ArticleLiterature Review

The spectrum of “off” in Parkinson's disease: What have we learned over 40 years?

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Abstract

The terms "on" and "off" were used by Marsden and his contemporaries over 40 years ago to describe times when Parkinson's disease patients experienced good motor function ("on") and immobility ("off"). Yet there remains no published consensus definition of "off", leading clinicians and patients to develop individualized impressions of "off" determinations. In this paper, we first discuss the evolution of the terminology and understanding of "off" states since Marsden's time, which now include non-motor as well as motor symptoms. We then review pathophysiology and risk factors for the development of "off" states as well as tools to detect the "off" state, before proposing a practical definition of "off" for consideration. A common, practical definition of the "off" state could improve clinical recognition of "off" symptoms and lead to significant benefit for patients.

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... Patients then experience a return of PD symptoms within relatively short periods of time despite their standard levodopa therapy, known as motor fluctuations or OFF periods [4]. OFF periods can also involve non-motor symptoms [5]. OFF periods may occur even with an oral regimen that has been adjusted to optimize its effect [4]. ...
... These two factors lead to response fluctuations through the day, consisting of times when there is good control of symptoms (called ON), and other times when benefit has worn off or not yet kicked in, with reemergence of parkinsonian signs and symptoms (called OFF). The exact reasons for the development of motor fluctuations are not fully elucidated, but it is thought that with the progressive loss of dopamine neurons over time, the ability of remaining neurons to store and release levodopa-derived dopamine over many hours is diminished and the duration of benefit from each levodopa dose shortens [5,6]. In addition, since levodopa is absorbed in the proximal small intestine, worsening gastroparesis may increase the time to absorption of oral levodopa, thereby delaying onset of benefit and increasing variability [7,8]. ...
... It is worth stating, however, that the treatment of non-motor symptoms, many of which fluctuate in concert with OFF periods, remains a largely unmet need in Parkinson's disease and non-motor symptoms constitute an important part of a patient's quality of life. None of the ondemand medications discussed above have been systematically evaluated for these symptoms, but this remains an active area of research [5,52]. ...
Article
Levodopa is the most effective symptomatic treatment for Parkinson’s disease (PD), but a major treatment challenge is that over time, many patients experience periods of return of PD symptoms intermittently through the day, known as OFF periods. OFF periods typically manifest as a return of motor symptoms but can also involve non-motor symptoms and these periods can disrupt good control of symptoms despite optimization of the oral levodopa regimen. OFF periods emerge in large measure due to a shortening of the duration of clinical benefit from oral levodopa, thought to be related to a progressive loss of dopamine neurons and their ability to store and release levodopa-derived dopamine over many hours. The problem is further compounded by impaired absorption of oral levodopa due to gastroparesis and other factors limiting its uptake in the small intestine, including competition for uptake by meals and their protein content. On demand therapies are now available for the treatment of OFF episodes in PD and are administered intermittently, on an as-needed basis, on top of the patient’s maintenance medication regimen. To be useful, an on demand medication should take effect more rapidly and reliably than oral levodopa. Options for on demand therapy for OFF periods have recently increased with the approval of levodopa inhalation powder and sublingual apomorphine as alternatives to the older option of subcutaneous apomorphine injection, each of which avoids the gastrointestinal tract and its potential for absorption delay. On demand therapy is now available for patients experiencing episodic or intermittent need for rapid and reliable onset of benefit. On demand therapy may also provide an alternative to more invasive treatment such as infusion of levodopa/carbidopa intestinal gel and for patients whose OFF episodes are not controlled despite deep brain stimulation.
... These features, with the variable exception of tremor, are typically improved by treatment with levodopa, and in early disease, this beneficial response is wellmaintained by intermittent dosing during waking hours. Over time, however, the duration and reliability of symptomatic benefit declines, leading to waking time being divided into time during which levodopa is providing good benefit, when responsive parkinsonian signs and symptoms are reduced and functional status is improved (ON), and time during which levodopa is not providing good benefit, when parkinsonian signs or symptoms re-emerge and functional status declines (OFF) [2][3][4]. Transitions between ON and OFF states are referred to as motor fluctuations [2,3]. ...
... Over time, however, the duration and reliability of symptomatic benefit declines, leading to waking time being divided into time during which levodopa is providing good benefit, when responsive parkinsonian signs and symptoms are reduced and functional status is improved (ON), and time during which levodopa is not providing good benefit, when parkinsonian signs or symptoms re-emerge and functional status declines (OFF) [2][3][4]. Transitions between ON and OFF states are referred to as motor fluctuations [2,3]. ...
... A "partial ON" occurs when the benefit from a dose of levodopa is less robust than is typical for a given patient. The presence of OFF symptoms in the morning, prior to the first dose of levodopa, is commonly referred to as "early morning akinesia" or "early morning OFF" and is likely related to loss of benefit from the previous day's medication [2,5]. For evaluations in clinical trials, patients may be seen in the so-called practically defined OFF state, in the morning after not having taken Parkinson's disease medications since the evening before, at least 12 h previously. ...
Article
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Levodopa is the most effective medication for the treatment of the motor symptoms of Parkinson’s disease. However, over time, the clinical response to levodopa becomes complicated by a reduction in the duration and reliability of motor improvement (motor fluctuations) and the emergence of involuntary movements (levodopa-induced dyskinesia). Strategies that have been attempted in an effort to delay the development of these motor complications include levodopa sparing and continuous dopaminergic therapy. Once motor complications occur, a wide array of medical treatments is available to maximize motor function through the day while limiting dyskinesia. Here, we review the clinical features, epidemiology, and risk factors for the development of motor complications, as well as strategies for their prevention and medical management.
... Over time, patients taking levodopa may experience motor complications, including motor fluctuations and dyskinesia [3]. Motor fluctuations consist of periods when motor (including bradykinesia) and some nonmotor symptoms improve after a dose of levodopa ("ON"), followed by periods when the dose no longer provides benefit and symptoms recur ("OFF" episodes) [1,4]. Approximately 50% of patients with PD develop "OFF" episodes after 5 years of levodopa treatment and 70% develop "OFF" episodes beyond 9 years [3]. ...
... Morning "OFF" is common throughout the course of PD, with an estimated prevalence of ~60% [5]. Morning "OFF" consists of morning akinesia or bradykinesia after waking and before onset of effect of the first daily levodopa dose [4]. The cause of morning "OFF" may reflect a combination of loss of benefit from the last levodopa dose the night before or delayed onset of the first daily levodopa dose, reflecting delayed gastric emptying and pharmacodynamic effects [4]. ...
... Morning "OFF" consists of morning akinesia or bradykinesia after waking and before onset of effect of the first daily levodopa dose [4]. The cause of morning "OFF" may reflect a combination of loss of benefit from the last levodopa dose the night before or delayed onset of the first daily levodopa dose, reflecting delayed gastric emptying and pharmacodynamic effects [4]. Morning "OFF" episodes cause significant disability, which negatively impact health-related quality of life [6]. ...
Article
Full-text available
Introduction Bradykinesia in Parkinson’s disease is a marker for clinical levodopa responsiveness, with persistent bradykinesia reflecting suboptimal response. We objectively measured prevalence and severity of morning bradykinesia using the Personal KinetiGraph® (PKG®). Methods Retrospective evaluation of a large global database of de-identified PKG assessments from individuals (N=12,840) in routine clinical care in the United States (US; n=3288). Median bradykinesia scores (mBKS) and median dyskinesia scores (mDKS) were calculated using a validated algorithm and previously established targets to evaluate percent time in bradykinesia, levodopa responsiveness, and prevalence and severity (0–5; 5=highest severity) of morning bradykinesia. Results mBKS was above target (≥26) in 65% of all individuals, and mDKS was above target (≥7) in 3%. Elevated percent time in bradykinesia occurred in 79%. Among individuals where levodopa responsiveness could be evaluated (n=1933), 31% had a significant response (≥1.15 postdose decrease in severity). Morning bradykinesia was identified in 85% of individuals with available morning data (1298/1524), and 64% (954/1501) experienced continued bradykinesia after the first daily levodopa dose. Morning bradykinesia was severe (4.0–4.7) in levodopa-responsive individuals regardless of percent time spent in bradykinesia. Conclusion Elevated mBKS was very common in the US. Most individuals taking levodopa had morning bradykinesia that persisted even after the first daily dose, and severity was high, indicating a need for additional treatment options.
... This phenomenon, referred to as "wearing-off, " is experienced eventually by around 70% of PwP. Wearing-off is preceded by a response to levodopa, which can be measured by a levodopa challenge test (Chou et al., 2018). The clinical assessment and classification of these transitions between the levodopa response and the "off " state have been comprehensively reviewed (Chou et al., 2018) and are referred to here as "fluctuations." ...
... Wearing-off is preceded by a response to levodopa, which can be measured by a levodopa challenge test (Chou et al., 2018). The clinical assessment and classification of these transitions between the levodopa response and the "off " state have been comprehensively reviewed (Chou et al., 2018) and are referred to here as "fluctuations." PwP do not always perceive wearing-off as re-emergence of bradykinesia (Stacy, 2010;Matthews et al., 2015) but may experience transitions to non-motor symptomologies (Matthews et al., 2015;Chou et al., 2018) and self-awareness of bradykinesia may be limited in some cases (Maier and Prigatano, 2017). ...
... The clinical assessment and classification of these transitions between the levodopa response and the "off " state have been comprehensively reviewed (Chou et al., 2018) and are referred to here as "fluctuations." PwP do not always perceive wearing-off as re-emergence of bradykinesia (Stacy, 2010;Matthews et al., 2015) but may experience transitions to non-motor symptomologies (Matthews et al., 2015;Chou et al., 2018) and self-awareness of bradykinesia may be limited in some cases (Maier and Prigatano, 2017). Consequently, treating clinicians are frequently unaware of the presence of "wearing-off " (Martinez-Martin and Hernandez, 2012;Erb et al., 2020). ...
Article
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Objectives The aim was to examine the role of sensor measurement in identifying and managing fluctuations in bradykinesia of Parkinson’s Disease.Method Clinical scales and data from wearable sensors obtained before and after optimization of treatment from 107 participants who participated in a previous study was used. Fluctuators were identified by a levodopa response or wearing off in their sensor data and were subdivided according to whether the sensor’s bradykinesia scores were in target range, representing acceptable bradykinesia for part of the dose (Controlled Fluctuator: n = 22) or above target for the whole dose period (Uncontrolled Fluctuator; n = 28). Uncontrolled Non-fluctuators (n = 24) were cases without a levodopa response or wearing-off and sensor bradykinesia scores above target throughout the day (un-controlled). Controlled Non-fluctuators (n = 33) were below target throughout the day (controlled) and used as a reference for good control (MDS-UPDRS III = 33 ± 8.6 and PDQ39 = 28 ± 18).ResultsTreating Fluctuators significantly improved motor and quality of life scores. Converting fluctuators into Controlled Non-fluctuators significantly improved motor, non-motor and quality of life scores and a similar but less significant improvement was obtained by conversion to a Controlled Fluctuator. There was a significantly greater likelihood of achieving these changes when objective measurement was used to guide management.Conclusions The sensor’s classification of fluctuators bore a relation to severity of clinical scores and treatment of fluctuation improved clinical scores. The sensor measurement aided in recognizing and removing fluctuations with treatment and resulted in better clinical scores, presumably by assisting therapeutic decisions.
... Motor fluctuations were defined as predictable wearing OFF, unpredictable ON-OFF fluctuations and sudden OFF periods according to UPDRS part IV (Fahn and Elton, 1987). Concerning motor fluctuations, we interviewed patients using the following definition: 'A generally predictable recurrence of motor or non-motor symptoms that precedes a scheduled dose and usually improves with the next dose of antiparkinsonian medication', as agreed by the 'Wearing OFF working group' in September 2004 (Chou et al., 2018). Dyskinesias were defined as abnormal involuntary movements, including chorea and dystonia, that could occur at peak dose or be diphasic; OFF-related dystonia was not included. ...
... However, this model is not supported by the findings of the present study, which suggest more profound effects of levodopa treatment on Parkinson's disease motor symptoms. We hypothesize a two-step mechanism: an early LDR phase with a rapid onset (within hours) likely promoted by presynaptic mechanisms and a late LDR phase (requiring days to weeks to build-up), which is more probably associated with postsynaptic changes (Zappia et al., 1999;Anderson and Nutt, 2011;Chou et al., 2018). Our data suggest that postsynaptic mechanisms alone would not entirely explain the significant change we found between the natural OFF and the overnight OFF after just a few levodopa doses in untreated patients with advanced disease. ...
Article
Full-text available
The natural pattern of progression of Parkinson's disease is largely unknown because patients are conventionally followed on treatment. As Parkinson's disease progresses, the true magnitude of the long-duration response to levodopa remains unknown, because it can only be estimated indirectly in treated patients. We aimed to describe the natural course of motor symptoms by assessing the natural OFF in consecutive Parkinson's disease patients never exposed to treatment (drug-naïve), and to investigate the effects of daily levodopa on the progression of motor disability in the OFF medication state over a 2-year period. In this prospective naturalistic study in sub-Saharan Africa, 30 Parkinson's disease patients (age at onset 58 ± 14 years, disease duration 7 ± 4 years) began levodopa monotherapy and were prospectively assessed using the Unified Parkinson's disease Rating Scale (UPDRS). Data were collected at baseline, at 1-year and 2-years follow-up. First-ever levodopa intake induced a significant improvement in motor symptoms (natural OFF versus ON state UPDRS-III 41.9 ± 15.9 versus 26.8 ± 15.1, respectively; P < 0.001). At 1-year follow-up, OFF state UPDRS-III score after overnight withdrawal of levodopa was considerably lower than natural OFF (26.5 ± 14.9; P < 0 .001). This effect was not modified by disease duration. At the 2-year follow-up, motor signs after overnight OFF (30.2 ± 14.2) were still 30% milder than natural OFF (P = 0.001). The ON state UPDRS-III at the first-ever levodopa challenge was similar to the overnight OFF score at 1-year follow-up and the two conditions were correlated (r = 0.72, P < 0.001). Compared to the natural progression of motor disability, levodopa treatment resulted in a 31% lower annual decline in UPDRS-III scores in the OFF state (3.33 versus 2.30 points/year) with a lower model's variance explained by disease duration (67% versus 36%). Using the equation regressed on pretreatment data, we predicted the natural OFF at 1-year and 2-year follow-up visits and estimated that the magnitude of the long-duration response to levodopa ranged between 60% and 65% of total motor benefit provided by levodopa, independently of disease duration (P = 0.13). Although levodopa therapy was associated with motor fluctuations, overnight OFF disability during levodopa was invariably less severe than the natural course of the disease, independently of disease duration. The same applies to the yearly decline in UPDRS-III scores in the OFF state. Further research is needed to clarify the mechanisms underlying the long-duration response to levodopa in Parkinson's disease. Understanding the natural course of Parkinson's disease and the long-duration response to levodopa may help to develop therapeutic strategies increasing its magnitude to improve patient quality of life and to better interpret the outcome of randomized clinical trials on disease-modifying therapies that still rely on the overnight OFF to define Parkinson's disease progression.
... Historically, this phenomenon was considered a transition from mobility ("on") to bradykinesia ("off") and referred to as "wearing-off" (4). However treating clinicians are frequently unaware of the presence of "wearing-off", (5,6) because PwP do not always recognise the accompanying symptomatology as re-emergence of bradykinesia (7)(8)(9) and may perceive them as a transitions to nonmotor symptomologies (9)(10)(11). ...
... Diaries require recognition of three states: "off", "on", and "dyskinesia". PwP who can recognise these states vary in the level of bradykinesia that they recognise as transitioning from "off" to "on" (11). Similarly, the level that PwP recognise as the transition to dyskinesia varies from subject to subject. ...
Preprint
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Background Fluctuations in motor function in Parkinson’s Disease (PD) are frequent and cause significant disability. Frequently device assisted therapies are required to treat them. Currently, fluctuations are self-reported through diaries and history yet frequently people with PD do not accurately identify and report fluctuations. As the management of fluctuations and the outcomes of many clinical trials depend on accurately measuring fluctuations a means of objectively measuring time spent with bradykinesia or dyskinesia would be important. The aim of this study was to present a system that uses wearable sensors to measure the percentage of time that bradykinesia or dyskinesia scores are above a target as a means for assessing levels of treatment and fluctuations in PD.Methods Data in a database of 228 people with Parkinson’s Disease and 157 control subjects, who had worn the Parkinsons Kinetigraph ((PKG, Global Kinetics Corporation TM , Australia) and scores from the Unified Parkinsons Disease Rating Scale (UPDRS) and other clinic scales were used. The PKG’s provided score for bradykinesia and dyskinesia every two minutes and these were compared to a previously established target range representing a UPDRS III score of 35. The proportion of these scores above target over the 6days that the PKG was worn were used to derive the percent time in bradykinesia (PTB) and percent time in dyskinesia (PTD). As well, a previously describe algorithm for estimating the amplitude of the levodopa response was used to determine whether a subject was a fluctuator or non-fluctuator. ResultsUsing this approach, a normal range of PTB and PTD based on Control subject was developed. The level of PTB and PTD experienced by people with PD was compared with their levels of fluctuation. There was a correlation (Pearsons ρ=0.4) between UPDRS II scores and PTB: the correlation between Parkinson Disease Questionnaire scores and UPDRS Total scores and PTB and slightly lower. PTB and PTD fell in response to treatment for bradykinesia or dyskinesia (respectively) with greater sensitivity than clinical scales.Conclusions This approach provides an objective assessment of the severity of fluctuations in Parkinsons Disease that could readily easily be used in routine care and in clinical trials.
... Parkinson's disease (PD) is the second most common neurodegenerative disease, following AD, with an age-dependent prevalence of 1-4% [96][97][98]. PD is a sporadic or familial inherited disease with complex symptoms that include resting tremor, bradykine-sia, increasing muscle tension, and postural instability [96,97]. PD is characterized at the molecular level by loss of dopaminergic neurons in the substantia nigra-a region in the midbrain-and accumulation of ubiquitin-and α-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs) [99,100]. ...
... Parkinson's disease (PD) is the second most common neurodegenerative disease, following AD, with an age-dependent prevalence of 1-4% [96][97][98]. PD is a sporadic or familial inherited disease with complex symptoms that include resting tremor, bradykine-sia, increasing muscle tension, and postural instability [96,97]. PD is characterized at the molecular level by loss of dopaminergic neurons in the substantia nigra-a region in the midbrain-and accumulation of ubiquitin-and α-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs) [99,100]. ...
Article
Full-text available
Wnt signaling pathways constitute a group of signal transduction pathways that direct many physiological processes such as development, growth and differentiation. Dysregulation of the pathway is thus associated with many pathological processes, including neurodegenerative diseases, metabolic disorders and cancer. At the same time, alterations are observed in plasma membrane compositions, lipid organizations, and ordered membrane domains in brain and metabolic diseases that are associated with Wnt signaling pathway activation. Here, we discuss the relationship between plasma membrane components, specifically ligands, (co) receptors, and extracellular or membrane-associated modulators, to activate Wnt pathways in several brain and metabolic diseases. Thus, Wnt-receptor complex can be targeted based on the composition and organization of the plasma membrane to develop effective targeted therapy drugs
... Historically, this phenomenon was considered a transition from mobility ("on") to bradykinesia ("off ") and referred to as "wearing-off " [4]. However treating clinicians are frequently unaware of the presence of "wearing-off ", [5,6] because PwP do not always recognise the accompanying symptomatology as re-emergence of bradykinesia [7][8][9] and may perceive them as a transitions to non-motor symptomologies [9][10][11]. Implicitly, "wearing-off " is preceded by a response to levodopa and typically occurs 3-4 h after that response. ...
... Diaries require recognition of three states: "off ", "on", and "dyskinesia". PwP who can recognise these states vary in the level of bradykinesia that they recognise as transitioning from "off " to "on" [11]. Similarly, the level that PwP recognise as the transition to dyskinesia varies from subject to subject. ...
Article
Full-text available
Background Fluctuations in motor function in Parkinson’s Disease (PD) are frequent and cause significant disability. Frequently device assisted therapies are required to treat them. Currently, fluctuations are self-reported through diaries and history yet frequently people with PD do not accurately identify and report fluctuations. As the management of fluctuations and the outcomes of many clinical trials depend on accurately measuring fluctuations a means of objectively measuring time spent with bradykinesia or dyskinesia would be important. The aim of this study was to present a system that uses wearable sensors to measure the percentage of time that bradykinesia or dyskinesia scores are above a target as a means for assessing levels of treatment and fluctuations in PD. Methods Data in a database of 228 people with Parkinson’s Disease and 157 control subjects, who had worn the Parkinson’s Kinetigraph ((PKG, Global Kinetics Corporation™, Australia) and scores from the Unified Parkinson’s Disease Rating Scale (UPDRS) and other clinic scales were used. The PKG’s provided score for bradykinesia and dyskinesia every two minutes and these were compared to a previously established target range representing a UPDRS III score of 35. The proportion of these scores above target over the 6 days that the PKG was worn were used to derive the percent time in bradykinesia (PTB) and percent time in dyskinesia (PTD). As well, a previously describe algorithm for estimating the amplitude of the levodopa response was used to determine whether a subject was a fluctuator or non-fluctuator. Results Using this approach, a normal range of PTB and PTD based on Control subject was developed. The level of PTB and PTD experienced by people with PD was compared with their levels of fluctuation. There was a correlation (Pearson’s ρ = 0.4) between UPDRS II scores and PTB: the correlation between Parkinson Disease Questionnaire scores and UPDRS Total scores and PTB and slightly lower. PTB and PTD fell in response to treatment for bradykinesia or dyskinesia (respectively) with greater sensitivity than clinical scales. Conclusions This approach provides an objective assessment of the severity of fluctuations in Parkinson’s Disease that could be used in in clinical trials and routine care.
... 7,8 While levodopa remains the cornerstone of Parkinson's disease therapy, 1,6,9 its use is limited by the emergence of motor complications, including periods of motor fluctuation, termed OFF episodes, and periods of dyskinesia. [10][11][12] By 5 years, approximately 50% of patients have dyskinesia and/or OFF, and 80-90% have these symptoms by 10 years. 13 Hence, as the neurodegenerative process progresses, the clinical response to levodopa becomes less predictable and more fragmented, with more frequent OFF episodes alternating with periods of ON with dyskinesia (non-troublesome and troublesome), both of which can adversely impact daily activities, health-related quality of life (HRQoL), care partner burden, and can result in additional healthcare costs. ...
... OFF reflects variable gastrointestinal absorption of oral levodopa, short levodopa plasma half-life, striatal denervation with loss of buffering capacity, postsynaptic changes, and non-dopaminergic dysregulation of glutamatergic and adenosinergic pathways. 12 Dyskinesia during ON occurs with suprathreshold plasma levodopa concentrations, serotonergic neuronal release of dopamine, and glutamatergic overactivity. 21 Traditionally, the approach to managing OFF time has been based on increasing the dosage/frequency of levodopa and/or adding adjunctive dopaminergic medication, but these adjustments can cause an increased incidence of dyskinesia. ...
... W ith progression of Parkinson's disease (PD), more than two-thirds of patients develop motor fluctuations, 1 particularly OFF periods, during which medications wear off gradually or abruptly, resulting in the return of parkinsonian features. 2 The severity and unpredictability of OFF time are major drivers of health-related quality of life among people with PD; 3 thus, the recognition and management of OFF symptoms is critical. Despite therapeutic advances over the last half-century, OFF symptoms remain a potentially disabling feature of the illness, 4 with patients relying on novel formulations of levodopa 5 or turning to surgical strategies 6 to address inadequate or unpredictable responses to medical therapy. ...
... By contrast, most literature for clinicians on the management of OFF periods focuses on the pharmacodynamics and pharmacokinetics of levodopa in advanced PD. 2,4,6 This highlights a potential unmet need to develop treatment strategies that address nonmotor triggers of OFF periods, beyond novel formulations of levodopa. In particular, the most commonly reported coping strategy for OFF symptoms was exercise. ...
Article
Purpose: Wearing off of Parkinson’s disease medication is common, but triggers and coping strategies for this transient phenomenon are poorly understood. We aimed to assess the lived experience of OFF periods for people with Parkinson’s disease. Methods: Participants in the longitudinal Fox Insight study who endorsed OFF periods were invited to complete a survey consisting of both multiple-choice and free-text responses. Descriptive statistics were used to summarize multiple-choice responses, and free-text responses were classified into themes through iterative discussion by 3 movement disorders specialists. Results: A total of 2110 participants (52.4% male) completed the survey. Tremor was the most common description of OFF periods (n = 1038, 49.2%), followed by gait changes (n = 535, 25.4%) and rigidity (n = 430, 20.4%). Of 1498 specific triggers for OFF symptoms, the most common was stress (n = 920, 61.4%), followed by anxiety/depression (n = 476, 31.8%) and tiredness/fatigue (n = 351, 23.4%). Common coping strategies (n = 1416 responses) included exercise (n = 678, 47.9%), taking a break (n = 504, 35.6%), and meditation (n = 276, 19.5%). Conclusions: Although OFF periods are common, the individual experiences of OFF vary. This knowledge could be used to develop new counseling strategies for OFF periods in people with Parkinson’s disease.
... Wearing-off, in which motor benefit decreases before the next levodopa dose is due, and delayed-on periods are the most common motor fluctuations, but sudden or unpredictable offperiods can also occur. 19 Levodopa-induced dyskinesia, involuntary choreiform or dystonic movements, typically worst at peak motor benefit, may also cause significant disability. The addition of dopamine agonists, MAOB-I or catechol-O-methyltransferase (COMT) inhibitors to a levodopa-based regimen have all been shown to reduce off-time and improve on-time, although all may result in more dyskinesia (Table 2). ...
... Non-motor fluctuations are well recognised and some may improve with optimisation of dopaminergic therapies to improve wearingoff. 19 Many non-motor symptoms have a non-dopaminergic or extra-nigral origin. Table 3 summarises the evidence base for management of some common non-motor symptoms, based on recent published guidance. ...
Article
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Parkinson's disease (PD) is diagnosed where bradykinesia occurs together with rigidity or tremor, in the presence of supporting features. The diagnosis is clinical, and attention should be paid to exclusion criteria indicating an alternative diagnosis and to 'red flag' features. There is no cure or disease-modifying treatment for PD, and the rate of progression is variable. The most effective symptomatic treatment remains levodopa, which has superior benefits for quality of life in early PD compared to other therapies. Motor fluctuations and dyskinesia later in the disease course can be improved with adjunctive treatments. Around 10% of patients per year with refractory motor fluctuations may be eligible for advanced therapies, including deep-brain stimulation surgery. There is emerging evidence for the management of non-motor symptoms in PD, and the importance of multidisciplinary care. In this article, the evidence base for optimal diagnosis and management of PD is discussed.
... The abrupt transitions between aberrant and baseline reach kinematics are reminiscent of "on/off" motor fluctuations observed in people with PD. With disease progression and prolonged treatment, patients often display sudden transitions between severe bradykinesia, good motor control, and levodopa-induced dyskinesias (Chou et al., 2018). Disease duration, degree of dopamine loss, and magnitude of treatment-related dopamine fluctuations are correlated (Abercrombie et al., 1990, de la Fuente-Fernández et al., 2004. ...
Thesis
Dexterous motor skills are essential for normal, everyday functioning but are impaired in many neurological disorders (e.g., Parkinson Disease, dystonia) or other central nervous system pathologies (e.g., stroke, tumor). Therefore, understanding the neural mechanisms that underlie dexterous skills is essential for developing effective therapies for these conditions, as well as for advancing fundamental models of motor control. The rodent skilled reaching task is commonly used to study dexterous motor skill learning and performance, as rodent reach-to-grasp movements are strikingly similar to those of humans. Until recently, implementing the skilled reaching task required significant time and effort, and analyses were limited to simple outcome measures (e.g., success rate) or required time-intensive and subjective manual analysis of skilled reaching videos. These limitations prevented detailed analysis of how neural circuits regulate dexterous skill learning and performance. I used a novel automated skilled reaching task combined with machine learning methods for markerless position tracking to extract detailed forelimb and digit kinematics as rats learned skilled reaching. I found that improvements in fine digit kinematics evolved over a longer timescale than improvements in gross forelimb kinematics. However, the improvements in fine digit kinematics continued even after success rate stabilized, suggesting that aspects of motor control that do not optimize task outcome are refined in skilled reaching. I also found that even after rats had achieved stable success rates, significant variability in reach-to-grasp movements still remained. Brain dopamine is essential for normal motor function as evidenced by its role in Parkinson Disease and other movement disorders. To determine the role of dopamine in skilled reaching performance, I optogenetically stimulated or inhibited substantia nigra pars compacta dopamine neurons as rats performed reach-to-grasp movements. I found that gross forelimb kinematics and coordination between gross and fine movements gradually changed with repeated manipulations. However, once aberrant kinematics were established, rats transitioned rapidly between baseline and aberrant kinematics in a dopamine-dependent manner. Together, these results suggest history-dependent effects of precisely-timed dopamine signals on dexterous motor skill performance, distinct from simple reinforcement learning or ‘vigor’ models of dopamine. This work establishes a paradigm for dissecting the neural circuitry that underlies dexterous motor skills, and highlights the importance of robust quantifiable measurements of movement kinematics. The characterization of how fine and gross motor control evolve as skilled reaching is learned provides a foundation for interpreting studies applying neural circuit manipulations during skilled reaching. Finally, our findings of the effects of dopamine manipulations on skilled reaching kinematics generated new hypotheses regarding dopaminergic control of coordinated movements and the pathophysiology of parkinsonism.
... The abrupt transitions between aberrant and baseline reach kinematics are reminiscent of 'on/off' motor fluctuations observed in people with PD. With disease progression and prolonged treatment, patients often display sudden transitions between severe bradykinesia, good motor control, and levodopa-induced dyskinesias (Chou et al., 2018). Disease duration, degree of dopamine loss, and magnitude of treatment-related dopamine fluctuations are correlated (Abercrombie et al., 1990;de la Fuente-Fernández et al., 2004). ...
Article
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Brain dopamine is critical for normal motor control, as evidenced by its importance in Parkinson Disease and related disorders. Current hypotheses are that dopamine influences motor control by ‘invigorating’ movements and regulating motor learning. Most evidence for these aspects of dopamine function comes from simple tasks (e.g. lever pressing). Therefore, the influence of dopamine on motor skills requiring multi-joint coordination is unknown. To determine the effects of precisely timed dopamine manipulations on the performance of a complex, finely coordinated dexterous skill, we optogenetically stimulated or inhibited midbrain dopamine neurons as rats performed a skilled reaching task. We found that reach kinematics and coordination between gross and fine movements progressively changed with repeated manipulations. However, once established, rats transitioned abruptly between aberrant and baseline reach kinematics in a dopamine-dependent manner. These results suggest that precisely timed dopamine signals have immediate and long-term influences on motor skill performance, distinct from simply ‘invigorating’ movement.
... In contrast, an "ON" episode is when a patient responds to medication and has good mobility and motor function. 1,6 Although treatment with dopamine agonists or other adjunctive therapies (eg, on-extenders) may decrease daily "OFF" time by 0.6 to 2.2 h, patients with PD still experience substantial "OFF" time despite optimized treatments. [7][8][9][10][11][12][13][14][15] Moreover, "OFF" episodes may have a significant negative impact on patient quality of life 16 and can make self-administration of treatment challenging, highlighting the need for on-demand treatments that can rapidly convert patients from "OFF" to FULL "ON" in a manner that can be managed by patients while experiencing symptoms. ...
Article
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Introduction: Several on-demand treatments are available for management of "OFF" episodes in patients with Parkinson's disease (PD). We evaluated patients' preferences for features of theoretical on-demand treatment options. Methods: In a discrete choice experiment, US adults with self-reported PD of ≥5 years, or <5 years with "OFF" episodes, taking oral carbidopa/levodopa, selected between pairs of theoretical on-demand treatments that varied by mode of administration (with and without mode-specific adverse events [AEs]), time to FULL "ON," duration of "ON," and out-of-pocket cost for a 30-day supply. Data were analyzed with a random parameters logit model; results were used to calculate relative importance of treatment attributes, preference shares, and willingness to pay. Results: Among 300 respondents, 98% had "OFF" episodes. Across the range of attribute levels included in the survey, avoiding $90 cost was most important to respondents, followed by a preferable mode of administration with associated AEs and decreasing time to FULL "ON." Duration of "ON" was relatively less important. On average, respondents preferred a theoretical dissolvable sublingual film versus other theoretical treatments with alternative modes of administration. Respondents were willing to pay $28-$52 US dollars to switch from least- to more-preferred mode of administration with associated AEs, $58 to reach FULL "ON" in 15 versus 60 min, and $9 to increase duration of FULL "ON" from 1 to 2 h. Conclusion: Respondents with PD valued lower out-of-pocket cost and a sublingual mode of administration with its associated AEs when choosing an on-demand treatment for "OFF" episodes.
... The EMG data were analyzed using the TRAS system (21). All tests were performed during the patients' "off " state (22). Resting and postural tremor frequency, tremor amplitude, and systolic patterns were recorded. ...
Article
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Background and Objective: Parkinson's disease developed from essential tremor (ET-PD) is a distinct clinical syndrome that is different from essential tremor (ET) and Parkinson's disease (PD). There is currently a lack of research on ET-PD. Tremor characteristics (amplitude and frequency) are primary quantitative indexes for diagnosing and monitoring of tremors. In this study, we aimed to explore specific clinical and electrophysiological biomarkers for the identification of ET-PD. Methods: The study included patients with ET-PD (n = 22), ET (n = 42), and tremor-dominant PD (t-PD, n = 47). We collected demographic data, clinical characteristics (including motor and non-motor symptoms), and tremor analysis. The frequency, amplitude, contracting patterns of resting tremor and postural tremor were collected. The analysis of ET-PD and ET/t-PD was compared. The receiver operating characteristic (ROC) curve was used to analyze the electrophysiological features in distinguishing ET-PD from ET or t-PD. Results: Compared with ET, hyposmia, bradykinesia, rigidity, postural abnormality, and resting tremor were more common in the ET-PD group (P = 0.01, 0.003, 0.001, 0.001, 0.019, respectively). The postural tremor frequencies of the head, upper limbs, and lower limbs were significantly lower in the ET-PD than in the ET (P = 0.007, 0.003, 0.035, respectively), which were the most appropriate variables for distinguishing ET-PD from ET (AUC: 0.775, 0.727, and 0.701, respectively). Compared with t-PD, bradykinesia, rigidity, postural abnormality (both P < 0.001), and resting tremor (P = 0.024) were less common in the ET-PD. The postural tremor amplitudes of the head and upper limbs were significantly higher in the ET-PD than in the t-PD (P = 0.022, 0.001, respectively), which were the most appropriate variables for distinguishing ET-PD from t-PD (AUC: 0.793 and 0.716). Conclusions: Hyposmia and electrophysiological biomarkers (postural tremor frequencies and amplitudes) help early recognition of ET-PD. © Copyright © 2020 Wang, Cao, Liu, Liu, Jiang, Ma, Wang, Yang, Chen and Feng.
... The mainstay of treatment for PD is oral carbidopa/levodopa (CD/LD) to replenish striatal dopamine levels [4]; however, 70% of patients develop motor fluctuations after 9 years of CD/LD treatment [5] that are characterized by episodes of suboptimal response to medication, resulting in the reappearance or worsening of their symptoms (''OFF'' episodes) [1]. Different types of ''OFF'' episodes can occur, including upon awakening (morning ''OFF'' or morning akinesia), at the end of a CD/LD dose (wearing ''OFF''), with delay in onset of effect from a CD/LD dose (delayed ''ON''), with failure of a CD/LD dose (suboptimal ''ON,'' dose failure), and unexpectedly, without an apparent dose relationship (unpredictable ''OFF'') [1,6]. ...
Article
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IntroductionIn a pivotal study, apomorphine sublingual film (APL; KYNMOBI®) was an effective and generally well-tolerated on-demand treatment of “OFF” episodes in patients with Parkinson’s disease (PD), approved across the dose range of 10–30 mg. Pharmacokinetics and comparative bioavailability of APL and two subcutaneous (SC) apomorphine formulations (SC-APO [APOKYN®] and SC-APO-GO [APO-go® PEN]) were evaluated in a randomized, three-way crossover, open-label study (NCT03292016).Methods Patients with PD and “OFF” episodes received an open-label randomized sequence of single doses of SC-APO and SC-APO-GO at the currently prescribed dose (2/3/4/5 mg) and APL doses with similar plasma exposure (15/20/25/30 mg) with ≥ 1-day washout between formulations. Plasma pharmacokinetics of apomorphine and apomorphine sulfate (major inactive metabolite) were measured 0–6 h postdose.ResultsMedian time to maximum plasma concentration (tmax) of apomorphine was 0.63–0.75 h for APL and 0.25–0.38 h for SC-APO and SC-APO-GO. Geometric mean maximum plasma concentration (Cmax) of apomorphine was 4.31–11.2 ng/ml across APL doses and was generally lower compared with SC apomorphine formulations within dose groups. Area under the concentration-time curve from time 0 to infinity (AUC∞) was similar across apomorphine formulations within most dose groups. Relative bioavailability of APL was ~ 17% of SC apomorphine by AUC∞; SC-APO and SC-APO-GO had similar bioavailability (98% and 83% by AUC∞ and Cmax, respectively). Apomorphine sulfate exposure was ~ three-fold higher for APL versus SC-APO and SC-APO-GO by AUC∞ and Cmax.Conclusion In patients with PD and “OFF” episodes, APL demonstrated lower Cmax and relative bioavailability but similar exposures (AUCs) versus SC apomorphine within the approved dose range.Trial RegistrationClinicalTrials.gov, NCT03292016.
... By definition, motor fluctuation is a phenomenon characterized by the worsening or reappearance of motor symptoms resulting in an "off" state, usually related to low levodopa serum levels [141]. Based on clinic-pharmacological observations, different patterns of levodopa-related motor fluctuations have been described as wearing-off (which is the most common), delayed-ON, no-ON, random ON-OFF [142]. LIDs include different hyperkinetic involuntary movements (most commonly chorea and dystonia), which occur most frequently when levodopa level is high in the plasma. ...
Article
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Parkinson’s disease (PD) is a neurodegenerative disease caused by loss of dopaminergic neurons in the midbrain. PD is clinically characterized by a variety of motor and nonmotor symptoms, and treatment relies on dopaminergic replacement. Beyond a common pathological hallmark, PD patients may present differences in both clinical progression and response to drug therapy that are partly affected by genetic factors. Despite extensive knowledge on genetic variability of dopaminergic receptors (DR), few studies have addressed their relevance as possible influencers of clinical heterogeneity in PD patients. In this review, we summarized available evidence regarding the role of genetic polymorphisms in DR as possible determinants of PD development, progression and treatment response. Moreover, we examined the role of DR in the modulation of peripheral immunity, in light of the emerging role of the peripheral immune system in PD pathophysiology. A better understanding of all these aspects represents an important step towards the development of precise and personalized disease-modifying therapies for PD.
... Motor fluctuations consist of periods when symptoms improve as a result of the beneficial effect of a carbidopa/levodopa dose ("ON") and periods when symptoms reemerge or worsen ("OFF" episodes) [25]. Motor fluctuations have been reported to occur in 38 to 50% of patients with PD within 2 years of initiating carbidopa/levodopa [26][27][28][29] and in nearly 100% of patients after 10 years of carbidopa/levodopa treatment [30]. In a survey conducted by the Michael J. Fox Foundation for Parkinson's Research,~65% of respondents reported spending at least 2 h of their day in "OFF" time and > 20% reported 4 h or more of "OFF" time [31]. ...
Article
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Background Many patients with Parkinson’s disease (PD) who receive carbidopa/levodopa experience symptom reemergence or worsening, or “OFF” episodes. This study assessed the association of “OFF” episodes with health-related quality of life (HRQoL). Methods US-specific data from the 2017 and 2019 Adelphi Real World Disease Specific Programme for PD, a real-world cross-sectional survey, were used. Neurologists provided data for 10–12 consecutive patients with PD who completed the 39-item Parkinson’s Disease Questionnaire (PDQ-39) and the EuroQol 5-Dimension (EQ-5D). Data were grouped by patients who experienced “OFF” episodes versus those who did not and by average hours of daily “OFF” time. Differences between patient groups were assessed for demographics and clinical characteristics; regression analyses were used to model the relationship between HRQoL and “OFF” episodes with age, sex, body mass index, current PD stage on the Hoehn and Yahr scale, and number of concomitant conditions related and unrelated to mobility as covariates. Results Data from 722 patients were analyzed. Overall, 321 patients (44%) had “OFF” episodes (mean of 2.9 h of daily “OFF” time). Patients who experienced “OFF” episodes were less likely to work full-time and more likely to live with family members other than their spouse/partner or reside in a long-term care facility than those without “OFF” episodes. The presence of “OFF” episodes, regardless of the average hours of daily “OFF” time, was significantly associated with high scores (reflecting poor HRQoL) on most PDQ-39 dimensions and the summary index and low scores (reflecting poor health status) on the EQ-5D health utility index, visual analog scale (VAS), and all dimensions. Furthermore, increased average hours of daily “OFF” time was significantly correlated with higher scores for all PDQ-39 dimensions and the summary index, as well as with the EQ-5D health utility index and VAS scores. Patients with “OFF” episodes experienced reduced HRQoL even after correcting for potentially confounding variables. Conclusions This study demonstrated that the occurrence of “OFF” episodes in patients with PD is associated with reduced HRQoL and that the impact on HRQoL increased incrementally with increasing average hours of daily “OFF” time.
... Generally, the initial clinical complication is a predictable end-of-dose deterioration in therapeutic benefit, commonly termed as wearing-off and characterized by a wide range of motor (MS) and non-motor symptoms (NMS) [6]. At present, extensive studies have documented the epidemiology, prediction, and management of daytime wearing-off [6][7][8][9][10][11][12][13]. By contrast, far less information can be obtained regarding this issue for early morning period as yet, among which early morning akinesia received relatively more attention [14][15][16][17][18][19][20][21]. ...
Article
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Background: Early morning off (EMO) is a common feature of Parkinson's disease (PD). This study aimed to characterize its clinical features and develop a convenient and pragmatic self-assessment instrument in a Chinese nationwide population. Methods: This study was conducted on 942 PD patients admitted to 55 clinic centers for movement disorders between June 2018 and May 2019 in China. Stepwise logistic regression analyses were performed to determine potential risk factors and the most predictive symptoms of EMO, as well as whether EMO was an independent risk factor of functional dependency in daily life. Based on this, a 7-question scale was derived for EMO screening. Diagnostic accuracy of this scale was assessed from the area under the receiver operative characteristic curve (AUROC) and its 95% confidence intervals (CIs). We further calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the optimal cutoff point. Results: EMO occurred in 49.2% of PD patients across all disease stages. We identified 7 symptoms most predictive of EMO, including bradykinesia or rigidity, excessive sweating or salivation, difficulty in turning on or getting out of bed, muscle cramp, fatigue or sleepiness, frozen state or freezing gait, and tremor. The resulting 7-item scale was confirmed to be of good discrimination with a relatively large AUROC of 0.83, a relatively high sensitivity of 75.7%, specificity of 77.5%, PPV of 76.5%, and NPV of 76.7%. Nonideal nighttime sleep, long PD duration, advanced H&Y stages, posture instability gait difficulty-dominant or mixed subtypes, and high levodopa dose were independently associated with increased risk of EMO. EMO patients were at 87% higher (OR = 1.87, 95%CI: 1.07-3.32) risk of experiencing functional dependency in daily living compared with their counterparts. Conclusions: We demonstrated that EMO is a common feature for PD patients across all disease stages and put forward an EMO-specific screening card of sufficient accuracy and brevity. Meanwhile we have thrown some light upon potential determinants and negative health effects of EMO. Our findings may exert great impact on improving the awareness, recognition and management of EMO in PD patients.
... It is well known that symptom severity in people with PD can fluctuate and can differ among limbs 3,7 . It has been suggested that a minimum of one wearable sensor per limb is required in order to obtain limb-specific symptom severity scores 16 . ...
Article
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Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms. Dyskinesia and motor fluctuations are complications of PD medications. An objective measure of on/off time with/without dyskinesia has been sought for some time because it would facilitate the titration of medications. The objective of the dataset herein presented is to assess if wearable sensor data can be used to generate accurate estimates of limb-specific symptom severity. Nineteen subjects with PD experiencing motor fluctuations were asked to wear a total of five wearable sensors on both forearms and shanks, as well as on the lower back. Accelerometer data was collected for four days, including two laboratory visits lasting 3 to 4 hours each while the remainder of the time was spent at home and in the community. During the laboratory visits, subjects performed a battery of motor tasks while clinicians rated limb-specific symptom severity. At home, subjects were instructed to use a smartphone app that guided the periodic performance of a set of motor tasks.
... However, neurologists still frequently fail to recognize "off" phenomena. 20 The 2013 study by Baek et al. 11 reviewing compliance with quality measure recommendations noted a 23.5% provider compliance rate for this measure. In a tertiary movement disorders clinic, the compliance rate for this measure was better (77%) but still leaves room for improvement. ...
... WO is recognised through history provided by the PwP to the assessing clinician. This interchange can be improved using self-rated questionnaires/diaries [15][16][17] and a structured interview by an experienced clinician [18] that aids the PwP in reporting motor [19][20][21] and non-motor transitions [21][22][23] from "on" to "off". Nevertheless, it is likely that 25% of WO remains undetected [24] with 30-50% of non-demented PD patients having impaired self-awareness of their motor complications [25]. ...
Article
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Background: Development of "Wearing Off" (WO) of motor and non-motor function in Parkinson's disease (PD) adversely affects quality of life. This suggest that identifying and treating WO is important. However, identification of WO depends on people with PD (PwP) recognising and reporting WO and there is a perception that WO may be significantly underestimated. Objective: We investigate the feasibility of identifying "Wearing Off" using objective measurement and assess the clinical benefit in rectifying it. Method: In this study, 200 PwP were studied for evidence of WO using a continuously worn wearable system. Eighty-five patients (43%) were found to have WO and treatment was changed to mitigate the effects of WO. Results: Factors, such as duration of disease, high baseline MDS-UPDRS (motor component), high Percent Time in Bradykinesia (PTB), high Levodopa Equivalent Daily Dose (LEDD), frequent Levodopa doses and younger age of onset, are associated with severity of motor complications. Patients with more severe WO experienced worse motor and non-motor symptoms and lower quality of life. Quality of life significantly improved in PwP when WO was treated. Conclusion: The findings reported in this study provide evidence that identifying and treating WO improves outcomes of PwP and that objective measurements may help clinicians to identify and treat WO.
... PD is an intrinsically fluctuating disorder. As the disease progresses, patients describe symptomatic daily variations [94], commonly attributed to the administration timing of anti-parkinsonian drugs. Patients suffer from disabling off periods, as the dopaminergic drugs fade away, or, conversely, troublesome dyskinesias arise in synchrony to peak levels of these same drugs [95]. ...
Article
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Increasing evidence suggests a role for circadian dysregulation in prompting disease-related phenotypes in mammals. Cancer and neurodegenerative disorders are two aging related diseases reported to be associated with circadian disruption. In this study, we investigated a possible effect of circadian disruption in Parkinson’s disease (PD) and colorectal cancer (CRC). We used high-throughput data sets retrieved from whole blood of idiopathic PD (IPD) patients and time course data sets derived from an in vitro model of CRC including the wildtype and three core-clock knockout (KO) cell lines. Several gene expression alterations in IPD patients resembled the expression profiles in the core-clock KO cells. These include expression changes in DBP, GBA, TEF, SNCA, SERPINA1 and TGFB1. Notably, our results pointed to alterations in the core-clock network in IPD patients when compared to healthy controls and revealed variations in the expression profile of PD-associated genes (e.g., HRAS and GBA) upon disruption of the core-clock genes. Our study characterizes changes at the transcriptomic level following circadian clock disruption on common cellular pathways associated with cancer and neurodegeneration (e.g., immune system, energy metabolism and RNA processing), and it points to a significant influence on the overall survival of colon cancer patients for several genes resulting from our analysis (e.g., TUBB6, PAK6, SLC11A1).
... The recording of EEG data and NIBS application during the ON medication may decrease inter-and intra-individual variability. During the OFFmedication motor and/or non-motor PD symptoms appear or are worsened, which are improved after the next dose of levodopa (43). Moreover, studies have shown marked differences in EEG comparing ON and OFF medication in spectral power, coherence, and phase-amplitude coupling (13,(44)(45)(46). ...
Article
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Parkinson’s Disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms, aside from alterations in the electroencephalogram (EEG) already registered. Non-invasive brain stimulation (NIBS) techniques have been suggested as an alternative rehabilitative therapy, but the neurophysiological changes associated with these techniques are still unclear. We aimed to identify the nature and extent of research evidence on the effects of NIBS techniques in the cortical activity measured by EEG in patients with PD. A systematic scoping review was configured by gathering evidence on the following bases: PubMed (MEDLINE), PsycINFO, ScienceDirect, Web of Science, and CINAHL. We included clinical trials with patients with PD treated with NIBS and evaluated by EEG pre-intervention and post-intervention. We use the criteria of Downs and Black to evaluate the quality of the studies. Repetitive transcranial magnetic stimulation, transcranial electrical stimulation, electrical vestibular stimulation, and binaural beats are non-invasive stimulation techniques used to treat cognitive and motor impairment in PD. This systematic scoping review found that the current evidence is suggestive that NIBS could change quantitative EEG in patients with PD. However, considering that the studies’ quality varied from poor to excellent, the low number of studies, variability in NIBS intervention, and quantitative EEG measures, we are not yet able to use the EEG outcomes to predict the cognitive and motor treatment response after brain stimulation. Based on our findings we recommend additional research efforts to validate EEG as a biomarker in noninvasive brain stimulation trials in PD.
... e presence of motor fluctuations included wearing-off (WO) and on-off phenomenon; WO was defined as "the generally predictable recurrence of motor and nonmotor symptoms before the scheduled doses of antiparkinsonian medication and improvements after next doses [9][10][11]." "On-off phenomenon" is characterized by ongoing predictable or unpredictable switching from being "on" with mobile with dyskinesia to being "off" and immobile during the course of a day [12]. Dyskinesia was defined as an involuntary, purposeless, predominantly choreic movement involving the muscles of the limbs, neck, trunk, or rarely face during the "on" period of PD patients [2]. ...
Article
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Objective: Motor complications are common in Parkinson's disease (PD). The reported occurrence of motor complications varies across regions and races. The aim of our study was to describe the development of dyskinesias and motor fluctuations among Chinese PD patients and the relative risk factors. Methods: In the current cross-sectional survey study, PD patients with motor fluctuations and dyskinesia were enrolled from March to November 2018 in Shaanxi province, a northwest area of China. Data were collected by the movement disorder specialists. A self-designed questionnaire was utilized during face-to-face interviews. In addition, the relevant factors of motor complications were analyzed by univariable and multivariable analyses. Results: Of the166 PD patients recruited, 52 (31.33%) and 25 (15.06%) patients had motor fluctuations and dyskinesia, respectively, which occurred in 6.76 ± 3.77 and 8.61 ± 4.46 years after the onset of motor symptoms and 5.37 ± 3.33 and 6.80 ± 3.43 years after the treatment of levodopa therapy, respectively. Patients with motor fluctuations and dyskinesias had longer disease duration, younger onset age, higher Hoehn-Yahr stages and UPDRS III scores, higher daily levodopa dosage and levodopa equivalent daily dose (LEDD), and longer duration of levodopa treatment (P < 0.05). Bradykinesia-rigidity dominant patients had higher incidences of motor fluctuations (61.54% vs 38.46%) and dyskinesias (68.00% vs 32.00%) than tremor-dominant patients (P < 0.05). Results of the multivariate logistic regression analyses showed that the duration of levodopa therapy, age of the onset, and bradykinesia-rigidity dominant type were independent risk factors of motor fluctuations (P < 0.05). In addition, duration of disease and bradykinesia-rigidity dominant type were independent risk factors of dyskinesia (P < 0.05). Conclusions: The rate of motor fluctuations was higher than dyskinesias in Chinese patients with Parkinson's disease. Patients with younger age onset, bradykinesia-rigidity dominant type, longer disease duration, and longer duration of levodopa therapy are more likely to develop motor complications.
... These often arise from a combination of factors including gastrointestinal dysmotility, the short half-life of orally administered immediate-release (IR) levodopa, and progressive striatal denervation with loss of buffering capacity and pulsatile stimulation of postsynaptic receptors [2][3][4]. This can result in disruptive troublesome dyskinesia that can emerge when levodopa levels are higher (peak-dose dyskinesia) [5,6]. Troublesome dyskinesia can also emerge at the beginning and end of a levodopa dose with lower levodopa levels (diphasic dyskinesias). ...
Article
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Introduction: A clinical trial in advanced Parkinson's disease (APD) has established the superiority of carbidopa/levodopa enteral suspension (CLES) in reducing total patient "off" time (OFF) and increasing total "on" time without troublesome dyskinesia (ON-woTD) over orally administered immediate-release carbidopa/levodopa tablets (IR-CL). However, temporal patterns of these improvements throughout the waking day have not been examined. In this analysis, time to ON-woTD after waking and patterns of motor-symptom control throughout the waking day were compared between CLES and IR-CL. Methods: Post hoc analyses of APD patient-diary data from the phase 3 randomized controlled trial were used to compare changes in time to ON-woTD after waking, motor-symptom control throughout the waking day, occurrence of extreme fluctuations between OFF and "on" with troublesome dyskinesia, and motor-state transitions with CLES versus IR-CL from baseline to week 12. Results: The sample included 33 CLES-treated and 30 IR-CL-treated patients. Among the CLES group, the percentage of patient days achieving ON-woTD within 30 min of waking was three times higher at week 12 versus baseline (33% vs. 11%, p = 0.0043); no significant change occurred with IR-CL. When the waking day was divided into four 4-h periods, CLES versus IR-CL treatment produced significantly greater reductions in OFF during three periods, and two periods had increased ON-woTD. Fewer CLES-treated patients had extreme fluctuations at week 12 (3% vs. 23%, p = 0.0224) compared to IR-CL-treated patients. From baseline to week 12, CLES-treated patients had greater reductions in the average number of motor-state transitions compared to IR-CL-treated patients (- 1.6, p = 0.0295). Conclusion: CLES-treated patients experienced a more rapid onset of ON-woTD after waking and greater consistency of ON-woTD throughout their waking day than IR-CL-treated patients.
... The decrease in efficacy of levodopa is attributed mainly to the continuous loss of DA cells, presenting an unmet medical need with no approved drug therapy. It requires a disease-modifying approaches that would delay or slow the clinical progression of the disease (reviews [1][2][3]). ...
Article
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Parkinson’s disease (PD) is characterized by a gradual degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpC). Levodopa, the standard PD treatment, provides the missing dopamine in SNpC, but ultimately after a honeymoon with levodopa treatment the neurodegenerative process and the progression of the disease continue. Aimed at prolonging the life of dopaminergic cells, we prepared the levodopa precursors SuperDopa (SD) and SueprDopamide (SDA), in which levodopa is merged with the antioxidant N-acetylcysteine (NAC) into a single molecule. Rotenone is a mitochondrial complex inhibitor often used as experimental model of PD. In vivo, SD and SDA treatment show a significant relief of motor disabilities in rotenone-injected rats. SD and SDA also lower rotenone-induced-α-synuclein (α-syn) expression in human SH-SY5Y cells, and α-syn oligomerization in α-syn-overexpressing-HEK293 cells. In the neuronal SH-SY5Y cells, SD and SDA reverse oxidative stress-induced phosphorylation of cJun-N-terminal kinase (JNK) and p38-mitogen-activated kinase (p38MAPK). Attenuation of the MAPK-inflammatory/apoptotic pathway in SH-SY5Y cells concurrent with protection of rotenone-triggered motor impairment in rats, is a manifestation of the combined antioxidant/anti-inflammatory activity of SD and SDA together with levodopa release. The concept of joined therapies into a single molecule, where levodopa precursors confer antioxidant activity by enabling NAC delivery across the BBB, provides a potential disease-modifying treatment for slowing PD progression.
... The "on" state is when PD patients experience a good motor function. The "off" state is when the symptoms of PD return [62]. ...
Article
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Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease characterized by movement disorders due to the progressive loss of dopaminergic neurons in the ventrolateral region of the substantia nigra pars compacta (SNpc). Apart from the cardinal motor symptoms such as rigidity and bradykinesia, non-motor symptoms including those associated with respiratory dysfunction are of increasing interest. Not only can they impair the patients’ quality of life but they also can cause aspiration pneumonia, which is the leading cause of death among PD patients. This narrative review attempts to summarize the existing literature on respiratory impairments reported in human studies, as well as what is newly known from studies in animal models of the disease. Discussed are not only respiratory muscle dysfunction, apnea, and dyspnea, but also altered central respiratory control, responses to hypercapnia and hypoxia, and how they are affected by the pharmacological treatment of PD.
... In addition to susceptibility to PD, neuroinflammation in the striatum as well as in the substantia nigra pars compacta may play an important role in the development of motor fluctuations in PD via presynaptic and post-synaptic mechanisms. The storage hypothesis for motor fluctuations posits that the loss of presynaptic dopaminergic terminals reduces the capacity for storage of dopamine in the striatum, thereby inhibiting the ability to compensate for oscillations in plasma levodopa levels, and neuroinflammation may contribute to this effect (43). Neuroinflammation and chronic overproduction and abnormal release of TNF-α by microglia may also contribute to the post-synaptic mechanisms of motor fluctuations, which may be associated with complex striatal functional abnormalities in basal ganglia motor circuits (44). ...
Article
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Background: Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by a clinical symptomatology involving both motor and non-motor symptoms. Motor complications associated with long-term dopaminergic treatment include motor fluctuations and levodopa-induced dyskinesia (LID), which may have a major impact on the quality of life. The clinical features and onset time of motor complications in the disease course are heterogeneous, and the etiology remains unknown. Objective: We aimed to identify genomic variants associated with the development of motor fluctuations and LID at 5 years after the onset of PD. Methods: Genomic data were obtained using Affymetrix Axiom KORV1.1 array, including an imputation genome-wide association study (GWAS) grid and other GWAS loci; functional variants of the non-synonymous exome; pharmacogenetic variants; variants in genes involved in absorption, distribution, metabolism, and excretion of drugs; and expression quantitative trait loci in 741 patients with PD. Results: FAM129B single-nucleotide polymorphism (SNP) rs10760490 was nominally associated with the occurrence of motor fluctuations at 5 years after the onset of PD [odds ratio (OR) = 2.9, 95% confidence interval (CI) = 1.8–4.8, P = 6.5 × 10−6]. GALNT14 SNP rs144125291 was significantly associated with the occurrence of LID (OR = 5.5, 95% CI = 2.9–10.3, P = 7.88 × 10−9) and was still significant after Bonferroni correction. Several other genetic variants were associated with the occurrence of motor fluctuations or LID, but the associations were not significant after Bonferroni correction. Conclusion: This study identified new loci associated with the occurrence of motor fluctuations and LID at 5 years after the onset of PD. However, further studies are needed to confirm our findings.
Article
Background The definition of off periods proposed in 2018 emphasizes functional disability as part of the o ff period experience, but limited research to date investigates the functional impact of off periods on persons with Parkinsons and carepartners. This study aimed to investigate the impact of off periods on both persons with Parkinsons and carepartners through interviews of dyads living with motor and/or non-motor fluctuations. Methods Investigators performed interviews separately with persons with Parkinsons and carepartners using a semi-structured questionnaire. Investigators used a qualitative descriptive approach to identify themes in interview transcripts relating to the impact of off periods on daily life. Identified themes were subsequently organized using World Health Organization quality of life domains. Results Twenty persons with Parkinsons and their carepartners (total n=40) participated in interviews. Persons with Parkinsons described impairments in level of independence (e.g. relating to employment, mobility, activities of daily living and medication timing), socialization, leisure activities, driving, physical function, and psychological experiences relating to off periods. Carepartners reported off period impacts on their own independence, socialization, leisure, and psychological experiences. Conclusions Clinicians should query the daily impact of off periods on both persons with Parkinsons and carepartners at clinical visits to inform treatment decisions and counseling. Measures of off period impact should be incorporated into clinical trials targeting fluctuations to fully understand the effects of interventions for fluctuations.
Preprint
Brain dopamine is critical for normal motor control, as evidenced by its importance in Parkinson Disease and related disorders. Current hypotheses are that dopamine influences motor control by 'invigorating' movements and regulating motor learning. Most evidence for these aspects of dopamine function comes from simple tasks (e.g., lever pressing). Therefore, the influence of dopamine on motor skills requiring multi-joint coordination is unknown. To determine the effects of precisely-timed dopamine manipulations on the performance of a complex, finely coordinated dexterous skill, we optogenetically stimulated or inhibited midbrain dopamine neurons as rats performed a skilled reaching task. We found that reach kinematics and coordination between gross and fine movements progressively changed with repeated manipulations. However, once established, rats transitioned abruptly between aberrant and baseline reach kinematics in a dopamine-dependent manner. These results suggest that precisely-timed dopamine signals have immediate and long-term influences on motor skill performance, distinct from simply 'invigorating' movement.
Thesis
La maladie de Parkinson (MP) est la deuxième maladie neurodégénérative la plus fréquente. Parmi les nombreux signes cliniques rapportés par les patients et observés par les médecins, les manifestations respiratoires sont encore très peu étudiées.Premièrement, la dyspnée, signe fonctionnel invalidant et altérant la qualité de vie, semble fréquente dans la MP mais sa prévalence et ses caractéristiques (dimension perceptive et réponse émotionnelle notamment) doivent être précisées. L'objectif de l'étude DYSPARK était de mieux définir le profil des patients dyspnéiques, le retentissement de la plainte respiratoire et de corréler ses caractéristiques avec des éléments cliniques de la MP afin de mieux appréhender sa physiopathologie.Deuxièmement, les anomalies ventilatoires objectives (explorations fonctionnelles respiratoires - EFR) sont encore mal connues dans la MP, de même que leur évolution. Une altération des volumes pulmonaires ou une atteinte de la musculature respiratoire pourraient avoir un retentissement sur le cours évolutif de la maladie. L'objectif de l'analyse d'une sous-population de la cohorte PRODIGY-PARK était de déterminer de façon prospective, sur 5 ans, le cours évolutif des données en EFR et leur impact pronostique potentiel.
Article
Parkinson’s Disease (PD) is a common neurodegenerative disorder and the leading cause of disability. It causes significant morbidity and disability through a plethora of symptoms, including movement disorders, sleep disturbances, and cognitive and psychiatric symptoms. The traditional pathogenesis theory of PD involves the loss of dopaminergic neurons in the substantia nigra (SN). Classically, treatment is pursued with an assortment of medications that are directed at overcoming this deficiency with levodopa being central to most treatment plans. Patients taking levodopa tend to experience “off episodes” with decreasing medication levels, causing large fluctuations in their symptoms. These off episodes are disturbing and a source of morbidity for these patients. Opicapone is a novel, peripherally acting Catechol-O-methyl transferase (COMT) inhibitor that is used as adjunctive therapy to carbidopa/levodopa for treatment and prevention of “off episodes.” It has been approved for use as an adjunct to levodopa since 2016 in Europe and has recently (April 2020) gained FDA approval for use in the USA. By inhibiting COMT, opicapone slows levodopa metabolism and increases its availability. Several clinical studies demonstrated significant improvement in treatment efficacy and reduction in duration of “off episodes.” The main side effect demonstrated was dyskinesia, mostly with the 100mg dose, which is higher than the approved, effective dose of 50mg. Post-marketing surveillance and analysis are required to further elucidate its safety profile and contribute to patient selection. This paper reviews the seminal and latest evidence in the treatment of PD “off episodes” with the novel drug Opicapone, including efficacy, safety, and clinical indications.
Article
Introduction : Levodopa is the most effective drug in the treatment of Parkinson’s disease, but its chronic treatment is linked to the occurrence of motor complications with fluctuations of motor performance and dyskinesia. Unpredictable OFF episodes can be severe and disabling and current rescue medications cannot always be used safely. A rescue therapy characterized by a rapid and predictable ON response and the safety profile of levodopa will represent a major advantage for patients affected from unresponsive OFF episodes. Areas covered : CVT-301 is new inhaled formulation of LD recently developed as a self-administered treatment for OFF periods. Herein, the pharmacodynamic and pharmacokinetic properties, efficacy, and safety of CVT-301 are reviewed. Expert opinion : CVT 301 may offer several potential advantages including increased systemic bioavailability through pulmonary absorption, rapid onset of action, avoidance of first-pass drug metabolism and less plasma level variability. It should be noted that the delivery device used has been described as relatively simple to use, but the few steps required to prepare and self-administer the dose can challenging for PD patients during their OFF state. Additionally, resolution of an OFF episode requires the administration of two capsules of CVT-301, which further complicates the use of the device.
Article
Treatment of Parkinson’s disease (PD) includes the administration of dopaminergic and occasionally non-dopaminergic drugs, in mono- or in combination therapy. One of the key drug used to treat Parkinson’s disease is levodopa considered a gold standard. In addition levodopa can also be used as a challenge test to confirm the accuracy of diagnosis of PD known as the “Levodopa challenge test”. However many non levodopa class of drugs are also used and consist of dopamine agonists (ADRs), MAO-B and COMT inhibitors, as well as drugs working on glutamate such as a group of drug with NMDA receptor inhibitor activity (amantadines). The successful treatment of PD therefore depends on the correct choice of drugs to initiate treatment and sustainance of such therapy. The main parameters for personolised treatment include the patient’s age, severity and pattern of motor deficit, the state of cognitive function and lifestyle. Levodopa, although the most effective, is almost invariably associated with motor fluctuations and dyskinesias. Before prescribing levodopa, in addition to MAO-B inhibitors and ADRs, amantadines can be used as a monotherapy. Once replacement of therapy is required, then it is necessary to use a coefficient to calculate an equivalent dose of levodopa known as the levodopa equivalent dose. Progression of PD is inevitable inspite of adequate symptomatic therapy and at the advanced stage of PD approaches for the management of motor complications of levodopa need to be considered. For motor fluctuations these strategies require a change in the dosage regimen of levodopa (daily dose and frequency of intake), as well as the addition of an adjunct drug – ADRs, MAO-B inhibitor or COMT inhibitor. When dyskinesias arise, the management depends on correct identification of the type of dyskiensias. The commonest type of dyskinesia is peak dose dyskinesias related to peak plasma levodopa levels after intake. Amantadine provides a quick and long-lasting antidyskinetic effect which has been confirmed in open label as well as double-blind placebo-controlled studies. Compared to аmantadine chloride, amantadine sulfate has more stable pharmacokinetic parameters and a better safety profile. In addition, parenteral administration of amantadine sulfate can be utilized for severely ill patients with akinetic crisis in PD. Amantadine also has a broad spectrum effect and these may include improvement of fatigue and apathy. Some data also suggest that the use of amantadine in patients may increase life expectancy, improve survival and reduce the risk of dementia.
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Aims Within 5 years of initiating carbidopa/levodopa, ∼50% of patients with Parkinson’s disease (PD) experience “OFF” episodes; little is known about the cost burden. We investigated the association of “OFF” episodes with patient characteristics, healthcare resource utilization (HCRU), and healthcare costs. Methods Analyses used neurologist-provided data from the US-specific 2017 and 2019 Adelphi Real World Disease Specific Programme for PD, including duration of “OFF” episodes and HCRU for 10–12 consecutive patients. Patients were grouped by presence/absence of “OFF” episodes and by average hours of daily “OFF” time. Between-group differences were assessed for demographics, personal circumstances, and clinical characteristics. Regression analyses modeled the relationship of “OFF” episodes with HCRU and costs. Results Of 1309 patients, 41% experienced “OFF” episodes, 25% of whom were “OFF” ≥4 hours/day. Patients having “OFF” episodes had more severe PD, were diagnosed for longer, and were younger than those without “OFF” (P < 0.0001). “OFF” episodes were associated with a greater number of prescribed PD drugs (P < 0.0001). Patients without “OFF” episodes were more likely to have full-time employment and less likely to be retired or unemployed because of PD (P < 0.001). Patients with and without “OFF” episodes had different living situations (P < 0.001): patients experiencing “OFF” were less likely to live alone and more likely to live in a nursing home and have a professional caregiver (P < 0.001). In the past 12 months, the number of hospitalizations, intensive care admissions, and emergency room visits; nights hospitalized; costs of consultations and hospitalizations; and total direct costs were all higher for patients experiencing “OFF” episodes (P < 0.05). Conclusion Patients with PD and “OFF” episodes had higher HCRU and costs than those without “OFF,” suggesting that “OFF” episodes contribute to the economic burden of PD. Further research is warranted to examine the extent that current PD treatments and treatment patterns impact HCRU and costs.
Article
Advanced Parkinson disease (PD) is associated with treatment-related motor fluctuations and reduced ability to perform activities of daily living. Progression of non-motor symptoms and medication-induced adverse effects complicate focused approach to motor symptom management, frequently accelerating reduced quality of life. It is thus critical for clinicians to consider disease progression versus therapeutic contributions when balancing management decisions. Such an approach requires careful recognition of inflection points resulting from therapeutic decisions and should prompt consideration of reduced pharmacologic burden and increased reliance on non-pharmacologic strategies in advanced disease. The successful approach to advanced PD requires a multidisciplinary effort focused on improving the patient’s and family’s quality of life, sometimes requiring sacrifice of motor symptom benefit. Here, we emphasize management strategies in advanced PD, focusing on the need to balance the therapeutic approach across advancing motor symptoms, progressive non-motor features, and potential pharmacologic adverse effects.
Article
Introduction The most widely used pharmacological treatment for Parkinson’s disease is levodopa, the precursor for dopamine formation in the brain. With time, the effectiveness of levodopa declines, and patients experience motor fluctuations, or OFF periods. A levodopa formulation administered via a capsule-based oral inhaler provides a new delivery mechanism for levodopa that provides rapid relief of OFF periods. Areas covered CVT-301 is a dry powder formulation designed to supply levodopa to the systemic circulation via pulmonary absorption. The technology, pharmacokinetics, efficacy, and safety data of this formulation are presented. Expert opinion Oral inhalation is a novel method of administration for levodopa that bypasses the gastrointestinal tract, allowing levodopa to enter the systemic circulation rapidly and more reliably than oral medications. Gastrointestinal dysfunction, a common feature of Parkinson’s disease, can lead to impaired absorption of oral medications. Pulmonary delivery rapidly elevates levodopa plasma concentrations to provide relief of OFF periods for patients receiving oral levodopa.
Article
Levodopa is the most effective therapy for Parkinson's disease; however, chronic treatment is associated with the development of OFF episodes, in which there is a return of parkinsonian features following a dose of levodopa and prior to the onset of benefit from the subsequent dose. OFF episodes can be a major source of disability for PD patients and frequently result in depression, apathy and an unwillingness to participate in social activities. Most currently available medical and surgical therapies are designed to reduce total daily OFF time but do not provide a rapid and reliable “on‐demand” therapy for individual OFF episodes. Indeed, responses to individual doses of levodopa during an acute OFF episode are unreliable, frequently leading to partial‐ON, delayed‐ON, or no‐ON responses even at different times in the same patient. There are now 3 therapies that are available for the on‐demand treatment of OFF episodes; subcutaneous injection of apomorphine, sublingual apomorphine film, and inhaled levodopa. The first has not enjoyed widespread use in the PD community, whereas the latter 2 therapies have only recently been approved. This review will consider the currently available on‐demand therapies and their potential advantages and disadvantages. © 2021 International Parkinson and Movement Disorder Society
Article
Introduction . Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in the population of older patients. Even though long-term combination therapy helps to cope with the main manifestations of PD. It inevitably leads to the appearance of such side effects as drowsiness, hallucinations, dyskinesia, and many others. [12]. Therefore, the search for effective antiparkinsonian drugs devoid of the above-mentioned adverse reactions remains an urgent task of modern neuropharmacology. The explored substances are derivatives of imidazole-4,5-dicarboxylic acid. These compounds belong to a fundamentally new class of N-methyl-D-aspartate ligands (NMDA) that are not channel blockers. Their pharmacological effect is realized due to interaction with the NMDA receptor recognition site, which, along with high efficiency, allows us to assume their higher safety, compared to previously existing channel blockers from the NMDA ligand group. Objective . Studing of the antiparkinsonian activity of new ligands of the glutamate NMDA-receptor complex-1,2-substituted imidazole-4,5-dicarboxylic acids on an experimental model of arecoline hyperkinesis. Materials and methods . Imidazole-dicarboxylic acid derivatives (IEM2258, IEM2248, IEM2247, and IEM1574) were injected into the lateral ventricles of the mouse brain 10 minutes before arecoline in a volume of 5 µl at doses of 0.1-0.5 µmol, then the latent period, intensity, and duration of tremor were recorded. Amantadine was used as a comparison drug. Results . Preliminary administration of the studied examined substances led to a significant decrease in the intensity and duration of arecoline tremor. The highest inhibitory activity with respect to the intensity and duration of the experimental tremor was demonstrated with the introduction of the compound IEM-2247 (at a dose of 0.1-0.5 mmol, the duration of the latent period of the tremor was 1.7-2.3 times longer than the control one, respectively, the duration of the tremor decreased by 1.5 - 2.5 times). Conclusions . The dose-dependent antiparkinsonian activity of imidazole-dicarboxylic acid derivatives is shown, indicating the prospects for the development of these substances and the further search for effective and safe antiparkinsonian agents among the compounds of this class.
Article
Introduction Apomorphine sublingual film is approved for the “on-demand” treatment of “OFF” episodes in Parkinson's disease (PD). Patients must undergo dose titration to determine their most effective and tolerable dose. We assessed whether higher doses than those that provide an initial “ON” response could yield more effective treatment. Methods Patients with PD were assessed in the “OFF” state and the apomorphine sublingual film dose was titrated to a level that provided a tolerable “ON” response. The dose was then increased by up to two dose levels, if tolerated. A comparison in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III scores was made following administration of the dose that provided the initial “ON” response and following the higher dose. Treatment-emergent adverse events were also reported. Results Thirty-five patients were titrated to higher apomorphine sublingual film doses than those that provided an initial “ON” response. A mean improvement in MDS-UPDRS Part III score was observed compared with the initial dose of 5.6 points (P = 0.034), 4.4 points (P = 0.009), and 3.7 points (P = 0.018) at 30, 60, and 90 min postdose, respectively. Adverse events were mild or moderate and resolved with dose reduction without concomitant treatment. Conclusion Higher doses of apomorphine sublingual film than those initially perceived to provide an “ON” response can be tolerated and provide additional improvement in motor function in many patients.
Article
Background: Aquatic therapy is one therapy option for people living with Parkinson's disease (PD). However, the optimal prescription, dosage, and delivery remain unclear. Objective: i) To generate consensus statements, ii) to establish evidence-based clinical practice aquatic therapy guidelines for PD. Methods: Seventy-three international experts were invited to participate in a 3-step modified Delphi study. Gaps in the aquatic therapy evidence, patient preferences, and stakeholder engagement were considered when developing the initial list of 43-statements identified by the research development group. Practice experts rated each statement on an 11-point Likert scale. Consensus for inclusion was set at a priori of ≥70%of respondents scoring an item ≥7. Two rounds of Delphi questionnaires were completed online, and the expert comments were analyzed using content analysis. An online consensus meeting with an expert subgroup (n = 10) then advised on the guideline's acceptability and debated items until consensus for inclusion was reached. Results: Fifty experts participated in the Delphi round one (83%response rate) and 45 in round two (90%response rate), representing 15 countries. In round one, 35 statements met the criteria for consensus. Content analysis informed the revised statements in round two, where 12 of the remaining 16 statements met consensus. The final agreed aquatic therapy guidelines include key information about dosage, content, safety, contraindications, and the optimal aquatic therapy delivery throughout the disease course. Conclusion: Stakeholders, including international practice experts, informed a rigorous evidence-based approach to integrate the best available evidence, patient preferences, and practice expertise to inform these guidelines.
Article
Parkinson's disease (PD) is a common neurodegenerative disorder. It is also the fastest-growing neurodegenerative disorder and has more than doubled between 1990 and 2016. Parkinson’s disease causes significant morbidity and disability from motor dysfunction, sleep disturbances, and cognitive and psychiatric symptoms. This paper reviews recent evidence in the treatment of PD “off” episodes with the novel drug opicapone, including its efficacy, safety, and clinical indications. Opicapone is a novel, peripherally acting catechol-O-methyl transferase (COMT) inhibitor used as adjunctive therapy to carbidopa/levodopa for treatment and prevention of "off” episodes. It has been approved for use as an adjunct to levodopa since 2016 in Europe and has recently (April 2020) gained FDA approval for use in the USA. By inhibiting COMT, opicapone slows levodopa metabolism and increases its availability. Several clinical studies demonstrated significant improvement in treatment efficacy and reduction in the duration of "off” episodes The main side effect demonstrated was dyskinesia, mostly with the 100 mg dose, which is higher than the approved, effective dose of 50 mg.
Article
Background: Inhalation of apomorphine could be a faster-acting and more user-friendly alternative to subcutaneous injection for treating off periods in Parkinson's disease (PD). Objective: The aim of this study was to compare the safety and pharmacokinetics of inhaled apomorphine (AZ-009) with subcutaneous apomorphine (APO-go PEN) in healthy volunteers (HVs) and to examine the safety, pharmacokinetics, and efficacy of AZ-009 in patients with PD. Methods: In part A of this study, eight HVs received 1 mg AZ-009 and 2 mg subcutaneous apomorphine in a randomized crossover manner. In the subsequent single ascending dose parts in HVs (part B, n = 16) and patients with PD (part C, n = 25), participants were randomized to placebo or AZ-009 up to 4 mg. In patients, after medication withdrawal, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III and on/off states were assessed predose and postdose. Results: AZ-009 was rapidly absorbed with peak plasma concentrations at 2 minutes, as compared to 30 minutes for subcutaneous apomorphine. Adverse events for AZ-009 were comparable to subcutaneous apomorphine, except for mild and transient throat irritation. Adverse events limited AZ-009 dose escalation in HVs to 3 mg. Patients tolerated up to 4 mg. In patients with PD, 2, 3, and 4 mg AZ-009 reduced mean Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score (standard deviation) by 10.7 (13.6), 12.8 (7.9), and 10.3 (3.7) points, respectively, compared to 4.8 (4.9) after placebo at 10 minutes postdose. The percentage of patients achieving full on within 45 minutes postdose increased dose dependently: 0% (placebo), 17% (2 mg), 50% (3 mg), and 83% (4 mg). Conclusions: AZ-009 appears to be a rapid-acting and reasonably well-tolerated formulation for treating off periods. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Article
Aim: To compare efficacy of apomorphine sublingual film (APL) and levodopa inhalation powder (CVT-301) for ‘on-demand’ treatment of Parkinson's disease ‘OFF’ episodes. Patients & methods: Patient-level data from an APL pivotal study were re-weighted to match average baseline characteristics from a CVT-301 study (SPAN-PD). Placebo-adjusted treatments were compared at week 12. Results: Improvements in predose Unified Parkinson's Disease Rating Scale Part III scores were significantly larger for APL versus CVT-301 at 60 min postdose (least squares mean difference-in-difference: -8.82; p = 0.002); difference at 30 min favored APL but was not statistically significant (-4.46; p = 0.103). Total daily ‘OFF’ time reductions were significantly larger for APL versus CVT-301 (-1.31 h; p = 0.013). Conclusion: Results suggest APL treatment may lead to improved efficacy versus CVT-301.
Article
Background In Japan, only two medications of immediate-release levodopa with distinct ratios of decarboxylase inhibitor (DCI), namely levodopa/benserazide 100/25 mg and levodopa/carbidopa 100/10 mg, are available for the treatment of Parkinson's disease (PD). The relationship between the difference in the DCI to levodopa ratio and the development of motor complications in long-term administration of levodopa is unknown. Purpose We assessed the duration from initiation of levodopa/DCI to the emergence of motor fluctuations in patients with PD treated with levodopa/benserazide and levodopa/carbidopa. Methods We retrospectively assessed the disease course, especially the period from the onset of motor symptoms or initiation of levodopa/DCI to the emergence of motor fluctuations, in patients with PD who were initially treated with either levodopa/benserazide (300/75 mg/day) or levodopa/carbidopa (300/30 mg/day). Results Of the 186 candidates, 52 patients were enrolled. The mean duration to the emergence of motor fluctuations in the levodopa/carbidopa group was significantly longer than that in the levodopa/benserazide group (5.0 ± 1.4 vs 3.1 ± 1.2 years, p < 0.01). The mean duration from onset of motor symptoms to the emergence of motor fluctuations in the levodopa/carbidopa group was also significantly longer than that in the levodopa/benserazide group (6.6 ± 1.6 vs 4.7 ± 1.3 years, p < 0.01). Conclusion Our study suggests that levodopa/carbidopa therapy with a DCI to levodopa ratio of 1:10 may delay the occurrence of motor fluctuations when compared to levodopa/benserazide therapy with that of 1:4. The difference in the blending ratio of levodopa/DCI may influence the disease progression in PD.
Article
Background: Recruitment and retention of participants in clinical trials for Parkinson's disease (PD) is challenging. A qualitative study embedded in the PD STAT multi-centre randomised controlled trial of simvastatin for neuroprotection in PD explored the motivators, barriers and challenges of participants, care partners and research staff. Objective: To outline a set of considerations informing a patient-centred approach to trial recruitment, retention, and delivery. Method: We performed semi-structured interviews and focus groups with a subset of trial participants and their care partners. Quantitative and qualitative data were obtained through surveys circulated among the 235 participants across 23 UK sites at the beginning, middle and end of the 2-year trial. We also interviewed and surveyed research staff at trial closure. Results: Twenty-seven people with PD, 6 care partners and 9 researchers participated in interviews and focus groups. A total of 463 trial participant survey datasets were obtained across three timepoints, and 53 staff survey datasets at trial closure. Trial participants discussed the physical and psychological challenges they faced, especially in the context of OFF state assessments, relationships, and communication with research staff. Care partners shared their insights into OFF state challenges, and the value of being heard by research teams. Research staff echoed many concerns with suggestions on flexible, person-centred approaches to maximising convenience, comfort, and privacy. Conclusion: These considerations, in favour of person-centred research protocols informed by the variable needs of participants, care partners and staff, could be developed into a set of recommendations for future trials.
Article
Parkinson's disease (PD) is characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta and other neuronal populations. The worldwide prevalence of PD is over 7 million and has been increasing more rapidly than many other neurodegenerative disorders. PD symptoms can be broadly divided into motor (slowness, stiffness, tremor) and non-motor symptoms (such as depression, dementia, psychosis, orthostatic hypotension). Patients can also have prodromal symptoms of rapid eye movement sleep behavior disorder, hyposmia, and constipation. The diagnosis of PD is mainly clinical, but dopamine transporter single-photon emission computed tomography can improve the accuracy of the diagnosis. Dopamine based therapies are used for the treatment of motor symptoms. Non-motor symptoms are treated with other medications such as selective serotonin reuptake inhibitors (depression/anxiety), acetylcholinesterase inhibitors (dementia), and atypical antipsychotics (psychosis). Patients with motor fluctuations or uncontrolled tremor, benefit from deep brain stimulation. Levodopa-carbidopa intestinal gel is an alternative to deep brain stimulation for uncontrolled motor fluctuations. Rehabilitative therapies such as physical, occupational, and speech therapy are important during all stages of the disease. Management of PD is complex but there have been significant advancements in the treatment of motor and non-motor symptoms over the past few years. This review discusses the updates in the medical and surgical management of PD.
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Effective management and development of new treatment strategies of motor symptoms in Parkinson's disease (PD) largely depend on clinical rating instruments like the Unified PD rating scale (UPDRS) and the modified abnormal involuntary movement scale (mAIMS). Regarding inter-rater variability and continuous monitoring, clinical rating scales have various limitations. Patient-administered questionnaires such as the PD home diary to assess motor stages and fluctuations in late-stage PD are frequently used in clinical routine and as clinical trial endpoints, but diary/questionnaire are tiring, and recall bias impacts on data quality, particularly in patients with cognitive dysfunction or depression. Consequently, there is a strong need for continuous and objective monitoring of motor symptoms in PD for improving therapeutic regimen and for usage in clinical trials. Recent advances in battery technology, movement sensors such as gyroscopes, accelerometers and information technology boosted the field of objective measurement of movement in everyday life and medicine using wearable sensors allowing continuous (long-term) monitoring. This systematic review summarizes the current wearable sensor-based devices to objectively assess the various motor symptoms of PD.
Article
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The complications of long-term levodopa therapy for Parkinson's disease (PD) include motor fluctuations, dyskinesias, and also nonmotor fluctuations-at least equally common, but less well appreciated-in autonomic, cognitive/psychiatric, and sensory symptoms. In seeking the pathophysiologic mechanisms, the leading hypothesis is that in the parkinsonian brain, intermittent, nonphysiological stimulation of striatal dopamine receptors destabilizes an already unstable system. Accordingly, a major goal of PD treatment in recent years has been the attainment of continuous dopaminergic stimulation (CDS)-or, less theoretically (and more clinically verifiable), continuous drug delivery (CDD). Improvements in the steadiness of the plasma profiles of various dopaminergic therapies may be a signal of progress. However, improvements in plasma profile do not necessarily translate into CDS, or even into CDD to the brain. Still, it is reassuring that clinical studies of approaches to CDD have generally been positive. Head-to-head comparative trials have often failed to uncover evidence favoring such approaches over an intermittent therapy. Nevertheless, the findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement. In vivo receptor binding studies may help to determine the degree of CDS that a dopaminergic therapy can confer. This may be a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy. Certainly, the complexities of optimal PD management, and the rationale for an underlying strategy such as CDS or CDD, have not yet been thoroughly elucidated.
Article
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Objective: This multicenter cross-sectional study aimed to investigate the clinical features and varieties of non-motor fluctuation in Parkinson's disease (PD). Methods: To identify motor and non-motor fluctuation, we employed the wearing-off questionnaire of 19 symptoms (WOQ-19) in 464 PD patients. We compared the frequency of levodopa-related fluctuation as identified by the WOQ-19 with recognition by neurologists. We compared patients with both motor and non-motor fluctuations with those who only had motor fluctuations. Non-motor fluctuations were separated into psychiatric, autonomic, and sensory categories for further analysis. Results: The patients' average age was 70.8 ± 8.4 years (mean ± SD) and disease duration was 6.6 ± 5.0 years. The frequency of motor fluctuations was 69% and for non-motor fluctuation 40%. Fifty-three percent of patients with motor fluctuations also had non-motor fluctuations, whereas 93% of patients with non-motor fluctuations also had motor fluctuations. The WOQ-19 showed a sensitivity of 82% but a specificity of only 40%. The patients with both non-motor and motor fluctuations exhibited more severe motor symptoms, more non-motor symptoms and higher levodopa daily doses (p < 0.05). Patients had significantly higher fluctuation rates if they had psychiatric (49%) and sensory (45%) symptoms than patients with autonomic symptoms (32%, p < 0.01). Forty-eight percent of patients with non-motor fluctuations exhibited more than one type of non-motor fluctuation. Conclusion: Forty percent of PD patients presented with non-motor fluctuations, and almost half of these exhibited more than one type. Appropriate recognition of levodopa-related fluctuations, both motor and non-motor, can lead to treatment modifications in PD patients.
Article
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Patients with Parkinson disease are increasingly recognized to suffer from non-motor symptoms in addition to motor symptoms. Many non-motor symptoms fluctuate in parallel with motor symptoms and in relationship to plasma levodopa levels. Though these symptoms are troublesome and result in reduced quality of life to patients and their caregivers, there has not been an objective method of recognizing and quantifying non-motor fluctuations (NMFs). This study sought to develop a patient-based instrument that would accurately capture the experience of patients with NMFs. Patient-based nominal group technique sessions, focus groups, and expert opinion were utilized in developing this questionnaire.
Article
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Long-term treatment of Parkinson's disease (PD) with dopaminergic therapy is associated with a re-emergence of PD symptoms, referred to as wearing-off. Signs of wearing-off encompass motor symptoms, such as slowness of movement and stiffness, and non-motor symptoms, including anxiety and fatigue. Both motor and non-motor symptoms impact significantly on the function and quality of life of PD patients. Early detection and management of wearing-off has been shown to improve patient symptoms; however, identification of wearing-off, particularly the non-motor symptoms, is hampered by a lack of patient education, awareness, patient-physician communication, and limited time for evaluation. Several questionnaires have been developed to aid the detection of wearing-off. This review investigates the development and use of the Wearing-Off Questionnaires (WOQ-32, WOQ-19, and WOQ-9), as well as their sensitivity and specificity in identifying wearing-off. The manuscript also provides an overview of the motor and non-motor signs of wearing-off and highlights the available treatment strategies for managing this potentially debilitating phenomenon.
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The nonmotor symptoms (NMS) of Parkinson's disease (PD) are less well recognised and can be more troublesome to patients and carers than classical motor features. NMS are frequently missed during routine consultations and such under-recognition may have implications on quality of care given that many NMS are treatable. To determine the proportion of patients not declaring NMS to healthcare professional (HCP) as assessed by self completion of the NMS questionnaire (NMSQuest), a validated, self-completing questionnaire with 30 items. Multicentre international study. The data was collected from PD patients across all age groups and stages attending outpatient clinics in specialist and care of the elderly settings. 242 patients recruited and undeclared NMS ranged from 31.8% (diplopia) to 65.2% (delusions). The most frequently nondeclared symptoms were delusions, daytime sleepiness, intense and vivid dreams, and dizziness. In many, appropriate treatments for undeclared NMS were started only after these were recognised following completion of NMSQuest. NMS of PD are frequently undeclared at routine hospital consultation and may be related to the fact that patients often do not link these symptoms with PD or may be too embarrassed to discuss these. Use of NMSQuest allows patients to flag symptoms which may be otherwise undeclared and remain untreated when potential treatments exist.
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In recent years, there has been increasing recognition of the features of Parkinson disease that are not related to nigrostriatal dopamine deficiency. This review addresses selected clinical, anatomic, pathologic, and biochemical correlates of the early premotor symptoms of Parkinson disease, later nonmotor fluctuations, and advanced dopa-unresponsive motor and nonmotor features. The recognition of early features that predate classic motor symptoms will be important as effective neuroprotective therapy becomes available. Later-stage features often contribute markedly to disability and impaired quality of life and, therefore, represent an important future therapeutic challenge.
Article
Only a few years after the introduction of levodopa, the first descriptions of motor fluctuations and dyskinesia related to dopaminergic therapy appeared. In PD, attention turned to their management, that had dampened the euphoria of the "levodopa miracle." It soon became clear that neuropsychiatric, autonomic, and sensory features also tend to develop fluctuations after chronic exposure to l-dopa. The diversity of fluctuating nonmotor symptoms, their largely subjective nature, coupled with a frequent lack of insight led to difficulties in identification and quantification. This may explain why, despite the high impact of nonmotor symptoms on patient autonomy and quality of life, evaluation of nonmotor fluctuations is not part of clinical routine. In view of the lack of specific validated assessment tools, detailed anamnesis should ideally be coupled with an evaluation in both ON and OFF drug conditions. The mechanisms of nonmotor fluctuations are not well understood. It is thought that they share dopaminergic presynaptic pharmacokinetic and postsynaptic pharmacodynamic mechanisms with the classical motor complications, but involve different neural pathways. Although symptoms fluctuate with dopaminergic treatment, serotonine and norepinephrine denervation, as well as interactions between neurotransmitter systems, probably contribute to their diversity. The lack of validated tools for assessment of these phenomena explains the almost complete absence of treatment studies. Management, largely resulting from expert opinion, includes psychiatric follow-up, nondopaminergic drugs, and advanced dopaminergic treatment, including drug delivery pumps and DBS. This review aims to provide a starting point for the understanding, diagnosis, and management of nonmotor fluctuations. © 2016 International Parkinson and Movement Disorder Society.
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Background: Since previous studies aimed to study nonmotor symptom (NMS) fluctuations in direct conjunction with motor oscillations, there are no data available on the temporal context of NMS fluctuations and motor oscillations in advanced Parkinson's disease (PD). Objective: To evaluate circadian patterns and temporal connections of NMS and motor fluctuations in PD. Methods: 15 controls, 17 non-fluctuating and 15 fluctuating PD patients completed two diaries by rating 4 key psychiatric (anxiety, depressive mood, inner restlessness, concentration/attention deficits), fatigue and 4 autonomic NMS (excessive sweating, sialorrhea, bladder urgency, dizziness) absent or present and motor function (Off, On with/without dyskinesia, and asleep) for every hour for 5 consecutive days. Results: NMS Off state hours (hours with NMS rated as present) were less frequent compared to motor Off state hours and NMS On-Off-switches were less prevalent compared to those of the motor state. Off time and number of On-Off-switches of psychiatric NMS were moderately correlated with motor Off time and number of motor On-Off switches on the individual patient level. Changes in NMS state occurred largely independent of changes in motor states with concordance rates of only 26-43% of all NMS changes for psychiatric and 7-17% for autonomic NMS. In controls and non-fluctuating PD patients, there were no NMS state switches in concordance to motor state switches. Conclusion: We provide first data on the temporal context of NMS fluctuations showing similar frequencies of psychiatric NMS Off, fatigue Off and motor Off times as well as their On-Off-fluctuations, but low concordance rates of NMS with motor On-Off-state switches. We found no evidence for NMS fluctuations in non-fluctuating PD patients. Our data implicate similar fluctuation patterns of mood NMS and motor function without close timing and/or different kinetics.
Article
Data on frequency, severity and correlations of NMS with motor complications are only available for a limited number of NMS. The NMS Scale (NMSS) is a validated tool to assess a broad range of NMS, which has not been used in NMS fluctuations. We assessed fluctuations of a broad range of non-motor symptom (NMS) for a 1-month time period in fluctuating Parkinson's disease (PD) in a multicenter cross-sectional study using the NMSS assessing NMS in motor On (NMSSOn) and Off state (NMSSOff) combined with clinical NMS and motor function scoring in 100 fluctuating PD patients. ΔNMSSOn/Off was defined as the differences of NMSS scores between On and Off. Complete NMSS datasets were available from 73 patients (53 % men; age: 68.2 ± 9.7 years) with mean total NMSS score in On state of 41.5 ± 37.6 and in Off state of 75.6 ± 42.3 (P < 0.001). Scores were higher in Off compared to On state for all domains except for domain "perceptual problems/hallucinations" (P = 0.608). Clinimetric properties of the NMSS were similar to those reported previously for NMS assessments independent of motor oscillations. NMSSOn, NMSSOff and ΔNMSSOn/Off showed weak to moderate correlations with demographics, indicators of motor symptom severity as well as with other measures of NMS, depression and quality of life. Correlations of NMSS items/domains with independent measures of related constructs were weak to moderate. In conclusion, when assessed with the NMSS, a broad range of NMS fluctuate with motor oscillations, but these fluctuations do neither correlate with motor function nor with measures of disease progression.
Article
Motor fluctuations are a major disabling complication in the treatment of Parkinson's disease. To investigate whether such oscillations in mobility can be attributed to changes in the synaptic levels of dopamine, me studied prospectively patients in the early stages of Parkinson's disease with a follow-up after at least 3 years of levodopa treatment. At baseline, 3 positron emission tomography (PET) scans using [C-11]raclopride before and after (1 hour and 4 hours) orally administered levodopa were performed on the same day for each patient. Patients who developed "wearing-off" fluctuations during the follow-up period had a different pattern of levodopa-induced changes in [C-11]raclopride binding potential (BP) from that observed in patients who were still stable by the end of the follow-up. Thus, I hour post-levodopa the estimated increase in the synaptic level of dopamine was 3 times higher in fluctuators than in stable responders. By contrast, only stable responders maintained increased levels of synaptic dopamine in the PET scan performed after 4 bouts. These results indicate that fluctuations in the synaptic concentration of dopamine precede clinically apparent "wearing-off" phenomena The rapid increase in synaptic levels of dopamine observed in fluctuators suggests that increased dopamine turnover might play a relevant role in levodopa-related motor complications.
Article
To describe demographic and clinical characteristics in a group of Parkinson's disease (PD) patients with non-motor fluctuations (NMF) and to evaluate the management of medications proposed to treat NMF.Methods Three hundred and three PD patients (mean age, 66 ± 10.3 years; mean disease duration, 10.1 ± 6.5 years) were enrolled. Each patient was interviewed in a non-directed fashion about the main NMF manifestations, i.e. dysautonomic, mental, and sensory symptoms. Both groups of patients with and without NMF were compared. Dysautonomia, motor fluctuations, age, disease duration, and LEDD were included in a multiple regression to determine which were predictive of NMF.ResultsNMF were found in 57 (19%) patients, mean age 65 ± 10.1 years, mean age at onset of PD 53.7 ± 10.9 years, mean disease duration 12.5 ± 6.9 years. NMF occurred on average 9.8 ± 7.7 years after the onset of PD. Fifty patients (86%) with NMF had also MF and 10 (21%) had PDD. Twenty-five (44%) patients suffered from sensory, 28 (49%) from autonomic and 25 (44%) from neuropsychiatric symptoms. Both disease and l-Dopa treatment durations, and LEDD were significantly higher in NMF patient's group. Motor fluctuations (p = 0.0016) and presence of dysautonomia (p = 0.007) were found to be two independent predictors of NMF.Conclusion The development of new instruments to assess NMF is crucial for optimized management of advanced PD.
Article
The recent formalization of clinical criteria for Parkinson's disease with dementia (PDD) codifies many studies on this topic, including those assessing biological correlates. These studies show that the emergence of PDD occurs on the background of severe dopamine deficits with, the main pathological drivers of cognitive decline being a synergistic effect between alpha-synuclein and Alzheimer's disease pathology. The presence of these pathologies correlates with a marked loss of limbic and cortically projecting dopamine, noradrenaline, serotonin, and acetylcholine neurons, although the exact timing of these relationships remains to be determined. Genetic factors, such as triplications in the α-synuclein gene, lead to a clear increased risk of PDD, whereas others, such as parkin mutations, are associated with a reduced risk of PDD. The very recent formalization of clinical criteria for PD with mild cognitive impairment (PD-MCI) allows only speculation on its biological and genetic bases. Critical assessment of animal models shows that chronic low-dose MPTP treatment in primates recapitulates PD-MCI over time, enhancing the current biological concept of PD-MCI as having enhanced dopamine deficiency in frontostriatal pathways as well as involvement of other neurotransmitter systems. Data from other animal models support multiple transmitter involvement in cognitive impairment in PD. Whereas dopamine dysfunction has been highlighted because of its obvious role in PD, the role of the other neurotransmitter systems, neurodegenerative pathologies, and genetic factors in PD-MCI remains to be fully elucidated. © 2014 International Parkinson and Movement Disorder Society
Article
Objective Assessing the frequency of Wearing-Off (WO) in Parkinson's disease (PD) patients, and its impact on Quality of Life (QoL). Methods Consecutive ambulatory patients, who were on dopaminergic treatment for ≥1 year, were included in this multicentre, observational cross-sectional study. In a single visit, WO was diagnosed based on neurologist assessment as well as using the validated Italian version of a patient self-rated 19-question Wearing-Off Questionnaire (WOQ-19); WO was defined for scores ≥ 2. QoL was evaluated by the 8-item Parkinson's Disease Questionnaire (PDQ-8). Results 617 subjects were included, with a mean anti-Parkinson treatment duration of 6.6 ± 4.6 years, 87.2% were on levodopa treatment. Neurologists identified presence of WO in 351 subjects (56.9%), whereas 415 subjects (67.3%) were identified by the self-administered WOQ-19. In patients with a <2.5 years disease duration, WO was diagnosed in 12 subjects (21.8%) by neurologists and in 23 subjects (41.8%) by the WOQ-19. The most frequent WO symptoms, as identified by WOQ-19, were “slowness of movements” (55.8%) and “reduced dexterity” (48.8%). Younger age, female gender, Unified Parkinson's Disease Rating Scale (UPDRS) part II score and duration of anti-Parkinson treatment were found significantly associated with WO. The number of motor (p < 0.0001) and non-motor (p < 0.0001) WO symptoms correlated with PDQ-8 total score. Conclusions WO is common already at the early stages of PD and is underestimated by routine neurological clinical evaluation. The number of WO symptoms, both motor and non motor, increases along with disease duration and has a negative impact on patients QoL.
Article
Objective: To evaluate frequency, severity, and correlation of nonmotor symptoms (NMS) with motor complications in fluctuating Parkinson disease (PD). Methods: The Multicenter NonMotor Fluctuations in PD cross-sectional study used clinical examination of 10 NMS (dysphagia, anxiety, depression, fatigue, excessive sweating, inner restlessness, pain, concentration/attention, dizziness, bladder urgency) quantified using a visual analogue scale (VAS) in motor-defined on (NMS(On)) and off state (NMS(Off)) combined with motor assessments and self-ratings at home in 100 patients with advanced PD. Results: All NMS except dysphagia, excessive sweating, and bladder urgency fluctuated in conjunction to motor fluctuations with more frequent and severe symptoms in off compared to on state. The proportions of patients experiencing autonomic/sensory NMS in both motor states were similar to those with these NMS exclusively in off state (ratios 0.4-1.3), while for mental/psychic NMS the proportions with exclusive manifestation in off state were higher (ratios 1.8-3.1). Demographic and clinical characteristics correlated neither with NMS frequency patterns and severities nor with ΔNMS(On/Off) severities (defined as the differences of VAS scores between on and off). Severities of NMS(on), NMS(Off), and ΔNMS(On/Off) did not correlate with motor function. Presence of anxiety, depression, fatigue, and pain had negative impact on health-related quality of life (HRQOL) measured by Parkinson's Disease Questionnaire-8 scoring independent of their occurrence with respect to motor state. Fluctuations of these NMS but not of fatigue deteriorated HRQOL. Conclusion: Patterns of NMS fluctuations are heterogeneous and complex, but psychic NMS fluctuate more frequently and severely. Demographic parameters and motor function do not correlate with NMS or nonmotor fluctuation severities in fluctuating PD.
Article
This study compares the sensitivity of a Patient Questionnaire versus information gathered by clinicians at a routine clinic visit in recognizing symptoms of wearing-off in early Parkinson's disease (PD). This Patient Questionnaire, containing 32 items representing a wide spectrum of motor and nonmotor wearing-off symptoms, was administered to subjects attending two PD clinics. The Patient Questionnaire results were compared to the information gathered by the clinician from the Unified Parkinson's Disease Rating Scale (UPDRS) Part IV, Question 36 and from a specific Clinical Assessment Question regarding loss of medication efficacy, wearing-off, sleepiness, dyskinesias, psychiatric complications, morning akinesia, other dopaminergic side effects, or none of the above. Examiners were blinded to study hypothesis and survey contents. Three hundred consecutive subjects with PD of <5 years duration were evaluated; the mean subject age was 72 ± 9.6 years and 60.2% were men. Subjects reporting wearing-off were significantly younger (69.9 vs. 74.7 years) and differed regarding duration of PD symptoms (3.7 vs. 3.1 years). Wearing-off was found in 181 subjects (62.6%) by one or more of the three measures. The most sensitive tool was the Patient Questionnaire, with 165 subjects (57.1%) indicating symptoms of wearing-off. Question 36 of the UPDRS was positive in 127 subjects (43.9%), and the Clinical Assessment Question identified 85 subjects (29.4%) as experiencing wearing-off. All of these results were found to differ significantly. The mean number of wearing-off symptoms reported by the 165 subjects indicating wearing-off on the clinical survey was 6.25, with tremor being the most common motor feature and tiredness the most common nonmotor feature. © 2005 Movement Disorder Society
Article
Wearing-off occurs in the majority of patients with Parkinson's disease after a few years of dopaminergic therapy. Because a variety of scales have been used to estimate wearing-off, the Movement Disorder Society commissioned a task force to assess their clinimetric properties. A systematic review was conducted to identify wearing-off scales that have either been validated or used in Parkinson's patients. A scale was designated "Recommended" if it had been used in clinical studies beyond the group that developed it, if it had been specifically used in Parkinson's disease reports, and if clinimetric studies had established that it is valid, reliable, and sensitive. "Suggested" scales met 2 of the above criteria, and those meeting 1 were "Listed." We identified 3 diagnostic and 4 severity rating scales for wearing-off quantification. Two questionnaires met the criteria to be Recommended for diagnostic screening (questionnaires for 19 and 9 items), and 1 was Suggested (questionnaire for 32 items). Only the patient diaries were Recommended to assess wearing-off severity, with the caveat of relatively limited knowledge of validity. Among the other severity assessment tools, the Unified Parkinson Disease Rating Scale version 3 and the version revised from the Movement Disorders Society were classified as Suggested, whereas the Treatment Response Scale was Listed.
Article
The symptoms of Parkinson's disease can become increasingly difficult to control as the disease advances. Levodopa remains the most efficacious therapy for symptomatic treatment. However, with long-term therapy motor and non-motor complications develop. There is now accumulating evidence that several factors - the progressive pathology of Parkinson's disease, the change in drug pharmacodynamics, and the pulsatile manner in which short-acting dopaminergic agents stimulate striatal dopamine receptors - are key contributors to the priming of the basal ganglia for induction of motor complications. In this paper, an overview of the different factors inducing motor fluctuations and the role of dopamine receptors stimulation is provided.
Article
Cognitive impairment in patients with Parkinson's disease is gaining increased clinical significance owing to the relative success of therapeutic approaches to the motor symptoms of this disorder. Early investigations contributed to the concept of subcortical dementia associated with bradyphrenia and cognitive rigidity. For cognition in parkinsonian disorders, this notion developed into the concept of mild cognitive impairment and fronto-executive dysfunction in particular, driven mainly by dopaminergic dysmodulation and manifesting as deficits in flexibility, planning, working memory, and reinforcement learning. However, patients with Parkinson's disease could also develop a syndrome of dementia that might depend on non-dopaminergic, cholinergic cortical dysfunction. Recent findings, supplemented by advances in neuroimaging and genetic research, reveal substantial heterogeneity in the range of cognitive deficits in patients with Parkinson's disease. Remediation and management prospects for these cognitive deficits are based on neuropharmacological and cognitive rehabilitation approaches.
Article
L-dopa is the most widely used and most effective therapy for Parkinson disease (PD), but chronic treatment is associated with motor complications in the majority of patients. It has been hypothesized that providing more continuous delivery of L-dopa to the brain would reduce the risk of motor complications, and that this might be accomplished by combining L-dopa with entacapone, an inhibitor of catechol-O-methyltransferase, to extend its elimination half-life. We performed a prospective 134-week double-blind trial comparing the risk of developing dyskinesia in 747 PD patients randomized to initiate L-dopa therapy with L-dopa/carbidopa (LC) or L-dopa/carbidopa/entacapone (LCE), administered 4x daily at 3.5-hour intervals. The primary endpoint was time to onset of dyskinesia. In comparison to LC, patients receiving LCE had a shorter time to onset of dyskinesia (hazard ratio, 1.29; p = 0.04) and increased frequency at week 134 (42% vs 32%; p = 0.02). These effects were more pronounced in patients receiving dopamine agonists at baseline. Time to wearing off and motor scores were not significantly different, but trended in favor of LCE treatment. Patients in the LCE group received greater L-dopa dose equivalents than LC-treated patients (p < 0.001). Initiating L-dopa therapy with LCE failed to delay the time of onset or reduce the frequency of dyskinesia compared to LC. In fact, LCE was associated with a shorter time to onset and increased frequency of dyskinesia compared to LC. These results may reflect that the treatment protocol employed did not provide continuous L-dopa availability and the higher L-dopa dose equivalents in the LCE group.
Article
Parkinson's disease is characterized primarily as a neurodegenerative disorder that leads to disabling motor and cognitive impairment. PD is less widely appreciated as a disease causing a substantial variety of pain syndromes, although the prevalence of pain in PD is approximately 40%. In a minority of patients, pain is so severe and intractable that it overshadows the motor symptoms of the disorder. In recent years, descriptive surveys of non-motor symptoms in PD have led to a classification of painful sensations into one or more of several categories: musculoskeletal pain, radicular or neuropathic pain, dystonia-related pain, akathitic discomfort, and primary, central parkinsonian pain. A framework for diagnosing and treating painful PD is described in this review, together with recent insignts into the neurophysiological mechanisms and substrates of pain in PD.
Article
Unlabelled: The majority of patients with Parkinson's disease (PD) on levodopa (LD) treatment usually experience motor fluctuations (MFs) within several years of initiation of treatment. Besides the classic MFs, many nonmotor fluctuations (NMFs) may occur in PD. NMFs appear both in the "on" state and "off" state. However, the clinical spectrum and the frequency of these symptoms are not well recognized. NMFs are usually mild and less disabling than MFs but sometimes can lead to unnecessary tests and therapies. NMFs occurring in association with the "on" state are better known and therefore more frequently diagnosed than those occurring in the "off" state. NMFs can be classified into three groups: autonomic, cognitive/psychiatric, and sensory. They include gastrointestinal and urinary symptoms, drenching sweats, temperature and blood-pressure changes, depression, anxiety, hallucinations, hypomania, moaning/screaming, confusion, cognitive dysfunction, sexual deviations and dopamine dysregulation syndrome (DDS), pain, akathisia, internal tremor, numbness/parasthesia, and dyspnea. Conclusion: Recognition of NMFs may prevent unnecessary diagnostic tests and may lead to treatment modifications aimed to minimize their occurrence.
Article
The motor complications associated with levodopa therapy, namely, fluctuations in motor response and dyskinesias, occur in the majority of Parkinson's disease patients. These complications can impair a patient's quality of life and even cause pronounced disability. "Off" states that result in freezing of gait and falling are disabling for many patients. Dyskinesias most commonly occur at peak dose and typically alternate with the wearing-off state. Once these problems appear, they usually persist, and the physician needs to make continual adjustments in medications to minimize these problems. Medical treatments should be attempted before treatments such as deep brain stimulation are considered because of the potential adverse effects that are associated with surgery. The timing of surgery, however, is also important because younger patients and less advanced patients tend to have a better outcome. There is thus a need for experienced and knowledgeable physicians and surgeons who are able to handle these motor complications. This review discusses available medications and surgical approaches, and their outcomes.
Article
We present a clinimetric assessment of the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). The MDS-UDPRS Task Force revised and expanded the UPDRS using recommendations from a published critique. The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver. Item-specific instructions and an appendix of complementary additional scales are provided. Movement disorder specialists and study coordinators administered the UPDRS (55 items) and MDS-UPDRS (65 items) to 877 English speaking (78% non-Latino Caucasian) patients with Parkinson's disease from 39 sites. We compared the two scales using correlative techniques and factor analysis. The MDS-UPDRS showed high internal consistency (Cronbach's alpha = 0.79-0.93 across parts) and correlated with the original UPDRS (rho = 0.96). MDS-UPDRS across-part correlations ranged from 0.22 to 0.66. Reliable factor structures for each part were obtained (comparative fit index > 0.90 for each part), which support the use of sum scores for each part in preference to a total score of all parts. The combined clinimetric results of this study support the validity of the MDS-UPDRS for rating PD.
Article
In dogs with gastric fistulas, intragastric pressure was measured with a flaccid ballon containing 500 ml of water. Graded doses of dopamine caused graded decreases in intragastric pressure. The effect was blocked by pimozide or by metoclopramide but was not significantly affected by phenoxybenzamine, propranolol, guanethidine, or FLA-63 (a beta-hydroxylase inhibitor). Pretreatment with metoclopramide or with pimozide shifted the volume-pressure diagram of the stomach to the left; that is, at any given volume the pressure was greater after than before these drugs. In dogs with vagally innervated gastric pouches and gastric fistulas, feeding for 1 min (while allowing the food to leave the stomach through the gastric fistula) caused a prompt decrease in pressure in the pouch that lasted for about 5 min. Pretreatment with metoclopramide decreased the magnitude and duration of this receptive relaxation. It is concluded that these findings are consistent with (but do not establish) the hypothesis that dopamine is the neurotransmitter for receptive relaxation of the stomach, because dopamine mimics receptive relaxation, and dopamine antagonists partially block reflexly induced receptive relaxation.
Article
Fluctuations in performance in patients with Parkinson's disease on chronic levodopa therapy (the "on-off" effect) are due to several factors. The increasing severity during treatment of early morning akinesia, "freezing" episodes, and end-of-dose deterioration are probably due to progression of the underlying disease. Peak-dose dyskinesia and peak-dose akinesia are due to levodopa over dosage. "Yo-yo-ing", which is the severest form of such fluctuation in mobility and dyskinesias, may represent the sum of these disorders.
Article
The patient with Parkinson' disease on chronic levodopa therapy, like the diabetic on insulin, is dependent on the drug. Like the diabetic, the patients with Parkinson's disease may run into problems during long-term treatment. Two have emerged as frequent and serious, an insidious and progressive loss of benefit and the appearance of progessively more severe fluctuations in disability. It is concluded that progression of the underlying pathology of the disease is probably responsible. Discovery of the exact causes for loss of benefit may provide a rational basis for new therapy.