There are many active research projects accessing and applying shared ADNI data. Use the search above to find specific research focuses on the active ADNI investigations. This information is requested annually as a requirement for data access.
| Principal Investigator | |
| Principal Investigator's Name: | Gillian Einstein |
| Institution: | University of Toronto |
| Department: | Psychology |
| Country: | |
| Proposed Analysis: | Introduction Early estrogen deprivation resulting from mid-life oophorectomy has been linked to a significantly greater risk of developing late-life Alzheimer’s disease (AD; Rocca et al., 2007). Nevertheless, little is known about the progression to AD in women with oophorectomy. Estrogens have antioxidant properties that prevent reactive oxygen species (ROS)-induced damage (Bellanti et al., 2013; Borrás et al., 2010). A potential mechanism driving greater AD risk in women with mid-life oophorectomy may be oxidative stress, whereby early loss of estrogens results in overproduction of ROS, ultimately leading to neurodegeneration, resting-state network disruptions, and cognitive dysfunction. The purpose of this retrospective analysis is to elucidate whether oxidative stress drives greater cognitive declines and structural and functional brain changes in women with oophorectomy, which eventually lead to AD. Hypotheses It is hypothesized that compared to women with intact ovaries and men, women with mid-life oophorectomy prior to spontaneous (natural) menopause will exhibit: 1) greater cognitive impairment, 2) more rapid neurodegeneration and brain network disruptions over time (reduced cortical thickness and volume of the prefrontal cortex, hypothalamus, and medial temporal lobe (MTL) structures, including the hippocampus, parahippocampus, perirhinal cortex, entorhinal cortex, and amygdala, greater white matter hyperintensity volume, and reduced resting-state network segregation), and 3) increased markers of oxidative stress that moderate these cognitive and brain changes. Additionally, it is hypothesized that women with mid-life oophorectomy taking hormone therapy (especially if estradiol-based) will exhibit some protection against oxidative stress, cognitive declines, neurodegeneration, and brain network disruptions. Methods A retrospective data analysis will be conducted using structural and functional MRI, biomarkers of oxidative stress, and neuropsychological data of women and men from the ADNI database. Participants with oophorectomy prior to spontaneous menopause will be compared to age- and education-matched male and female controls at baseline and longitudinally. Female control participants will have intact ovaries. Volume and cortical thickness of the prefrontal cortex, and MTL strucutres,, will be extracted using T1-weighted and T2-weighted images that will be processed through the CIVET (to obtain cortical thickness; Ad-Dab’bagh et al., 2006; Zijdenbos et al., 2002), Freesurfer automated segmentation pipelines (to obtain hippocampal volumes; http://surfer.nmr.mgh.harvard.edu/), and ASHS/ITK-SNAP (to obtain hippocampal subfield and extra-hippocampal volumes; Wolk et al., 2017). The MTL structures are amongst the first areas in the brain affected in AD (Gomez-Isla et al., 1996; Du et al., 2001; Braak & Tredici, 2012; Wolk et al., 2017). These structures have numerous projections to the PFC (Laroche, Davis & Jay, 2000; Thierry et al., 2000), which may also show neurodegeneration and disrupted function early in the course of AD (Baudic et al., 2006; Salat, Kaye & Janowsky, 2001). Hypothalamic regions will be segmented automatically as described by Billot et al 2020). There is some suggestion that this region is experiences subtle atrophy in AD (Billot et al 2020). In particular, the suprachiasnatic nucleus, which is responsible for maintaining the endogenous clock that maintains the human sleep-wake cycle, is sexually dimorphic in humans (Swaab et al 1985). This region may be an important overlooked region in understanding the sleep deficits observed in patients with AD. White matter hyperintensity volumes will be determined using T2-FLAIR images that will be processed through the SABRE pipeline (Dade et al., 2004). A whole-brain ROI-to-ROI approach will be used to characterize resting-state functional connectivity and resting-state network segregation using the CONN Connectivity Toolbox (Whitfield-Gabrieli & Nieto-Castanon, 2012) and the 100 ROIs, 17-network Schafer (2018) parcellation. Oxidative stress will be determined by isoprostane levels, a stable and reliable marker of lipid peroxidation (Milne et al., 2011), in the CSF, plasma, and urine of participants. Additionally, amyloid-beta and tau protein levels in the CSF and their localization in the brain determined from PET imaging are biomarkers of interest, as they are associated with increased oxidative stress (Zhao & Zhao, 2013) and are hallmarks of AD pathology (Spires-Jones & Hyman, 2014). Group differences in MMSE scores will be examined, and neuropsychological measures of executive function (Trails Making Task A & B and Digit Span) and episodic memory (Auditory Verbal Learning and Verbal Fluency tasks) will be studied. Mixed-effect models will be used to compare changes in brain volume, network segregation, and cognitive scores over time, and examine whether oxidative stress differentially moderates longitudinal changes across the three groups. Implications Results of this study will determine whether oxidative stress in women with mid-life oophorectomy, a group high-risk for late-life AD, drives greater cognitive declines and neuropathological symptoms of AD. The characterization of mechanisms and risk factors that differ by sex is becoming increasingly important as it is now estimated that two-thirds seniors with AD are women, and by age 45, the lifetime risk of Alzheimer’s Disease (AD) is twice as high in women as compared to men (Alzheimer’s Association, 2019). Studying the effects of early estrogen loss on brain health may offer key insights as to why more women than men develop AD. References Ad-Dab’bagh, Y., Einarson, D., Lyttelton, O., Muehlboeck, J.-S., Mok, K., Ivanov, O., Vincent, R.D., Lepage, C., Lerch, J., Fombonne, E., and Evans, A.C. (2006). The CIVET Image-Processing Environment: A Fully Automated Comprehensive Pipeline for Anatomical Neuroimaging Research. In Proceedings of the 12th Annual Meeting of the Organization for Human Brain Mapping, M. Corbetta, ed. (Florence, Italy, NeuroImage). http://www.bic.mni.mcgill.ca/users/yaddab/Yasser-HBM2006-Poster.pdf Alzheimer's Association. 2019 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2019 Mar;15(3):321-87. Baudic S, Barba GD, Thibaudet MC, Smagghe A, Remy P, Traykov L. Executive function deficits in early Alzheimer's disease and their relations with episodic memory. Archives of clinical neuropsychology. 2006 Jan 1;21(1):15-21. Bellanti F, Matteo M, Rollo T, De Rosario F, Greco P, Vendemiale G, Serviddio G. Sex hormones modulate circulating antioxidant enzymes: impact of estrogen therapy. Redox biology. 2013 Jan 1;1(1):340-6. Billot B, Bocchetta M, Todd E, Dalca AV, Rohrer JD, Iglesias JE. Automated segmentation of the hypothalamus and associated subunits in brain MRI. NeuroImage. 2020 Dec 1;223:117287. Borrás C, Gambini J, López-Grueso R, Pallardó FV, Viña J. Direct antioxidant and protective effect of estradiol on isolated mitochondria. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2010 Jan 1;1802(1):205-11. Braak H, Del Tredici K. Alzheimer’s disease: pathogenesis and prevention. Alzheimer's & Dementia. 2012 May 1;8(3):227-33. Dade, L. A., Gao, F. Q., Kovacevic, N., Roy, P., Rockel, C., O’Toole, C. M., … Black, S. E. (2004). Semiautomatic brain region extraction: a method of parcellating brain regions from structural magnetic resonance images. Du AT, Schuff N, Amend D, Laakso MP, Hsu YY, Jagust WJ, Yaffe K, Kramer JH, Reed B, Norman D, Chui HC. Magnetic resonance imaging of the entorhinal cortex and hippocampus in mild cognitive impairment and Alzheimer's disease. Journal of Neurology, Neurosurgery & Psychiatry. 2001 Oct 1;71(4):441-7. Gómez-Isla T, Price JL, McKeel Jr DW, Morris JC, Growdon JH, Hyman BT. Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. Journal of Neuroscience. 1996 Jul 15;16(14):4491-500. Laroche S, Davis S, Jay TM. Plasticity at hippocampal to prefrontal cortex synapses: dual roles in working memory and consolidation. Hippocampus. 2000;10(4):438-46. Milne GL, Yin H, Hardy KD, Davies SS, Roberts LJ. Isoprostane generation and function. Chemical reviews. 2011 Oct 12;111(10):5973-96. Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, De Andrade M, Melton L3. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007 Sep 11;69(11):1074-83. Schaefer A, Kong R, Gordon EM, Laumann TO, Zuo XN, Holmes AJ, Eickhoff SB, Yeo BT. Local-global parcellation of the human cerebral cortex from intrinsic functional connectivity MRI. Cerebral cortex. 2018 Sep 1;28(9):3095-114. Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron. 2014 May 21;82(4):756-71. Salat DH, Kaye JA, Janowsky JS. Selective preservation and degeneration within the prefrontal cortex in aging and Alzheimer disease. Archives of neurology. 2001 Sep 1;58(9):1403-8. Swaab DF, Fliers E, Partiman TS. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res. 1985 Sep 2;342(1):37-44. Thierry AM, Gioanni Y, Dégénétais E, Glowinski J. Hippocampo‐prefrontal cortex pathway: Anatomical and electrophysiological characteristics. Hippocampus. 2000;10(4):411-9. Whitfield-Gabrieli, S. and Nieto-Castanon, A., 2012. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain connectivity, 2(3), pp.125-141. Wolk DA, Das SR, Mueller SG, Weiner MW, Yushkevich PA, Alzheimer's Disease Neuroimaging Initiative. Medial temporal lobe subregional morphometry using high resolution MRI in Alzheimer's disease. Neurobiology of aging. 2017 Jan 1;49:204-13. Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer's disease. Oxidative medicine and cellular longevity. 2013 Oct;2013. Zijdenbos, A.P., Forghani, R., and Evans, A.C. (2002). Automatic Pipeline Analysis of 3-D MRI Data for Clinical Trials: Application to Multiple Sclerosis. IEEE TRANSACTIONS ON MEDICAL IMAGING 21, pp. 1280–1291. http://www.ncbi.nlm.nih.gov/pubmed/12585710 |
| Additional Investigators | |
| Investigator's Name: | Laura Gravelsins |
| Proposed Analysis: | Will be assisting with the analysis and write-up of the proposed project |
| Investigator's Name: | Nicole Gervais |
| Proposed Analysis: | Will be assisting with the analysis and write-up of the proposed project |
| Investigator's Name: | Reema Shafi |
| Proposed Analysis: | Will be assisting with the analysis and write-up of the proposed project |
| Investigator's Name: | Alana Brown |
| Proposed Analysis: | Will be assisting with the analysis and write-up of the proposed project |
| Investigator's Name: | Rebekah Reuben |
| Proposed Analysis: | Will be assisting with the analysis and write-up of the proposed project |
| Investigator's Name: | Mateja Perovic |
| Proposed Analysis: | Will be assisting with the analysis and write-up of the proposed project |
| Investigator's Name: | Laurice Karkaby |
| Proposed Analysis: | Will be assisting with the analysis and write-up of the proposed project |
