Do glia provide the link between low-grade systemic inflammation and normal cognitive ageing? A 1 H magnetic resonance spectroscopy study at 7 tesla.

Low-grade systemic inflammation contributes to ageing-related cognitive decline, possibly by triggering a neuroinflammatory response through glial activation. Using proton magnetic resonance spectroscopy (1 H-MRS) at 7T in normal human individuals from 18 to 79 years in a cross-sectional study, we previously observed higher regional levels of myo-inositol (mIns), total creatine (tCr) and total choline (tCho) in older than younger age groups. Moreover, visuo-spatial working memory (vsWM) correlated negatively with tCr and tCho in anterior cingulate cortex (ACC) and mIns in hippocampus and thalamus. As mIns, tCr and tCho are higher in glia than neurons, this suggest a potential in vivo connection between cognitive ageing and higher regional levels of glia-related metabolites. In the present study, we tested whether these metabolic differences may be related to low-grade systemic inflammation. In the same individuals, plasma concentrations of the proinflammatory markers C-reactive protein (CRP), interleukin 8 (IL-8), and tumour necrosis factor α (TNF-α) were measured on the same day as 1 H-MRS assessments. We tested whether CRP, IL-8, and TNF-α concentrations correlated with the levels of glia-related metabolites. CRP and IL-8, but not TNF-α, were higher in older (69-79 years) than younger (18-26 years) individuals. CRP correlated positively with thalamic mIns and negatively with vsWM. IL-8 correlated positively with ACC tCho and hippocampal mIns, but not with vsWM. Mediation analysis revealed an indirect effect of IL-8 on vsWM via ACC tCho. Together, these findings corroborate the role of glial cells, perhaps via their role in neuroinflammation, as part of the neurobiological link between systemic inflammation and cognitive ageing.

Regional Myo-Inositol, Creatine, and Choline Levels Are Higher at Older Age and Scale Negatively with Visuospatial Working Memory: A Cross-Sectional Proton MR Spectroscopy Study at 7 Tesla on Normal Cognitive Ageing.

Proton MR spectroscopy (1H-MRS) has been used to assess regional neurochemical brain changes during normal ageing, but results have varied. Exploiting the increased sensitivity at ultra-high field, we performed 1H-MRS in 60 healthy human volunteers to asses age-related differences in metabolite levels and their relation to cognitive ageing. Sex was balanced, and participants were assigned to a younger, middle, and older group according to their age, ranging from 18 to 79 years. They underwent 7T 1H-MRS of the ACC, DLPFC, hippocampus, and thalamus and performed a visuospatial working memory task outside the scanner. A multivariate ANCOVA revealed a significant overall effect of age group on metabolite levels in all regions. Higher levels in the middle than the younger group were observed for myo-inositol (mIns) in DLPFC and hippocampus and total choline (tCho) in ACC. Higher levels in the older than the younger group were observed for mIns in hippocampus and thalamus, total creatine (tCr) and tCho in ACC and hippocampus; lower levels of glutamate (Glu) were observed in DLPFC. Higher levels in the older than the middle group were observed for mIns in hippocampus, tCr in ACC and hippocampus, tCho in hippocampus, and total N-acetyl aspartate (tNAA) in hippocampus. Working memory performance correlated negatively with tCr and tCho levels in ACC and mIns levels in hippocampus and thalamus, but not with tNAA or glutamate levels. As NAA and Glu are commonly regarded to reflect neuronal health and function and concentrations of mIns, tCr, and tCho are higher in glia than neurons, the findings of this study suggest a potential in vivo connection between cognitive ageing and higher regional levels of glia-related metabolites.SIGNIFICANCE STATEMENT Neurochemical ageing is an integral component of age-related cognitive decline. Proton MR spectroscopy (1H-MRS) studies of in vivo neurochemical changes across the lifespan have, however, yielded inconclusive results. 1H-MRS at ultra-high field strength can potentially improve the consistency of findings. Using 7T 1H-MRS, we assessed levels of mIns, tCr, and tCho (glia-related metabolites) and tNAA and Glu (neuron-related metabolites) in ACC, DLPFC, hippocampus, and thalamus. We found higher levels of glia-related metabolites in all brain regions in older individuals. Working memory performance correlated negatively with regional levels of glia-related metabolites. This study is the first to investigate normal ageing in these brain regions using 7T 1H-MRS and findings indicate that glia-related metabolites could be valuable in cognitive ageing studies.

Correction to: Ultra-high field MR angiography in human migraine models: a 3.0 T/7.0 T comparison study.

After publication of the original article [1], the authors have notified us that an updated version of Figures 1, 2 and 3 should have been published. The incorrect and revised figures can be found below.

Ultra-high field MR angiography in human migraine models: a 3.0 T/7.0 T comparison study.

BACKGROUND: Sildenafil and calcitonin gene-related peptide both dilate the intradural segments of the middle meningeal artery measured with 3.0 tesla (T) MR angiography. Here we hypothesized that an increase in field strength to 7.0 T and concomitant enhanced voxel resolution would lower variance in measurements of dilation in the intradural middle meningeal artery. METHODS: Five subjects completed two sessions at respectively 3.0 T and 7.0 T. Each session comprised MR angiography scans once before and twice after administration of sildenafil, calcitonin gene-related peptide or placebo in a three-way, crossover, double-blind, placebo-controlled design. RESULTS: Standard deviations of arterial circumference revealed no difference between 3.0 T and 7.0 T measurements (p = 0.379). We found a decrease in standard deviation from our original angiography analysis software (QMra) to a newer (LAVA) software package (p < 0.001). Furthermore, we found that the dilation after sildenafil and calcitonin gene-related peptide were comparable between 3.0 T and 7.0 T. CONCLUSIONS: Our findings suggest no gain from the increase in voxel resolution but cemented dilatory findings from earlier. The implemented software update improved variance in circumference measurements in the intradural middle meningeal artery, which should be exploited in future studies. TRIAL REGISTRATION: The study is part of a parent study, which is registered at ClinicalTrials.gov ( NCT03143465 ).

Sildenafil and calcitonin gene-related peptide dilate intradural arteries: A 3T MR angiography study in healthy volunteers.

BACKGROUND: Sildenafil and calcitonin gene-related peptide are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have never been examined in vivo. Sildenafil is the only migraine-inducing compound for which cephalic, extracranial artery dilation is not reported. Here, we investigate the effects of sildenafil and calcitonin gene-related peptide on the extracranial and intradural parts of the middle meningeal artery. METHODS: In a double-blind, randomized, three-way crossover, placebo-controlled head-to-head comparison study, MR-angiography was recorded in healthy volunteers at baseline and twice after study drug (sildenafil/ calcitonin gene-related peptide/saline) administration. Circumferences of extracranial and intradural middle meningeal artery segments were measured using semi-automated analysis software. The area under the curve for circumference change was compared using paired t-tests between study days. RESULTS: Twelve healthy volunteers completed the study. The area under the curveBaseline-120min was significantly larger on both the sildenafil and the calcitonin gene-related peptide day in the intradural middle meningeal artery (calcitonin gene-related peptide, p = 0.013; sildenafil, p = 0.027) and the extracranial middle meningeal artery (calcitonin gene-related peptide, p = 0.0003; sildenafil, p = 0.021), compared to placebo. Peak intradural middle meningeal artery dilation was 9.9% (95% CI [2.9-16.9]) after sildenafil (T30min) and 12.5% (95% CI [8.1-16.8]) after calcitonin gene-related peptide (T30min). Peak dilation of the extracranial middle meningeal artery after calcitonin gene-related peptide (T30min) was 15.7% (95% CI [11.2-20.1]) and 18.9% (95% CI [12.8-24.9]) after sildenafil (T120min). CONCLUSION: An important novel finding is that both sildenafil and calcitonin gene-related peptide dilate intradural arteries, supporting the notion that all known pharmacological migraine triggers dilate cephalic vessels. We suggest that intradural artery dilation is associated with headache induced by calcitonin gene-related peptide and sildenafil.

Effects of sildenafil and calcitonin gene-related peptide on brainstem glutamate levels: a pharmacological proton magnetic resonance spectroscopy study at 3.0 T.

BACKGROUND: Studies involving human pharmacological migraine models have predominantly focused on the vasoactive effects of headache-inducing drugs, including sildenafil and calcitonin gene-related peptide (CGRP). However, the role of possible glutamate level changes in the brainstem and thalamus is of emerging interest in the field of migraine research bringing forth the need for a novel, validated method to study the biochemical effects in these areas. METHODS: We applied an optimized in vivo human pharmacological proton (1H) magnetic resonance spectroscopy (MRS) protocol (PRESS, repetition time 3000 ms, echo time 37.6-38.3 ms) at 3.0 T in combination with sildenafil and CGRP in a double-blind, placebo-controlled, randomized, double-dummy, three-way cross-over design. Seventeen healthy participants were scanned with the 1H-MRS protocol at baseline and twice (at 40 min and 140 min) after drug administration to investigate the sildenafil- and CGRP-induced glutamate changes in both brainstem and thalamus. RESULTS: The glutamate levels increased transiently in the brainstem at 40-70 min after sildenafil administration compared to placebo (5.6%, P = 0.039). We found no sildenafil-induced glutamate changes in the thalamus, and no CGRP-induced glutamate changes in the brainstem or thalamus compared to placebo. Both sildenafil and CGRP induced headache in 53%-62% of participants. We found no interaction in the glutamate levels in the brainstem or thalamus between participants who developed sildenafil and/or CGRP-induced headache as compared to participants who did not. CONCLUSIONS: The transient sildenafil-induced glutamate change in the brainstem possibly reflects increased excitability of the brainstem neurons. CGRP did not induce brainstem or thalamic glutamate changes, suggesting that it rather exerts its headache-inducing effects on the peripheral trigeminal pain pathways.

Design of Infusion Schemes for Neuroreceptor Imaging: Application to [(11)C]Flumazenil-PET Steady-State Study.

This study aims at developing a simulation system that predicts the optimal study design for attaining tracer steady-state conditions in brain and blood rapidly. Tracer kinetics was determined from bolus studies and used to construct the system. Subsequently, the system was used to design inputs for bolus infusion (BI) or programmed infusion (PI) experiments. Steady-state quantitative measurements can be made with one short scan and venous blood samples. The GABAA receptor ligand [(11)C]Flumazenil (FMZ) was chosen for this purpose, as it lacks a suitable reference region. Methods. Five bolus [(11)C]FMZ-PET scans were conducted, based on which population-based PI and BI schemes were designed and tested in five additional healthy subjects. The design of a PI was assisted by an offline feedback controller. Results. The system could reproduce the measurements in blood and brain. With PI, [(11)C]FMZ steady state was attained within 40 min, which was 8 min earlier than the optimal BI (B/I ratio = 55 min). Conclusions. The system can design both BI and PI schemes to attain steady state rapidly. For example, subjects can be [(11)C]FMZ-PET scanned after 40 min of tracer infusion for 40 min with venous sampling and a straight-forward quantification. This simulation toolbox is available for other PET-tracers.

Cortical N-acetyl aspartate is a predictor of long-term clinical disability in multiple sclerosis.

OBJECTIVE: To evaluate the prognostic value of the cortical N-acetyl aspartate to creatine ratio (NAA/Cr) in early relapsing-remitting multiple sclerosis (RRMS). METHODS: Sixteen patients with newly diagnosed RRMS were studied by serial MRI and MR spectroscopic imaging (MRSI) once every 6 months for 24 months. Clinical examinations, including the expanded disability status scale (EDSS), were performed at baseline, month 24, and at year 7. RESULTS: Baseline cortical NAA/Cr correlated inversely with EDSS at month 24 (r  =  -0·61, P < 0·05), and patients with EDSS ≧ 4 had a lower baseline cortical NAA/Cr compared to those with EDSS less than 4 (P < 0·05). Baseline cortical NAA/Cr also correlated inversely with EDSS at the 7-year follow-up (r  =  -0·56, P < 0·05), and patients with EDSS ≧ 4 had a lower baseline cortical NAA/Cr compared to those with EDSS less than 4 (P < 0·05). Baseline brain parenchymal fraction (BPF) correlated inversely with EDSS at month 24 (r  =  -0·61, P < 0·05), but not with EDSS at year 7. DISCUSSION: Cortical NAA/Cr in early RRMS correlated with clinical disability after 2 and 7 years and may be used as a predictor of long-term disease outcome.

Multiple sclerosis impairs regional functional connectivity in the cerebellum.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been used to study changes in long-range functional brain connectivity in multiple sclerosis (MS). Yet little is known about how MS affects functional brain connectivity at the local level. Here we studied 42 patients with MS and 30 matched healthy controls with whole-brain rs-fMRI at 3 T to examine local functional connectivity. Using the Kendall's Coefficient of Concordance, regional homogeneity of blood-oxygen-level-dependent (BOLD)-signal fluctuations was calculated for each voxel and used as a measure of local connectivity. Patients with MS showed a decrease in regional homogeneity in the upper left cerebellar hemisphere in lobules V and VI relative to healthy controls. Similar trend changes in regional homogeneity were present in the right cerebellar hemisphere. The results indicate a disintegration of regional processing in the cerebellum in MS. This might be caused by a functional disruption of cortico-ponto-cerebellar and spino-cerebellar inputs, since patients with higher lesion load in the left cerebellar peduncles showed a stronger reduction in cerebellar homogeneity. In patients, two clusters in the left posterior cerebellum expressed a reduction in regional homogeneity with increasing global disability as reflected by the Expanded Disability Status Scale (EDSS) score or higher ataxia scores. The two clusters were mainly located in Crus I and extended into Crus II and the dentate nucleus but with little spatial overlap. These findings suggest a link between impaired regional integration in the cerebellum and general disability and ataxia.

Monocular visual deprivation suppresses excitability in adult human visual cortex.

The adult visual cortex maintains a substantial potential for plasticity in response to a change in visual input. For instance, transcranial magnetic stimulation (TMS) studies have shown that binocular deprivation (BD) increases the cortical excitability for inducing phosphenes with TMS. Here, we employed TMS to trace plastic changes in adult visual cortex before, during, and after 48 h of monocular deprivation (MD) of the right dominant eye. In healthy adult volunteers, MD-induced changes in visual cortex excitability were probed with paired-pulse TMS applied to the left and right occipital cortex. Stimulus-response curves were constructed by recording the intensity of the reported phosphenes evoked in the contralateral visual field at range of TMS intensities. Phosphene measurements revealed that MD produced a rapid and robust decrease in cortical excitability relative to a control condition without MD. The cortical excitability returned to preinterventional baseline levels within 3 h after the end of MD. The results show that in contrast to the excitability increase in response to BD, MD acutely triggers a reversible decrease in visual cortical excitability. This shows that the pattern of visual deprivation has a substantial impact on experience-dependent plasticity of the human visual cortex.