Journal of Parkinson's Disease - Volume 14, issue 2

Authors: Okun, Michael S.

Article Type: Position Paper

Abstract: Persons with Parkinson’s disease (PD) and society at large can profit from a strategic investment into a forward leaning, practical, preventative, and proactive multidisciplinary care policy. The American healthcare system is not easily bent to accommodate this type of care, and thus a tax benefit is an attractive option. An individual federal income tax benefit of $6200 each year for every person residing in the US with a diagnosis of PD, could among other offerings provide monthly access to a licensed clinical social worker and access to mental health services. The implementation of more coordinated care has the potential reduce …the burden of depression, anxiety, and demoralization. Personal training would also be covered and directed by physical and occupational therapists. The combination of home-based and telemedicine services would have the added benefit of improving access. The tax benefit would also provide access to a dietician. This type of care strategy could be designed to proactively identify early signs of aspiration and urinary tract infections to ‘head off’ significant morbidity. A $6200/year individual tax benefit for those diagnosed with PD will thus translate into more fall prevention, more care in the home setting, less hospitalizations, less depression, less anxiety, less demoralization, better diets, and less persons placed in nursing facilities. Additionally, this tax benefit will provide the potential for billions of dollars in savings to the healthcare system. A tax benefit for PD is a practical preventative and proactive strategy which can serve to advantage both this generation and the next. Show more

Keywords: Multidisciplinary, law, economics, Medicare, expenses

DOI: 10.3233/JPD-240046

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 221-226, 2024

Authors: Koukoulis, Tiana F. | Beauchamp, Leah C. | Kaparakis-Liaskos, Maria | McQuade, Rachel M. | Purnianto, Adityas | Finkelstein, David I. | Barnham, Kevin J. | Vella, Laura J.

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is an increasingly common neurodegenerative disease. It has been suggested that the etiology of idiopathic PD is complex and multifactorial involving environmental contributions, such as viral or bacterial infections and microbial dysbiosis, in genetically predisposed individuals. With advances in our understanding of the gut-brain axis, there is increasing evidence that the intestinal microbiota and the mammalian immune system functionally interact. Recent findings suggest that a shift in the gut microbiome to a pro-inflammatory phenotype may play a role in PD onset and progression. While there are links between gut bacteria, inflammation, and PD, the bacterial products involved …and how they traverse the gut lumen and distribute systemically to trigger inflammation are ill-defined. Mechanisms emerging in other research fields point to a role for small, inherently stable vesicles released by Gram-negative bacteria, called outer membrane vesicles in disease pathogenesis. These vesicles facilitate communication between bacteria and the host and can shuttle bacterial toxins and virulence factors around the body to elicit an immune response in local and distant organs. In this perspective article, we hypothesize a role for bacterial outer membrane vesicles in PD pathogenesis. We present evidence suggesting that these outer membrane vesicles specifically from Gram-negative bacteria could potentially contribute to PD by traversing the gut lumen to trigger local, systemic, and neuroinflammation. This perspective aims to facilitate a discussion on outer membrane vesicles in PD and encourage research in the area, with the goal of developing strategies for the prevention and treatment of the disease. Show more

Keywords: Extracellular vesicles, Parkinson’s disease, bacteria, bacterial outer membrane vesicles, membrane particles, microbiota-gut-brain axis, lipopolysaccharide, endotoxin, inflammation, spread, innate immune response

DOI: 10.3233/JPD-230315

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 227-244, 2024

Authors: Finlay, Clare J. | Jackson, Michael J. | Fisher, Ria | Bundgaard, Christoffer | Rose, Sarah | Duty, Susan

Article Type: Research Article

Abstract: Background: Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson’s disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4 ) is a promising target since its activation would reduce glutamate release. Objective: We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia. Methods: The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing …abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats. Results: Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats. Conclusions: This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators. Show more

Keywords: Antidyskinetic, Parkinson’s disease, levodopa-induced dyskinesia, predictive validity, amantadine

DOI: 10.3233/JPD-230296

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 245-259, 2024

Authors: Cirillo, Rossella | Duperrier, Sandra | Parekh, Pathik | Millot, Mathilde | Li, Qin | Thiolat, Marie-Laure | Morelli, Micaela | Xie, Jing | Le Bars, Didier | Redouté, Jérôme | Bezard, Erwan | Sgambato, Véronique

Article Type: Short Communication

Abstract: Alterations of serotonin type 4 receptor levels are linked to mood disorders and cognitive deficits in several conditions. However, few studies have investigated 5-HT4 R alterations in movement disorders. We wondered whether striatal 5-HT4 R expression is altered in experimental parkinsonism. We used a brain bank tissue from a rat and a macaque model of Parkinson’s disease (PD). We then investigated its in vivo PET imaging regulation in a cohort of macaques. Dopaminergic depletion increases striatal 5-HT4 R in the two models, further augmented after dyskinesia-inducing L-Dopa. Pending confirmation in PD patients, the 5-HT4 R might offer a therapeutic …target for dampening PD’s symptoms. Show more

Keywords: Parkinson’s disease, serotonin, PET imaging, immunohistochemistry, experimental animal models, L-Dopa, movement disorders, parkinsonism, dyskinesia

DOI: 10.3233/JPD-230331

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 261-267, 2024

Authors: Kroneberg, Daniel | Al-Fatly, Bassam | Morkos, Cornelia | Steiner, Leon Amadeus | Schneider, Gerd-Helge | Kühn, A.

Article Type: Research Article

Abstract: Background: Additional stimulation of the substantia nigra (SNr) has been proposed to target axial symptoms and gait impairment in patients with Parkinson’s disease (PD). Objective: This study aimed to characterize effects of combined deep brain stimulation (DBS) of the subthalamic nucleus (STN) and SNr on gait performance in PD and to map stimulation sites within the SNr. Methods: In a double-blinded crossover design, 10 patients with PD and gait impairment underwent clinical examination and kinematic assessment with STN DBS, combined STN+SNr DBS and OFF DBS 30 minutes after reprogramming. To confirm stimulation within …the SNr, electrodes, active contacts, and stimulation volumes were modeled in a common space and overlap with atlases of SNr was computed. Results: Overlap of stimulation volumes with dorsolateral SNr was confirmed for all patients. UPDRS III, scoring of freezing during turning and transitioning, stride length, stride velocity, and range of motion of shank, knee, arm, and trunk as well as peak velocities during turning and transitions and turn duration were improved with STN DBS compared to OFF. On cohort level, no further improvement was observed with combined STN+SNr DBS but additive improvement of spatiotemporal gait parameters was observed in individual subjects. Conclusions: Combined high frequency DBS of the STN and dorsolateral SNr did not consistently result in additional short-term kinematic or clinical benefit compared to STN DBS. Stimulation intervals, frequency, and patient selection for target symptoms as well as target region within the SNr need further refinement in future trials. Show more

Keywords: Deep brain stimulation (DBS), Parkinson’s disease, gait analysis, substantia nigra

DOI: 10.3233/JPD-230181

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 269-282, 2024

Authors: Huang, Cheng-Ya | Chen, Yu-An | Wu, Ruey-Meei | Hwang, Ing-Shiou

Article Type: Research Article

Abstract: Background: Task prioritization involves allocating brain resources in a dual-task scenario, but the mechanistic details of how prioritization strategies affect dual-task walking performance for Parkinson’s disease (PD) are little understood. Objective: We investigated the performance benefits and corresponding neural signatures for people with PD during dual-task walking, using gait-prioritization (GP) and manual-prioritization (MP) strategies. Methods: Participants (N = 34) were asked to hold two inter-locking rings while walking and to prioritize either taking big steps (GP strategy) or separating the two rings (MP strategy). Gait parameters and ring-touch time were measured, and scalp electroencephalograph was performed. …Results: Compared with the MP strategy, the GP strategy yielded faster walking speed and longer step length, whereas ring-touch time did not significantly differ between the two strategies. The MP strategy led to higher alpha (8–12 Hz) power in the posterior cortex and beta (13–35 Hz) power in the left frontal-temporal area, but the GP strategy was associated with stronger network connectivity in the beta band. Changes in walking speed and step length because of prioritization negatively correlated with changes in alpha power. Prioritization-related changes in ring-touch time correlated negatively with changes in beta power but positively with changes in beta network connectivity. Conclusions: A GP strategy in dual-task walking for PD can enhance walking speed and step length without compromising performance in a secondary manual task. This strategy augments attentional focus and facilitates compensatory reinforcement of inter-regional information exchange. Show more

Keywords: Multitasking behavior, gait, attention, electroencephalography, electroencephalography phase synchronization, Parkinson’s disease

DOI: 10.3233/JPD-230245

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 283-296, 2024

Authors: Janz, Carin | Timpka, Jonathan | Rosqvist, Kristina | Paul, Gesine | Storch, Alexander | Odin, Per

Article Type: Research Article

Abstract: Background: Non-motor symptoms (NMS) reduce quality of life in Parkinson’s disease (PD) patients, who experience three times more NMS than individuals without PD. While there are international and national NMS treatment guidelines, their implication in clinical practice remains unclear. Objective: This study aimed to investigate the adherence to pharmacological NMS treatment guidelines in patients with mild to moderately severe PD. Methods: 220 PD patients with ≥1 NMS based on the Non-Motor Symptom Questionnaire and a Hoehn and Yahr stage ≤4 were randomly selected from the Swedish Parkinson registry and screened for inclusion. NMS …were evaluated using the International Parkinson and Movement Disorder Society–Non-Motor Rating Scale (MDS-NMS), Parkinson’s Disease Sleep Scale 2, Epworth Sleepiness Scale, and Hospital Anxiety and Depression Scale. Treatment was compared with Swedish national guidelines and international guidelines from the MDS Evidence-Based Medicine Committee. Results: Among 165 included patients, the median number of NMS was 14, and in median 7 symptoms were estimated to require treatment. The most common NMS requiring treatment were pain (69%) and urinary problems (56%). Treatment of depression and constipation demonstrated the highest adherence to guidelines (79% and 77%), while dysphagia and excessive daytime sleepiness exhibited the lowest adherence (0% and 4%). On average, only 32% of NMS were treated in accordance with guidelines. Conclusions: Adherence to pharmacological guidelines for NMS in patients with mild to severe PD was low. This study highlights the need for improved evaluation and treatment of NMS to enhance symptom management and quality of life among PD patients. Show more

Keywords: Movement disorder, Parkinson’s disease, disease management, guidelines, symptoms

DOI: 10.3233/JPD-230263

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 297-312, 2024

Authors: Gonçalves, Alexandra | Mendes, Alexandre | Damásio, Joana | Vila-Chã, Nuno | Boleixa, Daniela | Leal, Bárbara | Cavaco, Sara

Article Type: Research Article

Abstract: Background: A possible genetic contribution of dopamine D3 receptor (DRD3) to cognitive impairment in Parkinson’s disease (PD) has yet to be investigated. Objective: To explore the effects of rs6280 (Ser9Gly) genotype on PD patients’ cognitive performance and to clarify possible interactions with psychopathology. Methods: Two hundred and fifty-three consecutive PD patients underwent neurological and neuropsychological evaluations, which included: Unified Parkinson’s Disease Rating Scale (UPDRS), Hoehn & Yahr scale (H&Y), Dementia Rating Scale-2 (DRS-2), and Hospital Anxiety and Depression Scale (HADS). rs6280 polymorphism was genotyped for all PD patients and for 270 ethnically matched …healthy volunteers (HC). Non-parametric group comparisons and logistic regressions were used for data analyses. Results: rs6280 genotype did not differ between PD and HC groups. PD patients with rs6280 CC genotype had more impaired cognitive performance (i.e., <1st percentile of demographically adjusted norms) on DRS-2 subscales Initiation/Perseveration and Construction than those with TT genotype. These associations remained statistically significant when other covariates (e.g., demographic features, disease duration, severity of motor symptoms in OFF and ON states, anti-parkinsonian medication, and psychopathology symptoms) were taken into consideration. PD patients with rs6280 TC had less anxiety (i.e., HADS Anxiety≥11) than those with TT (p  = 0.012). This association was also independent of other covariates. Conclusions: Study findings suggest that rs6280 CC genotype predisposes to executive dysfunction and visuoconstructional deficits, whereas the heterozygous genotype protects from anxiety in PD. These effects do not appear to be dependent of one another. rs6280 is not a genotypic susceptibility factor for PD. Show more

Keywords: Parkinson’s disease, dopamine D3 receptor, cognition, anxiety

DOI: 10.3233/JPD-230292

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 313-324, 2024

Authors: Werner, Milton H. | Olanow, C. Warren | McGarry, Andrew | Meyer, Christopher | Kruger, Sydney | Klint, Carl | Pellecchia, Jacqueline | Walaker, Shannon | Ereshefsky, Larry | Blob, Lawrence | Hassman, Howard | Rodriguez, Carlos | Samara, Emil | Safirstein, Beth | Ellenbogen, Aaron

Article Type: Research Article

Abstract: Background: Pre-clinical studies suggest that c-Abl activation may play an important role in the etiology of Parkinson’s disease, making c-Abl an important target to evaluate for potential disease-modification. Objective: To assess safety, tolerability, and pharmacokinetics of the c-Abl inhibitor risvodetinib (IkT-148009) in healthy subjects and participants with Parkinson’s disease. Methods: Part 1 (single ascending dose (SAD)) and Part 2 (7-day multiple ascending dose (MAD)) studies were in healthy volunteers. Participants were randomized 3 : 1 across 9 SAD doses and 3 MAD doses of risvodetinib (IkT-148009) or placebo. Part 3 was a MAD study conducted at two doses …in 14 participants with mild-to-moderate PD (MAD-PD). Primary outcome measures were safety, tolerability and pharmacokinetics. Exploratory outcomes in PD participants included clinical measures of PD state, GI function, and cerebrospinal fluid (CSF) concentration. Results: 108 patients were treated with no dropouts. The SAD tested doses ranging from 12.5 to 325 mg, while the MAD tested 25 to 200 mg and MAD-PD tested 50 to 100 mg in Parkinson’s participants. All active doses had a favorable safety profile with no clinically meaningful adverse events. Single dose pharmacokinetics were approximately linear between 12.5 mg and 200 mg for both Cmax and AUC0 - inf without distinction between healthy volunteers and participants with PD. Exposures at each dose were high relative to other drugs in the same kinase inhibitor class. Conclusions: Risvodetinib (IkT-148009) was well tolerated, had a favorable safety and pharmacology profile over 7-day dosing, did not induce serious adverse events and did not appear to induce deleterious side-effects in participants administered anti-PD medications. Show more

Keywords: c-Abl inhibition, Parkinson’s disease, disease-modification, therapeutics, pharmacology, neurodegeneration

DOI: 10.3233/JPD-230319

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 325-334, 2024

Authors: Giannini, Giulia | Minardi, Raffaella | Barletta, Giorgio | Cani, Ilaria | Cecere, Annagrazia | Baldelli, Luca | Fiorentino, Alessia | Guaraldi, Pietro | Sambati, Luisa | Capellari, Sabina | Cortelli, Pietro | Carelli, Valerio | Calandra-Buonaura, Giovanna

Article Type: Research Article

Abstract: Background: Increased prevalence of cardiovascular autonomic failure might play a key role on Parkinson’s disease (PD) progression of glucocerebrosidase gene (GBA )-mutated patients, determining a malignant phenotype of disease in these patients. Objective: To objectively characterize, for the first time, the cardiovascular autonomic profile of GBA -mutated patients compared to idiopathic PD patients by means of cardiovascular reflex tests (CRTs). Methods: This is a case-control (1 : 2) study on PD patients belonging to well-characterized prospective cohorts. For each PD patient carrying GBA variants, two idiopathic PD patients, matched for sex and disease duration …at CRTs, were selected. Patients recruited in these cohorts underwent a complete clinical and instrumental evaluation including specific autonomic questionnaires, CRTs and extensive genetic analysis. Results: A total of 23 GBA -PD patients (19 males, disease duration 7.7 years) were included and matched with 46 non-mutated PD controls. GBA -mutated patients were younger than controls (59.9±8.1 vs. 64.3±7.2 years, p  = 0.0257) and showed a more severe phenotype. Despite GBA -mutated patients reported more frequently symptoms suggestive of orthostatic hypotension (OH) than non-mutated patients (39.1% vs 6.5%, p  = 0.001), the degree of cardiovascular autonomic dysfunction, when instrumentally assessed, did not differ between the two groups, showing the same prevalence of neurogenic OH, delayed OH and cardiovascular reflex impairment (pathological Valsalva maneuver). Conclusion: GBA -PD patients did not show different instrumental cardiovascular autonomic pattern than non-mutated PD. Our findings suggested that symptoms suggestive of OH should be promptly investigated by clinicians to confirm their nature and improve patient care and management. Show more

Keywords: Parkinson’s disease, cardiovascular autonomic failure, glucocerebrosidase (GBA) gene mutations, orthostatic hypotension, autonomic dysfunction, case-control study

DOI: 10.3233/JPD-230334

Citation: Journal of Parkinson's Disease, vol. 14, no. 2, pp. 335-346, 2024