Cognitive dysfunction in cancer: Neuroimaging and genetic approaches to identify biological mechanisms

Indiana University-Purdue University Indianapolis (IUPUI)Although cancer and treatment-associated cognitive dysfunction has been well-documented in the literature, much work remains to elucidate the biological mechanisms driving this effect, hampering current therapeutic efforts. To address this gap, we first reviewed studies utilizing neuroimaging to characterize cognitive dysfunction in cancer, as studies of neurodegenerative diseases point to neuroimaging as a sensitive measure of cognitive dysfunction. This review highlighted the need for longitudinal imaging studies of cancer and treatment-related changes in cerebral structure and function. Subsequently, we utilized multimodal neuroimaging techniques in a female breast cancer cohort to investigate the longitudinal impact of cancer and chemotherapy treatment on cerebral perfusion and gray matter. Our findings indicate that chemotherapy is associated with elevated perfusion, primarily in posterior brain regions, as well as depressed frontal perfusion associated with decreased frontal gray matter density. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. We also investigated the relationship of cognitive dysfunction and chemotherapy-induced peripheral neuropathy (CIPN), another type of chemotherapy-related nervous system sequelae, again utilizing multimodal, longitudinal neuroimaging, and found that peripheral neuropathy symptoms following chemotherapy were associated with changes in cerebral perfusion and gray matter density. Together, these findings support the hypothesis that multiple biological mechanisms drive cancer and treatment-related cognitive dysfunction. Interestingly, although cancer is associated with cognitive dysfunction, epidemiological studies have shown that cancer and Alzheimer's disease (AD) are inversely correlated. To extend our imaging analysis beyond breast cancer, we leveraged the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate the inverse relationship of cancer and AD and investigate the impact of both of these diseases on gray matter density. We found that though the inverse relationship of these diseases was replicated in the ADNI cohort, cancer history was associated with lower gray matter density, similar to findings from breast cancer studies, independent of AD diagnostic group. Finally, we reviewed microRNA studies, as microRNAs are important regulators of many cell signaling pathways and have been actively investigated in relation to both diseases. This review suggests several pathways that may be driving the inverse association and may contribute to cognitive dysfunction

Light-induced iodoperfluoroalkylation reactions of carbon-carbon multiple bonds in water

In this work we have undertaken the radical-induced addition of 1-iodo-n-perfluorobutane onto electron-rich alkenes, alkenes with electron withdrawing groups, and alkynes in water, initiated photochemically. The lack of hydrogen donor (i.e.: (Me 3Si) 3SiH) in our reaction medium facilitates a Halogen Atom-transfer reaction (HAT), affording the respective perfluorobutylated alkyl and alkenyl halides (iodides) in good yields in water. We have also found that water exerts a relevant solvent effect on the rates of perfluoroalkyl radical additions onto double and triple bonds. The stereoselectivity of the radical addition reaction of alkynes is studied. The novelty of this work relies on the photochemical generation of fluorinated radicals in water, and the Halogen Atom-transfer addition reactions of iodoperfluoroalkanes onto carbon-carbon unsaturated bonds in water induced by light.Fil: Slodowicz, Mariel Pamela. Universidad de Belgrano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Barata Vallejo, Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Vázquez, A.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Sbarbati Nudelman, N.. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Orgánica; ArgentinaFil: Postigo, Jose Alberto. Universidad de Belgrano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Variants in the Mitochondrial Intermediate Peptidase (MIPEP) Gene are Associated with Gray Matter Density in the Alzheimer’s Disease Neuroimaging Initiative Cohort

poster abstractCancer and Alzheimer’s disease (AD) incidence is inversely correlated, but the genetic underpinnings of this relationship remain to be elucidated. Recent findings identified lower gray matter density in frontal regions of participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with cancer history compared to those without such history, across diagnostic groups (Nudelman et al., 2014). Pathways proposed to impact cancer and AD, including metabolism and survival, may play an important role in the observed difference. To test this hypothesis, a genome-wide association study (GWAS) using mean frontal gray matter cluster values was performed for all Caucasian participants in this cohort with neuroimaging and genetic data (n=1405). Analysis covaried for age, sex, AD, and cancer history. Of the two genes with the most significant SNPs (p<10-5), WD repeat domain 5B (WDR5B) and mitochondrial intermediate peptidase (MIPEP), MIPEP was selected for further analysis given the hypothesis focus on metabolism. ANOVA analysis of MIPEP top SNP rs8181878 with frontal gray matter cluster values in SPSS indicated that while this SNP is significantly associated with gray matter density (p=2x10-6), no interaction was observed with cancer history or AD diagnosis. Furthermore, whole brain gray matter voxel-wise analysis of this SNP using Statistical Parametric Mapping 8 software showed that minor allele(s) of this SNP were significantly (PFWE<0.05) associated with higher gray matter density. These results suggest that the minor allele of MIPEP SNP rs8181878 may be protective against gray matter density loss, highlighting the importance of metabolic processes in aging and disease

An electroluminescent-piezoelectric flat-panel display device

A flat-panel, line display consisting of electroluminescent ZnS---Cu phosphors (EL) adjacent to piezoelectric voltage transformer elements (PE) has been fabricated to provide a controlled-movement luminescent light spot. Electroluminescence is excited by the electric fields generated at the surface of a piezoelectric element driven at its resonant frequency. The display is made up of thirty PE-EL units connected electrically in parallel, each unit resonating at a different frequency. Movement of the light spot over the face of the display is produced by frequency modulation of the voltages applied to the piezoelectric array, in the manner of a sweep frequency. Synchronized amplitude modulation permits the light spot to be localized and its movement to be controlled. The display has a sweep frequency range extending from 30 to 60 kc/s. PE-EL units under continuous operation generate 40 ft lamberts at 8[middle dot]8 Vrms, and can generate over 100 ft lamberts by overdriving at 40Vrms. In sweep operation at 100 c/s, the light output is 40 ft lamberts at 35 Vrms. Power consumption in this mode is less than 10 mW. EL fatigue is analyzed and minimized in this display sweep technique.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32284/1/0000351.pd

Association of cancer history with Alzheimer's disease onset and structural brain changes

Epidemiological studies show a reciprocal inverse association between cancer and Alzheimer's disease (AD). The common mechanistic theory for this effect posits that cells have an innate tendency toward apoptotic or survival pathways, translating to increased risk for either neurodegeneration or cancer. However, it has been shown that cancer patients experience cognitive dysfunction pre- and post-treatment as well as alterations in cerebral gray matter density (GMD) on MRI. To further investigate these issues, we analyzed the association between cancer history (CA±) and age of AD onset, and the relationship between GMD and CA± status across diagnostic groups in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort study. Data was analyzed from 1609 participants with information on baseline cancer history and AD diagnosis, age of AD onset, and baseline MRI scans. Participants were CA+ (N = 503) and CA− (N = 1106) diagnosed with AD, mild cognitive impairment (MCI), significant memory concerns (SMC), and cognitively normal older adults. As in previous studies, CA+ was inversely associated with AD at baseline (P = 0.025); interestingly, this effect appears to be driven by non-melanoma skin cancer (NMSC), the largest cancer category in this study (P = 0.001). CA+ was also associated with later age of AD onset (P < 0.001), independent of apolipoprotein E (APOE) ε4 allele status, and individuals with two prior cancers had later mean age of AD onset than those with one or no prior cancer (P < 0.001), suggesting an additive effect. Voxel-based morphometric analysis of GMD showed CA+ had lower GMD in the right superior frontal gyrus compared to CA− across diagnostic groups (Pcrit < 0.001, uncorrected); this cluster of lower GMD appeared to be driven by history of invasive cancer types, rather than skin cancer. Thus, while cancer history is associated with a measurable delay in AD onset independent of APOE ε4, the underlying mechanism does not appear to be cancer-related preservation of GMD

Bitangential interpolation in generalized Schur classes

Bitangential interpolation problems in the class of matrix valued functions in the generalized Schur class are considered in both the open unit disc and the open right half plane, including problems in which the solutions is not assumed to be holomorphic at the interpolation points. Linear fractional representations of the set of solutions to these problems are presented for invertible and singular Hermitian Pick matrices. These representations make use of a description of the ranges of linear fractional transformations with suitably chosen domains that was developed in a previous paper.Comment: Second version, corrected typos, changed subsection 5.6, 47 page

Analysis of the Inverse Association between Cancer and Alzheimer’s Disease: Results from the Alzheimer’s Disease Neuroimaging Initiative Cohort

poster abstractAlthough a number of studies support a reciprocal inverse association between diagnoses of cancer and Alzheimer’s disease (AD), to date there has not been any systemic investigation of the neurobiological impact of or genetic risk factors underlying this effect. To facilitate this goal, this study aimed to replicate the inverse association of cancer and AD using data from the NIA Alzheimer’s Disease Neuroimaging Initiative, which includes age-matched cases and controls with information on cancer history, AD progression, neuroimaging, and genomic data. Subjects included individuals with AD (n=234), mild cognitive impairment (MCI, n=542), and healthy controls (HC, n=293). After controlling for sex, education, race/ethnicity, smoking, and apolipoprotein E (APOE) e2/3/4 allele groups, cancer history was protective against baseline AD diagnosis (p=0.042), and was associated with later age of AD onset (p=0.001). Cancer history appears to result in a cumulative protective effect; individuals with more than one cancer had a later age of AD onset compared to those with only one cancer (p=0.001). Finally, a protective effect of AD was also observed in individuals who developed incident cancer after enrolling (post-baseline visit); 20 individuals with MCI and 9 HC developed cancer, while no AD patients had subsequent cancer diagnoses (p=0.013). This supports previous research on the inverse association of cancer and AD, and importantly provides novel evidence that this effect appears to be independent of APOE, the major known genetic risk factor for AD. Future analyses will investigate the neurobiological and genetic basis of this effect

Warping and vacua of (S)YM3+1(S)YM_{3+1}

We use dielectric branes to find non singular string theory duals of a perturbed 2+1 dimensional gauge theory living on D2 branes. By adding fermion masses we obtain theories with reduced supersymmetry. The Higgs vacua of the perturbed theory correspond to polarization of the D2 branes into D4 branes. The confining vacua correspond to polarization of the D2 branes into NS5 branes. We consider different mass perturbations. Adding three equal masses preserves N=2 supersymmetry. In this case there are no confining vacua. By adding a fourth fermion mass we break all the supersymmetry, and find confining vacua. We also obtain duals for domain walls, condensates, baryon vertices, glueballs and flux tubes. We comment on the Kahler potentials for the Higgs and confining phases. In the course of the calculations we also find a nontrivial consistency check of the NS5 brane action in a D2 brane background.Comment: 33 pages, 2 figures, LaTeX. A factor in the last term of (67) and some typos are corrected, references adde

Anticancer prodrugs of butyric acid and formaldehyde protect against doxorubicin-induced cardiotoxicity

Formaldehyde has been previously shown to play a dominant role in promoting synergy between doxorubicin (Dox) and formaldehyde-releasing butyric acid (BA) prodrugs in killing cancer cells. In this work, we report that these prodrugs also protect neonatal rat cardiomyocytes and adult mice against toxicity elicited by Dox. In cardiomyocytes treated with Dox, the formaldehyde releasing prodrugs butyroyloxymethyl diethylphosphate (AN-7) and butyroyloxymethyl butyrate (AN-1), but not the corresponding acetaldehyde-releasing butyroyloxydiethyl phosphate (AN-88) or butyroyloxyethyl butyrate (AN-11), reduced lactate dehydrogenase leakage, prevented loss of mitochondrial membrane potential (ΔΨm) and attenuated upregulation of the proapoptotic gene Bax. In Dox-treated mice, AN-7 but not AN-88 attenuated weight-loss and mortality, and increase in serum lactate dehydrogenase. These findings show that BA prodrugs that release formaldehyde and augment Dox anticancer activity also protect against Dox cardiotoxicity. Based on these observations, clinical applications of these prodrugs for patients treated with Dox warrant further investigation