Longitudinal structure-function correlates in elderly reveal MTL dysfunction with cognitive decline.

By integrating behavioral measures and imaging data, previous investigations have explored the relationship between biological markers of aging and cognitive functions. Evidence from functional and structural neuroimaging has revealed that hippocampal volume and activation patterns in the medial temporal lobe (MTL) may predict cognitive performance in old age. Most past demonstrations of age-related differences in brain structure-function were based on cross-sectional comparisons. Here, the relationship between 6-year intraindividual change in functional magnetic resonance imaging (fMRI) signal and change in memory performance over 2 decades was examined. Correlations between intraindividual change in fMRI signal during episodic encoding and change in memory performance measured outside of scanning were used as an estimate for relating brain-behavior changes. The results revealed a positive relationship between activation change in the hippocampus (HC) and change in memory performance, reflecting reduced hippocampal activation in participants with declining performance. Using a similar analytic approach as for the functional data, we found that individuals with declining performance had reduced HC volume compared with individuals with intact performance. These observations provide a strong link between cognitive change in older adults and MTL structure and function and thus provide insights into brain correlates of individual variability in aging trajectories.

Longitudinal evidence for diminished frontal cortex function in aging.

Cross-sectional estimates of age-related changes in brain structure and function were compared with 6-y longitudinal estimates. The results indicated increased sensitivity of the longitudinal approach as well as qualitative differences. Critically, the cross-sectional analyses were suggestive of age-related frontal overrecruitment, whereas the longitudinal analyses revealed frontal underrecruitment with advancing age. The cross-sectional observation of overrecruitment reflected a select elderly sample. However, when followed over time, this sample showed reduced frontal recruitment. These findings dispute inferences of true age changes on the basis of age differences, hence challenging some contemporary models of neurocognitive aging, and demonstrate age-related decline in frontal brain volume as well as functional response.

Personality traits predict response to novel and familiar stimuli in the hippocampal region.

Current evidence from genetic, neurochemical, and clinical research supports the notion that a combination of high novelty seeking and low harm avoidance traits (NS-ha) is reliably dissociable from the opposite personality profile (i.e., low novelty seeking and high harm avoidance, ns-HA). Little is known, however, about how the differences between these two types of personality are regulated by brain function. Here we used functional magnetic resonance imaging (fMRI) and recruited two groups of individuals, one group with the NS-ha profile and the other group with the ns-HA profile, to examine whether there is a difference between the two groups in their brain response to novel versus familiar word stimuli. Results revealed a differential pattern of response in an area in the hippocampal region, with the NS-ha group showing a greater sensitivity to novel stimuli and the ns-HA group demonstrating a greater response to familiar stimuli. We conclude that the response pattern to novel and familiar stimuli in the hippocampal region has a role in mediating differences between the NS-ha and ns-HA temperamental profiles.

Unintended consequences for patients of future personalized pharmacoprinting.

Manufacturing pharmaceuticals by the use of 3D printing is a promising way to achieve more personalized drug treatment. To effectively use this technology, patients need to continuously measure their health, and new decisions have to be taken, for example, regarding the number of daily drugs including how many active pharmaceutical substances these should contain along with decisions around size, shape and color. Positive as well as negative effects of pharmacoprinted medicine on patients are likely to occur. Negative consequences with influence on patient autonomy and role might include: patients not being capable or interested in conducting self-monitoring, loosing overview of the medical treatment, reducing the ability to perform self-regulation, loosing trust in the pharmacoprinted medicine, and not being interested in taking on a new role in medical decision making. These issues are discussed in the paper in order to prevent upcoming challenges in the area of pharmacoprinting.

Reduced functional brain activity response in cognitively intact apolipoprotein E epsilon4 carriers.

The apolipoprotein E epsilon4 (APOE epsilon4) is the main known genetic risk factor for Alzheimer's disease. Genetic assessments in combination with other diagnostic tools, such as neuroimaging, have the potential to facilitate early diagnosis. In this large-scale functional MRI (fMRI) study, we have contrasted 30 APOE epsilon4 carriers (age range: 49-74 years; 19 females), of which 10 were homozygous for the epsilon4 allele, and 30 non-carriers with regard to brain activity during a semantic categorization task. Test groups were closely matched for sex, age and education. Critically, both groups were cognitively intact and thus symptom-free of Alzheimer's disease. APOE epsilon4 carriers showed reduced task-related responses in the left inferior parietal cortex, and bilaterally in the anterior cingulate region. A dose-related response was observed in the parietal area such that diminution was most pronounced in homozygous compared with heterozygous carriers. In addition, contrasts of processing novel versus familiar items revealed an abnormal response in the right hippocampus in the APOE epsilon4 group, mainly expressed as diminished sensitivity to the relative novelty of stimuli. Collectively, these findings indicate that genetic risk translates into reduced functional brain activity, in regions pertinent to Alzheimer's disease, well before alterations can be detected at the behavioural level.

Social aspects in additive manufacturing of pharmaceutical products.

INTRODUCTION: Additive manufacturing (AM) techniques, such as drug printing, represent a new engineering approach that can implement the concept of personalized medicine via on-demand manufacturing of dosage forms with individually adjusted doses. Implementation of AM principles, such as pharmacoprinting, will challenge the entire drug distribution chain and affect the society at different levels. Areas covered: This work summarizes the concept of personalized medicine and gives an overview of possibilities for monitoring patients' health. The most recent activities in the field of printing technologies for fabrication of dosage forms and 'polypills' with flexible doses and tailored release profiles are reviewed. Different scenarios for the drug distribution chain with the required adjustments in drug logistics, quality systems and environmental safety are discussed, as well as whether AM will be used for production of on-demand medicine. The impact of such changes in the distribution chain on regulation, healthcare professionals and patients are highlighted. Expert opinion: Drug manufacturing by traditional methods is well-established, but it lacks the possibility for on-demand personalized drug production. With the recent approval of the first printed medicine, society should be prepared for the changes that will follow the introduction of printed pharmaceuticals.

Parietal cortex activation predicts memory decline in apolipoprotein E-epsilon4 carriers.

Apolipoprotein E-epsilon4 is the main known genetic risk factor for Alzheimer's disease. Functional abnormalities in the parietal cortex have been reported for Alzheimer's disease patients and also for those at risk. Hence, a critical question is whether measurements of parietal cortex integrity may predict negative outcome among at-risk persons. We studied nondemented apolipoprotein E-epsilon4 carriers and found a significant relationship between parietal blood-oxygen-level-dependent functional magnetic resonance imaging response during a word categorization task and subsequent episodic memory performance. Thus, the results show that parietal cortex alterations predict memory decline in nondemented apolipoprotein E-epsilon4 carriers, and hence likely progression to Alzheimer's disease.

Reduced hippocampal volume in non-demented carriers of the apolipoprotein E epsilon4: relation to chronological age and recognition memory.

Apolipoprotein E epsilon4 (APOE epsilon4) is the main known genetic risk factor for Alzheimer's disease (AD). Some previous studies have reported structural brain changes as well as cognitive deficits in non-demented APOE epsilon4 carriers, but the pattern of results is inconsistent and studies with larger sample sizes have been called for. Here we compared hippocampal volume and recognition-memory performance between AD-symptom-free carriers (N=30) and non-carriers (N=30) of the APOE epsilon4 (age range: 49-79 years). We observed reduced right hippocampal volume in APOE epsilon4 carriers, and found that the difference was most pronounced before the age of 65. Further, the APOE epsilon4 carriers made significantly more false alarms in the recognition-memory test, and the number of false alarms correlated significantly with right hippocampus volume. These results indicate that relatively young individuals at genetic risk for AD have smaller hippocampal volume and lower performance on hippocampal-dependent cognitive tasks. A question for the future is whether smaller hippocampal volume represents early-onset hippocampal volume reduction or an inherent trait.

General sale of non-prescription medicinal products: Comparing legislation in two European countries.

BACKGROUND: The number of non-prescription medicines (NPMs) available for self-medication is increasing within the European Union (EU). This can enhance the autonomy of individuals but is also connected with risks. Under an existing EU Directive, Sweden has only recently deregulated and made NPMs available in non-pharmacy outlets; The United Kingdom (UK) is a more established NPM market; both are guided by the same EU directives. OBJECTIVE: The aim of this study was to compare specific requirements under the legislation, rationales and outcomes regarding the sale of NPMs through non-pharmacy outlets between Sweden and the UK. METHOD: The main method was analysis of legislative text and policy documents, conducted in 2012. RESULTS: Both countries had specified medicines available to the public in non-pharmacy outlets, but with restrictions on different factors, e.g. placement and package size of the NPMs. The main rationales for legislation were quality and patient safety. NPMs for 51 ailments were available in the UK, compared to 35 in Sweden. CONCLUSION: Sweden had more extensive requirements, probably due to the market being more recently deregulated, while the UK represented a more mature market. There is a difference in the balance between confidence and control, as well as availability and safety when it comes to NPMs in non-pharmacy settings that needs to be further discussed.

Longer leukocyte telomere length is associated with smaller hippocampal volume among non-demented APOE ε3/ε3 subjects.

Telomere length shortens with cellular division, and leukocyte telomere length is used as a marker for systemic telomere length. The hippocampus hosts adult neurogenesis and is an important structure for episodic memory, and carriers of the apolipoprotein E ε4 allele exhibit higher hippocampal atrophy rates and differing telomere dynamics compared with non-carriers. The authors investigated whether leukocyte telomere length was associated with hippocampal volume in 57 cognitively intact subjects (29 ε3/ε3 carriers; 28 ε4 carriers) aged 49-79 yr. Leukocyte telomere length correlated inversely with left (r(s) = -0.465; p = 0.011), right (r(s) = -0.414; p = 0.025), and total hippocampus volume (r(s) = -0.519; p = 0.004) among APOE ε3/ε3 carriers, but not among ε4 carriers. However, the ε4 carriers fit with the general correlation pattern exhibited by the ε3/ε3 carriers, as ε4 carriers on average had longer telomeres and smaller hippocampi compared with ε3/ε3 carriers. The relationship observed can be interpreted as long telomeres representing a history of relatively low cellular proliferation, reflected in smaller hippocampal volumes. The results support the potential of leukocyte telomere length being used as a biomarker for tapping functional and structural processes of the aging brain.

Structure-function correlates of cognitive decline in aging.

To explore neural correlates of cognitive decline in aging, we used longitudinal behavioral data to identify two groups of older adults (n = 40) that differed with regard to whether their performance on tests of episodic memory remained stable or declined over a decade. Analysis of structural and diffusion tensor imaging (DTI) revealed a heterogeneous set of differences associated with cognitive decline. Manual tracing of hippocampal volume showed significant reduction in those older adults with a declining memory performance as did DTI-measured fractional anisotropy in the anterior corpus callosum. Functional magnetic resonance imaging during incidental episodic encoding revealed increased activation in left prefrontal cortex for both groups and additional right prefrontal activation for the elderly subjects with the greatest decline in memory performance. Moreover, mean DTI measures in the anterior corpus callosum correlated negatively with activation in right prefrontal cortex. These results demonstrate that cognitive decline is associated with differences in the structure as well as function of the aging brain, and suggest that increased activation is either caused by structural disruption or is a compensatory response to such disruption.