Application and validation of an algorithmic classification of early impairment in cognitive performance.

OBJECTIVE: Due to the long prodromal period for dementia pathology, approaches are needed to detect cases before clinically recognizable symptoms are apparent, by which time it is likely too late to intervene. This study contrasted two theoretically-based algorithms for classifying early cognitive impairment (ECI) in adults aged ≥50 enrolled in the Baltimore Longitudinal Study of Aging. METHOD: Two ECI algorithms were defined as poor performance (1 standard deviation [SD] below age-, sex-, race-, and education-specific means) in: (1) Card Rotations or California Verbal Learning Test (CVLT) immediate recall and (2) ≥1 (out of 2) memory or ≥3 (out of 6) non-memory tests. We evaluated concurrent criterion validity against consensus diagnoses of mild cognitive impairment (MCI) or dementia and global cognitive scores using receiver operating characteristic (ROC) curve analysis. Predictive criterion validity was evaluated using Cox proportional hazards models to examine the associations between algorithmic status and future adjudicated MCI/dementia. RESULTS: Among 1,851 participants (mean age = 65.2 ± 11.8 years, 50% women, 74% white), the two ECI algorithms yielded comparably moderate concurrent criterion validity with adjudicated MCI/dementia. For predictive criterion validity, the algorithm based on impairment in Card Rotations or CVLT immediate recall was the better predictor of MCI/dementia (HR = 3.53, 95%CI: 1.59-7.84) over 12.3 follow-up years. CONCLUSIONS: Impairment in visuospatial ability or memory may be capable of detecting early cognitive changes in the preclinical phase among cognitively normal individuals.

Prognostic Value of Learning and Retention Measures from the Free and Cued Selective Reminding Test to Identify Incident Mild Cognitive Impairment.

OBJECTIVE: To compare the predictive validity of learning and retention measures from the picture version of the Free and Cued Selective Reminding Test with Immediate Recall (pFCSRT + IR) for identifying incident mild cognitive impairment (MCI). METHODS: Learning was defined by the sum of free recall (FR) and retention by delayed free recall (DFR) tested 15-20 min later. Totally, 1422 Baltimore Longitudinal Study of Aging (BLSA) participants (mean age 69.6 years, 54% male, mean 16.7 years of education) without dementia or MCI received the pFCSRT + IR at baseline and were followed longitudinally. Cox proportional hazards models were used to evaluate the effect of baseline learning and retention on risk of MCI. RESULTS: In total, 187 participants developed MCI over a median of 8.1 years of follow-up. FR and DFR each predicted incident MCI adjusting for age, sex, and education. Also, each independently predicted incident MCI in the presence of the other with similar effect sizes: around 20% decrease in the hazard of MCI corresponding to one standard deviation increase in FR or DFR. CONCLUSION: The practice of preferring retention over learning to predict incident MCI should be reconsidered. The decision to include retention should be guided by time constraints and patient burden.

Prior psychosocial profile and perceived impact of the COVID-19 pandemic: insights from the Baltimore Longitudinal Study of Aging.

Stress, social isolation, and changes in health behaviors during the COVID-19 pandemic period may have a lasting influence on health. Here, the correlation between current or prior demographic, social and health related characteristics, including psychosocial factors with perceived impact of the COVID-19 pandemic assessed by questionnaire during the early pandemic period is evaluated among 770 participants of the Baltimore Longitudinal Study of Aging. In multinomial logistic regression models participants with higher pre-pandemic personal mastery, a construct related to self-efficacy, were more likely to report "both positive and negative" impact of the pandemic than a solely "negative" impact (OR: 2.17, 95% CI: 1.29-3.65). Higher perceived stress and frequent contact with family prior to the pandemic were also associated with pandemic impact. These observations highlight the relevance of psychosocial factors in the COVID-19 pandemic experience and identify characteristics that may inform interventions in future public health crises.

Apolipoprotein E ε4 allele effects on longitudinal cognitive trajectories are sex and age dependent.

INTRODUCTION: Questions remain about whether apolipoprotein E (APOE)-ε4 effects on cognitive decline are similar in men and women and how APOE-ε4 and age interact to influence decline in different cognitive domains. METHODS: In sex-stratified analyses, baseline age-dependent associations between APOE-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). RESULTS: In men, older baseline age was associated with greater effects of APOE-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater APOE-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant APOE-ε4 effects were found for language, visual-spatial ability, or processing speed. DISCUSSION: Results highlight the importance of considering sex and age when assessing APOE-ε4-associated vulnerability to cognitive decline.

Dietary antioxidant intake and its association with cognitive function in an ethnically diverse sample of US adults.

BACKGROUND: Dietary antioxidants can inhibit reactions accompanying neurodegeneration and thus prevent cognitive impairment. We describe associations of dietary antioxidants with cognitive function in a large biracial population, while testing moderation by sex, race, and age and mediation by depressive symptoms. METHODS: This was a cross-sectional analysis of 1274 adults (541 men and 733 women) aged 30 to 64 years at baseline (mean [standard deviation] = 47.5 [9.3]) in the Healthy Aging in Neighborhoods of Diversity Across the Lifespan Study, Baltimore city, MD. Cognitive performance in the domains of memory, language/verbal, attention, spatial, psychomotor speed, executive function, and global mental status were assessed. The 20-item Center for Epidemiologic Studies Depression Scale was used to measure depressive symptoms. Dietary intake was assessed with two 24-hour recalls, estimating daily consumption of total carotenoids and vitamins A, C, and E per 1000 kcal. RESULTS: Among key findings, 1 standard deviation (∼ 2.02 mg/1000 kcal) higher vitamin E was associated with a higher score on verbal memory, immediate recall (ß = +0.64 [0.19], p = .001), and better language/verbal fluency performance (ß = +0.53 [0.16], p = .001), particularly among the younger age group. Women with higher vitamin E intake (ß = +0.68 [0.21], p = .001) had better performance on a psychomotor speed test. The vitamin E-verbal memory association was partially mediated by depressive symptoms (proportion mediated = 13%-16%). CONCLUSIONS: In sum, future cohort studies and dietary interventions should focus on associations of dietary vitamin E with cognitive decline, specifically for domains of verbal memory, verbal fluency, and psychomotor speed.

Helicobacter pylori seropositivity and cognitive performance among US adults: evidence from a large national survey.

BACKGROUND: Helicobacter pylori seropositivity is a potential risk for poor cognition among US adults. METHODS: Cross-sectional data from the National Health and Nutrition Examination Survey III, Phase 1 (1988-1991), were used. Measures included age group-specific neuropsychological test batteries and two measures of H. pylori seropositivity (immunoglobulin G [IgG] and IgG CagA) (20-59 years old: n = 2090-2,248; 60-90 years old: n = 2123-2388). We explored sex- and race-specific associations. RESULTS: Using multiple ordinary least square and zero-inflated Poisson regression models, we detected a poorer performance among those 60-90 years old with H. pylori IgG+ versus IgG- on a verbal memory test (story recall, correct items), overall (ß = -0.04 [0.01], p = .010). Non-Hispanic (NH) blacks and women (20-59 years old) performed worse on the serial digits learning total errors (SDL-TE) when H. pylori IgG+ (versus IgG-), another verbal memory test (ß = +0.94 [0.40; p = .029] and ß = +1.19 [0.44; p = .012], respectively; p<.10 for interaction by sex and race). More trials to completion on this test (SDL-TTC) were also required among H. pylori IgG+ overall (20-59 years old; ß = +0.30 [0.13], p = .033). Other race-specific associations without significant interaction by race were detected in the same direction of worse performance with seropositivity in all three major race groups and for both age categories, covering several domains of cognition. CONCLUSIONS: H. pylori seropositivity markers were associated with poor cognition among US adults. Longitudinal research is needed to extrapolote those findings to cognitive decline, incident dementia, and Alzheimer's disease.

Associations of Olfaction With Longitudinal Trajectories of Brain Volumes and Neuropsychological Function in Older Adults.

BACKGROUND AND OBJECTIVES: Olfactory function declines with aging, and olfactory deficits are one of the earliest features of neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. Previous studies have shown that olfaction is associated with brain volumes and cognitive function, but data are exclusively cross-sectional. We aimed to examine longitudinal associations of olfaction with changes in brain volumes and neuropsychological function. METHODS: In the Baltimore Longitudinal Study of Aging, we chose the first assessment of olfaction to examine the associations with retrospective and prospective changes in neuropsychological performance and brain volumes in participants aged 50 years or older using linear mixed-effects models, adjusted for demographic variables and cardiovascular disease. Olfaction was measured as odor identification scores through the 16-item Sniffin' Sticks. RESULTS: We analyzed data from 567 (58% women, 42% men, 27% Black, 66% White, and 7% others) participants who had data on odor identification scores and brain volumetric MRI (n = 420 with retrospective repeats over a mean of 3.7 years, n = 280 with prospective repeats over a mean of 1.2 years). We also analyzed data from 754 participants (56% women, 44% men, 29% Black, 65% White, and 6% others) with neuropsychological assessments (n = 630 with retrospective repeats over a mean of 6.6 years, n = 280 with prospective repeats over a mean of 1.5 years). After adjustment, higher odor identification scores were associated with prior and subsequent slower brain atrophy in the entorhinal cortex (ß ± SE = 0.0093 ± 0.0031, p = 0.0028 and ß ± SE = 0.0176 ± 0.0073, p = 0.0169, respectively), hippocampus (ß ± SE = 0.0070 ± 0.0030, p = 0.0192 and ß ± SE = 0.0173 ± 0.0066, p = 0.0089, respectively), and additional frontal and temporal areas (all p < 0.05). Higher odor identification scores were also associated with prior slower decline in memory, attention, processing speed, and manual dexterity and subsequent slower decline in attention (all p < 0.05). Some associations were attenuated after exclusion of data points at and after symptom onset of cognitive impairment or dementia. DISCUSSION: In older adults, olfaction is related to brain atrophy of specific brain regions and neuropsychological changes in specific domains over time. The observed associations are driven, in part, by those who developed cognitive impairment or dementia. Future longitudinal studies with longer follow-ups are needed to understand whether olfactory decline precedes cognitive decline and whether it is mediated through regionally specific brain atrophy.

Pet ownership and maintenance of cognitive function in community-residing older adults: evidence from the Baltimore Longitudinal Study of Aging (BLSA).

Pet ownership has been associated with reduced deterioration in physical health as older adults age; little research focused on deterioration in cognitive function. We examine the relationship of pet, dog, cat ownership, and dog walking to changes in cognitive function among 637 generally healthy community-dwelling older adults (185 pet owners) aged 50-100 years (M = 68.3, SD = 9.6) within the BLSA. Cognitive assessments every 1-4 years over 1-13 years (M = 7.5, SD = 3.6) include the California Verbal Learning (Immediate, Short, Long Recall); Benton Visual Retention; Trail-Making (Trails A, B, B-A); Digit Span; Boston Naming (Naming); and Digit Symbol Substitution (Digit Symbol) Tests. In linear mixed models, deterioration in cognitive function with age was slower for pet owners than non-owners (Immediate, Short, Long Recall; Trails A,B,B-A; Naming; Digit Symbol); dog owners than non-owners (Immediate, Short Recall; Trails A,B; Naming; Digit Symbol); and cat owners than non-owners (Immediate, Short, Long Recall; Naming), controlling for age and comorbidities. Among dog owners (N = 73) walkers experienced slower deterioration than non-walkers (Trails B, B-A; Short Recall). All ps ≤ 0.05. We provide important longitudinal evidence that pet ownership and dog walking contribute to maintaining cognitive function with aging and the need to support pet ownership and dog walking in design of senior communities and services.

Application and validation of an algorithmic classification of early impairment in cognitive performance.

Objective: Due to the long prodromal period for dementia pathology, approaches are needed to detect cases before clinically recognizable symptoms are apparent, by which time it is likely too late to intervene. This study contrasted two theoretically-based algorithms for classifying early cognitive impairment (ECI) in adults aged ≥50 enrolled in the Baltimore Longitudinal Study of Aging. Method: Two ECI algorithms were defined as poor performance (1 standard deviation [SD] below age-, sex-, race-, and education-specific means) in: (1) Card Rotations or California Verbal Learning Test (CVLT) immediate recall and (2) ≥1 (out of 2) memory or ≥3 (out of 6) non- memory tests. We evaluated concurrent criterion validity against consensus diagnoses of mild cognitive impairment (MCI) or dementia and global cognitive scores using receiver operating characteristic (ROC) curve analysis. Predictive criterion validity was evaluated using Cox proportional hazards models to examine the associations between algorithmic status and future adjudicated MCI/dementia. Results: Among 1,851 participants (mean age=65.2±11.8 years, 50% women, 74% white), the two ECI algorithms yielded comparably moderate concurrent criterion validity with adjudicated MCI/dementia. For predictive criterion validity, the algorithm based on impairment in Card Rotations or CVLT immediate recall was the better predictor of MCI/dementia (HR=3.53, 95%CI: 1.59-7.84) over 12.3 follow-up years. Conclusions: Impairment in visuospatial ability or memory may be capable of detecting early cognitive changes in the preclinical phase among cognitively normal individuals.

Associations Between Objectively Measured Sleep and Cognition: Main Effects and Interactions With Race in Adults Aged ≥50 Years.

BACKGROUND: This study examined associations of actigraphy-estimated sleep parameters with concurrent and future cognitive performance in adults aged ≥ 50 years and explored interactions with race. METHODS: Participants were 435 cognitively normal adults in the Baltimore Longitudinal Study of Aging who completed wrist actigraphy at baseline (mean = 6.6 nights) and underwent longitudinal testing of memory, attention, executive function, language, and visuospatial ability. On average, participants with follow-up data were followed for 3.1 years. Primary predictors were baseline mean total sleep time, sleep onset latency, sleep efficiency (SE), and wake after sleep onset (WASO). Fully adjusted linear mixed-effects models included demographics, baseline health-related characteristics, smoking status, sleep medication use, APOE e4 carrier status, and interactions of each covariate with time. RESULTS: In adjusted models, higher SE (per 10%; B = 0.11, p = .012) and lower WASO (per 30 minutes; B = -0.12, p = .007) were associated with better memory cross-sectionally. In contrast, higher SE was associated with greater visuospatial ability decline longitudinally (B = -0.02, p = .004). Greater WASO was associated with poorer visuospatial ability cross-sectionally (B = -0.09, p = .019) but slower declines in visuospatial abilities longitudinally (B = 0.02, p = .002). Several sleep-cognition cross-sectional and longitudinal associations were stronger in, or limited to, Black participants (compared to White participants). CONCLUSIONS: This study suggests cross-sectional sleep-cognition associations differ across distinct objective sleep parameters and cognitive domains. This study also provides preliminary evidence for racial differences across some sleep-cognition relationships. Unexpected directions of associations between baseline sleep and cognitive performance over time may be attributable to the significant proportion of participants without follow-up data and require further investigation.

Alzheimer's disease genetic risk and cognitive reserve in relationship to long-term cognitive trajectories among cognitively normal individuals.

BACKGROUND: Both Alzheimer's disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition. METHODS: Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function. RESULTS: In mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition. CONCLUSIONS: These results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics.

Stress and cognitive function in Latino farmworkers.

BACKGROUND: Job stress has been associated with cognitive function, but the relationship is often overlooked when considering occupational health and safety issues of farmworkers. This study examined the relationship between stress and change in stress with change in cognitive function in a representative sample of 123 Latino farmworkers. METHODS: A prospective study design was used in which stress and cognitive function data were collected at baseline and at 3-month follow-up. Linear regression models were used for analyses. Potential confounders included baseline gender, age, education, number of years worked in U.S. agriculture, ever smoking status, self-rated health, and depressive symptoms. RESULTS: Baseline stress was significantly correlated with baseline cognitive function (r = -0.27; P < 0.001). Adjusting for confounders, increased baseline stress was associated with greater decline in cognitive function (P = 0.024). Short-term changes in stress were not associated with cognitive change in this cohort. CONCLUSIONS: Stress at work is an important risk factor for poor cognitive function. This analysis suggests several implications for the provision of health care and for the organization of work for farmworkers.

Herpes Viruses in the Baltimore Longitudinal Study of Aging: Associations With Brain Volumes, Cognitive Performance, and Plasma Biomarkers.

BACKGROUND AND OBJECTIVES: Although an infectious etiology of Alzheimer's Disease (AD) has received renewed attention with a particular focus on herpes viruses, the longitudinal effects of symptomatic herpes viruses (sHHV) infection on brain structure and cognition remain poorly understood, as does the effect of sHHV on AD/neurodegeneration biomarkers. METHODS: We used a longitudinal, community-based cohort to characterize the association of sHHV diagnoses with changes in 3T MRI brain volume and cognitive performance. Additionally, we related sHHV to cross-sectional differences in plasma biomarkers of AD (Aß42/40), astrogliosis (glial fibrillary acidic protein [GFAP]) and neurodegeneration (neurofilament light [NfL]). Baltimore Longitudinal Study of Aging (BLSA) participants were recruited from the community and assessed with serial brain MRIs and cognitive exams over an average of 3.4 (SD=3.2) and 8.6 (SD=7.7) years, respectively. sHHV classification used ICD9 codes documented at comprehensive health and functional screening evaluations at each study visit. Linear mixed effects and multivariable linear regression models were used in analyses. RESULTS: A total of 1,009 participants were included in the primary MRI analysis, 98% of whom were cognitively normal at baseline MRI (mean age = 65.7 years; 54.8% female). Having a sHHV diagnosis (N=119) was associated with longitudinal reductions in white matter volume (annual additional rate of change -0.34 cm3/year; p = 0.035), particularly in the temporal lobe. However, there was no association between sHHV and change in total brain, total gray matter, or AD signature region volume. Among the 119 participants with sHHV, exposure to antiviral treatment attenuated declines in occipital white matter (p = 0.04). Although the sHHV group had higher cognitive scores at baseline, sHHV diagnosis was associated with accelerated longitudinal declines in attention (annual additional rate of change -0.01 Z-score/year; p = 0.008). Additionally, sHHV diagnosis was associated with elevated plasma GFAP, but not related to Aß42/40 and NfL levels. DISCUSSION: These findings suggest an association of sHHV infection with white matter volume loss, attentional decline, and astrogliosis. Although the findings link sHHV to several neurocognitive features, the results do not support an association between sHHV and AD-specific disease processes.

Hippocampal activation and connectivity in the aging brain.

The hippocampus and underlying cortices are highly susceptible to pathologic change with increasing age. Using an associative face-scene (Face-Place) encoding task designed to target these regions, we investigated activation and connectivity patterns in cognitively normal older adults. Functional MRI scans were collected in 210 older participants (mean age = 76.4 yrs) in the Baltimore Longitudinal Study of Aging (BLSA). Brain activation patterns were examined during encoding of novel Face-Place pairs. Functional connectivity of the hippocampus was also examined during encoding, with seed regions placed along the longitudinal axis in the head, body and tail of the structure. In the temporal lobe, task activation patterns included coverage of the hippocampus and underlying ventral temporal cortices. Extensive activation was also seen in frontal, parietal and occipital lobes of the brain. Functional connectivity analyses during overall encoding showed that the head of the hippocampus was connected to frontal and anterior/middle temporal regions, the body with frontal, widespread temporal and occipital regions, and the tail with posterior temporal and occipital cortical regions. Connectivity limited to encoding of subsequently remembered stimuli showed a similar pattern for the hippocampal body, but differing patterns for the head and tail regions. These results show that the Face-Place task produces activation along the occipitotemporal visual pathway including medial temporal areas. The connectivity results also show that patterns of functional connectivity vary throughout the anterior-posterior extent of the hippocampus during memory encoding. As these patterns include regions vulnerable to pathologic change in early stages of Alzheimer's disease, continued longitudinal assessment of these individuals can provide valuable information regarding changes in brain-behavior relationships that may occur with advancing age and the onset of cognitive decline.

Pet Ownership Patterns and Successful Aging Outcomes in Community Dwelling Older Adults.

Introduction: Diminishing cognitive and physical functions, worsening psychological symptoms, and increased mortality risk and morbidity typically accompany aging. The aging population's health needs will continue to increase as the proportion of the population aged > 50 years increases. Pet ownership (PO) has been linked to better health outcomes in older adults, particularly those with chronic conditions. Much of the evidence is weak. Little is known about PO patterns as people age or the contribution of PO to successful aging in community-dwelling older adults. This study examines PO patterns among healthy community-dwelling older adults and the relationship of PO to cognitive and physical functions and psychological status. Methods: Participants in the Baltimore Longitudinal Study of Aging (> 50 years old, N = 378) completed a battery of cognitive, physical function, and psychological tests, as well as a PO questionnaire. Descriptive and non-parametric or general/generalized linear model analyses were conducted for separate outcomes. Results: Most participants (82%) had kept pets and 24% have pets: 14% dogs, 12% cats, 3% other pets. The most frequent reasons for having pets included enjoyment (80%) and companionship (66%). Most owners had kept the pet they had the longest for over 10 years (70%). PO was lower in older decades (p < 0.001). Pet owners were more likely to live in single-family homes and reside with others (p = 0.001) than non-owners. Controlling for age, PO was associated independently with better cognitive function (verbal leaning/memory p = 0.041), dog ownership predicted better physical function (daily energy expenditure, p = 0.018), and cat ownership predicted better cognitive functioning (verbal learning/memory, p = 0.035). Many older adults who did not own pets (37%) had regular contact with pets, which was also related to health outcomes. Conclusion: PO is lower at older ages, which mirrors the general pattern of poorer cognitive and physical function, and psychological status at older ages. PO and regular contact with pets (including PO) are associated with better cognitive status compared with those who did not own pets or had no regular contact with pets independent of age. Dog ownership was related to better physical function. Longitudinal analysis is required to evaluate the association of PO and/or regular contact with maintenance of health status over time.

Profiles of Cognitive Change in Preclinical and Prodromal Alzheimer's Disease Using Change-Point Analysis.

BACKGROUND: Alzheimer's disease (AD) is now understood to have a long preclinical phase in which pathology starts to accumulate in the absence of clinical symptoms. Identifying the temporal stages of accelerated cognitive decline in this phase may help in developing more sensitive neuropsychological tools for early screening of preclinical cognitive decline. Change-point analyses are increasingly used to characterize the temporal stages of accelerated cognitive decline in the preclinical stages of AD. However, statistical comparisons of change-points between specific cognitive measures have not been reported. OBJECTIVE: To characterize and compare the temporal stages of accelerated decline in performance on multiple cognitive tests in a sample of participants from the Baltimore Longitudinal Study on Aging (BLSA) who later developed AD. METHODS: 165 older adults (baseline age range: 61.1-91.2) from the BLSA developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures. RESULTS: Change-points followed by accelerated decline ranged from 15.5 years (Standard Error (S.E.) = 1.72) for Card Rotations to 1.9 years (S.E. = 0.68) for the Trail-Making Test Part A before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures. CONCLUSION: Results suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD.

Effects of race and socioeconomic status on the relative influence of education and literacy on cognitive functioning.

Previous research has shown that reading ability is a stronger predictor of cognitive functioning than years of education, particularly for African Americans. The current study was designed to determine whether the relative influence of literacy and education on cognitive abilities varies as a function of race or socioeconomic status (SES). We examined the unique influence of education and reading scores on a range of cognitive tests in low- and higher-SES African Americans and Whites. Literacy significantly predicted scores on all but one cognitive measure in both African American groups and low-SES Whites, while education was not significantly associated with any cognitive measure. In contrast, both education and reading scores predicted performance on many cognitive measures in higher-SES Whites. These findings provide further evidence that reading ability better predicts cognitive functioning than years of education and suggest that disadvantages associated with racial minority status and low SES affect the relative influence of literacy and years of education on cognition.

SPARCL1 Accelerates Symptom Onset in Alzheimer's Disease and Influences Brain Structure and Function During Aging.

We recently reported that alpha-2 macroglobulin (A2M) is a biomarker of neuronal injury in Alzheimer's disease (AD) and identified a network of nine genes co-expressed with A2M in the brain. This network includes the gene encoding SPARCL1, a protein implicated in synaptic maintenance. Here, we examine whether SPARCL1 is associated with longitudinal changes in brain structure and function in older individuals at risk for AD in the Baltimore Longitudinal Study of Aging. Using data from the Gene-Tissue Expression Project, we first identified two single nucleotide polymorphisms (SNPs), rs9998212 and rs7695558, associated with lower brain SPARCL1 gene expression. We then analyzed longitudinal trajectories of cognitive performance in 591 participants who remained cognitively normal (average follow-up interval: 11.8 years) and 129 subjects who eventually developed MCI or AD (average follow-up interval: 9.4 years). Cognitively normal minor allele carriers of rs7695558 who developed incident AD showed accelerated memory loss prior to disease onset. Next, we compared longitudinal changes in brain volumes (MRI; n = 120 participants; follow-up = 6.4 years; 826 scans) and resting-state cerebral blood flow (rCBF; 15O-water PET; n = 81 participants; follow-up = 7.7 years; 664 scans) in cognitively normal participants. Cognitively normal minor allele carriers of rs9998212 showed accelerated atrophy in several global, lobar, and regional brain volumes. Minor allele carriers of both SNPs showed longitudinal changes in rCBF in several brain regions, including those vulnerable to AD pathology. Our findings suggest that SPARCL1 accelerates AD pathogenesis and thus link neuroinflammation with widespread changes in brain structure and function during aging.

Sex-Dependent Associations of Serum Uric Acid with Brain Function During Aging.

Serum uric acid (SUA) is an abundant natural antioxidant capable of reducing cellular oxidation, a major cause of neurodegenerative disease. In line with this, SUA levels are lower in Alzheimer's disease; however, the association between SUA and cognition remains unclear. Results from studies examining the effects of SUA on cognition may be difficult to interpret in the context of normal versus pathological aging. This study examined sex-specific associations of baseline SUA with cognition during aging. Data from dementia-free participants initially aged 26-99 (N = 1,451) recruited for the Baltimore Longitudinal Study of Aging (BLSA), were used in the current analyses. SUA was assessed using blood samples collected during research visits. Cognition was measured using five composite scores (verbal memory, attention, executive function, language, and visuospatial ability). At the first study visit, compared with women, men were older, more likely to be White, had more years of education, higher baseline SUA levels, and higher cardiovascular risk scores. Higher baseline SUA was associated with attenuated declines in attention (ß= 0.006; p = 0.03) and visuospatial abilities (ß= 0.007; p = 0.01) in men. There was a trend to suggest higher baseline SUA in men was associated with attenuated declines in language, but this finding did not reach statistical significance (p = 0.09). There were no significant findings with SUA and cognition in women. In this sample of cognitively healthy, community-dwelling adults, we found that higher SUA levels at baseline were associated with attenuated declines in attention and visuospatial abilities in men. SUA was not associated with cognition or change in cognition over time in women.

A classification algorithm for predicting progression from normal cognition to mild cognitive impairment across five cohorts: The preclinical AD consortium.

INTRODUCTION: We established a method for diagnostic harmonization across multiple studies of preclinical Alzheimer's disease and validated the method by examining its relationship with clinical status and cognition. METHODS: Cognitive and clinical data were used from five studies (N = 1746). Consensus diagnoses established in each study used criteria to identify progressors from normal cognition to mild cognitive impairment. Correspondence was evaluated between these consensus diagnoses and three algorithmic classifications based on (1) objective cognitive impairment in 2+ tests only; (2) a Clinical Dementia Rating (CDR) of ≥0.5 only; and (3) both. Associations between baseline cognitive performance and cognitive change were each tested in relation to progression to algorithm-based classifications. RESULTS: In each study, an algorithmic classification based on both cognitive testing cutoff scores and a CDR ≥0.5 provided optimal balance of sensitivity and specificity (areas under the curve: 0.85-0.95). Over an average 6.6 years of follow-up (up to 28 years), N = 186 initially cognitively normal participants aged on average 64 years at baseline progressed (incidence rate: 15.3 people/1000 person-years). Baseline cognitive scores and cognitive change were associated with future diagnostic status using this algorithmic classification. DISCUSSION: Both cognitive tests and CDR ratings can be combined across multiple studies to obtain a reliable algorithmic classification with high specificity and sensitivity. This approach may be applicable to large cohort studies and to clinical trials focused on preclinical Alzheimer's disease because it provides an alternative to implementation of a time-consuming adjudication panel.