Dickerson et al. Neurology
Appendix-e1
Supplemental Materials and Methods
Participants
Sample 1 (MGH)
Recruitment and inclusion/exclusion criteria
The participants in this study were drawn from a longitudinal study (total n=379) that
recruited subjects from the community with and without memory difficulty to examine
the preclinical predictors of AD 1. Volunteers who responded to the advertisements then
underwent a multistage screening procedure. To be included in the parent longitudinal
study, participants had to be primarily English speaking, 65 or older; non-demented; and
free of significant underlying medical, neurological, or psychiatric illness (based on
standard laboratory tests and a comprehensive evaluation described below). Individuals
with major vascular risk factors or disease (i.e., atrial fibrillation, insulin dependent
diabetes mellitus, cerebral infarcts, cardiac bypass graft surgery) at baseline were
excluded. All subjects and informants provided informed consent in accordance with the
Human Research Committee of the Massachusetts General Hospital, Boston, MA.
Comprehensive evaluation of cognitive status and diagnostic assessment
A semi-structured evaluation was administered annually to determine each participant’s
overall cognitive status 2, 3. It includes a set of questions regarding memory and cognitive
abilities in daily life and functional status in complex and basic activities of daily living,
asked of the subject and an informant, and a standardized neurologic, psychiatric, and
mental status evaluation of the subject. At baseline in the longitudinal study, as a result of
this evaluation, participants were classified as cognitively normal (CN) or
questionably/very mildly impaired. The same evaluation was performed annually, and at
each subsequent visit participants were classified similarly as CN, questionably/very
mildly impaired, or—for those who had progressed to dementia at subsequent visits—
demented.
A consensus clinical diagnosis was assigned to participants who developed
significant cognitive and functional impairment, incorporating clinical history, medical
records, laboratory evaluation, mental status evaluation results obtained during the office
evaluation, and neuroimaging studies 1, 4. Individuals with dementia were classified as
AD or another diagnosis (e.g., frontotemporal dementia, vascular dementia) according to
standard criteria 4-6.
Neuropsychological measures
At baseline, a neuropsychological battery was administered to all subjects, as previously
described 1. The neuropsychological test battery was administered in a separate session
from the cognitive evaluation described above, and was scored in a fashion blind to other
information about the subject.
For the purposes of the present study, we computed a composite episodic memory
score based on three measures, including the California Verbal Learning Test (CVLT)7
Total Learning and Delayed Free Recall measures, as well as the Free and Cued Selective
Reminding Test8 Delayed Free Recall measure. First we calculated standardized scores
for each of these tests adjusted for age, gender, and education as follows. Using baseline
data from the sample as a whole, we performed a linear regression for each test score
using age, gender, and educational attainment as predictors, and saved the residuals from
this regression. For the subjects who were CN at baseline, we computed the mean and
standard deviation of these residuals. Standardized scores were then calculated for all
subjects by subtracting the mean of the CN subjects, and dividing by the standard
deviation in these CN subjects 9. For the present article, the standardized scores for the
three memory tests were averaged into a single Episodic Memory Z score. Thus, a
standardized score of -1.0 indicates that the subject was 1 standard deviation below
expected mean for a CN subject of the same age, gender, and level of educational
attainment.
Subject selection and outcome measures in the present analysis
For the present analyses, we included all subjects with a baseline cognitive evaluation
that indicated CN status and at least four annual follow-up visits, for a total of at least 5
years of follow-up (n=73). Based on the hypotheses of the present analysis, we further
restricted the sample to those individuals who remained CN at most recent follow-up
(CN-Stable) or those who were diagnosed with probable AD dementia (CN-AD
Converter), excluding individuals who were diagnosed with MCI or non-AD dementia.
This resulted in a sample size of 38, including 28 CN-Stable and 10 NC-AD Converters.
Of these, 3 CN and 2 AD participants had MRI scans that were not useable for the
present analyses.
Sample 2 (Rush)
Recruitment and inclusion/exclusion criteria
All participants were recruited for a longitudinal imaging project 10 from a) the
community by the Rush Alzheimer’s Disease Center (RADC; Chicago, IL); b) the
Religious Order Study (ROS), a longitudinal, clinico-pathologic investigation of aging
and AD in older nuns, priests and brothers 11-13; or c) the Rush Memory and Aging
Project (MAP), a separate longitudinal clinicopathologic investigation of aging and AD
14
. Subjects were excluded if there was evidence of other neurologic, psychiatric or
systemic conditions. It is important to note that all individuals included in the present
study who were classified as CN at baseline evaluation were not recruited from clinical
populations in which some individuals came in for a work-up but tested within normal
limits. Informed consent was obtained from all participants according to the rules of the
Human Investigation Committee of Rush University Medical Center.
Comprehensive evaluation of cognitive status and diagnostic assessment
All evaluations were carried out by the Rush Alzheimer’s Disease Center (RADC,
Chicago, IL) as previously described 10, 15. Briefly, the evaluation, which was given to all
participants in the study, incorporated the Consortium to Establish a Registry for
Alzheimer’s Disease (CERAD, 16) procedures and included a medical history,
neurological examination, neuropsychological testing, informant interview and blood
tests. All participants in the present study were classified as CN at baseline. This
diagnostic classification required the absence of neurologic, psychiatric or systemic
conditions that could cause cognitive impairment (e.g., stroke, alcoholism, major
depression, a history of temporal lobe epilepsy), a normal neurological examination,
normal cognition as determined by performance on neuropsychological tests, and an
MMSE 17 score ≥27. Longitudinal followup evaluations of each individual were
conducted annually, as part of the parent studies. For individuals determined to have
dementia, a consensus diagnosis was determined. Individuals with dementia were
classified as AD or another diagnosis (e.g., frontotemporal dementia, vascular dementia)
according to standard criteria 4-6. CDR ratings were not performed until relatively
recently in the Rush study, and so are not available for the present analysis.
Neuropsychological measures
The episodic memory tests administered to all participants and used to define a memory
deficit consisted of immediate and delayed recall of the East Boston Story 18 and of Story
A from the Logical Memory of the Wechsler memory scale–Revised 19. An additional
test involved the learning and retention of a 10-word list from the CERAD battery 16. The
three scores for this test included Word List Memory (the total number of words
immediately recalled after each of three consecutive presentations of the list), Word List
Recall (the number of words recalled after a delay), and Word List Recognition (the
number of words correctly recognized in a four-alternative, forced-choice format,
administered after Word List Recall). Summary scores were calculated for combined
performance on these memory tests by standardizing each of the seven episodic memory
scores 20. For this purpose, we used the mean and standard deviations of each test from
the baseline visits of the first wave of 86 participants entered into an ongoing longitudinal
project 10 and averaged the standardized values to obtain an Episodic Memory Z score.
Subject selection and outcome measures in the present analysis
For the present analyses, we included all subjects with a baseline cognitive evaluation
that indicated CN status and at least four annual follow-up visits (with the exception of
one participant who was followed for 3 years). Based on the hypotheses of the present
analysis, we further restricted the sample to those individuals who remained CN at most
recent follow-up (CN-Stable) or those who were diagnosed with probable AD dementia
(CN-AD Converter). This resulted in a sample size of 33, including 25 CN-Stable and 7
CN-AD Converters. All of these individuals had MRI scans that were useable for the
present analyses.
MRI Data Acquisition and Analysis
MRI Data Acquisition Parameters
For the MGH sample, the parameters were: repetition time/echo time (TR/TE) = 35
msec/5 msec; field of view = 22 cm; flip angle = 45°; number of excitations = 1; slice
thickness = 1.5 mm, 124 slices; matrix size = 256 x 256). For the Rush sample, the
parameters were: TR/TE = 33.3 msec/7 msec; field of view = 22 cm; flip angle = 35°;
number of excitations = 1; slice thickness = 1.6 mm, 124 slices; matrix size = 256 x 192).
MRI morphometric data analysis – Automated surface reconstruction and alignment of
participants
The MRI morphometric data analysis methods have been previously described in detail
21-26
. The FreeSurfer software used to perform the analyses and visualization employed in
this study, along with complete documentation, is freely available via the internet at
http://surfer.nmr.mgh.harvard.edu). The raw MRI volume for each participant was used
to segment cerebral white matter 25 and multiple subcortical grey matter and ventricular
regions 27, and to estimate the location of the gray/white boundary. Topological defects in
the gray/white boundary were corrected 28, and this gray/white boundary was used as the
starting point for a deformable surface algorithm designed to find the pial surface with
submillimeter precision 26. Cortical thickness measurements were obtained by calculating
the distance between those surfaces at each of approximately 160,000 points (per
hemisphere) across the cortical mantle (Fischl and Dale 2000). Mean thickness of each
subject’s entire cerebral cortex was then calculated. The methods for generation of
cortical surfaces and resultant thickness measurements have been shown to be reliable in
a test-retest study of a group of older participants scanned twice on the same scanner, as
well as across scanner manufacturers and 1.5T and 3.0T field strengths 29, 30, and in a
study of different sequence parameters 31. The accuracy of the thickness measures
derived from this technique has been previously validated by direct comparisons with
manual measures on postmortem brain 23 and on MRI data 21.
The surface representing the gray-white border was ‘‘inflated,” differences among
individuals in the depth of gyri and sulci were normalized as previously described 24, 25, 32,
and each subject’s reconstructed brain was then morphed and registered to an average
spherical surface representation that optimally aligns sulcal and gyral features across
participants. Thickness measures were then mapped to the inflated surface of each
participant’s reconstructed brain (Fischl, Sereno and Dale 1999). This procedure allows
visualization of data across the entire cortical surface (i.e., both the gyri and sulci)
without interference from cortical folding. The data were smoothed on the surface using
an iterative nearest-neighbor averaging procedure. One hundred iterations were applied,
which is equivalent to applying a 2-dimensional Gaussian smoothing kernel along the
cortical surface with a full-width/half-maximum of 18.4 mm. Data were then resampled
into a common spherical coordinate system (Fischl, Sereno, and others 1999). The
procedure provides accurate matching of morphologically homologous cortical locations
among participants on the basis of each individual’s anatomy, while minimizing
geometric distortion, resulting in a mean measure of cortical thickness for each group at
each point on the reconstructed surface.
MRI morphometric data analysis – Generation of cortical ROIs and quantification of
magnitude of thinning
The primary analytic approach employed in this study made use of “AD-signature”
regions of interest (ROIs) generated from a previous study and applied in an a priori
fashion to the subjects in the present analysis. In the previous study in which these ROIs
were identified, cortical thickness in patients with mild AD dementia was compared to
that of CN and regions of significant thinning were identified 33. The analysis generated
nine ROIs that were demonstrated to be consistently affected across four separate
samples of patients with mild AD 33, and which were subsequently demonstrated to be
useful in predicting dementia in patients with MCI 34. As illustrated in the Figure e2, the
MTL cortex ROI was localized in the rostral MTL spanning the crown of the
parahippocampal gyrus and extending into the fundus of the collateral sulcus, in a region
typically considered to include both entorhinal and perirhinal cortex. In addition to these
9 AD-signature ROIs, an ROI from the primary visual cortex (PVC) was used as in the
previous studies as a control region, hypothesized not to be affected in AD relative to
NC. The map in Supplemental Figure e2 shows the ROIs.
Using the spherical registration of each subject to the template, the ROIs were
mapped from the template back to each individual participant in the present analysis. For
each subject, mean cortical thickness within each ROI was calculated by deriving an
average of all of the thickness estimates at vertices that fell within the labeled ROI. For
each subject, the resultant ROI measures of cortical thickness were averaged across the
two hemispheres, and these values were used for further statistical analysis. In addition,
for each subject, a single summary measure was derived from the average thickness
across all 9 AD-related ROIs, the “AD-signature” ROI summary measure.
Results
In the MGH sample, CDR Sum-of-Boxes scores for the NC-AD Converter group at the
time of diagnosis of dementia were 6.9 (S.D. = 2.4) with the overall CDR ratings being
1.2 (S.D. = 0.5). CDR scores were not available for the Rush sample.
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