Lucia Macchiusi

Parkinson’s disease (PD) is a multisystem disorder, with early changes extending beyond basal ganglia circuitries and involving non-dopaminergic pathways, including cerebellar networks. Whether cerebellar dysfunction reflects a compensatory mechanism or an intrinsic hallmark of disease progression remains unresolved. In this cross-sectional study, we examined how cerebellar γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx) systems, as well as their excitatory/inhibitory (E/I) balance, are modulated along the disease course. As to ascertain how these mechanisms contribute to motor and non-motor features in the premotor and early stages of PD, 18 individuals with isolated REM sleep behavior disorder (iRBD), 20 de novo, drug-naïve PD (dnPD), and 18 matched healthy controls underwent clinical, cognitive, and neuropsychiatric assessments alongside cerebellar magnetic resonance spectroscopy (MRS, MEGA-PRESS, 3T). While cerebellar neurotransmitter levels did not differ significantly across groups, dnPD patients exhibited a shift toward hyperexcitability in the E/I ratio, without correlation to clinical or cognitive measures. In contrast, in iRBD, an inverse relationship between heightened GABAergic activity and neuropsychiatric symptoms emerged. These findings suggest an early, dynamic cerebellar involvement, potentially reflecting compensatory modulation of altered basal ganglia output. Our results support cerebellar GABA MRS as a promising biomarker and open perspectives for targeting non-dopaminergic pathways in PD.

Parkinson’s disease (PD) is a multisystem disorder, with early changes extending beyond basal ganglia circuitries and involving non-dopaminergic pathways, including cerebellar networks. Whether cerebellar dysfunction reflects a compensatory mechanism or an intrinsic hallmark of disease progression remains unresolved. In this cross-sectional study, we examined how cerebellar γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx) systems, as well as their excitatory/inhibitory (E/I) balance, are modulated along the disease course. As to ascertain how these mechanisms contribute to motor and non-motor features in the premotor and early stages of PD, 18 individuals with isolated REM sleep behaviour disorder (iRBD) 20 de novo, drug-naïve PD (dnPD), and 18 matched healthy controls underwent clinical, cognitive, and neuropsychiatric assessments alongside cerebellar magnetic resonance spectroscopy (MRS, MEGA-PRESS, 3T). While cerebellar neurotransmitter levels did not differ significantly across groups, dnPD patients exhibited a shift toward hyperexcitability in the E/I ratio, without correlation to clinical or cognitive measures. In contrast, in iRBD an inverse relationship between heightened GABAergic activity and neuropsychiatric symptoms emerged. These findings suggest an early, dynamic cerebellar involvement, potentially reflecting compensatory modulation of altered basal ganglia output. Our results support cerebellar GABA MRS as a promising biomarker and open perspectives for targeting non-dopaminergic pathways in PD.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a risk factor for developing Parkinson’s disease (PD) and may represent its prodromal state. We compared neuropsychological and neuropsychiatric phenotypes of idiopathic (i) RBD, PD and healthy comparators (HC) in order to identify iRBD specific characteristics. Thirty-eight patients with iRBD, 38 PD patients with RBD (PD + RBD), 38 PD patients without RBD (PD-RBD) and 38 HC underwent a comprehensive neurological, neuropsychological and neuropsychiatric evaluation. iRBD, PD + RBD and PD-RBD performed worse than HC in short-term verbal memory, praxia, language and executive functions. iRBD had higher levels of anxiety, depression, apathy and alexithymia than HC. iRBD had higher levels of apathy than PD + RBD. Both PD groups had higher levels of anxiety and depression than HC. Surprisingly, iRBD performed better than all groups in long-term verbal memory. Patients diagnosed with iRBD are characterized by poor global cognitive performance, but better long-term memory and higher levels of depression, anxiety, alexithymia and apathy. Alexithymia and apathy in patients diagnosed with iRBD may be the expression of precocious derangement of emotional regulation, subsequently observed also in PD. Cognitive and neuropsychiatric symptoms of iRBD are early clinical manifestations of widespread neurodegeneration.

Freezing of Gait (FoG) is a common symptom in Parkinson’s Disease (PD) occurring with significant variability and severity and is associated with increased risk of falls. FoG detection in everyday life is not trivial, particularly in patients manifesting the symptom only in specific conditions. Various wearable devices have been proposed to detect PD symptoms, primarily based on inertial sensors. We here report the results of the validation of a novel system based on a pair of pressure insoles equipped with a 3D accelerometer to detect FoG episodes. Twenty PD patients attended a motor assessment protocol organized into eight multiple video recorded sessions, both in clinical and ecological settings and both in the ON and OFF state. We compared the FoG episodes detected using the processed data gathered from the insoles with those tagged by a clinician on video recordings. The algorithm correctly detected 90% of the episodes. The false positive rate was 6% and the false negative rate 4%. The algorithm reliably detects freezing of gait in clinical settings while performing ecological tasks. This result is promising for freezing of gait detection in everyday life via wearable instrumented insoles that can be integrated into a more complex system for comprehensive motor symptom monitoring in PD.

Background: Mobile health, predominantly wearable technology and mobile apps, have been considered in Parkinson disease to provide valuable ecological data between face-to-face visits and improve monitoring of motor symptoms remotely. Objective: We explored the feasibility of using a technology-based mHealth platform comprising a smartphone in combination with a smartwatch and a pair of smart insoles, described in this study as the PD_manager system, to collect clinically meaningful data. We also explored outcomes and disease-related factors that are important determinants to establish feasibility. Finally, we further validated a tremor evaluation method with data collected while patients performed their daily activities. Methods: PD_manager trial was an open-label parallel group randomized study.The mHealth platform consists of a wristband, a pair of sensor insoles, a smartphone (with dedicated mobile Android apps) and a knowledge platform serving as the cloud backend. Compliance was assessed with statistical analysis and the factors affecting it using appropriate regression analysis. The correlation of the scores of our previous algorithm for tremor evaluation and the respective Unified Parkinson’s Disease Rating Scale estimations by clinicians were explored. Results: Of the 75 study participants, 65 (87%) completed the protocol. They used the PD_manager system for a median 11.57 (SD 3.15) days. Regression analysis suggests that the main factor associated with high use was caregivers’ burden. Motor Aspects of Experiences of Daily Living and patients’ self-rated health status also influence the system’s use. Our algorithm provided clinically meaningful data for the detection and evaluation of tremor. Conclusions: We found that PD patients, regardless of their demographics and disease characteristics, used the system for 11 to 14 days. The study further supports that mHealth can be an effective tool for the ecologically valid, passive, unobtrusive monitoring and evaluation of symptoms. Future studies will be required to demonstrate that an mHealth platform can improve disease management and care. Trial Registration: ISRCTN Registry ISRCTN17396879; http://www.isrctn.com/ISRCTN17396879 International Registered Report Identifier (IRRID): RR2-10.1186/s13063-018-2767-4

BACKGROUND Mobile health, predominantly wearable technology and mobile apps, have been considered in Parkinson disease to provide valuable ecological data between face-to-face visits and improve monitoring of motor symptoms remotely. OBJECTIVE We explored the feasibility of using a technology-based mHealth platform comprising a smartphone in combination with a smartwatch and a pair of smart insoles, described in this study as the PD_manager system, to collect clinically meaningful data. We also explored outcomes and disease-related factors that are important determinants to establish feasibility. Finally, we further validated a tremor evaluation method with data collected while patients performed their daily activities. METHODS PD_manager trial was an open-label parallel group randomized study.The mHealth platform consists of a wristband, a pair of sensor insoles, a smartphone (with dedicated mobile Android apps) and a knowledge platform serving as the cloud backend. Compliance was assessed with statistical analysis and the factors affecting it using appropriate regression analysis. The correlation of the scores of our previous algorithm for tremor evaluation and the respective Unified Parkinson’s Disease Rating Scale estimations by clinicians were explored. RESULTS Of the 75 study participants, 65 (87%) completed the protocol. They used the PD_manager system for a median 11.57 (SD 3.15) days. Regression analysis suggests that the main factor associated with high use was caregivers’ burden. Motor Aspects of Experiences of Daily Living and patients’ self-rated health status also influence the system’s use. Our algorithm provided clinically meaningful data for the detection and evaluation of tremor. CONCLUSIONS We found that PD patients, regardless of their demographics and disease characteristics, used the system for 11 to 14 days. The study further supports that mHealth can be an effective tool for the ecologically valid, passive, unobtrusive monitoring and evaluation of symptoms. Future studies will be required to demonstrate that an mHealth platform can improve disease management and care. INTERNATIONAL REGISTERED REPORT RR2-10.1186/s13063-018-2767-4