Parkinson's disease: recent development in therapies for advanced disease with a focus on deep brain stimulation (DBS) and duodenal levodopa infusion

Effective medical treatment for Parkinson's disease has been available for almost 40 years. After several years of treatment with L-dihydroxyphenylalanine (L-dopa, levodopa), however, fluctuations often occur. The patient may then experience random variations of the motor symptoms during the day. The medication becomes increasingly complicated. New therapeutic methods, deep brain stimulation and duodenal infusion of L-dopa, have proven to be very effective in stabilizing the fluctuations. A clinical update of Parkinson's disease is presented together with a short review of these two methods.     

Blockade of glutamatergic transmission as treatment for dyskinesias and motor fluctuations in Parkinson's disease

Summary In animal models of Parkinson's disease (PD), glutamate antagonists diminish levodopa (LD)-associated motor fluctuations and dyskinesias. We sought to investigate if these preclinical observations can be extended to the human disease, by evaluating the effects of three non-competitive NMDA antagonists (dextrorphan, dextromethorphan and amantadine) on the motor response to LD in patients with advanced PD. In four separate trials, adjuvant therapy with these drugs reduced LD-induced dyskinesias and motor fluctuations. These findings support the view that drugs acting to inhibit glutamatergic transmission at the NMDA receptor can ameliorate LD associated motor response complications.     

Recognition and treatment of response fluctuations in Parkinson's disease: review article

Summary.  Patients with Parkinson's disease (PD) by definition benefit from treatment with the dopamine precursor levodopa. However, after 5 years of therapy 50% of patients experience motor response complications (MRC's): the benefit from each dose becomes shorter (wearing-off fluctuations), more unpredictable (on-off fluctuations) and associated with involuntary movements (dyskinesias). In addition these patients suffer from fluctuations in motor function that are inherent to the disease itself. Recent findings have lead to the suggestion that hyperfunction of NMDA receptors on striatal efferent neurons, as a consequence of chronic non-physiologic dopaminergic stimulation, contributes to the pathogenesis of MRC's. In PD patients blockade of striatal glutamate receptors with several NMDA-antagonists improve MRC's. With progression of PD the severity and complexity of MRC's magnify, obfuscating their pattern and their relation to the medication cycle. Only through detailed history taking and patient education will the physician be able to clarify the situation and establish a rational, targeted approach to the treatment of patients with advanced PD complicated by motor fluctuations and dyskinesias. Received July 7, 2001 Accepted August 6, 2001 Published online September 10, 2002     

Dietary protein restriction impairs growth,immunity, and disease resistance in southern leopard frog tadpoles

The immune system is a necessary, but potentially costly, defense against infectious diseases. When nutrition is limited, immune activity may consume a significant amount of an organism’s energy budget. Levels of dietary protein affect immune system function; high levels can enhance disease resistance. We exposed southern leopard frog [Lithobates sphenocephalus (=Rana sphenocephala)] tadpoles to high and low protein diets crossed with the presence or absence of the pathogenic amphibian chytrid fungus (Batrachochytrium dendrobatidis; Bd) and quantified: (1) tadpole resistance to Bd; (2) tadpole skin-swelling in response to phytohaemagglutinin (PHA) injection (a measure of the T cell-mediated response of the immune system); (3) bacterial killing ability (BKA) of tadpole blood (a measure of the complement-mediated cytotoxicity of the innate immune system); and (4) tadpole growth and development. Tadpoles raised on a low-protein diet were smaller and less developed than tadpoles on a high-protein diet. When controlled for developmental stage, tadpoles raised on a low-protein diet had reduced PHA and BKA responses relative to tadpoles on a high-protein diet, but these immune responses were independent of Bd exposure. High dietary protein significantly increased resistance to Bd. Our results support the general hypothesis that host condition can strongly affect disease resistance; in particular, fluctuations in dietary protein availability may change how diseases affect populations in the field.     

快速眼动睡眠期行为障碍(RBD)的帕金森病临床特征分析

目的:探究合并不同发作形式的快速眼动睡眠期行为障碍(RBD)与帕金森病的临床特点及自主神经功能障碍变化。方法:采用快速眼动期睡眠行为障碍筛查量表及帕金森综合评分量表(Unified Parkinson's disease rating scale),对20例合并简单型(RBD)的帕金森病患者(RBD-简单组)与20例合并复杂型(RBD)的帕金森病患者(RBD-复杂组)进行研究。结果:两组帕金森病患者的一般情况、左旋多巴药物日剂量、疾病病程等无统计学差异(P>0.05)。合并复杂型(RBD)的帕金森病患者运动部分评分高于合并简单型(RBD)的帕金森病患者(P<0.05)。两组患者之间在非震颤、强直、运动减少症状均存在统计学差异(P<0.05),(RBD)复杂组评分均高于(RBD)简单组。多因素logistics回归显示,复杂型(RBD)的存在与UPDRS-Ш部分评分相关,而与年龄、病程、教育年限、左旋多巴药物日剂量等无显著相关,与运动减少症状最为相关,与震颤、非震颤、强直症状无相关性。两组患者运动障碍类型与(RBD)发作形式无明显相关性(P=0.108)。结论:合并复杂型(RBD)的帕金森病患者运动症状更重,并且累及运动障碍的诸多方面。帕金森病患者存在复杂型(RBD)症状主要与UPDRS-Ш评分相关,其中与运动减少方面显著相关。     

Dietary protein intake and skeletal-muscle protein metabolism in rats. Studies with salt-washed ribosomes and transfer factors

1. Aspects of skeletal muscle protein synthesis in vitro were studied in young rats given a low-protein diet for up to 10 days and during re-feeding with an adequate diet. 2. Partially purified muscle transfer factors (transferases I and II), crude and purified (NH(4)Cl-washed) ribosomes and a pH5 enzyme fraction were prepared for this purpose. 3. A marked decrease in the capacity of crude ribosomes to carry out cell-free polypeptide synthesis occurred within 4 days of feeding the low-protein diet. 4. The capacity of salt-washed ribosomes to promote amino acid polymerization, in the presence of added transfer factors and aminoacyl-tRNA, was only slightly decreased by the dietary treatment. 5. However, the capacity of salt-washed ribosomes to bind (14)C-labelled aminoacyl-tRNA was decreased by feeding the low-protein diet. 6. The capacity of the pH5 enzyme fraction to promote amino acid incorporation in a complete cell-free system was decreased within 2 days of feeding the low-protein diet. There is no evidence that the change is associated with aminoacyl-tRNA synthetase or binding enzyme activities of the pH5 fractions. 7. These changes are discussed in relation to the diminished rate of protein synthesis in the intact muscle cell when rats are given a low-protein diet.     

Amino Acids and Biogenic Amines in Cerebrospinal Fluid of Patients with Parkinson's Disease

To study changes in amino acid metabolism and biogenic amines in Parkinson's disease, we set up a prospective study and measured biogenic amines, their main metabolites, and 22 different amino acids, in cerebrospinal fluid of Parkinson's disease patients (n = 24) and age-matched controls (n = 30). A trend toward higher dopamine levels in Parkinson's disease patients was interpreted as an effect of treatment with levodopa and/or selegiline. Significantly lower concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in the Parkinson's disease group might reflect dopaminergic cell loss. Our results revealed decreased serotonin catabolism that was interpreted as an effect of treatment with selegiline. Whereas all amino acid levels were unchanged, taurine was significantly lower in Parkinson's disease patients. Studies showed that taurine exerts a trophic action on the central nervous system. In this view, decreased taurine in a neurodegenerative disorder as Parkinson's disease deserves attention.     

Nutritional control of branched chain alpha-ketoacid dehydrogenase in rat hepatocytes

Branched chain alpha-ketoacid dehydrogenase (EC 1.2.4.4) complex, the rate-limiting enzyme of branched chain amino acid catabolism in most tissues, is subject to regulation by covalent modification, with phosphorylation inactivating and dephosphorylation activating the complex. The enzyme complex from liver of chow-fed rats is mainly in the active form but that from liver of rats fed a low-protein diet is mainly in the inactive form. Isolated hepatocytes were used to identify factors that affect interconversion of branched chain alpha-ketoacid dehydrogenase. The enzyme present in hepatocytes of rats fed a low-protein diet appears much more responsive to regulation by covalent modification than the branched chain alpha-ketoacid dehydrogenase present in hepatocytes of normal chow-fed rats. alpha-Chloroisocaproate, a specific inhibitor of the kinase responsible for phosphorylation and inactivation of the complex, greatly stimulates oxidation of alpha-keto[1-14C]isovalerate by hepatocytes prepared from rats fed a low-protein diet but not from normal chow-fed rats. Oxidizable substrates are also much more effective inhibitors of branched chain alpha-ketoacid oxidation with hepatocytes from rats fed a low-protein diet than from normal chow-fed rats. Activity measurements with cell-free extracts suggest that changes in flux through the dehydrogenase with intact hepatocytes prepared from rats fed a low-protein diet are explained in large part by changes in the proportion of the enzyme in the active, dephosphorylated form. Regulation of liver branched chain alpha-ketoacid dehydrogenase by covalent modification functions to conserve branched chain amino acids for protein synthesis during periods of restricted dietary protein intake.     

Nitrogen levels in low-roughage diets for efficient rumen microbial protein production

The influence of dietary nitrogen (N) available in the rumen on the efficiency of microbial protein production was examined for 43 predominantly low-roughage diets given to cattle or sheep with rumen and duodenal (re-entrant) cannulae. The minimum amount of available N required for efficient microbial protein production was 2.0 g/100 g of organic matter actually digested in the rumen. When the diet supplied 2.7 g of available N/100 g of organic matter actually digested in the rumen, there was no net utilisation of recycled N.From this information, concentrations of N in organic matter required in low-roughage diets differing in organic matter digestibility and availability of dietary N have been calculated. Also a method of calculating the quantities of amino acid N and of particular amino acids absorbed from the small intestine from a knowledge of the diet composition is presented.     

Lifestyle regularity measured by the social rhythm metric in Parkinson's disease

Parkinson's disease (PD) is a chronic progressive motor disorder that may present with a spectrum of symptoms and disease severity. Therapy is frequently associated with motor fluctuations and dyskinesias; therefore, monitoring of motor fluctuations and daily abilities is important for adequate management. The Social Rhythm Metric (SRM) is a diary-like questionnaire that quantifies the extent to which a person's life is regular vs. irregular on a daily basis with respect to event timing. Lifestyle regularity has been assessed by the SRM in other clinical situations. The aim of this study was to evaluate lifestyle regularity in a population with PD using the SRM and its relationship to clinical and therapeutic factors. Twenty-eight consecutive patients with PD and 14 control subjects were studied. Severity of motor dysfunction was evaluated with the Unified Parkinson's Disease Rating Scale (UPDRS). Depressive symptoms were assessed with the Montgomery Asberg Depressive Rating Scale (MADRS), sleep quality with the Pittsburgh Sleep Quality Index (PSQI), and subjective daytime sleepiness with the Epworth sleepiness scale. Daily lifestyle regularity was assessed by the SRM for 2 weeks. Patients with PD had lower SRM scores than controls, and those with motor fluctuations had even lower scores (p=0.04). Patients with motor fluctuations showed more clinical disability (p=0.01), a worse quality of sleep (p=0.02), and more depressive symptoms (p=0.02). SRM results were correlated with PSQI values (p=0.016). Our findings show that the regularity of daily activities as measured by the SRM is disorganized in patients with PD and that this irregularity is related to sleep quality.     

The regulation of protein synthesis in the liver of rats. Mechanisms of dietary amino acid control in the immature animal

Weanling (23-day-old) rats were fed either on an amino acid-deficient diet (6% of casein, which in effect represents an `amino acid-deficient' diet) or on a diet containing an adequate amount of protein (18% of casein) for 28 days. The hepatic cells from the animals fed on the low-protein diet were characterized by low amino acid content, almost complete inhibition of cell proliferation and a marked decrease in cell volume, protein content and concentration of cytoplasmic RNA compared with cells from control rats. The lower concentration of cytoplasmic RNA was correlated with a decreased ribosomal-RNA content, of which a larger proportion was in the form of free ribosomes. The protein-synthetic competence and messenger-RNA content of isolated ribosomes from liver cells of protein-deprived animals were 40–50% of those noted in controls. At 1hr. after an injection of radioactive uridine, the specific radioactivity of liver total RNA was greater in the group fed on the low-protein diet, but the amount of label that was associated with cytoplasmic RNA or ribosomes was significantly less than that noted in control animals. From these data it was concluded that dietary amino acids regulate hepatic protein synthesis (1) by affecting the ability of polyribosomes to synthesize protein and (2) by influencing the concentration of cytoplasmic ribosomes. It is also tentatively hypothesized that the former process may be directly related to the concentration of cellular free amino acids, whereas the latter could be correlated with the ability of newly synthesized ribosomal sub-units to leave the nucleus.     

Effect of subthalamic nucleus or entopeduncular nucleus lesion on levodopa-induced neurochemical changes within the basal ganglia and on levodopa-induced motor alterations in 6-hydroxydopamine-lesioned rats

Inactivation of the subthalamic nucleus (STN) or the internal segment of the pallidum (GPi)/entopeduncular nucleus (EP) by deep brain stimulation or lesioning alleviates clinical manifestations of Parkinson's disease (PD) as well as reducing the side-effects of levodopa treatment. However, the effects of STN or entopeduncular nucleus (EP) lesion on levodopa-related motor fluctuations and on neurochemical changes induced by levodopa remain largely unknown. The effects of such lesions on levodopa-induced motor alterations were studied in 6-hydroxydopamine (6-OHDA)-lesioned rats and were assessed neurochemically by analyzing the functional activity of the basal ganglia nuclei, using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase as molecular markers of neuronal activity. At the striatal level, preproenkephalin (PPE) mRNA levels were analyzed. We found in 6-OHDA-lesioned rats that a unilateral STN or EP lesion ipsilateral to the 6-OHDA lesion had no effect on either the shortening in the duration of the levodopa-induced rotational response or the levodopa-induced biochemical changes in the basal ganglia nuclei. In contrast, overexpression of PPE mRNA due to levodopa treatment was reversed by the STN or EP lesion. Our study thus shows that lesion of the EP or STN may counteract some of the neurochemical changes induced by levodopa treatment within the striatum.     

Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial

A pilot clinical trial based on nutritional modulation was designed to assess the efficacy of a one-year low-protein diet in activating autophagy in skeletal muscle of patients affected by COL6/collagen VI-related myopathies. Ullrich congenital muscular dystrophy and Bethlem myopathy are rare inherited muscle disorders caused by mutations of COL6 genes and for which no cure is yet available. Studies in col6 null mice revealed that myofiber degeneration involves autophagy defects and that forced activation of autophagy results in the amelioration of muscle pathology. Seven adult patients affected by COL6 myopathies underwent a controlled low-protein diet for 12 mo and we evaluated the presence of autophagosomes and the mRNA and protein levels for BECN1/Beclin 1 and MAP1LC3B/LC3B in muscle biopsies and blood leukocytes. Safety measures were assessed, including muscle strength, motor and respiratory function, and metabolic parameters. After one y of low-protein diet, autophagic markers were increased in skeletal muscle and blood leukocytes of patients. The treatment was safe as shown by preservation of lean:fat percentage of body composition, muscle strength and function. Moreover, the decreased incidence of myofiber apoptosis indicated benefits in muscle homeostasis, and the metabolic changes pointed at improved mitochondrial function. These data provide evidence that a low-protein diet is able to activate autophagy and is safe and tolerable in patients with COL6 myopathies, pointing at autophagy activation as a potential target for therapeutic applications. In addition, our findings indicate that blood leukocytes are a promising noninvasive tool for monitoring autophagy activation in patients.     

Impaired translation initiation activation and reduced protein synthesis in weaned piglets fed a low-protein diet

Weanling mammals (including infants) often experience intestinal dysfunction when fed a high-protein diet. Recent work with the piglet (an animal model for studying human infant nutrition) shows that reducing protein intake can improve gut function during weaning but compromises the provision of essential amino acids (EAA) for muscle growth. The present study was conducted with weaned pigs to test the hypothesis that supplementing deficient EAA (Lys, Met, Thr, Trp, Leu, Ile and Val) to a low-protein diet may maintain the activation of translation initiation factors and adequate protein synthesis in tissues. Pigs were weaned at 21 days of age and fed diets containing 20.7, 16.7 or 12.7% crude protein (CP), with the low-CP diets supplemented with EAA to achieve the levels in the high-CP diet. On Day 14 of the trial, tissue protein synthesis was determined using the phenylalanine flooding dose method. Reducing dietary CP levels decreased protein synthesis in pancreas, liver, kidney and longissimus muscle. A low-CP diet reduced the phosphorylation of eukaryotic initiation factor (eIF) 4E-binding protein-1 (4E-BP1) in skeletal muscle and liver while increasing the formation of an inactive eIF4E.4E-BP1 complex in muscle. Dietary protein deficiency also decreased the phosphorylation of mammalian target of rapamycin (mTOR) and the formation of an active eIF4E.eIF4G complex in liver. These results demonstrate for the first time that chronic feeding of a low-CP diet suppresses protein synthesis in animals partly by inhibiting mTOR signaling. Additionally, our findings indicate that supplementing deficient EAA to low-protein diets is not highly effective in restoring protein synthesis or whole-body growth in piglets. We suggest that conditionally essential amino acids (e.g., glutamine and arginine) may be required to maintain the activation of translation initiation factors and optimal protein synthesis in neonates.     

Deep brain stimulation for Parkinson's disease

Deep brain stimulation at high frequency was first used in 1997 to replace thalamotomy in treating the characteristic tremor of Parkinson's disease, and has subsequently been applied to the pallidum and the subthalamic nucleus. The subthalamic nucleus is a key node in the functional control of motor activity in the basal ganglia. Its inhibition suppresses symptoms in animal models of Parkinson's disease, and high frequency chronic stimulation does the same in human patients. Acute and long-term results after deep brain stimulation show a dramatic and stable improvement of a patient's clinical condition, which mimics the effects of levodopa treatment. The mechanism of action may involve a functional disruption of the abnormal neural messages associated with the disease. Long-term changes, neural plasticity and neural protection might be induced in the network. Similar effects of stimulation and lesioning have led to the extension of this technique for other targets and diseases.     

Restoration by dietary glutamine of reduced tumor necrosis factor production in a low-protein-diet-fed rat model

Tumor necrosis factor-alpha (TNF) production by peritoneal macrophages and its dietary modification were investigated by using rats fed on a low-protein diet. The rats were given a 20% casein (control) diet or a 3% casein diet for 21 days, and TNF production was measured in activated macrophages of these animals. TNF production was significantly lower in macrophages from rats fed on the low-protein diet than that in macrophages from rats fed on the control diet. Oral administration of a cabbage extract, a known modulator of TNF production, to the low-protein-diet-fed rats significantly enhanced TNF production by macrophages. Glutamine supplementation to the low-protein diet significantly enhanced TNF production as well as TNF mRNA expression. These results indicate that the 3%-casein-diet-fed rat would be useful as a model for reduced TNF production in protein malnutrition. These results also suggest that glutamine administration restored the reduced TNF production associated with protein malnutrition.     

Proteomic profiling reveals oxidative phosphorylation pathway is suppressed in longissimus dorsi muscle of weaned piglets fed low-protein diet supplemented with limiting amino acids

Feeding high-protein diets in animals can lead to a decrease of nitrogen utilization efficiency, and then promote the environmental pollution. Recently, more reports have demonstrated that lowering protein level in diets supplemented with specific amino acids can address these problems. However, the whole proteome alteration in the skeletal muscle of weaned piglets fed low-protein diets is poorly understood. Here, we applied the isobaric tags for relative and absolute quantification approach to investigate this alteration. We fed weaned piglets with normal protein diet (20% crude protein) and low-protein diet supplemented with lysine, methionine, threonine, and tryptophan (17% crude protein) for 25 days. Then proteomic profiling of skeletal muscles was performed. In total, 1354 proteins were quantified in the porcine skeletal muscle proteome. 132 proteins were identified as differentially expressed proteins between the two groups. Differentially expressed proteins were significantly enriched in various nutrient metabolism including lipid, carbohydrate, and amino acid metabolism. Interestingly, a total of 20 differentially expressed proteins, which are involved in the oxidative phosphorylation pathway, were all down-regulated by the low-protein diet feeding. Further immunoblotting confirmed the down-regulations of MT-ATP8, COX2, NDUFA6, and SDHB, four selected proteins among these 20 proteins. Meanwhile, the ATP level in the low-protein diet group was also reduced. These findings for the first time reveal that oxidative phosphorylation pathway is suppressed in longissimus dorsi muscle of weaned piglets fed low-protein diet supplemented with limiting amino acids, which may provide new insights into further formula design and the choice of limiting amino acids in diets.     

Time course of urinary excretion of intraportal ammonia as uric acid and ammonia in chickens fed low- or high-protein diet

15N-ammonia was intraportally infused for 6 hr into chickens fed 5% or 20% protein diet to examine the time course of urinary excretion of intraportal ammonia and dietary effects on it. Urinary ammonia increased linearly for the first hour to the same extent in both dietary groups and thereafter further in the low-protein group. Urinary uric acid derived from the intraportal ammonia adaptively increased and reached a steady state level within 1.5 hr. This level was four times higher in the high-protein group. The infused ammonia was excreted into urine as both ammonia and uric acid, in relatively high proportions in the chickens fed the low-protein diet but was almost all excreted as uric acid in those fed the high-protein diet.     

Cellular principles underlying normal and pathological activity in the subthalamic nucleus

The motor symptoms of Parkinson's disease are associated with abnormal, correlated, low frequency, rhythmic burst activity in the subthalamic nucleus and connected nuclei. Research into the mechanisms controlling the pattern of subthalamic activity has intensified because therapies that manipulate the pattern of subthalamic activity, such as deep brain stimulation and levodopa administration, improve motor function in Parkinson's disease. Recent findings suggest that dopamine denervation of the striatum and extrastriatal basal ganglia profoundly alters the transmission and integration of glutamatergic cortical and GABAergic pallidal inputs to subthalamic neurons, leading to pathological activity that resonates throughout the basal ganglia and wider motor system.