Gait variability is linked to the atrophy of the Nucleus Basalis of Meynert and is resistant to STN DBS in Parkinson's disease

Atrophy of the Nucleus Basalis of Meynert predicts the progression of gait variability in Parkinson’s disease

10.1101/2020.05.12.20099523 ◽

2020 ◽

Author(s):

Kevin B. Wilkins ◽

Jordan E. Parker ◽

Helen M. Bronte-Stewart

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Process ◽

Higher Order ◽

Gait Variability ◽

Nucleus Basalis ◽

Nucleus Basalis Of Meynert ◽

Time Variability ◽

Swing Time ◽

Stn Dbs

AbstractParkinson’s disease (PD) is a systemic brain disorder where the cortical cholinergic network begins to degenerate early in the disease process. Readily accessible, quantitative, and specific behavioral markers of the cortical cholinergic network are lacking. Although degeneration of the dopaminergic network may be responsible for deficits in cardinal motor signs, the control of gait is a complex process and control of higher-order aspects of gait, such as gait variability, may be influenced by cognitive processes attributed to cholinergic networks. We investigated whether swing time variability, a metric of gait variability that is independent from gait speed, was a quantitative behavioral marker of cortical cholinergic network integrity in PD. Twenty-two individuals with PD and twenty-nine age-matched controls performed a validated stepping-in-place (SIP) task to assess swing time variability off all therapy. The PD cohort also underwent structural MRI scans to measure gray matter volume of the Nucleus Basalis of Meynert (NBM), the key node in the cortical cholinergic network. Swing time variability was also measured ON subthalamic nucleus (STN) deep brain stimulation (DBS) in PD individuals. A subset of eleven individuals with PD completed the SIP task again off all therapy after three years of continuous DBS. Clinical motor assessments were performed for each condition. Swing time variability was significantly greater (i.e., worse) in PD compared to controls and greater swing time variability was related to greater atrophy of the NBM. STN DBS significantly improved cardinal motor signs but did not improve swing time variability. Swing time variability worsened in PD, off therapy, after three years of continuous STN DBS, and NBM atrophy predicted the degree of increase. In contrast, cardinal motor signs did not progress. These results demonstrate that swing time variability is a reliable marker of cortical cholinergic health, and support a framework in which higher-order aspects of gait control in PD are reliant on the cortical cholinergic system, in contrast to other motor aspects of PD that rely on the dopaminergic network.

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Combined subthalamic and nucleus basalis of Meynert deep brain stimulation for Parkinson’s disease with dementia (DEMPARK-DBS): protocol of a randomized, sham-controlled trial

Neurological Research and Practice ◽

10.1186/s42466-020-00086-w ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Christine Daniels ◽

Frank Steigerwald ◽

Philipp Capetian ◽

Cordula Matthies ◽

Uwe Malzahn ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Deep Brain Stimulation ◽

Cognitive Decline ◽

Brain Stimulation ◽

Nucleus Basalis ◽

Nucleus Basalis Of Meynert ◽

Advanced Therapies ◽

Stn Dbs ◽

Deep Brain

Abstract Introduction Dementia in Parkinson’s disease (PDD) is a common non-motor symptom of advanced disease, associated with pronounced neocortical cholinergic deficits due to neurodegeneration of the nucleus basalis of Meynert (NBM) and its cholinergic terminals. In advanced PD, patients often require advanced therapies such as infusion therapy or deep brain stimulation (DBS) to improve motor control. However, patients with associated dementia are commonly excluded from DBS because of potential deterioration of cognitive functions. Yet marked reductions in dopaminergic medication and the subsequent risk of side effects (e.g., cognitive decline, psychosis, delirium) suggest that critical re-consideration of DBS of the subthalamic nucleus (STN-DBS) for advanced stages of PD and PDD is worthwhile. In this Phase 1b study, we will provide STN-DBS to a cohort of PDD patients with severe motor fluctuations and combine two additional electrodes for augmentative neurostimulation of the NBM. Methods We aim to include 12 patients with mild-to-moderately severe PDD who fulfill indication criteria regarding motor symptoms for STN-DBS. Eligible patients will undergo implantation of a neurostimulation system with bilateral electrodes in both the STN and NBM. After 12 weeks of STN-DBS (visit 1/V1), participants will be randomized to receive either effective neurostimulation of the NBM (group 1) or sham stimulation of the NBM (group 2). NBM-DBS will be activated in all participants after 24 weeks of blinded treatment (visit 2/V2). The primary outcome will be the safety of combined bilateral STN- and NBM-DBS, determined by spontaneously-reported adverse events. Other outcome measures will comprise changes on scales evaluating cognition, activities of daily living functioning and clinical global impression, as well as motor functions, mood, behavior, caregiver burden and health economic aspects, and several domain-specific cognitive tests. Changes in scores (V1 – V2) for both treatment arms will undergo analysis of covariances, with baseline scores as covariates. Perspective The feasibility and safety of combined STN-NBM-DBS in patients with PDD will be assessed to determine whether additional NBM-DBS improves or slows the progression of cognitive decline. Positive results would provide a basic concept for future studies evaluating the efficacy of NBM-DBS in larger PDD cohorts. Indirectly, proof-of-safety of STN-DBS in PDD might influence patient selection for this standard treatment option in advanced PD. Trial registration ClinicalTrials.gov identifier (NCT number): NCT02589925.

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