls. A secondary aim was to determine whether the relationship between plantar sensation and APRs is different across PwMS and control groups. METHODS: 122 PwMS and 48 age-matched controls underwent forward and backward support-surface perturbations from stance. The onset of the tibialis anterior (TA) and medial gastrocnemius (MG) were the primary reactive balance outcome measures for backward and forward losses of balance, respectively. Plantar sensation was measured as the vibration sensation threshold (VT). RESULTS: As expected, PwMS had significantly higher (i.e., worse) VT (p<0.001) and an increased MG and TA onset latency (TA: p<0.001, MG: p = 0.01) compared to the control group. A higher VT was related to increased MG (p<0.001) and TA latency (p<0.001) across all participants. However, no moderating effect of group (control or PwMS) was observed for the relationship between VT and muscle onset (MG: p = 0.14; TA: p = 0.34). CONCLUSION: PwMS demonstrated poorer plantar sensation and delayed muscle onset during APRs compared to controls. Plantar sensation was also related to muscle onset after perturbations in all participants. Although this relationship was not moderated by group, this may be related to the lack of dynamic range of VT scores in controls. These results indicate that plantar sensation may be related to reactive balance and provides insight into a potential contributing factor of delayed automatic postural responses in people with MS.

Effects of dual-tasking on time-to-boundary during stance in people with PD: A preliminary study.

BACKGROUND: Quiet stance is impacted by Parkinson's disease and dual-tasking. Recently developed outcomes such as the time-to-boundary provide unique insight into balance by integrating center of pressure position with base of support. However, little is known about the effects of Parkinson's disease on time-to-boundary. In particular, the effects of distracting cognitive tasks, and how people with Parkinson's disease prioritize balance and cognitive tasks are poorly understood. METHODS: 14 people with Parkinson's disease and 13 controls completed quiet standing and cognitive Stroop tasks separately (single-task) and together (dual-task). 2-dimentional, medio-lateral, and anterior-posterior time-to-boundary were calculated via force-plate data. Traditional sway outcomes, including sway area and path length, were also calculated. Cognitive performance was measured as the verbal reaction time after auditory stimulus delivery. Prioritization was assessed by taking the difference between cognitive and postural dual-task interference. FINDINGS: Time-to-boundary was worse in Parkinson's disease compared to controls (2-dimentional: p = .019; anterior-posterior: p = .062; medio-lateral: p = .012). Medio-lateral time-to-boundary, but not anterior-posterior, was significantly worse during dual-tasking than single-tasking (p = .024). Neurotypical adults tended to prioritize cognition over medio-lateral postural outcomes. INTERPRETATION: People with Parkinson's disease exhibit worse time-to-boundary than their neurotypical peers, and medio-lateral outcomes were sensitive to single to dual-task performance changes. Further, participants generally showed cognitive prioritization, such that cognitive performance was less impacted than medio-lateral postural outcomes by dual-tasking.

Anticipatory postural responses prior to protective steps are not different in people with PD who do and do not freeze.

BACKGROUND: Protective stepping after a loss of balance is related to falls. Anticipatory postural responses (APAs) prior to protective stepping can impact step performance, may be larger in people with PD, and have been suggested to be related to freezing of gait (FOG). However, whether people with PD and FOG (PD + FOG) exhibit larger APAs than people with PD and no FOG (PD-FOG) is unknown. RESEARCH QUESTION: Determine the impact of freezing status on APAs prior to protective steps, thus providing a better understanding of the link between FOG and APAs. METHODS: Twenty-eight people with PD (13 PD + FOG) were exposed to 50 support surface translations (25 forward, 25 backward, random order) resulting in protective steps. The size of medio-lateral weight shifts prior to the protective step (i.e. APAs), and the percentage of trials with an APA were calculated via force-plates. FOG status was assessed at the time of testing as well as 3.25(+/-0.43) years later. Participants without FOG at testing, but with FOG at follow-up were identified as "converters". RESULTS AND SIGNIFICANCE: For both forward and backward protective stepping, size and percentage trials with an APA were not statistically different between PD + FOG and PD-FOG, even after excluding converters from the PD-FOG group (p > 0.27 for all). No group by direction interactions were observed. These data suggest that, in mild to moderate PD, an inability to couple APAs with stepping, rather than an inappropriately sized APA, may be most related to freezing of gait.

First-trial protective step performance before and after short-term perturbation practice in people with Parkinson's disease.

BACKGROUND: Protective steps are critical for fall prevention and are altered in people with Parkinson's disease (PD). Previous work suggests that perturbation training, in which patients are exposed to repeated slips, may improve protective postural responses. However, these studies typically take the average performance of several postural responses before and after training. To reduce falls in the community, training must improve protective stepping after the first perturbation exposure. To date, no investigations have examined whether first-trial protective stepping is improved after training in people with PD. METHODS: First-trial protective stepping was measured in 14 people with PD and 9 healthy adults before and 24 h after 1 day of perturbation training. The primary outcome was margin of stability after a perturbation, a measure of protective stepping effectiveness. RESULTS: Margin of stability for the first perturbation was significantly (p = 0.001) improved on day 2 compared to before perturbation practice (day 1) in both groups. Furthermore, improvement in margin of stability was correlated with age and baseline stepping performance, such that older individuals and people with worse baseline performance showed the most pronounced improvement. CONCLUSIONS: Improving the first loss of balance after training is critical if such training is to reduce falls in people with PD. The observed improvement in first-trial protective stepping provides further support for perturbation training as a potential tool to improve protective steps and reduce falls in people with PD.

Effects of freezing of gait on postural motor learning in people with Parkinson's disease.

Protective postural responses, including stepping, to recover equilibrium are critical for fall prevention and are impaired in people with Parkinson's disease (PD) with freezing of gait (FoG). Improving protective postural responses through training may reduce falls in this population. However, motor learning, the basis of neurorehabilitation, is also impaired in people with PD and, in particular, people with PD who experience freezing. It is unknown whether people with PD who freeze can improve protective postural responses, and whether these improvements are similar to nonfreezers. Our goal was to assess whether people with freezing can improve protective postural responses and retain these improvements similarly to nonfreezers. Twenty-eight people with PD (13 freezers, 15 nonfreezers) were enrolled. Improvement in protective postural responses was assessed over the course of 25 forward and 25 backward support surface translations (delivered in pseudo-random order). Postural responses were re-assessed 24h later to determine whether improvements were retained. People who freeze did not improve or retain improvement in protective postural responses as well as nonfreezers in our primary outcome variable, center of mass (COM) displacement after perturbations (post hoc across group assessments: freezers- p=0.14 and nonfreezers- p=0.001, respectively). However, other protective stepping outcomes, including margin of stability, step length, and step time, improved similarly across groups. Significant improvements were retained in both groups. In conclusion, people with PD who freeze exhibited reduced ability to improve protective postural responses in some, but not all, outcome variables. Additional training may be necessary to improve protective postural responses in people with PD who freeze.

Supraspinal control of automatic postural responses in people with multiple sclerosis.

The neural underpinnings of delayed automatic postural responses in people with multiple sclerosis (PwMS) are unclear. We assessed whether white matter pathways of two supraspinal regions (the cortical proprioceptive Broadman's Area-3; and the balance/locomotor-related pedunculopontine nucleus) were related to delayed postural muscle response latencies in response to external perturbations. 19 PwMS (48.8±11.4years; EDSS=3.5 (range: 2-4)) and 12 healthy adults (51.7±12.2years) underwent 20 discrete, backward translations of a support surface. Onset latency of agonist (medial-gastrocnemius) and antagonist (tibialis anterior) muscles were assessed. Diffusion tensor imaging assessed white-matter integrity (i.e. radial diffusivity) of cortical proprioceptive and balance/locomotor-related tracts. Latency of the tibialis anterior, but not medial gastrocnemius was larger in PwMS than control subjects (p=0.012 and 0.071, respectively). Radial diffusivity of balance/locomotor tracts was higher (worse) in PwMS than control subjects (p=0.004), and was significantly correlated with tibialis (p=0.002), but not gastrocnemius (p=0.06) onset latency. Diffusivity of cortical proprioceptive tracts was not correlated with muscle onset. Lesions in supraspinal structures including the pedunculopontine nucleus balance/locomotor network may contribute to delayed onset of postural muscle activity in PwMS, contributing to balance deficits in PwMS.

Neural Control of Walking in People with Parkinsonism.

People with Parkinson's disease exhibit debilitating gait impairments, including gait slowness, increased step variability, and poor postural control. A widespread supraspinal locomotor network including the cortex, cerebellum, basal ganglia, and brain stem contributes to the control of human locomotion, and altered activity of these structures underlies gait dysfunction due to Parkinson's disease.

Do cognitive measures and brain circuitry predict outcomes of exercise in Parkinson Disease: a randomized clinical trial.

BACKGROUND: There is emerging research detailing the relationship between balance/gait/falls and cognition. Imaging studies also suggest a link between structural and functional changes in the frontal lobe (a region commonly associated with cognitive function) and mobility. People with Parkinson's disease have important changes in cognitive function that may impact rehabilitation efficacy. Our underlying hypothesis is that cognitive function and frontal lobe connections with the basal ganglia and brainstem posture/locomotor centers are responsible for postural deficits in people with Parkinson's disease and play a role in rehabilitation efficacy. The purpose of this study is to 1) determine if people with Parkinson's disease can improve mobility and/or cognition after partaking in a cognitively challenging mobility exercise program and 2) determine if cognition and brain circuitry deficits predict responsiveness to exercise rehabilitation. METHODS/DESIGN: This study is a randomized cross-over controlled intervention to take place at a University Balance Disorders Laboratory. The study participants will be people with Parkinson's disease who meet inclusion criteria for the study. The intervention will be 6 weeks of group exercise (case) and 6 weeks of group education (control). The exercise is a cognitively challenging program based on the Agility Boot Camp for people with PD. The education program is a 6-week program to teach people how to better live with a chronic disease. The primary outcome measure is the MiniBESTest and the secondary outcomes are measures of mobility, cognition and neural imaging. DISCUSSION: The results from this study will further our understanding of the relationship between cognition and mobility with a focus on brain circuitry as it relates to rehabilitation potential. TRIAL REGISTRATION: This trial is registered at clinical trials.gov (NCT02231073).

Natural hemozoin stimulates syncytiotrophoblast to secrete chemokines and recruit peripheral blood mononuclear cells.

BACKGROUND: Placental malaria is associated with local accumulation of parasitized erythrocytes, deposition of the parasite hemoglobin metabolite, hemozoin, and accumulation of mononuclear cells in the intervillous space. Fetal syncytiotrophoblast cells in contact with maternal blood are known to respond immunologically to cytoadherent Plasmodium falciparum-infected erythrocytes, but their responsiveness to hemozoin, a potent pro-inflammatory stimulator of monocytes, macrophages and dendritic cells, is not known. METHODS: The biochemical and immunological changes induced in primary syncytiotrophoblast by natural hemozoin was assessed. Changes in syncytiotrophoblast mitogen-activated protein kinase activation was assessed by immunoblotting and secreted cytokine and chemokine proteins were assayed by ELISA. Chemotaxis of peripheral blood mononuclear cells was assessed using a two-chamber assay system and flow cytometry was used to assess the activation of primary monocytes by hemozoin-stimulated syncytiotrophoblast conditioned medium. RESULTS: Hemozoin stimulation induced ERK1/2 phosphorylation. Treated cells secreted CXCL8, CCL3, CCL4, and tumor necrosis factor and released soluble intercellular adhesion molecule-1. Furthermore, the dependence of the hemozoin responses on ERK1/2 stimulation was confirmed by inhibition of chemokine release in syncytiotrophoblast treated with an ERK pathway inhibitor. Hemozoin-stimulated cells elicited the specific migration of PBMCs, and conditioned medium from the cells induced the upregulation of intercellular adhesion molecule-1 on primary monocytes. CONCLUSIONS: These findings confirm an immunostimulatory role for hemozoin and expand the cell types known to be responsive to hemozoin to include fetal syncytiotrophoblast. The results provide further evidence that syncytiotrophoblast cells can influence the local maternal immune response to placental malaria.

Sequence conservation in the rRNA first internal transcribed spacer region of Babesia gibsoni genotype Asia isolates.

Babesia gibsoni genotype Asia is a small, tick-transmitted intraerythrocytic protozoan that parasitizes dogs. Reports suggest that it is increasingly diagnosed in the United States. The clinical outcome of infection with this piroplasm is often variable, leading us to hypothesize that the different clinical outcomes resulting from B. gibsoni genotype Asia infection are due to genetically distinguishable strains that differ in virulence. As a first step to assess the genetic variability of B. gibsoni isolates originating from the southeastern United States, we sequenced the rRNA first internal transcribed spacer region of recent isolates from Georgia and Alabama, and compared these sequences with isolates originating from Japan and Australia. All isolates examined proved to be genetically identical at the first internal transcribed spacer region, although this region differed distinctly from other Babesia species and closely related apicomplexan species. Although negating our hypothesis, this information gives us insight into the recent evolutionary history and spread of B. gibsoni genotype Asia in dogs in the U.S. Our research suggests that the gradual rise in prevalence of canine babesiosis due to B. gibsoni genotype Asia in the United States may be a result of clonal expansion of a single strain within a susceptible host population.

Plasmodium falciparum-infected red blood cells selected for binding to cultured syncytiotrophoblast bind to chondroitin sulfate A and induce tyrosine phosphorylation in the syncytiotrophoblast.

An important pathogenic complication of malaria during human pregnancy is sequestration of Plasmodium-infected red blood cells (iRBCs) in the placental intervillous spaces. This sequestration is thought to be mediated in part by binding of the iRBCs to receptors expressed on the syncytiotrophoblast (ST) membrane. We report here the use of a dynamic system to study the consequences of this cytoadherence on ST function using human syncytiotrophoblast and the choriocarcinoma cell line, BeWo. Laboratory isolates of Plasmodium falciparum were selected for their ability to bind to ST and used to investigate binding-induced cellular changes in the ST. Treatment of the ST cells with chondroitinase ABC suggested that the selected parasites bind predominantly to chondroitin sulfate A, but other receptors for parasite binding may be involved. Intracellular signaling in the ST induced by iRBCs binding was investigated by assessing tyrosine phosphorylation of ST proteins following iRBC binding. We demonstrate for the first time that iRBC cytoadherence to syncytiotrophoblast enhances tyrosine phosphorylation of a series of proteins in these cells. This approach will be useful in further studies of ST function in the malaria-infected placenta, the dynamics of selection of syncytiotrophoblast-binding parasites, and the identification of new receptors for parasite cytoadherence in the placenta.

Novel alkyl-modified anionic siloxanes as pseudostationary phases for electrokinetic chromatography: II. Selectivity studied by linear solvation energy relationships.

Anionic, water-soluble siloxane polymers modified with different lengths of alkyl chains have very different selectivity than sodium dodecyl sulfate (SDS) micelles when used as pseudostationary phases in electrokinetic chromatography. The siloxanes in this study are random copolymers with side chains bearing sulfonate groups and alkyl groups (C8, C12, or C18), with the proportion of alkyl groups between 10 and 25% of the total. The differences in selectivity have been studied by linear solvation energy relationships (LSERs). The siloxanes in general have been found to be more cohesive, less polar, more able to interact with solutes through n- and pi-electrons, and more able to accept hydrogen bonds than SDS micelles, while the ability to act as hydrogen bond donors is not significantly different than SDS micelles. In addition, the performance in a pH 7.0 Tris buffer has been investigated and the siloxanes were found to have higher methylene selectivities and more variable electrophoretic mobilities than in borate buffers.

Alkyl modified anionic siloxanes as pseudostationary phases for electrokinetic chromatography. I. Synthesis and characterization.

Anionic water soluble siloxane polymers have been synthesized and characterized for electrokinetic chromatography. Siloxane polymers are of interest in electrokinetic chromatography because of the wide variety of chemistries that can be developed based on these backbones, including much of the stationary phase chemistry developed in the last 30 years. The siloxanes in this study have a sulfonate functional group. The siloxanes have different length alkyl chains (C8, C12, C18) attached to the backbone in differing densities. The methylene selectivity generally increases with increasing alkyl chain length and with increasing alkyl chain density. The electrophoretic mobility appears to pass through a maximum as more alkyl chain is added to the siloxane backbone. The efficiency also would seem to pass through a maximum as more alkyl chain is added. The chemical selectivities of the siloxane polymers are very different from sodium dodecyl sulfate but are similar to each other.

Effect of pendant chain lengths and backbone functionalities on the chemical selectivity of sulfonated amphiphilic copolymers as pseudo-stationary phases in electrokinetic chromatography.

Amphiphilic copolymers of AMPS (2-acrylamido-2-methyl-1-propanesulfonic acid) and hydrophobic monomers with various chemical structures were synthesized, characterized and used as novel electrokinetic chromatography polymeric pseudo-stationary phases, showing significant chemical selectivity differences from that of the conventional monomeric pseudo-stationary phase, sodium lauryl sulphate. Copolymers of AMPS and methacrylates with different pendant chain lengths (C8, C12 and C18) were investigated and no significant difference in chemical selectivity was observed among them. However, the spacer bonding chemistry was shown to contribute to significant chemical selectivity difference, e.g. poly(AMPS-lauryl methacrylate) showed different chemical selectivity from poly(AMPS-lauryl methacrylamide). Linear solvation energy relationship analysis of 20 solutes by eight different polymeric pseudo-stationary phases was employed to investigate the solute molecule structural contributions to the retention. Hydrogen-bonding properties (described by system constants b and a) of poly(AMPS-alkyl methacrylamide) were found stronger than those of poly(AMPS-alkyl methacrylate).

Synthesis and characterization of novel anionic siloxane polymers as pseudostationary phases for electrokinetic chromatography.

Four novel siloxane polymeric pseudostationary phases with three different ionic head groups have been synthesized and characterized for electrokinetic chromatography. Siloxane polymers are of interest in this application because of the wide range of chemistries that can be developed based on these backbones, including much of the chromatographic stationary phase chemistry developed in the last thirty years. All four of the siloxanes studied were synthesized by modification of a single methylhydrosiloxane polymer with highly acidic anionic functionalities. One of the siloxanes had both ionic groups and alkane chains attached to the siloxane backbone. The electrophoretic mobilities varied from being somewhat less than sodium dodecyl sulfate (SDS) to being much greater than SDS. The siloxanes substituted with ionic groups at all of the silicon sites showed significant nonequilibrium band broadening, severely limiting the efficiencies of these polymers. Substitution of 20% of the silicon sites with an alkyl group improved the efficiency of the separations and the peak symmetry. The chemical selectivities of the siloxane polymers are very different from SDS, but are similar to each other.

An anionic siloxane polymer as a pseudostationary phase for electrokinetic chromatography.

A novel polymeric pseudostationary phase for electrokinetic chromatography is introduced and characterized. Siloxane polymers are of interest for this application because of the range of chemistries that could be developed based on these backbones, and because successful development of siloxane polymers would make it possible to employ much of the stationary phase chemistry developed in the past thirty years. A commercially available water-soluble siloxane with a hydroxy-terminated alkyl group was converted to the sulfate derivative. This siloxane polymer is water-soluble, effectively eliminating this limitation associated with siloxane polymers. When employed as a pseudostationary phase, this compound provided rapid, efficient, and selective separations. The electrophoretic mobility of the polymer was less than sodium dodecyl sulfate (SDS) and poly(sodium 10-undecenylsulfate), providing a compressed migration time range, which is the main limiting factor for this polymer. The chemical selectivity of the siloxane sulfate was somewhat different than SDS micelles. The siloxane was employed in buffers modified with a large amount of acetonitrile to separate a number of polynuclear aromatic hydrocarbons. The addition of acetonitrile caused an apparent discontinuity in the electrophoretic mobility of the polymer, which may indicate a change in the structure with increasing organic solvent content.

EBL-1, a putative erythrocyte binding protein of Plasmodium falciparum, maps within a favored linkage group in two genetic crosses.

The Duffy binding-like (DBL) superfamily of Plasmodium falciparum encompasses genes which encode ligands for host cell receptors. This superfamily includes two distinct groups of genes, the var genes which encode antigenically variant cytoadherence proteins (PfEMP1), and the eba-175 gene which encodes a glycophorin A binding protein involved in erythrocyte invasion. Here we describe another DBL superfamily member related to eba-175, the ebl-1 gene. Like the eba-175 gene, ebl-1 is a single copy gene encoding DBL domains that have sequences and an overall arrangement distinct from var genes. The inheritance of ebl-1 was found to be strongly favored in two genetic crosses in which one parental clone lacked a chromosome segment carrying the gene. A proliferation phenotype has been previously linked to the same chromosome segment in the first genetic cross. These results suggest that ebl-1 and eba-175 are related members of a multigene family involved in the invasion of erythrocytes by P. falciparum.