Clinical Research Risk Assessment Among Individuals With Mild Cognitive Impairment

OBJECTIVE:: To determine whether individuals with mild cognitive impairment (MCI) differ from cognitively normal (NC) elders on a risk assessment task and whether participants and their study partners evaluate risk and benefit similarly. DESIGN:: Cross-sectional. SETTING:: University medical setting. PARTICIPANTS:: Seventy-nine participants (NC, n = 40; MCI, n = 39), age 60-90 years (73 ± 7 years; 53% women), and 64 study partners (NC, n = 36; MCI, n = 28), age 38-84 years (68 ± 10 years; 67% women). MEASUREMENTS:: Participants and study partners completed a risk assessment task that involved ranking from least to most risk four hypothetical vignettes for memory loss research (brain autopsy, blood draw, oral medication, neurosurgery). Participants also completed decisional capacity for research and neuropsychological protocols. RESULTS:: MCI participants' risk rankings differed from NC risk rankings (p <0.001) with MCI participants ranking brain autopsy higher and an oral medication trial lower. Demographic, decisional capacity, and neuropsychological variables could not explain MCI participant performances. Participants and their study partners had comparable risk assessment performance (p = 1.0). MCI study partners performed similar to their MCI participant counterparts but were different from NC study partners (p = 0.002; i.e., ranking autopsy higher and oral medication lower). CONCLUSION:: Findings suggest that individuals with MCI assess risk differently than NC peers by overestimating the risk (or underestimating the benefit) of brain autopsy and underestimating the risk (or overestimating the benefit) of oral medication. Study partners display a similar pattern. These observations may be secondary to MCI participants' (and their study partners') personal connection to the potential benefits of an experimental medication for memory loss.     

REPIMPACT - a prospective longitudinal multisite study on the effects of repetitive head impacts in youth soccer

Brain Imaging and Behavior - Repetitive head impacts (RHI) are common in youth athletes participating in contact sports. RHI differ from concussions; they are considered hits to the head that...     

Evolution of neuronal and glial tau isoforms in chronic traumatic encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy characterized by accumulation of hyperphosphorylated tau (p‐tau) in perivascular aggregates in neurons and glia at the depths of neocortical sulci and progresses to diffuse neocortical, allocortical and brainstem structures. The strongest risk factor is exposure to repetitive head impacts acquired most commonly through contact sports and military service. Given that CTE can only be definitively diagnosed after death, a better understanding of the cellular and molecular changes in CTE brains may lead to identification of mechanisms that could be used for novel biomarkers, monitoring progression or therapeutic development. Disruption of alternative pre‐mRNA splicing of tau mRNA plays a pathogenic role in tauopathy, with multiple characteristic patterns of isoform accumulation varying among tauopathies. Limited data are available on CTE, particularly at early stages. Using biochemical and histological approaches, we performed a detailed characterization of tau isoform signatures in post‐mortem human brain tissue from individuals with a range of CTE stages (n = 99). In immunoblot analyses, severity was associated with decreased total monomeric tau and increased total oligomeric tau. Immunoblot with isoform‐specific antisera revealed that oligomeric tau with three and four microtubule binding domain repeats (3R and 4R) also increased with CTE severity. Similarly, immunohistochemical studies revealed p‐tau accumulation consisting of both 3R and 4R in perivascular lesions. When the ratio of 4R:3R was analyzed, there was mixed expression throughout CTE stages, although 4R predominated in early CTE stages (I‐II), a 3R shift was observed in later stages (III‐IV). While neurons were found to contain both 3R and 4R, astrocytes only contained 4R. These 4R‐positive cells were exclusively neuronal at early stages. Overall, these findings demonstrate that CTE is a mixed 4R/3R tauopathy. Furthermore, histologic analysis reveals a progressive shift in tau isoforms that correlates with CTE stage and extent of neuronal pathology.     

Genetic analysis of three-dimensional shape of mouse lung tumors reveals eight lung tumor shape-determining (Ltsd) loci that are associated with tumor heterogeneity and symmetry

Most lung tumor linkage studies focus on identifying loci that confer susceptibility or resistance irrespective of the tumor types developed. However, different mouse strains develop different types of lung tumors. A major obstacle for genetic studies of these differences is the lack of reproducible, quantitative, and uniform assessment of tumor type. We have previously described a new variable (Rratio) that assesses the three-dimensional shape of lung tumors in a quantifiable way and showed that nonspherical tumors are correlated with tumor heterogeneity and with a tendency to asymmetrical growth (N. Tripodis and P. Demant, Exp. Lung Res., 27: 521-531, 2001). In the present study, we use the Rratio variable to search for quantitative trait loci affecting tumor phenotype. We tested the F(2) cross between the susceptible strain O20 and the recombinant congenic strain OcB-9. Both develop mixed alveolar and papillary lung tumors, and the OcB9 tumors are, on average, more elongated than the O20 ones. We mapped eight new lung tumor shape-determining loci (Ltsd1-8) involved in mutual interactions. Two of these loci, Ltsd1 and Ltsd3, seem to play a major role in tumor shape formation. The Ltsd4 locus was confirmed in a second F(2) cross between strain O20 and the recombinant congenic strain OcB-6. Genotype-phenotype associations show that nonspherical tumors are correlated with tumor heterogeneity and nonsymmetrical (focal) development of structures. Most of the new Ltsd loci map in regions where susceptibility to lung cancer (Sluc) loci have been previously mapped, raising the question of whether they are identical or closely linked loci. Based on models of tumor growth indicating that supply of nutrients and the ability to create a capillary network may be shape-determining factors (G. P. Pescarmona et al., Med. Hypoth., 53: 497-503, 1999), we suggest as likely candidates for the Ltsd loci genes involved in angiogenesis, vascularization, and capillary patterning. This is the first set of loci that affects qualitative aspects of lung tumors and may provide biologically and clinically interesting indicators of lung tumor progression.     

Complexity of lung cancer modifiers: mapping of thirty genes and twenty-five interactions in half of the mouse genome

BACKGROUND: Numerous low-penetrance genes control susceptibility to cancer in experimental animals, but the overall genetic information on this group of genes (i.e., number of loci and their mutual interactions) is missing. We performed a systematic search, scanning roughly half of the mouse genome for lung cancer susceptibility (Sluc) genes affecting tumor size or number by using mouse recombinant congenic (RC) strains. In each RC strain (OcB), approximately 12.5% of the genome is derived from the lung cancer-resistant strain B10.O20, whereas the rest is derived from the lung cancer-susceptible strain O20. METHODS: A total of 730 F2 hybrids from five (OcB x O20) crosses were tested. Pregnant mice were treated on day 18 of gestation with a single dose of N-ethyl-N-nitrosourea. When offspring were 16 weeks old, whole lungs were removed and sectioned semiserially, and the size of all lung tumors (n = 2658) was determined. Analysis of variance was used for detection of linkage, and models (including main effect and two-way interactions) were tested with a statistical program. RESULTS: We detected a total of 30 Sluc loci (16 new plus 14 previously reported) and 25 two-way interactions. Some of these interactions are counteracting (e.g., Sluc17 and Sluc20), resulting in the partial or total masking of the individual independent effect (main effect) of each involved locus. Seven loci (Sluc1, Sluc5, Sluc12, Sluc16, Sluc18, Sluc20, and Sluc26) and two interactions (Sluc5 x Sluc12 and Sluc5 x Sluc26) were detected in more than one RC strain. CONCLUSIONS: The extrapolation of our results to the whole genome suggests approximately 60 Sluc loci (90% confidence intervals = 42 to 78). Despite the genetic complexity of lung cancer, use of appropriate mapping strategies can identify a large number of responsible loci and can reveal their interactions. This study provides an insight into the genetic control of lung tumorigenesis and may serve as a paradigm for investigating the genetics of other cancer types.     

Genetic linkage of nuclear morphology of mouse lung tumors to the Kras-2 locus

Search for quantitative trait loci (QTLs) has been successful in the past decade by revealing numerous susceptibility to lung cancer loci in specially designed experimental crosses in mice. Although qualitative aspects of lung tumorigenesis are also genetically controlled, no loci affecting such traits have so far been identified. We analyzed a series of lung tumors derived from various inbred and recombinant congenic strains and F2 crosses for two histological characteristics: nuclear cytoplasmic invaginations (NCIs) and lymphocytic infiltration (LI) and performed linkage analysis. A significant linkage of the Kras-2 locus with presence or absence of NCI was detected. The implications of this linkage as well as the relationships between NCI, LI, tumor size and Kras-2 alleles are discussed.