Rehabilitation Engineering in Parkinson's disease

Impairment of postural control is a common consequence of Parkinson's disease (PD) that becomes more and more critical with the progression of the disease, in spite of the available medications. Postural instability is one of the most disabling features of PD and induces difficulties with postural transitions, initiation of movements, gait disorders, inability to live independently at home, and is the major cause of falls. Falls are frequent (with over 38% falling each year) and may induce adverse consequences like soft tissue injuries, hip fractures, and immobility due to fear of falling. As the disease progresses, both postural instability and fear of falling worsen, which leads patients with PD to become increasingly immobilized. The main aims of this dissertation are to: 1) detect and assess, in a quantitative way, impairments of postural control in PD subjects, investigate the central mechanisms that control such motor performance, and how these mechanism are affected by levodopa; 2) develop and validate a protocol, using wearable inertial sensors, to measure postural sway and postural transitions prior to step initiation; 3) find quantitative measures sensitive to impairments of postural control in early stages of PD and quantitative biomarkers of disease progression; and 4) test the feasibility and effects of a recently-developed audio-biofeedback system in maintaining balance in subjects with PD. In the first set of studies, we showed how PD reduces functional limits of stability as well as the magnitude and velocity of postural preparation during voluntary, forward and backward leaning while standing. Levodopa improves the limits of stability but not the postural strategies used to achieve the leaning. Further, we found a strong relationship between backward voluntary limits of stability and size of automatic postural response to backward perturbations in control subjects and in PD subjects ON medication. Such relation might suggest that the central nervous system presets postural response parameters based on perceived maximum limits and this presetting is absent in PD patients OFF medication but restored with levodopa replacement. Furthermore, we investigated how the size of preparatory postural adjustments (APAs) prior to step initiation depend on initial stance width. We found that patients with PD did not scale up the size of their APA with stance width as much as control subjects so they had much more difficulty initiating a step from a wide stance than from a narrow stance. This results supports the hypothesis that subjects with PD maintain a narrow stance as a compensation for their inability to sufficiently increase the size of their lateral APA to allow speedy step initiation in wide stance. In the second set of studies, we demonstrated that it is possible to use wearable accelerometers to quantify postural performance during quiet stance and step initiation balance tasks in healthy subjects. We used a model to predict center of pressure displacements associated with accelerations at the upper and lower back and thigh. This approach allows the measurement of balance control without the use of a force platform outside the laboratory environment. We used wearable accelerometers on a population of early, untreated PD patients, and found that postural control in stance and postural preparation prior to a step are impaired early in the disease when the typical balance and gait intiation symptoms are not yet clearly manifested. These novel results suggest that technological measures of postural control can be more sensitive than clinical measures. Furthermore, we assessed spontaneous sway and step initiation longitudinally across 1 year in patients with early, untreated PD. We found that changes in trunk sway, and especially movement smoothness, measured as Jerk, could be used as an objective measure of PD and its progression. In the third set of studies, we studied the feasibility of adapting an existing audio-biofeedback device to improve balance control in patients with PD. Preliminary results showed that PD subjects found the system easy-to-use and helpful, and they were able to correctly follow the audio information when available. Audiobiofeedback improved the properties of trunk sway during quiet stance. Our results have many implications for i) the understanding the central mechanisms that control postural motor performance, and how these mechanisms are affected by levodopa; ii) the design of innovative protocols for measuring and remote monitoring of motor performance in the elderly or subjects with PD; and iii) the development of technologies for improving balance, mobility, and consequently quality of life in patients with balance disorders, such as PD patients with augmented biofeedback paradigms.

The impact of cardiac rehabilitation on lifestyles, psychological correlates and the clinical course of cardiac disease

Objectives: The aim of this research was to evaluate the impact of Cardiac Rehabilitation (CR) on risky lifestyles, quality of life, psychopathology, psychological distress and well-being, considering the potential moderating role of depression, anxiety and psychosomatic syndromes on lifestyles modification. The influence of CR on cardiac morbidity and mortality was also evaluated. Methods: The experimental group (N=108), undergoing CR, was compared to a control group (N=85) of patients affected by cardiovascular diseases, not undergoing CR, at baseline and at 1-month, 6- and 12-months follow-ups. The assessment included: the Structured Clinical Interview for DSM-IV, the structured interview based on Diagnostic Criteria for Psychosomatic Research (DCPR), GOSPEL questionnaire on lifestyles, Pittsburgh Sleep Quality Index, Morisky Medication Adherence Scale, MOS 36-Item Short Form Health Survey, Symptom Questionnaire, Psychological Well-Being Scale and 14-items Type D Scale. Results: Compared to the control group, CR was associated to: maintenance of the level of physical activity, improvement of correct dietary behaviors and stress management, enhancement of quality of life and sleep; reduction of the most frequently observed psychiatric diagnoses and psychosomatic syndromes at baseline. On the contrary, CR was not found to be associated with: healthy dietary habits, weight loss and improvement on medications adherence. In addition, there were no relevant effects on sub-clinical psychological distress and well-being, except for personal growth and purpose in life (PWB). Also, CR did not seem to play a protective role against cardiac recurrences. The presence of psychosomatic syndromes and depressive disorders was a mediating factor on the modification of specific lifestyles. Conclusions: The findings highlight the need of a psychosomatic assessment and an evaluation of psychological sub-clinical symptomatology in cardiac rehabilitation, in order to identify and address specific factors potentially associated with the clinical course of the heart disease.

Evidence-based polytherapies and long-term mortality after acute myocardial infarction in very old subjects compared with elderly and adults: a nested case-control study

Background: Clinical trials have demonstrated that selected secondary prevention medications for patients after acute myocardial infarction (AMI) reduce mortality. Yet, these medications are generally underprescribed in daily practice, and older people are often absent from drug trials. Objectives: To examine the relationship between adherence to evidence-based (EB) drugs and post-AMI mortality, focusing on the effects of single therapy and polytherapy in very old patients (≥80 years) compared with elderly and adults (<80 years). Methods: Patients hospitalised for AMI between 01/01/2008 and 30/06/2011 and resident in the Local Health Authority of Bologna were followed up until 31/12/2011. Medication adherence was calculated as the proportion of days covered for filled prescriptions of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), β-blockers, antiplatelet drugs, and statins. We adopted a risk set sampling method, and the adjusted relationship between medication adherence (PDC≥75%) and mortality was investigated using conditional multiple logistic regression. Results: The study population comprised 4861 patients. During a median follow-up of 2.8 years, 1116 deaths (23.0%) were observed. Adherence to the 4 EB drugs was 7.1%, while nonadherence to any of the drugs was 19.7%. For both patients aged ≥80 years and those aged <80 years, rate ratios of death linearly decreased as the number of EB drugs taken increased. There was a significant inverse relationship between adherence to each of 4 medications and mortality, although its magnitude was higher for ACEIs/ARBs (adj. rate ratio=0.60, 95%CI=0.52–0.69) and statins (0.60, 0.50–0.72), and lower for β-blockers (0.75, 0.61–0.92) and antiplatelet drugs (0.73, 0.63–0.84). Conclusions: The beneficial effect of EB polytherapy on long-term mortality following AMI is evident also in nontrial older populations. Given that adherence to combination therapies is largely suboptimal, the implementation of strategies and initiatives to increase the use of post-AMI secondary preventive medications in old patients is crucial.

Dati preliminari dello studio multicentrico caso-controllo "Grave danno epatico acuto indotto da farmaci"

Il danno epatico indotto dall'assunzione di farmaci viene comunemente indicato con il termine inglese DILI (Drug-Induced Liver Injury). Il paracetamolo rappresenta la causa più comune di DILI, seguito da antibiotici, FANS e farmaci antitubercolari. In particolare, i FANS sono una delle classi di farmaci maggiormente impiegate in terapia. Numerosi case report descrivono pazienti che hanno sviluppato danno epatico fatale durante il trattamento con FANS; molti di questi farmaci sono stati ritirati dal commercio in seguito a gravi reazioni avverse a carico del fegato. L'ultimo segnale di epatotossicità indotto da FANS è associato alla nimesulide; in alcuni paesi europei come la Finlandia, la Spagna e l'Irlanda, la nimesulide è stata sospesa dalla commercializzazione perché associata ad un'alta frequenza di epatotossicità. Sulla base dei dati disponibili fino a questo momento, l'Agenzia Europea dei Medicinali (EMA) ha recentemente concluso che i benefici del farmaco superano i rischi; un possibile aumento del rischio di epatotossicità associato a nimesulide rimane tuttavia una discussione aperta di cui ancora molto si dibatte. Tra le altre classi di farmaci che possono causare danno epatico acuto la cui incidenza tuttavia non è sempre ben definita sono gli antibiotici, quali amoxicillina e macrolidi, le statine e gli antidepressivi.Obiettivo dello studio è stato quello di determinare il rischio relativo di danno epatico indotto da farmaci con una prevalenza d'uso nella popolazione italiana maggiore o uguale al 6%. E’ stato disegnato uno studio caso controllo sviluppato intervistando pazienti ricoverati in reparti di diversi ospedali d’Italia. Il nostro studio ha messo in evidenza che il danno epatico da farmaci riguarda numerose classi farmacologiche e che la segnalazione di tali reazioni risulta essere statisticamente significativa per numerosi principi attivi. I dati preliminari hanno mostrato un valore di odds ratio significativo statisticamente per la nimesulide, i FANS, alcuni antibiotici come i macrolidi e il paracetamolo.

Cognitive and behavioural assessment of parkinsonian syndromes at onset: a longitudinal study

Background: cognitive impairment is one of the non motor features widely descripted in parkinsonian syndrome, it has been related to the motor characteristics of the parkinsonian syndrome, associated with neuropsychiatric dysfunction and the characteristic sleep and autonomic features. It has been shown to be highly prevalent at all disease stages and to contribute significantly to disability. Objectives: aim of this study is to evaluate longitudinally the cognitive and behavioral characteristics of patients with a parkinsonian syndrome at onset; to describe the cognitive and behavioral characteristics of each parkinsonian syndrome; to define in PD patients at onset the presence of MCI or Parkinson disease dementia; to correlate the cognitive and behavioral characteristics with the features of the parkinsonian syndrome and with the associated sleep and autonomic features. Results: we recruited 55 patients, 22 did not present cognitive impairment both at T0 and at T1. 18 patients presented a progression of cognitive impairment. Progressive cognitively impaired patients were older and presented the worst motor phenotype. Progression of cognitive impairment was not associated to sleep and autonomic features. Conclusion: the evaluation of cognitive impairment could not be useful as a predictor of a correct diagnosis but each non motor domain will help to clarify and characterize the motor syndrome. The diagnosis of parkinsonian disorders lies in building a clinical profile in conjunction with other clinical characteristics such as mode of presentation, disease progression, response to medications, sleep and autonomic features.

Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy (NFLE).

Nocturnal Frontal Lobe Epilepsy (NFLE) is characterized by onset during infancy or childhood with persistence in adulthood, family history of similar nocturnal episodes simulating non-REM parasomnias (sleep terrors or sleepwalking), general absence of morphological substrates, often by normal interictal electroencephalographical recordings (EEGs) during wakefulness. A family history of epilepsy may be present with Mendelian autosomal dominant inheritance has been described in some families. Recent studies indicate the involvement of neuronal nicotinic acetylcholine receptors (nAChRs) in the molecular mechanisms of NFLE. Mutations in the genes encoding for the α4 (CHRNA4) and ß2 (CHRNB2) subunits of the nAChR induce changes in the biophysical properties of nAChR, resulting generally in a “gain of function”. Preclinical studies report that activation of a nuclear receptor called type peroxisome proliferator-activated receptor (PPAR-α) by endogenous molecules or by medications (e.g. fenofibrate) reduces the activity of the nAChR and, therefore, may decrease the frequency of seizures. Thus, we hypothesize that negative modulation of nAChRs might represent a therapeutic strategy to be explored for pharmacological treatment of this form of epilepsy, which only partially responds to conventional antiepileptic drugs. In fact, carbamazepine, the current medication for NFLE, abolishes the seizures only in one third of the patients. The aim of the project is: 1)_to verify the clinical efficacy of adjunctive therapy with fenofibrate in pharmacoresistant NFLE and ADNFLE patients; focousing on the analysis of the polysomnographic action of the PPAR- agonist (fenofibrate). 2)_to demonstrate the subtended mechanism of efficacy by means of electrophysiological and behavioral experiments in an animal model of the disease: particularly, transgenic mice carrying the mutation in the nAChR 4 subunit (Chrna4S252F) homologous to that found in the humans. Given that a PPAR-α agonist, FENOFIBRATE, already clinically utilized for lipid metabolism disorders, provides a promising therapeutic avenue in the treatment of NFLE\ADNFLE.