Sabrina Paganoni

Muscle synergy patterns as physiological markers of motor cortical damage.

The experimental findings herein reported are aimed at gaining a perspective on the complex neural events that follow lesions of the motor cortical areas. Cortical damage, whether by trauma or stroke, interferes with the flow of descending signals to the modular interneuronal structures of the spinal cord. These spinal modules subserve normal motor behaviors by activating groups of muscles as individual units (muscle synergies). Damage to the motor cortical areas disrupts the orchestration of the modules, resulting in abnormal movements. To gain insights into this complex process, we recorded myoelectric signals from multiple upper-limb muscles in subjects with cortical lesions. We used a factorization algorithm to identify the muscle synergies. Our factorization analysis revealed, in a quantitative way, three distinct patterns of muscle coordination—including preservation, merging, and fractionation of muscle synergies—that reflect the multiple neural responses that occur after cortical damage. These patterns varied as a function of both the severity of functional impairment and the temporal distance from stroke onset. We think these muscle-synergy patterns can be used as physiological markers of the status of any patient with stroke or trauma, thereby guiding the development of different rehabilitation approaches, as well as future physiological experiments for a further understanding of postinjury mechanisms of motor control and recovery.

BODY MASS INDEX, NOT DYSLIPIDEMIA, IS AN INDEPENDENT PREDICTOR OF SURVIVAL IN AMYOTROPHIC LATERAL SCLEROSIS

Introduction: Recent studies have provided conflicting data regarding the role of dyslipidemia in amyotrophic lateral sclerosis (ALS). The aim of this study was to determine whether cholesterol level are an independent predictor of survival in ALS. Methods: Cholesterol levels were measured in 427 ALS subjects from three clinical trial databases. Results: The LDL/HDL ratio did not decrease over time, despite significant declines in body mass index (BMI), forced vital capacity (FVC), and ALSFRS‐R. After adjusting for BMI, FVC, and age, the lipid ratio was not associated with survival. There was a “U”‐shaped association between BMI and mortality, with the highest survival at 30–35 kg/m2. The adjusted hazard ratio for the linear association between BMI and survival was 0.860 (95% CI 0.80–0.93, P = 0.0001). Conclusions: We found that dyslipidemia is not an independent predictor of survival in ALS. BMI is an independent prognostic factor for survival after adjusting for markers of disease severity. Muscle Nerve, 2011

Neurite extension in central neurons: a novel role for the receptor tyrosine kinases Ror1 and Ror2

Neurite elongation and branching are key cellular events during brain development as they underlie the formation of a properly wired neuronal network. Here we report that the receptor tyrosine kinases Ror1 and Ror2 modulate the growth of neurites as well as their branching pattern in hippocampal neurons. Upon Ror1 or Ror2 suppression using antisense oligonucleotides or RNA interference (RNAi), neurons extended shorter and less branched minor processes when compared to those in control cells. In addition, Ror-depleted cells elongated longer, albeit less branched, axons than seen in control cells. Conversely, Ror overexpression both in non-neuronal cells and in hippocampal neurons resulted in the enhanced extension of short and highly branched processes. These phenotypes were accompanied by changes in the microtubule-associated proteins MAP1B and MAP2. Taken together, these results support a novel role for Ror receptors as modulators of neurite extension in central neurons.

ROR1-ROR2 COMPLEXES MODULATE SYNAPSE FORMATION IN HIPPOCAMPAL NEURONS

Ror1 and Ror2, a small family of tyrosine kinase receptors, have been implicated in multiple aspects of brain development in C. elegans and X. laevis. More recently, we have shown that these receptors modulate the rate of neurite elongation in cultured rat hippocampal neurons. However, no information is available regarding a potential role of these receptors in other developmental milestones in mammalian central neurons. Neither is the identity known of the Ror ligand(s) and/or the signal transduction pathway(s) in which they participate. Here we report that the down regulation of either Ror1 or Ror2 led to a significant decrease in synapse formation in cultured hippocampal neurons. Simultaneous targeting of Ror proteins, however, did not result in an additive phenotype. Our results also indicated that Ror1 and Ror2 physically interact in the mouse brain, suggesting that they might function as heterodimers in central neurons. In addition, these Ror complexes interacted with Wnt-5a mediating its effects on synaptogenesis. Together, these data suggest that Ror proteins play a key role in Wnt-5a-activated signaling pathways leading to synapse formation in the mammalian CNS.

Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS)

Abstract The objective of this study was to characterize the diagnostic timelines and their predictors in people with amyotrophic lateral sclerosis (ALS). Patients were identified through ALS billing codes. Time from presenting symptom to first doctor visit, first doctor visit to suspected ALS diagnosis, suspected to confirmed ALS diagnosis, and presenting symptom to confirmed ALS diagnosis (total diagnostic time) were collected. Regression models were used to analyze the predictors of diagnostic delay. Three hundred and four ALS patients were included in the analysis. Median total diagnostic time was 11.5 months. Diagnostic timelines were longer in patients with age > 60 years (p < 0.001), sporadic ALS (p = 0.043), and limb onset (p = 0.010). The presence of fasciculations, slurred speech, and lower extremity weakness when symptoms were first noted were independent predictors of shorter time to ALS diagnosis (p = 0.04, p = 0.02, and p = 0.04, respectively). About half of the patients (52%) received an alternative diagnosis and each patient saw an average of three different physicians before ALS diagnosis was confirmed. In conclusion, diagnostic timelines in ALS are long, and patients see many physicians and receive multiple alternative diagnoses before the diagnosis of ALS is confirmed. Older age, sporadic disease, and limb onset can delay ALS diagnosis.

Expression and subcellular localization of Ror tyrosine kinase receptors are developmentally regulated in cultured hippocampal neurons

Ror1 and Ror2 are two novel receptor tyrosine kinases that have been implicated in neuronal differentiation in Caenorhabditis elegans. As a first step toward elucidating their role in the mammalian brain, we analyzed their expression and localization patterns in hippocampal neurons. Our results showed that both receptors are expressed from early stages of development and that their protein levels peak during periods of active synapse formation. Immunocytochemical analysis indicated that Ror1 and Ror2 are highly concentrated in the growth cones of immature neurons and are present throughout the somatodendritic compartment of mature hippocampal cells. Further analysis indicated that they are present not only in the cell membrane but also in Triton‐ and saponin‐insoluble fractions, suggesting that they may be associated with both the cytoskeleton and membrane‐bound organelles. Taken collectively, our results suggest that Ror1 and Ror2 might play a role during early stages of development in mammalian central neurons.

Electrodiagnostic Evaluation of Myopathies

Electrodiagnostic studies play an important role in the evaluation of patients suspected of having a myopathic disorder. They are used to exclude alternative diagnoses, confirm the presence of muscle disease, narrow down the differential, and identify an appropriate biopsy site. The most informative part of the electrodiagnostic study is needle electromyography. This allows for the analysis of spontaneous activity and motor unit action potential morphology and recruitment patterns. This article proposes a practical electrodiagnostic approach and describes the electrophysiologic patterns of the most commonly encountered myopathies.

Longitudinal monitoring of patients with Parkinson's disease via wearable sensor technology in the home setting

Objective longitudinal monitoring of symptoms related motor fluctuations can provide valuable information for the clinical management of patients with Parkinsons disease. Current methods for long-term monitoring of motor fluctuations, such as patient diaries, are ineffective due to their time consuming and subjective nature. Researchers have shown that wearable sensors such as accelerometers can be used to gather objective information about a patients motor symptoms. In this paper, we present preliminary results from our analysis on wearable sensor data gathered during longitudinal monitoring of 5 patients with PD. Our results indicate that it is possible to track longitudinal changes in motor symptoms by training a regression model based on Random Forests.

Differential subcellular localization of Ror tyrosine kinase receptors in cultured astrocytes.

Ror1 and Ror2 belong to a family of tyrosine kinase receptors that are highly conserved among species. They are expressed throughout the organism, including the central nervous system. In the present study, we analyzed the expression and subcellular localization of Ror1 and Ror2 in astrocytes by means of reverse transcription‐polymerase chain reaction, Western blot analysis, and immunocytochemistry. Our results indicated that both Ror1 and Ror2 are readily detectable in cultured astrocytes. They also showed that Ror1 and Ror2 are associated with different components of the cytoskeleton. While Ror1 co‐localized with F‐actin along stress fibers, Ror2 partially co‐localized with microtubules. In addition, our results suggest that Ror1 and Ror2 undergo different posttranslational modifications in cultured astrocytes. Ror1 is highly glycosylated in these cells. In contrast, no glycosylation was detected in Ror2. Taken together, these results suggest distinct roles for these tyrosine kinase receptors in astrocytes.

Urate as a Marker of Risk and Progression of Neurodegenerative Disease

Urate is a naturally occurring antioxidant whose levels are associated with reduced risk of developing Parkinson’s disease (PD) and Alzheimer’s disease. Urate levels are also associated with favorable progression in PD, amyotrophic lateral sclerosis, Huntington’s disease, and multisystem atrophy. These epidemiological data are consistent with laboratory studies showing that urate exhibits neuroprotective effects by virtue of its antioxidant properties in several preclinical models. This body of evidence supports the hypothesis that urate may represent a shared pathophysiologic mechanism across neurodegenerative diseases. Most importantly, beyond its role as a molecular predictor of disease risk and progression, urate may constitute a novel therapeutic target. Indeed, clinical trials of urate elevation in PD and amyotrophic lateral sclerosis are testing the impact of raising peripheral urate levels on disease outcomes. These studies will contribute to unraveling the neuroprotective potential of urate in human pathology. In parallel, preclinical experiments are deepening our understanding of the molecular pathways that underpin urate’s activities. Altogether, these efforts will bring about new insights into the translational potential of urate, its determinants, and its targets and their relevance to neurodegeneration.