The Moderating Effect of Physical Activity on the Association between White Matter Hyperintensities and Gait Characteristics

The objectives of this thesis were; 1) to assess the effect of white matter hyperintensities (WMH) burden on motor outcomes among older individuals in presence and absence of overt neurological conditions and 2) to evaluate whether physical activity (PA) moderated the association between WMH and gait velocity and stride time variability (STV), under single and dual-task conditions, in a geriatric clinic sample. Study 1 systematically reviewed the literature demonstrating that greater WMH burden was associated with predefined motor outcomes. Notably, gait velocity emerged as a well-studied characteristic. Study 2 confirmed that WMH negatively affected gait velocity. STV and dual-task gait conditions did not reveal significance. Additionally, PA did not moderate the association between WMH and gait velocity, although conditional effects showed significance for low and moderate levels of PA. This finding extends support for the efficacy of physical activity in attenuating the effects of WMH on mobility

Associations between mobility, cognition and callosal integrity in people with parkinsonism

Falls in people with parkinsonism are likely related to both motor and cognitive impairments. In addition to idiopathic Parkinson\u27s disease (PD), some older adults have lower body parkinsonism (a frontal gait disorder), characterized by impaired lower extremity balance and gait as well as cognition, but without tremor or rigidity. Neuroimaging during virtual gait suggests that interhemispheric, prefrontal cortex communication may be involved in locomotion, but contributions of neuroanatomy connecting these regions to objective measures of gait in people with parkinsonism remains unknown. Our objectives were to compare the integrity of fiber tracts connecting prefrontal and sensorimotor cortical regions via the corpus callosum in people with two types of parkinsonism and an age-matched control group and to relate integrity of these callosal fibers with clinical and objective measures of mobility and cognition. We recruited 10 patients with frontal gait disorders, 10 patients with idiopathic PD and 10 age-matched healthy control participants. Participants underwent cognitive and mobility testing as well as diffusion weighted magnetic resonance imaging to quantify white matter microstructural integrity of interhemispheric fiber tracts. People with frontal gait disorders displayed poorer cognitive performance and a slower, wider-based gait compared to subjects with PD and age-matched control subjects. Despite a widespread network of reduced white matter integrity in people with frontal gait disorders, gait and cognitive deficits were solely related to interhemispheric circuitry employing the genu of the corpus callosum. Current results highlight the importance of prefrontal interhemispheric communication for lower extremity control in neurological patients with cognitive dysfunction

White matter hyperintensities and lower extremity physical function before and after an aerobic exercise intervention in healthy older adults

Background: Age-related declines take many forms including white matter deterioration, cognitive impairments, and mobility limitations, all of which can have practical implications, such as falling and making risky pedestrian decisions. Modifiable lifestyle interventions, like physical activity, provide ways to mitigate or ameliorate the range of age-related declines. This dissertation examined the relationships between lower extremity physical function and a representative measure of age-related cerebral small vessel disease, white matter hyperintensity (WMH) volume in the brain, before and after an aerobic exercise intervention in a sample of relatively young and healthy older adults. Analyses also examined the role of WMH volume, physical function, and cognition on virtual reality street crossing risk assessment. Methods: Data were analyzed from 177 older adults (M age = 65) who completed the Fit and Active Senior Trial (FAST), a six-month physical activity intervention including three groups: stretching, strengthening, and stability (SSS); dance (Dance); aerobic walking (Walk). Results: The baseline relationship between greater WMH volume and worse lower extremity physical function was weak in this sample and, unsurprisingly, WMH volume did not change over the six-month intervention. Regardless of intervention group, greater standardized improvement in lower extremity physical function was significantly predicted by lower baseline WMH volume, greater baseline gait self-efficacy, and better baseline fitness, uniquely and in interaction. In a separate model, greater improvements in lower extremity physical function were observed in adults assigned to the Dance condition who had greater improvement in gait self-efficacy and/or lower initial WMH volume. Conclusions: The results reported here suggest that in sedentary older adults, the transition to physically active can benefit lower extremity physical function regardless of the type of activity. However, these gains seem to be greatest over the six-month period in individuals who at baseline have lower WMH volume, better gait self-efficacy, and better fitness

Slowing Down: Age-Related Neurobiological Predictors of Processing Speed

Processing speed, or the rate at which tasks can be performed, is a robust predictor of age-related cognitive decline and an indicator of independence among older adults. This review examines evidence for neurobiological predictors of age-related changes in processing speed, which is guided in part by our source based morphometry findings that unique patterns of frontal and cerebellar gray matter predict age-related variation in processing speed. These results, together with the extant literature on morphological predictors of age-related changes in processing speed, suggest that specific neural systems undergo declines and as a result slow processing speed. Future studies of processing speed – dependent neural systems will be important for identifying the etiologies for processing speed change and the development of interventions that mitigate gradual age-related declines in cognitive functioning and enhance healthy cognitive aging

Development of dementia in older adults : the body-mind connection

Over the past years, two major lines have emerged in the field of dementia research that are focused on: (1) The accurate and early prediction of dementia, and (2) The identification of modifiable factors for dementia prevention. This thesis has contributed to both. We explored the role played by the body-mind connection in cognitive aging by investigating whether motor functioning is a predictor of dementia and if different co-occurring diseases (i.e., multimorbidity [MM] patterns) are risk factors for dementia. We carried out four longitudinal studies, two for each research line, using 12 years of data from SNAC-K, a population-based study involving 3363 older adults, clinically assessed at regular intervals. Study I. Participants with both cognitive and motor dysfunctions demonstrated the highest hazard of developing dementia. After gait speed was added to cognitive assessment, the area under the curve (AUC) increased from 0.69 to 0.83 among the oldest participants. This increase was driven by a reduction in the proportion of false negatives, while the number of false positives (high specificity) remained low. Adding gait speed did not improve the predictive power of the cognitive battery in identifying dementia among younger-old adults. Study II. Individuals with concurrent cognitive and motor decline presented with a mixed and more rapidly evolving brain pathology on magnetic resonance imaging, affecting both gray and white matter. Adults experiencing only cognitive decline had a steeper hippocampal volume loss, whereas those exhibiting only motor decline displayed greater white matter hyperintensity burden. Study III. Individuals belonging to the neuropsychiatric, cardiovascular, and sensory impairment/cancer MM-patterns had the highest hazards of dementia, among those with MM. Inflammation (high C-reactive protein levels) increased dementia hazard within these three patterns, whereas being an APOE ε4-carrier heightened dementia hazard for neuropsychiatric and cardiovascular MM-patterns. Study IV. Exposure to air particulate matter ≤ 2.5μm [PM2.5] was found to increase dementia hazard by up to 50%. The presence of heart diseases (heart failure and ischemic heart disease) further amplified the risk, whereas stroke mediated up to 50% of the PM2.5-dementia association. Conclusions. The findings from these four studies underline the relevance of the body-mind connection in dementia development. An easy-to-obtain motor marker (gait speed) improved the ability of the cognitive test to detect future dementia. This could be explained by the mixed brain pathology, which we found to develop in individuals with fast and concomitant cognitive and motor decline. Specific MM-patterns seemed to increase dementia risk, an effect that was further accentuated by the presence of inflammation and genetic predisposition. Finally, cardiovascular diseases could be important in explaining the relation between PM2.5 and dementia risk. Further exploring the relation between body- and mind- related conditions could be essential in identifying at-risk populations and biomarkers for incipient dementia, and thus, in advancing our understanding of dementia in older adults

Gait decline while dual-tasking is an early sign of white matter deterioration in middle-aged and older adults

Loss of white matter integrity (WMI) is associated with gait deficits in middle-aged and older adults. However, these deficits are often only apparent under cognitively demanding situations, such as walking and simultaneously performing a secondary cognitive task. Moreover, evidence suggests that declining executive functions (EF) are linked to gait decline, and their co-occurrence may point to a common underlying pathology, i.e., degeneration of shared brain regions. In this study, we applied diffusion tensor imaging (DTI) and a standardized gait assessment under single- and dual-tasking (DT) conditions (walking and subtracting) in 74 middle-aged and older adults without any significant gait or cognitive impairments to detect subtle WM alterations associated with gait decline under DT conditions. Additionally, the Trail Making Test (TMT) was used to assess EF, classify participants into three groups based on their performance, and examine a possible interaction between gait, EF, and WMI. Gait speed and subtracting speed while dual-tasking correlated significantly with the fractional anisotropy (FA) in the bilateral anterior corona radiata (highest r = 0.51/p < 0.0125 FWE-corrected). Dual-task costs (DTC) of gait speed correlated significantly with FA in widespread pathways, including the corpus callosum, bilateral anterior and superior corona radiata, as well as the left superior longitudinal fasciculus (highest r = −0.47/p < 0.0125 FWE-corrected). EF performance was associated with FA in the left anterior corona radiata (p < 0.05); however, EF did not significantly mediate the effects of WMI on DTC of gait speed. There were no significant correlations between TMT and DTC of gait and subtracting speed, respectively. Our findings indicate that gait decline under DT conditions is associated with widespread WM deterioration even in middle-aged and older adults without any significant gait or cognitive impairments

Brain health: the importance of recognizing cognitive impairment: an IAGG consensus conference

Cognitive impairment creates significant challenges for patients, their families and friends, and clinicians who provide their health care. Early recognition allows for diagnosis and appropriate treatment, education, psychosocial support, and engagement in shared decision-making regarding life planning, health care, involvement in research, and financial matters. An IAGG-GARN consensus panel examined the importance of early recognition of impaired cognitive health. Their major conclusion was that case-finding by physicians and health professionals is an important step toward enhancing brain health for aging populations throughout the world. This conclusion is in keeping with the position of the United States' Centers for Medicare and Medicaid Services that reimburses for detection of cognitive impairment as part the of Medicare Annual Wellness Visit and with the international call for early detection of cognitive impairment as a patient's right. The panel agreed on the following specific findings: (1) validated screening tests are available that take 3 to 7 minutes to administer; (2) a combination of patient- and informant-based screens is the most appropriate approach for identifying early cognitive impairment; (3) early cognitive impairment may have treatable components; and (4) emerging data support a combination of medical and lifestyle interventions as a potential way to delay or reduce cognitive decline

Osteoarthritis, cerebrovascular dysfunction and the common denominator of inflammation: a narrative review

© 2018 The Author(s) Objective: Population-based cohort studies suggest an association between osteoarthritis (OA) and cerebrovascular disease, yet the mechanisms underlying vascular comorbidities in OA remain unclear. The purpose of this narrative review is to discuss the literature examining inflammation in OA with a focus on physiological mechanisms, and whether overlapping mechanisms exist in cerebrovascular dysfunction. Method: A literature search was conducted in PubMed using combinations of search terms: osteoarthritis, cerebrovascular (disease/dysfunction/risk), cardiovascular (disease/dysfunction/risk), aging/ageing, inflammation, inflammatory mediators, cytokine, c-reactive protein, interleukin, advanced glycation end-products, metabolic syndrome, reactive oxidative species, cognitive impairment, (vascular-related) dementia, small cerebral vessel disease, endothelial function, blood–brain barrier, gender/sex, hypertension, peripheral vascular health, and physical activity. Reference lists of identified articles were also researched manually. Results: Overlapping inflammatory factors that may contribute to onset and progression of both OA and cerebrovascular dysfunction are presented. We describe oxidative mechanisms involving pro-inflammatory cytokines and oxidative species, advanced glycation end-products, sex hormones, microvascular dysfunction and osteoprotegerin, and their specific roles in potentially contributing to OA and cerebrovascular dysfunction. Conclusion: Synthesis of the current literature suggests future investigations may benefit from directly testing cerebrovascular hemodynamics and cognitive function in individuals with or at risk of OA to elucidate common physiological mechanisms

Cardiovascular risk factor profiles in the development and progression of physical limitation in old age : a population-based study

Preservation of independence has been reported to be highly desired by older adults, even more than longevity. However, subclinical cardiovascular pathology can threaten a healthy older adult’s maintenance of physical function. Therefore, the aim of this thesis was to investigate the role and potential neuropathological mechanisms of cardiovascular disease-related risk factors in the development of physical limitation and disability in older adults. Data were taken from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K) for the initial three studies and from the embedded SNAC-K MRI sub-study for the final study. Study I. Over six years of follow-up, of the 1971 persons free of disability in activities of daily living (ADL) at baseline, 119 (6.0%) persons developed ADL-disability. Limitation in both the one-leg balance stand (<5 sec.) and walking speed (<0.8 m/s) tests at baseline were associated with increased risk of future ADL-disability, but having both simultaneously showed a 10-fold higher likelihood of future ADL-disability. Study II. In a sample free of cardiovascular diseases (CVDs) and physical limitation at baseline (n=1441), a greater cardiovascular risk burden, defined by the Framingham general cardiovascular risk score (FRS), was associated with increased risk of walking speed limitation over nine years of follow-up, but only in the younger-old adults (60-72 years old), not in the older-old (≥78 years old) (Hazard Ratio [HR] 1.09, 95% confidence interval [CI] 1.02–1.17; HR 0.98, 95% CI 0.92–1.03, respectively). Moreover, the FRS was not associated with future balance performance or muscle strength. Study III. In the sample free of CVD and ADL-disability at baseline (n=1756), among the younger-old adults, physical inactivity (HR 4.10, 95% CI 1.22-13.76), diabetes (HR 5.61, 95% CI 1.17-26.82), and high C-reactive protein (HR 95% 2.78, 95% CI 1.07-7.22) were associated with disability over nine years of follow-up. Among the older-old (≥78 years old), only physical inactivity was associated with greater risk of ADL-disability (HR 1.99, 95% CI 1.36-2.93), and walking speed modified this association, such that being physically inactive and having walking speed limitation, concomitantly, showed an even higher risk of ADL-disability. Study IV. A faster average annual decline in walking speed over nine years of follow-up, in older adults free of walking speed limitation at baseline (n=331), was observed for those with greater volumes of white matter hyperintensities (WMH) at baseline, or having a higher burden of brain abnormalities (WMH+lacunes+ perivascular spaces). Conclusion. Cardiovascular risk factors increase the risk of future physical limitation and disability, and brain abnormalities explain part of the underlying pathology driving the decline in physical function. However, risk profiles may differ between age groups of older adults, which suggests that interventions targeting decreasing cardiovascular risk may be more beneficial among younger-old adults, while older-old may benefit more from the maintenance of physical function