Diet with LPP for renal patients increases daily energy expenditure and improves motor function in Parkinsonian patients with motor fluctuations

Objective To establish whether a diet based on the usage of low-protein products for renal patients (LPP) is associated with higher energy expenditure (EE) than a free low-protein diet (NO-LPP) by calculating 24 h EE by indirect calorimetry using an electronic armband monitor. Design Randomized, cross-over, single-blind, pilot clinical trial performed comparing two different low-protein dietary regimens. Subjects Forty-two days with LPP and 42 days with NO-LPP regimen in six patients with Parkinson's disease with levodopa. Methods Monitoring patient response to two different nutritional schemes through indirect calorimetry (armband), BMI, Patient Global Improvement Scale. Results Mean total EE was 1731 ± 265 kcal/day with NO-LPP vs. 1903 ± 265 kcal/day with LPP (p = 0.02). Conclusions The usage of LPP increases EE and improves motor function in PD patients to a greater extent than NO-LPP dietary regimen. Calorie intake should be increased to prevent malnutrition in the long-term. Sponsorship Fondazione Grigioni per il Morbo di Parkinson.


Introduction
Parkinson'sd isease( PD) is ac ommon movement disorder (worldwide prevalence: 3-4:1000), which develops in the second half of life and is characterized by bradykinesia, rigidity,r estingt remor and postural instability (Zhang and Roman 1993;Quinn1 995). The disorder is the result of an eurodegenerative process that leads to the deatho fd opaminergic neuronsi nt he substantia nigral ocatedi nt he midbrain. The degenerative process is progressive and inevitably leadstomajor disability andmorbidity associated with high healthcare expenditure (Schapira 1999).I ts etiology has not beene lucidated; it is believedt hat the neuronald egeneration is due to a number of environmentalf actors in genetically susceptible subjects (Sherer et al. 2001).C urrent therapy is symptomatic and consists in the replacemento fd opamine, the neurotransmitter that the degenerated dopaminergic neurons no longerp roduce, by administering either aprecursorofdopamine (levodopa) and/or other compounds that stimulate dopaminergic receptors( dopamine agonists);l evodopa is the most effectiver eplacement therapy and soonerorlater it is addedtothe therapeutic regimenof all PD patients (Thanvi and Lo 2004). Also surgical symptomatic therapy exists, namely deep brain stimulation that consists in the stimulation of the damaged neuronal circuits via implanted electrodes; its use is confined to advanced cases that no longer respond to pharmacological therapy (Ahlskog 2001).
Most patients suffering from PD on treatment with levodopa experiencef requentp ostprandial motor blocks, i.e. periods of loss of efficacyo fp harmacological treatment, associated with ar eduction in quality of life (Thanvi andLo2 004).
The phenomenon has been ascribed also to the intake of amino acidsd uring ap rotein-rich meal, whichc ompete with levodopa, an eutral amino acid, for the same carriersd uring absorption from the gut and passage through the blood-brain barrier. Studies have shown that al ow-protein meal at midday improves motorfl uctuations and increases ON time (Juncos et al. 1987;Rileyand Lang1988;Carter et al. 1989;Duarte et al. 1993;Simon et al. 2004).Indeed, al ow-protein diet is recommended by the guidelines for the management of PD (Olanow et al. 2001;Italian Neurological Society 2003).
In aprevious4-month study (Barichella et al. 2006) adiet with acontrolled protein content(0.8 g/kg body weight) was comparedw ith al ow-protein diet based on the usage of low-protein food marketed for renal patients. The results showed that consumption of these foodsreduced daily time in OFF andenabled a reduction in pharmacological therapy in somecases. A reduction in bodyw eight during the first two months of consumptiono ft he specialf ood was observed. A possible explanation was that the improvement in motorf unction may haveb een associated with an increase in energy consumptiont hatw as not compensated by adequate caloryintake. This hypothesis, however, was not clearly supported by evidence.
The objective of this study was to establish whether al ow-protein diet basedo nt he usage of low-protein food for renal patients(LPP) is associated with higher energy expenditure (EE) than af ree low-protein diet (NO-LPP) by calculating 24 hE Eb yi ndirect calorimetryu sing an electronica rmband monitor (Jakicic et al. 2004).

Methods
This was ar andomized, cross-over, single-blind clinical trial performed comparing two different lowprotein dietaryr egimens. It was performed in the month of February 2006.
Six out of the 18 patients (30%) who took parti n the previous study with low-protein food for renal patientsw ere included (Barichella et al. 2006). The flow charto ft he study is shown in Ta ble I.
They were PD patientsd iagnosed accordingt o Brain BankC riteria (Hughese ta l. 1992) attending theI CP ParkinsonI nstitute,o nt reatment with levodopa,w ho were experiencing post-prandial motorb lockso fa tl east 30 min during the 5h after the midday meal.
All patients were examined by ap hysician specialized in nutrition and were interviewed by adieticianat baseline, after aM iniM ental State examination had been performed to exclude dementia. Theyw ere also interviewed by ad ieticians ot hat she could prepare a dietaryregimen tailored to the tastes of the patient in terms of sourceo fp rotein for the evening meal and saucef or the pasta at midday.P atients were weighed and their height was measured so that their BMI could be calculated. Caloryrequirements were calculated on the basis of basal metabolism estimated using the formula of Harrisa nd Benedict (1919)a nd adding 20 -30% according to reported physical activity.
Both dietaryr egimens provided on average the intake of 31.2kcal/kg ideal body weight (range 30.0-34.0kcal/kg), with calories spread outthroughout the day;t hey were both in compliance with the guidelines forhealthy nutrition in theItalian population (Guidelinesfor healthynutrition 2003).
Patients were given detailed instructions so that directc omparisons between low-protein food and common food could be made (seee xample of 1800 kcal diet in Ta ble III showing the difference in terms of protein content). Each dietw as followed for 7days before assessments.The content of LPP and common foodsu sedf or patient dietaryr egimens in terms of amino acidsc ompeting with levodopa for absorption is provided in Ta bles IVAa nd IVB. All assessments were madeb ys taff blindt ot he dietaryregimenofthe patient, who was instructed not to mention it to the examiners.
Patients were givens tudy diaries andw ere instructed to write down the following information everyd ay: hourso fs leep; waking hoursi nO N, i.e. timesw henm edication wasw orking andm otor symptomsa re controlled (with and without dyskinesias) andhoursinOFF,i.e. times when the medication was notw orking and symptoms reappeared; time of antiparkinsonian drug intake; time of meals; any deviations from the dietaryr egimen.
An armband (Bodymedia Sensewear Pro2)w as positioned on the right triceps of the patients for the whole 14 day period (24 hper day) of the study,sothat it could measure EE continuously.T he SenseWear Pro Armbande (Body Media, Pittsburgh, PA)i sa newly developed commercially available device to assess EE. It has alreadyb een extensivelyu sed for researchp urposesa nd its use has beenv alidated not only for usage in sports medicine (Fruin and Rankin 2004) and in particular environments,s uch as under water, but also during normal daily activity (Mignault et al 2005;Levine and Foster 2005).T he device is worno nt he right upper armo ver the triceps muscle and monitorsv arious physiological and movement parameters.D ataf rom av ariety of parameters including heat flux,a ccelerometry,g alvanic skin response, skin temperature, near-bodyt emperature and demographic characteristics (gender, age, height and body weight) are used to estimateE Eu tilizing proprietaryequations developed by the manufacturer. Due to its lightness and wearability,t he armband monitor is particularly suitable for continuous patient monitoring fors everal days.T he software data analysis was carried out at the end of eacho ft he 7d ays of the dietaryr egimenperiod.
At the end of each dietaryregimenthe patient global improvement (PGI) questionnaire was given to the patients, who completed it by themselves. The PGI serveda sa ni ndependent, yet patient-based assessmentofatreatment effect.
The primary endpoint was EE. The secondary endpoints were: 24 hO FF time, 24 hO Nt ime with and without dyskinesias.
The statistical analysis compared data related to days on balanced diet with data related to days on LPP diet using ANOVA.
Diaryc ards were coded with the number of the patient andt he allocated sequence (AB or BA). The person whoa nalyzed the data was blind to sequence.

Results
All six patients completed the study as per protocol and provided 84 valid diaries, 42 with LPP and 42 with NO-LPPregimen.

Armband results
The armband was wornbythe patients for 98% of the time in both the evaluation periods associated with the two nutritional schemes.
The daily hourso fs leep were similar in the two groups (7.68^1.94 with NO-LPPv s. 8.02^2.2 h with LPP). These results are consistent with the sleephours estimated from the patient diarya nalysis.
An increase in total EE of about1 0% was noticed for the LPP dietaryr egimen comparedt ot he NO-LPP diet: mean total EE was 1731^265 kcal/day with NO-LPPdiet vs. 1903^265 kcal/day with LPP ( p ¼ 0.02). Also the time spent in physical activity was longerwith LPP than with NO-LPPdiet (1.75^1.33 vs. 1.38^1.32 h; p ¼ 0.05).

PGI results
According to PGI questionnaires, all patients expressed ab enefitw ith LPP regimen( verym uch better n ¼ 2, muchb etter n ¼ 4) while no benefito r worsening were expressed with the NO-LPPdiet.
Ta ble IVA. Acomparison in protein content between LPP and common foods.

Discussion
This study shows that the LPPd ietaryr egimeni s associated with as ignificant increase in EE in fluctuating PD patients, as measured by the armband. This finding is consistent with the additional evidence of improvement in motor function in such patients, expressed as asignificant reduction in 24 hOFF time, according to both armband and patient diaryd ata. Theo nlyd ifferenceb etween thet wo low-protein dietaryregimens(oneusing low-proteinfoodfor renal patients andthe otherbeing afreelow-protein diet)was them idday meal proteinc ontent (withl ower protein contentf or thel ow-protein productf oodn utritional scheme); theprotein intake in theevening meal wasthe same.I ta ppears that thei ncreasei nE Ea nd greater improvement in motorf unctionw ithL PP wasd ue to better absorptionoflevodopaatmidday,lesshindered by lowerp rotein intake.C alorie intake andh ours of sleepw eres imilar in thet wo groupsa nd should not have influencedr esults.F urthermore,t hese results suggest that thee vening meal doesn ot play an importantroleindeterminingmotor performance.
An additional finding wasthe increase in ON periods with dyskinesias, accordingt ot he patientd iary data. Theo utputd atao ft he armbandd id note nableu st o addressthe issueofwhether thehigherEEcomes from an increase in physiologicalp hysicala ctivityo ri n dyskinesias. Accurate tuning of thealgorithm elaboratingthe accelerometersignals should be implementedto be able to distinguishb etween thet wo in subsequent studies. In anycase, theimprovement in PGIsuggests that thei ncreasei nd yskinesias didn ot counteract the benefit of improved motorf unction. Indeed,d yskinesias do nota lwaysc ause disability anda ctually show that levodopa is beinga bsorbeda nd is effective. In addition,i ti sw ellk nown that fluctuating patients (motor fluctuationsw erea ninclusion criterion)p refer dyskinesiast oO FF episodes,w hich were another inclusioncriterion, as patients hadtohavepostprandial OFFepisodes (Palmer et al.2 000).
The improvements achieved in OFF and ON time are consistent with those recordedi nt he previous study (Barichella et al. 2006), in which ad iet with a controlled protein content(0.8 g/kgbody weight) was compared with al ow-protein diet basedo nt he usage of low-protein food marketed for renal patients.
Ak ey issue in this study is the subjectivity of the patient diarydata and the novelty of the armband used for the measurement of the primarye ndpoint, EE. The use of patient diariesi sagenerally accepted method by regulatory authorities for the assessment of medicinal products (EMEA,CPMP/EWP/563/1995). Sensewear Pro2 has alreadybeen extensively used for researchp urposesa nd its use has been validated not only for usage in sports medicine and in particular environments, such as under water, but also during normal daily activity (Mignault et al. 2005 It would haveb een useful to measuret he blood levels of levodopa and of the amino acidsthat compete with the drug,a st his would enable us to understand where the competition occurs(at the blood-intestine and/or blood -brain barrier). However, the primary objective of ours tudy wasd ifferent,n amelyt o establish whether the body weight loss thato ccurs during LPP consumption is due to greater EE or not; our secondaryobjectives were to establish whether the ON periods associatedw ith dyskinesias increase and whether the evening meal has an influence or not. We havealready planned anotherstudy focusing on amino acid/levodopa competition, in whichb lood levelsw ill be measured.
Thus, the findings of this study suggest that the consumption of LPP for renal patients is asimple way to improvethe therapeutic efficacyoflevodopa, which does not appear to havea ny important drawbacks, as dyskinesias are not amajor problem and malnutrition can easily be prevented by increasing caloryintake. Its rationalei sb asedo nt he recommendation to reduce protein intake at midday in order to prevent their interference with levodopa absorption associated with postprandial OFF episodes, which is includedi n international guidelines for the management of PD (Olanow 2001;Italian Neurological Society 2003). Indeed,P Dp atients shouldc onsume these products, whichh aveb een on the market for more thana decade,only at midday and notthroughout the day as renal patients ( Kopple, 2001),s ot he overall risk of malnutrition in PD patientsi sl ower than in renal patients.
In conclusion, the consumptiono fr enal LPP is associated with an improvement in motorfunction and an increase in EE in PD patients to ag reater extent than NO-LPPdietaryregimen alone. The increase in EE shouldb et akeni nto account for the overall management of PD patients: calorie intake should be increased to prevent malnutrition in the long-term.