Assessment of the impact of the scanner-related factors on brain morphometry analysis with Brainvisa.

BACKGROUND: Brain morphometry is extensively used in cross-sectional studies. However, the difference in the estimated values of the morphometric measures between patients and healthy subjects may be small and hence overshadowed by the scanner-related variability, especially with multicentre and longitudinal studies. It is important therefore to investigate the variability and reliability of morphometric measurements between different scanners and different sessions of the same scanner. METHODS: We assessed the variability and reliability for the grey matter, white matter, cerebrospinal fluid and cerebral hemisphere volumes as well as the global sulcal index, sulcal surface and mean geodesic depth using Brainvisa. We used datasets obtained across multiple MR scanners at 1.5 T and 3 T from the same groups of 13 and 11 healthy volunteers, respectively. For each morphometric measure, we conducted ANOVA analysis and verified whether the estimated values were significantly different across different scanners or different sessions of the same scanner. The between-centre and between-visit reliabilities were estimated from their contribution to the total variance, using a random-effects ANOVA model. To estimate the main processes responsible for low reliability, the results of brain segmentation were compared to those obtained using FAST within FSL. RESULTS: In a considerable number of cases, the main effects of both centre and visit factors were found to be significant. Moreover, both between-centre and between-visit reliabilities ranged from poor to excellent for most morphometric measures. A comparison between segmentation using Brainvisa and FAST revealed that FAST improved the reliabilities for most cases, suggesting that morphometry could benefit from improving the bias correction. However, the results were still significantly different across different scanners or different visits. CONCLUSIONS: Our results confirm that for morphometry analysis with the current version of Brainvisa using data from multicentre or longitudinal studies, the scanner-related variability must be taken into account and where possible should be corrected for. We also suggest providing some flexibility to Brainvisa for a step-by-step analysis of the robustness of this package in terms of reproducibility of the results by allowing the bias corrected images to be imported from other packages and bias correction step be skipped, for example.

Multiomics Analysis of Structural Magnetic Resonance Imaging of the Brain and Cerebrospinal Fluid Metabolomics in Cognitively Normal and Impaired Adults.

INTRODUCTION: Integrating brain imaging with large scale omics data may identify novel mechanisms of mild cognitive impairment (MCI) and early Alzheimer's disease (AD). We integrated and analyzed brain magnetic resonance imaging (MRI) with cerebrospinal fluid (CSF) metabolomics to elucidate metabolic mechanisms and create a "metabolic map" of the brain in prodromal AD. METHODS: In 145 subjects (85 cognitively normal controls and 60 with MCI), we derived voxel-wise gray matter volume via whole-brain structural MRI and conducted high-resolution untargeted metabolomics on CSF. Using a data-driven approach consisting of partial least squares discriminant analysis, a multiomics network clustering algorithm, and metabolic pathway analysis, we described dysregulated metabolic pathways in CSF mapped to brain regions associated with MCI in our cohort. RESULTS: The multiomics network algorithm clustered metabolites with contiguous imaging voxels into seven distinct communities corresponding to the following brain regions: hippocampus/parahippocampal gyrus (three distinct clusters), thalamus, posterior thalamus, parietal cortex, and occipital lobe. Metabolic pathway analysis indicated dysregulated metabolic activity in the urea cycle, and many amino acids (arginine, histidine, lysine, glycine, tryptophan, methionine, valine, glutamate, beta-alanine, and purine) was significantly associated with those regions (P < 0.05). CONCLUSION: By integrating CSF metabolomics data with structural MRI data, we linked specific AD-susceptible brain regions to disrupted metabolic pathways involving nitrogen excretion and amino acid metabolism critical for cognitive function. Our findings and analytical approach may extend drug and biomarker research toward more multiomics approaches.

18F-Flortaucipir PET Associations with Cerebrospinal Fluid, Cognition, and Neuroimaging in Mild Cognitive Impairment due to Alzheimer's Disease.

BACKGROUND: Tau positron emission tomography (PET) imaging is used in research, but its relation to cerebrospinal fluid (CSF) tau and other Alzheimer's disease (AD)-related clinical measures is unclear in mild cognitive impairment with AD biomarkers (MCI-AD). OBJECTIVE: To determine associations between 18F-flortaucipir PET and CSF AD biomarkers, cognitive functioning, and neuroimaging measures in MCI-AD. METHODS: In 29 participants 50 years or older with MCI-AD, 18F-flortaucipir PET, CSF total tau (T-tau), phosphorylated tau181p (P-tau), amyloid-ß (Aß), structural MRI, and neuropsychological testing were collected as baseline assessments of an ongoing clinical trial. 11C-Pittsburgh compound B PET was simultaneously conducted in 20 participants. Associations between 18F-flortaucipir PET and these measures were assessed by multiple linear regression adjusted for potential confounders and using global, lobar, and voxel-wise standardized uptake value ratio (SUVr). RESULTS: Whole brain 18F-flortaucipir SUVr was significantly associated with CSF T-tau (r = 0.68, p < 0.001) and P-tau (r = 0.42, p = 0.04) after adjusting for age, sex, race, and education, with strongest associations in the temporal region (T-tau: r = 0.69, p < 0.001; P-tau: r = 0.49, p = 0.02). Voxel-wise analysis confirmed these regional associations. 18F-flortaucipir PET was also associated with CSF Aß (r = -0.45, p = 0.03), episodic memory (r = -0.61, p = 0.001), visuospatial working memory (r = -0.46, p = 0.02), and brain cortical thickness (r = -0.44, p = 0.03) but not hippocampal volume. In the amyloid PET subset, although 11C-PiB PET associated strongly with 18F-flortaucipir (r = 0.79, p≤0.001), associations were stronger between 11C-PiB and key outcomes, compared to 18F-flortaucipir. CONCLUSION: 18F-flortaucipir PET is moderately associated with CSF AD biomarkers and other AD-related phenotypes. The associations in this MCI-AD sample are stronger than previously described in other populations.

Effects of Candesartan vs Lisinopril on Neurocognitive Function in Older Adults With Executive Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Observational studies have suggested that angiotensin receptor blockers are associated with a unique cognitive protection. It is unclear if this is due to reduced blood pressure (BP) or angiotensin receptors type 1 blockade. Objective: To determine neurocognitive effects of candesartan vs lisinopril in older adults with mild cognitive impairment (MCI). Design, Setting, and Participants: This randomized clinical trial included participants aged 55 years or older with MCI and hypertension. Individuals were withdrawn from prior antihypertensive therapy and randomized in a 1 to 1 ratio to candesartan or lisinopril from June 2014 to December 2018. Participants underwent cognitive assessments at baseline and at 6 and 12 months. Brain magnetic resonance images were obtained at baseline and 12 months. This intent-to-treat study was double-blind and powered for a sample size accounting for 20% dropout. Data were analyzed from May to October 2019. Interventions: Escalating doses of oral candesartan (up to 32 mg) or lisinopril (up to 40 mg) once daily. Open-label antihypertensive drug treatments were added as needed to achieve BP less than 140/90 mm Hg. Main Outcomes and Measures: The primary outcome was executive function (measured using the Trail Making Test, Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research tool) and secondary outcomes were episodic memory (measured using the Hopkins Verbal Learning Test-Revised) and microvascular brain injury reflected by magnetic resonance images of white matter lesions. Results: Among 176 randomized participants (mean [SD] age, 66.0 [7.8] years; 101 [57.4%] women; 113 [64.2%] African American), 87 were assigned to candesartan and 89 were assigned to lisinopril. Among these, 141 participants completed the trial, including 77 in the candesartan group and 64 in the lisinopril group. Although the lisinopril vs candesartan groups achieved similar BP (12-month mean [SD] systolic BP: 130 [17] mm Hg vs 134 [20] mm Hg; P = .20; 12-month mean [SD] diastolic BP: 77 [10] mm Hg vs 78 [11] mm Hg; P = .52), candesartan was superior to lisinopril on the primary outcome of executive function measured by Trail Making Test Part B (effect size [ES] = -12.8 [95% CI, -22.5 to -3.1]) but not Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research score (ES = -0.03 [95% CI, -0.08 to 0.03]). Candesartan was also superior to lisinopril on the secondary outcome of Hopkins Verbal Learning Test-Revised delayed recall (ES = 0.4 [95% CI, 0.02 to 0.8]) and retention (ES = 5.1 [95% CI, 0.7 to 9.5]). Conclusions and Relevance: These findings suggest that in older adults with MCI, 1-year treatment with candesartan had superior neurocognitive outcomes compared with lisinopril. These effects are likely independent of the BP-lowering effect of candesartan. Trial Registration: ClinicalTrials.gov Identifier: NCT01984164.

Cardiovascular Response to Mental Stress in Mild Cognitive Impairment and its Association with Cerebral Perfusion.

Mental stress has been linked to various chronic diseases including Alzheimer's disease, but the mechanisms underlying cognitive decline with mental stress are unknown. Reduced cardiovascular response to stress is associated with cardiovascular disease, and the latter is associated with cognitive impairment. We measured electrodermal activity, blood pressure, and cardiac hemodynamics in cognitively normal and mild cognitive impairment (MCI) adults (n = 76, mean age = 58 years, 46% MCI) during rest, a math test, and face-name recall tasks to derive the following cardiovascular indicators: mean arterial pressure, heart rate, stroke volume and cardiac output. These indicators were compared between the two groups. Cerebral blood perfusion via arterial spin-labeling MRI was measured in a subgroup who underwent an MRI scan (n = 30). Following exposure to mental stress, a decrease in stroke volume (p = 0.024) and cardiac output (p = 0.005) was found in the MCI group, but an increase in both parameters in the cognitively normal group. This difference was largest during face-name recall (standardized difference in stroke volume = -0.50, p = 0.029, and in cardiac output = -0.52, p = 0.023). Cardiac output during mental stress, but not at rest, decreased with cerebral perfusion (normal: p = 0.078, ß= 1.97, R2 = 0.090; MCI: p = 0.007, ß= 2.02, R2 = 0.008). No significant difference was found between the two groups at rest. This preliminary study suggests that individuals with MCI have an insufficient cardiac output, and in turn lower cerebral perfusion in response to mental stress.

Differential Associations of Diastolic and Systolic Pressures With Cerebral Measures in Older Individuals With Mild Cognitive Impairment.

BACKGROUND: Reports on the relative importance of the diastolic and systolic blood pressures (DBP and SBP) in age-related cognitive decline are mixed. Investigating the relation between DBP/SBP and functional and structural brain changes could elucidate which of the 2 measures is more critically important for brain function and, consequently, cognitive impairment. METHODS: We investigated the association of SBP and DBP with cortical volume, cerebral blood flow (CBF), and white matter lesions (WML), in nondemented older adults with and without mild cognitive impairment (MCI; N = 265, 185 MCI, mean age = 64 years). Brachial blood pressure was measured twice while seated, and the average of the 2 measures was used. Cortical volume, gray matter (GM) CBF, and WML were estimated using T1-weighted imaging, arterial spin labeling, and fluid attenuation inversion recovery, respectively. RESULTS: Reduced cortical volume was associated with elevated DBP (ß= -0.18, P = 0.034) but not with SBP (ß = -0.10, P = 0.206). GM CBF was associated with DBP (ß = -0.13, P = 0.048) but not with SBP (ß = -0.07, P = 0.275). Likewise, CBF within brain regions where MCI patients showed hypoperfusion were only associated with DBP (DBP: ß = -0.17, P = 0.005; SBP: ß = -0.09, P = 0.120). WML volume was associated with both DBP (ß = 0.20, P = 0.005) and SBP (ß = 0.30, P < 0.001). For all measures, there was no interaction between DBP/SBP and cognitive status, indicating that these associations were independent of the cognitive status. CONCLUSIONS: Independently of the cognitive status, DBP is more critically important for GM volume and perfusion, whereas WML is associated with both blood pressures, likely reflecting long-term effect of hypertension and autoregulation dysfunction.

Structural and Functional Brain Changes at Early and Late Stages of Complex Regional Pain Syndrome.

Brain plasticity is demonstrated in complex regional pain syndrome (CRPS), although it is unclear how it modulates at different stages of CRPS. The observation that symptoms can progress over time suggests that the pattern of brain changes might also evolve. We measured structural and functional changes as well as sensorimotor integration at the early stage (ES) and late stage (LS) of CRPS. Twelve ES patients, 16 LS patients, and 16 age- and sex-matched controls were recruited. Gray matter (GM) volume was estimated using voxel-based morphometry. Cerebral perfusion was measured using arterial spin labeling, because it provides a measure of resting neural activity. Connectivity to sensorimotor regions was evaluated using blood-oxygen level-dependent images. The ES group showed reduced GM volume and perfusion in areas associated with spatial body perception, somatosensory cortex, and the limbic system, whereas the LS group exhibited increased perfusion in the motor cortex but no changes in GM volume. However, in the LS group, GM volume in areas associated with pain processing was negatively correlated with average pain levels, likely reflecting a response to ongoing pain. Furthermore, connectivity to sensorimotor cortex showed disruptions in regions associated with motor control and planning, implying impairment of higher-order motor control. PERSPECTIVE: This article presents brain changes at ES and LS of CRPS. We found different patterns of brain changes between these 2 stages. Understanding modulation of brain plasticity at different stages of CRPS could help understand the diversity in outcomes and treatment response and hopefully improve treatment planning.

Can time-resolved NIRS provide the sensitivity to detect brain activity during motor imagery consistently?

Previous functional magnetic resonance imaging (fMRI) studies have shown that a subgroup of patients diagnosed as being in a vegetative state are aware and able to communicate by performing a motor imagery task in response to commands. Due to the fMRI's cost and accessibility, there is a need for exploring different imaging modalities that can be used at the bedside. A promising technique is functional near infrared spectroscopy (fNIRS) that has been successfully applied to measure brain oxygenation in humans. Due to the limited depth sensitivity of continuous-wave NIRS, time-resolved (TR) detection has been proposed as a way of enhancing the sensitivity to the brain, since late arriving photons have a higher probability of reaching the brain. The goal of this study was to assess the feasibility and sensitivity of TR fNIRS in detecting brain activity during motor imagery. Fifteen healthy subjects were recruited in this study, and the fNIRS results were validated using fMRI. The change in the statistical moments of the distribution of times of flight (number of photons, mean time of flight and variance) were calculated for each channel to determine the presence of brain activity. The results indicate up to an 86% agreement between fMRI and TR-fNIRS and the sensitivity ranging from 64 to 93% with the highest value determined for the mean time of flight. These promising results highlight the potential of TR-fNIRS as a portable brain computer interface for patients with disorder of consciousness.

Lower Functional Connectivity of the Periaqueductal Gray Is Related to Negative Affect and Clinical Manifestations of Fibromyalgia.

Fibromyalgia (FM) syndrome is characterized by chronic widespread pain, muscle tenderness and emotional distress. Previous studies found reduced endogenous pain modulation in FM. This deficiency of pain modulation may be related to the attributes of chronic pain and other clinical symptoms experienced in patients with FM. Thus, we tested whether there is a link between the clinical symptoms of FM and functional connectivity (FC) of the periaqueductal gray (PAG), a key node of pain modulation. We acquired resting state 3T functional MRI (rsfMRI) data from 23 female patients with FM and 16 age- and sex- matched healthy controls (HC) and assessed FM symptoms with the Brief Pain Inventory (BPI), Fibromyalgia Impact Questionnaire (FIQ), Hospital Anxiety and Depression Scale (HADS) and Pain Catastrophizing Scale (PCS). We found that patients with FM exhibit statistically significant disruptions in PAG FC, particularly with brain regions implicated in negative affect, self-awareness and saliency. Specifically, we found that, compared to HCs, the FM patients had stronger PAG FC with the lingual gyrus and hippocampus but weaker PAG FC with regions associated with motor/executive functions, the salience (SN) and default mode networks (DMN). The attenuated PAG FC was also negatively correlated with FIQ scores, and positively correlated with the magnification subscale of the PCS. These alterations were correlated with emotional and behavioral symptoms of FM. Our study implicates the PAG as a site of dysfunction contributing to the clinical manifestations and pain in FM.

Basal Ganglia Perfusion in Fibromyalgia is Related to Pain Disability and Disease Impact: An Arterial Spin Labeling Study.

OBJECTIVES: Pain disability is a major impediment to fibromyalgia (FM) patients' quality of life. Neuroimaging studies have demonstrated abnormal pain processing in FM. However, it is not known whether there are brain abnormalities linked to pain disability. Understanding neural correlates of pain disability in FM, independent from pain intensity, could provide a framework to guide future more efficient therapy strategies to improve patients' functional ability. METHODS: We used arterial spin labeling to image cerebral blood flow (CBF) in 23 FM patients and 16 controls. Functional connectivity was also estimated using blood oxygenation level-dependent imaging to further investigate the possible underpinnings of the observed CBF changes. RESULTS: Among patients, CBF in the basal ganglia correlated negatively with pain disability index and positively with the overall impact of FM (Fibromyalgia Impact Questionnaire) but did not correlate with pain intensity. Whole-brain analysis revealed no CBF differences between the 2 groups; however, post hoc analysis in the basal ganglia showed CBF reductions mainly in the right putamen and right lateral globus pallidus in patients, likely reflecting the negative correlation with the pain disability index. However, the connectivity of the corresponding corticobasal ganglia-thalamus loop, that is, motor network (the connection between supplementary motor area, putamen, and thalamus) remained intact. DISCUSSION: Basal ganglia perfusion reflects long-term symptoms, including somatic and psychological components of FM rather than pain intensity. These CBF findings may reflect differences in behavioral and psychological responses between patients.

Changes in the sulcal size associated with autism spectrum disorder revealed by sulcal morphometry.

Autism spectrum disorder (ASD) is a complex, neurodevelopmental disorder with various structural abnormalities for different patient groups. Because of the heterogeneity of the disorder, several biomarkers have been suggested so far. Here, we explore the potential of sulcal surface and length as biomarkers. Three-dimensional T1-weighted images of 15 adolescents of normal intelligence with ASD and 15 age-, sex-, and intelligence quotient-matched control adolescents were analysed using Brainvisa 4.0 (http://www.brainvisa.info), which automatically extracts the cortical folds and labels them as 59 sulcal pieces. For each sulcus, the surface, length, and mean geodesic depth were computed using morphometry analysis within this software package. General linear model was conducted to compare the estimated values for the two groups, ASD and control. In the ASD group, the left insula and the right intraparietal sulcus (IPS) had significantly higher values for surface and length, respectively. Nonetheless for all sulcal pieces, the mean geodesic depth was not significantly different between the two groups. Our results suggest that sulcal surface and length can have correlation with morphological changes of cortex in ASD. Greater surface area and length in insula and IPS, respectively, may reflect greater folding. This could result in greater separation of functions with an impact upon the integrative functions of these regions.