Journal of Parkinson's Disease - Volume 11, issue 4

Authors: Park, Sang Hyun | Nam, Ga Eun | Han, Kyungdo | Huh, Youn | Kim, Wonsock | Lee, Min-Kyung | Koh, Eun-Sil | Kim, Eun Sook | Kim, Mee Kyung | Kwon, Hyuk-Sang | Kim, Seon Mee | Cho, Kyung Hwan | Park, Yong Gyu

Article Type: Research Article

Abstract: Background: The longitudinal association between dynamic changes in the metabolic syndrome (MS) status and Parkinson’s disease (PD) has been poorly studied. Objective: We examined whether dynamic changes in MS status are associated with altered risk for PD. Methods: This study was a nationwide retrospective cohort study. We enrolled 5,522,813 individuals aged≥40 years who had undergone health examinations under the National Health Insurance Service between 2009 and 2010 (two health examinations with a 2-year interval). Participants were followed up until the end of 2017. The participants were categorized into four groups according to MS status changes over …2 years: non-MS, improved MS, incident MS, and persistent MS groups. Multivariable Cox hazard regression was performed. Results: During the 7-year median follow-up, there were 20,524 cases of newly developed PD. Compared with non-MS group, improved, incident, and persistent MS groups for 2 years were significantly associated with higher risks of PD (model 3; hazard ratio: 1.12, 95%confidence interval: 1.06–1.19 [improved MS]; 1.15, 1.09–1.22 [incident MS]; and 1.25, 1.20–1.30 [persistent MS]). Individuals with incident and persistent abdominal obesity, low levels of high-density lipoprotein cholesterol, hypertriglyceridemia, and hyperglycemia had a significantly increased risks of PD compared with those without either condition over 2 years. Conclusion: Persistent and incident MS and its components may be risk factors for incident PD. Ever exposure to MS may also be associated with PD risk. Appropriate intervention for preventing and improving MS may be crucial in decreasing the PD incidence. Show more

Keywords: Metabolic syndrome, Parkinson’s disease, metabolic change, cohort

DOI: 10.3233/JPD-212589

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1751-1759, 2021

Authors: Youssef, Priscilla | Kim, Woojin S. | Halliday, Glenda M. | Lewis, Simon J.G. | Dzamko, Nicolas

Article Type: Research Article

Abstract: Background: The identification of reliable biomarkers in Parkinson’s disease (PD) would provide much needed diagnostic accuracy, a means of monitoring progression, objectively measuring treatment response, and potentially allowing patient stratification within clinical trials. Whilst the assessment of total alpha-synuclein in biofluids has been identified as a promising biomarker, conflicting trends in these levels across patient plasma samples relative to controls has limited its use. Different commercially available assay platforms that have been used to measure alpha-synuclein may contribute to different study outcomes. Objective: To compare different platform immunoassays for the measurement of total alpha-synuclein using the same plasma …samples from 49 PD patients and 47 controls. Methods: Total plasma alpha-synuclein concentrations were assessed using the BioLegend, MesoScale Discovery, and Quanterix platform in plasma samples from PD patients and matched controls. Results: A significant increase in total plasma alpha-synuclein was observed in PD patients using the Biolegend (10%), Mesoscale Discovery (13%) and Quanterix (39%) assays. The Mesoscale Discovery and Quanterix assays showed the strongest correlations (r  = 0.78, p  < 0.0001) with each other, whilst the Quanterix platform demonstrated the lowest variation and highest effect size. Inclusion of age, sex and hemoglobin levels as covariates in the analysis of total alpha-synuclein improved the ability of all three immunoassays to detect a significant difference between patients and controls. Conclusion: All three immunoassays were sensitive enough to detect group level differences between PD patients and controls, with the largest effect size observed with the Quanterix assay. These results may help inform assay choices in ongoing clinical trials. Show more

Keywords: Parkinson’s disease, ELISA, SIMOA, alpha-synuclein, blood

DOI: 10.3233/JPD-212694

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1761-1772, 2021

Authors: Dos Santos, Altair B. | Skaanning, Line K. | Mikkelsen, Eyd | Romero-Leguizamón, Cesar R. | Kristensen, Morten P. | Klein, Anders B. | Thaneshwaran, Siganya | Langkilde, Annette E. | Kohlmeier, Kristi A.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a neurodegenerative disorder associated with insoluble pathological aggregates of the protein α -synuclein. While PD is diagnosed by motor symptoms putatively due to aggregated α -synuclein-mediated damage to substantia nigra (SN) neurons, up to a decade before motor symptom appearance, patients exhibit sleep disorders (SDs). Therefore, we hypothesized that α -synuclein, which can be present in monomeric, fibril, and other forms, has deleterious cellular actions on sleep-control nuclei. Objective: We investigated whether native monomer and fibril forms of α -synuclein have effects on neuronal function, calcium dynamics, and cell-death-induction in two sleep-controlling nuclei: …the laterodorsal tegmentum (LDT), and the pedunculopontine tegmentum (PPT), as well as the motor-controlling SN. Methods: Size exclusion chromatography, Thioflavin T fluorescence assays, and circular dichroism spectroscopy were used to isolate structurally defined forms of recombinant, human α -synuclein. Neuronal and viability effects of characterized monomeric and fibril forms of α -synuclein were determined on LDT, PPT, and SN neurons using electrophysiology, calcium imaging, and neurotoxicity assays. Results: In LDT and PPT neurons, both forms of α -synuclein induced excitation and increased calcium, and the monomeric form heightened putatively excitotoxic neuronal death, whereas, in the SN, we saw inhibition, decreased intracellular calcium, and monomeric α -synuclein was not associated with heightened cell death. Conclusion: Nucleus-specific differential effects suggest mechanistic underpinnings of SDs’ prodromal appearance in PD. While speculative, we hypothesize that the monomeric form of α -synuclein compromises functionality of sleep-control neurons, leading to the presence of SDs decades prior to motor dysfunction. Show more

Keywords: Biomarkers, excessive daytime sleepiness, mechanism of disease, neurodegenerative diseases, neuronal alterations, prodromal phase, REM sleep behavior disorder

DOI: 10.3233/JPD-212554

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1773-1790, 2021

Authors: Folke, Jonas | Arkan, Sertan | Martinsson, Isak | Aznar, Susana | Gouras, Gunnar | Brudek, Tomasz | Hansen, Christian

Article Type: Research Article

Abstract: Background: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of α-syn aggregation in vivo and in vitro . However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies. Objective: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression of this isoform in cells, in tissue and in clinical material. Methods: To address this we used immunocytochemistry, immunohistochemistry, as …well as a novel quantitative DNAJB6 specific ELISA method. Results: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro , where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc ), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a. Conclusion: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression. Show more

Keywords: Alpha-synuclein, clinical samples, DNAJB6, neurodegeneration, synucleinopathy

DOI: 10.3233/JPD-202512

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1791-1803, 2021

Authors: Fellgett, Alison | Middleton, C. Adam | Munns, Jack | Ugbode, Chris | Jaciuch, David | Wilson, Laurence G. | Chawla, Sangeeta | Elliott, Christopher J.H.

Article Type: Research Article

Abstract: Background: Inherited mutations in the LRRK2 protein are common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S . An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian …activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2 -G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2 -G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2 -G2019S . Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease. Show more

Keywords: Bradykinesia, circadian rhythms, courtship memory, dopamine, Drosophila, Leucine-rich-repeat-kinase2, sleep, vision

DOI: 10.3233/JPD-202421

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1805-1820, 2021

Authors: Diwakarla, Shanti | McQuade, Rachel M. | Constable, Remy | Artaiz, Olivia | Lei, Enie | Barnham, Kevin J. | Adlard, Paul A. | Cherny, Robert A. | Di Natale, Madeleine R. | Wu, Hongyi | Chai, Xin-yi | Lawson, Victoria A. | Finkelstein, David I. | Furness, John B.

Article Type: Research Article

Abstract: Background: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson’s disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. Objective: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic …mice. Methods: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion (“treatment group”), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion (“prevention group”). Results: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. Conclusion: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD. Show more

Keywords: Parkinson’s disease, colonic propulsion, gut dysfunction, alpha-synuclein, ATH434, enteric neuropathy

DOI: 10.3233/JPD-212731

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1821-1832, 2021

Authors: Beach, Thomas G. | Adler, Charles H. | Sue, Lucia I. | Shill, Holly A. | Driver-Dunckley, Erika | Mehta, Shyamal H. | Intorcia, Anthony J. | Glass, Michael J. | Walker, Jessica E. | Arce, Richard | Nelson, Courtney M. | Serrano, Geidy E.

Article Type: Research Article

Abstract: Background: Braak and others have proposed that Lewy-type α-synucleinopathy in Parkinson’s disease (PD) may arise from an exogenous pathogen that passes across the gastric mucosa and then is retrogradely transported up the vagus nerve to the medulla. Objective: We tested this hypothesis by immunohistochemically staining, with a method specific for p-serine 129 α-synuclein (pSyn), stomach and vagus nerve tissue from an autopsy series of 111 normal elderly subjects, 33 with incidental Lewy body disease (ILBD) and 53 with PD. Methods: Vagus nerve samples were taken adjacent to the carotid artery in the neck. Stomach samples were …taken from the gastric body, midway along the greater curvature. Formalin-fixed paraffin-embedded sections were immunohistochemically stained for pSyn, shown to be highly specific and sensitive for α-synuclein pathology. Results: Median disease duration for the PD group was 13 years. In the vagus nerve none of the 111 normal subjects had pSyn in the vagus, while 12/26 ILBD (46%) and 32/36 PD (89%) subjects were pSyn-positive. In the stomach none of the 102 normal subjects had pSyn while 5/30 (17%) ILBD and 42/52 (81%) of PD subjects were pSyn-positive. Conclusion: As there was no pSyn in the vagus nerve or stomach of subjects without brain pSyn, these results support initiation of pSyn in the brain. The presence of pSyn in the vagus nerve and stomach of a subset of ILBD cases indicates that synucleinopathy within the peripheral nervous system may occur, within a subset of individuals, at preclinical stages of Lewy body disease. Show more

Keywords: Pathology, etiology, autopsy, gastrointestinal, peripheral nerve, pathogenesis

DOI: 10.3233/JPD-212733

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1833-1843, 2021

Authors: Chen, Yong-Ping | Gu, Xiao-Jing | Song, Wei | Hou, Yan-Bing | Ou, Ru-Wei | Zhang, Ling-Yu | Liu, Kun-Cheng | Su, Wei-Ming | Cao, Bei | Wei, Qian-Qian | Zhao, Bi | Wu, Ying | Shang, Hui-Fang

Article Type: Research Article

Abstract: Background: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson’s disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. Objective: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. Methods: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal …function-related genes and 52 lysosomal storage disorder genes. Results: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2 , MCOLN1 , LYST , VPS16 , and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. Conclusion: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence. Show more

Keywords: Parkinson’s disease, lysosomal genes, rare variants, burden analysis, genotype-phenotype correction

DOI: 10.3233/JPD-212658

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1845-1855, 2021

Authors: Brown, Gregory L. | Camacci, Mona L. | Kim, Sean D. | Grillo, Stephanie | Nguyen, James V. | Brown, Douglas A. | Ullah, Sarah P. | Lewis, Mechelle M. | Du, Guangwei | Kong, Lan | Sundstrom, Jeffrey M. | Huang, Xuemei | Bowie, Esther M.

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is marked clinically by motor symptoms and pathologically by Lewy bodies and dopamine neuron loss in the substantia nigra pars compacta (SNc). Higher iron accumulation, assessed by susceptibility MRI, also is observed as PD progresses. Recently, evidence has suggested that PD affects the retina. Objective: To better understand retinal alterations in PD and their association to clinical and SNc iron-related imaging metrics. Methods: Ten PD and 12 control participants (2 eyes each) from an ongoing PD imaging biomarker study underwent enhanced depth imaging optical coherence tomography evaluation. Choroidal (vascular) thickness and nerve …layers were measured in 4 subregions [superior, temporal, inferior, and nasal] and at 3 foveal distances (1, 1.5, and 3 mm). These metrics were compared between PD and control groups. For significantly different metrics, their associations with clinical [levodopa equivalent daily dosage (LEDD), motor and visuospatial function] and SNc susceptibility MRI metrics [R2* and quantitative susceptibility mapping (QSM)] were explored. Results: Compared to control participants, PD participants had a thicker choroid (p  = 0.005), but no changes in nerve layers. Higher mean choroidal thickness was associated with lower LEDD (p  < 0.01) and better visuospatial function (p  < 0.05). Subregion analyses revealed higher choroidal thickness correlated with lower LEDD and better motor and visuospatial measures. Higher mean choroidal thickness also was associated with lower nigral iron MRI (p  < 0.05). Conclusion: A small cohort of PD research participants displayed higher choroidal thickness that was related to better clinical performance and less nigral pathology. These intriguing findings warrant further investigation. Show more

Keywords: Choroid, optical coherence tomography, Parkinson’s disease, retina, susceptibility MRI, visuospatial function

DOI: 10.3233/JPD-212676

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1857-1868, 2021

Authors: Ye, Zheng | Hanssen, Henrike | Steinhardt, Julia | Tronnier, Volker | Rasche, Dirk | Brüggemann, Norbert | Münte, Thomas F.

Article Type: Research Article

Abstract: Background: Maintaining and manipulating sequences online is essential for language and memory. In Parkinson’s disease (PD), poor performance in sequencing tasks has been associated with basal ganglia dysfunction, especially subthalamic hyperactivity. Objective: This study is aimed to investigate the impact of high-frequency subthalamic nucleus (STN) deep brain stimulation (DBS) on sequence processing in PD. Methods: Twenty-nine patients with PD (17 women) completed a ‘before/after’ sentence task and a digit ordering task with STN DBS ON and OFF. In the sentence task, patients read a sequence of events expressed in the actual order of occurrence (‘after’ sentences) …or reversed order (‘before’ sentences) for comprehension. In the digit task, patients recalled a sequence of ordered digits (ordered trials) or reordered and recalled random digits in ascending order (random trials). Volumes of tissue activated (VTAs) were estimated for the motor and associative STN. Results: Patients were slower with STN DBS ON versus OFF in both tasks, although their motor symptoms were significantly improved under DBS. In the sentence task, patients showed higher ordering-related reaction time costs (‘before’ > ‘after’) with DBS ON versus OFF. Moreover, patients with larger left associative VTAs, smaller total motor VTAs, and more daily exposure to dopaminergic drugs tended to show larger reaction time cost increases under DBS. In the digit ordering task, patients with too large or too small right associative VTAs tended to show larger reaction time cost increases under DBS. Conclusion: Stimulating the STN, especially its associative part, might impair sequence processing in language and memory. Show more

Keywords: Parkinson’s disease, subthalamic nucleus, deep brain stimulation, sentence comprehension, temporal connectives, sequential working memory

DOI: 10.3233/JPD-212778

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1869-1879, 2021

Authors: Wong, Joshua K. | Hilliard, Justin D. | Holanda, Vanessa M. | Gunduz, Aysegul | Wagle Shukla, Aparna | Foote, Kelly D. | Okun, Michael S.

Article Type: Short Communication

Abstract: Deep brain stimulation (DBS) is an effective neuromodulatory therapy for Parkinson’s disease (PD). Early studies using globus pallidus internus (GPi) DBS for PD profiled the nucleus as having two functional zones. This concept disseminated throughout the neuromodulation community as the “GPi triangle”. Although our understanding of the pallidum has greatly evolved over the past 20 years, we continue to reference the triangle in our clinical decision-making process. We propose a new direction, termed the spatial boundary hypothesis, to build upon the 2-dimensional outlook on GPi DBS. We believe an updated 3-D GPi model can produce more consistent, positive patient outcomes.

Keywords: Deep brain stimulation, DBS, globus pallidus, GPi, Parkinson’s disease, targeting, neuromodulation

DOI: 10.3233/JPD-212820

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1881-1885, 2021

Authors: Wenzel, Gregor R. | Roediger, Jan | Brücke, Christof | Marcelino, Ana Luísa de A. | Gülke, Eileen | Pötter-Nerger, Monika | Scholtes, Heleen | Wynants, Kenny | Juárez Paz, León M. | Kühn, Andrea A.

Article Type: Research Article

Abstract: Background: Recent technological advances in deep brain stimulation (DBS) (e.g., directional leads, multiple independent current sources) lead to increasing DBS-optimization burden. Techniques to streamline and facilitate programming could leverage these innovations. Objective: We evaluated clinical effectiveness of algorithm-guided DBS-programming based on wearable-sensor-feedback compared to standard-of-care DBS-settings in a prospective, randomized, crossover, double-blind study in two German DBS centers. Methods: For 23 Parkinson’s disease patients with clinically effective DBS, new algorithm-guided DBS-settings were determined and compared to previously established standard-of-care DBS-settings using UPDRS-III and motion-sensor-assessment. Clinical and imaging data with lead-localizations were analyzed to evaluate characteristics of …algorithm-derived programming compared to standard-of-care. Six different versions of the algorithm were evaluated during the study and 10 subjects programmed with uniform algorithm-version were analyzed as a subgroup. Results: Algorithm-guided and standard-of-care DBS-settings effectively reduced motor symptoms compared to off-stimulation-state. UPDRS-III scores were reduced significantly more with standard-of-care settings as compared to algorithm-guided programming with heterogenous algorithm versions in the entire cohort. A subgroup with the latest algorithm version showed no significant differences in UPDRS-III achieved by the two programming-methods. Comparing active contacts in standard-of-care and algorithm-guided DBS-settings, contacts in the latter had larger location variability and were farther away from a literature-based optimal stimulation target. Conclusion: Algorithm-guided programming may be a reasonable approach to replace monopolar review, enable less trained health-professionals to achieve satisfactory DBS-programming results, or potentially reduce time needed for programming. Larger studies and further improvements of algorithm-guided programming are needed to confirm these results. Show more

Keywords: Deep brain stimulation, Parkinson’s disease, algorithm, wearable device feedback, double-blind, subthalamic nucleus

DOI: 10.3233/JPD-202480

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1887-1899, 2021

Authors: Simonet, Cristina | Galmes, Miquel A. | Lambert, Christian | Rees, Richard N. | Haque, Tahrina | Bestwick, Jonathan P. | Lees, Andrew J. | Schrag, Anette | Noyce, Alastair J.

Article Type: Research Article

Abstract: Background: Bradykinesia is the defining motor feature of Parkinson’s disease (PD). There are limitations to its assessment using standard clinical rating scales, especially in the early stages of PD when a floor effect may be observed. Objective: To develop a quantitative method to track repetitive tapping movements and to compare people in the early stages of PD, healthy controls, and individuals with idiopathic anosmia. Methods: This was a cross-sectional study of 99 participants (early-stage PD = 26, controls = 64, idiopathic anosmia = 9). For each participant, repetitive finger tapping was recorded over 20 seconds using a smartphone at 240 frames per …second. From each video, amplitude between fingers, frequency (number of taps per second), and velocity (distance travelled per second) was extracted. Clinical assessment was based on the motor section of the MDS-UPDRS. Results: People in the early stage of PD performed the task with slower velocity (p  < 0.001) and with greater frequency slope than controls (p  = 0.003). The combination of reduced velocity and greater frequency slope obtained the best accuracy to separate early-stage PD from controls based on metric thresholds alone (AUC = 0.88). Individuals with anosmia exhibited slower velocity (p  = 0.001) and smaller amplitude (p  < 0.001) compared with controls. Conclusion: We present a simple, proof-of-concept method to detect early motor dysfunction in PD. Mean tap velocity appeared to be the best parameter to differentiate patients with PD from controls. Patients with anosmia also showed detectable differences in motor performance compared with controls which may suggest that some were in the prodromal phase of PD. Show more

Keywords: Anosmia, bradykinesia, Parkinson’s disease, tapping test, technology

DOI: 10.3233/JPD-212683

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1901-1915, 2021

Authors: Turner, Travis H. | Atkins, Alexandra | Keefe, Richard S.E.

Article Type: Research Article

Abstract: Background: Cognitive impairment is common in Parkinson’s disease (PD) and highly associated with loss of independence, caregiver burden, and assisted living placement. The need for cognitive functional capacity tools validated for use in PD clinical and research applications has thus been emphasized in the literature. The Virtual Reality Functional Capacity Assessment Tool (VRFCAT-SL) is a tablet-based instrument that assesses proficiency for performing real world tasks in a highly realistic environment. Objective: The present study explored application of the VRFCAT-SL in clinical assessments of patients with PD. Specifically, we examined associations between VRFCAT-SL performance and measures of cognition, motor …severity, and self-reported cognitive functioning. Methods: The VRFCAT-SL was completed by a sample of 29 PD patients seen in clinic for a comprehensive neuropsychological evaluation. Fifteen patients met Movement Disorders Society Task Force criteria for mild cognitive impairment (PD-MCI); no patients were diagnosed with dementia. Non-parametric correlations between VRFCAT-SL performance and standardized neuropsychological tests and clinical measures were examined. Results: VRFCAT-SL performance was moderately associated with global rank on neuropsychological testing and discriminated PD-MCI. Follow-up analyses found completion time was associated with visual memory, sustained attention, and set-switching, while errors were associated with psychomotor inhibition. No clinical or motor measures were associated with VRFCAT-SL performance. Self-report was not associated with VRFCAT-SL or neuropsychological test performance. Conclusion: The VRFCAT-SL appears to provide a useful measure of cognitive functional capacity that is not confounded by PD motor symptoms. Future studies will examine utility in PD dementia. Show more

Keywords: Assessment, cognitive capacity, functional capacity, functional outcome, mild cognitive impairment, neuropsychology, Parkinson’s disease, virtual reality

DOI: 10.3233/JPD-212688

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1917-1925, 2021

Authors: Riggare, Sara | Hägglund, Maria | Bredenoord, Annelien L. | de Groot, Martijn | Bloem, Bastiaan R.

Article Type: Article Commentary

Abstract: Using Parkinson’s disease as an exemplary chronic condition, this Commentary discusses ethical aspects of using self-tracking for personal science, as compared to using self-tracking in the context of conducting clinical research on groups of study participants. Conventional group-based clinical research aims to find generalisable answers to clinical or public health questions. The aim of personal science is different: to find meaningful answers that matter first and foremost to an individual with a particular health challenge. In the case of personal science, the researcher and the participant are one and the same, which means that specific ethical issues may arise, such …as the need to protect the participant against self-harm. To allow patient-led research in the form of personal science in the Parkinson field to evolve further, the development of a specific ethical framework for self-tracking for personal science is needed. Show more

Keywords: Parkinson’s disease, self-tracking, ethics, remote monitoring, selfcare, patient empowerment

DOI: 10.3233/JPD-212647

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1927-1933, 2021

Authors: Fearn, Sarah | Bartolomeu Pires, Sandra | Agarwal, Veena | Roberts, Helen C. | Spreadbury, John | Kipps, Christopher

Article Type: Research Article

Abstract: Background: The reasons for acute hospital admissions among people with Parkinson’s disease are well documented. However, understanding of crises that are managed in the community is comparatively lacking. Most existing literature on the causes of crisis for people with Parkinson’s disease (PwP) uses hospital data and excludes the individual’s own perspective on the crisis trigger and the impact of the crisis on their care needs. Objective: To identify the causes and impact of crises in both community and hospital settings, from a patient and carer perspective. Methods: A total of 550 UK-based PwP and carers completed …a survey on (a) their own personal experiences of crisis, and (b) their general awareness of potential crisis triggers for PwP. Results: In addition to well-recognised causes of crisis such as falls, events less widely associated with crisis were identified, including difficulties with activities of daily living and carer absence. The less-recognised crisis triggers tended to be managed more frequently in the community. Many of these community-based crises had a greater impact on care needs than the better-known causes of crisis that more frequently required hospital care. PwP and carer responses indicated a good general knowledge of potential crisis triggers. PwP were more aware of mental health issues and carers were more aware of cognitive impairment and issues with medications. Conclusion: These findings could improve care of Parkinson’s by increasing understanding of crisis events from the patient and carer perspective, identifying under-recognised crisis triggers, and informing strategies for best recording symptoms from PwP and carers. Show more

Keywords: Parkinson’s disease, hospital admissions, care needs, crisis, patient perspective, resource use, activities of daily living, caregivers, surveys and questionnaires, content analysis

DOI: 10.3233/JPD-212641

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1935-1945, 2021

Authors: Jeong, Seong Ho | Yoo, Han Soo | Chung, Seok Jong | Jung, Jin Ho | Lee, Yang Hyun | Baik, Kyoungwon | Sohn, Young H. | Lee, Phil Hyu

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are the most common non-motor symptom in Parkinson’s disease (PD). Objective: To investigate the association between the burden of NPS and motor prognosis in patients with PD. Methods: We enrolled 329 drug-naïve patients with PD, who was non-demented and followed-up≥2 years after their first visit to the clinic with baseline dopamine transporter (DAT) imaging and neuropsychiatric inventory (NPI) scores. We performed a survival analysis and a linear mixed model analysis to assess longitudinal motor outcomes according to the NPI total score. Results: The Kaplan-Meier analysis showed no difference in the …development of levodopa-induced dyskinesia and wearing-off according to the NPI total score. However, higher burden of NPI total score was associated with earlier freezing of gait (FOG) development in the time-dependent Cox regression models after adjusting for age at symptom onset, sex, disease duration, Unified PD Rating Scale motor score, baseline Mini-Mental State Examination score, DAT activity in the posterior putamen and levodopa-equivalent daily dose (LEDD) (Hazard ratio 1.047, p  = 0.002). A linear mixed model analysis revealed that patients with a higher NPI total score had a more rapid LEDD increment (NPI×time, p  = 0.003). Among 52 patients with PD who eventually developed FOG during the follow-up period, there was a significant correlation between the NPI total score and time with FOG development (γ = –0.472; p  = 0.001) after adjusting for confounding factors. Conclusion: The present study demonstrated that the severity of NPS is a predictor of early freezing and motor progression in patients with PD. Show more

Keywords: Parkinson’s disease, neuropsychiatric symptoms, motor prognosis

DOI: 10.3233/JPD-212660

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1947-1956, 2021

Authors: Javidnia, Monica | Arbatti, Lakshmi | Hosamath, Abhishek | Eberly, Shirley W. | Oakes, David | Shoulson, Ira

Article Type: Research Article

Abstract: Background: Postural instability is an intractable sign of Parkinson’s disease, associated with poor disease prognosis, fall risk, and decreased quality of life. Objective: 1) Characterize verbatim reports of postural instability and associated symptoms (gait disorder, balance, falling, freezing, and posture), 2) compare reports with responses to three pre-specified questions from Part II of the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS), and 3) examine postural instability symptoms and MDS-UPDRS responses as predictors of future falls. Methods: Fox Insight research participants reported their problems attributed to PD in their own words using the Parkinson Disease …Patient Reports of Problems (PD-PROP). Natural language processing, clinical curation, and data mining techniques were applied to classify text into problem domains and clinically-curated symptoms. Baseline postural instability symptoms were mapped to MDS-UPDRS questions 2.11–2.13. T -tests and chi-square tests were used to compare postural instability reporters and non-reporters, and Cochran-Armitage trend tests were used to evaluate associations between PD-PROP and MDS-UPDRS responses; survival methods were utilized to evaluate the predictive utility of PD-PROP and MDS-UPDRS responses in time-to-fall analyses. Results: Of participants within 10 years of PD diagnosis, 9,692 (56.0%) reported postural instability symptoms referable to gait unsteadiness, balance, falling, freezing, or posture at baseline. Postural instability symptoms were significantly associated with patient-reported measures from the MDS-UPDRS questions. Balance problems reported on PD-PROP and MDS-UPDRS 2.11–2.13 measures were predictive of future falls. Conclusion: Verbatim-reported problems captured by the PD-PROP and categorized by natural language processing and clinical curation and MDS-UPDRS responses predicted falls. The PD-PROP output was more granular than, and as informative as, the categorical responses. Show more

Keywords: Clinical trials, disease progression, falling, observational research, patient-reported outcomes

DOI: 10.3233/JPD-212636

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1957-1964, 2021

Authors: Di Luca, Daniel G. | McArthur, Eric W. | Willis, Allison | Martino, Rosemary | Marras, Connie

Article Type: Research Article

Abstract: Background: Dysphagia is a frequent complication that may increase morbidity and mortality in Parkinson’s disease (PD). Nevertheless, there is limited data on its objective impact on healthcare outcomes. Objective: To investigate the outcomes associated with dysphagia in hospitalized patients with PD and associated healthcare costs and utilization. Methods: We performed a retrospective cohort study using the National Inpatient Sample (NIS) data from 2004 to 2014. A multivariable regression analysis was adjusted for demographic, and comorbidity variables to examine the association between dysphagia and associated outcomes. Logistic and negative binomial regressions were used to estimate odds or …incidence rate ratios for binary and continuous outcomes, respectively. Results: We identified 334,395 non-elective hospitalizations of individuals with PD, being 21,288 (6.36%) associated with dysphagia. Patients with dysphagia had significantly higher odds of negative outcomes, including aspiration pneumonia (AOR 7.55, 95%CI 7.29–7.82), sepsis (AOR 1.91, 95%CI 1.82–2.01), and mechanical ventilation (AOR 2.00, 95%CI 1.86–2.15). For hospitalizations with a dysphagia code, the length of stay was 44%(95%CI 1.43–1.45) longer and inpatient costs 46%higher (95%CI 1.44–1.47) compared to those without dysphagia. Mortality was also substantially increased in individuals with PD and dysphagia (AOR 1.37, 95%CI 1.29–1.46). Conclusion: In hospitalized patients with PD, dysphagia was a strong predictor of adverse clinical outcomes, and associated with substantially prolonged length of stay, higher mortality, and care costs. These results highlight the need for interventions focused on early recognition and prevention of dysphagia to avoid complications and lower costs in PD patients. Show more

Keywords: Dysphagia, Parkinson’s disease, neurodegenerative diseases, healthcare costs

DOI: 10.3233/JPD-212798

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1965-1971, 2021

Authors: Radojević, Branislava | Dragašević-Mišković, Nataša T. | Marjanović, Ana | Branković, Marija | Dobričić, Valerija | Milovanović, Andona | Tomić, Aleksandra | Svetel, Marina | Petrović, Igor | Jančić, Ivan | Stanisavljević, Dejana | Savić, Miroslav M. | Kostić, Vladimir S.

Article Type: Research Article

Abstract: Background: Recent studies explored polymorphisms of multiple genes as contributing to genetic susceptibility to psychosis in Parkinson’s disease (PDP). Objective: We aimed to examine the association of seven selected polymorphisms of genes related to dopamine pathways with PDP development. At the same time, demographic and clinical correlates of PDP were assessed. Methods: PD patients (n  = 234), treated with levodopa for at least two years, were genotyped for the rs4680 in COMT , rs6277, rs1076560, and rs2283265 in DRD2 , and rs1800497 and rs2734849 polymorphisms in ANKK1 genes. Also, variable number of tandem repeats polymorphism in …the DAT gene was examined. Each patient underwent comprehensive neurological examination, assessment of psychosis, as defined by the NINDS/NIMH criteria, as well as screening of depression, anxiety, and cognitive status. Results: Diagnostic criteria for PDP were met by 101 (43.2%) patients. They had longer disease duration, were taking higher doses of dopaminergic agents, and had higher scores of the motor and non-motor scales than the non-PDP group. Multivariate regression analysis revealed LEDD≥900 mg, Unified Parkinson’s Disease Rating Scale III part score, the Hamilton Depression Rating Scale score≥7, the Hamilton Anxiety Rating Scale score > 14,and GG homozygotes of rs2734849 ANKK1 as independent predictors of the onset of PDP. Conclusion: Besides previous exposure to dopaminergic drugs, impairment of motor status, depression and anxiety, as well-established clinical risk factors for the development of PDP, GG rs2734849 ANKK1 could also be a contributing factor, which requires addressing by future longitudinal studies. Show more

Keywords: COMT Val158Met , DAT1 SLC6A3 , DRD2 , genetic polymorphisms, hallucinations, Parkinson’s disease, psychosis

DOI: 10.3233/JPD-212716

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1973-1980, 2021

Authors: Heilbron, Karl | Jensen, Melanie P. | Bandres-Ciga, Sara | Fontanillas, Pierre | Blauwendraat, Cornelis | Nalls, Mike A. | Singleton, Andrew B. | Smith, George Davey | Cannon, Paul | Noyce, Alastair J. | The 23andMe Research Team

Article Type: Research Article

Abstract: Background: Tobacco smoking and alcohol intake have been identified in observational studies as potentially protective factors against developing Parkinson’s disease (PD); the impact of body mass index (BMI) on PD risk is debated. Whether such epidemiological associations are causal remains unclear. Mendelian randomsation (MR) uses genetic variants to explore the effects of exposures on outcomes; potentially reducing bias from residual confounding and reverse causation. Objective: Using MR, we examined relationships between PD risk and three unhealthy behaviours: tobacco smoking, alcohol intake, and higher BMI. Methods: 19,924 PD cases and 2,413,087 controls were included in the analysis. …We performed genome-wide association studies to identify single nucleotide polymorphisms associated with tobacco smoking, alcohol intake, and BMI. MR analysis of the relationship between each exposure and PD was undertaken using a split-sample design. Results: Ever-smoking reduced the risk of PD (OR 0.955; 95%confidence interval [CI] 0.921–0.991; p  = 0.013). Higher daily alcohol intake increased the risk of PD (OR 1.125, 95%CI 1.025–1.235; p  = 0.013) and a 1 kg/m2 higher BMI reduced the risk of PD (OR 0.988, 95%CI 0.979–0.997; p  = 0.008). Sensitivity analyses did not suggest bias from horizontal pleiotropy or invalid instruments. Conclusion: Using split-sample MR in over 2.4 million participants, we observed a protective effect of smoking on risk of PD. In contrast to observational data, alcohol consumption appeared to increase the risk of PD. Higher BMI had a protective effect on PD, but the effect was small. Show more

Keywords: Parkinson’s disease, 23andMe, smoking, alcohol, BMI

DOI: 10.3233/JPD-202487

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1981-1993, 2021

Authors: Snyder, Allison | Gruber-Baldini, Ann L. | Rainer von Coelln, F. | Savitt, Joseph M. | Reich, Stephen G. | Armstrong, Melissa J. | Shulman, Lisa M.

Article Type: Research Article

Abstract: Background: Cognitive impairment (CI) is common in Parkinson’s disease (PD) and an important cause of disability. Screening facilitates early detection of CI and has implications for management. Preclinical disability is when patients have functional limitations but maintain independence through compensatory measures. Objective: The objective of this study was to investigate the relationship between scores on the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) with levels of PD severity and disability. Methods: PD patients (n  = 2,234) in a large observational study were stratified by disease severity, based on Total Unified Parkinson’s Disease Rating Scale (Total …UPDRS) and Hoehn and Yahr (HY) stage. Using MMSE (n  = 1,184) or MoCA (n  = 1,050) and basic (ADL) and instrumental activities of daily living (IADL) scales for disability, linear regression analysis examined associations between cognitive status and disability. Results: Cognition and disability were highly correlated, with the strongest correlation between IADL and MoCA. Only 16.0% of mean MMSE scores were below threshold for CI (28) and only in advanced PD (Total UPDRS 60+, HY≥3). MoCA scores fell below CI threshold (26) in 66.2% of the sample and earlier in disease (Total UPDRS 30+, HY≥2), corresponding with impairments in ADLs. Conclusion: In a large clinical dataset, a small fraction of MMSE scores fell below cutoff for CI, reinforcing that MMSE is an insensitive screening tool in PD. MoCA scores indicated CI earlier in disease and coincided with disability. This study shows that MoCA, but not MMSE is sensitive to the emergence of early cognitive impairment in PD and correlates with the concomitant onset of disability. Show more

Keywords: Parkinson’s disease, cognitive impairment, cognitive screening, disability

DOI: 10.3233/JPD-212705

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 1995-2003, 2021

Authors: Hamada, Tomoya | Higashiyama, Yuichi | Saito, Asami | Morihara, Keisuke | Landin-Romero, Ramon | Okamoto, Mitsuo | Kimura, Katsuo | Miyaji, Yousuke | Joki, Hideto | Kishida, Hitaru | Doi, Hiroshi | Ueda, Naohisa | Takeuchi, Hideyuki | Tanaka, Fumiaki

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) in Parkinson’s disease (PD) is considered a risk factor for PD with dementia (PDD). Verbal fluency tasks are widely used to assess executive function in PDD. However, in cases of PD with MCI (PD-MCI), the relative diagnostic accuracy of different qualitative verbal fluency measures and their related neural mechanisms remain unknown. Objective: This study aimed to investigate the relative diagnostic accuracy of qualitative (clustering and switching) verbal fluency strategies and their correlates with functional imaging in PD-MCI. Methods: Forty-five patients with PD (26 with MCI and 19 without MCI) and 25 …healthy controls underwent comprehensive neurocognitive testing and resting-state functional magnetic resonance imaging. MCI in patients with PD was diagnosed according to established clinical criteria. The diagnostic accuracy of verbal fluency measures was determined via receiver operating characteristic analysis. Changes in brain functional connectivity between groups and across clinical measures were assessed using seed-to-voxel analyses. Results: Patients with PD-MCI generated fewer words and switched less frequently in semantic and phonemic fluency tasks compared to other groups. Switching in semantic fluency showed high diagnostic accuracy for PD-MCI and was associated with reduced functional connectivity in the salience network. Conclusion: Our results indicate that reduced switching in semantic fluency tasks is a sensitive and specific marker for PD-MCI. Qualitative verbal fluency deficits and salience network dysfunction represent early clinical changes observed in PD-MCI. Show more

Keywords: Brain connectivity, mild cognitive impairment, Parkinson’s disease, salience network, verbal fluency

DOI: 10.3233/JPD-202473

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2005-2016, 2021

Authors: Loftus, Andrea M. | Nielsen, Chloe | Corti, Emily J. | Starkstein, Sergio | Gasson, Natalie | Egan, Sarah J.

Article Type: Research Article

Abstract: Background: Recent research suggests that a significant number of those who receive advanced treatments for Parkinson’s disease (PD) do not report improvements for some symptoms, which may relate to their pre-treatment expectations. It is important that expectations of treatment are measured and discussed prior to advanced treatment. Objective: The primary aim of this study was to develop a measure of treatment expectations of two advanced-stage treatments in PD, deep brain stimulation (DBS), and Levodopa/Carbidopa Intestinal Gel (LCIG). A secondary aim was to explore potential predictors of treatment expectations. Methods: The questionnaire-based measure was developed by researchers …in conjunction with a highly experienced clinician, and evaluated treatment expectations in 189 people aged 46–91 years (M  = 71.35, SD  = 8.73; 61% male) with idiopathic PD. Results: The overall measure demonstrated excellent internal consistency (α = 0.96). Exploratory factor analysis suggested the scale was unidimensional for both DBS and LCIG. Participant expectations of the two treatments differed significantly, with expectations being higher for DBS. Perceived symptom severity was the strongest predictor of treatment expectations. Conclusion: This scale has potential to inform clinicians about client expectations prior to advanced stage therapy for PD, with a view to the management of these expectations. Further evaluation of the scale is required across different treatment contexts. Show more

Keywords: Parkinson’s disease, treatment expectations, deep brain stimulation, Levodopa/carbidopa intestinal gel, quality of life, psychological

DOI: 10.3233/JPD-212777

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2017-2026, 2021

Authors: Silbergleit, Alice K. | Schultz, Lonni | Hamilton, Kendra | LeWitt, Peter A. | Sidiropoulos, Christos

Article Type: Research Article

Abstract: Background: Hypokinetic dysarthria and dysphagia are known features of Parkinson’s disease; however, self-perception of their handicapping effects on emotional, physical, and functional aspects of quality of life over disease duration is less understood. Objective: 1) Based upon patient self-perception, to determine the relationship of the handicapping effects of dysphagia and dysphonia with time since diagnosis in individuals with Parkinson’s disease; 2)To determine if there is a relationship between voice and swallowing handicap throughout the course of Parkinson’s disease. Method: 277 subjects completed the Dysphagia Handicap Index and the Voice Handicap Index. Subjects were divided into three …groups based on disease duration: 0–4 years, 5–9 years, and 10 + years. Results: Subjects in the longer duration group identified significantly greater perceptions of voice and swallowing handicap compared to the shorter duration groups. There was a significant positive correlation between the DHI and VHI. Conclusion: Self-perception of swallowing and voice handicap in Parkinson’s disease are associated with later stages of disease and progress in a linear fashion. Self-perception of voice and swallowing handicap parallel each other throughout disease progression in Parkinson’s disease. Individuals may be able to compensate for changes in voice and swallowing early while sensory perceptual feedback is intact. Results support early targeted questioning of patient self-perception of voice and swallowing handicap as identification of one problem indicates awareness of the other, thus creating an opportunity for early treatment and maintenance of swallowing and communication quality of life for as long as possible. Show more

Keywords: Disease duration, dysarthria, dysphagia, handicapping effects, self-perception

DOI: 10.3233/JPD-212621

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2027-2034, 2021

Authors: Utz, Kathrin S. | Martini, Max | Mrochen, Anne | Lambrecht, Vera | Süß, Patrick | Renner, Bertold | Freiherr, Jessica | Schenk, Thomas | Winkler, Jürgen | Marxreiter, Franz

Article Type: Research Article

Abstract: Background: There is growing interest in non-motor symptoms in Parkinson’s disease (PD), due to the impact on quality of life. Anhedonia, the inability to experience joy and lust, has a prevalence of up to 46% in PD. The perception of pleasantness of an odor is reduced in anhedonia without PD. We previously showed a reduced hedonic olfactory perception in PD, i.e., patients evaluated odors as less pleasant or unpleasant compared to controls. This deficit correlated with anhedonia. Objective: We aimed to confirm these findings. Moreover, we hypothesized that the perception of pleasantness in PD is affected on a …multisensory level and correlates with anhedonia. Therefore, we assessed olfactory, visual and acoustic evaluation of pleasantness in PD and healthy individuals. Methods: Participants had to rate the pleasantness of 22 odors, pictures, and sounds on a nine-point Likert scale. Depression, anhedonia, and apathy were assessed by means of questionnaires. Results of the pleasantness-rating were compared between groups and correlated to scores of the questionnaires. Results: In particular pleasant and unpleasant stimuli across all three modalities are perceived less intense in PD, suggesting that a reduced range of perception of pleasantness is a multisensory phenomenon. However, only a reduction of visual hedonic perception correlated with anhedonia in PD. A correlation of reduced perception of pleasantness with apathy or depression was not present. Conclusion: We provide evidence for a multisensory deficit in the perception of pleasantness. Further studies should delineate the underlying neural circuity and the diagnostic value to detect neuropsychiatric symptoms in PD. Show more

Keywords: Parkinson’s disease, anhedonia, hyposmia, non-motor symptoms, depression, apathy, Sniffin’ Sticks, affective pictures

DOI: 10.3233/JPD-212812

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2035-2045, 2021

Authors: Luque-Casado, Antonio | Novo-Ponte, Sabela | Sánchez-Molina, José Andrés | Sevilla-Sánchez, Marta | Santos-García, Diego | Fernández-del-Olmo, Miguel

Article Type: Research Article

Abstract: Background: Despite the frequent use of the Timed Up and Go (TUG) test in clinical trials, evaluation of longitudinal test-retest reliability is generally lacking and still inconclusive for patients with Parkinson’s disease (PD). Objective: We aimed to further investigate long-term reliability and sensitivity of the TUG test among this population. Furthermore, we explored alternative assessment strategies of the test aimed at elucidating whether the inclusion or combination of timed trials may have potential implications on outcome measure. Methods: Relative and absolute reliability of the TUG performance were obtained in forty-three subjects with PD over three timed …trials in two different testing sessions separated by a two-months period. Results: Our results reported excellent intra-session and moderate inter-session reliability coefficients. The use of different assessment strategies of the TUG was found to have an important impact on outcome measure, highlighting the averaging of several timed trials in each testing session as a recommended alternative to minimize measurement error and increase reliability in longitudinal assessments. Nevertheless, beyond acceptable reliability, poor trial-to-trial stability of the measure appears to exist, since the ranges of expected variability upon retesting were wide and the incidence of spurious statistical effects was not negligible, especially in longitudinal repeated testing. Conclusion: Limitations may exist in the interpretation of the TUG outputs as part of longitudinal assessments aimed at evaluating treatment effectiveness in PD population. Researchers and practitioners should be aware of these concerns to prevent possible misrepresentations of functional ability in patients for a particular intervention. Show more

Keywords: Absolute reliability, intervention, learning effects, long-term, measurement error, minimal detectable change, relative reliability

DOI: 10.3233/JPD-212687

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2047-2055, 2021

Authors: Albrecht, Franziska | Pereira, Joana B. | Mijalkov, Mite | Freidle, Malin | Johansson, Hanna | Ekman, Urban | Westman, Eric | Franzén, Erika

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is characterized by motor deficits and brain alterations having a detrimental impact on balance, gait, and cognition. Intensive physical exercise can induce changes in the neural system, potentially counteracting neurodegeneration in PD and improving clinical symptoms. Objective: This randomized controlled trial investigated effects of a highly challenging, cognitively demanding, balance and gait training (HiBalance) program in participants with PD on brain structure. Methods: 95 participants were assigned to either the HiBalance or an active control speech training program. The group-based interventions were performed in 1-hour sessions, twice per week over a 10-week …period. Participants underwent balance, gait, cognitive function, and structural magnetic resonance imaging assessments before and after the interventions. Voxel-based morphometry was analyzed in 34 HiBalance and 31 active controls. Additionally, structural covariance networks were assessed. Results: There was no significant time by group interaction between the HiBalance and control training in balance, gait, or brain volume. Within-HiBalance-group analyses showed higher left putamen volumes post-training. In repeated measures correlation a positive linear, non-significant relationship between gait speed and putamen volume was revealed. In the HiBalance group we found community structure changes and stronger thalamic-cerebellar connectivity in structural covariance networks. Neither brain volume changes nor topology changes were found for the active controls after the training. Conclusion: Thus, subtle structural brain changes occur after balance and gait training. Future studies need to determine whether training modifications or other assessment methods lead to stronger effects. Show more

Keywords: Randomized controlled trial, magnetic resonance imaging, idiopathic Parkinson’s disease, gait, physical exercise, putamen, gray matter

DOI: 10.3233/JPD-212801

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2057-2071, 2021

Authors: Padmanabhan, Purnima | Sreekanth Rao, Keerthana | Gonzalez, Anthony J. | Pantelyat, Alexander Y. | Chib, Vikram S. | Roemmich, Ryan T.

Article Type: Research Article

Abstract: Background: Gait slowing is a common feature of Parkinson’s disease (PD). Many therapies aim to improve gait speed in persons with PD, but goals are often imprecise. How fast should each patient walk? And how do persons with PD benefit from walking faster? There is an important need to understand how walking speed affects fundamental aspects of gait—including energy cost and stability—that could guide individualized therapy decisions in persons with PD. Objective: We investigated how changes in walking speed affected energy cost and spatiotemporal gait parameters in persons with PD. We compared these effects between dopaminergic medication states …and to those observed in age-matched control participants. Methods: Twelve persons with PD and twelve control participants performed treadmill walking trials spanning at least five different speeds (seven speeds were desired, but not all participants could walk at the fastest speeds). Persons with PD participated in two walking sessions on separate days (once while optimally medicated, once after 12-hour withdrawal from dopaminergic medication). We measured kinematic and metabolic data across all trials. Results: Persons with PD significantly reduced energy cost by walking faster than their preferred speeds. This held true across medication conditions and was not observed in control participants. The patient-specific walking speeds that reduced energy cost did not significantly affect gait variability metrics (used as proxies for gait stability). Conclusion: The gait slowing that occurs with PD results in energetically suboptimal walking. Rehabilitation strategies that target patient-specific increases in walking speed could result in a less effortful gait. Show more

Keywords: Gait, Parkinson’s disease, rehabilitation, energy, dopamine

DOI: 10.3233/JPD-212613

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2073-2084, 2021

Authors: Kumar, Srishti | Shen, Julia W. | Grimes, David | Mestre, Tiago | Thavorn, Kednapa

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a complex and debilitating condition that requires care from a multispecialty team. The Integrated Parkinson Care Network (IPCN) is an innovative pragmatic care model that focuses on integrated care, self-management support and technology-enabled care. Objective: This study aims to estimate the costs of the IPCN and assess whether benefits gained from the intervention offset its costs based on a single center experience. Methods: We conducted a return on investment (ROI) analysis of the IPCN from a societal perspective. The ROI for the IPCN was estimated as a ratio …of the net savings and the intervention cost. The intervention cost was calculated as a sum of set-up and implementation costs. Cost savings was measured as the absolute reduction in the societal costs realized by PD patients. A positive ROI indicated that savings generated from the intervention offset its cost. Results: The total cost of the IPCN for 100 PD patients was C$135,669, or C$226 per patient per month. IPCN was associated with the reduction in societal cost of C$915 per patient per month (95%CI: –2,782, 951). The ROI per PD patient per month for the IPCN was 3.08 (95%CI: –0.60, 22.93), suggesting that for every C$1 invested in the IPCN, C$4.08 is gained through reduction in societal costs. The returns were greater among advanced PD patients. Conclusion: The IPCN has the potential to offer a good return on investment for PD patients, and its value for money is higher among advanced PD patients. Show more

Keywords: Economic evaluation, Parkinson’s disease, integrated care, self-management support, technology-enabled care

DOI: 10.3233/JPD-212578

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2085-2091, 2021

Authors: Nonnekes, Jorik | Koehler, Peter | Bloem, Bastiaan R.

Article Type: Article Commentary

DOI: 10.3233/JPD-212933

Citation: Journal of Parkinson's Disease, vol. 11, no. 4, pp. 2093-2094, 2021