Dr. Pasinetti presents: "Innate Neuroimmune Priming: Mechanisms and Potential Imaging Biomarkers" at TMII's STRIVE Seminar Series at Mount Sinai, YC in September 2018
As the Program Director of the
NIH /
NCCIH funded P50 Center on Molecular Integrative Neuroresilience, Pasinetti's focus is on understanding the molecular mechanisms and
pathophysiology that may be at the basis of stress-induced mood disorders, including
anxiety,
depression, and other
neuropsychiatric disorders, and their influence on
cognitive dysfunction.
At the
Veterans Health Administration, Pasinetti is the Director of the Basic and Biomedical Research and Training Program, Geriatric Research, Education, and Clinical Center (GRECC), as well as the Director of the Translational Neuroscience Laboratories at the
James J. Peters Veterans Affairs Medical Center (JJPVAMC).[3]
Pasinetti has an
h-index of 81, with over 20,000 citations.[4] He has published over 250 papers indexed in
PubMed, as well as 6 book chapters.[5]
Dr. Pasinetti's awards and honors include the
Mount Sinai School of Medicine Faculty Council Award for Academic Excellence, the Charles Dana Alliance for Brain Initiatives Award from the
Dana Foundation,[7] the Foundation Queen Sofia of Spain Research Center award on Alzheimer's Disease,[8] the Research Career Scientist Developmental Award from the
Veterans Health Administration,[9] the Zenith Award from the
Alzheimer's Association,[10] the Temple Foundation Discovery Award from the Alzheimer's Association,[10] the Nathan W. & Margaret T. Shock Aging Research Foundation Award from the
Gerontological Society of America, the Turken Family fellowship from the Alzheimer's Association (Los Angeles Chapter) and the Nathan Shock New Investigator Award of the Gerontological Society of America.[11] Dr. Pasinetti was also awarded the 2017 Mary Swartz Rose Senior Investigator Award by The
American Society for Nutrition and the American Society for Nutrition Foundation.
Most recently, Dr. Pasinetti was named an Honorary Fellow of The
University of Bergamo (
Università degli Studi di Bergamo).
Grants and Research
Pasinetti investigates the biological processes that occur when, during aging, subjects with normal cognitive function convert into the very earliest stages of
Alzheimer's disease (AD) and then to frank dementia. He identified
type 2 diabetes (T2D) as one of the major risk factors that might affect AD
neuropathology and
synaptic plasticity in part through
epigenetic mechanisms.[12] By conducting genome wide association studies to clarify the molecular mechanisms in subjects with T2D who might be predisposed to the onset of Alzheimer's disease,[13] Pasinetti found that a subpopulation of individuals with T2D have a genetic predisposition to AD based on the evidence of shared common T2D/AD single nucleotide polymorphisms in gene pathways involved in chromatin modification enzymes, among others. Through this research, Pasinetti and his colleagues provided the basis for novel therapeutic targets towards the preservation of cognitive health in a subset of T2D subjects at risk for developing AD.[12][14][15][16]
With his group, Pasinetti has led research investigations on the neuromolecular mechanisms underlying age-related
cognitive decline,
dementia, and stress-induced psychological and cognitive impairment with the goal of utilizing repurposed natural products, specifically
polyphenols, to promote resilience to such conditions.[17][18][19][20] With this in mind, Pasinetti initiated a drug repurposing study for AD, screening FDA-approved drugs and natural compounds for
amyloid-lowering and
anti-Aβ aggregation activities, and identified candidates for
in vivo testing in AD
animal models.[21][22][23][24] As a result of this study, Pasinetti's laboratory identified
antihypertensive drugs lacking cardiovascular side effects but with enhanced anti-Aβ
oligomerization activity.[25][26] Pasinetti's research has also validated that repurposing drugs that have already been well-characterized in terms of tolerability and safety profile may have several advantages over novel drugs. These studies provide new information about the potentially detrimental role of commonly prescribed drugs that can be used as a reference for physicians to consider, particularly when treating chronic degenerative disorders such as AD.[27][28][29]
Following these findings, as Chief of the Friedman Brain Institute Center of Excellence for Novel Approaches to Neurodiagnostics and Neurotherapeutics, Pasinetti developed drug discovery programs for Alzheimer's disease.[17][26][30] Here, he led a primary translational Center to determine whether interventions which appear to work in the preclinical animal model of the disease also show promise in treating patients who have the disease.[27][29][31]
Pasinetti is the Director of the NIH funded Botanical Center in Neuroresilience.[1] This Center supports three major projects which are being conducted through interdisciplinary collaborative efforts from Mount Sinai Hospital's Department of
Neuroscience, Department of
Neurology, Department of
Genetics and
Genomic Sciences, and the Friedman Brain Institute.[32][33] One project is the efficacy of using
polyphenols specifically as dietary supplements to promote resilience against stressful events and clarifying the role of the
microbiome at the
genomic level in the promotion of cognitive and psychological health.[31][33] This research is leading to safe and efficacious treatments of dietary botanical supplements to promote resilience in response to psychological and cognitive impairment.[32]
In a study released on February 2, 2018, scientists from the
Icahn School of Medicine at Mount Sinai, led by Dr. Giulio Maria Pasinetti, described an extensive analysis of two novel grape-derived
phytochemicals, or natural essential nutrients, dihydrocaffeic acid (DHCA) and
malvidin-3’-O-glucoside (Mal-gluc), which might be developed as therapeutic agents for the treatment of depression. The study demonstrated that DHCA reversed improper
epigenetic modifications that have been shown to promote the DNA transcription of numerous pro-inflammatory genes, such as
interleukin 6 (IL-6). Mal-gluc was found to increase the transcription of the Rac1 gene, which influences the expression of genes responsible for synaptic plasticity in the brain. It was demonstrated that treatment with both DHCA and Mal-gluc is effective in attenuating depression-like
phenotypes in a mouse model of increased systemic inflammation induced by transplantation of cells from the bone marrow of stress-susceptible mice. This Mount Sinai study provides novel preclinical evidence supporting the targeting of multiple key disease mechanisms through DNA epigenetic modification for the treatment of depression and strongly supports the need to test and identify novel compounds that target alternative pathologic mechanisms, such as inflammation and synaptic maladaptation, for individuals who are resistant to currently available treatments.[34]
With his involvement at the Veterans Administration, Pasinetti and his lab identified
biomarkers to help diagnose the two signature injuries of the recent wars in Iraq and Afghanistan:
mild traumatic brain injury (mTBI) and
post-traumatic stress disorder (PTSD). The focus was on
four specific non-coding miRNA which were all found at significantly lower levels in those Veterans who had
comorbid TBI plus PTSD, when compared to subjects who had only PTSD.[35][36] The availability of such biomarkers could provide more precise benchmarks and outcome measures in clinical trials of different TBI or PTSD therapies.
Pasinetti's lab is now working on tracing "downstream" molecular pathways in preclinical rodent models of mTBI, to eventually tie them back to TBI or PTSD symptoms and allow for identification of potential new drug targets to be further developed in the clinical setting.[37]
Taken together, the focus of Dr. Pasinetti's research determining the molecular basis of
neurodegenerative disorders and TBI to provide targets for novel therapies has the ultimate goal of identifying unique treatment strategies that can be translated to improve pharmacological treatment in clinical care.
^
abHo, Lap; Purohit, Dushyant; Haroutunian, Vahram; Luterman, James D.; Willis, Fitzroy; Naslund, Jan; Buxbaum, Joseph D.; Mohs, Richard C.; Aisen, Paul S.; Pasinetti, Giulio Maria (1 March 2001). "NEuronal cyclooxygenase 2 expression in the hippocampal formation as a function of the clinical progression of alzheimer disease". Archives of Neurology. 58 (3): 487–492.
doi:
10.1001/archneur.58.3.487.
PMID11255454.
^"Awardees". The Gerontological Society of America. Retrieved 4 October 2016.
^Pasinetti, Giulio (11 March 2015). "Novel role of red wine-derived polyphenols in the prevention of Alzheimerʼs disease dementia and brain pathology: experimental approaches and clinical implications". Planta Medica. 78 (15): E24.
doi:
10.1055/s-0035-1545846.
PMID25760447.
^
abDubner, Lauren; Wang, Jun; Ho, Lap; Ward, Libby; Pasinetti, Giulio M. (27 October 2015). "Recommendations for Development of New Standardized Forms of Cocoa Breeds and Cocoa Extract Processing for the Prevention of Alzheimer's Disease: Role of Cocoa in Promotion of Cognitive Resilience and Healthy Brain Aging". Journal of Alzheimer's Disease. 48 (4): 879–889.
doi:
10.3233/JAD-150536.
PMID26402120.