The addition of choline to parenteral nutrition.

Choline is a quaternary amine endogenously synthesized from the amino acid methionine or absorbed via the portal circulation. It is ubiquitous in the diet, although it has a greater presence in organ meats. Choline is an essential component of all cell membranes, and has been considered a required dietary nutrient since 1998 by the US Institute of Medicine's Food and Nutrition Board. Choline is necessary for DNA repair, mediated by its role as a methyl donor. It also serves as the precursor for the neurotransmitter acetylcholine. Evidence has accumulated that hepatic steatosis, which occurs during parenteral nutrition therapy, develops as a result of choline deficiency because endogenous production of choline from parenterally infused methionine is deficient. In addition, memory deficits and skeletal muscle abnormalities have been described, and choline deficiency appears to activate cellular apoptosis. Provision of intravenous choline ameliorates hepatic steatosis associated with parenteral nutrition infusion.

Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet.

Rennin-angiotensin system is involved in liver fibrogenesis through activating hepatic stellate cells (HSCs). Telmisartan (Tel) is an angiotensin II type 1 receptor antagonist, could function as a selective peroxisome proliferator-activated receptor gamma activator. Here we studied the effect of Tel on liver fibrosis, pre-neoplastic lesions in vivo and primary HSCs in vitro. In vivo study, we used the choline-deficient L-amino acid-defined (CDAA)-diet induced rat NASH model. The rats were fed the CDAA diet for 8 weeks to induce liver fibrosis and pre-neoplastic lesions, and then co-administrated with Tel for another 10 weeks. Tel prevented liver fibrogenesis and pre-neoplastic lesions by down-regulating TGFbeta1 and TIMP-1, 2 and increasing MMP-13 expression. Tel inhibited HSCs activation and proliferation. These results suggested that Tel could be a promising drug for NASH related liver fibrosis.

Choline deficiency increases lymphocyte apoptosis and DNA damage in humans.

BACKGROUND: Whereas deficiency of the essential nutrient choline is associated with DNA damage and apoptosis in cell and rodent models, it has not been shown in humans. OBJECTIVE: The objective was to ascertain whether lymphocytes from choline-deficient humans had greater DNA damage and apoptosis than did those from choline-sufficient humans. DESIGN: Fifty-one men and women aged 18-70 y were fed a diet containing the recommended adequate intake of choline (control) for 10 d. They then were fed a choline-deficient diet for up to 42 d before repletion with 138-550 mg choline/d. Blood was collected at the end of each phase, and peripheral lymphocytes were isolated. DNA damage and apoptosis were then assessed by activation of caspase-3, terminal deoxynucleotide transferase-mediated dUTP nick end-labeling, and single-cell gel electrophoresis (COMET) assays. RESULTS: All subjects fed the choline-deficient diet had lymphocyte DNA damage, as assessed by COMET assay, twice that found when they were fed the control diet. The subjects who developed organ dysfunction (liver or muscle) when fed the choline-deficient diet had significantly more apoptotic lymphocytes, as assessed by the activated caspase-3 assay, than when fed the control diet. CONCLUSIONS: A choline-deficient diet increased DNA damage in humans. Subjects in whom these diets induced liver or muscle dysfunction also had higher rates of apoptosis in their peripheral lymphocytes than did subjects who did not develop organ dysfunction. Assessment of DNA damage and apoptosis in lymphocytes appears to be a clinically useful measure in humans (such as those receiving parenteral nutrition) in whom choline deficiency is suspected.

Infantile cobalamin deficiency with cerebral lactate accumulation and sustained choline depletion.

A remarkable, intermittent sudden-onset vigilance and movement disorder in an exclusively breast-fed infant is reported, which was caused by cobalamin depletion due to maternal vitamin B12 malabsorption. The lack of cobalamin caused a severe encephalopathy in the infant, whose brain displayed a striking loss of volume and a delay of myelination. Proton magnetic resonance spectroscopy revealed an accumulation of lactate in the gray and white matter of the brain and a sustained depletion of choline-containing compounds in the white matter, reflecting a reversible disturbance of oxidative energy metabolism in brain cells and a long-lasting hypomyelination disorder. The clinical picture in conjunction with MRI and spectroscopic data of this case study yields more insight into the functions of cobalamin in the cerebral metabolism.

Free choline and phospholipid-bound choline concentrations in serum and dialysate during peritoneal dialysis in children and adults.

OBJECTIVES: This study tested whether continuous ambulatory peritoneal dialysis (CAPD) changes free or phospholipid-bound choline concentrations in serum or peritoneal dialysis fluid of patients with end stage renal disease (ESRD). DESIGN AND METHODS: Serum and dialysate choline and phospholipid-bound choline were measured before, during and after 6 h CAPD. RESULTS: Serum choline concentrations were higher in patients with ESRD compared with age-matched controls. CAPD lowered serum choline concentrations significantly although it did not influence phospholipid-bound choline. Choline accumulated in the dialysate, reaching 28.4 +/- 2.7 microM in children and 18.2 +/- 1.4 microM in adults, during six hours CAPD; phospholipid-bound choline increased to 22.9 +/- 2.5 microM and 10.8 +/- 1.4 microM in children and adults, respectively. The total daily loss of choline into the dialysate was 181 +/- 20 micromoles in children and 260 +/- 18 micromoles in adults. CONCLUSION: CAPD causes a substantial loss of choline into peritoneal dialysates and reduces serum choline concentrations significantly.

Choline and vitamin B12 deficiencies are interrelated in folate-replete long-term total parenteral nutrition patients.

BACKGROUND: Choline has recently been recognized as an essential nutrient, in part based on deficiency data in long-term home total parenteral nutrition (TPN) patients. Choline, a methyl donor in the metabolism of homocysteine, is intricately related to folate status, but little is known about choline and vitamin B12 status. Long-term TPN patients are also subject to vitamin B12 deficiency. OBJECTIVE: The objective of the study was to evaluate any interaction between choline, vitamin B12, and folate in patients with severe malabsorption syndromes, requiring long-term TPN. DESIGN: Plasma free choline, serum and red blood cell (RBC) folate, serum vitamin B12 methylmalonic acid, B6, and plasma total homocysteine concentrations were assayed by standard methods. Low choline was defined as values that fall 1 to < or =3 and marked low choline concentration as >3 SD below the control mean. RESULTS: Both low choline concentrations (52% were marked low, 33% low, 14% normal) and elevated methylmalonic acid concentrations (47%) were prevalent. Choline concentration was significantly lower and RBC folate higher in patients with elevated methylmalonic acid. Total homocysteine elevations were rare (3 of 21) and mild. CONCLUSIONS: These data suggest a strong interaction between vitamin B12 and choline deficiencies and folate status in this population, which may be due in part to variations in vitamin and choline delivery by TPN. Folate adequacy may increase B12 use for homocysteine metabolism, thus limiting B12 availability for methylmaIonic acid metabolism. Choline use may also increase, and choline deficiency may worsen if choline substitutes when the vitamin B12 side of the homocysteine metabolic pathway cannot be used.

[Cholinergic hypothesis and Alzheimer's disease: the place of donepezil (Aricept)]. / Hypothèse cholinergique et maladie d'Alzheimer: place du donepezil (Aricept).

This presentation has two objectives: 1) presenting the relationships between the clinical symptoms of Alzheimer's disease and cholinergic deficiency, 2) presenting the results obtained with Aricept (proprietary name of donepezil hydrochloride), one of the most recent drugs developed in the context of the cholinergic hypothesis. One of the earliest pathological events in Alzheimer's disease consists in the degeneration of cholinergic neurons in the subcortical regions and, more particularly, in Meynert's nucleus basalis which projects, in a topographically organized manner, to the cortical regions and hippocampus. Some of those regions less affected by the degenerative process nonetheless retain active post-junctional receptors. The disappearance of cholinergic neurons from the nucleus basalis induces disactivation of the cortical and limbic cells and is responsible for the clinical symptoms, such as attention, memory and behavioral disorders. The marketing authorization application for Aricept is based on various studies designed to enable preliminary dose determination and assess efficacy and safety. The first large-scale study designed to evaluate the efficacy of Aricept administered at a daily dosage of 5 to 10 mg was conducted over 14 weeks. The results show a significant improvement in cognitive function in the treatment groups, compared to the placebo groups. The difference emerged after 3 weeks of treatment, lasted throughout the 12 weeks of the study and was still very marked 3 weeks post-treatment discontinuation. The results of a second study conducted over 30 weeks were similar to the foregoing results. Compared to placebo, Aricept at a daily dosage of 5 to 10 mg induces a significant improvement in cognitive function and overall function. At week 24, the patients still showed performances that were superior to their baseline performances. In parallel with its cognitive effects, Aricept was also shown to improve the activities of everyday life and alleviate the distress of caregivers directly confronted with the behavioral disorders of patients suffering from Alzheimer's disease.

The Lewy body variant of Alzheimer's disease: clinical, pathophysiological and conceptual issues.

In 1923, Friedrich H. Lewy described dementia with Lewy bodies in a large proportion of his patients with paralysis agitans which had co-incident plaques and neurofibrillary tangles. The potential contribution of Lewy bodies to a dementia syndrome with fluctuating course, visual hallucinations, Parkinsonian features and neuroleptic hypersensitivity was rediscovered many decades later. The comorbidity of Alzheimer's and Parkinson's disease is not uncommon as both diseases show an exponential increase with advancing age and their coincidence is of great clinical importance. The combination of a cholinergic deficit--which is particularly severe due to the double pathology targeting the basal nucleus of Meynert--and a dopaminergic deficit requires cholinergic and cautious dopaminergic treatment. Excessive dopamine (L-dopa), antidopaminergic (neuroleptic) or anticholinergic treatment (anti-Parkinson or neuroleptic medication) may further complicate the condition, worsen extrapyramidal, psychotic or cognitive disturbances and even lead to a neuroleptic malignant syndrome.

Psychophysiological diagnostics in alcohol dependency: Fourier analysis of pupillary oscillations and the receptor test for determination of cholinergic deficiency.

Mnestic disturbances in alcoholics may be related to cholinergic deficiency as well as to central nervous system inactivation. After instillation of tropicamide, cholinergic receptors are blocked and pupillary dilatation occurs. It is assumed that the more severe the cognitive deterioration, the wider the pupillary dilatation. Pupillary oscillations reflect central activation. Changes of pupillary diameter after topical instillation of tropicamide and pupillary oscillations were measured in 44 alcohol-dependent patients aged 40-55 years, diagnosed according to the DSM-III-R as severe alcoholics (>7 symptoms), having been abstinent for at least 3 weeks (objectively tested with carbohydrate-deficient transferrin), compared with 18 healthy controls. The pupillary diameter of the left eye was measured eight times within 103 min, as were pupillary oscillations. Using Fourier analysis, the amplitudes of oscillations were measured in five frequency bands and the sum of the frequency bands was calculated. In addition, central activation was measured during a calculation test at 3 and 103 min. The pupillary dilatation of 22% in alcoholics compared to 14% of normal controls after tropicamide raises the question of a cholinergic deficit in alcohol dependence. With regard to basic activation, measured by Fourier analysis of pupillary oscillations, alcoholics demonstrated significantly lower power (sum of the frequency bands) than controls at baseline and at 3, 20, and 40 min (P < 0.01) as well as at 60, 80, 100, and 103 min (P < 0.05). After a cognitive task, a difference between alcoholics and healthy controls was found at 3 min. Alcoholics showed lower basic activation and decreased cognitive activation. By means of cross-validation, a differentiation between alcohol-dependent patients (n = 44 and n = 42 respectively) and normal controls (n = 18) was possible.