Long-lasting memory of jasmonic acid-dependent immunity requires DNA demethylation and ARGONAUTE1.

Stress can have long-lasting impacts on plants. Here we report the long-term effects of the stress hormone jasmonic acid (JA) on the defence phenotype, transcriptome and DNA methylome of Arabidopsis. Three weeks after transient JA signalling, 5-week-old plants retained induced resistance (IR) against herbivory but showed increased susceptibility to pathogens. Transcriptome analysis revealed long-term priming and/or upregulation of JA-dependent defence genes but repression of ethylene- and salicylic acid-dependent genes. Long-term JA-IR was associated with shifts in glucosinolate composition and required MYC2/3/4 transcription factors, RNA-directed DNA methylation, the DNA demethylase ROS1 and the small RNA (sRNA)-binding protein AGO1. Although methylome analysis did not reveal consistent changes in DNA methylation near MYC2/3/4-controlled genes, JA-treated plants were specifically enriched with hypomethylated ATREP2 transposable elements (TEs). Epigenomic characterization of mutants and transgenic lines revealed that ATREP2 TEs are regulated by RdDM and ROS1 and produce 21 nt sRNAs that bind to nuclear AGO1. Since ATREP2 TEs are enriched with sequences from IR-related defence genes, our results suggest that AGO1-associated sRNAs from hypomethylated ATREP2 TEs trans-regulate long-lasting memory of JA-dependent immunity.

Straight to test reduces time to investigation and treatment.

Straight to test (STT) is a recognised pathway for improving the waiting time for red flag referrals. Electronic patient care records (ECR) provide clinicians with a greater volume of clinical information allowing virtual triage and STT. We aimed to assess if using ECR and STT can reduce delays in diagnosis and treatment. A review of 300 colorectal referrals between 2018-2019 was performed. Patients awaiting an appointment were reviewed electronically, by a single colorectal surgeon and re-triaged STT if appropriate. The delay in time from referral to initial review was removed, creating a second group for statistical comparison to demonstrate time saved if the strategy was adopted at the point of original triage. 91.3% (n= 274) were red flag referrals. 94% (n=282) were sent STT. Patients processed via traditional referral and clinic had a median time to scope of 36 days compared with 22.5 days, p < 0.001 if triaged STT via virtual clinic. Median time to management was 59 days for traditional and 35 days for STT, p < 0.001.

The influence of speed and size on avian terrestrial locomotor biomechanics: Predicting locomotion in extinct theropod dinosaurs.

How extinct, non-avian theropod dinosaurs moved is a subject of considerable interest and controversy. A better understanding of non-avian theropod locomotion can be achieved by better understanding terrestrial locomotor biomechanics in their modern descendants, birds. Despite much research on the subject, avian terrestrial locomotion remains little explored in regards to how kinematic and kinetic factors vary together with speed and body size. Here, terrestrial locomotion was investigated in twelve species of ground-dwelling bird, spanning a 1,780-fold range in body mass, across almost their entire speed range. Particular attention was devoted to the ground reaction force (GRF), the force that the feet exert upon the ground. Comparable data for the only other extant obligate, striding biped, humans, were also collected and studied. In birds, all kinematic and kinetic parameters examined changed continuously with increasing speed, while in humans all but one of those same parameters changed abruptly at the walk-run transition. This result supports previous studies that show birds to have a highly continuous locomotor repertoire compared to humans, where discrete 'walking' and 'running' gaits are not easily distinguished based on kinematic patterns alone. The influences of speed and body size on kinematic and kinetic factors in birds are developed into a set of predictive relationships that may be applied to extinct, non-avian theropods. The resulting predictive model is able to explain 79-93% of the observed variation in kinematics and 69-83% of the observed variation in GRFs, and also performs well in extrapolation tests. However, this study also found that the location of the whole-body centre of mass may exert an important influence on the nature of the GRF, and hence some caution is warranted, in lieu of further investigation.

Using step width to compare locomotor biomechanics between extinct, non-avian theropod dinosaurs and modern obligate bipeds.

How extinct, non-avian theropod dinosaurs locomoted is a subject of considerable interest, as is the manner in which it evolved on the line leading to birds. Fossil footprints provide the most direct evidence for answering these questions. In this study, step width-the mediolateral (transverse) distance between successive footfalls-was investigated with respect to speed (stride length) in non-avian theropod trackways of Late Triassic age. Comparable kinematic data were also collected for humans and 11 species of ground-dwelling birds. Permutation tests of the slope on a plot of step width against stride length showed that step width decreased continuously with increasing speed in the extinct theropods (p < 0.001), as well as the five tallest bird species studied (p < 0.01). Humans, by contrast, showed an abrupt decrease in step width at the walk-run transition. In the modern bipeds, these patterns reflect the use of either a discontinuous locomotor repertoire, characterized by distinct gaits (humans), or a continuous locomotor repertoire, where walking smoothly transitions into running (birds). The non-avian theropods are consequently inferred to have had a continuous locomotor repertoire, possibly including grounded running. Thus, features that characterize avian terrestrial locomotion had begun to evolve early in theropod history.

Differential transcriptome expression in human nucleus accumbens as a function of loneliness.

Loneliness is associated with impaired mental and physical health. Studies of lonely individuals reported differential expression of inflammatory genes in peripheral leukocytes and diminished activation in brain reward regions such as nucleus accumbens, but could not address gene expression in the human brain. Here, we examined genome-wide RNA expression in post-mortem nucleus accumbens from donors (N=26) with known loneliness measures. Loneliness was associated with 1710 differentially expressed transcripts and genes from 1599 genes (DEGs; false discovery rate P<0.05, fold change ⩾|2|, controlling for confounds) previously associated with behavioral processes, neurological disease, psychological disorders, cancer, organismal injury and skeletal and muscular disorders, as well as networks of upstream RNA regulators. Furthermore, a number of DEGs were associated with Alzheimer's disease (AD) genes (that was correlated with loneliness in this sample, although gene expression analyses controlled for AD diagnosis). These results identify novel targets for future mechanistic studies of gene networks in nucleus accumbens and gene regulatory mechanisms across a variety of diseases exacerbated by loneliness.

Reframing climate change assessments around risk: recommendations for the US National Climate Assessment.

Climate change is a risk management challenge for society, with uncertain but potentially severe outcomes affecting natural and human systems, across generations. Managing climate-related risks will be more difficult without a base of knowledge and practice aimed at identifying and evaluating specific risks, and their likelihood and consequences, as well as potential actions to promote resilience in the face of these risks. We suggest three improvements to the process of conducting climate change assessments to better characterize risk and inform risk management actions.

Parkinsonism in Older Adults and Its Association With Adverse Health Outcomes and Neuropathology.

BACKGROUND: Mild parkinsonian signs have been documented in community-dwelling older adults without Parkinson's disease. We estimated the proportion of older adults with parkinsonism and examined its association with adverse health outcomes and indices of brain pathology. METHODS: Four parkinsonian signs were assessed with the motor portion of the Unified Parkinson's Disease Rating Scale in 2,962 older adults who agreed to annual evaluation and brain autopsy. We used Cox proportional hazards models to examine the association of parkinsonism (two or more signs) and possible parkinsonism (one sign) with adverse health outcomes and regression models in 1,160 decedents to examine the association of parkinsonism and neuropathology. RESULTS: At study entry about 25% (N = 776, 26.2%) had parkinsonism and 30% had possible parkinsonism (N = 885, 29.9%). Parkinsonism was strongly related to age. The frequency was 11.8% for people younger than 75 years, 29.1% for those aged 75-84 years, and 43.7% for those aged 85 years or older. Parkinsonism was associated with an increased hazard of death, of mild cognitive impairment, of Alzheimer's disease and disability. Individuals with possible parkinsonism also had an increased risk for adverse health outcomes compared to individuals without parkinsonism. Postmortem indices of macroscopic and microscopic infarcts, arteriolosclerosis, and atherosclerosis were associated with parkinsonism proximate to death. CONCLUSIONS: Parkinsonism is common in older adults and is associated with an increased risk of adverse health outcomes and postmortem indices of brain pathology. Its association with age suggests that it will increase in our aging population.

Warmer temperatures reduce the costs of inducible defences in the marine toad, Rhinella marinus.

Many of the far-reaching impacts of climate change on ecosystem function will be due to alterations in species interactions. However, our understanding of the effects of temperature on the dynamics of interactions between species is largely inadequate. Inducible defences persist in prey populations because defensive traits increase survival in the presence of predators but are costly when they are absent. Large-scale changes in the thermal climate are likely to alter the costs or benefits of these defences for ectotherms, whose physiological processes are driven by environmental temperature. A shift in costs of defensive traits would affect not only predator-prey interactions, but also the strength of selection for inducible defences in natural populations. We investigate the effect of temperature on the costs of behavioural defences in larvae of the marine toad, Rhinella marinus. Larvae were reared in the presence or absence of predator cues at both 25 and 30 °C. When exposed to predation cues, larvae reduced activity and spent less time feeding. Exposure to predation cues also reduced metabolic rate, presumably as a by-product of reducing activity levels. Larvae exposed to predation cues also grew more slowly, were smaller at metamorphosis and were poorer jumpers after metamorphosis--three traits associated with fitness in post-metamorphic anurans. We found that the costs of behavioural defences, in terms of larval growth, post-metamorphic size and jumping performance, were exacerbated at cooler temperatures. The thermal sensitivity of costs associated with defensive traits may explain geographic variation in plasticity of defensive traits in other species and suggests that changes in environmental temperature associated with climate change may affect predator-prey interactions in subtle ways not previously considered.

Balancing Biomechanical Constraints: Optimal Escape Speeds When There Is a Trade-off between Speed and Maneuverability.

The ability for prey to escape a pursuing predator is dependent both on the prey's speed away from the threat and on their ability to rapidly change directions, or maneuverability. Given that the biomechanical trade-off between speed and maneuverability limits the simultaneous maximization of both performance traits, animals should not select their fastest possible speeds when running away from a pursuing predator but rather a speed that maximizes the probability of successful escape. We explored how variation in the relationship between speed and maneuverability-or the shape of the trade-off-affects the optimal choice of speed for escaping predators. We used tablet-based games that simulated interactions between predators and prey (human subjects acting as predators attempting to capture "prey" moving across a screen). By defining a specific relationship between speed and maneuverability, we could test the survival of each of the possible behavioral choices available to this phenotype, i.e., the best combination of speed and maneuverability for prey fitness, based on their ability to escape. We found that the shape of the trade-off function affected the prey's optimal speed for success in escaping, the prey's maximum performance in escaping, and the breadth of speeds over which the prey's performance was high. The optimal speed for escape varied only when the trade-off between speed and maneuverability was non-linear. Phenotypes possessing trade-off functions for which maneuverability was only compromised at high speeds exhibited lower optimal speeds. Phenotypes that exhibited greater increases in maneuverability for any decrease in speed were more likely to have broader ranges of performance, meaning that individuals could attain their maximum performance across a broader range of speeds. We also found that there was a differential response of the subject's learning to these different components of locomotion. With increased experience through repeated trials, subjects were able to successfully catch faster and faster dots. However, no improvement was observed in the subject's ability to capture more maneuverable prey. Our work highlights the costs of high-speed movement on other traits, including maneuverability, which make the use of an animal's fastest speeds unlikely, even when attempting to escape predators. By investigating the shape of the trade-off functions between speed and maneuverability and the way the environment and morphology mediates this trade-off, we can begin to understand why animals choose to move at the speeds they do when they are running away from predators or attempting to capture prey.

Sex-specific trade-offs and compensatory mechanisms: bite force and sprint speed pose conflicting demands on the design of geckos (Hemidactylus frenatus).

One of the more intuitive viability costs that can result from the possession of exaggerated sexually selected traits is increased predation pressure as a result of reduced locomotor capacity. Despite mixed empirical support for such locomotor costs, recent studies suggest that such costs may be masked by compensatory traits that effectively offset any detrimental effects. In this study, we provide a comprehensive assessment of the locomotor costs associated with improved male-male competitive ability by simultaneously testing for locomotor trade-offs and potential compensatory mechanisms in territorial male and non-territorial female geckos. Fighting capacity and escape performance of male Asian house geckos (Hemidactylus frenatus) are likely to pose conflicting demands on the optimum phenotype for each task. Highly territorial and aggressive males may require greater investment in head size/strength but such an enhancement may affect overall escape performance. Among male geckos, we found that greater biting capacity because of larger head size was associated with reduced sprint performance; this trade-off was further exacerbated when sprinting on an incline. Females, however, showed no evidence of this trade-off on either flat or inclined surfaces. The sex specificity of this trade-off suggests that the sexes differ in their optimal strategies for dealing with the conflicting requirements of bite force and sprint speed. Unlike males, female H. frenatus had a positive association between hind-limb length and head size, suggesting that they have utilised a compensatory mechanism to alleviate the possible locomotor costs of larger head sizes. It appears that there is greater selection on traits that improve fighting ability (bite force) for males, but it is viability traits (sprint speed) that appear to be of greater importance for females. Our results emphasise that only by examining both functional trade-offs and potential compensatory mechanisms is it possible to discover the varied mechanisms affecting the morphological design of a species.

Increased aggression during pregnancy comes at a higher metabolic cost.

Aggressive behaviour is linked to fitness, but it is metabolically costly. Changes in metabolic demand during the reproductive cycle could constrain activity and thereby modulate behavioural phenotypes. We predicted that increased metabolic demands in late pregnancy would lead to reduced aggression and a lower metabolic cost of behaviour in the mosquitofish Gambusia holbrooki. Contrary to our prediction, females became more aggressive in late pregnancy, but metabolic scope (i.e. the metabolic energy available for activity and behaviour) decreased. Consequently, late-stage pregnant females spent significantly more of their available metabolic scope on aggressive behaviour. Hence, as pregnancy progressed, females showed increasingly risky behaviour by depleting metabolic resources available for activities other than fighting. We argue that the metabolic cost of behaviour, and possibly personality, is best expressed with reference to metabolic scope, rather than resting metabolic rates or concentrations of metabolites. This dependence on metabolic scope could render reproductive success sensitive to environmental changes.

Plasma biomarkers of depressive symptoms in older adults.

The pathophysiology of negative affect states in older adults is complex, and a host of central nervous system and peripheral systemic mechanisms may play primary or contributing roles. We conducted an unbiased analysis of 146 plasma analytes in a multiplex biochemical biomarker study in relation to number of depressive symptoms endorsed by 566 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) at their baseline and 1-year assessments. Analytes that were most highly associated with depressive symptoms included hepatocyte growth factor, insulin polypeptides, pregnancy-associated plasma protein-A and vascular endothelial growth factor. Separate regression models assessed contributions of past history of psychiatric illness, antidepressant or other psychotropic medicine, apolipoprotein E genotype, body mass index, serum glucose and cerebrospinal fluid (CSF) τ and amyloid levels, and none of these values significantly attenuated the main effects of the candidate analyte levels for depressive symptoms score. Ensemble machine learning with Random Forests found good accuracy (~80%) in classifying groups with and without depressive symptoms. These data begin to identify biochemical biomarkers of depressive symptoms in older adults that may be useful in investigations of pathophysiological mechanisms of depression in aging and neurodegenerative dementias and as targets of novel treatment approaches.

Perceived discrimination and cognition in older African Americans.

Existing evidence suggests that psychosocial stress is associated with cognitive impairment in older adults. Perceived discrimination is a persistent stressor in African Americans that has been associated with several adverse mental and physical health outcomes. To our knowledge, the association of discrimination with cognition in older African Americans has not been examined. In a cohort of 407 older African Americans without dementia (mean age = 72.9; SD = 6.4), we found that a higher level of perceived discrimination was related to poorer cognitive test performance, particularly episodic memory (estimate = -0.03; SE = .013; p < .05) and perceptual speed tests (estimate = -0.04; SE = .015; p < .05). The associations were unchanged after adjusting for demographics and vascular risk factors, but were attenuated after adjustment for depressive symptoms (Episodic memory estimate = -0.02; SE = 0.01; Perceptual speed estimate = -0.03; SE = 0.02; both p's = .06). The association between discrimination and several cognitive domains was modified by level of neuroticism. The results suggest that perceived discrimination may be associated with poorer cognitive function, but does not appear to be independent of depressive symptoms. (JINS, 2012, 18, 1-10).

A randomized clinical trial of anticaries therapies targeted according to risk assessment (caries management by risk assessment).

This randomized parallel group clinical trial assessed whether combined antibacterial and fluoride therapy benefits the balance between caries pathological and protective factors. Eligible, enrolled adults (n = 231), with 1-7 baseline cavitated teeth, attending a dental school clinic were randomly assigned to a control or intervention group. Salivary mutans streptococci (MS), lactobacilli (LB), fluoride (F) level, and resulting caries risk status (low or high) assays were determined at baseline and every 6 months. After baseline, all cavitated teeth were restored. An examiner masked to group conducted caries exams at baseline and 2 years after completing restorations. The intervention group used fluoride dentifrice (1,100 ppm F as NaF), 0.12% chlorhexidine gluconate rinse based upon bacterial challenge (MS and LB), and 0.05% NaF rinse based upon salivary F. For the primary outcome, mean caries increment, no statistically significant difference was observed (24% difference between control and intervention groups, p = 0.101). However, the supplemental adjusted zero-inflated Poisson caries increment (change in DMFS) model showed the intervention group had a statistically significantly 24% lower mean than the control group (p = 0.020). Overall, caries risk reduced significantly in intervention versus control over 2 years (baseline adjusted generalized linear mixed models odds ratio, aOR = 3.45; 95% CI: 1.67, 7.13). Change in MS bacterial challenge differed significantly between groups (aOR = 6.70; 95% CI: 2.96, 15.13) but not for LB or F. Targeted antibacterial and fluoride therapy based on salivary microbial and fluoride levels favorably altered the balance between pathological and protective caries risk factors.

Terminal dedifferentiation of cognitive abilities.

OBJECTIVE: To test the cognitive dedifferentiation hypothesis that cognitive abilities become increasingly correlated in late life. METHODS: Participants are 174 older persons without dementia at the beginning of a longitudinal clinical-pathologic cohort study. At annual intervals for 6 to 15 years prior to death, they completed a battery of cognitive performance tests from which previously established composite measures of episodic memory, semantic memory, working memory, and perceptual speed were derived. At death, there was a uniform neuropathologic assessment and levels of diffuse plaques, neuritic plaques, and neurofibrillary tangles were summarized in a composite measure. Change in the 4 cognitive outcomes was analyzed simultaneously in a mixed-effects model that allowed rate of decline to accelerate at a variable point before death. RESULTS: On average, cognitive decline before the terminal period was relatively gradual, and rates of change in different cognitive domains were moderately correlated, ranging from 0.25 (episodic memory-working memory) to 0.46 (episodic memory-semantic memory). By contrast, cognition declined rapidly during the terminal period, and rates of change in different cognitive functions were strongly correlated, ranging from 0.83 (working memory-perceptual speed) to 0.89 (episodic memory-semantic memory, semantic memory-working memory). Higher level of plaques and tangles on postmortem examination was associated with faster preterminal decline and earlier onset of terminal decline but not with rate of terminal decline or correlations between rates of change in different cognitive functions. CONCLUSION: In the last years of life, covariation among cognitive abilities sharply increases consistent with the cognitive dedifferentiation hypothesis.

Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory.

OBJECTIVE: Several genome-wide association studies (GWAS) have associated variants in late-onset Alzheimer disease (LOAD) susceptibility genes; however, these single nucleotide polymorphisms (SNPs) have very modest effects, suggesting that single SNP approaches may be inadequate to identify genetic risks. An alternative approach is the use of multilocus genotype patterns (MLGPs) that combine SNPs at different susceptibility genes. METHODS: Using data from 1,365 subjects in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study, we conducted a family-based association study in which we tabulated MLGPs for SNPs at CR1, BIN1, CLU, PICALM, and APOE. We used generalized estimating equations to model episodic memory as the dependent endophenotype of LOAD and the MLGPs as predictors while adjusting for sex, age, and education. RESULTS: Several genotype patterns influenced episodic memory performance. A pattern that included PICALM and CLU was the strongest genotypic profile for lower memory performance (ß = -0.32, SE = 0.19, p = 0.021). The effect was stronger after addition of APOE (p = 0.016). Two additional patterns involving PICALM, CR1, and APOE and another pattern involving PICALM, BIN1, and APOE were also associated with significantly poorer memory performance (ß = -0.44, SE = 0.09, p = 0.009 and ß = -0.29, SE = 0.07, p = 0.012) even after exclusion of patients with LOAD. We also identified genotype pattern involving variants in PICALM, CLU, and APOE as a predictor of better memory performance (ß = 0.26, SE = 0.10, p = 0.010). CONCLUSIONS: MLGPs provide an alternative analytical approach to predict an individual's genetic risk for episodic memory performance, a surrogate indicator of LOAD. Identifying genotypic patterns contributing to the decline of an individual's cognitive performance may be a critical step along the road to preclinical detection of Alzheimer disease.

Total daily physical activity and the risk of AD and cognitive decline in older adults.

OBJECTIVE: Studies examining the link between objective measures of total daily physical activity and incident Alzheimer disease (AD) are lacking. We tested the hypothesis that an objective measure of total daily physical activity predicts incident AD and cognitive decline. METHODS: Total daily exercise and nonexercise physical activity was measured continuously for up to 10 days with actigraphy (Actical®; Philips Healthcare, Bend, OR) from 716 older individuals without dementia participating in the Rush Memory and Aging Project, a prospective, observational cohort study. All participants underwent structured annual clinical examination including a battery of 19 cognitive tests. RESULTS: During an average follow-up of about 4 years, 71 subjects developed clinical AD. In a Cox proportional hazards model adjusting for age, sex, and education, total daily physical activity was associated with incident AD (hazard ratio = 0.477; 95% confidence interval 0.273-0.832). The association remained after adjusting for self-report physical, social, and cognitive activities, as well as current level of motor function, depressive symptoms, chronic health conditions, and APOE allele status. In a linear mixed-effect model, the level of total daily physical activity was associated with the rate of global cognitive decline (estimate 0.033, SE 0.012, p = 0.007). CONCLUSIONS: A higher level of total daily physical activity is associated with a reduced risk of AD.

Cognitive decline after hospitalization in a community population of older persons.

OBJECTIVE: To test the hypothesis that hospitalization in old age is associated with subsequent cognitive decline. METHODS: As part of a longitudinal population-based cohort study, 1,870 older residents of an urban community were interviewed at 3-year intervals for up to 12 years. The interview included a set of brief cognitive tests from which measures of global cognition, episodic memory, and executive function were derived. Information about hospitalization during the observation period was obtained from Medicare records. RESULTS: During a mean of 9.3 years, 1,335 of 1,870 persons (71.4%) were hospitalized at least once. In a mixed-effects model adjusted for age, sex, race, and education, the global cognitive score declined a mean of 0.031 unit per year before the first hospitalization compared with 0.075 unit per year thereafter, a more than 2.4-fold increase. The posthospital acceleration in cognitive decline was also evident on measures of episodic memory (3.3-fold increase) and executive function (1.7-fold increase). The rate of cognitive decline after hospitalization was not related to the level of cognitive function at study entry (r = 0.01, p = 0.88) but was moderately correlated with rate of cognitive decline before hospitalization (r = 0.55, p = 0.021). More severe illness, longer hospital stay, and older age were each associated with faster cognitive decline after hospitalization but did not eliminate the effect of hospitalization. CONCLUSION: In old age, cognitive functioning tends to decline substantially after hospitalization even after controlling for illness severity and prehospital cognitive decline.

Vitamin B12, cognition, and brain MRI measures: a cross-sectional examination.

OBJECTIVE: To investigate the interrelations of serum vitamin B12 markers with brain volumes, cerebral infarcts, and performance in different cognitive domains in a biracial population sample cross-sectionally. METHODS: In 121 community-dwelling participants of the Chicago Health and Aging Project, serum markers of vitamin B12 status were related to summary measures of neuropsychological tests of 5 cognitive domains and brain MRI measures obtained on average 4.6 years later among 121 older adults. RESULTS: Concentrations of all vitamin B12-related markers, but not serum vitamin B12 itself, were associated with global cognitive function and with total brain volume. Methylmalonate levels were associated with poorer episodic memory and perceptual speed, and cystathionine and 2-methylcitrate with poorer episodic and semantic memory. Homocysteine concentrations were associated with decreased total brain volume. The homocysteine-global cognition effect was modified and no longer statistically significant with adjustment for white matter volume or cerebral infarcts. The methylmalonate-global cognition effect was modified and no longer significant with adjustment for total brain volume. CONCLUSIONS: Methylmalonate, a specific marker of B12 deficiency, may affect cognition by reducing total brain volume whereas the effect of homocysteine (nonspecific to vitamin B12 deficiency) on cognitive performance may be mediated through increased white matter hyperintensity and cerebral infarcts. Vitamin B12 status may affect the brain through multiple mechanisms.

Hemoglobin level in older persons and incident Alzheimer disease: prospective cohort analysis.

OBJECTIVE: To test the hypothesis that level of hemoglobin is associated with incident Alzheimer disease (AD). METHODS: A total of 881 community-dwelling older persons participating in the Rush Memory and Aging Project without dementia and a measure of hemoglobin level underwent annual cognitive assessments and clinical evaluations for AD. RESULTS: During an average of 3.3 years of follow-up, 113 persons developed AD. In a Cox proportional hazards model adjusted for age, sex, and education, there was a nonlinear relationship between baseline level of hemoglobin such that higher and lower levels of hemoglobin were associated with AD risk (hazard ratio [HR] for the quadratic of hemoglobin 1.06, 95% confidence interval [CI] 1.01-1.11). Findings were unchanged after controlling for multiple covariates. When compared to participants with clinically normal hemoglobin (n = 717), participants with anemia (n = 154) had a 60% increased hazard for developing AD (95% CI 1.02-2.52), as did participants with clinically high hemoglobin (n = 10, HR 3.39, 95% CI 1.25-9.20). Linear mixed-effects models showed that lower and higher hemoglobin levels were associated with a greater rate of global cognitive decline (parameter estimate for quadratic of hemoglobin = -0.008, SE -0.002, p < 0.001). Compared to participants with clinically normal hemoglobin, participants with anemia had a -0.061 z score unit annual decline in global cognitive function (SE 0.012, p < 0.001), as did participants with clinically high hemoglobin (-0.090 unit/year, SE 0.038, p = 0.018). CONCLUSIONS: In older persons without dementia, both lower and higher hemoglobin levels are associated with an increased hazard for developing AD and more rapid cognitive decline.