Heterogeneity of Regional Brain Atrophy Patterns Associated with Distinct Progression Rates in Alzheimer’s Disease

We aimed to identify and characterize subtypes of Alzheimer’s disease (AD) exhibiting different patterns of regional brain atrophy on MRI using age- and gender-specific norms of regional brain volumes. AD subjects included in the Alzheimer''s Disease Neuroimaging Initiative study were classified into subtypes based on standardized values (Z-scores) of hippocampal and regional cortical volumes on MRI with reference to age- and gender-specific norms obtained from 222 cognitively normal (CN) subjects. Baseline and longitudinal changes of clinical characteristics over 2 years were compared across subtypes. Whole-brain-level gray matter (GM) atrophy pattern using voxel-based morphometry (VBM) and cerebrospinal fluid (CSF) biomarkers of the subtypes were also investigated. Of 163 AD subjects, 58.9% were classified as the “both impaired” subtype with the typical hippocampal and cortical atrophy pattern, whereas 41.1% were classified as the subtypes with atypical atrophy patterns: “hippocampal atrophy only” (19.0%), “cortical atrophy only” (11.7%), and “both spared” (10.4%). Voxel-based morphometric analysis demonstrated whole-brain-level differences in overall GM atrophy across the subtypes. These subtypes showed different progression rates over 2 years; and all subtypes had significantly lower CSF amyloid-β_1–42 levels compared to CN. In conclusion, we identified four AD subtypes exhibiting heterogeneous atrophy patterns on MRI with different progression rates after controlling the effects of aging and gender on atrophy with normative information. CSF biomarker analysis suggests the presence of Aβ neuropathology irrespective of subtypes. Such heterogeneity of MRI-based neuronal injury biomarker and related heterogeneous progression patterns should be considered in clinical trials and practice with AD patients.     

Characterization of a membrane-associated protein kinase of multidrug-resistant HL60 cells which phosphorylates P-glycoprotein

Cells containing increased levels of the membrane phosphoprotein P-glycoprotein exhibit a multidrug-resistant phenotype. In the present study we have analyzed protein kinases capable of phosphorylating P-glycoprotein in membranes of HL60 cells isolated for resistance to vincristine. Analysis of this system demonstrates that in isolated membranes the protein kinase inhibitor staurosporine greatly reduces P-glycoprotein phosphorylation. In contrast, the kinase inhibitor H-7 does not affect this reaction. Fractionation of solubilized membrane proteins from sensitive and resistant cells on DEAE-cellulose reveals a major protein kinase (PK-1) which exhibits optimal activity in the presence of Mn2+ and histone H1. This enzyme fraction does not contain detectable levels of protein kinase C or cAMP-dependent protein kinase. PK-1 phosphorylation of two endogenous proteins is, however, greatly enhanced in the presence of phosphatidylserine or phosphatidyl-inositol. In reaction mixtures containing Mg2+ or Mn2+ in the absence of phospholipid, PK-1 from resistant cells phosphorylates an endogenous protein of 180 kilodaltons (P180), which exhibits an electrophoretic mobility identical to P-glycoprotein. In parallel experiments with PK-1 from sensitive cells there is no detectable phosphorylation of a P180 protein. P180 phosphorylated by PK-1 from resistant cells is immunoprecipitated by antibody against P-glycoprotein. Additional studies demonstrate that PK-1 is capable of phosphorylating specific synthetic peptides which correspond to the sequence of P-glycoprotein. Peptide phosphorylation occurs at both serine and threonine residues. These studies thus identify a novel membrane-associated protein kinase in HL60 cells which is capable of phosphorylating P-glycoprotein. This enzyme may have an important role in regulating levels of multidrug resistance.     

Differentiation in cranial variables among six species of Hylopetes(Sciurinae: Pteromyini)

There is some discrepancy in the classification of different species of Hylopetes, particularly regarding systematic status of H. electilis and H. phayrei and their relationship to other species. In the present study, for the first time we have brought together six of the nine Hylopetes species and performed statistical analysis of 14 measurable cranial variables, analyzing in total 89 specimens,including H. electilis, H. alboniger, H. phayrei, H. lepidus, H. spadiceus, and H. nigripes. Both univariate and multivariate analysis results indicate that H. electilis can not only be obviously distinguished from H. phayrei, but also clearly differs from the other four Hylopetes species. These results sustain the contention that H. electilis is neither a synonym nor subspecies of H. phayrei, but should be considered a distinct and valid species. Subsequently, a straightforward discussion on the biogeography of Hylopetes in southeastern Asia gives further insight into the differentiation and variety of species belonging to this genus.     

Epidemic Spreading Model to Characterize Misfolded Proteins Propagation in Aging and Associated Neurodegenerative Disorders

Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer''s disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain''s clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer''s disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.     

HIV Infection and Awareness among Men Who Have Sex with Men–20 Cities,United States, 2008 and 2011

Over half of HIV infections in the United States occur among men who have sex with men (MSM). Awareness of infection is a necessary precursor to antiretroviral treatment and risk reduction among HIV-infected persons. We report data on prevalence and awareness of HIV infection among MSM in 2008 and 2011, using data from 20 cities participating in the 2008 and 2011 National HIV Behavioral Surveillance System (NHBS) among MSM. Venue-based, time-space sampling was used to recruit men for interview and HIV testing. We analyzed data for men who reported ≥1 male sex partner in the past 12 months. Participants who tested positive were considered to be aware of their infection if they reported a prior positive HIV test. We used multivariable analysis to examine differences between results from 2011 vs. 2008. HIV prevalence was 19% in 2008 and 18% in 2011 (p = 0.14). In both years, HIV prevalence was highest among older age groups, blacks, and men with lower education and income. In multivariable analysis, HIV prevalence did not change significantly from 2008 to 2011 overall (p = 0.51) or in any age or racial/ethnic category (p>0.15 in each category). Among those testing positive, a greater proportion was aware of their infection in 2011 (66%) than in 2008 (56%) (p<0.001). In both years, HIV awareness was higher for older age groups, whites, and men with higher education and income. In multivariable analysis, HIV awareness increased from 2008 to 2011 overall (p<0.001) and for all age and racial/ethnic categories (p<0.01 in each category). In both years, black MSM had the highest HIV prevalence and the lowest awareness among racial/ethnic groups. These findings suggest that HIV-positive MSM are increasingly aware of their infections.