Journal of Parkinson's Disease - Volume 12, issue 6

Authors: Salvatore, Michael F. | Soto, Isabel | Kasanga, Ella A. | James, Rachael | Shifflet, Marla K. | Doshier, Kirby | Little, Joel T. | John, Joshia | Alphonso, Helene M. | Cunningham, J. Thomas | Nejtek, Vicki A.

Article Type: Research Article

Abstract: Background: Rodent Parkinson’s disease (PD) models are valuable to interrogate neurobiological mechanisms of exercise that mitigate motor impairment. Translating these mechanisms to human PD must account for physical capabilities of the patient. Objective: To establish cardiovascular parameters as a common metric for cross-species translation of aerobic exercise impact. Method: We evaluated aerobic exercise impact on heart rate (HR) in 21 early-stage PD subjects (Hoehn Yahr ≤1.5) exercising in non-contact boxing training for ≥3 months, ≥3x/week. In 4-month-old Pink1 knockout (KO) rats exercising in a progressively-increased treadmill speed regimen, we determined a specific treadmill speed that increased …HR to an extent similar in human subjects. Results: After completing aerobic exercise for ∼30 min, PD subjects had increased HR∼35% above baseline (∼63% maximum HR). Motor and cognitive test results indicated the exercising subjects completed the timed up and go (TUG) and trail-making test (TMT-A) in significantly less time versus exercise-naïve PD subjects. In KO and age-matched wild-type (WT) rats, treadmill speeds of 8–10 m/min increased HR up to 25% above baseline (∼67% maximum HR), with no further increases up to 16 m/min. Exercised KO, but not WT, rats showed increased locomotor activity compared to an age-matched exercise-naïve cohort at 5 months old. Conclusion: These proof-of-concept results indicate HR is a cross-species translation parameter to evaluate aerobic exercise impact on specific motor or cognitive functions in human subjects and rat PD models. Moreover, a moderate intensity exercise regimen is within the physical abilities of early-stage PD patients and is therefore applicable for interrogating neurobiological mechanisms in rat PD models. Show more

Keywords: Exercise, Pink1, cardiovascular, Parkinson’s disease, aging, locomotor

DOI: 10.3233/JPD-223157

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1897-1915, 2022

Authors: Li, Chunyu | Ou, Ruwei | Hou, Yanbing | Chen, Yongping | Wei, Qianqian | Zhang, Lingyu | Lin, Junyu | Liu, Kuncheng | Huang, Jingxuan | Chen, Xueping | Song, Wei | Zhao, Bi | Wu, Ying | Shang, Huifang

Article Type: Short Communication

Abstract: Homozygous missense variants in PTRHD1 have been identified to cause parkinsonism by segregation analysis in families. Further replication in the Parkinson’s disease (PD) population might provide additional insight. Here, we analyzed the rare variants in a Chinese PD cohort (Ncase  = 1367, Ncontrol  = 3298) with whole exome sequencing. We did not identify the variants described in previous studies, and no patient carried other homozygous or compound heterozygous variants of PTRHD1 . Three rare variants were identified, but rare variants of PTRHD1 were not enriched in PD. Genetic screening suggested rare variants of PTRHD1 as disease cause were rare …in PD in East Asians. Show more

Keywords: PTRHD1, Parkinson’s disease, rare variant, burden analysis

DOI: 10.3233/JPD-223337

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1917-1920, 2022

Authors: Janzen, Annette | Vadasz, David | Booij, Jan | Luster, Markus | Librizzi, Damiano | Henrich, Martin T. | Timmermann, Lars | Habibi, Mahboubeh | Sittig, Elisabeth | Mayer, Geert | Geibl, Fanni | Oertel, Wolfgang

Article Type: Research Article

Abstract: Background: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Objective: We investigated the use of cardiac [123 I]meta-iodo-benzyl-guanidine scintigraphy ([123 I]MIBG) and olfactory testing— in comparison to [123 I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single photon emission computed tomography ([123 I]FP-CIT-SPECT)— for identifying iRBD patients as prodromal phenotype of PD/DLB. Methods: 37 RBD subjects underwent cardiac [123 I]MIBG and brain [123 I]FP-CIT-SPECT at baseline. Olfactory (Sniffin’ Sticks), cognitive and motor functions were tested annually for ∼4 years. Results: 29/37 (78.4%) subjects had a pathological [123 I]MIBG, of …whom 86.2% (25/29) presented at least a moderate hyposmia at baseline (threshold/discrimination/identification-(TDI-)score ≤25). 20/37 (54.1%) subjects had a pathological [123 I]FP-CIT-SPECT, always combined with a pathological [123 I]MIBG. In subjects with pathological [123 I]MIBG, olfactory function worsened (mainly due to threshold and discrimination subscores) from baseline to follow-up (p  = 0.005). Olfaction was more impaired in subjects with pathological [123 I]MIBG compared to those with normal [123 I]MIBG at baseline (p  = 0.001) and follow-up (p  < 0.001). UPDRS-III scores increased in subjects with both pathological [123 I]MIBG and [123 I]FP-CIT-SPECT. In this group, seven subjects phenoconverted to PD, all— except for one— presented with at least moderate hyposmia at baseline. Conclusion: A combination of the biomarkers “pathological [123 I]MIBG” and “hyposmia” likely identifies iRBD patients in an early prodromal stage of PD/DLB, i.e., before nigrostriatal degeneration is visualized. One-third of the subjects with pathological [123 I]MIBG had a normal [123 I]FP-CIT-SPECT. Noteworthy, in iRBD subjects with pathological [123 I]MIBG, olfactory impairment is progressive independent of the [123 I]FP-CIT-SPECT status. Show more

Keywords: Biomarker, cardiac [123I]MIBG scintigraphy, [123I]FP-CIT-SPECT, hyposmia, isolated rapid eye movement sleep behavior disorder, prodromal progression marker

DOI: 10.3233/JPD-223201

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1921-1935, 2022

Authors: Deng, Xiao | Saffari, Seyed Ehsan | Ng, Samuel Yong Ern | Chia, Nicole | Tan, Jayne Yi | Choi, Xinyi | Heng, Dede Liana | Xu, Zheyu | Tay, Kay-Yaw | Au, Wing-Lok | Liu, Nan | Ng, Adeline | Tan, Eng-King | Tan, Louis C.S.

Article Type: Research Article

Abstract: Background: Lipid biomarkers have potential neuroprotective effects in Parkinson’s disease (PD) and there is limited evidence in the field. Objective: This study aims to investigate the association between comprehensive blood lipid biomarkers and PD. Methods: A total of 205 PD patients and 102 non-PD subjects were included from Early Parkinson’s disease Longitudinal Singapore (PALS) cohort. We investigated 6 serum lipid biomarkers including total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo A1), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B). PD patients were further classified into mild cognitive impairment (MCI) and normal …cognition (NC) subgroups. We conducted a cross-sectionals study to examine the association between lipids and PD and further explored the relationship between lipids and PD-MCI. Results: PD patients had significantly lower level of lipid panel including TC, TG, HDL-C, Apo A1, LDL-C, and Apo B (all p  < 0.05). TC, TG, Apo A1, and Apo B levels were independent protective factors (p  < 0.05) for PD in the logistic regression model. PD-MCI group had significantly higher mean TC, TG, and Apo A1 levels compared to PD-NC group. Higher TC, TG, and Apo A1 levels were independent risk factors (p  < 0.05) for PD-MCI. Conclusion: We demonstrated that PD patients had significantly lower levels of lipid biomarkers while PD-MCI patients had higher levels of TC, TG, and Apo A1. TC, TG, and Apo A1 may be useful biomarkers for PD-MCI. Show more

Keywords: Parkinson’s disease, cognitive impairment, blood lipid biomarkers

DOI: 10.3233/JPD-213135

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1937-1943, 2022

Authors: Orso, Beatrice | Arnaldi, Dario | Peira, Enrico | Famá, Francesco | Giorgetti, Laura | Girtler, Nicola | Brugnolo, Andrea | Mattioli, Pietro | Biassoni, Erica | Donniaquio, Andrea | Massa, Federico | Bauckneht, Matteo | Miceli, Alberto | Morbelli, Silvia | Nobili, Flavio | Pardini, Matteo

Article Type: Research Article

Abstract: Background: Cognitive impairment is frequent in Parkinson’s disease (PD) and several neurotransmitter changes have been reported since the time of diagnosis, although seldom investigated altogether in the same patient cohort. Objective: Our aim was to evaluate the association between neurotransmitter impairment, brain metabolism, and cognition in a cohort of de novo , drug-naïve PD patients. Methods: We retrospectively selected 95 consecutive drug-naïve PD patients (mean age 71.89±7.53) undergoing at the time of diagnosis a brain [18 F]FDG-PET as a marker of brain glucose metabolism and proxy measure of neurodegeneration, [123 I]FP-CIT-SPECT as a marker and dopaminergic …deafferentation in the striatum and frontal cortex, as well as a marker of serotonergic deafferentation in the thalamus, and quantitative electroencephalography (qEEG) as an indirect measure of cholinergic deafferentation. Patients also underwent a complete neuropsychological battery. Results: Positive correlations were observed between (i) executive functions and left cerebellar cortex metabolism, (ii) prefrontal dopaminergic tone and working memory (r  = 0.304, p  = 0.003), (iii) qEEG slowing in the posterior leads and both memory (r  = 0.299, p  = 0.004) and visuo-spatial functions (r  = 0.357, p  < 0.001). Conclusions: In subjects with PD, the impact of regional metabolism and diffuse projection systems degeneration differs across cognitive domains. These findings suggest possible tailored approaches to the treatment of cognitive deficits in PD. Show more

Keywords: Cognition, [18F]FDGPET, EEG, [123I]FP-CIT SPECT, idiopathic Parkinson’s disease

DOI: 10.3233/JPD-223308

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1945-1955, 2022

Authors: Leodori, Giorgio | De Bartolo, Maria Ilenia | Fabbrini, Andrea | Costanzo, Matteo | Mancuso, Marco | Belvisi, Daniele | Conte, Antonella | Fabbrini, Giovanni | Berardelli, Alfredo

Article Type: Research Article

Abstract: Background: Patients with Parkinson’s disease (PD) and rest tremor may also have tremor during posture holding, with tremor being transiently suppressed during the transition between resting and posture holding. Other PD patients show no tremor suppression between resting and posture holding. The mechanisms responsible for tremor suppression in PD are unknown. Understanding the mechanisms of tremor suppression would expand our knowledge of tremor pathophysiology in PD. Objective: To investigate whether tremor suppression reflects the activity of the primary motor cortex (M1) and assess whether tremor features are different in patients with and without tremor suppression. Methods: We …compared corticomuscular coherence (CMC) at tremor frequency and transcranial magnetic stimulation tremor resetting between 10 PD patients with tremor suppression and 10 patients without suppression. We also compared tremor spectral features between the two groups. Results: Patients with tremor suppression had higher CMC at tremor frequency during both rest tremor and postural tremor, and a higher postural tremor resetting index and stability when compared with patients without tremor suppression. Rest tremor frequency was similar between the two groups, but postural tremor frequency was lower in patients with tremor suppression as compared to patients without. Conclusion: M1 plays a major role in tremor suppression in PD, and the mechanisms of postural tremor may differ between patients with and without tremor suppression. Show more

Keywords: Parkinson’s disease, tremor, motor cortex, clinical neurophysiology

DOI: 10.3233/JPD-223316

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1957-1963, 2022

Authors: Vinke, R. Saman | Georgiev, Dejan | Selvaraj, Ashok K. | Rahimi, Tahmina | Bloem, Bastiaan R. | Bartels, Ronald H.M.A. | Esselink, Rianne A.J.

Article Type: Short Communication

Abstract: There is evidence that men are more likely to undergo deep brain stimulation (DBS) for Parkinson’s disease (PD), suggesting that women are relatively undertreated. 121 consecutive PD patients undergoing awake DBS with microelectrode recording and intraoperative clinical testing (30 patients, 5 women) or asleep MRI-guided and CT-verified (91 patients, 38 women) bilateral subthalamic nucleus DBS were included in this study. The results showed an increase in the proportion of female patients from 16.7% to 41.8% after changing our operative technique (OR = 5.61; 95% CI: 1.52–20.78; p  = 0.010) from awake to asleep, suggesting that women are more likely to undergo DBS when …operated asleep. Show more

Keywords: Deep brain stimulation, gender, asleep, awake, MRI-guided, microelectrode recording

DOI: 10.3233/JPD-223315

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1965-1968, 2022

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

Article Type: Research Article

Abstract: Background: The Parkinson’s Disease Patient Report of Problems (PD-PROP) captures the problems and functional impact that patients report verbatim. Online research participation and advances in language analysis have enabled longitudinal collection and classification of symptoms as trial outcomes. Objective: Analyze verbatim reports longitudinally to examine postural-instability symptoms as 1) precursors of subsequent falling and 2) newly occurring symptoms that could serve as outcome measures in randomized controlled trials. Methods: Problems reported by >25,000 PD patients in their own words were collected online in the Fox Insight observational study and classified into symptoms by natural language processing, …clinical curation, and machine learning. Symptoms of gait, balance, falling, and freezing and associated reports of having fallen in the last month were analyzed over three years of longitudinal observation by a Cox regression model in a cohort of 8,287 participants. New onset of gait, balance, falling, and freezing symptoms was analyzed by Kaplan-Meier survival techniques in 4,119 participants who had not previously reported these symptoms. Results: Classified verbatim symptoms of postural instability were significant precursors of subsequent falling among participants who were older, female, and had longer PD duration. New onset of symptoms steadily increased and informed sample size estimates for clinical trials to reduce the onset of these symptoms. Conclusion: The tools to analyze symptoms reported by PD patients in their own words and capacity to enroll large numbers of research participants online support the feasibility and statistical power for conducting randomized clinical trials to detect effects of therapeutic interventions. Show more

Keywords: Falling, gait, machine learning, natural language processing, Parkinson’s disease, patient reported outcome measures, randomized controlled trials

DOI: 10.3233/JPD-223274

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1969-1978, 2022

Authors: Wilkins, Kevin B. | Petrucci, Matthew N. | Kehnemouyi, Yasmine | Velisar, Anca | Han, Katie | Orthlieb, Gerrit | Trager, Megan H. | O’Day, Johanna J. | Aditham, Sudeep | Bronte-Stewart, Helen

Article Type: Research Article

Abstract: Background: Assessment of motor signs in Parkinson’s disease (PD) requires an in-person examination. However, 50% of people with PD do not have access to a neurologist. Wearable sensors can provide remote measures of some motor signs but require continuous monitoring for several days. A major unmet need is reliable metrics of all cardinal motor signs, including rigidity, from a simple short active task that can be performed remotely or in the clinic. Objective: Investigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics …of all cardinal motor signs in PD. Methods: Ninety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and clinical motor assessment. Eighteen individuals were followed longitudinally with repeated assessments for an average of three years and up to six years. Results: QDG-RAFT metrics showed differences between PD and controls and provided correlated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment, and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy and showed differences between akinetic-rigid and tremor-dominant phenotypes, as well as people with and without FOG. Conclusions: QDG is a reliable technology, which could be used in the clinic or remotely. This could improve access to care, allow complex remote disease management based on data received in real time, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive motor metrics needed for therapeutic trials. Show more

Keywords: Alternating finger tapping, cardinal motor signs, freezing of gait, keyboard, Parkinson’s disease, phenotype, remote measurement, rigidity, Unified Parkinson’s Disease Rating Scale, wearables

DOI: 10.3233/JPD-223264

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1979-1990, 2022

Authors: Wang, Jian | Battioui, Chakib | McCarthy, Andrew | Dang, Xiangnan | Zhang, Hui | Man, Albert | Zou, Jasmine | Kyle, Jeffrey | Munsie, Leanne | Pugh, Melissa | Biglan, Kevin

Article Type: Research Article

Abstract: Background: PRESENCE was a Phase 2 trial assessing mevidalen for symptomatic treatment of Lewy body dementia (LBD). Participants received daily doses (10, 30, or 75 mg) of mevidalen (LY3154207) or placebo for 12 weeks. Objective: To evaluate if frequent cognitive and motor tests using an iPad app and wrist-worn actigraphy to track activity and sleep could detect mevidalen treatment effects in LBD. Methods: Of 340 participants enrolled in PRESENCE, 238 wore actigraphy for three 2-week periods: pre-, during, and post-intervention. A subset of participants (n  = 160) enrolled in a sub-study using an iPad trial app with 3 …tests: digital symbol substitution (DSST), spatial working memory (SWM), and finger-tapping. Compliance was defined as daily test completion or watch-wearing ≥23 h/day. Change from baseline to week 12 (app) or week 8 (actigraphy) was used to assess treatment effects using Mixed Model Repeated Measures analysis. Pearson correlations between sensor-derived features and clinical endpoints were assessed. Results: Actigraphy and trial app compliance was > 90% and > 60%, respectively. At baseline, daytime sleep positively correlated with Epworth Sleepiness Scale score (p  < 0.01). Physical activity correlated with improvement on Movement Disorder Society –Unified Parkinson Disease Rating Scale (MDS-UPDRS) part II (p  < 0.001). Better scores of DSST and SWM correlated with lower Alzheimer Disease Assessment Scale –Cognitive 13-Item Scale (ADAS-Cog13 ) (p  < 0.001). Mevidalen treatment (30 mg) improved SWM (p  < 0.01), while dose-dependent decreases in daytime sleep (10 mg: p  < 0.01, 30 mg: p  < 0.05, 75 mg: p  < 0.001), and an increase in walking minutes (75 mg dose: p  < 0.001) were observed, returning to baseline post-intervention. Conclusion: Devices used in the LBD population achieved adequate compliance and digital metrics detected statistically significant treatment effects. Show more

Keywords: Actigraphy, activity, cognition, digital biomarkers, Lewy body dementia, sleep

DOI: 10.3233/JPD-213126

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 1991-2004, 2022

Authors: Tosserams, Anouk | Nonnekes, Jorik

Article Type: Research Article

Abstract: The application of compensation strategies is an important element of gait rehabilitation in persons with Parkinson’s disease. While the efficacy of these strategies is generally very high, a tailored, personalized approach is necessary to determine the optimal strategies for every patient. We propose a straightforward, practical guide to the evaluation of compensation strategies in clinical practice: considering the primary gait target(s) to optimize functional mobility, the context in which the strategies will be employed in daily life, and patient-specific personal preferences. Furthermore, we introduce www.walkingwithparkinson.com as a resource on the available compensation strategies, developed specifically for persons with Parkinson’s …disease, their carers, and (allied) healthcare professionals. Show more

Keywords: Parkinson’s disease, gait, rehabilitation, physical therapy

DOI: 10.3233/JPD-223296

Citation: Journal of Parkinson's Disease, vol. 12, no. 6, pp. 2005-2008, 2022