Immunotherapy in progressive supranuclear palsy.

PURPOSE OF REVIEW: Progressive supranuclear palsy (PSP) is a progressive adult-onset neurodegenerative disease. Abnormally, phosphorylated forms of the microtubule-associated protein tau containing four repeat domains (4R-tau) aggregate in neurons. Additionally, increasing evidence suggests that secretion and uptake of fragments of abnormal 4R-tau may play a role in disease progression. This extracellular tau is a natural target for immunotherapy. RECENT FINDINGS: Three monoclonal antibodies targeting extracellular tau are in clinical stages of development. ABBV-8E12 and BIIB092 were safe in Phase 1, but both Phase two studies recently failed futility analyses. UCB0107 recently reported (in abstract form) Phase 1 safety results, and a Phase 2 study is under consideration. Stem cell therapy and the infusion of plasma are also being explored clinically. SUMMARY: The likely role of extracellular tau in the progression of PSP makes tau a natural target for targeted immunotherapy. Clinical trials are still in early stages, and although tau immunotherapy has largely been shown to be safe, efficacy has yet to be demonstrated.

Persistent residual errors in motor adaptation tasks: reversion to baseline and exploratory escape.

When movements are perturbed in adaptation tasks, humans and other animals show incomplete compensation, tolerating small but sustained residual errors that persist despite repeated trials. State-space models explain this residual asymptotic error as interplay between learning from error and reversion to baseline, a form of forgetting. Previous work using zero-error-clamp trials has shown that reversion to baseline is not obligatory and can be overcome by manipulating feedback. We posited that novel error-clamp trials, in which feedback is constrained but has nonzero error and variance, might serve as a contextual cue for recruitment of other learning mechanisms that would then close the residual error. When error clamps were nonzero and had zero variance, human subjects changed their learning policy, using exploration in response to the residual error, despite their willingness to sustain such an error during the training block. In contrast, when the distribution of feedback in clamp trials was naturalistic, with persistent mean error but also with variance, a state-space model accounted for behavior in clamps, even in the absence of task success. Therefore, when the distribution of errors matched those during training, state-space models captured behavior during both adaptation and error-clamp trials because error-based learning dominated; when the distribution of feedback was altered, other forms of learning were triggered that did not follow the state-space model dynamics exhibited during training. The residual error during adaptation appears attributable to an error-dependent learning process that has the property of reversion toward baseline and that can suppress other forms of learning.

Vigor of movements and the cost of time in decision making.

If we assume that the purpose of a movement is to acquire a rewarding state, the duration of the movement carries a cost because it delays acquisition of reward. For some people, passage of time carries a greater cost, as evidenced by how long they are willing to wait for a rewarding outcome. These steep discounters are considered impulsive. Is there a relationship between cost of time in decision making and cost of time in control of movements? Our theory predicts that people who are more impulsive should in general move faster than subjects who are less impulsive. To test our idea, we considered elementary voluntary movements: saccades of the eye. We found that in humans, saccadic vigor, assessed using velocity as a function of amplitude, was as much as 50% greater in one subject than another; that is, some people consistently moved their eyes with high vigor. We measured the cost of time in a decision-making task in which the same subjects were given a choice between smaller odds of success immediately and better odds if they waited. We measured how long they were willing to wait to obtain the better odds and how much they increased their wait period after they failed. We found that people that exhibited greater vigor in their movements tended to have a steep temporal discount function, as evidenced by their waiting patterns in the decision-making task. The cost of time may be shared between decision making and motor control.

Decay of motor memories in the absence of error.

When motor commands are accompanied by an unexpected outcome, the resulting error induces changes in subsequent commands. However, when errors are artificially eliminated, changes in motor commands are not sustained but show decay. Why does the adaptation-induced change in motor output decay in the absence of error? A prominent idea is that decay reflects the stability of the memory. We show results that challenge this idea and instead suggest that motor output decays because the brain actively disengages a component of the memory. Humans adapted their reaching movements to a perturbation and were then introduced to a long period of trials in which errors were absent (error-clamp). We found that, in some subjects, motor output did not decay at the onset of the error-clamp block but a few trials later. We manipulated the kinematics of movements in the error-clamp block and found that, as movements became more similar to subjects' natural movements in the perturbation block, the lag to decay onset became longer and eventually reached hundreds of trials. Furthermore, when there was decay in the motor output, the endpoint of decay was not zero but a fraction of the motor memory that was last acquired. Therefore, adaptation to a perturbation installed two distinct kinds of memories: (1) one that was disengaged when the brain detected a change in the task and (2) one that persisted despite it. Motor memories showed little decay in the absence of error if the brain was prevented from detecting a change in task conditions.

Predictive value of abbreviated olfactory tests in prodromal Parkinson disease.

There is disagreement in the literature whether olfaction may show specific impairments in Parkinson Disease (PD) and if olfactory tests comprised of selected odors could be more specific for diagnosis. We sought to validate previously proposed subsets of the University of Pennsylvania Smell Identification Test (UPSIT) odors for predicting conversion to PD in an independent, prodromal cohort. Conversion to PD was assessed in 229 participants in the Parkinson At Risk Study who completed baseline olfactory testing with the UPSIT and up to 12 years of clinical and imaging evaluations. No commercially available or proposed subset performed better than the full 40-item UPSIT. The proposed "PD-specific" subsets also did not perform better than expected by chance. We did not find evidence for selective olfactory impairment in Parkinson disease. Shorter odor identification tests, including commercially available 10-12 item tests, may have utility for ease of use and cost, but not for superior predictive value.

Serial olfactory testing for the diagnosis of prodromal Parkinson's disease in the PARS study.

BACKGROUND: The Parkinson Associated Risk Syndrome (PARS) study was designed to evaluate whether screening with olfactory testing and dopamine transporter (DAT) imaging could identify participants at risk for developing Parkinson's disease (PD). OBJECTIVE: Hyposmia on a single test has been associated with increased risk of PD, but, taken alone, lacks specificity. We evaluated whether repeating olfactory testing improves the diagnostic characteristics of this screening approach. METHODS: Participants completed up to 10 years of clinical and imaging evaluations in the PARS cohort. Olfaction was assessed with the University of Pennsylvania Smell Identification Test at baseline and on average 1.4 years later. Multiple logistic regression and Cox proportional hazards regression were used to estimate the hazard of development of clinical PD or abnormal DAT imaging. RESULTS: Of 186 participants who were initially hyposmic, 28% reverted to normosmia on repeat testing (reverters). No initially normosmic subjects and only 2% of reverters developed DAT imaging progression or clinical PD, compared to 29% of subjects with persistent hyposmia who developed abnormal DAT and 20% who developed clinical PD. The relative risk of clinical conversion to PD was 8.3 (95% CI:0.92-75.2, p = 0.06) and of abnormal DAT scan was 12.5 (2.4-156.2, p = 0.005) for persistent hyposmia, compared to reversion. CONCLUSIONS: Persistent hyposmia on serial olfactory testing significantly increases the risk of developing clinical PD and abnormal DAT imaging, compared to hyposmia on a single test. Repeat olfactory testing may be an efficient and cost-effective strategy to improve identification of at-risk patients for early diagnosis and disease modification studies.

Development and Impact of a Progressive Parental Leave Policy in a Neurology Residency.

Appropriate parental leave policies remain an unmet need in graduate medical education. Although legal and institutional guidelines allow for policies that support parental leave, there are many challenges and perceived barriers to consider in developing and implementing a successful policy. In 2018, we revised the parental leave policy for our neurology residency. Here we describe the development of our policy, measure its effects, and offer guidelines for other programs to develop a similar approach. We propose solutions to commonly encountered problems, focusing on training and education, staffing of clinical services, evolving legal requirements, resident well-being and equity, and financial support.

Overcoming Barriers to Parkinson Disease Trial Participation: Increasing Diversity and Novel Designs for Recruitment and Retention.

Parkinson disease (PD) is highly prevalent among neurodegenerative diseases, affecting a diverse patient population. Despite a general willingness of patients to participate in clinical trials, only a subset of patients enroll in them. Understanding the barriers to trial participation will help to alleviate this discrepancy and improve trial participation. Underrepresented minorities, older patients, and patients with more medical comorbidities in particular are underrepresented in research. In clinical trials, this has the effect of delaying trial completion, exacerbating disparities, and limiting our ability to generalize study results. Efforts to improve trial design and recruitment are necessary to ensure study enrollment reflects the diversity of patients with PD. At the trial design level, broadening inclusion criteria, attending to participant burden, and focusing on trial efficiency may help. At the recruitment stage, increasing awareness, with traditional outreach or digital approaches; improving engagement, particularly with community physicians; and developing targeted recruitment efforts can also help improve enrollment of underrepresented patient groups. The use of technology, for virtual visits, technology-based objective measures, and community engagement, can also reduce participant burden and increase recruitment. By designing trials to consider these barriers to trial participation, we can improve not only the access to research for all our patients but also the quality and generalizability of clinical research in PD.

A systematic review of burn injuries in low- and middle-income countries: Epidemiology in the WHO-defined African Region.

INTRODUCTION: According to the World Health Organization (WHO), burns result in the loss of approximately 18 million disability adjusted life years (DALYs) and more than 250,000 deaths each year, more than 90% of which are in low- and middle-income countries (LMICs). The epidemiology of these injuries, especially in the WHO-defined African Region, has yet to be adequately defined. METHODS: We performed a systematic review of the literature regarding the epidemiology of thermal, chemical, and electrical burns in the WHO-defined African Region. All articles indexed in PubMed, EMBASE, Web of Science, Global Health, and the Cochrane Library databases as of October 2015 were included. RESULTS: The search resulted in 12,568 potential abstracts. Through multiple rounds of screening using criteria determined a priori, 81 manuscripts with hospital-based epidemiology as well as eleven manuscripts that included population-based epidemiology were identified. Although the studies varied in methodology, several trends were noted: young children appear to be at most risk; most individuals were burned at home; and hot liquids and flame are the most common aetiologies. DISCUSSION: While more population-based research is essential to identifying specific risk factors for targeted prevention strategies, our review identifies consistent trends for initial efforts at eliminating these often devastating and avoidable injuries.

INTRODUCTION: Selon l'Organisation mondiale de la Santé (OMS), les brûlures résultent sur la perte d'environ 18 millions d'années de vie corrigées du facteur d'invalidité (AVCI) et sur plus de 250 000 décès chaque année, plus de 90% se produisant dans les pays à revenu faible et intermédiaire (PRFI). L'épidémiologie de ces blessures, notamment dans la région africaine de l'OMS, reste encore à définir adéquatement. MÉTHODES: Nous avons procédé à une revue systématique de la documentation relative à l'épidémiologie des brûlures thermiques, chimiques et électriques dans la région africaine de l'OMS. Tous les articles indexés dans les bases de données de PubMed, EMBASE, Web of Science, Global Health et de la Cochrane Library à compter d'octobre 2015 ont été inclus. RÉSULTATS: La recherche a produit 12 568 résumés potentiels. Par le biais de plusieurs séries de tri à l'aide de critères déterminés a priori, 81 manuscripts fournissant une épidémiologie dans le cadre hospitalier ainsi que 11 manuscripts incluant une épidémiologie basée sur la population ont été identifiés. Bien que les études variaient dans leur méthodologie, plusieurs tendances ont été observées: les jeunes enfants semblent constituer la population la plus à risque; la plupart des individus étaient brûlés à la maison; et les liquides chauds et les flammes constituent les étiologies les plus courantes. DISCUSSION: Si des études davantage basées sur la population sont essentielles pour identifier les facteurs de risque spécifiques en vue de stratégies de prévention ciblées, notre revue identifie des tendances constantes pour les efforts initiaux visant à éliminer ces blessures souvent dévastatrices et évitables.

Prevention of burn injuries in low- and middle-income countries: A systematic review.

According to the World Health Organization (WHO), burns result in more than 250,000 deaths and the loss of approximately 18 million disability adjusted life years (DALYs), more than 90% of which occur in low- and middle-income countries (LMICs), annually. This type of serious injury - one that is particularly devastating in LMICs - is preventable. To further explore the effectiveness of burn prevention strategies in LMICs, we performed a systematic review of the literature indexed in PubMed, EMBASE, Web of Science, Global Health, and the Cochrane Library databases as of October 2015. Our search resulted in 12,568 potential abstracts. Through multiple rounds of screening using criteria determined a priori, 11 manuscripts were identified for inclusion. The majority of these studies demonstrate reductions in hazardous behaviors, incidence of burns, morbidity, and mortality using educational programs, but also highlight other initiatives, such as media campaigns, as effective strategies. Given that only 11 manuscripts are highlighted in this review, it is evident that original research is lacking. Further studies of preventative efforts tailored to populations in LMICs are needed. It is also essential that these studies be founded in population-based epidemiology and use meaningful end points, such as reductions in incidence, morbidity, and mortality.

A memory of errors in sensorimotor learning.

The current view of motor learning suggests that when we revisit a task, the brain recalls the motor commands it previously learned. In this view, motor memory is a memory of motor commands, acquired through trial-and-error and reinforcement. Here we show that the brain controls how much it is willing to learn from the current error through a principled mechanism that depends on the history of past errors. This suggests that the brain stores a previously unknown form of memory, a memory of errors. A mathematical formulation of this idea provides insights into a host of puzzling experimental data, including savings and meta-learning, demonstrating that when we are better at a motor task, it is partly because the brain recognizes the errors it experienced before.