Multimodal response to levodopa treatment in advanced and late Parkinson’s disease

Parkinson’s disease (PD) is a progressive age-dependent neurodegenerative disease. Life expectancy increasing and a better knowledge in PD treatment management, including the advent of device-aided therapies, are likely to increase the number of patients who can reach an advanced disease stage and eventually enter the late stage (LS) of the disease in the next decades. LSPD is a recently recognized disease stage, in which patients are severely disable and dependent on activities of daily life (ADLs) due to the presence of poor treatment responsive motor and non-motor symptoms (NMS) thus highly impacting caregiver’s burden and social/health care system. Hence an operational clinical criteria to identify LSPD patients has been recently proposed suggesting adopt a Schwab and England activity of daily life score (S&E) < 50 in the MED ON condition. LSPD patients’ treatment management is challenging. Treatment-related adverse effects (AEs) are frequent and few evidence in terms of phamacological and non-pharmacological treatment efficacy are available as they are barely included in clinical or research studies and even the participation into routine hospital-based visits can be an unsurmountable limit. At the same time, even if general PD disease severity milestones have been described, we do not know how LSPD patients specifically progress, if they do evolve and if there are clinical markers or biomarkers of poor outcome that could be useful to focus specific therapeutic interventions for this specific disease stage. We aimed to deeply characterize the clinical phenotype, needs along with clinical markers or biomarkers of poor outcome of LSPD patients. As levodopa (L-dopa) is the mainstay of PD treatment and a simplification of treatment regimen in later disease stages has been suggested, we also aimed to investigate the real effect of L-dopa on motor symptoms and NMS among LSPD patients, if compared to advanced stage patients. Among NMS, we focused our work particularly on speech impairment, exploring speech response to L-dopa among LSPD patients and to fine stimulation parameters adjustment, in combination with L-dopa, in advanced PD patients submitted to deep brain stimulation (DBS). Participants were LSPD (Schwab and England ADL Scale [S&E] 3 in “MED ON” state) and advanced stage PD patients previously submitted to DBS. Cross-sectional data were obtained by means of a comprehensive clinical assessment including a L-dopa challenge test with a suprathreshold dose. A subgroup of thirteen LSPD patients underwent a neuroimaging study in order to study neuromelanin (NM) substantia nigra (SN) area changes in the latest disease stage if compared to previous ones. Automated analysis of speech were used to study the effect of a supramaximal L-dopa dose in twenty-four LSPD patients as well as L-dopa and frequency stimulation adjustment in twenty deep brain stimulated patients. Longitudinal data were collected only for LSPD patients. Descriptive, regression and survival curves analysis were performed. Fifty LSPD patients (female 46%) were included. Mean age was 77.5 ± 5.9 years and mean disease duration was 15.5± 6.5 years. At baseline, 76% had L-dopa-induced motor complications (MCs), mainly non-troublesome, 68%were demented, 54% had psychosis and 68% depression. Caregiver distress was high. L-dopa responsiveness was mild (18% ± 12 of improvement on MDS-UPDRS-III) and present only for appendicular signs, being tremor and rigidity the most responsive ones, while axial signs did not change. The clinical significance of this better motor response was marginal according to the Clinical Global Improvement Scale and the change in the S&E between OFF and ON state. The magnitude of L-dopa response correlated with the acute appearance of dyskinesias and the severity of MCs. After one-year, 20% of the patients were dead, 18% institutionalized in nursing home and 6% passed to a HY 5. MDS-UPDRS-motor mean score worsened 7.2 ± 10.3 points, corresponding to a 15.7% (±23.0) increase, with no difference between tremor-dominant versus akinetic-rigid phenotype or PD patients with/without dementia (PDD/non-PDD) at baseline. However, there was heterogeneity between patients in terms of disease progression, as 12 patients (37.5%) had a motor deterioration ≤ 3 points and 14 (43%) ≤ 5 points with concomitant worsening of the MDS-UPDRS-II (Motor Aspects of Experiences of Daily Living), of 2.1±4.1. Conversely, eleven cases (32%) did not deteriorate and, in fact, 10 of these improved between 1-6 points at the MDS-UPDRS-III. Overall NMS worsened, mostly in cognition/mood, urinary and gastrointestinal domains. Conversely, MCs improved despite similar L-dopa equivalent dose. Functional independence and quality of life worsened. Dysphagia severity at baseline predicted a poor combined outcome (death, being institutionalized or developing HY 5) (Hazard ratio 2.3, 95% CI 1.12- 4.4; p = 0.01) or death alone (Hazard ratio of 2.9, 95% CI 1.12- 8.6, p=0.04), whereas magnitude of L-dopa response of LSPD patients did not. SN area evaluated by NM-sensitive magnetic resonance imaging (MRI), resulted able to differentiate LSPD patients from both de novo PD patients and controls, though not founding statistical differences between LSPD patients and patients with two-five year disease duration. Performing an indirect comparison of the effect of L-dopa on motor symptoms and NMS among twenty LSPD patients and twenty-two, not-matched, advanced PD patients, a milder response on motor symptoms (11% vs. 37% of improvement on MDS-UPDRS-III) and an absence of response on NMS, namely anxiety, fatigue and pain, were found among LSPD patients, with concomitant higher frequency of drug-related AEs. Indeed orthostatic hypotension (OH) or drowsiness occurred among 35% of LSPD patients versus 13% of advanced PD patients, who still presented a benefit from L-dopa intake on pain and anxiety, while fatigue did not change. Scales applicability and blood pressure assessment while standing resulted challenging among LSPD patients with consequent missing data on depression, anxiety, pain and OH identification and possible underestimation of those symptoms. No effect of L-dopa was found on speech and voice by means of both automated analysis and clinical evaluation in LSPD patients. Respiratory support for speech and voice stability were the most affected speech and voice features among LSPD patients. Among axial symptoms, speech seemed to be the most L-dopa unresponsive one. Speech unresponsiveness to L-dopa was confirmed also among subthalamic (STN)-DBS treated patients with both mild and severe dysarthria, at least in combination with stimulation. Conversely, PD patients with severe dysarthria under chronic STN-DBS treatment showed a benefit of lowering frequency of stimulation from 130 Hz (High frequency stimulation [HFS]) to 60Hz (low frequency stimulation [LFS]), with concomitant increment of voltage, in order to keep constant the total energy delivered. Indeed speech intelligibility and articulatory diadochokinesis presented an acute improvement passing from HFS to LFS, as assessed by automated speech analysis and such a benefit, when present and clinically meaningful, lasted during six months with no motor worsening, though requiring medication adjustment. The present study provides further evidence to better delineate a recently recognized and poorly described PD stage. An extensive cross-sectional and longitudinal observation is proposed. LSPD patients clearly differ from previous stages in terms of both clinical features, needs, therapeutic response and drugs’ tolerability profile. Over one year, a heterogeneous disease progression of motor symptoms is still present and it seems even steeper if compared to previous stages, while functional independence globally worsened. As well as mild motor improvements are still possible with treatment adjustment, it is also possible to identify a clinical phenotype of LSPD patients who are likely to have a better response to L-dopa if compared to the other ones. Clinical assessment and therapeutic interventions for swallowing problems should be a priority. PDD or living in a nursing home remain other indicators of poor outcome. In the next few years the number of LSPD patients who have been previously submitted to device-aided therapies is expected to increase, bringing new clinical scenarios, such as the fine parameters adjustment of invasive treatment for challenging motor and NMS and the difficult management or eventual interruption of those treatments among elderly and frail LSPD patients. Overall, future research and fund allocations should be specifically oriented on LSPD patients, usually not included or considered in clinical trials or research studies, and on L-dopa not-responsive aspects and caregivers’ need

Years of Schooling, Human Capital and the Body Mass Index of European Females

We use the compulsory school reforms implemented in European countries after the II World War to investigate the causal effect of education on the Body Mass Index (BMI) and the incidence of overweight and obesity among European females. Our IV estimates suggest that years of schooling have a protective effect on BMI. The size of the estimated effect is not negligible but smaller than the one found in comparable recent work for the US. We depart from the current empirical literature in three main directions. First, we use a multi-country approach. Second, we complement the standard analysis of the causal impact of years of schooling on BMI with one relying on a broader measure of education, i.e. individual standardized cognitive tests, and show that the current focus in the literature on years of schooling as the measure of education is not misplaced. Last, we evaluate whether the current focus on conditional mean effects should be integrated with an approach which allows for heterogeneous responses to changes in compulsory education. Although our evidence based on quantile regressions is mixed, there is some indication that the protective effect of schooling does not increase monotonically from the lower to the upper quantile of the distribution of BMI. Rather, the marginal effect is stronger among overweight (but not obese) females than among females with BMI above 30.obesity, human capital, Europe

Years of Schooling, Human Capital and the Body Mass Index of European Females

We find that the protective effect of years of schooling on the BMI of European females is non negligible, but smaller than the one recently found for the US. By using individual standardized cognitive tests instead of years of schooling as the measure of education we show that the current focus in the literature on years of schooling is not misplaced. We also investigate whether the response to changes in compulsory education is heterogeneous, and find that the protective effect of schooling is stronger among overweight than among obese females.Obesity, human capital, Europe

Unfolding the link between big data analytics and supply chain planning

Big data analytics (BDA) has captured growing research interests in operations and supply chain management literature, yet, despite the significant implication, extant knowledge falls short in drawing the link between BDA and supply chain planning (SCP) with in a structured manner. This paper employs the Delphi technique to uncover the synergies between BDA technology, conceptualized as big data sources and BDA methods, and the SCP activities framed with the SCP matrix. The panel runs for three rounds with 35 experts including scholars, supply chain practitioners, and BDA specialists. The results of this paper suggest that the relevance of BDA depends on the focal SCP activity. Thirty-five projections are presented on the expected impact of BDA on SCP that are classified into three groups based on the significance of impact and probability of occurrence. This work advances the understanding of BDA in supply chain management drawing implications to prioritize BDA investment for SCP

Off-time Treatment Options for Parkinson’s Disease

Funding Information: Margherita Fabbri declares the following conflicts of interest: honoraria to speak: BIAL and AbbVie; Consultancy/ LVL Médicale. Raquel Barbosa declares the following conflicts of interest: financial support by Fundação para a Ciência e Tecnologia (FCT) through a Ph.D. Scholarship (SFRH/BD/143797/2019) and Prémio João Lobo Antunes by Santa Casa da Misericórdia de Lisboa. Olivier Rascol declares the following conficts of interest: advisory board and consultancy: BIAL; advisory boards and consultancy: AbbVie, Adamas, Acorda, Addex, AlzProtect, Apopharma, Astrazeneca, Axovant, Biogen, Britannia, Buckwang, Cerespir, Clevexel, Denali, INC Reasearch, Lundbeck, Lupin, Merck, MundiPharma, Neuratris, Neuroderm, Novartis, ONO Pharma, Osmotica, Parexel, Pfzer, Prexton Therapeutics, Quintiles, Roche, Sanof, Servier, Sunovion, Théranexus, Takeda, Teva, UCB, Vectura, Watermark Research, XenoPort, XO, and Zambon; grant: Agence Nationale de la Recherche (ANR), CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, MJFox Foundation, Programme Hospitalier de Recherche Clinique, European Commission (FP7, H2020), and Cure Parkinson IK; other: grant to participate in a symposium and contribute to the review of an IPMDS article . Publisher Copyright: © 2023, The Author(s).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.publishersversionepub_ahead_of_prin

In vitro leaf-derived organogenesis and somaclonal variant detection in Humulus lupulus L

The exploitation of somaclonal variation potentially could be a valid strategy to overcome the depletion of hop intraspecific agrobiodiversity. To increase somaclonal variation induction, it is possible to resort to several strategies including a differentiated starting explant material such as leaves, roots and stems, an extended time in which cultures are maintained in vitro, and a wellbalanced cytokinin/auxin ratio. In this research, firstly, the influence of growth regulator type and concentration and the effect of the period of in vitro hop leaf culture (6, 12, and 18 wk) were investigated. Secondly, cytofluorimetric and Random Amplification of Polymorphic DNA (RAPD) analyses were carried out to verify the occurrence of somaclonal variation. Adventitious shoots were obtained in all media containing 6-benzylaminopurine (BAP) (except BAP at lowest concentration tested), with no influence detected by culture period. Mutants were detected among regenerants (16.8%) with more than half of the tetraploids obtained from medium containing the highest BAP concentration (35.55 mM). Mutants detected by RAPD analysis were independent of the medium composition and time in culture. A strong influence regarding explant was observed where nearly half of mutants obtained originated from cultured leaf tissues. Further studies are needed to characterize the field performance of mutants

Assessment of Parkinson’s disease medication state through automatic speech analysis

Parkinson’s disease (PD) is a progressive degenerative disorder of the central nervous system characterized by motor and nonmotor symptoms. As the disease progresses, patients alternate periods in which motor symptoms are mitigated due to medication intake (ON state) and periods with motor complications (OFF state). The time that patients spend in the OFF condition is currently the main parameter employed to assess pharmacological interventions and to evaluate the efficacy of different active principles. In this work, we present a system that combines automatic speech processing and deep learning techniques to classify the medication state of PD patients by leveraging personal speech-based bio-markers. We devise a speakerdependent approach and investigate the relevance of different acoustic-prosodic feature sets. Results show an accuracy of 90.54% in a test task with mixed speech and an accuracy of 95.27% in a semi-spontaneous speech task. Overall, the experimental assessment shows the potentials of this approach towards the development of reliable, remote daily monitoring and scheduling of medication intake of PD patients.info:eu-repo/semantics/publishedVersio

Main reasons for rejection of deep brain stimulation surgery in candidates with Parkinson Disease

Abstract of the poster presented at the 2nd International Congress of CiiEM - Translational Research and Innovation in Human and Health Science. 11-13 June, 2017, Campus Egas Moniz, Monte de Caparica, Portugalinfo:eu-repo/semantics/publishedVersio

High frequency of psychosis in late-stage Parkinsońs disease.

BACKGROUND: Psychosis is a frequent non-motor symptom in Parkinson's disease (PD). Estimates of the frequency of Parkinsońs disease psychosis (PDP) vary widely. Knowledge about the frequency and phenomenology of psychosis in late-stage (LS) PD patients is limited.This study aimed to determine the frequency of psychosis in LSPD patients through clinical diagnostic interview (CDI) (gold standard), according to NINDS/NIMH diagnostic criteria for PDP. The secondary objectives were to characterize the phenomenology, to test selected instruments and assess their adequacy in comparison to CDI, and to assess the psychiatric comorbidities. METHODS: A cross-sectional study including LSPD patients (patients with ≥ 7 years from symptoms onset and Hoehn and Yahr scale score > 3 or a Schwab and England scale score < 50% in the ON condition) was conducted. Patients were subjected to psychiatric, neurological, and neuropsychological evaluations. Each patient was interviewed by a psychiatrist who performed a CDI. RESULTS: 92 LSPD patients were included. 55.4% experienced psychotic symptoms according to NINDS/NIMH diagnostic criteria for PDP. Hallucinations were present in 94.1% and delusions in 29.4% of the psychotic patients. Visual hallucinations were the most common (88.23%) psychotic symptom. 72.5% of LSPD patients with psychotic symptoms had at least one comorbid psychiatric diagnosis. Lower frequency of psychosis was found when the assessment was performed only through selected instruments rather than CDI. CONCLUSIONS: A high frequency (55.4%) of psychotic symptoms and comorbid psychiatric (72.5%) diagnosis were found in LSPD patients. The use of CDI, in addition to structured scales may increase the sensitivity of detecting psychotic symptoms

Home monitoring of motor fluctuations in Parkinson's disease patients

In Parkinson's disease, motor fluctuations (worsening of tremor, bradykinesia, freezing of gait, postural instability) affect up to 70% of patients within 9 years of \textsc {l}-dopa therapy. Nevertheless, the assessment of motor fluctuations is difficult in a medical office, and is commonly based on poorly reliable self-reports. Hence, the use of wearable sensors is desirable. In this preliminary trial, we have investigated bradykinesia and freezing of gait—FOG—symptoms by means of inertial measurement units. To this purpose, we have employed a single smartphone on the patient's waist for FOG experiment (38 patients), and on patient thigh for LA (93 subjects). Given the sound performance achieved in this trial (AUC = 0.97 for FOG and AUC = 0.92 for LA), motor fluctuations may be estimated in domestic environments. To this end, we plan to perform measures and data processing on SensorTile, a tiny IoT module including several sensors, a microcontroller, a BlueTooth low-energy interface and microSD card, implementing an electronic diary of motor fluctuations, posture and dyskinesia during activity of daily living