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Neuroradiology |
1 From the Department of Radiology, Duke University Medical Center, 1527 Hosp North, Box 3808, Durham, NC 27710 (J.R.P., L.W., S.K., S.E.P., P.M.D.); Department of Radiology, University of New South Wales, Sydney, Australia (M.J.S.); and Department of Radiology, University of North Carolina, Chapel Hill, NC (T.T.T.T.). Received October 31, 2006; revision requested January 5, 2007; revision received January 18; final version accepted March 1. Supported by NIH R01AG019728. Address correspondence to J.R.P. (e-mail: jeffrey.petrella{at}duke.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE...References |
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Materials and Methods: The institutional review board approved this HIPAA-compliant study, and each patient gave written informed consent. Seventy-five subjects (mean age, 72.9 years ± 7.2 [standard deviation]; 37 men, 38 women)—13 patients with mild AD, 34 individuals with amnestic MCI, and 28 healthy elderly control subjects—were imaged at 4.0 T during novel encoding (NE) and familiar encoding (FE) of face-name pairs presented within a block design for later retrieval. Blood oxygen level–dependent (BOLD) changes were assessed across the entire brain for each group. Between-subject analysis identified brain regions demonstrating a monotonic increase or decrease in activation magnitude, from control subjects to patients with MCI to patients with mild AD. BOLD response was also correlated with score on the delayed portion of the California Verbal Learning Test (CVLT).
Results: In controls, the task elicited positive activation (NE > FE) in the dorsolateral prefrontal, lateral parietal, and medial temporal regions, and negative activation (FE > NE) in the midline frontal and parietal regions. Along the spectrum from control subjects to patients with AD, there was decreasing activation in the medial temporal lobe (MTL), including the hippocampus and parahippocampal and fusiform gyri, and increasing activation in the posteromedial cortices (PMCs), primarily in the precuneus and posterior cingulate gyrus. Activation magnitude in the PMCs significantly (P < .001, r = –0.502) correlated with CVLT score.
Conclusion: Compared with activation in the MTL, deactivation in the PMCs could be a more sensitive marker of early AD at functional MR imaging.
© RSNA, 2007
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INTRODUCTION |
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Therefore, functional MR imaging in its current state remains a useful tool for examining how memory networks break down as AD progresses, although functional MR imaging findings remain short of their potential as a surrogate marker of disease in the individual patient. To explore the possible efficacy of functional MR imaging findings as surrogate markers of neuronal dysfunction in AD, an optimal strategy is to identify brain regions whose activation or deactivation magnitude demonstrates a strong monotonic relationship with cognitive function across the disease spectrum, from healthy control subjects to patients with MCI to patients with mild AD. Activation or deactivation in such regions could serve as an early diagnostic marker, as well as a prognostic indicator of future cognitive decline. Thus, the purpose of this study was to prospectively identify brain regions in which task-related changes in activation during a memory encoding task, measured with functional MR imaging, correlate with degree of memory impairment across AD, MCI, and elderly control subjects.
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MATERIALS AND METHODS |
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Entry Criteria
All subjects were fluent in English and had at least 8 years of formal education. Subjects underwent a clinical interview, a demographic inventory (age, sex, education), a focused neurologic and physical examination, and a review of the most recent routine blood test results in the patient's medical record, all performed by a single physician (P.M.D., a geriatric psychiatrist with 15 years of experience in evaluating patients with memory disorders). Subjects then underwent a detailed battery of neuropsychological screening tests (M.J.S., T.T.T.T., with 7 and 2 years of experience in neuropsychological testing, respectively), consisting of the California Verbal Learning Test (CVLT) II (21), the Logical Memory and Visual Reproduction tests from the Wechsler Memory Scale (WMS) III (22), the Mini-Mental State Examination (MMSE) (23), a Clinical Dementia Rating (CDR) (24) interview with patient and informant administered by a certified rater, the Beck II Depression Scale (25), and the Rosen-modified Hachinski vascular dementia rating scale (26).
Inclusion Criteria
Patients with mild AD met the following criteria: (a) a history of progressive cognitive worsening for at least 1 year; (b) a Rosen-modified Hachinski score of 4 or lower; (c) deficits in two or more cognitive domains on neuropsychologic tests and meeting National Institute of Neurological Disorders and Stroke-Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD (27); (d) an MMSE score of 20 or greater; and (e) a global CDR score of 1.0, with a memory score of at least 1.0.
Patients with MCI (amnestic type) met the following criteria: (a) recent history of symptomatic worsening in memory; (b) a Rosen-modified Hachinski score of 4 or lower; (c) an MMSE score of 22–30; (d) a global CDR score of 0.5 (questionable dementia), with a memory score of 0.5 or greater; (e) not meeting NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders IV, Text Revision criteria for dementia; (f) normal or near-normal independent function; and (g) absence of other factors that might have better explained memory loss (eg, depression). Criteria used for MCI were those accepted by the field for clinical research (28).
Control subjects met the following criteria: (a) a Rosen-modified Hachinski score of 4 or lower, (b) an MMSE score of 26–30, (c) a global CDR score and memory score of 0, and (d) normal or near-normal independent function. Control subjects did not meet NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders IV, Text Revision criteria for dementia.
Exclusion Criteria
Subjects were excluded on the basis of the following criteria: (a) uncontrolled depression or other psychiatric illness; (b) taking psychoactive medications known to substantially affect memory; (c) standard contraindications to MR imaging; (d) technical difficulties that prevented the completion of successful anatomic imaging or at least two of three functional MR imaging task runs or both; (e) excessive motion during the functional MR imaging examination in excess of 5 mm in any of three orthogonal directions, as determined by center-of-mass plots; and (f) inability to have his or her behavioral responses adequately monitored while in the imaging unit, evidenced by greater than 50% nonresponses.
Paradigm
Our study employed a face-name associative memory encoding task (11). Subjects were required to encode and later retrieve face-name associations of two conditions—novel face-name pairs and familiar face-name pairs—that were presented to the subject within a blocked experimental design. Sixty novel and two familiar face-name pairs were presented in three "runs," for 6 minutes 50 seconds per run. Stimuli were presented to subjects within the scanner with an audiovisual goggle system (Resonance Technology, Northridge, Calif), driven by input from a personal computer outside the imaging room. Behavioral responses were monitored by using a fiberoptic button box within the scanner. Nonresponses were considered incorrect responses.
Imaging
Imaging was performed with a 4.0-T MR imaging unit (LX NVi; GE Medical Systems, Milwaukee, Wis). Transverse T2-weighted spin-echo images (repetition time msec/echo time msec, 3000/80; matrix, 256 x 256; 3.75-mm thickness; 0.0-mm spacing; field of view, 240 mm) were obtained through the brain for diagnostic purposes to assess for intracranial pathologic features. Anatomic images, consisting of 44 contiguous 3.75-mm-thick coronal sections, were acquired for normalization of the functional images by using a high-spatial-resolution T1-weighted sequence (inversion recovery–prepared three-dimensional spoiled gradient-recalled acquisition in the steady state; 12.2/5.4; inversion time, 500 msec; flip angle, 20°; matrix, 256 x 256; field of view, 240 mm). During each of the three runs per subject, functional images, consisting of a time series of 164 T2*-weighted isotropic image volumes (inverse spiral imaging sequence; 2500/31; flip angle, 60°; matrix, 64 x 64; field of view, 240 mm), were acquired in the same 44 continuous coronal section locations used in the anatomic series.
Individual Subject Image Analysis
All anatomic and functional images were initially evaluated for quality-control purposes by using customized software that creates center-of-mass plots to detect excessive motion or section acquisition errors. Anatomic images were evaluated for intracranial disease by a board-certified neuroradiologist (J.R.P., with 12 years of experience interpreting brain MR imaging studies). Voxelwise analysis of data was performed by using statistical parametric mapping software (SPM2; Wellcome Department of Imaging Neuroscience, available at http://www.fil.ion.ucl.ac.uk/spm) (29). On the individual level, a general linear model was used to assess the magnitude of functional MR imaging signal intensity change by using a contrast map. This contrast, or activation magnitude difference, map represented the voxelwise difference in signal intensity magnitude between the novel encoding (NE) and the familiar encoding (FE) conditions across the entire brain and was used for all further functional MR imaging statistical analyses.
Statistical Analysis
Demographic and behavioral variables.—Statistical analysis of demographic and behavioral variables was performed with software (SPSS, version 12.2, 2004; SPSS, Chicago, Ill). Summary statistics were generated for age; years of education; MMSE, CVLT II, WMS III, Beck II, and Hachinski scores; performance on functional MR imaging tasks (percentage correct at novel and familiar trials); and number of nonrecorded responses. An analysis of variance with Student-Newman-Keuls post hoc testing was performed for all continuous variables, and a 
2 analysis was performed for sex and handedness across all three groups. A P value of less than .05 was considered to indicate a statistically significant difference.
Functional MR imaging activation.—Within-group t maps were created from the individual subject's contrast images for each of the three groups by using a one-sample analysis of variance. This allowed both "positive" (NE > FE) and "negative" activations (FE > NE) to be assessed simultaneously. Between-group analysis was performed from the individual subject's contrast images by using a random-effects analysis of covariance model with age as a covariate by using the following contrast: control = 1, MCI = 0, and mild AD = –1. This contrast tested the hypothesis that there are decreasing levels of activation magnitude from control subject to patient with MCI to patient with mild AD. Positive values for this contrast would support this hypothesis, whereas negative values would support the opposite hypothesis—that is, that there are increasing levels of activation magnitude from control subject to patient with MCI to patient with mild AD.
Correlation with CVLT.—Because the CVLT yielded the highest F value of all the neuropsychological tests in the analyses of variance across the three groups (see Results), we used this metric to test for a continuous association between brain activation and memory impairment. A correlation map between activation magnitude and memory loss severity was created by using CVLT II delayed recall scores across all subjects, independent of group assignment. Both positive and negative correlations were assessed. Scatterplots of several regions were created to illustrate the relationship between each subject's CVLT score and functional MR imaging signal intensity magnitude. Regions for the scatterplots were determined by clusters showing significant correlation of the functional MR imaging signal with the CVLT score. In the absence of a significant correlation, a cluster was chosen on the basis of a significant difference among the three groups in the analysis of covariance.
Cluster significance levels for all maps were set at P < .001 (uncorrected) with a 10-voxel cluster threshold—values comparable to, or more rigorous than, those used in prior studies that focused on the whole brain in similar populations (11,13,30).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE...References |
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE...References |
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Although functional MR imaging studies have consistently demonstrated reduced activation in the hippocampi of AD patients compared with that in control subjects (1–3), a number of studies of patients with MCI or asymptomatic genetically at-risk patients compared with control subjects have shown either increased (7–9) or decreased (5,10,12) hippocampal activation. These conflicting findings could reflect variations in tasks or subject samples. For example, it has been hypothesized that asymptomatic at-risk subjects or highly functioning patients with MCI may demonstrate compensatory hyperactivation in the hippocampus that is later lost as cognitive reserve diminishes (9). A recent study has demonstrated that less-impaired patients with MCI hyperactivate the hippocampus compared with healthy control subjects, whereas more-impaired patients with MCI hypoactivate the hippocampus (16). We did not find similar results, and reasons for the discrepancy might include differing samples of patients with MCI. Patients with MCI in our study were chosen on the basis of objective as opposed to subjective memory impairment. Indeed, the CVLT II delay scores of patients with MCI in our study were substantially worse (mean, 5.2 ± 2.6), than even those of the more-impaired MCI group (8.3 ± 4.7) in the latter study. While Celone et al (16) provide evidence for a nonlinear progression of hippocampal deficits, they do not rule out other patterns of activity change that were not explicitly modeled.
The most notable finding of our study was that increasing activation magnitude from control subject to patient with MCI to patient with mild AD was noted in a set of PMC structures, including the precuneus and the posterior cingulate gyrus. This was characterized by considerable deactivation in the control subjects, lesser deactivation in patients with MCI, and complete loss of deactivation, or even activation, in patients with AD (Fig 2b). Though the latter finding did not achieve significance in the within-group analysis of AD subjects, this is not inconsistent with the results of the between-group analysis of variance, which is influenced by changes across the continuum of the groups, regardless of whether a brain region is significantly activated in any of the three groups in the within-group analysis. The PMC has been found to be a key part of a "default network," including the medial frontal and lateral parietal regions, where normal subjects show deactivation during a task versus no task or during a high-level versus a low-level task condition (35–41). It has been suggested that this network is engaged in attending to environmental stimuli (37,41), planning future behaviors (42), self-awareness (43), and conscious processes (43,44). Electroencephalographic studies have also demonstrated a similar network of regions with common spontaneous power fluctuations (41,45). Furthermore, resting-state functional MR imaging studies show high temporal correlations in blood oxygen level–dependent signal across these regions, implying a functional connection (46,47).
Deactivations in the default network in AD have been studied. Lustig and colleagues (18) examined deactivation in a sample of 59 healthy subjects compared with that in 23 patients with AD. Young healthy subjects showed initial activation followed by deactivation in the PMC region during a semantic decision functional MR imaging task. On the same task, patients with AD showed not only an absence of deactivation in this region but also, in fact, low levels of activation (18). Absence of or diminished deactivation has also been observed in patients with MCI (16,19). Diminished deactivation in mild AD and MCI has been suggested to represent abnormally low default-mode network activity during the resting state with an inability to reallocate cognitive resources to other brain regions during the task state. Further examination of our data revealed negative activation magnitude in the PMCs in control subjects and positive activation magnitude in patients with AD, with intermediate values in patients with MCI. We extend the findings of two previous studies of the default network in MCI by demonstrating that PMC activation in the MCI group sits on a continuum from AD to healthy control subjects in a categorical analysis, when diagnostic group is used as the independent measure, as well as in a continuous analysis, when the CVLT II delay score is used as the independent measure. Similarly, if one takes sampling differences into account, our results complement those of Celone et al (16), who found a nonlinear relationship of activation magnitude in the PMC across the cognitive spectrum.
It should be noted that deactivation in the PMCs is not specific to any type of memory encoding but rather likely represents normal, beneficial, and efficient reallocation of neurocognitive resources (48). Thus, regardless of the type of memory encoding task or regions requiring cognitive resources—for example, the fusiform region for face processing or the Broca area for verbal processing—deactivation in the PMCs may drive and support activation in all these areas or vice versa. One may speculate that the best functional MR imaging marker of early cognitive dysfunction may incorporate both deactivation in the PMCs and activation in other regions directly involved in the encoding task. Supportively, we found that fusiform gyrus activation was positively correlated with the CVLT II delay score (Fig 4).
Although functional MR imaging, electroencephalographic, and positron emission tomography data suggest PMC involvement in early AD, it is not known if this involvement is a primary event or a secondary consequence of MTL disease, which occurs early on in AD. MTL regions, in particular the entorhinal and perirhinal cortex, are densely interconnected to the posterior cingulate cortex, and their disruption leads to PMC functional metabolic changes in both animals and humans (49–52). Thus, it is logical to hypothesize that AD-related loss of deactivation in PMC regions may result from structural or functional disconnection, or both, between the PMC and MTL. These data strongly support further investigation of changes in the PMC-MTL network as potential markers of prodromal AD.
From a diagnostic and treatment-monitoring standpoint, these data also suggest that functional changes in the PMCs may be a better functional MR imaging marker of memory impairment than those in the hippocampus. One explanation for this may be that the PMC is a larger region and, unlike the hippocampus, is far removed from the skull base, where susceptibility-induced artifacts from air-bone interfaces can alter the functional MR imaging signal (35). Thus, especially at high field strengths such as 4.0 T, the PMC may have a better signal-to-noise ratio than the MTL. Moreover, because PMC deactivation in healthy subjects is less task-specific than hippocampal activation, intra- and intersubject variance related to poor memory performance on a functional MR imaging task may be less. Further investigation is needed to assess whether the PMC is a diagnostic marker of choice for memory impairment.
A potential limitation of our study was a differential loss rate of subjects from the initial recruiting pool (total = 23.5% [23 of 98], control = 17.6% [six of 34], MCI = 22.7% [10 of 44], and AD = 35% [seven of 20]). It is therefore possible that subjects were not lost at random (eg, exclusion for excessive motion may have been more prevalent in the AD group). Another potential confounding variable is the significant difference in education levels between subject groups. Although the specific effects of these confounding variables are unknown, these issues are common to most functional MR imaging studies involving memory-impaired patients.
In conclusion, our study, which used high-field-strength MR imaging, revealed preservation of some areas of activation during face-name associative encoding across the cognitive spectrum, with an overall decrease in activation from control subject to patient with MCI to patient with mild AD. Decreases in activation magnitude from control subject to patient with MCI to patient with mild AD were noted in MTL structures; however, increases in activation magnitude were noted in the PMC region. PMC activation changes were larger in both magnitude and extent than those in the MTL. Because activation in the PMCs significantly correlated with neuropsychological test performance, while activation in the hippocampus did not, activation in the PMC may represent a better functional MR imaging marker of disease severity than activation in the hippocampus. To assess the clinical applicability of this finding, further studies are warranted to determine the sensitivity and the specificity of these changes in a larger and more diverse sample of subjects.
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ADVANCES IN KNOWLEDGE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE...References |
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IMPLICATION FOR PATIENT CARE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGE IMPLICATION FOR PATIENT CARE...References |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: AD = Alzheimer disease • CDR = Clinical Dementia Rating • CVLT = California Verbal Learning Test • FE = familiar encoding • MCI = mild cognitive impairment • MMSE = Mini-Mental State Examination • MNI = Montreal Neurological Institute • MTL = medial temporal lobe • NE = novel encoding • NINCDS-ADRDA = National Institute of Neurological Disorders and Stroke–Alzheimer Disease and Related Disorders Association • PMC = posteromedial cortex • WMS = Wechsler Memory Scale
Author contributions: Guarantors of integrity of entire study, J.R.P., P.M.D.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, J.R.P., L.W., S.K., M.J.S., S.E.P., P.M.D.; clinical studies, J.R.P., M.J.S., T.T.T.T., P.M.D.; statistical analysis, J.R.P., L.W., S.K., M.J.S., S.E.P.; and manuscript editing, J.R.P., L.W., S.E.P., P.M.D.
Authors stated no financial relationship to disclose.
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