Project Cohort Research Articles

Combined use of QRISK3 and SCORE2 increases identification of ankylosing spondylitis patients at high cardiovascular risk: Results from the CARMA Project cohort after 7.5 years of follow-up

ObjectiveTo establish the predictive value of the QRESEARCH risk estimator version 3 (QRISK3) algorithm in identifying Spanish patients with ankylosing spondylitis (AS) at high risk of cardiovascular (CV) events and CV mortality. We also sought to determine whether to combine QRISK3 with another CV risk algorithm: the traditional SCORE, the modified SCORE (mSCORE) EULAR 2015/2016 or the SCORE2 may increase the identification of AS patients with high-risk CV disease. MethodsInformation of 684 patients with AS from the Spanish prospective CARdiovascular in ReuMAtology (CARMA) project who at the time of the initial visit had no history of CV events and were followed in rheumatology outpatient clinics of tertiary centers for 7.5 years was reviewed. The risk chart algorithms were retrospectively tested using baseline data. ResultsAfter 4,907 years of follow-up, 33 AS patients had experienced CV events. Linearized rate=6.73 per 1000 person-years (95 % CI: 4.63, 9.44). The four CV risk scales were strongly correlated. QRISK3 correctly discriminated between people with lower and higher CV risk, although the percentage of accumulated events over 7.5 years was clearly lower than expected according to the risk established by QRISK3. Also, mSCORE EULAR 2015/2016 showed the same discrimination ability as SCORE, although the percentage of predicted events was clearly higher than the percentage of actual events. SCORE2 also had a strong discrimination capacity according to CV risk. Combining QRISK3 with any other scale improved the model. This was especially true for the combination of QRISK3 and SCORE2 which achieved the lowest AIC (406.70) and BIC (415.66), so this combination would be the best predictive model. ConclusionsIn patients from the Spanish CARMA project, the four algorithms tested accurately discriminated those AS patients with higher CV risk and those with lower CV risk. Moreover, a model that includes QRISK3 and SCORE2 combined the best discrimination ability of QRISK3 with the best calibration of SCORE2.

Ophthalmic Findings in Aboriginal Children with High Rates of Prenatal Alcohol Exposure and Fetal Alcohol Spectrum Disorder: The Lililwan Project

ABSTRACT Purpose To describe ophthalmic findings in an Indigenous paediatric population and the associations between fetal alcohol spectrum disorder (FASD), prenatal alcohol exposure (PAE), and eye anomalies. Methods Medical records were reviewed for eye problems, and eye assessments were conducted by an orthoptist or ophthalmologist in the Lililwan Project cohort, which comprised 108 (81%) of all children born between 2002 and 2003, and residing in the remote Fitzroy Valley, Western Australia in 2010. Values from ophthalmic assessments and prevalence of abnormalities were presented for the total cohort and stratified by group: FASD; PAE (no FASD); and No PAE. Results Of children, 55% had PAE and 19% FASD. Most (98%) had normal vision; 15.6% had keratometry cylinder values indicating astigmatism and potential for improved vision with glasses. Strabismus (22.3%), short palpebral fissure length (PFL; 21.3%), upslanting palpebral fissures (12.0%), follicular trachomatous inflammation (6.9%), abnormal slit lamp assessments (6.7%), retinal tortuosity (6.7%), and blepharoptosis (5.6%) were identified. Strabismus and trachoma rates were higher than in the general child population. Ophthalmic findings were similar between groups except for prevalence of short PFL (FASD > No PAE; p = 0.003); abnormal keratometry cylinder values (FASD [29.4%] and PAE (no FASD) [20.0%] > No PAE [5.3%]; p = 0.031) and blepharoptosis (FASD [9.5%] > other groups [0%]; p = 0.040). Conclusion Despite the small sample, some eye abnormalities were higher in children with PAE and/or FASD. Access to eye services or assessment of vision and structural eye anomalies is essential for Indigenous children, particularly those with PAE or FASD to allow early effective treatment.

Short physical performance battery is not associated with falls and injurious falls in older persons: longitudinal data of the SCOPE project

Key summary pointsAimOur objective was to study the predictive value of the Short Physical Performance Battery (SPPB) in the cohort of the SCOPE project on falls, injurious falls, and possible difference of prediction between indoors and outdoors falls.FindingsNo association of SPPB and falls was found in models adjusted for age, sex, marital status, number of medications, quality of life, handgrip strength, and muscle mass. While SPPB fails to differentiate between injurious and non-injurious falls (p = 0.48), a lower SPPB score was associated with falls at home (p < 0.01) after 24 months.MessageSBPP was not able to significantly predict the risk of falling as well as experiencing an injurious fall.

Does Escalating Violence and Associated Fear of Crime Worsen Psychological Well-Being in Community Dwellers Living in a Rural Setting? Results From the Atahualpa Project Cohort.

Escalating street violence and criminal homicides have an adverse impact on psychological well-being. However, these consequences have been difficult to evaluate. Using a recently validated scale, we aimed to assess the impact of fear of crime on the psychological status of middle-aged and older adults living in a rural setting afflicted by endemic violence. Participants were selected from Atahualpa residents included in previous studies targeting psychological distress in the population. A validated scale was used to objectively quantify fear of crime in participants. Differences in symptoms of depression and anxiety between baseline and follow-up were used as distinct dependent variables and the continuous score of the fear of crime scale was used as the independent variable. Linear regression models were fitted to assess the association between the exposure and the outcomes, after adjusting for relevant confounders. A total of 653 participants (mean age = 53.2 ± 11.5 years; 57% women) completed the requested tests. We found a 13% increase in symptoms of depression and anxiety during the peak of violence in the village compared with previous years. Linear regression models showed a significant association between the total score on the fear of crime questionnaire and worsening symptoms of depression (β = .24; 95% CI = 0.14-0.35) and anxiety (β = .31; 95% CI = 0.24-0.37), after adjustment for relevant confounders. This study shows a significant aggravating effect of fear of crime on pre-existing symptoms of depression and anxiety and a deleterious effect of these conditions on overall well-being.

Supporting Agency over Framing Authentic Design Problems

While project-based learning purportedly values student agency, supporting and managing this remains challenging. We conducted a design-based research study to understand how problem authenticity, and task and participant structures can contribute to students’ framing agency, in which students make decisions that are consequential to their learning through ill-structured problem framing. We compared three semesters of an undergraduate engineering design project (cohort 1 n=70; cohort 2 n=70; cohort 3 n=66). Discourse analysis of team talk highlights how task and participant structures supported students in the first and third cohorts to display framing agency. In contrast, cohort 2 displayed high agency over task completion, which they had framed as well-structured. We discuss implications for designing ill-structured learning in terms of participant and task structure and problem authenticity.

The association of dietary antioxidants and the inflammatory potential of the diet with poor physical function and disability in older Australian men: the Concord Health and Ageing in Men Project.

Our objective was to evaluate the association of antioxidant intake and the inflammatory potential of the diet with functional decline in older men. A diet history questionnaire was used to collect dietary intake data from men aged ≥ 75 years (n 794) participating in the Concord Health and Aging in Men Project cohort study. Intake of vitamins A, C, E and Zn were compared with the Australian Nutrient Reference Values to determine adequacy. The Energy-adjusted Dietary Inflammatory Index (E-DIITM) was used to assess the inflammatory potential of the diet. Physical performance data were collected via handgrip strength and walking speed tests, and activities of daily living (ADL) and instrumental activities of daily living (IADL) questionnaires, at baseline and 3-year follow-up (n 616). Logistic regression analysis was used to identify associations between diet and incident poor physical function and disability. Both poor antioxidant intake and high E-DII scores at baseline were significantly associated with poor grip strength and ADL disability at 3-year follow-up. No significant associations with walking speed or IADL disability were observed. Individual micronutrient analysis revealed a significant association between the lowest two quartiles of vitamin C intake and poor grip strength. The lowest quartiles of intake for vitamins A, C, E and Zn were significantly associated with incident ADL disability. The study observed that poor antioxidant and anti-inflammatory food intake were associated with odds of developing disability and declining muscle strength in older men. Further interventional research is necessary to clarify the causality of these associations.

Dietary oily fish intake is inversely associated with moderate-to-severe intracranial artery stenosis in older adults of indigenous Ecuadorian ancestry

Background and aimsInformation on the association between dietary oily fish intake and intracranial atherosclerosis is limited and contradictory. Inconsistencies might be in part related to heterogeneous designs and differences in race/ethnicity of study populations. We aim to assess whether oily fish intake is inversely associated with intracranial artery stenosis (ICAS) in frequent fish consumers of indigenous ancestry living in coastal Ecuador. MethodsThe study included 384 participants aged ≥60 years enrolled in the Atahualpa Project Cohort. Dietary oily fish intake was quantified systematically via validated surveys and all participants received a time-of-flight MRA of intracranial vessels. Poisson regression models, adjusted for demographics, level of education, traditional risk factors and severe tooth loss, were fitted to assess the association between amounts of oily fish intake and the number of intracranial arteries with moderate-to-severe (≥50 %) stenosis. ResultsParticipants had a mean age of 67.7 ± 7 years, and 56 % were women. The mean oily fish intake was 8.9 ± 5.2 servings/week; 283 (74 %) participants consumed ≥5.2 servings/week (2nd to 4th quartiles of fish intake). Forty-three (11 %) participants had at least one major intracranial artery with moderate-to-severe stenosis. Both univariate and multivariate models showed a significant inverse association between consumption of oily fish in the 2nd to 4th quartiles and ≥50 % stenosis in at least one artery (β: 0.46; 95 % C.I.: 0.27–077, and β: 0.52; 95 % C.I.: 0.30–0.90, respectively). ConclusionsConsumption of more than five oily fish servings/week is associated with lower prevalence of moderate-to-severe ICAS in indigenous Ecuadorians.

Risk of Alzheimer's disease is associated with longitudinal changes in plasma biomarkers in the multi-ethnic Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP) cohort.

Alzheimer's disease (AD) biomarkers can help differentiate cognitively unimpaired (CU) individuals from mild cognitive impairment (MCI) and dementia. The role of AD biomarkers in predicting cognitive impairment and AD needs examination. In 628 CU individuals from a multi-ethnic cohort, amyloid beta (Aβ)42, Aβ40, phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured in plasma. Higher baseline levels of p-tau181/Aβ42 ratio were associated with an increased risk of incident dementia. A biomarker pattern (with elevated Aβ42/Aβ40 but low p-tau181/Aβ42) was associated with decreased dementia risk. Compared to CU, participants who developed MCI or dementia had a rapid decrease in this protective biomarker pattern reflecting AD-specific pathological change. Elevated levels of AD biomarker p-tau181/Aβ42, by itself or combined with a low Aβ42/Aβ40 level, predicts clinically diagnosed AD. Individuals with a rapid change in these biomarkers may need close monitoring for the potential downward trajectory of cognition. We discuss a multi-ethnic, urban community study of elderly individuals. The study consisted of a longitudinal assessment over 6 years with repeated clinical assessments. The study used blood-based biomarkers as predictors of mild cognitive impairment and Alzheimer's disease.

Short-term prognosis of polypharmacy in elderly patients treated in emergency departments: results from the EDEN project.

Polypharmacy is a growing phenomenon among elderly individuals. However, there is little information about the frequency of polypharmacy among the elderly population treated in emergency departments (EDs) and its prognostic effect. This study aims to determine the prevalence and short-term prognostic effect of polypharmacy in elderly patients treated in EDs. A retrospective analysis of the Emergency Department Elderly in Needs (EDEN) project's cohort was performed. This registry included all elderly patients who attended 52 Spanish EDs for any condition. Mild and severe polypharmacy was defined as the use of 5-9 drugs and ⩾10 drugs, respectively. The assessed outcomes were ED revisits, hospital readmissions, and mortality 30 days after discharge. Crude and adjusted logistic regression analyses, including the patient's comorbidities, were performed. A total of 25,557 patients were evaluated [mean age: 78 (IQR: 71-84) years]; 10,534 (41.2%) and 5678 (22.2%) patients presented with mild and severe polypharmacy, respectively. In the adjusted analysis, mild polypharmacy and severe polypharmacy were associated with an increase in ED revisits [odds ratio (OR) 1.13 (95% confidence interval (CI): 1.04-1.23) and 1.38 (95% CI: 1.24-1.51)] and hospital readmissions [OR 1.18 (95% CI: 1.04-1.35) and 1.36 (95% CI: 1.16-1.60)], respectively, compared to non-polypharmacy. Mild and severe polypharmacy were not associated with increased 30-day mortality [OR 1.05 (95% CI: 0.89-2.26) and OR 0.89 (95% CI: 0.72-1.12)], respectively. Polypharmacy was common among the elderly treated in EDs and associated with increased risks of ED revisits and hospital readmissions ⩽30 days but not with an increased risk of 30-day mortality. Patients with polypharmacy had a higher risk of ED revisits and hospital readmissions ⩽30 days after discharge.

Low prevalence of archived integrase strand transfer inhibitors resistance associated mutations in Botswana before the roll out of dolutegravir based first line antiretroviral therapy.

We evaluated the prevalence of archived proviral drug resistance mutations (DRMs) associated with resistance to integrase strand transfer inhibitors (INSTIs) shortly before Botswana transitioned in 2016 to using dolutegravir (DTG)-based antiretroviral treatment in first-line regimens. We used the Stanford University HIV drug resistance database to analyze INSTI-resistance associated mutations (RAMs) in a large representative population-based cohort of adults recruited in 30 geographically dispersed communities as part of the Botswana Combination Prevention Project (BCPP) cohort from 2013 to 2018. A total of 5,144 HIV-1 proviral DNA sequences were included in our analysis; 1,281 sequences were from antiretroviral therapy (ART)-naïve individuals and 3,863 sequences were from non-nucleoside reverse transcriptase inhibitor (NNRTI) ART-experienced individuals. None of the sequences were from DTG-ART experienced participants. The overall prevalence of major INSTIs DRMs was 1.11% (95% CI 0.82-1.39%). The prevalence of INSTI DRMs in ART-naïve individuals was 1.64% (21/1,281) and 0.93% (36/3,863) in ART-experienced individuals. Major INSTI-RAMs detected in ART-naïve individuals were E138K (2/1,281; 0.16%), G140R (8/1,281;0.62%), E92G (2/1,281;0.16%), R263K (5/1,281; 0.4%), N155H (1/1,281; 0.08%), P145S (1/1,281;0.008%). Among the ART-experienced individuals, major INSTI RAMs detected were E138K (4/3,863; 0.10%), G140R (25/3,863;0.65%), G118R (2/3,863, 0.05%), R263K (4/3,863, 0.10%), T66I (1/3,863;0.03%), E138K + G140R (1/3,863, 0.03%|), G140R + R263K (1/3,863, 0.03%). High-level resistance to cabotegravir (CAB), elvitegravir (EVG), and raltegravir (RAL) was detected in 0.70, 0.16 and 0.06% of the individuals, respectively. Notably, bictegravir (BIC) and dolutegravir (DTG) showed no high-level resistance. The overall prevalence of archived INSTI RAMs in Botswana was low prior to transitioning to first-line DTG-based ART regimens, and did not differ between ART-naïve and ART-experienced individuals. Ongoing surveillance of INSTI DRMs in Botswana will allow for re-assessment of INSTI resistance risk following nationwide DTG rollout.

Effects of Frailty Syndrome on Osteoporosis, Focusing on the Mediating Effect of Muscle Strength and Balance in Community-Dwelling Older Adults (≥60 years) in Iran: Results From the Amirkola Health and Aging Project Cohort Study.

For older adults, maintaining muscle strength and balance is crucial to preserve an upright posture and independently manage their basic activities of daily living (ADL). This study aimed to examine whether muscle strength and balance mediate the relationship between frailty syndrome (FS) and osteoporosis in a large sample of community-dwelling older adults. This cross-sectional study is part of the second phase (2016-2017) of the Amirkola Health and Ageing Project (AHAP), a cohort study conducted on all elderly aged 60 and over in Amirkola, Northern Iran, since 2011. Data from 2018 older adults were collected by a trained person using bone mineral density (BMD), frailty index, activities of daily living (ADL), instrumental activities of daily living (IADL), handgrip strength (HGS), quadriceps muscle strength (QMS), Berg Balance Scale (BBS), and Timed Up and Go test (TUG test) and analyzed using analysis of variance, chi-square, and path analysis tests. The mean indices of femoral neck BMD and lumbar spine BMD, HGS, QMS, BBS, ADL, and IADL were lower in the frail older adults than in the pre-frail and non-frail older adults. In addition, the mean TUG test level was higher in the frail older adults than in the non-frail and pre-frail older adults. The results of the present study have indicated that frailty is significantly related to osteoporosis, and that balance and muscle strength can predict osteoporosis; these variables play a mediating role in the relationship between frailty and osteoporosis. From the results of the present study, it can be concluded that frailty may increase the odds of osteoporosis. The results of the current study have indicated that balance (BBS and TUG test) and muscle strength (HGS and QMS) are associated with osteoporosis and these variables play a mediating role in the relationship between frailty and osteoporosis.

Is the association between mothers’ autistic traits and childhood autistic traits moderated by maternal pre-pregnancy body mass index?

BackgroundPrevious studies showed that there is a positive association between mothers’ and children’s autistic traits. We also tested if this association is more pronounced in mothers with a higher pre-pregnancy body mass index (BMI).MethodThe study was embedded in two cohorts with information available for 4,659 participants from the Generation R and for 179 participants from the Cambridge Ultrasound Siblings and Parents Project (CUSP) cohort. In both cohorts, maternal autistic traits were assessed using the short form of the Autism Spectrum Quotient, and information about maternal height and weight before pregnancy was obtained by questionnaire. Child autistic traits were assessed with the short form of Social Responsiveness Scale in Generation R (M = 13.5 years) and with the Quantitative Checklist for Autism in Toddlers (Q-CHAT) in the CUSP cohort (M = 1.6 years).ResultHigher maternal autistic traits were associated with higher autistic traits in toddlerhood (CUSP cohort; βadjusted = 0.20, p < 0.01), in early childhood (Generation R; βadjusted = 0.19, p < 0.01), and in early adolescence (Generation R; βadjusted = 0.16, p < 0.01). Furthermore, a higher maternal pre-pregnancy BMI was associated with higher child autistic traits, but only in Generation R (βadjusted = 0.03, p < 0.01). There was no significant moderating effect of maternal pre-pregnancy BMI on the association between autistic traits of mothers and children, neither in Generation R nor in CUSP. In addition, child autistic traits scores were significantly higher in mothers who were underweight and in mothers who were overweight compared to mothers with a healthy weight.ConclusionWe confirm the association between maternal and child autistic traits in toddlerhood, early childhood, and early adolescence. Potential interacting neurobiological processes remain to be confirmed.

Effect of early‐ and mid‐life cognitive enrichment on Alzheimer’s disease pathology and late‐life cognition

AbstractBackgroundCognitive reserve and brain maintenance may explain individual differences in trajectories of cognitive and brain aging due to various life exposures (e.g., education, cognitive enrichment). Cognitive reserve refers to the advantages that life exposures exert on cognitive abilities despite brain aging or disease; brain maintenance refers to the protective effects of life exposures on the brain itself (e.g., reduced rate of neuropathology accumulation). Previous findings showed that early‐life cognitive enrichment (ELCE) was associated with slower cognitive decline, which was partially mediated through global Alzheimer’s disease pathology. Building on this work, this study investigated mediation by β‐amyloid and tau pathology (reflecting brain maintenance) as well as moderation by early‐ and mid‐life cognitive enrichment (ELCE, MLCE; reflecting cognitive reserve) on cognitive functioning at last visit proximate to death.MethodThere were 1015 community‐based participants (M baseline age = 82.57±6.35) from the Rush Memory and Aging Project (MAP) and Minority Aging Research Study (MARS) cohorts, who completed annual cognitive and clinical assessments. ELCE and MLCE composite measures were derived from z‐scored self‐reported indicators obtained at baseline (Table 1). Summary measures of β‐amyloid and tau burden were derived from immunohistochemistry at autopsy. Late‐life cognition was measured using a global composite of 19 z‐scored neuropsychological tests obtained at last visit. To test for cognitive reserve, separate linear regression models examined whether ELCE and MLCE moderated relations between β‐amyloid or tau and cognition, adjusted for age at death and sex. To test for brain maintenance, a series of mediation analyses examined whether β‐amyloid and/or tau burden mediated the relationship of ELCE and MLCE with cognition.ResultELCE (p = .005) and MLCE (p = .005) moderated the relationship between tau—but not β‐amyloid—and late‐life cognition proximate to death (Figure 1). Mediation analyses revealed an indirect effect of β‐amyloid—but not tau—on the relation between ELCE (B = 0.058, p = .004) and MLCE (B = 0.040, p = .03) and late‐life cognition (Figure 2).ConclusionELCE and MLCE improve late‐life cognition partially through reducing β‐amyloid, but not tau, accumulation (i.e., brain maintenance). In contrast, ELCE and MLCE are protective against late‐life cognitive impairment in the presence of tau pathology (i.e., cognitive reserve), but not β‐amyloid.

Bilingualism in adult population without cognitive impairment: its relationship with aging in structural neuroimaging. A cross‐sectional study.

AbstractBackgroundAging is consistently associated with cortical gray matter (GM) reductions. Bilingualism has been described as a potential reserve contributor for successful brain aging and has been associated with a variety of structural changes in cortical morphology. In this study we aim to: 1) Explore differences between bilinguals and monolinguals on the whole brain cortical thickness, area and volume, 2) explore if correlations between age and cortical measures are different between bilinguals and monolinguals, and 3) to evaluate age‐bilingualism interaction effects on the cortical characteristics.MethodCross‐sectional study with healthy volunteers from the Gipuzkoa Alzheimer Project (GAP) cohort. Cognitively unimpaired (CDR Global Score = 0) with available 3T MRI were included and classified as bilinguals or monolinguals based on daily use of both Spanish and Basque languages or only Spanish. Subjects with diffuse white matter lesions (Fazekas scale = 3) were excluded. Cortical reconstruction was performed with Freesurfer package v5.1. as described in Montal et al., 2017. Analyses were conducted in the whole brain using linear modeling of the maps and Monte Carlo simulation corrected for multiple comparisons as implemented in FreeSurfer’s QDEC interface.ResultSample included 88 bilinguals and 83 monolinguals (see Table 1 for demographic and clinical characteristics). Whole brain cortical thickness, area or volume were not significantly different between groups. Age‐cortical thickness and volume correlation maps showed broader areas of negative associations in the monolingual than in the bilingual group, and inverse associations in the relationship with area characterized by negative correlations in monolinguals and positive and negative correlations in bilinguals (Figure 1). More specifically, significant age‐bilingualism interactions were found for thickness in the right superiorfrontal gyrus (p = 0.012), and for the surface area, in the inferiorparietal (p = 0.0001), supramarginal (p = 0.043) and lingual (p = 0.042) regions of the left hemisphere.ConclusionCortical thickness and area variations occurring in relation to aging in cognitively healthy individuals could be modulated by bilingualism.

Association of Central Blood Pressure and Carotid Intima Media Thickness with New-Onset Hypertension in People with High Normal Blood Pressure.

People with high normal blood pressure (BP) have a higher risk of cardiovascular events than those with normal BP; therefore, progression to hypertension (HT) should be prevented. We aimed to assess the HT risk using central BP and carotid intima media thickness (CIMT) in people with high normal BP. This prospective cohort study used the Tohoku Medical Megabank Community-Based Project Cohort Study (conducted from 2013 in Miyagi Prefecture in Japan). The participants had a high normal BP, defined as a systolic BP of 120-139 mmHg and diastolic BP ＜90 mmHg using brachial BP measurement during the baseline survey. The outcome was new-onset HT during the secondary survey, conducted four years after the baseline survey. Overall, 4,021 participants with high normal BP during the baseline survey, with an average age of 58.7 years, were included; 1,030 (26%) were diagnosed with new-onset HT during the secondary survey, 3.5±0.7 years after the baseline survey. The multivariable odds ratio (95% confidence interval) for HT in the highest versus lowest quartile of central BP was 1.7 (1.2-2.4, p=0.0030), and that of CIMT was 1.8 (1.4-2.4, p＜0.001). Subgroup analysis according to age (＜60 and ≥ 60 years) and sex revealed that the central BP was influential in groups with younger age and female individuals; CIMT was influential in all groups. Higher central BP and thicker CIMT at the baseline were correlated with new-onset HT in individuals with high normal BP, independent of brachial systolic BP and other cardiovascular risk factors.

Regional cortical hypoperfusion observed in elderly adults prior to development of mild cognitive impairment

AbstractBackgroundCardiovascular disease is associated with increased risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD), although the underlying mechanisms are not well understood. While it has been theorised that cerebral hypoperfusion caused by heart failure may directly lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of AD, it has also been suggested that decreased perfusion occurs later in disease progression. We used arterial spin labelling (ASL) MRI to compare cerebral blood flow (CBF) between cognitively unimpaired elderly individuals who would remain cognitively stable and those who would later develop MCI to determine if hypoperfusion is detectable at a preclinical stage.Methods647 cognitively normal elderly participants with ASL and structural T1‐weighted MRI were selected from the Vallecas Project cohort, a single‐centre longitudinal study currently in its 12th year of annual follow‐up. 586 participants remained cognitively stable (CS) while 61 participants developed MCI over the course of the study. Cortical CBF maps derived from ASL images at the visit before MCI diagnosis were analysed in a voxelwise comparison with CS individuals, with age, sex, and total intracranial volume as covariates.ResultsCBF was significantly lower in the right insular cortex in future MCI converters than CS individuals (p&lt;0.05, family‐wise error (FWE) corrected). Hypoperfusion was also significant in the anterior corpus callosum in future converters.ConclusionCerebral hypoperfusion, as measured by ASL, can already be observed in individuals before the onset of clinical symptoms.

Telomere length in the superager sample of the Vallecas Project cohort

AbstractBackgroundSuperagers are individuals aged 80 and over with youthful episodic memory that can provide insights into protective mechanisms against age‐related memory loss and dementia. We aim to study telomere length in human superagers since telomere attrition is considered a hallmark of ageing and can explain some structural and functional changes occurring in an ageing organism. We therefore tested whether telomere length is associated with successful episodic memory of superagers.MethodTelomere length was measured in peripheral blood cells from 57 superagers (mean age 81.9 years ± 2.0 std, 61.4% women) and 48 age‐matched typical older adults with normal memory for age (mean age 82.4 years ± 1.9 std, 64.6% women) selected from the Vallecas Project cohort. A high‐throughput quantitative fluorescence in situ hybridization technique (HT Q‐FISH) (Life length, Spain) was used. This technology has a low detection limit of &lt; 100 bp, enabling the quantification of short telomeres that can be more informative of telomere dysfunction than centrality measures.ResultSuperagers have significantly shorter median telomere lengths than typical older adults (p = 0.0009, t = ‐3.4) and show a higher proportion of short telomeres (&lt;6 Kbp) (p = 0.0005, t = 3.6) and extremely short telomeres (&lt;3 Kbp) (p = 9. 4×10−5; t = 4.1) than typical older adults. Thus, superagers have shorter average telomere lengths and a higher proportion of short telomeres, which are most associated with genome instability.ConclusionThe successful episodic memory of our superager population is not associated with long telomere length or the presence of fewer short telomeres measured in a cross‐sectional setting. Further analysis exploring telomere attrition rate of these two groups over time may help to interpret the current findings.

Transcriptional risk score in Alzheimer’s disease: from pathology to cognition

AbstractBackgroundTranscriptional risk scores (TRS), a summation of polarized expression levels of functional genes, have been proposed for disease risk assessment using transcriptome profiles. Our previously developed blood‐based TRS showed associations with diagnosis and neuroimaging biomarkers for Alzheimer’s disease (AD). Here, we developed brain‐based TRS models and calculated TRS using brain tissue‐based transcriptome profiles.MethodWe integrated AD genome‐wide association study summary and expression quantitative trait locus data to prioritize target genes using Mendelian randomization and then calculated individual TRS by summing the polarized z‐scores over the target genes. We used brain transcriptome data from the Religious Orders Study and Rush Memory and Aging Project cohort (ROSMAP; N = 634) as a discovery set and the Mount Sinai Brain Bank cohort (MSBB; N = 244) as a replication set. We performed association analysis of TRS with AD diagnosis, amyloidopathy, tauopathy, and cross‐sectional and longitudinal cognitive function. We compared AD classification performance of TRS with polygenic risk scores (PRS) using a machine learning approach (Fig. 1).ResultHigher TRS values were significantly associated with AD compared to cognitively normal controls (Table 1). Higher TRS values were also related with amyloidopathy, tauopathy, poor cognitive performance, and faster cognitive decline. The AD classification performance of PRS was increased with the inclusion of TRS up to 12% with the area under the curve value of 0.842 (Fig. 2). These findings were replicated in the replication dataset.ConclusionOur results showed that brain‐based TRS is associated with AD pathology and clinical course. Furthermore, TRS improves the AD classification performance of PRS. Along with static PRS, dynamic TRS based on transcriptional expression levels at a given time could be a potential disease‐stage specific AD biomarker.

Regional cortical hypoperfusion observed in elderly adults prior to development of mild cognitive impairment

AbstractBackgroundCardiovascular disease is associated with increased risk of developing mild cognitive impairment (MCI) and Alzheimer’s disease (AD), although the underlying mechanisms are not well understood. While it has been theorised that cerebral hypoperfusion caused by heart failure may directly lead to the formation of amyloid plaques and neurofibrillary tangles characteristic of AD, it has also been suggested that decreased perfusion occurs later in disease progression. We used arterial spin labelling (ASL) MRI to compare cerebral blood flow (CBF) between cognitively unimpaired elderly individuals who would remain cognitively stable and those who would later develop MCI to determine if hypoperfusion is detectable at a preclinical stage.Method647 cognitively normal elderly participants with ASL and structural T1‐weighted MRI were selected from the Vallecas Project cohort, a single‐centre longitudinal study currently in its 12th year of annual follow‐up. 586 participants remained cognitively stable (CS) while 61 participants developed MCI over the course of the study. Cortical CBF maps derived from ASL images at the visit before MCI diagnosis were analysed in a voxelwise comparison with CS individuals, with age, sex, and total intracranial volume as covariates.ResultCBF was significantly lower in the right insular cortex in future MCI converters than CS individuals (p&lt;0.05, family‐wise error (FWE) corrected). Hypoperfusion was also significant in the anterior corpus callosum in future converters.ConclusionCerebral hypoperfusion, as measured by ASL, can already be observed in individuals before the onset of clinical symptoms.

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.

The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood. To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort. We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism. Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD. Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.