Subregional Hippocampal Thickness Abnormalities in Older Adults with a History of Heavy Cannabis Use.

Background and Aims: Legalization of cannabis (CB) for both medicinal and, in some states, recreational use, has given rise to increasing usage rates across the country. Of particular concern are indications that frequent CB use may be selectively harmful to the developing adolescent brain compared with adult-onset usage. However, the long-term effects of heavy, adolescent CB use on brain structure and cognitive performance in late-life remain unknown. A critical brain region is the hippocampus (HC), where there is a striking intersection between high concentrations of cannabinoid 1 (CB1) receptors and age-related pathology. Design: We investigated whether older adults (average age=66.6+7.2 years old) with a history of early life CB use show morphological differences in hippocampal subregions compared with older, nonusers. Methods: We performed high-resolution magnetic resonance imaging combined with computational techniques to assess cortical thickness of the medial temporal lobe, neuropsychological testing, and extensive drug use histories on 50 subjects (24 formerly heavy cannabis users [CB+ group] abstinent for an average of 28.7 years, 26 nonusers [CB- group]). We investigated group differences in hippocampal subregions, controlling for age, sex, and intelligence (as measured by the Wechsler Test of Adult Reading), years of education, and cigarette use. Results: The CB+ subjects exhibited thinner cortices in subfields cornu ammonis 1 [CA1; F(1,42)=9.96, p=0.0003], and CA2, 3, and the dentate gyrus [CA23DG; F(1,42)=23.17, p<0.0001], and in the entire HC averaged over all subregions [F(1,42)=8.49, p=0.006]. Conclusions: Negative effects of chronic adolescent CB use on hippocampal structure are maintained well into late life. Because hippocampal cortical loss underlies and exacerbates age-related cognitive decline, these findings have profound implications for aging adults with a history of early life usage. Clinical Trial Registration: ClinicalTrials.gov # NCT01874886

Multimodal Imaging of Alzheimer Pathophysiology in the Brain's Default Mode Network

The spatial correlations between the brain's default mode network (DMN) and the brain regions known to develop pathophysiology in Alzheimer's disease (AD) have recently attracted much attention. In this paper, we compare results of different functional and structural imaging modalities, including MRI and PET, and highlight different patterns of anomalies observed within the DMN. Multitracer PET imaging in subjects with and without dementia has demonstrated that [C-11]PIB- and [F-18]FDDNP-binding patterns in patients with AD overlap within nodes of the brain's default network including the prefrontal, lateral parietal, lateral temporal, and posterior cingulate cortices, with the exception of the medial temporal cortex (especially, the hippocampus) where significant discrepancy between increased [F-18]FDDNP binding and negligible [C-11]PIB-binding was observed. [F-18]FDDNP binding in the medial temporal cortex—a key constituent of the DMN—coincides with both the presence of amyloid and tau pathology, and also with cortical areas with maximal atrophy as demonstrated by T1-weighted MR imaging of AD patients

Five days at outdoor education camp without screens improves preteen skills with nonverbal emotion cues

AbstractA field experiment examined whether increasing opportunities for face-to-face interaction while eliminating the use of screen-based media and communication tools improved nonverbal emotion–cue recognition in preteens. Fifty-one preteens spent five days at an overnight nature camp where television, computers and mobile phones were not allowed; this group was compared with school-based matched controls (n=54) that retained usual media practices. Both groups took pre- and post-tests that required participants to infer emotional states from photographs of facial expressions and videotaped scenes with verbal cues removed. Change scores for the two groups were compared using gender, ethnicity, media use, and age as covariates. After five days interacting face-to-face without the use of any screen-based media, preteens’ recognition of nonverbal emotion cues improved significantly more than that of the control group for both facial expressions and videotaped scenes. Implications are that the short-term effects of increased opportunities for social interaction, combined with time away from screen-based media and digital communication tools, improves a preteen’s understanding of nonverbal emotional cues

Automated VOI Analysis in FDDNP PET Using Structural Warping: Validation through Classification of Alzheimer's Disease Patients

We evaluate an automated approach to the cortical surface mapping (CSM) method of VOI analysis in PET. Although CSM has been previously shown to be successful, the process can be long and tedious. Here, we present an approach that removes these difficulties through the use of 3D image warping to a common space. We test this automated method using studies of FDDNP PET in Alzheimer's disease and mild cognitive impairment. For each subject, VOIs were created, through CSM, to extract regional PET data. After warping to the common space, a single set of CSM-generated VOIs was used to extract PET data from all subjects. The data extracted using a single set of VOIs outperformed the manual approach in classifying AD patients from MCIs and controls. This suggests that this automated method can remove variance in measurements of PET data and can facilitate accurate, high-throughput image analysis

Five days at outdoor education camp without screens improves preteen skills with nonverbal emotion cues

A field experiment examined whether increasing opportunities for face-to-face interaction while eliminating the use of screen-based media and communication tools improved nonverbal emotion-cue recognition in preteens. Fifty-one preteens spent five days at an overnight nature camp where television, computers and mobile phones were not allowed; this group was compared with school-based matched controls (n = 54) that retained usual media practices. Both groups took pre- and post-tests that required participants to infer emotional states from photographs of facial expressions and videotaped scenes with verbal cues removed. Change scores for the two groups were compared using gender, ethnicity, media use, and age as covariates. After five days interacting face-to-face without the use of any screen-based media, preteens' recognition of nonverbal emotion cues improved significantly more than that of the control group for both facial expressions and videotaped scenes. Implications are that the short-term effects of increased opportunities for social interaction, combined with time away from screen-based media and digital communication tools, improves a preteen's understanding of nonverbal emotional cues. © 2014 The Authors. Published by Elsevier Ltd

Detection and Prevention of Cognitive Decline

Current diagnostic and treatment strategies for cognitive decline can help patients maintain cognitive ability and higher levels of function longer. Despite advances in detection and early treatment strategies, many patients do not receive proper assessments and available therapies. A systematic assessment strategy will increase the likelihood of an accurate diagnosis, which can facilitate pharmacologic and non-pharmacologic treatment plans that can have a meaningful impact on prognosis. Available data support the integration of healthy lifestyle strategies in the treatment plan to help to stabilize symptoms and potentially delay future cognitive decline. While investigators continue to pursue more effective detection, treatment, and prevention strategies, the scientific data support the use of symptomatic drug treatments and recommendations for healthy lifestyle behaviors to improve quality of life and potentially stave off future cognitive decline. Success of such healthy lifestyle programs involves educating participants on the connection between lifestyle and disease prevention, offering enjoyable exercises that target the patient's skill level, and providing feedback that motivates participants to continue their healthy behaviors so they become habits

Comparison of DC Bead-irinotecan and DC Bead-topotecan drug eluting beads for use in locoregional drug delivery to treat pancreatic cancer

DC Bead is a drug delivery embolisation system that can be loaded with doxorubicin or irinotecan for the treatment of a variety of liver cancers. In this study we demonstrate that the topoisomerase I inhibitor topotecan hydrochloride can be successfully loaded into the DC Bead sulfonate-modified polyvinyl alcohol hydrogel matrix, resulting in a sustained-release drug eluting bead (DEBTOP) useful for therapeutic purposes. The in vitro drug loading capacity, elution characteristics and the effects on mechanical properties of the beads are described with reference to our previous work with irinotecan hydrochloride (DEBIRI). Results showed that drug loading was faster when the solution was agitated compared to static loading and a maximum loading of ca. 40–45 mg topotecan in 1 ml hydrated beads was achievable. Loading the drug into the beads altered the size, compressibility moduli and colour of the bead. Elution was shown to be reliant on the presence of ions to perform the necessary exchange with the electrostatically bound topotecan molecules. Topotecan was shown by MTS assay to have an IC50 for human pancreatic adenocarcinoma cells (PSN-1) of 0.22 and 0.27 lM compared to 28.1 and 19.2 lM for irinotecan at 48 and 72 h, respectively. The cytotoxic efficacy of DEBTOP on PSN-1 was compared to DEBIRI. DEPTOP loaded at 6 & 30 mg ml-1, like its free drug form, was shown to be more potent than DEBIRI of comparable doses at 24, 48 & 72 h using a slightly modified MTS assay. Using a PSN-1 mouse xenograft model, DEBIRI doses of 3.3–6.6 mg were shown to be well tolerated (even with repeat administration) and effective in reducing the tumour size. DEBTOP however, was lethal after 6 days at doses of 0.83–1.2 mg but demonstrated reasonable efficacy and tolerability (again with repeat injection possible) at 0.2–0.4 mg doses. Care must therefore be taken when selecting the dose of topotecan to be loaded into DC Bead given its greater potency and potential toxicity

Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations

Mutations constitutively activating FLT3 kinase are detected in ∼30% of acute myelogenous leukemia (AML) patients and affect downstream pathways such as extracellular signal–regulated kinase (ERK)1/2. We found that activation of FLT3 in human AML inhibits CCAAT/enhancer binding protein α (C/EBPα) function by ERK1/2-mediated phosphorylation, which may explain the differentiation block of leukemic blasts. In MV4;11 cells, pharmacological inhibition of either FLT3 or MEK1 leads to granulocytic differentiation. Differentiation of MV4;11 cells was also observed when C/EBPα mutated at serine 21 to alanine (S21A) was stably expressed. In contrast, there was no effect when serine 21 was mutated to aspartate (S21D), which mimics phosphorylation of C/EBPα. Thus, our results suggest that therapies targeting the MEK/ERK cascade or development of protein therapies based on transduction of constitutively active C/EBPα may prove effective in treatment of FLT3 mutant leukemias resistant to the FLT3 inhibitor therapies