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Neural correlates of delayed episodic memory in patients with mild cognitive impairment—A FDG PET study
Neuroscience Letters 467 (2009) 100–104
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Neural correlates of delayed episodic memory in patients with mild cognitive impairment—A FDG PET study Oskar Dieter Peter Schönknecht a,b,∗ , Aoife Hunt b , Pablo Toro b , Marcus Henze c,d , Uwe Haberkorn c,d , Johannes Schröder b a
Department of Psychiatry and Psychotherapy, University Hospital Leipzig, Semmelweisstr. 10, 04103 Leipzig, Germany Section for Geriatric Psychiatry, Ruprecht-Karls-University Heidelberg, Voss-Str. 4, 69115 Heidelberg, Germany German Cancer Research Center (DKFZ) Heidelberg, Clinical Cooperation Unit Nuclear Medicine, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany d Department of Nuclear Medicine, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany b c
a r t i c l e
i n f o
Article history: Received 7 July 2009 Received in revised form 25 September 2009 Accepted 6 October 2009 Keywords: Mild cognitive impairment Episodic memory Neural correlates FDG PET
a b s t r a c t Mild cognitive impairment (MCI) is characterized by cognitive deficits which do not yet reach the threshold of dementia but represent a putative preclinical state of Alzheimer’s disease (AD). Little is known about the neural correlates of delayed episodic memory which is among the earliest signs of cognitive decline in patients at risk of developing AD. We performed resting state positron emission tomography (PET) with 18 Fluorodeoxyglucose (FDG) in patients with MCI, and hypothesized a correlation between delayed episodic memory performance and frontal glucose metabolism since the latter is relatively spared in the preclinical phase of the disease. 43 patients (age: 69.7 ± 7.9 years; 24 male, 19 female) with MCI were investigated by FDG PET. Significant positive correlations with delayed episodic memory performance were calculated by statistical parametric mapping. To our knowledge the present study is the first to demonstrate by FDG PET the neural correlates of delayed episodic memory in patients with MCI. Our study revealed a pattern of cerebral glucose metabolism including bifrontal regions which may contribute to the delayed episodic memory performance of patients with MCI. Since not all patients with MCI will further deteriorate, AD specific mechanism may not be concluded from the present study but warrant longitudinal investigations. © 2009 Elsevier Ireland Ltd. All rights reserved.
Mild cognitive impairment (MCI) is characterized by cognitive deficits which do not yet reach the threshold of dementia [35] but represent a putative preclinical state of Alzheimer’s disease (AD) [25] which can be further identified by neurochemical methods [24,34] and brain imaging [14,27]. Using positron emission tomography (PET) with 18 Fluorodeoxyglucose (FDG) as a tracer, a differentiation between normal aging and AD [6,18,30,36] could be demonstrated. In MCI, the regional cerebral metabolism is more variable depending on the cognitive abnormalities [1]. However, in patients with amnestic MCI a temporo-parietal and posterior cingulate impairment of glucose metabolism was more consistently reported compared to controls [9,13,19,28,29,37].
∗ Corresponding author at: University Hospital Leipzig, Department of Psychiatry, Semmelweisstr. 10, 04103 Leipzig, Germany. Tel.: +49 341 9724506; fax: +49 341 9724569. E-mail address: [email protected] (O.D.P. Schönknecht), [email protected] (A. Hunt), [email protected] (P. Toro), [email protected] (U. Haberkorn), [email protected] (J. Schröder). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.10.014
The functional cerebral changes underlying the respective cognitive deficits which are sometimes subtle are only partly understood [7]. Using FDG PET in patients with mild AD the neural correlates of episodic recall revealed an involvement of limbic structures while in the more severe AD patients a correlation with neocortical areas such as left temporo-parietal regions was found, indicating that in AD these regions may provide the neural basis for the rather inadequate compensation of cognitive dysfunction [12,11]. In contrast, in MCI little is known about the neural correlates of delayed episodic memory which is among the earliest signs of progressive cognitive decline [35]. However, since in the preclinical stage of AD the respective neuropathological changes are already present, a compensation for severe cognitive deficits can be assumed. To address this issue, we investigated the neural correlates of delayed episodic verbal memory by FDG PET in patients with MCI. We hypothesized a correlation between delayed episodic memory performance and frontal glucose metabolism since the latter is relatively spared in the preclinical phase of the disease. 43 patients (age: 69.7 ± 7.9 years; 24 male, 19 female) with MCI (criteria according to [31,35]) were recruited through the Section
O.D.P. Schönknecht et al. / Neuroscience Letters 467 (2009) 100–104
of Geriatric Psychiatry, University Hospital Heidelberg, and underwent extensive medical, neurological, neuropsychological, and psychiatric investigation including history taking, physical examination, and laboratory testing as well as cranial magnetic resonance imaging (MRI) and/or computerized tomography scan. Patients had at least 8 years of education and the Hachinski Ischemic Score modified by Loeb and Gandolfo [23] of the patients was less than three. Patients showed no focal signs on neurological examination and no evidence of relevant cerebrovascular changes on brain imaging. The control group consisted of 11 cognitively unimpaired subjects (age: 61.0 ± 6.4 years; 5 male, 6 female). The Mini Mental State Examination (MMSE) of the controls was 29.45 ± 0.8 [16]. The study was approved by the Ethics Committee of the University of Heidelberg and informed consent was obtained. The degree of cognitive impairment was rated on the MMSE. We applied the word list recall and word list correct recognition task (Consortium to Establish a Register for Alzheimer’s Disease neuropsychological test battery [26]) to investigate the delayed episodic memory performance. In the word list recall task, the delayed recall of high-frequency, high-imagery words presented earlier at a constant rate of one word every 2 s over three trials is tested. Here, no additional cues are given; the patient must spontaneously recall as many of the 10 words as he can. Instructions are: “Sometime earlier, you read out a list of 10 words, three times from this paper. Please, tell me those words again.” The word list correct recognition task is an extension of the word list memory task. Here the subject is presented with the original 10 words along with 10 new words; the task is to differentiate the old words from the new ones. The words are read by the subject, in a predetermined order, at the same steady pace of one word every 2 s. The subject is asked whether he recognizes the word as one previously read from the paper. In all patients PET was performed after at least a 6 h fast. Before injection of 225 MBq FDG, blood glucose levels were determined and were shown to be below 110 mg/dl in all patients. From 15 min before injection until 45 min after, patients rested in a quiet room with dimmed light. Then, emission scans over 20 min were acquired, followed by the transmission scans over 5 min using three 68 Ge line sources. Measurements were obtained with a whole-body PET system (ECAT EXACT HR+ , CTI, Knoxville, TN, USA) covering 155 mm in the axial field of view (63 transversal slices, thickness of each slices 2.4 mm). The scanner consisted of four rings with each 72 bismuth germanate detector blocks. Data were acquired in the more sensitive 3D mode without inter-slice tungsten septa, which was found to be equivalent to the 2D mode for quantification of radioactivity used in the clinical setting. The matrix size was 128 × 128 pixels. In 3D mode, the transaxial resolution is between 4.1 and 4.8 mm. Iterative image reconstruction used the ordered subsets-expectation maximization (OSEM) algorithm, implemented in the ECAT V7.1 software (Siemens Medical Systems Inc., Knoxville, TN, USA). Basic image processing was done by MEDx 3.0 (Sensor Systems Inc.) including statistical parametric mapping (SPM) routines (Wellcome Department of Cognitive Neurology, London) on a Silicon Graphics station. All data were spatially normalized by affine 12-parameter transformation to standard stereotactic space using the Montreal Neurological Institute (MNI) template [17]. Normalized images were represented on a 78 × 76 × 85 matrix and smoothed by a Gaussian filter of 12 mm full width of half maximum. Resting brain glucose metabolism reflects synaptic dysfunction as well as neuronal lesions but studies that performed voxel-based correction of resting brain glucose metabolism for cerebral atrophy could exclude artefacts due to cerebral atrophy [2,5,20,36]. Using a multi-subject design, age corrected positive correlations significant at p < 0.005 (uncorrected for multiple comparisons) were generated to assess the association of cerebral glucose
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Fig. 1. Section view of significantly reduced glucose metabolism in patients with mild cognitive impairment compared to controls as obtained from statistical parametric mapping (coordinates x: −28, y: 20, z: −10), t-values ranges from low (red) to high (yellow) as indicated by the pseudocolored bar.
metabolism and neuropsychological test performance (clusters size >40 voxels) within the patient group. Cerebral glucose metabolism was regressed on the delayed episodic test performance. By using this analysis we could not completely avoid type 1 errors but performed a less liberal calculation [21,22] than many studies applying SPM correlation procedures. The resulting cerebral structures were identified by their coordinates according to the Talairach atlas [38]. Data were derived from the MNI template and had to be transformed to Talairach atlas coordinates using appropriate algorithms (http://www.mrc-cbu.cam.ac.uk). Between group comparison of cerebral glucose metabolism revealed in the MCI patients compared to the controls a significant reduction of glucose metabolism in the left parietal cortex (Brodmann area 39, z-score 3.5, Talairach coordinates (x, y, z): −28, −55, 36), left occipital cortex (Brodmann area 18, z-score 4.3, Talairach coordinates (x, y, z): −10, −76, −2), left cingulate cortex (Brodmann area 32, z-score 3.8, Talairach coordinates (x, y, z): −7, 21, 38), right frontal lobe, subcallosal cortex (Brodmann area 25, z-score 3.6, Talairach coordinates (x, y, z): 7, 16, −12), left (z-score 4.7, Talairach coordinates (x, y, z): 20, 6, −7) and right putamen (z-score 4.5, Talairach coordinates (x, y, z): 19, 9, 0) (Fig. 1). The investigation of the delayed episodic memory of the MCI patients (MMSE score 26.6 ± 2.2 points) revealed the following results (z-score): word list recall scores: −1.6 ± 1.5; word recognition scores: −2.4 ± 3.0. Between CERAD test scores and cerebral glucose metabolism significant positive correlations occurred (Fig. 2). Peak data as revealed by SPM procedures are shown in Table 1. Word list recall performance was significantly correlated with bihemispheric superior and middle frontal, left inferior frontal, right medial frontal, left caudate, thalamus, insula and right putamen glucose metabolism. Word list recognition performance was significantly correlated with bihemispheric parahippocampal, left inferior frontal, left middle frontal, left putamen, left insula, and right superior frontal, right medial frontal, right middle frontal, and right pulvinar glucose metabolism.
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Fig. 2. Significant positive correlations between delayed episodic memory test performance and regional cerebral glucose metabolism in patients with mild cognitive impairment as obtained from statistical parametric mapping.
The present study demonstrates to our knowledge for the first time neural correlates as indicated by FDG PET of delayed episodic memory performance in patients with MCI. As to be expected, the MCI patients showed a slightly impaired performance in delayed episodic memory as it had been reported in a larger patient sample [3] as well as in a population-based study [35]. Since MCI may comprise patients in a putative preclinical state of AD we hypothesized an association of frontal glucose metabolism and delayed episodic memory performance. In extension of previous studies investigating the neural correlates of delayed episodic memory in AD patients, our findings indicate an association of a pattern of cerebral glucose metabolism including bifrontal cortices with the delayed episodic memory performance in patients with MCI [39].
In the present study, we performed a between group comparison with cognitively unimpaired controls demonstrating in the MCI patients a diversified regional cerebral reduction of glucose metabolism as it was expected in previous studies [28]. In the MCI patients, however, a significant reduction of glucose metabolism did not occur in the inferior, medial, middle or superior frontal cortices. While a correlation of delayed memory function with left frontal glucose metabolism has been described in patients with AD [39], the correlation with the right frontal glucose metabolism adds new information on the cerebral regions involved in the respective cognitive function in patients with MCI [4,33] and corresponds to what has been reported in healthy persons [8]. Since in our
Table 1 Significant correlations between delayed episodic memory test performance and regional cerebral glucose metabolism in patients with mild cognitive impairment (n = 43). Region Word list recall L thalamus L insula L temporal lobe caudate L superior frontal gyrus L superior frontal gyrus L middle frontal gyrus R medial frontal gyrus R medial frontal gyrus R middle frontal gyrus R superior frontal gyrus R middle frontal gyrus L insula R putamen L inferior frontal gyrus Word list recognition L parahippocampal gyrus L putamen L insula R pulvinar R parahippocampal gyrus R superior frontal gyrus R superior frontal gyrus R medial frontal gyrus L inferior frontal gyrus L middle frontal gyrus R middle frontal gyrus R middle frontal gyrus
BA
13 10 10 47 10 10 47 9 10 13 47 30 13 27 8 8 32 45 10 11 11
x
y
z
z-score
p-Value
−18 −32 −36 −15 −24 −32 13 17 34 19 34 −27 22 −40
−34 −40 −40 53 55 39 51 53 37 35 35 26 8 12
9 19 5 17 6 −5 −8 6 −5 33 19 5 11 −10
3.5 3.4 3.1 3.4 3.0 2.7 3.4 2.8 3.4 3.4 2.5 3.2 3.0 2.8
<0.001 <0.001 <0.005 <0.001 <0.005 <0.005 <0.001 <0.005 <0.001 <0.001 <0.005 <0.001 <0.005 <0.005
−22 −32 −40 4 17 20 13 13 −31 −22 31 29
−38 −23 −1 −30 −34 35 26 10 24 53 39 32
1 −1 0 5 1 47 47 43 4 20 −9 −16
3.5 3.1 3.0 3.4 2.8 3.3 2.8 3.1 3.1 3.1 2.9 2.6
<0.001 <0.005 <0.005 <0.001 <0.005 <0.001 <0.005 <0.005 <0.005 <0.005 <0.005 <0.005
Cluster extension 54 53 229
121 337
46 43 42 273
104 100 62 48 39 73
R = right, L = left, BA = Brodmann area. Bold markings delineate a cluster and the peak z-value. Brain regions are indicated by Talairach and Tournoux coordinates, x, y and z. x: the medial to lateral distance relative to the midline (positive: right hemisphere), y: the anterior to posterior distance relative to the anterior commissure (positive: anterior), z: the superior to inferior distance relative to the anterior commissure-posterior commissure line (positive: superior).
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study, the glucose metabolism of the MCI patients did not differ from controls in the frontal cortices, cerebral lesions as detectable by FDG PET should not be expected there. This finding is in accordance with the assumption that cognitive functions in MCI may rely on several brain regions rather than being highly localized [7,10,21]. By the results of our study we may not definitely conclude a compensation of underlying pathophysiological changes. However, based on the finding that the MCI patients were less impaired in the delayed episodic memory performance than most AD patients are [39], the bifrontal correlation may relate to a reallocated frontal recruitment in patients with MCI. Accordingly, the term reallocation of regional cerebral glucose metabolism may better describe the findings of the present study. This holds particularly true since in the MCI patients the delayed episodic memory performance was not fully compensated for but still showed a clinically significant impairment. When interpreting the results of the present study we also have to consider that the MCI syndrome comprises a heterogenous group of cognitively impaired patients as indicated by Mosconi et al. [28] that warrants longitudinal investigations. As to be expected, word list recognition performance was also significantly correlated with the left parahippocampal gyrus being in accordance with studies hypothesizing an impact of left-side limbic structures on conscious recollection of information [12]. Apart from these expected correlations, significant correlations between delayed word recall scores and glucose metabolism in thalamus, caudate, putamen and left insula cortex arose. Taken together these regions may contribute to the cognitive performance of the MCI patients. Insula cortex activation has been described in neuroimaging studies of pain and distress [15] but recently it was associated with negative emotions during decision making [32]. The finding of a significant correlation with the right caudate concurs with a study by Thomas et al. [40] who found a significant correlation between implicit learning performance and right caudate activation using functional MRI. Limitations of the present study include the etiological heterogeneity of the MCI syndrome which requires further diagnostic measures such as brain imaging or cerebrospinal fluid tau protein concentration. Otherwise, the vast majority of patients developing AD show a long course of MCI before the threshold of dementia is reached, and therefore the preclinical AD may be investigated during the MCI stage [35]. To this concern, the restriction to the MCI patients with mnestic deficits improved the inclusion of patients at risk of developing AD. Since inclusion criteria for MCI comprised immediate or delayed memory impairment, the variability of the outcome measure “delayed verbal episodic memory” was not limited. Since time to conversion to dementia differs among the MCI patients investigated, and some should never develop AD, results specific to an underlying AD pathology warrant further follow-up investigations of patients with MCI rather than the inclusion of AD patients who were not investigated during the stage of MCI. Limitations of the present study include also partial volume effects which were minimized by the high spatial resolution capacity of the PET imaging technique; moreover, atrophic changes may have only minor effects on cerebral glucose metabolism in the patients as demonstrated by a previous study [36]. In order to distinguish changes in cerebral glucose metabolism associated with conversion to AD during follow-up longitudinal studies are needed. In conclusion, our study revealed a pattern of cerebral glucose metabolism including bifrontal regions which may contribute to the delayed episodic memory performance of patients with MCI. Since not all patients with MCI will further deteriorate, AD specific mechanism may not be concluded from the present study but warrant longitudinal investigations.
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Neural correlates of delayed episodic memory in patients with mild cognitive impairment—A FDG PET study Oskar Dieter Peter Schönknecht a,b,∗ , Aoife Hunt b , Pablo Toro b , Marcus Henze c,d , Uwe Haberkorn c,d , Johannes Schröder b a
Department of Psychiatry and Psychotherapy, University Hospital Leipzig, Semmelweisstr. 10, 04103 Leipzig, Germany Section for Geriatric Psychiatry, Ruprecht-Karls-University Heidelberg, Voss-Str. 4, 69115 Heidelberg, Germany German Cancer Research Center (DKFZ) Heidelberg, Clinical Cooperation Unit Nuclear Medicine, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany d Department of Nuclear Medicine, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany b c
a r t i c l e
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Article history: Received 7 July 2009 Received in revised form 25 September 2009 Accepted 6 October 2009 Keywords: Mild cognitive impairment Episodic memory Neural correlates FDG PET
a b s t r a c t Mild cognitive impairment (MCI) is characterized by cognitive deficits which do not yet reach the threshold of dementia but represent a putative preclinical state of Alzheimer’s disease (AD). Little is known about the neural correlates of delayed episodic memory which is among the earliest signs of cognitive decline in patients at risk of developing AD. We performed resting state positron emission tomography (PET) with 18 Fluorodeoxyglucose (FDG) in patients with MCI, and hypothesized a correlation between delayed episodic memory performance and frontal glucose metabolism since the latter is relatively spared in the preclinical phase of the disease. 43 patients (age: 69.7 ± 7.9 years; 24 male, 19 female) with MCI were investigated by FDG PET. Significant positive correlations with delayed episodic memory performance were calculated by statistical parametric mapping. To our knowledge the present study is the first to demonstrate by FDG PET the neural correlates of delayed episodic memory in patients with MCI. Our study revealed a pattern of cerebral glucose metabolism including bifrontal regions which may contribute to the delayed episodic memory performance of patients with MCI. Since not all patients with MCI will further deteriorate, AD specific mechanism may not be concluded from the present study but warrant longitudinal investigations. © 2009 Elsevier Ireland Ltd. All rights reserved.
Mild cognitive impairment (MCI) is characterized by cognitive deficits which do not yet reach the threshold of dementia [35] but represent a putative preclinical state of Alzheimer’s disease (AD) [25] which can be further identified by neurochemical methods [24,34] and brain imaging [14,27]. Using positron emission tomography (PET) with 18 Fluorodeoxyglucose (FDG) as a tracer, a differentiation between normal aging and AD [6,18,30,36] could be demonstrated. In MCI, the regional cerebral metabolism is more variable depending on the cognitive abnormalities [1]. However, in patients with amnestic MCI a temporo-parietal and posterior cingulate impairment of glucose metabolism was more consistently reported compared to controls [9,13,19,28,29,37].
∗ Corresponding author at: University Hospital Leipzig, Department of Psychiatry, Semmelweisstr. 10, 04103 Leipzig, Germany. Tel.: +49 341 9724506; fax: +49 341 9724569. E-mail address: [email protected] (O.D.P. Schönknecht), [email protected] (A. Hunt), [email protected] (P. Toro), [email protected] (U. Haberkorn), [email protected] (J. Schröder). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.10.014
The functional cerebral changes underlying the respective cognitive deficits which are sometimes subtle are only partly understood [7]. Using FDG PET in patients with mild AD the neural correlates of episodic recall revealed an involvement of limbic structures while in the more severe AD patients a correlation with neocortical areas such as left temporo-parietal regions was found, indicating that in AD these regions may provide the neural basis for the rather inadequate compensation of cognitive dysfunction [12,11]. In contrast, in MCI little is known about the neural correlates of delayed episodic memory which is among the earliest signs of progressive cognitive decline [35]. However, since in the preclinical stage of AD the respective neuropathological changes are already present, a compensation for severe cognitive deficits can be assumed. To address this issue, we investigated the neural correlates of delayed episodic verbal memory by FDG PET in patients with MCI. We hypothesized a correlation between delayed episodic memory performance and frontal glucose metabolism since the latter is relatively spared in the preclinical phase of the disease. 43 patients (age: 69.7 ± 7.9 years; 24 male, 19 female) with MCI (criteria according to [31,35]) were recruited through the Section
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of Geriatric Psychiatry, University Hospital Heidelberg, and underwent extensive medical, neurological, neuropsychological, and psychiatric investigation including history taking, physical examination, and laboratory testing as well as cranial magnetic resonance imaging (MRI) and/or computerized tomography scan. Patients had at least 8 years of education and the Hachinski Ischemic Score modified by Loeb and Gandolfo [23] of the patients was less than three. Patients showed no focal signs on neurological examination and no evidence of relevant cerebrovascular changes on brain imaging. The control group consisted of 11 cognitively unimpaired subjects (age: 61.0 ± 6.4 years; 5 male, 6 female). The Mini Mental State Examination (MMSE) of the controls was 29.45 ± 0.8 [16]. The study was approved by the Ethics Committee of the University of Heidelberg and informed consent was obtained. The degree of cognitive impairment was rated on the MMSE. We applied the word list recall and word list correct recognition task (Consortium to Establish a Register for Alzheimer’s Disease neuropsychological test battery [26]) to investigate the delayed episodic memory performance. In the word list recall task, the delayed recall of high-frequency, high-imagery words presented earlier at a constant rate of one word every 2 s over three trials is tested. Here, no additional cues are given; the patient must spontaneously recall as many of the 10 words as he can. Instructions are: “Sometime earlier, you read out a list of 10 words, three times from this paper. Please, tell me those words again.” The word list correct recognition task is an extension of the word list memory task. Here the subject is presented with the original 10 words along with 10 new words; the task is to differentiate the old words from the new ones. The words are read by the subject, in a predetermined order, at the same steady pace of one word every 2 s. The subject is asked whether he recognizes the word as one previously read from the paper. In all patients PET was performed after at least a 6 h fast. Before injection of 225 MBq FDG, blood glucose levels were determined and were shown to be below 110 mg/dl in all patients. From 15 min before injection until 45 min after, patients rested in a quiet room with dimmed light. Then, emission scans over 20 min were acquired, followed by the transmission scans over 5 min using three 68 Ge line sources. Measurements were obtained with a whole-body PET system (ECAT EXACT HR+ , CTI, Knoxville, TN, USA) covering 155 mm in the axial field of view (63 transversal slices, thickness of each slices 2.4 mm). The scanner consisted of four rings with each 72 bismuth germanate detector blocks. Data were acquired in the more sensitive 3D mode without inter-slice tungsten septa, which was found to be equivalent to the 2D mode for quantification of radioactivity used in the clinical setting. The matrix size was 128 × 128 pixels. In 3D mode, the transaxial resolution is between 4.1 and 4.8 mm. Iterative image reconstruction used the ordered subsets-expectation maximization (OSEM) algorithm, implemented in the ECAT V7.1 software (Siemens Medical Systems Inc., Knoxville, TN, USA). Basic image processing was done by MEDx 3.0 (Sensor Systems Inc.) including statistical parametric mapping (SPM) routines (Wellcome Department of Cognitive Neurology, London) on a Silicon Graphics station. All data were spatially normalized by affine 12-parameter transformation to standard stereotactic space using the Montreal Neurological Institute (MNI) template [17]. Normalized images were represented on a 78 × 76 × 85 matrix and smoothed by a Gaussian filter of 12 mm full width of half maximum. Resting brain glucose metabolism reflects synaptic dysfunction as well as neuronal lesions but studies that performed voxel-based correction of resting brain glucose metabolism for cerebral atrophy could exclude artefacts due to cerebral atrophy [2,5,20,36]. Using a multi-subject design, age corrected positive correlations significant at p < 0.005 (uncorrected for multiple comparisons) were generated to assess the association of cerebral glucose
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Fig. 1. Section view of significantly reduced glucose metabolism in patients with mild cognitive impairment compared to controls as obtained from statistical parametric mapping (coordinates x: −28, y: 20, z: −10), t-values ranges from low (red) to high (yellow) as indicated by the pseudocolored bar.
metabolism and neuropsychological test performance (clusters size >40 voxels) within the patient group. Cerebral glucose metabolism was regressed on the delayed episodic test performance. By using this analysis we could not completely avoid type 1 errors but performed a less liberal calculation [21,22] than many studies applying SPM correlation procedures. The resulting cerebral structures were identified by their coordinates according to the Talairach atlas [38]. Data were derived from the MNI template and had to be transformed to Talairach atlas coordinates using appropriate algorithms (http://www.mrc-cbu.cam.ac.uk). Between group comparison of cerebral glucose metabolism revealed in the MCI patients compared to the controls a significant reduction of glucose metabolism in the left parietal cortex (Brodmann area 39, z-score 3.5, Talairach coordinates (x, y, z): −28, −55, 36), left occipital cortex (Brodmann area 18, z-score 4.3, Talairach coordinates (x, y, z): −10, −76, −2), left cingulate cortex (Brodmann area 32, z-score 3.8, Talairach coordinates (x, y, z): −7, 21, 38), right frontal lobe, subcallosal cortex (Brodmann area 25, z-score 3.6, Talairach coordinates (x, y, z): 7, 16, −12), left (z-score 4.7, Talairach coordinates (x, y, z): 20, 6, −7) and right putamen (z-score 4.5, Talairach coordinates (x, y, z): 19, 9, 0) (Fig. 1). The investigation of the delayed episodic memory of the MCI patients (MMSE score 26.6 ± 2.2 points) revealed the following results (z-score): word list recall scores: −1.6 ± 1.5; word recognition scores: −2.4 ± 3.0. Between CERAD test scores and cerebral glucose metabolism significant positive correlations occurred (Fig. 2). Peak data as revealed by SPM procedures are shown in Table 1. Word list recall performance was significantly correlated with bihemispheric superior and middle frontal, left inferior frontal, right medial frontal, left caudate, thalamus, insula and right putamen glucose metabolism. Word list recognition performance was significantly correlated with bihemispheric parahippocampal, left inferior frontal, left middle frontal, left putamen, left insula, and right superior frontal, right medial frontal, right middle frontal, and right pulvinar glucose metabolism.
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Fig. 2. Significant positive correlations between delayed episodic memory test performance and regional cerebral glucose metabolism in patients with mild cognitive impairment as obtained from statistical parametric mapping.
The present study demonstrates to our knowledge for the first time neural correlates as indicated by FDG PET of delayed episodic memory performance in patients with MCI. As to be expected, the MCI patients showed a slightly impaired performance in delayed episodic memory as it had been reported in a larger patient sample [3] as well as in a population-based study [35]. Since MCI may comprise patients in a putative preclinical state of AD we hypothesized an association of frontal glucose metabolism and delayed episodic memory performance. In extension of previous studies investigating the neural correlates of delayed episodic memory in AD patients, our findings indicate an association of a pattern of cerebral glucose metabolism including bifrontal cortices with the delayed episodic memory performance in patients with MCI [39].
In the present study, we performed a between group comparison with cognitively unimpaired controls demonstrating in the MCI patients a diversified regional cerebral reduction of glucose metabolism as it was expected in previous studies [28]. In the MCI patients, however, a significant reduction of glucose metabolism did not occur in the inferior, medial, middle or superior frontal cortices. While a correlation of delayed memory function with left frontal glucose metabolism has been described in patients with AD [39], the correlation with the right frontal glucose metabolism adds new information on the cerebral regions involved in the respective cognitive function in patients with MCI [4,33] and corresponds to what has been reported in healthy persons [8]. Since in our
Table 1 Significant correlations between delayed episodic memory test performance and regional cerebral glucose metabolism in patients with mild cognitive impairment (n = 43). Region Word list recall L thalamus L insula L temporal lobe caudate L superior frontal gyrus L superior frontal gyrus L middle frontal gyrus R medial frontal gyrus R medial frontal gyrus R middle frontal gyrus R superior frontal gyrus R middle frontal gyrus L insula R putamen L inferior frontal gyrus Word list recognition L parahippocampal gyrus L putamen L insula R pulvinar R parahippocampal gyrus R superior frontal gyrus R superior frontal gyrus R medial frontal gyrus L inferior frontal gyrus L middle frontal gyrus R middle frontal gyrus R middle frontal gyrus
BA
13 10 10 47 10 10 47 9 10 13 47 30 13 27 8 8 32 45 10 11 11
x
y
z
z-score
p-Value
−18 −32 −36 −15 −24 −32 13 17 34 19 34 −27 22 −40
−34 −40 −40 53 55 39 51 53 37 35 35 26 8 12
9 19 5 17 6 −5 −8 6 −5 33 19 5 11 −10
3.5 3.4 3.1 3.4 3.0 2.7 3.4 2.8 3.4 3.4 2.5 3.2 3.0 2.8
<0.001 <0.001 <0.005 <0.001 <0.005 <0.005 <0.001 <0.005 <0.001 <0.001 <0.005 <0.001 <0.005 <0.005
−22 −32 −40 4 17 20 13 13 −31 −22 31 29
−38 −23 −1 −30 −34 35 26 10 24 53 39 32
1 −1 0 5 1 47 47 43 4 20 −9 −16
3.5 3.1 3.0 3.4 2.8 3.3 2.8 3.1 3.1 3.1 2.9 2.6
<0.001 <0.005 <0.005 <0.001 <0.005 <0.001 <0.005 <0.005 <0.005 <0.005 <0.005 <0.005
Cluster extension 54 53 229
121 337
46 43 42 273
104 100 62 48 39 73
R = right, L = left, BA = Brodmann area. Bold markings delineate a cluster and the peak z-value. Brain regions are indicated by Talairach and Tournoux coordinates, x, y and z. x: the medial to lateral distance relative to the midline (positive: right hemisphere), y: the anterior to posterior distance relative to the anterior commissure (positive: anterior), z: the superior to inferior distance relative to the anterior commissure-posterior commissure line (positive: superior).
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study, the glucose metabolism of the MCI patients did not differ from controls in the frontal cortices, cerebral lesions as detectable by FDG PET should not be expected there. This finding is in accordance with the assumption that cognitive functions in MCI may rely on several brain regions rather than being highly localized [7,10,21]. By the results of our study we may not definitely conclude a compensation of underlying pathophysiological changes. However, based on the finding that the MCI patients were less impaired in the delayed episodic memory performance than most AD patients are [39], the bifrontal correlation may relate to a reallocated frontal recruitment in patients with MCI. Accordingly, the term reallocation of regional cerebral glucose metabolism may better describe the findings of the present study. This holds particularly true since in the MCI patients the delayed episodic memory performance was not fully compensated for but still showed a clinically significant impairment. When interpreting the results of the present study we also have to consider that the MCI syndrome comprises a heterogenous group of cognitively impaired patients as indicated by Mosconi et al. [28] that warrants longitudinal investigations. As to be expected, word list recognition performance was also significantly correlated with the left parahippocampal gyrus being in accordance with studies hypothesizing an impact of left-side limbic structures on conscious recollection of information [12]. Apart from these expected correlations, significant correlations between delayed word recall scores and glucose metabolism in thalamus, caudate, putamen and left insula cortex arose. Taken together these regions may contribute to the cognitive performance of the MCI patients. Insula cortex activation has been described in neuroimaging studies of pain and distress [15] but recently it was associated with negative emotions during decision making [32]. The finding of a significant correlation with the right caudate concurs with a study by Thomas et al. [40] who found a significant correlation between implicit learning performance and right caudate activation using functional MRI. Limitations of the present study include the etiological heterogeneity of the MCI syndrome which requires further diagnostic measures such as brain imaging or cerebrospinal fluid tau protein concentration. Otherwise, the vast majority of patients developing AD show a long course of MCI before the threshold of dementia is reached, and therefore the preclinical AD may be investigated during the MCI stage [35]. To this concern, the restriction to the MCI patients with mnestic deficits improved the inclusion of patients at risk of developing AD. Since inclusion criteria for MCI comprised immediate or delayed memory impairment, the variability of the outcome measure “delayed verbal episodic memory” was not limited. Since time to conversion to dementia differs among the MCI patients investigated, and some should never develop AD, results specific to an underlying AD pathology warrant further follow-up investigations of patients with MCI rather than the inclusion of AD patients who were not investigated during the stage of MCI. Limitations of the present study include also partial volume effects which were minimized by the high spatial resolution capacity of the PET imaging technique; moreover, atrophic changes may have only minor effects on cerebral glucose metabolism in the patients as demonstrated by a previous study [36]. In order to distinguish changes in cerebral glucose metabolism associated with conversion to AD during follow-up longitudinal studies are needed. In conclusion, our study revealed a pattern of cerebral glucose metabolism including bifrontal regions which may contribute to the delayed episodic memory performance of patients with MCI. Since not all patients with MCI will further deteriorate, AD specific mechanism may not be concluded from the present study but warrant longitudinal investigations.
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