Brain Α-Tocopherol Concentration is Inversely Associated with Neurofibrillary Tangle Counts in Brain Regions Affected in Earlier Braak Stages: A Cross-Sectional Finding in the Oldest Old.

Objectives: Higher vitamin E status has been associated with lower risk of Alzheimer's disease (AD). However, evidence of the association of vitamin E concentration in neural tissue with AD pathologies is limited. Design: The cross-sectional relationship between the human brain concentrations of α- and γ-tocopherol and the severity of AD pathologies - neurofibrillary tangle (NFT) and neuritic plaque (NP) - was investigated. Setting & Participants: Brains from 43 centenarians (≥ 98 years at death) enrolled in the Phase III of the Georgia Centenarian Study were collected at autopsy. Measurements: Brain α- and γ-tocopherol concentrations (previously reported) were averaged from frontal, temporal, and occipital cortices. NP and NFT counts (previously reported) were assessed in frontal, temporal, parietal, entorhinal cortices, amygdala, hippocampus, and subiculum. NFT topological progression was assessed using Braak staging. Multiple linear regression was performed to assess the relationship between tocopherol concentrations and NP or NFT counts, with and without adjustment for covariates. Results: Brain α-tocopherol concentrations were inversely associated with NFT but not NP counts in amygdala (ß = -2.67, 95% CI [-4.57, -0.79]), entorhinal cortex (ß = -2.01, 95% CI [-3.72, -0.30]), hippocampus (ß = -2.23, 95% CI [-3.82, -0.64]), and subiculum (ß = -2.52, 95% CI [-4.42, -0.62]) where NFT present earlier in its topological progression, but not in neocortices. Subjects with Braak III-IV had lower α-tocopherol (median = 69,622 pmol/g, IQR = 54,389-72,155 pmol/g) than those with Braak I-II (median = 72,108 pmol/g, IQR = 64,056-82,430 pmol/g), but the difference was of borderline significance (p = 0.063). γ-Tocopherol concentrations were not associated with either NFT or NP counts in any brain regions assessed. Conclusions: Higher brain α-tocopherol level is specifically associated with lower NFT counts in brain structures affected in earlier Braak stages. Our findings emphasize the possible importance of α-tocopherol intervention timing in tauopathy progression and warrant future clinical trials.

Enhanced Learning through Multimodal Training: Evidence from a Comprehensive Cognitive, Physical Fitness, and Neuroscience Intervention.

The potential impact of brain training methods for enhancing human cognition in healthy and clinical populations has motivated increasing public interest and scientific scrutiny. At issue is the merits of intervention modalities, such as computer-based cognitive training, physical exercise training, and non-invasive brain stimulation, and whether such interventions synergistically enhance cognition. To investigate this issue, we conducted a comprehensive 4-month randomized controlled trial in which 318 healthy, young adults were enrolled in one of five interventions: (1) Computer-based cognitive training on six adaptive tests of executive function; (2) Cognitive and physical exercise training; (3) Cognitive training combined with non-invasive brain stimulation and physical exercise training; (4) Active control training in adaptive visual search and change detection tasks; and (5) Passive control. Our findings demonstrate that multimodal training significantly enhanced learning (relative to computer-based cognitive training alone) and provided an effective method to promote skill learning across multiple cognitive domains, spanning executive functions, working memory, and planning and problem solving. These results help to establish the beneficial effects of multimodal intervention and identify key areas for future research in the continued effort to improve human cognition.

Underlying sources of cognitive-anatomical variation in multi-modal neuroimaging and cognitive testing.

Healthy adults have robust individual differences in neuroanatomy and cognitive ability not captured by demographics or gross morphology (Luders, Narr, Thompson, & Toga, 2009). We used a hierarchical independent component analysis (hICA) to create novel characterizations of individual differences in our participants (N=190). These components fused data across multiple cognitive tests and neuroanatomical variables. The first level contained four independent, underlying sources of phenotypic variance that predominately modeled broad relationships within types of data (e.g., "white matter," or "subcortical gray matter"), but were not reflective of traditional individual difference measures such as sex, age, or intracranial volume. After accounting for the novel individual difference measures, a second level analysis identified two underlying sources of phenotypic variation. One of these made strong, joint contributions to both the anatomical structures associated with the core fronto-parietal "rich club" network (van den Heuvel & Sporns, 2011), and to cognitive factors. These findings suggest that a hierarchical, data-driven approach is able to identify underlying sources of individual difference that contribute to cognitive-anatomical variation in healthy young adults.

Cognitive and anatomical data in a healthy cohort of adults.

We present data from a sample of 190 healthy adults including assessments of 4 cognitive factor scores, 12 cognitive tests, and 115 MRI-assessed neuroanatomical variables (cortical thicknesses, cortical and sub-cortical volumes, fractional anisotropy, and radial diffusivity). These data were used in estimating underlying sources of individual variation via independent component analysis (Watson et al., In press) [25].

What can other animals tell us about human social cognition? An evolutionary perspective on reflective and reflexive processing.

Human neuroscience has seen a recent boom in studies on reflective, controlled, explicit social cognitive functions like imitation, perspective-taking, and empathy. The relationship of these higher-level functions to lower-level, reflexive, automatic, implicit functions is an area of current research. As the field continues to address this relationship, we suggest that an evolutionary, comparative approach will be useful, even essential. There is a large body of research on reflexive, automatic, implicit processes in animals. A growing perspective sees social cognitive processes as phylogenically continuous, making findings in other species relevant for understanding our own. One of these phylogenically continuous processes appears to be self-other matching or simulation. Mice are more sensitive to pain after watching other mice experience pain; geese experience heart rate increases when seeing their mate in conflict; and infant macaques, chimpanzees, and humans automatically mimic adult facial expressions. In this article, we review findings in different species that illustrate how such reflexive processes are related to ("higher order") reflexive processes, such as cognitive empathy, theory of mind, and learning by imitation. We do so in the context of self-other matching in three different domains-in the motor domain (somatomotor movements), in the perceptual domain (eye movements and cognition about visual perception), and in the autonomic/emotional domain. We also review research on the developmental origin of these processes and their neural bases across species. We highlight gaps in existing knowledge and point out some questions for future research. We conclude that our understanding of the psychological and neural mechanisms of self-other mapping and other functions in our own species can be informed by considering the layered complexity these functions in other species.