Unhealthy white matter connectivity, cognition, and racialization in older adults.

INTRODUCTION: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non-Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology-affected regions and cognition. METHODS: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions. Individual regression models tested associations of UWMC in beta-amyloid (Aß) or tau pathology-affected regions with cognition overall, stratified by racialized group, and with a racialized group interaction. RESULTS: In 201 older adults ranging from cognitively unimpaired to AD, BA participants exhibited greater UWMC and worse cognition than nHW participants. UWMC was negatively associated with cognition in 17 and 5 Aß- and tau-affected regions, respectively. Racialization did not modify these relationships. DISCUSSION: Differential UWMC burden, not differential UWMC-and-cognition associations, may drive clinical AD disparities between racialized groups. HIGHLIGHTS: Unhealthy white matter connectivity (UWMC) in Alzheimer's disease (AD) pathology-affected brain regions is associated with cognition. Relationships between UWMC and cognition are similar between Black American (BA) and non-Hispanic White (nHW) individuals. More UWMC may partially drive higher clinical AD burden in BA versus nHW populations. UWMC risk factors, particularly social and environmental, should be identified.

Dynamic impairment classification through arrayed comparisons.

The multivariate normative comparison (MNC) method has been used for identifying cognitive impairment. When participants' cognitive brain domains are evaluated regularly, the longitudinal MNC (LMNC) has been introduced to correct for the intercorrelation among repeated assessments of multiple cognitive domains in the same participant. However, it may not be practical to wait until the end of study for diagnosis. For example, in participants of the Multicenter AIDS Cohort Study (MACS), cognitive functioning has been evaluated repeatedly for more than 35 years. Therefore, it is optimal to identify cognitive impairment at each assessment, while the family-wise error rate (FWER) is controlled with unknown number of assessments in future. In this work, we propose to use the difference of consecutive LMNC test statistics to construct independent tests. Frequency modeling can help predict how many assessments each participant will have, so Bonferroni-type correction can be easily adapted. A chi-squared test is used under the assumption of multivariate normality, and permutation test is proposed where this assumption is violated. We showed through simulation and the MACS data that our method controlled FWER below a predetermined level.

An ortholog of the Vasa intronic gene is required for small RNA-mediated translation repression in Chlamydomonas reinhardtii.

Small RNAs (sRNAs) associate with Argonaute (AGO) proteins in effector complexes, termed RNA-induced silencing complexes (RISCs), which regulate complementary transcripts by translation inhibition and/or RNA degradation. In the unicellular alga Chlamydomonas, several metazoans, and land plants, emerging evidence indicates that polyribosome-associated transcripts can be translationally repressed by RISCs without substantial messenger RNA (mRNA) destabilization. However, the mechanism of translation inhibition in a polyribosomal context is not understood. Here we show that Chlamydomonas VIG1, an ortholog of the Drosophila melanogaster Vasa intronic gene (VIG), is required for this process. VIG1 localizes predominantly in the cytosol and comigrates with monoribosomes and polyribosomes by sucrose density gradient sedimentation. A VIG1-deleted mutant shows hypersensitivity to the translation elongation inhibitor cycloheximide, suggesting that VIG1 may have a nonessential role in ribosome function/structure. Additionally, FLAG-tagged VIG1 copurifies with AGO3 and Dicer-like 3 (DCL3), consistent with it also being a component of the RISC. Indeed, VIG1 is necessary for the repression of sRNA-targeted transcripts at the translational level but is dispensable for cleavage-mediated RNA interference and for the association of the AGO3 effector with polyribosomes or target transcripts. Our results suggest that VIG1 is an ancillary ribosomal component and plays a role in sRNA-mediated translation repression of polyribosomal transcripts.

Differential Effects of AIDS and Chronic Human Immunodeficiency Virus Infection on Gray Matter Volume.

BACKGROUND: Age, human immunodeficiency virus (HIV) infection, illicit drug use, and central nervous system (CNS) opportunistic infections can affect brain structure, with the striatum being particularly sensitive to HIV effects. Nevertheless, the impact of non-CNS AIDS-defining illness (ADI) on brain structure has been less investigated. We examined ADI and HIV effects on brain volume. METHODS: In a cross-sectional study, including 95 virally suppressed seropositive and 84 demographically matched, seronegative participants, we examined serostatus and ADI effects. Cortical and subcortical gray matter volume (GMV) regions of interest were estimated with computational neuroanatomy techniques applied to high-resolution, T1-weighted magnetic resonance imaging data. Linear regression was used to model HIV serostatus and ADI effects on global and regional GMV, adjusting for age, sex, CD4 nadir, drug use, and total intracranial volume. RESULTS: While HIV serostatus was associated with lower striatal volume (B = -.59 [95% confidence interval {CI}, -1.08 to -.10]), co-occurring ADI was independently associated with lower striatal volume (B = -.73 [95% CI, -1.36 to -.09]). ADI was also associated with lower global (B = -19.35 [95% CI, -32.42 to -6.29]) and regional GMV. CONCLUSIONS: While HIV infection is associated with a localized effect on striatal structure, having a prior ADI is a strong predictor of smaller global and regional GMV. The lack of interaction between HIV serostatus or ADI with age suggests that chronic HIV infection and ADI have independent effects on brain structure, without associated accelerated lower volume with age. ADI history should be incorporated into statistical adjustments in HIV neuroimaging analysis. These findings also lend support to current HIV treatment guidelines urging prompt antiretroviral therapy initiation after HIV diagnosis.

Cardiac-induced cerebral pulsatility, brain structure, and cognition in middle and older-aged adults.

Changes of cardiac-induced regional pulsatility can be associated with specific regions of brain volumetric changes, and these are related with cognitive alterations. Thus, mapping of cardiac pulsatility over the entire brain can be helpful to assess these relationships. A total of 108 subjects (age: 66.5 ± 8.4 years, 68 females, 52 healthy controls, 11 subjective cognitive decline, 17 impaired without complaints, 19 MCI and 9 AD) participated. The pulsatility map was obtained directly from resting-state functional MRI time-series data at 3T. Regional brain volumes were segmented from anatomical MRI. Multidomain neuropsychological battery was performed to test memory, language, attention and visuospatial construction. The Montreal Cognitive Assessment (MoCA) was also administered. The sparse partial least square (SPLS) method, which is desirable for better interpreting high-dimensional variables, was applied for the relationship between the entire brain voxels of pulsatility and 45 segmented brain volumes. A multiple holdout SPLS framework was used to optimize sparsity for assessing the pulsatility-volume relationship model and to test the reliability by fitting the models to 9 different splits of the data. We found statistically significant associations between subsets of pulsatility voxels and subsets of segmented brain volumes by rejecting the omnibus null hypothesis (any of 9 splits has p < 0.0056 (=0.05/9) with the Bonferroni correction). The pulsatility was positively associated with the lateral ventricle, choroid plexus, inferior lateral ventricle, and 3rd ventricle and negatively associated with hippocampus, ventral DC, and thalamus volumes for the first pulsatility-volume relationship. The pulsatility had an additional negative relationship with the amygdala and brain stem volumes for the second pulsatility-volume relationship. The spatial distribution of correlated pulsatility was observed in major feeding arteries to the brain regions, ventricles, and sagittal sinus. The indirect mediating pathways through the volumetric changes were statistically significant between the pulsatility and multiple cognitive measures (p < 0.01). Thus, the cerebral pulsatility, along with volumetric measurements, could be a potential marker for better understanding of pathophysiology and monitoring disease progression in age-related neurodegenerative disorders.

Estrogen, brain structure, and cognition in postmenopausal women.

Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.

Quantifying diagnostic accuracy improvement of new biomarkers for competing risk outcomes.

The net reclassification improvement (NRI) and the integrated discrimination improvement (IDI) were originally proposed to characterize accuracy improvement in predicting a binary outcome, when new biomarkers are added to regression models. These two indices have been extended from binary outcomes to multi-categorical and survival outcomes. Working on an AIDS study where the onset of cognitive impairment is competing risk censored by death, we extend the NRI and the IDI to competing risk outcomes, by using cumulative incidence functions to quantify cumulative risks of competing events, and adopting the definitions of the two indices for multi-category outcomes. The "missing" category due to independent censoring is handled through inverse probability weighting. Various competing risk models are considered, such as the Fine and Gray, multistate, and multinomial logistic models. Estimation methods for the NRI and the IDI from competing risk data are presented. The inference for the NRI is constructed based on asymptotic normality of its estimator, and the bias-corrected and accelerated bootstrap procedure is used for the IDI. Simulations demonstrate that the proposed inferential procedures perform very well. The Multicenter AIDS Cohort Study is used to illustrate the practical utility of the extended NRI and IDI for competing risk outcomes.

Electrochemistry of Quinones with Respect to their Role in Biomedical Chemistry.

Quinones are ubiquitous in nature and form one of the largest class of antitumor agents approved for clinical use. They are known to be efficient in inhibiting cancer cells growth. Under physiological conditions they can undergo non-enzymatic one-electron reduction to give the moderately toxic species of semiquinone radical-anion. Thus, electrochemical study of quinones might provide a basic knowledge on semi-quinone radicals formation in both in vivo and in vitro under different media. Several processes are outlined briefly and discussed in the present article. Previously we investigated the electrochemical and spectral properties of ω-N-quinonyl amino acids. Such quinone-bearing peptides are known to be cytotoxic and of potential clinical significance. We were able to prove that the ω-amino quinonyl compounds are very effective in producing stable semiquinone radicals. Moreover, a direct relation was found between the first reduction potentials of the quinonyl moiety and their reactivity towards the ω-amino acids. In order to increase our knowledge of such amino quinonyl compounds and enlarge the arsenal of such cytotoxic compounds, a series of N,N-diquinonyl amines (1-6) bearing an internal proton (stems from the NH moiety) were synthesized. Their electron-transfer capabilities were probed by cyclic voltammetry measurements, in dichloromethane. It was found that the acidic NH group linking the two quinonyl moieties undergoes an initial electrochemical reduction step and generates a nitride anion. This step is followed by further reductions to yield quasi-stable semiquinone radicals and polyanions, Since these acidic diquinones (1-6) serve also as a source of internal proton donors even in non-polar medium, they might cause protonation of basic radical-anions and polyanion intermediates during the various electrochemical stages. The processes are demonstrated and discussed by analyzing different mechanistic schemes. The successful generation of relatively stable semiquinone radicals is a prerequisite for the manifestation of site directed antitumor activity by these bis-quinonyl amino derivatives. Based on the values of their redox potentials some of them could be promising candidates for clinical development.

Longitudinal multivariate normative comparisons.

Motivated by the Multicenter AIDS Cohort Study (MACS), we develop classification procedures for cognitive impairment based on longitudinal measures. To control family-wise error, we adapt the cross-sectional multivariate normative comparisons (MNC) method to the longitudinal setting. The cross-sectional MNC was proposed to control family-wise error by measuring the distance between multiple domain scores of a participant and the norms of healthy controls and specifically accounting for intercorrelations among all domain scores. However, in a longitudinal setting where domain scores are recorded multiple times, applying the cross-sectional MNC at each visit will still have inflated family-wise error rate due to multiple testing over repeated visits. Thus, we propose longitudinal MNC procedures that are constructed based on multivariate mixed effects models. A χ2 test procedure is adapted from the cross-sectional MNC to classify impairment on longitudinal multivariate normal data. Meanwhile, a permutation procedure is proposed to handle skewed data. Through simulations we show that our methods can effectively control family-wise error at a predetermined level. A dataset from a neuropsychological substudy of the MACS is used to illustrate the applications of our proposed classification procedures.

Evaluating the Spectrum of Cognitive-Motor Relationships During Dual-Task Jump Landing.

Cognitive function plays a role in understanding noncontact anterior cruciate ligament injuries, but the research into how cognitive function influences sport-specific movements is underdeveloped. The purpose of this study was to determine how various cognitive tasks influenced dual-task jump-landing performance along with how individuals' baseline cognitive ability mediated these relationships. Forty female recreational soccer and basketball players completed baseline cognitive function assessments and dual-task jump landings. The baseline cognitive assessments quantified individual processing speed, multitasking, attentional control, and primary memory ability. Dual-task conditions for the jump landing included unanticipated and anticipated jump performance, with and without concurrent working memory and captured visual attention tasks. Knee kinematics and kinetics were acquired through motion capture and ground reaction force data. Jumping conditions that directed visual attention away from the landing, whether anticipated or unanticipated, were associated with decreased peak knee flexion angle (P < .001). No interactions between cognitive function measures and jump-landing conditions were observed for any of the biomechanical variables, suggesting that injury-relevant cognitive-motor relationships may be specific to secondary task demands and movement requirements. This work provides insight into group- and subject-specific effects of established anticipatory and novel working memory dual-task paradigms on the neuromuscular control of a sport-specific movement.

Studying the neuropsychological sequelae of SARS-CoV-2: lessons learned from 35 years of neuroHIV research.

The virology of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the human immune response to the virus are under vigorous investigation. There are now several reports describing neurological symptoms in individuals who develop coronavirus disease 2019 (COVID-19), the syndrome associated with SARS-CoV-2 infection. The prevalence, incidence, and clinical course of these symptoms will become clearer in the coming months and years through epidemiological studies. However, the long-term neurological and cognitive consequence of SARS-CoV-2 infection will remain conjectural for some time and will likely require the creation of cohort studies that include uninfected individuals. Considering the early evidence for neurological involvement in COVID-19 it may prove helpful to compare SARS-CoV-2 with another endemic and neurovirulent virus, human immunodeficiency virus-1 (HIV-1), when designing such cohort studies and when making predictions about neuropsychological outcomes. In this paper, similarities and differences between SARS-CoV-2 and HIV-1 are reviewed, including routes of neuroinvasion, putative mechanisms of neurovirulence, and factors involved in possible long-term neuropsychological sequelae. Application of the knowledge gained from over three decades of neuroHIV research is discussed, with a focus on alerting researchers and clinicians to the challenges in determining the cause of neurocognitive deficits among long-term survivors.

Neuroprotective effect of placenta-derived mesenchymal stromal cells: role of exosomes.

We have established early-gestation chorionic villus-derived placenta mesenchymal stromal cells (PMSCs) as a potential treatment for spina bifida (SB), a neural tube defect. Our preclinical studies demonstrated that PMSCs have the potential to cure hind limb paralysis in the fetal lamb model of SB via a paracrine mechanism. PMSCs exhibit neuroprotective function by increasing cell number and neurites, as shown by indirect coculture and direct addition of PMSC-conditioned medium to the staurosporine-induced apoptotic human neuroblastoma cell line, SH-SY5Y. PMSC-conditioned medium suppressed caspase activity in apoptotic SH-SY5Y cells, suggesting that PMSC secretome contributes to neuronal survival after injury. As a part of PMSC secretome, PMSC exosomes were isolated and extensively characterized; their addition to apoptotic SH-SY5Y cells mediated an increase in neurites, suggesting that they exhibit neuroprotective function. Proteomic and RNA sequencing analysis revealed that PMSC exosomes contain several proteins and RNAs involved in neuronal survival and development. Galectin 1 was highly expressed on the surface of PMSCs and PMSC exosomes. Preincubation of exosomes with anti-galectin 1 antibody decreased their neuroprotective effect, suggesting that PMSC exosomes likely impart their effect via binding of galectin 1 to cells. Future studies will include in-depth analyses of the role of PMSC exosomes on neuroprotection and their clinical applications.-Kumar, P., Becker, J. C., Gao, K., Carney, R. P., Lankford, L., Keller, B. A., Herout, K., Lam, K. S., Farmer, D. L., Wang, A. Neuroprotective effect of placenta-derived mesenchymal stromal cells: role of exosomes.

Joint coordination when running in minimalist, neutral, and ultra-cushioning shoes.

Ultra-cushioning (ULTRA) shoes are new to the running shoe market. Several studies have evaluated kinematics and kinetics while running in ULTRA shoes, however it remains unknown how such shoes influence joint coordination. Therefore, the purpose of this study was to evaluate lower extremity coordination and coordination variability when running in minimalist (MIN), traditional (NEUT) and ULTRA shoes. Fifteen runners ran for ten minutes in each shoe type. Coordination patterns and coordination variability were assessed for rearfoot-tibia, rearfoot-knee, and tibia-knee couplings using a modified vector coding method during early, mid, and late stance periods. During late stance ULTRA shoes resulted in more antiphase coordination than MIN (p =.036) or NEUT (p =.047) shoes and less in-phase coordination than MIN (p =.048) or NEUT (p =.013) shoes. During late stance there was also more proximal phase rearfoot-knee coordination in ULTRA shoes than in either MIN (p =.039) or NEUT (p =.005) shoes and less in-phase coordination in ULTRA shoes than in NEUT shoes (p =.006). There were no differences in coordination variability between shoes during any phase. The differences in coordination may have implications for tissue loading and injury development when running in ULTRA shoes..

Surviving Lambs with Myelomeningocele Repaired in utero with Placental Mesenchymal Stromal Cells for 6 Months: A Pilot Study.

BACKGROUND: Fetal repair of myelomeningocele (MMC) with placental mesenchymal stromal cells (PMSCs) rescues ambulation in the ovine model up to 48 h postnatally. Outcomes past 48 h are unknown as MMC lambs have not been survived past this timepoint. OBJECTIVE: We aimed to survive lambs for 6 months following the fetal repair of MMC with PMSCs. METHODS: Fetal MMC lambs were repaired with PMSCs. Lambs received either no additional treatment or postnatal bracing and physical therapy (B/PT). Motor function was assessed with the sheep locomotor rating (SLR). Lambs with an SLR of 15 at birth were survived for 6 months or until a decline in SLR less than 15, whichever came first. All lambs underwent a perimortem MRI. RESULTS: The lambs with no postnatal treatment (n = 2) had SLR declines to 7 and 13 at 29 and 65 days, respectively, and were euthanized. These lambs had a spinal angulation of 57° and 47°, respectively. The B/PT lamb (n = 1) survived for 6 months with a sustained SLR of 15 and a lumbar angulation of 42°. CONCLUSION: Postnatal physical therapy and bracing counteracted the inherent morbidity of the absent paraspinal muscles in the ovine MMC model allowing for survival and maintenance of rescued motor function of the prenatally treated lamb up to 6 months.

A Decade of Experience with the Ovine Model of Myelomeningocele: Risk Factors for Fetal Loss.

INTRODUCTION: The ovine model is the gold standard large animal model of myelomeningocele (MMC); however, it has a high rate of fetal loss. We reviewed our experience with the model to determine risk factors for fetal loss. METHODS: We performed a retrospective review from 2009 to 2018 to identify operative factors associated with fetal loss (early fetal demise, abortion, or stillbirth). Operative risk factors included gestational age at operation, operative time, reduction of multiple gestations, amount of replaced amniotic fluid, ambient temperature, and method of delivery. RESULTS: MMC defects were created in 232 lambs with an overall survival rate of 43%. Of the 128 fetuses that died, 53 (42%) had demise prior to repair, 61 (48%) aborted, and 14 (11%) were stillborn. Selective reduction of multiple gestations in the same uterine horn was associated with increased fetal demise (OR 3.03 [95% CI 1.29-7.05], p = 0.01). Later gestational age at MMC repair and Cesarean delivery were associated with decreased abortion/stillbirth (OR 0.90 [95% CI 0.83-0.90], p = 0.03, and OR 0.37 [95% CI 0.16-0.31], p = 0.02), respectively. CONCLUSION: Avoiding selective reduction, repairing MMC later in gestation, and performing Cesarean delivery decreases the rate of fetal loss in the ovine MMC model.

Temporal variability in size and growth of Atlantic herring in the Gulf of Maine.

Variability in life history traits and structural diversity of commercially exploited fishes in response to stress can impact their population dynamics and sustainability. Using data from a fishery dependent sampling program from 1978 to 2011, we evaluated temporal variability of size and growth of adult Atlantic herring (Clupea harengus) in the Gulf of Maine. We then developed and tested the hypotheses on the links of such temporal changes to population density and environmental factors and found decreases in size and growth potential. Generalized additive models found that density dependence was the main driver of such changes over sea surface temperature and salinity. Our results highlight the importance of density dependent processes in regulating growth and population size structure for Atlantic herring in the Gulf of Maine.

Knee Kinetics During Squats of Varying Loads and Depths in Recreationally Trained Women.

Flores, V, Becker, J, Burkhardt, E, and Cotter, J. Knee kinetics during squats of varying loads and depths in recreationally trained women. J Strength Cond Res 34(7): 1945-1952, 2020-The back squat exercise is typically practiced with varying squat depths and barbell loads. However, depth has been inconsistently defined, resulting in unclear safety precautions when squatting with loads. In addition, women exhibit anatomical and kinematic differences to men, which may predispose them to knee joint injuries. The purpose of this study was to characterize peak knee extensor moments (pKEMs) at 3 commonly practiced squat depths of above-parallel, parallel, and full depths, and with 3 loads of 0 (unloaded), 50, and 85% depth-specific 1 repetition maximum (1RM) in recreationally active women. Nineteen women (age, 25.1 ± 5.8 years; body mass, 62.5 ± 10.2 kg; height, 1.6 ± 0.10 m; mean ± SD) performed squats of randomized depth and load. Inverse dynamics were used to obtain pKEMs from 3-dimensional knee kinematics. Depth and load had significant interaction effects on pKEMs (p = 0.014). Significantly greater pKEMs were observed at full depth compared with parallel depth with 50% 1RM load (p = 0.001, d = 0.615) and 85% 1RM load (p = 0.010, d = 0.714). Greater pKEMs were also observed at full depth compared with above-parallel depth with 50% 1RM load (p = 0.003, d = 0.504). Results indicate that effect of load on female pKEMs do not follow a progressively increasing pattern with either increasing depth or load. Therefore, when high knee loading is a concern, individuals must carefully consider both the depth of squat being performed and the relative load they are using.

HIV infection and age effects on striatal structure are additive.

The age of the HIV-infected population is increasing. Although many studies document gray matter volume (GMV) changes following HIV infection, GMV also declines with age. Findings have been inconsistent concerning interactions between HIV infection and age on brain structure. Effects of age, substance use, and inadequate viral suppression may confound identification of GMV serostatus effects using quantitative structural measures. In a cross-sectional study of HIV infection, including 97 seropositive and 84 seronegative, demographically matched participants, ages 30-70, we examined serostatus and age effects on GMV and neuropsychological measures. Ninety-eight percent of seropositive participants were currently treated with anti-retroviral therapies and all were virally suppressed. Gray, white, and CSF volumes were estimated using high-resolution T1-weighted MRI. Linear regression modeled effects of serostatus, age, education, comorbidities, and magnetic field strength on brain structure, using both a priori regions and voxel-based morphometry. Although seropositive participants exhibited significant bilateral decreases in striatal GMV, no serostatus effects were detected in the thalamus, hippocampus, or cerebellum. Age was associated with cortical, striatal, thalamic, hippocampal, and cerebellar GMV reductions. Effects of age and serostatus on striatal GMV were additive. Although no main effects of serostatus on neuropsychological performance were observed, serostatus moderated the relationship between pegboard performance and striatal volume. Both HIV infection and age were associated with reduced striatal volume. The lack of interaction of these two predictors suggests that HIV infection is associated with premature, but not accelerated, brain age. In serostatus groups matched on demographic and clinical variables, there were no observed differences in neuropsychological performance. Striatal GMV measures may be promising biomarker for use in studies of treated HIV infection.

High-dimensional longitudinal classification with the multinomial fused lasso.

We study regularized estimation in high-dimensional longitudinal classification problems, using the lasso and fused lasso regularizers. The constructed coefficient estimates are piecewise constant across the time dimension in the longitudinal problem, with adaptively selected change points (break points). We present an efficient algorithm for computing such estimates, based on proximal gradient descent. We apply our proposed technique to a longitudinal data set on Alzheimer's disease from the Cardiovascular Health Study Cognition Study. Using data analysis and a simulation study, we motivate and demonstrate several practical considerations such as the selection of tuning parameters and the assessment of model stability. While race, gender, vascular and heart disease, lack of caregivers, and deterioration of learning and memory are all important predictors of dementia, we also find that these risk factors become more relevant in the later stages of life.

Systemic inflammation as a predictor of brain aging: Contributions of physical activity, metabolic risk, and genetic risk.

Inflammatory processes may contribute to risk for Alzheimer's disease (AD) and age-related brain degeneration. Metabolic and genetic risk factors, and physical activity may, in turn, influence these inflammatory processes. Some of these risk factors are modifiable, and interact with each other. Understanding how these processes together relate to brain aging will help to inform future interventions to treat or prevent cognitive decline. We used brain magnetic resonance imaging (MRI) to scan 335 older adult humans (mean age 77.3 ±â€¯3.4 years) who remained non-demented for the duration of the 9-year longitudinal study. We used structural equation modeling (SEM) in a subset of 226 adults to evaluate whether measures of baseline peripheral inflammation (serum C-reactive protein levels; CRP), mediated the baseline contributions of genetic and metabolic risk, and physical activity, to regional cortical thickness in AD-relevant brain regions at study year 9. We found that both baseline metabolic risk and AD risk variant apolipoprotein E ε4 (APOE4), modulated baseline serum CRP. Higher baseline CRP levels, in turn, predicted thinner regional cortex at year 9, and mediated an effect between higher metabolic risk and thinner cortex in those regions. A higher polygenic risk score composed of variants in immune-associated AD risk genes (other than APOE) was associated with thinner regional cortex. However, CRP levels did not mediate this effect, suggesting that other mechanisms may be responsible for the elevated AD risk. We found interactions between genetic and environmental factors and structural brain health. Our findings support the role of metabolic risk and peripheral inflammation in age-related brain decline.