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The European Medicines Agency adopted their Geriatric Medicines Strategy more than a decade ago. The strategy aims at elucidating the evidence basis for marketing authorization of new medicines which will be used in the older population, and at ensuring the appropriate communication of findings to the patient and healthcare provider. During the past decade new tools and data sources have emerged to support the strategy goals, and their use should be considered. Possible concrete actions are presented to improve the design of clinical trials, the data collection both pre- and post-approval, the assessment of the findings, and the communication to assist informed prescription and safe medicine taking. Implementation and prioritization of these actions should be done from the perspective of addressing the needs of patients while maximizing efficient use of resources, with the aim of integrating geriatric aspects into routine medicines development and assessment.
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BACKGROUND: Quantitative 3D movement analysis using inertial measurement units (IMUs) allows for a more detailed characterization of motor patterns than clinical assessment alone. It is essential to discriminate between gait features that are responsive or unresponsive to current therapies to better understand the underlying pathophysiological basis and identify potential therapeutic strategies. OBJECTIVES: This study aims to characterize the responsiveness and temporal evolution of different gait subcomponents in Parkinson's disease (PD) patients in their OFF and various ON states following levodopa administration, utilizing both wearable sensors and the gold-standard MDS-UPDRS motor part III. METHODS: Seventeen PD patients were assessed while wearing a full-body set of 15 IMUs in their OFF state and at 20-minute intervals following the administration of a supra-threshold levodopa dose. Gait was reconstructed using a biomechanical model of the human body to quantify how each feature was modulated. Comparisons with non-PD control subjects were conducted in parallel. RESULTS: Significant motor changes were observed in both the upper and lower limbs according to the MDS-UPDRS III, 40 minutes after levodopa intake. IMU-assisted 3D kinematics detected significant motor alterations as early as 20 minutes after levodopa administration, particularly in upper limbs metrics. Although all "pace-domain" gait features showed significant improvement in the Best-ON state, most rhythmicity, asymmetry, and variability features did not. CONCLUSION: IMUs are capable of detecting motor alterations earlier and in a more comprehensive manner than the MDS-UPDRS III. The upper limbs respond more rapidly to levodopa, possibly reflecting distinct thresholds to levodopa across striatal regions.
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Antiparkinsonianos , Marcha , Levodopa , Enfermedad de Parkinson , Humanos , Levodopa/uso terapéutico , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Masculino , Fenómenos Biomecánicos , Femenino , Anciano , Persona de Mediana Edad , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/administración & dosificación , Marcha/efectos de los fármacos , Trastornos Neurológicos de la Marcha/fisiopatología , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Trastornos Neurológicos de la Marcha/diagnóstico , Trastornos Neurológicos de la Marcha/etiología , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Data on the long-term survival and incidence of disability milestones after subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) is limited. OBJECTIVES: To estimate mortality and assess the frequency/time-to-development of disability milestones (falls, freezing, hallucinations, dementia, and institutionalization) among PD patients post STN-DBS. METHODS: A longitudinal retrospective study of patients undergoing STN-DBS. For mortality, Cox proportional hazards regression analysis was performed. For disease milestones, competing risk analyses were performed and cumulative incidence functions reported. The strength of association between baselines features and event occurrence was calculated based on adjusted hazard ratios. RESULTS: The overall mortality for the 109 patients was 16 % (62.1 ± 21.3 months after surgery). Falls (73 %) and freezing (47 %) were both the earliest (40.4 ± 25.4 and 39.6 ± 28.4 months, respectively) and most frequent milestones. Dementia (34 %) and hallucinations (32 %) soon followed (56.2 ± 21.2 and mean 60.0 ± 20.7 months after surgery, respectively). Higher ADL scores in the OFF state and higher age at surgery were associated with falls, freezing, dementia and institutionalization. CONCLUSIONS: Long-term mortality rate is low after STN-DBS. Disease milestones occur later during the disease course, with motor milestones appearing first and at a higher frequency than cognitive ones.
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Estimulación Encefálica Profunda , Demencia , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/complicaciones , Núcleo Subtalámico/fisiología , Estudios de Seguimiento , Estudios Retrospectivos , Estimulación Encefálica Profunda/efectos adversos , Alucinaciones , Demencia/complicaciones , Resultado del TratamientoRESUMEN
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E7, the guidance for the conduct of clinical trials in people older than age 65 years, dates from 1994. Since then, the inclusion of older people in clinical trials has hardly improved, particularly for the oldest old age group (individuals older than age 75 years), which is the fastest growing demographic bracket in the EU. Even though most medications are taken by this group, relevant endpoints and safety outcomes for this cohort are rarely included and reported, both in clinical trials and regulatory approval documents. To improve the critical appraisal and the regulatory review of medicines taken by frail older adults, eight recommendations are presented and discussed in this Health Policy. These recommendations are brought together from different perspectives and experience of the treatment of older patients. On one side, the perspective of medical practitioners from various clinical disciplines, with their direct experience of clinical decision making; on the other, the perspective of regulators assessing the data submitted in medicine registration dossiers, their relevance to the risk-benefit balance for older patients, and the communication of the findings in the product information. Efforts to improve the participation of older people in clinical trials have been in place for more than a decade, with little success. The recommendations presented here are relevant for stakeholders, authorities, pharmaceutical companies, and researchers alike, as the implementation of these measures is not under the capacity of a single entity. Improving the inclusion of frail older adults requires awareness, focus, and action on the part of those who can effect a much needed change.
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Fragilidad , Anciano de 80 o más Años , Anciano , Humanos , Anciano Frágil , ComunicaciónRESUMEN
Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration.
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Conservadores de la Densidad Ósea , Fracturas Óseas , Osteoartritis , Osteoporosis , Deficiencia de Vitamina D , Humanos , Anciano , Calcifediol , Vitamina D , Deficiencia de Vitamina D/epidemiología , Osteoporosis/tratamiento farmacológico , Vitaminas/uso terapéutico , Conservadores de la Densidad Ósea/uso terapéutico , Suplementos Dietéticos/efectos adversos , Fracturas Óseas/prevención & control , Osteoartritis/tratamiento farmacológicoRESUMEN
Background: Physiotherapists have an ethical, professional, and regulatory responsibility for safety in all aspects of patient care. Notwithstanding, the adverse events issue has been inadequately addressed in the rehabilitation research field. Objectives: To determine the frequency and characterize the adverse events that occur during or in between physiotherapy sessions for parkinsonian syndromes. Methods: An exploratory clinical study was conducted. Physiotherapists were asked to actively report the adverse events that occurred during or between sessions for parkinsonian syndromes. Results: A total of 100 patients were enrolled in the study, which resulted in 1845 sessions. The most common adverse events reported were falls, pain/discomfort, and hypotension, with a total of 128 adverse events reported. Conclusions: During the physiotherapy sessions, adverse events do occur. Future research should clarify the relationship between AE occurrence and the type of intervention as well as causality and risk-minimization strategies.
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X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease.
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Raquitismo Hipofosfatémico Familiar , Factor-23 de Crecimiento de Fibroblastos , Osteoartritis , Síndrome Debilitante , Adulto , Animales , Raquitismo Hipofosfatémico Familiar/diagnóstico , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Raquitismo Hipofosfatémico Familiar/genética , Raquitismo Hipofosfatémico Familiar/metabolismo , Factor-23 de Crecimiento de Fibroblastos/metabolismo , Humanos , Osteoartritis/diagnóstico , Osteoartritis/tratamiento farmacológico , Osteoartritis/genética , Osteoartritis/metabolismo , Calidad de Vida , Síndrome Debilitante/diagnóstico , Síndrome Debilitante/tratamiento farmacológico , Síndrome Debilitante/genética , Síndrome Debilitante/metabolismoRESUMEN
Osteoporosis care has evolved markedly over the last 50 years, such that there are now an established clinical definition, validated methods of fracture risk assessment and a range of effective pharmacological agents. Currently, bone-forming (anabolic) agents, in many countries, are used in those patients who have continued to lose bone mineral density (BMD), patients with multiple subsequent fractures or those who have fractured despite treatment with antiresorptive agents. However, head-to-head data suggest that anabolic agents have greater rapidity and efficacy for fracture risk reduction than do antiresorptive therapies. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) convened an expert working group to discuss the tools available to identify patients at high risk of fracture, review the evidence for the use of anabolic agents as the initial intervention in patients at highest risk of fracture and consider the sequence of therapy following their use. This position paper sets out the findings of the group and the consequent recommendations. The key conclusion is that the current evidence base supports an "anabolic first" approach in patients found to be at very high risk of fracture, followed by maintenance therapy using an antiresorptive agent, and with the subsequent need for antiosteoporosis therapy addressed over a lifetime horizon.
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Anabolizantes , Conservadores de la Densidad Ósea , Osteoporosis , Fracturas Osteoporóticas , Anabolizantes/farmacología , Anabolizantes/uso terapéutico , Densidad Ósea , Conservadores de la Densidad Ósea/uso terapéutico , Humanos , Osteoporosis/complicaciones , Osteoporosis/tratamiento farmacológico , Fracturas Osteoporóticas/tratamiento farmacológico , Fracturas Osteoporóticas/prevención & controlRESUMEN
BACKGROUND: In 2016, an expert working group was convened under the auspices of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and formulated consensus recommendations for the conduct of clinical trials for drugs to prevent or treat sarcopenia. AIMS: The objective of the current paper is to provide a 2020 update of the previous recommendations in accordance with the evidence that has become available since our original recommendations. METHODS: This paper is based on literature reviews performed by members of the ESCEO working group and followed up with face to face meetings organized for the whole group to make amendments and discuss further recommendations. RESULTS: The randomized placebo-controlled double-blind parallel-arm drug clinical trials should be the design of choice for both phase II and III trials. Treatment and follow-up should run at least 6 months for phase II and 12 months for phase III trials. Overall physical activity, nutrition, co-prescriptions and comorbidity should be recorded. Participants in these trials should be at least 70-years-old and present with a combination of low muscle strength and low physical performance. Severely malnourished individuals, as well as bedridden patients, patients with extremely limited mobility or individuals with physical limitations clearly attributable to the direct effect of a specific disease, should be excluded. Multiple outcomes are proposed for phase II trials, including, as example, physical performance, muscle strength and mass, muscle metabolism and muscle-bone interaction. For phase III trials, we recommend a co-primary endpoint of a measure of functional performance and a Patient Reported Outcome Measure. CONCLUSION: The working group has formulated consensus recommendations on specific aspects of trial design, and in doing so hopes to contribute to an improvement of the methodological robustness and comparability of clinical trials. Standardization of designs and outcomes would advance the field by allowing better comparison across studies, including performing individual patient-data meta-analyses, and different pro-myogenic therapies.
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Osteoartritis , Osteoporosis , Preparaciones Farmacéuticas , Sarcopenia , Anciano , Humanos , Fuerza Muscular , Sarcopenia/tratamiento farmacológicoRESUMEN
BACKGROUND: Depression is common in patients after acute coronary syndromes (ACS) and with stable coronary artery disease (CAD) and has been associated with increased mortality and morbidity. However, it is unclear whether selective serotonin receptor inhibitors (SSRIs) reduce mortality or cardiac events in patients with CAD and depression. OBJECTIVE: We conducted a systematic review and meta-analysis to assess the effects of SSRIs on cardiovascular events in depressed CAD patients. METHODS: The CENTRAL, MEDLINE, and PsycINFO databases were searched (April 2020) for randomized controlled trials (RCTs) and extended follow-up analyses of RCTs that compared SSRIs with placebo or no intervention in patients with CAD and depression. The primary outcomes were all-cause mortality, cardiovascular mortality, and myocardial infarction incidence. The results were calculated through random-effect meta-analyses and reported in terms of risk ratio (RR) with 95% confidence intervals (CI). RESULTS: We retrieved 8 RCTs (2 of which with extended follow-up analyses), comprising a total of 1148 patients. 7 studies only included post-ACS patients. SSRIs were associated with a significantly lower risk of myocardial infarction in patients with CAD and depression (RR 0.54, 95% CI 0.34-0.86), and in post-ACS patients with depression (RR 0.56, 95% CI 0.35-0.90). We found no statistically significant difference in all-cause mortality, cardiovascular mortality, hospitalizations, angina, congestive heart failure, or stroke incidence. CONCLUSION: The use of SSRIs in post-ACS patients with depression was associated with a 44% relative risk reduction of myocardial infarction. No difference in mortality was found. Given that the quality of the evidence was low, further research is warranted.
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Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Causas de Muerte/tendencias , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/mortalidad , Depresión/complicaciones , Depresión/tratamiento farmacológico , Salud Global , Humanos , Morbilidad/tendencias , Tasa de Supervivencia/tendenciasRESUMEN
BACKGROUND: Parkinsonian variant of multiple system atrophy is a neurodegenerative disorder frequently misdiagnosed as Parkinson's disease. No early imaging biomarkers currently differentiate these disorders. METHODS: Simple visual imaging analysis of the substantia nigra and locus coeruleus in neuromelanin-sensitive magnetic resonance imaging and nigrosome 1 in susceptibility-weighted sequences was performed in thirty patients with parkinsonian variant of multiple system atrophy fulfilling possible/probable second consensus diagnostic criteria. The neuromelanin visual pattern was compared to patients with Parkinson's disease with the same disease duration (n = 10) and healthy controls (n = 10). Substantia nigra semi-automated neuromelanin area/signal intensity was compared to the visual data. RESULTS: Groups were similar in age, sex, disease duration, and levodopa equivalent dose. Hoehn & Yahr stage was higher in parkinsonian multiple system atrophy patients, 69% of whom had normal neuromelanin size/signal, significantly different from Parkinson's disease patients, and similar to controls. Nigrosome 1 signal was lost in 74% of parkinsonian multiple system atrophy patients. Semi-automated neuromelanin substantia nigra signal, but not area, measurements were able to differentiate groups. CONCLUSIONS: In patients with parkinsonism, simple visual magnetic resonance imaging analysis showing normal neuromelanin substantia nigra and locus coeruleus, combined with nigrosome 1 loss, allowed the distinction of the parkinsonian variant of multiple system atrophy from Parkinson's disease and healthy controls. This easy and widely available method was superior to semi-automated measurements in identifying specific imaging changes in substantia nigra and locus coeruleus.
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Locus Coeruleus/diagnóstico por imagen , Melaninas/análisis , Atrofia de Múltiples Sistemas/diagnóstico por imagen , Neuroimagen/métodos , Sustancia Negra/diagnóstico por imagen , Anciano , Biomarcadores/análisis , Diagnóstico Diferencial , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Locus Coeruleus/patología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/patología , Enfermedad de Parkinson/diagnóstico , Sustancia Negra/patologíaRESUMEN
INTRODUCTION: Caregivers play a major role in providing all the support and care in daily activities for their relatives with dementia. To fully describe the influence of dementia caregiving on family caregivers' life, we conducted a systematic review including caregivers' perceptions about the positive and negative aspects of caring and the expressed factors. MATERIALS AND METHODS: We conducted a systematic review including articles from January 1998 to July 2020. Qualitative studies reporting family caregivers' perceptions about their experiences and the effects/impact of dementia caregiving were eligible. Two authors extracted the data independently, and the analysis focused on the positive and negative aspects of dementia caregiving in caregivers' life. RESULTS: Eighty-one studies with 3347 participants were included in this review. The positive aspects of caregiving in caregivers' life encompass personal accomplishment and strengthening relationships, which were enhanced by good medical counselling/formal care support and family/friends support. The negative aspects included emotional and social aspects experienced by caregivers. Other factors such as inappropriate medical/formal care support, illness progression and the costs of dementia contributed to negative appraisal. DISCUSSION AND IMPLICATIONS: The findings provide insights into the holistic experience of caring for a person with dementia revelling the major positive and negative aspects underlying the caregiver role. The evidence emphasises the need 'to focus on positive aspects' and targeted interventions aimed at reducing the negative impact of caregiving, which has serious consequences on caregivers' quality of life. A multicomplex intervention for dementia informal caregiving should be developed, committing the society to promote mental health, address these community needs and improve the quality of life of the person with dementia and their family caregivers.
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We report two cases of cerebral venous thrombosis associated with the use of compounded preparations containing several active substances prescribed for weight loss. In both cases there is suspicion of additive/synergic interaction with oral contraceptives. The adverse drug reactions were considered serious, being life-threatening and causing hospitalisation for days.
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Fármacos Antiobesidad/efectos adversos , Composición de Medicamentos , Obesidad/tratamiento farmacológico , Tromboembolia Venosa/inducido químicamente , Sistemas de Registro de Reacción Adversa a Medicamentos , Anticonceptivos Orales/efectos adversos , Combinación de Medicamentos , Femenino , Humanos , Persona de Mediana EdadRESUMEN
Development of novel therapies for Duchenne muscular dystrophy (DMD) are driving the need for more efficient ways of detecting changes in disease- progression in DMD [1]. However, medicines' approval must be based on outcome measures that are acceptable from a regulatory perspective. In this article, European regulators provide an update on the recent regulatory consideration of a new endpoint (Stride Velocity 95th Centile (SV95C)) that could be used in therapeutic DMD trials. This new endpoint aims to quantify a patient's ambulation directly, reliably and continuously in a home environment with a wearable device.
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Distrofia Muscular de Duchenne/fisiopatología , Caminata , Dispositivos Electrónicos Vestibles/normas , Fenómenos Biomecánicos , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Determinación de Punto Final , Europa (Continente) , Marcha , Humanos , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/rehabilitación , Proyectos de InvestigaciónRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disorder known for the typical motor features associated. Pathologically, it is characterized by the intracellular accumulation of alpha-synuclein (aSyn) in Lewy bodies and Lewy neurites. Currently, there are no established biochemical markers for diagnosing or for following disease progression, a major limitation for the clinical practice. Posttranslational modifications (PTMs) in aSyn have been identified and implicated on its pathobiology. Since aSyn is abundant in blood erythrocytes, we aimed to evaluate whether PTMs of aSyn in the blood might hold value as a biomarker for PD. We examined 58 patients with PD and 30 healthy age-matched individuals. We found that the levels of Y125 phosphorylated, Y39 nitrated, and glycated aSyn were increased in PD, while those of SUMO were reduced. A combinatory analysis of the levels of these PTMs resulted in an increased sensitivity, with an area under curve (AUC) of 0.843 for PD versus healthy controls, and correlated with disease severity and duration. We conclude that the levels of these selected PTMs hold strong potential as biochemical markers for PD. Ultimately, our findings might facilitate the monitoring of disease progression in clinical trials, opening the possibility for developing more effective therapies against PD.
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Enfermedad de Parkinson/sangre , Procesamiento Proteico-Postraduccional , alfa-Sinucleína/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , alfa-Sinucleína/aislamiento & purificaciónRESUMEN
BACKGROUND: A specific T1-weighted magnetic resonance imaging (MRI) sequence has been shown to detect substantia nigra (SN) neuromelanin (NM) signal changes that accurately discriminate Parkinson's disease (PD) patients from controls, even in early disease stages. However, it is unclear what happens to these SN changes in later disease stages and if they can be a marker of disease progression. OBJECTIVE: to investigate the pattern of SN-NM area loss and contrast ratio (CR) intensity changes in late-stage PD (LSPD) compared to earlier disease stages. METHODS: A comparative cross-sectional study was performed, analyzing SN-NM MRI signal in LSPD (Schwab and England Activities of Daily Living Scale scoreâ<50 or Hoehn Yahr Stage [HY]â>3), comparing this group with de novo, 2-5 year PD and controls. SN-NM signal area and CR values for the internal and lateral SN regions were obtained with semi-automated methods. RESULTS: 13 LSPD, 12 de novo patients with PD, 10 PD patients with a 2-5 year disease duration, and 10 controls were included. NM signal area was significantly decreased in LSPD compared to de novo PD (P-valueâ=â0.005; sensitivity: 75%; specificity 92% and AUC: 0.86). In the lateral SN region, a decrease in the CR was detected in all PD groups compared to controls; despite not reaching statistical significance, a slight increment was observed comparing LSPD to 2-5 year PD. NM signal area significantly correlated with HY (Râ=â-0.37; Pâ<â0.05) and Movement disorder Society Unified Parkinson's Disease Rating Scale part II (MDS-UPDRS) (Râ=â-0.4; Pâ<â0.05) while a weak correlation was found with MDS-UPDRS part III (Râ=â-0.26; P: 0.1). CONCLUSION: SN area evaluated by NM-sensitive MRI may be a promising biomarker of nigral degeneration and disease progression in PD patients.
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Melaninas/metabolismo , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patología , Anciano , Biomarcadores/metabolismo , Estudios Transversales , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Sensibilidad y Especificidad , Sustancia Negra/metabolismoRESUMEN
Endocrine drugs are agents directed to a malfunctioning endocrine path. Several agents are secreted in or target the nervous system, and are thus more prone to cause neurologic adverse events (AEs). This chapter focuses on commonly used endocrine agents directed to the hypothalamus-pituitary axis, thyroid, and antidiabetic agents. The therapeutic agents are discussed in terms of indication, mechanism of action, description, and frequency of AEs, and risk factors for occurrence where available.
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Antagonistas de Hormonas/efectos adversos , Enfermedades del Sistema Nervioso/inducido químicamente , Diabetes Mellitus/tratamiento farmacológico , Enfermedades del Sistema Endocrino/tratamiento farmacológico , Humanos , Hipoglucemiantes/efectos adversosRESUMEN
Mutations in the LRRK2 and GBA genes are increasingly recognized as frequent determinants of familial and sporadic Parkinson's disease (PD). However, for several populations, accurate data on the prevalence and types of mutations are not available, because previous studies have not investigated the complete coding regions of these genes in large samples. We studied 312 PD patients ascertained at a single centre in Lisbon, Portugal. In 61 patients, with familial PD, we sequenced the entire open reading frames and exon-intron boundaries of LRRK2 and GBA. In LRRK2, we identified ten heterozygous p.Gly2019Ser (16.4%), and two heterozygous p.Arg1441His carriers (3.3%); furthermore, six patients each carried a novel LRRK2 heterozygous variant (five coding and one 3'-UTR variants) of undetermined pathogenic role. Segregation of the p.Arg1441His mutation with PD was observed in the families of both carriers. None of these variants were identified in 138 healthy controls. Screening of GBA revealed no mutations. In the remaining 251 PD patients (25 familial and 226 sporadic) we found ten additional carriers of the heterozygous p.Gly2019Ser and no carriers of the other mutations. Thus, the p.Gly2019Ser mutation was detected in a total number of 20 carriers out of 312 patients (6.4%), including twelve familial (14%) and eight sporadic patients (3.5%). This comprehensive study confirms that p.Gly2019Ser is the most important genetic cause of PD known so far in Portugal and supports the contention that p.Arg1441His is also a PD-causing mutation. These findings have relevance for the genetic testing and counseling of PD patients in this population.