White matter hyperintensities correlate to cognition and fiber tract integrity in older adults with HIV.

Our aim was to examine the clinical relevance of white matter hyperintensities (WMH) in HIV. We used an automated approach to quantify WMH volume in HIV seropositive (HIV+; n = 65) and HIV seronegative (HIV-; n = 29) adults over age 60. We compared WMH volumes between HIV+ and HIV- groups in cross-sectional and multiple time-point analyses. We also assessed correlations between WMH volumes and cardiovascular, HIV severity, cognitive scores, and diffusion tensor imaging variables. Serostatus groups did not differ in WMH volume, but HIV+ participants had less cerebral white matter (mean: 470.95 [43.24] vs. 497.63 [49.42] mL, p = 0.010). The distribution of WMH volume was skewed in HIV+ with a high proportion (23%) falling above the 95th percentile of WMH volume defined by the HIV- group. Serostatus groups had similar amount of WMH volume growth over time. Total WMH volume directly correlated with measures of hypertension and inversely correlated with measures of global cognition, particularly in executive functioning, and psychomotor speed. Greater WMH volume was associated with poorer brain integrity measured from diffusion tensor imaging (DTI) in the corpus callosum and sagittal stratum. In this group of HIV+ individuals over 60, WMH burden was associated with cardiovascular risk and both worse diffusion MRI and cognition. The median total burden did not differ by serostatus; however, a subset of HIV+ individuals had high WMH burden.

Increased subcortical neural activity among HIV+ individuals during a lexical retrieval task.

BACKGROUND: Deficits in lexical retrieval, present in approximately 40% of HIV+ patients, are thought to reflect disruptions to frontal-striatal functions and may worsen with immunosuppression. Coupling frontal-striatal tasks such as lexical retrieval with functional neuroimaging may help delineate the pathophysiologic mechanisms underlying HIV-associated neurological dysfunction. OBJECTIVE: We examined whether HIV infection confers brain functional changes during lexical access and retrieval. It was expected that HIV+ individuals would demonstrate greater brain activity in frontal-subcortical regions despite minimal differences between groups on neuropsychological testing. Within the HIV+ sample, we examined associations between indices of immunosuppression (recent and nadir CD4+ count) and task-related signal change in frontostriatal structures. Method16 HIV+ participants and 12 HIV- controls underwent fMRI while engaged in phonemic/letter and semantic fluency tasks. Participants also completed standardized measures of verbal fluency RESULTS: HIV status groups performed similarly on phonemic and semantic fluency tasks prior to being scanned. fMRI results demonstrated activation differences during the phonemic fluency task as a function of HIV status, with HIV+ individuals demonstrating significantly greater activation in BG structures than HIV- individuals. There were no significant differences in frontal brain activation between HIV status groups during the phonemic fluency task, nor were there significant brain activation differences during the semantic fluency task. Within the HIV+ group, current CD4+ count, though not nadir, was positively correlated with increased activity in the inferior frontal gyrus and basal ganglia. CONCLUSION: During phonemic fluency performance, HIV+ patients recruit subcortical structures to a greater degree than HIV- controls despite similar task performances suggesting that fMRI may be sensitive to neurocompromise before overt cognitive declines can be detected. Among HIV+ individuals, reduced activity in the frontal-subcortical structures was associated with lower CD4+ count.

A Diagnostic Dilemma: Similarity of Neuroradiological Findings in Central Nervous System Hemophagocytic Lymphohistiocytosis and Aspergillosis.

Central nervous system (CNS) involvement in the context of hemophagocytic lymphohistiocytosis (HLH) is not uncommon. Given the immunosuppressive nature of HLH therapy, infectious complications are also seen. We describe a 9-year-old male who developed acute neurological decline secondary to aspergillosis while undergoing HLH therapy. The significant overlap observed in CNS neuroimaging of HLH and aspergillosis and the subtleties that may help differentiate the two are discussed. The importance of obtaining tissue for definitive diagnosis is underscored.

Anoikis-resistant subpopulations of human osteosarcoma display significant chemoresistance and are sensitive to targeted epigenetic therapies predicted by expression profiling.

BACKGROUND: Osteosarcoma (OS) is the most common type of solid bone cancer, with latent metastasis being a typical mode of disease progression and a major contributor to poor prognosis. For this to occur, cells must resist anoikis and be able to recapitulate tumorigenesis in a foreign microenvironment. Finding novel approaches to treat osteosarcoma and target those cell subpopulations that possess the ability to resist anoikis and contribute to metastatic disease is imperative. Here we investigate anchorage-independent (AI) cell growth as a model to better characterize anoikis resistance in human osteosarcoma while using an expression profiling approach to identify and test targetable signaling pathways. METHODS: Established human OS cell lines and patient-derived human OS cell isolates were subjected to growth in either adherent or AI conditions using Ultra-Low Attachment plates in identical media conditions. Growth rate was assessed using cell doubling times and chemoresistance was assessed by determining cell viability in response to a serial dilution of either doxorubicin or cisplatin. Gene expression differences were examined using quantitative reverse-transcription PCR and microarray with principal component and pathway analysis. In-vivo OS xenografts were generated by either subcutaneous or intratibial injection of adherent or AI human OS cells into athymic nude mice. Statistical significance was determined using student's t-tests with significance set at α=0.05. RESULTS: We show that AI growth results in a global gene expression profile change accompanied by significant chemoresistance (up to 75 fold, p<0.05). AI cells demonstrate alteration of key mediators of mesenchymal differentiation (ß-catenin, Runx2), stemness (Sox2), proliferation (c-myc, Akt), and epigenetic regulation (HDAC class 1). AI cells were equally tumorigenic as their adherent counterparts, but showed a significantly decreased rate of growth in-vitro and in-vivo (p<0.05). Treatment with the pan-histone deacetylase inhibitor vorinostat and the DNA methyltransferase inhibitor 5-azacytidine mitigated AI growth, while 5-azacytidine sensitized anoikis-resistant cells to doxorubicin (p<0.05). CONCLUSIONS: These data demonstrate remarkable plasticity in anoikis-resistant human osteosarcoma subpopulations accompanied by a rapid development of chemoresistance and altered growth rates mirroring the early stages of latent metastasis. Targeting epigenetic regulation of this process may be a viable therapeutic strategy.

Decreased white matter integrity in neuropsychologically defined mild cognitive impairment is independent of cortical thinning.

Improved understanding of the pattern of white matter changes in early and prodromal Alzheimer's disease (AD) states such as mild cognitive impairment (MCI) is necessary to support earlier preclinical detection of AD, and debate remains whether white matter changes in MCI are secondary to gray matter changes. We applied neuropsychologically based MCI criteria to a sample of normally aging older adults; 32 participants met criteria for MCI and 81 participants were classified as normal control (NC) subjects. Whole-head high resolution T1 and diffusion tensor imaging scans were completed. Tract-Based Spatial Statistics was applied and a priori selected regions of interest were extracted. Hippocampal volume and cortical thickness averaged across regions with known vulnerability to AD were derived. Controlling for corticalthic kness, the MCI group showed decreased average fractional anisotropy (FA) and decreased FA in parietal white matter and in white matter underlying the entorhinal and posterior cingulate cortices relative to the NC group. Statistically controlling for cortical thickness, medial temporal FA was related to memory and parietal FA was related to executive functioning. These results provide further support for the potential role of white matter integrity as an early biomarker for individuals at risk for AD and highlight that changes in white matter may be independent of gray matter changes.

Strategy use and verbal memory in older adults: The role of intellectual functioning and the preferential impact of semantic clustering.

Objective: The relative importance of various mechanisms supporting declarative verbal memory among older adults remains uncertain. The present study examined the impact of strategy use (specifically semantic clustering) versus other variables known to impact memory performance (age, sex, education, FSIQ, processing speed, and executive functioning) on verbal memory functioning among healthy older adults.Methods: Healthy older adults from the California Verbal Learning Test, Second Edition standardization sample were selected (N = 242). Relationships between verbal memory, demographics variables, and neuropsychological factors were established, and a hierarchical regression analysis was conducted to examine the individual contributions of these variables in predicting memory performance.Results: Bivariate correlations suggested that memory was significantly related to demographic factors, IQ, executive functioning, and semantic clustering. Importantly, hierarchical regression analysis revealed that semantic clustering significantly and independently contributed to recall performance beyond the demonstrated impacts of FSIQ, speed, executive functioning, and demographic variables. Furthermore, FSIQ did not moderate the relationship between semantic clustering and memory indicating that this strategy is an important factor in bolstering recall, independent of FSIQ.Conclusions: Our results highlight the critical importance of semantic clustering utilization in enhancing memory performance among healthy older adults.

Depressive Symptom Profiles Predict Specific Neurodegenerative Disease Syndromes in Early Stages.

Background: During early stages, patients with neurodegenerative diseases (NDG) often present with depressive symptoms. However, because depression is a heterogeneous disorder, more precise delineation of the specific depressive symptom profiles that arise early in distinct NDG syndromes is necessary to enhance patient diagnosis and care. Methods and Findings: Five-hundred and sixty four participants self-reported their depressive symptoms using the Geriatric Depression Scale (GDS), including 111 healthy older control subjects (NC) and 453 patients diagnosed with one of six NDGs who were at the mild stage of disease (CDR® Dementia Staging Instrument ≤ 1) [186 Alzheimer's disease (AD), 76 behavioral variant frontotemporal dementia (bvFTD), 52 semantic variant primary progressive aphasia (svPPA), 46 non-fluent variant PPA (nfvPPA), 49 progressive supranuclear palsy syndrome (PSPS), 44 corticobasal syndrome (CBS)]. The GDS was divided into subscales based on a previously published factor analysis, representing five symptoms (dysphoria, hopelessness, withdrawal, worry, and cognitive concerns). Mixed models were created to examine differences in depression subscale by group, and logistic regression analyses were performed to determine if patterns of depressive symptoms could predict a patient's NDG syndrome. PSPS patients presented with a hopeless, dysphoric, and withdrawn pattern, while patients with CBS presented with a similar but less severe pattern. Worry was a key symptom in the profile of patients with svPPA, while ADs only had abnormally elevated cognitive concerns. Depressive profile accurately predicted NDG diagnosis at a rate of between 70 and 84% accuracy. Conclusions: These results suggest that attention to specific depressive symptom profile can improve diagnostic sensitivity and can be used to provide more individualized patient care.

Functional consequences of HIV-associated neuropsychological impairment.

This review focuses on the "real world" implications of infection with HIV/AIDS from a neuropsychological perspective. Relevant literature is reviewed which examines the relationships between HIV-associated neuropsychological impairment and employment, driving, medication adherence, mood, fatigue, and interpersonal functioning. Specifically, the relative contributions of medical, cognitive, psychosocial, and psychiatric issues on whether someone with HIV/AIDS will be able to return to work, adhere to a complicated medication regimen, or safely drive a vehicle will be discussed. Methodological issues that arise in the context of measuring medication adherence or driving capacity are also explored. Finally, the impact of HIV/AIDS on mood state, fatigue, and interpersonal relationships are addressed, with particular emphasis on how these variables interact with cognition and independent functioning. The purpose of this review is to integrate neuropsychological findings with their real world correlates of functional behavior in the HIV/AIDS population.

Long-term test-retest reliability of the California Verbal Learning Test - second edition.

OBJECTIVE: Aging is often associated with declines in episodic memory. Reliable tracking of memory requires assessment instruments that are stable over time to better understand changes potentially attributable to neurodegenerative disease. While prior studies support the test-retest reliability of memory instruments over brief intervals, follow-up testing in clinical settings typically occurs at least one-year later. The present study evaluated the long-term test-retest reliability of the California Verbal Learning Test - second edition (CVLT-2), a widely used measure of episodic learning and memory. METHOD: One hundred and fifty seven healthy older adults (mean age = 68.47 years; education = 17.28 years) underwent repeat assessment at an average of 1.30 years apart. Participants underwent repeat assessment using either parallel or alternate forms at follow-up. We utilized a standardized regression-based (SRB) approach to determine statistically significant changes in test scores over time. RESULTS: This study revealed modest 1-year test-retest correlation coefficients for the primary CVLT-2 measures (range = .57-.69) Results of SRB formulae are provided to assist clinicians with defining clinically relevant cognitive change on the CVLT-2 while controlling for confounding factors. CONCLUSIONS: Findings from this study support repeat test administration of the CVLT-2 over longer periods, and may enhance its applicability in determining longitudinal change in memory performance.

Glucose Dysregulation Interacts With APOE-∊4 to Potentiate Temporoparietal Cortical Thinning.

We examined the interactive effects of apolipoprotein ∊4 (APOE-∊4), a risk factor for Alzheimer's disease (AD), and diabetes risk on cortical thickness among 107 healthy elderly participants; in particular, participants included 27 APOE-∊4+ and 80 APOE-∊4- controls using T1-weighted structural magnetic resonance imaging. Regions of interests included select frontal, temporal, and parietal cortical regions. Among APOE-∊4, glucose abnormalities independently predicted reduced cortical thickness among temporoparietal regions but failed to predict changes for noncarriers. However, among noncarriers, age independently predicted reduced cortical thickness among temporoparietal and frontal regions. Diabetes risk is particularly important for the integrity of cortical gray matter in APOE-∊4 and demonstrates a pattern of thinning that is expected in preclinical AD. However, in the absence of this genetic factor, age confers risk for reduced cortical thickness among regions of expected compromise. This study supports aggressive management of cerebrovascular factors and earlier preclinical detection of AD among individuals presenting with genetic and metabolic risks.

Mild Cognitive Impairment is Associated With White Matter Integrity Changes in Late-Myelinating Regions Within the Corpus Callosum.

Degenerative brain changes in Alzheimer's disease may occur in reverse order of normal brain development based on the retrogenesis model. This study tested whether evidence of reverse myelination was observed in mild cognitive impairment (MCI) using a data-driven analytic approach based on life span developmental data. Whole-brain high-resolution diffusion tensor imaging scans were obtained for 31 patients with MCI and 79 demographically matched healthy older adults. Comparisons across corpus callosum (CC) regions of interest (ROIs) showed decreased fractional anisotropy (FA) in the body but not in the genu or splenium; early-, middle-, and late-myelinating ROIs restricted to the CC revealed decreased FA in late- but not early- or middle-myelinating ROIs. Voxelwise group differences revealed areas of lower FA in MCI, but whole-brain differences were equally distributed across early-, middle-, and late-myelinating regions. Overall, results within the CC support the retrogenesis model, although caution is needed when generalizing these results beyond the CC.

Interactive effects of apolipoprotein E4 and diabetes risk on later myelinating white matter regions in neurologically healthy older aged adults.

Possession of the apolipoprotein E4 (APOE4) allele and diabetes risk are independently related to reduced white matter (WM) integrity that may contribute to the development of Alzheimer's disease (AD). The purpose of this study is to examine the interactive effects of APOE4 and diabetes risk on later myelinating WM regions among healthy elderly individuals at risk of AD. A sample of 107 healthy elderly (80 APOE4-/27 APOE4+) individuals underwent structural magnetic resonance imaging/diffusion tensor imaging (DTI). Data were prepared using Tract-Based Spatial Statistics, and a priori regions of interest (ROIs) were extracted from T1-based WM parcellations. Regions of interest included later myelinating frontal/temporal/parietal WM regions and control regions measured by fractional anisotropy (FA). There were no APOE group differences in DTI for any ROI. Within the APOE4 group, we found negative relationships between hemoglobin A1c/fasting glucose and APOE4 on FA for all later myelinating WM regions but not for early/middle myelinating control regions. Results also showed APOE4/diabetes risk interactions for WM underlying supramarginal, superior temporal, precuneus, superior parietal, and superior frontal regions. Results suggest interactive effects of APOE4 and diabetes risk on later myelinating WM regions, which supports preclinical detection of AD among this particularly susceptible subgroup.

Cognitive reserve as a protective factor in older HIV-positive patients at risk for cognitive decline.

The present study examined the impact of cognitive reserve in maintaining intact neuropsychological (NP) function among older HIV-positive individuals, a uniquely at-risk subgroup. Participants included 129 individuals classified by HIV serostatus, age group, and NP impairment. A three-way analysis of variance (ANOVA) followed by a series of within-group ANOVA and multiple regression analyses were conducted to investigate the pattern of cognitive reserve (vs. other protective) influence among groups with varying risks of NP impairment. Results indicated a significant age × HIV status interaction, with older HIV-positive individuals demonstrating higher cognitive reserve than subgroups with less risk for NP compromise (younger age and/or HIV-negative). Results demonstrated higher cognitive reserve specific to NP-intact older HIV-positive individuals. Within this group, the interaction of younger age and higher cognitive reserve independently contributed to cognitive status when controlling for psychiatric, immunological, and psychosocial protective mechanisms, suggesting the importance of cognitive reserve beyond other protective mechanisms in maintaining optimal NP functioning in those individuals most at risk. Alongside younger age, factors contributing to cognitive reserve (i.e., education and estimated premorbid intelligence) may provide substantial benefit for older HIV-positive adults who are at high risk for NP compromise.

Basal ganglia structures differentially contribute to verbal fluency: evidence from Human Immunodeficiency Virus (HIV)-infected adults.

BACKGROUND: The basal ganglia (BG) are involved in executive language functions (i.e., verbal fluency) through their connections with cortical structures. The caudate and putamen receive separate inputs from prefrontal and premotor cortices, and may differentially contribute to verbal fluency performance. We examined BG integrity in relation to lexico-semantic verbal fluency performance among older HIV infected adults. METHOD: 20 older (50+ years) HIV+ adults underwent MRI and were administered measures of semantic and phonemic fluency. BG (caudate, putamen) regions of interest were extracted. RESULTS: Performance on phonemic word generation significantly predicted caudate volume, whereas performance on phonemic switching predicted putamen volume. CONCLUSIONS: These findings suggest a double dissociation of BG involvement in verbal fluency tasks with the caudate subserving word generation and the putamen associated with switching. As such, verbal fluency tasks appear to be selective to BG function.

Medication and finance management among HIV-infected adults: the impact of age and cognition.

This study examined the effects of aging and cognitive impairment on medication and finance management in an HIV sample. We observed main effects of age (older < younger) and neuropsychological impairment on functional task performance. Interactions between age and cognition demonstrated that older impaired individuals performed significantly more poorly than all other comparison groups. There were no relationships between laboratory performance and self-reported medication and finance management. The interaction of advancing age and cognitive impairment may confer significant functional limitations for HIV individuals that may be better detected by performance-based measures of functional abilities rather than patient self-report.

Depression, cognition, and self-appraisal of functional abilities in HIV: an examination of subjective appraisal versus objective performance.

Depression frequently co-occurs with HIV infection and can result in self-reported overestimates of cognitive deficits. Conversely, genuine cognitive dysfunction can lead to an under-appreciation of cognitive deficits. The degree to which depression and cognition influence self-report of capacity for instrumental activities of daily living (IADLs) requires further investigation. This study examined the effects of depression and cognitive deficits on self-appraisal of functional competence among 107 HIV-infected adults. As hypothesized, higher levels of depression were found among those who over-reported problems in medication management, driving, and cognition when compared to those who under-reported or provided accurate self-assessments. In contrast, genuine cognitive dysfunction was predictive of under-reporting of functional deficits. Together, these results suggest that over-reliance on self-reported functional status poses risk for error when diagnoses require documentation of both cognitive impairment and associated functional disability in everyday life.

In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells.

Although the existence of mammary stem cells has been suggested by serial transplantation studies in mice, their identification has been hindered by the lack of specific surface markers, and by the absence of suitable in vitro assays for testing stem cell properties: self-renewal and ability to generate differentiated progeny. We have developed an in vitro cultivation system that allows for propagation of human mammary epithelial cells (HMECs) in an undifferentiated state, based on their ability to proliferate in suspension, as nonadherent mammospheres. We demonstrate that nonadherent mammospheres are enriched in early progenitor/stem cells and able to differentiate along all three mammary epithelial lineages and to clonally generate complex functional structures in reconstituted 3D culture systems. Gene expression analysis of cells isolated from nonadherent mammospheres revealed overlapping genetic programs with other stem and progenitor cells and identified new markers that may be useful in the identification of mammary stem cells. The isolation and characterization of these stem cells should help elucidate the molecular pathways that govern normal mammary development and carcinogenesis.