Journal of Parkinson's Disease - Volume 8, issue 2

Authors: Curry, Daniel W. | Stutz, Bernardo | Andrews, Zane B. | Elsworth, John D.

Article Type: Review Article

Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by the accumulation of intracellular α-synuclein aggregates and the degeneration of nigrostriatal dopaminergic neurons. While no treatment strategy has been proven to slow or halt the progression of the disease, there is mounting evidence from preclinical PD models that activation of 5′-AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. Numerous dietary supplements and pharmaceuticals (e.g., metformin) that increase AMPK activity are available for use in humans, but clinical studies of their effects in PD patients are limited. AMPK is an evolutionarily conserved serine/threonine kinase that is …activated by falling energy levels and functions to restore cellular energy balance. However, in response to certain cellular stressors, AMPK activation may exacerbate neuronal atrophy and cell death. This review describes the regulation and functions of AMPK, evaluates the controversies in the field, and assesses the potential of targeting AMPK signaling as a neuroprotective treatment for PD. Show more

Keywords: 5′-AMP-activated protein kinase, metformin, resveratrol, mitochondria, autophagy, Parkinson’s disease, alpha-synuclein

DOI: 10.3233/JPD-171296

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 161-181, 2018

Authors: Roheger, Mandy | Kalbe, Elke | Liepelt-Scarfone, Inga

Article Type: Review Article

Abstract: Background: Cognitive dysfunction is one of the most prevalent non-motor symptoms in Parkinson’s disease (PD), often experienced as more debilitating for patients and caregivers than motor problems. Therefore, a deeper understanding of the course of cognitive decline and the identification of valid progression markers for Parkinson’s disease dementia (PDD) is essential. Objective: This systematic review summarizes the current state of knowledge on cognitive decline over time by reporting effect sizes of cognitive changes in neuropsychological tests. METHODS: 1368 studies were identified by a PubMed database search and 25 studies by additionally scanning previous literature. After screening …all records, including 69 full-text article reviews, 12 longitudinal studies on the progression of cognitive decline in PD met our criteria (e.g., sample size ≥50 patients). Results: Only a few studies monitored cognitive decline over a longer period (>4 years). Most studies focused on the evaluation of change in global cognitive state by use of the Mini-Mental State Examination, whereas the use of neuropsychological tests was highly heterogenic among studies. Only one study evaluated patients’ cognitive performance in all specified domains (executive function, attention & working memory, memory, language, and visual-spatial function) allowing for diagnosis of cognitive impairment according to consensus guidelines. Medium to strong effect sizes could only be observed in studies with follow-up intervals of four years or longer. Conclusions: The results emphasize the need for the assessment of larger PD cohorts over longer periods of follow-up with a comprehensive neuropsychological battery. Show more

Keywords: Parkinson’s disease, cognition, longitudinal, progression, dementia

DOI: 10.3233/JPD-181306

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 183-193, 2018

Authors: Axelsen, Tobias M. | Woldbye, David P.D.

Article Type: Review Article

Abstract: The current mainstay treatment of Parkinson’s disease (PD) consists of dopamine replacement therapy which, in addition to causing several side effects, does not delay disease progression. The field of gene therapy offers a potential means to improve current therapy. The present review gives an update of the present status of gene therapy for PD. Both non-disease and disease modifying transgenes have been tested for PD gene therapy in animal and human studies. Non-disease modifying treatments targeting dopamine or GABA synthesis have been successful and promising at improving PD symptomatology in randomized clinical studies, but substantial testing remains before these can …be implemented in the standard clinical treatment repertoire. As for disease modifying targets that theoretically offer the possibility of slowing the progression of disease, several neurotrophic factors show encouraging results in preclinical models (e.g., neurturin, GDNF, BDNF, CDNF, VEGF-A). However, so far, clinical trials have only tested neurturin, and, unfortunately, no trial has been able to meet its primary endpoint. Future clinical trials with neurotrophic factors clearly deserve to be conducted, considering the still enticing goal of actually slowing the disease process of PD. As alternative types of gene therapy, opto- and chemogenetics might also find future use in PD treatment and novel genome-editing technology could also potentially be applied as individualized gene therapy for genetic types of PD. Show more

Keywords: Gene therapy, Parkinson’s disease targets, dopamine, GAD, neurotrophic factors, NRTN, CDNF, MANF, BDNF, GDNF, optogenetics, chemogenetics, genome editing

DOI: 10.3233/JPD-181331

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 195-215, 2018

Authors: Katsaiti, Irene | Nixon, John

Article Type: Research Article

Abstract: Background: A qualified consensus suggests that a combination of levodopa with a peripherally acting dopa decarboxylase inhibitor continues to present the gold standard treatment of Parkinson’s disease (PD). However, as the disease progresses the therapeutic window of levodopa becomes narrowed. Pharmacological strategies for motor fluctuations are focused on providing less pulsatile and more continuous dopaminergic stimulation. Peripheral catechol-O -methyltransferase (COMT) inhibition improves the bioavailability of levodopa and results in a prolonged response. Objective: The primary aim of this study was to investigate the efficacy and safety of the two available COMT inhibitors; entacapone and tolcapone and the recently …introduced opicapone. Methods: Electronic databases were systematically searched for original studies published within the last 37 years. In addition, lists of identified studies, reviews and their references were examined. Results: Twelve studies fulfilled the inclusion criteria. 3701 patients with PD were included in this systematic review. Conclusions: Adjuvant treatment of PD patients experiencing motor fluctuations with entacapone resulted in improvement of motor function and was well tolerated. Therefore, entacapone presented an acceptable benefit to risk ratio. Tolcapone appeared to result in a greater therapeutic effect. However, this was not consistent across all motor variables and studies, and thus would not support its use, given the current onerous monitoring that is required. Opicapone was not associated with adverse reactions in a phase III trial but did not present a greater efficacy than entacapone, and thus further studies are required in order to illustrate its cost effectiveness. Show more

Keywords: COMT, neurology, Parkinson’s disease, pharmacotherapy

DOI: 10.3233/JPD-171225

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 217-231, 2018

Authors: Alzahrani, Hamad | Venneri, Annalena

Article Type: Research Article

Abstract: Background: Cognitive impairments are the most common non-motor symptoms in Parkinson’s disease (PD). These symptoms have a negative impact on patients’ quality of life and daily living activities. This review will focus on published articles that investigated the efficacy of cognitive rehabilitation in PD. Objectives: To review the existing literature on the efficacy of cognitive rehabilitation in PD and highlight the most effective form of intervention to prevent cognitive decline. This review will also point out any limitations and provide directions for future research. Methods: Published articles available in the Web of Science and PubMed databases …up to November 2017 were reviewed for possible inclusion. We identified 15 articles that examined the effects of cognitive rehabilitation in PD and met inclusion criteria. Results: The main outcomes of this review indicated that, although previous studies used different cognitive rehabilitation methodologies, all studies reported cognitive improvements on at least one cognitive domain. Additionally, the most frequent cognitive domains showing improvements are executive functions and attention. Conclusion: This review reports the outcomes of studies that examined the effectiveness of cognitive rehabilitation in PD. It also points out the limitations of the studies indicating the limited availability of follow up data on the long-term effects of cognitive interventions. The review also highlights the fact that some of the studies did not include a PD group who did not undergo training. There remains, therefore, a need for longitudinal studies to investigate the potential long term benefits of cognitive training. In addition, future investigations should examine whether any disease characteristics such as disease stage, degree of cognitive impairment and/or the dominant side (right/left) or specific motor symptoms (rigidity/tremor) influence treatment efficacy. Show more

Keywords: Attention, cognitive rehabilitation, cognitive training, executive function

DOI: 10.3233/JPD-171250

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 233-245, 2018

Authors: Athauda, Dilan | Maclagan, Kate | Budnik, Natalia | Zampedri, Luca | Hibbert, Steve | Skene, Simon S. | Chowdhury, Kashfia | Aviles-Olmos, Iciar | Limousin, Patricia | Foltynie, Thomas

Article Type: Research Article

Abstract: Background: Exenatide is a GLP-1 receptor agonist that was recently studied for potential disease-modifying effects in a randomised, placebo-controlled clinical trial in patients with moderate stage Parkinson’s disease, and showed positive effects on the motor severity of the disease which were sustained 12 weeks beyond the period of exenatide exposure. Analysis of pre-defined secondary outcomes revealed no statistically significant differences between patients treated with exenatide in total non-motor symptom burden and overall quality of life measures. Objective: The response of individual non-motor symptoms to an intervention may vary and thus this post hoc analysis was conducted to …explore the possible effects of exenatide compared to placebo on individual non-motor symptoms. Results: Compared to placebo, patients treated with exenatide-once weekly had greater improvements in individual domains assessing mood/depression across all observer-rated outcome measures after 48 weeks including the “mood/apathy” domain of the NMSS, – 3.3 points (95% CI – 6.2, – 0.4), p  = 0.026; the “mood” score (Q1.3+Q1.4 of the MDS-UPDRS Part 1), – 0.3 points (95% CI – 0.6, – 0.1), p  = 0.034; and a trend in the MADRS total score, – 1.7 points (95% CI – 3.6, 0.2), p  = 0.071. In addition, there was an improvement in the “emotional well-being” domain of the PDQ-39 of 5.7 points ((95% CI – 11.3, – 0.1), p  = 0.047 though these improvements were not sustained 12 weeks after exenatide withdrawal. At 48 weeks these changes were of a magnitude that would be subjectively meaningful to patients and were not associated with changes in motor severity or other factors, suggesting exenatide may exert independent effects on mood dysfunction. Conclusions: These exploratory findings will contribute to the design of future trials to confirm the extent of motor and non-motor symptom effects of exenatide in larger cohorts of patients. Show more

Keywords: Parkinson’s disease, exenatide, non-motor symptoms, clinical trial, GLP-1 agonist

DOI: 10.3233/JPD-181329

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 247-258, 2018

Authors: Hogg, Elliot | Athreya, Kishore | Basile, Christina | Tan, Echo E. | Kaminski, Jan | Tagliati, Michele

Article Type: Research Article

Abstract: Background: Reduced glucose tolerance has been long recognized as a potential risk factor for Parkinson’s disease (PD), and increasing scrutiny is currently being placed on insulin resistance (IR) as a pathologic driver of neurodegeneration. However, the prevalence of IR in PD is unknown. Objective: To determine IR prevalence in non-diabetic patients with PD and to correlate IR with other metabolic indicators, motor and non-motor symptoms (NMS) of PD, and quality of life (QoL). Methods: Non-diabetic patients with a diagnosis of PD were identified and tested for fasting insulin, fasting glucose, and HbA1c. Patients were also offered …to take a battery of clinical tests (MoCA, NMSQ, and PDQ-39) and had their PD medications, height, weight, and other demographic features recorded. IR was defined as HOMA-IR≥2.0 and/or HbA1c≥5.7. IR abnormalities were correlated with BMI and demographic features, in addition to motor and NMS. Results: 154 subjects (109 M, 45F, mean age 67.7±10.5) were included in this study. Mean HOMA-IR was 2.3±1.8. Ninety out of 154 (58.4%) subjects had abnormal IR. IR was more frequent in overweight and obese subjects (61.1% and 82.8% respectively) than normal weight subjects (41.5%). Multivariate analysis showed that BMI was the only significant predictor of IR (p  < 0.0001). There was no significant correlation between HOMA-IR and MoCA, PDQ-39, and NMSQ scores. Conclusions: IR is prevalent in PD and it correlates with BMI. A correlation between IR with cognitive and QoL measures cannot be determined on the basis of this sample. Show more

Keywords: Body mass index, cognition, insulin resistance, Parkinson’s disease

DOI: 10.3233/JPD-181305

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 259-265, 2018

Authors: Momin, Sheikh | Mahlknecht, Philipp | Georgiev, Dejan | Foltynie, Thomas | Zrinzo, Ludvic | Hariz, Marwan | Zacharia, Andre | Limousin, Patricia

Article Type: Research Article

Abstract: Background: Whilst changes in the frequency of subthalamic deep brain stimulation (STN-DBS) have been proposed to improve control of tremor or axial motor features in Parkinson’s disease (PD), little is known about the effects of frequency changes on upper limb motor function, particularly bradykinesia. Objective: To investigate the acute effects of various STN-DBS frequencies (40–160 Hz, 40 Hz intervals) on upper limb motor function. Methods: We carried out a randomised, double-blind study on 20 PD patients with chronic STN-DBS using the Simple and Assembly components of the Purdue Pegboard (PP) test and a modified upper limb version of …the UPDRS-III (UL-UPDRS-III). Results: There was no significant effect of frequency on bradykinesia on the Simple PP task or the UL-UPDRS-III. There was an effect of frequency on the Assembly PP score when comparing all frequencies (p  = 0.019) and between 80 Hz and 130 Hz (p  = 0.007), with lower frequencies yielding a better performance. Rigidity and Tremor scores were significantly reduced with higher (>80 Hz) compared to lower (40 Hz) frequencies. Conclusions: Our findings suggest that a wide range of frequencies are efficacious in improving acute upper-limb motor function. Reducing the frequency of stimulation down to 80 Hz is safe and has a similar clinical effect to higher frequencies. Therefore, a wider range of frequencies are available when it comes adjusting patients’ acute settings without the risk of worsening bradykinesia. Show more

Keywords: Bradykinesia, deep brain stimulation, Parkinson’s disease, rigidity, subthalamic nucleus, tremor

DOI: 10.3233/JPD-171150

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 267-271, 2018

Authors: Dayal, Viswas | Grover, Timothy | Limousin, Patricia | Akram, Harith | Cappon, Davide | Candelario, Joseph | Salazar, Maricel | Tripoliti, Elina | Zrinzo, Ludvic | Hyam, Jonathan | Jahanshahi, Marjan | Hariz, Marwan | Foltynie, Thomas

Article Type: Research Article

Abstract: Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for selected Parkinson’s disease (PD) patients, but therapy is often limited by side effects. Previous studies indicate an inverse relationship of the therapeutic window (TW) to pulse width (PW) settings down to 60μs, but there is limited data available on the effect of shorter PWs. Objective: To define the TW of STN-DBS in PD at PW of 30μs (PW30) relative to standard PW settings at 60μs (PW60), and to compare speed of gait and speech intelligibility on the two PW conditions. Methods: Monopolar review data …of 15 consecutive PD patients who had screening of contacts performed at PW60 and PW30 was used to calculate the TW at each contact. We compared the TWs of the most efficacious contact per STN, and a secondary analysis was performed comparing all contacts. Speed of gait with a timed 10 metre walk test, speech intelligibility, and perceptual characteristics of speech were also compared at the efficacy thresholds for PW60 and PW30. Results: The TW was significantly greater at PW30 [3.8±1.6mA] than at PW60 [1.7±1.1mA]. In the secondary analysis, 110 TWs could be calculated and these remained significantly higher at PW30. The timed 10 metre walk at PW30 was faster than at PW60, and perceptual rating scores of speech were significantly improved at PW30. Conclusions: STN-DBS in PD patients using a PW of 30μs significantly increases the TW compared to standard PW settings, and this effect is consistent across all contacts of an electrode. Speed of gait and perceptual speech scores are also improved at 30μs settings. Show more

Keywords: Deep brain stimulation, Parkinson’s disease, subthalamic nucleus, electrical parameters, pulse width, side effects, speech intelligibility, gait

DOI: 10.3233/JPD-171272

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 273-279, 2018

Authors: Ferris, Craig F. | Morrison, Thomas R. | Iriah, Sade | Malmberg, Samantha | Kulkarni, Praveen | Hartner, Jochen C. | Trivedi, Malav

Article Type: Research Article

Abstract: Background: Genetic models of Parkinson’s disease (PD) coupled with advanced imaging techniques can elucidate neurobiological disease progression, and can help identify early biomarkers before clinical signs emerge. PTEN-induced putative kinase 1 (PINK1) helps protect neurons from mitochondrial dysfunction, and a mutation in the associated gene is a risk factor for recessive familial PD. The PINK1 knockout (KO) rat is a novel model for familial PD that has not been neuroradiologically characterized for alterations in brain structure/function, alongside behavior, prior to 4 months of age. Objective: To identify biomarkers of presymptomatic PD in the PINK1 -/- rat at 3 …months using magnetic resonance imaging techniques. Methods: At postnatal weeks 12-13; one month earlier than previously reported signs of motor and cognitive dysfunction, this study combined imaging modalities, including assessment of quantitative anisotropy across 171 individual brain areas using an annotated MRI rat brain atlas to identify sites of gray matter alteration between wild-type and PINK1 -/- rats. Results: The olfactory system, hypothalamus, thalamus, nucleus accumbens, and cerebellum showed differences in anisotropy between experimental groups. Molecular analyses revealed reduced levels of glutathione, ATP, and elevated oxidative stress in the substantia nigra, striatum and deep cerebellar nuclei. Mitochondrial genes encoding proteins in Complex IV, along with mRNA levels associated with mitochondrial function and genes involved in glutathione synthesis were reduced. Differences in brain structure did not align with any cognitive or motor impairment. Conclusions: These data reveal early markers, and highlight novel brain regions involved in the pathology of PD in the PINK1 -/- rat before behavioral dysfunction occurs. Show more

Keywords: PTEN-induced putative kinase 1, diffusion weighted imaging, biomarkers, Parkinson’s disease, quantitative anisotropy, substantia nigra

DOI: 10.3233/JPD-171273

Citation: Journal of Parkinson's Disease, vol. 8, no. 2, pp. 281-301, 2018