Incident MCI Research Articles

Advanced Diffusion MRI of White Matter in Aging and AD

AbstractChanges in brain white matter occur in normal aging and prior to the onset of cognitive impairment. We have shown that advanced diffusion MRI and biophysical modeling yield sensitive and specific metrics that distinguish age‐related (e.g. myelin remodeling) from amyloid‐related pathological processes (e.g. myelin repair) in the preclinical stage. In this presentation we provide an update on our ongoing observational longitudinal study to determine the extent to which these metrics can serve as predictive biomarkers of incident cognitive impairment. Cognitively unimpaired older adults completed brain MRI (including Diffusional Kurtosis Imaging) and standard clinical procedures (NACC UDS v3) at baseline and ∼2 years later, with 91.2% retention and 13.1% incident MCI (CDR = 0.5) at follow‐up. We found that in participants with preclinical AD, late‐myelinating white matter tracts demonstrate signs of myelin repair/gliosis as evidenced by greater diffusion restriction. We also observed that greater diffusion restriction predicts incident MCI over and above age, a finding we did not observe with other AD neuroimaging biomarkers of amyloid pathology, neurodegeneration, and white matter lesions. In the next 5 years of funding, we will expand our cohort in size and representativeness, incorporate complementary MRI biomarkers of myelin/gliosis (i.e. myelin water imaging [ViSTa] and 1H‐MRS of myo‐inositol and NAA) to test our inferences, and further develop diffusion MRI‐based biophysical modeling techniques (i.e. Fiber Ball Imaging‐based white matter modeling). Expected outcomes from this work include clinically feasible MRI biomarkers with which to empirically test a proposed conceptual model of white matter‐related changes in aging and AD, thereby providing translational support for trials of myelin/glia‐focused therapies which are grossly underexplored for asymptomatic AD. Our goal is to have an impact on the evolving conceptualization of how aging leads to AD and, critically, to illuminate novel mechanisms by which AD can be prevented or treated.

Late‐life social activity and subsequent risk of dementia and mild cognitive impairment

AbstractBackgroundPrevious research reported associations between more social engagement and better cognitive health. Social engagement is a multidimensional construct encompassing interrelated but distinct domains such as social activity, social network size, perceived social support, and loneliness. These domains are not equally amenable to interventions. We therefore focused on late‐life social activity, as a potentially modifiable facet of social engagement, and examined its relation to risks of dementia and MCI, independent of other aspects of social engagement, lifestyle, and health.MethodIn the Rush Memory and Aging Project (MAP), 1923 older adults without dementia at baseline were followed longitudinally, with annual clinical evaluation of dementia and MCI. The frequency of participation in six common social activities was assessed by a validated scale at baseline (mean = 2.6, range: 1‐4.3), as were size of social network, perceived social support, and perceived loneliness. A clinical diagnosis of MCI or dementia was rendered annually based on cognitive tests and diagnostic classification by a clinician. We used Cox proportional hazard models to quantify associations between social activity score and incident dementia or MCI. Primary models controlled for demographics; additional models included covariates for health, other social engagement indicators, and income. In secondary analyses, to consider reverse causality, we excluded participants who developed MCI or dementia within two years after baseline.ResultDuring a mean follow‐up of 6.7 (std = 4.7) years, 545 (28%) participants developed dementia, and 695 (49% of those without MCI at baseline) developed MCI. Each one‐unit increment in social activity score was associated with a 37% reduction in dementia risk [HR = 0.63, 95% CI: 0.53‐0.74] after adjusting for age, sex, education, race/ethnicity, and marital status (Figure 1A). Social activity was also related to a lower risk of MCI [HR = 0.77, 95% CI: 0.66‐0.89] (Figure 1B). Results were not meaningfully different after adjusting for vascular disease burden, BMI, ADL disability, physical activity, depressive symtoms, social network size, social support, social isolation, and income. Excluding participants who developed MCI or dementia soon after baseline did not change the patterns.ConclusionKeeping socially active at older age is related to lower dementia risk, possibly informing strategies for developing preventive interventions.

Clinical Manifestations.

Mild behavioral impairment (MBI) identifies a high-risk group for Alzheimer's disease and related dementias (ADRD), leveraging the risk associated with later-life emergent and persistent neuropsychiatric symptoms (NPS). MBI may act as a complementary behavioral analog to later-life emergent cognitive symptoms (mild cognitive impairment, MCI). These constructs are not mutually exclusive and can co-occur. We characterized the relationship between MBI, grey matter volume in the hippocampus and entorhinal cortex, and incident cognitive decline in older adults with normal cognition (NC) and MCI. Seven-hundred-forty-two participants were included from the National Alzheimer's Coordinating Center Uniform Dataset. The Normative Morphometry Image Statistics tool was used to generate estimates of grey matter volume for the bilateral hippocampi and entorhinal cortices, normalized by age, sex, total intracranial volume, and image quality. NPS were evaluated using the informant-rated Neuropsychiatric Inventory Questionnaire, from which MBI scores were derived based on a published algorithm. Associations between MBI status and the regions-of-interest were modelled separately in NC and MCI using multivariable linear regressions, adjusting for education and clinical-MRI visit interval time. Associations between MBI status and incident cognitive decline were modelled using Cox proportional hazards regressions. Participant characteristics are summarized in Table 1. As per Figures 1 and 2, NC participants with MBI had lower grey matter volume in the bilateral hippocampi (B = -0.40, 95%CI:[-0.66, -0.15], p = .004), and a greater hazard of incident MCI or dementia, than those without MBI (HR = 3.34, 95%CI:[2.04, 5.48), p<.001). NC MBI+ participants also had lower grey matter volume in the bilateral entorhinal cortices compared to NC MBI- participants, although not statistically significant (B = -0.13, 95%CI:[-0.35, -0.08], p = .22). In MCI, participants with MBI had lower grey matter volume bilaterally in both the hippocampus (B = -0.46, 95%CI:[-0.80, -0.12], p = .01) and entorhinal cortex (B = -0.42, 95%CI:[-0.76, -0.12], p = .009), and had greater progression-rates to dementia (HR = 4.13, 95%CI:[2.45, 6.94), p<.001), than those without MBI. Our findings suggest that evaluating dementia-free older adults for MBI status in conjunction with cognitive status identifies a group further along the ADRD continuum than those without MBI, who have greater baseline atrophy in key ADRD regions and greater progression rates to later cognitive stages.

Can Mild Cognitive Impairment be Preempted? Modifiable Risk factors for MCI in a Rust Belt Community

Background/ObjectiveMild cognitive impairment (MCI) in community samples differs from MCI in clinical samples in several ways. MCI in the community is more heterogenous, with fewer individuals progressing to dementia and more reverting to normal cognition. In a sample from a rust belt, low SES, small town region, we examined the relationship between benzodiazepine (BZD) use, anticholinergic drug use, and anxiety with MCI. MethodsThe studies examining BZDs and anticholinergic drugs used a population-based cohort (n=1959) of adults age 65 and over. The anxiety study used a subset of this larger sample (n=364) who experienced anxiety and MCI at different time-points during a 3-year period. Participants were followed annually. At each time point, we assessed their medication use, anxiety symptoms, perceived stress, depressive symptoms, and Clinical Dementia Rating (CDR®), where CDR=0.5 was operationalized as MCI. The studies examining BZDs and anticholinergic drugs examined time to incident MCI (CDR=0.5) and incident dementia (CDR ≥ 1) among participants who were cognitively normal at baseline (CDR=0). The study examining anxiety included people with normal cognition or MCI (CDR ≤ 0.5) at baseline and looked at the bidirectional relationship between anxiety and MCI and its potential mediators. ResultsBZD use and anticholinergic drug use are each associated with development of MCI but not with development of dementia. There is a significant bidirectional relationship between anxiety and MCI that is mediated through perceived stress. ConclusionsIn a population-based sample of cognitively normal older adults, BZD and anticholinergic drug use are associated with developing MCI, but not dementia. Older adults with anxiety are at higher risk of developing MCI, and older adults with MCI are at higher risk of developing anxiety. Deprescribing BZDs and anticholinergic drugs and treating anxiety and stress could have a significant impact on incident MCI in the community.

Natural premature menopause relates to higher risk of mild cognitive impairment and Alzheimer’s disease and related dementias in APOE‐ε4 carriers only

AbstractBackgroundOverall risk of Alzheimer’s disease (AD) and APOE‐ε4‐related risk for AD is higher among women than men, but the sex‐specific biological underpinnings of these sex differences are unknown. Earlier age at menopause has been associated with higher risk of AD and related dementias (ADRD); however, it is unclear whether this relationship holds among naturally menopausal (versus surgically menopausal) women only or whether it is impacted by APOE‐ε4 genetic risk. We examined the association of natural premature (occurring ≤40 years of age) menopause with MCI and ADRD risk among older women and whether this relationship was moderated by APOE‐ε4 genotype.MethodThis study included 3,557 older women (age range: 65‐79 years at baseline; all White; 5.3% premature menopause; 25.5% APOE‐ε4 carriers) from the Women’s Health Initiative Memory Study (WHIMS) who experienced menopause spontaneously and not as a result of hysterectomy or bilateral oophorectomy. All participants had data on reproductive history, APOE genotype and longitudinal cognitive evaluations, and were cognitively unimpaired at baseline (follow‐up time: range = 0.92‐24.19, mean = 9.92 years). Incident MCI and ADRD were determined with a comprehensive neuropsychological battery and centrally adjudicated by a panel of specialists with expertise in dementia diagnosis. A set of Cox regression models was applied to determine whether premature menopause and its interaction with APOE‐ε4 carrier status was associated with risk of MCI or ADRD, adjusting for age, education, cardiovascular risk factors, parity, age at menarche, past contraceptive use and current or past hormone therapy use and the timing of initiation relative to menopause.ResultThe APOE‐ε4 X premature menopause interaction was significant (p = .04). Among APOE‐ε4 allele carriers, premature (vs. non‐premature) menopause was associated with an approximate two‐fold increased risk of MCI/ADRD (HR = 2.05, 95%CI: 1.22‐3.44). No such association was present among women without an APOE‐ε4 allele (HR = 1.16, 95%CI: 0.72‐1.86).ConclusionNatural premature vs non‐premature menopause was associated with two‐fold higher risk of MCI/ADRD but only among APOE‐ε4 carriers. Results suggest interactive effects of premature menopause and the APOE‐ε4 genotype. Future studies are needed to determine whether the menopause and APOE‐ε4 pathophysiological mechanisms of dyslipidemia, inflammation and brain metabolism deficiencies may explain this association.

Characterization of subjective cognitive concerns (SCC) in a racially/ethnically diverse community‐based elderly cohort: Results from the Einstein Aging Study (EAS)

AbstractBackgroundSCC may play an important role in identification of pre‐clinical dementia, especially among individuals who experienced disparities. A small number of studies examined the differential prediction of objective cognitive decline between blacks and whites using SCC, yielding mixed results. It is important to identify any differential patterns of SCC endorsement among racially diverse groups to enhance the ability to capture current and future cognitive status.MethodUsing data from the EAS, a longitudinal community residing cohort aged 70+, an SCC composite was derived using 22 self‐reported items. Cognitive status was diagnosed by consensus conference (dementia, MCI, cognitively normal). Objective cognition was measured using 3 factor scores (memory, executive function, global/verbal) derived from a principal component analysis of our neuropsychological battery. Multiple linear regression models were used to evaluate racial differences in SCC at baseline for those who were cognitively normal, as well as to determine whether there was a differential association between SCC and objective cognition among racial groups. Cox models were applied to determine if there was racial heterogeneity for the effect of SCC on incident MCI, adjusting for demographics, estimated premorbid intelligence, medical co‐morbidities, and depressive symptoms.Result1720 participants of non‐Hispanic white or black race were cognitively normal at baseline and included in these analyses. There was no significant difference between blacks and whites on the SCC composite; however, there was a significant interaction between race and SCC on 2 of 3 objective cognition factors. Having more SCC at baseline was associated with worse objective cognitive performance in the memory and global/verbal domains in white and black participants, but the association was significantly weaker among blacks. While SCC was associated with greater risk of incident MCI (&lt;0.0001), there was no significant interaction between race and SCC on incident MCI.ConclusionDespite having weaker, though still significant, associations with memory and global/verbal tasks in blacks compared to whites, SCC consistently predicted incident MCI across the two races. Future work should expand upon these results through replication in other diverse samples, inclusion of informant report data, and investigation of differential change in SCC over time and in relation to clinical conversion.

Longitudinal online weekly health reports of non‐cognitive symptoms and events can differentiate incident MCI from stable cognitively healthy older adults

AbstractBackgroundChanges in mood, loneliness, pain, and need for assistance may be potential early markers of cognitive decline in older adults. These changes can be subtle, and fluctuating, and thus easily missed during intermittent clinic visits. Continuous long‐term monitoring of these self‐reported internal states and needs, and their relationship to developing cognitive impairment has not been assessed.MethodWeekly online reports of health‐related activities and mood in relation to MCI were assessed over four years in volunteers participating in the Oregon Life Laboratory, a study using home‐based unobtrusive remote sensing and monitoring of physical, cognitive, behavioral, physiological, and health‐related activities. Participants were older adult computer users living in retirement communities and free‐standing homes.ResultThe analytic sample included 129 cognitively healthy volunteers with a mean monitoring period of 2.9 ± 1.2 years completing 16,738 online surveys. Mean age was 83.5 ±7.8 years, mean education was 15.7 ± 2.7 years, and 76% were female. Twenty‐two participants (17%) developed MCI or dementia while 107 remained cognitively healthy. Results from longitudinal models with dichotomous outcomes including 1) loneliness, 2) low mood, 3) pain intensity and pain interference, and 4) in‐home assistance were run adjusting for covariates. Over time, those destined to develop MCI reported: 1) more loneliness (p=0.049), 2) more low mood (p=0.07), 3) greater pain intensity (p=0.026) and pain interference (p=0.011), and 4) needing more in‐home assistance (p=0.022) than those remaining cognitively healthy. Baseline standard clinical scale scores assessing these symptoms were not clinically concerning nor predictive of MCI. Baseline mean pain intensity scores (range: 0‐9) were 2.2 ± 2.0 among incident MCI and 1.8 ± 2.0 in stable cognitively healthy participants (p=0.23). Geriatric Depression Scale baseline scores were 1.0 ± 1.5 in incident MCI and 1.1 ± 1.7 in stable cognitively healthy participants (p=0.82).ConclusionContinuous home‐based online assessment of non‐cognitive aspects of function or internal states (loneliness, mood, pain, needing more assistance) can be sensitive early indicators of changes in brain function leading to cognitive decline. These clinically important measures may reflect both direct as well as indirect relationships to underlying neuropathology.

Incident MCI and dementia in Hispanic and non‐Hispanic whites: Implications for ethnic comparisons of risk in Alzheimer’s Disease Center data

AbstractBackgroundRecruitment strategies have different levels of success in reaching Hispanic populations, potentially introducing bias in large multicenter datasets, such as the National Alzheimer’s Coordinating Center (NACC). The purpose of this study is to examine differences in incident mild cognitive impairment (MCI) and dementia between Hispanic and non‐Hispanic whites.MethodWe included NACC data from 23,963 participants with &gt;1 follow‐up visit. Additional inclusion criteria were: age 60+, did not have Downs syndrome, ethnicity Hispanic or non‐Hispanic, primary race as white, and cognitively normal or diagnosed with MCI at baseline. An event (i.e., conversion) was defined as the first visit/subject age when diagnosed with MCI or Dementia. To compare age‐of‐conversion between Hispanic and non‐Hispanic whites, we used Cox proportional hazard models with variable entry setup. Separate models were fit for baseline cognitive status (MCI vs. normal). Model covariates included sex; educational attainment; baseline diabetes, hypertension, and cardiac event status; referral source; family history of dementia; and primary etiology (for baseline MCI subgroup only). Unadjusted Kaplan‐Meier curves were calculated between Hispanic and White non‐Hispanic subjects for both baseline cognitive strata and outcome (conversion only vs. combined).ResultNormal cognition Hispanic participants exhibited significant elevated risk of conversion compared to White non‐Hispanic participants (HR=1.316, p=0.005), but risk was non‐significant for the composite event (HR=1.176, p=0.069). For baseline MCI participants, Hispanic ethnicity was significantly associated with reduced risk of both conversion and conversion/death (conversion HR=0.734, p=0.002; conversion/death HR=0.699, p&lt;0.001). In all models, referral sources other than health professional were associated with reduced risk of event. Family history of dementia was associated with increased risk of conversion and conversion/death for those with normal baseline cognition (conversion HR=1.216, p&lt;0.001; conversion/death HR=1.084, p=0.048), but not for those with baseline MCI.ConclusionWhite participants with MCI, referred by clinicians exhibited greater likelihood of disease progression. These data suggest that Hispanic and non‐Hispanic whites in NACC may not be comparable. Therefore, caution should be exercised when interpreting analyses of data examining ethnic differences in incident MCI and dementia.

Comparing versions of the memory binding test: Predictive validity for incident aMCI and incident dementia

AbstractBackgroundThe Memory Binding Test (MBT) Version 1 demonstrated significant predictive validity for incident amnestic MCI (aMCI) and incident dementia. Version 2 of the MBT was developed to be briefer because brevity is essential for screening. Herein we aimed to compare the two versions in terms of predictive validity for aMCI and dementia, separately.MethodAs sub‐studies of the Einstein Aging Study (EAS), the two MBT versions were administered to two independent study samples between May 2003 and December 2007 at baseline, and these participants were followed up to Jan 2017 (For differences in versions see Table 1). The EAS enrolls a systematically recruited community sample of adults age over 70. The two versions were evaluated in parallel using the same methodologies. We evaluated a range of cut‐scores on the MBT score of choice, the Total Items in the Paired condition (TIP), including the empirical optimal cut‐score which maximized the sum of sensitivity and specificity from the cross‐sectional discriminative analyses. The predictive validity was assessed by Kaplan‐Meier curves, log‐rank tests and Cox regressions.ResultPredicting incident aMCI: Both versions were strong predictors of incident aMCI (Table 2): For the empirical optimal scores for TIP, hazard ratio (HR)=2.33, 95% CI: (1.26, 4.29), p=.007 for Version 1, HR=3.38, 95% CI: (1.09, 10.5), p=0.04 for Version 2; for a range of TIP scores (17−22): HR range: 2.27−6.07, p ≤ .01, for Version 1, and 2.67−5.91, p≤.04 for Version 2. Predicting incident dementia: Both versions were strong predictors of incident dementia (Table 3): For the empirical optimal scores for TIP, HR=8.32, 95% CI: (3.51, 19.7), p&lt;.0001 for Version 1, HR=9.30, 95% CI: (3.43, 25.2), p&lt;.0001 for Version 2; for a range of TIP scores (17−23): HR range: 3.09−8.32, p ≤ .003, for Version 1, and 6.40−9.30, p&lt;.0001 for Version 2.ConclusionThe predictive validity for incident aMCI and incident dementia was strong and similar for the two versions of the MBT based on the overlapping confidence intervals. These results strongly support the hypothesis that poor performance on memory binding is an important marker for the early detection of aMCI and dementia.

Assessing functional disability in individuals with MCI and dementia

AbstractBackgroundMild cognitive impairment (MCI) and dementia are among the most disabling conditions. Patients with MCI and dementia may experience difficulties in executing instrumental activities of daily living (IADL), resulting in distress for patients and families. Measuring and understanding abilities to execute IADL is important to understand how MCI and dementia impacts patients’ functioning. We explored the factor structure of the Functional Activities Questionnaire as a measure of functional disability in a sample with MCI and dementia.MethodsParticipants were 198 enrollees in the Wisconsin ADRC who had MCI, and dementia. Not applicable responses were counted as missing data, resulting in 98 participants in main analyses. The majority of participants were male (61.1%) and Caucasian (88.4%). Average age at baseline was 73.76 (SD=8.90). We conducted the following analysis: exploratory factor analysis (EFA), reliability analysis, correlation analysis, and Mann‐Whitney U test.ResultsThe Kaiser–Meyer–Olkin (KMO) measure of sampling adequacy was .89, and the Barlett’s test of sphericity was significant, χ 2(45,N=98)=717.24, p&lt;.001, indicating suitability for factor analysis. Kaiser–Guttman’s criterion and Cattell’s scree test both indicated a single‐factor measurement structure, accounting for 64% of the total variance. The Cronbach’s alpha was found to be .94 for the FAQ. Functional disability was positively correlated with neuropsychiatric symptoms (r=.43, p&lt;.001), CDR global score (r=.79, p&lt;.001), and lack of independence (r=.66, p&lt;.001). A Mann‐Whitney U test showed that individuals with dementia had significantly higher levels of functional disability than those with MCI (U=214.00, p&lt;.001).ConclusionThe FAQ was found to be a unidimensional, reliable, and valid measure of functional disability. Participants with higher scores on the FAQ endorsed greater levels of neuropsychiatric symptoms, symptoms of cognitive impairment, and dependence to others. As expected, those with dementia had higher levels of functional disability/limitations. Future research may examine whether functional disability/limitations predicts incident MCI or dementia in cognitively normal individuals.

Metabolic Profiling of Cognitive Aging in Midlife.

Alzheimer’s dementia (AD) begins many years before its clinical symptoms. Metabolic dysfunction represents a core feature of AD and cognitive impairment, but few metabolomic studies have focused on cognitive aging in midlife. Using an untargeted metabolomics approach, we identified metabolic predictors of cognitive aging in midlife using fasting plasma sample from 30 middle-aged (mean age 57.2), male-male twin pairs enrolled in the Vietnam Era Twin Study of Aging (VETSA). For all twin pairs, one twin developed incident MCI, whereas his co-twin brother remained to be cognitively normal during an average 5.5-year follow-up. Linear mixed model was used to identify metabolites predictive of MCI conversion or cognitive change over time, adjusting for traditional risk factors. Results from twins were replicated in an independent cohort of middle-aged adults (mean age 59.1) in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Results in twins showed that higher baseline levels of four plasma metabolites, including sphingomyelin (d18:1/20:1 and d18:2/20:0), sphingomyelin (d18:1/22:1, d18:2/22:0, and d16:1/24:1), DAG (18:2/20:4), and hydroxy-CMPF, were significantly associated with a slower decrease in one or more domains of cognitive function. The association of sphingomyelin (d18:1/20:1 and d18:2/20:0) was replicated in WRAP. Our results support that metabolic perturbation occurs many years before cognitive impairment and plasma metabolites may serve as early biomarkers for prediction or monitoring of cognitive aging and AD in midlife.

Kidney function changes and their relation with the progression of cerebral small vessel disease and cognitive decline

AimsWe aimed to study whether worsening in markers of kidney function parallels the progression in cerebral small vessel disease (cSVD) and cognitive decline. MethodsData from the ISSYS (Investigating Silent Strokes in Hypertensives Study), a longitudinal population-based study in hypertensives aged 50–70 and dementia and stroke-free at baseline. At both visits, patients underwent a brain MRI, a cognitive diagnosis (normal aging or mild cognitive impairment, [MCI]) and urine and blood sampling collection.We assessed the incidence of infarcts and cerebral microbleeds, and the progression of white matter hyperintensities at periventricular (PVH) and deep areas.We determined changes in albumin-creatinine ratio and estimated glomerular filtration rate (eGFR). These changes were dichotomized into microalbuminuria at follow-up —either in subjects with or without baseline microalbuminuria— and significant decline in eGFR —lowest quintile of eGFR change (−10.57 mL/min/1.73m2)—. Results360 patients were followed-up for 4 years. 80 (23%) patients presented microalbuminuria at follow-up and 68 (20.1%) experienced a significant eGFR decline.Considering cSVD change, we found a relationship between microalbuminuria at follow-up and progression in PVH (β = 0.31, P-value = .01).Regarding cognitive decline, presence of microalbuminuria at follow-up related to a steeper decrease in memory function (β = −0.36, P-value<.01). Moreover, patients with significant decline in eGFR were at higher risk of incident MCI (OR = 3.54, P-value = .02). These associations were independent of progression of cSVD. ConclusionThe worsening in markers of kidney function paralleled the decrease in cognition and the progression of cSVD, and this may be explained by common shared underlying risk factors.

ANALYSIS OF REST-ACTIVITY RHYTHMS AND RISK OF INCIDENT MILD COGNITIVE IMPAIRMENT AND DEMENTIA IN OLDER WOMEN

In older adults, desynchronized circadian rhythms have been associated with medical illness, including Alzheimer Disease. Activity, which can be easily measured using actigraphy over consecutive 24-hour periods, is a valid marker of entrained sleep phase and correlates with entrained endogenous circadian phase. We compare results of both parametric and non-parametric analyses to test the association of rest-activity patterns with incident MCI and dementia in 2132 older women who had 2 or more 24-hrs periods of actigraphy data collected at baseline. Follow-up neuropsychological testing approximately 5 years later is used to classify women as normal, MCI, or dementia. Logistic regression models are adjusted for age, clinic site, race, education, body mass index, functional status, comorbidities, medication use, and health habits. Results suggest the importance of overall amplitude and rhythmicity, as well as timing of activity patterns over the 24-hour day as risk factors for incident MCI/dementia.

Silent brain infarctions and cognition decline: systematic review and meta-analysis.

Silent brain infarction (SBI) may be associated with cognitive decline in the general population. We systematically reviewed prior literature on: (1) SBI and cognition cross-sectionally; (2) baseline SBI and future cognitive decline and risk for cognitive disorders including dementia, and (3) incident SBI and the emergence of cognitive decline or cognitive disorders. The MEDLINE and EMBASE databases were searched for relevant studies. Data were independently extracted by two reviewers. Quality was assessed using the Newcastle Ottawa Scale. Data were pooled using a random effects model when more than two comparable estimates were found. Thirty relevant studies were identified: 17 had a cross-sectional design, 10 evaluated the association of baseline SBI with future cognitive decline, and 5 evaluated the association of incident SBI with cognitive decline. Most cross-sectional studies reported lower cognitive performance in persons with SBI. The pooled risk for incident dementia in persons with SBI was 1.48 (95% CI 1.12-1.97), but there was significant heterogeneity (p = 0.009); removing one outlier eliminated the heterogeneity (p = 0.53), giving a lower but still significant estimate (hazard ratio 1.27, 95% CI 1.06-1.51). The pooled risk for incident MCI was not increased in persons with SBI (hazard ratio 0.83, 95% CI 0.40 to 1.72), but there was significant heterogeneity (p < 0.001). The appearance of new SBI was associated with steeper rate of cognitive decline and the appearance of dementia. SBI are associated with worse cognition and increased risk for dementia. More standardization of cognitive assessment methods would facilitate future cross-study comparisons.

1013 Novel Quantitative EEG Exposures and Risk of Incident MCI and Dementia in Older Women

1013 Novel Quantitative EEG Exposures and Risk of Incident MCI and Dementia in Older Women

Abstract 150: Cerebral Microbleeds and Cognition in Lacunar Stroke Patients: The Secondary Prevention of Small Subcortical Strokes Trial

Background: Cerebral microbleeds (CMBs) have been associated with cognitive dysfunction. However, characterization of CMBs and cognitive dysfunction in a large population of stroke patients is lacking. We aimed to characterize the association of CMBs with cognitive function in lacunar stroke patients and the response to assigned treatments in the Secondary Prevention of Small Subcortical Strokes (SPS3) trial. Methods: SPS3 was a randomized trial comparing two systolic blood pressure targets and two antiplatelet regimens in 3020 dementia-free patients with symptomatic, MRI-confirmed lacunar stroke. Participants underwent detailed neuropsychological testing covering multiple domains, including short delay recall, long delay recall, discriminability, block design, symbol search, grooved pegboard, controlled oral word association and clock drawing, at baseline and then annually for 5 years. Participants with axial MRI T2*- GRE sequences allowing for CMB detection and Cognitive Abilities Screening Instrument (CASI) Z scores available at baseline were included in the current analysis. Results: CMBs were present in 30% of 1225 eligible patients (mean age 63 years, 35% women) with median follow up of 3 years. Patients with CMBs had greater proportion of mild cognitive impairment (MCI; 56% vs. 42%, p&lt;0.0001) and lower cognitive scores at baseline (mean CASI Z score -0.9 vs. -0.5, p&lt;0.0001), including significantly lower scores across most of the individual cognitive domains tested. During follow-up, in 578 participants without MCI, there was no difference in the rate of incident MCI in patients with CMBs (29%, 41/143) and those without CMBs (26%, 111/435; p=0.50). Trends in cognitive decline over time were not statistically significantly different between the two groups. There were no interactions between CMBs and treatment assignments for cognitive outcomes. Conclusions: In this largest reported cohort assessing the association between CMBs and post-stroke cognitive impairment, CMBs were associated with lower cognitive scores and greater rates of MCI at baseline. However, changes over time in cognition were similar in lacunar stroke patients with and without CMBs who receive adequate vascular risk management.

A GLOBAL MEASURE OF BRAIN AGE IS MORE SENSITIVE THAN HIPPOCAMPAL VOLUME IN PREDICTING INCIDENT MILD COGNITIVE IMPAIRMENT IN COMMUNITY-LIVING INDIVIDUALS

Although some brain regions and particularly the hippocampus have been shown to be sensitive predictors of dementia, they perform less well in relation to MCI. Moreover, by their nature they ignore large parts of the brain which may contain important predictive information. To address this gap we applied a machine learning approach to assess an individual's “observed” brain age and to test its predictive value for incident MCI over a 12-year follow-up. Community-living individuals from the PATH project (n=412, 49% female, 63.1 years) free of dementia and MCI at baseline participated in the study. Thirty-eight participants developed MCI over a mean follow-up of 11.3 years. Hippocampal volumes were segmented with Freesurfer 5.3. BrainAGE was computed based on a published method (Franke et al., 2012; Franke et al., 2010) which uses relevance vector regression (RVR), a machine learning approach based on pattern recognition. The initial model is trained on gray matter segments from a large normative sample. In a second step, the trained algorithm is applied to the gray matter segments of individual scans and generates an estimated brain age. The difference between estimated age and chronological age yields the so-called brain Age Gap Estimate (AGE). Associations between AGE, hippocampal volume, and MCI risk were assessed with Cox proportional hazard ratios while controlling for chronological age, sex, education and intra-cranial volume. AGE ranged from -11 to +14 (mean -0.35, SD=3.60) with larger values indicating accelerated ageing. Cox regression analyses revealed that every one additional year of AGE above chronological age was associated with a 10% increased risk (HR 1.10, 95%CI 1.01–1.21, p= 0.033) of developing MCI over the follow-up. In contrast, neither left (HR 1.00, 95%CI 1.00–1.00, p= 0.441) nor right (HR 1.00, 95%CI 1.00–1.00, p= 0.782) hippocampal volumes significantly predicted MCI incidence. Brain Age Gap Estimate (AGE), but not hippocampal volume, was found to be a significant predictor of incident MCI in this relatively young community-based sample. These findings suggest that machine learning approaches which integrate diffuse brain health information across the whole brain may be useful in identifying individuals at risk early in the disease process.

SPARCL1 ACCELERATES SYMPTOM ONSET IN ALZHEIMER’S DISEASE AND INFLUENCES BRAIN STRUCTURE AND FUNCTION DURING AGING

Recent evidence indicates that the expression of SPARCL1, an astrocyte-secreted synaptogenic protein, is dysregulated in Alzheimer's disease (AD). However, the precise relationship between altered SPARCL1 expression and AD pathogenesis remains unclear. Here, we examined associations between single nucleotide polymorphisms (SNPs) in the SPARCL1 gene and several AD-related endophenotypes, including rates of brain atrophy, trajectories of cognitive performance, and longitudinal changes in resting-state regional cerebral blood flow (rCBF), in the Baltimore Longitudinal Study of Aging (BLSA). We first identified SPARCL1 SNPs associated with altered gene expression of SPARCL1 in the brain (GTEx: http://www.gtexportal.org/home/). We selected two variants, rs9998212 and rs7695558, that are associated with reduced gene expression in the hippocampus and frontal cortex, respectively (Broad Institute SNP Annotation and Proxy Search: http://archive.broadinstitute.org/mpg/snap/ldsearchpw.php). In the BLSA neuroimaging substudy (BLSA-NI), we compared longitudinal changes in brain volumes (MRI; n=120 participants; 56–85 years old; number of scans= 826) and rCBF (measured by 15O - water PET; n=81 participants; 56–85 years old; number of scans= 664) in cognitively normal participants between carriers and non-carriers of the SPARCL1 minor alleles. We then analyzed longitudinal changes in cognitive performance of 591 participants who remained cognitively normal (mean age at first assessment: 61 years; range: 45–93 years) and 129 subjects who eventually developed MCI or AD (mean age at first assessment: 73 years; range: 59–89 years), comparing minor allele carriers versus non-carriers. Both SPARCL1 SNPs were associated with longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology (e.g., inferior temporal cortex and precuneus). Furthermore, SPARCL1 SNP rs9998212 was associated with widespread and significantly faster rates of brain atrophy in cognitively normal individuals. Lastly, in participants who developed incident MCI or AD, SPARCL1 SNP rs7695558 was associated with faster memory decline prior to disease onset. These findings suggest that SPARCL1 may influence the early stages of AD pathogenesis through widespread effects on brain structure and function. These biological actions may be mediated through its role in synaptic repair during neuronal injury in AD.

A PROSPECTIVE LONGITUDINAL STUDY OF PARKINSON’S DISEASE DEMENTIA

More than half of Parkinson's disease (PD) patients develop some kind of cognitive impairment during the disease course, which significantly affects the quality of life, prognosis and mortality of these patients. The aim of this study was to report the predictors of Parkinson's disease dementia (PDD) in a three year prospective study. In this longitudinal study, a comprehensive neuropsychological battery covering five domains (attention/working memory, executive, verbal, and visual memory, language, and visuospatial) was administered to 132 nondemented PD patients and to 105 healthy matched controls (HC). Patients were classified as having normal cognition, MCI, or dementia at baseline and followed in yearly intervals for 3 consecutive years. Kaplan-Meier curves and Cox proportional hazard models were used to examine cognitive decline and its predictors. Patients averaged 69,8 years of age, 66% men, who had PD on average for 9,3 years. 15% of incident MCI cases had progressed to dementia by the last follow up. In a multivariate analysis, predictors of future decline were older age (p<0.001), male sex (p<0.005), higher Unified Parkinson's Disease Rating Scale motor score (p<0.001), presence of freezing (p<0.005), worse global cognitive score (p< 0.001) and REM sleep behavior disorder (p<0.005). Transition to dementia, occurs frequently in PD. Certain clinical and cognitive variables may be useful in predicting the progression of cognitive impairment.

Erythrocyte omega-3 fatty acids are inversely associated with incident dementia: Secondary analyses of longitudinal data from the Women's Health Initiative Memory Study (WHIMS)

ObjectiveTo assess whether red blood cell (RBC) docosahexaenoic acid and eicosapentaenoic acid (DHA+EPA) levels have a protective association with the risk of dementia in older women. MethodsRBC DHA+EPA levels were assessed at baseline, and cognitive status was evaluated annually in a cohort of 6706 women aged ≥65 years who participated in the Women's Health Initiative Memory Study (WHIMS). Cox regression was used to quantify the association between RBC DHA+EPA and the risk of probable dementia, independent of major dementia risk factors. ResultsDuring a median follow-up period of 9.8 years, 587 incident cases of probable dementia were identified. After adjusting for demographic, clinical, and behavioral risk factors, a one standard deviation increase in DHA+EPA levels was associated with a significantly lower risk of dementia (HR = 0.92, 95% CI: 0.84, 1.00; p < 0.05). This effect estimate did not meaningfully change after further adjustment for baseline cognitive function and APOE genotype. For women with high DHA+EPA exposure (1SD above mean) compared to low exposure (1SD below mean), the adjusted 15-year absolute risk difference for dementia was 2.1% (95% CI: 0.2%, 4.0%). In secondary analyses, we also observed a protective association with longitudinal change in Modified Mini-Mental State (3MS) Exam scores, but no significant association with incident MCI, PD/MCI, or baseline 3MS scores. DiscussionHigher levels of DHA+EPA may help protect against the development of dementia. Results from prospective randomized controlled trials of DHA+EPA supplementation are needed to help clarify whether this association is causal.