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AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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TaubCONNECT Research Perspectives:
September 2019



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August 2019:

» Neuroinflammation in Frontotemporal Lobar Degeneration Revealed by 11Cā€PBR28 PET

» Live Imaging of ESCRT Proteins in Microfluidically Isolated Hippocampal Axons


July 2019:

» Alzheimer's Association International Conference (AAIC 2019)


June 2019:

» #1 CpGā€Related SNPs in the MS4A Region Have a Doseā€Dependent Effect on Risk of Lateā€“Onset Alzheimer Disease

» #2 MFN2 Mutations in Charcotā€“Marieā€“Tooth Disease Alter Mitochondria-Associated ER Membrane Function but Do Not Impair Bioenergetics


May 2019:

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

» #2 Brain Biomarkers and Cognition Across Adulthood


April 2019:

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

» #2 Brain Arterial Dilatation and the Risk of Alzheimer's Disease


March 2019:

» #1 Elevated Cellular Cholesterol in Familial Alzheimer's Presenilin 1 Mutation is Associated with Lipid Raft Localization of Ī²-Amyloid Precursor Protein

» #2 FDG-PET Patterns Associated with Underlying Pathology in Corticobasal Syndrome


February 2019:

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

» #2 Exercise-linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimerā€™s Models


January 2019:

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

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


December 2018:

» #1 Epigenome-Wide Study Uncovers Large-Scale Changes in Histone Acetylation Driven by Tau Pathology in Aging and Alzheimerā€™s Human Brains

» #2 Semantic Network Function Captured by Word Frequency in Nondemented APOE Īµ4 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:

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

» #2 An MRI Measure of Degenerative and Cerebrovascular Pathology in Alzheimer Disease

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


September 2018:

» #1 Clinical Experience with Cerebrospinal Fluid AĪ²42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia

» #2 Evaluation of TDP-43 Proteinopathy and Hippocampal Sclerosis in Relation to APOE Īµ4 Haplotype Status: A Community-Based Cohort Study


August 2018:

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

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

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


July 2018:

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

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


June 2018:

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

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


May 2018:

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

» #2 Oligomeric AĪ²1-42 Triggers the Generation of a Retrograde Signaling Complex from Sentinel mRNAs in Axons


April 2018:

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

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


March 2018:

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

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


February 2018:

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

» #2 Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

» #3 A Transcriptomic Atlas of Aged Human Microglia


January 2018:

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

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




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

   
Jose Gutierrez-Contreras, MD, MPH    Adam M. Brickman, PhD

White matter hyperintensities (WMH) on T2-weighted magnetic resonance (MR) imaging are typical in older adults and have been linked to several poor health outcomes, including cognitive impairment and Alzheimerā€™s disease (AD). The presence and severity of WMH have traditionally been attributed to occlusive arteriopathy, but recent evidence also implicates deep medullary venule collagenosis and associated vasogenic edema. Historically, postmortem analyses have been the sole way to analyze cerebral veins, but susceptibility-weighted imaging (SWI)ā€”a new, non-invasive technique to enhance contrast in MR imagingā€”can now used to examine cortical veins in vivo.

A new study by the laboratory of Dr. Adam Brickman, along with HHMI student and lead author Alexander Houck (University of Tennessee) and Columbia Neurologist Dr. Jose Gutierrez, used SWI to visualize and measure the diameters of large draining veins in the brain to test the hypothesis that cerebral basal vein dilation is related to WMH volume. As recently published in the American Journal of Neuroradiology, they found that increased diameters of the internal cerebral veins and the basal veins of Rosenthal were associated with greater WMH volume. The strongest association for the internal cerebral veins was in the parietal lobe, the brain region where past studies have most consistently identified a correlation between WMH and AD. The strongest association for the basal veins of Rosenthal was in the frontal lobe.

WMH on T2 FLAIR
Figure 1: Four sample images of WMH on T2 FLAIR, labeled for quantification using an intensity threshold with our software. A, Minimal WMHs. B, Mild WMHs. C, Moderate WMHs. D, Severe WMHs.

Overall, their study provides evidence of the relationship between WMHs and both the internal cerebral veins and the basal veins of Rosenthal. According to the authors, "it is unclear whether this association is merely correlative or if there is a causation between these pathologies. There are many avenues that can expand on this research in the future." The Brickman lab is in the process of developing methods for perivascular space quantification, which could be used to determine whether these spaces relate to cerebral venous diameter. The authors further suggest additional topics of analyses and techniques worthy of pursuit, concluding that "with the aging population, the clinical implications are clear: Understanding the etiology of this relationship might lead to therapeutic and preventative techniques to combat vascular disease and its downstream effects."

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



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


Ottavio Arancio, MD, PhD

Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimerā€™s disease (AD). However, despite the strong correlation between oTau and AD pathology, the molecular mechanisms by which tau protein induces synaptic dysfunction and memory impairment remain unknown.

There is a broad consensus that cyclic adenosine monophosphate (cAMP) responsive element binding (CREB) protein plays a crucial role in memory consolidation. CREB is at the crossroads of several molecular pathways and mechanisms that have been proposed as potential therapeutic targets against AD, including the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) dependent protein kinases (PKG)/CREB pathway, which is particularly attractive because drugs boosting it, especially phosphodiesterase 5 (PDE5) inhibitors, are widely used for the therapy of erectile dysfunction and pulmonary hypertension, and it is therefore plausible that their administration is compatible with therapeutic usage.

NO, a gaseous molecule produced by the NO-synthase enzyme is involved in various steps of brain physiology, from development to synaptic plasticity and memory. Intriguingly, proteomic and metabolomic studies have revealed disrupted NO homeostasis in AD [33]. Moreover, up-regulation of the NO cascade through drugs acting on its various molecular components has provided favorable results in studies aimed at finding strategies to counteract the damage of synaptic plasticity and memory by oligomers of AĪ², another toxic protein in AD. Given that oTau share a common molecular mechanism with AĪ² oligomers when they impair memory and long-term potentiation (LTP) in mice, a new study by the laboratory of Dr. Ottavio Arancio, including lead author Erica Acquarone, along with Dr. Jole Fiorito from the New York Institute of Technology, used a combination of biochemical, electrophysiological and behavioral techniques to investigate whether the oTau-induced damage of synaptic function and memory can be rescued via up-regulation of the NO cascade.

As recently published in Molecular Neurodegeneration, their findings provide a novel view on how oTau affects synaptic plasticity and memory, pointing at the NO cascade as a second messenger pathway that can be exploited to counteract tau-induced damage of synaptic plasticity and memory (Figure 9), and offering a new window of therapeutic opportunities against AD and other neurodegenerative diseases characterized by an increase in oTau.

Figure 9: oTau effect on the NO signaling cascade. Left panel shows the cascade under physiological conditions. NO is produced by the enzyme nitric oxide synthase (NOS) that converts L-arginine into L-citrulline. NO activates soluble guanilyl cyclase (sGC), which produces cyclic guanosine monosphosphate (cGMP) from guanosine triphosphate (GTP). cGMP is degraded into 5'-GMP by phosphodiesterase 5 (PDE5). The increase of cGMP levels activates cGMP-dependent protein kinase (PKG), which induces phosphorylation of cAMP-responsive element binding (CREB) and enhancement of synaptic plasticity and memory. In the presence of oTau (central panel), phosphorylation of CREB is reduced as the signaling cascade is down regulated (shown by narrower arrows), leading to an impairment of synaptic plasticity and memory processes. Treatment with PDE5 inhibitors (right panel) rescues the levels of cGMP leading to increased CREB phosphorylation and normal synaptic plasticity and memory.

Ottavio Arancio, MD, PhD
Professor of Pathology and Cell Biology (in the Taub Institute)
oa1@cumc.columbia.edu



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

Yaakov Stern, PhD
Yaakov Stern, PhD

In 2019, the Alzheimerā€™s Association (AA) reported national average annual Medicaid payment per person for individuals with dementia ($8,565) to be 23 times greater than for those without dementia ($365). The vast majority of studies that do not include Medicaid spending may substantially underestimate increased total payer costs related to dementia care. A new study by Dr. Yaakov Stern and colleagues from Neurology and Taub, along with first author Dr. Carolyn Zhu (Mount Sinai), sought to identify a more comprehensive perspective on the expenditures associated with dementia by examining data with both Medicare and Medicaid claims from the multiethnic Washington Heights-Inwood Columbia Aging Project (WHICAP).

Now published in The Journals of Gerontology, results show that in participants who had full Medicaid coverage, average annual Medicaid expenditures were substantially higher for those with dementia than those without ($50,270 vs. $21,966, p<0.001), but Medicare expenditures did not differ by dementia status ($8,458 vs. $9,324, p=0.19). In participants who did not have any Medicaid coverage, average annual Medicare expenditures were substantially higher for those with dementia than those without dementia ($12,408 vs. $8,113, p=0.02). In adjusted models, dementia was associated with a $6,278 increase in annual Medicaid spending per person after controlling for other characteristics. This work provides important insight regarding the cost of dementia in a diverse, extremely vulnerable population by highlighting cost differences due to dementia related to Medicaid.

Yaakov Stern, PhD
Professor of Neuropsychology (in Neurology, in Psychiatry, in the Gertrude H. Sergievsky Center, and in the Taub Institute)
ys11@cumc.columbia.edu



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