Faculty Bibliography

BACKGROUND:PD diagnosis is based primarily on clinical criteria and can be inaccurate. Biological markers, such as α-synuclein aggregation, that reflect ongoing pathogenic processes may increase diagnosis accuracy and allow disease progression monitoring. Though α-synuclein aggregation assays have been published, reproducibility, standardization, and validation are key challenges for their development as clinical biomarkers. OBJECTIVE:To cross-validate two α-synuclein seeding aggregation assays developed to detect pathogenic oligomeric α-synuclein species in CSF using samples from the same PD patients and healthy controls from the BioFIND cohort. METHODS:CSF samples were tested by two independent laboratories in a blinded fashion. BioFIND features standardized biospecimen collection of clinically typical moderate PD patients and nondisease controls. α-synuclein aggregation was measured by protein misfolding cyclic amplification (Soto lab) and real-time quaking-induced conversion (Green lab). Results were analyzed by an independent statistician. RESULTS:Measuring 105 PD and 79 healthy control CSF samples, these assays showed 92% concordance. The areas under the curve from receiver operating characteristic curve analysis for the diagnosis of PD versus healthy controls were 0.93 for protein misfolding cyclic amplification, 0.89 for real-time quaking-induced conversion, and 0.95 when considering only concordant assay results. Clinical characteristics of false-positive and -negative subjects were not different from true-negative and -positive subjects, respectively. CONCLUSIONS:These α-synuclein seeding aggregation assays are reliable and reproducible for PD diagnosis. Assay parameters did not correlate with clinical parameters, including disease severity or duration. This assay is highly accurate for PD diagnosis and may impact clinical practice and clinical trials. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Tuberculosis (TB) surpassed HIV as the world's leading infectious cause of death in 2014. Although billions of dollars have been invested to reduce the global burden of pulmonary TB, tuberculous meningitis (TBM), the most lethal manifestation of the disease, has remained largely neglected with a paucity of evidence-based guidelines. Research is urgently needed to obtain reliable estimates of the global incidence of TBM, develop high performance technologies to detect TBM in CSF, and evaluate drug regimens with greater penetration of the CNS.

Background: Myopia's axial elongation of the eye causes an irregularly shaped retina. Cross-sectional studies show that increasing diopters and axial lengths in myopia correlate negatively with Optical Coherence Tomography (OCT) derived measures of Retinal Nerve Fiber Layer (RNFL) thickness. This has largely precluded including OCT data from high myopia individuals in Multiple Sclerosis (MS) and other studies. OCT is a promising marker of neurodegeneration in MS. However, the impact of high myopia in longitudinal studies remains to be investigated.
Objective(s): To assess the impact of high myopia on rates of change in OCT retinal layer thicknesses in MS patients and healthy controls (HC).
Method(s): A 1:2 age and sex matching scheme was used in the MS [13 high myopia (MSHM): 26 non myopia (MSNM)] and HC [7 high myopia (HCHM): 14 non myopia (HCNM)] cohorts. OCT thickness measures of the peripapillary RNFL (pRNFL), ganglion cell+inner plexiform layer (GCIP), and other retinal layers were determined using a validated segmentation algorithm. Mixed effects linear regression was used in statistical analyses.
Result(s): Baseline MSHM eyes had lower GCIP (-4.01 mum, p = 0.06) and pRNFL thicknesses (-8.15 mum, p = 0.04), as compared to MSNM eyes. HC GCIP and pRNFL thicknesses were lower in HCHM than HCNM eyes (-4.15 mum, p = 0.01 and -0.84 mum, p = 0.83 respectively). Despite cross-sectional differences in retinal layer thicknesses in eyes stratified by myopia, longitudinal (median duration of follow-up= 4.6, 6.9, 4.0, 5.1 years in MSHM, MSNM, HCHM, and HCNM respectively) rates of retinal layer change did not differ between participants with and without high myopia. In the MS cohort, rates of thinning were significant in both groups but there was no difference between rates of GCIP and pRNFL thinning among MSHM and MSNM (DELTA0.07 mum/y, p = 0.71 and DELTA0.12 mum/y, p = 0.52 respectively) eyes. Similarly, no difference in rates of GCIP and pRNFL change was found between HCHM and HCNM (DELTA0.06 mum/y, p = 0.49 and DELTA0.21 mum/y, p = 0.22 respectively) eyes. Similar results were observed for the inner and outer nuclear layers in MS and HCs.
Conclusion(s): Although cross-sectional retinal thickness measures may vary due to myopia, longitudinal rates of retinal change appear unaffected. Therefore, despite longstanding opinion, our findings suggest high myopia may not confound longitudinal OCT analyses. Future research is needed to verify and validate our preliminary findings in larger, longitudinal studies

Background: Optical coherence tomography (OCT) studies have shown that retinal nerve fiber layer (RNFL) and ganglion cell + inner plexiform layer (GCIP) thinning are accelerated in multiple sclerosis (MS). Increased inner nuclear layer (INL) thickness has been associated with inflammatory disease activity, but decreased thicknesses of the INL and outer nuclear layer (ONL) have also been identified in a subset of patients with more severe disability. INL atrophy has also been found post-mortem in MS eyes, more frequently in progressive MS (PMS). These data suggest that there exist differences in retinal pathology at various stages of the disease, however these have been incompletely characterized, as the vast majority of OCT studies comparing retinal measures between MS subtypes have been cross-sectional, with small numbers of PMS eyes.
Objective(s): To assess the effects of age and MS subtype on longitudinal changes in retinal layer thicknesses.
Method(s): A cohort of MS patients and healthy controls (HC), followed with serial spectral-domain OCT, was evaluated. Retinal layer thicknesses were derived utilizing a validated, automated segmentation algorithm. Statistical analyses were performed with mixed-effects linear regression models.
Result(s): Data from 364 MS (178 relapsing-remitting MS [RRMS], 186 PMS) and 66 HC participants were analyzed. Median follow-up duration was 3.6 years. Higher age was associated with slower rates of RNFL atrophy in MS (p<0.001), but not in HC. Rates of GCIP atrophy did not differ across age in MS, but in HC higher age was associated with accelerated rates of GCIP atrophy (p=0.006). The proportion of RNFL and GCIP atrophy in MS attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. PMS was independently associated with accelerated RNFL and GCIP atrophy compared to RRMS (RNFL: p=0.002; GCIP: p=0.001). Higher age was associated with accelerated INL and ONL atrophy and this relationship was similar in MS and HC. INL and ONL atrophy rates were faster in PMS compared to HC (INL: p=0.03; ONL: p=0.04) and RRMS (INL: p=0.008; ONL: p=0.01), but did not differ between RRMS and HC.
Conclusion(s): PMS is independently associated with accelerated retinal layer atrophy, and INL and ONL atrophy may be novel biomarkers of neurodegeneration in PMS. The effects of normal aging on retinal layer thicknesses should be considered when designing clinical trials incorporating OCT measures as outcomes

Background: The retinal microcirculation has been studied in various diseases including multiple sclerosis (MS). However, inter-eye correlations and potential differences of the retinal blood flow velocity (BFV) remain largely unstudied, but may be important in guiding eye selection, as well as the design and interpretation of studies assessing or utilizing retinal BFV.
Objective(s): The primary aim of this study was to determine inter-eye correlations in BFVs in healthy controls (HCs). Since prior studies raise the possibility of reduced BFV in MS eyes, a secondary aim was to compare retinal BFVs between MS eyes, grouped based on optic neuritis (ON) history, and HC eyes.
Method(s): Macular arteriole and venule BFVs were determined using a retinal function imager (RFI) in both eyes of 20 HCs. One eye from a total of 38 MS patients comprising 13 eyes with ON (MSON) and 25 eyes without ON (MSNON) history were similarly imaged with RFI.
Result(s): OD (right) and OS (left) BFVs were not significantly different in arterioles (OD: 3.95 +/- 0.59 mm/s; OS: 4.08 +/- 0.60 mm/s, P = 0.10) or venules (OD: 3.11 +/- 0.46 mm/s; OS: 3.23 +/- 0.52 mm/s, P = 0.06) in HCs. Very strong inter-eye correlations were also found between arteriolar (r = 0.84, P < 0.001) and venular (r = 0.87, P < 0.001) BFVs in HCs. Arteriolar (3.48 +/- 0.88 mm/s) and venular (2.75 +/- 0.53 mm/s) BFVs in MSNON eyes were significantly lower than in HC eyes (P = 0.009 and P = 0.005 respectively). Similarly, arteriolar (3.59 +/- 0.69 mm/s) and venular (2.80 +/- 0.45 mm/s) BFVs in MSON eyes were also significantly lower than in HC eyes (P = 0.046 and P = 0.048 respectively). Arteriolar and venular BFVs in MSON and MSNON eyes did not differ from each other (P = 0.42 and P = 0.48 respectively).
Conclusion(s): Inter-eye arteriolar and venular BFVs do not differ significantly in HCs and are strongly correlated. Our findings support prior observations that arteriolar and venular BFVs may be reduced in MS eyes. Moreover, this seems to be the case in both MS eyes with and without a history of ON, raising the possibility of global blood flow alterations in MS. Future larger studies are needed to assess differences in BFVs between MSON and MSNON eyes

PURPOSE OF REVIEW/OBJECTIVE:Sepsis-3 guidelines have implications in a deeper understanding of the biopathology of the disease. Further, the review focuses on timely topics and new literature on fluid resuscitation, the value of steroids in sepsis, and new therapeutic options such as angiotensin II, vitamin C, and thiamine as well as the emerging role of procalcitonin (PCT) in managing antibiotics. RECENT FINDINGS/RESULTS:Traditional therapies such as type of crystalloid fluid administration and steroid therapy for sepsis are currently under re-evaluation. Angiotensin II is investigated for reversing vasodilatory shock. The role of capillary endothelium leak and cellular metabolism can be affected by vitamin C and thiamine levels. Biomarker level trends, specifically PCT, can aid clinical suspicion of infection. SUMMARY/CONCLUSIONS:Sepsis-3 shifts the focus from a noninfectious inflammatory process and an emphasis on a dysregulated host response to infection. Hyperchloremic crystalloid resuscitation is associated with poor clinical outcomes. Steroid administration can reverse shock physiology; however, mortality benefits remain uncertain. Angiotensin II, vitamin C, and thiamine are novel treatment options that need further validation. PCT assays can help discern between infectious and noninfectious inflammation.

Introduction: Natalizumab, approved for 300 mg intravenous every-4-weeks dosing, is associated with PML risk. Objective(s): To determine whether natalizumab EID is associated with reduced PML risk compared with SID. Patients and Methods: Average dosing intervals (ADIs) were >= 3 to < 5 weeks for SID and > 5 to <= 12 weeks for EID. The primary analysis assessed ADI in the last 18 months of infusion history. The secondary analysis identified any prolonged period of EID at any time in the infusion history. The tertiary analysis assessed ADI over the full infusion history. Result(s): In primary analyses, median exposure (months) was 44 for SID and 59 for EID. The PML HR (95% confidence interval) was 0.06 (0.01-0.22; P < 0.001) for primary and 0.12 (0.05-0.29; P < 0.001) for secondary analyses; no EID PML cases were observed in tertiary analyses (Kaplan-Meier log-rank test P = 0.02). Discussion(s): NA. Conclusion(s): In JCV Ab + patients, natalizumab EID is associated with a clinically and statistically significant reduction in PML risk as compared with SID.

Introduction: Dans PARADIGMS, premiere etude phase III en double aveugle dans la SEP pediatrique, le fingolimod a diminue significativement le taux annualise de poussees (TAP) de 82 % versus l'interferon (IFN) beta-1a. Objectifs: Effectuer des analyses dans des sous-groupes (anticorps neutralisants anti-IFN, naifs de traitement); evaluer l'effet chez les patients plus jeunes et prepuberes, la progression du handicap, la qualite de vie. Patients et Methodes: Les analyses de sous-groupes des criteres principal (TAP) et secondaire principal (nouvelles lesions T2, NT2) et post-hoc sur la progression confirmee du handicap ont ete realisees. La qualite de vie (QdV) liee a la sante a ete evaluee par les patients ou les parents a l'aide du questionnaire PedsQL (Quality of Life) avant et a la fin de l'etude (jusqu'a 2 ans): changements du score total et des scores sante physique et sante psychosociale. Resultats: Dans toutes les analyses de sous-groupes, le fingolimod a diminue significativement le TAP (81,5-85,8 %) et NT2 (47,6-53,4 %) versus l'IFNbeta-1a. Le risque de progression du handicap confirmee a 3 mois etait reduit de 77,2 % ([HR] = 0,23, p = 0,007). L'analyse post-hoc a confirme son effet positif sur les scores totaux et de sante physique de QdV rapportes par les patients et les parents, et de sante psychosociale rapporte par les patients versus l'IFN beta-1a (tous p < 0,05). Discussion(s): Le fingolimod dans la SEP pediatrique a ete associe a un controle de l'activite de la maladie dans toutes les analyses complementaires, chez les patients traites precedemment ou non, et ce de maniere plus marquee chez les patients plus jeunes. Des benefices sur la progression du handicap ont ete observes sur une duree de traitement allant jusqu'a 2 ans. Conclusion(s): Le fingolimod versus IFN beta-1a a ete associe a une amelioration significative du controle de l'activite de la maladie et de la qualite de vie liee a la sante.

BACKGROUND:In children with spastic cerebral palsy (CP), the treatment of equinus foot with Achilles tendon lengthening (ATL) surgery is associated with high incidence of overcorrection, which may result in crouch gait. AIM/OBJECTIVE:We aimed to assess if gait pattern in preoperative time could be a predictor of the surgery outcome. DESIGN/METHODS:Cross-sectional retrospective study. SETTING/METHODS:Movement Analysis Lab of IRCCS San Raffaele Pisana Hospital in Rome (Italy). POPULATION/METHODS:Eighteen children (mean age 9.6±4.7 years) with spastic diplegia CP who underwent bilateral ATL surgery to correct equinus foot were involved. METHODS:Participants underwent 3D gait analysis before and approximately 12 months after surgery. Primary measures were spatiotemporal, kinematic (summarized by Gait Variable Scores, GVSs) and kinetic parameters. The gait patterns for each leg was defined from kinematic data, using a quantitative classification: plantar flexor knee extension (PFKE) index. The CP group was split into true equinus and jump gait. RESULTS:The equinus foot was successfully corrected as demonstrated by the improvement of GVS ankle dorsi-plantarflexion. However, there was a high rate of overcorrection in the true equinus, characterized by increases in knee flexion-extension GVS (8.7° pre vs. 16.7° post P<0.05) and knee flexion angle at initial contact (5.2° vs. 20.6° P<0.05) and by a decrease in the maximum ankle power generated at push-off (1.49 vs. 0.83 W/kg P<0.05). CONCLUSIONS:Assessment of motor phenotype in preoperative time are good predictors of the results of ATL surgery. In children with true equinus gait, the increase of knee flexion subsequent to ATL is an early indicator that this technique will lead to crouch gait. These results show the influence of true equinus and jump gait patterns on the outcomes of the ATL. CLINICAL REHABILITATION IMPACT/CONCLUSIONS:Therefore, we propose that this approach could have clinical value to evaluate and prescribe rehabilitation in children with CP disease, proposing different solutions depending on motor phenotype.