Thesis advisor: Tricia H. Burdo / Human immunodeficiency virus-associated peripheral neuropathy (HIVPN) continues to be a prevalent comorbidity of HIV infection, despite virologic control due to effective antiretroviral therapy (ART). Symptoms include bilateral tingling, numbness, and pain in distal extremities. Severity of symptoms is associated with a loss of intraepidermal nerve fiber density (IENFD) in the feet. Damage to the dorsal root ganglia (DRG) has also been observed in postmortem tissue analysis from patients with HIV-PN. Treatment options are limited due to a lack of understanding of the disease pathogenesis. Chronic monocyte activation and accumulation of macrophages in peripheral nervous system (PNS) tissues has been reported but few studies have directly demonstrated the role of monocyte/macrophage activation and traffic in the pathogenesis of HIV-PN. The central hypothesis of this thesis is that monocyte activation and traffic mediates PNS neuronal damage. We addressed this hypothesis in several ways. In chapter 2, we describe pathology seen in a rapid disease progression animal model of HIV-PN. We found that an early loss of IENFD preceded a loss of small diameter DRG neurons. In chapter 3, we associated DRG pathology with an accumulation of inflammatory macrophages surrounding DRG neurons. Increased monocyte traffic to the DRG was associated with severity of DRG pathology and with a loss of IENFD. In chapter 4, we directly tested the impact of monocyte traffic on DRG pathology by blocking leukocyte traffic with an anti-VLA-4 antibody, natalizumab. Blocking cell traffic reduced accumulation of macrophages in the DRG and improved pathology. Next we treated animals with methylglyoxal-bisguanylhydrazone (MGBG) to specifically target myeloid cells and reduce their activation. MGBG treatment improved DRG pathology and reduced accumulation of macrophages in tissues. Having demonstrated the role of monocyte traffic and activation, we aimed to identify signaling proteins and inflammatory proteins associated with PNS pathology. We found elevated monocyte chemoattractants in DRG tissue and elevated markers of monocyte activation in plasma that were associated with a loss of IENFD. Together, these studies demonstrate that systemic monocyte activation, macrophage accumulation in DRG tissue, and monocyte traffic plays a major role in SIV-PN pathogenesis. These studies provide novel insight into immune mechanisms that impact neuronal loss during SIV infection. Thus, modulating macrophage activation and reducing monocyte traffic may have therapeutic benefits to patients suffering from or at risk of developing HIV-PN. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Background: Peripheral neuropathy is a common treatment-related adverse effect associated with vincristine. Vincristine is a major CYP3A4 substrate and is often administered alongside the neurokinin-1 (NK-1) receptor antagonists, aprepitant or fosaprepitant, which are moderate CYP3A4 inhibitors. This inhibition may result in increased concentrations of vincristine and an increased incidence of toxicity. Objective:The primary objective of this study was to investigate if there is a clinically significant drug interaction between vincristine and aprepitant or fosaprepitant resulting in early-onset peripheral neuropathy. The secondary objective of this study was to investigate the cumulative rate of chemotherapy-induced peripheral neuropathy (CIPN). Methodology:This was a single-centered, retrospective, cohort chart review. Patients receiving vincristine-based chemotherapy between 1 July 2010 through 30 June 2018 were identified and reviewed for concomitant use of aprepitant or fosaprepitant and incidence of neuropathy. Early-onset CIPN was defined as neuropathy onset during the first cycle of chemotherapy. Results:A total of 115 subjects were retrospectively reviewed over the study period, of whom 71 were included in the aprepitant/fosaprepitant group and 44 were included in the group without a NK-1 receptor antagonist. Of the subjects who received aprepitant/fosaprepitant, 26.7% experienced early-onset peripheral neuropathy as compared to 22.7% in the group without a NK-1 receptor antagonist (P = 0.627). Overall, CIPN was higher in the group who received aprepitant/fosaprepitant compared to the group without (56% vs. 36%, P = 0.036). Conclusion:There appears to be an increased risk of CIPN with the concomitant use of vincristine and aprepitant or fosaprepitant.

La fonction d’équilibration est une fonction complexe qui implique une interaction entre les systèmes somatosensoriel, vestibulaire et visuelle qui en assurent la régulation. En pathologie, le contrôle de la posture et de l’équilibre peut être atteint comme dans le cas de neuropathies périphériques qui se caractérisent par une atteinte des fibres sensitives et motrices de niveau variable. Les neuropathies à prédominance sensitive sont dénommées neuropathies ataxiantes ; elles se caractérisent au niveau des membres inférieurs par l’atteinte proprioceptive qui peut entraîner des troubles de la posture et de l’équilibre en condition statique, dynamique ou encore lors de la marche. Ce travail rapporte trois méthodes d’évaluation élaborées dans les trois conditions d’équilibration afin de mieux caractériser les troubles de l’équilibre de cette population. L’évaluation de l’équilibre en condition statique sur une plateforme de force nous a permis de caractériser le poids des atteintes sensorielles et motrices dans les neuropathies à condition d’y inclure la mesure du paramètre de limite de l’équilibre qui dissocie le plus ces deux composantes. En condition dynamique, l’analyse de l’équilibre sur une plateforme de force motorisée « IsiMove » nous a permis de créer un score composé qui discrimine les troubles de l’équilibre d’une population de sujets ataxiques caractérisé par une instabilité majeure en conditions quasi statique (basse fréquence de déstabilisation) et une instabilité moins marquée en conditions plus dynamiques (hautes fréquences). Au cours de la marche, les lunettes eye-tracker se sont avérées constituer un outil pertinent pour l’analyse de la compensation visuelle, à la fois reproductible et sensible à la pathologie. Cette technologie nous a aidés à caractériser quantitativement une stratégie visuelle mise en place par les patients ataxiques lors de la locomotion. Les résultats de ce travail de thèse ouvrent différentes perspectives en ce qui concerne l’élaboration de programmes de rééducation plus spécifiques pour cette population, et la caractérisation instrumentale de nouveaux profils de troubles de l’équilibre des patients présentant une instabilité d’origine neurologique. / The balance function is a complex function that involves interaction between the somatosensory, the vestibular and the visual systems, the latter ensuring the equilibrium function regulation. In pathology, the control of posture and balance can be impaired as in the case of peripheral neuropathies, characterized by the impairment of sensory and motor fibers of variable level. Predominantly sensory neuropathies are called ataxic neuropathies; they are characterized by proprioceptive impairment in the lower limbs that can lead to disorders of posture and balance in static or dynamic condition, or even during gait. This study reports three assessment methods developed under the three balance conditions to better characterize balance disorders concerning this population. Balance assessment under static condition on a force platform has enabled us to characterize the weight of the sensory and motor impairments in neuropathies, provided that by the inclusion of measuring the limits of equilibrium balance parameter, which separates the most these two components. Under dynamic conditions, the analysis of balance on the motorized force platform "IsiMove" allowed us to create a composed score that distinguishes balance disorders in a population of ataxic subjects, which is characterized by major instability in quasi-static conditions (low frequency instability) and a less marked instability in more dynamic conditions (high frequencies). During gait, the eye tracker glasses have proven to be a relevant tool for the analysis of visual compensation, both reproducible and sensitive to the pathology. This technology has helped us to quantitatively characterize the visual strategy implemented by ataxic patients during locomotion. The results of this thesis open different perspectives regarding the development of more specific rehabilitation programs for this population. It also opens different perspectives on the instrumental characterization of new profiles of balance disorders in patients with instability of neurological origin.

Neuropathy is a nerve disorder found in HIV disease and diabetes mellitus that indicates damage in the peripheral nervous system. Burning, tingling, stabbing, shooting, and painful sensations in the hands and feet are common symptoms of this chronic disorder, and no treatments are available that repair the nerves. The approved pain treatments are few and only available for the diabetic neuropathy population. A mixed-methods study of archival data was performed to compare patients with painful neuropathy (PN) associated with 2 diseases: HIV (HIV-PN) and diabetes mellitus (DPN). This study examined the similarities and differences of the pain narratives and common pain questionnaires from 12 HIV-PN and 11 DPN subjects. An independent t test of the Visual Analog Scale, Numeric Rating Scale, Brief Pain Intensity subscale, and the Short Form McGill Pain questionnaire failed to reject the null hypothesis that HIV-PN and DPN have equal pain levels. The qualitative analysis revealed 8 shared themes in both groups, with footwear challenges reported as the primary theme. This finding supports the many shared themes between these groups, yet education addressing these themes is minimal. One contrasting theme, privacy, was detected in the HIV-PN group, correlating statistically with the Beck Depression Inventory findings of guilt feelings. The theme of exercise was unique for the DPN group. Both groups had paralinguistic and nonverbal elements discovered in the recordings demonstrating the need for future research to explore these components. Results of education and research themes of privacy in the HIV-PN group and pain communication strategies for both groups will increase understanding of etiology, intervention, and patterns of pain for those diagnosed with neuropathy.

Indiana University-Purdue University Indianapolis (IUPUI) / The purpose of this prospective, observational study was to determine if a technique used to detect early signs of small-fiber neuropathy (local skin heating) could detect signs of small-fiber taxane-induced peripheral neuropathy (TIPN) in breast cancer survivors (BCS) during the first 6 weeks of Taxol®. Aims of the study were to compare the mean size of (1) axon reflexes and (2) axon flares (both markers of small fiber nerve function) in BCS receiving Taxol® to the size of reflexes/flares in healthy female controls (HCs). A third aim was to determine whether the size of axon reflexes/flares correlated with (a) overall TIPN severity and (b) severity of individual signs/symptoms of TIPN during early Taxol®. Data for the study was collected from nine BCS and 20 HCs (N = 29). All BCS had first-time, non-metastatic cancer and received weekly or bi-weekly Taxol®. Data was collected at 3 time-points: Time 1 (day 0, before Taxol®), Time 2 (day 14), and Time 3 (day 42). Axon reflexes and flares were generated using a validated 40-minute skin heating protocol. Axon reflexes were measured using laser Doppler Flowmetry. Axon flares were measured using full-field laser perfusion imaging. TIPN was measured using the 5-item Short Form of the Total Neuropathy Score (Reduced Version). Results identified potential signs of small-fiber TIPN in BCS after 6 weeks of Taxol®. Contrary to expectation, axon reflexes were larger for BCS at Time 3 than HCs, suggesting that Taxol® may be associated with an increase in small-fiber nerve function like that seen in pre-clinical studies. Clinical signs/symptoms of TIPN were not significantly correlated with axon reflexes or axon flares at the same time point. Analyses of axon flare size were confounded by issues with the data. These results add to the growing body of evidence showing that Taxol® affects small-diameter sensory nerves and provides the first evidence in humans that changes in small-fiber nerve function may be detectable after just 6 weeks of Taxol® therapy. Studies in larger samples are needed to validate these findings.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21041号 / 人健博第57号 / 新制||人健||4(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 市橋 則明, 教授 田村 恵子, 教授 万代 昌紀 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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Background: Vascular dysfunction due to hyperglycemia in individuals with diabetes is a factor contributing to distal symmetric polyneuropathy (DSP). Reactive oxygen species (ROS) reduce the bioavailability of nitric oxide (NO), a powerful vasodilator, resulting in reduced circulation and nerve ischemia. Increases in blood NO concentrations and circulation have been attributed to whole body vibration (WBV). The purpose of this study was to the determine the effects of low frequency, low amplitude WBV on whole blood NO concentration and skin blood flow (SBF) in individuals with symptoms of DSP. Research Design and Methods: Ten subjects with diabetes and impaired sensory perception in the lower limbs participated in this cross-over study. Each submitted to two treatment conditions, WBV and sham, with a one week washout period between. Blood draws for NO analysis and Doppler laser image scans of SBF were performed before, immediately after and following a 5 minute recovery of each the treatments. Results: Low frequency, low amplitude WBV vibration significantly increased skin blood flow compared to the sham condition (p=0.0115). Whole blood nitric oxide concentrations did not differ between the WBV and sham condition immediately or 5 minutes post-treatment ( p=0.1813) Conclusions: These findings demonstrate that subjects with diabetes respond to whole body vibration with increased skin blood flow compared to sham condition. The implication is that WBV is a potential non-pharmacological therapy for neurovascular complications of diabetes.