Hypometabolism and Altered Cerebrospinal Fluid Markers in Normal Apolipoprotein E E4 Carriers with Subjective Memory Complaints

Mosconi, Lisa; Santi, Susan De; Bryś, Mirosław; Tsui, Wai; Pirraglia, Elizabeth; Głodzik-Sobańska, Lidia; Rich, Kenneth; Switalski, Remigius; Mehta, Pankaj; Praticò, Domenico; Zinkowski, Raymond; Blennow, K.; Leon, Mony J. de

doi:10.1016/j.biopsych.2007.05.030

Cited by 216 publications

(188 citation statements)

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“…The current results are also in concordance with a previous study by Mosconi et al 10 demonstrating FDG hypometabolism in the parahippocampus in CN older individuals with an APOE e4 allele and SMCs, further supporting the idea that alterations in the MTL may be a specific marker of subclinical changes in cognition in preclinical AD. Although we were not able to unravel the relationships among genotype, amyloid, SMCs, and metabolism in the current study, we did find, in line with the findings of Mosconi et al, a significantly increased percentage of APOE e4 carriers in the Ab 1 group (61.4%).…”

Section: Methodssupporting

confidence: 93%

“…Whereas most studies have reported an association between SMCs and Ab, [3][4][5][6] others could not demonstrate this relationship. 7 Previous studies with fluorodeoxyglucose (FDG)-PET, a biomarker supposed to reflect neuronal integrity, 8 have demonstrated hypometabolism when comparing cognitively normal (CN) individuals with and without SMCs, but the results have been inconsistent as to which brain regions show hypometabolism, e.g., the precuneus, 9 parietotemporal and parahippocampal gyrus, 10 or periventricular region. 11 These inconsistent patterns of FDG-PET hypometabolism could be due to several factors, including the use of different techniques to measure SMCs.…”

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confidence: 99%

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Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden

et al. 2017

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Objective: To identify the functional and pathologic correlates underlying subjective memory complaints (SMCs) in cognitively normal older adults.Methods: Two hundred fifty-one older adults underwent resting-state fluorodeoxyglucose (FDG)-PET and Pittsburg compound B-PET b-amyloid (Ab) imaging and filled out a questionnaire regarding SMCs. Participants were classified into 2 groups based on their Ab burden. Age-adjusted voxel-wise correlations were used to examine SMCs, amyloid status (Ab 1 vs Ab 2 ), and the interaction between SMCs and Ab status as predictors of metabolism. Region-of-interest (ROI) analyses were performed to confirm the whole-brain analyses and to test for additional covariates.Results: Greater SMCs correlated with decreased FDG metabolism in the bilateral precuneus, bilateral inferior parietal lobes, right inferior temporal lobe, right medial frontal gyrus, and right orbitofrontal gyrus. A significant interaction effect between SMCs and amyloid burden was found such that Ab 1 individuals with increased complaints had decreased FDG metabolism in the bilateral medial temporal lobes. ROI analyses confirmed the voxel-wise analyses result in that decreased precuneus metabolism was associated with greater SMCs regardless of Ab status, age, or thickness, whereas the relationship between hippocampal metabolism and SMCs was a function of Ab, even after adjustment for age, hippocampal volume, or depressive symptoms.Conclusions: These data show the relevant role of posterior and anterior midline regions in SMCs in older individuals. Decreased hippocampal metabolism may be a specific marker of subclinical changes in cognition due to amyloid pathology. However, longitudinal studies are needed to determine whether our findings foreshadow clinical decline. Neurology ® 2017;88:1759-1767 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; CN 5 cognitively normal; FDG 5 fluorodeoxyglucose; FDR 5 false discovery rate; GDS 5 Geriatric Depression Scale; MFG 5 middle frontal gyrus; MGH 5 Massachusetts General Hospital; MTL 5 medial temporal lobe; PiB 5 Pittsburg compound B; ROI 5 region of interest; SMC 5 subjective memory complaint.Subjective memory complaint (SMC) is defined by self-reports of memory worsening and objective memory performance in the normal adjusted range. SMCs are common in the elderly population without dementia, with an estimated prevalence range between 22% and 56%, 1 and have been associated with increased risk of incident Alzheimer disease (AD). 2 Despite the high prevalence of self-perceived changes in memory among older adults, relatively little is known about its functional and pathologic correlates, especially in the preclinical stages of AD. This information is crucial because SMCs alone may have insufficient sensitivity and specificity to predict the development of dementia.With regard to SMCs and b-amyloid (Ab; one hallmark of AD pathology most commonly used to define the preclinical stage), previous studies have found conflicting results. Whereas most studies have reported an a...

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Section: Methodssupporting

confidence: 93%

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confidence: 99%

Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden

et al. 2017

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“…FDG PET studies in non-demented individuals report that, as compared to e4 non-carriers, ApoE e4 homozygotes (therefore, with a particularly high risk of developing AD) have a significantly reduced CMRglc in the same brain regions as clinically affected AD patients, including the posterior cingulate/precuneus, parietal, temporal and prefrontal regions [59]. As compared to e4 noncarriers, ApoE e4 heterozygotes show similar, but milder, hypometabolism within the same brain regions found to be affected in AD patients and in ApoE e4 homozygotes [59][60][61][62]. There is evidence that the metabolic reductions in ApoE e4 carriers are more progressive (25 % decline in CMRglc over a two-year interval) and correlate with the reductions in cognitive performance [63].…”

Section: Fdg Pet and Apoe-associated Genetic Riskmentioning

confidence: 93%

FDG PET and the genetics of dementia

Nacmias

Berti

Piaceri

et al. 2013

Clin Transl Imaging

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Dementias are the most common neurodegenerative diseases and they are increasingly becoming a major public health problem. The most common form of dementia, affecting over 20 million people worldwide, is Alzheimer's disease (AD). AD is a neurodegenerative disease of the central nervous system mainly found in older adults, with an incidence that increases with age. With the development of newer technologies, including genetic screening technologies and PET/MRI scanning, the role of genetic studies and neuroimaging is being redefined; indeed, these approaches are able to provide support not only in the clinical diagnosis of dementia, but also in its presymptomatic evaluation. Many researchers agree that early identification of AD, before abnormal accumulation of amyloid and tau proteins, could provide an opportunity to hinder the progression of the disease. [18 F]2-fluoro-2-deoxy-D-glucose (FDG) PET studies have shown that decreased glucose metabolism in AD precedes clinical diagnosis and that the degree of clinical disability in AD correlates closely with the magnitude of the reduction in brain glucose metabolism. Data on presymptomatic mutation carriers from families with known early-onset autosomal dominant AD (familial AD) show reductions in the cerebral metabolic rate of glucose (CMRglc), consistent with the expected AD PET pattern, in the absence of severe atrophy on MRI. These results suggest that PET CMRglc measures have the potential to serve as preclinical biomarkers of dementia, useful also for tracking disease progression. This review highlights the role of genetics and FDG PET in understanding the pathogenesis of dementia.

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“…In AD, consistent patterns of localized hypometabolism have been described from early disease stages, involving initially and most significantly the precuneus and posterior cingulate gyrus (Minoshima et al 1997;Chételat et al 2003;Mosconi 2005;Kawachi et al 2006), and implicating also the hippocampus, amygdala, parahippocampal gyrus, and the lateral parietal and temporal neocortices (Mosconi et al 2004(Mosconi et al , 2008aJagust 2006;Petrie et al 2009). There have also been PET studies documenting regional brain glucose metabolism variations as a function of the apolipoprotein E (APOE) genotype in non-demented individuals, with glucose hypometabolism being associated with the presence of the APOE ε4 allele (Drzezga et al 2005;Mosconi et al 2008b; the major genetic risk factor for AD; Corder et al 1993).…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular risk in cognitively preserved elderlies is associated with glucose hypometabolism in the posterior cingulate cortex and precuneus regardless of brain atrophy and apolipoprotein gene variations

Tamashiro-Duran

Squarzoni

Duran

et al. 2012

AGE

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Cardiovascular risk factors (CVRF) possibly contribute to the emergence of Alzheimer's disease (AD). Fluorodeoxyglucose-positron emission tomography (FDG-PET) has been widely used to demonstrate specific patterns of reduced cerebral metabolic rates of glucose (CMRgl) in subjects with AD and in non-demented AGE (2013) 35:777-792 DOI 10.1007 Electronic supplementary material The online version of this article (doi:10.1007/s11357-012-9413-y) contains supplementary material, which is available to authorized users. carriers of the apolipoprotein ε4 (APOE ε4) allele, the major genetic risk factor for AD. However, functional neuroimaging studies investigating the impact of CVRF on cerebral metabolism have been scarce to date. The present FDG-PET study investigated 59 cognitively preserved elderlies divided into three groups according to their cardiovascular risk based on the Framingham 10-year risk Coronary Heart Disease Risk Profile (low-, medium-, and high-risk) to examine whether different levels of CVRF would be associated with reduced CMRgl, involving the same brain regions affected in early stages of AD. Functional imaging data were corrected for partial volume effects to avoid confounding effects due to regional brain atrophy, and all analyses included the presence of the APOE ε4 allele as a confounding covariate. Significant cerebral metabolism reductions were detected in the high-risk group when compared to the low-risk group in the left precuneus and posterior cingulate gyrus. This suggests that findings of brain hypometabolism similar to those seen in subjects with AD can be detected in association with the severity of cardiovascular risk in cognitively preserved individuals. Thus, a greater knowledge about how such factors influence brain functioning in healthy subjects over time may provide important insigths for the future development of strategies aimed at delaying or preventing the vascular-related triggering of pathologic brain changes in the AD.

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Hypometabolism and Altered Cerebrospinal Fluid Markers in Normal Apolipoprotein E E4 Carriers with Subjective Memory Complaints

Cited by 216 publications

References 59 publications

Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden

Hippocampal hypometabolism in older adults with memory complaints and increased amyloid burden

FDG PET and the genetics of dementia

Cardiovascular risk in cognitively preserved elderlies is associated with glucose hypometabolism in the posterior cingulate cortex and precuneus regardless of brain atrophy and apolipoprotein gene variations

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