Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Quantification of Head Tremors in Medical Conditions: A Comparison of Analyses Using a 2D Video Camera and a 3D Wireless Inertial Motion Unit.

This study compares two methods to quantify the amplitude and frequency of head movements in patients with head tremor: one based on video-based motion analysis, and the other using a miniature wireless inertial magnetic motion unit (IMMU). Concomitant with the clinical assessment of head tremor severity, head linear displacements in the frontal plane and head angular displacements in three dimensions were obtained simultaneously in forty-nine patients using one video camera and an IMMU in three experimental conditions while sitting (at rest, counting backward, and with arms extended). Head tremor amplitude was quantified along/around each axis, and head tremor frequency was analyzed in the frequency and time-frequency domains. Correlation analysis investigated the association between the clinical severity of head tremor and head linear and angular displacements. Our results showed better sensitivity of the IMMU compared to a 2D video camera to detect changes of tremor amplitude according to examination conditions, and better agreement with clinical measures. The frequency of head tremor calculated from video data in the frequency domain was higher than that obtained using time-frequency analysis and those calculated from the IMMU data. This study provides strong experimental evidence in favor of using an IMMU to quantify the amplitude and time-frequency oscillatory features of head tremor, especially in medical conditions.

Visual hallucinations and illusions in Parkinson's disease: the role of ocular pathology.

INTRODUCTION: Whether different mechanisms, particularly ocular pathology, could lead to the emergence of visual hallucinations (VH) (defined as false perceptions with no external stimulus) versus visual illusions (VI) (defined as a misperception of a real stimulus) in Parkinson's disease (PD) remains debated. We assessed retinal, clinical and structural brain characteristics depending on the presence of VH or VI in PD. METHODS: In this case-control study, we compared retinal thickness using optical coherence tomography (OCT), between PD patients with: VI (PD-I; n = 26), VH (PD-H; n = 28), and without VI or VH (PD-C; n = 28), and assessed demographic data, disease severity, treatment, anatomical and functional visual complaints, cognitive and visuo-perceptive functions and MRI brain volumetry for each group of PD patients. RESULTS: Parafoveal retina was thinner in PD-H compared to PD-C (p = 0.005) and PD-I (p = 0.009) but did not differ between PD-I and PD-C (p = 0.85). Multivariate analysis showed that 1/retinal parafoveal thinning and total brain gray matter atrophy were independently associated with the presence of VH compared to PD-I; 2/retinal parafoveal thickness, PD duration, sleep quality impairment and total brain gray matter volume were independent factors associated with the presence of VH compared to PD-C; 3/anterior ocular abnormalities were the only factor independently associated with the presence of illusions compared to PD-C. CONCLUSION: These findings reinforce the hypothesis that there may be different mechanisms contributing to VH and VI in PD, suggesting that these two entities may also have a different prognosis rather than simply lying along a continuous spectrum. REGISTRATION NUMBER: Clinicaltrials.gov number NCT01114321.

Glucose dysregulation in Parkinson's disease: Too much glucose or not enough insulin?

OBJECTIVE: To detect changes in glucose regulation in moderate to advanced Parkinson's disease (PD) patients in response to oral glucose intake. METHODS: Blood glucose and insulin kinetics during a 75-g Oral Glucose Tolerance Test (OGTT) were compared between 50 PD patients and 50 healthy controls (CT) matched for body mass index (BMI), age and sex. Potential relationships between changes in glucose kinetics and clinical parameters were analyzed including Parkinson's disease severity and autonomic function using SCOPA-AUT (Scales for Outcomes in Parkinson's disease, Autonomic dysfunction). RESULTS: Blood glucose was significantly higher at T90 (p = 0.04) and T150 (p = 0.01) in PD patients compared to healthy matched controls. Moreover, the total area under time curve (AUC) for the blood glucose levels was significantly higher in PD patients compared to healthy controls (1187 ±â€¯229 vs 1101 ±â€¯201 mmol min.l-1; p = 0.05). Simultaneously, no significant increase of insulin levels was observed in PD patients compared to controls. Higher blood glucose levels were associated with higher BMI (p < 0.001), female gender (p < 0.033), longer duration of PD (p = 0.001), lower dose of dopaminergic treatment (p = 0.023), and higher score of dysautonomia (p = 0.017). CONCLUSION: Glucose control is impaired in moderate to advanced non-diabetic PD patients, due to impaired adaptive insulin response which may be a novel non-motor consequence of PD associated dysautonomia.

Incobotulinum toxin A in Parkinson's disease with foot dystonia: A double blind randomized trial.

INTRODUCTION: Plantar flexion of toe dystonia is very painful and leads to difficulties in walking. The objective of this study was to investigate the effect of incobotulinum toxin A (Xeomin) in the treatment of this type of dystonia in parkinsonian patients, using a randomized, double blind, placebo-controlled trial. METHODS: 45 parkinsonian patients with painful dystonic plantar flexion of toes were injected either with incobotulinum toxin A (Btx group), or with placebo in two muscle targets: the Flexor digitorum longus and the Flexor digitorum brevis. Three groups were compared: the first group received placebo in the Flexor digitorum longus and 100UI of Btx in the Flexor digitorum brevis (n = 16); the second group received 100 UI of Btx in the Flexor digitorum longus and placebo in the Flexor digitorum brevis (n = 13); and the third group, 2 injections of placebo (n = 16). The patients were injected in the same way twice with an interval of 3 months. The primary endpoint was measured six weeks after injections with the Clinical Global Impression (CGI) of change. Dystonia severity and associated pain were also assessed. RESULTS: Mean CGI was improved in the Btx group compared to the placebo group (P = 0.039). A significant reduction of pain and dystonia severity were observed in patients treated with Btx compared to baseline but no improvement was noted when compared to placebo group. No difference of efficacy was highlighted between the two injection sites. CONCLUSIONS: Btx injections are effective for improving clinical state of parkinsonian patients with plantar flexion of toe dystonia.

Impact of Mood and Behavioral Disorders on Quality of Life in Parkinson's disease.

BACKGROUND: Mood symptoms negatively affect quality of life of Parkinson's disease (PD); however little is known about the impact of behavioral disorders such as impulse control disorders, and non-motor fluctuations on quality of life. OBJECTIVE: To assess the impact of mood and behavioral disorders on quality of life in PD. METHODS: 136 (84% male) PD were included (mean age: 61 ± 8y; mean duration of disease: 8.8 ± 5.4y). Mood symptoms, behavioral disorders and non-motor fluctuations were detected and quantified using the recently validated "Ardouin Scale of Behavior in Parkinson's Disease". Motor symptoms were assessed using UPDRS and quality of life with the "39-item Parkinson's Disease Questionnaire". RESULTS: Both motor and non-motor factors significantly affected the quality of life of PD patients. Multivariate regression of the relationship between items of the quality of life questionnaire and the Ardouin Scale showed that alteration of patients' quality of life was strongly correlated with the presence of mood symptoms (such as depression, anxiety ...) and with non-motor fluctuations (especially in the OFF period). A significant correlation was also found between the number of symptoms and their severity, and the quality of life deterioration. Some behavioral disorders (compulsive buying / eating behavior) also negatively affected patient's quality of life to a lesser extent. Alternatively, excess in motivation and hobbyism behaviors had a positive impact on mobility and emotional well-being dimensions respectively of quality of life. CONCLUSIONS: This study shows the main impact of mood symptoms and non-motor fluctuations on worsening quality of life in PD.

International validation of a behavioral scale in Parkinson's disease without dementia.

The "Ardouin Scale of Behavior in Parkinson's Disease" is a new instrument specifically designed for assessing mood and behavior with a view to quantifying changes related to Parkinson's disease, to dopaminergic medication, and to non-motor fluctuations. This study was aimed at analyzing the psychometric attributes of this scale in patients with Parkinson's disease without dementia. In addition to this scale, the following measures were applied: the Unified Parkinson's Disease Rating Scale, the Montgomery and Asberg Depression Rating Scale, the Lille Apathy Rating Scale, the Bech and Rafaelsen Mania Scale, the Positive and Negative Syndrome Scale, the MacElroy Criteria, the Patrick Carnes criteria, the Hospital Anxiety and Depression Scale, and the Mini-International Neuropsychiatric Interview. Patients (n=260) were recruited at 13 centers across four countries (France, Spain, United Kingdom, and United States). Cronbach's alpha coefficient for domains ranged from 0.69 to 0.78. Regarding test-retest reliability, the kappa coefficient for items was higher than 0.4. For inter-rater reliability, the kappa values were 0.29 to 0.81. Furthermore, most of the items from the Ardouin Scale of Behavior in Parkinson's Disease correlated with the corresponding items of the other scales, depressed mood with the Montgomery and Asberg Depression Rating Scale (ρ=0.82); anxiety with the Hospital Anxiety and Depression Scale-anxiety (ρ=0.56); apathy with the Lille Apathy Rating Scale (ρ=0.60). The Ardouin Scale of Behavior in Parkinson's disease is an acceptable, reproducible, valid, and precise assessment for evaluating changes in behavior in patients with Parkinson's disease without dementia.

Dopamine replacement therapy and deep brain stimulation of the subthalamic nuclei induce modulation of emotional processes at different spatial frequencies in Parkinson's disease.

BACKGROUND: Deep brain stimulation of the subthalamic nuclei (STN-DBS) is an effective treatment for the most severe forms of Parkinson's disease (PD) and is intended to suppress these patients' motor symptoms. However, be it in association with Dopamine Replacement Therapy (DRT) or not, STN-DBS may in some cases induce addictive or emotional disorders. OBJECTIVE: In the current study, we suggest that PD patients suffer from emotional deficits that have not been revealed in previous studies because in those experiments the stimuli were displayed for a time long enough to allow patients to have recourse to perceptual strategies in order to recognize the emotional facial expressions (EFE). METHODS: The aim of the current article is to demonstrate the existence of emotional disorders in PD by using a rapid presentation of the visual stimuli (200-ms display time) which curtails their perceptual analysis, and to determine whether STN-DBS, either associated or not associated with DRT, has an impact on the recognition of emotions. RESULTS: The results show that EFE recognition performance depends on both STN-DBS ('on' vs. 'off') and medication ('on' vs. 'off'), but also that these variables have an interactive influence on EFE recognition performance. Moreover, we also reveal how these EFE impairments depend on different spatial frequencies perceptual channels (related to different cortical vs. subcortical neural structures). CONCLUSIONS: The effect of PD without therapy seems to be particularly acute for LSF emotional faces, possibly due to a subcortical dysfunction. However, our results indicate that the joint action of STN-DBS and DRT could also disrupt recognition of emotional expressions at the level of occipito-temporal cortical areas (processing HSF visual information) inducing broad global impairment of EFE at the level of HSF visual channels.

Motor cortex stimulation does not improve dystonia secondary to a focal basal ganglia lesion.

OBJECTIVE: To assess the efficacy of epidural motor cortex stimulation (MCS) on dystonia, spasticity, pain, and quality of life in patients with dystonia secondary to a focal basal ganglia (BG) lesion. METHODS: In this double-blind, crossover, multicenter study, 5 patients with dystonia secondary to a focal BG lesion were included. Two quadripolar leads were implanted epidurally over the primary motor (M1) and premotor cortices, contralateral to the most dystonic side. The leads were placed parallel to the central sulcus. Only the posterior lead over M1 was activated in this study. The most lateral or medial contact of the lead (depending on whether the dystonia predominated in the upper or lower limb) was selected as the anode, and the other 3 as cathodes. One month postoperatively, patients were randomly assigned to on- or off-stimulation for 3 months each, with a 1-month washout between the 2 conditions. Voltage, frequency, and pulse width were fixed at 3.8 V, 40 Hz, and 60 µs, respectively. Evaluations of dystonia (Burke-Fahn-Marsden Scale), spasticity (Ashworth score), pain intensity (visual analog scale), and quality of life (36-Item Short Form Health Survey) were performed before surgery and after each period of stimulation. RESULTS: Burke-Fahn-Marsden Scale, Ashworth score, pain intensity, and quality of life were not statistically significantly modified by MCS. CONCLUSIONS: Bipolar epidural MCS failed to improve any clinical feature in dystonia secondary to a focal BG lesion. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that bipolar epidural MCS with the anode placed over the motor representation of the most affected limb failed to improve any clinical feature in dystonia secondary to a focal BG lesion.

Rapid Presentation of Emotional Expressions Reveals New Emotional Impairments in Tourette's Syndrome.

OBJECTIVE: Based on a variety of empirical evidence obtained within the theoretical framework of embodiment theory, we considered it likely that motor disorders in Tourette's syndrome (TS) would have emotional consequences for TS patients. However, previous research using emotional facial categorization tasks suggests that these consequences are limited to TS patients with obsessive-compulsive behaviors (OCB). METHOD: These studies used long stimulus presentations which allowed the participants to categorize the different emotional facial expressions (EFEs) on the basis of a perceptual analysis that might potentially hide a lack of emotional feeling for certain emotions. In order to reduce this perceptual bias, we used a rapid visual presentation procedure. RESULTS: Using this new experimental method, we revealed different and surprising impairments on several EFEs in TS patients compared to matched healthy control participants. Moreover, a spatial frequency analysis of the visual signal processed by the patients suggests that these impairments may be located at a cortical level. CONCLUSION: The current study indicates that the rapid visual presentation paradigm makes it possible to identify various potential emotional disorders that were not revealed by the standard visual presentation procedures previously reported in the literature. Moreover, the spatial frequency analysis performed in our study suggests that emotional deficit in TS might lie at the level of temporal cortical areas dedicated to the processing of HSF visual information.

Deep brain stimulation of the subthalamic nucleus regulates postabsorptive glucose metabolism in patients with Parkinson's disease.

OBJECTIVE: Subthalamic nucleus-deep brain stimulation (STN-DBS) is an alternative treatment for patients with uncontrolled symptoms of Parkinson's disease (PD), but it has other nonmotor impact. Because STN-DBS alters the energy expenditure in humans, we hypothesized that STN-DBS may affect postabsorptive glucose metabolism in patients with PD. RESEARCH DESIGN AND METHODS: Endogenous glucose production (EGP) and whole-body glucose disposal rates (GDRs) were assessed in the postabsorptive state during a primed continuous iv infusion of D-[6,6-(2)H2]glucose for 5 hours in 8 STN-DBS-treated patients with PD, without (Stim-OFF) and during STN-DBS (Stim-ON) treatment. EGP and GDR in PD patients were compared with glucose kinetics of 8 matched healthy control subjects. Plasma concentrations of insulin, glucagon, and free fatty acids were also determined. RESULTS: EGP and GDR were higher in PD patients in Stim-OFF conditions than in the control group (2.62 ± 0.09 vs 2.27 ± 0.10 mg/kg·min, P < .05). Despite no significant changes in blood glucose throughout the kinetic study, a significant and consistent 22% decrease in EGP occurred in PD patients during Stim-ON (2.04 ± 0.07 mg/kg(-1)·min(-1); P < .01), and whole-body glucose kinetics in Stim-ON patients were no more different from those of the control subjects (P = NS). No difference in insulin, glucagon, or free fatty acid concentrations was observed in the patients between Stim-OFF and Stim-ON conditions. CONCLUSIONS: Deep brain stimulation in patients with PD affects EGP glucose disposal, suggesting that a cross talk between the central nervous system and peripheral tissues may regulate glucose homeostasis.

Is R2* a new MRI biomarker for the progression of Parkinson's disease? A longitudinal follow-up.

PURPOSE: To study changes of iron content in basal ganglia in Parkinson's disease (PD) through a three-year longitudinal follow-up of the effective transverse relaxation rate R2*, a validated MRI marker of brain iron content which can be rapidly measured under clinical conditions. METHODS: Twenty-seven PD patients and 26 controls were investigated by a first MRI (t0). Longitudinal analysis was conducted among the 18 controls and 14 PD patients who underwent a second MRI (t1) 3 years after. The imaging protocol consisted in 6 gradient echo images obtained at different echo-times for mapping R2*. Quantitative exploration of basal ganglia was performed by measuring the variation of R2* [R2*(t1) - R2*(t0)] in several regions of interest. RESULTS: During the three-year evolution of PD, R2* increased in Substantia nigra (SN) (by 10.2% in pars compacta, p = 0.001, and 8.1% in pars reticulata, p = 0.013) and in the caudal putamen (11.4%, p = 0.011), without significant change in controls. Furthermore, we showed a positive correlation between the variation of R2* and the worsening of motor symptoms of PD (p = 0.028). CONCLUSION: Significant variation of R2* was longitudinally observed in the SN and caudal putamen of patients with PD evolving over a three-year period, emphasizing its interest as a biomarker of disease progression. Our results suggest that R2* MRI follow-up could be an interesting tool for individual assessment of neurodegeneration due to PD, and also be useful for testing the efficiency of disease-modifying treatments.

The combined effect of subthalamic nuclei deep brain stimulation and L-dopa increases emotion recognition in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (DBS) is a widely used surgical technique to suppress motor symptoms in Parkinson's disease (PD), and as such improves patients' quality of life. However, DBS may produce emotional disorders such as a reduced ability to recognize emotional facial expressions (EFE). Previous studies have not considered the fact that DBS and l-dopa medication can have differential, common, or complementary consequences on EFE processing. A thorough way of investigating the effect of DBS and l-dopa medication in greater detail is to compare patients' performances after surgery, with the two therapies either being administered ('on') or not administered ('off'). We therefore used a four-condition (l-dopa 'on'/DBS 'on', l-dopa 'on'/DBS 'off', l-dopa 'off'/DBS 'on', and l-dopa 'off'/DBS 'off') EFE recognition paradigm and compared implanted PD patients to healthy controls. The results confirmed those of previous studies, yielding a significant impairment in the detection of some facial expressions relative to controls. Disgust recognition was impaired when patients were 'off' l-dopa and 'on' DBS, and fear recognition impaired when 'off' of both therapies. More interestingly, the combined effect of both DBS and l-dopa administration seems much more beneficial for EFE recognition than the separate administration of each individual therapy. We discuss the implications of these findings in the light of the inverted U curve function that describes the differential effects of dopamine level on the right orbitofrontal cortex (OFC). We propose that, while l-dopa could "overdose" in dopamine the ventral stream of the OFC, DBS would compensate for this over-activation by decreasing OFC activity, thereby restoring the necessary OFC-amygdala interaction. Another finding is that, when collapsing over all treatment conditions, PD patients recognized more neutral faces than the matched controls, a result that concurs with embodiment theories.

Prevalence and phenomenology of olfactory hallucinations in Parkinson's disease.

BACKGROUND: Although visual hallucinations in Parkinson's disease (PD) have been described in several major studies, little is known about olfactory hallucinations (OHs). METHODS: The authors performed a detailed analysis of OHs in a cohort of 87 Parkinsonian patients to estimate the prevalence of OHs and describe their phenomenology. They also evaluated smelling abilities in terms of detection and identification. Assessment of both, OHs and olfactory function, was also performed using a control group of 40 normal subjects. RESULTS: Nine patients exhibited OHs compared with none of the controls, giving a prevalence of 10% for OHs in patients. OHs were described as rare, short-lasting, unpleasant odours which are not frightening since clearly identified by the patient as hallucinations. Parkinsonian patients with OHs exhibited olfactory impairment of detection and identification compared with controls, but there was no difference in their olfactory abilities from Parkinsonian patients without OHs. CONCLUSIONS: In conclusion, OHs should be added to the list of non-motor PD symptoms that can occur early or late in the course of PD. The authors' study did not reveal any significant difference in terms of olfactory abilities between patients with or without OHs. However, olfactory impairment is well documented in Parkinsonian patients and cannot be totally ruled out as a risk factor for OHs. The authors recognise that complex mechanisms are probably involved in this phenomenon.

Body weight gain and deep brain stimulation.

Deep brain stimulation (DBS) is a neurosurgical technique that has now been available for some 25 years. It is used in the treatment of various motor disorders, e.g. Parkinson's disease (PD), essential tremor and dystonia, and neuropsychiatric illnesses, e.g. obsessive-compulsive disorder and Tourette syndrome. The surgical targets of DBS include the thalamic ventralis intermedius nucleus (Vim), the globus pallidus internus (GPi) and more recently the subthalamic nucleus (STN), currently considered as the reference target in the treatment of PD. In the last ten years, most studies in PD patients have described a rapid and marked weight gain in the months following DBS of the STN. This weight gain sometimes induces obesity and can have metabolic repercussions. The physiopathological mechanisms responsible for the weight gain are multifactorial (changes in energy metabolism and eating behaviour, reduction of motor complications, etc.). This review reports current knowledge concerning weight changes in patients treated by DBS with different surgical targets. It also describes the mechanisms responsible for weight gain and the health outcome for the patients.

Prostasomes as potential modulators of tyrosine phosphorylation in human spermatozoa.

Prostasomes, vesicles present in human semen, are known to play a role in male fertility. However, the mechanisms involved are still poorly understood. The present study looks at the direct influence of different concentrations of prostasomes on human sperm function in conditions supporting capacitation in vitro. Five million Percoll selected spermatozoa were incubated for 3 h at 37°C under an atmosphere of 5% CO2 in air, in 100 µl Biggers Whitten Whittingham's medium (BWW) containing polyvinyl alcohol (PVA, 1 mg/ml) and bovine serum albumin (BSA; 3 mg/ml) in the absence or presence of increasing concentrations of prostasomes (expressed in terms of their cholesterol content: 15; 30; 45 nmoles per 100 µL of incubation medium). After in vitro exposure of spermatozoa to prostasomes, our data indicate that i) tyrosine phosphorylation intensity of the 107 KDa protein band was dose dependently lower and ii) the percentage of viable and progressive motile spermatozoa was unchanged and the percentage of non-progressive motility decreased. In addition, the incubation of prostasomes with spermatozoa resulted in an enrichment of their lipid content. Our experiments suggest that adhesion of prostasomes to spermatozoa could be responsible for the decrease in Tyrosine phosphorylation and the alteration of the mean curvilinear velocity (VCL) and the average path velocity (VAP).

Reduction of low grade inflammation restores blunting of postprandial muscle anabolism and limits sarcopenia in old rats.

Ageing is characterized by a decline in muscle mass that could be explained by a defect in the regulation of postprandial muscle protein metabolism. Indeed, the stimulatory effect of food intake on protein synthesis and its inhibitory effect on proteolysis is blunted in old muscles from both animals and humans. Recently, low grade inflammation has been suspected to be one of the factors responsible for the decreased sensitivity of muscle protein metabolism to food intake. This study was undertaken to examine the effect of long-term prevention of low grade inflammation on muscle protein metabolism during ageing. Old rats (20 months of age) were separated into two groups: a control group and a group (IBU) in which low grade inflammation had been reduced with a non-steroidal anti inflammatory drug (ibuprofen). After 5 months of treatment, inflammatory markers and cytokine levels were significantly improved in treated old rats when compared with the controls: -22.3% fibrinogen, -54.2% alpha2-macroglobulin, +12.6% albumin, -59.6% IL(6) and -45.9% IL(1beta) levels. As expected, food intake had no effect on muscle protein synthesis or muscle proteolysis in controls whereas it significantly increased muscle protein synthesis by 24.8% and significantly decreased proteolysis in IBU rats. The restoration of muscle protein anabolism at the postprandial state by controlling the development of low grade inflammation in old rats significantly decreased muscle mass loss between 20 and 25 months of age. In conclusion, the observations made in this study have identified low grade inflammation as an important target for pharmacological, nutritional and lifestyle interventions that aim to limit sarcopenia and muscle weakness in the rapidly growing elderly population in Europe and North America.

Increased availability of leucine with leucine-rich whey proteins improves postprandial muscle protein synthesis in aging rats.

OBJECTIVE: We previously found that aging was characterized by a decreased sensitivity of muscle protein synthesis to leucine and that a free leucine-supplemented diet corrected this defect in old rats and elderly humans. The present experiment was undertaken to evaluate the efficiency of selected leucine-rich proteins to stimulate postprandial muscle protein synthesis in old rats to optimize nutritional protein support in the elderly. METHODS: Sixty rats (22 mo old) received an experimental meal for the first hour of feeding and a standard diet for the rest of the day for 30 d. Experimental meals contained milk proteins that differed in leucine content: beta-lactoglobulin (14.5% leucine), Prolacta (13.4%), alpha-lactalbumin (10.9%), and casein (10%). As a control, a fifth group was added that received herring flour protein (7.3% leucine). Muscle protein synthesis was determined in vivo in the postprandial state at the end of the 30-d nutritional period using the flooding dose method (1-(13)C phenylalanine). RESULTS: Leucine intake and plasma leucine concentrations were significantly increased in rats fed meals containing the leucine-rich proteins (i.e., beta-lactoglobulin and Prolacta). As previously observed with free leucine-supplemented meals, postprandial muscle protein synthesis was significantly improved in rats fed the meals containing the leucine-rich proteins. Interestingly, the beneficial effect was maintained after the 30-d supplementation. CONCLUSION: The results indicated that leucine-rich proteins were efficient in improving muscle protein synthesis in old rats. Thus, nutritional supplements containing such proteins may be efficient in preventing sarcopenia in the elderly and would represent a safe and optimized nutritional strategy. However, further experiments are necessary to determine the duration of such nutritional support to obtain a significant protein gain in muscle.

Postprandial leucine deficiency failed to alter muscle protein synthesis in growing and adult rats.

OBJECTIVE: This study examined the effect of a specific acute postprandial leucine deficiency on skeletal muscle protein synthesis in growing and adult rats. Because the anabolic action of dietary leucine supplementation is controversial, except during aging, we hypothesized that the maximum leucine effect might be already achieved for a normal postprandial rise of leucine. Preventing this rise during the 1- to 3-h period after feeding may reveal the leucine regulation. METHODS: On the day of the experiment, rats were fasted (postabsorptive, PA group) or fed for 1 h a control meal (postprandial, control, PP group) or a leucine-poor meal (postprandial, PP-Leu group). Muscle protein synthesis was assessed in vivo, over the 1- to 3-h period after meal distribution, using the flooding dose method (L-1-(13)C phenylalanine). RESULTS: As expected, the postprandial increase in plasma free leucine was specifically abolished after feeding the leucine-poor meal, whereas all the other plasma free amino acids were roughly at normal postprandial levels. Plasma insulin increased after feeding in young rats but was constant in adult rats. Plasma insulin was similar whatever dietary leucine levels. Rates of muscle protein synthesis were stimulated by feeding in gastrocnemius and soleus muscles from young rats but only in gastrocnemius muscles from adult rats. The PP-Leu group did not differ from the control PP group regarding muscle protein synthesis. CONCLUSION: The rise in plasma free leucine is not required for the stimulation of muscle protein synthesis during the 1- to 3-h period after feeding young and adult rats, as previously observed in old rats.