Parmera, Jacy Bezerra;
Wrigley, Sarah;
Cullinane, Patrick W;
Revesz, Tamas;
Jaunmuktane, Zane;
Warner, Thomas T;
De Pablo-Fernandez, Eduardo;
(2025)
The impact of cognitive impairment and Alzheimer's disease neuropathological changes on gait, freezing and falls in Parkinson's disease.
Parkinsonism & Related Disorders
, 135
, Article 107826. 10.1016/j.parkreldis.2025.107826.
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Abstract
Background: The longitudinal impact of cognitive impairment and Alzheimer's disease neuropathological changes (ADNC) on gait dysfunction in Parkinson's disease (PD) requires further evaluation. This study aimed to investigate the association between cognitive impairment and ADNC on gait disturbances in PD. // Methods: Retrospective cohort study of pathology-confirmed PD patients with brain donation to the Queen Square Brain Bank between 2010 and 2022. Cognitive parameters (latency to dementia, hallucinations, and cholinesterase inhibitors prescription) and gait outcomes (falls, freezing (FoG), wheelchair use, postural instability and gait difficulty subtype (PIGD)) were collected from medical records. Lewy pathology and ADNC were assessed using standard staging systems. Cox proportional and logistic regression analyses estimated the associated risk of cognitive parameters and pathological changes with gait outcomes. // Results: A total of 140 PD patients (mean onset 60.7 years) were included. Dementia increased risk of future falls (Hazard Ratio (HR) 0.88; 95 %CI 0.84–0.92), wheelchair dependence (HR 0.84; 95 %CI 0.78–0.89), FoG severity (Odds Ratio(OR) 0.88; 95 %CI 0.77–0.98) and the PIGD subtype (OR 0.80; 95 %CI 0.69–0.92). Hallucinations increased FoG risk (HR 0.95; 95 %CI 0.92–0.99) and the PIGD subtype (OR 0.86; 95 %CI 0.75–0.97). Global ADNC and amyloid-β deposition were associated with earlier (HR 5.17; 95 %CI 1.50–17.78) and more severe gait freezing (OR 2.13; 95 %CI 1.25–3.62). // Conclusion: Cognitive impairment and hallucinations are risk factors for future gait disturbances and FoG in PD. Global ADNC (particularly amyloid-β deposition) likely contribute to the pathophysiology of FoG, with potential therapeutic implications.
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