Main focus areas in research on Alzheimer’s disease Maryam Zahmatkesh M.Sc, Ph.D

Main focus areas in research on Alzheimer’s diseaseMaryam Zahmatkesh M.Sc, Ph.D Department of Neuroscience and Addiction StudiesSchool of Advanced Technologies in MedicineTehran University of Medical Sciences

Prevalence of dementia is expected to grow exponentially Hampel H, et al., Nat Rev Neurol. 2018

Dementia vs. Alzheimer’s • Alzheimer’s is actually the most common type of dementia, accounting for 60-80% of cases. • Other varieties of the disease include:– Vascular dementia– Dementia with Lewy bodies– Mixed dementia– Parkinson’s disease– Frontotemporal dementia– Creutzfeldt-Jakob disease– Normal pressure hydrocephalus– Huntington’s Disease– Wernicke-Korsakoff Syndrome

Several neuropathological studies have shown that in the real life clinical setting, ‘pure’ aetiologiesamong dementia syndromes are relatively rare There is neuropathological overlap between dementia aetiologies Peter Paul De Deyn. Nat Rev Neurol. 2015

Alzheimer diseaseFirst clinically recognized in 1901 by Alois Alzheimer Alzheimer disease is not a single disorder

Part a adapted with permission from Spielmeyer, W. Histopathologie des Nervensystems (Julius Springer, 1922), Julius Springer. Part b adapted with permission from Braak, H. & Braak, E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol. Aging 18, 351–357 (1997), Elsevier Masters, C. L. et al. (2015) Nat. Rev. Dis.

Biomarkers • Vitagenes • Epigenetics • Neuroprotective compounds • Enhancement of Antiaging factors • Neurohormones

CNS injury pathophysiology A continuum of biomarkers Mondello S, et al., Expert Rev MolDiagn January 2011

Preclinical stage • We will focus on the preclinical stage when the time window for effective prevention and treatment is wider. • Preclinical AD patients are cognitively normal (Bateman et al, 2012). • To achieve the optimal efficacy, any therapy should be initiated as early as possible, although early diagnosis of AD is difficult. • The identification of early diagnostic and progression biomarkers, as well as novel targets for drug designs, are needed. Sancesario GM, Bernardini S. ClinBiochem. 2018

Peter Paul De Deyn. Nat Rev Neurol. 2015

CSF biomarkers for dementias Peter Paul De Deyn. Nat Rev Neurol. 2015

TREM2 signallingpathways Colonna M, Wang Y. Nat Rev Neurosci. 2016

sTREM2 cerebrospinal fluid levels are a potent biomarker for microglia activity in early-stage Alzheimer’s disease • Cross-sectional multicenter study. • 150 controls and 63 preclinical AD, • 111 MCI-AD, • 200 AD dementia subjects Suárez-CalvetM, et al., EMBO Mol Med. 2016

Alteration of CSF and plasmaAnnexinV+CD61−CD144+ endothelial-drivedmicroparticles levels Hosseinzadeh S, Zahmatkesh M., et al., Behavioural Brain Research, 2013

The decrease in expression of DHCR24 preceded the onset of the cognitive impairment. Hosseinzadeh S, Zahmatkesh M., et al., Behavioural Brain Research, 2015

Vitagenes • Protective genes called vitagenes that control aging • These include members of the heat shock protein (Hsp) family, such as heme oxygenase-1, Hsp72, Hsp70 Thioredoxin/Thioredoxin reductase, and Sirtuins. Lu RC, et al., Biomed Res Int. 2014;

Epigenetics in Alzheimer's Disease • DNA methylation is the most widely studied epigenetic mechanism. In eukaryotes, it consists of the covalent addition of a methyl group at the 5-position of cytosines, and it is usually associated with gene silencing. This methylation occurs on cytosines that are followed by guanines (CpGdinucleotides).

Epigenetic mechanisms in the nervous system Urdinguio RG, et al., Lancet Neurol. 2009

Athanasopoulos D, et al., Epigenetics. Adv Nutr. 2016

Adipokines • White adipose tissue is an endocrine tissue that secretes adipokines, which exert pleiotropic effects in different tissues. Several adipokine receptors including adiponectin, leptin, and resistinreceptors are abundantly expressed in different brain regions. • Dysregulation of adipokine production and/or levels is associated with neurological and neurodegenerative diseases that can notably be a result of obesity-related metabolic disorders. • It is indicated that hypoadiponectinemia in the brain may be implicated in neurodegeneration during aging. Ng RC, Chan KH. Int J Mol Sci. 2017

AD risk factors and associated miRNAs Reddy PH, et al., BiochemBiophys Res Commun. 2017

Klotho Enhancers

Adeli S, Zahmatkesh M, et al., Progress in Neuro-Psychopharmacology & Biological Psychiatry 72 (2017)

Oxytocin • Cortisol • Neurosteroids • Erythropoietin • Thyroid • Vitamin D Neurohormones • Insulin • Melatonin • Apelin • Natriuretic • IGF-1 • Orexin • Cortistatin • Vasopressin • CART • Leptin • Somatostatin • Angiotensin

Factors affecting the response of the brain to hormone replacement therapy

Complexity of clinical trials • AD is inherently a multifactorial syndrome, and individual patients present with a wide variety of pathologies, as a consequence of comorbidities, life history, and genotypes. • In fact, neuropathologic evidence suggests that different pathologies converge in the brains of elderly people with dementia. This suggests that the biological processes driving the clinical phenotype can differ markedly from patient to patient. • The complexity of clinical trials for AD has also contributed to the therapeutic failure rate. The clinical outcome metrics related to cognition and function are highly variable, not only due to the inherent variability in the pathological processes, but also the impact of co-medications and genotypes both within and across patient groups, necessitating large sample size and treatment duration to detect remediation. Geerts H, et al., Alzheimers Dement. 2016

“Turning big data into smart data” • It “is about putting together rather than taking apart, integration rather than reduction. Brain Health Modeling Initiative (BHMI). • The objective of this initiative is to accelerate biomarker and therapeutic development by raising the awareness of integrative analyticsand mechanism-based computational approaches that optimize the use of complex big data to generate a more accurate and actionable understanding of the disease. Geerts H, et al., Alzheimers Dement. 2016

Interactomics • There is an urgent need for novel, noninvasive biomarkers to diagnose Alzheimer’s disease (AD) in the predementia stages and to predict the rate of decline. • Interactomics is a discipline at the intersection of bioinformatics and biology that deals with studying both the interactions and the consequences of those interactions between and among proteins, and other molecules within a cell.

Electrophysiological phenomenon of Alzheimer’s disease • Electrophysiological brain changes may provide a more expansive understanding of AD. • Changes in the electrophysiology of the brain are foundational to the association or interaction of the concepts. • Electrophysiological brain changes occur and affect cortical areas to generate or manifest symptoms from onset and across the stages of AD, which may be prior to pathological changes. Anghinah, R., et al. (2011). Arquivos De Neuro-Psiquiatria,

Effect of GVS on c-Fos activity in CA1 area *p<0.05 compared with other groups Ghahraman, Zahmatkesh et al., 2016

Effect of GVS on percent time & path length in target quadrant *p<0.001compared with control or ICV-saline groups #p=0.001 compared with ICV-STZ/GVS-II group *p<0.001compared with control or ICV-saline groups #p=0.001 compared with ICV-STZ/GVS-II group Ghahraman, Zahmatkesh et al., Physiology & Behaviour, 2016

Main focus areas in research on Alzheimer’s diseaseMaryam Zahmatkesh M.Sc, Ph.D Department of Neuroscience and Addiction StudiesSchool of Advanced Technologies in MedicineTehran University of Medical Sciences

Main focus areas in research on Alzheimer’s disease Maryam Zahmatkesh M.Sc, Ph.D