Relationships between plasma neurofilament light chain protein, cognition, and brain aging in people with HIV.

OBJECTIVE: Neurofilament light chain protein (NfL) is a marker of neuronal injury and neurodegeneration. Typically assessed in cerebrospinal fluid, recent advances have allowed this biomarker to be more easily measured in plasma. This study assesses plasma NfL in people with HIV (PWH) compared with people without HIV (PWoH), and its relationship with cognitive impairment, cardiovascular risk, and a neuroimaging metric of brain aging [brain-age gap (BAG)]. DESIGN: One hundred and four PWH (HIV RNA <50 copies/ml) and 42 PWoH provided blood samples and completed a cardiovascular risk score calculator, neuroimaging, and cognitive testing. METHOD: Plasma NfL was compared between PWoH and PWH and assessed for relationships with age, HIV clinical markers, cardiovascular disease risk, cognition, and BAG (difference between a brain-predicted age and chronological age). RESULTS: Plasma NfL was not significantly different between PWoH and PWH. Higher NfL related to increasing age in both groups. Plasma NfL was not associated with typical HIV disease variables. Within PWH, NfL was higher with higher cardiovascular risk, cognitive impairment and a greater BAG. CONCLUSION: Virally suppressed PWH who are cognitively normal likely do not have significant ongoing neurodegeneration, as evidenced by similar plasma NfL compared with PWoH. However, NfL may represent a biomarker of cognitive impairment and brain aging in PWH. Further research examining NfL with longitudinal cognitive decline is needed to understand this relationship more fully.

Accentuated Paralimbic and Reduced Mesolimbic D2/3-Impulsivity Associations in Parkinson's Disease.

Impulsivity is a behavioral trait that is elevated in many neuropsychiatric disorders. Parkinson's disease (PD) patients can exhibit a specific pattern of reward-seeking impulsive-compulsive behaviors (ICBs), as well as more subtle changes to generalized trait impulsivity. Prior studies in healthy controls (HCs) suggest that trait impulsivity is regulated by D2/3 autoreceptors in mesocorticolimbic circuits. While altered D2/3 binding is noted in ICB+ PD patients, there is limited prior assessment of the trait impulsivity-D2/3 relationship in PD, and no prior direct comparison with patterns in HCs. We examined 54 PD (36 M; 18 F) and 31 sex- and age-matched HC (21 M; 10 F) subjects using [18F]fallypride, a high-affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). Subcortical and cortical assessment exclusively used ROI or exploratory-voxelwise methods, respectively. All completed the Barratt Impulsiveness Scale, a measure of trait impulsivity. Subcortical ROI analyses indicated a negative relationship between trait impulsivity and D2/3 BPND in the ventral striatum and amygdala of HCs but not in PD. By contrast, voxelwise methods demonstrated a positive trait impulsivity-D2/3 BPND correlation in ventral frontal olfactocentric-paralimbic cortex of subjects with PD but not HCs. Subscale analysis also highlighted different aspects of impulsivity, with significant interactions between group and motor impulsivity in the ventral striatum, and attentional impulsivity in the amygdala and frontal paralimbic cortex. These results suggest that dopamine functioning in distinct regions of the mesocorticolimbic circuit influence aspects of impulsivity, with the relative importance of regional dopamine functions shifting in the neuropharmacological context of PD.SIGNIFICANCE STATEMENT The biological determinants of impulsivity have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease. This is the first study to evaluate a large cohort of Parkinson's disease patients and age-matched healthy controls with a measure of trait impulsivity and concurrent [18F]fallypride PET, a method that allows quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in the trait impulsivity-dopamine relationship, including (1) loss of subcortical relationships present in the healthy brain and (2) emergence of a new relationship in a limbic cortical area. This illustrates the loss of mechanisms of behavioral regulation present in the healthy brain while suggesting a potential compensatory response and target for future investigation.

Sex-specific associations between plasma interleukin-6 and depression in persons with and without HIV.

Background: Persons with HIV (PWH) have both more frequent depression and higher levels of plasma inflammatory biomarkers compared to persons without HIV (PWoH). Inflammation and depressive symptoms are linked, including in PWH; however, it is unclear whether these associations differ by HIV serostatus and biological sex. Methods: Six plasma inflammatory biomarkers were assessed using samples from PWH and PWoH who participated in six NIH-funded studies through the UCSD HIV Neurobehavioral Research Program (HNRP) from 2011 to 2019. Factor analysis was performed to identify intercorrelated groups of biomarkers. Factors and their components were then examined for relationships with Beck Depression Inventory-II (BDI-II) and modifying effects of sex or HIV serostatus using multivariable linear regression, adjusting for demographics, substance use diagnoses, and relevant co-morbidities. Results: Participants included 150 PWH (age = 48.3 ± 13.1 yr; 88% biologically male) and 138 PWoH (age = 46.3 ± 15.9; 56% male). Two inflammatory factors were identified: Factor 1 loaded on interleukin-6 (IL-6), C-reactive protein (CRP), and D-dimer; Factor 2 loaded on interleukin-8, chemokine C-C ligand 2 (CCL2), and chemokine C-X-C ligand 10 (CXCL10). Sex modified the effect of Factor 1 on BDI-II, with a more positive association for men than women (p = 0.04). No significant association between Factor 2 and BDI-II was found. Of the biomarkers in Factor 1, only IL-6 was significantly associated with BDI-II and was modified by sex (p = 0.003). In sex-stratified analysis, a positive association was found for men (ß = 5.42; 95% confidence interval = [1.32, 9.52]) but not women (ß = -3.88; 95% C.I. = [-11.02, 3.26]). No HIV-related interactions were detected. Interpretation: We identified a depression-associated inflammatory factor present in both PWH and PWoH, consistent with prior studies of PWH only. The association was driven by a correlation between IL-6 and depression exclusively in men, suggesting that the depression-inflammation link differs by sex. Future studies of depression etiology or treatment, including those on persons with HIV, should consider the impact of biological sex in both design and analysis.

Increased Peripheral Inflammation Is Associated With Structural Brain Changes and Reduced Blood Flow in People With Virologically Controlled HIV.

BACKGROUND: While antiretroviral therapy (ART) has improved outcomes for people with HIV (PWH), brain dysfunction is still evident. Immune activation and inflammation remain elevated in PWH receiving ART, thereby contributing to morbidity and mortality. Previous studies demonstrated reduced functional and structural changes in PWH; however, underlying mechanisms remain elusive. METHODS: Our cohort consisted of PWH with ART adherence and viral suppression ( < 50 copies/mL; N = 173). Measurements included immune cell markers of overall immune health (CD4/CD8 T-cell ratio) and myeloid inflammation (CD16+ monocytes), plasma markers of inflammatory status (soluble CD163 and CD14), and structural and functional neuroimaging (volume and cerebral blood flow [CBF], respectively). RESULTS: Decreased CD4/CD8 ratios correlated with reduced brain volume, and higher levels of inflammatory CD16+ monocytes were associated with reduced brain volume in total cortex and gray matter. An increase in plasma soluble CD14-a marker of acute peripheral inflammation attributed to circulating microbial products-was associated with reduced CBF within the frontal, parietal, temporal, and occipital cortices and total gray matter. CONCLUSIONS: CD4/CD8 ratio and number of CD16+ monocytes, which are chronic immune cell markers, are associated with volumetric loss in the brain. Additionally, this study shows a potential new association between plasma soluble CD14 and CBF.

Machine Learning Approaches to Understand Cognitive Phenotypes in People With HIV.

Cognitive disorders are prevalent in people with HIV (PWH) despite antiretroviral therapy. Given the heterogeneity of cognitive disorders in PWH in the current era and evidence that these disorders have different etiologies and risk factors, scientific rationale is growing for using data-driven models to identify biologically defined subtypes (biotypes) of these disorders. Here, we discuss the state of science using machine learning to understand cognitive phenotypes in PWH and their associated comorbidities, biological mechanisms, and risk factors. We also discuss methods, example applications, challenges, and what will be required from the field to successfully incorporate machine learning in research on cognitive disorders in PWH. These topics were discussed at the National Institute of Mental Health meeting on "Biotypes of CNS Complications in People Living with HIV" held in October 2021. These ongoing research initiatives seek to explain the heterogeneity of cognitive phenotypes in PWH and their associated biological mechanisms to facilitate clinical management and tailored interventions.

Effects of clinical, comorbid, and social determinants of health on brain ageing in people with and without HIV: a retrospective case-control study.

BACKGROUND: Neuroimaging reveals structural brain changes linked with HIV infection and related neurocognitive disorders; however, group-level comparisons between people with HIV and people without HIV do not account for within-group heterogeneity. The aim of this study was to quantify the effects of comorbidities such as cardiovascular disease and adverse social determinants of health on brain ageing in people with HIV and people without HIV. METHODS: In this retrospective case-control study, people with HIV from Washington University in St Louis, MO, USA, and people without HIV identified through community organisations or the Research Participant Registry were clinically characterised and underwent 3-Tesla T1-weighted MRI between Dec 3, 2008, and Oct 4, 2022. Exclusion criteria were established by a combination of self-reports and medical records. DeepBrainNet, a publicly available machine learning algorithm, was applied to estimate brain-predicted age from MRI for people with HIV and people without HIV. The brain-age gap, defined as the difference between brain-predicted age and true chronological age, was modelled as a function of clinical, comorbid, and social factors by use of linear regression. Variables were first examined singly for associations with brain-age gap, then combined into multivariate models with best-subsets variable selection. FINDINGS: In people with HIV (mean age 44·8 years [SD 15·5]; 78% [296 of 379] male; 69% [260] Black; 78% [295] undetectable viral load), brain-age gap was associated with Framingham cardiovascular risk score (p=0·0034), detectable viral load (>50 copies per mL; p=0·0023), and hepatitis C co-infection (p=0·0065). After variable selection, the final model for people with HIV retained Framingham score, hepatitis C, and added unemployment (p=0·0015). Educational achievement assayed by reading proficiency was linked with reduced brain-age gap (p=0·016) for people without HIV but not for people with HIV, indicating a potential resilience factor. When people with HIV and people without HIV were modelled jointly, selection resulted in a model containing cardiovascular risk (p=0·0039), hepatitis C (p=0·037), Area Deprivation Index (p=0·033), and unemployment (p=0·00010). Male sex (p=0·078) and alcohol use history (p=0·090) were also included in the model but were not individually significant. INTERPRETATION: Our findings indicate that comorbid and social determinants of health are associated with brain ageing in people with HIV, alongside traditional HIV metrics such as viral load and CD4 cell count, suggesting the need for a broadened clinical perspective on healthy ageing with HIV, with additional focus on comorbidities, lifestyle changes, and social factors. FUNDING: National Institute of Mental Health, National Institute of Nursing Research, and National Institute of Drug Abuse.

Machine Learning Quantifies Accelerated White-Matter Aging in Persons With HIV.

BACKGROUND: Persons with HIV (PWH) undergo white matter changes, which can be quantified using the brain-age gap (BAG), the difference between chronological age and neuroimaging-based brain-predicted age. Accumulation of microstructural damage may be accelerated in PWH, especially with detectable viral load (VL). METHODS: In total, 290 PWH (85% with undetectable VL) and 165 HIV-negative controls participated in neuroimaging and cognitive testing. BAG was measured using a Gaussian process regression model trained to predict age from diffusion magnetic resonance imaging in publicly available normative controls. To test for accelerated aging, BAG was modeled as an age × VL interaction. The relationship between BAG and global neuropsychological performance was examined. Other potential predictors of pathological aging were investigated in an exploratory analysis. RESULTS: Age and detectable VL had a significant interactive effect: PWH with detectable VL accumulated +1.5 years BAG/decade versus HIV-negative controls (P = .018). PWH with undetectable VL accumulated +0.86 years BAG/decade, although this did not reach statistical significance (P = .052). BAG was associated with poorer global cognition only in PWH with detectable VL (P < .001). Exploratory analysis identified Framingham cardiovascular risk as an additional predictor of pathological aging (P = .027). CONCLUSIONS: Aging with detectable HIV and cardiovascular disease may lead to white matter pathology and contribute to cognitive impairment.

The Structural and Functional Correlates of Frailty in Persons With Human Immunodeficiency Virus.

BACKGROUND: Persons with HIV (PWH) are at increased risk of frailty, a clinically recognizable state of increased vulnerability resulting from aging-associated decline in multiple physiologic systems. Frailty is often defined by the Fried criteria, which includes subjective and objective standards concerning health resiliency. However, these frailty metrics do not incorporate cognitive performance or neuroimaging measures. METHODS: We compared structural (diffusion tensor imaging [DTI]) and functional (cerebral blood flow [CBF]) neuroimaging markers in PWH with frailty and cognitive performance. Virologically controlled PWH were dichotomized as either frail (≥3) or nonfrail (<3) using the Fried criteria. Cognitive Z-scores, both domain (executive, psychomotor speed, language, and memory) and global, were derived from a battery of tests. We identified three regions of reduced CBF, based on a voxel-wise comparison of frail PWH compared with nonfrail PWH. These clusters (bilateral frontal and posterior cingulate) were subsequently used as seed regions of interest (ROIs) for DTI probabilistic white matter tractography. RESULTS: White matter integrity connecting the ROIs was significantly decreased in frail compared with nonfrail PWH. No differences in cognition were observed between frail and nonfrail PWH. However, reductions in white matter integrity among these ROIs was significantly associated with worse psychomotor speed and executive function across the entire cohort. CONCLUSIONS: We conclude that frailty in PWH can lead to structural and functional brain changes, including subtle changes that are not detectable by standard neuropsychological tests. Multimodal neuroimaging in conjunction with frailty assessment could identify pathological brain changes observed in PWH.

Effects of Framingham 10-Year Cardiovascular Risk Score and Viral Load on Brain Integrity in Persons With HIV.

BACKGROUND: Combination antiretroviral therapy (cART) has allowed for viral load (VL) suppression and increased life expectancy for persons with HIV (PWH). Altered brain integrity, measured by neuropsychological (NP) performance and neuroimaging, is still prevalent among virally suppressed PWH. Age-related conditions such as cardiovascular disease may also affect brain integrity. This study investigated the effects of cardiovascular risk, VL, and HIV serostatus on cerebral blood flow (CBF), brain volumetrics, and cognitive function in PWH and persons without HIV (PWoH). METHODS: Ten-year cardiovascular risk, using the Framingham Heart Study criteria, was calculated in PWH (n = 164) on cART with undetectable (≤20 copies/mL; n = 134) or detectable (>20 copies/mL; n = 30) VL and PWoH (n = 66). The effects of cardiovascular risk on brain integrity (CBF, volume, and cognition) were compared for PWH (undetectable and detectable VL) and PWoH. RESULTS: PWH had smaller brain volumes and worse NP scores than PWoH. PWH with detectable and undetectable VL had similar brain integrity measures. Higher cardiovascular risk was associated with smaller volumes and lower CBF in multiple brain regions for PWH and PWoH. Significant interactions between HIV serostatus and cardiovascular risk on brain volumes were observed in frontal, orbitofrontal, and motor regions. Cardiovascular risk was not associated with cognition for PWH or PWoH. CONCLUSIONS: Neuroimaging, but not cognitive measures, was associated with elevated cardiovascular risk. HIV serostatus was associated with diminished brain volumes and worse cognition while CBF remained unchanged, reflecting potential protective effects of cART. Neuroimaging measures of structure (volume) and function (CBF) may identify contributions of comorbidities, but future longitudinal studies are needed.

Physical Therapy in Women with Early Stage Lipedema: Potential Impact of Multimodal Manual Therapy, Compression, Exercise, and Education Interventions.

Background: Lipedema is a distinct adipose disorder from obesity necessitating awareness as well as different management approaches to address pain and optimize quality of life (QoL). The purpose of this proof-of-principle study is to evaluate the therapeutic potential of physical therapy interventions in women with lipedema. Methods and Results: Participants with Stage 1-2 lipedema and early Stage 0-1 lymphedema (n = 5, age = 38.4 ± 13.4 years, body mass index = 27.2 ± 4.3 kg/m2) underwent nine visits of physical therapy in 6 weeks for management of symptoms impacting functional mobility and QoL. Pre- and post-therapy, participants were scanned with 3 Tesla sodium and water magnetic resonance imaging (MRI), underwent biophysical measurements, and completed questionnaires measuring function and QoL (patient-specific functional scale, PSFS, and RAND-36). Pain was measured at each visit using the 0-10 visual analog scale (VAS). Treatment effect was calculated for all study variables. The primary symptomatology measures of pain and function revealed clinically significant post-treatment improvements and large treatment effects (Cohen's d for pain VAS = -2.5 and PSFS = 4.4). The primary sodium MRI measures, leg skin sodium, and subcutaneous adipose tissue (SAT) sodium, reduced following treatment and revealed large treatment effects (Cohen's d for skin sodium = -1.2 and SAT sodium = -0.9). Conclusions: This proof-of-principle study provides support that persons with lipedema can benefit from physical therapy to manage characteristic symptoms of leg pain and improve QoL. Objective MRI measurement of reduced tissue sodium in the skin and SAT regions indicates reduced inflammation in the treated limbs. Further research is warranted to optimize the conservative therapy approach in lipedema, a condition for which curative and disease-modifying treatments are unavailable.

Accelerated Brain Aging and Cerebral Blood Flow Reduction in Persons With Human Immunodeficiency Virus.

BACKGROUND: Persons with human immunodeficiency virus (PWH) are characterized by altered brain structure and function. As they attain normal lifespans, it has become crucial to understand potential interactions between human immunodeficiency virus (HIV) and aging. However, it remains unclear how brain aging varies with viral load (VL). METHODS: In this study, we compare magnetic resonance imaging (MRI) biomarkers among PWH with undetectable VL (UVL; ≤50 genomic copies/mL; n = 230), PWH with detectable VL (DVL; >50 copies/mL; n = 93), and HIV-uninfected (HIV-) controls (n = 206). To quantify gray matter cerebral blood flow (CBF), we utilized arterial spin labeling. To measure structural aging, we used a publicly available deep learning algorithm to estimate brain age from T1-weighted MRI. Cognitive performance was measured using a neuropsychological battery covering 5 domains. RESULTS: Associations between age and CBF varied with VL. Older PWH with DVL had reduced CBF vs PWH with UVL (P = .02). Structurally predicted brain aging was accelerated in PWH vs HIV- controls regardless of VL (P < .001). Overall, PWH had impaired learning, executive function, psychomotor speed, and language compared to HIV- controls. Structural brain aging was associated with reduced psychomotor speed (P < .001). CONCLUSIONS: Brain aging in HIV is multifaceted. CBF depends on age and current VL and is improved by medication adherence. By contrast, structural aging is an indicator of cognitive function and reflects serostatus rather than current VL.

Mapping the orbitofrontal cortex using temporal fluctuations in cerebral blood flow.

INTRODUCTION: The orbitofrontal cortex (OFC) is involved in diverse cognitive and behavioral processes including incentive valuation, decision-making, and reinforcement learning. Anatomic and cytoarchitectonic studies divide the OFC along both medial-lateral and rostral-caudal axes. OFC regions diverge in structure and function, assessed in vivo using white matter tractography and blood oxygenation level-dependent (BOLD) MRI, respectively. However, interpretation of T2 *-weighted BOLD is limited by susceptibility artifacts in the inferior frontal lobes, with the spatial pattern of these artifacts frequently assuming the geometry of OFC organization. Here, we utilize a novel perfusion-weighted arterial spin labeling (ASL) functional connectivity approach, which is minimally susceptibility-weighted, to test the hypothesis that OFC topology reflects correlated temporal hemodynamic activity. METHODS: In healthy participants (n = 20; age = 29.5 ± 7.3), 3D ASL scans were acquired (TR/TE = 3,900/13 ms; spatial resolution = 3.8 mm isotropic). To evaluate reproducibility, follow-up scanning on a separate day was performed on a participant subset (n = 8). ASL-based connectivity was modeled for gray matter OFC voxels, and k-means clustering (k = 2-8) applied to correlation statistics. RESULTS: These approaches revealed both medial-lateral and rostral-caudal OFC divisions, confirming our hypothesis. Longitudinal reproducibility testing revealed 84% voxel clustering agreement between sessions for the k = 2 solution. CONCLUSION: To our knowledge, this constitutes the first in vivo cortical parcellation based on perfusion fluctuations. Our approach confirms functional OFC subdivisions predicted from anatomy using a less susceptibility-sensitive method than the conventional approach.

Network Localization of Alien Limb in Patients with Corticobasal Syndrome.

OBJECTIVE: Perirolandic atrophy occurs in corticobasal syndrome (CBS) but is not specific versus progressive supranuclear palsy (PSP). There is heterogeneity in the locations of atrophy outside the perirolandic cortex and it remains unknown why atrophy in different locations would cause the same CBS-specific symptoms. In prior work, we used a wiring diagram of the brain called the human connectome to localize lesion-induced disorders to symptom-specific brain networks. Here, we use a similar technique termed "atrophy network mapping" to localize single-subject atrophy maps to symptom-specific brain networks. METHODS: Single-subject atrophy maps were generated by comparing cortical thickness in patients with CBS versus controls. Next, we performed seed-based functional connectivity using a large normative connectome to determine brain regions functionally connected to each patient's atrophied locations. RESULTS: Patients with CBS had perirolandic atrophy versus controls at the group level, but locations of atrophy in CBS were heterogeneous outside of the perirolandic cortex at the single-subject level (mean spatial correlation = 0.04). In contrast, atrophy occurred in locations functionally connected to the perirolandic cortex in all patients with CBS (spatial correlation = 0.66). Compared with PSP, patients with CBS had atrophy connected to a network of higher-order sensorimotor regions beyond perirolandic cortex, matching a CBS atrophy network from a recent meta-analysis. Finally, atrophy network mapping identified a symptom-specific network for alien limb, matching a lesion-induced alien limb network and a network associated with agency in healthy subjects. INTERPRETATION: We identified a syndrome-specific network for CBS and symptom-specific network for alien limb using single-subject atrophy maps and the human connectome. ANN NEUROL 2020;88:1118-1131.

Magnetic resonance imaging and bioimpedance evaluation of lymphatic abnormalities in patients with breast cancer treatment-related lymphedema.

PURPOSE: Breast cancer treatment-related lymphedema (BCRL) evaluation is frequently performed using portable measures of limb volume and bioimpedance asymmetry. Here quantitative magnetic resonance imaging (MRI) is applied to evaluate deep and superficial tissue impairment, in both surgical and contralateral quadrants, to test the hypothesis that BCRL impairment is frequently bilateral and extends beyond regions commonly evaluated with portable external devices. METHODS: 3-T MRI was applied to investigate BCRL topographical impairment. Female BCRL (n = 33; age = 54.1 ± 11.2 years; stage = 1.5 ± 0.8) and healthy (n = 33; age = 49.4 ± 11.0 years) participants underwent quantitative upper limb MRI relaxometry (T2), bioimpedance asymmetry, arm volume asymmetry, and physical evaluation. Parametric tests were applied to evaluate study measurements (i) between BCRL and healthy participants, (ii) between surgical and contralateral limbs, and (iii) in relation to clinical indicators of disease severity. Two-sided p-value < 0.05 was required for significance. RESULTS: Bioimpedance asymmetry was significantly correlated with MRI-measured water relaxation (T2) in superficial tissue. Deep muscle (T2 = 37.6 ± 3.5 ms) and superficial tissue (T2 = 49.8 ± 13.2 ms) relaxation times were symmetric in healthy participants. In the surgical limbs of BCRL participants, deep muscle (T2 = 40.5 ± 4.9 ms) and superficial tissue (T2 = 56.0 ± 14.8 ms) relaxation times were elevated compared to healthy participants, consistent with an edematous micro-environment. This elevation was also observed in contralateral limbs of BCRL participants (deep muscle T2 = 40.3 ± 5.7 ms; superficial T2 = 56.6 ± 13.8 ms). CONCLUSIONS: Regional MRI measures substantiate a growing literature speculating that superficial and deep tissue, in surgical and contralateral quadrants, is affected in BCRL. The implications of these findings in the context of titrating treatment regimens and understanding malignancy recurrence are discussed.

Neuroimaging of Cerebral Blood Flow and Sodium in Women with Lipedema.

OBJECTIVE: Lipedema is characterized by pain, fatigue, and excessive adipose tissue and sodium accumulation of the lower extremities. This case-control study aims to determine whether sodium or vascular dysfunction is present in the central nervous system. METHODS: Brain magnetic resonance imaging was performed at 3 T in patients with lipedema (n = 15) and control (n = 18) participants matched for sex, age, race, and BMI. Standard anatomical imaging and intracranial angiography were applied to evaluate brain volume and vasculopathy, respectively; arterial spin labeling and sodium magnetic resonance imaging were applied to quantify cerebral blood flow (CBF) (milliliters per 100 grams of tissue/minute) and brain tissue sodium content (millimoles per liter), respectively. A Mann-Whitney U test (significance criteria P < 0.05) was applied to evaluate group differences. RESULTS: No differences in tissue volume, white matter hyperintensities, intracranial vasculopathy, or tissue sodium content were observed between groups. Gray matter CBF was elevated (P = 0.03) in patients with lipedema (57.2 ± 9.6 mL per 100 g/min) versus control participants (49.8 ± 9.1 mL per 100 g/min). CONCLUSIONS: Findings provide evidence that brain sodium and tissue fractions are similar between patients with lipedema and control participants and that patients with lipedema do not exhibit abnormal radiological indicators of intracranial vasculopathy or ischemic injury. Potential explanations for elevated CBF are discussed in the context of the growing literature on lipedema symptomatology and vascular dysfunction.

Upper and Lower Extremity Measurement of Tissue Sodium and Fat Content in Patients with Lipedema.

OBJECTIVE: The aim of this study is to compare tissue sodium and fat content in the upper and lower extremities of participants with lipedema versus controls using magnetic resonance imaging (MRI). METHODS: MRI was performed at 3.0 T in females with lipedema (n = 15, age = 43.2 ± 10.0 years, BMI = 30.3 ± 4.4 kg/m2 ) and controls without lipedema (n = 14, age = 42.8 ± 13.2 years, BMI = 28.8 ± 4.4 kg/m2 ). Participants were assessed for pain and disease stage. Sodium MRI was performed in the forearm and calf to quantify regional tissue sodium content (TSC, mmol/L). Chemical-shift-encoded water-fat MRI was performed in identical regions for measurement of fat/water (ratio). RESULTS: In the calf, skin TSC (16.3 ± 2.6 vs. 14.4 ± 2.2 mmol/L, P = 0.04), muscle TSC (20.3 ± 3.0 vs. 18.3 ± 1.7 mmol/L, P = 0.03), and fat/water (1.03 ± 0.37 vs. 0.56 ± 0.21 ratio, P < 0.001) were significantly higher in participants with lipedema versus control participants. In the forearm, skin TSC (13.4 ± 3.3 vs. 12.0 ± 2.3 mmol/L, P = 0.2, Cohen's d = 0.50) and fat/water (0.65 ± 0.24 vs. 0.48 ± 0.24 ratio, P = 0.07, Cohen's d = 0.68) demonstrated moderate effect sizes in participants with lipedema versus control participants. Calf skin TSC was significantly correlated with pain (Spearman's rho = 0.55, P = 0.03) and disease stage (Spearman's rho = 0.82, P < 0.001) among participants with lipedema. CONCLUSIONS: MRI-measured tissue sodium and fat content are significantly higher in the lower extremities, but not upper extremities, of patients with lipedema compared with BMI-matched controls.

Using deep learning for a diffusion-based segmentation of the dentate nucleus and its benefits over atlas-based methods.

The dentate nucleus (DN) is a gray matter structure deep in the cerebellum involved in motor coordination, sensory input integration, executive planning, language, and visuospatial function. The DN is an emerging biomarker of disease, informing studies that advance pathophysiologic understanding of neurodegenerative and related disorders. The main challenge in defining the DN radiologically is that, like many deep gray matter structures, it has poor contrast in T1-weighted magnetic resonance (MR) images and therefore requires specialized MR acquisitions for visualization. Manual tracing of the DN across multiple acquisitions is resource-intensive and does not scale well to large datasets. We describe a technique that automatically segments the DN using deep learning (DL) on common imaging sequences, such as T1-weighted, T2-weighted, and diffusion MR imaging. We trained a DL algorithm that can automatically delineate the DN and provide an estimate of its volume. The automatic segmentation achieved higher agreement to the manual labels compared to template registration, which is the current common practice in DN segmentation or multiatlas segmentation of manual labels. Across all sequences, the FA maps achieved the highest mean Dice similarity coefficient (DSC) of 0.83 compared to T1 imaging ( DSC = 0.76 ), T2 imaging ( DSC = 0.79 ), or a multisequence approach ( DSC = 0.80 ). A single atlas registration approach using the spatially unbiased atlas template of the cerebellum and brainstem template achieved a DSC of 0.23, and multi-atlas segmentation achieved a DSC of 0.33. Overall, we propose a method of delineating the DN on clinical imaging that can reproduce manual labels with higher accuracy than current atlas-based tools.

Quantitative magnetization transfer imaging of the human locus coeruleus.

The locus coeruleus (LC) is the major origin of norepinephrine in the central nervous system, and is subject to age-related and neurodegenerative changes, especially in disorders such as Parkinson's disease and Alzheimer's disease. Previous studies have shown that neuromelanin (NM)-sensitive MRI can be used to visualize the LC, and it is hypothesized that magnetization transfer (MT) effects are the primary source of LC contrast. The aim of this study was to characterize the MT effects in LC imaging by applying high spatial resolution quantitative MT (qMT) imaging to create parametric maps of the macromolecular content of the LC and surrounding tissues. Healthy volunteers (n = 26; sex = 17 F/9M; age = 41.0 ±â€¯19.1 years) underwent brain MRI on a 3.0 T scanner. qMT data were acquired using a 3D MT-prepared spoiled gradient echo sequence. A traditional NM scan consisting of a T1-weighted turbo spin echo sequence with MT preparation was also acquired. The pool-size ratio (PSR) was estimated for each voxel using a single-point qMT approach. The LC was semi-automatically segmented on the MT-weighted images. The MT-weighted images provided higher contrast-ratio between the LC and surrounding pontine tegmentum (PT) (0.215 ±â€¯0.031) than the reference images without MT-preparation (-0.005 ±â€¯0.026) and the traditional NM images (0.138 ±â€¯0.044). The PSR maps showed significant differences between the LC (0.090 ±â€¯0.009) and PT (0.188 ±â€¯0.025). The largest difference between the PSR values in the LC and PT was observed in the central slices, which also correspond to those with the highest contrast-ratio. These results highlight the role of MT in generating NM-related contrast in the LC, and should serve as a foundation for future studies aiming to quantify pathological changes in the LC and surrounding structures in vivo.

Dopamine effects on frontal cortical blood flow and motor inhibition in Parkinson's disease.

Parkinson's disease (PD) is characterized by dysfunction in frontal cortical and striatal networks that regulate action control. We investigated the pharmacological effect of dopamine agonist replacement therapy on frontal cortical activity and motor inhibition. Using Arterial Spin Labeling MRI, we examined 26 PD patients in the off- and on-dopamine agonist medication states to assess the effect of dopamine agonists on frontal cortical regional cerebral blood flow. Motor inhibition was measured by the Simon task in both medication states. We applied the dual process activation suppression model to dissociate fast response impulses from motor inhibition of incorrect responses. General linear regression model analyses determined the medication effect on regional cerebral blood flow and motor inhibition, and the relationship between regional cerebral blood flow and motor inhibitory proficiency. We show that dopamine agonist administration increases frontal cerebral blood flow, particularly in the pre-supplementary motor area (pre-SMA) and the dorsolateral prefrontal cortex (DLPFC). Higher regional blood flow in the pre-SMA, DLPFC and motor cortex was associated with better inhibitory control, suggesting that treatments which improve frontal cortical activity could ameliorate motor inhibition deficiency in PD patients.

White matter differences between essential tremor and Parkinson disease.

OBJECTIVE: To assess white matter integrity in patients with essential tremor (ET) and Parkinson disease (PD) with moderate to severe motor impairment. METHODS: Sedated participants with ET (n = 57) or PD (n = 99) underwent diffusion tensor imaging (DTI) and fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity values were computed. White matter tracts were defined using 3 well-described atlases. To determine candidate white matter regions that differ between ET and PD groups, a bootstrapping analysis was applied using the least absolute shrinkage and selection operator. Linear regression was applied to assess magnitude and direction of differences in DTI metrics between ET and PD populations in the candidate regions. RESULTS: Fractional anisotropy values that differentiate ET from PD localize primarily to thalamic and visual-related pathways, while diffusivity differences localized to the cerebellar peduncles. Patients with ET exhibited lower fractional anisotropy values than patients with PD in the lateral geniculate body (p < 0.01), sagittal stratum (p = 0.01), forceps major (p = 0.02), pontine crossing tract (p = 0.03), and retrolenticular internal capsule (p = 0.04). Patients with ET exhibited greater radial diffusivity values than patients with PD in the superior cerebellar peduncle (p < 0.01), middle cerebellar peduncle (p = 0.05), and inferior cerebellar peduncle (p = 0.05). CONCLUSIONS: Regionally, distinctive white matter microstructural values in patients with ET localize to the cerebellar peduncles and thalamo-cortical visual pathways. These findings complement recent functional imaging studies in ET but also extend our understanding of putative physiologic features that account for distinctions between ET and PD.