Journal of Parkinson's Disease - Volume Pre-press, issue Pre-press

Authors: Jones, Jolynn | Nielson, Spencer A. | Trout, Jonathan | Swenson, Mckaella | Reiley, Joseph | Tanner, Jared | Bowers, Dawn | Kay, Daniel B.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is associated with sleep disturbance (SD) and sleep-related impairment (SRI). Validation of self-report measures of these problems is needed in PD. The Patient-Reported Outcomes Measurement Information System (PROMIS) includes tools that assess these problems (PROMIS-SD and PROMIS-SRI, respectively). Objective: This study aimed to further validate these measures in individuals with PD and matched controls. Methods: Individuals with early-stage PD (n =50) and matched controls (n =48) completed measures of SD including the PROMIS-SD, Pittsburgh Sleep Quality Index (PSQI), and Insomnia Severity Index (ISI). They also completed measures of daytime impairment including the …PROMIS-SRI, Epworth Sleepiness Scale, State-Trait Anxiety Inventory, Beck Depression Inventory 2nd edition, and Parkinson’s Disease Questionnaire-39. Internal consistency for the PROMIS measures were assessed using Cronbach’s α coefficient and item-total correlations in the total sample. Convergent and divergent validity of the PROMIS item banks were assessed using Spearman correlations. Results: The PROMIS item banks had excellent internal consistency (α >0.94). Supporting convergent validity, the PROMIS-SD had strong correlations with other measures of SD (ρ >0.70, for PSQI and ISI) and the PROMIS-SRI had moderate to strong correlations with all measures of daytime impairment (ρ =0.41–0.72). Supporting divergent validity within the PD group, the PROMIS-SD correlated more strongly with SRI than with the Parkinson’s Disease Questionnaire total score, a metric of PD related impairment. Conclusion: In middle-aged and older adults, with and without early-stage PD, the PROMIS-SD and PROMIS-SRI are reliable and valid measures of SD and SRI, respectively. Show more

Keywords: Parkinson’s disease, sleep, validation study, patient-reported outcome measures

DOI: 10.3233/JPD-202429

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Rodríguez, Miguel Ángel | Crespo, Irene | del Valle, Miguel | Olmedillas, Hugo

Article Type: Article Commentary

DOI: 10.3233/JPD-212541

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-2, 2021

Authors: Contin, Manuela | Lopane, Giovanna | Cortelli, Pietro | Sambati, Luisa | Mohamed, Susan | Calandra-Buonaura, Giovanna

Article Type: Research Article

Abstract: Background: Differential diagnosis between Parkinson’s disease (PD) and atypical parkinsonisms (APs) may be difficult at disease onset. The response to levodopa (LD) is a key supportive feature but its definition is largely empirical. Studies evaluating this issue by quantitative tests are scanty. Objective: We aimed to assess the utility of a subacute low LD dose kinetic-dynamic test in the differential diagnosis between PD and APs. It was applied at the baseline of a prospective follow-up in patients with parkinsonian signs within three years of disease motor onset (“BoProPark” cohort) and eventually diagnosed as PD or APs according to …consensus criteria. Methods: Patients under at least 3-month LD therapy received a first morning fasting dose of LD/benserazide or carbidopa (100/25 mg) and underwent simultaneous serial assessments of plasma LD concentration and alternate finger tapping frequency up to 3 h. The main outcome was the extent of LD motor response, calculated by the area under the 3 h tapping effect–time curve (AUC_ETap). A receiver operating characteristic (ROC) curve analysis was performed to establish the optimal AUC_ETap cut-off to differentiate PD and APs. Results: The first 100 consecutive “BoProPark” patients were analyzed. Forty-seven patients were classified as possible, 37 as probable PD and 16 as APs. AUC_ETap medians were similar in the PD subgroups but reduced to a third in APs (p  <  0.001). The optimal AUC_ETap cut-off value was >2186 [(tap/min) x min], with a sensitivity of 92% and a specificity of 75%. Accuracy of the test was 0.85 (95% CI 0.74–0.95), p  <  0.0001. Conclusion: The estimation of 3 h AUC_ETap after a subacute low LD dose proved a reliable, objective tool to assess LD motor response in our cohort of patients. AUC_ETap value rounded to ≥2200 supports PD diagnosis, while lower values may alert to AP diagnoses. Show more

Keywords: Keywords: Levodopa, Parkinson’s disease, atypical parkinsonisms, alternate finger tapping test, kinetics-dynamics

DOI: 10.3233/JPD-202262

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Isaacson, Jonathan R. | Brillman, Salima | Chhabria, Nisha | Isaacson, Stuart H.

Article Type: Other

Abstract: Background: The diagnosis of Parkinson’s disease (PD) is primarily clinical, but in cases of diagnostic uncertainty, evaluation of nigrostriatal dopaminergic degeneration (NSDD) by imaging of the dopamine transporter using DaTscan with single-photon emission computed tomography (SPECT) brain imaging may be helpful. Objective/Methods: In the current paper, we describe clinical scenarios for which DaTscan imaging was used in a prospective case series of 201 consecutive patients in whom a movement disorder specialist ordered DaTscan imaging to clarify NSDD. We describe the impact of DaTscan results on changing or confirming pre-DaTscan clinical diagnosis and on post-DaTscan treatment changes. …Results/Conclusion: DaTscan imaging can be useful in several clinical scenarios to determine if NSDD is present. These include in patients with early subtle symptoms, suboptimal response to levodopa, prominent action tremor, drug-induced parkinsonism, and in patients with lower extremity or other less common parkinsonism clinical presentations. We also found DaTscan imaging to be useful to determine underlying NSDD in patients with PD diagnosis for 3-5 years but without apparent clinical progression or development of motor fluctuations. Overall, in 201 consecutive patients with clinically questionable NSDD, DaTscan was abnormal in 58.7% of patients, normal in 37.8%, and inconclusive in 3.5%. DaTscan imaging changed clinical diagnosis in 39.8% of patients and led to medication therapy changes in 70.1% of patients. Show more

DOI: 10.3233/JPD-202506

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2021

Authors: Zhang, Zijuan | Hao, Li | Shi, Ming | Yu, Ziyang | Shao, Simai | Yuan, Ye | Zhang, Zhenqiang | Hölscher, Christian

Article Type: Research Article

Abstract: Background: Glucagon-like peptide 2 (GLP-2) is a peptide hormone derived from the proglucagon gene expressed in the intestines, pancreas and brain. Some previous studies showed that GLP-2 improved aging and Alzheimer’s disease related memory impairments. Parkinson’s disease (PD) is a progressive neurodegenerative disorder, and to date, there is no particular medicine reversed PD symptoms effectively. Objective: The aim of this study was to evaluate neuroprotective effects of a GLP-2 analogue in the 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) PD mouse model. Methods: In the present study, the protease resistant Gly(2)-GLP-2 (50 nmol/kg ip.) analogue has been tested for …14 days by behavioral assessment, transmission electron microscope, immunofluorescence histochemistry, enzyme-linked immunosorbent assay and western blot in an acute PD mouse model induced by MPTP. For comparison, the incretin receptor dual agonist DA5-CH was tested in a separate group. Results: The GLP-2 analogue treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement imbalance of mice. Gly(2)-GLP-2 treatment also protected dopaminergic neurons and restored tyrosine hydroxylase expression levels in the substantia nigra. Gly(2)-GLP-2 furthermore reduced the inflammation response as seen in lower microglia activation, and decreased NLRP3 and interleukin-1β pro-inflammatory cytokine expression levels. In addition, the GLP-2 analogue improved MPTP-induced mitochondrial dysfunction in the substantia nigra. The protective effects were comparable to those of the dual agonist DA5-CH. Conclusion: The present results demonstrate that Gly(2)-GLP-2 can attenuate NLRP3 inflammasome-mediated inflammation and mitochondrial damage in the substantia nigra induced by MPTP, and Gly(2)-GLP-2 shows neuroprotective effects in this PD animal model. Show more

Keywords: GLP-1, growth factor, inflammation, insulin, mitochondria, Parkinson’s disease

DOI: 10.3233/JPD-202318

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Mazza, Melissa Conti | Nguyen, Victoria | Beilina, Alexandra | Karakoleva, Ema | Coyle, Michael | Ding, Jinhui | Bishop, Christopher | Cookson, Mark R.

Article Type: Research Article

Abstract: Background: Coding mutations in the LRRK2 gene, encoding for a large protein kinase, have been shown to cause familial Parkinson’s disease (PD). The immediate biological consequence of LRRK2 mutations is to increase kinase activity, suggesting that inhibition of this enzyme might be useful therapeutically to slow disease progression. Genome-wide association studies have identified the chromosomal loci around LRRK2 and one of its proposed substrates, RAB29, as contributors towards the lifetime risk of sporadic PD. Objective: Considering the evidence for interactions between LRRK2 and RAB29 on the genetic and protein levels, we set out to determine whether there are …any consequences on brain function with aging after deletion of both genes. Methods: We generated a double knockout mouse model and performed a battery of motor and non-motor behavioral tests. We then investigated postmortem assays to determine the presence of PD-like pathology, including nigral dopamine cell count, astrogliosis, microgliosis, and striatal monoamine content. Results: Behaviorally, we noted only that 18–24-month Rab29 -/-  and double (Lrrk2 -/-  /Rab29 -/-  ) knockout mice had diminished locomotor behavior in open field compared to wildtype mice. However, no genotype differences were seen in the outcomes that represented PD-like pathology. Conclusion: These results suggest that depletion of both LRRK2 and RAB29 is tolerated, at least in mice, and support that this pathway might be able to be safely targeted for therapeutics in humans. Show more

Keywords: LRRK2, RAB29, dopamine, Parkinson’s disease, behavior

DOI: 10.3233/JPD-202172

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Del Din, Silvia | Kirk, Cameron | Yarnall, Alison J. | Rochester, Lynn | Hausdorff, Jeffrey M.

Article Type: Review Article

Abstract: The increasing prevalence of neurodegenerative conditions such as Parkinson’s disease (PD) and related mobility issues places a serious burden on healthcare systems. The COVID-19 pandemic has reinforced the urgent need for better tools to manage chronic conditions remotely, as regular access to clinics may be problematic. Digital health technology in the form of remote monitoring with body-worn sensors offers significant opportunities for transforming research and revolutionizing the clinical management of PD. Significant efforts are being invested in the development and validation of digital outcomes to support diagnosis and track motor and mobility impairments “off-line”. Imagine being able to remotely assess …your patient, understand how well they are functioning, evaluate the impact of any recent medication/intervention, and identify the need for urgent follow-up because things are changing? This could offer new pragmatic solutions for personalized care and clinical research. So the question remains: how close are we to achieving this? Here, we describe the state-of-the-art based on representative papers published between 2017 and 2020. We focus on remote (i.e., real-world, daily-living) monitoring of PD using body-worn sensors (e.g., accelerometers, inertial measurement units) for assessing motor symptoms and their complications. Despite the tremendous potential, existing challenges exist (e.g., validity, regulatory) that are preventing the widespread clinical adoption of body-worn sensors as a digital outcome. We propose a roadmap with clear recommendations for addressing these challenges and future directions to bring us closer to the implementation and widespread adoption of this important way of improving the clinical care, evaluation, and monitoring of PD. Show more

Keywords: Parkinson’s disease, remote monitoring, real-world, wearables, motor symptoms, accelerometer

DOI: 10.3233/JPD-202471

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Amundsen Huffmaster, Sommer L. | Petrucci, Matthew N. | Linn-Evans, Maria E. | Chung, Jae Woo | Howell, Michael J. | Videnovic, Aleksandar | Tuite, Paul J. | Cooper, Scott E. | MacKinnon, Colum D.

Article Type: Research Article

Abstract: Background: Subtle gait deficits can be seen in people with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD), a prodromal stage of Parkinson’s disease (PD) and related alpha-synucleinopathies. It is unknown if the presence and level of REM sleep without atonia (RSWA, the electromyographic hallmark of RBD) is related to the severity of gait disturbances in people with PD. Objective: We hypothesized that gait disturbances in people with mild to moderate PD would be greater in participants with RSWA compared to those without RSWA and matched controls, and that gait impairment would correlate with measures of RSWA. …Methods: Spatiotemporal characteristics of gait were obtained from 41 people with PD and 21 age-matched controls. Overnight sleep studies were used to quantify muscle activity during REM sleep and group participants with PD into those with RSWA (PD-RSWA+, n  = 22) and normal REM sleep muscle tone (PD-RSWA-, n  = 19). Gait characteristics were compared between groups and correlated to RSWA. Results: The PD-RSWA+ group demonstrated significantly reduced gait speed and step lengths and increased stance and double support times compared to controls, and decreased speed and cadence and increased stride velocity variability compared to PD-RSWA- group. Larger RSWA scores were correlated with worse gait impairment in the PD group. Conclusion: The presence and level of muscle tone during REM sleep is associated with the severity of gait disturbances in PD. Pathophysiological processes contributing to disordered gait may occur earlier and/or progress more rapidly in people with PD and RBD. Show more

Keywords: Parkinson’s disease, REM sleep without atonia, gait

DOI: 10.3233/JPD-202098

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: van Wamelen, Daniel J. | Urso, Daniele | Chaudhuri, Kallol Ray

Article Type: Research Article

Abstract: Background: Several smaller-scale studies have shown that motor performance in Parkinson’s disease (PD) fluctuates throughout the day. Studies focusing on de novo patients are, however, lacking. Objective: To evaluate the effect of clock time on motor performance in de novo drug-naïve patients with PD. Methods: We retrieved MDS-UPDRS III scores for 421 de novo PD patients from the PPMI cohort and stratified them into three groups based on time of assessment: group 1) 7:00–10:00; group 2) 10:00–13:00, and group 3) 13:00–18:00. Groups were compared using Kruskal-Wallis test and results corrected for multiple testing. …In addition, we obtained 27 wearable sensor reports, objectively capturing bradykinesia scores in a home setting over a 6-day continuous period, in 12 drug-naïve patients from the Parkinson’s Kinetigraph Registry held at King’s College Hospital London. Time spent in severe bradykinesia scores were broken down into five daytime (06:00–21:00) three-hourly epochs and scores compared using the Friedman test. Results: There were no group differences in demographic or other clinical variables for the cross-sectional analysis. MDS-UPDRS III total scores worsened significantly during the course of the day (median 18 (group 1); 20 (group 2); and 23 (group 3); p  = 0.001). In the longitudinal wearable sensor cohort, diurnal variations were present in percentage of time spent in severe bradykinesia (p  <  0.001) with the lowest percentage during the 09:00–12:00 epoch (69.56±16.68%), when most patients are awake and start daily activity, and the highest percentage during the 18:00–21:00 epoch (73.58±16.35%). Conclusion: This exploratory study shows the existence of a diurnal pattern of motor function in patients with de novo PD. The results obtained were corroborated by objective measurements in a small longitudinal cohort confirming a similar diurnal motor score variation. Show more

Keywords: Parkinson’s disease, circadian rhythm, diurnal rhythm, bradykinesia, motor

DOI: 10.3233/JPD-202352

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Deischinger, Carola | Dervic, Elma | Kaleta, Michaela | Klimek, Peter | Kautzky-Willer, Alexandra

Article Type: Research Article

Abstract: Background: In general, the risk to develop Parkinson’s disease (PD) is higher in men compared to women. Besides male sex and genetics, research suggests diabetes mellitus (DM) is a risk factor for PD as well. Objective: In this population-level study, we aimed at investigating the sex-specific impact of DM on new diagnoses of PD. Methods: Medical claims data were analyzed in a cross-sectional study in the Austrian population between 1997 and 2014. In the age group of 40–79 and 80+, 235,268 patients (46.6%females, 53.4%males) with DM were extracted and compared to 1,938,173 non-diabetic controls (51.9%females, 48.1%males) …in terms of risk of developing PD. Results: Men with DM had a 1.46 times increased odds ratio (OR) to be diagnosed with PD compared to non-diabetic men (95%CI 1.38–1.54, p  <  0.001). The association of DM with newly diagnosed PD was significantly greater in women (OR = 1.71, 95%CI 1.60–1.82, p  <  0.001) resulting in a relative risk increase of 1.17 (95%CI 1.11–1.30) in the age group 40 to 79 years. In 80+-year-olds the relative risk increase is 1.09 (95%CI 1.01–1.18). Conclusion: Although men are more prone to develop PD, women see a higher risk increase in PD than men amongst DM patients. Show more

Keywords: Diabetes mellitus, Parkinson’s disease, women’s health, sex differences

DOI: 10.3233/JPD-202486

Citation: Journal of Parkinson's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021