At the Mount Sinai Alzheimer’s Disease Research Center, we are conducting a variety of research projects, both statistical and laboratory based. Our studies explore the roles and relationships of depression, neurogenerative diseases, biomarkers, and DNA methylation. We strive to understand the underlying mechanisms of the pathology of cognitive decline in order to translate this knowledge into new and improved therapies.
Current Research Education Component (REC) Scholars
We are currently involved in two research projects.
Exploring the Relationship of Old-Age Depression and Cognition
This research investigates the relationship of old-age depression and cognition. It strives to disentangle the role of specific depression sub-dimensions in cognitive decline and incident dementia.
We use longitudinal data from the Geriatric Depression Scale (GDS) and comprehensive cognitive testing to examine these associations in two populations:
- Older adults with type 2 diabetes who are at increased risk for both depression and dementia, using the Israel Diabetes and Cognitive Decline (IDCD) study
- A general sample of older adults interested in participating in clinical trials related to Alzheimer's disease and related dementias, using the National Alzheimer's Coordinating Center Uniform Data Set (NACC-UDS)
In the IDCD study, we have found a strong and consistent relationship between apathy with a faster decline in global cognition and executive functions after adjustment for socio-demographic, cardiovascular, and diabetes-related characteristics. We have also found that other depression dimensions (depressed mood, anxiety, hopelessness, and subjective memory complaint) were not related to cognitive decline. Within the NACC-UDS sample, we found associations of subjective memory complaint and hopelessness dimensions with a faster rate of cognitive decline.
We are conducting additional studies to better understand these findings, given the limitations of questionnaires in capturing different aspects of depression. Specifically, we are trying to better characterize specific depression phenotypes by using novel technologies that may more granularly define specific dimensions of depression. We are focusing largely on speech analysis. Thus far, we have been exploring two potential methodologies:
- MyndYou platform, which uses artificial intelligence to collect passive data via smartphones, then uses algorithms based on the complexity principle to detect subtle changes in cognitive function and behavior
- Automated analysis, which is largely focused on prosodic qualities of speech to characterize depression and apathy. This is a collaboration with the Penn Frontotemporal Degeneration Center at the Department of Neurology of the University of Pennsylvania.
The principal investigator is Laili Soleimani, MD, Assistant Professor, Department of Psychiatry, Icahn School of Medicine at Mount Sinai.
Tauopathies and Cognitive Degeneration
Tauopathies are neurodegenerative diseases that create an unhealthy aggregation of tau protein in the brain. These diseases vary in symptoms and neuropathology. While some are caused by genetic mutation, most are non-familial. The research objective of is to characterize the clinical, genetic, and transcriptomic profile of age-related sporadic toxic tau aggregation and to functionally validate these features in stem cell models and post-mortem brain tissue.
To date, we have obtained and transformed autopsy-confirmed patient-derived dermal tissue with a neuropathological diagnosis of sporadic tauopathy into stem cells. We are working toward characterizing the functional, genetic, and transcriptomic signatures of these cells. To this end, we are using a 3D bioreactor cell culture system to produce robust neuronal organoids that better represents the 3D milieu of in vivo tissue conditions. We are studying fibroblasts from post-mortem subjects, which provides us with access to fresh frozen and fixed brain from those same subjects. This approach enables us to directly compare gene expression in the stem cells to the donor brain tissue. The study builds on earlier genetic investigations of primary age-related tauopathy and progressive supranuclear palsy, which uncovered previously underexplored risk loci. We are exploring whether these loci play a biochemical and immunohistochemical in the tau immunocomplex and alter tau splicing.
We hypothesize that modulating these candidate loci in our organoid models will alter tau expression and splicing patterns. Functionally, we anticipate finding both overlapping and convergent phenotypic outcomes (i.e., axon outgrowth, cellular viability), based on the genetic and transcriptomic architecture of these sporadic cell lines. The long-term research goal is to leverage these stem cells models and subsequent novel genetic and transcriptomic pathways to assist in drug screens for the development of novel therapeutic agents to specifically combat toxic tau aggregation.
The principal investigator is Kurt Farrell, PhD, of the Department of Pathology and Laboratory Medicine, Nash Family Department of Neuroscience, Friedman Brain Institute, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai.
ADRC Developmental Projects: Recent Awardees
We have recently initiated in two additional research projects.
Quantifying Beta Amyloid Plaque Aggregation in Alzheimer’s Diseases Using 7T MRI
Researchers can only identify Alzheimer’s disease (AD) definitively detecting biomarkers under microscopy, postmortem. Since definitive diagnosis comes too late to affect how doctors manage the condition, our research seeks to develop r an accurate, noninvasive technique to identify onset of AD.
Higher regional brain iron concentrations in patients with AD are associated with beta amyloid plaques and neurofibrillary tangles. In addition, research demonstrates that iron accumulation increases production of amyloid precursor protein and thus might be directly involved in formation of beta amyloid plaques. The detection of amyloid plaques on magnetic resonance imaging (MRI) relies on precise co-localization of these deposits with iron, which allows them to appear more conspicuous. MRI at ultra-high field strength, such as 7T, increases sensitivity by offering improved signal-to-noise ratio and magnetic resonance contrast. Researchers use high-field MRI to study AD non-invasively and in vivo. This suggests that AD tissue containing amyloid plaque has greater magnetic susceptibility at 7T MRI than healthy tissue. These features may elucidate pathology underlying susceptibility changes over time in AD patients.
The principal investigator is Akbar Alipour, PhD, Postdoctoral Fellow, at the Radiology Department, BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai.
A Novel Epigenetic Mark in Alzheimer’s Disease and Aging
DNA methylation plays important roles in healthy development and human diseases. Recent studies report a novel form of DNA methylation in the human genome, opening a new dimension to study human biology and diseases. However, several studies have also highlighted a few technical biases in studying this novel form of DNA methylation, posing a significant challenge.
Our preliminary data suggest that this novel form of methylation may be correlated with aging and AD, although more rigorous characterization is necessary. Our research goal is to further investigate this novel DNA methylation by making developing technological approaches to detect it more reliably. In addition, we hope to discover novel biological insights into the diverse DNA modification events in the human genome. We will collaborate with the leading expertise of ADRC investigators and build on the rich collection of brain tissues, hoping to help better understand aging and AD.
The principal investigator is Gang Fang, PhD, Associate Professor, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai.