Activity In Parkinson's Disease Research Articles

A link between synaptic plasticity and reorganization of brain activity in Parkinson's disease

The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's disease (PD) where functional up-regulation of postsynaptic D2 receptors has been documented while its significance at the neural activity level has never been identified. We investigated cortico-subcortical plasticity in PD using the oculomotor system as a model to study reorganization of dopaminergic networks. This model is ideal because this system reorganizes due to frontal-to-parietal shifts in blood oxygen level-dependent (BOLD) activity. We tested the prediction that functional activation plasticity is associated with postsynaptic dopaminergic modifications by combining positron emission tomography/functional magnetic resonance imaging to investigate striatal postsynaptic reorganization of dopamine D2 receptors (using 11C-raclopride) and neural activation in PD. We used covariance (connectivity) statistics at molecular and functional levels to probe striato-cortical reorganization in PD in on/off medication states to show that functional and molecular forms of reorganization are related. D2 binding across regions defined by prosaccades showed increased molecular connectivity between both caudate/putamen and hyperactive parietal eye fields in PD in contrast with frontal eye fields in controls, in line with the shift model. Concerning antisaccades, parietal-striatal connectivity dominated in again in PD, unlike frontal regions. Concerning molecular-BOLD covariance, a striking sign reversal was observed: PD patients showed negative frontal-putamen functional-molecular associations, consistent with the reorganization shift, in contrast with the positive correlations observed in controls. Follow-up analysis in off-medication PD patients confirmed the negative BOLD-molecular correlation. These results provide a link among BOLD responses, striato-cortical synaptic reorganization, and neural plasticity in PD.

Exposure to varenicline protects against locomotor alteration in a MPTP mouse model of Parkinson's disease.

The beneficial effects of drugs that act via nicotinic acetylcholine receptors (nAChRs) on Parkinson's disease (PD) symptomatology may explain the negative correlation between cigarette smoking and risk of this neurological condition. Varenicline, an α4β2 nAChR partial agonist approved for smoking cessation treatments, could be valuable for PD treatment. Here, we investigated varenicline effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD mouse model. From postnatal day (PN) 90 to PN119, male C57BL/6 mice were exposed daily to varenicline (2 mg/kg) by gavage. After that, MPTP was injected (30 mg/kg, ip) once a day for five days. At PN125, locomotor and anxiety-like effects were assessed with the open field test. At PN126, immobile behavior was assessed with the forced swimming test. At PN127, the frontal cerebral cortex was collected to evaluate dopamine and DOPAC levels. To verify whether varenicline was protective during the MPTP insult, a separate group of MPTP animals received varenicline from PN90 to PN124. MPTP reduced cortical dopamine content and increased dopamine turnover. Those effects were not reversed by varenicline treatment. Interestingly, varenicline reversed the MPTP-induced hyperactivity in the open field. Both maintenance of varenicline treatment during MPTP exposure or its interruption before MPTP exposure elicited similar results. No alterations were observed in anxiety-like behavior or in immobility time. Altogether, these findings suggested that varenicline treatment reduced the MPTP-induced hyperactivity, but did not protect against dopaminergic damage. Based on this partial protective effect, varenicline could exert neuroprotective effects on circuits that control motor activity in PD.

Stakeholder perceptions of components of a Parkinson disease care management intervention, care coordination for health promotion and activities in Parkinson\u2019s disease (CHAPS)

BackgroundA recent nurse-led proactive care management intervention, Care Coordination for Health Promotion and Activities in Parkinson Disease (CHAPS), improved care quality when compared to usual care in a randomized controlled trial. Therefore, stakeholder (patient participants, nurse care managers, and Parkinson disease (PD) specialists) perceptions of key intervention components merit evaluation to inform decisions about dissemination.MethodsThis multi-site study occurred in five southwest United States Veterans Health Administration medical centers. Stakeholders were surveyed on their perceptions of CHAPS including the CHAPS Assessment, CHAPS nurse care managers, the Siebens Domain Management Model™ (a practical clinical model), and the Siebens Health Care Notebook (Notebook) (self-care tool). Participants’ electronic medical records were abstracted for perceptions of the Notebook. Statistical analysis software was used to provide summary statistics; open card sorting methodology was used to identify themes and attributes in qualitative data including usability of some components.ResultsParticipants, overall, highly rated their medication self-management, acknowledged some challenges with the CHAPS self-care tools, reported knowledge of PD specialist follow-up and PD red flags, and rated CHAPS nurse care managers as helpful. Nurse care manager responses indicated the CHAPS Assessment and Program highly facilitated care of their patients. Most all PD specialists would refer other patients to CHAPS. Nurse care manager and PD specialist responses indicated improved participant management of their PD. Three themes emerged in participant perceptions of the Notebook: Notebook Assets (e.g., benefits and features-liked); Deferring Notebook Review (e.g., no time to review); and Reasons for Not Using (e.g., participant preference). Shared attributes regarding the Siebens Domain Management Model and Notebook usability, reported by nurse care managers, were user-friendly, person/patient-centered, and organized. Some challenges to their use were also reported.ConclusionsOverall, stakeholder perceptions of the proactive nurse-led CHAPS intervention indicated its value in the care of individuals with PD. Responses about the CHAPS Assessment, Siebens Domain Management Model, and Notebook self-care tool signified their usefulness. Stakeholders’ constructive suggestions indicated their engagement in CHAPS. These findings support CHAPS dissemination and contribute to research in care management.Trial registrationClinicalTrials.gov as NCT01532986, registered on January 13, 2012.

Increased microglial activation in patients with Parkinson disease using [18F]-DPA714 TSPO PET imaging

IntroductionIncreasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [11C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [18F]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status. MethodsPD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [18F]-DPA714 and [11C]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests. ResultsPD patients showed significantly higher [18F]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [11C]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction). Conclusion[18F]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients. Trial registrationTrial registration: INFLAPARK, NCT02319382. Registered 18 December 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02319382.

Action fluency identifies different sex, age, global cognition, executive function and brain activation profile in non-demented patients with Parkinson's disease.

Patients with Parkinson's disease (PD) have difficulties processing action words, which could be related to early cognitive decline. The action fluency test can be used to quickly and easily assess the processing of action words in PD. The goal of this study was to characterize how the action fluency test relates to personal characteristics, disease factors, cognition, and neural activity in PD. Forty-eight participants with PD (34 male, 14 female) and 35 control participants (16 male, 19 female) completed functional neuroimaging using a set-shifting task and a neuropsychological assessment including the action fluency test. PD participants with a score one standard deviation below the norm or lower on the action fluency test were identified. All PD participants with poor performance (PD-P, n = 15) were male. They were compared to male PD participants with scores within the normal range (PD-N, n = 19) and male healthy controls (HC, n = 16). PD-P were older, had lower global cognition scores, lower executive functions scores, and decreased activity in fronto-temporal regions compared with PD-N. There was no difference between the two PD groups in terms of the duration of the disease, dose of dopaminergic medication, and severity of motor symptoms. PD-N were younger than HC, but there was no other significant difference between these groups. The action fluency test identified a subgroup of PD patients with distinct sex, age, global cognition, executive functions, and brain activity characteristics. Implications for the evaluation of cognition are discussed.

Mitochondrial Supercomplexes: Physiological Organization and Dysregulation in Age-Related Neurodegenerative Disorders.

Several studies suggest that the assembly of mitochondrial respiratory complexes into structures known as supercomplexes (SCs) may increase the efficiency of the electron transport chain, reducing the rate of production of reactive oxygen species. Therefore, the study of the (dis)assembly of SCs may be relevant for the understanding of mitochondrial dysfunction reported in brain aging and major neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Here we briefly reviewed the biogenesis and structural properties of SCs, the impact of mtDNA mutations and mitochondrial dynamics on SCs assembly, the role of lipids on stabilization of SCs and the methodological limitations for the study of SCs. More specifically, we summarized what is known about mitochondrial dysfunction and SCs organization and activity in aging, AD and PD. We focused on the critical variables to take into account when postmortem tissues are used to study the (dis)assembly of SCs. Since few works have been performed to study SCs in AD and PD, the impact of SCs dysfunction on the alteration of brain energetics in these diseases remains poorly understood. The convergence of future progress in the study of SCs structure at high resolution and the refinement of animal models of AD and PD, as well as the use of iPSC-based and somatic cell-derived neurons, will be critical in understanding the biological relevance of the structural remodeling of SCs.

Association Between a Variable Number Tandem Repeat Polymorphism Within the DAT1 Gene and the Mesolimbic Pathway in Parkinson's Disease.

The loss of ventral striatal dopaminergic neurons in Parkinson's disease (PD) predicts an impact on the reward system. The ventrostriatal system is involved in motivational processing and its dysfunction may be related to non-motor symptoms such as depression and apathy. We previously documented that patients with PD had blunted Blood Oxygen Level Dependent functional magnetic resonance imaging (BOLD fMRI) reward task related activity during both reward anticipation (i.e., in the ventral striatum) and reward outcome (i.e., in the orbitofrontal cortex). Evidence for the modulation of brain function by dopaminergic genes in PD is limited. Genes implicated in dopamine transmission, such as the dopamine transporter gene (DAT1) may influence the clinical heterogeneity seen in PD, including reward processing. This study therefore sought to determine whether genetic differences in the DAT gene are associated with brain activity associated with response to reward in PD patients and controls. A sample of PD cases on treatment (n = 15) and non-PD controls (n = 30) from an ethnic group unique to South Africa were genotyped. We found a three-way interaction between GENOTYPE × BOLD fMRI REWARD × DIAGNOSIS [F(1, 40) = 4.666, p = 0.037, partial η2 = 0.104]. PD patients with the DAT1 homozygous 10/10 repeat genotype showed a relative decrease in orbitofrontal cortex reward outcome related activity compared to the patient group who did not have this repeat. PD patients with other genotypes showed an expected increase in orbitofrontal cortex reward outcome related activity compared to controls. Given the small sample size of the PD group with the 10/10 repeat, these results should be considered preliminary. Nevertheless, these preliminary findings highlight the potential modulation of dopamine transporter polymorphisms on orbitofrontal reward system activity in PD and highlight the need for further studies.

Beneficial effects of long term caloric vestibular stimulation on changes in brain neurotransmitter dopamine and locomotor activity in Parkinson’s Disease induced rats

Parkinson's Disease (PD) is a neurodegenerative disorder caused due to deficiency of Dopamine in the Substantia nigra. The existing pharmaceutical treatments are not meeting the need, whereas deep brain stimulation is not suitable for patients with co-morbidities. Therefore, a need for non-invasive and conventional treatment with fewer side effects is required. So we have tried a simple method of Caloric Vestibular Stimulation (CVS) for the long term and assessed its neuroprotective effect in PD induced rats. In the present study, 30 adult male Wistar albino rats (250 - 300g) were randomly assigned into five groups. Group 1 control, Group 2 was induced with Parkinson’s disease using rotenone, Group 3 was PD induced and CVS gave for 45 days, Group 4 was PD induced for 21 days and left untreated to study for its recovery, Group 5 was given CVS only for 45 days. The behavioral activity was recorded using an actophotometer and to assess the function of the nigrostriatal pathway. Dopamine produced in the striatum was measured using reverse-phase HPLC. Results showed significant (P&lt; 0.05) alteration in dopamine and locomotor activity in PD, which was significantly (P&lt; 0.05) improved by warm water CVS administration in Parkinson's disease-induced rat. In this aspect, CVS can be utilized as a conventional treatment method for PD and thus recommended for further investigations towards translational treatment in humans for Parkinson’s disease.

The Associations Between Physical Activity, Sleep, and Mood with Pain inPeople with Parkinson's Disease: An Observational Cross-Sectional Study.

Pain is common in Parkinson's disease (PD). In general and chronic pain populations, physical inactivity, poor sleep, and anxiety are associated with worse pain. However, little is known about these potential predictors of pain in PD. This cross-sectional observational study investigated associations between measures of physical activity, sleep, and mood with pain in people with PD. Pain was measured using the King's PD Pain Scale and the Brief Pain Inventory (pain severity and interference) in 52 participants with PD. Independent variables were categorised by demographics (age, gender), disease severity (MDS-UPDRS) and duration, central sensitization (Central Sensitization Inventory), physical activity (Incidental and Planned Exercise Questionnaire), sleep (Pittsburgh Sleep Quality Index), and mood (Hospital Anxiety and Depression Scale). Univariate regression analyses showed that increased disease severity, longer disease duration, greater central sensitization, increased physical activity, poor sleep, anxiety, and depression were associated with worse pain in one or more pain measures (p < 0.05). Multivariate regression models accounted for 56% of the variance in the King's Pain Scale, 25% pain severity and 36% in pain interference. Poor sleep independently contributed to worse pain scores in all models (β 0.3-0.4, p < 0.05). Increased physical activity, poor sleep, anxiety, and depression are associated with worse pain scores in people with PD. For optimal management of pain in people with PD, sleep and mood may need to be addressed. Further, the nature of the relationship between physical activity and pain in PD requires further investigation.

Striatal dopamine motor and non-motor network and cortical activity in Parkinson disease: a correlation study between 123I-FP-CIT SPECT and FDG PET (5269)

Striatal dopamine motor and non-motor network and cortical activity in Parkinson disease: a correlation study between 123I-FP-CIT SPECT and FDG PET (5269)

Sympathetic nervous activity and hemoglobin levels in de novo Parkinson's disease.

Sympathetic nervous denervation may be associated with the development of anemia. We aimed to investigate the association between sympathetic nervous denervation and hemoglobin levels in patients with Parkinson's disease (PD). As indices of sympathetic nervous denervation, we investigated resting norepinephrine levels, increased norepinephrine levels after tilt-up, cardiac uptake of 123I-metaiodobenzylguanidine, supine blood pressure, and the degree of orthostatic hypotension in 132 patients with de novo PD. Older age, female sex, severe motor dysfunction, and lower body mass index were associated with decreased hemoglobin levels. After adjustment for these covariables, resting norepinephrine levels were negatively associated with hemoglobin levels. Hemoglobin levels were not associated with cardiac sympathetic denervation or orthostatic intolerance. Hemoglobin levels in PD seem to be closely related to noradrenergic nervous activity and nigrostriatal dopaminergic degeneration. In contrast to expectations, decreased hemoglobin levels were associated with increased whole-body sympathetic nervous activity in PD.

ReadySteady intervention to promote physical activity in older adults with Parkinson's disease: Study design and methods

The main motor impairments of gait and balance experienced by people with Parkinson's disease (PD) contribute to a sedentary lifestyle, resulting in poor physical conditioning, loss of functional independence, and reduced quality of life. Despite the known benefits of physical activity in PD, the majority of older adults with PD are insufficiently active. Few studies incorporate behavioral change approaches to promoting physical activity in PD. The main goal of this research is to foster community mobility in older adults with PD by promoting physical activity and improving gait patterns using a theory-based behavioral change intervention. The ReadySteady intervention combines wellness motivation theory with polestriding physical activity, which has been shown to be beneficial for people with PD. The intervention will be tested using a randomized controlled design, including inactive older adults diagnosed with PD. Participants will be randomly assigned the 12-week ReadySteady intervention, 12-week polestriding, and education intervention, or 12-week education intervention. Thirty-six older adults with PD will participate in each of the interventions. Level of physical activity, clinical scores, quantitative measures of gait and balance control, and motivational variables for each intervention will be measured at three time points: pre-intervention, post-intervention (12 weeks), and follow-up (24 weeks). If the intervention is beneficial, it may serve as a sustainable addition to current practice in health promotion efforts serving the PD population.

Long-Term Exposure to PFE-360 in the AAV-α-Synuclein Rat Model: Findings and Implications.

Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with impaired motor function and several non-motor symptoms, with no available disease modifying treatment. Intracellular accumulation of pathological α-synuclein inclusions is a hallmark of idiopathic PD, whereas, dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial PD that is clinically indistinguishable from idiopathic PD. Recent evidence supports the hypothesis that an increase in LRRK2 kinase activity is associated with the development of not only familial LRRK2 PD, but also idiopathic PD. Previous reports have shown preclinical effects of LRRK2 modulation on α-synuclein-induced neuropathology. Increased subthalamic nucleus (STN) burst firing in preclinical neurotoxin models and PD patients is hypothesized to be causally involved in the development of the motor deficit in PD. To study a potential pathophysiological relationship between α-synuclein pathology and LRRK2 kinase activity in PD, we investigated the effect of chronic LRRK2 inhibition in an AAV-α-synuclein overexpression rat model. In this study, we report that chronic LRRK2 inhibition using PFE-360 only induced a marginal effect on motor function. In addition, the aberrant STN burst firing and associated neurodegenerative processes induced by α-synuclein overexpression model remained unaffected by chronic LRRK2 inhibition. Our findings do not strongly support LRRK2 inhibition for the treatment of PD. Therefore, the reported beneficial effects of LRRK2 inhibition in similar α-synuclein overexpression rodent models must be considered with prudence and additional studies are warranted in alternative α-synuclein-based models.

Electroskip auditory biofeedback in a patient with Parkinson disease: a case report.

The purpose of this case study was to observe the effects of a rehabilitation program with an audio-biofeedback technology device called Electroskip in a patient with Parkinson disease. The patient was a 61-year-old man with moderate Parkinson disease (Hoehn and Yahr Parkinson’s scale stage III) and dementia who had progressive episodes of freezing of gait. The patient also had a history of recent falls. The patient completed a 6-week rehabilitation program focused on functional tasks, balance and gait training while using Electroskip technology, which is a wireless, wearable device that sends a discrete real-time generative audio-biofeedback signal when the user steps on either the heel or toe force sensors positioned under the innersoles. The outcome measures included the Timed Up and Go test, the modified Gait Abnormality Rating Scale, the modified Parkinson’s Activity Scale, and the Freezing of Gait Questionnaire. The patient completed 17 of the 18 scheduled training sessions and all testing sessions; no adverse events occurred during the rehabilitation program and high satisfaction levels were reported by the patient and family after completion of the 6-week rehabilitation program. Clinically significant improvements were seen in all measures at 6 weeks. The results of this report suggest that a rehabilitation program focused on functional tasks, balance, and gait training using the Electroskip technology may be beneficial for improving gait and balance in a patient with moderate Parkinson disease. Future work is needed to determine the effectiveness of Electroskip technology by means of randomized controlled trials.

Comparing self-reported and objective monitoring of physical activity in Parkinson disease

IntroductionMonitoring physical activity is important in Parkinson disease (PD), but patient recall may be unreliable. We examined relationships between self-reported activity, objective monitoring, and clinical characteristics. MethodsParticipants completed the self-reported Physical Activity Scale in the Elderly (PASE) to determine subjective minutes of moderate-vigorous physical activity (MVPA); a subset wore an Actigraph monitor capturing step count and objective MVPA using a PD-specific algorithm. Relationships between subjective and objective measurements were determined using partial correlations controlling for age and disease stage. ResultsSixty-six subjects completed subjective reporting; median age (interquartile range [IQR]) was 70 (69–74) years and median disease duration (IQR) was 4 (1.5–7.5) years. Age-adjusted median PASE was 135.3. Median daily step count was 3615 (IQR 1772–4870), which was moderately well-correlated with PASE (ρ = 0.56, p = 0.003). Median MVPA was 8.1 min/day (IQR 2.2–23.2), which was not correlated with PASE (ρ = -0.003, p = 0.98). ConclusionsPhysical activity in this cohort of Veterans with PD is low and consists mostly of low-intensity steps rather than MVPA. The symptomatic and disease-modifying potential of lower intensity activity is uncertain. These data emphasize the need for interventions to increase MVPA in PD and the importance of objective monitoring using wearable technology.

Specific intranasal and central trigeminal electrophysiological responses in Parkinson's disease.

Olfactory dysfunction is a frequent early non-motor symptom of Parkinson's disease (PD). There is evidence that with regard to trigeminal perception, PD-related olfactory dysfunction is different from other olfactory disorders. More specifically, trigeminal sensitivity, when measured behaviorally, was unimpaired in PD patients as opposed to patients with non-Parkinsonian olfactory dysfunction (NPOD). We sought to investigate the trigeminal pathway by measuring electrophysiological recordings from the nasal epithelium and EEG-derived event-related potentials in response to a specific trigeminal stimulus in 21 PD patients and compare them to 23 patients with NPOD and 25 controls (C). The peripheral trigeminal response, as measured by the negative-mucosa potential, showed no difference between patients with PD and controls whereas PD patients showed faster responses than patients with NPOD, the latter having shown slower and larger responses than controls (18 PD, 14 NPOD, 20 C). The central trigeminal response, as measured by event-related potentials, revealed larger early component response in PD patients compared to patients with NPOD (15 PD, 21 NPOD, 23 C). As expected, psychophysical olfactory testing showed impaired olfactory function in both groups of patients as opposed to controls. Discriminant analysis revealed a model that could predict group membership for 80% of participants based on the negative-mucosa potential latency, olfactory threshold and discrimination tests. These results provide novel insights into the pattern of trigeminal activation in PD which will help to differentiate PD-related olfactory loss from NPOD, a crucial step towards establishing early screening batteries for PD including smell tests.

The Interaction Between Neuroinflammation and β-Amyloid in Cognitive Decline in Parkinson's Disease.

Activated microglia have been reported to play an important role in Parkinson's disease (PD). A more rapid cognitive decline has been associated with deposits of β-amyloid. In this study, the aim was to evaluate the role of brain β-amyloid and its relationship with activated microglia in PD patients with normal and impaired cognition. We studied 17 PD patients with normal cognition (PDn), 12 PD patients with mild cognitive impairment (PD-MCI), and 12 healthy controls (HCs) with [11C] Pittsburgh compound B (PIB) to assess the impact of β-amyloid deposition in the brain on microglial activation evaluated using the translocator protein 18-kDa (TSPO) radioligand [18F]-FEPPA. [11C] PIB distribution volume ratio was measured in cortical and subcortical regions. [18F]-FEPPA total distribution volume values were compared for each brain region between groups to evaluate the effect of PIB positivity while adjusting for the TSPO rs6971 polymorphism. Factorial analysis of variance revealed a significant main effect of PIB positivity in the frontal lobe (F(1, 34) = 7.1, p = 0.012). Besides the frontal (p = 0.006) and temporal lobe (p = 0.001), the striatum (p = 0.018), the precuneus (p = 0.019), and the dorsolateral prefrontal cortex (p = 0.010) showed significant group × PIB positivity interaction effects. In these regions, PD-MCIs had significantly higher FEPPA VT if PIB-positive. Our results indicate an interaction between amyloid-β deposition and microglial activation in PD. Further investigations are necessary to evaluate if amyloid deposits cause neuroinflammation and further neurodegeneration or if increased microglia activation develops as a protective response.

Targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase involved in multiple cellular processes and signaling pathways. LRRK2 mutations are associated with autosomal-inherited Parkinson's disease (PD), and evidence suggests that LRRK2 pathogenic variants generally increase kinase activity. Therefore, inhibition of LRRK2 kinase function is a promising therapeutic strategy for PD treatment. The search for drug-like molecules capable of reducing LRRK2 kinase activity in PD led to the design of selective LRRK2 inhibitors predicted to be within the CNS drug-like space. This review highlights the journey that translates chemical tools for interrogating the role of LRRK2 in PD into promising drug candidates, addressing the challenges in discovering selective and brain-penetrant LRRK2 modulators and exploring the structure-activity relationship of distinct LRRK2 inhibitors.

Effect of Temperature and pH on the Secondary Structure and Denaturation Process of Jumbo Squid Hepatopancreas Cathepsin D.

Cathepsin D is a lysosomal enzyme that is found in all organisms acting in protein turnover, in humans it is present in some types of carcinomas, and it has a high activity in Parkinson's disease and a low activity in Alzheimer disease. In marine organisms, most of the research has been limited to corroborate the presence of this enzyme. It is known that cathepsin D of some marine organisms has a low thermostability and that it has the ability to have activity at very acidic pH. Cathepsin D of the Jumbo squid (Dosidicus gigas) hepatopancreas was purified and partially characterized. The secondary structure of these enzymes is highly conserved so the role of temperature and pH in the secondary structure and in protein denaturation is of great importance in the study of enzymes. The secondary structure of cathepsin D from jumbo squid hepatopancreas was determined by means of circular dichroism spectroscopy. In this article, our purpose was to determine the secondary structure of the enzyme and how it is affected by subjecting it to different temperature and pH conditions. Circular dichroism technique was used to measure the modifications of the secondary structure of cathepsin D when subjected to different treatments. The methodology consisted in dissecting the hepatopancreas of squid and freeze drying it. Then a crude extract was prepared by mixing 1: 1 hepatopancreas with assay buffer, the purification was in two steps; the first step consisted of using an ultrafiltration membrane with a molecular cut of 50 kDa, and the second step, a pepstatin agarose resin was used to purification the enzyme. Once the enzyme was purified, the purity was corroborated with SDS PAGE electrophoresis, isoelectric point and zymogram. Circular dichroism is carried out by placing the sample with a concentration of 0.125 mg / mL in a 3 mL quartz cell. The results were obtained in mdeg (millidegrees) and transformed to mean ellipticity per residue, using 111 g/mol molecular weight/residue as average. Secondary-structure estimation from the far-UV CD spectra was calculated using K2D Dichroweb software. It was found that α helix decreases at temperatures above 50 °C and above pH 4. Heating the enzyme above 70°C maintains a low percentage of α helix and increases β sheet. Far-UV CD measurements of cathepsin D showed irreversible thermal denaturation. The process was strongly dependent on the heating rate, accompanied by a process of oligomerization of the protein that appears when the sample is heated, and maintained a certain time at this temperature. An amount typically between 3 and 4% α helix of their secondary structure remains unchanged. It is consistent with an unfolding process kinetically controlled due to the presence of an irreversible reaction. The secondary structure depends on pH, and a pH above 4 causes α helix structures to be modified. In conclusion, cathepsin D from jumbo squid hepatopancreas showed retaining up to 4% α helix at 80°C. The thermal denaturation of cathepsin D at pH 3.5 is under kinetic control and follows an irreversible model.

The Association between Prefrontal Cortex Activity and Turning Behavior in People with and without Freezing of Gait

Turning elicits Freezing of Gait (FoG) episodes in people with Parkinson's disease (PD) and is thought to require higher cortical control compared to straight ahead gait. Functional near infrared spectroscopy (fNIRS) has been used to examine prefrontal cortex (PFC) activity while walking, but the relationship between PFC activity and turn performance remains unclear. The aim of this pilot study was to examine PFC activity during turning in PD and healthy controls, and to investigate the association between PFC activity and turning.Thirty-two subjects, 15 freezers (PD + FoG) and 17 non-freezers (PD − FoG), and 8 controls were asked to perform a 2-min turning-in-place test under single-task (ST) and dual-task (DT) conditions. Each participant wore an fNIRS system to measure changes in oxyhemoglobin, as measure of PFC activity, and inertial sensors to quantify turning.Our results show a significant group (p = .050), task (p = .039), and interaction (p = .047) for the PFC activity during turning. Specifically, PD + FoG show higher PFC during turning compared to the other groups; PFC activity during DT is overall different compared to ST with an opposite trend in PD + FoG compared to controls and PD − FoG. In addition, higher PFC is associated with worse FoG in PD + FoG (r = 0.57, p = .048) and with lower number of turns in PD − FoG (r = −0.70, p = .002).The increased PFC activity in PD and the association between higher PFC activity and poorer turning performance may be a sign of poor movement automaticity in PD. Although further investigations are required, these pilot findings may guide development of personalized treatments to improve motor automaticity in PD.