Cerebral Glucose Metabolism is Associated with Verbal but not Visual

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Journal of Alzheimer’s Disease xx (20xx) x–xx DOI 10.3233/JAD-151084 IOS Press

Cerebral Glucose Metabolism is Associated with Verbal but not Visual Memory Performance in Community-Dwelling Older Adults Samantha L. Gardenera,b,1 , Hamid R. Sohrabia,b,c,1 , Kai-kai Shena,b,d , Stephanie R. Rainey-Smitha,b , Michael Weinborna,b,e , Kristyn A. Batesb,f , Tejal Shaha,b , Jonathan K. Fosterg , Nat Lenzob,h , Olivier Salvadod , Christoph Laskei , Simon M. Lawsa,b,j , Kevin Taddeia,b , Giuseppe Verdilea,b,k and Ralph N. Martinsa,b,c,∗ a Centre

of Excellence for Alzheimer’s disease Research & Care, School of Medical Sciences, Edith Cowan University, Joondalup, Western Australia, Australia b Sir James McCusker Alzheimer’s Disease Research Unit (Hollywood Private Hospital), Perth, Western Australia, Australia c School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Western Australia d Australian eHealth Research Centre, Commonwealth Scientific and Industrial Research Organisation, Brisbane, Queensland, Australia e School of Psychology, University of Western Australia, Crawley, Western Australia f The School of Animal Biology, University of Western Australia, Crawley, WA, Australia g Neurosciences Unit, Health Department of WA, School of Psychology and Speech Pathology, Curtin University of Technology, Perth, Western Australia, Australia h Oceanic Medical Imaging, Hollywood Medical Centre, Nedlands, Western Australia, Australia i Section for Dementia Research, Hertie Institute of Clinical Brain Research, Department of Psychiatry and Psychotherapy, University of Tübingen and German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany j Cooperative Research Centre for Mental Health, Carlton, Victoria, Australia k School of Biomedical Sciences, Faculty of Health Sciences, Curtin University of Technology, Bentley, Western Australia, Australia Handling Associate Editor: Ariel Graff-Guerrero

Accepted 9 February 2016

Abstract. Increasing evidence suggests that Alzheimer’s disease (AD) sufferers show region-specific reductions in cerebral glucose metabolism, as measured by [18 F]-fluoro-2-deoxyglucose positron emission tomography (18 F-FDG PET). We investigated preclinical disease stage by cross-sectionally examining the association between global cognition, verbal and visual memory, and 18 F-FDG PET standardized uptake value ratio (SUVR) in 43 healthy control individuals, subsequently focusing

1 These

authors contributed equally to this work. to: Professor Ralph N. Martins, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, ∗ Correspondence

Joondalup, Western Australia 6027, Australia. Tel.: +61 8 9347 4200; Fax: +61 8 9347 4299; E-mail: [email protected].

ISSN 1387-2877/16/$35.00 © 2016 – IOS Press and the authors. All rights reserved

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S.L. Gardener et al. / Glucose metabolism is associated with memory

on differences between subjective memory complainers and non-memory complainers. The 18 F-FDG PET regions of interest investigated include the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. In the cohort as a whole, verbal logical memory immediate recall was positively associated with 18 F-FDG PET SUVR in both the left hippocampus and right amygdala. There were no associations observed between global cognition, delayed recall in logical memory, or visual reproduction and 18 F-FDG PET SUVR. Following stratification of the cohort into subjective memory complainers and non-complainers, verbal logical memory immediate recall was positively associated with 18 F-FDG PET SUVR in the right amygdala in those with subjective memory complaints. There were no significant associations observed in non-memory complainers between 18 F-FDG PET SUVR in regions of interest and cognitive performance. We observed subjective memory complaint-specific associations between 18 F-FDG PET SUVR and immediate verbal memory performance in our cohort, however found no associations between delayed recall of verbal memory performance or visual memory performance. It is here argued that the neural mechanisms underlying verbal and visual memory performance may in fact differ in their pathways, and the characteristic reduction of 18 F-FDG PET SUVR observed in this and previous studies likely reflects the pathophysiological changes in specific brain regions that occur in preclinical AD. Keywords: Brain glucose metabolism, cognition, memory

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F-FDG PET, subjective memory complaints, verbal memory, visual

INTRODUCTION Alzheimer’s disease (AD) is an age-related neurodegenerative disorder that results in the progressive loss of cognitive functions. [18 F]-fluoro2-deoxyglucose positron emission tomography (18 FFDG PET) measures cerebral glucose metabolism, a marker of synaptic functioning, which for more than a decade has been used to assist the diagnosis of AD [1]. While hypometabolism is not specific to AD and has been observed in other neurodegenerative diseases [2], there is increasing evidence that AD patients show reductions in cerebral glucose metabolism, as measured by 18 F-FDG PET standardized uptake value ratio (18 F-FDG PET SUVR), in specific brain regions. Previous findings have shown that AD patients show a pattern of bilateral 18 F-FDG PET SUVR reductions in the hippocampus, posterior cingulate, inferior parietal, and frontal cortices, with sparing of the basal ganglia, thalamus, cerebellum, and primary sensorimotor cortex [3–9]. Individuals with mild cognitive impairment (MCI, a preclinical condition associated with an increased likelihood of conversion to AD) demonstrate hypometabolism in the hippocampus and parietal cortex [8, 10]. Reductions in 18 F-FDG PET SUVR can consistently be detected in MCI patients compared to age-matched cognitively healthy controls [5, 6, 10, 11]. Furthermore, Edison et al. [12] demonstrated significantly decreased hippocampal and amygdala glucose metabolism in eight of 12 AD participants, while 18 F-FDG PET SUVR reductions in the hippocampus have also been shown to predict transition

from cognitively healthy status to MCI and AD [4, 13]. Importantly, de Leon et al. [4] found decreased 18 F-FDG PET SUVR in the entorhinal cortex at baseline was the most accurate regional predictor of clinical classification progression to MCI or AD over three years. The majority of previous research focuses on 18 F-FDG PET SUVR in the three major clinical classification groups of AD, MCI, and cognitively healthy controls, and few studies have investigated the association between cognitive function and 18 F-FDG PET SUVR. In one of these few studies, 18 mild AD participants, 24 MCI participants, and 18 healthy controls were examined by Devanand and colleagues [14]. These researchers noted that 18 F-FDG PET SUVR in the parietal cortex and precuneus region showed the strongest correlations with performance on the Mini-Mental State Examination (MMSE), Selective Reminder Test total recall and delayed recall (12-item, 6-trial version), and the Alzheimer’s Disease Assessment Scale – Cognition. 18 F-FDG PET SUVR in the hippocampus also showed significant correlations with all of the above cognitive measures excluding the Alzheimer’s Disease Assessment Scale- Cognition. Subjective memory complaint (SMC) is a frequent phenomenon associated with aging. Although it is subjective, the presence of SMC has been shown to be predictive for objectively measured cognitive decline [15–18]. We have previously shown that those with SMC demonstrated hypometabolism in the anterior and posterior cingulate cortex, and in the temporal associated cortices, whereas those without SMC


(i.e., non-memory complainers (NMC)) showed no significant pattern of glucose hypometabolism [19]. However, this latter study did not address whether glucose metabolism correlated with cognition; this was the focus of the current study. 18 F-FDG PET has the potential to detect presymptomatic alterations in neuronal activity, and to assist in the identification of individuals at risk for cognitive decline and subsequently AD. Continued study is required to determine the clinical utility of 18 F-FDG PET SUVR reductions in cognitively healthy individuals. In the present study, we aimed to investigate the association between verbal memory, visual memory, and 18 F-FDG PET SUVR in cognitively healthy individuals, focusing on potential differences between SMCs and NMCs. Decline in episodic memory (both verbal and visual) is the primary diagnostic feature for AD [20–23]. It has been noted that even in the preclinical stages of AD, visual memory impairment can predict AD [24]. However, to date, studies reporting on episodic verbal memory and episodic visual memory in association with glucose metabolism are sparse; the current investigation of these two domains will provide novel findings and will contribute to the field. The 18 F-FDG PET regions of interest (ROIs) targeted in our hypotheses included the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. These ROIs were selected a priori based on their frequent citation in published literature as demonstrating hypometabolism in AD and other clinical classifications [3–14, 25]. METHODS Study design This was a cross-sectional study conducted with 43 subjects drawn from a larger community based longitudinal study investigating potential neuropsychological and biological correlates of age-related cognitive change, namely the Western Australia Memory Study [26–29]. Participants who were willing to undergo an 18 F-FDG PET scan, had given informed consent, and who had no clinical, neurological, or psychiatric conditions affecting nervous system function diagnosed within the last 5 years were included in the current study. All participants had an MMSE score ≥27. We utilized the generally followed three MMSE cut-off levels employed to classify the severity of cognitive impairment

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including ‘no cognitive impairment’ = 24–30; ‘mild cognitive impairment’ = 18–23; ‘severe cognitive impairment’ = 0–17 [30]. Using an MMSE cut-off of 27 (well above the original cut-off score for dementia) minimized the risk of cognitively-impaired patients being included in the healthy control cohort. It should be noted that all participants were communitydwelling older adults and were living independently at the time of the study. Furthermore, the cognitive profiles of those participants with potential MCI presentation were closely examined and recruitment decisions were finalized by the study clinicians prior to enrolment into the study. The study was approved by the institutional ethics committees of Hollywood Private Hospital, Edith Cowan University, and the University of Western Australia. 18 F-FDG

PET imaging

18 F-FDG

PET was performed using standard brain imaging protocols on a GSO Philips Allegro PET camera, as reported previously [19]. Participants fasted for a minimum of 4 h prior to tracer administration. Subsequently, approximately 185 megabecquerel (MBq; 5 – 7 MBq/kg) FDG was administered via a peripheral intravenous cannula while the subjects rested in a quiet room. Imaging commenced 45 minpost isotope administration. Emission and transmission images were obtained over a 20-min period. Quantitative analysis of 18 F-FDG PET images was performed using the capAIBL PET-only approach [31, 32]. We quantified 18 F-FDG retention using a standardized uptake value ratio (SUVR), which represents tracer uptake divided by the average uptake in the cerebellum (as reference). The SUVR was computed for neocortex as the mean SUVR in the grey matter (GM) masked neocortical region, which comprised the frontal, superior parietal, lateral temporal, occipital, and anterior and posterior cingulate regions. We also analyzed SUVR retention in the GM masked neocortical ROIs including the dorsolateral prefrontal, ventrolateral prefrontal, orbitofrontal, straight gyrus, temporoccipital, temporal, inferior temporal, amygdala, hippocampus, parahippocampus, fusiform, supramarginal gyrus, angular gyrus, entorhinal, superior parietal, and posterior cingulate regions. The definition of these ROIs is based on the Automated Anatomical Labelling [AAL; 33]. The SUVRs for the dorsolateral prefrontal, ventrolateral prefrontal, orbitofrontal, and gyrus rectus were summed to form an overall score for the frontal

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cortex. The SUVRs for the temporoccipital, temporal, inferior temporal, amygdala, hippocampus, parahippocampus, fusiform, and entorhinal regions were summed to form an overall score for the temporal cortex. The SUVRs for the supramarginal gyrus and angular gyrus were summed to form an overall score for the inferior parietal region. Genotyping Fasting blood samples obtained using standard venipuncture of the antecubital vein were collected into ethylenediaminetetraacetic acid (EDTA) tubes containing Prostaglandin E1 (Sapphire Biosciences, 33·3 Nanogram/milliliter (ng/ml)) to prevent platelet activation. Whole blood was centrifuged to separate leucocytes. Deoxyribonucleic acid (DNA) was isolated from the leucocytes, using Qiagen Midiprep kits, and Apolipoprotein E (APOE) genotype was subsequently determined using polymerase chain reaction amplification and restriction enzyme digest techniques [34]. Cognitive measures SMC status was determined using participant response to the first question of the memory subset of the Cambridge Mental Disorders of the Elderly Examination (CAMDEX-R): “Do you have difficulty with your memory? No/Yes” [35]. This question was used to allocate participants into SMC and NMC groups. The logical memory I and II tests from the Wechsler Memory Scale (WMS)-III [36] were used as measures of immediate and delayed verbal memory. In this task, the examiner reads a short story to the participant and then prompts them to recall as much information from the story as possible (logical memory immediate recall). Twenty five to thirty five minutes following the first administration of the story, participants are again asked to recall as much information from the story as they can (logical memory delayed recall). The test was scored based on the number of correct items recalled. The WMS-III visual reproduction I and II subtests were used as measures of immediate and delayed visual memory. In this task, participants are asked to observe five designs for ten seconds each and draw them immediately from memory (visual reproduction immediate recall). Twenty five to thirty five minutes later, the participants are again asked to draw the five designs previously observed (visual reproduction delayed

recall). Each item within the designs has a score of 0 to 2, which are then summed to give an overall score for each of the five designs. The overall score for the five designs are then summed to give total visual reproduction immediate recall and visual reproduction delayed recall scores. In addition, the MMSE as a measure of general cognitive functioning. MMSE provides a rapid yet reliable measure of global cognitive functioning with a cut off score of 24 and below for the diagnosis of dementia [37]. Statistical analysis All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL) version 22. A p-value of 0.01 or smaller determined a significant result to balance the risk of type I and type II errors, due to the large number of statistical tests performed. Means, standard deviations and percentages are provided in Table 1 for the entire cohort as well as following stratification by SMC status. Independent samples t-test and chi square (χ2 ) analyses were conducted to evaluate group differences, as appropriate. Due to the small number of APOE ␧4 allele carriers in the cohort (n = 12), analyses were not completed following stratification by APOE ␧4 allele carriage. The APOE ␧4 allele is the most common genetic risk factor for AD, it is over-represented in sporadic and familial AD cases, and is present in over 50% of late-onset AD cases [38]. Hierarchical multiple linear regressions were used to analyze associations between 18 F-FDG PET ROIs (dependent variable) and cognitive test scores (independent variables) in the cohort as a whole. Age (years), gender, and APOE genotype (absence of ␧4 allele versus presence of either one or two ␧4 alleles) were included as independent variables in Block 1, and logical memory immediate recall and visual reproduction immediate recall were included as independent variables in Block 2. Following this procedure, logical memory delayed recall and visual reproduction delayed recall were exchanged for logical memory immediate recall and visual reproduction immediate recall in Block 2. This analysis was repeated following stratification of the cohort by SMC status. Education level (≤12 years, or >12 years) was not significantly different between our stratified groups, and was found not to be associated with any of our cognitive or 18 F-FDG PET variables, so was not entered into the regression models.


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Table 1 Descriptive statistics for the whole cohort and subgroups of the cohort based on stratification by subjective memory complaint status. Total sample (n = 43) Age, y Gender, male; n (%) Education,≤12 y; n (%) Presence of APOE ␧4 allele; n (%) Subjective memory complainer; n (%) MMSE score 18 F-FDG PET regions of interest: Left hippocampus Right hippocampus Left posterior cingulate Right posterior cingulate Left superior parietal Right superior parietal Left amygdala Right amygdala Left entorhinal Right entorhinal Frontal cortex† Temporal cortex¶ Inferior parietal Global SUVR Cognitive measures: Logical Memory I Immediate Recall Logical Memory II Delayed Recall Visual Reproduction I Immediate Recall Visual Reproduction II Delayed Recall

Non-memory complainers (n = 23)

29.17 ± 0.8

28.65 ± 1.8

0.248

0.771 ± 0.08 0.788 ± 0.07 1.262 ± 0.11 1.278 ± 0.10 1.105 ± 0.11 1.073 ± 0.11 0.753 ± 0.07 0.779 ± 0.07 0.589 ± 0.11 0.584 ± 0.10 9.118 ± 0.81 4.317 ± 0.42 13.139 ± 1.20 1.121 ± 0.10

0.775 ± 0.07 0.788 ± 0.06 1.269 ± 0.10 1.278 ± 0.09 1.109 ± 0.10 1.085 ± 0.10 0.747 ± 0.07 0.777 ± 0.06 0.608 ± 0.11 0.586 ± 0.11 9.049 ± 0.77 4.307 ± 0.35 13.116 ± 1.14 1.119 ± 0.09

0.766 ± 0.09 0.789 ± 0.09 1.255 ± 0.11 1.277 ± 0.11 1.100 ± 0.13 1.060 ± 0.11 0.760 ± 0.08 0.781 ± 0.08 0.567 ± 0.10 0.580 ± 0.08 9.196 ± 0.87 4.329 ± 0.50 13.166 ± 1.30 1.124 ± 0.11

0.710 0.961 0.655 0.956 0.812 0.460 0.574 0.834 0.214 0.846 0.561 0.863 0.893 0.893

13.09 ± 4.23 11.48 ± 4.62 80.39 ± 18.11 59.22 ± 23.24

68 ± 11.4 8 (40) 10 (50) 0 (0)

p-values for subjective memory complaint differences

66 ± 10.1 18 (42) 21 (49) 12 (28) 20 (47) 28.93 ± 1.4

12.42 ± 4.52 10.26 ± 5.21 73.93 ± 18.95 52.79 ± 23.40

66 ± 8.9 10 (43) 11 (48) 12 (52)

Subjective memory complainers (n = 20)

11.65 ± 4.82 8.85 ± 5.60 66.50 ± 17.47 45.40 ± 21.85

0.568 0.532 0.565 0.000∗

0.304 0.099 0.015 0.052

Unless otherwise described, data are presented as mean ± standard deviation of the mean. APOE, Apolipoprotein E; MMSE, Mini-Mental State Examination; SUVR, standardized uptake value ratio; y, years. Bold indicates statistical significance (∗ p < 0.01). Characteristics compared using independent samples t-test for continuous variables and χ2 for categorical variables. † Frontal cortex is the sum of the left and right dorsolateral prefrontal, ventrolateral prefrontal, orbitofrontal, and straight gyrus. ¶ Temporal cortex is the sum of the left and right temporoccipital, temporal, inferior temporal, amygdala, hippocampus, parahippocampus, entorhinal, and fusiform. Inferior parietal is the sum of the left and right supramarginal gyrus and angular gyrus.

RESULTS The cohort comprised 43 participants (42% male) with an average age of 66 years. Twenty eight percent were carriers of the APOE ␧4 allele (genotypes ␧2/4, ␧3/4 or ␧4/4) and over 45% had 12 or less years of education (Table 1). Figure 1 shows a representation of the cohort mean 18 F-FDG PET SUVRs for our regions of interest. We investigated the associations between 18 F-FDG PET SUVR in our ROIs and cognitive performances using hierarchical linear regressions controlling for APOE ␧4 allele carrier status, gender, and age. Logical memory immediate recall was positively associated with 18 F-FDG PET SUVR in the left hippocampus (␤ = 0.373; p = 0.008; Figure 2A), and the right amygdala (␤ = 0.467; p = 0.001; Figure 2B). There were no significant 18 F-FDG PET SUVR associations with logical memory delayed recall, or visual reproduction immediate or delayed recall (Table 2).

Next we examined the differences between SMCs and NMCs in our cohort with respect to rates of glucose metabolism and cognitive performance. There were no statistically significant differences in glucose metabolism or cognitive performance between these two groups. Hierarchical multiple linear regressions were undertaken to analyze the association between cognitive test performance and 18 F-FDG PET SUVR in ROIs when the cohort was stratified by SMC status. In SMCs, logical memory immediate recall was positively associated with 18 F-FDG PET SUVR in the right amygdala (␤ = 0.557; p = .009; Figure 2C), with no significant associations observed between cognitive performance and 18 F-FDG PET SUVR in our regions of interest in non-memory complainers (Table 3). The association between 18 F-FDG PET SUVR and global cognitive functioning, as measured using the MMSE was also examined. However, the hierarchical

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Fig. 1. Representation of the cohort mean 18 F-FDG PET SUVRs for our regions of interest. The 18 F-FDG PET SUVR is colour-coded and mapped to the cortical surface. FDG, Fluoro-2-deoxyglucose; Inf, inferior; L, left; PET, positron emission tomography; R, right; Post, posterior; Sup, superior; SUVR, standardized uptake value ratio.

linear regressions results were not significant for any of the areas of interest. DISCUSSION The objective of this study was to investigate the association between verbal logical memory and visual memory (immediate and delayed recall) with cerebral glucose metabolism in cognitively healthy individuals, focusing on potential differences between those with subjective memory complaints and non-memory complainers. In the cohort as a whole, logical memory immediate recall was positively associated with glucose metabolism in both the left hippocampus and right amygdala (after controlling for APOE ␧4 allele carrier status, gender, and age). There were no associations observed between delayed recall on logical memory or visual reproduction, or visual reproduction immediate recall and 18 F-FDG PET SUVR. When differences between SMCs and NMCs in our cohort with respect to glucose metabolism and cognitive performance were assessed, we observed a positive association between 18 F-FDG PET SUVR in the right amygdala and logical memory immediate recall score in those with a SMC, whilst no associations were observed in NMCs. The characteristic reduction of cerebral glucose metabolism seen in this and previous studies reflects the pathophysiological changes in specific brain areas

that occur in AD [8]. In cognitively healthy controls and those with MCI, the entorhinal cortex and hippocampus are the brain regions which most consistently demonstrate early AD-related changes, with clinically diagnosed AD patients typically showing additional pathology in neocortical areas. These findings are consistent with the proposal that AD pathology likely begins in the entorhinal cortex and hippocampus during the preclinical stage of the disease, later spreading to widespread neocortical sites in association with clinical diagnosis [5]. The entorhinal cortex and hippocampus are important structures for memory function; these regions are particularly vulnerable to neurofibrillary tangle pathology, which is one of the pathological hallmarks of AD [39, 40] and neuronal loss [41]. Li et al. [3] found reduced global 18 F-FDG PET SUVR in AD participants (n = 17), and reduced 18 FFDG PET SUVR in the hippocampal and inferior parietal lobe in MCI participants (n = 13) compared to cognitively healthy controls (n = 7). Further, mean levels of 18 F-FDG PET SUVR in the parietal cortex and additionally the temporal cortex were shown to be reduced by 20% in 12 participants with AD compared to eight cognitively healthy controls, and this decrease correlated with performance on the MMSE, immediate recall, and recognition memory test for words scores [12]. Several studies have found reductions in 18 F-FDG PET SUVR in the posterior cingulate in those with AD; specifically,


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Fig. 2. Region-specific associations between 18 F-FDG PET SUVR and logical memory immediate recall score in the cohort as a whole and subjective memory complainers. A) Higher 18 F-FDG PET SUVR in the left hippocampus is associated with increased logical memory immediate recall performance in the cohort as a whole. B) Higher 18 F-FDG PET SUVR in the right amygdala is associated with increased logical memory immediate recall performance in those reporting subjective memory complaints. C) Higher 18 F-FDG PET SUVR in the right amygdala is associated with increased logical memory immediate recall performance in those reporting subjective memory complaints. Hierarchical linear regression analysis. Model includes age, gender, and APOE ␧4 allele carriage as covariates. APOE, Apolipoprotein E; FDG, Fluoro-2-deoxyglucose; PET, positron emission tomography; SUVR, standardized uptake value ratio.

Minoshima et al. [11] found those with mild AD had a 21-22% reduction in the posterior cingulate and cinguloparietal transitional area. One of the most interesting findings of the current study is the regional change in 18 F-FDG PET SUVR that was observed in subjective memory complainers compared to non-memory complainers. The occurrence of SMC is common within the aging population, although investigations into whether subjective memory complaints precede AD have produced somewhat divergent results. Several studies have found SMCs to be associated with later diagnosis with AD; for example Geerlings et al. [15] found participants with normal cognition and SMC at baseline had a higher chance of incident AD after an average of 3.2 years than those with no memory

complaint at baseline. In contrast to this, Schofield et al. [42] found that SMCs in participants with baseline normal cognition did not predict future cognitive decline. It is plausible that elderly people may notice their memory deteriorating at a time when cognitive tests are still unable to verify these changes, and a longer follow-up period may be required to detect an association between memory complaint and incident AD. By comparison, few studies have investigated the effect of SMC on glucose metabolism. Rimajova et al. [19] investigated SMC in APOE ␧4 allele carriers and observed hypometabolism in the anterior and posterior cingulate cortex and in the temporal associated cortices in SMCs, with no significant pattern of glucose hypometabolism observed in NMCs. The current study found specific associations between

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Table 2 Results of linear regressions examining the association between 18 F-FDG PET regions of interest and cognitive performance in the cohort as a whole; standardized ␤ values and p-values shown. Logical Memory I Immediate Recall ␤ Left hippocampus 0.373 Right hippocampus 0.319 Left posterior cingulate 0.081 Right posterior cingulate 0.032 Left superior parietal –0.059 Right superior parietal –0.027 Left amygdala 0.354 Right amygdala 0.467 Left entorhinal 0.101 Right entorhinal –0.013 0.198 Frontal cortex† Temporal cortex¶ 0.172 Inferior parietal 0.233 Global SUVR 0.094

p-value 0.008∗ 0.028 0.585 0.842 0.689 0.852 0.019 0.001∗∗ 0.490 0.930 0.205 0.257 0.113 0.518

Logical Memory II Delayed Recall

Visual Reproduction I Immediate Recall

Visual Reproduction II Delayed Recall

␤

p-value

␤

p-value

␤

p-value

0.256 0.198 –0.045 –0.106 –0.115 –0.043 0.196 0.221 –0.014 –0.072 0.082 0.134 0.121 –0.036

0.087 0.200 0.767 0.508 0.456 0.770 0.227 0.169 0.927 0.639 0.612 0.392 0.431 0.810

–0.222 –0.233 –0.093 –0.060 –0.139 –0.011 –0.270 –0.322 0.051 –0.019 –0.141 –0.086 –0.160 –0.114

0.143 0.144 0.575 0.734 0.401 0.948 0.102 0.037 0.754 0.912 0.414 0.610 0.325 0.480

–0.074 0.041 0.185 0.196 0.057 0.198 –0.080 –0.060 0.228 0.182 0.058 0.010 0.064 0.152

0.618 0.788 0.226 0.226 0.712 0.184 0.621 0.706 0.128 0.241 0.723 0.950 0.678 0.311

Model includes age, gender, and APOE ␧4 allele carriage as covariates. Bold indicates statistical significance (∗ p < 0.01; ∗∗ p < 0.001). APOE, Apolipoprotein E; FDG, Fluoro-2-deoxyglucose; PET, positron emission tomography; SUVR, standardized uptake value ratio. † Frontal cortex is the sum of the left and right dorsolateral prefrontal, ventrolateral prefrontal, orbitofrontal, and straight gyrus. ¶ Temporal cortex is the sum of the left and right temporoccipital, temporal, inferior temporal, amygdala, hippocampus, parahippocampus, entorhinal, and fusiform. Inferior parietal is the sum of the left and right supramarginal gyrus and angular gyrus.

glucose metabolism in the amygdala and hippocampus of those reporting SMC, and associations with the posterior cingulate and superior parietal regions in NMCs. As previously mentioned, the hippocampus is one of the first regions to exhibit AD pathology. The findings of the current study therefore appear consistent with the notion that SMC represents the first clinical manifestation of dementia. There are limitations to our report; this is a crosssectional study, so the findings should be interpreted with caution. Our results do not allow inferences to be drawn regarding decreased 18 F-FDG PET SUVR and future AD risk; the findings indicate only that in our cohort as a whole and specifically in SMCs, there was a decreased 18 F-FDG PET SUVR in areas known to be associated with neuropathology in AD. Additionally, we studied a relatively small sample size of 43 participants, which resulted in group sizes between 20 and 23 participants when the cohort was stratified according to SMC status. This small sample size may have made some associations undetectable while inflating other associations. Future work in larger cohorts collecting longitudinal data is therefore required to validate our findings. Furthermore, we were unable to stratify the cohort to investigate systematically the effect of APOE ␧4 allele status, due to the small number (n = 12) of APOE ␧4 allele carriers in the current study. However when APOE ␧4 allele status was removed from the linear regression models the strength of the observed

associations did change, suggesting APOE ␧4 allele status was contributing to these associations. Possession of the APOE ␧4 allele increases the risk of AD, with several studies showing that the risk of AD increases as a function of the number of APOE ␧4 alleles carried. More specifically, empirical findings indicate that APOE alleles in the order of ␧4/␧4>␧4/␧3>␧4/␧2>␧3/␧3>␧3/␧2>␧2/␧2 positively influence an individual’s risk of developing AD [38, 43]. The use of single questions for measuring SMC status has previously been shown to be a reliable and valid technique [15, 44], and is commonly used in research [45], however we acknowledge that there is still a small risk of inaccuracy using this single question to allocate participants into SMC and NMC groups. Another factor which could affect SMC status is depression; however, there is no evidence, to our knowledge, that shows depression modulates the relationship between SMC and 18 F-FDG PET. There are many studies that have shown depression and SMC to be associated, concluding, however, that SMCs are not just secondary to depression [18, 46–48]. For example, Scheef and colleagues [47] noted their SMC subjects had slightly higher depression scores, yet there was no change in the results (longitudinal memory decline in the SMC group was associated with reduced glucose metabolism in the right precuneus at baseline) even when the depression score was included in the analysis. In multiple papers,

␤

0.227 0.163 0.077 0.094 –0.298 –0.182 0.187 0.415 –0.123 –0.124 0.130 0.082 0.096 0.003

0.265 0.448 0.733 0.685 0.178 0.389 0.418 0.063 0.568 0.528 0.591 0.732 0.668 0.988

p-value

␤ 0.526 0.441 0.073 0.007 0.136 0.103 0.510 0.557 0.246 0.073 0.301 0.207 0.332 0.192

0.013 0.028 0.750 0.978 0.511 0.626 0.017 0.009∗ 0.224 0.758 0.200 0.310 0.111 0.377

p-value

SMC ␤ 0.217 0.225 0.064 0.003 –0.204 –0.081 0.115 0.202 –0.252 –0.017 0.104 0.109 0.094 0.020

0.310 0.284 0.756 0.989 0.339 0.682 0.645 0.392 0.260 0.938 0.662 0.652 0.679 0.922

p-value

NMC ␤ 0.354 0.265 –0.071 –0.103 –0.022 0.046 0.351 0.308 0.203 –0.014 0.154 0.199 0.227 0.007

0.103 0.202 0.748 0.665 0.912 0.826 0.108 0.159 0.341 0.955 0.503 0.332 0.286 0.975

p-value

SMC

Logical Memory II Delayed Recall ␤ –0.111 –0.135 –0.060 0.109 0.097 0.089 –0.267 –0.150 –0.221 –0.303 0.006 –0.068 –0.205 0.029

0.654 0.611 0.830 0.704 0.715 0.730 0.350 0.569 0.407 0.220 0.984 0.819 0.460 0.915

p-value

NMC ␤ –0.150 –0.059 0.045 0.038 –0.130 0.107 –0.082 –0.254 0.249 0.367 –0.095 0.140 0.065 0.046

0.460 0.762 0.850 0.883 0.553 0.632 0.689 0.214 0.243 0.155 0.696 0.510 0.757 0.838

p-value

SMC

Visual Reproduction I Immediate Recall ␤ 0.170 0.362 0.484 0.556 0.442 0.449 0.169 0.319 0.217 0.177 0.399 0.304 0.312 0.476

0.420 0.089 0.028 0.013 0.046 0.032 0.494 0.178 0.324 0.408 0.101 0.214 0.177 0.922

p-value

NMC ␤

–0.126 –0.044 –0.022 –0.029 –0.171 0.044 –0.143 –0.219 0.150 0.217 –0.168 –0.092 –0.057 –0.042

0.548 0.830 0.922 0.905 0.398 0.834 0.497 0.311 0.480 0.386 0.468 0.651 0.787 0.843

p-value

SMC

Visual Reproduction II Delayed Recall

Model includes age, gender, and APOE ␧4 allele carriage as covariates. Bold indicates statistical significance (∗ p < 0.01). APOE, Apolipoprotein E; FDG, Fluoro-2-deoxyglucose; PET, positron emission tomography; NMC, non-memory complaint; SMC, subjective memory complaint; SUVR, standardized uptake value ratio. † Frontal cortex is the sum of the left and right dorsolateral prefrontal, ventrolateral prefrontal, orbitofrontal, and straight gyrus. ¶ Temporal cortex is the sum of the left and right temporoccipital, temporal, inferior temporal, amygdala, hippocampus, parahippocampus, entorhinal, and fusiform. Inferior parietal is the sum of the left and right supramarginal gyrus and angular gyrus.

Left hippocampus Right hippocampus Left posterior cingulate Right posterior cingulate Left superior parietal Right superior parietal Left amygdala Right amygdala Left entorhinal Right entorhinal Frontal cortex† Temporal cortex¶ Inferior parietal Global SUVR

NMC

Logical Memory I Immediate Recall

Table 3 Results of linear regressions examining the association between 18 F-FDG PET regions of interest and cognitive performance following stratification of the cohort by subjective memory complaint status; standardized ␤ values and p-values shown.

S.L. Gardener et al. / Glucose metabolism is associated with memory 9

10


Jessen and colleagues [18, 46] have concluded that beyond factors affecting one’s own experience of memory (e.g., depression), SMC is likely to reflect initial impairment specifically related to the future manifestation of AD [46], additionally finding results did not change when rate of depressive symptoms were included in analysis (even though those with an SMC had higher rates of depressive symptoms compared with those with no concerns) [18]. Ideally, adding a depression scale as a covariate will control for depression; however, depression scores for these participants were not available. In light of the findings of previous literature, dividing participants into SMCs and NMCs in the current study appears to be plausible. Many aspects of our study provide confidence in our findings. As a distinct strength of the current study, we have utilized a well-characterized cohort and have taken a conservative approach to analysis by controlling for a range of relevant demographic variables and used a p-value of 0.01 to determine statistical significance. Existing large multicenter 18 F-FDG PET studies have typically focused on diagnostic accuracy of 18 F-FDG PET for AD rather than examining presymptomatic cognitive performance and longitudinal decline. However, 18 F-FDG PET can assist in determining the time course for cerebral metabolic progression from the preclinical to symptomatic stage of AD, help to identify homogenous subject groups for study in experimental and clinical trial protocols, and offer an objective and less invasive approach to presymptomatic metabolic monitoring during experimental therapeutic trials. Although neural mechanisms underlying the associations observed cannot be distinguished from the current study, our results suggest that the pathways for verbal and visual memory may differ, as we saw associations with verbal memory but not with visual memory. We can also hypothesize that the pathways for immediate recall and delayed recall may differ, as we again saw associations with only immediate recall in this study. However, these findings should be examined in other studies with larger sample size prior to further conclusion. In summary, we here report associations between glucose metabolism and immediate verbal memory performance in the cohort as a whole and in those with a SMC, with no associations observed with visual memory performance, or delayed verbal memory performance. Specifically, verbal logical memory immediate recall was positively associated with glu-

cose metabolism in the left hippocampus and right amygdala in the cohort as a whole, and with just the right amygdala in those with a SMC. These observations contribute to our knowledge concerning brain glucose metabolism measured via 18 F-FDG PET at presymptomatic stages (SMC) of AD in older individuals. The results presented here are part of an ongoing longitudinal study. Future work will address the relationship between reduced glucose metabolism at baseline and cognitive decline after a decade of follow-up. ACKNOWLEDGMENTS HRS’s research has been supported by grants and funds from Edith Cowan University, the Neurotrauma Research Program and the McCusker Charitable Foundation (Western Australia). HRS is supported by the Cooperative Research Centre (CRC) for Mental Health Australia. This study was supported by the National Health and Medical Research Council of Australia (Grant Number: 324100 awarded to RNM), the McCusker Alzheimer’s Research Foundation Inc., Hollywood Private Hospital, and the McCusker Charitable Foundation. Authors’ disclosures available online (http://j-alz. com/manuscript-disclosures/15-1084r2). REFERENCES [1]

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