Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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TaubCONNECT Research Perspectives:
April 2017





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» #1 Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes

» #2 Polygenic Risk Scores in Familial Alzheimer Diseases

» #1 Local Synthesis of Dynein Cofactors Matches Retrograde Transport to Acutely Changing Demands

» #2 Association of Obstructive Sleep Apnea with Episodic Memory and Cerebral Microvascular Pathology: A Preliminary Study

» #1 Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease

» #2 Novel Genetic Loci Underlying Human Intracranial Volume Identified Through Genome-Wide Association

» #3 Relation of Dysglycemia to Structural Brain Changes in a Multiethnic Elderly Cohort

» #1 Unbiased Drug Screening Identified New Cellular Pathways that Regulate Apolipoprotein E Secretion in Human Primary Astrocytes

» #2 APrediction of Relapse After Discontinuation of Antipsychotic Treatment in Alzheimer's Disease: The Role of Hallucinations

» #1 Activating Transcription Factor 4 (ATF4) Modulates Rho GTPase Levels and Function via Regulation of RhoGDIα

» #2 Brain Regions Involved in Arousal and Reward Processing are Associated with Apathy in Alzheimer's Disease and Frontotemporal Dementia

» First Place: White Matter Changes in Alzheimer's Disease

» First Place: Understanding the Role of Phosphoinositide Dysregulation in Endolysosomal Dysfunction: Implications for Alzheimer's Disease

» #1 Time-Dependent Reversal of Synaptic Plasticity Induced by Physiological Concentrations of Oligomeric Aβ42: An Early Index of Alzheimer's Disease

» #2 Evidence that COMT Genotype and Proline Interact on Negative-Symptom Outcomes in Schizophrenia and Bipolar Disorder

» #1 3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice

» #2 LRRK2 and RAB7L1 Coordinately Regulate Axonal Morphology and Lysosome Integrity in Diverse Cellular Contexts

» Alzheimer's Association International Conference (AAIC 2016)

» #1 Neuronal activity enhances tau propagation and tau pathology

» #2 Sleep Disordered Breathing and White Matter Hyperintensities in Community-Dwelling Elders

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

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

» #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 β 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




Brain Atrophy Can Introduce Age-Related Differences in BOLD Response

Qolamreza R. Razlighi, PhD

This project attempts to address one of the longstanding and key issues in the studies of brain aging using functional magnetic resonance imaging (fMRI). Use of fMRI in studies of aging is often hampered by uncertainty about age-related differences in the actual neuronal activity or in the amplitude of the hemodynamic response. Such uncertainty introduces a significant challenge in the interpretation of the fMRI results, making it almost impossible to disentangle whether or not the observed age-related differences are due to the differences in the underlying neuronal activity or due to age-related differences in hemodynamic response. Even though this issue has been extensively investigated in the field of neuroimaging, there is currently no consensus about the existence and potential sources of age-related hemodynamic alterations. Results from existing studies often contradict each other, making it extremely difficult to draw any conclusion.


Figure 1. Brain activation induced by visual (top row) and auditory (bottom row) stimuli illustrated by color-coded z-statistics overlaid on the MNI template for (b) young subjects, (c) old subjects, and (d) the contrast between young and old subjects.
 

Figure 2. Differences between extracted HRFs from young (red curves) and old (blue curves) subjects using visual and auditory stimulation in real fMRI data. (a) standard space with linear (affine) registration, and (c) native space analysis without registration. The significant difference in the magnitude is marked with * and in the delay (from peak to baseline) is marked by † (P<0.05, outliers excluded).

In the present study, published online in the journal of Human Brain Mapping, Drs. Qolamreza "Ray" Razlighi, Xueqing Liu (Biomedical Engineering), and colleagues used an event-related fMRI experiment with two robust and well-studied stimuli (visual and auditory) to detect a significant age-related difference in the amplitude of response to auditory stimulus (figure 1). Accounting for brain atrophy by circumventing spatial normalization and processing the data in subjects' native space eliminated these observed differences (figure 2). In addition, Dr. Razlighi and colleagues simulated fMRI data using age differences in brain morphology while controlling hemodynamic impulse response function (HRF) shape. Analyzing these simulated fMRI data using standard image processing resulted in differences in HRF amplitude, which were eliminated when the data were analyzed in subjects' native space. These results indicate that age-related atrophy introduces inaccuracy in co-registration to standard space, which subsequently appears as attenuation in BOLD response amplitude. According to the authors, their findings explain most of the existing contradictory reports regarding age-related differences in the fMRI BOLD responses.

Qolamreza R. Razlighi, PhD
Assistant Professor of Neuroimaging (in Neurology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)
Adjunct Assistant Professor in Biomedical Engineering
Quantitative Neuroimaging Lab
qr2108@cumc.columbia.edu



Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities

Sandra Barral, PhD   
Sandra Barral, PhD    Nicole Schupf, PhD

The factors that characterize successful aging and exceptional longevity are not fully established. As the proportion of elderly adults in the population grows, predictors of exceptional longevity become increasingly important to allow the development of approaches to promote healthy aging. Exceptional longevity can be defined in a number of ways, including survival to a specific extreme age (longevity), disability-free (active life expectancy), disease-free (healthy aging), or cognitively intact survival, and studies have also demonstrated a strong familial component to exceptional longevity.

Drs. Sandra Barral, Nicole Schupf, and colleagues in the Long Life Family Study (LLFS) have been studying the role of cognition in exceptional longevity in a cohort of multigenerational families in the United States and Denmark, where long-lived individuals, their siblings, and their offspring were recruited for an examination that characterized key intermediate phenotypes of longevity, including major chronic diseases, risk factors, physical and cognitive function, blood-based and genetic biomarkers.

Studies in diverse elderly populations have consistently reported that age-related cognitive impairment is associated with higher risk of mortality, even after adjustment for a variety of health conditions, lifestyle factors, and socio-demographic characteristics. Results from the LLFS have consistently suggested that preservation of cognitive function is a key feature of exceptional longevity. Previous work by Dr. Barral and colleagues found that offspring of probands from the LLFS showed better cognitive performance on multiple cognitive tasks compared with individuals without a family history of longevity, and showed that exceptional episodic memory performance strongly aggregates in the LLFS families and may be genetically modulated. In this study, published in the Journals of Gerontology: Medical Sciences, Barral et al. investigated whether LLFS families with exceptional cognition may also show more favorable profiles of other age-related biomarkers.

Families were categorized as showing exceptional cognition if two or more offspring of exceptionally long lived probands scored high on a composite set of cognitive tasks. Then, families with exceptional cognition were compared with families without exceptional cognition for longevity and for 28 traits from 5 health-related domains (cognitive, cardiovascular, metabolic, physical, and pulmonary). Families with exceptional cognition showed significantly higher family longevity and had a significantly better metabolic/cardiovascular profile than those of LLFS participants from non-exceptional cognition families. The healthier metabolic profile was related to obesity in an age-dependent fashion. The prevalence of obesity in families with exceptional cognition was significantly lower compared with families without exceptional cognition (38% vs 51%, p = .015) among family members less than 80 years of age. However, among members of families with exceptional cognition 80 years of age and older, the prevalence of obesity was higher (40% vs 38%, p = .011). These findings are consistent with previous work showing a broadly consistent protective association of obesity with cognitive function in late-life, that is, overweight and obese elderly subjects are at lower risk of cognitive impairment. Families with exceptional cognition also showed better physical/pulmonary function than families without exceptional cognition (β = 0.51, SE = 0.25, p = .042). Thus, exceptional longevity, like other complex traits, appears to be a multidimensional phenotype, that likely includes multiple domains such as cognition, metabolic, physical/pulmonary, and cardiovascular traits, each of them measuring multiple and correlated indicators of healthy aging.

Sandra Barral, PhD
Assistant Professor of Neurogenetics (in Neurology, the Gertrude H. Sergievsky Center, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUMC
smb2174@cumc.columbia.edu

Nicole Schupf, PhD
Professor of Epidemiology (in Neurology, Psychiatry, the Gertrude H. Sergievsky Center, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)
ns24@cumc.columbia.edu



 



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