Domain-specific Cognitive Decline Research Articles

In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease.

See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline.

Mixed neuropathologies and associations with domain-specific cognitive decline.

To test whether decline in specific cognitive domains associated with Alzheimer disease neuropathologic change (ADNC) is modified by co-occurrence of other neuropathologies such as Lewy body disease (LBD) or vascular brain injury (VBI). Data came from 1,603 autopsied participants evaluated at US Alzheimer's Disease Centers. Standardized z scores in memory, attention, language, and executive function were derived from neuropsychological test scores assessed at each annual visit. Multivariable linear mixed-effects models assessed associations between neuropathologies and longitudinal trajectories of domain scores. Compared to other participants, those with ADNC + LBD generally had worse cognitive trajectories, particularly lower initial executive function and faster attention decline. Participants with ADNC + VBI typically had less impairment and slower decline. Interactions were significant between LBD and ADNC for memory (p = 0.046) and between VBI and ADNC for language (p = 0.03); decline was slower than expected if these neuropathologies acted additively on the rate of decline. In secondary models, these interactions were limited to those with high ADNC (but not intermediate ADNC). In a subset of 260 participants with data on microinfarct location, cortical and subcortical microinfarcts were associated with decline in memory, language, and executive function in those without ADNC, but this effect was reduced among those with ADNC. ADNC + LBD (but not ADNC + VBI) was associated with poorer executive function and attention compared to other pathology groupings. However, the effect of co-occurring pathologies on cognitive trajectories may depend on the severity of ADNC. Future studies using antemortem biomarkers should seek to replicate these neuropathologic observations.

LONGITUDINAL ASSOCIATIONS OF TYPE 2 DIABETES MELLITUS WITH COGNITIVE DECLINE AND BRAIN ATROPHY

Type 2 Diabetes Mellitus (T2DM) increases the risk of dementia. However, little is known as to whether T2DM is associated with decline in specific cognitive domains or brain atrophy. Participants were from the Cognition and Diabetes in Older Tasmanians study. Neuropsychological tests of processing speed, executive function and memory as well as Magnetic Resonance Imaging (MRI) were performed at baseline, 2.6 and 4.6 years. Multivariable mixed models were used to compare decline in cognition and brain atrophy over time in those with (n=349) and those without T2D (n=362) adjusting for age, sex and education, and for brain atrophy, total intracranial volume. The mean age of the sample was 70.0 (SD 7.4) years (range 55–90) with 56.% males. There were significant T2D×time interactions for tests of memory [the Hopkins Immediate (β-0.36 95%CI -0.55, -0.17 p<0.001) and the Hopkins Delay (β-0.13, 95%CI -0.22, -0.03; p=0.01)]; Attention [Digit span β-0.10 95%CI -0.21 -0.00; p=0.047] and executive function [COWAT category β -0.28 95% CI -0.43, -0.12 p=0.001], such that people with T2D demonstrated greater decline. There were no interactions (p>0.05) for tests of processing speed (digit symbol coding or symbol search) or inhibition (Stroop colour test). Although T2D was associated with smaller brain volumes at all time points (β-14133.7 95%CI -22045.67, -6221.722, p<0.001), there was no significant T2D×time interaction (p=0.58) for brain volume over time. In older people, T2D is associated with greater decline in cognition. It is possible that the effect of T2D on brain volumes begins earlier (midlife) and requires synergy with other neurodegenerative or vascular disease to accelerate decline at later age.

Gait Rather Than Cognition Predicts Decline in Specific Cognitive Domains in Early Parkinson's Disease.

BackgroundDementia is significant in Parkinson’s disease (PD) with personal and socioeconomic impact. Early identification of risk is of upmost importance to optimize management. Gait precedes and predicts cognitive decline and dementia in older adults. We aimed to evaluate gait characteristics as predictors of cognitive decline in newly diagnosed PD.MethodsOne hundred and nineteen participants recruited at diagnosis were assessed at baseline, 18 and 36 months. Baseline gait was characterized by variables that mapped to five domains: pace, rhythm, variability, asymmetry, and postural control. Cognitive assessment included attention, fluctuating attention, executive function, visual memory, and visuospatial function. Mixed-effects models tested independent gait predictors of cognitive decline.ResultsGait characteristics of pace, variability, and postural control predicted decline in fluctuating attention and visual memory, whereas baseline neuropsychological assessment performance did not predict decline.ConclusionsThis provides novel evidence for gait as a clinical biomarker for PD cognitive decline in early disease.

Hippocampal and white matter hyperintensity volumes are associated with domain-specific cognitive decline: the Northern Manhattan Study (S18.004)

Hippocampal and white matter hyperintensity volumes are associated with domain-specific cognitive decline: the Northern Manhattan Study (S18.004)

Cognitive Deficits Post-Traumatic Brain Injury and Their Association with Injury Severity and Gray Matter Volumes.

Traumatic brain injury (TBI) is known to have a substantial though highly variable impact on cognitive abilities. Due to the wide range of cognitive abilities among healthy individuals, an objective assessment of TBI-related cognitive loss requires an accurate measurement of pre-morbid cognitive performance. To address this problem, we recruited 50 adults who sustained a TBI and had performed a cognitive baseline assessment in adolescence as part of the aptitude tests mandated by the Israeli Defense Forces. This group was matched with non-injured controls (n = 35). Pre- and post-injury cognitive assessments consisted of three domains-namely, verbal abstraction, mathematical reasoning, and non-verbal abstract reasoning (from the Wechsler Adult Intelligence Scale-Third Edition). The difference between post- and pre-injury scores was calculated as a measure of domain-specific cognitive decline. Voxel-based regression was used to correlate cognitive decline with modulated gray matter probability maps controlling for age, Glasgow Coma Scale, and total intracranial volume. Using objectively assessed cognitive scores, we found that abstract reasoning declined in both moderate-severe and mild TBI patients, whereas verbal abstraction declined only in the moderate-severe group. Mathematical reasoning was not affected by TBI. In the TBI patients, non-verbal abstract reasoning post-pre-injury change scores were negatively correlated with the volume of the insula. We conclude that access to pre-morbid neuropsychological data may have facilitated the discovery of the effects of mild TBI on abstract reasoning, as well as a significant correlation between TBI-related decline in this cognitive domain and the volume of the bilateral insula, both of which had not been appreciated in the past.

Comparison of Gait Parameters forPredicting Cognitive Decline: TheMayoClinic Study of Aging.

Previous studies reported that slower gait speed might predict cognitive impairment and dementing illnesses, supporting the role of gait speed as a possible subclinical marker of cognitive impairment. However, the predictive value of other gait parameters for cognitive decline is unclear. To investigate and compare the association with, and prediction of, specific gait parameters for cognition in a population-based sample. The analysis included 3,426 cognitively normal participants enrolled in the Mayo Clinic Study of Aging. At baseline and every 15 months (mean follow-up = 1.93 years), participants had a study coordinator evaluation, neurological examination, and a neuropsychological assessment using nine tests that covered four domains. Gait parameters were assessed with the GAITRite® instrument. General linear mixed effects models were used to compute the annualized rate of change in cognitive domain z-scores, controlling for age, sex, education, depression, comorbidities, body mass index, APOE ɛ4 allele, and visit number, and excluding individuals with a history of stroke, alcoholism, Parkinson's disease, subdural hematoma, and normal pressure hydrocephalus. Spatial (stride length), temporal (ambulatory time, gait speed, step count, cadence, double support time), and spatiotemporal (cadence) gait parameters, and greater intraindividual variability in stride length, swing time, and stance time were associated with a significant decline in global cognition and in specific domains including memory, executive function, visuospatial, and language. Spatial, temporal, and spatiotemporal measures of gait and greater variability of gait parameters were associated with and predictive of both global- and domain-specific cognitive decline.

Inflammatory Biomarkers Predict Domain-Specific Cognitive Decline in Older Adults.

Vascular risk factors, including inflammation, may contribute to dementia development. We investigated the associations between peripheral inflammatory biomarkers and cognitive decline in five domains (memory, construction, language, psychomotor speed, and executive function). Community-dwelling older adults from the Ginkgo Evaluation of Memory Study (n = 1,159, aged 75 or older) free of dementia at baseline were included and followed for up to 7 years. Ten biomarkers were measured at baseline representing different sources of inflammation: vascular inflammation (pentraxin 3 and serum amyloid P), endothelial function (endothelin-1), metabolic function (adiponectin, resistin, and plasminogen activating inhibitor-1), oxidative stress (receptor for advanced glycation end products), and general inflammation (interleukin-6, interleukin-2, and interleukin-10). A combined z-score was created from these biomarkers to represent total inflammation across these sources. We utilized generalized estimating equations that included an interaction term between z-scores and time to assess effect of inflammation on cognitive decline, adjusting for demographics (such as age, race/ethnicity, and sex), cardiovascular risk factors, and apolipoprotein E ε4 carrier status. A Bonferroni-adjusted significance level of .01 was used. We explored associations between individual biomarkers and cognitive decline without adjustment for multiplicity. The combined inflammation z-score was significantly associated with memory and psychomotor speed (p < .01). Pentraxin 3, serum amyloid P, endothelin-1, and interleukin-2 were associated with change in at least one cognitive domain (p < .05). Our results suggest that total inflammation is associated with memory and psychomotor speed. In particular, systemic inflammation, vascular inflammation, and altered endothelial function may play roles in domain-specific cognitive decline of nondemented individuals.

CHINESE DIETARY PATTERNS AND DOMAIN-SPECIFIC COGNITIVE DECLINE IN THE ELDERLY

CHINESE DIETARY PATTERNS AND DOMAIN-SPECIFIC COGNITIVE DECLINE IN THE ELDERLY

Alcohol Consumption and Incident Dementia: Evidence from the Sydney Memory and Ageing Study.

Alcohol consumption is a potentially modifiable risk factor for dementia, but the literature is not completely consistent. This inconsistency may be partly due to an interaction with the apolipoprotein E (APOE) genotype, an established risk factor for Alzheimer's dementia. The aim of this study was to examine whether alcohol consumption is associated with incident dementia or decline in specific cognitive domains over 4 years, and if this effect is modified by APOEɛ4 status. Non-demented community dwelling older adults (70-90 years) from an ongoing longitudinal study were assessed for cognitive impairment in attention/processing speed, language, executive function, visuospatial ability, and memory. Incident dementia was diagnosed according to DSM-IV criteria. Compared to those who did not drink in the previous 12 months, neither low consumption (HR 0.64 95% CI 0.3-1.4) or risky consumption (HR 0.58 95% CI 0.2-1.5) was associated with incident dementia. Carriers of the APOEɛ4 allele were more likely to develop dementia, but there was no significant interaction with alcohol consumption.

Hearing Impairment and Incident Dementia and Cognitive Decline in Older Adults: The Health ABC Study.

Age-related peripheral hearing impairment (HI) is prevalent, treatable, and may be a risk factor for dementia in older adults. In prospective analysis, we quantified the association of HI with incident dementia and with domain-specific cognitive decline in memory, perceptual speed, and processing speed. Data were from the Health, Aging and Body Composition (Health ABC) study, a biracial cohort of well-functioning adults aged 70-79 years. Dementia was defined using a prespecified algorithm incorporating medication use, hospital records, and neurocognitive test scores. A pure-tone average in decibels hearing level (dBHL) was calculated in the better hearing ear using thresholds from 0.5 to 4kHz, and HI was defined as normal hearing (≤25 dBHL), mild (26-40 dBHL), and moderate/severe (>40 dBHL). Associations between HI and incident dementia and between HI and cognitive change were modeled using Cox proportional hazards models and linear mixed models, respectively. Three-hundred eighty seven (20%) participants had moderate/severe HI, and 716 (38%) had mild HI. After adjustment for demographic and cardiovascular factors, moderate/severe audiometric HI (vs. normal hearing) was associated with increased risk of incident dementia over 9 years (hazard ratio: 1.55, 95% confidence interval [CI]: 1.10, 2.19). Other than poorer baseline memory performance (difference of -0.24 SDs, 95% CI: -0.44, -0.04), no associations were observed between HI and rates of domain-specific cognitive change during 7 years of follow-up. HI is associated with increased risk of developing dementia in older adults. Randomized trials are needed to determine whether treatment of hearing loss could postpone dementia onset in older adults.

Abstract P153: Association of Habitual Milk Intake with Cognitive Decline From Mid-life to Late-life: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study (NCS)

Background: Animal models and large population studies have related habitual milk intake to impaired cognitive performance via oxidative stress, but results are inconclusive. We report on the association of milk intake at midlife with 20-year cognitive decline in ARIC-NCS cohort. Methods: Average daily milk intake was assessed in 15,766 ARIC study participants with a standardized FFQ administered at cohort inception in 1987-1989. Reported milk intake was categorized as almost never, &lt;1glass/day, 1 glass/day, &gt;1 glass/day. Domain-specific and global cognitive decline was assessed on three occasions from 1990 through 2013, testing Delayed Word Recall (memory), Digit Symbol Substitution (executive function), and Word Fluency (language). A mixed effects model adjusted for age, race, sex, education, smoking, physical activity and ApoE4 was used to evaluate the association of milk intake with change in cognitive performance over 20 years. The MICE method was used to account for attrition. Results: Among 13,821 participants in the analytic set, the distribution of milk intake across the above four categories was 18.7%, 35.8%, 27.3%, and 18.1%, respectively. In race-combined fully adjusted models greater milk intake was associated with greater cognitive decline (Figure) as indicated by a significant trend (p=0.018). The average difference in the 20-year rate of change in global z between those who reported almost never drinking milk and those who consumed &gt;1glass/day was -0.053 [95%CI: -0.092, -0.014], approximately equivalent to 1 year of additional cognitive aging. The trend met nominal statistical significance in Whites, but not African Americans. Conclusions: Results of this study add to reports indicating that greater milk intake may be associated with greater rate of cognitive decline. Replication of these results and insights into interactions with the intestinal microbiota and other putative modifying factors of the reported association is warranted considering the widely prevalent intake of milk in US adults.

Predictors of cognitive decline and treatment response in a clinical trial on suspected prodromal Alzheimer's disease

We determined the value of hippocampus (Hp) and basal forebrain (BF) volumes for predicting cognitive decline and treatment response in a double-blind, randomized, placebo-controlled phase 4 trial at 28 academic centers (France) in patients with amnestic mild cognitive impairment (MCI) receiving Donepezil 10 mg daily or placebo over 12 months, and 6 months open label follow-up. Outcome measures were the rates of global and domain specific cognitive decline as non-primary efficacy endpoint. The intention-to-treat (ITT) sample analyzed comprised 215 cases. Baseline Hp volume was a significant predictor of rates of change in global cognitive function in linear mixed effects models. This effect was independent of treatment. BF volume was not associated with rates of global or domain specific cognitive decline. Rates of delayed free recall decline were higher in MCI cases treated with donepezil compared to placebo. Only Hp, but not BF volume was a useful predictor of cognitive decline in suspected prodromal AD patients. Both Hp and BF volumes were poor predictors of treatment response, questioning previous approaches on predicting treatment response without placebo control. Trial registrationclinicalTrials.gov Identifier NCT00403520.

Assessing the association between homocysteine and cognition: reflections on Bradford Hill, meta-analyses, and causality.

Hyperhomocysteinemia is a recognized risk factor for cognitive decline and incident dementia in older adults. Two recent reports addressed the cumulative epidemiological evidence for this association but expressed conflicting opinions. Here, the evidence is reviewed in relation to Sir Austin Bradford Hill's criteria for assessing "causality," and the latest meta-analysis of the effects of homocysteine-lowering on cognitive function is critically examined. The meta-analysis included 11 trials, collectively assessing 22,000 individuals, that examined the effects of B vitamin supplements (folic acid, vitamin B12, vitamin B6) on global or domain-specific cognitive decline. It concluded that homocysteine-lowering with B vitamin supplements has no significant effect on cognitive function. However, careful examination of the trials in the meta-analysis indicates that no conclusion can be made regarding the effects of homocysteine-lowering on cognitive decline, since the trials typically did not include individuals who were experiencing such decline. Further definitive trials in older adults experiencing cognitive decline are still urgently needed.

Longitudinal Relationships Between Cognitive Decline and Gait Slowing: The Tasmanian Study of Cognition and Gait.

Gait slowing and cognitive decline are both common in older people. Although cross-sectionally related, the longitudinal associations between specific cognitive functions and gait speed are less well understood. We aimed to determine whether decline in specific cognitive domains are associated with change in gait speed. Participants aged 60-85, randomly selected from the electoral roll, were assessed twice over 3 years. Gait speed was obtained using the GAITRite walkway. Raw scores from a cognitive battery were subjected to principal component analyses deriving summary domains of executive function, processing speed, memory, and visuospatial ability. Multivariable linear regression was used to examine the associations between change in each cognitive domain and change in gait speed, adjusting for covariates and stratifying for the presence of baseline cognitive impairment. Mean age at baseline was 71.1 years (SD = 6.7) and 56% (159/284) were men. Mean follow-up was 2.55 (0.47) years. Decline in executive function, but not other cognitive domains (p > .05), was associated with decline in gait speed, cm/s (β = -3.55, 95% CI = -5.49, -1.61; p < .001), both in the presence and absence of baseline cognitive impairment. Stronger associations were seen for those with baseline multiple domain cognitive impairment (β = -6.38, 95% CI = -12.49, -0.27) and nonamnestic single-domain cognitive impairment (β = -7.74, 95% CI = -14.76, -0.72). Decline in nonamnestic function (specifically executive function) was associated with decline in gait speed irrespective of the presence of baseline cognitive impairment. Strategies to improve or maintain executive function may prevent gait slowing.

Early onset APOE E4-negative Alzheimer’s disease patients show faster cognitive decline on non-memory domains

Age at onset and APOE E4-genotype have been shown to influence clinical manifestation of Alzheimer’s disease (AD). We investigated rate of decline in specific cognitive domains according to age at onset and APOE E4-genotype in patients with AD. 199 patients with probable AD underwent at least two annual neuropsychological assessments. Patients were classified according to age-at-onset (≤65 years vs >65 years) and APOE genotype (positive vs negative). The neuropsychological test battery compromised tests for memory, language, attention, executive and visuo-spatial functioning. For each domain compound z-scores were calculated, based on the baseline performance of patients. Average duration of follow-up was 1.5±1 years. We used linear mixed models (LMM) to estimate effects of age, APOE and age⁎APOE on cognitive decline over time. At baseline, patients were 65±8 years, 98(49%) were female and MMSE was 22±4. LMM showed that early onset patients declined faster on executive functioning (β±SE:−0.09±0.06) than late onset patients, but age was not related to decline in the other cognitive domains. APOE E4 negative patients declined faster on language than APOE E4 positive patients (β±SE:−0.1±0.06). When we took age and APOE genotype into account simultaneously, we found that compared to late onset-E4 positive patients, early onset-E4 negative patients declined faster on language (β±SE:−0.36±0.1), attention (β±SE:−0.42±0.1), executive (β±SE:−0.41±0.1) and visuo-spatial functioning (β±SE:−0.43±0.1). Late onset-E4 negative and early onset-E4 positive patients showed intermediate rates of decline. We found no differences in decline on memory. We found that patients who develop AD despite absence of the two most important risk factors, show steepest cognitive decline on non-memory cognitive domains.

Fluid intelligence and brain functional organization in aging yoga and meditation practitioners.

Numerous studies have documented the normal age-related decline of neural structure, function, and cognitive performance. Preliminary evidence suggests that meditation may reduce decline in specific cognitive domains and in brain structure. Here we extended this research by investigating the relation between age and fluid intelligence and resting state brain functional network architecture using graph theory, in middle-aged yoga and meditation practitioners, and matched controls. Fluid intelligence declined slower in yoga practitioners and meditators combined than in controls. Resting state functional networks of yoga practitioners and meditators combined were more integrated and more resilient to damage than those of controls. Furthermore, mindfulness was positively correlated with fluid intelligence, resilience, and global network efficiency. These findings reveal the possibility to increase resilience and to slow the decline of fluid intelligence and brain functional architecture and suggest that mindfulness plays a mechanistic role in this preservation.

Over the Hill at 24: Persistent Age-Related Cognitive-Motor Decline in Reaction Times in an Ecologically Valid Video Game Task Begins in Early Adulthood

Typically studies of the effects of aging on cognitive-motor performance emphasize changes in elderly populations. Although some research is directly concerned with when age-related decline actually begins, studies are often based on relatively simple reaction time tasks, making it impossible to gauge the impact of experience in compensating for this decline in a real world task. The present study investigates age-related changes in cognitive motor performance through adolescence and adulthood in a complex real world task, the real-time strategy video game StarCraft 2. In this paper we analyze the influence of age on performance using a dataset of 3,305 players, aged 16-44, collected by Thompson, Blair, Chen & Henrey [1]. Using a piecewise regression analysis, we find that age-related slowing of within-game, self-initiated response times begins at 24 years of age. We find no evidence for the common belief expertise should attenuate domain-specific cognitive decline. Domain-specific response time declines appear to persist regardless of skill level. A second analysis of dual-task performance finds no evidence of a corresponding age-related decline. Finally, an exploratory analyses of other age-related differences suggests that older participants may have been compensating for a loss in response speed through the use of game mechanics that reduce cognitive load.

Abstract P3-11-01: Prospective study of cognitive function in women with early stage breast cancer: Predictors of cognitive decline and relationship to cognitive complaints

Abstract Background: Cognitive complaints are common among women receiving adjuvant therapy (Rx) for early stage breast cancer (ESBC). Longitudinal prospective data is needed to understand cognitive complaints and decline. We conducted a prospective trial to evaluate the effects of chemotherapy (CTX) and hormone therapy (HRx) on brain and cognitive function in patients with ESBC using objective &amp; subjective tests as well as MRI/PET imaging. Methods: Eligibility included female patients planning to receive adjuvant Rx for ESBC. Patients were enrolled in 3 treatment groups: CTX, CTX and HRx, and HRx, with a 4th no disease age and education matched control group. Patients underwent a battery of objective and subjective cognitive tests before start of Rx, 1 month after CTX or 5 months after start of HRx (FU1), then 9 months (FU2) and 18 months (FU3) after Rx. Brain MRI, PET &amp; serum estradiol (E) were performed at baseline, FU1 &amp; FU3. Results: 81 patients were enrolled as follows: 14 CTX, 33 CTX &amp; HRx, 22 HRx, and 12 control. 90% completed FU1, 72% FU2, &amp; 62% FU3, with 29 patients waiting to complete testing. Demographics were similar between groups: median age 54, 78% Caucasian. At each FU, approximately 25% of patients showed cognitive decline using a reliable change index; 51% showed decline at ≥ 1 time point, primarily in tests of executive function &amp; verbal memory. 62 - 77% of patients who declined later stabilized or improved. Compared to controls, receipt of HRx (OR 4.94, p = .004) but not serum E, menopausal status, CTX, demographic factors, depression, or fatigue, were significant predictors of decline at any time point. Rx group did not predict cognitive complaints (FACT-Cog). At FUP1, depression, fatigue, and decline in letter fluency predicted overall cognitive complaints, but HRx did not. Cognitive complaints were predicted by domain-specific cognitive decline: memory decline predicted memory complaints, and verbal fluency decline predicted verbal fluency complaints, even after controlling for depression and fatigue. Additional analyses will be presented as more patients complete follow-up testing. Conclusion: Decline in cognitive function is common in patients receiving adjuvant Rx for ESBC. Ongoing HRx was a risk factor for worse cognitive function, but not for perceived cognitive problems. Other Rx and patient related factors did not predict decline. Perceived cognitive problems were predicted by depression, fatigue, and letter fluency decline, with specific cognitive complaints predicted by domain-specific declines. Patients should be aware that HRx may be a risk factor for cognitive decline, while depression, fatigue, and cognitive decline predicted cognitive complaints. Intervention studies, including assessment for depression and fatigue, should be offered to patients who complain of cognitive changes and particularly to patients treated with HRx. Funding: NIH R01 1AG025303-01A2. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-11-01.

P2‐169: Slow gait predicts cognitive decline: A population‐based cohort study

Gait may be susceptible to age-related changes that depend on the individual characteristics and on the concurrent presence of other diseases. Some studies have reported that gait abnormalities may be associated with cognitive impairment and dementing illnesses, supporting the role of an association between gait and cognitive impairment. However, it is unclear which gait components have been associated with a future cognitive decline. Participants included 1,341 subjects who were enrolled in the Mayo Clinic Study of Aging (MCSA) and were examined with a computerized gait instrument, GAITRite, at two or more visits. Visits, including neurological and neuropsychological evaluations, were conducted approximately 15 months apart. The primary gait assessments were three spatio-temporal parameters: stride length, cadence, and velocity. Outcomes included the Short Test of Mental Status (STMS) and global and domain-specific Z-scores. Domain-specific Z-scores were calculated using nine neuropsychological tests covering four domains: memory, attention/executive functioning, language, and visuospatial ability. Linear mixed effects models were used to assess differences in the annualized rate of change in cognitive domain scores associated with differences in the gait measures at baseline while adjusting for age, sex, education, APOE genotype, hypertension, diabetes and dyslipidemia. Participants with lower cadence, velocity, and amplitude of the stride length experienced significantly larger declines in global cognition, memory, and executive function. Lower gait measures were also significantly associated with a greater decline on the STMS. The average decrease in the STMS associated with a 10 steps per minute lower cadence was 0.07 points per year (95% CI: 0.02 - 0.12, P = 0.01). The average decrease in the STMS associated with a 1 meter per second slower velocity was 0.5 points per year (95% CI: 0.2 - 0.8, P = 0.002). Excluding persons with stroke, parkinsonism, vascular dementia, head injury, or normal pressure hydrocephalus from the analyses did not affect the results. Our study is consistent with previous reports. In particular, we observed an association between reduced gait velocity, cadence, and stride length and global- and domain-specific cognitive decline in a large population based cohort.