Experimentally Induced Reductions in Alcohol Consumption and Brain, Cognitive, and Clinical Outcomes in Older Persons With and Those Without HIV Infection (30-Day Challenge Study): Protocol for a Nonrandomized Clinical Trial.

BACKGROUND: Both alcohol consumption and HIV infection are associated with worse brain, cognitive, and clinical outcomes in older adults. However, the extent to which brain and cognitive dysfunction is reversible with reduction or cessation of drinking is unknown. OBJECTIVE: The 30-Day Challenge study was designed to determine whether reduction or cessation of drinking would be associated with improvements in cognition, reduction of systemic and brain inflammation, and improvement in HIV-related outcomes in adults with heavy drinking. METHODS: The study design was a mechanistic experimental trial, in which all participants received an alcohol reduction intervention followed by repeated assessments of behavioral and clinical outcomes. Persons were eligible if they were 45 years of age or older, had weekly alcohol consumption of 21 or more drinks (men) or 14 or more drinks (women), and were not at high risk of alcohol withdrawal. After a baseline assessment, participants received an intervention consisting of contingency management (money for nondrinking days) for at least 30 days followed by a brief motivational interview. After this, participants could either resume drinking or not. Study questionnaires, neurocognitive assessments, neuroimaging, and blood, urine, and stool samples were collected at baseline, 30 days, 90 days, and 1 year after enrollment. RESULTS: We enrolled 57 persons with heavy drinking who initiated the contingency management protocol (mean age 56 years, SD 4.6 years; 63%, n=36 male, 77%, n=44 Black, and 58%, n=33 people with HIV) of whom 50 completed 30-day follow-up and 43 the 90-day follow-up. The planned study procedures were interrupted and modified due to the COVID-19 pandemic of 2020-2021. CONCLUSIONS: This was the first study seeking to assess changes in brain (neuroimaging) and cognition after alcohol intervention in nontreatment-seeking people with HIV together with people without HIV as controls. Study design strengths, limitations, and lessons for future study design considerations are discussed. Planned analyses are in progress, after which deidentified study data will be available for sharing. TRIAL REGISTRATION: ClinicalTrials.gov NCT03353701; https://clinicaltrials.gov/study/NCT03353701. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53684.

Sex differences in cognitive function among people with HIV-1 clade C infection in Northern India.

Human immunodeficiency virus-1 (HIV-1) clade C is the most prevalent form of HIV-1 comprising nearly 46% of global infections and is the dominant subtype in India. Despite its predominance, the impact of HIV-1 clade C infection on cognitive function has been understudied in comparison with other subtypes, notably clade B, which is primarily found in Europe and North America. Few studies have assessed cognitive impairment in antiretroviral therapy (ART) naïve men and women with HIV-1 clade C infection. In this study conducted in Northern India, differences in neuropsychological functioning were compared between 109 participants (70 men, 39 women) with untreated HIV-1 clade C infection and 110 demographically matched healthy controls (74 men, 36 women). A comprehensive neuropsychological battery was used to examine depression, self-assessment of functioning, and cognitive performance in six domains of functioning. Group differences were assessed by HIV-1 status and sex, controlling for age and education. Results indicated that cognitive deficits were substantially greater among male participants with HIV-1 clade C compared to male controls in all domains of cognitive functioning; in contrast, women with HIV-1 clade C had only minor deficits compared to healthy female participants. In addition, a larger proportion of men with HIV-1 clade C exhibited high levels of depression than women with HIV-1 clade C. These findings suggest that untreated HIV-1 clade C infection in men can have debilitating effects on neuropsychological function and depression, and stress the importance of facilitating rapid access to treatment to reduce the impact of HIV-1 infection.

Brain MRI segmentation of Zika-Exposed normocephalic infants shows smaller amygdala volumes.

BACKGROUND: Infants with congenital Zika syndrome (CZS) are known to exhibit characteristic brain abnormalities. However, the brain anatomy of Zika virus (ZIKV)-exposed infants, born to ZIKV-positive pregnant mothers, who have normal-appearing head characteristics at birth, has not been evaluated in detail. The aim of this prospective study is, therefore, to compare the cortical and subcortical brain structural volume measures of ZIKV-exposed normocephalic infants to age-matched healthy controls. METHODS AND FINDINGS: We acquired T2-MRI of the whole brain of 18 ZIKV-exposed infants and 8 normal controls on a 3T MRI scanner. The MR images were auto-segmented into eight tissue types and anatomical regions including the white matter, cortical grey matter, deep nuclear grey matter, corticospinal fluid, amygdala, hippocampus, cerebellum, and brainstem. We determined the volumes of these regions and calculated the total intracranial volume (TICV) and head circumference (HC). We compared these measurements between the two groups, controlling for infant age at scan, by first comparing results for all subjects in each group and secondly performing a subgroup analysis for subjects below 8 weeks of postnatal age at scan. ZIKV-exposed infants demonstrated a significant decrease in amygdala volume compared to the control group in both the group and subgroup comparisons (p<0.05, corrected for multiple comparisons using FDR). No significant volume differences were observed in TICV, HC, or any specific brain tissue structures or regions. Study limitations include small sample size, which was due to abrupt cessation of extramural funding as the ZIKV epidemic waned. CONCLUSION: ZIKV-exposed infants exhibited smaller volumes in the amygdala, a brain region primarily involved in emotional and behavioral processing. This brain MRI finding may lead to poorer behavioral outcomes and warrants long-term monitoring of pediatric cases of infants with gestational exposure to Zika virus as well as other neurotropic viruses.

Resting state connectivity in people living with HIV before and after stopping heavy drinking.

Background: Heavy alcohol use in people living with HIV (PLWH) has widespread negative effects on neural functioning. It remains unclear whether experimentally-induced reduction in alcohol use could reverse these effects. We sought to determine the effects of 30-days drinking cessation/reduction on resting state functional connectivity in people with and without HIV. Methods: Thirty-five participants (48.6% PLWH) demonstrating heavy alcohol use attempted to stop drinking for 30 days via contingency management (CM). MRI was acquired at baseline and after thirty days, and functional connectivity across five resting-state fMRI (rsfMRI) networks was calculated with the Conn toolbox for Matlab and examined in relation to transdermal alcohol concentration (TAC) recorded by the ankle-worn secure continuous remote alcohol monitor (SCRAM) and self-reported alcohol use (timeline follow-back; TLFB). Associations between alcohol use and reduction, HIV status, functional connectivity, and change in functional connectivity across five major rsfMRI networks were determined relative to the pre- and post-CM timepoints. Results: Baseline resting-state functional connectivity was not significantly associated with average TAC-AUC during the pre-CM period, though higher self-reported alcohol use over the preceding 30 days was significantly associated with higher baseline connectivity within the Dorsal Attention Network (DAN; p-FDR < 0.05). Baseline connectivity within the Salience network was significantly negatively related to objective drinking reduction after intervention (DAN; p-FDR < 0.05), whereas baseline connectivity within the Limbic network was positively associated with self-reported drinking reduction (p-FDR < 0.05). Change in between-networks functional connectivity after intervention was significantly positively associated with biosensor-confirmed drinking reduction such that higher reduction was associated with stronger connectivity between the limbic and fronto-parietal control networks (p-FDR < 0.05). PLWH with lower DAN connectivity at baseline demonstrated poorer alcohol reduction than those with higher DAN connectivity at baseline. Discussion: Lower resting-state functional connectivity of the Salience network significantly predicted stronger drinking reduction across all participants, suggesting a potential biomarker for reduced susceptibility to the environmental and social cues that often make alcohol use reduction attempts unsuccessful. Increased between-networks connectivity was observed in participants with higher alcohol reduction after CM, suggesting a positive benefit to brain connectivity associated with reduced drinking. PLWH with lower baseline DAN connectivity may not benefit as greatly from CM for alcohol reduction.

Neurometabolite alterations in traumatic brain injury and associations with chronic pain.

Traumatic brain injury (TBI) can lead to a variety of comorbidities, including chronic pain. Although brain tissue metabolite alterations have been extensively examined in several chronic pain populations, it has received less attention in people with TBI. Thus, the primary aim of this study was to compare brain tissue metabolite levels in people with TBI and chronic pain (n = 16), TBI without chronic pain (n = 17), and pain-free healthy controls (n = 31). The metabolite data were obtained from participants using whole-brain proton magnetic resonance spectroscopic imaging (1H-MRSI) at 3 Tesla. The metabolite data included N-acetylaspartate, myo-inositol, total choline, glutamate plus glutamine, and total creatine. Associations between N-acetylaspartate levels and pain severity, neuropathic pain symptom severity, and psychological variables, including anxiety, depression, post-traumatic stress disorder (PTSD), and post-concussive symptoms, were also explored. Our results demonstrate N-acetylaspartate, myo-inositol, total choline, and total creatine alterations in pain-related brain regions such as the frontal region, cingulum, postcentral gyrus, and thalamus in individuals with TBI with and without chronic pain. Additionally, NAA levels in the left and right frontal lobe regions were positively correlated with post-concussive symptoms; and NAA levels within the left frontal region were also positively correlated with neuropathic pain symptom severity, depression, and PTSD symptoms in the TBI with chronic pain group. These results suggest that neuronal integrity or density in the prefrontal cortex, a critical region for nociception and pain modulation, is associated with the severity of neuropathic pain symptoms and psychological comorbidities following TBI. Our data suggest that a combination of neuronal loss or dysfunction and maladaptive neuroplasticity may contribute to the development of persistent pain following TBI, although no causal relationship can be determined based on these data.

Whole-brain MR spectroscopic imaging reveals regional metabolite abnormalities in perinatally HIV infected young adults.

Perinatally acquired HIV (PHIV) has been associated with brain structural and functional deficiencies, and with poorer cognitive performance despite the advent of antiretroviral therapy (ART). However, investigation of brain metabolite levels in PHIV measured by proton magnetic resonance spectroscopy (MRS) methods, is still limited with often inconclusive or contradictory findings. In general, these MRS-based methods have used a single voxel approach that can only evaluate metabolite concentrations in a few select brain anatomical regions. Additionally, most of the published data have been on children perinatally infected with HIV with only a few studies examining adult populations, though not exclusively. Therefore, this prospective and cross-sectional study aims to evaluate metabolite differences at the whole-brain level, using a unique whole-brain proton magnetic resonance spectroscopy imaging (MRSI) method, in a group of PHIV infected young adults (N = 28) compared to age and gender matched control sample (N = 28), and to find associations with HIV clinical factors and neurocognitive scores. MRSI data were acquired on a 3T scanner with a TE of 70 ms. Brain metabolites levels of total N-acetylaspartate (tNAA), total choline (tCho) and total creatine (tCre), as well as ratios of tNAA/tCre, tCho/tCre, and tNAA/tCho, were obtained from the whole brain level and evaluated at the level of gray matter (GM) and white matter (WM) tissue types and anatomical regions of interest (ROI). Our results indicate extensive metabolic abnormalities throughout the brains of PHIV infected subjects with significantly elevated levels of tCre and tCho, notably in GM regions. Decreases in tNAA and ratios of tNAA/tCre and tNAA/tCho were also found mostly in WM regions. These metabolic alterations indicate increased glial activation, inflammation, neuronal dysfunction, and energy metabolism in PHIV infected individuals, which correlated with a reduction in CD4 cell count, and lower cognitive scores. Our findings suggest that significant brain metabolite alterations and associated neurological complications persist in the brains of those with PHIV on long-term ART, and advocates the need for continued monitoring of their brain health.

Cross-sectional analysis of whole-brain microstructural changes in adult patients with bipolar and unipolar depression by diffusion kurtosis imaging.

RATIONALE AND OBJECTIVES: More than half of the bipolar depression (BD) subjects are misdiagnosed as unipolar depression (UD) due to lack of objective diagnostic criteria. We aimed to identify microstructural neuronal changes differentiating BD from UD groups using diffusion kurtosis imaging (DKI). The objective of the study is to identify an objective neuro-imaging marker to differentiate BD from UD. MATERIALS AND METHODS: A prospective, cross-sectional study included total of 62 subjects with diagnosis of bipolar depression (n = 21), unipolar depression (n = 21), and healthy controls (n = 20). All subjects underwent diffusion-weighted imaging (b = 0,1000,2000) of the whole brain on 3-Tesla MR scanner. DKI data was analyzed using 189 region whole-brain atlas. Eight diffusion and kurtosis metrics including mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), fractional anisotropy (FA), mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), and kurtosis fractional anisotropy (FKA) were measured against these 189 regions. Principle component analysis (PCA) was utilized to identify the most significant regions of the brain. ANOVA with post hoc tests was used for analyzing these regions. RESULTS: BD group showed increased MD, RD, decreased AK at the left amygdala and decreased MK and RK at the right hemi-cerebellum. UD group showed increased MK and RK at the right external capsule; and increased AK, MK, and RK at the right amygdala. CONCLUSION: The right and left amygdala, right external capsule, and right hemi-cerebellum showed microstructural abnormalities capable of differentiating BD and UD groups. Diffusion imaging especially DKI can aid in management of depression patients.

Multidimensional pain phenotypes after Traumatic Brain Injury.

More than 50% of individuals develop chronic pain following traumatic brain injury (TBI). Research suggests that a significant portion of post-TBI chronic pain conditions is neuropathic in nature, yet the relationship between neuropathic pain, psychological distress, and somatosensory function following TBI is not fully understood. This study evaluated neuropathic pain symptoms, psychological and somatosensory function, and psychosocial factors in individuals with TBI (TBI, N = 38). A two-step cluster analysis was used to identify phenotypes based on the Neuropathic Pain Symptom Inventory and Beck's Anxiety Inventory scores. Phenotypes were then compared on pain characteristics, psychological and somatosensory function, and psychosocial factors. Our analyses resulted in two different neuropathic pain phenotypes: (1) Moderate neuropathic pain severity and anxiety scores (MNP-AS, N = 11); and (2) mild or no neuropathic pain symptoms and anxiety scores (LNP-AS, N = 27). Furthermore, the MNP-AS group exhibited greater depression, PTSD, pain severity, and affective distress scores than the LNP-AS group. In addition, thermal somatosensory function (difference between thermal pain and perception thresholds) was significantly lower in the MNP-AS compared to the LNP-AS group. Our findings suggest that neuropathic pain symptoms are relatively common after TBI and are not only associated with greater psychosocial distress but also with abnormal function of central pain processing pathways.

Age-Associated Gut Dysbiosis, Marked by Loss of Butyrogenic Potential, Correlates With Altered Plasma Tryptophan Metabolites in Older People Living With HIV.

BACKGROUND: Imbalance in tryptophan (TRP) metabolism and its neuroactive metabolites, serotonin and kynurenine (KYN), is a known pathogenic mechanism underlying neurocognitive impairment. Gut microbiota plays an important role in TRP metabolism, and the production of these neuroactive molecules affects neurocognitive function. Although both HIV infection and normal aging independently induce gut dysbiosis and influence TRP metabolism, their interactive effects on compositional/functional changes in gut microbiota and consequent alterations in TRP metabolites remain largely undetermined. METHODS: Older people living with HIV infection (PLWH, aged 50-70 years, n = 22) were enrolled in this cross-sectional pilot study. Metagenomic analysis of fecal microbiome using 16S Ribosomal ribonucleic acid gene sequencing and metabolomics analysis of plasma using mass spectrometry with a reverse-phase iquid chromatography tandem mass spectrometry were performed. Statistical analyses included the univariate linear regression and Spearman correlation analyses. RESULTS: Age-associated changes in plasma levels of key neuroactive TRP metabolites, serotonin and KYN, were seen in PLWH. Specifically, we observed age-dependent decreases in serotonin and increases in KYN and KYN-to-TRP ratio, indicative of dysfunctional TRP metabolism. Furthermore, the gut dysbiosis seen in older PLWH is characterized by a reduction of Firmicutes/Bacteroidetes ratio and butyrate-producing microbial families Lachnospiraceae and Lactobacillaceae. Of importance, correspondent with gut dysbiosis, increasing age was significantly associated with decreased plasma butyrate levels, which in turn correlated positively with serotonin and negatively with KYN/TRP ratio. CONCLUSIONS: Age-dependent gut microbial dysbiosis distinguished by a decrease in butyrogenic potential is a key pathogenic feature associated with the shift in TRP metabolism from serotonin to KYN in older PLWH.

Comparative Evaluation of Diffusion Kurtosis Imaging and Diffusion Tensor Imaging in Detecting Cerebral Microstructural Changes in Alzheimer Disease.

OBJECTIVE: Comparative evaluation of diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) using a whole-brain atlas to comprehensively evaluate microstructural changes in the brain of Alzheimer disease (AzD) patients. METHODS: Twenty-seven AzD patients and 25 age-matched controls were included. MRI data was analyzed using a whole-brain atlas with inclusion of 98 region of interests. White matter (WM) microstructural changes were assessed by Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), Kurtosis fractional anisotropy (KFA), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK). Gray matter (GM) integrity was evaluated using KFA, MK, RK, AK and MD. Comparison of the DKI and DTI metrics were done using student t-test (p ≤ 0.001). RESULTS: In AzD patients widespread increase in MD, AD and RD were found in various WM and GM region of interests. The extent of abnormality for DKI parameters was more limited in both GM and WM regions and revealed reduced kurtosis values except in lentiform nuclei. Both DKI and DTI parameters were sensitive to detect abnormality in WM areas with coherent and complex fiber arrangement. Receiver operating characteristic curve analysis for hippocampal values revealed the highest specificity of 88% for AK <0.6965 and highest sensitivity of 95.2% for MD >1.2659. CONCLUSION: AzD patients have microstructural changes in both WM and GM and are well-depicted by both DKI and DTI. The alterations in kurtosis parameters, however, are more limited and correlate with areas in the brain primarily involved in cognition.

Whole brain atlas-based diffusion kurtosis imaging parameters for evaluation of minimal hepatic encephalopathy.

BACKGROUND AND PURPOSES: Minimal hepatic encephalopathy (MHE) has no recognizable clinical symptoms, but patients have cognitive and psychomotor deficits. Hyperammonemia along with neuroinflammation lead to microstructural changes in cerebral parenchyma. Changes at conventional imaging are detected usually at the overt clinical stage, but microstructural alterations by advanced magnetic resonance imaging techniques can be detected at an early stage. MATERIALS AND METHODS: Whole brain diffusion kurtosis imaging (DKI) data acquired at 3T was analyzed to investigate microstructural parenchymal changes in 15 patients with MHE and compared with 15 age- and sex-matched controls. DKI parametric maps, namely kurtosis fractional anisotropy (kFA), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK), were evaluated at 64 white matter (WM) and gray matter (GM) regions of interest (ROIs) in the whole brain and correlated with the psychometric hepatic encephalopathy score (PHES). RESULTS: The MHE group showed a decrease in kFA and AK across the whole brain, whereas MK and RK decreased in WM ROIs but increased in several cortical and deep GM ROIs. These alterations were consistent with brain regions involved in cognitive function. Significant moderate to strong correlations (-0.52 to -0.66; 0.56) between RK, MK and kFA kurtosis metrics and PHES were observed. CONCLUSION: DKI parameters show extensive microstructural brain abnormalities in MHE with minor correlation between the severity of tissue damage and psychometric scores.

Evaluation of cerebral microstructural changes in adult patients with obstructive sleep apnea by MR diffusion kurtosis imaging using a whole-brain atlas.

PURPOSE: The association between obstructive sleep apnea (OSA) and cognitive impairment is well-recognized, but little is known about neural derangements that underlie this phenomenon. The purpose of this study was to evaluate the utility of diffusion kurtosis imaging (DKI) using a whole-brain atlas to comprehensively assess microstructural tissue changes in the brain of patients with OSA. METHODS: This prospective study was conducted in 20 patients with moderate-to-severe OSA and 20 age- and gender-matched controls. MRI data acquisition was performed with 3 Tesla and data was analyzed using a whole-brain atlas. DKI data were processed and transformed into a brain template space to obtain various kurtosis parameters including axial kurtosis (AK), radial kurtosis (RK), mean kurtosis (MK), and kurtosis fractional anisotropy (KFA) using a 189-region brain atlas in the same template space. These kurtosis measurements were further analyzed using a student t-test in order to determine kurtosis measurements that present significant differences between the OSA patient set and the control set. RESULTS: Significant differences (P < 0.05) were found in AK (54 regions), RK (10 regions), MK (6 regions) and KFA (41 regions) values in patients with OSA as compared to controls. DKI indices, using an atlas-based whole-brain analysis approach used in our study, showed widespread involvement of the anatomical regions in patients with OSA. CONCLUSION: The kurtosis parameters are more sensitive in demonstrating abnormalities in brain tissue structural organization at the microstructural level before any detectable changes appear in conventional MRI or other imaging modalities.

Longitudinal MR Spectroscopy Shows Altered Metabolism in Traumatic Brain Injury.

BACKGROUND AND PURPOSE: Brain trauma is known to result in heterogeneous patterns of tissue damage and altered neuronal and glial metabolism that evolve over time following injury; however, little is known on the longitudinal evolution of these changes. In this study, magnetic resonance spectroscopic imaging (MRSI) was used to map the distributions of altered metabolism in a single subject at five time points over a period of 28 months following injury. METHODS: Magnetic resonance imaging and volumetric MRSI data were acquired in a subject that had experienced a moderate traumatic brain injury (Glasgow Coma Scale 13) at five time points, from 7 weeks to 28 months after injury. Maps of N-acetylaspartate (NAA), total choline (Cho), and total creatine signal were generated and differences from normal control values identified using a z-score image analysis method. RESULTS: The z-score metabolite maps revealed areas of significantly reduced NAA and increased Cho, predominately located in frontal and parietal white matter, which evolved over the complete course of the study. A map of the ratio of Cho/NAA showed the greatest sensitivity to change, which indicated additional metabolic changes throughout white matter. The metabolic changes reduced over time following injury, though with abnormal values remaining in periventricular regions. CONCLUSIONS: The use of z-score image analysis for MRSI provides a method for visualizing diffuse changes of tissue metabolism in the brain. This image visualization method is of particularly effective for visualizing widespread and diffuse metabolic changes, such as that due to traumatic injury.

Glutathione Conformations and Its Implications for in vivo Magnetic Resonance Spectroscopy.

Glutathione (GSH) is a major antioxidant in humans that is involved in the detoxification of reactive radicals and peroxides. The molecular structural conformations of GSH depend on the surrounding micro-environment, and it has been experimentally evaluated using NMR and Raman spectroscopic techniques as well as by molecular dynamics simulation studies. The converging report indicates that GSH exists mainly in two major conformations, i.e., "extended" and "folded". The NMR-derived information on the GSH conformers is essential to obtain optimal acquisition parameters in in vivo MRS experiments targeted for GSH detection. To further investigate the implications of GSH conformers in in vivo MRS studies and their relative proportions in healthy and pathological conditions, a multi-center clinical research study is necessary with a common protocol for GSH detection and quantification.

Young adults perinatally infected with HIV perform more poorly on measures of executive functioning and motor speed than ethnically matched healthy controls.

Perinatal HIV is associated with significant neurocognitive morbidities, but few studies have examined cognitive impact of early HIV infection on patients surviving to adulthood. The purpose of this study was to evaluate neurocognitive outcomes among a cohort of perinatally infected young adults. Individuals between the ages of 18 and 24 with perinatal infection were recruited for this cross-sectional study along with similarly aged healthy controls. Participants completed an MRI and brief neuropsychological assessment battery. Multivariate analysis of covariance controlling for age, gender, race/ethnicity, and education was completed to detect differences between the HIV+ and control groups. Multivariable linear regression was performed to assess HIV-associated factors potentially impacting neuropsychological findings among the HIV+ group. Twenty-nine HIV+ young adults and 13 healthy controls were included in the study. After adjusting for age and sociodemographic variables, the HIV+ group scored lower on attention/working memory (Digit Span (p = .008) and Letter-Number Sequencing (p = .038)), set-shifting (DKEFS Trail Making Test Condition 4 (p = .026) and motor speed (DKEFS Trail Making Test Condition 5 (p = .003)). For the HIV+ group, nadir CD4 was associated with better Letter-Number Sequencing score (p = .029) and use of highly active antiretroviral therapy was associated with better performance on Category Fluency (p = .040). After controlling for sociodemographic variables, executive dysfunction persists among young adults with perinatal HIV infection in comparison to controls. Future studies to further elucidate the impact of executive dysfunction on independent living and functional outcomes are indicated.

A large-scale multicentre cerebral diffusion tensor imaging study in amyotrophic lateral sclerosis.

OBJECTIVE: Damage to the cerebral tissue structural connectivity associated with amyotrophic lateral sclerosis (ALS), which extends beyond the motor pathways, can be visualised by diffusion tensor imaging (DTI). The effective translation of DTI metrics as biomarker requires its application across multiple MRI scanners and patient cohorts. A multicentre study was undertaken to assess structural connectivity in ALS within a large sample size. METHODS: 442 DTI data sets from patients with ALS (N=253) and controls (N=189) were collected for this retrospective study, from eight international ALS-specialist clinic sites. Equipment and DTI protocols varied across the centres. Fractional anisotropy (FA) maps of the control participants were used to establish correction matrices to pool data, and correction algorithms were applied to the FA maps of the control and ALS patient groups. RESULTS: Analysis of data pooled from all centres, using whole-brain-based statistical analysis of FA maps, confirmed the most significant alterations in the corticospinal tracts, and captured additional significant white matter tract changes in the frontal lobe, brainstem and hippocampal regions of the ALS group that coincided with postmortem neuropathological stages. Stratification of the ALS group for disease severity (ALS functional rating scale) confirmed these findings. INTERPRETATION: This large-scale study overcomes the challenges associated with processing and analysis of multiplatform, multicentre DTI data, and effectively demonstrates the anatomical fingerprint patterns of changes in a DTI metric that reflect distinct ALS disease stages. This success paves the way for the use of DTI-based metrics as read-out in natural history, prognostic stratification and multisite disease-modifying studies in ALS.

Subacute Pain after Traumatic Brain Injury Is Associated with Lower Insular N-Acetylaspartate Concentrations.

Persistent pain is experienced by more than 50% of persons who sustain a traumatic brain injury (TBI), and more than 30% experience significant pain as early as 6 weeks after injury. Although neuropathic pain is a common consequence after CNS injuries, little attention has been given to neuropathic pain symptoms after TBI. Magnetic resonance spectroscopy (MRS) studies in subjects with TBI show decreased brain concentrations of N-acetylaspartate (NAA), a marker of neuronal density and viability. Although decreased brain NAA has been associated with neuropathic pain associated with spinal cord injury (SCI) and diabetes, this relationship has not been examined after TBI. The primary purpose of this study was to test the hypothesis that lower NAA concentrations in brain areas involved in pain perception and modulation would be associated with greater severity of neuropathic pain symptoms. Participants with TBI underwent volumetric MRS, pain and psychosocial interviews. Cluster analysis of the Neuropathic Pain Symptom Inventory subscores resulted in two TBI subgroups: The Moderate Neuropathic Pain (n = 17; 37.8%), with significantly (p = 0.038) lower insular NAA than the Low or no Neuropathic Pain group (n = 28; 62.2%), or age- and sex-matched controls (n = 45; p < 0.001). A hierarchical linear regression analysis controlling for age, sex, and time post-TBI showed that pain severity was significantly (F = 11.0; p < 0.001) predicted by a combination of lower insular NAA/Creatine (p < 0.001), lower right insular gray matter fractional volume (p < 0.001), female sex (p = 0.005), and older age (p = 0.039). These findings suggest that neuronal dysfunction in brain areas involved in pain processing is associated with pain after TBI.

Distributions of Magnetic Resonance Diffusion and Spectroscopy Measures with Traumatic Brain Injury.

Magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) studies have demonstrated that measures of altered metabolism and axonal injury can be detected following traumatic brain injury. The aim of this study was to characterize and compare the distributions of altered image parameters obtained by these methods in subjects with a range of injury severity and to examine their relative sensitivity for diagnostic imaging in this group of subjects. DTI and volumetric magnetic resonance spectroscopic imaging data were acquired in 40 subjects that had experienced a closed-head traumatic brain injury, with a median of 36 d post-injury. Voxel-based analyses were performed to examine differences of group mean values relative to normal controls, and to map significant alterations of image parameters in individual subjects. The between-group analysis revealed widespread alteration of tissue metabolites that was most strongly characterized by increased choline throughout the cerebrum and cerebellum, reaching as much as 40% increase from control values for the group with the worse cognitive assessment score. In contrast, the between-group comparison of DTI measures revealed only minor differences; however, the Z-score image analysis of individual subject DTI parameters revealed regions of altered values relative to controls throughout the major white matter tracts, but with considerable heterogeneity between subjects and with a smaller extent than the findings for altered metabolite measures. The findings of this study illustrate the complimentary nature of these neuroimaging methods.

Whole-brain proton MR spectroscopic imaging in Parkinson's disease.

BACKGROUND AND PURPOSE: To examine the distributions of proton magnetic resonance spectroscopy (MRS) observed metabolites in Parkinson's disease (PD) throughout the whole brain. METHODS: Twelve PD patients and 18 age-matched controls were studied using neuropsychological testing, MRI and volumetric MR spectroscopic imaging. Average values of signal normalized metabolite values for N-acetyl-aspartate, total-creatine, and total-choline (NAA, total-Cre, total-Cho, respectively) and their ratios were calculated for gray matter (GM) and white matter (WM) in each lobar brain region. RESULTS: Analyses revealed altered metabolite values in PD subjects relative to controls within the GM of the temporal lobe (right: elevated Cre, P = .027; decreased NAA/Cre, P = .019; decreased Cho/Cre, P = .001 and left: decreased NAA/Cre; P = .001, decreased Cho/Cre, P = .007); the right occipital lobe (decreased NAA, P = .032 and NAA/Cre, P = .016); and the total cerebrum GM (decreased NAA/Cre, P = .029). No meaningful correlations were obtained between abnormal metabolite values and the neuropsychological measures. CONCLUSIONS: PD is associated with widespread alterations of brain metabolite concentrations, with a primary finding of increased creatine. Higher creatine values in our PD sample may reflect greater neuronal energy expenditure early in the disease process that is compensatory. This is the first whole brain MRS study of PD that has examined metabolite changes across a large fraction of the brain volume, including the cortical mantle.