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Visual dysfunction predicts Parkinson's-linked cognitive decline 18 months ahead

Simple vision tests can predict which people with Parkinson’s disease will develop cognitive impairment and possible dementia 18 months later, according to a study from University College London (UCL).

The study adds to evidence that vision changes precede the cognitive decline that occurs in many, but not all, people with Parkinson’s.

In another study, the same research team found that structural and functional connections of brain regions become decoupled throughout the entire brain in people with Parkinson’s disease, particularly among people with vision problems.

The two studies together show how losses and changes to the brain’s wiring underlie the cognitive impairment experienced by many people with Parkinson’s disease.

Lead author Dr Angeliki Zarkali (Dementia Research Centre, UCL Queen Square Institute of Neurology) said: “We have found that people with Parkinson’s disease who have visual problems are more likely to get dementia, and that appears to be explained by underlying changes to their brain wiring.

“Vision tests might provide us with a window of opportunity to predict Parkinson’s dementia before it begins, which may help us find ways to stop the cognitive decline before it’s too late.”

For the first study the researchers studied 77 people with Parkinson’s disease and found that simple vision tests predicted who would go on to get dementia after a year and a half. Dementia is a common, debilitating aspect of Parkinson’s disease, estimated to affect roughly 50% of people within 10 years of a Parkinson’s diagnosis.

These longitudinal findings add weight to previous studies that were done at one time point, which had suggested that performance in vision tests, involving commonly used eye charts and skewed images of cats and dogs, was linked to the risk of cognitive decline.

The study also found that those who went on to develop Parkinson’s dementia had losses in the wiring of the brain, including in areas relating to vision and memory. The researchers used recently developed methods to analyse finely detailed MRI scans, enabling them to pick up the damage to the brain’s white matter. The researchers identified white matter damage to some of the long-distance wiring connecting the front and back of the brain, which helps the brain to function as a cohesive whole network.

The second study involved 88 people with Parkinson’s disease (33 of whom had visual dysfunction and were thus judged to have a high risk of dementia) and 30 healthy adults as a control group, whose brains were imaged using MRI scans.

In the healthy brain, there is a correlation between how strong the structural (physical) connections between two regions are, and how much those two regions are connected functionally. That coupling is not uniform across the brain, as there is some degree of decoupling in the healthy brain, particularly in areas involved in higher-order processing, which might provide the flexibility to enable abstract reasoning. Too much decoupling appears to be linked to poor outcomes.

The researchers found that people with Parkinson’s disease exhibited a higher degree of decoupling across the whole brain. Areas at the back of the brain, and less specialised areas, had the most decoupling in Parkinson’s patients.

Parkinson’s patients with visual dysfunction had more decoupling in some, but not all brain regions, particularly in memory-related regions in the temporal lobe.

The research team also found changes to the levels of some neurotransmitters (chemical messengers) in people at risk of cognitive decline, suggesting that receptors for those transmitters may be potential targets for new drug treatments for Parkinson’s dementia. Notably, while dopamine is known to be implicated in Parkinson’s, the researchers found that other neurotransmitters – acetylcholine, serotonin and noradrenaline – were particularly affected in people at risk of cognitive decline.

Angeliki said: “The two papers together help us to understand what’s going on in the brains of people with Parkinson’s who experience cognitive decline, as it appears to be driven by a breakdown in the wiring that connects different brain regions.”

Dr Rimona Weil (UCL Queen Square Institute of Neurology), senior author of both papers, said: “Our findings could be valuable for clinical trials, by showing that vision tests can help us identify who we should be targeting for trials of new drugs that might be able to slow Parkinson’s. And ultimately if effective treatments are found, then these simple tests may help us identify who will benefit from which treatments.”

The researchers were supported by Alzheimer’s Research UK, Wellcome, and the National Institute for Health Research UCLH Biomedical Research Centre.

 

Study details (1)
Visual Dysfunction Predicts Cognitive Impairment and White Matter Degeneration in Parkinson's Disease

Angeliki Zarkali, Peter McColgan, Louise-Ann Leyland, Andrew J Lees, Rimona S Weil

Published in Movement Disorders on 9 January 2021

Abstract
Background
Visual dysfunction predicts dementia in Parkinson's disease (PD), but whether this translates to structural change is not known. The objectives of this study were to identify longitudinal white matter changes in patients with Parkinson's disease and low visual function and also in those who developed mild cognitive impairment.
Methods
We used fixel‐based analysis to examine longitudinal white matter change in PD. Diffusion MRI and clinical assessments were performed in 77 patients at baseline (22 low visual function/55 intact vision and 13 PD‐mild cognitive impairment/51 normal cognition) and 25 controls and again after 18 months. We compared microstructural changes in fiber density, macrostructural changes in fiber bundle cross‐section and combined fiber density and cross‐section, across white matter, adjusting for age, sex, and intracranial volume.
Results
Patients with PD and visual dysfunction showed worse cognitive performance at follow‐up and were more likely to develop mild cognitive impairment compared with those with normal vision (P = 0.008). Parkinson's with poor visual function showed diffuse microstructural and macrostructural changes at baseline, whereas those with mild cognitive impairment showed fewer baseline changes. At follow‐up, Parkinson's with low visual function showed widespread macrostructural changes, involving the fronto‐occipital fasciculi, external capsules, and middle cerebellar peduncles bilaterally. No longitudinal change was seen in those with mild cognitive impairment at baseline or converters, even when the 2 groups were combined.
Conclusion
Parkinson's patients with poor visual function show increased white matter damage over time, providing further evidence for visual function as a marker of imminent cognitive decline. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

 

Study details (2)
Organisational and neuromodulatory underpinnings of structural-functional connectivity decoupling in patients with Parkinson’s disease

Angeliki Zarkali, Peter McColgan, Louise-Ann Leyland, Andrew J Lees, Geraint Rees, Rimona S Weil

Published in Organisational Biology on 19 January 2021

Abstract
Parkinson’s dementia is characterised by changes in perception and thought, and preceded by visual dysfunction, making this a useful surrogate for dementia risk. Structural and functional connectivity changes are seen in humans with Parkinson’s disease, but the organisational principles are not known. We used resting-state fMRI and diffusion-weighted imaging to examine changes in structural-functional connectivity coupling in patients with Parkinson’s disease, and those at risk of dementia. We identified two organisational gradients to structural-functional connectivity decoupling: anterior-to-posterior and unimodal-to-transmodal, with stronger structural-functional connectivity coupling in anterior, unimodal areas and weakened towards posterior, transmodal regions. Next, we related spatial patterns of decoupling to expression of neurotransmitter receptors. We found that dopaminergic and serotonergic transmission relates to decoupling in Parkinson’s overall, but instead, serotonergic, cholinergic and noradrenergic transmission relates to decoupling in patients with visual dysfunction. Our findings provide a framework to explain the specific disorders of consciousness in Parkinson’s dementia, and the neurotransmitter systems that underlie these.

 

[link url="https://movementdisorders.onlinelibrary.wiley.com/doi/full/10.1002/mds.28477 (Open access)"]Movement Disorders study (Open access)[/link]

 

[link url="https://www.nature.com/articles/s42003-020-01622-9"]Communications Biology study (Open access)[/link]

 

 

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