The use of a low phenylalanine diet in response to the challenging behaviour of a man with untreated phenylketonuria and profound learning disabilities

If phenylketonuria (PKU) is not treated from an early age with a reduced phenylalanine diet, irreversible brain damage may occur. Although dietary intervention can do nothing to alter this impairment once it occurs, there is some evidence to suggest that a low phenylalanine diet may help to reduce the level of behavioural disturbances frequently experienced by people with untreated PKU. Using this evidence, dietary intervention was used in response to the challenging behaviour of a 30-year-old man with profound learning disabilities. Initial improvements were observed, but overall the results were inconclusive. Possible confounding factors are discussed. An unusual reaction to neuroleptic medication whilst on the diet is also documented.     

Maternal dietary zinc supplementation prevents aberrant behaviour in an object recognition task in mice offspring exposed to LPS in early pregnancy

Maternal infection during pregnancy is associated with an increased risk of neurodevelopmental damage. While the mechanism is unclear accumulating evidence suggests that the maternal inflammatory response may be responsible. Metallothionein (MT) is a zinc (Zn)-binding protein that when induced in the mother's liver during the acute phase response has been found to cause a fetal Zn deficiency. Infection-mediated fetal Zn deficiency in early pregnancy has been shown to cause teratogenicity which can be prevented by dietary Zn supplementation throughout pregnancy. This study examined whether cognitive impairments can be caused by lipopolysaccharide (LPS) administration early in pregnancy and whether dietary Zn supplementation can ameliorate these changes. Maternal inflammation induced by LPS at gestation day (GD) 8 did not affect spatial learning or memory of adult mice offspring in a water cross-maze escape task. However, in an object recognition task, where control mice demonstrated good visual recognition memory by exploring a novel object more than a familiar object, LPS-treated offspring demonstrated abnormal perseverant exploration towards the familiar object that cannot be explained in full by impaired object recognition memory. In comparison, offspring of mice from dams given LPS and dietary Zn supplementation displayed normal object recognition task performance. Microarray analysis on the brain of GD 12 fetuses did not identify any differentially expressed genes between treatment groups. This study demonstrates that LPS administration in early pregnancy can cause an anomaly in object recognition that can be measured in adult offspring. This aberrant behaviour can be prevented by dietary Zn supplementation during pregnancy, thus providing a nutritional strategy to limit neurodevelopmental damage caused by infections early in pregnancy.     

Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia

Schizophrenia is associated with a broad range of neurodevelopmental, structural and behavioral abnormalities that often progress with or without treatment. Evidence indicates that such neurodevelopmental abnormalities may result from defective genes and/or non-genetic factors such as pre-natal and neonatal infections, birth complications, famines, maternal malnutrition, drug and alcohol abuse, season of birth, sex, birth order and life style. Experimentally, these factors have been found to cause the cellular metabolic stress that often results in oxidative stress, such as increased cellular levels of reactive oxygen species (ROS) over the antioxidant capacity. This can trigger the oxidative cell damage (i.e., DNA breaks, protein inactivation, altered gene expression, loss of membrane lipid-bound essential polyunsaturated fatty acids [EPUFAs] and often apoptosis) contributing to abnormal neural growth and differentiation. The brain is preferentially susceptible to oxidative damage since it is under very high oxygen tension and highly enriched in ROS susceptible proteins, lipids and poor DNA repair. Evidence is increasing for increased oxidative stress and cell damage in schizophrenia. Furthermore, treatments with some anti-psychotics together with the lifestyle and dietary patterns, that are pro-oxidant, can exacerbate the oxidative cell damage and trigger progression of neuropathology. Therefore, adjunctive use of dietary antioxidants and EPUFAs, which are known to regulate the growth factors and neuroplasticity, can effectively improve the clinical outcome. The dietary supplementation of either antioxidants or EPUFAs, particularly omega-3 has already been found to improve some psychopathologies. However, a combination of antioxidants and omega-3 EPUFAs, particularly in the early stages of illness, when brain has high degree of neuroplasticity, potentially may be even more effective for long-term improved clinical outcome of schizophrenia.     

Prevention of oxidative stress-mediated neuropathology and improved clinical outcome by adjunctive use of a combination of antioxidants and omega-3 fatty acids in schizophrenia

Summary

Schizophrenia is associated with a broad range of neurodevelopmental, structural and behavioral abnormalities that often progress with or without treatment. Evidence indicates that such neurodevelopmental abnormalities may result from defective genes and/or non-genetic factors such as pre-natal and neonatal infections, birth complications, famines, maternal malnutrition, drug and alcohol abuse, season of birth, sex, birth order and life style. Experimentally, these factors have been found to cause the cellular metabolic stress that often results in oxidative stress, such as increased cellular levels of reactive oxygen species (ROS) over the antioxidant capacity. This can trigger the oxidative cell damage (i.e., DNA breaks, protein inactivation, altered gene expression, loss of membrane lipid-bound essential polyunsaturated fatty acids [EPUFAs] and often apoptosis) contributing to abnormal neural growth and differentiation. The brain is preferentially susceptible to oxidative damage since it is under very high oxygen tension and highly enriched in ROS susceptible proteins, lipids and poor DNA repair. Evidence is increasing for increased oxidative stress and cell damage in schizophrenia. Furthermore, treatments with some anti-psychotics together with the lifestyle and dietary patterns, that are pro-oxidant, can exacerbate the oxidative cell damage and trigger progression of neuropathology. Therefore, adjunctive use of dietary antioxidants and EPUFAs, which are known to regulate the growth factors and neuroplasticity, can effectively improve the clinical outcome. The dietary supplementation of either antioxidants or EPUFAs, particularly omega-3 has already been found to improve some psychopathologies. However, a combination of antioxidants and omega-3 EPUFAs, particularly in the early stages of illness, when brain has high degree of neuroplasticity, potentially may be even more effective for long-term improved clinical outcome of schizophrenia.     

Qualitative analysis of feeding behaviour through dietary selection of nutrients

Studies of brain mechanisms controlling food intake and feeding behaviour have often neglected interactions between total food (energy) intake and qualitative aspects of the dietary intake. Generally, experimental animals are presented with a single diet of fixed nutritional composition. Thus, if as a result of a given treatment, an animal has an increased or decreased appetite for a specific nutrient, then this could manifest itself as an increase or decrease in intake from the sole diet offered. As selection of food is a characteristic behaviour of all animals, and their ability to monitor intake of specific nutrients is well known, then, giving experimental animals a choice of dietary constituents could result in a wider understanding of central mechanisms governing food intake. Exploiting the ability of rats to select dietary protein and carbohydrate has suggested that brain 5-hydroxytryptamine (5-HT) is involved in the regulation of protein/carbohydrate intake. Evidence from human studies suggests that appetite disturbances which occur in obese and mood-disturbed individuals may be linked to an impaired functioning of the brain 5-HT system.     

Barbiturates in the treatment of epilepsy in people with intellectual disability

Barbiturates are effective drugs in the treatment of epileptic disorder. The systemic side-effects are minimal. The main limiting factor is the presence of cognitive and behavioural problems. Relevant research is presented in this paper; however, it is somewhat difficult to extrapolate some of these experiences to a population of children and adults with intellectual disability and epilepsy. Recent reviews of this subject have suggested that, although the cognitive deficiencies seem to be a serious problem when phenobarbital is given in high doses, the problem is much less severe when the doses are on the low side. The most consistent findings with regard to behaviour are the exacerbation of behaviour disorders (mostly hyperactivity), as well as sleep disorders and depression in individuals who already have a predisposition to these disorders. However, the clinical experience of many professionals involved with the care of people with intellectual disability strongly suggests that barbiturates, and especially phenobarbital, produces intolerable side-effects at the point that the use of phenobarbital has been reduced to a minimum, and it is no longer considered a drug of choice. It is probably that the simultaneous presence of brain damage, epilepsy, intellectual disability and psychiatric disorders in people with intellectual disability is responsible for the high incidence of behaviour problems observed by clinicians.     

Two subjects, each with a brain lesion and each prone to criminal behaviour: a plea for the involvement of a behavioural neurologist in the forensic psychiatric evaluation of such cases

Interest in the neurobiology of criminal behaviour is increasing. Recent research emphasises the important role played by the frontal lobe in the processing of emotional and social information and in the controlling of behaviour. Damage to specific frontal structures in the brain may therefore lead to antisocial and criminal behaviour. On the basis of the case histories of two suspects with brain lesions, the impact of such damage on the forensic psychiatric diagnosis is discussed. A plea is made for the more frequent involvement of a neurologist in the diagnostic evaluation usually undertaken by the forensic psychiatrist.     

Therapeutic potential of vitamin E and its derivatives in traumatic brain injury-associated dementia

Traumatic brain injury is one of the most common causes for intervention in neurosurgery. Apart from its acute consequence, it can represent a further burden on individuals as well as society by being associated with significant comorbidity—mainly early-onset dementia. Oxidative stress is one of the crucial mechanisms conferring the damage to nervous tissue, and it is believed it could be, to some extent, influenced by dietary composition, largely by antioxidants contained in the diet. Under stressful conditions, cell-derived reactive oxygen species in the brain can induce the formation of lipid peroxides and the shifting of redox homeostasis. This review discusses the potential of vitamin E as a potent antioxidant and its derived molecules, including vitamin E-based lazaroids, in traumatic brain injury, summarizing the current state of knowledge of its role in TBI-associated dementia.     

Neurodevelopmental theories of schizophrenia--preclinical studies

Schizophrenia is a complex disorder of unknown origin, characterised by abnormalities in the realms of perception, thinking and the experience of emotions that onset is restricted to young adulthood. Many techniques that range from neuropathology to neuroimaging identified subtle brain abnormalities particularly in frontal, temporal cortex, hippocampus, basal ganglia and cerebellum. Neurodevelopmental models of schizophrenia test hypotheses that this disease is caused by a defect in cerebral development which results in altered neural connectivity, brain neurochemistry and aberrant behaviour observed in adult life. Recent evidence indicates that neonatal hippocampal damage may affect prefrontal neuronal integrity. The developmental lesion model appears to have predictive validity because treatment with antipsychotic drugs normalises some abnormal behaviour changes. Therefore it will be a useful paradigm in the work on new therapies and in providing new insights about pathophysiology and etiology of schizophrenia.     

Oestradiol Differentially Influences Feeding Behaviour Depending on Diet Composition in Female Rhesus Monkeys

In females, cyclical changes in the ovarian hormone oestradiol are known to modulate feeding behaviour. However, what is less clear is how these behavioural effects of oestradiol are modified by the macronutrient content of a diet. In the present study, we report data showing that oestradiol treatment results in both significantly smaller meals and a reduced total calorie intake in ovariectomised, socially-housed female rhesus macaques when only chow diet is available. Conversely, during a choice dietary condition where both palatable and chow options are available, oestradiol treatment had no observable, attenuating effect on calorie intake. During this choice dietary phase, all animals consumed more of the palatable diet than chow diet; however, oestradiol treatment appeared to further increase preference for the palatable diet. Finally, oestradiol treatment increased snacking behaviour (i.e. the consumption of calories outside of empirically defined meals), regardless of diet condition. These findings illustrate how oestradiol differentially influences feeding behaviour depending on the dietary environment and provides a framework in which we can begin to examine the mechanisms underlying these observed changes.     

Effects of Dietary Supplementation with N-Acetyl Cysteine, Acetyl-l-Carnitine and S-Adenosyl Methionine on Cognitive Performance and Aggression in Normal Mice and Mice Expressing Human ApoE4

In addition to cognitive impairment, behavioral changes such as aggressive behavior, depression, and psychosis accompany Alzheimer’s Disease. Such symptoms may arise due to imbalances in neurotransmitters rather than overt neurodegeneration. Herein, we demonstrate that combined administration of N-acetyl cysteine (an antioxidant and glutathione precursor that protects against Abeta neurotoxicity), acetyl-l-carnitine (which raises ATP levels, protects mitochondria, and buffers Abeta neurotoxicity), and S-adenosylmethionine (which facilitates glutathione usage and maintains acetylcholine levels) enhanced or maintain cognitive function, and attenuated or prevented aggression, in mouse models of aging and neurodegeneration. Enhancement of cognitive function was rapidly reversed upon withdrawal of the formulation and restored following additional rounds supplementation. Behavioral abnormalities correlated with a decline in acetylcholine, which was also prevented by this nutriceutical combination, suggesting that neurotransmitter imbalance may contribute to their manifestation. Treatment with this nutriceutical combination was able to compensate for lack of dietary folate and vitamin E, coupled with administration of dietary iron as a pro-oxidant (which collectively increase homocysteine and oxidative damage to brain tissue), indicating that it provided antioxidant neuroprotection. Maintenance of neurotransmitter levels and prevention of oxidative damage underscore the efficacy of a therapeutic approach that utilizes a combination of neuroprotective agents. An erratum to this article can be found at     

Frontal syndrome as a consequence of lesions in the pedunculopontine tegmental nucleus: a short theoretical review

In this review, it is argued that the consequence of bilateral damage to the pedunculopontine tegmental nucleus (PPTg) in experimental animals is the production of a form of frontal syndrome. Frontal syndrome is a term used to describe the behavioural consequences of damage to the frontal lobes in human patients. These behavioural changes can be classified as disinhibition of behaviour (a release of behavioural control), the production of inappropriate behaviour (which in patients can be either inappropriate actions or verbal behaviour), and the production of perseverative behaviour (the maintenance of an action beyond the point at which it should have been terminated). The psychological changes which underlie these behavioural changes are thought to involve executive functions, which include such things as the prospective planning of sequences of actions, attentional shifting and working memory. In this review, I attempt to demonstrate two things: first, that there are significant anatomical connections from frontostriatal systems to the PPTg. The motor cortex projects directly to the PPTg while the prefrontal cortex contacts it via striatal circuitry, forming clear routes by which the frontal lobes can communicate with the PPTg. Second, having established the existence of connections between frontostriatal systems and the PPTg, behavioural data are described. Experimental animals bearing bilateral lesions of the PPTg have been examined in a wide variety of tasks. Animals bearing such lesions are not impaired in basic processes of feeding, drinking, locomotion, or grooming and simple observation of lesioned rats' normal behaviour reveals no obvious gross impairment in function. However, the results of more subtle tests reveal a wide variety of deficits in various tasks. The outcome of these experiments are in many ways contradictory, but in the vast majority of cases, the changes can be described as involving disinhibition of behaviour, the release of inappropriate behaviour, and the production of perseverative behaviour. Anatomical and behavioural data support the conclusion that there are functional connections between frontal systems and the PPTg. This review also discusses what psychological processes might be served by such connections.     

Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach

Spontaneously hypertensive stroke-prone rats (SHRSP) develop brain abnormalities invariably preceded by the accumulation of acute-phase proteins in body fluids. This study describes the sequence of pathological events, and in particular the involvement of inflammation, at the onset of brain injury in this animal model. In SHRSP subjected to permissive dietary treatment, the appearance of brain damage and of altered permeability of the blood-brain barrier (BBB) was monitored over time by magnetic resonance imaging (MRI) after intravenous injection of gadolinium. The protein content in cerebrospinal fluid and brain extracts was analyzed by two-dimensional electrophoresis. Gadolinium diffusion showed impairment of the BBB after 42 +/- 3 days from the start of salt loading, simultaneously with the detection of brain abnormalities by MRI. Tissue lesions were initially localized at one or more small foci and then spread throughout the brain in the form of fibrinoid necrosis. This type of lesion is characterized by fibrin deposition, in particular around the vessels; loss of tissue texture; and infiltration of macrophages and lymphocytes. High levels of plasma-derived proteins of molecular mass up to >130 kDa were detected in the cerebrospinal fluid after MRI had revealed brain abnormalities. Plasma proteins extravasated from brain vessels were immunodetected in tissue homogenates from affected areas. The results obtained in this study provide new insights into the pathogenesis of the spontaneous brain damage in SHRSP and in particular on the involvement of the inflammatory cascade. These studies may be useful in evaluating new pharmacological strategies aimed at preventing/treating brain diseases.     

Regulation of progestin receptor expression in the developing rat brain by a dopamine d1 receptor antagonist

Steroid receptors within the developing brain influence a variety of cellular processes that endure into adulthood, altering both behaviour and physiology. Therefore, it is important to understand how steroid receptor expression is regulated during early brain development. Most studies indicate that oestradiol, by acting upon oestrogen receptors, increases the expression of progestin receptors in the developing brain. We have recently observed an additional mechanism by which dopamine can increase the expression of progestin receptors in developing female rat brain. That is, we found that a dopamine D1 receptor agonist can further increase progestin receptor expression by activating oestrogen receptors in a ligand-independent manner within restricted areas of female brain; however, it is unclear whether dopamine D1 receptors are involved in the normally occurring expression of progestin receptors in developing male and female brain. To investigate this, we examined whether a dopamine D1 receptor antagonist can disrupt the normal developmental expression of progestin receptors in both male and female rat brain. We report that treatment with a dopamine D1 receptor antagonist reduces progestin receptor expression within some, but not all, regions of the developing rat brain in a sex-specific manner. Some of the current findings also suggest that dopamine might be acting to prevent sex differences in progestin receptor expression in some areas while contributing to a sex difference in other areas.     

Neurophysiologic follow-up of long-term dietary treatment in adult-onset adrenoleukodystrophy

OBJECTIVE: To monitor the effects of dietary treatment in adult-onset adrenoleukodystrophy (ALD) by means of somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs). BACKGROUND: SEPs and MEPs have proved useful in revealing signs of progressively severe, central dying-back axonopathy in early stages of adult-onset ALD. METHODS: Eight patients with adult-onset ALD underwent clinical examination, brain and spine MRI, and SEP and MEP studies before and after 3 years of Lorenzo's oil dietary therapy. RESULTS: Before treatment, brain MRI was normal in five patients. Three of these patients had pure spinal SEP abnormalities and in the remaining two patients SEPs showed signs of involvement of both the spinal and cerebral somatosensory tracts. After treatment, the three patients with pure spinal abnormalities showed clinical and neurophysiologic worsening, whereas the two patients with a more advanced stage of disease (exhibited by SEPs) showed substantially unchanged clinical and neurophysiologic features. The patients with abnormal brain MRI at the onset of treatment showed clinical and neurophysiologic worsening. CONCLUSIONS: Lorenzo's oil therapy had no effect on patients with evidence of inflammatory brain lesions. Moreover, in patients without clear signs of inflammatory damage, this treatment does not modify significantly the natural course of the disease. However, because effective treatments should begin before the onset of severe neurologic symptoms, SEPs and MEPs should be considered to evaluate the effectiveness of other experimental treatments in the patient with a negative brain MRI.     

Vitamin D deficiency during various stages of pregnancy in the rat; its impact on development and behaviour in adult offspring

Developmental vitamin D (DVD) deficiency alters brain development and behaviour in the rat. The aim of this study was to vary levels of vitamin D deficiency during gestation and examine the effects on developmental milestones and behaviour in adult offspring. By manipulating the withdrawal and reintroduction of vitamin D in the diet of female Sprague-Dawley rats, their offspring were subjected to four different prenatal vitamin D conditions: (a) control (normal vitamin D throughout gestation); (b) early-DVD deficiency; (c) late-DVD deficiency; and (d) full-DVD deficiency. We show that the standard measure for vitamin D status, 25(OH)D(3), can be significantly manipulated within 7 days by dietary intervention. We also show that levels of the active form of this vitamin, 1,25(OH)(2)D(3), replete within the same time frame as 25(OH)D(3) but are slower to deplete. Developmental milestones remained normal across all four dietary groups. Concerning the adult behavioural phenotype, both full- and late-DVD deficiency were associated with MK-801-induced hyperlocomotion. Overall, these data suggest that vitamin D deficiency restricted to late gestation only is sufficient to disrupt adult brain functioning in the rat. These findings suggest there may be a therapeutic window for maternal dietary intervention in the DVD model of psychosis.     

Cranial computed tomography in a patient with a variant form of maple syrup urine disease

A male infant, who was suspected to be a case of variant form of maple syrup urine disease (MSUD) has been given dietary treatment since the age of 9 months. Prior to the treatment, computed tomography (CT) showed abnormally high lucidity in the cerebral white matter area with the marked narrowness in size of the frontal horn of lateral ventricles. As the treatment proceeded, clinical symptoms alleviated, and CT findings have gradually changed with the result of improved density of the white matter. 2 months after starting the treatment, however, the patient suddenly developed a hyperaminoacidemic crisis that lasted 4-5 days. Despite this hyperaminoacidemia, CT scan taken during the crisis have revealed unexpectedly normal lucidity of the white matter as well as the normal width of the frontal horn. From these findings it was concluded that markedly lucent area in CT findings prior to the treatment was not due to an acute change in serum aminoacid concentration, but rather to chronic brain edema which had insidiously and gradually developed.     

Is schizophrenia a metabolic brain disorder? Membrane phospholipid dysregulation and its therapeutic implications.

The dysregulation of membrane phospholipid metabolism exists throughout the body from the onset of psychosis in schizophrenic patients. This dysregulation is primarily due to altered contents of phospholipid bound EPUFAs, AA and DHA. These EPUFAs are highly enriched in the brain and are crucial for brain and behavioral development. A phospholipid metabolic defect may preexist the onset of psychosis, even through early embryonic stages. Because these membrane phospholipids play a crucial role in the membrane receptor-mediated signal transduction of several neuro-transmitters and growth factors, their altered metabolism may contribute to the reported abnormal information processing in schizophrenia. Severity of symptoms seems to correlate with the membrane AA and DHA status, which is influenced by patients' dietary intake and lifestyle. Such a metabolic defect can be prevented, however, and some membrane pathology can be corrected by dietary supplementation with a combination of AA and DHA and antioxidants such as vitamins E and C. In schizophrenia, it may be advisable to provide supplementation at the early stages of illness, when brain has a high degree of plasticity. Finally, at this time, supplementation has to be considered as an augmentation of conventional antipsychotic treatment.     

Phenylketonuria in pediatric neurology practice: a series of 146 cases

The neurologic manifestations of patients with phenylketonuria treated at different ages are illustrated in this series of 146 cases, including 9 sib pairs. In addition to well-known findings such as mental retardation, autistic features, microcephaly, and tremor, motor retardation was common and responded promptly to dietary treatment. Hypotonia and diminished reflexes were more frequent findings than hypertonia. Four sib pairs showed divergent features, such as the later-treated sibling having higher function than the early-treated one. Because siblings have a similar genotype and similar environmental and dietary conditions, this observation can be explained by differences in phenylalanine transport to the brain or additional metabolic or perinatal factors influencing the neurologic outcome.