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TaubCONNECT Research Perspectives:
February 2018





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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

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


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


December 2017:

» #1 Neuronal Hyperactivity Due to Loss of Inhibitory Tone in APOE4 Mice Lacking Alzheimer's Disease-Like Pathology
and
» The Endosomal–Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo

» #2 The Historical Progression from ADL Scrutiny to IADL to Advanced ADL: Assessing Functional Status in the Earliest Stages of Dementia

November 2017:

» First Place: A CSF Proteomic Screen Links Retromer to Alzheimer's Pathogenic Pathways and Suggests Endosomal-Trafficking Biomarkers

» First Place: Microglia Identity in the Aged and AD Human Brain

October 2017:

» #1 Intra-Axonal Synthesis of SNAP25 is Required for the Formation of Presynaptic Terminals

» #2 Increased Localization of APP-C99 in Mitochondria-associated ER Membranes Causes Mitochondrial Dysfunction in Alzheimer Disease

September 2017:

» #1 Atabilization of Dynamic Microtubules by mDia1 Drives Tau-dependent Aβ1-42 Synaptotoxicity

» #2 An xQTL Map Integrates the Genetic Architecture of the Human Brain's Transcriptome and Epigenome

August 2017:

» #1 Abolishing Tau Cleavage by Caspases at Aspartate421 Causes Memory/Synaptic Plasticity Deficits and Pre-Pathological Tau Alterations

» #2 Mediterranean Diet and Cognitive Health: Initial Results from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD)

July 2017:

» #1 Abnormal Neurofilament Inclusions and Segregations in Dorsal Root Ganglia of A Charcot-Marie-Tooth Type 2E Mouse Model

» #2 LTP and Memory Impairment Caused by Extracellular Aβ and Tau Oligomers is APP-Dependent

June 2017:

» #1 Post translational Remodeling of Ryanodine Receptor Induces Calcium Leak Leading to Alzheimer's Disease like Pathologies and Cognitive Deficits

» #2 Neuropathologic Features of TOMM40 '523 Variant on Late-Life Cognitive Decline

May 2017:

» #1 Memory-Enhancing Effects of GEBR-32a, a New PDE4D Inhibitor Holding Promise for the Treatment of Alzheimer's Disease

» #2 An Approach to Studying the Neural Correlates of Reserve

April 2017:

» #1 Brain Atrophy Can Introduce Age-Related Differences in BOLD Response

» #2 Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities

March 2017:

» #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

February 2017:

» #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

January 2017:

» #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




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

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

Anosognosia, or unawareness of memory loss, is a common feature of Alzheimer's disease (AD). This disorder in self-awareness has been linked to a variety of negative personal and societal consequences. There is a growing yet incomplete understanding of the ways in which self-awareness breaks down in AD. Existing models of anosognosia, or global awareness, have outlined the ways in which dysfunctional cognition, particularly memory and executive functioning, may produce disordered self-awareness. However, as disruptions to memory and executive function do not fully explain anosognosia in AD, it is clear that other mechanisms are at play in the deterioration of self-awareness. Currently, there is a drive in both the cognitive and motor literatures towards a dynamic and multifaceted notion of self-awareness wherein factors specific to metacognition, or knowledge of one’s own cognition, are key for producing this fascinating disorder.


Figure: Solid lines represent relationships found in this current study. Dotted arrows represent relationships previously shown in anosognosia for hemiplegia but not assessed in this study (see Jenkinson & Fotopoulou, 2010; Saj et al., 2014; Vocat et al., 2013). CRA – Clinically rated awareness; SRD – Subjective rating discrepancy; Cm – memory comparator; Cn – motor comparator (Agnew & Morris, 1998).

In this vein, the Taub Institute laboratory of Dr. Stephanie Cosentino has developed a novel line of research dedicated to examining how disruption to different types of metacognition, or self-evaluative processes, may contribute to anosognosia in AD. Previous work from the Cosentino lab showed that individuals with anosognosia have difficulty with self-awareness at a more "local" level, that is, with monitoring their memory from moment to moment. In the present study, recently published in Cortex, Dr. Cosentino, lead author Silvia Chapman, and colleagues asked whether disruption to this local level of self-monitoring is domain specific or whether it is present across different functional domains. Both memory and motor monitoring were examined in relation to anosognosia in a group of 35 patients with AD recruited from the Department of Neurology Division of Aging and Dementia. Interestingly, while results supported a "cross-domain" association between memory and motor monitoring processes, only memory monitoring was associated with anosognosia. That is, deterioration of awareness in AD was found to occur in a domain specific manner. Results have implications for current models of awareness (see figure 1), such that two separate levels of awareness seem to exist, and lower levels feed higher levels within a specific functional domain.

Silvia Chapman, MS
Staff Associate in the Taub Institute
sc4056@cumc.columbia.edu

Stephanie Cosentino, PhD
Associate Professor of Neuropsychology (in Neurology, the Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)
sc2460@cumc.columbia.edu



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

   
Sara Ebrahimi Nasrabady, MD/PhD    Adam M. Brickman, PhD

The Taub Institute laboratory of Dr. Adam Brickman uses neuroimaging technologies to elucidate brain-behavior relationships related to cognitive aging and neurodegenerative disorders. A series of recent observations showed that white matter abnormalities visualized on MRI scanning are related to risk, course, and genetics of Alzheimer’s disease (AD) and likely represent a core feature of the disorder. Using translational neuroscience approaches, the laboratory is turning to the histopathology of brain tissue to elucidate the mechanistic underpinnings of these radiological abnormalities.

A recent review article in Acta Neuropathologica Communications led by Dr. Sara Ebrahimi Nasrabady, a postdoctoral research fellow in Dr. Brickman's laboratory, together with CUIMC collaborator Dr. James E. Goldman and graduate student Batool Rizvi, probed a variety of structural, histopathological, and biochemical pathologies that characterize the white matter of AD patients. Their review describes evidence for white matter abnormalities in AD, with a focus on myelin and oligodendrocytes, and discusses the relationship between these white matter changes and the hallmark pathological features of AD.


Figure: Summary of the pathological cascades, and their relation with each other, occurring during the development of Alzheimer's disease in white matter and cortex. While ischemia, excitotoxicity, oxidative stress, and iron overload in white matter damage oligodendrocytes, on one hand, and amyloid toxicity affects them, on the other hand, the iron released from damaged oligodendrocytes promotes amyloid polymerization and deposition in grey matter. The consequent demyelination and axonal loss result in further white matter damage and neuronal dysfunction. Neuronal dysfunction is also a result of amyloid deposition in cortex and a proposed cause for white matter abnormalities in AD patients.

In AD, oligodendrocytes, or their precursors, responsible for remyelination of damaged white matter areas are altered in number and in DNA stability, and are functionally less efficient in the presence of genetic changes, excitotoxicity, oxidative stress, increased iron levels, hypoxia/ischemia and vascular pathology that are common in AD. Here, Nasrabady et al. conclude that white matter abnormalities—impaired myelin and oligodendrocytes, in particular—promote cognitive impairment and AD pathology, and may be important preventative or treatment targets.

Sara Ebrahimi Nasrabady, MD/PhD
Postdoctoral Research Fellow in the Late-life Neuropsychiatric Disorders Research Training program (T32), Department of Psychiatry
se2351@cumc.columbia.edu

Adam M. Brickman, PhD
Associate Professor of Neuropsychology in Neurology, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center
amb2139@cumc.columbia.edu











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