Pedunculopontine Nucleus Microstructure Predicts Postural and Gait Symptoms in Parkinson's Disease

Craig, Chesney E.; Jenkinson, Ned; Brittain, John-Stuart; Grothe, Michel J.; Rochester, Lynn; Silverdale, Monty; Alho, Ana Tereza Di Lorenzo; Alho, Eduardo Joaquim Lopes; Holmes, Paul S.; Ray, Nicola

doi:10.1002/mds.28051

Cited by 29 publications

(25 citation statements)

References 36 publications

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“…Recently, Alho et al [53] developed a stereotactic map of the bilateral PPN to facilitate targeting of this nucleus for deep brain stimulation. Using this map along with DTI in a longitudinal cohort, we found that diffusivity in the PPN, but not Ch4, predicted future PIGD symptoms in PD [54]. This relationship was independent from the relationship between caudate dopamine deficiency and future PIGD, suggesting dopaminergic and cholinergic contributions to PIGD are distinct.…”

Section: Recent Vacht Pet and Ppn Mri Studies Provide Novel Insights Into Cholinergic System Changes Underlying Postural Instability And mentioning

confidence: 84%

New Developments in Cholinergic Imaging in Alzheimer and Lewy Body Disorders

Craig

Ray

Müller

et al. 2020

Curr Behav Neurosci Rep

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Purpose of Review This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders. Recent FindingsThe spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors. Multimodal imaging approaches, such as PET-MRI or multiligand PET offer new insights into the dynamic and interactive roles of the cholinergic system at both local and larger-scale neural network levels.Summary Our understanding of the heterogeneous roles of the cholinergic system in age-related diseases is evolving. Multimodal imaging approaches that provide complimentary views of the cholinergic system will be necessary to shed light on the impact of cholinergic degeneration on regional and large-scale neural networks that underpin clinical symptom manifestation in neurodegeneration.

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Section: Recent Vacht Pet and Ppn Mri Studies Provide Novel Insights Into Cholinergic System Changes Underlying Postural Instability And mentioning

confidence: 84%

New Developments in Cholinergic Imaging in Alzheimer and Lewy Body Disorders

Craig

Ray

Müller

et al. 2020

Curr Behav Neurosci Rep

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“…Although the NBM is the key node in the cortical cholinergic system, the pedunculopontine nucleus (PPN) provides cholinergic input at the level of the brainstem and the thalamus and is implicated in gait impairment in PD ( Craig et al, 2020 ; Jenkinson et al, 2009 ; Lau et al, 2015 ; Thevathasan et al, 2018 ). Impaired cholinergic integrity of the PPN is strongly related to falls and posture ( Müller et al, 2013 ), and its position in the brainstem allows it to serve as a final outflow block influencing gait ( Lewis and Shine, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

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

Wilkins

Parker

Brontë‐Stewart

2020

Neurobiology of Disease

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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.

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“…Changes in brain structure have been shown to correlate with the risk or extent of gait dysfunction in PD. Loss of microstructural integrity can be seen in PPN in patients who go on to develop a PIGD phenotype, even in early disease stages, 45 as with the finding of relatively lower signaling in the caudate nuclei on dopamine-transporter radioligand imaging. 46 Disproportionate loss of neuromelanin in the substantia nigra is also seen on MRI in PIGD in comparison to tremor-predominant phenotypes.…”

Section: Key Associations With Gait Dysfunction In Pdmentioning

confidence: 92%

Current Perspectives on the Assessment and Management of Gait Disorders in Parkinson’s Disease

Smith¹,

Brazier²,

Henderson³

2021

NDT

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Gait dysfunction is a key defining feature of Parkinson’s disease (PD), and is associated with symptoms of freezing and an increased risk of falls. In this narrative review, we cover the putative mechanisms of gait dysfunction in PD, the assessment of gait abnormalities, and the management of symptoms caused by the inherent difficulty in walking. Our understanding of the causes of gait problems in PD has progressed in recent times, moving from neurocognitive theory to correlates of affected neuronal pathways. In particular, this can be shown to correspond with abnormalities in responses to dual-task paradigms and dysfunction in cholinergic signaling. Great progress has been made in the sophistication and precision of gait assessment; however, it has firmly remained in the research domain. There is significant momentum behind wearable technologies that can be used by patients in their own environment, acting as digital biomarkers that can not only reflect progression but also independently discriminate PD from non-PD individuals. The treatment of gait dysfunction has historically relied on physical therapies and training combined with a view to mitigating the impact of such consequences as falls. Pharmacological therapies that are the mainstay of treatment in PD have tended to address symptoms like bradykinesia; however, optimization of dopaminergic therapies likely has a positive effect on quality of gait. Other targets have been assessed with the goal of improving gait, of which medications that improve cholinergic signaling appear most promising. Neuromodulation techniques are increasingly used in the form of deep-brain stimulation; however, standard targets, such as the globus pallidus interna, have a modest effect on gait. Considerable benefit has been seen through targeting the pedunculopontine nucleus, and a dual-target approach may be warranted. Stimulation of the spinal cord and brain through direct or magnetic approaches has been assessed, but requires further evidence.

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Pedunculopontine Nucleus Microstructure Predicts Postural and Gait Symptoms in Parkinson's Disease

Cited by 29 publications

References 36 publications

New Developments in Cholinergic Imaging in Alzheimer and Lewy Body Disorders

New Developments in Cholinergic Imaging in Alzheimer and Lewy Body Disorders

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

Current Perspectives on the Assessment and Management of Gait Disorders in Parkinson’s Disease

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