key: cord-315613-javtkg5m
authors: Calderón-Garcidueñas, Lilian; Torres-Solorio, Ana Karen; Kulesza, Randy J.; Torres-Jardón, Ricardo; González-González, Luis Oscar; García-Arreola, Berenice; Chávez-Franco, Diana A.; Luévano-Castro, Samuel C.; Hernández-Castillo, Ariatna; Carlos-Hernández, Esperanza; Solorio-López, Edelmira; Crespo-Cortés, Celia Nohemí
title: Gait and balance disturbances are common in young urbanites and associated with cognitive impairment. Air pollution and the historical development of Alzheimer’s disease in the young
date: 2020-09-02
journal: Environ Res
DOI: 10.1016/j.envres.2020.110087
sha: 
doc_id: 315613
cord_uid: javtkg5m

To determine whether gait and balance dysfunction are present in young urbanites exposed to fine particular matter PM(2.5) ≥ annual USEPA standard, we tested gait and balance with Tinetti and Berg tests in 575 clinically healthy subjects, age 21.0±5.7y who were residents in Metropolitan Mexico City, Villahermosa and Reynosa. The Montreal Cognitive Assessment was also applied to an independent cohort n:76, age 23.3± 9.1y. In the 575 cohort, 75.4% and 34.4% had abnormal total Tinetti and Berg scores and high risk of falls in 17.2% and 5.7% respectively. BMI impacted negatively Tinetti and Berg performance. Gait dysfunction worsen with age and males performed worse than females. Gait and balance dysfunction were associated with mild cognitive impairment MCI (19.73%) and dementia (55.26%) in 57/76 and 19 cognitively intact subjects had gait and balance dysfunction. Seventy-five percent of urbanites exposed to PM(2.5) had gait and balance dysfunction. For MMC residents-with historical documented Alzheimer disease (AD) and CSF abnormalities, these findings suggest Alzheimer Continuum is in progress. Early development of a Motoric Cognitive Risk Syndrome ought to be considered in city dwellers with normal cognition and gait dysfunction. The AD research frame in PM(2.5) exposed young urbanites should include gait and balance measurements. Multicity teens and young adult cohorts are warranted for quantitative gait and balance measurements and neuropsychological and brain imaging studies in high vs low PM(2.5) exposures. Early identification of gait and balance impairment in young air pollution-exposed urbanites would facilitate multidisciplinary prevention efforts for modifying the course of AD.

Gait, equilibrium and postural disorders are linked to neurological and neurodegenerative pathologies. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Gait is a complex activity requiring the activation of the cerebral cortex, basal ganglia, cerebellum, brainstem, spinal cord and the musculoskeletal system. [14] [15] [16] [17] [18] Independent papers by Kaoru Takakusaki, Klaus Jahn and Anat Mirelman et al., [14] [15] [16] extensively discuss human locomotion and the key regions associated with gait and posture i.e., the mesencephalic locomotor region (MLR) and its projections to the pontomedullary reticular formation; the subthalamic locomotor region (SLR) and the cerebellar locomotor region (CLR). Jahn et al., 15 studies in imaging human supraspinal locomotor brainstem and cerebellum are of particular interest in this paper given their clinical relevance and the connections of gait initiation and speed regulation pacemakers with anatomical structures such as the inter-fastigial cerebellum, midbrain tegmentum, cerebellar vermis and pontine reticular formation. Strikingly, motor imagery and actual movement activate not only premotor and supplementary motor areas, but also cingulate and parietal cortical areas. 15 The importance of postural control and cerebellar gait input has been put forward independently by Armstrong and Orlovsky 17, 18 and support the integration of widespread locomotor structures from proprioceptive, exteroceptive, visual, vestibular, cerebellar, dorsal brainstem and cortical input for gait initiation and modulation. 15 Thus, it is not a surprise gait pathology is described in the elderly especially in relation to neurodegenerative and dementia pathologies. [19] [20] [21] [22] [23] [24] [25] [26] Associations between gray matter volume and gait parameters in mild cognitive impairment (MCI) patients (temporal lobe) and controls (frontal areas in healthy elderly), suggest a relationship between dementia-related pathology and gait dysfunction 24 that becomes clear in Alzheimer's disease (AD) patients when applying the Dual-Task Gait Performance testing. 27 Patients with dementia had significantly higher dual-J o u r n a l P r e -p r o o f task cost (DTC) in counting gait and naming animals conditions vs individuals with subjective cognitive impairment (SCI) and MCI. 27 Tian et al., 26 have shown that greater rate of increase in lap time variability from a 400-m walk differentiates individuals who eventually develop MCI/AD from controls, supporting early pathology likely impacts the automaticity of walking.

Motoric cognitive risk syndrome (MCR) 28 characterized by subjective cognitive complaints and slow gait is common across the world with a prevalence of 9.7%. 29 Gait abnormalities are common in MCR and are associated with accelerated functional decline and gray matter atrophy in motor, insular and prefrontal cortex linked to the control aspects of gait such as motor planning and modulation. 30 Muurling et al., 31 have shown an association between gait specific measures related to pace and rhythm, cerebrospinal fluid (CSF) hyperphosphorylated tau and dementia. Muurling's work is key for this investigation given that Metropolitan Mexico City residents show evidence of Alzheimer's disease in 202/203 forensic autopsy cases age 25.36 ± 9.23 y, CSF Aβ1-42, BDNF, α-synuclein, and inflammatory markers are evolving in young urbanites showing underperformance in cognitive processes, and abnormal brainstem evoked potentials. [32] [33] [34] [35] [36] [37] [38] These findings support a spectrum of cognitive, imaging and gait abnormalities in the elderly population and that gait abnormalities could indeed be an early indication of a high risk for MCI and dementia.

It is striking there are very few gait studies in young adults if we indeed recognize neurodegenerative processes take several decades to evolve 39, 40 and if biologically defined AD is more prevalent that clinically defined AD. 40 Heijnen and Rietdyk 41 in a study of 94 undergraduate students found falls are the third leading cause of unintentional injuries for young adults ages 18-35y. These young adults fell once out of every 18 perceived slips and trips -this J o u r n a l P r e -p r o o f is not a trivial problem for a population with no risk factors for diseases affecting gait and dynamic equilibrium.

Given these findings we are concerned young Metropolitan Mexico City (MMC) residents exposed to concentrations of fine particulate matter (PM 2.5 ) above the United States Environmental Protection Agency (USEPA) standard and in conjunction with a historical documentation of Alzheimer pathology progressive changes 32 42, 43 We hypothesized that Alzheimer neurodegenerative processes given rise to cognitive deficits, could also involve gait and balance dysfunction, particularly because we have extensively documented brainstem hyperphosphorylated tau, beta amyloid and alpha-synuclein in pediatric and young adults MMC forensic autopsies. 32, 44 The purpose of this study was to document gait and balance alterations and cognitive deficits in a cross sectional study of 575 clinically healthy adults, average age 21.03±5.76y residents in Mexican cities with concentrations of fine particulate matter PM 2.5 above the USEPA annual standard. Our first aim was to score a selected balance scale: Berg 45,46 and a performance-gait and balance scale: Tinetti 47, 48 in our young cohort. The second aim was to measure cognitive performance plus Tinetti and Berg in an independent cohort (n:76) to determine if an association between gait, balance and cognition deficits is present given the AD Continuum described in similar age MMC cohorts. 32, 34 The Montreal Cognitive Assessment version 7, translated into Spanish, was our selected instrument. 36, 37 MoCA covers several J o u r n a l P r e -p r o o f cognitive domains including episodic memory, language, attention, orientation, visuospatial and executive functions and has been validated in Mexican populations. [49] [50] [51] [52] [53] Early identification of gait and balance impairment in young air pollution-exposed urbanites would facilitate multidisciplinary prevention efforts for modifying the course of AD.

The Mexican urban areas selected were Metropolitan Mexico City (MMC), Villahermosa and Reynosa. Selection was based on geographic location, urban characteristics and stable air pollutant levels in the last 2 decades. The focus was on PM 2.5 (≤2.5 µm particles) and we selected to illustrate their behavior for 2017 -the year previous to this clinical study-based on 24-hr and annual USEPA standards. Supplemental Table 1 shows a summary of the main characteristics of the study urban areas, sources of particulate matter and pertinent references. Figure 1 shows As shown in Figure 1 , the higher daily PM 2.5 averages were registered in MMC. The J o u r n a l P r e -p r o o f normal gait, ataxic gait, antalgic gait, cautious gait, frontal gait, hemiparetic gait, spastic gait and shuffling gait as per the Guidelines for gait assessment in the Canadian Consortium on neurodegeneration in aging. 54 Tinetti gait and balance 47,48 evaluations consisted of two parts.

The first part is a static examination of standing that includes 13 items: standing position, ability to stand up and to resist external destabilizations. Each item is scored from 1 (normal) to 3

(abnormal). The second part is based on a gait observation with nine items, scored as 1 normal to 2. The gait score is 12 and the balance score is 16. The Berg Balance Scale (BBS) 45, 46 consists of 14 items assessing the ability to stand up and to maintain standing position despite perturbations.

Each item is scored from 0 (unable) to 4 (safely done) with a maximum score of 56.

We had an independent clinically healthy cohort n:76, age 23. 56 Petersen original Delayed Recall Score plus VIS, EIS and LIS were also used. 55

We first calculated the summary statistics of the Berg and Tinetti scores in the cohorts. Then, we tested the equality of mean scores of each meaningful pair. For the total Tinetti score we used ≥24 as of low risk of falling, 19-23 moderate risk and ≤18 as high risk. For the BBS we used 50-56 as normal, ≤49 abnormal. 61 We created three cohorts based on MoCA: Normal, MCI and D.

The cut-off points are based on total MoCA scores, normal ≥26, MCI 24-25, D ≤23. We tested the equality of mean scores of each meaningful pair. We calculated the index scores in each J o u r n a l P r e -p r o o f cohort as well. We also fit a multiple linear regression of the total Tinetti, Berg and MoCA score on Age, BMI, Gender, and Education years. We ran the regression models for each of the aforementioned groups. All statistical analyses were made using Excel and the statistical software 'R' (http://www.r-project.org/).

All 651 participants were residents in urban areas with concentrations of PM 2.5 above the annual USEPA standard. MMC residents were exposed to high concentrations of PM 2.5 , including secondary aerosols and ozone for the last 15 years. 57 Historically, the problem of air pollution in MMC 58 

We analysed the results of both tests by residency ( Table 1 ).The lowest score for Tinetti gait was in Villahermosa, a city with significant oil industry-associated air pollution, average low cognitive scores in the range of dementia and high BMI in young adults. 37 The lowest score of Tinetti balance was for MMC residents. Reynosa residents, with the lowest air pollution concentrations had the highest scores for both tests. 

Gait and balance dysfunction are present in ~ 75% of 575 seemingly healthy young adults age 21.04±5.76y residing in Mexican cities with concentrations of fine particulate matter PM 2.5 above the current USEPA annual standard. High risk of falls was detected in 17.2% and 5.7% of them using Tinetti and Berg instruments, respectively.

Young adults are showing higher fall risk and significant cognitive deficits in the absence of risk factors commonly associated with cognition impairment and dementia at younger ages. 66 Outstandingly, these young adults with College education belong to the same socio-economic status as the 203 MMC subjects ≤40y staged for AD with Alzheimer Continuum. 32, 67, 68 In the forensic autopsy study 32 , age and cumulative lifelong concentrations of PM 2.5 were significant for developing NFT V. In the same autopsy cohorts, magnetic, combustion-derived nanoparticles are associated with early and progressive damage to the neurovascular unit, making the issue of nanoparticulate matter air pollution in MMC residents relevant to our discussion. 69 We have cognitive complaints-described in elderly cohorts. 28, 29, 74 Our findings in the 575 young cohort with gait and balance abnormalities ought to be discussed on the bases of the extensive literature available in gait, mobility, cognition, Alzheimer and air pollution. First, there is no question about the high risk of falls in older people and the validity of paradigms linking shared brain pathways in mobility, falls and cognition. [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] Key to this discussion is the association between specific gray matter networks, normal pace walking speed, dual-task costs and different cognitive domains 76 and the strong evidence that shared neural systems responsible for gait speed and processing speed are indeed subjected to age and dementia-associated pathological changes. 83 On the other hand, the extensive work on the Motoric Cognitive Risk Syndrome (MCR) defined as a pre-dementia syndrome characterized by subjective cognitive complaints and slow gait, the association between gait decline and mild cognitive impairment (MCI) and the cognitive and motor trajectories in their path to dementia are obligated topics in this discussion. [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] Montero-Odasso et al., paper is critical. 95 The authors did a 5y prospective longitudinal study of 154 adults ≥65y without dementia at day 0 and defined J o u r n a l P r e -p r o o f motor and cognitive decline in those who progressed to dementia versus those who did not. 95 The authors concluded decline in serial measures of gait velocity, had a higher attributable risk for incident dementia than did cognitive decline alone and the highest risk for dementia was in subjects with a decline over time of both gait velocity and cognition. 95 is not confined to supratentorial regions, it also involves the brainstem tracts and nuclei. 38 Indeed, the significant alterations to the brainstem auditory evoked potentials are related to the damage combination of WM tracts and auditory nuclei, a finding evolving in MMC residents as their aged and one of our proposed non-invasive markers of Alzheimer Continuum. 38, 39 Metabolic and genetic factors also have to be considered when we analyzed motor and cognitive decline and the work of Sathyan et al., 88 nanoparticles to the brain. 36, 37, 72, 96, 105, 106 Beauchet et al., 107 put forward a biologically plausible explanation for the correlation between greater subvolumes of the somatosensory cortex and hippocampus reported in fallers compared to non-fallers: a possible brain compensatory mechanism involving spatial navigation and integration of sensory information. Indeed, in explaining increased gain in the auditory pathway (measured as brainstem auditory evoked potentials) in MMC residents we strongly supported compensatory plasticity, neuroinflammation, and AD continuum as strong players in MMC residents. 38 We have to fully agree with Beauchet et al., 85 that the MCR-related smaller global and regional gray matter volumes involving premotor and prefrontal cortices, could be used to predict cortical neurodegenerative changes. Based on our MRI/MRS studies in MMC residents, we also are of the opinion volumetric changes in hippocampus 78 and entorhinal cortex 80 are not early findings and we have a higher likelihood of detecting MRS changes, as shown in MMC young residents. 108, 109 The key question to be asked for Metropolitan Mexico City residents is why are we seen gait and balance dysfunction in seemingly healthy young adults 21 107 biological explanation for a possible brain compensatory mechanism has to be entertained. Indeed,compensatory plasticity, neuroinflammation, and AD continuum are playing a role in the auditory pathway increased gain over time in MMC residents. 38 3.The portal of entry of fine PM and nanoparticles (NPs) ought to be considered. The inhalation respiratory portal is important, however the gastrointestinal/neuroenteric portal could also be extraordinary important in some people. The GI system includes an extensive biological barrier, but ingestion of NPs will impact the microbiota and mucus and an altered intestinal homeostasis is an expected outcome. NPs taken through the GI pathway can access the brainstem directly, We strongly support that in highly exposed PM 2.5 populations, clinical gait assessment and quantitative gait parameters should be included in their neuropsychological assessment, along BAEPs, olfaction and cognition tests. The use of a computerized walkway and the inclusion of key variables for gait (pace, rhythm and variability), stride length, swing time, stride length variability, swing time variability along balance testing ought to be included.

The concept of Alzheimer's disease as defined by the National Institute on Aging and

Alzheimer's Association Research Framework 39 : Alzheimer's disease is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers, is a welcome biologic construct enabling researchers to add variables to the frame work aimed to an accurate characterization and understanding of the sequence of events that lead to cognitive impairment. The fact that biologically defined Alzheimer disease is more J o u r n a l P r e -p r o o f prevalent than clinically defined probable Alzheimer disease at any age is a crucial piece of information 40 ,one that obligates us to use every potential early marker to identify subjects in the early stages of AD and defining early gait and balance abnormalities is part of the strategy.

A major advantage of our research design is the access to Mexican subjects with similar socioeconomic status, formal education years, nutrition patterns, etc., enabling us to rule out the possibility that these key variables will modify our results across different urban areas. We selected healthy young individuals and we have a detailed description of AD pathology in 203

consecutive MMC forensic autopsies, ages 11 months to 40 years with no extra-neural pathology, allowing us to put forward direct correlations with the MoCA results in MMC residents and indirectly with residents across the country. 32, 36, 37 The study has shortcomings. Our major gap is the lack of funding to purchase a computerized walkway and to do APOE genotyping that will allow us to identify subjects with earlier stages of AD. 32

The association between gait and balance dysfunction with MCI and dementia scores in cohorts of 23y olds supports AD Continuum and we need to contemplate an early development of a Motoric Syndrome in the 19 adults with gait dysfunction and normal cognition. We strongly support Alzheimer's disease is preventable in the scenario of air pollution. As such, we enthusiastically endorse screening for gait and balance abnormalities as part of the AD research frame in PM 2.5 exposed young adults, children and teens.

J o u r n a l P r e -p r o o f

Gait disorders

Balance and mobility in geriatric patients : Assessment and treatment of neurological aspects

The Aging Vestibular System: Dizziness and Imbalance in the Elderly

Balance and Gait Represent Independent Domains of Mobility in Parkinson Disease

Abnormality of gait as a predictor of non-Alzheimer's dementia

Impaired perception of surface tilt in progressive supranuclear palsy

Gait slowing as a predictor of incident dementia: 6-year longitudinal data from the Sydney Older Persons Study

Relationship between Gait Parameters and Postural Stability in Early and Late Parkinson's Disease and Visual Feedback-Based Balance Training Effects. Open Access Maced

Cerebellar White Matter Damage Is Associated With Postural Sway Deficits in People With Multiple Sclerosis

Assessment and rehabilitation of central sensory impairments for balance in mTBI using auditory biofeedback: a randomized clinical trial

Minor gait impairment despite white matter damage in pure small vessel disease

Pedunculopontine Nucleus Degeneration Contributes to Both Motor and Non-Motor Symptoms of Parkinson's Disease

Neurophysiology of gait: from the spinal cord to the frontal lobe

Imaging human supraspinal locomotor centers in brainstem and cerebellum

The supraspinal control of mammalian locomotion

From mollusc to man

Gait Disorders in Alzheimer's Disease and Other Dementias: There is Something in the Way You Walk

Overlap Between Apolipoprotein Eε4 Allele and Slowing Gait Results in Cognitive Impairment

Gait and apathy as relevant symptoms of subcortical vascular dementia

Day-to-Day Variability of Postural Sway and Its Association With Cognitive Function in Older Adults: A Pilot Study

Association Between Gait, Cognition, and Gray Matter Volumes in Mild Cognitive Impairment and Healthy Controls

Do Alzheimer's and Lewy body disease have discrete pathological signatures of gait?

Lap Time Variability From a 400-m Walk Is Associated With Future Mild Cognitive Impairment and Alzheimer's Disease

Are Cognitive Subtypes Associated with Dual-Task Gait Performance in a Clinical Setting?

Gait dysfunction in motoric cognitive risk syndrome

Motoric cognitive risk syndrome: Multicountry prevalence and dementia risk

Gray Matter Volume Covariance Network Associated with the Motoric Cognitive Risk Syndrome: A Multicohort MRI Study

Gait Disturbances Are Associated with Increased Cognitive Impairment and Cerebrospinal Fluid Tau Levels in a Memory Clinic Cohort

Hallmarks of Alzheimer disease are evolving relentlessly in Metropolitan Mexico City infants, children and young adults. APOE4 carriers have higher suicide risk and higher odds of reaching NFT stage V at ≤ 40 years of age

Prion Cellular Protein (PrP(C)), Interleukin-6 (IL-6), Interleukin 1 Receptor Antagonist (IL-1Ra), and interleukin-2 (IL-2) in Cerebrospinal Fluid and MIF in Serum Differentiate Urban Children Exposed to Severe vs

Cerebrospinal Fluid Biomarkers in Highly Exposed PM2.5 Urbanites: The Risk of Alzheimer's and Parkinson's Diseases in Young Mexico City Residents

Non-Phosphorylated Tau in Cerebrospinal Fluid Is a Marker of Alzheimer's Disease Continuum in Young Urbanites Exposed to Air Pollution

Alzheimer disease starts in childhood in polluted Metropolitan Mexico City. A major health crisis in progress

Mild Cognitive Impairment and Dementia Involving Multiple Cognitive Domains in Mexican Urbanites

Alzheimer's Disease Continuum, and Air Pollution: Peripheral and Central Auditory System Dysfunction Evolves Across Pediatric and Adult Urbanites

NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease

Prevalence of Biologically vs Clinically Defined Alzheimer Spectrum Entities Using the National Institute on Aging-Alzheimer's Association Research Framework

Falls in young adults: Perceived causes and environmental factors assessed with a daily online survey

Air pollution is associated with brainstem auditory nuclei pathology and delayed brainstem auditory evoked potentials

the blood-brain-barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults

Measuring balance in the elderly: preliminary development of an instrument

Clinical and laboratory measures of postural balance in an elderly population

Fall risk index for elderly patients based on number of chronic disabilities

The Tinetti test: Babylon in geriatric assessment

MoCA: a brief screening tool for mild cognitive impairment

Lacking Pace but Not Precision: Age-Related Information Processing Changes in Response to a Dynamic Attentional Control Task

Alzheimer's Disease Neuroimaging Initiative. Effects of Normative adjustments to the Montreal Cognitive Assessment

Cognitive Screening Instruments

Canadian Gait and Cognition Network. Guidelines for Gait Assessments in the Canadian Consortium on Neurodegeneration in Aging (CCNA)

Mild cognitive impairment as a diagnostic entity

Montreal cognitive assessment memory index score (MoCA-MIS) as a predictor of conversion from mild cognitive impairment to Alzheimer's disease

Experience from Integrated Air Quality Management in the Mexico City Metropolitan Area and Singapore

Ozone's threat hits back Mexico City

Atmospheric blockages as trigger of environmental contingencies in Mexico City

Políticas públicas y su efecto en la calidad del aire de la Zona Metropolitana de la Ciudad de México

Instituto de Investigaciones Dr

Nanoparticle size distributions in Mexico City

An overview of the MILAGRO 2006 Campaign: Mexico City emissions and their transport and transformation

Organic Compound in Airborne Particles and their Genotoxic Effects in Mexico City

PM speciation and sources in Mexico during the MILAGRO-2006 Campaign

Young-onset dementia

The preclinical phase of the pathological process underlying sporadic Alzheimer's disease

Phases of A beta-deposition in the human brain and its relevance for the development of AD

Combustion-derived nanoparticles in key brain target cells and organelles in young urbanites: Culprit hidden in plain sight in Alzheimer's disease development

Magnetite pollution nanoparticles in the human brain

Combustion-and friction-derived magnetic air pollution nanoparticles in human hearts

Air Pollution, Combustion and Friction Derived Nanoparticles, and Alzheimer's Disease in Urban Children and Young Adults

Hosted and free-floating metal-bearing atmospheric nanoparticles in Mexico City

Motoric cognitive risk syndrome and predictors of transition to dementia: A multicenter study

Consensus on Shared Measures of Mobility and Cognition: From the Canadian Consortium on Neurodegeneration in Aging (CCNA)

Gray matter volume covariance networks associated with dual-task cost during walking-while-talking

Multisensory Integration Predicts Balance and Falls in Older Adults

Slowing gait and risk for cognitive impairment: The hippocampus as a shared neural substrate

Relationship Between Mood, Thinking, and Walking: A Systematic Review Examining Depressive Symptoms, Executive Function, and Gait

Entorhinal Cortex Volume Is Associated with Dual-Task Gait Cost Among Older Adults With MCI: Results from the Gait and Brain Study

The Impact of Mild Cognitive Impairment on Gait and Balance: A Systematic Review and Meta-Analysis of Studies Using Instrumented Assessment

Qualitative neurological gait abnormalities, cardiovascular risk factors and functional status in older community-dwellers without neurological diseases: The Healthy Brain Project

Gray matter volume covariance patterns associated with gait speed in older adults: a multi-cohort MRI study

Gait and dementia

Association of Motoric Cognitive Risk Syndrome with Brain Volumes: Results from the GAIT Study

The association between pain and prevalent and incident motoric cognitive risk syndrome in older adults

Frailty and Risk of Incident Motoric Cognitive Risk Syndrome

Genetic basis of motoric cognitive risk syndrome in the Health and Retirement Study

Motoric Cognitive Risk Syndrome: Could It Be Defined Through Increased Five-Times-Sit-to-Stand Test Time, Rather Than Slow Walking Speed?

White matter integrity is associated with gait impairment and falls in mild cognitive impairment. Results from the gait and brain study

Guidelines for Assessment of Gait and Reference Values for Spatiotemporal Gait Parameters in Older Adults: The Biomathics and Canadian Gait Consortiums Initiative

Alzheimer Disease, Biomarkers, and Clinical Symptoms-Quo Vadis?

Mapping Associations Between Gait Decline and Fall Risk in Mild Cognitive Impairment

Overlap Between Apolipoprotein Eε4 Allele and Slowing Gait Results in Cognitive Impairment

Canadian Gait and Cognition Network. Motor and Cognitive Trajectories Before Dementia: Results from Gait and Brain Study

Prefrontal white matter pathology in air pollution exposed Mexico City young urbanites and their potential impact on neurovascular unit dysfunction and the development of Alzheimer's disease

Apolipoprotein E4, Gender, Body Mass Index, Inflammation, Insulin Resistance, and Air Pollution Interactions: Recipe for Alzheimer's Disease Development in Mexico City Young Females

Metabolic Syndrome and the Cellular Phase of Alzheimer's Disease

Impact of Metabolic Syndrome on Neuroinflammation and the Blood-Brain Barrier

Sex-specific relationship of cardiometabolic syndrome with lower cortical thickness

Impact of race/ethnicity on insulin resistance and hypertriglyceridaemia

Associations of insulin resistance with cognition in individuals without diagnosed diabetes: Results from the Hispanic Community Health Study/Study of Latinos

The association between insulin resistance, metabolic variables, and depressive symptoms in Mexican-American elderly: A populationbased study

Gray matter volume and dual-task gait performance in mild cognitive impairment

Airborne Magnetite-and Iron-Rich Pollution Nanoparticles: Potential Neurotoxicants and Environmental Risk Factors for Neurodegenerative Disease, Including Alzheimer's Disease

Vehicle-Derived Fe-Bearing Nanoparticles in the Urban Environment: A Review

Biomathics and Canadian Gait Consortium. Association Between Falls and Brain Subvolumes: Results from a Cross-Sectional Analysis in Healthy Older Adults

A Critical Proton MR Spectroscopy Marker of Alzheimer's Disease Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE ɛ4 Mexico City Children and Their Parents

Decreases in Short Term Memory, IQ, and Altered Brain Metabolic Ratios in Urban Apolipoprotein ε4 Children Exposed to Air Pollution

Combustion-derived nanoparticles, the neuroenteric system, cervical vagus, hyperphosphorylated alpha synuclein and tau in young Mexico City residents

Alzheimer's disease and alpha-synuclein pathology in the olfactory bulbs of infants, children, teens and adults ≤ 40 years in Metropolitan Mexico City. APOE4 carriers at higher risk of suicide accelerate their olfactory bulb pathology

Oral uptake of nanoparticles: human relevance and the role of in vitro systems

Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues

Mucus: An Underestimated Gut Target for Environmental Pollutants and Food Additives. Microorganisms

Mucus and microbiota as emerging players in gut nanotoxicology: The example of dietary silver and titanium dioxide nanoparticles

Combustion and frictionderived nanoparticles and industrial-sourced nanoparticles: The culprit of Alzheimer and Parkinson's diseases

The complex genetics of gait speed: genome-wide meta-analysis approach

♦ Mexico City 575 urbanites 21.0±5.7y had abnormal Tinetti 75% and Berg 34%

♦ High risk of falls in 17% (Tinetti) and 5.7% (Berg) is of deep concern

♦Gait and balance dysfunction are associated with MCI and dementia scores

LCG study concept and design, analysis and interpretation of data, writing, drafting and revising the manuscript, study supervision and coordination, funding. AKTS, RJK analysis and interpretation of data, writing, drafting and revising the manuscript. PSM statistical analysis, writing, drafting and revising the manuscript. RTJ air pollution sections writing, drafting and revising the manuscript. DACF, SCLC, BGA, LCGG, ECH, ESL, AHC, CNCC acquisition of data, study supervision and coordination, analysis and interpretation of data. All other authors acquisition of data, study supervision and coordination and revising the manuscript.
