Association of Bilateral Salpingo-Oophorectomy Before Menopause Onset With Medial Temporal Lobe Neurodegeneration | Dementia and Cognitive Impairment | JAMA Neurology | JAMA Network
[Skip to Navigation]
Sign In
Figure 1.  Study Sample
Study Sample

BSO indicates bilateral salpingo-oophorectomy; MCSA, Mayo Clinic Study of Aging; MOA-2, Mayo Clinic Cohort Study of Oophorectomy and Aging-2; MRI, magnetic resonance imaging; PET, positron emission tomography; PiB, Pittsburgh compound B.

Figure 2.  Imaging Characteristics in Women Who Underwent Bilateral Salpingo-Oophorectomy (BSO) vs Control Participants
Imaging Characteristics in Women Who Underwent Bilateral Salpingo-Oophorectomy (BSO) vs Control Participants

Box plots show median and interquartile ranges. Amygdala volume was smaller and parahippocampal-entorhinal cortex was thinner on structural magnetic resonance imaging, and entorhinal white matter fractional anisotrophy was lower on diffusion tensor imaging in women who had undergone BSO than in control participants. Hippocampal volume was calculated as raw right plus left hippocampal volumes, adjusted for total intracranial volume. To derive the total intracranial volume–adjusted hippocampal volume, we fit a linear regression model among 133 participants with normal cognitive function aged 30 to 59 years to predict hippocampal volume from total intracranial volume.13 There were no statistically significant differences in hippocampal volume, cortical Pittsburgh compound B (PiB) standard uptake value ratio, or white matter hyperintensity volume between women who had undergone BSO and control participants.

Table.  Demographics, Global Cognitive Status, and Imaging Characteristics of the Study Samplea
Demographics, Global Cognitive Status, and Imaging Characteristics of the Study Samplea
1.
Rocca  WA, Bower  JH, Maraganore  DM,  et al.  Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.  Neurology. 2007;69(11):1074-1083. doi:10.1212/01.wnl.0000276984.19542.e6PubMedGoogle ScholarCrossref
2.
Rocca  WA, Gazzuola-Rocca  L, Smith  CY,  et al.  Accelerated accumulation of multimorbidity after bilateral oophorectomy: a population-based cohort study.  Mayo Clin Proc. 2016;91(11):1577-1589. doi:10.1016/j.mayocp.2016.08.002PubMedGoogle ScholarCrossref
3.
Parker  WH, Broder  MS, Chang  E,  et al.  Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study.  Obstet Gynecol. 2009;113(5):1027-1037. doi:10.1097/AOG.0b013e3181a11c64PubMedGoogle ScholarCrossref
4.
Bove  R, Secor  E, Chibnik  LB,  et al.  Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women.  Neurology. 2014;82(3):222-229. doi:10.1212/WNL.0000000000000033PubMedGoogle ScholarCrossref
5.
Rocca  WA, Gazzuola Rocca  L, Smith  CY,  et al.  Cohort profile: the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) in Olmsted County, Minnesota (USA).  BMJ Open. 2017;7(11):e018861. doi:10.1136/bmjopen-2017-018861PubMedGoogle ScholarCrossref
6.
Roberts  RO, Geda  YE, Knopman  DS,  et al.  The Mayo Clinic Study of Aging: design and sampling, participation, baseline measures and sample characteristics.  Neuroepidemiology. 2008;30(1):58-69. doi:10.1159/000115751PubMedGoogle ScholarCrossref
7.
Schwarz  CG, Gunter  JL, Wiste  HJ,  et al; Alzheimer’s Disease Neuroimaging Initiative.  A large-scale comparison of cortical thickness and volume methods for measuring Alzheimer’s disease severity.  Neuroimage Clin. 2016;11:802-812. doi:10.1016/j.nicl.2016.05.017PubMedGoogle ScholarCrossref
8.
Jack  CR  Jr, Lowe  VJ, Senjem  ML,  et al.  11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment.  Brain. 2008;131(Pt 3):665-680. doi:10.1093/brain/awm336PubMedGoogle ScholarCrossref
9.
Fischl  B.  FreeSurfer.  Neuroimage. 2012;62(2):774-781. doi:10.1016/j.neuroimage.2012.01.021PubMedGoogle ScholarCrossref
10.
Raz  L, Jayachandran  M, Tosakulwong  N,  et al.  Thrombogenic microvesicles and white matter hyperintensities in postmenopausal women.  Neurology. 2013;80(10):911-918. doi:10.1212/WNL.0b013e3182840c9fPubMedGoogle ScholarCrossref
11.
Schwarz  CG, Reid  RI, Gunter  JL,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Improved DTI registration allows voxel-based analysis that outperforms tract-based spatial statistics.  Neuroimage. 2014;94:65-78. doi:10.1016/j.neuroimage.2014.03.026PubMedGoogle ScholarCrossref
12.
Oishi  K, Zilles  K, Amunts  K,  et al.  Human brain white matter atlas: identification and assignment of common anatomical structures in superficial white matter.  Neuroimage. 2008;43(3):447-457. doi:10.1016/j.neuroimage.2008.07.009PubMedGoogle ScholarCrossref
13.
Jack  CR  Jr, Wiste  HJ, Weigand  SD,  et al.  Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: a cross-sectional study.  Lancet Neurol. 2014;13(10):997-1005. doi:10.1016/S1474-4422(14)70194-2PubMedGoogle ScholarCrossref
14.
Crary  JF, Trojanowski  JQ, Schneider  JA,  et al.  Primary age-related tauopathy (PART): a common pathology associated with human aging.  Acta Neuropathol. 2014;128(6):755-766. doi:10.1007/s00401-014-1349-0PubMedGoogle ScholarCrossref
15.
Mosconi  L, Berti  V, Quinn  C,  et al.  Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging.  Neurology. 2017;89(13):1382-1390. doi:10.1212/WNL.0000000000004425PubMedGoogle ScholarCrossref
16.
DeCarli  C, Frisoni  GB, Clark  CM,  et al; Alzheimer’s Disease Cooperative Study Group.  Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia.  Arch Neurol. 2007;64(1):108-115. doi:10.1001/archneur.64.1.108PubMedGoogle ScholarCrossref
Brief Report
January 2019

Association of Bilateral Salpingo-Oophorectomy Before Menopause Onset With Medial Temporal Lobe Neurodegeneration

Author Affiliations
  • 1Department of Radiology, Mayo Clinic, Rochester, Minnesota
  • 2Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 3Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 4Department of Information Technology, Mayo Clinic, Rochester, Minnesota
  • 5Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
  • 6Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
  • 7Department of Surgery, Mayo Clinic, Rochester, Minnesota
JAMA Neurol. 2019;76(1):95-100. doi:10.1001/jamaneurol.2018.3057
Key Points

Question  Do women who underwent bilateral salpingo-oophorectomy before menopause show greater medial temporal lobe structural changes, β-amyloid accumulation, and white matter lesion load on neuroimaging later in life compared with a control group?

Findings  In this case-control study, women with bilateral salpingo-oophorectomy before menopause had smaller amygdala volumes, thinner parahippocampal-entorhinal cortices, and lower entorhinal white matter fractional anisotropy values compared with control participants.

Meaning  Abrupt hormonal changes associated with bilateral salpingo-oophorectomy in premenopausal women may lead to medial temporal lobe structural abnormalities later in life; because alterations in structural imaging biomarkers of the medial temporal lobe neurodegeneration may precede clinical symptoms of dementia, longitudinal follow-up of this cohort with cognitive testing is necessary.

Abstract

Importance  There is an increased risk of cognitive impairment or dementia in women who undergo bilateral salpingo-oophorectomy (BSO) before menopause. However, data are lacking on the association of BSO before menopause with imaging biomarkers that indicate medial temporal lobe neurodegeneration and Alzheimer disease pathophysiology.

Objective  To investigate medial temporal lobe structure, white matter lesion load, and β-amyloid deposition in women who underwent BSO before age 50 years and before reaching natural menopause.

Design, Setting, and Participants  This nested case-control study of women in the population-based Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) and in the Mayo Clinic Study of Aging (MCSA) in Olmsted County, Minnesota, included women who underwent BSO from 1988 through 2007 and a control group from the intersection of the 2 cohorts. Women who underwent BSO and control participants who underwent a neuropsychological evaluation, magnetic resonance imaging (MRI), and Pittsburgh compound B positron emission tomography (PiB-PET) were included in the analysis. Data analysis was performed from November 2017 to August 2018.

Exposure  Bilateral salpingo-oophorectomy in premenopausal women who were younger than 50 years.

Main Outcomes and Measures  Cortical β-amyloid deposition on PiB-PET scan was calculated using the standard uptake value ratio. White matter hyperintensity volume and biomarkers for medial temporal lobe neurodegeneration (eg, amygdala volume, hippocampal volume, and parahippocampal-entorhinal cortical thickness) on structural MRI and entorhinal white matter fractional anisotropy on diffusion tensor MRI were also measured.

Results  Forty-one women who underwent BSO and 49 control participants were recruited. One woman was excluded from the BSO group after diagnosis of an ovarian malignant condition, and 6 women were excluded from the control group after undergoing BSO after enrollment. Twenty control participants and 23 women who had undergone BSO completed all examinations. The median (interquartile range [IQR]) age at imaging was 65 (62-68) years in the BSO group and 63 (60-66) years in the control group. Amygdala volume was smaller in the BSO group (median [IQR], 1.74 [1.59-1.91] cm3) than the control group (2.15 [2.05-2.37] cm3; P < .001). The parahippocampal-entorhinal cortex was thinner in the BSO group (median [IQR], 3.91 [3.64-4.00] mm) than the control group (3.97 [3.89-4.28] mm; P = .046). Entorhinal white matter fractional anisotropy was lower in the BSO group (median [IQR], 0.19 [0.18-0.22]) than the control group (0.22 [0.20-0.23]; P = .03). Women were treated with estrogen in both groups (BSO, n = 22 of 23 [96%]; control, n = 10 of 19 [53%]). Global cognitive status test results did not differ between the groups.

Conclusions and Relevance  Abrupt hormonal changes associated with BSO in premenopausal women may lead to medial temporal lobe structural abnormalities later in life. Longitudinal evaluation is needed to determine whether cognitive decline follows.

Introduction

Women who undergo bilateral salpingo-oophorectomy (BSO) before the onset of menopause have an accelerated accumulation of multimorbidity, with an increased risk of aging-associated neurological diseases, including dementia.1-3 Furthermore, surgical menopause at an early age was associated with Alzheimer disease (AD) pathology at autopsy.4 Because imaging biomarkers associated with cognitive impairment and dementia precede the clinical symptoms, and may provide insight into the underlying causative mechanisms of cognitive impairment and dementia later in life, we investigated β-amyloid deposition (primary outcome), magnetic resonance imaging (MRI)–based biomarkers of medial temporal lobe neurodegeneration, and white matter hyperintensity volume in women who underwent BSO before age 50 years and before reaching natural menopause.

Methods

The Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) is a population-based cohort study that includes women who underwent BSO before age 50 years and before reaching natural menopause from 1988 through 2007 and an age-matched control group who had not undergone bilateral oophorectomy before age 50 years.5 The Mayo Clinic Study of Aging (MCSA) is another population-based cohort study, which includes participants with normal cognitive aging, mild cognitive impairment, and dementia.6 All MCSA participants are invited to undergo MRI and Pittsburgh compound B (PiB) positron emission tomography (PET). Both study cohorts are representative of the geographically defined population of Olmsted County, Minnesota. In the current study, women with BSO and control-participant women from the MOA-2 cohort who later were enrolled in the MCSA and underwent a neuropsychological evaluation, MRI, and PiB-PET scan were included (Figure 1). This study was approved by the Mayo Clinic institutional review board, and written informed consent was obtained from all participants.

Global cognitive status was assessed using the short test of mental status, and combining 9 tests into a global cognitive status score.6 The MRI studies were performed at 3-T (GE Healthcare). Previously described and validated MRI analysis methods were used.7,8 Hippocampal and amygdala volumes were adjusted for total intracranial volume. Parahippocampal-entorhinal cortical thickness was measured using FreeSurfer version 5.3 (Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital).9 A semi-automated segmentation10 of fluid-attenuated inversion recovery (FLAIR) images was used for white matter hyperintensity volume quantification and adjusted for total intracranial volume. Cerebral infarcts were also evaluated. Previously described and validated methods were used to process diffusion tensor imaging scans.11 Entorhinal white matter fractional anisotropy, which includes the perforant pathway, was quantified using the Johns Hopkins University atlas.12 A PET and computed tomography scanner with 3-dimensional mode (GE Healthcare) was used for PET imaging, and image analysis was performed using an automated image processing pipeline.8 Cortical β-amyloid deposition on PiB-PET scan was calculated using standard uptake value ratio.

Statistical Analysis

Wilcoxon rank sum tests, rank regression tests adjusted for total intracranial volume, and Fisher exact tests were used for comparisons of the BSO and control groups. Correlations between imaging biomarkers and global cognitive status scores were assessed using Spearman correlations, and the P values were adjusted for multiple comparisons using the false-discovery rate. Statistical significance was considered at the 2-sided α level of .05.

Results

A total of 43 women fulfilled the inclusion criteria, including 23 who had undergone BSO and 20 control participants. The median age at oophorectomy in the BSO group was 46 (interquartile range [IQR], 45-48) years. Age at imaging and frequency of APOE ε4 carriers did not differ between the groups. Among the 23 women who underwent BSO with hysterectomy, 22 (96%) took unopposed estrogen for a median duration of 10 (IQR, 5-13) years after surgery. Oral conjugated equine estrogen was the most common type used (n = 15 of 22 [68%]), typically at a dosage of 0.625 mg/d. Among the 20 control-participant women, 19 (95%) reached menopause during the study follow-up, 17 (85%) had natural menopause, and 10 of 19 (53%) took estrogen for a median duration of 10 (IQR, 6-16) years. The most common type used was oral conjugated equine estrogen at a dosage of 0.625 mg/d (n = 9 of 10 [90%]) with progestin (oral medroxyprogesterone acetate at 2.5 mg/d; n = 8 of 19 [42%]) for a median duration of 9 (IQR, 4-13) years. Although the frequency of mild cognitive impairment diagnosis was slightly higher in the BSO group (n = 3 [13%]) compared with the control group (n = 1 [5%]; P = .40), the short test of mental status, global cognitive status scores, and the Beck depression and anxiety inventory scores did not differ between the groups (Table).

On structural MRI, median (IQR) amygdala volume was smaller (BSO group, 1.74 [1.59-1.91] cm3; control group: 2.15 [2.05-2.37] cm3; P < .001), median (IQR) parahippocampal-entorhinal cortex was thinner (BSO group: 3.91 [3.64-4.00] mm; control group: 3.97 [3.89-4.28] mm; P = .046), and the entorhinal white matter fractional anisotropy on diffusion tensor imaging was lower (BSO group: 0.19 [0.18-0.22]; control group: 0.22 [0.20-0.23]; P = .03) in the BSO group compared with the control group (Table). Smaller hippocampal volume on MRI and higher cortical PiB standard uptake value ratio on PiB-PET scan were observed in the BSO group compared with the control group, but these results did not reach statistical significance (Figure 2). The results did not change noticeably in sensitivity analyses that added 4 women who had an MRI but not a PiB-PET scan, and in sensitivity analyses that removed 4 women who had mild cognitive impairment at the time of imaging testing (data not shown).

White matter hyperintensity volume and the frequency of infarctions did not differ between the groups. Imaging biomarkers were not associated with the global cognitive status score, and Beck Anxiety Inventory and Beck Depression Inventory scores after correcting for multiple comparisons using false-discovery rate.

Discussion

In this study, women who underwent BSO before age 50 years and before reaching natural menopause had smaller amygdala volumes, thinner parahippocampal-entorhinal cortices, and lower entorhinal white matter fractional anisotropy values compared with control-participant women.

There is an increased risk of cognitive impairment or dementia1 and presence of AD pathology4 in women who undergo BSO before menopause. However, imaging biomarkers associated with AD pathophysiology that precede cognitive impairment have not been studied in these women. Results of the present study suggest that women who underwent early BSO have biomarker abnormalities associated with neurodegeneration in the medial temporal lobe. In particular, the entorhinal cortex, which is one of the regions involved with neurofibrillary tangle pathology during the preclinical stages of AD, as well as primary age-associated taupathy.14 In addition, a thinner entorhinal cortex and lower fractional anisotropy on diffusion tensor imaging in the BSO group suggest a disruption in the entorhinal white matter microstructure that includes the perforant pathway carrying the connections between the entorhinal cortex and the hippocampus. Although not statistically significant in this small explorative sample, a difference in hippocampal volumes and cortical PiB uptake in the BSO group compared with the control group suggests the occurrence of early biomarker changes associated with AD pathophysiology.

Premenopausal oophorectomy–induced estrogen deficiency is thought to be the primary cause of the increased risk of cognitive impairment or dementia in women with BSO before the onset of menopause.1 Furthermore, AD biomarker abnormalities have been observed more frequently in women undergoing menopause compared with premenopausal women, after controlling for age.15 In our study, 96% of the women with BSO were treated with estrogen (primarily oral conjugated equine estrogen), for a median of 10 years after BSO; however, this type and duration of hormonal treatment after BSO does not seem to be sufficient to prevent structural changes in the medial temporal lobe later in life. Further research into the type of estrogen treatments used, route of administration, dosing, and influence of the other ovarian hormones and hormones of the pituitary-ovarian axis is needed.

Limitations

Lower hippocampal volume and higher cortical β-amyloid accumulation observed in the BSO group compared with the control group may have failed to reach statistical significance because of the small sample size. Because structural imaging biomarkers of medial temporal lobe neurodegeneration are associated with cognitive impairment and dementia later in life,16 findings of the current study support the association between BSO in premenopausal women and an increased risk of cognitive decline and dementia.1,4

Conclusions

Abrupt hormonal changes because of BSO in premenopausal women may lead to medial temporal lobe structural abnormalities later in life. Because alterations in structural imaging biomarkers of neurodegeneration in the medial temporal lobe precede clinical symptoms of dementia, enlargement and longitudinal follow-up of this cohort is needed.

Back to top
Article Information

Corresponding Author: Kejal Kantarci, MD, Department of Radiology, Mayo Clinic and Foundation, 200 First St SW, Rochester, MN 55905 (kantarci.kejal@mayo.edu).

Accepted for Publication: August 16, 2018.

Published Online: October 15, 2018. doi:10.1001/jamaneurol.2018.3057

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2018 Zeydan B et al. JAMA Neurology.

Author Contributions: Dr Kantarci had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Zeydan, Miller, Rocca, Kantarci.

Acquisition, analysis, or interpretation of data: Zeydan, Tosakulwong, Schwarz, Senjem, Gunter, Reid, Gazzuola Rocca, Lesnick, Smith, Bailey, Lowe, Roberts, Jack, Petersen, Mielke, Rocca, Kantarci.

Drafting of the manuscript: Zeydan, Schwarz, Lesnick, Mielke.

Critical revision of the manuscript for important intellectual content: Zeydan, Tosakulwong, Schwarz, Senjem, Gunter, Reid, Gazzuola Rocca, Lesnick, Smith, Bailey, Lowe, Roberts, Jack, Petersen, Miller, Rocca, Kantarci.

Statistical analysis: Zeydan, Tosakulwong, Schwarz, Gunter, Lesnick, Smith, Bailey, Rocca, Kantarci.

Obtained funding: Lowe, Petersen, Miller, Kantarci.

Administrative, technical, or material support: Schwarz, Senjem, Smith, Lowe, Roberts, Jack, Petersen, Miller, Kantarci.

Supervision: Lowe, Miller, Kantarci.

Conflict of Interest Disclosures: Dr Jack consults for Lily and serves on an independent data monitoring board for Roche (uncompensated); he also receives research support from NIH and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic. Dr Kantarci serves on the data safety monitoring board for Takeda Global Research and Development Center, Inc; receives research support from Avid Radiopharmaceuticals and Eli Lilly; and receives funding from the National Institutes of Health. Dr Lowe consults for Bayer Schering Pharma, Piramal Life Sciences, and Merck Research and receives research support from GE Healthcare, Siemens Molecular Imaging, AVID Radiopharmaceuticals, and the National Institute on Aging and National Cancer Institute. Dr Mielke served as a consultant to Eli Lilly and Lysosomal Therapeutics Inc, receives research support from the National Institutes of Health (grant R01 AG49704) and the Department of Defense (grant W81XWH-15-1), and receives unrestricted research grants from Biogen and Lundbeck. Dr Miller receives funding from the National Institutes of Health. Dr Petersen receives funding from the National Institutes of Health, has served on the National Advisory Council on Aging and on the scientific advisory boards of Pfizer, GE Healthcare, Elan Pharmaceuticals, Wyeth Pharmaceuticals, and Janssen Alzheimer Immunotherapy, has received publishing royalties from Oxford University Press, and has been a consultant for Roche Incorporated, Merck, Genentech, Biogen, and Eli Lilly. Dr Schwarz receives funding from the National Institutes of Health.

Funding/Support: This study was funded by National Institutes of Health (grants U54 AG044170, Drs Miller and Mielke; RF1 AG55151, Dr Mielke; U01 AG06786, Dr Petersen; RF1 AG57547 and R01 AG40042, Dr Kantarci; and R01 AG034676 and R01 AG052425, Dr Rocca).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Rocca  WA, Bower  JH, Maraganore  DM,  et al.  Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause.  Neurology. 2007;69(11):1074-1083. doi:10.1212/01.wnl.0000276984.19542.e6PubMedGoogle ScholarCrossref
2.
Rocca  WA, Gazzuola-Rocca  L, Smith  CY,  et al.  Accelerated accumulation of multimorbidity after bilateral oophorectomy: a population-based cohort study.  Mayo Clin Proc. 2016;91(11):1577-1589. doi:10.1016/j.mayocp.2016.08.002PubMedGoogle ScholarCrossref
3.
Parker  WH, Broder  MS, Chang  E,  et al.  Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study.  Obstet Gynecol. 2009;113(5):1027-1037. doi:10.1097/AOG.0b013e3181a11c64PubMedGoogle ScholarCrossref
4.
Bove  R, Secor  E, Chibnik  LB,  et al.  Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women.  Neurology. 2014;82(3):222-229. doi:10.1212/WNL.0000000000000033PubMedGoogle ScholarCrossref
5.
Rocca  WA, Gazzuola Rocca  L, Smith  CY,  et al.  Cohort profile: the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 (MOA-2) in Olmsted County, Minnesota (USA).  BMJ Open. 2017;7(11):e018861. doi:10.1136/bmjopen-2017-018861PubMedGoogle ScholarCrossref
6.
Roberts  RO, Geda  YE, Knopman  DS,  et al.  The Mayo Clinic Study of Aging: design and sampling, participation, baseline measures and sample characteristics.  Neuroepidemiology. 2008;30(1):58-69. doi:10.1159/000115751PubMedGoogle ScholarCrossref
7.
Schwarz  CG, Gunter  JL, Wiste  HJ,  et al; Alzheimer’s Disease Neuroimaging Initiative.  A large-scale comparison of cortical thickness and volume methods for measuring Alzheimer’s disease severity.  Neuroimage Clin. 2016;11:802-812. doi:10.1016/j.nicl.2016.05.017PubMedGoogle ScholarCrossref
8.
Jack  CR  Jr, Lowe  VJ, Senjem  ML,  et al.  11C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment.  Brain. 2008;131(Pt 3):665-680. doi:10.1093/brain/awm336PubMedGoogle ScholarCrossref
9.
Fischl  B.  FreeSurfer.  Neuroimage. 2012;62(2):774-781. doi:10.1016/j.neuroimage.2012.01.021PubMedGoogle ScholarCrossref
10.
Raz  L, Jayachandran  M, Tosakulwong  N,  et al.  Thrombogenic microvesicles and white matter hyperintensities in postmenopausal women.  Neurology. 2013;80(10):911-918. doi:10.1212/WNL.0b013e3182840c9fPubMedGoogle ScholarCrossref
11.
Schwarz  CG, Reid  RI, Gunter  JL,  et al; Alzheimer’s Disease Neuroimaging Initiative.  Improved DTI registration allows voxel-based analysis that outperforms tract-based spatial statistics.  Neuroimage. 2014;94:65-78. doi:10.1016/j.neuroimage.2014.03.026PubMedGoogle ScholarCrossref
12.
Oishi  K, Zilles  K, Amunts  K,  et al.  Human brain white matter atlas: identification and assignment of common anatomical structures in superficial white matter.  Neuroimage. 2008;43(3):447-457. doi:10.1016/j.neuroimage.2008.07.009PubMedGoogle ScholarCrossref
13.
Jack  CR  Jr, Wiste  HJ, Weigand  SD,  et al.  Age-specific population frequencies of cerebral β-amyloidosis and neurodegeneration among people with normal cognitive function aged 50-89 years: a cross-sectional study.  Lancet Neurol. 2014;13(10):997-1005. doi:10.1016/S1474-4422(14)70194-2PubMedGoogle ScholarCrossref
14.
Crary  JF, Trojanowski  JQ, Schneider  JA,  et al.  Primary age-related tauopathy (PART): a common pathology associated with human aging.  Acta Neuropathol. 2014;128(6):755-766. doi:10.1007/s00401-014-1349-0PubMedGoogle ScholarCrossref
15.
Mosconi  L, Berti  V, Quinn  C,  et al.  Sex differences in Alzheimer risk: Brain imaging of endocrine vs chronologic aging.  Neurology. 2017;89(13):1382-1390. doi:10.1212/WNL.0000000000004425PubMedGoogle ScholarCrossref
16.
DeCarli  C, Frisoni  GB, Clark  CM,  et al; Alzheimer’s Disease Cooperative Study Group.  Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia.  Arch Neurol. 2007;64(1):108-115. doi:10.1001/archneur.64.1.108PubMedGoogle ScholarCrossref
×