Plasma proteomic analysis on neuropathic pain in idiopathic peripheral neuropathy patients.

BACKGROUND AND AIMS: Why only half of the idiopathic peripheral neuropathy (IPN) patients develop neuropathic pain remains unknown. By conducting a proteomics analysis on IPN patients, we aimed to discover proteins and new pathways that are associated with neuropathic pain. METHODS: We conducted unbiased mass-spectrometry proteomics analysis on blood plasma from 31 IPN patients with severe neuropathic pain and 29 IPN patients with no pain, to investigate protein biomarkers and protein-protein interactions associated with neuropathic pain. Univariate modeling was done with linear mixed modeling (LMM) and corrected for multiple testing. Multivariate modeling was performed using elastic net analysis and validated with internal cross-validation and bootstrapping. RESULTS: In the univariate analysis, 73 proteins showed a p-value <.05 and 12 proteins showed a p-value <.01. None were significant after Benjamini-Hochberg adjustment for multiple testing. Elastic net analysis created a model containing 12 proteins with reasonable discriminatory power to differentiate between painful and painless IPN (false-negative rate 0.10, false-positive rate 0.18, and an area under the curve 0.75). Eight of these 12 proteins were clustered into one interaction network, significantly enriched for the complement and coagulation pathway (Benjamini-Hochberg adjusted p-value = .0057), with complement component 3 (C3) as the central node. Bootstrap validation identified insulin-like growth factor-binding protein 2 (IGFBP2), complement factor H-related protein 4 (CFHR4), and ferritin light chain (FTL), as the most discriminatory proteins of the original 12 identified. INTERPRETATION: This proteomics analysis suggests a role for the complement system in neuropathic pain in IPN.

Detecting cortical responses to continuous running speech using EEG data from only one channel.

OBJECTIVE: To explore the detection of cortical responses to continuous speech using a single EEG channel. Particularly, to compare detection rates and times using a cross-correlation approach and parameters extracted from the temporal response function (TRF). DESIGN: EEG from 32-channels were recorded whilst presenting 25-min continuous English speech. Detection parameters were cross-correlation between speech and EEG (XCOR), peak value and power of the TRF filter (TRF-peak and TRF-power), and correlation between predicted TRF and true EEG (TRF-COR). A bootstrap analysis was used to determine response statistical significance. Different electrode configurations were compared: Using single channels Cz or Fz, or selecting channels with the highest correlation value. STUDY SAMPLE: Seventeen native English-speaking subjects with mild-to-moderate hearing loss. RESULTS: Significant cortical responses were detected from all subjects at Fz channel with XCOR and TRF-COR. Lower detection time was seen for XCOR (mean = 4.8 min) over TRF parameters (best TRF-COR, mean = 6.4 min), with significant time differences from XCOR to TRF-peak and TRF-power. Analysing multiple EEG channels and testing channels with the highest correlation between envelope and EEG reduced detection sensitivity compared to Fz alone. CONCLUSIONS: Cortical responses to continuous speech can be detected from a single channel with recording times that may be suitable for clinical application.

Small fiber neuropathy associated with SARS-CoV-2 infection.

INTRODUCTION/AIMS: The development and persistence of neurological symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is referred to as "long-haul" syndrome. We aimed to determine whether small fiber neuropathy (SFN) was associated with SARS-CoV-2 infection. METHODS: We retrospectively studied the clinical features and outcomes of patients who were referred to us between May 2020 and May 2021 for painful paresthesia and numbness that developed during or after SARS-CoV-2 infection and who had nerve conduction studies showing no evidence of a large fiber polyneuropathy. RESULTS: We identified 13 patients, Eight women and five men with age ranging from 38-67 y. Follow-up duration ranged from 8 to 12 mo. All patients developed new-onset paresthesias within 2 mo following SARS-CoV-2 infection, with an acute onset in seven and co-existing autonomic symptoms in seven. Three patients had pre-existing but controlled neuropathy risk factors. Skin biopsy confirmed SFN in six, all of whom showed both neuropathy symptoms and signs, and two also showed autonomic dysfunction by autonomic function testing (AFT). Of the remaining seven patients who had normal skin biopsies, six showed no clinical neuropathy signs and one exhibited signs and had abnormal AFT. Two patients with markedly reduced intraepidermal nerve fiber densities and one with normal skin biopsy had severe and moderate coronavirus disease 2019 (COVID-19); the remainder experienced mild COVID-19 symptoms. Nine patients received symptomatic neuropathy treatment with paresthesias controlled in seven (77.8%). DISCUSSION: Our findings suggest that symptoms of SFN may develop during or shortly after COVID-19. SFN may underlie the paresthesias associated with long-haul post-COVID-19 symptoms.

Auditory Brainstem Response Detection Using Machine Learning: A Comparison With Statistical Detection Methods.

OBJECTIVES: The primary objective of this study was to train and test machine learning algorithms to be able to detect accurately whether EEG data contains an auditory brainstem response (ABR) or not and recommend suitable machine learning methods. In addition, the performance of the best machine learning algorithm was compared with that of prominent statistical detection methods. DESIGN: Four machine learning algorithms were trained and evaluated using nested k-fold cross-validation: a random forest, a convolutional long short-term memory network, a stacked ensemble, and a multilayer perceptron. The best method was evaluated on a separate test set and compared with conventional detection methods: Fsp, Fmp, q-sample uniform scores test, and Hotelling's T2 test. The models were trained and tested on simulated data that were generated based on recorded ABRs collected from 12 normal-hearing participants and no-stimulus EEG data from 15 participants. Simulation allowed the ground truth of the data ("response present" or "response absent") to be known. RESULTS: The sensitivity of the best machine learning algorithm, a stacked ensemble, was significantly greater than that of the conventional detection methods evaluated. The stacked ensemble, evaluated using a bootstrap approach, consistently achieved a high and stable level of specificity across ensemble sizes. CONCLUSIONS: The stacked ensemble model presented was more effective than conventional statistical ABR detection methods and the alternative machine learning approaches tested. The stacked ensemble detection method may have potential both in automated ABR screening devices as well as in evoked potential software, assisting clinicians in making decisions regarding a patient's ABR threshold. Further assessment of the model's generalizability using a large cohort of subject recorded data, including participants of different ages and hearing status, is a recommended next step.

Autoimmune conditions in the World Trade Center general responder cohort: A nested case-control and standardized incidence ratio analysis.

BACKGROUND: The World Trade Center (WTC) general responder cohort (GRC) was exposed to environmental toxins possibly associated with increased risk of developing autoimmune conditions. OBJECTIVES: Two study designs were used to assess incidence and risks of autoimmune conditions in the GRC. METHODS: Three clinically trained professionals established the status of possible GRC cases of autoimmune disorders adhering to diagnostic criteria, supplemented, as needed, by specialists' review of consenting responders' medical records. Nested case-control analyses using conditional logistic regression estimated the risk associated with high WTC exposure (being in the 9/11/2001 dust cloud or ≥median days' response worked) compared with low WTC exposure (all other GRC members'). Four controls were matched to each case on age at case diagnosis (±2 years), sex, race/ethnicity, and year of program enrollment. Sex-specific and sensitivity analyses were performed. GRC age- and sex-adjusted standardized incidence ratios (SIRs) were compared with the Rochester Epidemiology Project (REP). Complete REP inpatient and outpatient medical records were reviewed by specialists. Conditions meeting standardized criteria on ≥2 visits were classified as REP confirmed cases. RESULTS: Six hundred and twenty-eight responders were diagnosed with autoimmune conditions between 2002 and 2017. In the nested case-control analyses, high WTC exposure was not associated with autoimmune domains and conditions (rheumatologic domain odds ratio [OR] = 1.03, 95% confidence interval [CI] = 0.77, 1.37; rheumatoid arthritis OR = 1.12, 95% CI = 0.70, 1.77). GRC members had lower SIR than REP. Women's risks were generally greater than men's. CONCLUSIONS: The study found no statistically significant increased risk of autoimmune conditions with WTC exposures.

Quality of life in subjects with upper- and lower-limb spasticity treated with incobotulinumtoxinA.

BACKGROUND: We evaluated quality of life among subjects with upper- and lower-limb spasticity who received escalating doses of incobotulinumtoxinA (total body doses up to 800 U) in the prospective, single-arm, dose-titration TOWER study. METHODS: In this exploratory trial, subjects (N = 155; 18-80 years of age) with upper- and lower-limb spasticity due to cerebral causes who were deemed to require total body doses of up to 800 U incobotulinumtoxinA received three consecutive injection cycles of incobotulinumtoxinA (400, 600, and up to 800 U), each with 12 to 16 weeks' follow-up. QoL was assessed using the EuroQol 5-dimensions questionnaire, three-level (EQ-5D), before and 4 weeks post-injection in each injection cycle and at the end of injection cycle 3. RESULTS: The mean EQ-5D visual analog scale scores of 155 participants continuously improved from study baseline to 4 weeks post-injection in all injection cycles (mean [standard deviation] change 6.7 [14.1], 9.6 [16.3], and 8.6 [17.0] for injection cycles 1, 2, and 3, respectively; p < 0.0001 for all, paired sample t-test). In general, among those with a change in the EQ-5D rating of their condition, the proportion of subjects with 'improvement' was greater than that with 'worsening' for individual EQ-5D dimensions across all injection cycles. At the end of injection cycle 3, the proportion of subjects rating their condition as 'normal' increased from study baseline for all dimensions, and there was a ≥ 46% reduction in the proportion of subjects with a rating of 'severe impairment'. CONCLUSION: These preliminary results suggest that escalating incobotulinumtoxinA doses up to 800 U are associated with improvement in quality of life ratings in subjects with multifocal upper- and lower-limb spasticity, and form a basis for future comparator studies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01603459. Date of registration: May 22, 2012.

Diabetic Neuropathy.

Diabetes mellitus is becoming increasingly common worldwide. As this occurs, there will be an increase in the prevalence of known comorbidities from this disorder of glucose metabolism. One of the most disabling adverse comorbidities is diabetic neuropathy. The most common neuropathic manifestation is distal symmetric polyneuropathy, which can lead to sensory disturbances, including diminished protective sense, making patients prone to foot injuries. However, focal, multifocal, and autonomic neuropathies are also common. Diabetic nerve pain and Charcot osteoarthropathy are advanced neuropathic conditions that portend a severe deterioration in quality of life. To combat these symptoms, along with glycemic control and establishment of health care systems to educate and support patients with the complexities of diabetes, there are pharmacologic remedies to ameliorate the neurologic symptoms. Several guidelines and review boards generally recommend the use of tricyclic antidepressants, serotonin/norepinephrine-reuptake inhibitors, α-2-delta ligands, and anticonvulsants as medications to improve painful diabetic neuropathy and quality of life.

Peripheral Neuropathy Research Registry: A prospective cohort.

The Peripheral Neuropathy Research Registry (PNRR) is a prospective cohort of peripheral neuropathy (PN) patients focused on idiopathic axonal peripheral neuropathy. Patients with diabetic, human immunodeficiency virus-, and chemotherapy-induced peripheral neuropathies are enrolled as comparison groups. The PNRR is a multi-center collaboration initiated and funded by the Foundation for Peripheral Neuropathy (FPN) with the objective to recruit a well characterized cohort of patients with different phenotypes and symptoms in each diagnostic category, and to advance research through development of biomarkers and identification of previously unknown causes of PN. The overall goal of the initiative is to find disease-altering treatments and better symptom relief for patients. We present the study design, types of data collected, and characteristics of the first 1150 patients enrolled. We also discuss ongoing analyses on this dataset, including untargeted-omics methodologies.

Improved Detection of Vowel Envelope Frequency Following Responses Using Hotelling's T2 Analysis.

OBJECTIVES: Objective detection of brainstem responses to natural speech stimuli is an important tool for the evaluation of hearing aid fitting, especially in people who may not be able to respond reliably in behavioral tests. Of particular interest is the envelope frequency following response (eFFR), which refers to the EEG response at the stimulus' fundamental frequency (and its harmonics), and here in particular to the response to natural spoken vowel sounds. This article introduces the frequency-domain Hotelling's T (HT2) method for eFFR detection. This method was compared, in terms of sensitivity in detecting eFFRs at the fundamental frequency (HT2_F0), to two different single-channel frequency domain methods (F test on Fourier analyzer (FA) amplitude spectra [FA-F-Test] and magnitude-squared coherence [MSC]) in detecting envelope following responses to natural vowel stimuli in simulated data and EEG data from normal-hearing subjects. Sensitivity was assessed based on the number of detections and the time needed to detect a response for a false-positive rate of 5%. The study also explored whether a single-channel, multifrequency HT2 (HT2_3F) and a multichannel, multifrequency HT2 (HT2_MC) could further improve response detection. DESIGN: Four repeated words were presented sequentially at 70 dB SPL LAeq through ER-2 insert earphones. The stimuli consisted of a prolonged vowel in a /hVd/ structure (where V represents different vowel sounds). Each stimulus was presented over 440 sweeps (220 condensation and 220 rarefaction). EEG data were collected from 12 normal-hearing adult participants. After preprocessing and artifact removal, eFFR detection was compared between the algorithms. For the simulation study, simulated EEG signals were generated by adding random noise at multiple signal to noise ratios (SNRs; 0 to -60dB) to the auditory stimuli as well as to a single sinusoid at the fluctuating and flattened fundamental frequency (f0). For each SNR, 1000 sets of 440 simulated epochs were generated. Performance of the algorithms was assessed based on the number of sets for which a response could be detected at each SNR. RESULTS: In simulation studies, HT2_3F significantly outperformed the other algorithms when detecting a vowel stimulus in noise. For simulations containing responses only at a single frequency, HT2_3F performs worse compared with other approaches applied in this study as the additional frequencies included do not contain additional information. For recorded EEG data, HT2_MC showed a significantly higher response detection rate compared with MSC and FA-F-Test. Both HT2_MC and HT2_F0 also showed a significant reduction in detection time compared with the FA-F-Test algorithm. Comparisons between different electrode locations confirmed a higher number of detections for electrodes close to Cz compared to more peripheral locations. CONCLUSION: The HT2 method is more sensitive than FA-F-Test and MSC in detecting responses to complex stimuli because it allows detection of multiple frequencies (HT2_F3) and multiple EEG channels (HT2_MC) simultaneously. This effect was shown in simulation studies for HT2_3F and in EEG data for the HT2_MC algorithm. The spread in detection time across subjects is also lower for the HT2 algorithm, with decision on the presence of an eFFR possible within 5 min.

Envelope frequency following responses are stronger for high-pass than low-pass filtered vowels.

BACKGROUND: To assess hearing in response to speech, the envelope frequency following response (FFR) can be observed at the fundamental frequency of a vowel stimulus and its harmonics. FFRs are complex non-linear phenomena, which require better understanding for allowing robust inferences on the assessment of hearing and hearing aid fitting. OBJECTIVES: To evaluate the effect of stimulus bandwidth on FFR detection rates using filtered vowel stimuli with equal sound levels. DESIGN: FFRs were collected whilst presenting repeated vowels (in consonant-vowel-consonant format) filtered into different bandwidths. Eighty stimuli per word were presented at 70 dB SPL LAeq through insert earphones with an inter-stimulus interval of 1 s. Responses were detected using frequency-domain Hotelling's T2 (HT2) tests for individual multiples of the fundamental frequency (F0) and for combinations of F0 multiples. STUDY SAMPLE: A total of 11 native English-speaking subjects with normal hearing thresholds. RESULTS: Average detection rates are highest (69%) with stimuli high-pass filtered >1000 Hz, and significantly lower for low-pass filtered stimuli (40%). CONCLUSIONS: High-pass filtered vowels therefore appear to elicit stronger FFRs than low-pass filtered vowels at the same dB SPL LAeq. For testing hearing using band-limited speech, filtering effects (due to hearing loss, hearing aid setting or stimulus choice) on responses must be considered.

Learning About Love: A Meta-Analytic Study of Individually-Oriented Relationship Education Programs for Adolescents and Emerging Adults.

Despite recent policy initiatives and substantial federal funding of individually oriented relationship education programs for youth, there have been no meta-analytic reviews of this growing field. This meta-analytic study draws on 17 control-group studies and 13 one-group/pre-post studies to evaluate the effectiveness of relationship education programs on adolescents' and emerging adults' relationship knowledge, attitudes, and skills. Overall, control-group studies produced a medium effect (d = .36); one-group/pre-post studies also produced a medium effect (d = .47). However, the lack of studies with long-term follow-ups of relationship behaviors in the young adult years is a serious weakness in the field, limiting what we can say about the value of these programs for helping youth achieve their aspirations for healthy romantic relationships and stable marriages.

Prevalence and Correlates of Persistent HIV-1 RNA in Cerebrospinal Fluid During Antiretroviral Therapy.

BACKGROUND: Neurocognitive disorders remain common among human immunodeficiency virus (HIV)-positive adults, perhaps owing to persistent HIV-1 RNA in cerebrospinal fluid (CSF) during antiretroviral therapy (ART). METHODS: Using a single-copy assay, we measured HIV-1 RNA levels in CSF and plasma specimens from 220 HIV-positive adults who were taking suppressive ART. Fifty-five participants were tested twice. RESULTS: HIV-1 RNA was detected in 42.3% of CSF and 65.2% of plasma samples. Correlates of higher CSF HIV-1 RNA levels included higher nadir and current CD4+ T-cell counts, a plasma HIV-1 RNA level of ≥ 1 copy/mL, and a lower central nervous system penetration-effectiveness score (model P < .001). Worse neurocognitive performance was associated with discordance in HIV-1 RNA detection between plasma and CSF, lower overall CSF HIV-1 RNA level, and longer ART duration, among others (model P < .001). In the longitudinal subgroup, CSF HIV-1 RNA persisted in most participants (69%) over 7 months. CONCLUSIONS: Low-level HIV-1 RNA in CSF is common during suppressive ART and is associated with low-level HIV-1 RNA in blood, better immune status, and lower ART drug distribution into CSF. The association between HIV-1 RNA discordance and HIV-associated neurocognitive disorder (HAND) may reflect compartmentalization. The relationship between HAND, lower HIV-1 RNA levels in CSF, and lower CD4+ T-cell counts may reflect disturbances in the immune response to HIV-1 in the CNS.

Predictive control of intersegmental tarsal movements in an insect.

In many animals intersegmental reflexes are important for postural and movement control but are still poorly undesrtood. Mathematical methods can be used to model the responses to stimulation, and thus go beyond a simple description of responses to specific inputs. Here we analyse an intersegmental reflex of the foot (tarsus) of the locust hind leg, which raises the tarsus when the tibia is flexed and depresses it when the tibia is extended. A novel method is described to measure and quantify the intersegmental responses of the tarsus to a stimulus to the femoro-tibial chordotonal organ. An Artificial Neural Network, the Time Delay Neural Network, was applied to understand the properties and dynamics of the reflex responses. The aim of this study was twofold: first to develop an accurate method to record and analyse the movement of an appendage and second, to apply methods to model the responses using Artificial Neural Networks. The results show that Artificial Neural Networks provide accurate predictions of tarsal movement when trained with an average reflex response to Gaussian White Noise stimulation compared to linear models. Furthermore, the Artificial Neural Network model can predict the individual responses of each animal and responses to others inputs such as a sinusoid. A detailed understanding of such a reflex response could be included in the design of orthoses or functional electrical stimulation treatments to improve walking in patients with neurological disorders as well as the bio/inspired design of robots.

Assessment of autonomic symptoms in a medically complex, urban patient population.

PURPOSE: Urban, minority communities are disproportionately affected by the chronic diseases associated with autonomic neuropathy; however validated measures of autonomic symptoms have not been studied in these complex populations. We sought to validate the Autonomic Symptom Profile (ASP) in a low income, medically complex, urban patient population. METHODS: Ninety-seven adults were recruited from the outpatient neurology clinic of an academic medical center serving the East Harlem neighborhood of New York City. Participants completed the ASP, and underwent a comprehensive neurologic examination, and a standardized battery of autonomic function tests (quantitative sweat testing, heart rate response to deep breathing (HRDB), Valsalva maneuver, and tilt table). Burden of chronic disease was summarized using the Charlson co-morbidity index (CCI), and detailed medication history was obtained. RESULTS: The ASP displayed good internal consistency (Cronbach's α = .88), even among lower literacy participants. In univariate analyses, the ASP was correlated with HRDB (r = -.301, p = .002), a marker of cardiac autonomic neuropathy, with the CCI (r = .37, p < .001), and with use of medications with autonomic effects [t(95) = -2.13, p = .036]. However, in multivariate analysis, only the CCI remained significant. CONCLUSIONS: In this urban, predominantly minority patient population, the symptoms captured by the ASP were more closely associated with burden of medical disease than with autonomic dysfunction. Due to this lack of specificity, it is essential that results from autonomic questionnaires be interpreted in the context of the neurologic history and exam, burden of co-morbid illness and medications, and most importantly autonomic function tests.

Anemia and Red Blood Cell Indices Predict HIV-Associated Neurocognitive Impairment in the Highly Active Antiretroviral Therapy Era.

BACKGROUND: Anemia has been linked to adverse human immunodeficiency virus (HIV) outcomes, including dementia, in the era before highly active antiretroviral therapy (HAART). Milder forms of HIV-associated neurocognitive disorder (HAND) remain common in HIV-infected persons, despite HAART, but whether anemia predicts HAND in the HAART era is unknown. METHODS: We evaluated time-dependent associations of anemia and cross-sectional associations of red blood cell indices with neurocognitive impairment in a multicenter, HAART-era HIV cohort study (N = 1261), adjusting for potential confounders, including age, nadir CD4(+) T-cell count, zidovudine use, and comorbid conditions. Subjects underwent comprehensive neuropsychiatric and neuromedical assessments. RESULTS: HAND, defined according to standardized criteria, occurred in 595 subjects (47%) at entry. Mean corpuscular volume and mean corpuscular hemoglobin were positively associated with the global deficit score, a continuous measure of neurocognitive impairment (both P < .01), as well as with all HAND, milder forms of HAND, and HIV-associated dementia in multivariable analyses (all P < .05). Anemia independently predicted development of HAND during a median follow-up of 72 months (adjusted hazard ratio, 1.55; P < .01). CONCLUSIONS: Anemia and red blood cell indices predict HAND in the HAART era and may contribute to risk assessment. Future studies should address whether treating anemia may help to prevent HAND or improve cognitive function in HIV-infected persons.

Genome-wide association study of HIV-associated neurocognitive disorder (HAND): A CHARTER group study.

HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive, and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded. Neurocognitive outcomes included GDS-defined neurocognitive impairment (NCI; binary GDS, 366 cases with GDS ≥ 0.5 and 684 controls with GDS < 0.5, and GDS as a continuous variable) and Frascati HAND definitions that incorporate assessment of functional impairment by self-report and performance-based criteria. Genotype data were obtained using the Affymetrix Human SNP Array 6.0 platform. Multivariable logistic or linear regression-based association tests were performed for GDS-defined NCI and HAND. GWAS results did not reveal SNPs meeting the genome-wide significance threshold (5.0 × 10-8 ) for GDS-defined NCI or HAND. For binary GDS, the most significant SNPs were rs6542826 (P = 8.1 × 10-7 ) and rs11681615 (1.2 × 10-6 ), both located on chromosome 2 in SH3RF3. The most significant SNP for continuous GDS was rs11157436 (P = 1.3 × 10-7 ) on chromosome 14 in the T-cell-receptor alpha locus; three other SNPs in this gene were also associated with binary GDS (P ≤ 2.9 × 10-6 ). This GWAS, conducted among ART-era participants from a single cohort with robust neurological phenotyping, suggests roles for several biologically plausible loci in HAND that deserve further exploration. © 2017 Wiley Periodicals, Inc.

Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients.

Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n = 272, mean duration 17.9 months) or LPV/r (n = 173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p < 0.001), were less likely to have AIDS (p < 0.001) or hepatitis C virus (HCV) coinfection (p < 0.05), had higher CD4+ T cell nadirs (p < 0.001), had lower peak (p < 0.001) and current (p < 0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p < 0.001). Overall, EFV users had worse speed of information processing (p = 0.04), verbal fluency (p = 0.03), and working memory (p = 0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n = 329), EFV users performed poorly, whereas among HCV seropositives (n = 116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n = 269), EFV users had worse speed of information processing (p = 0.02) and executive functioning (p = 0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.

Persistent CSF but not plasma HIV RNA is associated with increased risk of new-onset moderate-to-severe depressive symptoms; a prospective cohort study.

Major depressive disorder is the most common neuropsychiatric complication in human immunodeficiency virus (HIV) infections and is associated with worse clinical outcomes. We determined if detectable cerebrospinal fluid (CSF) HIV ribonucleic acid (RNA) at threshold ≥50 copies/ml is associated with increased risk of depression. The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort is a six-center US-based prospective cohort with bi-annual follow-up of 674 participants. We fit linear mixed models (N = 233) and discrete-time survival models (N = 154; 832 observations) to evaluate trajectories of Beck Depression Inventory (BDI) II scores and the incidence of new-onset moderate-to-severe depressive symptoms (BDI ≥ 17) among participants on combination antiretroviral therapy (cART), who were free of depression at study entry and received a minimum of three CSF examinations over 2496 person-months follow-up. Detectable CSF HIV RNA (threshold ≥50 copies/ml) at any visit was associated with a 4.7-fold increase in new-onset depression at subsequent visits adjusted for plasma HIV RNA and treatment adherence; hazard ratio (HR) = 4.76, (95 % CI 1.58-14.3); P = 0.006. Depression (BDI) scores were 2.53 points higher (95 % CI 0.47-4.60; P = 0.02) over 6 months if CSF HIV RNA was detectable at a prior study visit in fully adjusted models including age, sex, race, education, plasma HIV RNA, duration and adherence of CART, and lifetime depression diagnosis by Diagnostic Statistical Manual (DSM-IV) criteria. Persistent CSF but not plasma HIV RNA is associated with an increased risk for new-onset depression. Further research evaluating the role of immune activation and inflammatory markers may improve our understanding of this association.

Apolipoprotein E ε4 genotype status is not associated with neuroimaging outcomes in a large cohort of HIV+ individuals.

Previous neuroimaging studies suggest a negative relationship between the apolipoprotein (ApoE) ε4 allele and brain integrity in human immunodeficiency virus (HIV)-infected (HIV+) individuals, although the presence of this relationship across adulthood remains unclear. The purpose of this study is to clarify the discrepancies using a large, diverse group of HIV+ individuals and multiple imaging modalities sensitive to HIV. The association of ApoE ε4 with structural neuroimaging and magnetic resonance spectroscopy (MRS) was examined in 237 HIV+ individuals in the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Cortical and subcortical gray matter, abnormal and total white matter, ventricles, sulcal cerebrospinal fluid (CSF), and cerebellar gray matter, white matter, and CSF volumes, and MRS concentrations of myo-inositol, creatine, N-acetyl-aspartate, and choline in the frontal white matter (FWM), frontal gray matter (FGM), and basal ganglia were examined. Secondary analyses explored this relationship separately in individuals ≥50 years old (n = 173) and <50 years old (n = 63). No significant differences were observed between ApoE ε4+ (ApoE ε3/ε4 and ApoE ε4/ε4) individuals (n = 69) and ApoE ε4- (ApoE ε2/ε3 and ApoE ε3/ε3) individuals (n = 167). When individuals were further divided by age, no significant genotype group differences were identified in individuals <50 or ≥50 years of age on any neuroimaging outcome. The ApoE ε4 allele did not affect brain integrity in this large, diverse sample of HIV+ individuals. The effects of ApoE ε4 may not be apparent until more advanced ages and may be more prominent when present along with other risk factors for neuronal damage.