Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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TaubCONNECT Research Perspectives:
May 2016





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» #1 White Matter Hyperintensities are a Core Feature of Alzheimer's Disease: Evidence From the Dominantly Inherited Alzheimer Network

» #2 Parkinson's Disease: Guilt by Genetic Association

» #1 PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease

» #2 PP2A Methylation Controls Sensitivity and Resistance to β-Amyloid–Induced Cognitive and Electrophysiological Impairments

» #1 Tau-driven 26S Proteasome Impairment and Cognitive Dysfunction can be Prevented Early in Disease by Activating cAMP-PKA Signaling

» #2 Older Adults with Poor Self-rated Memory have less Depressive Symptoms and Better Memory Performance when Perceived Self-efficacy is High

» #1 Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory

» #2 Examining the Pathways Between Self-Awareness and Well-Being in Mild to Moderate Alzheimer Disease

» #3 Mediterranean Diet and Brain Structure in a Multiethnic Elderly Cohort

» #1 Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates

» #2 Telomere Longitudinal Shortening as a Biomarker for Dementia Status of Adults With Down Syndrome

» #1 The Reference Ability Neural Network Study: Life-time stability of reference-ability neural networks derived from task maps of young adults

» #2 Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease

» #1 First Place: DREADDs Activation in the Medial Entorhinal Cortex (MEC) of EC-Tau Mice

» #1 First Place: Amyloid Precursor Protein (APP) is Ubiquitinated at Multiple Sites in the COOH-Terminal Domain as a Signal for Endosomal Sorting

» #1 F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease

» #2 The keystone of Alzheimer pathogenesis might be sought in Aβ physiology

» #1 Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

» #2 Brain Amyloid Deposition and Longitudinal Cognitive Decline in Nondemented Older Subjects: Results from a Multi-Ethnic Population

» #1 Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome

» #2 Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease

» #1 SUMO1 Affects Synaptic Function, Spine Density and Memory

» #2 Connectivity and Circuitry in a Dish Versus in a Brain

» #1 Making Cognitive Latent Variables Manifest: Distinct Neural Networks For Fluid Reasoning And Processing Speed

» #2 Functional Network Mediates Age-related Differences in Reaction Time: a Replication and Extension Study

» #3 Self-Efficacy Buffers the Relationship between Educational Disadvantage and Executive Functioning

» #1 Specific Downregulation of Hippocampal ATF4 Reveals a Necessary Role in Synaptic Plasticity and Memory

» #2 Mediterranean Diet and Leukocyte Telomere Length in a Multi-ethnic Elderly Population

» #1 Cerebellum can serve as a pseudo-reference region in Alzheimer's disease to detect neuroinflammation measured with PET radioligand binding to translocator protein (TSPO)

» #2 Assembly and Interrogation of Alzheimer's Disease Genetic Networks Reveal Novel Regulators of Progression

» Neurotherapeutics: Rethinking Alzheimer's Disease Therapies

» #1 Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau

» #2 Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community

» #3 Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar

» Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease

» Lobar Microbleeds Are Associated with a Decline in Executive Functioning in Older Adults

» Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

» Inbreeding among Caribbean Hispanics from the Dominican Republic and its effects on risk of Alzheimer disease

» Coding mutations in SORL1 and Alzheimer's disease

» First Place: Pathogenic Role of Formin-mediated Stable Detyrosinated
     Microtubule Inductionby Amyloid beta

» First Place: Differential responsiveness to entorhinal cortical input distinguishes CA1 pyramidal neuron subpopulations

» Soluble amyloid beta levels are elevated in the white matter of Alzheimer's patients, independent of cortical plaque severity

» A Time Course Analysis of the Electrophysiological Properties of Neurons Differentiated from Human Induced Pluripotent Stem Cells (iPSCs)

» Axonally Synthesized ATF4 Transmits a Neurodegenerative Signal across Brain Regions

» Olfactory Dysfunction in the Elderly: Basic Circuitry and Alterations with Normal Aging and Alzheimer's Disease

» Neurological disorders: Quality-control pathway unlocked

» Estrogen Receptor α Variants Modify Risk for Alzheimer's Disease in a Multiethnic Female Cohort

» Combined suppression of CASP2 and CASP6 protects retinal ganglion cells from apoptosis and promotes axon regeneration through CNTF-mediated JAK/STAT signalling and Guidelines

» Local synthesis of TC10 is required for membrane expansion during axon outgrowth

» Dynamin 1 is Required for Memory Formation

» Behavioral Assays with Mouse Models of Alzheimer's Disease: Practical Considerations and Guidelines

» Biobanked Alzheimer's Brain Tissue Yields Living Neurons

» Picomolar Amyloid-ß Peptides Enhance Spontaneous Astrocyte Calcium Transients




White Matter Integrity as a Mediator in the Relationship between Dietary Nutrients and Cognition in the Elderly

   
Yian Gu, PhD    Adam M. Brickman, PhD

Mounting evidence suggests that dietary factors are associated with risk for Alzheimer’s disease and cognitive decline among the elderly. Previous work from Dr. Gu and others have shown that dietary factors are also implicated in maintaining brain macrostructures, such as brain volumes assessed by magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) is a sensitive MRI-based neuroimaging technique that assesses the integrity of white matter microstructure by measuring diffusion properties of water in the brain, and studies have shown that DTI metrics predict dementia or cognitive impairment. However, little is known about the association of dietary patterns with microstructural brain imaging markers such as white matter integrity.


Fig. 1. Mediation model for composite memory score. Models were analyzed using Preacher and Hayes's (Preacher and Hayes 2008) PROCESS SPSS macro. β indicate standardized beta weights and were estimated from models adjusted for age, sex, education, ethnicity, APOE, and caloric intake. The 95%CI indicates the 10000 sample bootstrapped 95% confidence intervals for the indirect effects. A 95%CI not including 0 indicates statistic significance. R2 indicates the fit of the mediation model. Acronyms: fractional anisotropy (FA); confidence interval (CI).

Recently published in the Annals of Neurology, Dr. Gu, Dr. Adam Brickman, and colleagues investigated the association between dietary nutrient intake and white matter integrity among 239 elderly (≥65 years) participants of the Washington Heights/Hamilton Heights Inwood Columbia Aging Project (WHICAP). The study also evaluated the extent to which the association between nutrient intake and cognition is due to the variability in white matter microstructure. The white matter integrity in the study was assessed using DTI, and the most widely used metric derived from DTI, fractional anisotropy (FA), was used in the analysis. Higher FA values indicate greater directionality of diffusion and preserved microstructure. Dietary data were collected using food frequency questionnaire, and nutrient patterns were derived from principal component analysis based on energy-adjusted intake of 24 selected nutrients. Generalized linear models were used to assess the association between nutrient patterns and mean FA of 26 white matter tracts. Mediation analysis was used to determine if FA mediates the nutrient-cognition relationship. All models were adjusted for age at time of scan, gender, ethnicity, education, caloric intake, and Apolipoprotein genotype.

In the current study, results showed that there was a positive association between a principal component analysis-derived nutrient pattern (omega-3 and omega-6 poly-unsaturated fatty acids and vitamin E) and better white matter integrity, indicated by higher value of DTI metric FA. Those with the highest tertile of nutrient pattern score had a mean of 0.01 (p=0.01) higher FA value than those with the lowest tertile, similar to the effect of a ten-year decrease in age (b for age=−0.001, p=0.01). In addition, the study also found that FA mediated the relationship between this nutrient pattern and memory, language, visuospatial and speed/executive function, and mean cognitive scores. This study offers important evidence to support a positive association between consumption of poly-unsaturated fatty acids and vitamin E rich foods and white matter integrity in the elderly, as well as the role brain white matter plays in the relationship between diet and cognition.

Yian Gu, PhD
Assistant Professor of Neuropsychology
yg2121@cumc.columbia.edu

Adam M. Brickman, PhD
Associate Professor of Neuropsychology
amb2139@cumc.columbia.edu



Dementia Risk and Protective Factors Differ in the Context of Memory Trajectory Groups

   
Laura Zahodne, PhD     Jennifer J. Manly, PhD

There is great heterogeneity in the trajectories of memory performance in late life. Some adults enter late life with above average memory performance but experience steep declines, while some enter late life with below average memory performance and enjoy many years of cognitive stability. Dr. Laura Zahodne and colleagues from the Taub Institute previously used the data-driven approach of growth mixture modeling to identify four distinct subgroups of older adults in the Washington Heights-Inwood Columbia Aging Project (WHICAP) based on repeated memory assessments: "Stable-High," "Stable-Low," "Decline," and "Rapid Decline." While individuals showing memory decline were more likely to develop incident dementia, each of the four subgroups contained individuals who converted to dementia.

In a recent follow-up study published in the Journal of Alzheimer's Disease, Zahodne et al. showed that the predictive value of several well-known dementia risk and protective factors differed across the four memory trajectory subgroups. For example, higher educational attainment did not protect against incident dementia for older adults showing the steepest memory declines, in whom stroke and APOE genotype were most predictive of conversion. These findings suggest that there are different pathways to dementia in older adults, and resilience or vulnerability factors may modify the influence of specific dementia risk/protective factors. Dementia risk profiles may be improved by considering interactions between risk/protective factors and a patient's unique cognitive history.

Laura Zahodne, PhD
Associate Research Scientist
lbz2105@cumc.columbia.edu

Jennifer J. Manly, PhD
Associate Professor of Neuropsychology
jjm71@cumc.columbia.edu



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