Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.

Mothers whose infants varied in early biological characteristics (born at term, n ϭ 120; born at very low birth weight [VLBW], n ϭ 144) were randomized to a target group (n ϭ 133) or developmental feedback comparison group (n ϭ 131) to determine whether learning responsive behaviors would facilitate infant development. The target condition included videotaped examples, problem-solving activities, and mothers' critique of their own behaviors through video procedures across 10 home visits. All target versus comparison mothers showed greater increases across multiple responsiveness behaviors observed in 4 assessments conducted across 6 -13 months of age; changes in emotionally supportive behaviors were strongest for target mothers of infants born at VLBW. Increased maternal responsiveness facilitated greater growth in target infants' social, emotional, communication, and cognitive competence, supporting a causal role for responsiveness on infant development. Although benefits were generally comparable across risk groups, aspects of social and emotional skills showed greater change for those born at VLBW. Evidence for responsiveness as a multidimensional construct was provided as well as the importance of different aspects of responsiveness mediating the effect of the intervention on different infant skill domains.

The role of early versus ongoing maternal responsiveness in predicting cognitive and social development was examined in home visits for mothers, full-term children (n = 103), and medically low-risk (n = 102) and high-risk (n = 77) preterm children at 5 ages. There were 4 maternal clusters based on warm and contingent responsiveness behaviors observed early (at 6, 12, and 24 months) and late (at 3 and 4 years): high early, high late; high early, low late; low early, moderate late; and low early, low late. Children, especially preterm children, showed faster cognitive growth when mothers were consistently responsive. Social growth was similar in the consistently responsive (high-high) and the early-responsive inconsistent (high-low) clusters, but greater deceleration at 4 years among children with mothers in the inconsistent cluster refuted the notion of a unique role for early responsiveness. The importance of consistent responsiveness, defined by an affective-emotional construct, was evident even when a broader constellation of parenting behaviors was considered.

This study examined the optimal timing (infancy, toddler-preschool, or both) for facilitating responsive parenting and the intervention effects on maternal behaviors and child social and communication skills for children who vary in biological risk. The intervention during infancy, Playing and Learning Strategies (PALS I), showed strong changes in maternal affective-emotional and cognitively responsive behaviors and infants' development. However, it was hypothesized that a 2nd intervention dose in the toddler-preschool period was needed for optimal results. Families from the PALS I phase were rerandomized into either the PALS II, the toddler-preschool phase, or a Developmental Assessment Sessions condition, resulting in 4 groups. Facilitation of maternal warmth occurred best with the PALS I intervention, while cognitive responsive behaviors were best supported with the PALS II intervention. Behaviors that required responsiveness to the child's changing signals (contingent responsiveness, redirecting) required the intervention across both the early and later periods. Keywordsparenting; responsiveness; early intervention; child outcomes Responsive parenting described from different theoretical frameworks (e.g., attachment) emphasizes an affective-emotional style with positive affection and high levels of warmth and nurturance (Darling & Steinberg, 1993), responses that are contingently linked to children's signals, and acceptance of children as unique individuals (Ainsworth, Blehar, Waters, & Wall, 1978;Bornstein, 1985). From a sociocultural framework, the behaviors that fit into this style have been expanded to include cognitively responsive behaviors such as maintaining children's focus of interest (Akhtar, Dunham, & Dunham, 1991;Tomasello & Farrar, 1986) and the use of rich verbal input that is responsive to children's signals Tamis-LeMonda, Bornstein, & Baumwell, 2001 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript parenting as critically important for its role in providing a strong foundation for children to develop optimally (Ainsworth et al., 1978;Bornstein, 1985). Through repeated experiences of responsive interactions with parents that incorporate these behaviors, children are thought to internalize and generalize their learning to new experiences (e.g., Ainsworth et al., 1978;Bornstein & Tamis-LeMonda, 1989;Grusec & Goodnow, 1994). It also has been documented that parents can be supported through interventions to increase this aspect of parenting that, in turn, has facilitated a range of children's outcomes (Juffer, Hoksbergen, Riksen-Walraven, & Kohnstamm, 1997;Landry, Smith, & Swank, 2006; Van Zeigl, Mesman, Van IJzendoorn, Bakermans-Kranenburg, & Juffer, 2006).What is less well understood is whether there are developmental periods during which the influence of this parenting style is particularly important or whether consistency in responsive parenting is needed. For example, some theories identify responsive parenting during infancy as most critical, while others d...

The present study examined whether parenting and child characteristics of 2- and 3 1/2-year-old children had common paths of influence on their 4 1/2-year independent cognitive and social functioning. Structural equation modeling was guided by hypotheses that assumed children's later independence is facilitated by specialized parental support in early social interactions. To address the importance of variability in early development for understanding children's later independence, we included 104 term and 185 preterm children, as they are known to differ in early skills. As predicted, mothers' maintaining of children's interests indirectly supported 4 1/2-year cognitive and social independence through a direct, positive influence on 2- and 3 1/2-year skills. Directiveness positively supported children's early cognitive and responsiveness skills but by 3 1/2 years, high levels of this behavior had a direct, negative influence on their cognitive and social independence at 4 1/2 years. Whereas high levels of maintaining interests across these ages support later independence, directiveness needs to decrease in relation to children's increasing competencies. Results support a theoretical framework that emphasizes the importance of the social context for understanding the origins of children's later independent functioning.

Growth modeling was used to examine the relation of early parenting behaviors (averaged across 6 and 12 months) with rates of change in children's cognitive-language and social response and initiating skills assessed at 6, 12, 24, and 40 months. Groups of full-term (n = 112) and very low birth weight children, divided into medically low (n = 114) and high risk (HR; n = 73), were included to evaluate whether children who vary in their rate of development are influenced in different ways by early parenting styles. Parenting behaviors that were sensitive to children's focus of interest and did not highly control or restrict their behaviors predicted greater increases and faster rates of cognitive-language and social development, with relations stronger for the HR versus the other two groups. These maternal behaviors may provide the support all infants need to establish an optimal early foundation for later development and the specific support HR children need to learn in spite of early attentional and organizational problems. Across the past several decades, studies have examined aspects of early parenting that promote children's competencies, such as cooperation, self-assertion, initiative, and independence in problem solving (e.g.

At the postsynaptic membrane of glutamatergic synapses, the cAMP-dependent protein kinase (PKA), protein kinase C (PKC), and calcineurin (CaN) anchoring protein AKAP79/150 is recruited to NMDA and AMPA glutamate receptors by postsynaptic density (PSD)-95 family membrane-associated guanylate kinase (MAGUK) scaffold proteins. These signaling scaffold complexes may function to regulate receptor phosphorylation in synaptic plasticity. Thus, it is important to understand regulation of AKAP79/150 targeting to synapses and recruitment to PSD-MAGUK complexes. AKAP79 is targeted to the plasma membrane by an N-terminal basic domain that binds phosphatidylinositol-4,5-bisphosphate (PI-4,5-P(2)) and is regulated by PKC phosphorylation and calmodulin binding. Here we demonstrate that this same domain also binds F-actin in a calmodulin- and PKC-regulated manner, targets to membrane ruffles enriched in F-actin and PI-4,5-P(2) in COS7 cells, and localizes to dendritic spines with F-actin and PSD-MAGUKs in hippocampal neurons. Inhibition of actin polymerization disrupted AKAP79 targeting of PKA and CaN to ruffles in COS7 cells and endogenous AKAP79/150 dendritic spine localization with PKA, CaN, and PSD-MAGUKs in neurons. AKAP79/150 postsynaptic localization was rapidly regulated by NMDA receptors through CaN activation and F-actin remodeling, further suggesting that AKAP79/150 signaling scaffold targeting depends on actin dynamics. NMDA receptor activation also regulated dendritic spine localization of PKA and CaN and association of the AKAP79/150-PKA complex with PSD-MAGUKs. Because AMPA receptor PKA phosphorylation and synaptic localization are regulated by similar NMDA receptor-CaN signaling pathways linked to hippocampal long-term depression, this regulation of AKAP79/150 postsynaptic targeting might be important for synaptic plasticity.

Discovering the processes through which early adverse experiences affect children’s nervous-system development, health, and behavior is critically important for developing effective interventions. However, advances in our understanding of these processes have been constrained by conceptualizations that rely on categories of adversity that are overlapping, have vague boundaries, and lack consistent biological evidence. Here, we discuss central problems in understanding the link between early-life adversity and children’s brain development. We conclude by suggesting alternative formulations that hold promise for advancing knowledge about the neurobiological mechanisms through which adversity affects human development.