Regional Cerebral Glucose Metabolism in Monozygotic Twins Discordant for Alzheimer’s Disease

Järvenpää, Tarja; Räihä, Ismo; Kaprio, Jaakko; Koskenvuo, Markku; Laine, Matti; Kurki, Timo; Vahlberg, Tero; Viljanen, Tapio; Ahonen, Kirsi; Rinne, Juha O.

doi:10.1159/000072809

Cited by 25 publications

(6 citation statements)

References 36 publications

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“…A total of 395 peripheral blood samples from Finnish and Swedish cohorts and 12 brain samples from NIH NeuroBioBank were analyzed in this study (Table 1). In more detail, the older Finnish twin cohort [35, 36] of 2483 individuals, born 1922–1937, had been previously screened for cognitive functions by phone interview [37], and the discordant twin pairs were invited to neuropsychological testing, brain magnetic resonance imaging, PET amyloid imaging [18, 38–41], and collection of EDTA blood samples. Based on the overall evaluation, a diagnosis of AD was made (29 pairs).…”

Section: Methodsmentioning

confidence: 99%

Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer’s disease

et al. 2019

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Background Alzheimer’s disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs. Results Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ≤ 0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer’s disease and becomes differentially methylated after disease onset. Conclusions DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer’s disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels. Electronic supplementary material The online version of this article (10.1186/s13148-019-0729-7) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer’s disease

et al. 2019

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“…Although it may represent an indirect marker of cortical vulnerability to the degenerative process, it does not determine the occurrence of dementia; for instance, reduction in glucose metabolism in temporal cortex was found in cognitively discordant monozygotic twins [126,127]. The link with APOε genotype is also difficult to interpret.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals

Łazarczyk

Hof

Bouras

et al. 2012

BMC Med

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Since the first description of the case of Auguste Deter, presented in Tübingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controversial. The fate of such individuals, who are cognitively intact, but positive for some early AD biomarkers, is currently uncertain at best. In this report, we advocate the point of view that although most of these preclinical cases will evolve to clinically overt AD, some appear to have efficient compensatory mechanisms and virtually never develop dementia. We critically review the currently available early AD markers, discuss their clinical relevance, and propose a novel classification of preclinical AD, designating these non-progressing cases as 'stable asymptomatic cerebral amyloidosis'.

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“…Autopsy and neuropathological examination were conducted. One MIRAS patient (III‐12), four carriers (III‐8, III‐23, IV‐5 and IV‐12), and six control individuals (two controls were non‐carrier members of this family: IV‐6 and IV‐13) were studied with F‐18 fluorodeoxyglucose positron emission tomography (FDG‐PET) and magnetic resonance imaging (MRI) with methods previously described (18–20).…”

Section: Methodsmentioning

confidence: 99%

Do carriers of POLG mutation W748S have disease manifestations?

et al. 2007

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Mitochondrial recessive ataxia syndrome (MIRAS) is a common cause of autosomal recessive juvenile- or adult-onset ataxia, at least in Scandinavia. MIRAS patients are homozygous or compound heterozygous for POLG mutations W748S and A467T. Because many first-degree relatives of MIRAS patients in the studied families have reported neurological symptoms and some recent studies have suggested dominant negative effect of these mutations, a careful family study of heterozygotes was needed. We investigated all available members of the original large MIRAS family with W748S mutation. Neurological symptoms and signs were present in a number of carriers, but clearly defined neurological diseases did not segregate consistently with the mutation. Sensory polyneuropathy as a subclinical finding was observed in the majority of carriers examined. By positron emission tomography, cerebral glucose metabolism was moderately reduced in two out of four heterozygotes compared with severe reduction in one MIRAS patient. In conclusion, W748S heterozygotes showed no clinically manifesting phenotype.

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Regional Cerebral Glucose Metabolism in Monozygotic Twins Discordant for Alzheimer’s Disease

Cited by 25 publications

References 36 publications

Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer’s disease

Peripheral blood DNA methylation differences in twin pairs discordant for Alzheimer’s disease

Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals

Do carriers of POLG mutation W748S have disease manifestations?

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