3D Kinematics Quantifies Gait Response to Levodopa earlier and to a more Comprehensive Extent than the MDS-Unified Parkinson's Disease Rating Scale in Patients with Motor Complications.

BACKGROUND: Quantitative 3D movement analysis using inertial measurement units (IMUs) allows for a more detailed characterization of motor patterns than clinical assessment alone. It is essential to discriminate between gait features that are responsive or unresponsive to current therapies to better understand the underlying pathophysiological basis and identify potential therapeutic strategies. OBJECTIVES: This study aims to characterize the responsiveness and temporal evolution of different gait subcomponents in Parkinson's disease (PD) patients in their OFF and various ON states following levodopa administration, utilizing both wearable sensors and the gold-standard MDS-UPDRS motor part III. METHODS: Seventeen PD patients were assessed while wearing a full-body set of 15 IMUs in their OFF state and at 20-minute intervals following the administration of a supra-threshold levodopa dose. Gait was reconstructed using a biomechanical model of the human body to quantify how each feature was modulated. Comparisons with non-PD control subjects were conducted in parallel. RESULTS: Significant motor changes were observed in both the upper and lower limbs according to the MDS-UPDRS III, 40 minutes after levodopa intake. IMU-assisted 3D kinematics detected significant motor alterations as early as 20 minutes after levodopa administration, particularly in upper limbs metrics. Although all "pace-domain" gait features showed significant improvement in the Best-ON state, most rhythmicity, asymmetry, and variability features did not. CONCLUSION: IMUs are capable of detecting motor alterations earlier and in a more comprehensive manner than the MDS-UPDRS III. The upper limbs respond more rapidly to levodopa, possibly reflecting distinct thresholds to levodopa across striatal regions.

Long-term follow-up of subthalamic nucleus deep brain stimulation in patients with Parkinson's disease: An analysis of survival and disability milestones.

BACKGROUND: Data on the long-term survival and incidence of disability milestones after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) is limited. OBJECTIVES: To estimate mortality and assess the frequency/time-to-development of disability milestones (falls, freezing, hallucinations, dementia, and institutionalization) among PD patients post STN-DBS. METHODS: A longitudinal retrospective study of patients undergoing STN-DBS. For mortality, Cox proportional hazards regression analysis was performed. For disease milestones, competing risk analyses were performed and cumulative incidence functions reported. The strength of association between baselines features and event occurrence was calculated based on adjusted hazard ratios. RESULTS: The overall mortality for the 109 patients was 16 % (62.1 ± 21.3 months after surgery). Falls (73 %) and freezing (47 %) were both the earliest (40.4 ± 25.4 and 39.6 ± 28.4 months, respectively) and most frequent milestones. Dementia (34 %) and hallucinations (32 %) soon followed (56.2 ± 21.2 and mean 60.0 ± 20.7 months after surgery, respectively). Higher ADL scores in the OFF state and higher age at surgery were associated with falls, freezing, dementia and institutionalization. CONCLUSIONS: Long-term mortality rate is low after STN-DBS. Disease milestones occur later during the disease course, with motor milestones appearing first and at a higher frequency than cognitive ones.

Handicap as a Measure of Perceived-Health Status in Parkinson's Disease.

Background: Handicap is a patient-centered measure of health status that encompasses the impact of social and physical environment on daily living, having been assessed in advanced and late-stage Parkinson's Disease (PD). Objective: To characterize the handicap of a broader sample of patients. Methods: A cross-sectional study of 405 PD patients during the MDS-UPDRS Portuguese validation study, using the MDS-UPDRS, Unified Dyskinesias Rating Scale, Nonmotor symptoms questionnaire, PDQ-8 and EQ-5D-3L. Handicap was measured using the London Handicap Scale (LHS). Results: Mean age was 64.42 (±10.3) years, mean disease duration 11.30 (±6.5) years and median HY 2 (IQR, 2-3). Mean LHS was 0.652 (±0.204); "Mobility," "Occupation" and "Physical Independence" were the most affected domains. LHS was significantly worse in patients with longer disease duration, older age and increased disability. In contrast, PDQ-8 did not differentiate age groups. Handicap was significantly correlated with disease duration (r = -0.35), nonmotor experiences of daily living (EDL) (MDS-UPDRS-I) (r = -0.51), motor EDL (MDS-UPDRS-II) (r = -0.69), motor disability (MDS-UPDRS-III) (r = -0.49), axial signs of MDS-UPDRS-III (r = -0.55), HY (r = -0.44), presence of nonmotor symptoms (r = -0.51) and PDQ-8 index (r = -0.64) (all P < 0.05). Motor EDL, MDS-UPDRS-III and PDQ-8 independently predicted Handicap (adjusted R 2 = 0.582; P = 0.007). Conclusions: The LHS was easily completed by patients and caregivers. Patients were mild-moderately handicapped, which was strongly determined by motor disability and its impact on EDL, and poor QoL. Despite correlated, handicap and QoL seem to differ in what they measure, and handicap may have an added value to QoL. Handicap seems to be a good measure of perceived-health status in a broad sample of PD.

Multiple keratotic projections on the palms and soles.

Spiny keratoderma (SKD) is a rare palmoplantar keratoderma that presents with few to numerous millimetric hyperkeratotic projections on the palms and soles. It has been described with both hereditary and acquired variants. The acquired form, which presents in older adults, has been associated with a variety of systemic diseases and malignant conditions. In patients suspected of having acquired spiny keratoderma, an evaluation for malignant conditions may be warranted. Treatment with topical keratolytics or topical and oral retinoids is usually insufficient. Herein, we present the case of a 58-year-old man diagnosed with idiopathic SKD.

Modulating Influence of State Anxiety on the Effect of Midazolam on Postsurgical Pain.

Anxiety contributes to postsurgical pain, and midazolam is frequently prescribed preoperatively. Conflicting results have been described concerning the impact of midazolam on pain. This study aims to evaluate the effect of systemic midazolam on pain after open inguinal hernia repair, clarifying its relationship with preoperative anxiety. A prospective observational cohort study was conducted in three Portuguese ambulatory units between September 2018 and March 2020. Variable doses of midazolam were administered. Postsurgical pain was evaluated up to three months after surgery. We enrolled 306 patients and analyzed 281 patients. The mean preoperative anxiety Numeric Rating Scale score was 4 (3) and the mean Surgical Fear Questionnaire score was 22 (16); the mean midazolam dose was 1.7 (1.1) mg with no correlation to preoperative anxiety scores. Pain ≥4 was present in 67% of patients 24 h after surgery and in 54% at seven days; at three months, 27% were classified as having chronic postsurgical pain. Preoperative anxiety correlated to pain severity at all time points. In multivariable regression, higher midazolam doses were associated with less pain during the first week, with no apparent effect on chronic pain. However, subgroup analyses uncovered an effect modification according to preoperative anxiety: the decrease in acute pain occurred in the low-anxiety patients with no effect on the high-anxiety group. Inversely, there was an increase in chronic postsurgical pain in the very anxious patients, without any effect on the low-anxiety group. Midazolam, generally used as an anxiolytic, might impact distinctively on pain depending on anxiety.

High frequency of Depressive Disorders and Suicidal Phenomena in Late-Stage Parkinson´s Disease - A Cross-Sectional Study.

BACKGROUND: Depressive disorders (DD) are widely recognized as one of the most frequent neuropsychiatric disorders in Parkinson´s disease. Patients with late-stage Parkinson´s disease (LSPD) continue to be a neglected population, and little is known about DD frequency in LSPD. OBJECTIVES: To determine the frequency of DD in LSPD patients through a clinical diagnostic interview (CDI) and according to diagnostic DSM- 5 criteria. Secondary objectives were to determine the predictive ability of depressive scales to detect DD, to identify potential predictors of DD in LSPD and, to evaluate suicidal phenomena in LSPD. METHODS: A cross-sectional study including LSPD patients (≥7 years from symptom onset and Hoehn and Yahr scale score >3 or a Schwab and England scale score <50% in the ON condition) was conducted. Patients were subjected to psychiatric, neurological, and neuropsychological evaluations. Six depression scales were applied. RESULTS: 92 LSPD patients were included. 59.78% of LSPD patients had a current diagnosis of DD according to CDI, 38.04% patients had a diagnosis of major depressive disorder, and 21.72% non-major depressive disorder. Suicidal ideation was present in 36.96% of patients. All applied scales were able to detect depressive disorders. CONCLUSIONS: More than half of LSPD patients met DD diagnostic criteria and over one-third were diagnosed with major depressive disorder. Overall, the LSPD population seem to have a unique clinical phenotype regarding the frequency and features of DD, whose early identification and treatment could improve the quality of life of patients and caregivers.

Trial of Deferiprone in Parkinson's Disease.

BACKGROUND: Iron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear. METHODS: We conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome. RESULTS: A total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants. CONCLUSIONS: In participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks. (Funded by the European Union Horizon 2020 program; FAIRPARK-II ClinicalTrials.gov number, NCT02655315.).

Personalized Care in Late-Stage Parkinson's Disease: Challenges and Opportunities.

Late-stage Parkinson's disease (LSPD) patients are highly dependent on activities of daily living and require significant medical needs. In LSPD, there is a significant caregiver burden and greater health economic impact compared to earlier PD stages. The clinical presentation in LSPD is dominated by motor and non-motor symptoms (NMS) that most of the time have a sub-optimal to no response to dopaminergic treatment, especially when dementia is present. Non-pharmacological interventions, including physiotherapy, cognitive stimulation, speech, occupational therapy, and a specialized PD nurse, assume a key role in LSPD to mitigate the impact of disease milestones or prevent acute clinical worsening and optimize the management of troublesome NMS. However, the feasibility of these approaches is limited by patients' cognitive impairment and the difficulty in delivering care at home. The present care challenge for LSPD is the ability to offer a person-centered, home-delivered palliative care model based on Advanced Care Planning. An ongoing European multicentric project, PD_Pal, aims to address this challenge.

Profile of cognitive impairment in late-stage Parkinson's disease.

INTRODUCTION: The profile of cognitive impairment associated with the late stages of Parkinson's disease (LSPD) is rarely reported. Its characterization is necessary to better understand the cognitive changes that occur as the disease progresses and to better contribute to its management. METHODS: In this cross-sectional study, we characterized the cognitive profile of LSPD patients using the comprehensive assessment methodology proposed by the International Parkinson and Movement Disorders Society Task Force. The association of clinical and demographic variables with dementia diagnosis was also investigated using binary logistic regression analysis. RESULTS: Eighty-four LSPD patients were included (age 75.4 ± 6.9; disease duration 16.9 ± 7.5). Fifty-four (64.3%) were classified as demented and presented a global impairment cognitive profile. In the nondemented group (N = 30), 25 (83.3%) LSPD patients met the diagnostic criteria for mild cognitive impairment, mostly with multiple domain impairment (96.0%) and a heterogeneous profile. Memory was the most frequent and severely impaired cognitive domain in both groups. Disease disability, orientation, complex order comprehension, verbal learning, and visuoconstructive abilities were significantly associated with dementia diagnosis (p < .05). CONCLUSIONS: Cognitive impairment in multiple domains was common in LSPD patients. The most frequent and prominent deficits were in the memory domain, with a strong interference from attention impairment. Disease disability, orientation, complex order comprehension, verbal learning, and visuoconstructive abilities proved to be important determinants for dementia diagnosis.

Total Knee Arthroplasty: Superiority of Intra-Articular Tranexamic Acid Over Intravenous and Cell Salvage as Blood Sparing Strategy - A Retrospective Study.

PURPOSE: Total knee arthroplasty is associated with considerable perioperative hemorrhage. The decrease in hemoglobin concentration and the need for allogenic blood transfusion are related to increased morbidity and mortality. Strategies for minimizing perioperative bleeding are used, such as tranexamic acid and cell salvage. The study aimed to compare intravenous, intra-articular tranexamic acid and cell salvage protocols regarding perioperative hemoglobin variation. Secondary outcomes included blood loss; allogenic transfusions; complications and in-hospital stay. PATIENTS AND METHODS: Patients submitted to unilateral total knee arthroplasty between January and December 2018 were retrospectively evaluated. After excluding 62 patients, 204 were subdivided into 3 groups according to the protocol used. Statistical analysis was performed with SPSS version 26.0. One-way ANOVA and Kruskal-Wallis tests were used. Considered a p-value of <0.05 for statistical significance. RESULTS: Variation of hemoglobin in the intra-articular tranexamic acid group was significantly lower than that of intravenous (p < 0.001) and cell salvage (p = 0.001) groups. Blood loss, variation of hematocrit, need for blood transfusion and in-hospital stay were also statistically significantly lower in the intra-articular tranexamic acid group. The only related complications were in the intravenous tranexamic acid group. No thromboembolic complications were identified which further solidifies the safety of tranexamic acid administration. CONCLUSION: This data shows superiority of the intra-articular administration of tranexamic acid over the other techniques in total knee arthroplasty. We propose this protocol as an efficient, low-risk blood-sparing strategy.

Emergency department and hospital utilisation and expenditures in the last year of life: retrospective chronic diseases cohort study.

OBJECTIVES: We aimed to examine the influence of chronic diseases in emergency department (ED) and inpatient utilisation and expenditures in the 12 months before death. METHODS: Retrospective cohort study of ED and inpatient database. Adults deceased at a hospital in Portugal in 2013 were included. We tested the influence of chronic diseases on the number of ED visits, hospital admissions and expenditures using generalised linear models. RESULTS: The study included 484 patients (81.8% ≥65 years, median two chronic diseases). Nearly all (91.3%) attended the ED in the 12 months before death. The median number of admissions was 1, median expenditure was €6159. Adjusting for confounders, chronic pulmonary disease increased ED and inpatient utilisation (1.49; 95% CI: 1.22 to 1.83; 95% CI 1.29, 1.09 to 1.51). Increased ED utilisation was observed for patients with renal disease, dementia and metastatic solid tumour (1.40, 95% CI 1.15 to 1.71; 1.39, 95% CI 1.11 to 1.75; 1.31, 95% CI 1.07 to 1.60). Other malignancies showed increased inpatient utilisation (1.24, 95% CI 1.09 to 1.42). The number of chronic conditions had a considerable effect on expenditures (3: 2.08, 95% CI 1.44 to 2.99; ≥4: 4.02, 95% CI 2.51 to 6.45). CONCLUSION: We found a high use of hospitals at the end of life, particularly EDs. Our findings suggest that people with cancer, renal disease, chronic pulmonary disease and dementia are relevant when developing cost-effective alternatives to hospital care.

miR-335 Targets LRRK2 and Mitigates Inflammation in Parkinson's Disease.

Parkinson's disease (PD) is mainly driven by dopaminergic neuronal degeneration in the substantia nigra pars compacta accompanied by chronic neuroinflammation. Despite being mainly sporadic, approximately 10% of all cases are defined as heritable forms of PD, with mutations in the leucine-rich repeat kinase (LRRK2) gene being the most frequent known cause of familial PD. MicroRNAs (miRNAs or miRs), including miR-335, are frequently deregulated in neurodegenerative diseases, such as PD. Here, we aimed to dissect the protective role of miR-335 during inflammation and/or neurodegenerative events in experimental models of PD. Our results showed that miR-335 is significantly downregulated in different PD-mimicking conditions, including BV2 microglia cells stimulated with lipopolysaccharide (LPS) and/or overexpressing wild-type LRRK2. Importantly, these results were confirmed in serum of mice injected with 1-methyl-1-4-phenyl-1,2,3,6-tetrahydripyridine hydrochloride (MPTP), and further validated in patients with idiopathic PD (iPD) and those harboring mutations in LRRK2 (LRRK2-PD), thus corroborating potential clinical relevance. Mechanistically, miR-335 directly targeted LRRK2 mRNA. In the BV2 and N9 microglia cell lines, miR-335 strongly counteracted LPS-induced proinflammatory gene expression, and downregulated receptor interacting protein 1 (RIP1) and RIP3, two important players of necroptotic and inflammatory signaling pathways. Further, miR-335 inhibited LPS-mediated ERK1/2 activation. LRRK2-Wt-induced proinflammatory gene expression was also significantly reduced by miR-335 overexpression. Finally, in SH-SY5Y neuroblastoma cells, miR-335 decreased the expression of pro-inflammatory genes triggered by α-synuclein. In conclusion, we revealed novel roles for miR-335 in both microglia and neuronal cells that strongly halt the effects of classical inflammatory stimuli or LRRK2-Wt overexpression, thus attenuating chronic neuroinflammation.

Clinical Diagnostic Criteria Have a High Impact on the Frequency of Dementia in Late-Stage Parkinson's Disease.

Background: Cognitive impairment is a potential late feature of Parkinson's disease (PD). However, studies in patients with late-stage PD are lacking due to the particular characteristics of this population. Objectives: To evaluate the frequency of dementia in late-stage PD patients and to assess the impact of using different diagnostic criteria. Methods: We conducted a cross-sectional study to estimate the frequency of dementia in late-stage PD patients using the International Parkinson and Movement Disorders Society (MDS) (Level II) clinical diagnostic criteria as the primary outcome. We also applied other diagnostic criteria [MDS (Level I), DSM-IV, and DSM-5 criteria] to determine their applicability and impact on dementia frequency. Results: 93 participants with a mean age of 75.8 years (SD 6.8) and 16.5 years (SD 7.5) of disease duration were included. 64.3% were classified as demented using the International Parkinson and Movement Disorders Society (MDS) (Level II) clinical diagnostic criteria. We observed a high discrepancy on the frequency of dementia depending on the criteria applied [6.2% with MDS (Level I), 58.8% with DSM-IV, and 72.0% with DSM-5 criteria]. Conclusions: We found a frequency of dementia below what was observed in similar populations. The particular characteristics of our sample may have contributed as protective factors for late-stage dementia. Dementia frequency varied depending on the criteria used mainly due to the presence of major depression.

Target identification for small-molecule discovery in the FOXO3a tumor-suppressor pathway using a biodiverse peptide library.

Genetic screening technologies to identify and validate macromolecular interactions (MMIs) essential for complex pathways remain an important unmet need for systems biology and therapeutics development. Here, we use a library of peptides from diverse prokaryal genomes to screen MMIs promoting the nuclear relocalization of Forkhead Box O3 (FOXO3a), a tumor suppressor more frequently inactivated by post-translational modification than mutation. A hit peptide engages the 14-3-3 family of signal regulators through a phosphorylation-dependent interaction, modulates FOXO3a-mediated transcription, and suppresses cancer cell growth. In a crystal structure, the hit peptide occupies the phosphopeptide-binding groove of 14-3-3ε in a conformation distinct from its natural peptide substrates. A biophysical screen identifies drug-like small molecules that displace the hit peptide from 14-3-3ε, providing starting points for structure-guided development. Our findings exemplify "protein interference," an approach using evolutionarily diverse, natural peptides to rapidly identify, validate, and develop chemical probes against MMIs essential for complex cellular phenotypes.