Alzheimer’s& Dementia: Diagnosis, Assessment & Disease Monitoring 9 (2017) 41-50 Neuroimaging Entorhinal and transentorhinal atrophy in mild cognitive impairment using longitudinal diffeomorphometry Daniel J. Twarda,b,*, Chelsea S. Sicata, Timothy Browna, Arnold Bakkerc, Michela Gallagherd, Marilyn Alberte, Michael Millera,b,f, for the Alzheimer’s Disease Neuroimaging Initiative aCenter for Imaging Science, Johns Hopkins University, Baltimore, MD, USA bDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA cDepartment of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA dDepartment of Psychological and Brain Sciences, Johns Hopkins School of Arts and Sciences, Baltimore, MD, USA eDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA fKavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD, USA Abstract Introduction: Autopsy findings have shown the entorhinal cortex and transentorhinal cortex are among the earliest sites of accumulation of pathology in patients developing Alzheimer’s disease. Methods: Here, we study this region in subjects with mild cognitive impairment (n 5 36) and in control subjects (n 5 16). The cortical areas are manually segmented, and local volume and shape changes are quantified using diffeomorphometry, including a novel mapping procedure that reduces variability in anatomic definitions over time. Results: We find significant thickness and volume changes localized to the transentorhinal cortex through high field strength atlasing. Discussion: This demonstrates that in vivo neuroimaging biomarkers can detect these early changes among subjects with mild cognitive impairment. Ó 2017 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). Keywords: Entorhinal cortex; Mild cognitive impairment; Braak staging; Diffeomorphometry; Shape analysis; Longitudinal analysis 1. Background AD and has been used to define a subtype of MCI called amnestic MCI [3]. Quantitative studies of autopsied brains The anatomic localization of the early pathologic changes from well-characterized patients at this phase of AD have associated with Alzheimer’s disease (AD) aligns with the demonstrated a substantial loss of neurons in the entorhinal clinical presentation of most patients in the early symptom- cortex (ERC) [4–6]. A broad consensus now exists on this atic phase of AD. By clinical, cognitive, and functional locus for early neurodegeneration and the subsequent criteria, mild cognitive impairment (MCI) is considered an spread of pathology along connectional pathways as intermediate state between individuals who are cognitively disease progresses causing further symptomatic worsening normal and those with a clinical diagnosis of dementia through the stages of dementia. [1,2]. Impairment of episodic memory, that is, the ability Against this background, localized anatomic change in the to acquire and retain new information about life events, medial temporal lobe observed using structural magnetic that is greater than expected for a person’s age is most resonance imaging (MRI) has provided an indirect measure commonly observed in subjects with MCI who progress to of neuronal injury [7,8]. In particular, entorhinal cortical atrophy has been identified as one of the MRI measures that *Corresponding author. Tel.: 11-410-516-3826; Fax: 11-410-516- predicts longitudinal progression among symptomatic cases, 4594. with greater atrophy associated with greater clinical disease E-mail address: [email protected] severity [9–12] (also see recent review [13]). ERC atrophy http://dx.doi.org/10.1016/j.dadm.2017.07.005 2352-8729/ Ó 2017 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 42 D.J. Tward et al. / Alzheimer’s& Dementia: Diagnosis, Assessment & Disease Monitoring 9 (2017) 41-50 detected by MRI has also been predictive of progression from from subjects who met ADNI criteria for MCI at baseline normal cognition to MCI [14]. Such atrophy has been associ- were selected for analysis. Inclusion criteria for subjects ated with impairment on multiple memory tests confirming with MCI included evidence of impaired performance on that this atrophy has clinical relevance for patients [15]. Logical Memory Subtest of the Wechsler Memory Scale The field of computational anatomy [16] has been working (based on age and education adjusted norms), a score of clin- toward addressing the need for quantitative, well-researched, ical dementia rating (CDR) 0.5, and a clinical diagnosis of standardized structural imaging biomarkers for neurodegener- MCI. The MCI subjects were all selected to be amyloid b pos- ative disease. Patterns of atrophy at the population and individ- itive based on cerebrospinal fluid cutoff values established by ual level are described quantitatively by constructing smooth the ADNI Biospecimen Core (i.e., less than a cutoff score of mappings (diffeomorphisms) that identify correspondences 192 pg/mL) [21] and age between 55 and 85 years. between a well-characterized template image and a given The criteria for control status in ADNI included evidence patient image. Properties of these mappings, such as how of performance within the normal range on the Logical much they expand or contract, are used to give a quantitative Memory Subtest of the Wechsler Memory Scale (based on description of biological change. These tools have been previ- age and education adjusted norms), a score of CDR 5 0, ously applied to a study of the medial temporal lobe [17], and the absence of a clinical diagnosis of MCI or dementia. where significant atrophy was found present in the most lateral Control subjects were included only if they were amyloid b portion of the ERC. In this study, we use structural MRI to negative (greater than a cutoff of 192 pg/mL). In total, 36 investigate the cortical region further lateral, the transentorhi- subjects with amnestic MCI and 16 control subjects were nal cortex (TEC), which is one of the sites of the earliest selected. Their baseline demographics and cognitive scores detected pathology as reported by Braak and Braak [18]. are summarized in Table 1. Because of its proximity to meninges and the oculomotor nerve, as well as the fact that its definition is specified by distant landmarks rather than local contrast changes [19], 2.2. Manual segmentation protocol this area is difficult for automatic segmentation techniques. Analysis included subjects who had no discontinuity in Although some techniques [20] are addressing these con- their collateral sulcus (type I variant described in [22] and cerns, we choose to use manual segmentations in this study. further discussed in [23]) and was restricted to the left side In this context, one important source of variability is the con- of the MRI scan. Most subjects examined were found to sistency of segmentations over time. have this anatomic variant on the left side, but many had Our approach to overcoming this limitation is to develop alternative variants on the right. Only subjects scanned for a longitudinal filtering procedure, passing a template seg- at least three time points for more than 2 years were mentation through each time point along a continuous trajec- included. Most were scanned at 6, 12, and 24 months after tory. This allows data to be shared between various time baseline. Data for one subject is shown in Fig. 1 left panel. points, removing noise associated with variable structure We denote the ith subject’s jth scan time as tij. definition over time. The trajectory we choose is modeled ERC and TEC were segmented manually, using anatomic by two geodesics through the space of diffeomorphisms, boundaries described in [19]. As seen in the coronal plane, one from template to baseline and other from baseline the boundaries can be described by through each follow up. This leads to a procedure that is essentially linear regression through the high-dimensional Rostral: 4 mm rostral to hippocampal head space of images. Caudal: 2 mm caudal to gyrus intralimbicus We study a sample of subjects from the Alzheimer’s dis- Medial: As far as visible gray/white boundary ease neuroimaging initiative (ADNI) who are cognitively Lateral: Deepest part of collateral sulcus normal or have MCI by clinical and cognitive criteria at Segmentations were performed in Seg3D version 1 [24]. baseline. We measure volume changes over time to compute One example is shown in the coronal plane in Fig. 1 right volumetric atrophy rate due to MCI, and we measure local volume and thickness over time to compute the spatial distri- Table 1 bution of these changes. Regions where atrophy is signifi- Baseline demographic information for control and mild cognitive cantly different between groups are identified using impairment (MCI) groups permutation testing, controlling for multiple comparisons Parameter Control MCI using the maximum statistic. Number 16 36 Age 71.7 6 6.01 72.0 6 7.61 2. Methods Female gender 43.8% 50.0% CDR 0 6 0 1.57 6 0.719 6 6 2.1. Subjects Mini-Mental State Examination 29.4 1.03 27.4 1.77 Wechsler Memory Scale (WMS) Logical 14.3 6 2.27 3.42 6 2.55 Data used in the preparation of this article were obtained Memory (Immediate) 6 6 from the ADNI database (adni.loni.usc.edu). MRI scans WMS Logical Memory (Delayed) 15.2 3.22 7.06 3.22 D.J. Tward et al. / Alzheimer’s& Dementia: Diagnosis, Assessment & Disease Monitoring 9 (2017) 41-50 43 Fig. 1. Left panel: A time series for one subject with MCI is shown, with structural imaging together with medial temporal lobe segmentations (magenta, hip- pocampus; cyan, amygdala; red, ERC; green, TEC; blue, perirhinal cortex). Volumetry of the ERC 1 TEC is shown indicating a trend of 25% atrophy per year for more than 2 years.