Journal of Parkinson's Disease - Volume 12, issue 1

Authors: Ragothaman, Anjanibhargavi | Miranda-Dominguez, Oscar | Brumbach, Barbara H. | Giritharan, Andrew | Fair, Damien A. | Nutt, John G. | Mancini, Martina | Horak, Fay B.

Article Type: Research Article

Abstract: Background: Instrumented measures of balance and gait measure more specific balance and gait impairments than clinical rating scales. No prior studies have used objective balance/gait measures to examine associations with ventricular and brain volumes in people with Parkinson’s disease (PD). Objective: To test the hypothesis that larger ventricular and smaller cortical and subcortical volumes are associated with impaired balance and gait in people with PD. Methods: Regional volumes from structural brain images were included from 96 PD and 50 control subjects. Wearable inertial sensors quantified gait, anticipatory postural adjustments prior to step initiation (APAs), postural responses …to a manual push, and standing postural sway on a foam surface. Multiple linear regression models assessed the relationship between brain volumes and balance/gait and their interactions in PD and controls, controlling for sex, age and corrected for multiple comparisons. Results: Smaller brainstem and subcortical gray matter volumes were associated with larger sway area in people with PD, but not healthy controls. In contrast, larger ventricle volume was associated with smaller APAs in healthy controls, but not in people with PD. A sub-analysis in PD showed significant interactions between freezers and non-freezers, in several subcortical areas with stride time variability, gait speed and step initiation. Conclusion: Our models indicate that smaller subcortical and brainstem volumes may be indicators of standing balance dysfunction in people with PD whereas enlarged ventricles may be related to step initiation difficulties in healthy aging. Also, multiple subcortical region atrophy may be associated with freezing of gait in PD. Show more

Keywords: Balance, brain volume, gait, Parkinson’s disease

DOI: 10.3233/JPD-202403

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 283-294, 2022

Authors: Ren, Chao | He, Kai-Jie | Hu, Hua | Zhang, Jin-Bao | Dong, Li-Guo | Li, Dan | Chen, Jing | Mao, Cheng-Jie | Wang, Fen | Liu, Chun-Feng

Article Type: Research Article

Abstract: Background: Previous investigations have suggested that decreased expression of glutamate transporter-1 (GLT-1) is involved in glutamate excitotoxicity and contribute to the development of Parkinson’s disease (PD), GLT-1 is decreased in animal models of PD. GLT-1 is mainly expressed in astrocytes, and the striatum is a GLT-1-rich brain area. Objective: The aim was to explore the function and mechanism of astrocytic GLT-1 in PD-like changes. Methods: In the study, PD-like changes and their molecular mechanism in rodents were tested by a behavioral assessment, micro-positron emission tomography/computed tomography (PET/CT), western blotting, immunohistochemical and immunofluorescence staining, and high performance …liquid chromatography pre-column derivatization with O-pthaldialdehida after downregulating astrocytic GLT-1 in vivo and in vitro . Results: In vivo , after 6 weeks of brain stereotactic injection of adeno-associated virus into the striatum, rats in the astrocytic GLT-1 knockdown group showed poorer motor performance, abnormal gait, and depression-like feature; but no olfactory disorders. The results of micro-PET/CT and western blotting indicated that the dopaminergic system was impaired in astrocytic GLT-1 knockdown rats. Similarly, tyrosine hydroxylase (TH) positive immune-staining in neurons of astrocytic GLT-1 knockdown rats showed deficit in cell count. In vitro , knockdown of astrocytic GLT-1 via RNA interference led to morphological injury of TH-positive neurons, which may be related to the abnormal calcium signal induced by glutamate accumulation after GLT-1 knockdown. Furthermore, the GLT-1 agonist ceftriaxone showed a protective effect on TH-positive neuron impairment. Conclusion: The present findings may shed new light in the future prevention and treatment of PD based on blocking glutamate excitotoxicity. Show more

Keywords: GLT-1, astrocyte, Parkinson’s disease, glutamate, calcium signaling

DOI: 10.3233/JPD-212640

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 295-314, 2022

Authors: Santos García, Diego | García Roca, Lucía | de Deus Fonticoba, Teresa | Cores Bartolomé, Carlos | Naya Ríos, Lucía | Canfield, Héctor | Paz González, Jose M. | Martínez Miró, Cristina | Jesús, Silvia | Aguilar, Miquel | Pastor, Pau | Planellas, Lluís | Cosgaya, Marina | García Caldentey, Juan | Caballol, Nuria | Legarda, Ines | Hernández Vara, Jorge | Cabo, Iria | López Manzanares, Lydia | González Aramburu, Isabel | Ávila Rivera, Maria A. | Gómez Mayordomo, Víctor | Nogueira, Víctor | Puente, Víctor | Dotor García-Soto, Julio | Borrué, Carmen | Solano Vila, Berta | Álvarez Sauco, María | Vela, Lydia | Escalante, Sonia | Cubo, Esther | Carrillo Padilla, Francisco | Martínez Castrillo, Juan C. | Sánchez Alonso, Pilar | Alonso Losada, Maria G. | López Ariztegui, Nuria | Gastón, Itziar | Kulisevsky, Jaime | Blázquez Estrada, Marta | Seijo, Manuel | Rúiz Martínez, Javier | Valero, Caridad | Kurtis, Mónica | de Fábregues, Oriol | González Ardura, Jessica | Alonso Redondo, Ruben | Ordás, Carlos | López Díaz L, Luis M. | McAfee, Darrian | Martinez-Martin, Pablo | Mir, Pablo | COPPADIS Study Group

Article Type: Research Article

Abstract: Background: Constipation has been linked to cognitive impairment development in Parkinson’s disease (PD). Objective: Our aim was to analyze cognitive changes observed in PD patients and controls from a Spanish cohort with regards to the presence or not of constipation. Methods: PD patients and controls recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017 were followed-up during 2 years. The change in cognitive status from baseline (V0) to 2-year follow-up was assessed with the PD-CRS (Parkinson’s Disease Cognitive Rating Scale). Subjects with a score ≥1 on item 21 of …the NMSS (Non-Motor Symptoms Scale) at baseline (V0) were considered as “with constipation”. Regression analyses were applied for determining the contribution of constipation in cognitive changes. Results: At V0, 39.7% (198/499) of PD patients presented constipation compared to 11.4% of controls (14/123) (p  < 0.0001). No change was observed in cognitive status (PD-CRS total score) neither in controls without constipation (from 100.24±13.72 to 100.27±13.68; p  = 0.971) and with constipation (from 94.71±10.96 to 93.93±13.03; p  = 0.615). The PD-CRS total score decreased significantly in PD patients with constipation (from 89.14±15.36 to 85.97±18.09; p  < 0.0001; Coehn’s effect = –0.35) compared to patients without constipation (from 93.92±15.58 to 93.14±17.52; p  = 0.250) (p  = 0.018). In PD patients, to suffer from constipation at V0 was associated with a decrease in the PD-CRS total score from V0 to V2 (β= –0.1; 95% CI, –4.36 – –0.27; p  = 0.026) and having cognitive impairment at V2 (OR = 1.79; 95% CI, 1.01 – 3.17; p  = 0.045). Conclusion: Constipation is associated with cognitive decline in PD patients but not in controls. Show more

Keywords: Cognition, constipation, impairment, non-motor symptoms, Parkinson’s disease

DOI: 10.3233/JPD-212868

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 315-331, 2022

Authors: Sosero, Yuri L. | Yu, Eric | Estiar, Mehrdad A. | Krohn, Lynne | Mufti, Kheireddin | Rudakou, Uladzislau | Ruskey, Jennifer A. | Asayesh, Farnaz | Laurent, Sandra B. | Spiegelman, Dan | Trempe, Jean-François | Quinnell, Timothy G. | Oscroft, Nicholas | Arnulf, Isabelle | Montplaisir, Jacques Y. | Gagnon, Jean-François | Desautels, Alex | Dauvilliers, Yves | Gigli, Gian Luigi | Valente, Mariarosaria | Janes, Francesco | Bernardini, Andrea | Sonka, Karel | Kemlink, David | Oertel, Wolfgang | Janzen, Annette | Plazzi, Giuseppe | Antelmi, Elena | Biscarini, Francesco | Figorilli, Michela | Puligheddu, Monica | Mollenhauer, Brit | Trenkwalder, Claudia | Sixel-Döring, Friederike | Cochen De Cock, Valérie | Monaca, Christelle Charley | Heidbreder, Anna | Ferini-Strambi, Luigi | Dijkstra, Femke | Viaene, Mineke | Abril, Beatriz | Boeve, Bradley F. | Postuma, Ronald B. | Rouleau, Guy A. | Ibrahim, Abubaker | Stefani, Ambra | Högl, Birgit | Hu, Michele T.M. | Gan-Or, Ziv

Article Type: Research Article

Abstract: Background: PSAP encodes saposin C, the co-activator of glucocerebrosidase, encoded by GBA . GBA mutations are associated with idiopathic/isolated REM sleep behavior disorder (iRBD), a prodromal stage of synucleinopathy. Objective: To examine the role of PSAP mutations in iRBD. Methods: We fully sequenced PSAP and performed Optimized Sequence Kernel Association Test in 1,113 iRBD patients and 2,324 controls. We identified loss-of-function (LoF) mutations, which are very rare in PSAP , in three iRBD patients and none in controls (uncorrected p  = 0.018). Results: Two variants were stop mutations, p.Gln260Ter and …p.Glu166Ter, and one was an in-frame deletion, p.332_333del. All three mutations have a deleterious effect on saposin C, based on in silico analysis. In addition, the two carriers of p.Glu166Ter and p.332_333del mutations also carried a GBA variant, p.Arg349Ter and p.Glu326Lys, respectively. The co-occurrence of these extremely rare PSAP LoF mutations in two (0.2%) GBA variant carriers in the iRBD cohort, is unlikely to occur by chance (estimated co-occurrence in the general population based on gnomAD data is 0.00035%). Although none of the three iRBD patients with PSAP LoF mutations have phenoconverted to an overt synucleinopathy at their last follow-up, all manifested initial signs suggestive of motor dysfunction, two were diagnosed with mild cognitive impairment and all showed prodromal clinical markers other than RBD. Their probability of prodromal PD, according to the Movement Disorder Society research criteria, was 98% or more. Conclusion: These results suggest a possible role of PSAP variants in iRBD and potential genetic interaction with GBA , which requires additional studies. Show more

Keywords: REM sleep behavior disorder, PSAP, saposin C, Parkinson’s disease, GBA, glucocerebrosidase, genetics

DOI: 10.3233/JPD-212867

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 333-340, 2022

Authors: Karabayir, Ibrahim | Butler, Liam | Goldman, Samuel M. | Kamaleswaran, Rishikesan | Gunturkun, Fatma | Davis, Robert L. | Ross, G. Webster | Petrovitch, Helen | Masaki, Kamal | Tanner, Caroline M. | Tsivgoulis, Georgios | Alexandrov, Andrei V. | Chinthala, Lokesh K. | Akbilgic, Oguz

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) is a chronic, disabling neurodegenerative disorder. Objective: To predict a future diagnosis of PD using questionnaires and simple non-invasive clinical tests. Methods: Participants in the prospective Kuakini Honolulu-Asia Aging Study (HAAS) were evaluated biannually between 1995–2017 by PD experts using standard diagnostic criteria. Autopsies were sought on all deaths. We input simple clinical and risk factor variables into an ensemble-tree based machine learning algorithm and derived models to predict the probability of developing PD. We also investigated relationships of predictive models and neuropathologic features such as nigral neuron density. Results: …The study sample included 292 subjects, 25 of whom developed PD within 3 years and 41 by 5 years. 116 (46%) of 251 subjects not diagnosed with PD underwent autopsy. Light Gradient Boosting Machine modeling of 12 predictors correctly classified a high proportion of individuals who developed PD within 3 years (area under the curve (AUC) 0.82, 95%CI 0.76–0.89) or 5 years (AUC 0.77, 95%CI 0.71–0.84). A large proportion of controls who were misclassified as PD had Lewy pathology at autopsy, including 79%of those who died within 3 years. PD probability estimates correlated inversely with nigral neuron density and were strongest in autopsies conducted within 3 years of index date (r  = –0.57, p  < 0.01). Conclusion: Machine learning can identify persons likely to develop PD during the prodromal period using questionnaires and simple non-invasive tests. Correlation with neuropathology suggests that true model accuracy may be considerably higher than estimates based solely on clinical diagnosis. Show more

Keywords: Parkinson’s disease, Lewy body pathology, neuron density, machine learning

DOI: 10.3233/JPD-212876

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 341-351, 2022

Authors: Yoon, Seo Yeon | Heo, Seok-Jae | Kim, Yong Wook | Yang, Seung Nam | Moon, Hyun Im

Article Type: Research Article

Abstract: Background: Ankylosing spondylitis (AS) is an immune-mediated, chronic inflammatory rheumatic disorder. The etiology of Parkinson’s disease (PD) is multifactorial; however, inflammation is receiving an increasing amount of attention as an underlying cause of the neurodegenerative process of PD. Objective: We performed a nationwide longitudinal, population-based matched cohort study to assess the association with the later development of parkinsonism in Korea. Methods: This study was conducted using records from the Health Insurance Review and Assessment Service database. The cumulative incidence rate of PD was estimated. Fine–Gray subdistribution hazard models were used to identify hazards associated with PD …development based on the presence of AS. Exposure to anti-inflammatory drugs was measured and analyzed to determine the protective effect of these medications. Additionally, the hazard ratio (HR) for atypical parkinsonism was estimated. Results: The results of the Fine–Gray subdistribution hazard model revealed that the HR for PD development in the AS group was 1.82 (95%confidence interval [CI], 1.38–2.39, p  < 0.001). A significant decrease in PD development was observed in patients with AS taking non-steroidal anti-inflammatory drugs (NSAIDs). The HR for atypical parkinsonism in the AS group was 3.86 (95%CI, 1.08–13.78, p  < 0.05). Conclusion: We found that AS was associated with an increased risk of PD and atypical parkinsonism. NSAIDs used for AS control have some protective effects against PD. Further studies assessing whether biological treatment mitigates PD risk in patients with high activity are warranted. Show more

Keywords: Ankylosing spondylitis, Parkinson’s disease, population-based cohort, National Health Insurance

DOI: 10.3233/JPD-212878

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 353-360, 2022

Authors: Thieken, Franziska | Timmermann, Lars | Sohrabi, Keywan | Woopen, Christiane | Schmitz-Luhn, Björn | Janhsen, Anna | Eggers, Carsten

Article Type: Research Article

Abstract: Background: Parkinsonian syndromes are heterogeneous chronic neurodegenerative disorders associated with both motor and non-motor symptoms. The symptoms have major psychosocial effects on the quality of life of patients and can be a burden for caregivers. So far, several questionnaires have been developed to assess quality of life in Parkinsonism, but none of these include the positive sides on well-being such as personal and social resilience factors. Objective: The aim of this study is to develop a digital framework for a longitudinal assessment of quality of life during the progression of Parkinson’s disease. Methods: …The CHAPO model (Challenges and Potentials) has been established in a vast study by Wagner et al. to assess the quality of life of older people. This model includes environmental and individual factors, life chances, and life results, such as individual life evaluation, from a subjective as well as an objective point of view. Therefore, it has been adapted in several development steps to include the specific aspects that affect quality of life in Parkinsonian syndromes. The development process included 6 steps: definition, refinement, operationalization, piloting/debriefing, adjustment, and integration. Results: The development of the CHAPO-PD model has been completed and it represents the first main result of this study. Conclusion: By taking a holistic understanding of quality of life into account, we expect to detect previously unrecognized factors, which correlate to the subjective well-being of Parkinson’s disease patients, and aim to use these findings to improve the health care structures for patients with Parkinson’s disease and related disorders. Show more

Keywords: Parkinson’s disease, health-related quality of life, holistic, assessment tool, prognostication, personalized care

DOI: 10.3233/JPD-202391

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 361-370, 2022

Authors: Myers, Taylor L. | Augustine, Erika F. | Baloga, Elizabeth | Daeschler, Margaret | Cannon, Paul | Rowbotham, Helen | Chanoff, Eli | 23andMe Research Team | Jensen-Roberts, Stella | Soto, Julia | Holloway, Robert G. | Marras, Connie | Tanner, Caroline M. | Dorsey, E. Ray | Schneider, Ruth B.

Article Type: Research Article

Abstract: Background: Traditional in-person Parkinson’s disease (PD) research studies are often slow to recruit and place unnecessary burden on participants. The ongoing COVID-19 pandemic has added new impetus to the development of new research models. Objective: To compare recruitment processes and outcomes of three remote decentralized observational PD studies with video visits. Methods: We examined the number of participants recruited, speed of recruitment, geographic distribution of participants, and strategies used to enhance recruitment in FIVE, a cross-sectional study of Fox Insight participants with and without PD (n  = 203); VALOR-PD, a longitudinal study of 23andMe, Inc. research participants …carrying the LRRK2 G2019S variant with and without PD (n  = 277); and AT-HOME PD, a longitudinal study of former phase III clinical trial participants with PD (n  = 226). Results: Across the three studies, 706 participants from 45 U.S. states and Canada enrolled at a mean per study rate of 4.9 participants per week over an average of 51 weeks. The cohorts were demographically homogenous with regard to race (over 95%white) and level of education (over 90%with more than a high school education). The number of participants living in primary care Health Professional Shortage Areas in each study ranged from 30.3–42.9%. Participants reported interest in future observational (98.5–99.6%) and interventional (76.1–87.6%) research studies with remote video visits. Conclusion: Recruitment of large, geographically dispersed remote cohorts from a single location is feasible. Interest in participation in future remote decentralized PD studies is high. More work is needed to identify best practices for recruitment, particularly of diverse participants. Show more

Keywords: Parkinson’s disease, telemedicine, recruitment, decentralized

DOI: 10.3233/JPD-212935

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 371-380, 2022

Authors: Bange, Manuel | Gonzalez-Escamilla, Gabriel | Marquardt, Tabea | Radetz, Angela | Dresel, Christian | Herz, Damian | Schöllhorn, Wolfgang Immanuel | Groppa, Sergiu | Muthuraman, Muthuraman

Article Type: Research Article

Abstract: Background: Movement execution is impaired in patients with Parkinson’s disease. Evolving neurodegeneration leads to altered connectivity between distinct regions of the brain and altered activity at interconnected areas. How connectivity alterations influence complex movements like drawing spirals in Parkinson’s disease patients remains largely unexplored. Objective: We investigated whether deteriorations in interregional connectivity relate to impaired execution of drawing. Methods: Twenty-nine patients and 31 age-matched healthy control participants drew spirals with both hands on a digital graphics tablet, and the regularity of drawing execution was evaluated by sample entropy. We recorded resting-state fMRI and task-related EEG, and …calculated the time-resolved partial directed coherence to estimate effective connectivity for both imaging modalities to determine the extent and directionality of interregional interactions. Results: Movement performance in Parkinson’s disease patients was characterized by increased sample entropy, corresponding to enhanced irregularities in task execution. Effective connectivity between the motor cortices of both hemispheres, derived from resting-state fMRI, was significantly reduced in Parkinson’s disease patients in comparison to controls. The connectivity strength in the nondominant to dominant hemisphere direction in both modalities was inversely correlated with irregularities during drawing, but not with the clinical state. Conclusion: Our findings suggest that interhemispheric connections are affected both at rest and during drawing movements by Parkinson’s disease. This provides novel evidence that disruptions of interhemispheric information exchange play a pivotal role for impairments of complex movement execution in Parkinson’s disease patients. Show more

Keywords: Parkinson’s disease, motor control, neural effective connectivity, fMRI

DOI: 10.3233/JPD-212840

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 381-395, 2022

Authors: Marques, Ana | Taylor, Natasha L. | Roquet, Daniel | Beze, Steven | Chassain, Carine | Pereira, Bruno | O’Callaghan, Claire | Lewis, Simon J.G. | Durif, Franck

Article Type: Research Article

Abstract: Background: Visual illusions (VI) in Parkinson’s disease (PD) are generally considered as an early feature of the psychosis spectrum leading to fully formed visual hallucinations (VH), although this sequential relationship has not been clearly demonstrated. Objective: We aimed to determine whether there are any overlapping, potentially graded patterns of structural and functional connectivity abnormalities in PD with VI and with VH. Such a finding would argue for a continuum between these entities, whereas distinct imaging features would suggest different neural underpinnings for the phenomena. Methods: In this case control study, we compared structural and resting state …functional MRI brain patterns of PD patients with VH (PD-H, n  = 20), with VI (PD-I, n  = 19), and without VH or VI (PD-C, n  = 23). Results: 1) PD-H had hypo-connectivity between the ILO and anterior cingulate precuneus and parahippocampal gyrus compared to PD-C and PD-I; 2) In contrast, PD-I had hyper-connectivity between the inferior frontal gyrus and the postcentral gyrus compared to PD-C and PD-H. Moreover, PD-I had higher levels of functional connectivity between the amygdala, hippocampus, insula, and fronto-temporal regions compared to PD-H, together with divergent patterns toward the cingulate. 3) Both PD-I and PD-H had functional hypo-connectivity between the lingual gyrus and the parahippocampal region vs. PD-C, and no significant grey matter volume differences was observed between PD-I and PD-H. Conclusion: Distinct patterns of functional connectivity characterized VI and VH in PD, suggesting that these two perceptual experiences, while probably linked and driven by at least some similar mechanisms, could reflect differing neural dysfunction. Show more

Keywords: Parkinson’s disease, hallucinations, illusions, neuroimaging, visuo-perception

DOI: 10.3233/JPD-212838

Citation: Journal of Parkinson's Disease, vol. 12, no. 1, pp. 397-409, 2022