Changes in Cerebrospinal Fluid, Liver and Intima-media-thickness Biomarkers in Patients with HIV-associated Neurocognitive Disorders Randomized to a Less Neurotoxic Treatment Regimen.

The prevalence of neurocognitive impairment in people living with HIV is estimated between 30 and 50%. The pathogenesis of HIV-associated neurocognitive disorders is complex and multifactorial. Aim of the study was to measure the change in CSF biomarkers, Fibroscan and IMT measurements in PLWH with HAND randomized to a less neurotoxic regimen, or continuing their treatment. Adult patients with HAND were screened and enrolled if presenting no major resistance associated mutations, no HIV viral replication, not on efavirenz or darunavir, with R5-tropic HIV and without major confounding conditions. Lumbar puncture, IMT and Fibroscan measurements were performed. After 1:1 randomization to a less neurotoxic regimen consisting of darunavir/cobicistat plus emtricitabine plus maraviroc, or mantaining actual care, tests were repeated after 24 weeks: CSF biomarkes (HIV RNA, tau, p-tau, Beta-amyloid1-42, S100Beta and neopterin) were included. Non-parametric tests (Mann-Whitney and Wilcoxon's) were used. 28 participants completed the study. Male and European ancestry were prevalent; median age was 55 years (51-60). All patients were virally suppressed; median CD4 + count was 626 cell/uL (469-772). Baseline characteristics were similar between the study arms. A significant decrease in CSF p-tau and an increase in CSF neopterin and NFL were observed. We observed a significant reduction in liver stiffness at W24. Despite a small sample size we observed changes in neuromarkers and in hepatic stiffness in patients randomized to the experimental arm. We observed changes in CSF biomarkers (lower phosphorylated-tau and higher neopterin and NFL) that need to be replicated in large cohorts. Subclinical neurotoxicity may be observed in patients with HAND and warrants prospective studies.

Elevation of brain ADC (apparent diffusion coefficient) in HIV-associated neurocognitive disorders and evolution after treatment: A pilot study.

BACKGROUND: Thirty to 50% of HIV-infected patients develop HIV-Associated Neurocognitive Disorders (HAND) despite virological control. The previously published Neuro+3 study showed their neurocognitive status can be improved by intensifying antiviral therapy. Our study is a part of the Neuro3+ study and aims to study apparent diffusion coefficient (ADC) as a biomarker for neurological improvement. PATIENTS AND METHODS: We prospectively included 31 patients with HAND. They received therapy with better CNS Penetration Effectiveness (CPE) score with two-year follow-up. Cognitive status was assessed at day 0 (D0) and week 96 (W96) using Frascati 3-stage classification and Global Deficit Score (GDS). Brain MRI at D0 and W96 assessed morphological data (white matter hyperintensities, opportunistic infections, ischemic lesions, atrophy) and measured whole brain apparent diffusion coefficient (ADC). We compared their data with a control group of 20 healthy patients with similar ages and sex ratio. RESULTS: After ARV intensification, cognitive status was significantly improved: GDS (n = 1,4 vs 1,0 p = 0.01) and Frascati scale (2HAD/22MND/7ANI vs 1HAD/8MND/17ANI p = 0.001). Mean ADC was significantly higher in patients at inclusion than in controls (0.88 × 10-3 mm2/s ± 0.06 vs 0.81 × 10-3 mm2/s ± 0.04, p = 0.0001). ADC decreased after treatment (0.88 × 10-3 mm2/s ± 0.06 vs 0.85 × 10-3 mm2/s ± 0.06 (p = 0,04). In subgroup analysis, ADC significantly decreased in clinically improved patients (0.89 × 10-3 mm2/s ± 0.07 vs 0.85 × 10-3 mm2/s ± 0.07 (p = 0,03)) and did not significantly change in non-clinically improved patients (0.86 × 10-3 mm2/s ± 0.07 vs 0.84 × 10-3 mm2/s ± 0.07 (p = 0,31)). After treatment, there was no significant difference between patients and controls (0.85 × 10-3 mm2/s ± 0.06 vs 0.81 × 10-3 mm2/s ± 0.04, p = 0.17). CONCLUSION: Whole-brain ADC is a good biomarker of HIV-associated neurocognitive disorders. It is significantly increased in patients with HAND compared with controls and significantly decreases after treatment. It is all the more important to have a quantitative biomarker as conventional imaging does not contribute to the diagnosis.

Exploratory Assessment of K-means Clustering to Classify 18F-Flutemetamol Brain PET as Positive or Negative.

RATIONALE: We evaluated K-means clustering to classify amyloid brain PETs as positive or negative. PATIENTS AND METHODS: Sixty-six participants (31 men, 35 women; age range, 52-81 years) were recruited through a multicenter observational study: 19 cognitively normal, 25 mild cognitive impairment, and 22 dementia (11 Alzheimer disease, 3 subcortical vascular cognitive impairment, and 8 Parkinson-Lewy Body spectrum disorder). As part of the neurocognitive and imaging evaluation, each participant had an 18F-flutemetamol (Vizamyl, GE Healthcare) brain PET. All studies were processed using Cortex ID software (General Electric Company, Boston, MA) to calculate SUV ratios in 19 regions of interest and clinically interpreted by 2 dual-certified radiologists/nuclear medicine physicians, using MIM software (MIM Software Inc, Cleveland, OH), blinded to the quantitative analysis, with final interpretation based on consensus. K-means clustering was retrospectively used to classify the studies from the quantitative data. RESULTS: Based on clinical interpretation, 46 brain PETs were negative and 20 were positive for amyloid deposition. Of 19 cognitively normal participants, 1 (5%) had a positive 18F-flutemetamol brain PET. Of 25 participants with mild cognitive impairment, 9 (36%) had a positive 18F-flutemetamol brain PET. Of 22 participants with dementia, 10 (45%) had a positive 18F-flutemetamol brain PET; 7 of 11 participants with Alzheimer disease (64%), 1 of 3 participants with vascular cognitive impairment (33%), and 2 of 8 participants with Parkinson-Lewy Body spectrum disorder (25%) had a positive 18F-flutemetamol brain PET. Using clinical interpretation as the criterion standard, K-means clustering (K = 2) gave sensitivity of 95%, specificity of 98%, and accuracy of 97%. CONCLUSIONS: K-means clustering may be a powerful algorithm for classifying amyloid brain PET.

Clinically accessible neuroimaging predictors of post-stroke neurocognitive disorder: a prospective observational study.

BACKGROUND: Neurocognitive disorder (NCD) is common in stroke survivors. We aimed to identify clinically accessible imaging markers of stroke and chronic pathology that are associated with early post-stroke NCD. METHODS: We included 231 stroke survivors from the "Norwegian Cognitive Impairment after Stroke (Nor-COAST)" study who underwent a standardized cognitive assessment 3 months after the stroke. Any NCD (mild cognitive impairment and dementia) and major NCD (dementia) were diagnosed according to "Diagnostic and Statistical Manual of Mental Disorders (DSM-5)" criteria. Clinically accessible imaging findings were analyzed on study-specific brain MRIs in the early phase after stroke. Stroke lesion volumes were semi automatically quantified and strategic stroke locations were determined by an atlas based coregistration. White matter hyperintensities (WMH) and medial temporal lobe atrophy (MTA) were visually scored. Logistic regression was used to identify neuroimaging findings associated with major NCD and any NCD. RESULTS: Mean age was 71.8 years (SD 11.1), 101 (43.7%) were females, mean time from stroke to imaging was 8 (SD 16) days. At 3 months 63 (27.3%) had mild NCD and 65 (28.1%) had major NCD. Any NCD was significantly associated with WMH pathology (odds ratio (OR) = 2.73 [1.56 to 4.77], p = 0.001), MTA pathology (OR = 1.95 [1.12 to 3.41], p = 0.019), and left hemispheric stroke (OR = 1.8 [1.05 to 3.09], p = 0.032). Major NCD was significantly associated with WMH pathology (OR = 2.54 [1.33 to 4.84], p = 0.005) and stroke lesion volume (OR (per ml) =1.04 [1.01 to 1.06], p = 0.001). CONCLUSION: WMH pathology, MTA pathology and left hemispheric stroke were associated with the development of any NCD. Stroke lesion volume and WMH pathology were associated with the development of major NCD 3 months after stroke. These imaging findings may be used in the routine clinical setting to identify patients at risk for early post-stroke NCD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02650531 , Registered 8 January 2016 - Retrospectively registered.

Caffeine exposure in utero is associated with structural brain alterations and deleterious neurocognitive outcomes in 9-10 year old children.

Caffeine, a very widely used and potent neuromodulator, easily crosses the placental barrier, but relatively little is known about the long-term impact of gestational caffeine exposure (GCE) on neurodevelopment. Here, we leverage magnetic resonance imaging (MRI) data, collected from a very large sample of 9157 children, aged 9-10 years, as part of the Adolescent Brain and Cognitive Developmentsm (ABCD ®) study, to investigate brain structural outcomes at 27 major fiber tracts as a function of GCE. Significant relationships between GCE and fractional anisotropy (FA) measures in the inferior fronto-occipito fasciculus and corticospinal tract of the left hemisphere (IFOF-LH; CST-LH) were detected via mixed effects binomial regression. We further investigated the interaction between these fiber tracts, GCE, cognitive measures (working memory, task efficiency), and psychopathology measures (externalization, internalization, somatization, and neurodevelopment). GCE was associated with poorer outcomes on all measures of psychopathology but had negligible effect on cognitive measures. Higher FA values in both fiber tracts were associated with decreased neurodevelopmental problems and improved performance on both cognitive tasks. We also identified a decreased association between FA in the CST-LH and task efficiency in the GCE group. These findings suggest that GCE can lead to future neurodevelopmental complications and that this occurs, in part, through alteration of the microstructure of critical fiber tracts such as the IFOF-LH and CST-LH. These data suggest that current guidelines regarding limiting caffeine intake during pregnancy may require some recalibration.

Reversible splenial lesion syndrome associated with SARS-CoV-2 infection in two children.

BACKGROUND: Reversible splenial lesion syndrome (RESLES) is characterized by a temporary lesion in the splenium of the corpus callosum, emerging related to encephalitis, seizures, antiepileptic drug withdrawal, or metabolic disturbances. Among RESLES, mild encephalitis/encephalopathy with reversible splenial lesion (MERS) has been defined as a distinct clinicoradiologic syndrome associated with viral infections. CASE PRESENTATION: We report two children with multisystem inflammatory syndrome-children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who developed RESLES during the disease course. Encephalopathy was the main central nervous system symptom. Both of the children showed a rapid recovery, and brain magnetic resonance imaging revealed complete resolution of the splenial lesion within 1 week. CONCLUSION: The complete resolution of the splenial lesion and rapid recovery from encephalopathy in RESLES associated with SARS CoV-2 were similar to observed in MERS.

Early pediatric chronic kidney disease is associated with brain volumetric gray matter abnormalities.

BACKGROUND: The impact of pediatric chronic kidney disease (pCKD) on the brain remains poorly defined. The objective of this study was to compare brain morphometry between children with early-stage pCKD and typically developing peers using structural magnetic resonance imaging (MRI). METHODS: The sample age range was 6-16 years. A total of 18 children with a diagnosis of pCKD (CKD stages 1-3) due to congenital anomalies of the kidney and urinary tract and 24 typically developing peers were included. Volumetric data from MRI and neurocognitive testing were compared using linear models including pCKD status, age, maternal education level, and socioeconomic status. RESULTS: Cerebellar gray matter volume was significantly smaller in pCKD, t(38) = -2.71, p = 0.01. In contrast, cerebral gray matter volume was increased in pCKD, t(38) = 2.08, p = 0.04. Reduced cerebellum gray matter volume was associated with disease severity, operationalized as estimated glomerular filtration rate (eGFR), t(14) = 2.21, p = 0.04 and predicted lower verbal fluency scores in the pCKD sample. Enlarged cerebral gray matter in the pCKD sample predicted lower scores on mathematics assessment. CONCLUSIONS: This study provides preliminary evidence for a morphometric underpinning to the cognitive deficits observed in pCKD. IMPACT: The impact of pediatric chronic kidney disease (CKD) on the brain remains poorly defined, with no data linking brain morphometry and observed cognitive deficits noted in this population. We explored the relationship between brain morphometry (using structural magnetic resonance imaging), cognition, and markers of CKD. Cerebellar and cerebral gray matter volumes are different in early CKD. Volumetric decreases in cerebellar gray matter are predicted by lower eGFR, suggesting a link between disease and brain morphometry. Reduced cerebellar gray matter predicted lower verbal fluency for those with pCKD. Enlarged cerebral gray matter in the pCKD sample predicted lower mathematics performance.

Study on brain structure network of patients with delayed encephalopathy after carbon monoxide poisoning: based on diffusion tensor imaging.

OBJECTIVE: To analyze the network alteration characteristics of brain structure network in patients with delayed encephalopathy after CO poisoning (DEACMP) based on diffusion tensor imaging (DTI), and to explore the structural correlation neuroimaging mechanism of DEACMP cognitive impairment. METHODS: DTI scanning was performed in 33 patients with DEACMP and 25 healthy controls (HCs) who were matched in age and sex. The whole brain was divided into 90 regions by automated anatomical marker templates. The continuous tracing method was used to reconstruct the brain fiber bundle connection and construct the brain structure weighted network. The global and regional properties were computed by graph theoretical analysis. To compare the brain network regional properties between the DEACMP group and the HCs group, two-sample t test (false discovery rate correction, P < 0.05) was utilized. The correlations between the brain structural network properties and clinical parameters were further analyzed. RESULTS: Both of the two groups were found to follow the efficient small-world characteristics. The shortest path length of the DEACMP group increased (Lp = 0.86 ± 0.05), whereas global efficiency (Eglob = 9.60 ± 2.65) and local efficiency (Eloc = 17.98 ± 3.89) decreased. Moreover, the core nodes of the DEACMP group's default network, highlighting network, central execution network, and visual area, were decreased (P < 0.05, FDR correction). The left amygdala node degree of DEACMP group was positively correlated with MMSE and MoCA scores of the clinical scale (r = 0.863, P = 0.001, r = 0.525, P = 0.021). The node degree value of the left lingual gyrus was positively correlated with MoCA score (r = 0.406, P = 0.019) and negatively correlated with CDR score (r = -0.563, P = 0.016). The efficiency value of the right dorsolateral superior frontal gyrus in the DEACMP group was negatively correlated with the CDR score (r = -0.377, P = 0.031). CONCLUSION: By comparing the differences and changes in the topological properties and nodes of the brain structure network between DEACMP group and HCs group, the degree of related brain regions, especially the damage of higher brain functions in DEACMP patients, was verified, which was helpful to understand the cognitive damage caused by CO poisoning and to predict the efficacy of late remodeling. Small-worldness is a dynamic reorganization of the small-world topology and its community structure from the brain network to provide system-wide flexibility and adaptability (Barbey in Trends Cogn Sci 22(1):8-20, 2018). The combination with DTI is helpful for the accurate localization of brain structural damage, especially in DEACMP patients.

Neuroimaging and Cognitive Evidence for Combined HIV-Alcohol Effects on the Central Nervous System: A Review.

Alcohol use disorder (AUD) among people living with HIV (PLWH) is a significant public health concern. Despite the advent of effective antiretroviral therapy, up to 50% of PLWH still experience worsened neurocognition, which comorbid AUD exacerbates. We report converging lines of neuroimaging and neuropsychological evidence linking comorbid HIV/AUD to dysfunction in brain regions linked to executive function, learning and memory, processing speed, and motor control, and consequently to impairment in daily life. The brain shrinkage, functional network alterations, and brain metabolite disruption seen in individuals with HIV/AUD have been attributed to several interacting pathways: viral proteins and EtOH are directly neurotoxic and exacerbate each other's neurotoxic effects; EtOH reduces antiretroviral adherence and increases viral replication; AUD and HIV both increase gut microbial translocation, promoting systemic inflammation and HIV transport into the brain by immune cells; and HIV may compound alcohol's damaging effects on the liver, further increasing inflammation. We additionally review the neurocognitive effects of aging, Hepatitis C coinfection, obesity, and cardiovascular disease, tobacco use, and nutritional deficiencies, all of which have been shown to compound cognitive changes in HIV, AUD, and in their comorbidity. Finally, we examine emerging questions in HIV/AUD research, including genetic and cognitive protective factors, the role of binge drinking in HIV/AUD-linked cognitive decline, and whether neurocognitive and brain functions normalize after drinking cessation.

Evolving evidence on a link between the ZMYM3 exceptionally long GA-STR and human cognition.

The human X-linked zinc finger MYM-type protein 3 (ZMYM3) contains the longest GA-STR identified across protein-coding gene 5' UTR sequences, at 32-repeats. This exceptionally long GA-STR is located at a complex string of GA-STRs with a human-specific formula across the complex as follows: (GA)8-(GA)4-(GA)6-(GA)32 (ZMYM3-207 ENST00000373998.5). ZMYM3 was previously reported among the top three genes involved in the progression of late-onset Alzheimer's disease. Here we sequenced the ZMYM3 GA-STR complex in 750 human male subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 268) and matched controls (n = 482). We detected strict monomorphism of the GA-STR complex, except of the exceptionally long STR, which was architecturally skewed in respect of allele distribution between the NCD cases and controls [F (1, 50) = 12.283; p = 0.001]. Moreover, extreme alleles of this STR at 17, 20, 42, and 43 repeats were detected in seven NCD patients and not in the control group (Mid-P exact = 0.0003). A number of these alleles overlapped with alleles previously found in schizophrenia and bipolar disorder patients. In conclusion, we propose selective advantage for the exceptional length of the ZMYM3 GA-STR in human, and its link to a spectrum of diseases in which major cognition impairment is a predominant phenotype.

Chronic cerebral hypoperfusion: An undefined, relevant entity.

Despite the large body of data available, chronic cerebral hypoperfusion lacks an operative definition. In a tautological way, the term hypoperfusion is being referred to conditions of "inadequate blood flow", "defects of perfusion" or "dysfunction of autoregulation". The chronicity refers to sustained conditions or wavering states characterized by repeated phases of inefficient functional hyperemia. The phenomenon may affect the whole brain or defined areas. A few defined clinical disorders, including heart failure, hypotension, atherosclerosis of large or small vessels and carotid stenosis are thought to cause progressive brain disorders due to chronic hypoperfusion. The clinical relevance manifests mostly as neurocognitive disorders associated with neuroimaging changes.The available data support a conceptual framework that considerschronic cerebral hypoperfusiona likely, relevant pathogenic mechanism for the neurodegeneration-like progression of the neurocognitive disorders. The relationship between neuropathology, cerebral perfusion, and symptoms progression is, however, elusive for several aspects. Typical microangiopathy findings, such as MRI white matter hyperintensities, may appear in individuals without any cerebrovascular risk or vascular lesions. Pathology features of the MRI changes, such as demyelination and gliosis, may result from dysfunction of the neuro-vascular unit not directly associated withvascular mechanisms. In this review, we aim to overview the most common clinical conditions thought to reflect chronic hypoperfusion.

Toward a Sequential Strategy for Diagnosing Neurocognitive Disorders: A Consensus from the "Act On Dementia" European Joint Action.

Neurocognitive disorders causing progressive cognitive, functional, and behavioral impairment remain underdiagnosed. The needs for a timely diagnosis are now widely acknowledged since person-centered care helps to preserve life quality and prevent crises. One powerful barrier to detection in primary care is the lack of an easy-to-follow stepwise approach, grounded in evidence and consistent with high-quality specialty practice. To help fill this gap, the current European Joint Action proposes a graduated diagnosis strategy tailored to the patients' needs and wills, clarifying appropriate components for primary and specialty care. This strategy considers a first evaluation in primary care that may detect a neurocognitive disorder, that would lead to a second evaluation step allowing etiological diagnosis hypotheses performed mostly by the specialist. A third evaluation stage considering some biological, electrophysiological, or neuroimaging complementary techniques would be proposed to atypical cases or patients willing to consider access to research.

The bivariate distribution of amyloid-ß and tau: relationship with established neurocognitive clinical syndromes.

Large phenotypically diverse research cohorts with both amyloid and tau PET have only recently come into existence. Our objective was to determine relationships between the bivariate distribution of amyloid-ß and tau on PET and established clinical syndromes that are relevant to cognitive ageing and dementia. All individuals in this study were enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive ageing, or the Mayo Alzheimer Disease Research Center, a longitudinal study of individuals recruited from clinical practice. We studied 1343 participants who had amyloid PET and tau PET from 2 April 2015 to 3 May 2019, and met criteria for membership in one of five clinical diagnostic groups: cognitively unimpaired, mild cognitive impairment, frontotemporal dementia, probable dementia with Lewy bodies, and Alzheimer clinical syndrome. We examined these clinical groups in relation to the bivariate distribution of amyloid and tau PET values. Individuals were grouped into amyloid (A)/tau (T) quadrants based on previously established abnormality cut points of standardized uptake value ratio 1.48 (A) and 1.33 (T). Individual participants largely fell into one of three amyloid/tau quadrants: low amyloid and low tau (A-T-), high amyloid and low tau (A+T-), or high amyloid and high tau (A+T+). Seventy per cent of cognitively unimpaired and 74% of FTD participants fell into the A-T- quadrant. Participants with mild cognitive impairment spanned the A-T- (42%), A+T- (28%), and A+T+ (27%) quadrants. Probable dementia with Lewy body participants spanned the A-T- (38%) and A+T- (44%) quadrants. Most (89%) participants with Alzheimer clinical syndrome fell into the A+T+ quadrant. These data support several conclusions. First, among 1343 participants, abnormal tau PET rarely occurred in the absence of abnormal amyloid PET, but the reverse was common. Thus, with rare exceptions, amyloidosis appears to be required for high levels of 3R/4R tau deposition. Second, abnormal amyloid PET is compatible with normal cognition but highly abnormal tau PET is not. These two conclusions support a dynamic biomarker model in which Alzheimer's disease is characterized first by the appearance of amyloidosis and later by tauopathy, with tauopathy being the proteinopathy associated with clinical symptoms. Third, bivariate amyloid and tau PET relationships differed across clinical groups and thus have a role for clarifying the aetiologies underlying neurocognitive clinical syndromes.

Longitudinal brain atrophy patterns and neuropsychological performance in older adults with HIV-associated neurocognitive disorder compared with early Alzheimer's disease.

Older HIV-infected patients are at risk for both HIV-associated neurocognitive disorder (HAND) and Alzheimer's disease. We investigated neuroimaging and neuropsychological performance of 61 virally suppressed older adults with HAND (mean (SD) age 64.3 (3.9) years), 53 demographically matched individuals with mild cognitive impairment of the Alzheimer's type (MCI-AD; 65.0 [4.8]), and 89 healthy controls (65.0 [4.3]) cross-sectionally and over 20 months. At the baseline, both disease groups exhibited lower volumes in multiple cortical and subcortical regions compared with controls. Hippocampal volume differentiated MCI-AD from HAND. Cognitively, MCI-AD performed worse on memory and language compared with HAND. Adjusted longitudinal models revealed greater diffuse brain atrophy in MCI-AD compared with controls, whereas HAND showed greater atrophy in frontal gray matter and cerebellum compared with controls. Comparing HAND with MCI-AD showed similar atrophy rates in all brain regions explored, with no significant findings. MCI-AD exhibited more pronounced language decline compared with HAND. These findings reveal the need for further work on unique cognitive phenotypes and neuroimaging signatures of HAND compared with early AD, providing preliminary clinical insight for differential diagnosis of age-related brain dysfunction in geriatric neuroHIV.

Imaging correlates of the blood-brain barrier disruption in HIV-associated neurocognitive disorder and therapeutic implications.

OBJECTIVE: HIV-associated neurocognitive disorders (HANDs) in the context of suppressive combination antiretroviral therapy (cART) still occur. We explored the role of blood-brain barrier (BBB) disruption in the pathogenesis of HAND in the context of fully suppressive cART using dynamic contrast enhanced perfusion (DCE-P) MRI. DCE-P is a new MRI technique that measures capillary permeability as an indicator for BBB integrity. We hypothesized that virally suppressed incident HAND would be associated with an impaired BBB as determined by DCE-P. DESIGN: A cross sectional study. METHODS: K-trans, a metric derivative of DCE-P, was obtained from different regions of the brain in a cohort of 20 patients with HAND who were virally suppressed in both cerebrospinal fluid (CSF) and blood compared with CSF and blood markers of neuroinflammation as well as with neurometabolites derived from magnetic resonance (MR) spectroscopy. RESULTS: The K-trans data showed significantly impaired BBB in HAND patients when compared with the controls in the regions of the basal ganglia and anterior frontal white matter (both P < 0.0001). CSF neopterin and CSF/serum albumin ratio correlated positively with K-trans but not with blood levels. CONCLUSION: This study indicates that HAND in the context of viral suppression is associated with BBB disruption and the DCE MR derived K-trans metric is a very sensitive parameter to identify the BBB disruption. The finding of region-specific BBB disruption rather than globally and the lack of correlation with blood markers of neuroinflammation suggest that HIV and not systemic inflammation is driving the BBB disturbance and that the BBB disruption is a consequence of HIV already in the brain as opposed to HIV first causing BBB disruption then brain disease.

Changes in functional brain networks and neurocognitive function in Chinese gynecological cancer patients after chemotherapy: a prospective longitudinal study.

BACKGROUND: Previous neurocognitive assessments in non-central nervous system cancers highlight the high incidence of neurocognitive dysfunction in this study population. However, there have been few studies exploring neurocognitive dysfunction induced by chemotherapy in gynecological cancer patients. This prospective longitudinal study was conducted to assess neurocognitive functioning and functional brain networks in Chinese gynecological cancer patients pre- and post-chemotherapy, while additionally including age-matched healthy subjects as the control group. METHODS: All research participants were evaluated using a resting-state functional magnetic resonance imaging and neurocognition assessment. Behavioral data were conducted using SPSS for descriptive statistics, correlation and comparison analyses. Preprocessing of MRI (Magnetic Resonance Imaging) data and network analyses were performed using GRETNA (Graph Theoretical Network Analysis). RESULTS: A total of 40 subjects joined this study, with 20 subjects in each group. With the exception of the mean of psychomotor speed, there was no significant difference pre-chemotherapy between patients and healthy controls in neurocognitive test mean scores (Ps > 0.05). During the post-chemotherapy assessment, there were significant differences in the mean scores of neurocognitive tests (including Digit Span tests, verbal memory, immediate recall, delayed recall, and information processing speed tests) (all Ps < 0 .05). Longitudinal graph analysis revealed statistically significant differences in the patient group, with significant decreases in both local efficiency (P < 0.01) and global efficiency (P = 0.04). Lower raw TMT-A scores were significantly associated with lower local efficiency (r = 0.37, P = 0.03). Lower verbal memory scores were statistically significant and associated with lower global efficiency (r = 0.54, P = 0.02) in the patient group, but not in the healthy control group. CONCLUSIONS: This study found that the risk of brain function and neurocognitive changes following chemotherapy could potentially guide patients in making appropriate treatment decisions, and this study may identify a cohort that could be suited for study of an intervention.

Automated diagnosis of HIV-associated neurocognitive disorders using large-scale Granger causality analysis of resting-state functional MRI.

HIV-associated neurocognitive disorders (HAND) represent an important source of neurologic complications in individuals with HIV. The dynamic, often subclinical, course of HAND has rendered diagnosis, which currently depends on neuropsychometric (NP) evaluation, a challenge for clinicians. Here, we present evidence that functional brain connectivity, derived by large-scale Granger causality (lsGC) analysis of resting-state functional MRI (rs-fMRI) time-series, represents a potential biomarker to address this critical diagnostic need. Brain graph properties were used as features in machine learning tasks to 1) classify individuals as HIV+ or HIV- and 2) to predict overall cognitive performance, as assessed by NP scores, in a 22-subject (13 HIV-, 9 HIV+) cohort. Over nearly all seven brain parcellation templates considered, support vector machine (SVM) classifiers based on lsGC-derived brain graph features significantly outperformed those based on conventional Pearson correlation (PC)-derived features (p<0.05, Bonferroni-corrected). In a second task for which the objective was to predict the overall NP score of each subject, the lsGC-based SVM regressors consistently outperformed the PC-based regressors (p<0.05, Bonferroni-corrected) on nearly all templates. With the widely used Automated Anatomical Labeling (AAL90) template, it was determined that the brain regions that figured most strongly in the SVM classifiers included those of the default mode network (posterior cingulate cortex, angular gyrus) and basal ganglia (caudate nucleus), dysfunction in both of which have been observed in previous structural and functional analyses of HAND.

Intra-individual variability in neurocognitive function in schizophrenia: relationships with the corpus callosum.

Patients with schizophrenia not only have impairments in neurological function, but also have instability and variability in neurocognitive function. However, previous researchers have not fully studied the relationships between dispersion across multiple neurocognitive domains and white matter (WM) structures of the brain. This study focuses on intra-individual variability (IIV) in patients with schizophrenia and its relationship with WM integrity of the corpus callosum (CC). Thirty-eight patients with schizophrenia were enrolled in the study. All subjects underwent assessments of neurocognitive function using the Korean-Wechsler Adult Intelligence Scale-Revised (K-WAIS-R) and the severity of clinical symptoms using the Positive and Negative Syndrome Scale (PANSS). IIV across subtests of the K-WAIS-R was calculated using the Holtzer's equation. Tract-based spatial statistics were used to analyze diffusion tensor images. In subjects with schizophrenia, a negative correlation was found between IIV in performance intelligence quotient (PIQ) and fractional anisotropy (FA) values in the genu of the CC. In addition, FA values of the same region were negatively correlated with the total and subscale scores of positive symptoms and general psychopathology from the PANSS. Our findings suggest that the genu of the CC may play an important role in IIV in PIQ and symptomatology in patients with schizophrenia.

A 14-Year-Old Boy With Fevers, Cytopenias, and Neurocognitive Decline.

A 14-year-old boy presented to our institution with a 1-month history of neurocognitive decline and intermittent fevers. His history was significant for fevers, headaches, and a 10-lb weight loss. Previous examinations by multiple medical providers were significant only for bilateral cervical lymphadenopathy. Previous laboratory workup revealed leukopenia, neutropenia, and elevated inflammatory markers. Despite improvement in his laboratory values after his initial presentation, his fevers persisted, and he developed slowed and "jerky" movements, increased sleep, slurred speech, delusions, visual hallucinations, and deterioration in his school performance. A brain MRI performed at an outside hospital before admission at our institution was concerning for patchy, increased T2 and fluid-attenuated inversion recovery signal intensity in multiple areas, including the basal ganglia. After transfer to our institution and admission to the pediatric hospital medicine team, the patient had an acute decompensation. Our subspecialists will discuss the initial evaluation, workup, differential diagnosis, definitive diagnosis, and subsequent management of this patient.