Gender differences in non-motor fluctuations in Parkinson's disease.

Non-motor symptoms (NMS) and Non-motor fluctuations (NMF) in Parkinson's Disease (PD) are common, involving several domains and affecting quality of life. Aim of the study is to estimate the burden of NMF in PD patients and to evaluate the possible gender effect. PD patients fulfilling the MDS-PD diagnostic criteria attending the "Parkinson's Disease and Movement Disorders Centre" of the University of Catania were evaluated using the Non-Motor Fluctuations Assessment (NoMoFA) Questionnaire. NoMoFA items were also grouped into the following domains: cognitive, mood, sleep/fatigue, dysautonomia, hallucination/perception and miscellaneous domains were identified. One-hundred and twenty-one patients with PD (67 men, 55.4%; mean age 70.2 ± 8.9 years, disease duration 8.3 ± 4.6 years) were evaluated. All PD patients reported at least one NMS, whereas 87 (71.9%) also reported NMF. "Feel sluggish or had low energy levels" (47.2%) along with "Feel excessively sleepy during the day" (40.0%) were the most common NMF reported in the whole sample. The majority of PD patients reported the presence of NMF during the OFF state (79, 65.3%). At multivariate analysis, NMF were positively associated with the female gender (adjusted OR 3.13; 95%CI 1.21-8.11 p-value 0.01). Women with PD had higher NMF scores especially in depression/anxiety, sleep/fatigue and dysautonomia domains. Our study reported the presence of a gender-related pattern in the frequency of NMS and NMF in PD patients, with female gender associated with a higher risk of developing NMF, highlighting the need for personalized treatment strategies when addressing NMF.

Opicapone versus placebo in the treatment of Parkinson's disease patients with end-of-dose motor fluctuation-associated pain: rationale and design of the randomised, double-blind OCEAN (OpiCapone Effect on motor fluctuations and pAiN) trial.

BACKGROUND: Optimisation of dopaminergic therapy may alleviate fluctuation-related pain in Parkinson's disease (PD). Opicapone (OPC) is a third-generation, once-daily catechol-O-methyltransferase inhibitor shown to be generally well tolerated and efficacious in reducing OFF-time in two pivotal trials in patients with PD and end-of-dose motor fluctuations. The OpiCapone Effect on motor fluctuations and pAiN (OCEAN) trial aims to investigate the efficacy of OPC 50 mg in PD patients with end-of-dose motor fluctuations and associated pain, when administered as adjunctive therapy to existing treatment with levodopa/dopa decarboxylase inhibitor (DDCi). METHODS: OCEAN is a Phase IV, international, multicentre, randomised, double-blind, placebo-controlled, parallel-group, interventional trial in PD patients with end-of-dose motor fluctuations and associated pain. It consists of a 1-week screening period, 24-week double-blind treatment period and 2-week follow-up period. Eligible patients will be randomised 1:1 to OPC 50 mg or placebo once daily while continuing current treatment with levodopa/DDCi and other chronic, stable anti-PD and/or analgesic treatments. The primary efficacy endpoint is change from baseline in Domain 3 (fluctuation-related pain) of the King's Parkinson's disease Pain Scale (KPPS). The key secondary efficacy endpoint is change from baseline in Domain B (anxiety) of the Movement Disorder Society-sponsored Non-Motor rating Scale (MDS-NMS). Additional secondary efficacy assessments include other domains and total scores of the KPPS and MDS-NMS, the Parkinson's Disease Questionnaire (PDQ-8), the MDS-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts III and IV, Clinical and Patient's Global Impressions of Change, and change in functional status via Hauser's diary. Safety assessments include the incidence of treatment-emergent adverse events. The study will be conducted in approximately 140 patients from 50 clinical sites in Germany, Italy, Portugal, Spain and the United Kingdom. Recruitment started in February 2021 and the last patient is expected to complete the study by late 2022. DISCUSSION: The OCEAN trial will help determine whether the use of adjunctive OPC 50 mg treatment can improve fluctuation-associated pain in PD patients with end-of-dose motor fluctuations. The robust design of OCEAN will address the current lack of reliable evidence for dopaminergic-based therapy in the treatment of PD-associated pain. TRIAL REGISTRATION: EudraCT number 2020-001175-32 ; registered on 2020-08-07.

Do neuropsychiatric fluctuations temporally match motor fluctuations in Parkinson's disease?

INTRODUCTION: In Parkinson's disease (PD), non-motor fluctuations (NMFs), especially neuropsychiatric fluctuations, often coexist with motor fluctuations (MFs) but are often under-recognized by physicians and patients. OBJECTIVE: To investigate the relationship between MFs and neuropsychiatric fluctuations in PD. METHODS: PD patients with MFs and NMFs were enrolled. The Parkinson's Kinetigraph (PKG), a wearable device to detect MFs and dyskinesia, was used to confirm and measure MFs. The Neuropsychiatric Fluctuation Scale (NFS), a scale composed by subscores for both the ON and OFF neuropsychiatric states, was used to identify and quantify neuropsychiatric fluctuations. Patients were asked to wear the PKG for six consecutive days to identify the ON and OFF motor periods, and then to fill the NFS during the ON and OFF motor periods for three consecutive days wearing the PKG. The PKG system provided a bradykinesia score (BKS) and a dyskinesia score (DKS). Relations between BKS, DKS, and ON and OFF NFS subscores were analyzed. RESULTS: In 18 PD patients, anxiety, apathy, and depression characterized the OFF condition, whereas self-confidence, competency, and interest in doing things were typically in the ON condition. There was a positive correlation between the BKS and the OFF NFS subscores (p = 0.036, r = 0.51), whereas no correlation was found between the DKS and the ON NFS subscores (p = 0.38, r = 0.22). CONCLUSION: Neuropsychiatric fluctuations temporarily matched the OFF MFs only in the OFF condition. These findings are useful to better manage OFF NMSs and support the need to further investigate associations between non-motor and motor symptoms in PD patients.

Validation of a non-motor fluctuations questionnaire in Parkinson's disease.

INTRODUCTION: Non-motor fluctuations (NMF) in Parkinson's disease (PD) remain poorly recognized but have a high impact on patients' quality of life. The lack of assessment tools limits our understanding of NMF, compromising appropriate management. Our objective was to validate a hetero-questionnaire for NMF in PD patients at different stages of the disease: without treatment, without motor fluctuations, with motor fluctuations. METHODS: We included patients in 15 centers in France. Our questionnaire, NMF-Park, resulted from previous studies, allowing us to identify the more pertinent NMF for evaluation. Patients reported the presence (yes or no) of 22 selected NMF, and their link with dopaminergic medications. The assessment was repeated at one and two years to study the progression of NMF. We performed a metrological validation of our questionnaire. RESULTS: We included 255 patients (42 without treatment, 88 without motor fluctuations and 125 with motor fluctuations). After metrological validation, three dimensions of NMF were found: dysautonomic; cognitive; psychiatric. The sensory/pain dimension described in the literature was not statistically confirmed by our study. DISCUSSION: Our questionnaire was validated according to clinimetric standards, for different stages of PD. It was clinically coherent with three homogeneous dimensions. It highlighted a link between fatigue, visual accommodation disorder, and cognitive fluctuations; and the integration of sensory/pain fluctuations as part of dysautonomic fluctuations. It focused exclusively on NMF, which is interesting considering the described differences between non-motor and motor fluctuations. CONCLUSION: Our study validated a hetero-questionnaire of diagnosis for NMF for different stages of PD.

Non-Motor Fluctuations in Parkinson's Disease: Validation of the Non-Motor Fluctuation Assessment Questionnaire.

BACKGROUND: In patients with Parkinson's disease (PD), sleep, mood, cognitive, autonomic, and other non-motor symptoms may fluctuate in a manner similar to motor symptoms. OBJECTIVES: To validate a final version of a patient-rated questionnaire that captures the presence and severity of non-motor fluctuations in levodopa-treated PD patients (NoMoFA). METHODS: We recruited PD subjects from five movement disorders centers across the US and Canada. We assessed the internal consistency, floor and ceiling effects, test-retest reliability, and concurrent validity of NoMoFA. Classical test theory and item response theory methods informed item reduction and Delphi process yielded a final questionnaire. RESULTS: Two hundred subjects and their care-partners participated in the study (age: 66.4 ± 9.6 years; disease duration: 9 ± 5.5 years; median Hoehn and Yahr [H&Y] OFF: 3 [range 1-5]; mean Unified Parkinson's Disease Rating Scale (UPDRS) III ON score: 27.4 ± 14.9). Acceptability of the scale was adequate. There were floor effects in 8/28 items. Cronbach's alpha was 0.894. While eight items had "item-to-total" correlations below the cutoff of 0.4, removing these items did not improve Cronbach's alpha. Test-retest reliability was acceptable (intraclass correlation coefficient [ICC] 0.73; 95% confidence interval, 0.64-0.80). Concurrent validity was adequate with all Spearman's rho values comparing NoMoFA score to other measures of parkinsonian severity showing significance and in the expected direction. A final Delphi panel eliminated one item to avoid redundancy. CONCLUSIONS: The final 27-item self-administered NoMoFA is a valid and reliable questionnaire, capturing both static and fluctuating non-motor symptoms in PD. © 2021 International Parkinson and Movement Disorder Society.

Disease stage dependency of motor and non-motor fluctuations in Parkinson's disease.

Recent data suggested a decrease in non-motor fluctuations in late-stage Parkinson's disease (PD), but systematic data on non-motor fluctuations over the whole disease course are mainly lacking. We performed a meta-analysis of two studies with very similar cross-sectional cohort designs, namely the German multicenter Non Motor Fluctuation in PD study and the Swedish part of the European multicenter study Care for Late Stage Parkinsonism. We included only patients with documented motor fluctuations in the analyses. Disease stage was estimated using the Hoehn and Yahr score, motor symptoms using the Unified PD Rating Scale part III motor score and non-motor symptom (NMS) fluctuations using the modified version of the NMS scale assessing a broad range of NMS in motor On and Off state. We included 101 patients (55% men; median age: 71 (interquartile range, IQR 65-78) years with Hoehn and Yahr stages ranging from 1 to 5 [median (IQR) 3.0 (2.0-4.0); distribution of patients in Hoehn and Yahr stages was n = 42 (42%) in stages 2/3 and n = 48 (48%) in stages 4/5]. We found a clear dependency of non-motor burden on Hoehn and Yahr stage with increasing symptom severity, but decreasing fluctuation amplitudes for motor and NMS (difference of symptom severity between On and Off state) with disease stage progression. Indeed, in Hoehn and Yahr stage 5, we did not detect significant NMS fluctuations. Multivariate regression with major demographic and clinical covariates confirmed these results. In conclusion, NMS fluctuations showed a similar disease stage dependency as observed for motor fluctuations with decreasing fluctuation amplitude with disease progression.

Nonmotor fluctuations: phenotypes, pathophysiology, management, and open issues.

Parkinson's disease (PD) is a neurodegenerative multisystem disorder characterized by progressive motor symptoms such as bradykinesia, tremor and muscle rigidity. Over the course of the disease, numerous non-motor symptoms, sometimes preceding the onset of motor symptoms, significantly impair patients' quality of life. The significance of non-motor symptoms may outweigh the burden through progressive motor incapacity, especially in later stages of the disease. The advanced stage of the disease is characterized by motor complications such as fluctuations and dyskinesias induced by the long-term application of levodopa therapy. In recent years, it became evident that various non-motor symptoms such as psychiatric symptoms, fatigue and pain also show fluctuations after chronic levodopa therapy (named non-motor fluctuations or NMFs). Although NMFs have moved into the focus of interest, current national guidelines on the treatment of PD may refer to non-motor symptoms and their management, but do not mention NMF, and do not contain recommendations on their management. The present article summarizes major issues related to NMF including clinical phenomenology and pathophysiology, and outlines a number of open issues and topics for future research.

Quantitative assessment of non-motor fluctuations in Parkinson's disease using the Non-Motor Symptoms Scale (NMSS).

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.

The influence of sex on non-motor wearing-off in Parkinson's disease: A WORK-PD post-hoc study.

INTRODUCTION: The wearing-off phenomenon is characterized by the recurrence of motor and non-motor symptoms of Parkinsonism during a period free from levodopa. It is a pivotal aspect marking the end of the pharmacological "honeymoon" period in Parkinson's disease (PD). A growing body of literature is connecting sex with the likelihood of developing fluctuations. We investigated such an association in a post-hoc analysis of the large WORK-PD study. METHODS: WORK-PD analyzed the usability of the wearing-off questionnaire 19 (WOQ19) in clinical practice and included cross-sectional data on age, disease duration, time on levodopa, Hoehn and Yahr stage, and WOQ19 scores of 532 PD patients. In the present study, we selected patients with an exposure time to levodopa of at least 1 year. RESULTS: A total of 380 patients were included. Women reported a higher number of wearing-off symptoms than men (6.09 ± 3.39 vs 4.96 ± 3.11, p = 0.0006). Sex groups also differed in non-motor symptoms (2 ± 1.9 vs 1.5 ± 1.5, p = 0.021), particularly behavioral wearing-off scores being higher in women (p < 0.001). The latter were primarily featured by anxiety-related phenomena. Finally, there was a significant interaction between behavioral symptoms, sex, and age at onset (df = 2, F = 9.79, p < 0.0001), whereas no such interaction was observed with levodopa exposure and motor impairment, unlike motor symptoms. DISCUSSION: Women showed a greater propensity than men to experience wearing-off, particularly non-motor fluctuations on the anxiety spectrum. The latter may demonstrate a lesser reliance on dopamine compared to motor symptoms. This observation could be underpinned by biological variances between genders at the neurotransmitter level.

NoMoFa as a new tool to evaluate the impact of deep brain stimulation on non-motor fluctuations: A new perspective.

BACKGROUND: Non-motor symptoms and non-motor fluctuations (NMF) in Parkinson's disease (PD) strongly affect health-related quality of life (HRQoL) and disability. The impact of deep brain stimulation (DBS) on NMF remains an area of uncertainty. The aim is to evaluate the impact of DBS on NMF, using the recently validated Non-Motor Fluctuation Assessment (NoMoFa), and to explore the correlation between NMF and motor symptoms, motor complications (MC), and HRQoL post-surgical improvement. METHODS: We prospectively evaluated consecutive patients undergoing subthalamic DBS (STN-DBS), at baseline and 6-months after surgery. Assessments included the NoMoFa questionnaire, the MDS-sponsored Unified Parkinson's Disease Rating Scale, and the 39-Item Parkinson's Disease Questionnaire. Pre- and post-surgical NoMoFa scores were compared using the Wilcoxon Signed rank-test. Linear regression analysis evaluated: a) the correlation between NoMoFa scores, motor and MC improvement, correcting for age, disease duration, and dopaminergic therapy reduction; b) the correlation between HRQoL and NMF improvement, correcting for age, disease duration, motor and MC improvement. RESULTS: Twenty patients were evaluated. Total NMF score significantly improved (44.6 %, [IQR = 18.3-100]; p = 0.022), particularly in Off condition (52.0 %, [IQR = 25.4-100]; p = 0.009); we observed strong correlation between NMF and MC improvement (Beta = 0.728; p = 0.006), mainly driven by the mitigation of unpredictable Off (Beta = 0.905; p < 0.001). Even after adjusting for potential confounders, the reduction of NMF independently correlated with increased HRQoL (Beta = 0.714; p = 0.010). CONCLUSIONS: STN-DBS demonstrated strong beneficial effect on NMF, resulting in significant improvement of HRQoL. This underlines the importance of recognizing NMF as a significant factor to be considered in the selection of patients eligible for STN-DBS.

Pain Fluctuations in Parkinson's Disease and Their Association with Motor and Non-Motor Fluctuations.

Background: Pain fluctuations are a characteristic phenomenon in advanced Parkinson's disease (PD), but their temporal association with motor and non-motor symptom (NMS) fluctuations remains largely enigmatic. Moreover, data on their importance for disease severity perception and health-related quality-of-life (hr-QoL) is limited. Objective: To dissect pain fluctuations with respect to pain type and frequency patterns, and their association with motor and non-motor fluctuations. Methods: Prospective observational cohort study in advanced PD assessing symptom fluctuations by simultaneous hourly ratings using the PD Home diary (Off, On, Dyskinetic state), a pain diary (assessing 9 pain types) and a non-motor diary (10 key NMS) based on validated instruments. Results: Forty-seven out of 55 eligible participants with fluctuating PD (51% men, median age 65, median disease duration 10 years) had sufficient datasets (>95% of hours) from 2 consecutive days. Pain was reported in 35% of waking hours with clear circadian rhythm peaking in early morning Off periods and clustering during motor Off state (49% of Off state hours with pain). Main NMS co-fluctuating with pain were "Fatigue" and "Inner Restlessness". Simultaneous assessment of global disease severity by participants revealed that pain was associated with worse disease severity only in motor On and Dyskinetic state but not in Off state, which translated into significant correlations of daily pain times with hr-QoL only during motor On and Dyskinetic state. Conclusions: Aside from treating motor Off periods, specific recognition of pain particularly during motor On and Dyskinetic state comprises an important aspect for disease management in advanced PD.

Oscillations of the frequency and severity of pain over the day (also called pain fluctuations) are common in advanced Parkinson's disease (PD). However, their relationship with oscillations of motor and other non-motor symptoms remains unclear. Moreover, only very little data exists on how pain impacts disease severity perception and quality of life for the patients. The present study thus aimed to better understand pain fluctuations and their association with motor and non-motor symptoms in advanced PD. We conducted a prospective observational cohort study in advanced PD patients. Participants rated their symptoms hourly on two consecutive days using three diaries: the PD Home diary (for motor fluctuations), a pain diary (assessing several pain types), and a non-motor diary covering 10 key non-motor symptoms. Pain occurred during 35% of waking hours with a clear circadian rhythm peaking in the early morning and clustering during motor "Off" states as characterized by pronounced motor symptoms. The main non-motor symptoms associated with pain were "Fatigue" and "Inner Restlessness." Interestingly, pain severity correlated with health-related quality of life only during motor "On" state (defined as a state with good mobility and motor function) and "Dyskinetic" state characterized by the occurrence of involuntary movements, but not during motor "Off" periods. In conclusion, in managing advanced PD, recognizing pain during motor "On" and Dyskinetic states is crucial beyond just addressing motor "Off" periods. This understanding can significantly impact disease management and improve patients' quality of life.

Advanced Parkinson's disease treatment patterns in Italy: an observational study interim analysis.

BACKGROUND: Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD. PATIENTS AND METHODS: PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview. RESULTS: Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%). CONCLUSION: This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.

Patients with Parkinson's disease (PD) often exhibit fluctuations in their response to oral levodopa; however, real-world studies on the management of these fluctuations are lacking. This planned interim analysis of the real-world, multicentre, observational PD Fluctuations treatment Pathway (PD-FPA) study found that adequate levodopa dosing and adjunctive medications can stabilize Italian patients with advanced PD and improve their quality of life.

Off-time Treatment Options for Parkinson's Disease.

Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in responsiveness to dopaminergic drug treatments. MF are characterized by the loss of a stable response to levodopa over the nychthemeron with the reappearance of motor (and non-motor) parkinsonian clinical signs at various moments during the day and night. They normally appear after a few years of levodopa treatment and with a variable, though overall increasing severity, over the disease course. The armamentarium of first-line treatment options has widened in the last decade with new once-a-daily compounds, including a catechol O-methyltransferase inhibitor - Opicapone-, two MAO-B inhibitors plus channel blocker - Zonisamide and Safinamide and one amantadine extended-release formulation - ADS5012. In addition to apomorphine injection or oral levodopa dispersible tablets, which have been available for a long time, new on-demand therapies such as apomorphine sublingual or levodopa inhaled formulations have recently shown efficacy as rescue therapies for Off-time treatment. When the management of MF becomes difficult in spite of oral/on-demand options, more complex therapies should be considered, including surgical, i.e. deep brain stimulation, or device-aided therapies with pump systems delivering continuous subcutaneous or intestinal levodopa or subcutaneous apomorphine formulation. Older and less commonly used ablative techniques (radiofrequency pallidotomy) may also be effective while there is still scarce data regarding Off-time reduction using a new lesional approach, i.e. magnetic resonance-guided focused ultrasound. The choice between the different advanced therapies options is a shared decision that should consider physician opinion on contraindication/main target symptom, patients' preference, caregiver's availability together with public health systems and socio-economic environment. The choice of the right/first add-on treatment is still a matter of debate as well as the proper time for an advanced therapy to be considered. In this narrative review, we discuss all the above cited aspects of MF in patients with PD, including their phenomenology, management, by means of pharmacological and advanced therapies, on-going clinical trials and future research and treatment perspectives.

Acute effect of levodopa on orthostatic hypotension and its association with motor responsiveness in Parkinson's disease: Results of acute levodopa challenge test.

OBJECTIVE: Levodopa administration can induce or worsen orthostatic hypotension (OH) in patients with Parkinson's disease (PD). Understanding of acute OH post levodopa (AOHPL) is important for rational drug use in PD patients. Primary objective of this study was to investigate the incidence of AOHPL in PD patients. The secondary objectives were a) hemodynamic character of AOHPL; b) risk factors of AOHPL; c) relationship between motor responsiveness and blood pressure (BP) change. METHODS: 490 PD inpatients underwent acute levodopa challenge test (LCT). Supine-to-standing test (STS) was done 4 times during LCT, including before levodopa and every hour post levodopa intake within 3 h. Patients were classified into two groups, AOHPL and non-AOHPL. A comprehensive set of clinical features scales was assessed, including both motor (e.g., motor response, wearing-off) and nonmotor symptoms (e.g., autonomic dysfunction, neuropsychology). RESULTS: 33.1% PD patients had OH before drug, 50.8% the same subjects had AOHPL during levodopa effectiveness. PD patients who had better response to levodopa likely to have lower standing mean artery pressure (MAP) and severer systolic BP drop after levodopa intake. BP increased when the motor performance worsened and vice versa. Beneficial response was a risk factors of AOHPL (OR = 1.624, P = 0.017). CONCLUSIONS: AOHPL was very common in PD patients. We suggested that PD patients with risk factors should monitor hemodynamic change during LCT to avoid AOHPL following the introduction or increase of oral levodopa. The fluctuations of BP were complicated and multifactorial, likely caused by the process of PD and levodopa both.

Both Motor and Non-Motor Fluctuations Matter in the Clinical Management of Patients with Parkinson's Disease: An Exploratory Study.

Non-motor symptoms (NMS) characterize the Parkinson's disease (PD) clinical picture, and as well as motor fluctuations, PD patients can also experience NMS fluctuations (NMF). The aim of this observational study was to investigate the presence of NMS and NMF in patients with PD using the recently validated Non-Motor Fluctuation Assessment questionnaire (NoMoFa) and to evaluate their associations with disease characteristics and motor impairment. Patients with PD were consecutively recruited, and NMS, NMF, motor impairment, motor fluctuations, levodopa-equivalent daily dose, and motor performance were evaluated. One-third of the 25 patients included in the study (10 females, 15 males, mean age: 69.9 ± 10.3) showed NMF, and patients with NMF presented a higher number of NMS (p < 0.01). Static NMS and NoMoFa total score were positively associated with motor performance assessed with the Global Mobility Task (p < 0.01 and p < 0.001), and the latter was also correlated with motor impairment (p < 0.05) but not with motor fluctuations. Overall, this study shows evidence that NMF are frequently reported by mild-to-moderate PD patients and associated with an increased number of NMS. The relationship between NoMoFa total score and motor functioning highlights the importance of understanding the clinical role of NMS and NMF in the management of PD patients.

Non-Oral Drug Delivery in Parkinson's Disease: Current Applications and Future.

Parkinson's disease (PD) is a type of movement disorder that affects the ability to perform daily activities. It is considered that 1 million people in the U.S. and more than 10 million people worldwide live with PD. It is a chronic and progressive disease, so symptoms worsen over the time. Patients experience motor symptoms such as tremors, stiffness and slow motion, and non-motor symptoms such as sleep problems, constipation, anxiety, depression and fatigue. Dopaminergic drugs are critical for treating motor symptoms in PD. Levodopa (L-DOPA) is the "gold standard" medication for the control of motor symptoms. Because of the progression of the disease, the effectiveness of oral L-DOPA decreases over time and motor fluctuations such as "delayed ON", "no ON" and unpredictable "ON-OFF" periods appear. These motor fluctuations affect the quality of life of the patient at a high rate and the patient has problems in fulfilling his daily morning routines. Gastrointestinal (GI) problems, as the common non-motor symptom, are the most important cause of motor fluctuations that occur because of inadequate oral treatment with the progression of PD. When oral treatments are not sufficient, non-oral treatments that are not affected by GI problems are required. In this review, the treatment strategies, developed and approved non-oral drug delivery systems in the early and advanced stages of PD are emphasized.

Characterization of Non-Motor Fluctuations Using the Movement Disorder Society Non-Motor Rating Scale.

Background: Non-motor fluctuations (NMF) in people with Parkinson's disease (PwP) are clinically important yet understudied. Objective: To study NMF in PwP using both the Movement Disorder Society Non-Motor Rating Scale (MDS-NMS) NMF subscale and wearable sensors. Methods: We evaluated differences in overall burden of NMF and of specific NMF across disease durations: <2 years (n = 33), 2-5 years (n = 35), 5-10 years (n = 33), and > 10 years (n = 31). In addition, wearable triaxial sensor output was used as an exploratory outcome for early morning "off" periods. Results: Significant between-group differences were observed for MDS-NMS NMF total scores (P < 0.001), and specifically for depression, anxiety, fatigue and cognition, with both NMF prevalence and burden increasing in those with longer disease duration. Whereas only 9.1% with a short disease duration had NMF (none of whom had dyskinesia), in PwP with a disease duration of >10 years this was 71.0% (P < 0.001). From a motor perspective, dyskinesia severity increased evenly with increasing disease duration, while NMF scores in affected individuals showed an initial increase with largest differences between 2-5 years disease duration (P < 0.001), with plateauing afterwards. Finally, we observed that the most common NMF symptoms in patients with sensor-confirmed early morning "off" periods were fluctuations in cognitive capabilities, restlessness, and excessive sweating. Conclusions: Non-motor fluctuations prevalence in PwP increases with disease duration, but in a pattern different from motor fluctuations. Moreover, NMF can occur in PwP without dyskinesia, and in those with NMF the severity of NMF increases most during years 2-5 after diagnosis.

Gender Differences in Levodopa Pharmacokinetics in Levodopa-Naïve Patients With Parkinson's Disease.

Background: Levodopa (LD) is the most effective drug in the treatment of Parkinson's disease (PD). Unfortunately, prolonged use of LD leads to complications, mainly motor/non-motor fluctuations (MNMF) and dyskinesias (DYS). Women seem more prone to develop such LD-related complications. Nonetheless, there is a paucity of prospective studies examining gender-related predictors of MNMF and DYS. Among several factors, which concur with a very complex scenario, changes in LD pharmacokinetics influence the drug's effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in patients with PD at their first-ever intake of LD. Materials and Methods: This is a multicentric study enrolling patients with PD, who were LD-naïve and received a single dose of LD/benserazide (100/25 mg) formulation. All participants gave their written informed consent, and the study was approved by the local Ethics Committees. To measure plasma LD concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, t 1/2), fasting blood samples were collected before drug intake and then at 8-time points until 260 min. LD concentrations were measured by ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Multiple linear regression analyses were performed to identify the predictors of the parameters. Results: Thirty-five patients (16 women and 19 men) were consecutively enrolled. Area under curve (AUC) and maximum plasma concentration (Cmax) were significantly higher in women than men (p = 0.0006 and p = 0.0014, respectively). No statistically significant difference was found regarding Tmax and t 1/2. Multiple linear regression analyses revealed that female sex (ß = 1.559116, 95% CI 0.8314479 2.286785; p < 0.0001) and body mass index (BMI) (ß = -0.0970631, 95% CI -0.1733004 -0.0208258; p = 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (ß = 1,582.499, 95% CI 731.581 2,433.417; p = 0.001). Moreover, only BMI significantly predicted t 1/2 (ß = 0.0756267, 95% CI 0.0143407 0.1369126; p = 0.017). Stratifying by gender, BMI was confirmed to significantly predict t 1/2 in women (ß = 0.1300486, 95% CI 0.0172322 0.242865; p = 0.027), but not in men. Conclusion: This study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD.

Redefining the strategy for the use of COMT inhibitors in Parkinson's disease: the role of opicapone.

INTRODUCTION: Levodopa remains the gold-standard Parkinson's disease (PD) treatment, but the inevitable development of motor complications has led to intense activity in pursuit of its optimal delivery. AREAS COVERED: Peripheral inhibition of dopa-decarboxylase has long been considered an essential component of levodopa treatment at every stage of illness. In contrast, only relatively recently have catechol-O-methyltransferase (COMT) inhibitors been utilized to block the other major pathway of degradation and optimize levodopa delivery to the brain. First and second-generation COMT inhibitors were deficient because of toxicity, sub-optimal pharmacokinetics or a short duration of effect. As such, they have only been employed once 'wearing-off' has developed. However, the third-generation COMT inhibitor, opicapone has overcome these difficulties and exhibits long-lasting enzyme inhibition without the toxicity observed with previous generations of COMT inhibitors. In clinical trials and real-world PD studies opicapone improves the levodopa plasma profile and results in a significant improvement in ON time in 'fluctuating' disease, but it has not yet been included in the algorithm for early treatment. EXPERT OPINION: This review argues for a shift in the positioning of COMT inhibition with opicapone in the PD algorithm and lays out a pathway for proving its effectiveness in early disease.

Associations Between Fluctuations in Daytime Sleepiness and Motor and Non-Motor Symptoms in Parkinson's Disease.

BACKGROUND: Non-motor fluctuations are a major concern in Parkinson's disease (PD), and they have been categorized into neuropsychiatric, autonomic and sensory fluctuations. However, this categorization does not include sleep and sleep-related features, and the association between daytime sleepiness and other motor and/or non-motor fluctuations in PD remains to be elucidated. OBJECTIVE: To investigate the relationship between daytime sleepiness and other non-motor and motor fluctuations in people with PD. METHODS: A three-day home diary recording daytime sleepiness, mood, anxiety, and motor symptoms was used along with the Karolinska Sleepiness Scale (KSS) and 6 days of accelerometer (Parkinson's KinetiGraph™; PKG™) registration to detect motor fluctuations among people with a DaTSCAN verified clinical PD diagnosis (32 men; mean PD duration, 8.2 years). Participants were categorized as motor fluctuators or non-fluctuators according to the UPDRS part IV and/or the presence of motor and non-motor fluctuations. RESULTS: Fifty-two people with PD participated. Daytime sleepiness correlated significantly with motor symptoms, mood and anxiety among those classified as motor fluctuators (n = 28). Motor fluctuators showed stronger correlations between the individual mean level of all diary variables (daytime sleepiness, anxiety, mood and motor symptoms) when compared to the non-fluctuators (n = 24). Stronger positive within-individual correlations were found among fluctuators in comparison to non-fluctuators. In general, PKG data did not correlate with diary data. CONCLUSION: Episodes of daytime sleepiness, as reported by home diaries, were associated with other self-reported non-motor and motor fluctuations, but were not supported by PKG data.