Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
March 2021





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February 2020:

Plasma P-Tau181, P-Tau217, and Other Blood-Based Alzheimer's Disease Biomarkers in a Multi-Ethnic, Community Study

Pathogenic Role of Delta 2 Tubulin in Bortezomib-Induced Peripheral Neuropathy


November 2020:

Association of APOE E2 Genotype with Alzheimer's and Non-Alzheimer's Neurodegenerative Pathologies

APOE Ε4 and Resting-State Functional Connectivity in Racially/Ethnically Diverse Older Adults

Assessment of Leisure Time Physical Activity and Brain Health in a Multiethnic Cohort of Older Adults

Alzheimer-Related Altered White Matter Microstructural Integrity in Down Syndrome: a Model for Sporadic AD?


October 2020:

Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces Aβ and tau pathology in the hippocampus

Alzheimer-Related Cerebrovascular Disease in Down Syndrome

Depression is Associated With Preserved Cortical Thickness Relative to Apathy in Frontotemporal Dementia


July 2020:

Endothelial Activation of Caspase-9 Promotes Neurovascular Injury in Retinal Vein Occlusion

Proteomic Profiles for Alzheimer's Disease and Mild Cognitive Impairment Among Adults with Down Syndrome Spanning Serum and Plasma: An Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) Study

Cognitive Tests aid in Clinical Differentiation of Alzheimer's Disease Versus Alzheimer's Disease with Lewy Body Disease: Evidence from a Pathological Study


June 2020:

Tau is not Necessary for Amyloid-Beta-Induced Synaptic and Memory Impairments

IL-27: An Endogenous Constitutive Repressor of Human Monocytes

Subgingival Microbiome and Clinical Periodontal Status in an Elderly Cohort: The WHICAP Ancillary Study of Oral Health


May 2020:

"Everything Hurts!" Distress in Semantic Variant Primary Progressive Aphasia

Metabolic Correlates of Prevalent Mild Cognitive Impairment and Alzheimer's Disease in Adults with Down Syndrome

Down Syndrome: Distribution of Brain Amyloid in Mild Cognitive Impairment


April 2020:

Cortical Thickness and its Associations with Age, Total Cognition and Education Across the Adult Lifespan

Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers

Phospholipase D1 Ablation Disrupts Mouse Longitudinal Hippocampal Axis Organization and Functioning


March 2020:

Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Profilin 1 Delivery Tunes Cytoskeletal Dynamics Toward CNS Axon Regeneration

Human Herpesvirus 6 Detection in Alzheimer's Disease Cases and Controls Across Multiple Cohorts


February 2020:

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

Exceptionally Low Likelihood of Alzheimer’s Dementia in APOE2 Homozygotes from a 5,000-Person Neuropathological Study


January 2020:

Microglial Activation, but not Tau Pathology, is Independently Associated with Amyloid Positivity and Memory Impairment

CRISPR/Cas9 Editing of APP C-Terminus Attenuates β-Cleavage and Promotes α-Cleavage


December 2019:

Activity-Dependent Nucleation of Dynamic Microtubules at Presynaptic Boutons Controls Neurotransmission

Role of Tau Protein in Remodeling of Circadian Neuronal Circuits and Sleep

Sleep Fragmentation, Microglial Aging, and Cognitive Impairment in Adults with and Without Alzheimer's Dementia


November 2019:

First Place: Studying Biochemical Mechanisms of Protective Gene Variants in Isogenic Stem Cell-derived Early Onset Alzheimer’s Disease Models

First Place: Glial Heterogeneity in Normal Human Cortex and Huntington Disease Interrogated Through Single Cell Nuclear RNA Sequencing


October 2019:

Pum2 Shapes the Transcriptome in Developing Axons through Retention of Target mRNAs in the Cell Body

Promotion of Axon Growth by the Secreted End of a Transcription Factor


September 2019:

Increased Diameters of the Internal Cerebral Veins and the Basal Veins of Rosenthal Are Associated with White Matter Hyperintensity Volume

Synaptic and Memory Dysfunction Induced by Tau Oligomers is Rescued by up-regulation of the Nitric Oxide Cascade

Medicaid Contributes Substantial Costs to Dementia Care in an Ethnically Diverse Community Population


August 2019:

Neuroinflammation in Frontotemporal Lobar Degeneration Revealed by 11C‐PBR28 PET

Live Imaging of ESCRT Proteins in Microfluidically Isolated Hippocampal Axons


July 2019:

Alzheimer's Association International Conference (AAIC 2019)


June 2019:

CpG‐Related SNPs in the MS4A Region Have a Dose‐Dependent Effect on Risk of Late–Onset Alzheimer Disease

MFN2 Mutations in Charcot–Marie–Tooth Disease Alter Mitochondria-Associated ER Membrane Function but Do Not Impair Bioenergetics


May 2019:

Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease

Brain Biomarkers and Cognition Across Adulthood


April 2019:

Predicting Cognitive Improvement in Normal Pressure Hydrocephalus Patients Using Preoperative Neuropsychological Testing and Cerebrospinal Fluid Biomarkers

Brain Arterial Dilatation and the Risk of Alzheimer's Disease


March 2019:

Elevated Cellular Cholesterol in Familial Alzheimer's Presenilin 1 Mutation is Associated with Lipid Raft Localization of β-Amyloid Precursor Protein

FDG-PET Patterns Associated with Underlying Pathology in Corticobasal Syndrome


February 2019:

Effect of Aerobic Exercise on Cognition in Younger Adults: A Randomized Clinical Trial

Exercise-linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimer’s Models


January 2019:

A Tau Homeostasis Signature Is Linked with the Cellular and Regional Vulnerability of Excitatory Neurons to Tau Pathology

Between-network Functional Connectivity Is Modified by Age and Cognitive Task Domain


December 2018:

Epigenome-Wide Study Uncovers Large-Scale Changes in Histone Acetylation Driven by Tau Pathology in Aging and Alzheimer’s Human Brains

Semantic Network Function Captured by Word Frequency in Nondemented APOE ε4 Carriers


November 2018:

First Place: NSUN2 is Dysregulated in Alzheimer's Disease

First Place: High-throughput Disease Modeling to Uncover Shared and Unique Characteristics Among Neurodegenerative Diseases


October 2018:

Homeostatic Plasticity Scales Dendritic Spine Volumes and Changes the Threshold and Specificity of Hebbian Plasticity

An MRI Measure of Degenerative and Cerebrovascular Pathology in Alzheimer Disease

Integrative Transcriptome Analyses of the Aging Brain Implicate Altered Splicing in Alzheimer's Disease Susceptibility


September 2018:

Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia

Evaluation of TDP-43 Proteinopathy and Hippocampal Sclerosis in Relation to APOE ε4 Haplotype Status: A Community-Based Cohort Study


August 2018:

A Multi-Omic Atlas of the Human Frontal Cortex for Aging and Alzheimer's Disease Research

An Alzheimer's Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation Consistent with a Retromer Trafficking Defect

Letter and Category Fluency Performance Correlates with Distinct Patterns of Cortical Thickness in Older Adults


July 2018:

Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

Whole-exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer's Disease


June 2018:

Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease

Preparation of Tau Oligomers After the Protein Extraction from Bacteria and Brain Cortices


May 2018:

Whole Genome Sequencing in Caribbean Hispanic Families Associated with Late-Onset Alzheimer's Disease (LOAD)

Oligomeric Aβ1-42 Triggers the Generation of a Retrograde Signaling Complex from Sentinel mRNAs in Axons


April 2018:

Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein

Medical Retirement from Sport after Concussions: A Practical Guide for a Difficult Discussion


March 2018:

Cross Domain Self-Monitoring in Anosognosia for Memory Loss in Alzheimer's Disease

White Matter Changes in Alzheimer's Disease: A Focus on Myelin and Oligodendrocytes


February 2018:

ZCCHC17 is a Master Regulator of Synaptic Gene Expression in Alzheimer's Disease

Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

A Transcriptomic Atlas of Aged Human Microglia


January 2018:

Neuronal Lysosomal Dysfunction Releases Exosomes Harboring APP C-terminal Fragments and Unique Lipid Signatures

An Inflammation-Related Nutrient Pattern is Associated with Both Brain and Cognitive Measures in a Multiethnic Elderly Population




Optimizing Subjective Cognitive Decline to Detect Early Cognitive Dysfunction

Silvia Chapman, MS    Stephanie Cosentino, PhD
Silvia Chapman, PhD    Stephanie Cosentino, PhD

Subjective Cognitive Decline (SCD) is the subjective perception that one’s cognition has declined, before such decline is evident on standard diagnostic testing. SCD is believed to precede the Mild Cognitive Impairment (MCI) stage of AD when, by definition, cognitive deficits are objectively evident. SCD’s potential as a marker of pre-clinical AD was suggested decades ago, but is now receiving renewed attention after a series of studies linking SCD to brain-based AD biomarkers such as amyloid and tau accumulation and brain degeneration. In contrast to such biomarkers, SCD is non-invasive, inexpensive, and easily obtainable. Moreover, while brain biomarkers do not always evolve into clinical dementia (the relevant outcome for the patient), SCD is presumably the beginning of the dementing process. However, in order to determine the true utility of SCD as a harbinger of AD, it is critical to identify better understand the myriad of factors which influence subjective perceptions of cognition.

A new study by Drs. Stephanie Cosentino, first author Silvia Chapman, and colleagues highlights the importance of refining the way in which SCD is assessed when determining its utility as a marker of preclinical AD. As part of an ongoing NIH R01 study, the group prospectively manipulated the way in which SCD was measured (i.e., in general, compared to 5 years ago, or compared to others your age), and how participants were asked to respond (i.e., yes/no versus Likert scale). The group then examined these different SCD scores in relation to a series of novel and sensitive memory tasks. As recently published in the Journal of Alzheimer’s Disease, Chapman and colleagues showed that age-anchored SCD (i.e., "Do you have memory difficulties compared to others your age?), when measured on a Likert scale, best approximates individuals' objective performance on the challenging memory measures. These results are in line with the idea that a certain degree of memory decline is expected and experienced with typical aging, and underscore the importance of carefully refining the assessment of SCD to avoid capturing complaints indicative of typical aging. Ongoing work by this group is examining SCD as a predictor of longitudinal cognitive decline as well as in relation to AD biomarkers, and investigating how person-specific factors (e.g., personality, attitudes about aging, metacognition) influence the utility of SCD as a marker of early disease, with the goal of establishing an SCD assessment for older adults in primary care and other clinical settings.

Silvia Chapman, PhD
Postdoctoral Research Scientist (in the Taub Institute and Sergievsky Center)
sc4056@cumc.columbia.edu

Stephanie Cosentino, PhD
Associate Professor of Neuropsychology (in Neurology, the Sergievsky Center and the Taub Institute)
sc2460@cumc.columbia.edu



The AD Tau Core Spontaneously Self-Assembles and Recruits Full-Length Tau to Filaments

Anthony Fitzpatrick, PhD Anthony Fitzpatrick, PhD

Tau accumulation is a major pathological hallmark of Alzheimer’s disease (AD) and other tauopathies, but the mechanism(s) of tau aggregation remains unclear. Taking advantage of the identification of tau filament cores by cryoelectron microscopy, Carlomagno and colleagues, including Taub faculty member Dr. Anthony Fitzpatrick, demonstrate in Cell Reports that the AD tau core possesses the intrinsic ability to spontaneously aggregate in the absence of an inducer, with antibodies generated against AD tau core filaments detecting AD tau pathology.

The AD tau core also drives aggregation of full-length wild-type tau, increases seeding potential, and templates abnormal forms of tau present in brain homogenates and antemortem cerebrospinal fluid (CSF) from patients with AD in an ultrasensitive real-time quaking-induced conversion (QuIC) assay (Figure 1).

the AD tau filament core
Figure 1: Carlomagno et al. demonstrate the AD tau filament core is able to spontaneously aggregate and recruit full-length wild-type tau to filaments andthat abnormal tau species in brain and CSF from AD patients template the AD core in a real-time QuIC assay.

Finally, they show that the filament cores in corticobasal degeneration (CBD) and Pick’s disease (PiD) similarly assemble into filaments under physiological conditions. These results document an approach to modeling tau aggregation and have significant implications for in vivo investigation of tau transmission and biomarker development.

Anthony Fitzpatrick, PhD
Assistant Professor of Biochemistry and Molecular Biophysics
Anthony.Fitzpatrick@columbia.edu



Olfactory Impairment is Related to Tau Pathology and Neuroinflammation in Alzheimer's Disease

Julia Klein    William Charles Kreisl, MD
Julia Klein (MD Candidate)    William C. Kreisl, MD

Large community cohort studies by Taub investigators Drs. Richard Mayeux, Davangere Devanand, and others have demonstrated that low University of Pennsylvania Smell Identification Test (UPSIT) scores predict cognitive decline in cognitively normal elders and patients with mild cognitive impairment (MCI). In addition, several studies, including those by Dr. William C. Kreisl, have investigated the relationships between UPSIT and in vivo measures of AD pathology, particularly amyloid. As further demonstrated by the work of Dr. Kreisl, neuroinflammation is also associated with AD pathology and cognitive decline and can be quantified using PET radioligands, such as 11C-PBR28, that bind the 18 kDa translocator protein (TSPO), a marker of immune activation. However, to date, no study has evaluated the relationship between odor identification and neuroinflammation.


Figure 1: Relationship between UPSIT score and 11C-PBR28 PET. Lower UPSIT scores were associated with greater 11C-PBR28 binding when all participants were included in medial temporal cortex (r = –0.58, p <  0.01) and combined middle and inferior temporal gyri (r = –0.47, p <  0.01). Correlations remained when only amyloid-positive participants were included (medial temporal cortex: r = –0.74, p <  0.01; combined middle and inferior temporal gyri: r = –0.47, p = 0.02) but not when only amyloid-negative participants were included. Data corrected for age, sex, and TSPO genotype.

Thus, a new study by Dr. Kreisl and colleagues from Taub, including Weill Cornell Medical Student and T35 Summer Research Trainee Julia Klein, sought to determine the relationship between odor identification and neuroinflammation, measured by 11C-PBR28 PET. They further evaluated relationships between odor identification and tau pathology using PET imaging with 18F-MK-6240, a highly specific radioligand for phosphorylated tau, and CSF concentrations of total tau (t-tau) and phosphorylated tau (p-tau), and the relationship between odor identification and amyloid pathology using CSF concentrations of amyloid-β (Aβ 42).

As recently published in the Journal of Alzheimer’s Disease, their findings demonstrate that olfactory identification is negatively associated with progression along the AD clinical continuum, such that amyloid-positive patients had lower UPSIT scores than amyloid-negative controls, and that UPSIT score positively correlated with cognitive performance and hippocampal volume. Klein et al. further found that UPSIT score negatively correlated with PET and CSF measures of tau pathology and neuroinflammation. Taken together, these results suggest that odor identification worsens with AD progression in a manner that may be related to both tau and neuroinflammatory burden.

William C. Kreisl, MD
Boris and Rose Katz Assistant Professor of Neurology (in the Taub Institute)
wck2107@cumc.columbia.edu



Race/ethnicity and Gender Modify the Association Between Diet and Cognition in U.S. Older Adults: National Health and Nutrition Examination Survey 2011-2014

Yian Gu, MD, MS, PhD
Yian Gu, MD, MS, PhD

There is emerging evidence supporting protective roles of certain dietary patterns on cognitive aging and dementia prevention, but it remains unclear whether the association between diet and cognition is similar across different racial/ethnic groups or between women and men. In a new study based on data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014—a nationally representative sample with men and women participants of multiple racial/ethnic groups—Drs. Yian Gu and Jing Guo, together with collaborator Alanna Moshfegh from the United States Department of Agriculture (USDA), found that higher adherence to Mediterranean-type Diet (MeDi) was associated with better cognition in older adults aged 60 years and older.

As recently reported in Alzheimer’s & Dementia: Translational Research & Clinical Interventions, they further found that the association between MeDi and cognition was stronger in men than in women and was significant in non-Hispanic Whites but not in other racial/ethnic groups (including non-Hispanic Blacks, Hispanics, and others). Identifying the modification effects by race/ethnicity and gender for the diet-cognition association can help with developing subpopulation-specific preventive measures for cognitive aging.

Yian Gu, MD, MS, PhD
Assistant Professor (in the department of Neurology, Department of Epidemiology, and Taub Institute)
yg2121@cumc.columbia.edu



Insights Into the Role of Diet and Dietary Flavanols in Cognitive Aging: Results of a Randomized Controlled Trial

Richard P. Sloan, PhD       
Richard P. Sloan, PhD    Adam M. Brickman, PhD    Scott Small, MD

Previous research by Drs. Scott Small, Adam Brickman, and others supports a potential causal link between cognitive aging and functional changes in the dentate gyrus (DG), a hippocampal region vulnerable to aging. In a prior proof-of-concept study, Small and Brickman showed that a smaller-scale flavanol-based dietary intervention resulted in improved performance on "object-recognition" tasks associated with cognitive function localized to the DG. Their latest study, co-led by Drs. Small and Richard Sloan (Psychiatry), aimed to replicate and expand their initial findings through a 20-week placebo-controlled cocoa flavanol-based clinical dietary intervention study in 211 healthy older participants.

The investigators examined a range of flavanol intake amounts and assessed the persistence of effects on cognitive function related to multiple brain regions. As recently reported in Scientific Reports, flavanol intake did not improve performance on the object-recognition task, the study's primary endpoint, failing to replicate previous findings. However, list learning-task performance was improved by the dietary flavanol intervention, again raising the possibility that—at the population level—flavanol-based dietary interventions may have a beneficial impact on cognitive aging.

Figure 3. Concentration of 5-(3ʹ,4ʹ-dihydroxyphenyl)-γ-valerolactone metabolites (gVLM) in plasma at baseline, 12 weeks after daily intake of placebo and flavanols at a low (260 mg), medium (510 mg) and high (770 mg) intake level, and at 20 weeks after washout (8 weeks). Data are presented as the individual concentration of gVLM for each volunteer (black lines) and as the mean (red dashed line) over time.

Richard P. Sloan, PhD
Nathaniel Wharton Professor of Behavioral Medicine (in Psychiatry) at the Columbia University Medical Center
rps7@cumc.columbia.edu

Adam M. Brickman, PhD
Professor of Neuropsychology in Neurology (in The Taub Institute, The Sergievsky Center)
amb2139@cumc.columbia.edu

Scott Small, MD
Boris and Rose Katz Professor of Neurology (in The Taub Institute, The Sergievsky Center, Radiology and in Psychiatry)
sas68@cumc.columbia.edu

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