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

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-? (A?) 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 A?, 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 A?, 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-?4 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.

SUBMITTER: Roussotte FF

PROVIDER: S-EPMC4937804 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Roussotte Florence F FF Narr Katherine L KL Small Gary W GW Thompson Paul M PM

Neuroreport 20160801 12

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 modul ...[more]

PMID: 27380243

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Project description:BackgroundLongitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.ObjectiveTo examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.MethodsL-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.ResultsAll biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.ConclusionLongitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

Project description:BackgroundDementia with Lewy bodies (DLB) is more prevalent in men than in women. In addition, post-mortem studies found sex differences in underlying pathology. It remains unclear whether these differences are also present antemortem in in vivo biomarkers, and whether sex differences translate to variability in clinical manifestation. The objective of this study was to evaluate sex differences in cerebrospinal fluid (CSF) biomarker concentrations (i.e., alpha-synuclein (α-syn), amyloid β1-42 (Aβ42), total tau (Tau), phosphorylated tau at threonine 181 (pTau)) and clinical characteristics in DLB.MethodsWe included 223 DLB patients from the Amsterdam Dementia Cohort, of which 39 were women (17%, age 70 ± 6, MMSE 21 ± 6) and 184 men (83%, age 68 ± 7, MMSE 23 ± 4). Sex differences in CSF biomarker concentrations (i.e., α-syn, Aβ42, Tau, and pTau) were evaluated using age-corrected general linear models (GLM). In addition, we analyzed sex differences in core clinical features (i.e., visual hallucinations, parkinsonism, cognitive fluctuations, and REM sleep behavior disorder (RBD) and cognitive test scores using age- and education-adjusted GLM.ResultsWomen had lower CSF α-syn levels (F 1429 ± 164 vs M 1831 ± 60, p = 0.02) and CSF Aβ42 levels (F 712 ± 39 vs M 821 ± 18, p = 0.01) compared to men. There were no sex differences for (p) Tau concentrations (p > 0.05). Clinically, women were older, had a shorter duration of complaints (F 2 ± 1 vs M 4 ± 3, p < 0.001), more frequent hallucinations (58% vs 38%, p = 0.02), and scored lower on MMSE and a fluency task (MMSE, p = 0.02; animal fluency, p = 0.006). Men and women did not differ on fluctuations, RBD, parkinsonism, or other cognitive tests.ConclusionsWomen had lower Aβ42 and α-syn levels than men, alongside a shorter duration of complaints. Moreover, at the time of diagnosis, women had lower cognitive test scores and more frequent hallucinations. Based on our findings, one could hypothesize that women have a more aggressive disease course in DLB compared to men. Future research should investigate whether women and men with DLB might benefit from sex-specific treatment strategies.

Dataset Information

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

Publications

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

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