Parietal Gray Matter Research Articles

Proton Magnetic Resonance Spectroscopy (1H-MRS)-Based Neurometabolite Levels and Cognitive Function in Relation to Visceral Obesity and Non-Alcoholic Fatty Liver Disease (P14-019-19)

ObjectivesIntra-abdominal adiposity in the viscera and liver, compared to total adiposity, carries a higher metabolic risk, and it varies substantially by sex and race. We examined the association of neurometabolites and cognitive function with visceral obesity and non-alcoholic fatty liver disease (NAFLD) in multiethnic older adults. MethodsThe Multiethnic Cohort Brain-Gut-Adiposity Study included 100 participants aged 61–77 years, who were recruited into balanced strata by sex, ancestry (Japanese, Native Hawaiian or white) and body mass index (BMI) levels (range: 18.0–44.9 kg/m2). We measured the concentration of key brain metabolites in the frontal and parietal gray matter (GM) and frontal white matter using 1H-MRS and assessed cognitive function using the Modified Mini-Mental State (3MS) and the NIH Toolbox (NIHTB) tests. Mean neurometabolite levels and cognition scores were compared by visceral obesity (visceral fat area at L1-L5 > 150 cm2) and NAFLD (liver fat >5.0%) status determined by abdominal MR imaging, while adjusting for age, sex, race, education, dual energy X-ray absorptiometry-based total adiposity and other confounders. ResultsThe prevalence of visceral obesity was 52%, NAFLD 32%, and both conditions 27%. Participants with visceral obesity had higher adjusted mean levels of total glutamate [11.6 (11.3, 12.0) vs. 10.8 (10.4, 11.2) mM/kg; P = 0.01] and myo-inositol [5.2 (5.0, 5.4) vs. 4.7 (4.6, 4.9) mM/kg; P = 0.004] in the parietal GM but had similar levels of total choline, total creatine and N-acetylaspartate. NAFLD status was not significantly associated with the levels of neurometabolites. No significant interaction was detected between the two conditions: participants with either condition compared to those with neither showed a trend toward higher levels of myo-inositol [5.2 (4.9, 5.5) vs. 4.8 (4.5, 5.0) mM/kg; P = 0.07]. Further, participants with NAFLD scored lower for crystallized cognition for language [113 (110, 117) vs. 118 (116, 120); P = 0.02], in particular for reading ability [113 (109, 117) vs. 119 (117, 123); P = 0.03]. ConclusionsResults of this comprehensive, pilot imaging study suggest that, regardless of total adiposity and race/ethnicity, high visceral adiposity is associated with elevated concentrations of inflammatory neurometabolites, and NAFLD is associated with reduced language abilities. Funding SourcesNational Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute).

Three-dimensional pseudocontinuous arterial spin labeling and susceptibility-weighted imaging associated with clinical progression in amnestic mild cognitive impairment and Alzheimer's disease.

Background:This study aimed to evaluate the value of 3-dimensional pseudocontinuous arterial spin labeling (3D-pcASL) and susceptibility-weighted imaging (SWI) for the early disease-sensitive markers of conversion from amnestic MCI (aMCI) to Alzheimer disease (AD) in this process.Methods:Forty patients with aMCI and AD respectively were recruited in the study, and 40 healthy subjects were taken as controls. Data were recorded using 3T MR scanner. We assessed the cerebral blood flow (CBF) in 11 different regions of interest, and counted number of microhemorrhages (MB) in 3 regions of brain lobes, bilateral basal ganglia/thalamus, and brain stem/cerebellum, and then investigated correlations between Montreal Cognitive Assessment (MoCA) scores, CBF, and susceptibility-weighted imaging (SWI) features in these 3 groups.Results:The results revealed that for AD patients, the MoCA scores and CBF values in frontal gray matter (FGM), occipital gray matter (OGM), temporal gray matter (TGM), parietal gray matter (PGM), hippocampus, anterior cingulate cortex (ACC), precuneus, posterior cingulate cortex (PCC), precuneus, basal ganglia and thalamus decreased compared with aMCI patients and control group, and significant difference was revealed among the 3 groups. While in cerebellum, statistical significance was only found between AD patients and control group. On SWI, the average numbers of hemorrhage in regions of lobes for AD patients were significantly higher than aMCI patients and control group. The same results occurred in the bilateral basal ganglia/thalamus. We further found the MoCA score was positively correlated with CBF, but negatively correlated with hypointense signal on SWI.Conclusion:3D-pCASL and SWI have promising potential to be biomarkers for conversion from aMCI to AD in this process.

Brain structure and trait impulsivity: A comparative VBM study contrasting neural correlates of traditional and alternative concepts in healthy subjects

Impulsivity as a trait modulates a range of cognitive functions, e.g. planning, decision-making, or response inhibition. Recent behavioural and psychometric findings challenge both the neurobiological models as well as the conceptualisation of psychometric measures of impulsivity. In the present study, we aimed to test the association of brain structure with the Barratt Impulsiveness Scale (BIS-11), a commonly applied self-rating instrument for impulsivity, using both the classical three-factor-model for impulsive behaviour (motor (IM), attentional (IA) and non-planning impulsivity (INP)), as well as the recently proposed alternative model contrasting inability to wait for reward (IWR) as an index of impulsive choice and rapid response style (RRS) as an index of impulsive action. We analysed brain structural data in a community sample of 85 healthy individuals, who completed the BIS-11, using voxel-based morphometry (CAT12: Computational Anatomy Toolbox 12). Regional volumes were correlated with the three traditional BIS-11 subscales, as well as IWR and RRS. BIS-11 total score was positively correlated with right inferior parietal, postcentral, and supramarginal grey matter (p < 0.05, FWE cluster-level corrected). Attentional impulsivity (IA) was also positively correlated with right inferior and superior parietal and supramarginal gyri. Comparison of the other scales did show some divergence, but most correlations did not survive correction for multiple comparisons. Our findings suggest that difference facets of trait impulsivity might be related to different brain areas, and might thus dissociate along distinct but overlapping neural networks. In contrast to lesion or patient studies, these analyses delineate physiological variance, and can thus help to conceptualise network models in the absence of pathology.

Global brain ischemia in a dog with concurrent multiorgan dysfunction syndrome after bite wound trauma

BackgroundBite wounds are one of the most common traumatic injuries in dogs and depending on their severity, location, etc., urgent care including antibiotic therapy may be necessary. Serious complications can result from these injuries, such as multiple organ dysfunction syndrome (MODS), as well as a generalized reduction in cerebral perfusion, e.g. during cardiac arrest, shock, or severe hypotension that may cause global brain ischemia (GBI).Case presentationA 5-year-old spayed female Maltese dog was presented with generalized seizures, ataxia, and obtunded mentation. The dog was injured by severe bite wounds that penetrated its abdomen and had received blood transfusions, antibiotic therapy (including metronidazole and cefazoline) and underwent emergency surgery 4 days before its visit. Based on a clinical examination, intracranial hypoxic damage with elevated intra-cranial pressure and MODS were highly suspected, and GBI was confirmed following magnetic resonance imaging. Increased signal intensity diffusely distributed in the olfactory bulb and frontal, temporal, and parietal grey matter was evident on the T2-weighted and fluid attenuated inversion recovery transverse images, along with corresponding high signal intensity observed on diffusion weighted imaging. During the 10-month follow-up period, the clinical signs gradually improved, but intermittent circling and cognitive dysfunction deficits remained.ConclusionsGBI should be included among the differential diagnoses in case of any peracute non-progressive neurological dysfunction that occurs with episodes of hypotension or hypoxia. The abnormal signal intensity observed on diffusion weighted imaging was a useful indicator for diagnosing this condition. Long-term medical management with antibiotics and anti-convulsant and anti-oxidant therapies were considered to be helpful in managing the GBI concurrent with MODS in this dog.

P300, Gray Matter Volume and Individual Characteristics Correlates in Healthy Elderly.

We investigated whether P300-ERP and cognitive test performance differ for age, sex, and education in two groups of healthy elderly, and verified whether any correlations exist between P300 amplitude and latency and gray matter volume using whole brain voxel-by-voxel-based mapping, controlling for age, education, sex and Total Intracranial Volume (TIV). We used 32 channel electroencephalograms (EEG) to record the P300 responses and 3T Magnetic Resonance Imaging (MRI) to determine gray matter volume. We recruited 36 native-Dutch speaking healthy older subjects, equally divided in two sub-groups of 52–64 and 65–76 years old, administered a battery of cognitive tests and recorded their demographics, EEGs and task performance; additionally, 16 adults from the second sub-group underwent an MRI scan. We found significant differences between age groups in their cognitive tests performance, P300 amplitudes for the frontal and parietal electrodes for the most difficult task, and P300 latencies for frontal, central and parietal electrodes for all three tasks difficulty levels. Interesting, sex and education affected cognitive and P300 results. Higher education was related to higher accuracy, and P300 amplitudes and shorter latencies. Moreover, females exhibited higher P300 amplitudes and shorter latencies, and better cognitive tasks performance compared to males. Additionally, for the 16 adults underwent to MRI scan, we found positive correlations between P300 characteristics in frontal, central and parietal areas and gray matter volume, controlling for demographic variables and TIV, but also showing that age, sex, and education correlate with gray matter volume. These findings provide support that age, sex, and education affect an individual’s cognitive, neurophysiological and structural characteristics, and therefore motivate the need to further investigate these in relation to P300 responses and gray matter volume in healthy elderly.

In vivo binding of a tau imaging probe, [11 C]PBB3, in patients with progressive supranuclear palsy.

Background[11C]pyridinyl‐butadienyl‐benzothiazole 3 is a PET imaging agent designed for capturing pathological tau aggregates in diverse neurodegenerative disorders, and would be of clinical utility for neuropathological investigations of PSP.ObjectivesTo explore the usefulness of [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET in assessing characteristic distributions of tau pathologies and their association with clinical symptoms in the brains of living PSP patients.MethodsWe assessed 13 PSP patients and 13 age‐matched healthy control subjects. Individuals negative for amyloid β PET with [11C]Pittsburgh compound B underwent clinical scoring, MR scans, and [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET.ResultsThere were significant differences in binding potential for [11C]pyridinyl‐butadienyl‐benzothiazole 3 between PSP patients and healthy control subjects (P = 0.02). PSP patients exhibited greater radioligand retention than healthy control subjects in multiple brain regions, including frontoparietal white matter, parietal gray matter, globus pallidus, STN, red nucleus, and cerebellar dentate nucleus. [11C]pyridinyl‐butadienyl‐benzothiazole 3 deposition in frontoparietal white matter, but not gray matter, was correlated with general severity of parkinsonian and PSP symptoms, whereas both gray matter and white matter [11C]pyridinyl‐butadienyl‐benzothiazole 3 accumulations in the frontoparietal cortices were associated with nonverbal cognitive impairments. Autoradiographic and fluorescence labeling with pyridinyl‐butadienyl‐benzothiazole 3 was observed in gray matter and white matter of PSP motor cortex tissues.ConclusionsOur findings support the in vivo detectability of tau fibrils characteristic of PSP by [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET, and imply distinct and synergistic contributions of gray matter and white matte tau pathologies to clinical symptoms. [11C]pyridinyl‐butadienyl‐benzothiazole 3/PET potentially provides a neuroimaging‐based index for the evolution of PSP tau pathologies promoting the deterioration of motor and cognitive functions. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Abstract TMP112: Evidence of Diffuse Cortical Vascular Dysfunction in Patients With White Matter Hyperintensities

Introduction: White matter hyper intensities (WMHs) on T2 FLAIR images, are associated with cognitive decline in older populations. WMHs exhibit diminished vascular reactivity compared to normal appearing white matter (Sam et al. AJNR 2016). We hypothesize that patients with WMHs have diminished cortical vascular reactivity compared to controls. Methods: 23 patients with WMHs and 21 controls were studied. Patient inclusion criteria were: no cortical infarcts, Fazekas Grade &gt;= 2, no vascular stenoses &gt;= 70%, and no history of cardio/pulmonary disease. MRI protocol and vasodilatory stimulus The 3T MRI protocol included a 1 mm isotopic T1 3D sequence and a 3.5 mm isotropic T2* BOLD sequence (30 msec echo time). Cerebrovascular reactivity ( CVR ) was measured using 2 step changes in end-tidal pCO2 (from 40 to 50mmHg) using a controlled gas delivery system (RespirAct TM ) during BOLD imaging. Recent work has shown an age invariant cortical response to this stimulus delivery method (McKetton et al Neuroimage 2018). Image Analysis CVR magnitude maps, expressed in %BOLD/mmHg, were generated by calculating the linear regression of the BOLD response with the pCO2. The BOLD response was fitted with an exponential function in order to measure its time characteristic TAU providing a measure of speed of vascular response. Maps were corrected for partial volume errors. (Figure 1A). Average CVR and TAU within frontal, occipital, parietal and temporal grey matter were calculated for all subjects. t-tests corrected for multiple comparisons were calculated between patients and controls. Results: CVR magnitude was lower and TAU longer in patients with WMHs compared to normal controls in all four lobes (p &lt; 0.05) (Figure 1B). Conclusions: Patients with moderate to severe WMHs show diffuse impairment of vascular reactivity affecting the cerebral cortex even in the absence of significant large vessel steno-occlusive disease and in the absence of visible cortical disease on MRI.

Longitudinal association between brain volume change and gait speed in a general population.

To determine the association between brain structural changes and gait speed in a four-year longitudinal prospective cohort study. A total of 767 well-functioning community-dwelling participants, free of arthritis, silent infarct, stroke, dementia, head injury, and cancer, completed baseline brain magnetic resonance imaging scan and gait speed tests between 2011 and 2014, and follow-up tests between 2015 and 2017. The gait test consisted of measuring the elapsed time to walk four meters at usual speed. To estimate whether brain volume changes predict gait speed decline at follow-up, a generalized linear regression model was used after adjusting for potential confounding factors including gait speed at baseline. Participants who experienced ≥0.05 m/s gait speed decline, previously defined as a clinically meaningful decline, were more likely to be women, less likely to be smokers, and had lower physical activity scores (p = 0.003, p = 0.025, and p = 0.006, respectively), as compared to those who did not experience the decline. Also, they demonstrated smaller volumes of hippocampus, total gray matter, parietal gray matter, temporal gray matter, and temporal white matter (p = 0.004, p = 0.042, p = 0.021, p = 0.001, and p = 0.004, respectively). Even after correcting the significance level due to multiple comparisons, overall gray matter and overall white matter volume changes during four-year follow-up period showed significant associations with gait speed at follow-up (p < 0.001 and p = 0.002). Regarding region-specific volumes, frontal white matter and parietal gray matter volume changes demonstrated significant associations with gait speed (p = 0.002, p = 0.004, respectively). In a four-year longitudinal study among 767 well-functioning community-dwelling healthy participants from a general population, we observed a significant association between brain volume changes and gait speed.

Variability of apparent diffusion coefficient in the brain in women during follicular and luteal phases of the menstrual cycle.

To investigate the variability of apparent diffusion coefficient (ADC) in the brain in women during follicular and luteal phases of the menstrual cycle. The present study included 32 females of reproductive age with regular menstruation. The participants were divided into two groups as group 1: females in the follicular phase, and group 2: females in the luteal phase. The regions of interest were manually drawn on the structures of the T2-weighted images (frontal gray and white matter, parietal gray and white matter, temporal gray and white matter, occipital gray and white matter, cerebellar gray and white matter, caudate nucleus, putamen, thalamus, internal capsule, pons, cerebrospinal fluid (CSF) in the frontal and in the occipital horn of the lateral ventricle and CSF in the middle part of the lateral ventricle). ADC values were averaged for each patient. We used Kruskal-Wallis ANOVA for more than two groups but used Mann Whitney U test for comparison of ADC values between the group of 18 females in the follicular phase and the group of 14 females in the luteal phase. No statistically significant differences were observed among the groups in terms of the ADC value of each neuroanatomic structure that was evaluated. We did not determine a significant difference among volunteers at the two different phases of the menstrual cycle in terms of ADC values measured from different regions of the brain. However, although not statistically significant, ADC values measured from almost all parts of the brain were higher at the luteal phase than at the follicular phase.

Parietal lobe volume distinguishes attentional control in bilinguals and monolinguals: A structural MRI study

Research suggests that bilingualism is associated with increases in parietal gray matter volume (GMV). These parietal GMV increases are a source of variability that may help explain the reported bilingual/monolingual differences in attentional control. The current study examined how parietal GMV variability and a participant's language background predicted Simon task performance. GMV measures were extracted from the bilateral angular and supramarginal gyri from participants’ MRI scans using Freesurfer image analysis suite. Contrary to expectations, bilinguals did not outperform monolinguals on the Simon task. In fact, bilinguals had slower response times across all conditions of the task (incongruent, congruent, and neutral) than monolinguals. In addition, GMV in the right supramarginal gyrus was negatively associated with response times for congruent trials for bilinguals, and positively associated with these response times for monolinguals. The difference in the relationships between parietal GMV and task performance suggests that bilinguals rely on spatial attention to complete the Simon task, while monolinguals may rely on verbal attention. These results help to connect bilingual advantages in tasks requiring spatial attention (e.g., attentional control) with bilingual disadvantages in tasks requiring verbal attention (e.g., verbal fluency).

Association between Subcortical Morphology and Cerebral White Matter Energy Metabolism in Neonates with Congenital Heart Disease

Complex congenital heart disease (CHD) is associated with neurodevelopmental impairment, the mechanism of which is unknown. Cerebral cortical dysmaturation in CHD is linked to white matter abnormalities, including developmental vulnerability of the subplate, in relation to oxygen delivery and metabolism deficits. In this study, we report associations between subcortical morphology and white matter metabolism in neonates with CHD using quantitative magnetic resonance imaging (MRI) and spectroscopy (MRS). Multi-modal brain imaging was performed in three groups of neonates close to term-equivalent age: (1) term CHD (n = 56); (2) preterm CHD (n = 37) and (3) preterm control group (n = 22). Thalamic volume and cerebellar transverse diameter were obtained in relation to cerebral metrics and white matter metabolism. Short echo single-voxel MRS of parietal and frontal white matter was used to quantitate metabolites related to brain maturation (n-acetyl aspartate [NAA], choline, myo-inositol), neurotransmitter (glutamate), and energy metabolism (glutamine, citrate, creatine and lactate). Multi-variate regression was performed to delineate associations between subcortical morphological measurements and white matter metabolism controlling for age and white matter injury. Reduced thalamic volume, most pronounced in the preterm control group, was associated with increased citrate levels in all three group in the parietal white matter. In contrast, reduced cerebellar volume, most pronounced in the preterm CHD group, was associated with reduced glutamine in parietal grey matter in both CHD groups. Single ventricle anatomy, aortic arch obstruction, and cyanotic lesion were predictive of the relationship between reduced subcortical morphometry and reduced GLX (particularly glutamine) in both CHD cohorts (frontal white matter and parietal grey matter). Subcortical morphological associations with brain metabolism were also distinct within each of the three groups, suggesting these relationships in the CHD groups were not directly related to prematurity or white matter injury alone. Taken together, these findings suggest that subplate vulnerability in CHD is likely relevant to understanding the mechanism of both cortical and subcortical dysmaturation in CHD infants. Future work is needed to link this potential pattern of encephalopathy of CHD (including the constellation of grey matter, white matter and brain metabolism deficits) to not only abnormal fetal substrate delivery and oxygen conformance, but also regional deficits in cerebral energy metabolism.

Parietal Involvement in Constructional Apraxia as Measured Using the Pentagon Copying Task

Deficits in copying (“constructional apraxia”) is generally defined as a multifaceted deficit. The exact neural correlates of the different types of copying errors are unknown. To assess whether the different categories of errors on the pentagon drawing relate to different neural correlates, we examined the pentagon drawings of the MMSE in persons with subjective cognitive complaints, mild cognitive impairment, or early dementia due to Alzheimer’s disease. We adopted a qualitative scoring method for the pentagon copy test (QSPT) which categorizes different possible errors in copying rather than the dichotomous categories “correct” or “incorrect.” We correlated (regional) gray matter volumes with performance on the different categories of the QSPT. Results showed that the total score of the QSPT was specifically associated with parietal gray matter volume and not with frontal, temporal, and occipital gray matter volume. A more fine-grained analysis of the errors reveals that the intersection score and the number of angles share their underlying neural correlates and are associated with specific subregions of the parietal cortex. These results are in line with the idea that constructional apraxia can be attributed to the failure to integrate visual information correctly from one fixation to the next, a process called spatial remapping.

Anomalous Brain Development Is Evident in Preschoolers With Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurological disorder with symptom onset early in childhood. Growing evidence suggests anomalous brain development across multiple brain regions is evident in school-aged children; however, few studies have examined whether such differences are notable in the preschool years when symptom onset typically occurs. High resolution anatomical (MPRAGE) images and cognitive and behavioral measures were analyzed in a total of 90 medication-naïve preschoolers, ages 4-5 years (52 with ADHD, 38 controls; 64.4% boys). Results revealed reductions in bilateral frontal, parietal, and temporal lobe gray matter volumes in children with ADHD relative to typically developing children, with largest effect sizes noted for right frontal and left temporal lobe volumes. Examining frontal lobe sub-regions, the largest between group effect sizes were evident for left orbitofrontal cortex, left primary motor cortex (M1), and left supplementary motor complex (SMC). ADHD-related reductions in specific sub-regions (left prefrontal, left premotor, left frontal eye field, left M1, and right SMC) were significantly correlated with symptom severity, such that higher ratings of hyperactive/impulsive symptoms were associated with reduced cortical volumes. These findings represent the first comprehensive examination of cortical volume in preschool children with ADHD, providing evidence that anomalous brain structure in ADHD is evident very early in development. Furthermore, findings set the stage for developing our understanding of the way in which developmental trajectories of anomalous brain development are associated with the unfolding of symptoms in childhood ADHD. (JINS, 2018, 24, 531-539).

Brain Magnetic Resonance Imaging Findings in Children and Young Adults With CKD

The neuroanatomic basis for cognitive impairment in chronic kidney disease (CKD) is incompletely characterized. We performed advanced quantitative structural magnetic resonance imaging (MRI) to determine whether CKD affects brain structure and whether poorer neurocognitive performance in CKD is associated with structural brain differences. Cross-sectional. 85 individuals with CKD stages 2 to 5 and 63 healthy controls, aged 8 to 25 years PREDICTORS: CKD versus control, estimated glomerular filtration rate (eGFR), and kidney transplant status were analyzed as predictors of MRI findings. MRI volumes in 19 prespecified regions of gray matter (GM), white matter (WM), and cerebrospinal fluid were analyzed as predictors of neurocognitive performance (median z scores) in 7 prespecified domains. 19 prespecified brain regions of interest (ROIs) in 7 prespecified domains. Neurocognitive performance in 7 prespecified domains. ROI volumes were compared in CKD versus controls using unadjusted t tests and analysis of covariance (ANCOVA). Associations of ROI volumes with eGFR and kidney transplant status in participants with CKD were analyzed using ANCOVA and linear regression. Associations of neurocognitive performance and ROI volumes were analyzed by linear regression. Participants with CKD had lower whole-brain, cortical, and left parietal GM volumes than controls in unadjusted analyses, but no differences were found in adjusted analysis. In participants with CKD, lower eGFR was associated with higher WM volume in whole-brain (P=0.05) and frontal (P=0.04) ROIs, but differences were not significant after multiple comparisons correction. Kidney transplant recipients had lower GM volumes in whole-brain (P=0.01; Q=0.06), frontal (P=0.02; Q=0.08), and left and right parietal (P=0.01; Q=0.06; and P=0.03; Q=0.1) ROIs and higher whole-brain WM volume (P=0.04; Q=0.1). Neurocognitive performance in the CKD group was not associated with ROI volumes. Unable to assess changes in brain structure and kidney function over time; analysis limited to prespecified ROIs and neurocognitive domains. CKD in children and young adults may be associated with lower GM and higher WM volumes in some ROIs. Differences were relatively subtle in the CKD group as a whole, but were more prominent in recipients of a kidney transplant. However, neurocognitive performance was not explained by differences in brain ROI volumes, suggesting a functional rather than structural basis for neurocognitive impairment in CKD.

Deep gray matter volume loss drives disability worsening in multiple sclerosis.

ObjectiveGray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS.MethodsWe analyzed 3,604 brain high‐resolution T1‐weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing‐remitting [RRMS], 128 secondary‐progressive [SPMS], and 125 primary‐progressive [PPMS]), over an average follow‐up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow‐up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time‐to‐EDSS progression.ResultsSPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time‐to‐EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow‐up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (–1.45%), PPMS (–1.66%), and RRMS (–1.34%) than CIS (–0.88%) and HCs (–0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (–1.21%) was significantly faster than RRMS (–0.76%), CIS (–0.75%), and HCs (–0.51%). Similarly, the rate of parietal GM atrophy in SPMS (–1.24‐%) was faster than CIS (–0.63%) and HCs (–0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001).InterpretationThis large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210–222

Measuring Cerebral and Cerebellar Glutathione in Children Using 1H MEGA-PRESS MRS.

Glutathione is an important antioxidant in the human brain and therefore of interest in neurodegenerative disorders. The purpose of this study was to investigate the feasibility of measuring glutathione in healthy nonsedated children by using the 1H Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence at 3T and to compare glutathione levels between the medial parietal gray matter and the cerebellum. Glutathione was measured using MEGA-PRESS MRS (TR = 1.8 seconds, TE = 131 ms) in the parietal gray matter (35 × 25 × 20 mm3) of 6 healthy children (10.0 ± 2.4 years of age; range, 7-14 years; 3 males) and in the cerebellum of 11 healthy children (12.0 ± 2.7 years of age; range, 7-16 years; 6 males). A postprocessing pipeline was developed to account for frequency and phase variations in the edited ON and nonedited OFF spectra. Metabolites were quantified with LCModel and reported both as ratios and water-scaled values. Glutathione was quantified in the ON-OFF spectra, whereas total NAA, total Cho, total Cr, mIns, Glx, and taurine were quantified in the OFF spectra. We found significantly higher glutathione, total Cho, total Cr, mIns, and taurine in the cerebellum (P < .01). Glx and total NAA were significantly higher in the parietal gray matter (P < .01). There was no significant difference in glutathione/total Cr (P = .93) between parietal gray matter and cerebellum. We demonstrated that glutathione measurement in nonsedated children is feasible. We found significantly higher glutathione in the cerebellum compared with the parietal gray matter. Metabolite differences between the parietal gray matter and cerebellum agree with published MRS data in adults.

Getting Lost Behavior in Patients with Mild Alzheimer's Disease: A Cognitive and Anatomical Model.

Getting lost behavior (GLB) in the elderly is believed to involve poor top-down modulation of visuospatial processing, by impaired executive functions. However, since healthy elderly and elderly with Alzheimer's disease (AD) experience a different pattern of cognitive decline, it remains unclear whether this hypothesis can explain GLB in dementia. We sought to identify whether poor executive functions and working memory modulate the relationship between visuospatial processing and prevalence of GLB in healthy elderly and patients with AD. Complementary to this, we explored whether brain regions critical for executive functions modulate the relationship between GLB and brain regions critical for visuospatial processing. Ninety-two participants with mild AD and 46 healthy age-matched controls underwent neuropsychological assessment and a structural MRI. GLB was assessed using a semistructured clinical interview. Path analysis was used to explore interactions between visuospatial deficits, executive dysfunction/working memory, and prevalence of GLB, in AD and controls independently. For both healthy controls and patients with mild AD, visuospatial processing deficits were associated with GLB only in the presence of poor working memory. Anatomically, GLB was associated with medial temporal atrophy in patients with mild AD, which was not strengthened by low frontal gray matter (GM) volume as predicted. Instead, medial temporal atrophy was more strongly related to GLB in patients with high frontal GM volumes. For controls, GLB was not associated with occipital, parietal, medial temporal, or frontal GM volume. Cognitively, a top-down modulation deficit may drive GLB in both healthy elderly and patients with mild AD. This modulation effect may be localized in the medial temporal lobe for patients with mild AD. Thus, anatomical substrates of GLB in mild AD may not follow the typical top-down modulation mechanisms often reported in the healthy aging population. Implications advance therapeutic practices by highlighting the need to target both working memory and visuospatial deficits simultaneously, and that anatomical substrates of GLB may be disease specific.

Sex hormones and brain volumes in a longitudinal study of middle-aged men in the CARDIA study.

IntroductionSeveral findings suggest that testosterone (T) is neuroprotective and that declining T levels during aging are associated with cognitive and brain pathologies; however, little is known on T and brain health in middle‐age. We examined the relationships of total T, bioavailable T, and sex hormone binding globulin (SHBG) levels with total and regional gray matter (GM) and white matter (WM) volumes in middle‐aged men. We also evaluated the association of sex hormone levels with cognitive function.MethodsAnalysis included 267 community‐dwelling men participating in the Coronary Artery Risk Development in Young Adults (CARDIA) brain magnetic resonance imaging (MRI) substudy. Total T, bioavailable T, and SHBG levels were measured at three times from the 2nd to 4th decade of life; brain volumes were measured at the ages of 42–56. Associations were estimated using linear regression models, adjusted for several potential confounders.ResultsHigher SHBG levels were associated with greater total WM volume (+3.15 cm3 [95% confidence interval [CI] = 0.01, 6.28] per one standard deviation higher SHBG). Higher SHBG levels were associated with lower total and regional GM volumes overall and significantly with smaller parietal GM volume (−0.96 cm3 [95%CI = −1.71, −0.21]). T levels were not related to brain volumes. Neither T nor SHBG levels were associated with cognitive function.ConclusionResults suggest a role for SHBG in structural brain outcomes in men and emphasize the value of investigating SHBG levels as modulators of sex hormone and metabolic pathways regulating brain and behavioral characteristics in men.

TLR4 Methylation Moderates the Relationship Between Alcohol Use Severity and Gray Matter Loss.

Alcohol use disorders (AUDs) are associated with decreased gray matter, and neuroinflammation is one mechanism through which alcohol may confer such damage, given that heavy alcohol use may promote neural damage via activation of toll-like receptor 4 (TLR4)-mediated inflammatory signaling cascades. We previously demonstrated that TLR4 is differentially methylated in AUD compared with control subjects, and the present study aims to extend this work by examining whether TLR4 methylation moderates the relationship between alcohol use and gray matter. We examined TLR4 methylation and gray matter thickness in a large sample (N = 707; 441 males) of adults (ages 18-56) reporting a range of AUD severity (mean Alcohol Use Disorders Identification Test score = 13.18; SD = 8.02). We used a series of ordinary least squares multiple regression equations to regress gray matter in four bilateral brain regions (precuneus, lateral orbitofrontal, inferior parietal, and superior temporal) on alcohol use, TLR4 methylation, and their interaction, controlling for demographic, psychological, and other substance use variables. After we corrected for multiple tests, a significant Alcohol × TLR4 Methylation interaction emerged in the equations modeling left precuneus and right inferior parietal gray matter. Follow-up analyses examining the nature of these interactions demonstrated a significant negative association between alcohol and precuneus and inferior parietal gray matter in individuals with low TLR4 methylation, but no relationship between alcohol and gray matter in the high methylation group. These findings suggest that TLR4 methylation may be protective against the damage conferred by alcohol on precuneus and inferior parietal gray matter, thereby implicating TLR4 for further investigation as a possible AUD treatment target.

Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy.

We explored the establishment of abnormal blood-brain barrier (BBB) permeability and its relationship to neuropathogenesis during primary human immunodeficiency virus (HIV) infection by evaluating the cerebrospinal fluid (CSF) to serum albumin quotient (QAlb) in patients with primary HIV infection. We also analyzed effects of initiating combination antiretroviral therapy (cART). The QAlb was measured in longitudinal observational studies of primary HIV infection. We analyzed trajectories of the QAlb before and after cART initiation, using mixed-effects models, and associations between the QAlb and the CSF level of neurofilament light chain (NFL), the ratio of N-acetylaspartate to creatinine levels (a magnetic resonance spectroscopy neuronal integrity biomarker), and neuropsychological performance. The baseline age-adjusted QAlb was elevated in 106 patients with primary HIV infection (median time of measurement, 91 days after infection), compared with that in 64 controls (P = .02). Before cART initiation, the QAlb increased over time in 84 participants with a normal baseline QAlb (P = .006) and decreased in 22 with a high baseline QAlb (P = .011). The QAlb did not change after a median cART duration of 398 days, initiated at a median interval of 225 days after infection (P = .174). The QAlb correlated with the NFL level at baseline (r = 0.497 and P < .001) and longitudinally (r = 0.555 and P < .001) and with the ratio of N-acetylaspartate to creatinine levels in parietal gray matter (r = -0.352 and P < .001 at baseline and r = -0.387 and P = .008 longitudinally) but not with neuropsychological performance. The QAlb rises during primary HIV infection, associates with neuronal injury, and does not significantly improve over a year of treatment. BBB-associated neuropathogenesis in HIV-infected patients may initiate during primary infection.