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

ABSTRACT: Parkinson'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 subthalamic nucleus (STN) deep brain stimulation (PD-DBS cohort) and twenty-nine age-matched controls performed a validated stepping-in-place (SIP) task to assess swing time variability off all therapy. The PD-DBS cohort underwent structural MRI scans to measure gray matter volume of the Nucleus Basalis of Meynert (NBM), the key node in the cortical cholinergic network. In order to determine the role of the dopaminergic system on swing time variability, it was measured ON and OFF STN DBS in the PD-DBS cohort, and on and off dopaminergic medication in a second PD cohort of thirty-two individuals (PD-med). A subset of eleven individuals in the PD-DBS cohort completed the SIP task again off all therapy after three years of continuous DBS to assess progression of gait impairment. 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, as was gait speed. STN DBS significantly improved cardinal motor signs and gait speed but did not improve swing time variability, which was replicated in the second cohort using dopaminergic medication. Swing time variability continued to worsen in PD, off therapy, after three years of continuous STN DBS, and NBM atrophy showed a trend for predicting 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.

SUBMITTER: Wilkins KB

PROVIDER: S-EPMC7711311 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionDementia 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.MethodsWe 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.PerspectiveThe 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 registrationClinicalTrials.gov identifier (NCT number): NCT02589925.

Project description:BackgroundSome people with Parkinson's disease (PD) report poorer dynamic postural stability following high-frequency deep brain stimulation of the subthalamic nucleus (STN-DBS), which may contribute to an increased falls risk. However, some studies have shown low-frequency (60 Hz) STN-DBS improves clinical measures of postural stability, potentially providing support for this treatment. This double-blind randomised crossover study aimed to investigate the effects of low-frequency STN-DBS compared to high-frequency stimulation on objective measures of gait rhythmicity in people with PD.MethodsDuring high- and low-frequency STN-DBS and while off-medication, participants completed assessments of symptom severity and walking (e.g., Timed Up-and-Go). During comfortable walking, the harmonic ratio, an objective measures of gait rhythmicity, was derived from head- and trunk-mounted accelerometers to provide insight in dynamic postural stability. Lower harmonic ratios represent less rhythmic walking and have discriminated people with PD who experience falls. Linear mixed model analyses were performed on fourteen participants.ResultsLow-frequency STN-DBS significantly improved medial-lateral and vertical trunk rhythmicity compared to high-frequency. Improvements were independent of electrode location and total electrical energy delivered. No differences were noted between stimulation conditions for temporal gait measures, clinical mobility measures, motor symptom severity or the presence of gait retropulsion.ConclusionsThis study provides evidence for the acute benefits of low-frequency stimulation for gait outcomes in STN-DBS PD patients, independent of electrode location. However, the perceived benefits of this therapy may be diminished for people who experienced significant tremor pre-operatively, as lower frequencies may cause these symptoms to re-emerge.Trial registrationThis study was prospectively registered with the Australian and New Zealand Clinical Trials Registry on 5 June 2018 (ACTRN12618000944235).

Project description:ImportanceCorticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD.ObjectiveTo investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes.Design, setting, and participantsIn this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings.Main outcomes and measuresDemographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation.ResultsIn total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n?=?163), lower in typical AD (10 [5-16]; n?=?937), and lowest in limbic predominant AD (8 [5-11], n?=?163) (P?<?.001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n?=?148), higher in typical AD (25 [19-30]; n?=?727), and highest in limbic predominant AD (26 [19-32]; n?=?127) (P?=?.002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (?, -1.5; 95% CI, -2.9 to -0.15; P?=?.03) and typical AD (?, -3.2; 95% CI, -3.9 to -2.4; P?<?.001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (?, 2.5; 95% CI, 1.4-3.5; P?<?.001), apolipoprotein E ?4 allele (?, 1.3; 95% CI, 0.15-2.5; P?=?.03), and lower Mini-Mental State Examination scores (?, -1.8; 95% CI, -3.2 to -0.31; P?=?.02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases.Conclusions and relevanceThese data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.

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

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