Objective: To investigate the association between clinical markers of cognitive impairment, severity, and distribution of Alzheimer’s disease neuropathological changes (ADNC) with gait difficulties, freezing of gait (FoG), and falls in a large group of pathology-confirmed Parkinson’s disease (PD) patients.

Background: Gait impairment, FoG, and falls are disabling manifestations of PD [1]. Cognitive dysfunction and gait disturbances are pathophysiologically connected, commonly associated, and are defining features of the clinical heterogeneity in PD [2]. Although prior studies using in vivo biomarkers suggested that amyloid-β and tau deposition may also contribute to gait and balance impairments in early PD, its longitudinal relationship and the association with ADNC have not yet been elucidated [3,4].

Method: Retrospective analysis of a pathology-confirmed PD cohort with brain donation between January 2010 and February 2022. Data on clinical markers of cognitive dysfunction (cognition at onset, visual hallucinations, latency to dementia, and use of cholinesterase inhibitors) and gait outcomes (falls, postural instability and gait difficulties (PIGD) subtype, onset, and severity of FoG) were retrospectively collected from medical records. Distribution of Lewy pathology and ADNC were assessed using standard staging systems.

Results: One hundred and forty patients were included (80 men [57.1%]; mean [SD] age at diagnosis, 60.7 [12.0]). Cox proportional hazard regression models showed an increased adjusted risk of FoG for early hallucinations (HR 0.96; 95% CI, 0.92 – 0.99) and higher severity of amyloid-β AD neuropathology (high National Institute on Aging– Alzheimer’s Association (NIA-AA) score HR 4.04 (1.17 – 14.00); p = 0.028). Also, the risk of moderate to severe FoG was also associated with a higher ADNC. Early dementia showed an increased adjusted risk of falls (HR 0.89; 95% CI  0.86 – 0.92 ; p < .001) and the PIGD subtype.

Conclusion: Cognitive dysfunction was associated with earlier gait disturbances, falls, and FoG in PD. ADNC showed an association with earlier and more severe FoG. The potential role of ADNC in gait and falls in PD opens new potential therapeutic avenues with important clinical implications.

References: 1. Mirelman A, Bonato P, Camicioli R, et al. Gait impairments in Parkinson’s disease. Lancet Neurol 2019;18:697-708.
2. De Pablo-Fernandez E, Lees AJ, Holton JL, Warner TT. Prognosis and Neuropathologic Correlation of Clinical Subtypes of Parkinson Disease. JAMA Neurol 2019
3. Kim R, Lee J, Kim HJ, et al. CSF β-amyloid(42) and risk of freezing of gait in early Parkinson disease. Neurology 2019;92:e40-e47.
4. Müller ML, Frey KA, Petrou M, et al. β-Amyloid and postural instability and gait difficulty in Parkinson’s disease at risk for dementia. Mov Disord 2013;28:296-301.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-impact-of-cognitive-impairment-and-alzheimers-disease-neuropathological-changes-on-gait-and-falls-in-parkinsons-disease/