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Visual Abstract, Alzheimer’s disease (AD) starts decades before clinical symptoms appear. Low-glucose utilization in regions of the cerebral cortex marks early AD. To identify these regions, we conducted a voxel-wise meta-analysis of previous studies conducted with positron emission tomography that compared AD patients with healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, and middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes that show spatial correlation across the cerebral cortex between their expression and this hypometabolism. Of the six brains in the Atlas, one demonstrated a strong spatial correlation between gene expression and hypometabolism. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when comparing this donor’s brain with the other five donors. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which encode primarily cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes increases progressively across AD-associated states of microglial activation. In addition, genes involved in cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, and vacuole sorting are associated with the hypometabolism map. These genes suggest disruption of the protein life cycle and neuroimmune activation. Taken together, our molecular characterization reveals a link to AD-associated hypometabolism that may be relevant to preclinical stages of AD.

Alzheimer’s disease (AD) starts decades before clinical symptoms appear. Low glucose utilization in regions of the cerebral cortex marks early AD and is clinically useful. To identify these regions, we conducted a voxel-wise meta-analysis of positron emission tomography studies that compared AD patients with healthy controls. This meta-analysis included 27 studies that assayed glucose utilization in 915 AD patients and 715 healthy controls. The resulting map marks hypometabolism in the posterior cingulate, middle frontal, angular gyrus, middle and inferior temporal regions. Using the Allen Human Brain Atlas, we identified genes with expression patterns associated with this hypometabolism pattern in the cerebral cortex. Of the six brains in the Atlas, one demonstrated a strong spatial association with the hypometabolism pattern. Previous neuropathological assessment of this brain from a 39-year-old male noted a neurofibrillary tangle in the entorhinal cortex. Using the transcriptomic data, we estimate lower proportions of neurons and more microglia in the hypometabolic regions when compared with the other five brains. Within this single brain, signal recognition particle (SRP)-dependent cotranslational protein targeting genes, which primarily encode cytosolic ribosome proteins, are highly expressed in the hypometabolic regions. Analyses of human and mouse data show that expression of these genes progressively increases across AD-associated states of microglial activation. In addition, genes involved in cell killing, chronic inflammation, ubiquitination, tRNA aminoacylation, and vacuole sorting are associated with the hypometabolism map. These genes suggest disruption of the protein life cycle and neuroimmune activation. Taken together, our molecular characterization of cortical hypometabolism reveals a molecular link to AD associated hypometabolism that may be relevant to preclinical stages.

Oophorectomy prior to menopause is associated with late-life dementia. Memory decline may start within 6 months after oophorectomy in middle-aged women, suggested by lower verbal and working memory performance. Unknown is whether such changes persist beyond 6 months, and whether they are reversed by estradiol. Short-term benefits of estradiol on verbal memory following oophorectomy were observed in one study, but longer term effects remain unknown. In the present study, middle-aged BRCA1/2 mutation carriers with early oophorectomy at least 1 year prior to study onset were tested on verbal and working memory with results stratified by (1) current estradiol use (n = 22) or (2) no history of estradiol use (n = 24), and compared to age-matched premenopausal controls (n = 25). Both memory abilities were adversely affected by oophorectomy, but only working memory was maintained by estradiol. Estrogen metabolite levels correlated with working memory, suggesting a role for estradiol in preserving this ability. Memory decline appears to persist after early oophorectomy, particularly for women who do not take estradiol.

Background Obesity, a major risk factor for cardiometabolic disease, is associated with lower cognitive performance from childhood to senescence, especially on tasks of executive function. In the cardiovascular domain, fat stored viscerally rather than elsewhere in the body carries particularly high risk. It is unknown whether this is also true in case of obesity-cognition relationships. The aim of this study is to assess the cross-sectional relationship between visceral fat (VF) and cognitive performance in a community sample of healthy adolescents. Methods In a community-based sample of 983 adolescents (12–18 years old, 480 males), VF was quantified using magnetic resonance imaging, total body fat was measured using a multifrequency bioimpedance and cognitive performance was assessed using a battery of cognitive tests measuring executive function and memory. Results We found that larger volumes of VF were associated with lower performance on six measures of executive function (p=0.0001 to 0.02). We also found that the association of VF with executive function was moderated by sex for a subset of measures, such that relationship was present mainly in females and not in males (sex-by-VF interaction: p=0.001 to 0.04). These relationships were independent of the quantity of total body fat and a number of potential confounders, including age, puberty stage and household income. Conclusions Our results suggest that the adverse association between obesity and executive function may be attributed to fat stored viscerally and not to fat stored elsewhere in the body. They also suggest that females compared with males may be more sensitive to the potentially detrimental effects of VF on cognition.

Fluctuations in ovarian hormones across the menstrual cycle have long been considered a determinant of mood in women. The majority of studies, however, use menstrual cycle phase as proxy for hormone levels. We measured ovarian hormone levels directly in order to examine the relationship between daily hormone levels and mood in non-help-seeking women. Participants (n = 19) provided daily information about their positive and negative moods, and collected their first morning-voided urine for 42 days, which was analyzed for estrogen and progesterone metabolites (E1G and PdG). The independent contributions of daily E1G, PdG, stress, physical health, and weekly social support, were calculated for 12 daily mood items, and composite measures of positive and negative mood items, using linear mixed models. E1G or PdG contributed to few mood items: E1G measured 2 days prior contributed negatively to the model for Motivation, while E1G measured 3 days prior contributed negatively to Getting Along with Others, and E1G measured 4 days prior contributed negatively to Anxiety. PdG, measured the same day and 1 day prior, contributed positively to the models of Irritability, and PdG measured 5 days prior contributed positively to Difficulty Coping. By contrast, the variables stress and physical health contributed significantly to all the mood items, as well as both composite positive and negative mood measures. These findings demonstrate that, compared to stress and physical health, ovarian hormones make only a small contribution to daily mood. Thus, fluctuations in ovarian hormones do not contribute significantly to daily mood in healthy women.

Importance Early adversity is an important risk factor that relates to internalizing symptoms and altered brain structure. Objective To assess the direct effects of early adversity and child internalizing symptoms (ie, depression, anxiety) on cortical gray matter (GM) volume, as well as the extent to which early adversity associates with variation in cortical GM volume indirectly via increased levels of internalizing symptoms. Design, Setting, and Participants A prospective investigation of associations between adversity within the first 6 years of life, internalizing symptoms during childhood and early adolescence, and altered brain structure in late adolescence (age, 18-21 years) was conducted in a community-based birth cohort in England (Avon Longitudinal Study of Parents and Children). Participants from the cohort included 494 mother-son pairs monitored since the mothers were pregnant (estimated date of delivery between April 1, 1991, and December 31, 1992). Data collection for the present study was conducted between April 1, 1991, and November 30, 2010; the neuroimaging data were collected between September 1, 2010, and November 30, 2012, and data analyses for the present study occurred between January 25, 2013, and February 15, 2015. Risk factors were adversity within the first 6 years of the child's life (including prenatal exposure) and the child's internalizing symptoms between age 7 and 13 years. Exposures Early childhood adversity. Main Outcomes and Measures The main outcomewas GMvolume of cortical regions previously associated with major depression measured through T1-weighted magnetic resonance images collected in late adolescence. Results Among 494 young men included in this analysis, early adversity was directly associated with lower GMvolumes in the anterior cingulate cortex (β = ..18; P = .01) and higher GM volume in the precuneus (β = .18; P = .009). Childhood internalizing symptoms were associated with lower GMvolume in the right superior frontal gyrus (β = ..20; P = .002). Early adversity was also associated with higher levels of internalizing symptoms (β = .37; P

Distinct differences in the human voice emerge during adolescence, with males producing deeper and more resonant voices than females by the end of sexual maturation. Using magnetic resonance images of heads and voice recordings obtained in 532 typically developing adolescents, we investigate what might be the drivers of this change in voice, and the subjective judgment of the voice "maleness" and "femaleness". We show clear sex differences in the morphology of voice-related structures during adolescence, with males displaying strong associations between age (and puberty) and both vocal-fold and vocal-tract length; this was not the case in female adolescents. At the same time, males (compared with females) display stronger associations between age (and puberty) with both fundamental frequency and formant position. In males, vocal morphology was a mediator in the relationship between bioavailable testosterone and acoustic indices. Subjective judgment of the voice sex could be predicted by the morphological and acoustic parameters in males only: the length of vocal folds and its acoustic counterpart, fundamental frequency, is a larger predictor of subjective "maleness" of a voice than vocal-tract length and formant position.

Prenatal exposure to maternal cigarette smoking is a well-established risk factor for obesity, but the underlying mechanisms are not known. Preference for fatty foods, regulated in part by the brain reward system, may contribute to the development of obesity.To examine whether prenatal exposure to maternal cigarette smoking is associated with enhanced fat intake and risk for obesity, and whether these associations may be related to subtle structural variations in brain regions involved in reward processing.Cross-sectional study of a population-based cohort.The Saguenay Youth Study, Quebec, Canada.A total of 378 adolescents (aged 13 to 19 years; Tanner stage 4 and 5 of sexual maturation), half of whom were exposed prenatally to maternal cigarette smoking (mean [SD], 11.1 [6.8] cigarettes/d).Fat intake was assessed with a 24-hour food recall (percentage of energy intake consumed as fat). Body adiposity was measured with anthropometry and multifrequency bioimpedance. Volumes of key brain structures involved in reward processing, namely the amygdala, nucleus accumbens, and orbitofrontal cortex, were measured with magnetic resonance imaging.Exposed vs nonexposed subjects exhibited a higher total body fat (by approximately 1.7 kg; P = .009) and fat intake (by 2.7%; P = .001). They also exhibited a lower volume of the amygdala (by 95 mm3; P.001) but not of the other 2 brain structures. Consistent with its possible role in limiting fat intake, amygdala volume correlated inversely with fat intake (r = -0.15; P = .006).Prenatal exposure to maternal cigarette smoking may promote obesity by enhancing dietary preference for fat, and this effect may be mediated in part through subtle structural variations in the amygdala.