Declining motor and cognitive functioning and the role of gait in dementia

Poor motor function, including gait dysfunction, is often observed in people with dementia.1O'Keeffe ST Kazeem H Philpott RM Playfer JR Gosney M Lye M Gait disturbance in Alzheimer's disease: a clinical study.Age Ageing. 1996; 25: 313-316Crossref PubMed Scopus (0) Google Scholar Recent evidence suggests that poor motor function might even precede the onset of dementia.2Collyer TA Murray AM Woods RL et al.Association of dual decline in cognition and gait speed with risk of dementia in older adults.JAMA Netw Open. 2022; 5e2214647Crossref PubMed Scopus (24) Google Scholar, 3Nyul-Toth A DelFavero J Mukli P et al.Early manifestation of gait alterations in the Tg2576 mouse model of Alzheimer's disease.Geroscience. 2021; 43: 1947-1957Crossref PubMed Scopus (13) Google Scholar In The Lancet Healthy Longevity, Shahram Oveisgharan and colleagues4Oveisgharan S Wang T Barnes LL Schneider JA Bennett DA Buchman AS The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study.Lancet Healthy Longev. 2024; (published online April 3.)https://doi.org/10.1016/S2666-7568(24)00033-3Google Scholar provide insights into the timing of motor (gait and hand strength) and cognitive decline and how their trajectories relate to neuropathological data. To accomplish this, the authors leveraged rich longitudinal data combined with autopsy data from the Religious Orders Study (ROS), the Rush Memory and Aging Project (MAP), and the Minority Aging Research Study (MARS) cohorts.4Oveisgharan S Wang T Barnes LL Schneider JA Bennett DA Buchman AS The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study.Lancet Healthy Longev. 2024; (published online April 3.)https://doi.org/10.1016/S2666-7568(24)00033-3Google Scholar The authors used functional mixed-effects models to flexibly model changing associations between non-linear trajectories of gait, hand strength, and cognition with neuropathology outcomes. On average, decline in gait and hand strength preceded decline in cognition. Oveisgharan and colleagues also observed varied associations between different neuropathologies and decline in gait, hand strength, and cognition. From these findings, the authors emphasised that macroinfarcts were associated with gait decline before they were associated with cognitive decline (9·25 vs 6·65 years before death). By contrast, tau tangles were associated with cognitive decline before they were associated with gait and hand strength decline (more than 11 years before death vs 3·49 and 3·57 years before death).4Oveisgharan S Wang T Barnes LL Schneider JA Bennett DA Buchman AS The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study.Lancet Healthy Longev. 2024; (published online April 3.)https://doi.org/10.1016/S2666-7568(24)00033-3Google Scholar On the basis of the relative timing of associations between gait impairment, macroinfarcts, and tau tangles, the authors argue that gait impairment could serve as a clinical proxy for the risk of cognitive impairment, particularly vascular cognitive impairment. However, the findings are likely to be relevant to cognitive impairment more generally, given that mixed pathology is the norm rather than the exception,5Nichols E Merrick R Hay SI et al.The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia.Lancet Healthy Longev. 2023; 4: e115-e125Summary Full Text Full Text PDF PubMed Google Scholar with Alzheimer's disease and vascular pathologies commonly co-occurring. The link between gait impairment and vascular pathology is supported by previous evidence6Verghese J Lipton RB Hall CB Kuslansky G Katz MJ Buschke H Abnormality of gait as a predictor of non-Alzheimer's dementia.N Engl J Med. 2002; 347: 1761-1768Crossref PubMed Scopus (570) Google Scholar, 7Dougherty RJ Wanigatunga AA An Y et al.Walking energetics and white matter hyperintensities in mid-to-late adulthood.Alzheimers Dement (Amst). 2023; 15e12501Google Scholar and highlights the notion that different pathologies can lead to different clinical symptoms and outcomes. Interestingly, of the five vascular pathologies considered in Oveisgharan and colleagues' study4Oveisgharan S Wang T Barnes LL Schneider JA Bennett DA Buchman AS The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study.Lancet Healthy Longev. 2024; (published online April 3.)https://doi.org/10.1016/S2666-7568(24)00033-3Google Scholar (macroinfarcts, microinfarcts, atherosclerosis, arteriosclerosis, and cerebral amyloid angiopathy), only macroinfarcts were associated with gait. This raises questions about the robustness of associations with the vascular phenotype beyond macroinfarcts. However, analytical models included all pathologies simultaneously, which might have led to attenuated associations with other vascular pathologies if vascular pathologies were highly intercorrelated. Although Oveisgharan and colleagues' results provide evidence that macroinfarcts were associated with declining gait that preceded associations with cognitive decline, several factors might preclude the use of gait impairment as a clinical proxy for risk of cognitive decline. First, it is important to consider that group-level patterns might not adequately inform individual-level decision making, particularly in the presence of heterogeneity among subgroups.8Dahabreh IJ Hayward R Kent DM Using group data to treat individuals: understanding heterogeneous treatment effects in the age of precision medicine and patient-centred evidence.Int J Epidemiol. 2016; 45: 2184-2193PubMed Google Scholar Second, ideal clinical proxies are specific (ie, they uniquely signal the trait of interest and are not associated with unrelated phenotypes). However, Oveisgharan and colleagues show that there was considerable residual decline in gait function after accounting for the included pathologies, suggesting that there are other factors related to gait function (eg, musculoskeletal disorders), which are likely to be unrelated to cognitive phenotypes. This finding raises doubts about using gait dysfunction as a standalone marker for predicting the development of neuropathologies or cognitive impairment. However, it does not preclude its use in combination with other clinical markers. Third, the use of gait dysfunction as a clinical marker for cognitive impairment also requires a clear understanding of normative values. Although some normative data exist,9Hollman JH McDade EM Petersen RC Normative spatiotemporal gait parameters in older adults.Gait Posture. 2011; 34: 111-118Crossref PubMed Scopus (516) Google Scholar norms might vary by ethnicity and age.10Chandhanayingyong C Adulkasem N Asavamongkolkul A et al.Establishing normative values for performance-based tests in older Thai adults: a nationwide cross-sectional study.Arch Phys Med Rehabil. 2024; (published online Feb 15.)https://doi.org/10.1016/j.apmr.2024.01.023Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Strengths of the ROS, MAP, and MARS cohorts include rich autopsy and longitudinal data. However, some limitations of the data might affect the interpretation and generalisability of the findings. Although autopsy data provide detailed information on brain pathologies, they provide only a single snapshot in time. Furthermore, individuals who die and therefore provide autopsy data are likely to be different from those who are alive, potentially leading to selection bias. Having information on pathologies at multiple timepoints would create a more precise temporal characterisation of motor and cognitive decline with the accumulation of pathologies. Additionally, the ROS and MAP cohorts are predominantly composed of White and highly educated individuals; although this study included the MARS cohort, which focuses on African American older adults, less than 2% of participants were from MARS.4Oveisgharan S Wang T Barnes LL Schneider JA Bennett DA Buchman AS The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort study.Lancet Healthy Longev. 2024; (published online April 3.)https://doi.org/10.1016/S2666-7568(24)00033-3Google Scholar Given the selective nature of the sample, it will be important to evaluate the generalisability of the findings. Despite the caveats and limitations, the study by Oveisgharan and colleagues used novel methods to provide interesting insights into associations between motor decline and the neuropathological underpinnings of dementia. Functional mixed-effects models are a potentially valuable tool for characterising the timing of non-linear associations, which is especially important for studying complex neurodegenerative diseases, which develop over decades. Findings on gait and macroinfarcts add to the body of evidence on the ties between gait, vascular pathologies, and dementia and will hopefully inspire future research to better understand the accumulating observational evidence. JR declares funding from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Alzheimer's Society of Canada, Alzheimer's Association, Dr Sandra Black Centre for Brain Resilience and Recovery, University of Toronto, and the Harquail Centre for Neuromodulation. EN declares funding from the National Institutes of Health National Institute of Ageing (3R01AG030153). The time course of motor and cognitive decline in older adults and their associations with brain pathologies: a multicohort studyOur findings suggest that average motor decline in older adults precedes cognitive decline. Macroinfarcts but not tau tangles are associated with declining gait function that precedes cognitive decline. This suggests the need for further studies to test if gait impairment is a clinical proxy for preclinical vascular cognitive impairment. Full-Text PDF Open Access

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