Effect of a four-week oral Phe administration on neural activation and cerebral blood flow in adults with early-treated phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) is a rare inborn error of metabolism characterized by impaired catabolism of the amino acid phenylalanine (Phe) into tyrosine. Cross-sectional studies suggest slight alterations in cognitive performance and neural activation in adults with early-treated PKU. The influence of high Phe levels on brain function in adulthood, however, remains insufficiently studied. Therefore, we aimed to explore the effect of a four-week period of oral Phe administration - simulating a controlled discontinuation of Phe restriction and raising Phe to an off-diet scenario - on working memory-related neural activation and cerebral blood flow (CBF). METHODS: We conducted a randomized, placebo-controlled, double-blind, crossover, non-inferiority trial to assess the effect of a high Phe load on working memory-related neural activation and CBF in early-treated adults with classical PKU. Twenty-seven patients with early-treated classical PKU were included and underwent functional magnetic resonance imaging (fMRI) of the working memory network and arterial spin labeling (ASL) MRI to assess CBF before and after a four-week intervention with Phe and placebo. At each of the four study visits, fMRI working memory task performance (reaction time and accuracy) and plasma Phe, tyrosine, and tryptophan levels were obtained. Additionally, cerebral Phe was determined by 1H-MR spectroscopy. RESULTS: Plasma Phe and cerebral Phe were significantly increased after the Phe intervention. However, no significant effect of Phe compared to placebo was found on neural activation and CBF. Regarding fMRI task performance, a significant impact of the Phe intervention on 1-back reaction time was observed with slower reaction times following the Phe intervention, whereas 3-back reaction time and accuracy did not differ following the Phe intervention compared to the placebo intervention. CONCLUSION: Results from this present trial simulating a four-week discontinuation of the Phe-restricted diet showed that a high Phe load did not uniformly affect neural markers and cognition in a statistically significant manner. These results further contribute to the discussion on safe Phe levels during adulthood and suggest that a four-week discontinuation of Phe-restricted diet does not demonstrate significant changes in brain function.

Effect of Genetic Risk on the Relationship Between rs-fMRI Complexity and Tau and Amyloid PET in Alzheimer's Disease.

Reduced functional magnetic resonance imaging (fMRI)-complexity in Alzheimer's disease (AD) progression has been demonstrated and found to be associated with tauopathy and cognition. However, association of fMRI-complexity with amyloid and influence of genetic risk (APOEɛ4) remain unknown. Here we investigate the association between fMRI-complexity, tau-PET, and amyloid-PET as well as influence of APOE genotype using multivariate generalized linear models. We show that fMRI-complexity has a strong association with tau but not amyloid deposition and that the presence of an APOEɛ4 allele enhances this effect. Thus fMRI-complexity provides a surrogate marker of impaired brain functionality in AD progression.

Cerebral blood flow and white matter alterations in adults with phenylketonuria.

BACKGROUND: Phenylketonuria (PKU) represents a congenital metabolic defect that disrupts the process of converting phenylalanine (Phe) into tyrosine. Earlier investigations have revealed diminished cognitive performance and changes in brain structure and function (including the presence of white matter lesions) among individuals affected by PKU. However, there exists limited understanding regarding cerebral blood flow (CBF) and its potential associations with cognition, white matter lesions, and metabolic parameters in patients with PKU, which we therefore aimed to investigate in this study. METHOD: Arterial spin labeling perfusion MRI was performed to measure CBF in 30 adults with early-treated classical PKU (median age 35.5 years) and 59 healthy controls (median age 30.0 years). For all participants, brain Phe levels were measured with 1H spectroscopy, and white matter lesions were rated by two neuroradiologists on T2 weighted images. White matter integrity was examined with diffusion tensor imaging (DTI). For patients only, concurrent plasma Phe levels were assessed after an overnight fasting period. Furthermore, past Phe levels were collected to estimate historical metabolic control. On the day of the MRI, each participant underwent a cognitive assessment measuring IQ and performance in executive functions, attention, and processing speed. RESULTS: No significant group difference was observed in global CBF between patients and controls (F (1, 87) = 3.81, p = 0.054). Investigating CBF on the level of cerebral arterial territories, reduced CBF was observed in the left middle and posterior cerebral artery (MCA and PCA), with the most prominent reduction of CBF in the anterior subdivision of the MCA (F (1, 87) = 6.15, p = 0.015, surviving FDR correction). White matter lesions in patients were associated with cerebral blood flow reduction in the affected structure. Particularly, patients with lesions in the occipital lobe showed significant CBF reductions in the left PCA (U = 352, p = 0.013, surviving FDR correction). Additionally, axial diffusivity measured with DTI was positively associated with CBF in the ACA and PCA (surviving FDR correction). Cerebral blood flow did not correlate with cognitive performance or metabolic parameters. CONCLUSION: The relationship between cerebral blood flow and white matter indicates a complex interplay between vascular health and white matter alterations in patients with PKU. It highlights the importance of considering a multifactorial model when investigating the impact of PKU on the brain.

Mechanical bidomain model of cardiac muscle with unequal anisotropy ratios.

The properties of cardiac muscle are anisotropic, and the degree of anisotropy may be different in the intracellular and extracellular spaces. In the electrical bidomain model, such "unequal anisotropy ratios" of the conductivity lead to unanticipated behavior. In the mechanical bidomain model, unequal anisotropy ratios of the mechanical moduli might also result in unanticipated behavior. In this study, mathematical modeling based on the mechanical bidomain model is used to calculate the distribution of mechanotransduction in cardiac tissue when it is stretched. This analysis demonstrates that unexpected phenomena arise when the mechanical anisotropy ratios are unequal.