Visuo-Motor Coordination Deficits and Motor Impairments in Parkinson's Disease

BACKGROUND: Visuo-motor coordination (VMC) requires normal cognitive executive functionality, an ability to transform visual inputs into movement plans and motor-execution skills, all of which are known to be impaired in Parkinson's disease (PD). Not surprisingly, a VMC deficit in PD is well documented. Still, it is not known how this deficit relates to motor symptoms that are assessed routinely in the neurological clinic. Such relationship should reveal how particular motor dysfunctions combine with cognitive and sensory-motor impairments to produce a complex behavioral disability. METHODS AND FINDINGS: Thirty nine early/moderate PD patients were routinely evaluated, including motor Unified Parkinson's Disease Rating Scale (UPDRS) based assessment, A VMC testing battery in which the subjects had to track a target moving on screen along 3 different paths, and to freely trace these paths followed. Detailed kinematic analysis of tracking/tracing performance was done. Statistical analysis of the correlations between measures depicting various aspects of VMC control and UPDRS items was performed. The VMC measures which correlated most strongly with clinical symptoms represent the ability to organize tracking movements and program their direction, rather than measures representing motor-execution skills of the hand. The strong correlations of these VMC measures with total UPDRS score were weakened when the UPDRS hand-motor part was considered specifically, and were insignificant in relation to tremor of the hand. In contrast, all correlations of VMC measures with the gait/posture part of the UPDRS were found to be strongest. CONCLUSIONS: Our apparently counterintuitive findings suggest that the VMC deficit pertains more strongly to a PD related change in cognitive-executive control, than to a reduction in motor capabilities. The recently demonstrated relationship between gait/posture impairment and a cognitive decline, as found in PD, concords with this suggestion and may explain the strong correlation between VMC dysfunction and gait/posture impairment. Accordingly, we propose that what appears to reflect a motor deficit in fact represents a multisystem failure, dominated by a cognitive decline

Computational analysis of the LRRK2 interactome

LRRK2 was identified in 2004 as the causative protein product of the Parkinson’s disease locus designated PARK8. In the decade since then, genetic studies have revealed at least 6 dominant mutations in LRRK2 linked to Parkinson’s disease, alongside one associated with cancer. It is now well established that coding changes in LRRK2 are one of the most common causes of Parkinson’s. Genome-wide association studies (GWAs) have, more recently, reported single nucleotide polymorphisms (SNPs) around the LRRK2 locus to be associated with risk of developing sporadic Parkinson’s disease and inflammatory bowel disorder. The functional research that has followed these genetic breakthroughs has generated an extensive literature regarding LRRK2 pathophysiology; however, there is still no consensus as to the biological function of LRRK2. To provide insight into the aspects of cell biology that are consistently related to LRRK2 activity, we analysed the plethora of candidate LRRK2 interactors available through the BioGRID and IntAct data repositories. We then performed GO terms enrichment for the LRRK2 interactome. We found that, in two different enrichment portals, the LRRK2 interactome was associated with terms referring to transport, cellular organization, vesicles and the cytoskeleton. We also verified that 21 of the LRRK2 interactors are genetically linked to risk for Parkin- son’s disease or inflammatory bowel disorder. The implications of these findings are discussed, with particular regard to potential novel areas of investigation

Can we respond mindfully to distressing voices? A systematic review of evidence for engagement, acceptability, effectiveness and mechanisms of change for mindfulness-based interventions for people distressed by hearing voices

Adapted mindfulness-based interventions (MBIs) could be of benefit for people distressed by hearing voices. This paper presents a systematic review of studies exploring this possibility and we ask five questions: (1) Is trait mindfulness associated with reduced distress and disturbance in relation to hearing voices? (2) Are MBIs feasible for people distressed by hearing voices? (3) Are MBIs acceptable and safe for people distressed by hearing voices? (4) Are MBIs effective at reducing distress and disturbance in people distressed by hearing voices? (5) If effective, what are the mechanisms of change through which MBIs for distressing voices work? Fifteen studies were identified through a systematic search (n = 479). In relation to the five review questions: (1) data from cross-sectional studies showed an association between trait mindfulness and distress and disturbance in relation to hearing voices; (2) evidence from qualitative studies suggested that people distressed by hearing voices could engage meaningfully in mindfulness practice; (3) MBIs were seen as acceptable and safe; (4) there were no adequately powered RCTs allowing conclusions about effectiveness to be drawn; and (5) it was not possible to draw on robust empirical data to comment on potential mechanisms of change although findings from the qualitative studies identified three potential change processes; (i) reorientation of attention; (ii) decentring; and (iii) acceptance of voices. This review provided evidence that MBIs are engaging, acceptable, and safe. Evidence for effectiveness in reducing distress and disturbance is lacking however. We call for funding for adequately powered RCTs that will allow questions of effectiveness, maintenance of effects, mechanisms of change and moderators of outcome to be definitively addressed

Cancer outcomes among Parkinson's disease patients with leucine rich repeat kinase 2 mutations, idiopathic Parkinson's disease patients, and nonaffected controls

BACKGROUND: Increased cancer risk has been reported in Parkinson's disease (PD) patients carrying the leucine rich repeat kinase 2 (LRRK2) G2019S mutation (LRRK2-PD) in comparison with idiopathic PD (IPD). It is unclear whether the elevated risk would be maintained when compared with unaffected controls. METHODS: Cancer outcomes were compared among 257 LRRK2-PD patients, 712 IPD patients, and 218 controls recruited from 7 LRRK2 consortium centers using mixed-effects logistic regression. Data were then pooled with a previous study to examine cancer risk between 401 LRRK2-PD and 1946 IPD patients. RESULTS: Although cancer prevalence was similar among LRRK2-PD patients (32.3%), IPD patients (27.5%), and controls (27.5%; P = 0.33), LRRK2-PD had increased risks of leukemia (odds ratio [OR] = 4.55; 95% confidence interval [CI], 1.46-10.61) and skin cancer (OR = 1.61; 95% CI, 1.09-2.37). In the pooled analysis, LRRK2-PD patients had also elevated risks of leukemia (OR = 9.84; 95% CI, 2.15-44.94) and colon cancer (OR = 2.34; 95% CI, 1.15-4.74) when compared with IPD patients. CONCLUSIONS: The increased risks of leukemia as well as skin and colon cancers among LRRK2-PD patients suggest that LRRK2 mutations heighten risks of certain cancers. © 2019 International Parkinson and Movement Disorder Society

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

Coupling between leg muscle activation and EEG during normal walking, intentional stops, and freezing of gait in Parkinson's disease

In this paper, we apply novel techniques for characterizing leg muscle activation patterns via electromyograms (EMGs) and for relating them to changes in electroencephalogram (EEG) activity during gait experiments. Specifically, we investigate changes of leg-muscle EMG amplitudes and EMG frequencies during walking, intentional stops, and unintended freezing-of-gait (FOG) episodes. FOG is a frequent paroxysmal gait disturbance occurring in many patients suffering from Parkinson's disease (PD). We find that EMG amplitudes and frequencies do not change significantly during FOG episodes with respect to walking, while drastic changes occur during intentional stops. Phase synchronization between EMG signals is most pronounced during walking in controls and reduced in PD patients. By analyzing cross-correlations between changes in EMG patterns and brain-wave amplitudes (from EEGs), we find an increase in EEG-EMG coupling at the beginning of stop and FOG episodes. Our results may help to better understand the enigmatic pathophysiology of FOG, to differentiate between FOG events and other gait disturbances, and ultimately to improve diagnostic procedures for patients suffering from PD. Copyright © 2019 Günther, Bartsch, Miron-Shahar, Hassin-Baer, Inzelberg, Kurths, Plotnik and Kantelhardt

Beyond self-report: a review of physiological and neuroscientific methods to investigate consumer behavior

The current paper investigates the value and application of a range of physiological and neuroscientific techniques in applied marketing research and consumer science, highlighting new insights from research in social psychology and neuroscience. We review measures of sweat secretion, heart rate, facial muscle activity, eye movements, and electrical brain activity, using techniques including skin conductance, pupillometry, eyetracking, and magnetic brain imaging. For each measure, after a brief explanation of the underlying technique, we illustrate concepts and mechanisms that the measure allows researchers in marketing and consumer science to investigate, with a focus on consumer attitudes and behavior. By providing reviews on recent research that applied these methods in consumer science and relevant related fields, we also highlight methodological and theoretical strengths and limitations, with an emphasis on ecological validity. We argue that the inclusion of physiological and neuroscientific techniques can advance consumer research by providing insights into the often unconscious mechanisms underlying consumer behavior. Therefore, such technologies can help researchers and marketing practitioners understand the mechanisms of consumer behavior and improve predictions of consumer behavior

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

Self-selected gait speed - over ground versus self-paced treadmill walking, a solution for a paradox

BACKGROUND: The study of gait at self-selected speed is important. Traditional gait laboratories being relatively limited in space provide insufficient path length, while treadmill (TM) walking compromises natural gait by imposing speed variables. Self-paced (SP) walking can be realized on TM using feedback-controlled belt speed. We compared over ground walking vs. SP TM in two self-selected gait speed experiments: without visual flow, and while subjects were immersed in a virtual reality (VR) environment inducing natural visual flow. METHODS: Young healthy subjects walked 96 meters at self-selected comfortable speed, first over ground and then on the SP TM without (n=15), and with VR visual flow (n=11). Gait speed was compared across conditions for four 10 m long segments (7.5 – 17.5, 30.5 – 40.5, 55.5 – 65.5 and 78.5-88.5 m). RESULTS: During over ground walking mean (± SD) gait speed was equal for both experimental groups (1.50 ± 0.13 m/s). Without visual flow, gait speed over SP TM was smaller in the first and second epochs as compared to over ground (first: 1.15 ±0.18 vs. second: 1.53 ± 0.13 m/s; p<0.05), and was comparable in the third and fourth (1.45 ± 0.19 vs. 1.49 ± 0.15 m/s; p>0.3). With visual flow, gait speed became comparable to that of over ground performance already in the first epoch (1.43 ± 0.22 m/s; p>0.17). Curve fitting analyses estimated that steady state velocity in SP TM walking is reached after shorter distanced passed with visual flow (24.6 ± 14.7 m) versus without (36.5 ± 18.7 m, not statistically significant; p=0.097). Steady state velocity was estimated to be higher in the presence of visual flow (1.61 ± 0.17 m/s) versus its absence (1.42 ± 1.19 m/s; p<0.05). CONCLUSIONS: The SP TM walking is a reliable method for recording typical self-selected gait speed, provided that sufficient distance is first passed for reaching steady state. Seemingly, in the presence of VR visual flow, steady state of gait speed is reached faster. We propose that the gait research community joins forces to standardize the use of SP TMs, e.g., by unifying protocols or gathering normative data