Age Differentiation within Gray Matter, White Matter, and between Memory and White Matter in an Adult Life Span Cohort.

It is well established that brain structures and cognitive functions change across the life span. A long-standing hypothesis called "age differentiation" additionally posits that the relations between cognitive functions also change with age. To date, however, evidence for age-related differentiation is mixed, and no study has examined differentiation of the relationship between brain and cognition. Here we use multigroup structural equation models (SEMs) and SEM trees to study differences within and between brain and cognition across the adult life span (18-88 years) in a large (N > 646, closely matched across sexes), population-derived sample of healthy human adults from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.org). After factor analyses of gray matter volume (from T1- and T2-weighted MRI) and white matter organization (fractional anisotropy from diffusion-weighted MRI), we found evidence for the differentiation of gray and white matter, such that the covariance between brain factors decreased with age. However, we found no evidence for age differentiation among fluid intelligence, language, and memory, suggesting a relatively stable covariance pattern among cognitive factors. Finally, we observed a specific pattern of age differentiation between brain and cognitive factors, such that a white matter factor, which loaded most strongly on the hippocampal cingulum, became less correlated with memory performance in later life. These patterns are compatible with the reorganization of cognitive functions in the face of neural decline, and/or with the emergence of specific subpopulations in old age.SIGNIFICANCE STATEMENT The theory of age differentiation posits age-related changes in the relationships among cognitive domains, either weakening (differentiation) or strengthening (dedifferentiation), but evidence for this hypothesis is mixed. Using age-varying covariance models in a large cross-sectional adult life span sample, we found age-related reductions in the covariance among both brain measures (neural differentiation), but no covariance change among cognitive factors of fluid intelligence, language, and memory. We also observed evidence of uncoupling (differentiation) between a white matter factor and cognitive factors in older age, most strongly for memory. Together, our findings support age-related differentiation as a complex, multifaceted pattern that differs for brain and cognition, and discuss several mechanisms that might explain the changing relationship between brain and cognition

A watershed model of individual differences in fluid intelligence

Fluid intelligence is a crucial cognitive ability that predicts key life outcomes across the lifespan. Strong empirical links exist between fluid intelligence and processing speed on the one hand, and white matter integrity and processing speed on the other. We propose a watershed model that integrates these three explanatory levels in a principled manner in a single statistical model, with processing speed and white matter figuring as intermediate endophenotypes. We fit this model in a large (N=555) adult lifespan cohort from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) using multiple measures of processing speed, white matter health and fluid intelligence. The model fit the data well, outperforming competing models and providing evidence for a many-to-one mapping between white matter integrity, processing speed and fluid intelligence. The model can be naturally extended to integrate other cognitive domains, endophenotypes and genotypes

Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The TYACSS (Teenage and Young Adult Cancer Survivor Study)

Background: Survivors of teenage and young adult (TYA) cancer are at risk of cerebrovascular events, but the magnitude of and extent to which this risk varies by cancer type, decade of diagnosis, age at diagnosis and attained age remains uncertain. This is the largest ever cohort study to evaluate the risks of hospitalisation for a cerebrovascular event among long-term survivors of TYA cancer. Methods:The population-based Teenage and Young Adult Cancer Survivor Study (N=178,962) was linked to Hospital Episode Statistics data for England to investigate the risks of hospitalisation for a cerebrovascular event among 5-year survivors of cancer diagnosed when aged 15-39 years. Observed numbers of first hospitalisations for cerebrovascular events were compared to that expected from the general population using standardised hospitalisation ratios (SHR) and absolute excess risks (AER) per 10,000 person-years. Cumulative incidence was calculated with death considered a competing risk. Results: Overall, 2,782 cancer survivors were hospitalised for a cerebrovascular event—40% higher than expected (SHR=1.4, 95% confidence interval [CI]=1.3-1.4). Survivors of central nervous system (CNS) tumours (SHR=4.6, CI=4.3-5.0), head & neck tumours (SHR=2.6, CI=2.2-3.1) and leukaemia (SHR=2.5, CI=1.9-3.1) were at greatest risk. Males had a significantly higher AER than females (AER=7 versus 3), especially among head & neck tumour survivors (AER=30 versus 11). By age 60, 9%, 6% and 5% of CNS tumour, head & neck tumour, and leukaemia survivors, respectively, had been hospitalised for a cerebrovascular event. Beyond age 60, every year 0.4% of CNS tumour survivors were hospitalised for a cerebral infarction (versus 0.1% expected. Whereas at any age, every year 0.2% of head & neck tumour survivors were hospitalised for a cerebral infarction 7 (versus 0.06% expected). Conclusions: Survivors of a CNS tumour, head & neck tumour, and leukaemia are particularly at risk of hospitalisation for a cerebrovascular event. The excess risk of cerebral infarction among CNS tumour survivors increases with attained age. For head & neck tumour survivors this excess risk remains high across all ages. These groups of survivors, and in particular males, should be considered for surveillance of cerebrovascular risk factors and potential pharmacological interventions for cerebral infarction prevention

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study

BACKGROUND: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used. METHODS: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated. RESULTS: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4-5.2) decreasing to 1.2 (95% confidence interval, 1.1-1.3) for individuals aged 35 to 39 years (2P for trend <0.0001). Similar patterns were observed for both standardized mortality ratios and absolute excess risks for ischemic heart disease, valvular heart disease, and cardiomyopathy. Survivors of Hodgkin lymphoma, acute myeloid leukaemia, genitourinary cancers other than bladder cancer, non-Hodgkin lymphoma, lung cancer, leukaemia other than acute myeloid, central nervous system tumour, cervical cancer, and breast cancer experienced 3.8, 2.7, 2.0, 1.7, 1.7, 1.6, 1.4, 1.3 and 1.2 times the number of cardiac deaths expected from the general population, respectively. Among survivors of Hodgkin lymphoma aged over 60 years, almost 30% of the total excess number of deaths observed were due to heart disease. CONCLUSIONS: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines

The Golden Beauty: Brain Response to Classical and Renaissance Sculptures

Is there an objective, biological basis for the experience of beauty in art? Or is aesthetic experience entirely subjective? Using fMRI technique, we addressed this question by presenting viewers, naïve to art criticism, with images of masterpieces of Classical and Renaissance sculpture. Employing proportion as the independent variable, we produced two sets of stimuli: one composed of images of original sculptures; the other of a modified version of the same images. The stimuli were presented in three conditions: observation, aesthetic judgment, and proportion judgment. In the observation condition, the viewers were required to observe the images with the same mind-set as if they were in a museum. In the other two conditions they were required to give an aesthetic or proportion judgment on the same images. Two types of analyses were carried out: one which contrasted brain response to the canonical and the modified sculptures, and one which contrasted beautiful vs. ugly sculptures as judged by each volunteer. The most striking result was that the observation of original sculptures, relative to the modified ones, produced activation of the right insula as well as of some lateral and medial cortical areas (lateral occipital gyrus, precuneus and prefrontal areas). The activation of the insula was particularly strong during the observation condition. Most interestingly, when volunteers were required to give an overt aesthetic judgment, the images judged as beautiful selectively activated the right amygdala, relative to those judged as ugly. We conclude that, in observers naïve to art criticism, the sense of beauty is mediated by two non-mutually exclusive processes: one based on a joint activation of sets of cortical neurons, triggered by parameters intrinsic to the stimuli, and the insula (objective beauty); the other based on the activation of the amygdala, driven by one's own emotional experiences (subjective beauty)

Ingestion of micronutrient fortified breakfast cereal has no influence on immune function in healthy children: A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>This study investigated the influence of 2-months ingestion of an "immune" nutrient fortified breakfast cereal on immune function and upper respiratory tract infection (URTI) in healthy children during the winter season.</p> <p>Methods</p> <p>Subjects included 73 children (N = 42 males, N = 31 females) ranging in age from 7 to 13 years (mean ± SD age, 9.9 ± 1.7 years), and 65 completed all phases of the study. Subjects were randomized to one of three groups--low, moderate, or high fortification--with breakfast cereals administered in double blinded fashion. The "medium" fortified cereal contained B-complex vitamins, vitamins A and C, iron, zinc, and calcium, with the addition of vitamin E and higher amounts of vitamins A and C, and zinc in the "high" group. Immune measures included delayed-typed hypersensitivity, global IgG antibody response over four weeks to pneumococcal vaccination, salivary IgA concentration, natural killer cell activity, and granulocyte phagocytosis and oxidative burst activity. Subjects under parental supervision filled in a daily log using URTI symptoms codes.</p> <p>Results</p> <p>Subjects ingested 3337 ± 851 g cereal during the 2-month study, which represented 14% of total diet energy intake and 20-85% of selected vitamins and minerals. Despite significant increases in nutrient intake, URTI rates and pre- to- post-study changes in all immune function measures did not differ between groups.</p> <p>Conclusions</p> <p>Data from this study indicate that ingestion of breakfast cereal fortified with a micronutrient blend for two winter months by healthy, growing children does not significantly influence biomarkers for immune function or URTI rates.</p

Chk2 and p53 Are Haploinsufficient with Dependent and Independent Functions to Eliminate Cells after Telomere Loss

The mechanisms that cells use to monitor telomere integrity, and the array of responses that may be induced, are not fully defined. To date there have been no studies in animals describing the ability of cells to survive and contribute to adult organs following telomere loss. We developed assays to monitor the ability of somatic cells to proliferate and differentiate after telomere loss. Here we show that p53 and Chk2 limit the growth and differentiation of cells that lose a telomere. Furthermore, our results show that two copies of the genes encoding p53 and Chk2 are required for the cell to mount a rapid wildtype response to a missing telomere. Finally, our results show that, while Chk2 functions by activating the p53-dependent apoptotic cascade, Chk2 also functions independently of p53 to limit survival. In spite of these mechanisms to eliminate cells that have lost a telomere, we find that such cells can make a substantial contribution to differentiated adult tissues

Different regression equations relate age to the incidence of Lauren types 1 and 2 stomach cancer in the SEER database: these equations are unaffected by sex or race

BACKGROUND: Although impacts upon gastric cancer incidence of race, age, sex, and Lauren type have been individually explored, neither their importance when evaluated together nor the presence or absence of interactions among them have not been fully described. METHODS: This study, derived from SEER (Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute) data, analyzed the incidences of gastric cancer between the years 1992–2001. There were 7882 patients who had developed gastric cancer. The total denominator population was 145,155, 669 persons (68,395,787 for 1992–1996, 78,759,882 for 1997–2001). Patients with multiple tumors were evaluated as per the default of the SEER*Stat program. 160 age-, five year period (1992–1996 vs 1997–2001)-, sex-, race (Asian vs non-Asian)-, Lauren type- specific incidences were derived to form the stratified sample evaluated by linear regression. (160 groups = 2 five year periods × 2 race groups × 2 sexes × 2 Lauren types × 10 age groups.) Linear regression was used to analyze the importance of each of these explanatory variables and to see if there were interactions among the explanatory variables. RESULTS: Race, sex, age group, and Lauren type were found to be important explanatory variables, as were interactions between Lauren type and each of the other important explanatory variables. In the final model, the contribution of each explanatory variable was highly statistically significant (t > 5, d.f. 151, P < 0.00001). The regression equation for Lauren type 1 had different coefficients for the explanatory variables Race, Sex, and Age, than did the regression equation for Lauren type 2. CONCLUSION: The change of the incidence of stomach cancer with respect to age for Lauren type 1 stomach cancer differs from that for Lauren type 2 stomach cancers. The relationships between age and Lauren type do not differ across gender or race. The results support the notion that Lauren type 1 and Lauren type 2 gastric cancers have different etiologies and different patterns of progression from pre-cancer to cancer. The results should be validated by evaluation of other databases