Incident Mild Cognitive Impairment Research Articles

Minor neuropsychological deficits in SCD: Association with AD biomarkers and cognitive decline

AbstractBackgroundThe clinical relevance and longitudinal impact of minor neuropsychological deficits (MND) in cognitively normal memory clinic patients with subjective cognitive decline (SCD) is still unclear. To address this, we set out to investigate whether MND in SCD patients are related to Alzheimer´s disease (AD) pathology and future cognitive decline. In addition, we wanted to assess whether SCD patients have an increased risk of neuropathology and cognitive decline even in the absence of MND.MethodWe included 233 cognitively normal, healthy control participants (HC) without subjective cognitive concerns and 439 memory clinic SCD patients with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. Participants, who scored at least 0.5SD below the mean on a composite measure calculated from the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological assessment battery, were classified as having MND. We compared the resulting participant groups regarding their baseline CSF Aβ42/40, p‐tau181, t‐tau and Aβ42/p‐tau181 levels, longitudinal preclinical Alzheimer´s cognitive composite (PACC5) trajectories and risk of progression to incident mild cognitive impairment (MCI).ResultCompared to SCD patients without MND (n = 384), SCD patients with MND (n = 55, 12.5% of SCD sample) showed significantly elevated CSF AD biomarker levels, accelerated PACC5 decline and a higher risk of progression to incident MCI. Baseline MND had a positive predictive value of 57.0% (95%CI: 38.5‐75.4) and a negative predictive value of 86.0% (95%CI: 81.9‐90.1) for the progression to incident MCI within 3 years. SCD patients without MND showed increased PACC5 decline and a higher risk of incident MCI compared to HC participants without MND (n = 215), but did not differ from HC participants in their CSF biomarker levels.ConclusionMND are a risk factor for AD pathology and cognitive decline in memory clinic patients with SCD. The assessment of MND could thus provide useful information for AD risk stratification and enrichment in SCD samples. Importantly, SCD patients still have an increased risk for cognitive decline in the absence of MND.

Longitudinal changes of self‐ and informant‐reported cognitive decline in elderly with regard to clinical progression and amyloid‐status

AbstractBackgroundSelf‐ and informant‐reports of cognitive decline have been previously associated with a higher risk of cognitive decline in elderly. Yet, few studies assessed their longitudinal changes over time with regard to both incident mild cognitive impairment (iMCI) and Alzheimer’s disease (AD) pathology. This study aims at describing these links to better understand which trajectories are indicative of higher AD‐risk.MethodWe used data from 501 participants followed‐up annually (2.51±1.35 years) in the DELCODE project. All were cognitively unimpaired, and had an amyloid measurement available, at inclusion. Among them, 145 were amyloid‐positive, and 65 progressed to iMCI during the follow‐up period (31 iMCI‐Aß+). The SCD‐Interview was used to measure (i) the number of cognitive domains in which the participants or its relative perceived a decline (i.e., self‐ and informant‐SCD‐I), and (ii) the number of fulfilled SCD‐plus criteria. Linear mixed‐effect models were used to assess SCD trajectories over time, according to four groups defined by amyloid status and clinical progression (Stable‐Aß‐, Stable‐Aß+, iMCI‐Aß‐ and iMCI‐Aß+). Analyses were adjusted for age, sex and education; and their interaction with time.ResultBoth self‐SCD‐I levels and SCD‐plus scores decreased significantly over time, without significant differences between groups (Figure 1A, 1B). Conversely, informant‐SCD‐I levels did not significantly change over time in the whole sample, although slopes significantly differed between groups. Compared to the Stable‐Aß‐ group, there was a greater increase over time of informant‐SCD‐I report only in iMCI‐Aß+ [est 0.16, SE 0.05, p<.001] (Figure 1C). The resulting discrepancy score (Self‐SCD‐I minus Informant‐SCD‐I) tended to decrease over time with significant differences between groups. Compared to the Stable‐Aß‐ group, the discrepancy score showed a faster decrease over time in iMCI‐Aß+ [est ‐0.21, SE 0.056 p<.001] (Figure 1D).ConclusionLongitudinal patterns in subjective reports of cognitive decline might help identify preclinical AD subjects at higher risk of clinical progression. Specifically, an increase of informant‐reported cognitive decline over time may indicate objective cognitive decline in amyloid‐positive subjects. Conversely, the decrease of self‐reported cognitive decline over time, regardless of the group, may reflect generally reduced concerns after inclusion, or result from current limitations in longitudinal SCD assessment.

Subtle cognitive difficulties increase risk of neurodegeneration, incident mild cognitive impairment, and dementia in older women.

AbstractBackgroundIdentifying individuals with preclinical Alzheimer’s disease and related disorders (ADRD) is important for prevention and eventual treatment. Here we aimed to integrate overall test performance with episodic memory process scores in a cohort of older women to identify those with subtle cognitive difficulties (SCD; e.g., individuals with the earliest declines in cognitive ability preceding a diagnosis of mild cognitive impairment (MCI) or dementia) and determine subsequent risk of MCI, dementia, and neuroimaging indices of neurodegeneration.MethodParticipants included 2,186 community‐dwelling older women without MCI or dementia (Mage = 73.4±3.8 years) who completed a comprehensive neuropsychological assessment as part of the Women’s Health Initiative Study of Cognitive Aging (WHISCA: 1999‐2000). Women were assessed annually for MCI and dementia until 2021, and 1,024 women underwent structural magnetic resonance imaging (sMRI) of the brain in 2005‐6. Women were classified as cognitively normal (CN), early SCD (e‐SCD; two episodic memory process scores 1 SD below normative means or one process score and one performance score 1 SD below normative means), or late SCD (l‐SCD; two overall performance scores 1 SD below normative means) at WHISCA baseline using validated criteria from the Alzheimer’s Disease Neuroimaging Cohort (Thomas et al., 2018 Journal of Alzheimer’s Disease). We used Cox proportional hazards to examine associations between SCD status and risk of developing MCI/dementia. Linear regressions were used to examine associations between SCD status and MRI indices of AD‐related neurodegeneration, global cerebrovascular damage, and brain volumes of structures that make up the medial temporal lobe. All associations were adjusted for sociodemographic, lifestyle, and clinical characteristics.ResultWomen with e‐SCD and l‐SCD were 1.58 (p<0.001) and 3.01 (p<0.001) times as likely to develop MCI/dementia compared to CN women, respectively (Figure 1). Women with l‐SCD (β = 0.20; p<0.001) had more AD‐related neurodegeneration compared to CN women (Table 1). Women with e‐SCD had marginally significantly greater AD‐related neurodegeneration (β = 0.14; p = 0.073) and had smaller volumes in the entorhinal cortex (β = ‐0.22; p = 0.009) compared to CN women.ConclusionOur study demonstrates the usefulness of the SCD criteria for the early identification of cognitively normal women who are at increased risk of MCI, dementia, and neurodegeneration.

Longitudinal changes of self‐ and informant‐reported cognitive decline in elderly with regard to clinical progression and amyloid‐status

AbstractBackgroundSelf‐ and informant‐reports of cognitive decline have been previously associated with a higher risk of cognitive decline in elderly. Yet, few studies assessed their longitudinal changes over time with regard to both incident mild cognitive impairment (iMCI) and Alzheimer’s disease (AD) pathology. This study aims at describing these links to better understand which trajectories are indicative of higher AD‐risk.MethodWe used data from 501 participants followed‐up annually (2.51±1.35 years) in the DELCODE project. All were cognitively unimpaired, and had an amyloid measurement available, at inclusion. Among them, 145 were amyloid‐positive, and 65 progressed to iMCI during the follow‐up period (31 iMCI‐Aß+). The SCD‐Interview was used to measure (i) the number of cognitive domains in which the participants or its relative perceived a decline (i.e., self‐ and informant‐SCD‐I), and (ii) the number of fulfilled SCD‐plus criteria. Linear mixed‐effect models were used to assess SCD trajectories over time, according to four groups defined by amyloid status and clinical progression (Stable‐Aß‐, Stable‐Aß+, iMCI‐Aß‐ and iMCI‐Aß+). Analyses were adjusted for age, sex and education; and their interaction with time.ResultsBoth self‐SCD‐I levels and SCD‐plus scores decreased significantly over time, without significant differences between groups (Figure 1A, 1B). Conversely, informant‐SCD‐I levels did not significantly change over time in the whole sample, although slopes significantly differed between groups. Compared to the Stable‐Aß‐ group, there was a greater increase over time of informant‐SCD‐I report only in iMCI‐Aß+ [est 0.16, SE 0.05, p<.001] (Figure 1C). The resulting discrepancy score (Self‐SCD‐I minus Informant‐SCD‐I) tended to decrease over time with significant differences between groups. Compared to the Stable‐Aß‐ group, the discrepancy score showed a faster decrease over time in iMCI‐Aß+ [est ‐0.21, SE 0.056 p<.001] (Figure 1D).ConclusionLongitudinal patterns in subjective reports of cognitive decline might help identify preclinical AD subjects at higher risk of clinical progression. Specifically, an increase of informant‐reported cognitive decline over time may indicate objective cognitive decline in amyloid‐positive subjects. Conversely, the decrease of self‐reported cognitive decline over time, regardless of the group, may reflect generally reduced concerns after inclusion, or result from current limitations in longitudinal SCD assessment.

Vitamin D deficiency may increase the risk of developing cognitive impairment especially for APOE e4 non‐carriers

AbstractBackgroundVitamin D has been reported to play a role for neural protection and anti‐inflammation. However, its effects on the risk of cognitive decline has been inconsistent. Apolipoprotein E (APOE) could be a possible modulator of such influences as it takes part in the transport of cholesterol sharing a synthetic pathway with vitamin D and APOE e4 isoform is a well‐known significant risk factor of cognitive impairment. This study aimed to demonstrate the effects of vitamin D on incident cognitive impairment including mild cognitive impairment (MCI) and dementia and to explore its associations according to APOE e4 allele presence.MethodWe enrolled 1,271 cognitively normal community‐dwelling adults aged 60 years or older from the participants in the Korean Longitudinal Study on Cognitive Aging and Dementia. They were evaluated every two years from 2010 to 2018. We measured serum 25‐hydroxyvitamin D [25(OH)D] level and administered diagnostic assessment on MCI and dementia at every evaluation. We grouped the serum 25(OH)D into three levels as sufficient (> 30 ng/mL), insufficient (20 – 29.9 ng/mL), and deficient (< 20 ng/mL). We examined the associations of serum 25(OH)D level with the risks of incident MCI and dementia using Cox proportional hazard models adjusting for potential confounders. Then we also analyzed these effects in the APOE e4 non‐carriers and carriers separately.Result221 subjects showed a progression to MCI or dementia while 1,050 remained unchanged or improved cognitive function during follow‐up period. Participants who had deficient vitamin D concentration showed significant associations with a higher risk of cognitive decline (HR = 2.945, 95% CI = 1.088 – 7.970, p = 0.033) compared to sufficient 25(OH)D level group. APOE e4 non‐carriers who were vitamin D deficiency at baseline were 3.3‐fold more likely to suffer progression of cognitive impairment (HR = 3.308, 95% CI = 1.050 – 10.426, p = 0.041), whereas APOE e4 carriers did not show significant correlations of 25(OH)D levels with such progression (p > 0.05).ConclusionThese results indicate that vitamin D deficiency may increase the risk of developing cognitive impairment and the effects would be greater for APOE e4 non‐carriers compared to APOE e4 carriers.

Six Year Effects of Hearing Treatment on Cognitive Decline and Dementia: Design and Statistical Considerations of the Aging and Cognitive Health Evaluation in Elders – Brain Health Follow‐Up Study

AbstractBackgroundHearing loss is associated with cognitive decline and dementia. The ongoing ACHIEVE Study was the first randomized trial to test the effects of hearing treatment on three‐year cognitive change. The ACHIEVE – Brain Health Follow‐Up Study will extend follow‐up to six years post‐randomization to determine the long‐term and potentially nonlinear effects of hearing treatment vs. health education control with delayed treatment on dementia and cognitive decline.MethodsParticipants will be recruited from the 977 participants enrolled in the ACHIEVE Study. After Year 3, hearing intervention participants will continue to receive hearing care and the control group will be offered the hearing intervention. Co‐primary study outcomes will be cognitive decline and a composite of incident mild cognitive impairment (MCI)/probable dementia. Secondary outcomes include domain‐specific cognitive decline, brain structural changes on magnetic resonance imaging (MRI), and other functional outcomes (e.g., physical activity, social isolation). Power analyses for the co‐primary outcomes assumed an annual attrition rate of 10% and an immediate, lagged, or cumulative treatment effect.ResultsWhen comparing multi‐year cognitive decline (Table 1), in the scenario of a constant treatment effect that assumes a strong and immediate treatment effect, the benefit of extended follow‐up is not greater power, but additional information on the long‐term effects of hearing intervention. In a scenario of a lagged treatment effect, a two‐year lag in the treatment effect causes the Year 3 assessment to be severely underpowered (28%) but provides sufficient power (80%) at Year 6 despite attrition. In a scenario of a cumulative treatment effect that increases with time, analyses are similarly underpowered at Year 3 (65%) but not at Year 6 (82%). The same pattern is evident when estimating the power at Year 3 (57%) and Year 6 (80%) to detect incident MCI/probable dementia in a Cox regression model that assumes a protective hazard ratio of 0.70 (Figure 1).ConclusionAcross all non‐constant scenarios of potential treatment effect, six years of follow‐up increases precision and provides valuable information to better delineate long‐term cognitive trajectories. The ACHIEVE ‐ Brain Health Follow‐Up Study will be completed in 2025.

Brain pathological mechanism of weight loss preceding incident mild cognitive impairment

AbstractBackgroundWeight loss in late life is associated with a higher risk of dementia and higher mortality. However, the temporal and etiological associations between weight loss and mild cognitive impairment (MCI) remain unclear.MethodWe examined 709 Alzheimer’s Disease Neuroimaging Initiative participants to investigate body mass index (BMI) trajectories preceding the progression from normal cognition to MCI (N‐t‐M progression), and to explore the association between brain pathology and BMI trajectories preceding incident MCI.ResultDuring N‐t‐M progression, participants developed multiple brain pathologies, and amyloid β (Aβ) accumulation in the frontotemporal region at baseline was associated with decreased BMI (Figure 1, false discovery rate‐corrected p<0.05). For pathological changes, participants had increased accumulation of Aβ and tau, accelerated hypometabolism, and decreased gray matter volume in the brain during N‐t‐M progression. More importantly, accelerated hypometabolism (p<0.001) and gray matter atrophy (p = 0.011) were associated with a rapid decline in BMI during N‐t‐M progression.ConclusionThese findings highlight the importance of regular monitoring of weight changes in older adults as faster BMI decline and lower BMI may be the result of brain pathology and associated with rapid progression of pathology, and provide a theoretical basis for strategies to minimize weight loss to prevent or delay MCI onset.

Social connections and risk of incident mild cognitive impairment, dementia, and mortality in 13 longitudinal cohort studies of ageing

Background:Good social connections are proposed to positively influence the course of cognitive decline by stimulating cognitive reserve and buffering harmful stress-related health effects. Prior meta-analytic research has uncovered links between social connections and the risk of poor health outcomes such as mild cognitive impairment, dementia, and mortality. These studies have primarily used aggregate data from North America and Europe with limited markers of social connections. Further research is required to explore these associations longitudinally across a wider range of social connection markers in a global setting.Research Objective:We examined the associations between social connection structure, function, and quality and the risk of our primary outcomes (mild cognitive impairment, dementia, and mortality).Method:Individual participant-level data were obtained from 13 longitudinal studies of ageing from across the globe. We conducted survival analysis using Cox regression models and combined estimates from each study using two-stage meta-analysis. We examined three social constructs: connection structure (living situation, relationship status, interactions with friends/family, community group engagement), function (social support, having a confidante) and quality (relationship satisfaction, loneliness) in relation to the risks of three primary outcomes (mild cognitive impairment, dementia, and mortality). In our partially adjusted models, we included age, sex, and education and in fully adjusted models used these variables as well as diabetes, hypertension, smoking, cardiovascular risk, and depression.Preliminary results of the ongoing study:In our fully adjusted models we observed: a lower risk of mild cognitive impairment was associated with being married/in a relationship (vs. being single), weekly community group engagement (vs. no engagement), weekly family/friend interactions (vs. not interacting), and never feeling lonely (vs. often feeling lonely); a lower risk of dementia was associated with monthly/weekly family/friend interactions and having a confidante (vs. no confidante); a lower risk of mortality was associated with living with others (vs. living alone), yearly/monthly/weekly community group engagement, and having a confidante.Conclusion:Good social connection structure, function, and quality are associated with reduced risk of incident MCI, dementia, and mortality. Our results provide actionable evidence that social connections are required for healthy ageing.

A Twin Analysis of AD Brain Signatures and Abnormal White Matter

AbstractBackgroundAlzheimer’s disease (AD) and vascular disease frequently co‐occur and may interact additively or synergistically on risk for cognitive decline, though the degree of shared overlap between these pathologies remains unclear. Our group has demonstrated the utility of AD signatures, or composite MRI metrics in brain regions associated with AD pathology, for prediction of AD‐related changes beginning in midlife. Our novel signature based on gray matter mean diffusivity (MD) aided 12‐year prediction of incident mild cognitive impairment among cognitively unimpaired adults in their 50s, captured unique phenotypic and genetic variance not otherwise explained by an AD signature based on cortical thickness/volume or general brain aging, and robustly predicted thickness/volume signatures over a decade later. Here, we leveraged twin data from the Vietnam Era Twin Study of Aging (VETSA) to delineate shared and unique genetic and environmental influences on two AD signatures and white matter hyperintensities (WMHs), which have been consistently linked to vascular origin.MethodParticipants were 512 men from the VETSA (age = 67.52, SD = 2.60). Our validated thickness/volume signature, novel MD signature based on the same brain regions as the thickness/volume signature, and WMH volume were used in biometrical twin analyses to examine their phenotypic, genetic, and environmental relationships. We adjusted each AD signature for an MRI‐based measure of brain age to detect associations with WMH that were specific to AD‐related brain regions versus general brain aging. We also examined regional WMH parcellations.ResultPhenotypic and genetic correlations demonstrated significant associations between the MD signature and WMH (rp = 0.26 [95% CI: 0.15, 0.36]; rg = 0.34 [95% CI: 0.10, 0.57]). In contrast, phenotypic and genetic correlations between the thickness/volume signature and WMHs were nonsignificant. Environmental correlations between each AD signature and WMH were similarly nonsignificant. Results were similar for each WMH parcellation, suggesting global WMH effects.ConclusionA gray matter MD signature and WMHs share significant genetic influences, whereas a thickness/volume signature was not associated with WMHs. AD signatures based on brain microstructure, such as the MD signature, may capture very early AD‐related and vascular‐related changes that are not captured by a macrostructural signature at the same timepoint.

Association of estimated white matter hyperintensity age with cognition in hypertensive elderly

AbstractBackgroundHypertension is associated with white matter hyperintensity (WMH) and cognitive impairment. Further, WMH is associated with cognitive impairment including executive, attention and visuospatial functions. The aim of this study was to investigate the effects of controlled hypertension (cHT) and previously developed concept, ‘WMH age’ on cognitive function and the mediating role of WMH in the effect of cHT on cognitive impairment.MethodWe enrolled 855 Koreans without dementia aged 60 years or older, 326 of whom completed 2‐year follow‐up assessment. We measured their blood pressure thrice in a sitting position using an automated blood pressure monitoring device. We estimated ‘WMH age’ of every participant using previously developed WMH probability map of healthy older Koreans. We analyzed the mediating effect of WMH age in the association of cHT and cognitive function using the PROCESS Macro model.ResultOld WMH age was associated with a faster decline in the Mini‐Mental Status Examination (MMSE; p = .003), Consortium to Establish a Registry for Alzheimer’s Disease total score (CERAD‐TS; p = .003), and Frontal Assessment Battery (FAB; p = .007). Old WMH age showed an approximately‐six times higher risk of incident mild cognitive impairment (OR = 6.47, 95% CI = 1.37 – 9.50, p = .024) compared to young or normal WMH age over the 2‐year follow‐up period in the cHT group. WMH age mediated the effects of cHT on the MMSE, CERAD‐TS, and FAB scores at baseline and two‐year follow‐up period.ConclusionWMH mediates the adverse effect of hypertension on cognitive function. Elders with cHT who have older WMH age may be at a higher risk of cognitive decline.

A Twin Analysis of AD Brain Signatures and Abnormal White Matter

AbstractBackgroundAlzheimer’s disease (AD) and vascular disease frequently co‐occur and may interact additively or synergistically on risk for cognitive decline, though the degree of shared overlap between these pathologies remains unclear. Our group has demonstrated the utility of AD signatures, or composite MRI metrics in brain regions associated with AD pathology, for prediction of AD‐related changes beginning in midlife. Our novel signature based on gray matter mean diffusivity (MD) aided 12‐year prediction of incident mild cognitive impairment among cognitively unimpaired adults in their 50s, captured unique phenotypic and genetic variance not otherwise explained by an AD signature based on cortical thickness/volume or general brain aging, and robustly predicted thickness/volume signatures over a decade later. Here, we leveraged twin data from the Vietnam Era Twin Study of Aging (VETSA) to delineate shared and unique genetic and environmental influences on two AD signatures and white matter hyperintensities (WMHs), which have been consistently linked to vascular origin.MethodParticipants were 512 men from the VETSA (age = 67.52, SD = 2.60). Our validated thickness/volume signature, novel MD signature based on the same brain regions as the thickness/volume signature, and WMH volume were used in biometrical twin analyses to examine their phenotypic, genetic, and environmental relationships. We adjusted each AD signature for an MRI‐based measure of brain age to detect associations with WMH that were specific to AD‐related brain regions versus general brain aging. We also examined regional WMH parcellations.ResultPhenotypic and genetic correlations demonstrated significant associations between the MD signature and WMH (rp = 0.26 [95% CI: 0.15, 0.36]; rg = 0.34 [95% CI: 0.10, 0.57]). In contrast, phenotypic and genetic correlations between the thickness/volume signature and WMHs were nonsignificant. Environmental correlations between each AD signature and WMH were similarly nonsignificant. Results were similar for each WMH parcellation, suggesting global WMH effects.ConclusionA gray matter MD signature and WMHs share significant genetic influences, whereas a thickness/volume signature was not associated with WMHs. AD signatures based on brain microstructure, such as the MD signature, may capture very early AD‐related and vascular‐related changes that are not captured by a macrostructural signature at the same timepoint.

Changes in Body Mass Index and Incident Mild Cognitive Impairment Among African American Older Adults.

Previous research suggests a decline in body mass index (BMI) among older adults is associated with negative health outcomes, including mild cognitive impairment (MCI) and incident dementia. However, no studies have examined the effects of education or developing MCI on BMI trajectories over time. The purpose of this investigation was to characterize trajectories of change in BMI among older adults who develop MCI. Participants were from the Minority Aging Research Study (MARS), a longitudinal cohort study of cognitive decline and Alzheimer's disease in older African Americans living in the greater Chicago, Illinois, area. The study included annual clinical evaluations of cognitive status, as well as measurements of height and weight for BMI calculation. Older African American participants without cognitive impairment at baseline were included in the present analysis (N = 436, 78% women, mean baseline age = 72 [SD = 5.7], mean education = 15 [SD = 3.5]). In piecewise linear mixed-effects models that included a random intercept and 2 random slopes, BMI declined over time (B = -0.20, SE = 0.02, p < .001), with a faster decline after MCI diagnosis (additional decline, B = -0.15, SE = 0.06, p = .019). Older age was associated with lower baseline BMI (B = -0.19, SE = 0.05, p < .001), as was higher education (B = -0.34, SE = 0.09, p < .001). Further, higher education was associated with a slower decline in BMI before MCI (B = 0.02, SE = 0.006, p = .001), but a faster decline after MCI (B = -0.06, SE = 0.022, p = .003). These results suggest an accelerated decline in BMI following an MCI diagnosis, with higher education related to an even faster BMI decline.

Abstract 16573: Orthostatic Blood Pressure Changes and Cognitive Function: Insights From the SPRINT MIND Trial

Introduction: The association between orthostatic blood pressure (BP) changes and cognitive function has not been thoroughly investigated. Moreover, whether orthostatic hypotension or hypertension modifies the effects of intensive BP control on cognitive outcomes is unknown. Hypothesis: We hypothesized that orthostatic BP changes were associated with cognitive function and the effects of intensive BP control on cognitive outcomes might be different among individuals with/without orthostatic hypotension or hypertension. Methods: We performed a post hoc analysis of SPRINT MIND, a randomized controlled trial evaluating the effects of intensive vs. standard SBP control on cognitive outcomes in hypertensive patients. The relationships between baseline orthostatic BP changes (defined as baseline standing systolic BP [SBP]–baseline seated SBP) and probable dementia (PD) and mild cognitive impairment (MCI) were analyzed. The competing risk proportional hazards regression and cubic spline regression were used in analysis. Results: A total of 8547 participants (mean [SD] age, 67.9 [9.3] years; 5543 [64.9] men) were included in this analysis. In the crude model, the restricted cubic spline analysis showed L-shaped associations between orthostatic SBP change and new-onset PD and MCI (all P for nonlinearity&lt;0.05). However, these associations all disappeared after adjustment for covariates. Moreover, orthostatic diastolic BP change was not associated with the PD or MCI incidence. Intensive BP control did not alter the risk of PD or MCI in patients with/without orthostatic hypotension or hypertension. Conclusions: Orthostatic BP changes were not associated with the risk of PD or MCI; baseline orthostatic hypotension or hypertension did not influence the effects of intensive BP control on cognitive outcomes. These results are hypothesis-generating and merit further study.

Abstract 12741: Malignant Left Ventricular Hypertrophy and Risk of Cognitive Impairment or Probable Dementia: A Post Hoc Analysis of the SPRINT Trial

Background: Left ventricular hypertrophy (LVH) accompanied by biomarker of myocardial injury as measured by high sensitivity cardiac troponin (hs-cTnT) and neurohormonal activation, as measured by N-terminal pro-B-type natriuretic peptide (NT-proBNP), indicates a malignant form of LVH. While malignant LVH has been linked to poor CVD outcomes, its association with cognitive outcomes is unclear. Aim: To examine the association of malignant LVH with cognitive outcomes in the Systolic Blood Pressure Intervention Trial (SPRINT). Hypothesis: Malignant LVH is associated with incident cognitive outcomes. Methods: We performed a post hoc analysis of 8,027 SPRINT participants with at least one cognitive assessment. Participants were classified into six groups based on the presence or absence of LVH assessed by 12-lead electrocardiogram (ECG), and elevations in levels of hs-cTnT ≥14 ng/L or NT-proBNP ≥125 pg/mL at baseline visit. The adjudicated outcome of incident probable dementia or mild cognitive impairment (MCI) or a composite outcome of probable dementia or mild cognitive impairment. Cox proportional hazard models were used to examine the association of baseline LVH/biomarker groups with incident cognitive outcomes. Results: During a median follow-up of 5 years, 597, 306, and 818 participants developed MCI, dementia, and composite outcome respectively. Compared with participants without LVH or elevated biomarkers, participants with LVH or elevated biomarkers, either in isolation or combined, had a higher risk of MCI and composite outcome. Highest risk for composite outcome was observed in those with concomitant LVH and elevated levels of both biomarkers. There was no significant association between LVH/biomarkers with incident probable dementia except for those with concomitant LVH and elevated levels of both biomarkers ( Table ). Conclusions: Among SPRINT participants, malignant LVH is associated with mild cognitive impairment and probable dementia.

Sex-modified association between grip strength and mild cognitive impairment: a cross-sectional and follow-up study in rural China

BackgroundThe sex difference in the association between grip strength and mild cognitive impairment (MCI) remains controversial and unclear.MethodsThis is a part of a chronic disease cohort study conducted in rural areas, Fuxin, Liaoning Province, China. At the baseline survey, a total of 2633 participants aged 35- 85 were included in the cross-sectional study. Handgrip strength (HGS, kg) was measured by a dynamometer (Jamar +). MCI were assessed using the Chinese version of the Montreal Cognitive Assessment-Basic (MOCA-BC). Then, a total of 1667 cognitively normal individuals (NCs) were planed to follow up and to assess the incident MCI after two years. We used logistic regression to examine the association between HGS (as a continuous variable and quintiles) and MCI and analyzed the interaction between sex and HGS on MCI. Models stratified by sex were adjusted for demographic information (age, ethnicity, education, marital status, income, physical labor level), modifiable risk factors (body mass index, smoking, drinking) and disease history (hypertension, diabetes, dyslipidemia and coronary heart disease). Baseline MOCA-BC scores were additionally adjusted in the longitudinal study.ResultsIn the cross-sectional study, participants were on average 56.6 ± 9.8 years, and 1713 (65.1%) were females. In the cohort study, 743 individuals were followed up with an average age of 55.9 ± 9.6 years, which included 530 (71.3%) females. The cumulative incidence of MCI over a two-year period was 17.1%. In the cross-sectional study, compared to the highest quintile of HGS, the lowest HGS was associated with higher risk of MCI in males (odds ratio [OR]: 2.66; 95% confidence interval [CI]: 1.54, 4.64) and females (OR: 1.70; 95% CI: 1.17, 2.49) with adjustment of potential confounding factors. In the cohort study, compared to the highest quintile of HGS, the lowest HGS was associated with an increased risk of incident MCI in females (OR: 3.93; 95% CI: 1.39, 13.01) but not in males (OR: 0.56; 95% CI: 0.11, 2.94, P for interaction = 0.015).ConclusionsLower grip strength is a risk factor for mild cognitive impairment and predicts a higher risk of MCI in females.

6 Depressive Symptoms are Associated With Decline Over Time in Verbal Fluency Performance in Female but not Male Community-Dwelling Older Adults

Objective:Late-life depression is prevalent among older adults and the presence of depressive symptoms has been shown to be associated cross-sectionally with worse verbal fluency performance. There is limited and mixed evidence as to whether depressive symptoms impact change in verbal fluency performance over time, and whether gender impacts this relationship.Participants and Methods:Participants were community-dwelling older adults who were dementia-free at baseline (N = 522; M age = 75.96, SD + 6.46 years). Baseline depressive symptoms were measured using the Geriatric Depression Scale. Category fluency and letter fluency performance, using the Controlled Oral Word Association Test (COWAT), were examined annually. Linear mixed effects models stratified by gender examined whether associations between baseline depressive symptoms and changes in fluency performance over five years were different in female (n = 289) as compared to male (n = 233) participants. Sensitivity analyses excluding participants with prevalent or incident mild cognitive impairment (MCI) (n = 141), excluding participants with incident dementia (n = 28), and excluding participants with prevalent or incident MCI or incident dementia (n = 169) were run. All analyses were adjusted for age, years of education, estimated premorbid functioning, and health comorbidities.Results:Depression was minimal across participants (m = 4.72, SD + 3.96). A subset of participants (n = 44) reported “possible depression,” namely levels suggestive of subclinical depression, according to clinical cutoffs. The “possible depression” group included 31 females (10.73% of females) and 13 males (5.58% of males), and the “no depression” group included 258 females (89.27% of females) and 220 males (94.42% of males). Baseline levels of depressive symptoms suggestive of subclinical depression were associated with worse decline in category fluency performance during longitudinal follow-up in females (estimate = -0.16, p = .002) but not males (estimate = -0.03, p = .658). Results remained the same when excluding prevalent and incident MCI cases (estimate = -0.19, p = .005), excluding incident dementia cases (estimate = -0.12, p = .017), and excluding prevalent and incident MCI and incident dementia cases (estimate = -0.20, p = .004). Letter fluency performance did not decline over time and was not influenced by levels of depressive symptoms in females (estimate = -0.03, p = .502) or males (estimate = 0.05, p = .452).Conclusions:Baseline presence of depressive symptoms suggestive of subclinical depression was associated with worse decline in category fluency performance during longitudinal follow-up in female but not male participants. Letter fluency performance did not decline and was not impacted by levels of depressive symptoms. Results remained significant when accounting for covariates and potential confounders. The present study elucidated the combined influence of gender and depressive symptoms on change in fluency performance in older adults and can aid in identifying individuals who may be at a greater risk of cognitive decline.

Prevalence and incidence of mild cognitive impairment in adults with diabetes in the United States

BackgroundLimited evidence exists about the prevalence and incidence of mild cognitive impairment (MCI) in individuals with diabetes in the U.S. We aimed to address such knowledge gaps using a nationally representative study dataset. MethodWe conducted a secondary analysis from the Health and Retirement Study (HRS) (1996–2018). The sample for examining the prevalence of MCI was14,988, with 4192 (28.0%) having diabetes, while the sample for the incidence was 21,824, with 1534 (28.0%) having diabetes. ResultsParticipants with diabetes had a higher prevalence of MCI than those without diabetes (19.9 % vs. 14.8 %; odds ratio [95 % confidence interval] (OR[95 %CI]): 1.468 [1.337, 1.611], p <.001). The incidence of MCI in participants with/without newly diagnosed diabetes was 42.9 % vs. 31.6 % after a mean 10-year follow-up, with the incidence rate ratio (IRR) [95 %CI] (1.314 [1.213, 1.424], p <.001). Newly diagnosed diabetes was associated with elevated risks of MCI compared with non-diabetes, with the uncontrolled hazard ratio (HR) [95 %CI] (1.498 [1.405, 1.597], p <.001). ConclusionsUsing a nationally representative study data in the U.S., participants with diabetes had a higher prevalence and incidence of MCI than those without diabetes. Findings show the importance of developing interventions tailored to the needs of individuals with diabetes and cognitive impairment.

MRI Visible Perivascular Spaces and the Risk of Incident Mild Cognitive Impairment in a Community Sample.

Magnetic resonance imaging (MRI) visible perivascular spaces (PVS) are associated with the risk of incident dementia but their association with the early stages of cognitive impairment remains equivocal. We examined the association between MRI visible PVS and the risk of incident mild cognitive impairment (MCI) in the community-based Framingham Heart Study (FHS). FHS participants aged at least 50 years free of stroke, cognitive impairment, and dementia at the time of MRI were included. PVS were rated according to severity in the basal ganglia and centrum semiovale (CSO) using established criteria. Cox regression analyses were used to relate PVS to incident MCI adjusted for demographic and cardiovascular variables. The mean age of the sample (1,314 participants) at MRI was 68 years (SD, 9; 54% women). There were 263 cases of incident MCI over a median 7.4 years follow-up (max, 19.8 years). MCI risk increased with higher PVS severity in the CSO. Relative to persons with the lowest severity rating, persons with the highest severity rating in the CSO had a higher risk of incident MCI (hazard ratio [HR] = 2.55; 95% confidence interval [CI], 1.48-4.37; p = 0.0007). In secondary analysis, this association seemed stronger in women. Risk of incident MCI was nominally higher for participants with the highest severity grade of PVS in the basal ganglia, though not statistically significant relative to the lowest grade (HR = 2.19; 95% CI, 0.78-6.14; p = 0.14). PVS burden in the CSO may be a risk marker for early cognitive impairment.

A - 18 Predicting Incident Amnestic Mild Cognitive Impairment and Alzheimer's Disease with a Computerized Neuropsychological Assessment Device: Comparative Clinical Utility.

Computerized neuropsychological assessment devices (CNADs) offer improved accessibility to screen for neurodegeneration, although their clinical utility is yet to be established. We evaluated the efficacy of a CNAD to predict incident amnestic mild cognitive impairment and Alzheimer's disease (aMCI/ad) compared to a conventional paper-and-pencil screening tool and PET amyloid beta (AB). Data were collected from the longitudinal observational Alzheimer's Disease Neuroimaging Initiative 3. Participants were cognitively normal at baseline (N = 315, mean age = 72.9 +/- 7.1, 59.4% female, 16.8 +/- 2.3years of education, 91.4% White, 33.7% APOE4+). Over four years, 26 (8.3%) participants converted to aMCI and 3 (1.0%) individuals developed ad. Prognostic validity was compared between three measures assessed at baseline. Computerized visual episodic memory scores were evaluated using the One Card Learning (OCL) test. Conventional screening was conducted using the Montreal Cognitive Assessment (MoCA). PET AB+ was quantified as ≥2 SD whole cerebellum referenced region standardized uptake value ratios. Area under the curve (AUC) analyses using logistic regression were adjusted for age, sex, education, race, and APOE4+ status. OCL accuracy yielded AUC = 0.67, p = 0.003, 95% CI [0.58, 0.76]. Total MoCA score demonstrated AUC = 0.75, p < 0.001, 95% CI [0.67, 0.83]. PET AB+ produced AUC = 0.68, p = 0.001, 95% CI [0.58, 0.79]. When assessed at baseline, the MoCA provided the greatest clinical utility to predict incident aMCI/ad. Baseline OCL accuracy and PET AB+ were similarly effective for determining future cognitive decline. Further research is needed to examine the utility of CNADs before they are integrated into clinical practice.

Associations of circulating saturated long-chain fatty acids with risk of mild cognitive impairment and Alzheimer’s disease in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort

No study has examined the associations between peripheral saturated long-chain fatty acids (LCFAs) and conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). This study aimed to examine whether circulating saturated LCFAs are associated with both risks of incident MCI from cognitively normal (CN) participants and incident AD progressed from MCI in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. We conducted analysis of data from older adults aged 55-90 years who were recruited at 63 sites across the USA and Canada. We examined associations between circulating saturated LCFAs (i.e., C14:0, C16:0, C18:0, C20:0) and risk for incident MCI in CN participants, and incident AD progressed from MCI. 829 participants who were enrolled in ADNI-1 had data on plasma saturated LCFAs, of which 618 AD-free participants were included in our analysis (226 with normal cognition and 392 with MCI; 60.2% were men). Cox proportional-hazards models were used to account for time-to-event/censor with a 48-month follow-up period for the primary analysis. Other than C20:0, saturated LCFAs were associated with an increased risk for AD among participants with MCI at baseline (Hazard ratios (HRs)=1.3 to 2.2, P=0.0005 to 0.003 in fully-adjusted models). No association of C20:0 with risk of AD among participants with MCI was observed. No associations were observed between saturated LCFAs and risk for MCI among participants with normal cognition. Saturated LCFAs are associated with increased risk of progressing from MCI to AD. This finding holds the potential to facilitate precision prevention of AD among patients with MCI. National Institutes of Health.