Samuel T. Nemanich

Predictors of gait speeds and the relationship of gait speeds to falls in men and women with Parkinson disease.

Gait difficulties and falls are commonly reported in people with Parkinson disease (PD). Reduction in gait speed is a major characteristic of Parkinsonian gait, yet little is known about its underlying determinants, its ability to reflect an internal reservation about walking, or its relationship to falls. To study these issues, we selected age, disease severity, and nonmotor factors (i.e., depression, quality of life, balance confidence, and exercise beliefs and attitudes) to predict self-selected (SELF), fast-as-possible (FAST), and the difference (DIFF) between these walking speeds in 78 individuals with PD. We also examined gender differences in gait speeds and evaluated how gait speeds were related to a retrospective fall report. Age, disease severity, and balance confidence were strong predictors of SELF, FAST, and, to a lesser extent, DIFF. All three parameters were strongly associated with falling. DIFF was significantly greater in men compared to women and was significantly associated with male but not female fallers. The results supported the clinical utility of using a suite of gait speed parameters to provide insight into the gait difficulties and differentiating between fallers in people with PD.

Genomic and Metabolic Disposition of Non-Obese Type 2 Diabetic Rats to Increased Myocardial Fatty Acid Metabolism

Lipotoxicity of the heart has been implicated as a leading cause of morbidity in Type 2 Diabetes Mellitus (T2DM). While numerous reports have demonstrated increased myocardial fatty acid (FA) utilization in obese T2DM animal models, this diabetic phenotype has yet to be demonstrated in non-obese animal models of T2DM. Therefore, the present study investigates functional, metabolic, and genomic differences in myocardial FA metabolism in non-obese type 2 diabetic rats. The study utilized Goto-Kakizaki (GK) rats at the age of 24 weeks. Each rat was imaged with small animal positron emission tomography (PET) to estimate myocardial blood flow (MBF) and myocardial FA metabolism. Echocardiograms (ECHOs) were performed to assess cardiac function. Levels of triglycerides (TG) and non-esterified fatty acids (NEFA) were measured in both plasma and cardiac tissues. Finally, expression profiles for 168 genes that have been implicated in diabetes and FA metabolism were measured using quantitative PCR (qPCR) arrays. GK rats exhibited increased NEFA and TG in both plasma and cardiac tissue. Quantitative PET imaging suggests that GK rats have increased FA metabolism. ECHO data indicates that GK rats have a significant increase in left ventricle mass index (LVMI) and decrease in peak early diastolic mitral annular velocity (E’) compared to Wistar rats, suggesting structural remodeling and impaired diastolic function. Of the 84 genes in each the diabetes and FA metabolism arrays, 17 genes in the diabetes array and 41 genes in the FA metabolism array were significantly up-regulated in GK rats. Our data suggest that GK rats’ exhibit increased genomic disposition to FA and TG metabolism independent of obesity.

Freezing of gait is associated with increased saccade latency and variability in Parkinson's disease.

OBJECTIVE Freezing of gait (FOG) is a locomotor disturbance in Parkinson disease (PD) related to impaired motor automaticity. In this study, we investigated the impact of freezing on automaticity in the oculomotor system using an anti-saccade paradigm. METHODS Subjects with PD with (PD-FOG, n=13) and without (PD-NON, n=13) FOG, and healthy age-matched controls (CTRL, n=12) completed automatic pro-saccades and non-automatic anti-saccades. Primary outcomes were saccade latency, velocity, and gain. RESULTS PD-FOG (pro-saccade latency=271ms, anti-saccade latency=412ms) were slower to execute both types of saccades compared to PD-NON (253ms, 330ms) and CTRL (246ms, 327ms). Saccade velocity and gain variability was also increased in PD-FOG. CONCLUSIONS Saccade performance was affected in PD-FOG for both types of saccades, indicating differences in automaticity and control in the oculomotor system related to freezing. SIGNIFICANCE These results and others show that FOG impacts non-gait motor functions, suggesting global motor impairment in PD-FOG.

In vivo multi‐tissue efficacy of peroxisome proliferator‐activated receptor‐γ therapy on glucose and fatty acid metabolism in obese type 2 diabetic rats

To identify the disturbances in glucose and lipid metabolism observed in type 2 diabetes mellitus, we examined the interaction and contribution of multiple tissues (liver, heart, muscle, and brown adipose tissue) and monitored the effects of the Peroxisome Proliferator‐Activated Receptor‐γ (PPARγ) agonist rosiglitazone (RGZ) on metabolism in these tissues.

Sexual dimorphism in myocardial acylcarnitine and triglyceride metabolism

BackgroundCardiovascular disease is the leading cause of death among diabetic patients. Importantly, recent data highlight the apparent sexual dimorphism in the pathogenesis of cardiovascular disease in diabetics with respect to both frequency- and age-related risk factors. The disposition to cardiovascular disease among diabetic patients has been attributed, at least in part, to excess lipid supply to the heart culminating in lipotoxicity of the heart and downstream derangements. A confounding factor in obese animal models of diabetes is that increased peripheral lipid availability to the heart can induce cardio-metabolic remodeling independent of the underlying pathophysiology of diabetes, thus masking the diabetic phenotype. To that end, we hypothesized that the use of non-obese diabetic (NOD) animal models will reveal metabolic signatures of diabetes in a sex-specific manner.MethodsTo test this hypothesis, male and female NOD Goto-Kakizaki (GK) rats were used to assess the expression profile of 84 genes involved in lipid metabolism. In parallel, targeted lipidomics analysis was performed to characterize sex differences in homeostasis of non-esterified fatty acids (NEFA), acylcarnitines (AC), and triglycerides (TG).ResultsOur analysis revealed significant sex differences in the expression of a broad range of genes involved in transport, activation, and utilization of lipids. Furthermore, NOD male rats exhibited enhanced oxidative metabolism and accumulation of TG, whereas female NOD rats exhibited reduced TG content coupled with accumulation of AC species. Multi-dimensional statistical analysis identified saturated AC16:0, AC18:0, and AC20:0 as dominant metabolites in mediating sex differences in AC metabolism. Confocal microscopy of rat cardiomyocytes exposed to AC14:0, AC16:0, and AC18:0 confirmed induction of ROS with AC18:0 being more potent followed by AC14:0.ConclusionOverall, we demonstrate sex differences in myocardial AC and TG metabolism with implications for therapy and diagnosis of diabetic cardiovascular disease.

Kinetic analysis of FDG in rat liver: effect of dietary intervention on arterial and portal vein input.

INTRODUCTION Dietary conditions may affect liver [(18)F]FDG kinetics due to arterial and portal vein (PV) input. The purpose of this study was to evaluate kinetic models of [(18)F]FDG metabolism under a wide range of dietary interventions taking into account variations in arterial (HA) and portal vein (PV) input. METHODS The study consisted of three groups of rats maintained under different diet interventions: 12 h fasted, 24 h fasted and those fed with high fructose diet. [(15)O]H₂O PET imaging was used to characterize liver flow contribution from HA and PV to the livers dual input function (DIF). [(18)F]FDG PET imaging was used to characterize liver metabolism. Differences in [(18)F]FDG kinetics in HA, PV and liver under different diet interventions were investigated. An arterial to PV Transfer Function (TF) was optimized in all three dietary states to noninvasively estimate PV activity. Finally, two compartment 3-parameter (2C3P), two compartment 4-parameter (2C4P), two compartment 5-parameter (2C5P), and three compartment 5-parameter (3C5P) models were evaluated and compared to describe the kinetics of [(18)F]FDG in the liver across diet interventions. Sensitivity of the compartmental models to ratios of HA to PV flow fractions was further investigated. RESULTS Differences were found in HA and PV [(18)F]FDG kinetics across 12h fasted, 24h fasted and high fructose fed diet interventions. A two exponential TF model was able to estimate portal activity in all the three diet interventions. Statistical analysis suggests that a 2C3P model configuration was adequate to describe the kinetics of [(18)F]FDG in the liver under wide ranging dietary interventions. The net influx of [(18)F]FDG was lowest in the 12h fasted group, followed by 24 h fasted group, and high fructose diet. CONCLUSIONS A TF was optimized to non-invasively estimate PV time activity curve in different dietary states. Several kinetic models were assessed and a 2C3P model was sufficient to describe [(18)F]FDG liver kinetics despite differences in HA and PV kinetics across wide ranging dietary interventions. The observations have broader implications for the quantification of liver metabolism in metabolic disorders and cancer, among others.

Reduced after-effects following podokinetic adaptation in people with Parkinson's disease and freezing of gait

INTRODUCTION Gait dysfunction is common in people with Parkinsons disease (PD). Freezing of gait (FOG) is one such gait disturbance that significantly impacts mobility and quality of life in PD. Recent evidence suggests that cerebellar connectivity may differ in people with PD and FOG (PD+FOG) relative to those without FOG (PD-FOG). Investigation of gait adaptation, or the ability to change gait patterns in response to external perturbations, is cerebellum-dependent, is a practical means of probing cerebellar integrity and may provide additional insights regarding the FOG phenomenon. METHODS In this study, we investigated gait adaptation in PD and FOG by measuring after-effects, namely whole-body rotation, following stepping on a rotating disc in PD+FOG compared to PD-FOG and older healthy adults. We refer to the period of stepping on the rotating disc as the podokinetic (PK) stimulation and after-effects as podokinetic after-rotation (PKAR). Our primary measure of adaptation was the magnitude and rate of decay of the after-effects. RESULTS We noted that PKAR was diminished in PD+FOG compared to the other groups, indicating reduced storage of the adapted gait pattern in PD+FOG. In the PD groups, FOG explained about 20% of the variability in peak velocity. Furthermore, these differences were independent of stepping cadence or motor sign severity. CONCLUSION Our results show that gait adaptation is impaired in PD+FOG, suggesting the cerebellum may be differentially impacted in PD+FOG compared to PD-FOG. This supports previous neuroimaging evidence of cerebellar dysfunction in PD+FOG. Overall, these data further our understanding of gait deficits in PD+FOG.

How do age and nature of the motor task influence visuomotor adaptation

Visuomotor adaptation with prism glasses is a paradigm often used to understand how the motor system responds to visual perturbations. Both reaching and walking adaptation have been documented, but not directly compared. Because the sensorimotor environment and demands are different between reaching and walking, we hypothesized that characteristics of prism adaptation, namely rates and aftereffects, would be different during walking compared to reaching. Furthermore, we aimed to determine the impact of age on motor adaptation. We studied healthy younger and older adults who performed visually guided reaching and walking tasks with and without prism glasses. We noted age effects on visuomotor adaptation, such that older adults adapted and re-adapted slower compared to younger adults, in accord with previous studies of adaptation in older adults. Interestingly, we also noted that both groups adapted slower and showed smaller aftereffects during walking prism adaptation compared to reaching. We propose that walking adaptation is slower because of the complex multi-effector and multi-sensory demands associated with walking. Altogether, these data suggest that humans can adapt various movement types but the rate and extent of adaptation is not the same across movement types nor across ages.

A PET-Compatible Tissue Bioreactor for Research, Discovery, and Validation of Imaging Biomarkers and Radiopharmaceuticals: System Design and Proof-of-Concept Studies

Research and discovery of novel radiopharmaceuticals and targets thereof generally involves initial studies in cell cultures, followed by animal studies, both of which present several inherent limitations. The objective of this work was to develop a tissue bioreactor (TBR) enabling modulation of the microenvironment and to integrate the TBR with a small-animal PET scanner to facilitate imaging biomarker research and discovery and validation of radiopharmaceuticals. Methods: The TBR chamber is a custom-blown, water-jacketed, glass vessel enclosed in a circulating perfusion bath powered by a peristaltic pump, which is integrated within the field of view of the PET scanner. The chamber is in series with a gas exchanger and a vessel for degassing the system during filling. Dissolved oxygen/temperature probes and septa for injection or sampling are located at the inlet and outlet of the cell chamber. A pH probe is located at the chamber outlet. Effluent is collected in the fraction collector as mixed-cup samples. In addition, both medium and tissue chamber can be sampled to investigate tissue and secretory products through multiscale analysis. As a proof of concept, we studied the effects of lipids on glucose uptake using HepG2 cells. To that end, we varied the nutrient substrate environment over a period of approximately 27 d, before and after the addition of lipids, and studied the effects of pioglitazone, a peroxisome proliferator-activated receptor γ agonist, on lipid and glucose uptake. In parallel, the TBR was imaged by PET in conjunction with 11C-palmitate in the presence and absence of lipids to characterize 11C-palmitate uptake. Results: The O2 consumption, glucose consumption, lactate production, and free fatty acid consumption and production rates were consistent in demonstrating the effects of lipids on glucose uptake. Pioglitazone exhibited improved glucose uptake within 3 d of treatment. Semiquantitative analysis suggested that lipids induced greater 11C-palmitate uptake. Conclusion: The integrated TBR offers a platform to monitor and modulate the tissue microenvironment, thus facilitating tissue-specific imaging and therapeutic biomarkers of disease, identification of molecular diagnostic markers, and validation of radiopharmaceuticals in both rodent and human cell lines.

A Case of Apparent Upper-Body Freezing in Parkinsonism while Using a Wheelchair

Freezing of gait (FOG) is a common, disabling gait disturbance in Parkinson’s disease (PD) and other Parkinsonian syndromes. Freezing also occurs during non-gait movements involving the upper limbs. The mechanisms underlying freezing are complex, likely involving motor, cognitive, and sensory systems that contribute to the episodes. Here, we reported a 60-year-old female with a 24-year history of parkinsonism who experienced significant FOG when ambulatory. Disease progression resulted in her permanent use of a powered wheelchair. While using the power chair, the patient experiences apparent paroxysmal freezing in the hand and arm used to steer and propel the chair. These episodes, some lasting up to several minutes, occur only in circumstances (e.g., entering and leaving an elevator) that are similar to environments known to elicit and exacerbate FOG. Episodes are transient and can be volitionally interrupted by the patient but sometimes require external assistance. Therapeutic intervention for this type of potential freezing has yet to be determined. This case may provide insight into the complex nature of freezing behavior and suggests a need for new approaches to treating non-traditional freezing behavior.