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The uptake, at rest, of 99mTc-exametazime into different brain regions was compared using SPECT for 20 elderly subjects with major depressive disorder, 20 with Alzheimer-type dementia, and 30 age-matched normal volunteers. Uptake was referred to calcarine-occipital cortex as a reference sensory area. Cross-sectional differences between the three groups were highly statistically significant, but reflected primarily the reductions in cortical uptake in the Alzheimer group. A detailed comparison of depressed patients and controls identified decrements in anterior cingulate, temporal and frontal cortex and in caudate and thalamus in men only. These decrements were correlated with impairment of performance on a trail-making task, but were also associated with continuing treatment with antidepressants or benzodiazepines. However, most depressed patients had quantitatively normal scans for posterior parietal association cortex, and this suggests that SPECT may find a limited role in the differential diagnosis of depression and dementia. The reduced brain function in some depressed patients may parallel the findings from studies of brain structure in elderly depressives; there was between good outcome at 6-18 months and increased tracer uptake in subcortical areas.

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BackgroundMany genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of “doctor-diagnosed asthma”, thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes.MethodsWe conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9,568 individuals from five UK birth-cohorts.Results44 independent SNPs were associated with early-onset persistent, 25 with preschool remitting, 33 with mid-childhood remitting and 32 with late onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 (ANXA1), p<6.7×10−9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction inANXA1expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1−/−deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge.ConclusionsWe discovered a novel locus uniquely associated with early-onset persistent wheeze, identified the most likely causative variant, and showed thatANXA1may play a role in regulating the pulmonary immune response to allergens. Targeting this pathway in persistent disease may represent an exciting therapeutic prospect.