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Published online before print June 23, 2008, 10.1148/radiol.2482070938

(Radiology 2008;248:590.)

A more recent version of this article appeared on August 1, 2008
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© RSNA, 2008

Neuroradiology

Whole-Brain Atrophy Rate and Cognitive Decline: Longitudinal MR Study of Memory Clinic Patients1

Jasper D. Sluimer, MD, Wiesje M. van der Flier, PhD, Giorgos B. Karas, MD, Nick C. Fox, MD, FRCP, Philip Scheltens, MD, PhD, Frederik Barkhof, MD, PhD, and Hugo Vrenken, PhD

1 From the Alzheimer Centre and Department of Diagnostic Radiology (J.D.S., G.B.K., F.B., H.V.), Image Analysis Centre (J.D.S., F.B.), Department of Neurology (W.M.v.d.F., P.S.), and Department of Physics and Medical Technology (J.D.S., H.V.), Vrije Universiteit Medical Centre (VUMC), De Boelelaan 1117, 1007 MB Amsterdam, the Netherlands; and Dementia Research Centre, Institute of Neurology (N.C.F.), University College London, London, England. Received June 1, 2007; revision requested July 31; revision received October 18; accepted December 28; final version accepted February 19, 2008. J.D.S. supported by grant 03514 from the Internationale Stichting Alzheimer Onderzoek and the Image Analysis Center. The Alzheimer Center VUMC is supported by Alzheimer Nederland and Stichting VUMC funds. The clinical database structure was developed with funding from Stichting Dioraphte. Address correspondence to J.D.S. (e-mail: jd.sluimer{at}vumc.nl).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Purpose: To prospectively determine whole-brain atrophy rate in mild cognitive impairment (MCI) and Alzheimer disease (AD) and its association with cognitive decline, and investigate the risk of progression to dementia in initially nondemented patients given baseline brain volume and whole-brain atrophy rate.

Materials and Methods: This study was IRB approved; written informed consent was obtained; and included 65 AD patients (38 women, 27 men; age, 52–81 years), 45 MCI patients (22 women, 23 men; age, 56–80 years), 27 patients with subjective complaints (12 women, 15 men; age, 50–87 years), and 10 healthy controls (six women, four men; age, 53–80 years). Two magnetic resonance (MR) images were acquired at average interval of 1.8 years ± 0.7 (standard deviation). Baseline brain volume and whole-brain atrophy rates were measured on three-dimensional T1-weighted MR images (1.0 T; single slab, 168 sections; matrix size, 256 x 256; field of view, 250 mm; voxel size, 1 x 1 x 1.5 mm; repetition time msec/echo time msec/inversion time msec, 15/7/300; and flip angle, 15°). Associations were assessed by using partial-correlations. Cox proportional hazards models were used to estimate risk of developing dementia.

Results: Baseline brain volume was lowest in AD but did not differ significantly between MCI, subjective complaints, and control groups (P > .38). Whole-brain atrophy rates were higher in AD (–1.9% per year ± 0.9) than MCI (–1.2% per year ± 0.9, P = .003) patients, who had higher whole-brain atrophy rates than patients with subjective complaints (–0.7% per year ± 0.7, P = .03) and controls (–0.5% per year ± 0.5, P = .05). Whole-brain atrophy rate correlated with annualized Mini-Mental State Examination (MMSE) change (r = 0.48, P < .001), while baseline volume did not (r = 0.11, P = .22). Cox models showed that—after correction for age, sex, and baseline MMSE—a higher whole-brain atrophy rate was associated with an increased risk of progression to dementia (highest vs lowest tertile [hazard ratio, 3.6; 95% confidence interval: 1.2, 11.4]).

Conclusion: Whole-brain atrophy rate was strongly associated with cognitive decline. In nondemented participants, a high whole-brain atrophy rate was associated with an increased risk of progression to dementia.

© RSNA, 2008


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Alzheimer disease (AD) is characterized by an insidious onset of progressive cognitive decline. The term mild cognitive impairment (MCI) is used to describe patients who do not fulfill clinical criteria for dementia but do have objective evidence of memory deficits. MCI patients are at an increased risk of developing AD (1); however, not all patients diagnosed with MCI progress to AD. Some develop another type of dementia, while others improve or remain clinically stable (2,3).

Structural magnetic resonance (MR) imaging allows tissue loss (atrophy) to be assessed in vivo (4). Many studies in AD focused on the medial temporal lobe, known to be affected early in the disease (5–8). However, atrophy is not limited to this region. Neocortical loss and enlargement of the ventricles have been reported at an early stage (9,10). It has been suggested that whole-brain atrophy rate is more sensitive to the earliest disease changes than brain volume measurement at a single time point (11–14). Reported whole-brain atrophy rates in AD range from 1% to 4% per year (15–18), while healthy elderly patients have age-related atrophy rates ranging from 0.2% to 0.7% per year (19,20). Relatively few studies have addressed the issue of whole-brain atrophy rates across the cognitive spectrum of normal cognition, MCI, and AD (11,21,22).

Thus, the purpose of this study was to prospectively determine the whole-brain atrophy rate in MCI and AD and its association with cognitive decline, as well as to investigate the risk of progression to dementia in initially nondemented patients given baseline brain volume and whole-brain atrophy rate.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Patients
Baseline clinical assessment.—The study was approved by the institutional ethical review board. All participants (or caregivers) gave written informed consent. We included 65 patients with (38 women, 27 men; age, 52–81 years), 45 patients with MCI (22 women, 23 men; age, 56–80 years), and 27 patients with subjective complaints (12 women, 15 men; age, 50–87 years). Patients underwent a standard clinical assessment including medical history, physical and neurologic examination, psychometric evaluation, and brain MR imaging. The Mini-Mental State Examination (MMSE) was used as a measure of general cognitive function (23). Diagnoses were established during a multidisciplinary consensus meeting according to the Petersen criteria for MCI (24) and the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer Disease and Related Disorders Association criteria for probable AD (25). When all clinical investigations were normal (ie, MCI criteria were not fulfilled), patients were considered to have subjective complaints. Additionally, we included 10 healthy control individuals without cognitive complaints (six women, four men; age, 53–80 years), recruited from caregivers, who were willing to undergo the same diagnostic procedure as patients attending our memory clinic.

Clinical assessment at follow-up.—Nondemented participants (MCI and subjective complaints) visited the memory clinic annually. Diagnostic classification was reevaluated at follow-up. The clinical diagnosis of dementia was determined according to published consensus criteria (24–28). Of 45 MCI patients, 17 patients remained stable, 23 progressed to AD, two progressed to frontotemporal lobar degeneration (26), two progressed to vascular dementia (27), and one progressed to dementia with Lewy bodies (28). Of 27 patients with subjective complaints, 20 patients remained stable while three patients progressed to MCI, three progressed to AD, and one progressed to frontotemporal lobar degeneration. All healthy controls without complaints remained stable.

MR Imaging and Evaluation
Between 2004 and 2006 all patients attending our memory clinic were invited for repeat MR imaging. Follow-up time is defined as that between the two MR images (mean interval, 1.8 years ± 0.7; range, 11 months to 4 years 2 months). MR imaging was performed with a 1.0-T imager (Magnetom Impact; Siemens, Erlangen, Germany) and included coronal T1-weighted three-dimensional magnetization-prepared rapid acquisition gradient-echo volumes (single slab, 168 sections; matrix size, 256 x 256; field of view, 250 x 250 mm; voxel size, 1 x 1 x 1.5 mm; repetition time msec/echo time msec/inversion time msec, 15/7/300; flip angle, 15°). A total of 159 patients agreed to undergo MR twice (71 with AD, 49 with MCI, 29 with subjective complaints, and 10 controls). Participants were included only (a) if they had two images of adequate quality, performed on the same imager by using the same imaging protocol; (b) if no nonneurodegenerative pathologic evidence could explain that cognitive impairment was present, as judged by one radiologist (F.B., with 15 years experience in dementia); or (c) if fully-automated Structural Image Evaluation, using Normalization, of Atrophy (SIENA) or the cross-sectional processing counterpart (SIENAX) did not yield errors, as checked by a blinded rater (J.D.S., with 4 years experience in dementia, MR imaging, and analysis). Consequently, we excluded 12 patients: two because of movement artifacts in the original MR data, seven patients showed nonneurodegenerative pathologic evidence associated with cognitive impairment (one hydrocephalus, one tumor, one hemorrhage, and four patients fulfilled National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherché et l'Enseignement en Neurosciences criteria for vascular dementia), and three patients because of remaining nonbrain tissue after processing. A total of 147 participants were included (65 with AD, 45 with MCI, 27 with subjective complaints, and 10 with controls).

Normalized baseline brain volume and percentage brain volume change (PBVC) between two time points were measured from the magnetization-prepared rapid acquisition gradient-echo images by using SIENAX and SIENA, two fully automated techniques that are part of the FMRIB Software Library (14,29).

Whole-brain atrophy rate was measured with SIENA. Briefly, the brain was extracted by using the brain extraction tool (29). Compared with standard SIENA and cross-sectional SIENAX, the procedure to remove nonbrain tissue was slightly modified because the brain extraction tool often leaves substantial amounts of nonbrain tissue when using a single-slab three-dimensional magnetization-prepared rapid acquisition gradient-echo sequence, while also removing cortex in some areas (30). To remove all nonbrain tissue without losing cortex, we incorporated registration of a template mask to the individual image. After brain extraction, the two brain images were aligned to each other, while using the skull images to constrain the registration scaling. Both brain images were resampled in the space halfway between the two. Next, tissue type segmentation was performed to find brain/nonbrain edge points, and for each edge point, perpendicular edge displacement between baseline and repeated images was measured. The mean edge displacement was automatically converted to a global estimate of PBVC between the two time points.

Baseline brain volume, normalized for subject head size, was measured with SIENAX. Briefly, after brain extraction, tissue type segmentation with partial volume estimation was carried out to calculate total volume of brain tissue. In addition, to correct for interindividual differences in head size, a volumetric scaling factor was obtained by registering the brain image to MNI152 (Montreal Neurological Institute, Montreal, Canada) space, by using an affine transformation (ie, a linear transformation with 12 degrees of freedom), and by using the skull to constrain the registration scaling. Baseline brain volume, normalized for subject head size, was then obtained by multiplying the volume of brain tissue by the volumetric scaling factor. We used the baseline normalized brain volume as a cross-sectional measure, and whole-brain atrophy rate (measured as PBVC) as a longitudinal measure of atrophy.

Statistical Analysis
Statistical analysis was performed (J.D.S. and W.M.v.d.F.) with software (SPSS, version 12.0, 2003; SPSS, Chicago, Ill). PBVC and change in MMSE were annualized by dividing by the intermediate time between observations, in years. Diagnostic groups were compared with {chi}2 tests for sex. For continuous variables (age, MMSE, MMSE change, MR image interval, normalized baseline brain volume, whole-brain atrophy rate) we used analysis of variance, with age and sex as covariates. Post hoc comparisons were performed by using a Bonferroni test. Box-and-whisker plots of baseline brain volume and whole-brain atrophy rate, arranged by diagnostic group, were constructed. Associations of baseline brain volume and whole-brain atrophy rate with MMSE and MMSE change were assessed by using partial correlations, corrected for age and sex. Scatterplots of baseline brain volume and whole-brain atrophy rate versus annual change in MMSE were created. Within the group of initially nondemented participants, we assessed the predictive value of baseline brain volume and whole-brain atrophy rate by using Cox proportional hazards models, which account for variability in length of follow-up. Among the initially nondemented patients, baseline brain volume and whole-brain atrophy rate were categorized in tertiles and entered as categorical variables in the model. Hazard ratios with 95% confidence intervals are presented. First (model 1), unadjusted hazard ratios were presented. In model 2, sex and age were corrected for, and in model 3, baseline MMSE was added as an additional covariate. The main outcome was progression to dementia and the second outcome was progression to AD, which excludes six patients who developed a different kind of dementia. Time-to-event curves were constructed with the Kaplan-Meier method. A P value of less than .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Brain Volume and Whole-Brain Atrophy Rate
There were group differences for both baseline brain volume and whole-brain atrophy rate (Table 1, Fig 1). Post hoc Bonferroni-corrected tests illustrated that brain volume at baseline was lowest for the AD group (compared with MCI, P = .09; compared with subjective complaints, P < .001; and compared with controls P < .01), but the MCI group did not differ from either the subjective complaint group (P = .38) or control group (P = .48). No difference between patients with subjective complaints and controls was found (P > .99).


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  		Table 1. Demographics and Clinical Variables for Each Diagnostic Group

 

Figure 1
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  		Figure 1: Box-and-whisker plot of (left) baseline brain volume and (right) whole-brain atrophy rate, by diagnostic group (C = controls, SC = subjective complaints). Horizontal line inside box is median value. Differences between groups were assessed by using analysis of variance (age and sex were covariates with post hoc Bonferroni correction). * = P < .05, ** = P < .01, *** = P < .001.

 
By contrast, annualized whole-brain atrophy rates (measured as PBVC) not only differentiated the AD group from all other groups, it also showed differences between the other groups. AD patients had higher whole-brain atrophy rates compared with MCI (P = .003), who in turn had higher whole-brain atrophy rates compared with subjective complaints (P = .025) and controls (P = .05). No difference was found between subjective complaints and controls (P > .99) (Fig 2).


Figure 2
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  		Figure 2: Baseline axial MR images of individual edge-displacement maps. Mild (dark blue) to severe (light blue) local contraction implies atrophy. Mild (red) to severe (yellow) expansion of brain tissue is also visible. For display purposes, edge motion was truncated at 1 mm. A, 74-year-old patient with subjective complaints: normalized baseline brain volume, 1471 mL; whole-brain atrophy rate, –0.7% per year. B, 80-year-old patient with MCI who did not progress to AD: normalized baseline brain volume, 1607 mL; whole-brain atrophy rate, –0.6% per year. C, 67-year-old patient with MCI who progressed to AD: normalized baseline brain volume, 1548 mL; whole-brain atrophy rate, –1.9% per year. D, 63-year-old patient diagnosed with Alzheimer disease at baseline: normalized baseline brain volume, 1286 mL; whole-brain atrophy rate, –4.2% per year.

 
Cognitive Decline
To investigate whether baseline brain volume and whole-brain atrophy rate reflected cognitive decline, we assessed associations with baseline MMSE and annualized MMSE change (Fig 3). Partial correlations corrected for age and sex showed that across the whole sample, baseline brain volume correlated with baseline MMSE (r = 0.32, P < .001) but not with annualized change in MMSE (r = 0.11, P = .22). However, whole-brain atrophy rate (measured as PBVC) was associated with baseline MMSE (r = 0.48, P < .001) and change in MMSE (r = 0.48, P < .001). Further evaluation of correlations within diagnostic groups showed that baseline brain volume was not associated with either MMSE or MMSE change within any of the groups. By contrast, whole-brain atrophy rate within the AD group was associated with MMSE (r = 0.37, P < .01) and MMSE change (r = 0.34, P < .01). Within the MCI group, whole-brain atrophy rate was associated with MMSE change (r = 0.33, P < .05) but not with baseline MMSE (r = 0.09, P = .61). No such associations were found among patients with subjective complaints or controls.


Figure 3
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  		Figure 3: Scatterplots of (left) baseline brain volume and (right) whole-brain atrophy rate by annual change in MMSE. Data for entire spectrum of cognitive decline are presented. No association between baseline brain volume and annual MMSE decline was found (left, partial correlation, correcting for age and sex, r = 0.11, P = .22). In contrast, whole-brain atrophy rate was associated with annualized MMSE change (right, r = 0.48, P < .001). Subsequent evaluation of correlations within diagnostic groups showed that whole-brain atrophy rate was associated with annualized MMSE change within AD group (r = 0.34, P < .01), and within MCI group (r = 0.33, P < .05). No associations were found among healthy controls or subjective memory complaints. + = healthy controls, {triangleup} = subjective memory complaints, {square} = MCI, {circ} = AD.

 
Prediction of Progression to Dementia
Finally, we assessed the predictive value of baseline brain volume and whole-brain atrophy rate for progression to dementia in initially nondemented patients (n = 82) by using tertiles of MR imaging measurements (Fig 4, Table 2). Baseline brain volumes were 1603 mL ± 40 in the large tertile, 1512 mL ± 26 in the middle tertile, and 1410 mL ± 46 in the small tertile. Whole-brain atrophy rates were –0.2% per year ± 0.2 in the lowest tertile, –0.8% per year ± 0.2 in the moderate tertile, and –1.8% per year ± 0.8 in the high tertile. Compared with a large baseline brain volume, a small volume was associated with a threefold increased risk of progression to dementia in the unadjusted model. However, after adjusting for age, sex, and baseline MMSE, this effect largely disappeared. Patients in the moderate whole-brain atrophy rate tertile had a twofold—though not significantly—increased risk of progression to dementia, in comparison with patients with a low whole-brain atrophy rate. A high whole-brain atrophy rate (highest tertile) was associated with a more than fourfold increased risk of progression to dementia. These results remained significant after correction for age, sex, and baseline MMSE. When the analysis was restricted to progression to AD (ie, excluding the six patients who progressed to another type of dementia), all results were essentially unchanged. When corrected for age, sex, and baseline MMSE (model 3), smaller baseline brain volumes were associated with a modest—although not significantly—increased risk of progression to AD (middle: hazard ratio, 1.8; 95% confidence interval: 0.5, 6.6 and small: hazard ratio, 1.9; 95% confidence interval: 0.5, 7.3), while whole-brain atrophy rate was associated with a more strongly increased risk of progression to AD (moderate: hazard ratio, 1.3; 95% confidence interval: 0.4, 4.8 and high: hazard ratio, 3.5; 95% confidence interval: 1.1, 11.2).


Figure 4
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  		Figure 4: Kaplan-Meier curve of time to conversion in initially nondemented patients (n = 82) depending on (left) baseline brain volume and (right) whole-brain atrophy rate. Baseline brain volume and whole-brain atrophy rate were divided in tertiles. Numbers at risk are displayed below graph. Participants reaching end of follow-up period without progression to dementia were censored (+).

 

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  		Table 2. Hazard Ratios and 95% Confidence Intervals for Progression to Dementia

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Our study results show that while baseline brain volume was significantly lower in AD patients than in those with subjective complaints and controls, it did not distinguish AD from MCI, nor could MCI be distinguished from subjective complaints and controls by using baseline brain volume. In contrast, whole-brain atrophy rates were able to separate AD from MCI and MCI from subjective memory complaints and controls, which illustrated that the whole-brain atrophy rate is more sensitive than cross-sectional brain volume. The clinical relevance of this marker was demonstrated by the association of whole-brain atrophy rate with baseline cognition and rate of cognitive decline. Finally, for initially nondemented patients, a high whole-brain atrophy rate was associated with increased risk of progression to dementia.

Our results confirm those of previous studies that showed an increased whole-brain atrophy rate in AD versus controls. Our control group had a whole-brain atrophy rate of 0.5% per year, which is in the middle of the previously reported range of rates of 0.2%–0.7% per year (19,20). The AD patients had an annualized whole-brain atrophy rate of 1.9%, almost fourfold higher than controls. This is similar to previously reported rates in AD, which are most typically around 2% per year (15,31), although reported whole-brain atrophy rates in AD range from 1% to 4%, probably depending on the characteristics of the AD population, and method of atrophy rate calculation (17,18,32,33). We extend those earlier findings showing that while there was no difference in baseline brain volume, the whole-brain atrophy rate for the MCI group with 1.2% per year was twice higher than among controls. This value is somewhat higher than the 0.7% per year observed in a previous study (21). That study used a boundary shift integral to assess whole-brain atrophy, and is the only other study that assessed the risk of progression to dementia in the nondemented. They report a slightly increased risk of progression to dementia. Two other studies used brain segmentation to measure whole-brain atrophy rates (11,22). One of these studies assessed association of whole-brain atrophy rates with age, but not with cognitive decline (11). Both studies did not assess risk of progression to dementia. Our study adds to these previous observations by investigating a large cohort, recruited in a clinical setting, which covers the entire cognitive spectrum. We have used a well-defined, easily accessible, fully automated atrophy measurement technique. Furthermore, we used the MMSE, the most commonly used clinical cognition test, to check for associations with whole-brain atrophy rates. Finally, we assessed the risk of progression to dementia, and found a more than threefold risk of progression to dementia for participants with a higher rate of atrophy.

Whole-brain atrophy rate was more sensitive than baseline brain volume in distinguishing between the diagnostic groups. Whole-brain atrophy rate showed a clear distinction between groups, while baseline brain volume could only distinguish AD. A higher sensitivity of longitudinal atrophy in the detection of subtle differences in whole-brain and localized atrophy rates has been reported in AD and other neurodegenerative disease (34–36). The higher sensitivity of whole-brain atrophy rate can in part be attributed to the fact that when a subject is compared with him- or herself instead of with a standard brain template, the confounding influence of interindividual variability is reduced, reducing the measurement error.

Among nondemented patients, a higher whole-brain atrophy rate was associated with a greater risk of progression to dementia. A small brain volume was associated with a threefold increased risk of progression to dementia, although this effect largely disappeared after correcting for age, sex, and baseline MMSE. By contrast, a high whole-brain atrophy rate was associated with a more than fourfold increased risk of progression to dementia, which remained significant after correcting for age, sex, and baseline MMSE.

Our study included the entire cognitive spectrum: patients with AD and MCI, patients with subjective complaints (who, in fact, can be considered normal at baseline, since all baseline clinical investigations were normal), and individuals without complaints. No differences were found between patients with subjective complaints and controls. Pooling these two groups would not have altered the results of this study. Furthermore, we included a relatively large number of participants from one center. All participants were carefully defined by using a standardized diagnostic battery. As a consequence, they are characterized in a uniform manner and the diagnosis was determined by using a multidisciplinary team. MR was always performed with the same imager and with the same protocol.

A limitation of our study was that MR imaging of our participants was available for only two time points. In future studies, more than two MR images per patient could be obtained to increase power and sensitivity, and to monitor the course of the disease. Furthermore, since no postmortem verification of diagnosis was available—which is considered the standard of reference for diagnosing AD—we cannot exclude the possibility that some of our AD patients were misdiagnosed. However, all patients fulfilled National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer Disease and Related Disorders Association clinical criteria for probable AD, which was confirmed at baseline and at follow-up in multidisciplinary consensus meetings.

Our study confirms that whole-brain atrophy rate discriminates between diagnostic groups better than does cross-sectional brain volume. The clinical relevance of whole-brain atrophy rate is demonstrated by the association with cognition and cognitive decline. Since individuals with a higher whole-brain atrophy rate had greater risks of progression to dementia, repeat MR imaging may be helpful in the diagnostic work-up of patients suspected of having dementia.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE
 References
 


   IMPLICATIONS FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
References
 


   ACKNOWLEDGMENTS
 
We thank Bas Jasperse, MD, PhD, VU University Medical Center, for his help in developing software.


   FOOTNOTES
 

Abbreviations: AD = Alzheimer disease • MCI = mild cognitive impairment • MMSE = Mini-Mental State Examination • PBVC = percentage brain volume change • SIENA = structural image evaluation, using normalization, of atrophy • SIENAX = SIENA cross-sectional counterpart

Author contributions: Guarantors of integrity of entire study, J.D.S., P.S., F.B., H.V.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, J.D.S., N.C.F., F.B., H.V.; clinical studies, J.D.S., W.M.v.d.F., G.B.K., P.S., F.B., H.V.; statistical analysis, J.D.S., W.M.v.d.F., H.V.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 

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