Plasma choline concentration varies with different dietary levels of vitamins B6, B12 and folic acid in rats maintained on choline-adequate diets.

Choline is an important component of the human diet and is required for the endogenous synthesis of choline-containing phospholipids, acetylcholine and betaine. Choline can also be synthesised de novo by the sequential methylation of phosphatidylethanolamine to phosphatidylcholine. Vitamins B6, B12 and folate can enhance methylation capacity and therefore could influence choline availability not only by increasing endogenous choline synthesis but also by reducing choline utilisation. In the present experiment, we determined whether combined supplementation of these B vitamins affects plasma choline concentration in a rat model of mild B vitamin deficiency which shows moderate increases in plasma homocysteine. To this end, we measured plasma choline and homocysteine concentrations in rats that had consumed a B vitamin-poor diet for 4 weeks after which they were either continued on the B vitamin-poor diet or switched to a B vitamin-enriched diet for another 4 weeks. Both diets contained recommended amounts of choline. Rats receiving the B vitamin-enriched diet showed higher plasma choline and lower plasma homocysteine concentrations as compared to rats that were continued on the B vitamin-poor diet. These data underline the interdependence between dietary B vitamins and plasma choline concentration, possibly via the combined effects of the three B vitamins on methylation capacity.

Efficacy of a medical food in mild Alzheimer's disease: A randomized, controlled trial.

OBJECTIVE: To investigate the effect of a medical food on cognitive function in people with mild Alzheimer's disease (AD). METHODS: A total of 225 drug-naïve AD patients participated in this randomized, double-blind controlled trial. Patients were randomized to active product, Souvenaid, or a control drink, taken once-daily for 12 weeks. Primary outcome measures were the delayed verbal recall task of the Wechsler Memory Scale-revised, and the 13-item modified Alzheimer's Disease Assessment Scale-cognitive subscale at week 12. RESULTS: At 12 weeks, significant improvement in the delayed verbal recall task was noted in the active group compared with control (P = .021). Modified Alzheimer's Disease Assessment Scale-cognitive subscale and other outcome scores (e.g., Clinician Interview Based Impression of Change plus Caregiver Input, 12-item Neuropsychiatric Inventory, Alzheimer's disease Co-operative Study-Activities of Daily Living, Quality of Life in Alzheimer's Disease) were unchanged. The control group neither deteriorated nor improved. Compliance was excellent (95%) and the product was well tolerated. CONCLUSIONS: Supplementation with a medical food including phosphatide precursors and cofactors for 12 weeks improved memory (delayed verbal recall) in mild AD patients. This proof-of-concept study justifies further clinical trials.

The potential role of nutritional components in the management of Alzheimer's Disease.

Epidemiological evidence linking nutrition to the incidence and risk of Alzheimer Disease is rapidly increasing. The specific nutritional deficiencies in Alzheimer patients may suggest a relative shortage of specific macro- and micronutrients. These include omega-3 fatty acids, several B-vitamins and antioxidants such as vitamins E and C. Recent mechanistic studies in cell systems and animal models also support the idea that nutritional components are able to counteract specific aspects of the neurodegenerative and pathological processes in the brain. In addition, it has been shown that several nutritional components can also effectively stimulate membrane formation and synapse formation as well as improve behavior and cerebrovascular health. The suggested synergy between nutritional components to improve neuronal plasticity and function is supported by epidemiological studies as well as experimental studies in animal models. The ability of nutritional compositions to stimulate synapse formation and effectively reduce Alzheimer Disease neuropathology in these preclinical models provides a solid basis to predict potential to modify the disease process, especially during the early phases of Alzheimer Disease.

Long-lasting effects of neonatal dexamethasone treatment on spatial learning and hippocampal synaptic plasticity: involvement of the NMDA receptor complex.

The effects of neonatal dexamethasone (DEX) treatment on spatial learning and hippocampal synaptic plasticity were investigated in adult rats. Spatial learning in reference and working memory versions of the Morris maze was impaired in DEX-treated rats. In hippocampal slices of DEX rats, long-term depression was facilitated and potentiation was impaired. Paired-pulse facilitation was normal, suggesting a postsynaptic defect as cause of the learning and plasticity deficits. Western blot analysis of hippocampal postsynaptic densities (PSD) revealed a reduction in NR2B subunit protein, whereas the abundance of the other major N-methyl-D-aspartate (NMDA) receptor subunits (NR1, NR2A), AMPA receptor subunits (GluR2/3), scaffolding proteins, and Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII) were unaltered. This selective reduction in NR2B likely resulted from altered receptor assembly rather than subunit expression, because the abundance of NR2B in the homogenate and crude synaptosomal fractions was unaltered. In addition, the activity of alphaCaMKII, an NMDA receptor complex associated protein kinase, was increased in PSD of DEX rats. The results indicate that neonatal treatment with DEX causes alterations in composition and function of the hippocampal NMDA receptor complex that persist into adulthood. These alterations likely explain the deficits in hippocampal synaptic plasticity and spatial learning induced by neonatal DEX treatment.

Tolerability and safety of Souvenaid in patients with mild Alzheimer's disease: results of multi-center, 24-week, open-label extension study.

BACKGROUND: The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer's disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. OBJECTIVE: In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. METHODS: Patients with mild AD (n = 201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. RESULTS: Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. CONCLUSION: Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT.

Neonatal dexamethasone treatment affects social behaviour of rats in later life.

Synthetic glucocorticoids, like dexamethasone (DEX), have been frequently administered to premature infants to prevent chronic lung disease. Major concern has arisen about the long-term neurodevelopmental sequelae of this DEX treatment. In the present study, we found that neonatal DEX treatment in rats, using a treatment protocol resembling the one used in the clinical situation, increased social play behaviour in juvenile life. Furthermore, neonatal DEX treatment increased sexual motivation and intromission behaviour in the bi-level chamber, decreased submissive behaviour during an aggressive encounter, and impaired social memory in adulthood. These changes in social behaviour are not due to a general behavioural impairment since anxiety behaviour in the elevated plus maze and exploratory activity in the open-field were not affected in DEX rats. In addition, DEX rats showed no alteration in the total duration of social interest or social activity during a social interaction test. These effects of neonatal DEX treatment on behaviour later in life likely result from neurodevelopmental actions of the hormone since we found no differences in received maternal care between DEX and SAL treated pups. Together these results indicate that neonatal treatment with DEX selectively alters aspects of the behavioural response to social challenges. Thus, neonatal DEX treatment may lead to inappropriate interactions with conspecifics later in life. These data therefore warrant investigation of lasting and potentially adverse effects of treatment of human neonates with DEX on social functioning.

Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination.

Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models.

The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer's disease: a randomised controlled study.

BACKGROUND: Synaptic loss is a major hallmark of Alzheimer's disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to enhance synapse formation and function and has been shown to improve memory performance in patients with mild AD in two randomised controlled trials. OBJECTIVE: To explore the effect of Souvenaid compared to control product on brain activity-based networks, as a derivative of underlying synaptic function, in patients with mild AD. DESIGN: A 24-week randomised, controlled, double-blind, parallel-group, multi-country study. PARTICIPANTS: 179 drug-naïve mild AD patients who participated in the Souvenir II study. INTERVENTION: Patients were randomised 1∶1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. OUTCOME: In a secondary analysis of the Souvenir II study, electroencephalography (EEG) brain networks were constructed and graph theory was used to quantify complex brain structure. Local brain network connectivity (normalised clustering coefficient gamma) and global network integration (normalised characteristic path length lambda) were compared between study groups, and related to memory performance. RESULTS: THE NETWORK MEASURES IN THE BETA BAND WERE SIGNIFICANTLY DIFFERENT BETWEEN GROUPS: they decreased in the control group, but remained relatively unchanged in the active group. No consistent relationship was found between these network measures and memory performance. CONCLUSIONS: The current results suggest that Souvenaid preserves the organisation of brain networks in patients with mild AD within 24 weeks, hypothetically counteracting the progressive network disruption over time in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function. Secondly, we conclude that advanced EEG analysis, using the mathematical framework of graph theory, is useful and feasible for assessing the effects of interventions. TRIAL REGISTRATION: Dutch Trial Register NTR1975.

Nutritional approaches in the risk reduction and management of Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous and devastating neurodegenerative disease with increasing socioeconomic burden for society. In the past 30 y, notwithstanding advances in the understanding of the pathogenesis of the disease and consequent development of therapeutic approaches to novel pathogenic targets, no cure has so far emerged. This contribution focuses on recent nutritional approaches in the risk reduction and management of AD with emphasis on factors providing a rationale for nutritional approaches in AD, including compromised nutritional status, altered nutrient uptake and metabolism, and nutrient requirements for synapse formation. Collectively these factors are believed to result in specific nutritional requirement in AD. The chapter also emphasizes investigated nutritional interventions in patients with AD, including studies with single nutrients and with the specific nutrient combination Fortasyn Connect and discusses the current shift of paradigm to intervene in earlier stages of AD, which offers opportunities for investigating nutritional strategies to reduce the risk for disease progression. Fortasyn Connect was designed to enhance synapse formation and function in AD by addressing the putative specific nutritional requirements and contains docosahexaenoic acid, eicosapentaenoic acid, uridine-5'-mono-phosphate, choline, phospholipids, antioxidants, and B vitamins. Two randomized controlled trials (RCTs) with the medical food Souvenaid, containing Fortasyn Connect, showed that this intervention improved memory performance in mild, drug-naïve patients with AD. Electroencephalography outcome in one of these clinical studies suggests that Souvenaid has an effect on brain functional connectivity, which is a derivative of changed synaptic activity. Thus, these studies suggest that nutritional requirements in AD can be successfully addressed and result in improvements in behavioral and neuro-physiological alterations that are characteristic to AD. The recent advance of methodologies and techniques for early diagnosis of AD facilitates the investigation of strategies to reduce the risk for AD progression in the earliest stages of the disease. Nutrition-based approaches deserve further investigation as an integral part of such strategies due to their low risk for side effects and their potential to affect pathological processes of very early AD.

A specific multi-nutrient diet reduces Alzheimer-like pathology in young adult AßPPswe/PS1dE9 mice.

Diet is an important lifestyle factor implicated in the etiology of Alzheimer's disease (AD), but so far it is not fully elucidated to which nutrients the suggested protective effect of diet can be attributed. Recent evidence obtained in the amyloid-ß 1-42 (Aß(42)) infusion model in rats has shown that a multi-nutrient intervention known as Fortasyn™ Connect (FC) may protect the central cholinergic system against Aß(42)-induced toxicity. FC comprises the nutritional precursors and cofactors for membrane synthesis, viz. docosahexaenoic acid (DHA), eicosapentaenoic acid, uridine-mono-phosphate (UMP), choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium. In order to investigate whether the combined administration of these nutrients may also affect AD-like pathology, we now evaluated the effects of the FC diet intervention in the transgenic AßPP(swe)/PS1(dE9) mouse model with endogenous Aß production. In addition we evaluated the effects of diets containing the individual nutrients DHA and UMP and their combination in this model. Between the age of 3 and 6 months, FC diet decreased brain Aß levels and amyloid plaque burden in the hippocampus of AßPP/PS1 mice. The FC diet also reduced ongoing disintegrative degeneration in the neocortex, as indicated by Amino Cupric Silver staining. Although all three DHA-containing diets were equally effective in changing brain fatty acid profiles, diets differentially affected amyloid-related measures, indicating that effects of DHA may depend on its dietary context. The current data, showing that dietary enrichment with FC reduces AD-like pathology in AßPP/PS1 mice, confirm and extend our previous findings in the Aß(42) infusion model and favor the combined administration of relevant nutrients.

Efficacy of Souvenaid in mild Alzheimer's disease: results from a randomized, controlled trial.

Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimer's disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p = 0.023; Cohen's d = 0.21; 95% confidence interval [-0.06]-[0.49]). A trend for an effect was observed on the NTB total composite z-score (p = 0.053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]). No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.

Is it prudent to add n-3 long-chain polyunsaturated fatty acids to paediatric enteral tube feeding?

Nutritional support, as complete enteral tube feeding, is needed by many paediatric patients and must provide sufficient nutrients for normal growth and development. Enteral feeds contain the parent essential fatty acids, linoleic acid and α-linolenic acid, but often do not contain n-3 long-chain polyunsaturated fatty acids. Available data suggest that biosynthesis of eicosapentaenoic acid and docosahexaenoic acid from α-linolenic acid is low in humans and varies between individuals. Long-term enteral feeding with formulae devoid of eicosapentaenoic acid and docosahexaenoic acid may result in low levels in plasma and tissues, potentially affecting immune and neurological function. Currently there is insufficient evidence to define the quantitative eicosapentaenoic acid and docosahexaenoic acid requirements for healthy children, or those with various disease states. Nevertheless, it appears prudent to supply children on long-term enteral nutrition with a dietary source of eicosapentaenoic acid and docosahexaenoic acid. A reasonable approach would be to provide amounts matching intakes of healthy children complying with the advice to consume 1-2 portions of oily fish per week. Further studies are needed to investigate the effects of different amounts of eicosapentaenoic acid and/or docosahexaenoic acid in enteral nutrition on polyunsaturated fatty acid status and the functional and clinical consequences in children.

Utility of imaging for nutritional intervention studies in Alzheimer's disease.

Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder and the leading cause of dementia, wherein synapse loss is the strongest structural correlate with cognitive impairment. Basic research has shown that dietary supply of precursors and co-factors for synthesis of neuronal membranes enhances the formation of synapses. Daily intake of a medical food containing a mix of these nutrients for 12 weeks in humans improved memory, measured as immediate and delayed verbal recall by the Wechsler Memory Scale-revised, in patients with very mild AD (MMSE 24-26). An improvement of immediate verbal recall was noted following 24 weeks of intervention in an exploratory extension of the study. These data suggest that the intervention may improve synaptic formation and function in early AD. Here we review emerging technologies that help identify changes in pathological hallmarks in AD, including synaptic function and loss of connectivity in the early stages of AD, before cognitive and behavioural symptoms are observable. These techniques include the detection of specific biomarkers in the cerebrospinal fluid, as well as imaging procedures such as fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid PET, structural/functional magnetic resonance imaging, diffusion tensor imaging, magnetoencephalography (MEG) and electroencephalography (EEG). Such techniques can provide new insights into the functional and structural changes in the brain over time, and may therefore help to develop more effective AD therapies. In particular, nutritional intervention studies that target synapse formation and function may benefit from these techniques, especially FDG-PET and EEG/MEG employed in the preclinical or early stages of the disease.

Can nutrients prevent or delay onset of Alzheimer's disease?

Age-related changes in nutritional status can play an important role in brain functioning. Specific nutrient deficiencies in the elderly, including omega-3 fatty acids, B-vitamins, and antioxidants among others, may exacerbate pathological processes in the brain. Consequently, the potential of nutritional intervention to prevent or delay cognitive impairment and the development of Alzheimer's disease (AD) is a topic of growing scientific interest. This review summarizes epidemiological studies linking specific nutritional deficiencies to mild cognitive impairment (MCI), as well as completed and ongoing nutritional studies in prevention of MCI and AD. Processes that underlie AD pathogenesis include: membrane/synaptic degeneration, abnormal protein processing (amyloid-beta, tau), vascular risk factors (hypertension, hypercholesterolemia), inflammation, and oxidative stress. Consideration of mechanistic evidence to date suggests that several nutritional components can effectively counteract these processes, e.g., by promoting membrane formation and synaptogenesis, enhancing memory/behavior, improving endothelial function, and cerebrovascular health. The literature reinforces the need for early intervention in AD and suggests that multi-nutritional intervention, targeting multiple aspects of the neurodegenerative process during the earliest possible phase in the development of the disease, is likely to have the greatest therapeutic potential.

Reduced life expectancy in rats after neonatal dexamethasone treatment.

The glucocorticoid dexamethasone (Dex) is widely used in preterm infants for the prevention of chronic lung disease. However, major concern has arisen about the long-term sequelae of this therapy. Here we report that neonatal treatment with dexamethasone significantly shortens the lifespan by 25% of male rats (28.6 +/- 1.1 to 21.3 +/- 0.8 mo) and by 18% of female rats (26.9 +/- 1.8 to 22.0 +/- 0.7 mo). Histopathological examination indicated end-stage cardiac and renal failure as the cause of premature death. Furthermore, Dex-treated rats showed symptoms of hypertension at young adult age, which worsened with increasing age. Thus, a brief period of glucocorticoid treatment during early life results in untimely death presumably due to cardiovascular and renal disease later in life. These serious, adverse long-term consequences call for prudence with glucocorticoid treatment of human preterm infants and careful follow-up of young adults with a history of neonatal glucocorticoid treatment.

Suppression of physiological cardiomyocyte proliferation in the rat pup after neonatal glucocorticosteroid treatment.

BACKGROUND: Glucocorticosteroids (mostly dexamethasone) are widely used to prevent chronic lung disease in premature infants. Neonatal rats treated with dexamethasone have been shown to have reduced cardiac mass and cardiomyocyte hypertrophy, suggesting a lower number of cardiomyocytes at adult age, and a severely reduced life expectancy. In the present study we tested the hypothesis that a lower number of cardiomyocytes in later life is caused by a reduced cardiomyocyte proliferation and/or by early cell death (apoptosis). METHODS AND RESULTS: Rat pups received dexamethasone or saline control on day 1, 2 and 3 and were sacrificed at day 0, 2, 4, 7 and 21. The cardiomyocytes of dexamethasone treated pups showed a reduced proliferation as indicated by a lower mitotic index and reduced number of Ki-67 positive cardiomyocytes on day 2 and 4 as compared to day 0 and day 7 and also as compared to the age-matched saline pups. On day 7 and day 21 the mitotic index was not different between groups. From day 2 onward up to day 21 dexamethasone treated pups showed a lower number of cardiomyocytes. The cardiomyocytes showed no signs (<<1%) of apoptosis (Caspase-3 and cleaved-PARP) in any group. CONCLUSION: The temporary suppression of cardiomyocyte hyperplasia found in dexamethasone treated pups eventually leads to a reduced number and hypertrophy of cardiomyocytes during adult life.

Enhanced glucocorticoid feedback inhibition of hypothalamo-pituitary-adrenal responses to stress in adult rats neonatally treated with dexamethasone.

We studied the long-term effect of neonatal treatment with the synthetic glucocorticoid dexamethasone (DEX) on stress responsivity later in life. It was found that the plasma adrenocorticotropin hormone (ACTH) and corticosterone (CORT) responses induced by novelty or conditioned fear stress were markedly attenuated in adult rats that had been neonatally treated with DEX as compared with saline (SAL)-treated controls. Since there were no differences in the heart rate, body temperature, plasma noradrenaline, plasma adrenaline and behavioral responses to these stressors, this points to a deficit within the hypothalamic-pituitary-adrenal (HPA) axis of DEX rats. We found no differences between DEX and SAL rats in basal plasma CORT concentrations measured throughout the circadian cycle, nor in the fraction unbound of CORT circulating under resting conditions, indicating normal tonic regulation of the HPA axis in DEX rats. Since we also found no differences in the hormonal responses induced by intravenous injection of graded doses of ACTH or corticotropin-releasing hormone (CRH), we investigated the sensitivity of the HPA response to stress for inhibition by glucocorticoids. Pretreatment with a low dose of CORT that did not affect the HPA response of SAL rats markedly inhibited the ACTH and CORT responses induced by novelty stress in DEX rats. This strongly suggests that an enhanced corticosteroid feedback underlies the blunted HPA response to stress in DEX rats. Finally, using quantitative immunocytochemistry, we found an increase in arginine-vasopressin (AVP) but not CRH stores in the external zone of the median eminence, suggesting an altered AVP/CRH ratio in the secretory output of the hypophysiotropic paraventricular nucleus. Taken together, our results show that exposure to DEX during early life leads to hyporesponsivity of the HPA axis to stress most likely due to hypersensitivity of the axis for negative feedback by corticosteroids at the suprapituitary level.

Alterations in adult rat heart after neonatal dexamethasone therapy.

Glucocorticoid treatment in preterm babies to prevent chronic lung disease causes myocardial hypertrophy and increased myocardial protein content. Although these changes are thought to be transient, there is evidence that dexamethasone (DEX) induces permanent myocardial abnormalities as well. We investigated whether a therapeutic course of neonatal DEX in rat pups produces anatomic and biochemical alterations in rat hearts during adult life. Twenty-four rat pups were treated with DEX on d 1, 2, and 3 (0.5, 0.3, and 0.1 micro g/g) of life, with doses proportional to those used in preterm babies. Twenty-four control pups were treated with saline. At d 7, wk 8, or wk 45 (n = 8 per group) rats were killed. The anatomic parameters measured were body weight (Bw, in grams), heart (myocardial) weight (Hw, in milligrams), and the Hw:Bw ratio. Myocardial total protein (Prot) and DNA content were determined, and the Prot:DNA ratio was calculated. Histopathology and morphometry were performed on 45-wk-old rat hearts. In DEX-treated rat pups, at d 7, Bw and Hw were lower and the Hw:Bw ratio was increased. DNA content was lower, Prot higher, and Prot:DNA ratio was increased. In 8-wk-old rats Bw, Hw, DNA content, Prot content or Prot:DNA ratio did not differ between groups, but the Prot:DNA ratio still tended to be higher in DEX-treated rats. In 45-wk-old rats Hw and Hw:Bw ratio were significantly lower and Prot:DNA ratio higher in DEX-treated rats. Histopathologic analysis showed larger cardiomyocyte volume, length, and width, indicating hypertrophy, and increased collagen, indicating early degeneration of individual myocytes. In conclusion, neonatal DEX treatment in rat pups causes a permanent decrease in heart weight, as well as hypertrophy and early degeneration of cardiomyocytes during adulthood.