Long-term dietary intervention with low Phe and/or a specific nutrient combination improve certain aspects of brain functioning in phenylketonuria (PKU)

Introduction In phenylketonuria (PKU), a gene mutation in the phenylalanine metabolic pathway causes accumulation of phenylalanine (Phe) in blood and brain. Although early introduction of a Phe-restricted diet can prevent severe symptoms from developing, patients who are diagnosed and treated early still experience deficits in cognitive functioning indicating shortcomings of current treatment. In the search for new and/or additional treatment strategies, a specific nutrient combination (SNC) was postulated to improve brain function in PKU. In this study, a long-term dietary intervention with a low-Phe diet, a specific combination of nutrients designed to improve brain function, or both concepts together was investigated in male and female BTBR PKU and WT mice. Material & methods 48 homozygous wild-types (WT, +/+) and 96 PKU BTBRPah2 (-/-) male and female mice received dietary interventions from postnatal day 31 till 10 months of age and were distributed in the following six groups: high Phe diet (WT C-HP, PKU C-HP), high Phe plus specific nutrient combination (WT SNC-HP, PKU SNC-HP), PKU low-Phe diet (PKU C-LP), and PKU low-Phe diet plus specific nutrient combination (PKU SNC- LP). Memory and motor function were tested at time points 3, 6, and 9 months after treatment initiation in the open field (OF), novel object recognition test (NOR), spatial object recognition test (SOR), and the balance beam (BB). At the end of the experiments, brain neurotransmitter concentrations were determined. Results In the NOR, we found that PKU mice, despite being subjected to high Phe conditions, could master the task on all three time points when supplemented with SNC. Under low Phe conditions, PKU mice on control diet could master the NOR at all three time points, while PKU mice on the SNC supplemented diet could master the task at time points 6 and 9 months. SNC supplementation did not consistently influence the performance in the OF, SOR or BB in PKU mice. The low Phe diet was able to normalize concentrations of norepinephrine and serotonin; however, these neurotransmitters were not influenced by SNC supplementation. Conclusion This study demonstrates that both a long-lasting low Phe diet, the diet enriched with SNC, as well as the combined diet was able to ameliorate some, but not all of these PKU-induced abnormalities. Specifically, this study is the first long-term intervention study in BTBR PKU mice that shows that SNC supplementation can specifically improve novel object recognition

Reducing the Effects of Aging on Cognition with Therapeutic Intervention of an Oral multi‐Nutrient combination (REACTION): Study Design and Baseline Results

Background Alzheimer’s Disease (AD) is the most common cause of dementia, and the risk of developing AD increases with age. Age‐related cognitive decline (ARCD) refers to the cognitive changes that can occur in individuals because of aging. Research suggests that the underlying mechanism behind ARCD is a loss of synaptic plasticity and altered dendritic spine morphology. Similarly, the cognitive changes in AD are also thought to arise from impaired synaptic plasticity and dendritic spine loss. Souvenaid, contains a specific combination of precursors and cofactors for phospholipid biosynthesis, and has shown beneficial effects on memory, cognition, and brain atrophy in prodromal AD. In addition, data from this previous study imply a stronger effect would be expected in participants at earlier stages of prodromal AD. To test the effect of Souvenaid in ARCD, the REACTION (Reducing the Effects of Aging on Cognition with Therapeutic Intervention of an Oral multi‐Nutrient combination) pilot study was developed. Method REACTION1 is a 6‐month single‐center randomized, double‐blind placebo‐controlled pilot clinical trial. The study factors in local COVID‐19 restrictions and is conducted fully virtually. Participants will be aged 55‐89 with ARCD, and screened and randomized to the oral multi‐nutrient combination (Souvenaid) or placebo on a 1:1 basis. The main outcome of this trial is feasibility (recruitment rate and time, adherence rate and retention rate). Other outcomes include memory (e.g. Ray Verbal Learning Task), cognition (e.g. Oral Trail Making Test), and quality of life (e.g. Amsterdam IADL Questionnaire) outcome measures. Result Of 141 inquiries over 7 months, 60 eligible participants were recruited. 54 were successfully screened for randomization. As of 3 Feb 2022, 47 participants have been randomized to placebo or Souvenaid (6 are awaiting randomization, 1 withdrew prior to randomization.) Detailed baseline characteristics of the study population will be presented at the meeting, including descriptive statistics on demographics and the inclusion criteria such as the RBANS, MoCA and SCD 9‐item brief screening tool score. Conclusion With the rapidly growing prevalence of ARCD and limited pharmacological curative treatment options currently available, nutritional interventions may potentially play an important role to prevent or delay the onset of ARCD. 1. Clinicaltrial.gov identifier: NCT0414762

Replication Data for: Long-term dietary intervention with low Phe and/or a specific nutrient combination improve certain aspects of brain functioning in Phenylketonuria (PKU)

48 Homozygous wild-types (WT, +/+) and 96 PKU BTBRPah2 (-/-) male and female mice started dietary treatment on postnatal day 31 up to 10 months of age in the following six groups: WT control diet (WT C-HP), WT normal diet plus specific nutrient combination (WT SNC-HP), PKU normal diet (PKU C-HP), PKU normal diet plus specific nutrient combination (PKU SNC-HP), PKU low-Phe diet (PKU C-LP), and PKU low-Phe diet plus specific nutrient combination (PKU SNC-LP). Mice were tested three times (4,7, and 10 months) after treatment initiation during four behavioural tasks: open field (OF), novel object recognition task (NOR), spatial object recognition task (SOR), and balance beam task (BB). The results are stored in three zipped folders: Measurements.zip: Excel files with the results of the various behavioral tasks at 4, 7 and 10 months of age StatisticalAnalyses.zip: SPSS files (.sav) of the various behavioral tasks Neurotransmitters: Results and statistical analysis of the various neurotransmitter levels per mouse </ul

Replication Data for: Long-term dietary intervention with low Phe and/or a specific nutrient combination improve certain aspects of brain functioning in Phenylketonuria (PKU)

48 Homozygous wild-types (WT, +/+) and 96 PKU BTBRPah2 (-/-) male and female mice started dietary treatment on postnatal day 31 up to 10 months of age in the following six groups: WT control diet (WT C-HP), WT normal diet plus specific nutrient combination (WT SNC-HP), PKU normal diet (PKU C-HP), PKU normal diet plus specific nutrient combination (PKU SNC-HP), PKU low-Phe diet (PKU C-LP), and PKU low-Phe diet plus specific nutrient combination (PKU SNC-LP). Mice were tested three times (4,7, and 10 months) after treatment initiation during four behavioural tasks: open field (OF), novel object recognition task (NOR), spatial object recognition task (SOR), and balance beam task (BB). The results are stored in three zipped folders: Measurements.zip: Excel files with the results of the various behavioral tasks at 4, 7 and 10 months of age StatisticalAnalyses.zip: SPSS files (.sav) of the various behavioral tasks Neurotransmitters: Results and statistical analysis of the various neurotransmitter levels per mouse </ul

Nutritional Supplementation Reduces Lesion Size and Neuroinflammation in a Sex-Dependent Manner in a Mouse Model of Perinatal Hypoxic-Ischemic Brain Injury

Perinatal hypoxia-ischemia (HI) is a major cause of neonatal brain injury, leading to long-term neurological impairments. Medical nutrition can be rapidly implemented in the clinic, making it a viable intervention to improve neurodevelopment after injury. The omega-3 (n-3) fatty acids docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3), uridine monophosphate (UMP) and choline have previously been shown in rodents to synergistically enhance brain phospholipids, synaptic components and cognitive performance. The objective of this study was to test the efficacy of an experimental diet containing DHA, EPA, UMP, choline, iodide, zinc, and vitamin B12 in a mouse model of perinatal HI. Male and female C57Bl/6 mice received the experimental diet or an isocaloric control diet from birth. Hypoxic ischemic encephalopathy was induced on postnatal day 9 by ligation of the right common carotid artery and systemic hypoxia. To assess the effects of the experimental diet on long-term motor and cognitive outcome, mice were subjected to a behavioral test battery. Lesion size, neuroinflammation, brain fatty acids and phospholipids were analyzed at 15 weeks after HI. The experimental diet reduced lesion size and neuroinflammation specifically in males. In both sexes, brain n-3 fatty acids were increased after receiving the experimental diet. The experimental diet also improved novel object recognition, but no significant effects on motor performance were observed. Current data indicates that early life nutritional supplementation with a combination of DHA, EPA, UMP, choline, iodide, zinc, and vitamin B12 may provide neuroprotection after perinatal HI

Juvenile Antioxidant Treatment Prevents Adult Deficits in a Developmental Model of Schizophrenia

SummaryAbnormal development can lead to deficits in adult brain function, a trajectory likely underlying adolescent-onset psychiatric conditions such as schizophrenia. Developmental manipulations yielding adult deficits in rodents provide an opportunity to explore mechanisms involved in a delayed emergence of anomalies driven by developmental alterations. Here we assessed whether oxidative stress during presymptomatic stages causes adult anomalies in rats with a neonatal ventral hippocampal lesion, a developmental rodent model useful for schizophrenia research. Juvenile and adolescent treatment with the antioxidant N-acetyl cysteine prevented the reduction of prefrontal parvalbumin interneuron activity observed in this model, as well as electrophysiological and behavioral deficits relevant to schizophrenia. Adolescent treatment with the glutathione peroxidase mimic ebselen also reversed behavioral deficits in this animal model. These findings suggest that presymptomatic oxidative stress yields abnormal adult brain function in a developmentally compromised brain, and highlight redox modulation as a potential target for early intervention