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Article ; Online: Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.

Walsh, Darren J / Bernard, David J / Fiddler, Joanna L / Pangilinan, Faith / Esposito, Madison / Harold, Denise / Field, Martha S / Parle-McDermott, Anne / Brody, Lawrence C

PNAS nexus

2024 Volume 3, Issue 4, Page(s) pgae116

Abstract: One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the ... ...

Abstract	One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.
Language	English
Publishing date	2024-03-15
Publishing country	England
Document type	Journal Article
ISSN	2752-6542
ISSN (online)	2752-6542
DOI	10.1093/pnasnexus/pgae116
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Article ; Online: Mito-SiPE is a sequence-independent and PCR-free mtDNA enrichment method for accurate ultra-deep mitochondrial sequencing.

Walsh, Darren J / Bernard, David J / Pangilinan, Faith / Esposito, Madison / Harold, Denise / Parle-McDermott, Anne / Brody, Lawrence C

Communications biology

2022 Volume 5, Issue 1, Page(s) 1269

Abstract: The analysis of somatic variation in the mitochondrial genome requires deep sequencing of mitochondrial DNA. This is ordinarily achieved by selective enrichment methods, such as PCR amplification or probe hybridization. These methods can introduce bias ... ...

Abstract	The analysis of somatic variation in the mitochondrial genome requires deep sequencing of mitochondrial DNA. This is ordinarily achieved by selective enrichment methods, such as PCR amplification or probe hybridization. These methods can introduce bias and are prone to contamination by nuclear-mitochondrial sequences (NUMTs), elements that can introduce artefacts into heteroplasmy analysis. We isolated intact mitochondria using differential centrifugation and alkaline lysis and subjected purified mitochondrial DNA to a sequence-independent and PCR-free method to obtain ultra-deep (>80,000X) sequencing coverage of the mitochondrial genome. This methodology avoids false-heteroplasmy calls that occur when long-range PCR amplification is used for mitochondrial DNA enrichment. Previously published methods employing mitochondrial DNA purification did not measure mitochondrial DNA enrichment or utilise high coverage short-read sequencing. Here, we describe a protocol that yields mitochondrial DNA and have quantified the increased level of mitochondrial DNA post-enrichment in 7 different mouse tissues. This method will enable researchers to identify changes in low frequency heteroplasmy without introducing PCR biases or NUMT contamination that are incorrectly identified as heteroplasmy when long-range PCR is used.
MeSH term(s)	Animals ; Mice ; DNA, Mitochondrial/genetics ; Genome, Mitochondrial ; Mitochondria/genetics ; Polymerase Chain Reaction ; Sequence Analysis, DNA/methods
Chemical Substances	DNA, Mitochondrial
Language	English
Publishing date	2022-11-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-022-04182-2
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Article ; Online: The Differential Influence of Immune, Endocytotic, and Lipid Metabolism Genes on Amyloid Deposition and Neurodegeneration in Subjects at Risk of Alzheimer's Disease.

Femminella, Grazia Daniela / Harold, Denise / Scott, James / Williams, Julie / Edison, Paul

Journal of Alzheimer's disease : JAD

2020 Volume 79, Issue 1, Page(s) 127–139

Abstract: Background: Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer's disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) ...

Abstract	Background: Over 20 single-nucleotide polymorphisms (SNPs) are associated with increased risk of Alzheimer's disease (AD). We categorized these loci into immunity, lipid metabolism, and endocytosis pathways, and associated the polygenic risk scores (PRS) calculated, with AD biomarkers in mild cognitive impairment (MCI) subjects. Objective: The aim of this study was to identify associations between pathway-specific PRS and AD biomarkers in patients with MCI and healthy controls. Methods: AD biomarkers ([18F]Florbetapir-PET SUVR, FDG-PET SUVR, hippocampal volume, CSF tau and amyloid-β levels) and neurocognitive tests scores were obtained in 258 healthy controls and 451 MCI subjects from the ADNI dataset at baseline and at 24-month follow up. Pathway-related (immunity, lipid metabolism, and endocytosis) and total polygenic risk scores were calculated from 20 SNPs. Multiple linear regression analysis was used to test predictive value of the polygenic risk scores over longitudinal biomarker and cognitive changes. Results: Higher immune risk score was associated with worse cognitive measures and reduced glucose metabolism. Higher lipid risk score was associated with increased amyloid deposition and cortical hypometabolism. Total, immune, and lipid scores were associated with significant changes in cognitive measures, amyloid deposition, and brain metabolism. Conclusion: Polygenic risk scores highlights the influence of specific genes on amyloid-dependent and independent pathways; and these pathways could be differentially influenced by lipid and immune scores respectively.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Aniline Compounds ; Brain/diagnostic imaging ; Brain/metabolism ; Case-Control Studies ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/genetics ; Cognitive Dysfunction/metabolism ; Cognitive Dysfunction/pathology ; Endocytosis/genetics ; Ethylene Glycols ; Female ; Fluorodeoxyglucose F18 ; Humans ; Immunity/genetics ; Linear Models ; Lipid Metabolism/genetics ; Male ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide ; Positron-Emission Tomography ; Radiopharmaceuticals
Chemical Substances	Amyloid beta-Peptides ; Aniline Compounds ; Ethylene Glycols ; Radiopharmaceuticals ; Fluorodeoxyglucose F18 (0Z5B2CJX4D) ; florbetapir (6867Q6IKOD)
Language	English
Publishing date	2020-11-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-200578
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Article: Monitoring of emerging contaminants of concern in the aquatic environment: a review of studies showing the application of effect-based measures

Yusuf, Azeez / O'Flynn, Dylan / White, Blanaid / Holland, Linda / Parle-McDermott, Anne / Lawler, Jenny / McCloughlin, Thomas / Harold, Denise / Huerta, Belinda / Regan, Fiona

Analytical methods. 2021 Nov. 11, v. 13, no. 43

2021

Abstract: Water scarcity is increasingly a global cause of concern mainly due to widespread changes in climate conditions and increased consumptive water use driven by the exponential increase in population growth. In addition, increased pollution of fresh water ... ...

Abstract	Water scarcity is increasingly a global cause of concern mainly due to widespread changes in climate conditions and increased consumptive water use driven by the exponential increase in population growth. In addition, increased pollution of fresh water sources due to rising production and consumption of pharmaceuticals and organic chemicals will further exacerbate this concern. Although surface water contamination by individual chemicals is often at very low concentration, pharmaceuticals for instance are designed to be efficacious at low concentrations, creating genuine concern for their presence in freshwater sources. Furthermore, the additive impact of multiple compounds may result in toxic or other biological effects that otherwise will not be induced by individual chemicals. Globally, different legislative frameworks have led to pre-emptive efforts which aim to ensure good water ecological status. Reports detailing the use and types of effect-based measures covering specific bioassay batteries that can identify specific mode of actions of chemical pollutants in the aquatic ecosystem to evaluate the real threat of pollutants to aquatic lives and ultimately human lives have recently emerged from monitoring networks such as the NORMAN network. In this review, we critically evaluate some studies within the last decade that have implemented effect-based monitoring of pharmaceuticals and organic chemicals in aquatic fauna, evaluating the occurrence of different chemical pollutants and the impact of these pollutants on aquatic fauna with special focus on pollutants that are contaminants of emerging concern (CEC) in urban wastewater. A critical discussion on studies that have used effect-based measures to assess biological impact of pharmaceutical/organic compound in the aquatic ecosystem and the endpoints measurements employed is presented. The application of effect-based monitoring of chemicals other than assessment of water quality status is also discussed.
Keywords	aquatic ecosystems ; aquatic environment ; bioassays ; drugs ; fauna ; freshwater ; humans ; population growth ; surface water ; toxicity ; wastewater ; water pollution ; water quality ; water shortages
Language	English
Dates of publication	2021-1111
Size	p. 5120-5143.
Publishing place	The Royal Society of Chemistry
Document type	Article
ZDB-ID	2515210-5
ISSN	1759-9679 ; 1759-9660
ISSN (online)	1759-9679
ISSN	1759-9660
DOI	10.1039/d1ay01184g
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Article: A review of pharmaceutical occurrence and pathways in the aquatic environment in the context of a changing climate and the COVID-19 pandemic

O'Flynn, Dylan / Lawler, Jenny / Yusuf, Azeez / Parle-McDermott, Anne / Harold, Denise / Mc Cloughlin, Thomas / Holland, Linda / Regan, Fiona / White, Blánaid

Analytical methods. 2021 Feb. 11, v. 13, no. 5

2021

Abstract: Active pharmaceutical ingredients (APIs) are increasingly being identified as contaminants of emerging concern (CECs). They have potentially detrimental ecological and human health impacts but most are not currently subject to environmental regulation. ... ...

Abstract	Active pharmaceutical ingredients (APIs) are increasingly being identified as contaminants of emerging concern (CECs). They have potentially detrimental ecological and human health impacts but most are not currently subject to environmental regulation. Addressing the life cycle of these pharmaceuticals plays a significant role in identifying the potential sources and understanding the environmental impact that pharmaceuticals may have in surface waters. The stability and biological activity of these “micro-pollutants” can lead to a pseudo persistence, with ensuing unknown chronic behavioural and health-related effects. Research that investigates pharmaceuticals predominantly focuses on their occurrence and effect within surface water environments. However, this review will help to collate this information with factors that affect their environmental concentration. This review focuses on six pharmaceuticals (clarithromycin, ciprofloxacin, sulfamethoxazole, venlafaxine, gemfibrozil and diclofenac), chosen because they are heavily consumed globally, have poor removal rates in conventional activated sludge wastewater treatment plants (CAS WWTPs), and are persistent in the aquatic environment. Furthermore, these pharmaceuticals are included in numerous published prioritisation studies and/or are on the Water Framework Directive (WFD) “Watch List” or are candidates for the updated Watch List (WL). This review investigates the concentrations seen in European Union (EU) surface waters and examines factors that influence final concentrations prior to release, thus giving a holistic overview on the source of pharmaceutical surface water pollution. A period of 10 years is covered by this review, which includes research from 2009–2020 examining over 100 published studies, and highlighting that pharmaceuticals can pose a severe risk to surface water environments, with each stage of the lifecycle of the pharmaceutical determining its concentration. This review additionally highlights the necessity to improve education surrounding appropriate use, disposal and waste management of pharmaceuticals, while implementing a source directed and end of pipe approach to reduce pharmaceutical occurrence in surface waters.
Keywords	COVID-19 infection ; European Union ; activated sludge ; aquatic environment ; bioactive properties ; ciprofloxacin ; clarithromycin ; climate ; diclofenac ; education ; environmental impact ; environmental law ; gemfibrozil ; human health ; prioritization ; risk ; sulfamethoxazole ; surface water ; wastewater treatment ; water pollution
Language	English
Dates of publication	2021-0211
Size	p. 575-594.
Publishing place	The Royal Society of Chemistry
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2515210-5
ISSN	1759-9679 ; 1759-9660
ISSN (online)	1759-9679
ISSN	1759-9660
DOI	10.1039/d0ay02098b
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Article ; Online: Effects of complement gene-set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls.

Holland, Jessica F / Cosgrove, Donna / Whitton, Laura / Harold, Denise / Corvin, Aiden / Gill, Michael / Mothersill, David O / Morris, Derek W / Donohoe, Gary

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

2020 Volume 183, Issue 8, Page(s) 445–453

Abstract: Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. ...

Abstract	Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. Following on previous findings of association between both C4 and other complement-related variants and memory function, we tested the hypothesis that polygenic scores calculated based on identified schizophrenia risk alleles within the "complement" system would be broadly associated with memory function and associated brain structure. We tested this using a polygenic risk score (PRS) calculated for complement genes, but excluding C4 variants. Higher complement-based PRS scores were observed to be associated with lower memory scores for the sample as a whole (N = 620, F change = 8.25; p = .004). A significant association between higher PRS and lower hippocampal volume was also observed (N = 216, R
MeSH term(s)	Adult ; Brain/metabolism ; Brain/pathology ; Case-Control Studies ; Cerebral Cortex/metabolism ; Cerebral Cortex/pathology ; Complement C4/genetics ; Female ; Follow-Up Studies ; Genetic Markers ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Immunologic Factors/genetics ; Ireland/epidemiology ; Male ; Multifactorial Inheritance ; Polymorphism, Single Nucleotide ; Prognosis ; Psychotic Disorders/epidemiology ; Psychotic Disorders/genetics ; Psychotic Disorders/pathology ; Risk Factors
Chemical Substances	Complement C4 ; Genetic Markers ; Immunologic Factors
Language	English
Publishing date	2020-09-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2108616-3
ISSN	1552-485X ; 1552-4841 ; 0148-7299
ISSN (online)	1552-485X
ISSN	1552-4841 ; 0148-7299
DOI	10.1002/ajmg.b.32820
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Article ; Online: A review of pharmaceutical occurrence and pathways in the aquatic environment in the context of a changing climate and the COVID-19 pandemic.

O'Flynn, Dylan / Lawler, Jenny / Yusuf, Azeez / Parle-McDermott, Anne / Harold, Denise / Mc Cloughlin, Thomas / Holland, Linda / Regan, Fiona / White, Blánaid

Analytical methods : advancing methods and applications

2021 Volume 13, Issue 5, Page(s) 575–594

Abstract	Active pharmaceutical ingredients (APIs) are increasingly being identified as contaminants of emerging concern (CECs). They have potentially detrimental ecological and human health impacts but most are not currently subject to environmental regulation. Addressing the life cycle of these pharmaceuticals plays a significant role in identifying the potential sources and understanding the environmental impact that pharmaceuticals may have in surface waters. The stability and biological activity of these "micro-pollutants" can lead to a pseudo persistence, with ensuing unknown chronic behavioural and health-related effects. Research that investigates pharmaceuticals predominantly focuses on their occurrence and effect within surface water environments. However, this review will help to collate this information with factors that affect their environmental concentration. This review focuses on six pharmaceuticals (clarithromycin, ciprofloxacin, sulfamethoxazole, venlafaxine, gemfibrozil and diclofenac), chosen because they are heavily consumed globally, have poor removal rates in conventional activated sludge wastewater treatment plants (CAS WWTPs), and are persistent in the aquatic environment. Furthermore, these pharmaceuticals are included in numerous published prioritisation studies and/or are on the Water Framework Directive (WFD) "Watch List" or are candidates for the updated Watch List (WL). This review investigates the concentrations seen in European Union (EU) surface waters and examines factors that influence final concentrations prior to release, thus giving a holistic overview on the source of pharmaceutical surface water pollution. A period of 10 years is covered by this review, which includes research from 2009-2020 examining over 100 published studies, and highlighting that pharmaceuticals can pose a severe risk to surface water environments, with each stage of the lifecycle of the pharmaceutical determining its concentration. This review additionally highlights the necessity to improve education surrounding appropriate use, disposal and waste management of pharmaceuticals, while implementing a source directed and end of pipe approach to reduce pharmaceutical occurrence in surface waters.
MeSH term(s)	Animals ; Aquatic Organisms/drug effects ; COVID-19/epidemiology ; Climate Change ; Drug Industry ; Ecotoxicology ; European Union ; Humans ; Pandemics ; Persistent Organic Pollutants/isolation & purification ; Persistent Organic Pollutants/metabolism ; Persistent Organic Pollutants/pharmacology ; Pharmaceutical Preparations/isolation & purification ; Pharmaceutical Preparations/metabolism ; Plants/drug effects ; SARS-CoV-2 ; Water Pollutants, Chemical/isolation & purification ; Water Pollutants, Chemical/metabolism ; Water Pollutants, Chemical/pharmacology ; Water Purification
Chemical Substances	Pharmaceutical Preparations ; Water Pollutants, Chemical
Language	English
Publishing date	2021-01-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2515210-5
ISSN	1759-9679 ; 1759-9660
ISSN (online)	1759-9679
ISSN	1759-9660
DOI	10.1039/d0ay02098b
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Article ; Online: Monitoring of emerging contaminants of concern in the aquatic environment: a review of studies showing the application of effect-based measures.

Yusuf, Azeez / O'Flynn, Dylan / White, Blanaid / Holland, Linda / Parle-McDermott, Anne / Lawler, Jenny / McCloughlin, Thomas / Harold, Denise / Huerta, Belinda / Regan, Fiona

Analytical methods : advancing methods and applications

2021 Volume 13, Issue 43, Page(s) 5120–5143

Abstract	Water scarcity is increasingly a global cause of concern mainly due to widespread changes in climate conditions and increased consumptive water use driven by the exponential increase in population growth. In addition, increased pollution of fresh water sources due to rising production and consumption of pharmaceuticals and organic chemicals will further exacerbate this concern. Although surface water contamination by individual chemicals is often at very low concentration, pharmaceuticals for instance are designed to be efficacious at low concentrations, creating genuine concern for their presence in freshwater sources. Furthermore, the additive impact of multiple compounds may result in toxic or other biological effects that otherwise will not be induced by individual chemicals. Globally, different legislative frameworks have led to pre-emptive efforts which aim to ensure good water ecological status. Reports detailing the use and types of effect-based measures covering specific bioassay batteries that can identify specific mode of actions of chemical pollutants in the aquatic ecosystem to evaluate the real threat of pollutants to aquatic lives and ultimately human lives have recently emerged from monitoring networks such as the NORMAN network. In this review, we critically evaluate some studies within the last decade that have implemented effect-based monitoring of pharmaceuticals and organic chemicals in aquatic fauna, evaluating the occurrence of different chemical pollutants and the impact of these pollutants on aquatic fauna with special focus on pollutants that are contaminants of emerging concern (CEC) in urban wastewater. A critical discussion on studies that have used effect-based measures to assess biological impact of pharmaceutical/organic compound in the aquatic ecosystem and the endpoints measurements employed is presented. The application of effect-based monitoring of chemicals other than assessment of water quality status is also discussed.
MeSH term(s)	Ecosystem ; Fresh Water/chemistry ; Humans ; Organic Chemicals ; Water Pollutants, Chemical/analysis ; Water Quality
Chemical Substances	Organic Chemicals ; Water Pollutants, Chemical
Language	English
Publishing date	2021-11-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2515210-5
ISSN	1759-9679 ; 1759-9660
ISSN (online)	1759-9679
ISSN	1759-9660
DOI	10.1039/d1ay01184g
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Article ; Online: Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls.

Holland, Jessica F / Cosgrove, Donna / Whitton, Laura / Harold, Denise / Corvin, Aiden / Gill, Michael / Mothersill, David O / Morris, Derek W / Donohoe, Gary

Genes, brain, and behavior

2019 Volume 18, Issue 8, Page(s) e12602

Abstract: Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune-relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was ... ...

Abstract	Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune-relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene-set with an identified role in "complement" function (excluding C4A), we used MAGMA to test if this gene-set was enriched for genes associated with human intelligence and SZ risk, using genome-wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene-set analysis with a complement gene-set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene-based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome-wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.
MeSH term(s)	Adult ; Cognition ; Complement C1 Inhibitor Protein/genetics ; Female ; Genome-Wide Association Study ; Humans ; Intelligence/genetics ; Male ; Middle Aged ; Polymorphism, Genetic ; Psychotic Disorders/genetics
Chemical Substances	Complement C1 Inhibitor Protein ; SERPING1 protein, human
Language	English
Publishing date	2019-08-30
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2075819-4
ISSN	1601-183X ; 1601-1848
ISSN (online)	1601-183X
ISSN	1601-1848
DOI	10.1111/gbb.12602
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Article ; Online: Can Studies of Neuroinflammation in a TSPO Genetic Subgroup (HAB or MAB) Be Applied to the Entire AD Cohort?

Fan, Zhen / Harold, Denise / Pasqualetti, Giuseppe / Williams, Julie / Brooks, David J / Edison, Paul

Journal of nuclear medicine : official publication, Society of Nuclear Medicine

2015 Volume 56, Issue 5, Page(s) 707–713

Abstract: Unlabelled: Neuroinflammation plays a significant role in Alzheimer disease (AD), and translocator protein (TSPO) PET imaging allows us to quantify this process. However, the binding of second-generation TSPO tracers depends on the TSPO genotype coded ... ...

Abstract	Unlabelled: Neuroinflammation plays a significant role in Alzheimer disease (AD), and translocator protein (TSPO) PET imaging allows us to quantify this process. However, the binding of second-generation TSPO tracers depends on the TSPO genotype coded by the rs6971 single-nucleotide polymorphism, with a 40%-50% increase in BP in high-affinity binders (HABs) compared with mixed-affinity binders (MABs), whereas low-affinity binders (LABs) are unsuitable for evaluation. Hence, several studies are using either HAB alone or HAB and MAB subjects. To translate the findings of neuroinflammation studies to the entire population, it is crucial to establish the influence of TSPO genotypes on AD. Here, we investigated whether different TSPO genotypes influence cognitive function, amyloid load, and disease progression over time. Methods: We evaluated 798 subjects (225 control, 388 with mild cognitive impairment [MCI], and 185 with AD) from the Alzheimer's Disease Neuroimaging Initiative database at baseline and during follow-up. All subjects were screened for TSPO genotype and underwent detailed clinical and neuropsychologic assessments yearly for 4 y. Of the 798 subjects, 255 also had T1- and T2-weighted MR imaging and amyloid PET with (11)C-Pittsburgh compound B or (18)F-florbetapir. Results: We demonstrated that all TSPO binding groups (HAB, MAB, and LAB) have same level of amyloid load in AD and MCI subjects. We also demonstrated that the prevalence is 50.3% for HAB, 41.2% for MAB, and 8.5% for LAB, without a statistical difference among the AD, MCI, and control groups. During longitudinal follow-up, the mean change in neuropsychometric test scores on the Mini-Mental State Examination, the cognitive and modified Alzheimer Disease Assessment Scales (ADASs), and the Geriatric Depression Scale over time were similar in AD and MCI subjects among the 3 TSPO binding groups. Analysis of the covariates showed that diagnostic group (control, MCI, AD), apolipoprotein E4 status, and sex had a significant effect on decline on the modified Alzheimer Disease Assessment Scale (>3 points of the scale), but age and TSPO genotype did not. Conclusion: This study suggests that information obtained from evaluating a subgroup of AD or MCI subject using second-generation TSPO tracers can be translated to the entire AD and MCI population. Thus, we can study fewer AD subjects in evaluating new antineuroinflammatory and antimicroglial agents in intervention studies and in observational studies evaluating the role of neuroinflammation.
MeSH term(s)	Aged ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/genetics ; Cognitive Dysfunction/metabolism ; Cohort Studies ; Female ; Genotype ; Humans ; Inflammation/diagnostic imaging ; Inflammation/genetics ; Inflammation/metabolism ; Longitudinal Studies ; Male ; Polymorphism, Single Nucleotide ; Positron-Emission Tomography ; Protein Binding ; Receptors, GABA/genetics ; Receptors, GABA/metabolism
Chemical Substances	Receptors, GABA ; TSPO protein, human
Language	English
Publishing date	2015-04-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80272-4
ISSN	1535-5667 ; 0097-9058 ; 0161-5505 ; 0022-3123
ISSN (online)	1535-5667
ISSN	0097-9058 ; 0161-5505 ; 0022-3123
DOI	10.2967/jnumed.114.149443
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