Parkinsonian gait in aging: A feature of Alzheimer's pathology?

Highlights

• Low level of Aβ-42 is associated with parkinsonian gait.

• Parkinsonian gait may be a phenotype of Alzheimer's pathology.

• A phenotype-based gait approach is a useful screening tool for Alzheimer's disease.

Abstract

Introduction

Central neurological gait abnormalities (CNGA; i.e. frontal or parkinsonian) are frequently associated with neurodegenerative conditions in older adults, but their pathophysiological substrates remain poorly described. This cross-sectional study aims to assess the association between cerebrospinal fluid (CSF) Alzheimer's biomarkers and CNGA.

Methods

CSF biomarkers (phosphor-tau, total tau and Aβ_1–42) were measured in 52 patients with CNGA (77.33 ± 6.09 years; 28.8% female). Gait phenotypes were evaluated by two diagnosis-blinded assessors and classified as frontal gait, parkinsonian gait or other gait abnormalities.

Results

Parkinsonian gait was significantly associated with a decreased CSF Aβ₄₂ even after adjusting on age, gender, comorbidities and white matter changes (β: −0.32; 95% CI: [−340.6; −22.9]; p value: 0.026). Phosphor-tau and total tau were not associated with any other CNGA (i.e. frontal gait and other gait abnormalities).

Discussion

Parkinsonian gait represents a gait phenotype of Alzheimer's pathology in patients with CNGA.

Introduction

Gait disorders are common in aging (Sudarsky, 1990) affecting >80% of adults older than 85 (Snijders et al., 2007a). Beside non-neurological gait disorders and peripheral neuropathy, brain disorders are a frequent cause of gait abnormalities, concerning 20% of older adults (Mahlknecht et al., 2013; Verghese et al., 2002a). The phenotypes of the central neurological gait abnormalities (CNGA) include frontal, parkinsonian and other abnormal gait patterns that are found in neurological diseases, such as Parkinson's disease (PD), vascular dementia or normal pressure hydrocephalus (NPH) (Snijders et al., 2007b; Verghese et al., 2002b). CNGA represent a diagnostic challenge for clinicians because their sensitivity and specificity for a definite neurological diagnosis are poor (Sudarsky, 1990). For example, parkinsonian gait is common in PD, but also found in NPH, vascular dementia or other neurodegenerative conditions (Mahlknecht et al., 2013). On the other hand, a specific pathology, such as vascular dementia, may present with various phenotypes of gait disorders (i.e. frontal, parkinsonian, etc.) (Verghese et al., 2002a). Therefore, a phenotype-based approach of gait disorders rather than the classic disease-based approach might be more relevant to disentangle the pathophysiological mechanisms underlying gait disorders.

Various pathological mechanisms, such as white matter abnormalities (Allali et al., 2016), α-synuclein or amyloid deposition, contribute to CNGA in aging. Amyloidopathy has been associated with parkinsonism in non-PD patients with CNGA (Allali et al., 2018) and in dopa-resistant gait disorders of PD patients (Rochester et al., 2017). This observation suggests that parkinsonism represents a clinical phenotype related to Alzheimer's pathology. However, the relationship between gait phenotypes and amyloidopathy has been never studied yet.

Therefore, we propose to study the association between cerebrospinal fluid (CSF) Aβ_1–42, total tau (t-tau), and tau phosphorylated at threonine 181 (phosphor-tau) and gait phenotypes in older adults with CNGA. Based on previous studies that showed an association between parkinsonism and amyloidopathy (Allali et al., 2018; Bohnen et al., 2014; Ding et al., 2017), we hypothesized that parkinsonian gait will be associated with decreased CSF Aβ_1–42. Establishing an association between central neurological gait abnormalities and Alzheimer's pathology could disentangle the neuropathological substrates of gait phenotypes and improve the screening approach to Alzheimer's pathology.