Elderberry diet ameliorates motor function and prevents oxidative stress-induced cell death in rat models of Huntington disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder which begins in the striatum and then spreads to other neural areas. Known as a progressive movement cognitive disorder, HD has no efficient therapy. Although the exact mechanism of HD is still unknown, several different etiological processes such as oxidative stress have been shown to play critical roles. Also, the current evidence indicates a strong correlation between immune activation and neural damage induced by neuroinflammatory and apoptotic agents in neurodegenerative disorders. Thus, natural products like Elderberry (EB) could be considered as a novel and potential therapeutic candidate for the treatment of this disease. In this study EB was added to the daily ration of ordinary rats for two months in order to ameliorate inflammatory and oxidative responses in rats injected with 3-nitropropionic acid (3-NP) in an experimental model of HD. Using Rotarod and electromyography setups, we showed that EB diet significantly recovered motor failure and muscle incoordination in 3-NP injected rats compared to the control group. Also, the molecular findings implied that EB diet led to a significant drop in 3-NP induced growth in caspase-3 and TNF-α concentration. The treatment also improved striatal antioxidative capacity by a significant reduction in ROS and a remarkable rise in GSH, which might be correlated with motor recovery in the tests. In sum, the findings demonstrate the advantages of EB treatment in the HD rat model with a score of beneficial anti-oxidative and anti-inflammatory effects.

Dietary Intake, Mediterranean Diet Adherence and Caloric Intake in Huntington's Disease: A Review.

Decades of research and experimental studies have investigated Huntington's disease (HD), a rare neurodegenerative disease. Similarly, several studies have investigated whether high/moderate adherence to the Mediterranean Diet and specific macro and micronutrients can decrease cognitive loss and provide a neuroprotective function to neurons. This review systematically identifies and examines studies that have investigated Mediterranean Diet adherence, micro- and macronutrients, supplementation and caloric intake in people with HD, in order to identify if dietary exposures resulted in improvement of disease symptoms, a delay in age of onset or if they contributed to an earlier age of onset in people with HD. A systematic search of PubMed, Directory of open access journal and HubMed was performed independently by two reviewers using specific search terms criteria for studies. The identified abstracts were screened and the studies were included in the review if they satisfied predetermined inclusion criteria. Reference screening of included studies was also performed. A total of 18 studies were included in the review. A few studies found that patients who had high/moderate adherence to Mediterranean Diet showed a slight improvement in their Unified Huntington's Disease Rating Scale and Total Functional Capacity. In addition, people with HD who had high Mediterranean Diet adherence showed an improvement in both cognitive and motor scores and had a better quality of life compared to patients who had low Mediterranean Diet adherence. Furthermore, a few studies showed that supplementation with specific nutrients, such as triheaptanoin, L-acetyl-carnitine and creatine, had no beneficial effect on the patients' Unified Huntington's Disease Rating Scale score. A few studies suggest that the Mediterranean Diet may confer a motor and cognitive benefit to people with HD. Unfortunately, there was little consistency among study findings. It is important for more research to be conducted to have a better understanding of which dietary exposures are beneficial and may result delaying age of onset or disease progression in people with HD.

Curcumin dietary supplementation ameliorates disease phenotype in an animal model of Huntington's disease.

Huntington's disease (HD) has traditionally been described as a disorder purely of the brain; however, evidence indicates that peripheral abnormalities are also commonly seen. Among others, severe unintended body weight loss represents a prevalent and often debilitating feature of HD pathology, with no therapies available. It correlates with disease progression and significantly affects the quality of life of HD patients. Curcumin, a naturally occurring polyphenol with multiple therapeutic properties, has been validated to exert important beneficial effects under health conditions as well as in different pathological settings, including neurodegenerative and gastrointestinal (GI) disorders. Here, we investigated the potential therapeutic action that curcumin-supplemented diet may exert on central and peripheral dysfunctions in R6/2 mice, a well-characterized HD animal model which recapitulates some features of human pathology. Maintenance of normal motor function, protection from neuropathology and from GI dysfunction and preservation of GI emptying and conserved intestinal contractility, proved the beneficial role of life-long dietary curcumin in HD and corroborated the potential of the compound to be exploited to alleviate very debilitating symptoms associated with the disease.

Dietary Polyphenols: A Multifactorial Strategy to Target Alzheimer's Disease.

Ageing is an inevitable fundamental process for people and is their greatest risk factor for neurodegenerative disease. The ageing processes bring changes in cells that can drive the organisms to experience loss of nutrient sensing, disrupted cellular functions, increased oxidative stress, loss of cellular homeostasis, genomic instability, accumulation of misfolded protein, impaired cellular defenses and telomere shortening. Perturbation of these vital cellular processes in neuronal cells can lead to life threatening neurological disorders like Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Lewy body dementia, etc. Alzheimer's Disease is the most frequent cause of deaths in the elderly population. Various therapeutic molecules have been designed to overcome the social, economic and health care burden caused by Alzheimer's Disease. Almost all the chemical compounds in clinical practice have been found to treat symptoms only limiting them to palliative care. The reason behind such imperfect drugs may result from the inefficiencies of the current drugs to target the cause of the disease. Here, we review the potential role of antioxidant polyphenolic compounds that could possibly be the most effective preventative strategy against Alzheimer's Disease.

Customized Dietary Intervention Avoids Unintentional Weight Loss and Modulates Circulating miRNAs Footprint in Huntington's Disease.

SCOPE: Huntington's disease (HD) is a rare progressive neurodegenerative disorder of genetic origin, with no definitive treatment. Unintentional weight loss (UWL) is a clinical feature of symptomatic HD subjects. To prevent UWL, a customized HD diet is designed and its impact on plasma miRNA HD footprint and neurological parameters is examined. METHODS AND RESULTS: Eleven participants are included, BMI ≤ 18 kg m-2 or UWL of 5% in 6 months or 10% in a year. Diet design is based on nutritional surveys and interviews of participants and caregivers and on published literature review. Twelve-month dietary intervention, with follow-up every 3 months, induces high diet adherence, which manages to curb UWL in all participants (73% gained weight). Noticeable increases in fat mass and leptin levels are obtained. The results also show significant decrease in the expression of 19 miRNAs, which are previously reported to be upregulated in HD-patients versus healthy controls: revealing hsa-miR-338-3p, hsa-miR-128-3p, hsa-miR-23a-3p, and hsa-miR-24-3p as potential HD-biomarkers. The diminished expression of hsa-miR-100-5p reflects the general maintenance of the functional status. Cognitive status is improved in six of 11 participants, while only three present better motor-score values. CONCLUSION: A customized HD-diet prevents UWL and modified miRNAs HD-footprint. The normalization of miRNA values suggests its potentially use as HD-biomarkers.

Time-Restricted Feeding Improves Circadian Dysfunction as well as Motor Symptoms in the Q175 Mouse Model of Huntington's Disease.

Huntington's disease (HD) patients suffer from a progressive neurodegeneration that results in cognitive, psychiatric, cardiovascular, and motor dysfunction. Disturbances in sleep/wake cycles are common among HD patients with reports of delayed sleep onset, frequent bedtime awakenings, and fatigue during the day. The heterozygous Q175 mouse model of HD has been shown to phenocopy many HD core symptoms including circadian dysfunctions. Because circadian dysfunction manifests early in the disease in both patients and mouse models, we sought to determine if early intervention that improve circadian rhythmicity can benefit HD and delay disease progression. We determined the effects of time-restricted feeding (TRF) on the Q175 mouse model. At six months of age, the animals were divided into two groups: ad libitum (ad lib) and TRF. The TRF-treated Q175 mice were exposed to a 6-h feeding/18-h fasting regimen that was designed to be aligned with the middle of the time when mice are normally active. After three months of treatment (when mice reached the early disease stage), the TRF-treated Q175 mice showed improvements in their locomotor activity rhythm and sleep awakening time. Furthermore, we found improved heart rate variability (HRV), suggesting that their autonomic nervous system dysfunction was improved. Importantly, treated Q175 mice exhibited improved motor performance compared to untreated Q175 controls, and the motor improvements were correlated with improved circadian output. Finally, we found that the expression of several HD-relevant markers was restored to WT levels in the striatum of the treated mice using NanoString gene expression assays.

Biochemical Properties and Neuroprotective Effects of Compounds in Various Species of Berries.

Several species of berries, such as blueberries (Vaccinium angustifolium) and lingonberries (Vaccinium vitis-idaea L.), have attracted much scientific attention in recent years, especially due to their reported antioxidant and anti-inflammatory properties. Berries, as with other types of plants, have developed metabolic mechanisms to survive various environmental stresses, some of which involve reactive oxygen species. In addition, the fruits and leaves of berries have high amounts of polyphenols, such as flavonoids, which act as potent antioxidants. These compounds could potentially be beneficial for brain aging and neurodegenerative disorders. There are now several studies documenting the beneficial effects of various berries in cell models of neurotoxicity as well as in vivo models of neurodegenerative disease. In the current review, we discuss the metabolic strategies that plants and animals have developed in order to combat reactive oxygen species. We then discuss issues of bioavailability of various compounds in mammals and provide a synopsis of studies demonstrating the neuroprotective ability of berries and polyphenols. We also summarize findings from our own research group. For example, we have detected various polyphenols in samples of blueberries and lingonberries and have found that the leaves have a much higher antioxidant capacity than the fruits. Extracts from these species have also demonstrated neuroprotective effects in cellular models of toxicity and inflammation, which are being further pursued in animal models.

Therapeutic Effects of Anthocyanins and Environmental Enrichment in R6/1 Huntington's Disease Mice.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disease with no effective treatment or cure. Environmental enrichment has been used to slow processes leading to ageing and neurodegenerative diseases including HD. Phenolic phytochemicals including anthocyanins have also been shown to improve brain function in ageing and neurodegenerative diseases. OBJECTIVE: This study examined the effects of anthocyanin dietary supplementation and environmental enrichment on behavioural phenotypes and brain cholesterol metabolic alterations in the R6/1 mouse model of HD. METHODS: R6/1 HD mice and their wild-type littermate controls were randomised into the different experimental conditions, involving either environmentally enriched versus standard housing conditions, or anthocyanin versus control diet. Motor dysfunction was assessed from 6 to 26 weeks using the RotaRod and the hind-paw clasping tests. Gas chromatography - tandem mass spectrometry was used to quantify a broad range of sterols in the striatum and cortex of R6/1 HD mice. RESULTS: Anthocyanin dietary supplementation delayed the onset of motor dysfunction in female HD mice. Environmental enrichment improved motor function and the hind paw clasping phenotype in male HD mice only. These mice also had lower levels of cholesterol oxidation products in the cortex compared to standard-housed mice. CONCLUSION: Both anthocyanin supplementation and environmental enrichment are able to improve the motor dysfunction phenotype of R6/1 mice, however the effectiveness of these interventions was different between the two sexes. The interventions examined did not alter brain cholesterol metabolic deficits that have been reported previously in this mouse model of HD.

Partial Amelioration of Peripheral and Central Symptoms of Huntington's Disease via Modulation of Lipid Metabolism.

BACKGROUND: Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder characterized by uncontrollable dance-like movements, as well as cognitive deficits and mood changes. A feature of HD is a metabolic disturbance that precedes neurological symptoms. In addition, brain cholesterol synthesis is significantly reduced, which could hamper synaptic transmission. OBJECTIVE: Alterations in lipid metabolism as a potential target for therapeutic intervention in the R6/2 mouse model of HD were examined. METHODS: Electrophysiological recordings in vitro examined the acute effects of cholesterol-modifying drugs. In addition, behavioral testing, effects on synaptic activity, and measurements of circulating and brain tissue concentrations of cholesterol and the ketone ß-hydroxybutyrate (BHB), were examined in symptomatic R6/2 mice and littermate controls raised on normal chow or a ketogenic diet (KD). RESULTS: Whole-cell voltage clamp recordings of striatal medium-sized spiny neurons (MSNs) from symptomatic R6/2 mice showed increased frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) compared with littermate controls. Incubation of slices in cholesterol reduced the frequency of large-amplitude sIPSCs. Addition of BHB or the Liver X Receptor (LXR) agonist T0901317 reduced the frequency and amplitude of sIPSCs. Surprisingly, incubation in simvastatin to reduce cholesterol levels also decreased the frequency of sIPSCs. HD mice fed the KD lost weight more gradually, performed better in an open field, had fewer stereotypies and lower brain levels of cholesterol than mice fed a regular diet. CONCLUSIONS: Lipid metabolism represents a potential target for therapeutic intervention in HD. Modifying cholesterol or ketone levels acutely in the brain can partially rescue synaptic alterations, and the KD can prevent weight loss and improve some behavioral abnormalities.

Long-Term use of Modified Diets in Huntington's Disease: A Descriptive Clinical Practice Analysis on Improving Dietary Enjoyment.

Dysphagia is a very common occurrence in Huntington's disease (HD). As such, many people with HD require texture modified diets. This commentary discusses the implications for individuals living long-term on modified diets, including the loss of sensory stimulation and dietary enjoyment. Clinical practice analyses of two interventions aimed at promoting dietary satisfaction and involvement in food preparation for those with HD are described and parameters for future research are discussed.

Factors associated with Mediterranean diet adherence in Huntington's disease.

BACKGROUND & AIMS: Little is known about the importance of the Mediterranean Diet (MeDi) and dietary intake as environmental neuroprotective factors in Huntington's disease (HD); so, we evaluated and analyzed the prevalence and factors associated with MeDi adherence, and dietary intake in HD. METHODS: Spanish participants of the European Huntington Disease Network (EHDN) Registry study diagnosed with HD or premanifest HD gene carriers were included from June 2012 to August 2013. Self-reported dietary intake was collected by 3-day dietary record, MeDi adherence was assessed by 0-9 range (proposed by Trichopoulou et al.) and, other contributing factors related to nutrition were collected by telephone. Demographics and clinical variables were obtained from the EHDN Registry study database. Association of HD with MeDi adherence and nutritional characteristics were performed using logistic regression models. RESULTS: Ninety eight participants were included in the study, median age of 48 years (38-60 range), and median total functional capacity (TFC) 9 (5-13 range). HD severity was similar between participants with low vs moderate/high MeDi; however, quality of life (P = 0.009) was significantly higher among participants with moderate/high MeDi adherence. In terms of nutrients, higher MUFA/SFA intake was moderately correlated with better TFC and Unified HD Rating Scale (UHDRS) cognitive. Better TFC was associated with having a caregiver (OR = 11.86, P < 0.001), and non-smoking (OR = 0.21, P = 0.013). Moderate adherence to MeDi, was associated with older participants (OR = 1.19, P = 0.031), lower comorbidity (OR = 0.18, P = 0.018), lower UHDRS motor (OR = 0.90, P = 0.041), and lower risk for abdominal obesity (OR = 0.02, P = 0.011). CONCLUSIONS: In HD the moderate MeDi adherence is associated with better quality of life, lower comorbidity, lower motor impairment and lower risk for abdominal obesity compared to those participants with low MeDi adherence.

Protection by dietary restriction in the YAC128 mouse model of Huntington's disease: Relation to genes regulating histone acetylation and HTT.

Huntington's disease (HD) is a fatal neurodegenerative disease characterized by metabolic, cognitive, and motor deficits. HD is caused by an expanded CAG repeat in the first exon of the HTT gene, resulting in an expanded polyglutamine section. Dietary restriction (DR) increases lifespan and ameliorates age-related pathologies, including in a model of HD, but the mechanisms mediating these protective effects are unknown. We report metabolic and behavioral effects of DR in the full-length YAC128 HD mouse model, and associated transcriptional changes in hypothalamus and striatum. DR corrected many effects of the transgene including increased body weight, decreased blood glucose, and impaired motor function. These changes were associated with reduced striatal human (but not mouse) HTT expression, as well as alteration in gene expression regulating histone acetylation modifications, particularly Hdac2. Other mRNAs related to Huntington's pathology in striatal tissue showed significant modulation by the transgene, dietary restriction or both. These results establish a protective role of DR in a transgenic model that contains the complete human HTT gene and for the first time suggest a role for DR in lowering HTT level, which correlates with severity of symptoms.

Huntington Disease - principles and practice of nutritional management.

Huntington disease (HD) is a degenerative brain disease clinically manifested by the characteristic triad: physical symptoms including involuntary movements and poor coordination, cognitive changes with less ability to organize routine tasks, and some emotional and behavioral disturbances. For patients with HD, feeding is one of the problems they have to face. People with HD often have lower than average body weight and struggle with malnutrition. As a part of therapy, good nutrition is an intervention maintaining health and functional ability for maximally prolonged time. In the early stages of HD, small amounts of blenderized foods given orally are recommended. In more advanced stages, enteral nutrition is essential using gastric, or jejunal tubes for short term. Most severe cases require gastrostomy or gastrojejunostomy. Although enteral feeding is well tolerated by most of the patients, a number of complications may occur, including damage to the nose, pharynx, or esophagus, aspiration pneumonia, sinusitis, metabolic imbalances due to improper nutrient and fluid supply, adverse effects affecting gastrointestinal system, and refeeding syndrome.

Improvement of neuropathology and transcriptional deficits in CAG 140 knock-in mice supports a beneficial effect of dietary curcumin in Huntington's disease.

BACKGROUND: No disease modifying treatment currently exists for Huntington's disease (HD), a fatal neurodegenerative disorder characterized by the formation of amyloid-like aggregates of the mutated huntingtin protein. Curcumin is a naturally occurring polyphenolic compound with Congo red-like amyloid binding properties and the ability to cross the blood brain barrier. CAG140 mice, a knock-in (KI) mouse model of HD, display abnormal aggregates of mutant huntingtin and striatal transcriptional deficits, as well as early motor, cognitive and affective abnormalities, many months prior to exhibiting spontaneous gait deficits, decreased striatal volume, and neuronal loss. We have examined the ability of life-long dietary curcumin to improve the early pathological phenotype of CAG140 mice. RESULTS: KI mice fed a curcumin-containing diet since conception showed decreased huntingtin aggregates and increased striatal DARPP-32 and D1 receptor mRNAs, as well as an amelioration of rearing deficits. However, similar to other antioxidants, curcumin impaired rotarod behavior in both WT and KI mice and climbing in WT mice. These behavioral effects were also noted in WT C57Bl/6 J mice exposed to the same curcumin regime as adults. However, neither locomotor function, behavioral despair, muscle strength or food utilization were affected by curcumin in this latter study. The clinical significance of curcumin's impairment of motor performance in mice remains unclear because curcumin has an excellent blood chemistry and adverse event safety profile, even in the elderly and in patients with Alzheimer's disease. CONCLUSION: Together with this clinical experience, the improvement in several transgene-dependent parameters by curcumin in our study supports a net beneficial effect of dietary curcumin in HD.

A ketogenic diet delays weight loss and does not impair working memory or motor function in the R6/2 1J mouse model of Huntington's disease.

Ketogenic diets are high in fat and low in carbohydrates, and have long been used as an anticonvulsant therapy for drug-intractable and pediatric epilepsy. Additionally, ketogenic diets have been shown to provide neuroprotective effects against acute and chronic brain injury, including beneficial effects in various rodent models of neurodegeneration. Huntington's disease is a progressive neurodegenerative disease characterized by neurological, behavioral and metabolic dysfunction, and ketogenic diets have been shown to increase energy molecules and mitochondrial function. We tested the effects of a ketogenic diet in a transgenic mouse model of Huntington's disease (R6/2 1J), with a focus on life-long behavioral and physiological effects. Matched male and female wild-type and transgenic mice were maintained on a control diet or were switched to a ketogenic diet fed ad libitum starting at six weeks of age. We found no negative effects of the ketogenic diet on any behavioral parameter tested (locomotor activity and coordination, working memory) and no significant change in lifespan. Progressive weight loss is a hallmark feature of Huntington's disease, yet we found that the ketogenic diet-which generally causes weight loss in normal animals-delayed the reduction in body weight of the transgenic mice. These results suggest that metabolic therapies could offer important benefits for Huntington's disease without negative behavioral or physiological consequences.

Altered cholesterol and fatty acid metabolism in Huntington disease.

Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.

Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington's disease.

We previously identified a systemic metabolic defect associated with early weight loss in patients with Huntington's disease (HD), suggesting a lack of substrates for the Krebs cycle. Dietary anaplerotic therapy with triheptanoin is used in clinical trials to promote energy production in patients with peripheral and brain Krebs cycle deficit, as its metabolites - C5 ketone bodies - cross the blood-brain barrier. We conducted a short-term clinical trial in six HD patients (UHDRS (Unified Huntington Disease Rating Scale)=33+/-13, 15-49) to monitor the tolerability of triheptanoin. We also assessed peripheral markers of short-term efficacy that were shown to be altered in the early stages of HD, that is, low serum IGF1 and (31)P-NMR spectroscopy (NMRS) in muscle. At baseline, (31)P-NMRS displayed two patients with end-exercise muscle acidosis despite a low work output. On day 2, the introduction of triheptanoin was well tolerated in all patients, and in particular, there was no evidence of mitochondrial overload from triheptanoin-derived metabolites. After 4 days of triheptanoin-enriched diet, muscle pH regulation was normalized in the two patients with pretreatment metabolic abnormalities. A significant increase in serum IGF1 was also observed in all patients (205+/-60 ng/ml versus 246+/-68 ng/ml, P=0.010). This study provides a rationale for extending our anaplerotic approach with triheptanoin in HD.

Cystamine and intrabody co-treatment confers additional benefits in a fly model of Huntington's disease.

Huntington's disease (HD) is a lethal, neurodegenerative disorder caused by expansion of the polyglutamine repeat in the Huntingtin gene (HTT), leading to mutant protein misfolding, aggregation, and neuronal death. Feeding a Drosophila HD model cystamine, or expressing a transgene encoding the anti-htt intracellular antibody (intrabody) C4-scFv in the nervous system, demonstrated therapeutic potential, but suppression of pathology was incomplete. We hypothesized that a combinatorial approach entailing drug and intrabody administration could enhance rescue of HD pathology in flies and that timing of treatment would affect outcomes. Feeding cystamine to adult HD flies expressing the intrabody resulted in a significant, additional rescue of photoreceptor neurodegeneration, but no additional benefit in longevity. Feeding cystamine during both larval and adult stages produced the converse result: longevity was significantly improved, but increased photoreceptor survival was not. We conclude that cystamine-intrabody combination therapies can be effective, reducing neurodegeneration and prolonging survival, depending on administration protocols.

Harris-Benedict equation estimations of energy needs as compared to measured 24-h energy expenditure by indirect calorimetry in people with early to mid-stage Huntington's disease.

Weight loss and energy metabolism are important clinical research areas in understanding the disease mechanisms in Huntington's disease. Having an accurate method to estimate expected total energy expenditure would likely facilitate the development of studies about these features of the disease. The Harris-Benedict equation is a formula commonly used to estimate basal energy expenditure of individuals, adjusted for height, weight, age and gender. This estimate is then multiplied by a physical activity factor to estimate total daily energy needs to maintain the given weight. Data from 24-h indirect calorimetry was utilized to derive an adjustment formula for the physical activity factor of the Harris-Benedict equation for 13 early to mid-stage Huntington's disease patients. The adjusted activity factor provided the most accurate estimate of energy needs. This adjusted formula can be used in clinical assessments of Huntington's disease patients, as well as in research studies when indirect calorimetry has not been performed.

Weight loss in neurodegenerative disorders.

Unintended weight loss frequently complicates the course of many neurodegenerative disorders and can contribute substantially to both morbidity and mortality. This will be illustrated here by reviewing the characteristics of unintended weight loss in the three major neurodegenerative disorders: Alzheimer's disease, Parkinson's disease and Huntington's disease. A common denominator of weight loss in these neurodegenerative disorders is its typically complex pathophysiology. Timely recognition of the underlying pathophysiological process is of crucial importance, since a tailored treatment of weight loss can considerably improve the quality of life. This treatment is, primarily, comprised of a number of methods of increasing energy intake. Moreover, there are indications for defects in the systemic energy homeostasis and gastrointestinal function, which may also serve as therapeutic targets. However, the clinical merits of such interventions have yet to be demonstrated.