Onset Of Non-motor Symptoms Research Articles

Age-Dependent Neuropsychiatric Symptoms in the NF-κB/c-Rel Knockout Mouse Model of Parkinson's Disease.

Non-motor symptoms are frequently observed in Parkinson’s disease (PD) and precede the onset of motor deficits by years. Among them, neuropsychiatric symptoms, including anxiety, depression, and apathy, are increasingly considered as a major challenge for patients with PD and their caregivers. We recently reported that mice lacking the nuclear factor-κB (NF-κB)/c-Rel protein (c-rel–/– mice) develop an age-dependent PD-like pathology and phenotype characterized by the onset of non-motor symptoms, including constipation and hyposmia, starting at 2 months of age, and motor deficits at 18 months. To assess whether c-rel–/– mice also suffer from neuropsychiatric symptoms, in this study we tested different cohorts of wild-type (wt) and c-rel–/– mice at 3, 6, 12, and 18–20 months with different behavioral tests. Mice lacking c-Rel displayed anxiety and depressive-like behavior starting in the premotor phase at 12 months, as indicated by the analysis with the open field (OF) test and the forced swim test with water wheel (FST), respectively. A deficit in the goal-oriented nesting building test was detected at 18–20 months, suggesting apathetic behavior. Taken together, these results indicate that c-rel–/– mice recapitulate the onset and the progression of PD-related neuropsychiatric symptoms. Therefore, this animal model may represent a valuable tool to study the prodromal stage of PD and for testing new therapeutic strategies to alleviate neuropsychiatric symptoms.

The Gut-Brain Axis and Its Relation to Parkinson's Disease: A Review.

Parkinson’s disease is a chronic neurodegenerative disease characterized by the accumulation of misfolded alpha-synuclein protein (Lewy bodies) in dopaminergic neurons of the substantia nigra and other related circuitry, which contribute to the development of both motor (bradykinesia, tremors, stiffness, abnormal gait) and non-motor symptoms (gastrointestinal issues, urinogenital complications, olfaction dysfunction, cognitive impairment). Despite tremendous progress in the field, the exact pathways and mechanisms responsible for the initiation and progression of this disease remain unclear. However, recent research suggests a potential relationship between the commensal gut bacteria and the brain capable of influencing neurodevelopment, brain function and health. This bidirectional communication is often referred to as the microbiome–gut–brain axis. Accumulating evidence suggests that the onset of non-motor symptoms, such as gastrointestinal manifestations, often precede the onset of motor symptoms and disease diagnosis, lending support to the potential role that the microbiome–gut–brain axis might play in the underlying pathological mechanisms of Parkinson’s disease. This review will provide an overview of and critically discuss the current knowledge of the relationship between the gut microbiota and Parkinson’s disease. We will discuss the role of α-synuclein in non-motor disease pathology, proposed pathways constituting the connection between the gut microbiome and the brain, existing evidence related to pre- and probiotic interventions. Finally, we will highlight the potential opportunity for the development of novel preventative measures and therapeutic options that could target the microbiome–gut–brain axis in the context of Parkinson’s disease.

Autophagy Disruptions Associated With Altered Optineurin Expression in Extranigral Regions in a Rotenone Model of Parkinson's Disease.

The motor features of Parkinson's disease (PD) primarily result from a lesion to the nigrostriatal dopamine system. Numerous non-motor symptoms occur in PD, many of which are postulated to stem from pathology outside of the nigrostriatal dopamine system. Perturbations to protein trafficking, disruption of mitochondrial integrity, and impaired autophagy have repeatedly been implicated in dopaminergic neuron cell death. Previously, we demonstrated that multiple markers of autophagy are disrupted in a rotenone model of PD, with alterations occurring prior to an overt lesion to the nigrostriatal dopamine system. Whether these events occur in extra-nigral nuclei in PD and when relative to a lesion in the nigrostriatal dopamine system are generally unknown. The primary goal of these studies was to determine whether autophagy disruptions, in non-dopaminergic neuronal populations occur in an environmental model of PD utilizing a mitochondrial toxin. Here, we utilized the rat rotenone PD model, with sampling time-points before and after an overt lesion to the nigrostriatal dopamine system. In analyzing autophagy changes, we focused on optineurin (OPTN) and the autophagy marker, LC3. OPTN is an autophagy cargo adapter protein genetically linked to amyotrophic lateral sclerosis and glaucoma. In the present study, we observed OPTN enrichment in all PD-relevant brain regions examined. Further, alterations in OPTN and LC3 expression and colocalized puncta suggest specific impairments to autophagy that will inform future mechanistic studies. Thus, our data suggest that autophagy disruptions may be critical to PD pathogenesis in non-dopaminergic neurons and the onset of non-motor symptoms.

Restless legs syndrome: associated non-motor symptoms and medical comorbidities: a controlled study

Introduction: Restless legs syndrome (RLS) is a chronic sensorimotor disorder characterized by discomfort or pain, predominantly in the legs, resulting in an urge to move during times of rest. These disturbances are often accompanied by sleep fragmentation, which can significantly increase medical comorbidities over time and can have a detrimental effect on a patient’s overall quality of life. In this retrospective study, we examined the temporal relationship between the time of RLS diagnosis and the onset of non-motor symptoms (NMS) and medical comorbidities. Patients and methods: Thirty-six RLS patients were evaluated for age at: symptom onset, time of diagnosis, time of occurrence of NMS, and medical comorbidities. We used structured interviews, validated questionnaires, and past medical records to aggregate and verify patient data. There was no clinical evidence to suggest secondary RLS in any patient at time of diagnosis. Results: Twenty-five patients were diagnosed as having RLS alone and eleven were diagnosed with RLS and Parkinson’s disease (RLS + PD). In the RLS + PD group, irrespective of which disorder presented first, we found that patients exhibited symptoms of RLS at a significantly later age than those patients with RLS alone (P,0.05). The incidence and severity of NMS were significantly higher in the RLS + PD group compared to RLS alone and controls (P,0.001). Increased risk of RLS was identified in patients exhibiting mood changes and sleep deficits, and these risk factors manifested 5 and 10 years prior, respectively, to their diagnosis. Conclusion: Primary RLS develops earlier in those patients who only have RLS compared to those who later also develop PD. Mood and sleep impairment can be present years prior to the diagnosis of RLS. Other medical comorbidities associated with RLS included hypertension, hyperlipidemia, arthritis, chronic pain, and diabetes.

The onset of nonmotor symptoms in Parkinson's disease (the ONSET PD study).

Nonmotor symptoms (NMS) in Parkinson's disease (PD) can precede onset of motor symptoms. Relationship between premotor symptoms onset and motor features is limited. Our aim is to describe the presence and perceived onset of NMS in PD as well as their possible association with motor phenotype. Presence and onset of NMS were assessed by a custom-made questionnaire in 109 newly diagnosed untreated PD patients and 107 controls from 11 Spanish and Austrian centers. Seventeen of thirty-one NMS were more common in patients than controls (P < 0.05). They were usually mild and frequently reported to occur at different time-spans before motor symptoms. Anhedonia, apathy, memory complaints, and inattention occurred more frequently during the 2-year premotor period. Those reported more frequently in the 2- to 10-year premotor period were smell loss, mood disturbances, taste loss, excessive sweating, fatigue, and pain. Constipation, dream-enacting behavior, excessive daytime sleepiness, and postprandial fullness were frequently perceived more than 10 years before motor symptoms. No correlation between NMS burden and motor severity, age, or gender was observed. NMS associated in four clusters: rapid eye movement sleep behavior disorder symptoms-constipation, cognition-related, mood-related, and sensory clusters. No cluster was associated with a specific motor phenotype or severity. NMS are common in early unmedicated PD and frequently reported to occur in the premotor period. They are generally mild, but a patient subgroup showed high NMS burden mainly resulting from cognition-related symptoms. Certain NMS when present at the time of assessment or in the premotor stage, either alone or in combination, allowed discriminating PD from controls.

Drug therapy in patients with Parkinson’s disease

Parkinson`s disease (PD) is a progressive, disabling neurodegenerative disorder with onset of motor and non-motor features. Both reduce quality of life of PD patients and cause caregiver burden. This review aims to provide a survey of possible therapeutic options for treatment of motor and non motor symptoms of PD and to discuss their relation to each other. MAO-B-Inhibitors, NMDA antagonists, dopamine agonists and levodopa with its various application modes mainly improve the dopamine associated motor symptoms in PD. This armentarium of PD drugs only partially influences the onset and occurrence of non motor symptoms. These PD features predominantly result from non dopaminergic neurodegeneration. Autonomic features, such as seborrhea, hyperhidrosis, orthostatic syndrome, salivation, bladder dysfunction, gastrointestinal disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis, cognitive dysfunction with impaired execution and impulse control may appear. Drug therapy of these non motor symptoms complicates long-term PD drug therapy due to possible occurrence of drug interactions, - side effects, and altered pharmacokinetic behaviour of applied compounds. Dopamine substituting compounds themselves may contribute to onset of these non motor symptoms. This complicates the differentiation from the disease process itself and influences therapeutic options, which are often limited because of additional morbidity with necessary concomitant drug therapy.