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Background: Research shows that individuals with Parkinson's disease (PD) who have a postural instability and gait difficulties (PIGD) subtype have a faster disease progression compared to those with a tremor dominant (TD) subtype. Nevertheless, our understanding of the structural brain changes contributing to these clinical differences remains limited, primarily because many brain imaging techniques are only capable of detecting changes in the later stages of the disease. Objective: Free water (FW) has emerged as a robust progression marker in several studies, showing increased values in the posterior substantia nigra that predict symptom worsening. Here, we examined longitudinal FW changes in TD and PIGD across multiple brain regions. Methods: Participants were TD and PIGD enrolled in the Parkinson's Progression Marker Initiative (PPMI) study who underwent diffusion MRI at baseline and 2 years later. FW changes were quantified for regions of interest (ROI) within the basal ganglia, thalamus, brainstem, and cerebellum. Results: Baseline FW in all ROIs did not differ between groups. Over 2 years, PIGD had a greater percentage increase in FW in the putamen, globus pallidus, and cerebellar lobule V. A logistic regression model incorporating percent change in motor scores and FW in these brain regions achieved 91.4% accuracy in discriminating TD and PIGD, surpassing models based solely on clinical measures (74.3%) or imaging (76.1%). Conclusion: The results further suggest the use of FW to study disease progression in PD and provide insight into the differential course of brain changes in early-stage PD subtypes.

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BACKGROUND: Despite the significant impact of lower limb symptoms on everyday life activities in Parkinson's disease (PD), knowledge of the neural correlates of lower limb deficits is limited. OBJECTIVE: We ran an fMRI study to investigate the neural correlates of lower limb movements in individuals with and without PD. METHODS: Participants included 24 PD and 21 older adults who were scanned while performing a precisely controlled isometric force generation task by dorsiflexing their ankle. A novel MRI-compatible ankle dorsiflexion device that limits head motion during motor tasks was used. The PD were tested on their more affected side, whereas the side in controls was randomized. Importantly, PD were tested in the off-state, following overnight withdrawal from antiparkinsonian medication. RESULTS: The foot task revealed extensive functional brain changes in PD compared to controls, with reduced fMRI signal during ankle dorsiflexion within the contralateral putamen and M1 foot area, and ipsilateral cerebellum. The activity of M1 foot area was negatively correlated with the severity of foot symptoms based on the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III). CONCLUSION: Overall, current findings provide new evidence of brain changes underlying motor symptoms in PD. Our results suggest that pathophysiology of lower limb symptoms in PD appears to involve both the cortico-basal ganglia and cortico-cerebellar motor circuits.

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BACKGROUND: Much of our understanding of the deficits in force control in Parkinson's disease (PD) relies on findings in the upper extremity. Currently, there is a paucity of data pertaining to the effect of PD on lower limb force control. OBJECTIVE: The purpose of this study was to concurrently evaluate upper- and lower-limb force control in early-stage PD and a group of age- and gender-matched healthy controls. METHODS: Twenty individuals with PD and twenty-one healthy older adults participated in this study. Participants performed two visually guided, submaximal (15% of maximum voluntary contractions) isometric force tasks: a pinch grip task and an ankle dorsiflexion task. PD were tested on their more affected side and after overnight withdrawal from antiparkinsonian medication. The tested side in controls was randomized. Differences in force control capacity were assessed by manipulating speed-based and variability-based task parameters. RESULTS: Compared with controls, PD demonstrated slower rates of force development and force relaxation during the foot task, and a slower rate of relaxation during the hand task. Force variability was similar across groups but greater in the foot than in the hand in both PD and controls. Lower limb rate control deficits were greater in PD with more severe symptoms based on the Hoehn and Yahr stage. CONCLUSIONS: Together, these results provide quantitative evidence of an impaired capacity in PD to produce submaximal and rapid force across multiple effectors. Moreover, results suggest that force control deficits in the lower limb may become more severe with disease progression.

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BACKGROUND AND OBJECTIVES: To review the current evidence on the options available for initiating dopaminergic treatment of motor symptoms in early-stage Parkinson disease and provide recommendations to clinicians. METHODS: A multidisciplinary panel developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence. RESULTS: Initial treatment with levodopa provides superior motor benefit compared to treatment with dopamine agonists, whereas levodopa is more likely than dopamine agonists to cause dyskinesia. The comparison of different formulations of dopamine agonists yielded little evidence that any one formulation or method of administration is superior. Long-acting forms of levodopa and levodopa with entacapone do not appear to differ in efficacy from immediate-release levodopa for motor symptoms in early disease. There is a higher risk of impulse control disorders associated with the use of dopamine agonists than levodopa. Recommendations on initial therapy for motor symptoms are provided to assist the clinician and patient in choosing between treatment options and to guide counseling, prescribing, and monitoring of efficacy and safety.

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OBJECTIVE: To provide evidence-based recommendations for treatment of adults with an unprovoked first seizure. METHODS: We defined relevant questions and systematically reviewed published studies according to the American Academy of Neurology's classification of evidence criteria; we based recommendations on evidence level. RESULTS AND RECOMMENDATIONS: Adults with an unprovoked first seizure should be informed that their seizure recurrence risk is greatest early within the first 2 years (21%-45%) (Level A), and clinical variables associated with increased risk may include a prior brain insult (Level A), an EEG with epileptiform abnormalities (Level A), a significant brain-imaging abnormality (Level B), and a nocturnal seizure (Level B). Immediate antiepileptic drug (AED) therapy, as compared with delay of treatment pending a second seizure, is likely to reduce recurrence risk within the first 2 years (Level B) but may not improve quality of life (Level C). Over a longer term (>3 years), immediate AED treatment is unlikely to improve prognosis as measured by sustained seizure remission (Level B). Patients should be advised that risk of AED adverse events (AEs) may range from 7% to 31% (Level B) and that these AEs are likely predominantly mild and reversible. Clinicians' recommendations whether to initiate immediate AED treatment after a first seizure should be based on individualized assessments that weigh the risk of recurrence against the AEs of AED therapy, consider educated patient preferences, and advise that immediate treatment will not improve the long-term prognosis for seizure remission but will reduce seizure risk over the subsequent 2 years.

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