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Article ; Online: The C677T variant in MTHFR modulates associations between blood-based and cerebrospinal fluid biomarkers of neurodegeneration.

Roussotte, Florence F / Narr, Katherine L / Small, Gary W / Thompson, Paul M

2016 Volume 27, Issue 12, Page(s) 948–951

Abstract: The C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene results in reduced enzymatic activity and elevated blood levels of homocysteine. Plasma levels of apolipoprotein E (ApoE) are negatively correlated with cerebral ... ...

Abstract	The C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene results in reduced enzymatic activity and elevated blood levels of homocysteine. Plasma levels of apolipoprotein E (ApoE) are negatively correlated with cerebral amyloid burden, but plasma homocysteine concentrations are associated with increased amyloid-β (Aβ) deposition in the brain. Here, we sought to determine whether associations between low plasma ApoE levels and elevated in-vivo amyloid burden were modulated by carrying the C677T variant. We tested this hypothesis in a large sample of elderly participants from the Alzheimer's Disease Neuroimaging Initiative. We used general linear models to examine associations between plasma homocysteine concentrations, circulating ApoE levels, cerebrospinal fluid concentrations of Aβ, and their modulation by MTHFR and ApoE genotype. Age, sex, and dementia status were included as covariates in all analyses. Higher circulating levels of ApoE predicted increased cerebrospinal fluid concentrations of Aβ, indicating lower in-vivo burden, in C-allele carriers, but not in homozygotes at the C677T variant, who showed significant elevations in plasma homocysteine levels. This modulation by the MTHFR genotype did not remain significant after controlling for ApoE genotype. In T-homozygotes who do not carry the ApoE-ε4 allele, the relationship between low plasma ApoE levels and an increased risk of dementia is likely obscured by the presence of elevated plasma homocysteine. This report suggests the value of genotyping patients at the C677T functional variant when using plasma ApoE levels as a preclinical biomarker for Alzheimer's disease.
Language	English
Publishing date	2016-08-17
Publishing country	England
Document type	Journal Article
ZDB-ID	1049746-8
ISSN	1473-558X ; 0959-4965
ISSN (online)	1473-558X
ISSN	0959-4965
DOI	10.1097/WNR.0000000000000636
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Article: The C677T variant in

Roussotte, Florence F / Hua, Xue / Narr, Katherine L / Small, Gary W / Thompson, Paul M

Biological psychiatry. Cognitive neuroscience and neuroimaging

2017 Volume 2, Issue 3, Page(s) 280–288

Abstract: Introduction: The C677T functional variant in the methylene-tetrahydrofolate reductase (: Methods and materials: Here, 3D magnetic resonance imaging data was analyzed from 738 individuals (age: 75.5 ± 6.8 years; 438 men/300 women) including 173 ... ...

Abstract	Introduction: The C677T functional variant in the methylene-tetrahydrofolate reductase ( Methods and materials: Here, 3D magnetic resonance imaging data was analyzed from 738 individuals (age: 75.5 ± 6.8 years; 438 men/300 women) including 173 Alzheimer's patients, 359 subjects with mild cognitive impairment, and 206 healthy older adults, scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: We found that this variant associates with localized brain atrophy, after controlling for age, sex, and dementia status, in brain regions implicated in both intellectual and emotional functioning, notably the medial orbitofrontal cortices. The medial orbitofrontal cortex is involved in the cognitive modulation of emotional processes, and localized atrophy in this region was previously linked with both cognitive impairment and depressive symptoms. Here, we report that increased plasma homocysteine mediates the association between Conclusion: This study sheds light on important relationships between vascular risk factors, age-related cognitive decline, and late-life depression, and represents a significant advance in our understanding of clinically relevant associations relating to
Language	English
Publishing date	2017-01-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	2879089-3
ISSN	2451-9030 ; 2451-9022
ISSN (online)	2451-9030
ISSN	2451-9022
DOI	10.1016/j.bpsc.2016.09.005
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Article ; Online: Focus on: structural and functional brain abnormalities in fetal alcohol spectrum disorders.

Nunez, C Christopher / Roussotte, Florence / Sowell, Elizabeth R

Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism

2013 Volume 34, Issue 1, Page(s) 121–131

Abstract: Children exposed to alcohol prenatally can experience significant deficits in cognitive and psychosocial functioning as well as alterations in brain structure and function related to alcohol's teratogenic effects. These impairments are present both in ... ...

Abstract	Children exposed to alcohol prenatally can experience significant deficits in cognitive and psychosocial functioning as well as alterations in brain structure and function related to alcohol's teratogenic effects. These impairments are present both in children with fetal alcohol syndrome (FAS) and in children with heavy in utero alcohol exposure who do not have facial dysmorphology required for the FAS diagnosis. Neuropsychological and behavioral studies have revealed deficits in most cognitive domains measured, including overall intellectual functioning, attention/working memory, executive skills, speed of processing, and academic skills in children and adolescents across the range of fetal alcohol spectrum disorders (FASD). As with neuro-psychological studies, brain-imaging studies have detected differences in brain structure related to alcohol exposure in multiple brain systems and abnormalities in the white matter that connects these brain regions. Several studies have found relationships between these morphological differences and cognitive function, suggesting some clinical significance to the structural brain abnormalities. Concentrations of neurotransmitter metabolites within the brains of prenatally exposed children also appear to be altered, and functional imaging studies have identified significant differences in brain activation related to working memory, learning, and inhibitory control in children and adolescents with FASD.
MeSH term(s)	Alcohol Drinking/adverse effects ; Alcohol Drinking/epidemiology ; Animals ; Brain/drug effects ; Brain/pathology ; Brain/physiology ; Cognition Disorders/diagnosis ; Cognition Disorders/epidemiology ; Cognition Disorders/physiopathology ; Female ; Fetal Alcohol Spectrum Disorders/diagnosis ; Fetal Alcohol Spectrum Disorders/epidemiology ; Fetal Alcohol Spectrum Disorders/physiopathology ; Humans ; Pregnancy
Language	English
Publishing date	2013-04-12
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1498691-7
ISSN	1930-0573 ; 1535-7414 ; 0090-838X
ISSN (online)	1930-0573
ISSN	1535-7414 ; 0090-838X
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Article ; Online: The C677T Variant in MTHFR Modulates Associations Between Brain Integrity, Mood, and Cognitive Functioning in Old Age

Roussotte, Florence F. / Hua, Xue / Narr, Katherine L. / Small, Gary / Thompson, Paul M.

Society of Biological Psychiatry Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. 2016,

2016

Abstract: The C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene leads to reduced enzymatic activity and elevated blood homocysteine levels. Hyperhomocysteinemia has been linked with higher rates of cardiovascular diseases, cognitive ...

Abstract	The C677T functional variant in the methylene-tetrahydrofolate reductase (MTHFR) gene leads to reduced enzymatic activity and elevated blood homocysteine levels. Hyperhomocysteinemia has been linked with higher rates of cardiovascular diseases, cognitive decline, and late-life depression.Three-dimensional magnetic resonance imaging data were analyzed from 738 individuals (aged 75.5 ± 6.8 years; 438 men, 300 women), including 173 patients with Alzheimer's disease, 359 subjects with mild cognitive impairment, and 206 healthy older adults, scanned as part of the Alzheimer's Disease Neuroimaging Initiative.We found that this variant associates with localized brain atrophy, after controlling for age, sex, and dementia status, in brain regions implicated in both intellectual and emotional functioning, notably the medial orbitofrontal cortices. The medial orbitofrontal cortex is involved in the cognitive modulation of emotional processes, and localized atrophy in this region was previously linked with both cognitive impairment and depressive symptoms. Here, we report that increased plasma homocysteine level mediates the association between MTHFR genotype and lower medial orbitofrontal volumes and that these volumes mediate the association between cognitive decline and depressed mood in this elderly cohort. We additionally show that vitamin B12 deficiency interacts with the C677T variant in the cause of hyperhomocysteinemia.This study sheds light on important relationships between vascular risk factors, age-related cognitive decline, and late-life depression and represents a significant advance in our understanding of clinically relevant associations relating to MTHFR genotype.
Keywords	Age-related cognitive decline ; Brain atrophy ; Homocysteine ; Late-life depression ; MRI ; MTHFR
Language	English
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	2879089-3
ISSN	2451-9030 ; 2451-9022
ISSN (online)	2451-9030
ISSN	2451-9022
DOI	10.1016/j.bpsc.2016.09.005
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Article ; Online: Altered regional brain volumes in elderly carriers of a risk variant for drug abuse in the dopamine D2 receptor gene (DRD2).

Roussotte, Florence F / Jahanshad, Neda / Hibar, Derrek P / Thompson, Paul M

Brain imaging and behavior

2014 Volume 9, Issue 2, Page(s) 213–222

Abstract: Dopamine D2 receptors mediate the rewarding effects of many drugs of abuse. In humans, several polymorphisms in DRD2, the gene encoding these receptors, increase our genetic risk for developing addictive disorders. Here, we examined one of the most ... ...

Abstract	Dopamine D2 receptors mediate the rewarding effects of many drugs of abuse. In humans, several polymorphisms in DRD2, the gene encoding these receptors, increase our genetic risk for developing addictive disorders. Here, we examined one of the most frequently studied candidate variant for addiction in DRD2 for association with brain structure. We tested whether this variant showed associations with regional brain volumes across two independent elderly cohorts, totaling 1,032 subjects. We first examined a large sample of 738 elderly participants with neuroimaging and genetic data from the Alzheimer's Disease Neuroimaging Initiative (ADNI1). We hypothesized that this addiction-related polymorphism would be associated with structural brain differences in regions previously implicated in familial vulnerability for drug dependence. Then, we assessed the generalizability of our findings by testing this polymorphism in a non-overlapping replication sample of 294 elderly subjects from a continuation of the first ADNI project (ADNI2) to minimize the risk of reporting false positive results. In both cohorts, the minor allele-previously linked with increased risk for addiction-was associated with larger volumes in various brain regions implicated in reward processing. These findings suggest that neuroanatomical phenotypes associated with familial vulnerability for drug dependence may be partially mediated by DRD2 genotype.
MeSH term(s)	Aged ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Brain/pathology ; Cognitive Dysfunction/genetics ; Cognitive Dysfunction/pathology ; Cohort Studies ; Databases, Factual ; Disease Progression ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Heterozygote ; Humans ; Imaging, Three-Dimensional ; Magnetic Resonance Imaging ; Male ; Organ Size/genetics ; Polymorphism, Single Nucleotide ; Receptors, Dopamine D2/genetics ; Substance-Related Disorders/genetics
Chemical Substances	DRD2 protein, human ; Receptors, Dopamine D2
Language	English
Publishing date	2014-03-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2377165-3
ISSN	1931-7565 ; 1931-7557
ISSN (online)	1931-7565
ISSN	1931-7557
DOI	10.1007/s11682-014-9298-8
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Article ; Online: Imaging the impact of prenatal alcohol exposure on the structure of the developing human brain.

Lebel, Catherine / Roussotte, Florence / Sowell, Elizabeth R

Neuropsychology review

2011 Volume 21, Issue 2, Page(s) 102–118

Abstract: Prenatal alcohol exposure has numerous effects on the developing brain, including damage to selective brain structure. We review structural magnetic resonance imaging (MRI) studies of brain abnormalities in subjects prenatally exposed to alcohol. The ... ...

Abstract	Prenatal alcohol exposure has numerous effects on the developing brain, including damage to selective brain structure. We review structural magnetic resonance imaging (MRI) studies of brain abnormalities in subjects prenatally exposed to alcohol. The most common findings include reduced brain volume and malformations of the corpus callosum. Advanced methods have been able to detect shape, thickness and displacement changes throughout multiple brain regions. The teratogenic effects of alcohol appear to be widespread, affecting almost the entire brain. The only region that appears to be relatively spared is the occipital lobe. More recent studies have linked cognition to the underlying brain structure in alcohol-exposed subjects, and several report patterns in the severity of brain damage as it relates to facial dysmorphology or to extent of alcohol exposure. Future studies exploring relationships between brain structure, cognitive measures, dysmorphology, age, and other variables will be valuable for further comprehending the vast effects of prenatal alcohol exposure and for evaluating possible interventions.
MeSH term(s)	Alcohols/adverse effects ; Behavioral Symptoms/etiology ; Behavioral Symptoms/pathology ; Brain/growth & development ; Brain/pathology ; Brain Mapping ; Developmental Disabilities/complications ; Developmental Disabilities/etiology ; Developmental Disabilities/pathology ; Facial Asymmetry ; Female ; Fetal Alcohol Spectrum Disorders/pathology ; Humans ; Magnetic Resonance Imaging ; Male ; Pregnancy ; Prenatal Exposure Delayed Effects/physiopathology
Chemical Substances	Alcohols
Language	English
Publishing date	2011-03-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1062572-0
ISSN	1573-6660 ; 1040-7308
ISSN (online)	1573-6660
ISSN	1040-7308
DOI	10.1007/s11065-011-9163-0
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Article ; Online: Structural, metabolic, and functional brain abnormalities as a result of prenatal exposure to drugs of abuse: evidence from neuroimaging.

Roussotte, Florence / Soderberg, Lindsay / Sowell, Elizabeth

Neuropsychology review

2010 Volume 20, Issue 4, Page(s) 376–397

Abstract: Prenatal exposure to alcohol and stimulants negatively affects the developing trajectory of the central nervous system in many ways. Recent advances in neuroimaging methods have allowed researchers to study the structural, metabolic, and functional ... ...

Abstract	Prenatal exposure to alcohol and stimulants negatively affects the developing trajectory of the central nervous system in many ways. Recent advances in neuroimaging methods have allowed researchers to study the structural, metabolic, and functional abnormalities resulting from prenatal exposure to drugs of abuse in living human subjects. Here we review the neuroimaging literature of prenatal exposure to alcohol, cocaine, and methamphetamine. Neuroimaging studies of prenatal alcohol exposure have reported differences in the structure and metabolism of many brain systems, including in frontal, parietal, and temporal regions, in the cerebellum and basal ganglia, as well as in the white matter tracts that connect these brain regions. Functional imaging studies have identified significant differences in brain activation related to various cognitive domains as a result of prenatal alcohol exposure. The published literature of prenatal exposure to cocaine and methamphetamine is much smaller, but evidence is beginning to emerge suggesting that exposure to stimulant drugs in utero may be particularly toxic to dopamine-rich basal ganglia regions. Although the interpretation of such findings is somewhat limited by the problem of polysubstance abuse and by the difficulty of obtaining precise exposure histories in retrospective studies, such investigations provide important insights into the effects of drugs of abuse on the structure, function, and metabolism of the developing human brain. These insights may ultimately help clinicians develop better diagnostic tools and devise appropriate therapeutic interventions to improve the condition of children with prenatal exposure to drugs of abuse.
MeSH term(s)	Brain/abnormalities ; Brain/metabolism ; Brain/pathology ; Brain Mapping ; Diagnostic Imaging/classification ; Female ; Functional Laterality ; Humans ; Pregnancy ; Prenatal Exposure Delayed Effects/etiology ; Prenatal Exposure Delayed Effects/metabolism ; Prenatal Exposure Delayed Effects/pathology ; Substance-Related Disorders/complications
Language	English
Publishing date	2010-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1062572-0
ISSN	1573-6660 ; 1040-7308
ISSN (online)	1573-6660
ISSN	1040-7308
DOI	10.1007/s11065-010-9150-x
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Article ; Online: Combined effects of Alzheimer risk variants in the CLU and ApoE genes on ventricular expansion patterns in the elderly.

Roussotte, Florence F / Gutman, Boris A / Madsen, Sarah K / Colby, John B / Thompson, Paul M

The Journal of neuroscience : the official journal of the Society for Neuroscience

2014 Volume 34, Issue 19, Page(s) 6537–6545

Abstract: The C allele at the rs11136000 locus in the clusterin (CLU) gene is the third strongest known genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent genome-wide association study of LOAD found the strongest evidence of association with ... ...

Abstract	The C allele at the rs11136000 locus in the clusterin (CLU) gene is the third strongest known genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent genome-wide association study of LOAD found the strongest evidence of association with CLU at rs1532278, in high linkage disequilibrium with rs11136000. Brain structure and function are related to the CLU risk alleles, not just in LOAD patients but also in healthy young adults. We tracked the volume of the lateral ventricles across baseline, 1-year, and 2-year follow-up scans in a large sample of elderly human participants (N = 736 at baseline), from the Alzheimer's Disease Neuroimaging Initiative, to determine whether these CLU risk variants predicted longitudinal ventricular expansion. The rs11136000 major C allele-previously linked with reduced CLU expression and with increased risk for dementia-predicted faster expansion, independently of dementia status or ApoE genotype. Further analyses revealed that the CLU and ApoE risk variants had combined effects on both volumetric expansion and lateral ventricle surface morphology. The rs1532278 locus strongly resembles a regulatory element. Its association with ventricular expansion was slightly stronger than that of rs11136000 in our analyses, suggesting that it may be closer to a functional variant. Clusterin affects inflammation, immune responses, and amyloid clearance, which in turn may result in neurodegeneration. Pharmaceutical agents such as valproate, which counteract the effects of genetically determined reduced clusterin expression, may help to achieve neuroprotection and contribute to the prevention of dementia, especially in carriers of these CLU risk variants.
MeSH term(s)	Aged ; Aging/physiology ; Alleles ; Alzheimer Disease/genetics ; Apolipoproteins E/genetics ; Brain Mapping ; Clusterin/genetics ; DNA/genetics ; Female ; Genome-Wide Association Study ; Genotype ; Humans ; Image Processing, Computer-Assisted ; Lateral Ventricles/physiology ; Magnetic Resonance Imaging ; Male ; Real-Time Polymerase Chain Reaction ; Regression Analysis ; Risk
Chemical Substances	Apolipoproteins E ; Clusterin ; DNA (9007-49-2)
Language	English
Publishing date	2014-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.5236-13.2014
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Article ; Online: Neuroimaging and genetic risk for Alzheimer's disease and addiction-related degenerative brain disorders.

Roussotte, Florence F / Daianu, Madelaine / Jahanshad, Neda / Leonardo, Cassandra D / Thompson, Paul M

Brain imaging and behavior

2013 Volume 8, Issue 2, Page(s) 217–233

Abstract: Neuroimaging offers a powerful means to assess the trajectory of brain degeneration in a variety of disorders, including Alzheimer's disease (AD). Here we describe how multi-modal imaging can be used to study the changing brain during the different ... ...

Abstract	Neuroimaging offers a powerful means to assess the trajectory of brain degeneration in a variety of disorders, including Alzheimer's disease (AD). Here we describe how multi-modal imaging can be used to study the changing brain during the different stages of AD. We integrate findings from a range of studies using magnetic resonance imaging (MRI), positron emission tomography (PET), functional MRI (fMRI) and diffusion weighted imaging (DWI). Neuroimaging reveals how risk genes for degenerative disorders affect the brain, including several recently discovered genetic variants that may disrupt brain connectivity. We review some recent neuroimaging studies of genetic polymorphisms associated with increased risk for late-onset Alzheimer's disease (LOAD). Some genetic variants that increase risk for drug addiction may overlap with those associated with degenerative brain disorders. These common associations offer new insight into mechanisms underlying neurodegeneration and addictive behaviors, and may offer new leads for treating them before severe and irreversible neurological symptoms appear.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Alzheimer Disease/physiopathology ; Brain/pathology ; Brain/physiopathology ; Genetic Predisposition to Disease ; Humans ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/pathology ; Neurodegenerative Diseases/physiopathology ; Neuroimaging ; Substance-Related Disorders/genetics ; Substance-Related Disorders/pathology ; Substance-Related Disorders/physiopathology
Language	English
Publishing date	2013-10-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2377165-3
ISSN	1931-7565 ; 1931-7557
ISSN (online)	1931-7565
ISSN	1931-7557
DOI	10.1007/s11682-013-9263-y
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Article ; Online: In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults.

Roussotte, Florence F / Siddarth, Prabha / Merrill, David A / Narr, Katherine L / Ercoli, Linda M / Martinez, Jacqueline / Emerson, Natacha D / Barrio, Jorge R / Small, Gary W

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry

2017 Volume 26, Issue 1, Page(s) 13–22

Abstract: Objective: Growing evidence supports an association between increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to ...

Abstract	Objective: Growing evidence supports an association between increased blood pressure and: (a) poor cognitive performance in older adults, and (b) various biomarkers of increased Alzheimer's disease (AD) neuropathology. The objective of this study was to determine whether systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly associated with cognitive functioning in non-demented adults, and to examine in vivo AD pathology as a possible mediator of this association. Methods: Positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP) provide in vivo measurements of plaque and tangle burden. A total of 101 non-demented older subjects with blood pressure data and FDDNP-PET scans were drawn from a larger study of predictors of cognitive decline. A neuropsychological test battery was used to compute "global cognitive scores" (averaged across five key domains), which served as an index of general cognitive functioning. Results: Higher DBP (but not SBP) was significantly associated with lower cognitive scores, controlling for age, sex, antihypertensive medication use, and ApoE genotype (η Conclusions: By suggesting a mediation of the relationship between DBP and cognitive functioning by FDDNP-PET binding, this study advances our understanding of some potential predictors of cognitive decline in non-demented adults, and underscores the importance of devising early multimodal interventions to more effectively combat degenerative brain disorders.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Blood Pressure/physiology ; Cognitive Dysfunction/diagnosis ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/physiopathology ; Female ; Humans ; Hypertension/physiopathology ; Male ; Middle Aged ; Neurofibrillary Tangles/metabolism ; Nitriles ; Plaque, Amyloid/diagnostic imaging ; Positron-Emission Tomography/methods
Chemical Substances	2-(1-(6-((2-fluoroethyl)(methyl)amino)-2-naphthyl)ethylidene)malononitrile ; Nitriles
Language	English
Publishing date	2017-09-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1278145-9
ISSN	1545-7214 ; 1064-7481
ISSN (online)	1545-7214
ISSN	1064-7481
DOI	10.1016/j.jagp.2017.09.001
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