Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria

BackgroundPhenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis.MethodsWe therefore assessed in vivo striatal dopamine D2/3 receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available.ResultsMean D2/3R availability was significantly higher (13%; p = 0.032) in the PKU group (n = 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p < 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p < 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p = 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r = 0.72, p = 0.003) and the error rate during a cognitive flexibility task (r = 0.59, p = 0.020).ConclusionsThese findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.

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A Meta-Analysis of Executive Functions in Frontal Cortex: Comparing Healthy and Neuropsychiatric Groups

10.1101/335109 ◽

2018 ◽

Cited By ~ 1

Author(s):

Abigail B. Waters ◽

Lance P. Swenson ◽

David A. Gansler

Keyword(s):

Executive Functioning ◽

Executive Functions ◽

Effect Size ◽

Adaptive Functioning ◽

Meta Analysis ◽

Neuropsychological Testing ◽

Healthy Controls ◽

Adult Performance ◽

The Relationship

AbstractBackgroundThe neural architecture of executive functions remains a topic of considerable clinical and academic interest in the clinical neurosciences, given its strength as a transdiagnostic predictor of adaptive functioning with high heritability. In recent years, meta-analyses have shown a consistent relationship between prefrontal cortex size and executive functioning task performance in healthy adults and lesion patients, with increases in measures of cortical size (i.e., volume or thickness) associated with better executive functioning performance. There is a gap in meta-analytic literature assessing these relationships in neuropsychiatric populations, their effects relative to healthy controls, and differential contributions of brains regions and neuropsychological paradigms.MethodsWe conducted a meta-analysis of published studies (k =30) that assessed the relationship between executive functions and frontal regions in vivo (N = 1935) for both healthy (20 samples) and neuropsychiatric (21 samples) adults. Random effects modeling was used to calculate mean effect sizes and CIs.ResultsLarger volumes and thickness were associated with better executive functioning in both healthy (r =.35, 95% CI =.29 -.39) and neuropsychiatric populations (r =.47, 95% CI =.40 -.51), with the effect size for neuropsychiatric populations being significantly larger compared to healthy controls. While there was variability between tasks, there were no significant differences in effect size between neuropsychological paradigms or brain region classification.ConclusionsThese results indicate the relationship between healthy adult performance on neuropsychological testing is less associated with cortical size compared to neuropsychiatric adults.

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Increased Thromboxane Biosynthesis in Essential Thrombocythemia

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649916 ◽

1995 ◽

Vol 74 (05) ◽

pp. 1225-1230 ◽

Cited By ~ 71

Author(s):

Bianca Rocca ◽

Giovanni Ciabattoni ◽

Raffaele Tartaglione ◽

Sergio Cortelazzo ◽

Tiziano Barbui ◽

...

Keyword(s):

Platelet Count ◽

Platelet Activation ◽

Essential Thrombocythemia ◽

Therapeutic Strategy ◽

Low Dose ◽

Thrombotic Risk ◽

Dose Aspirin ◽

Gender And Age ◽

Low Dose Aspirin

SummaryIn order to investigate the in vivo thromboxane (TX) biosynthesis in essential thromboeythemia (ET), we measured the urinary exeretion of the major enzymatic metabolites of TXB2, 11-dehydro-TXB2 and 2,3-dinor-TXB2 in 40 ET patients as well as in 26 gender- and age-matched controls. Urinary 11-dehydro-TXB2 was significantly higher (p <0.001) in thrombocythemic patients (4,063 ± 3,408 pg/mg creatinine; mean ± SD) than in controls (504 ± 267 pg/mg creatinine), with 34 patients (85%) having 11-dehydro-TXB2 >2 SD above the control mean. Patients with platelet number <1,000 × 109/1 (n = 25) had significantly higher (p <0.05) 11 -dehydro-TXB2 excretion than patients with higher platelet count (4,765 ± 3,870 pg/mg creatinine, n = 25, versus 2,279 ± 1,874 pg/mg creatinine, n = 15). Average excretion values of patients aging >55 was significantly higher than in the younger group (4,784 ± 3,948 pg/mg creatinine, n = 24, versus 2,405 ± 1,885 pg/mg creatinine, n = 16, p <0.05). Low-dose aspirin (50 mg/d for 7 days) largely suppressed 11-dehydro-TXB2 excretion in 7 thrombocythemic patients, thus suggesting that platelets were the main source of enhanced TXA2 biosynthesis. The platelet count-corrected 11-dehydro-TXB2 excretion was positively correlated with age (r = 0.325, n = 40, p <0.05) and inversely correlated with platelet count (r = -0.381, n = 40, p <0.05). In addition 11 out of 13 (85%) patients having increased count-corrected 11-dehydro-TXB2 excretion, belonged to the subgroup with age >55 and platelet count <1,000 × 1099/1. We conclude that in essential thrombocythemia: 1) enhanced 11-dehydro-TXB2 excretion largely reflects platelet activation in vivo;2) age as well as platelet count appear to influence the determinants of platelet activation in this setting, and can help in assessing the thrombotic risk and therapeutic strategy in individual patients.

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The Prevalence and Maladjustments According to Persistence & Decline of Childhood ADHD and Late-onset of Adulthood ADHD in College Students: Executive Functioning Deficits, Psychopathology and Interpersonal Problems

Korean Journal of Clinical Psychology ◽

10.15842/kjcp.2020.39.2.005 ◽

2020 ◽

Vol 39 (2) ◽

pp. 134-147

Author(s):

Sun Ju Kim ◽

Eun Hye Ha

Keyword(s):

College Students ◽

Executive Functioning ◽

Late Onset ◽

Interpersonal Problems ◽

Childhood Adhd ◽

Executive Functioning Deficits

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Influence of chronotype on daily mood fluctuations: pilot study in patients with depression

BJPsych Open ◽

10.1192/bjo.2019.103 ◽

2020 ◽

Vol 6 (2) ◽

Author(s):

Konstantin F. Brückmann ◽

Jürgen Hennig ◽

Matthias J. Müller ◽

Stanislava Fockenberg ◽

Anne-Marthe Schmidt ◽

...

Keyword(s):

Clinical Trials ◽

Pilot Study ◽

Negative Affect ◽

Clinical Setting ◽

Early Morning ◽

Healthy Controls ◽

Patient Subgroup ◽

Depression Risk ◽

Gender And Age ◽

The Relationship

Summary Depression risk is associated with a late chronotype pattern often described as an ‘evening chronotype’. Fluctuations in mood over consecutive days have not yet been measured according to chronotype in in-patients with depression. A total of 30 in-patients with depression and 32 healthy controls matched for gender and age completed a chronotype questionnaire and twice-daily ratings on mood for 10 consecutive days (registered in the German Clinical Trials Register: DRKS00010215). The in-patients had Saturdays and Sundays as hospital-leave days. The relationship between chronotype and daily mood was mediated by the weekday–weekend schedule with higher levels of negative affect in the evening-chronotype patient subgroup at weekends. Results are discussed with respect to a probably advantageous standardised clinical setting with early morning routines, especially for patients with evening chronotypes.

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Iron accumulation in the oculomotor nerve of the progressive supranuclear palsy brain

Scientific Reports ◽

10.1038/s41598-021-82469-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hansol Lee ◽

Myung Jun Lee ◽

Eun-Joo Kim ◽

Gi Yeong Huh ◽

Jae-Hyeok Lee ◽

...

Keyword(s):

High Resolution ◽

Progressive Supranuclear Palsy ◽

Oculomotor Nerve ◽

Iron Accumulation ◽

Blue Staining ◽

Normal Brain ◽

Myelinated Fiber ◽

Healthy Controls ◽

Icp Ms

AbstractAbnormal iron accumulation around the substantia nigra (SN) is a diagnostic indicator of Parkinsonism. This study aimed to identify iron-related microarchitectural changes around the SN of brains with progressive supranuclear palsy (PSP) via postmortem validations and in vivo magnetic resonance imaging (MRI). 7 T high-resolution MRI was applied to two postmortem brain tissues, from one normal brain and one PSP brain. Histopathological examinations were performed to demonstrate the molecular origin of the high-resolution postmortem MRI findings, by using ferric iron staining, myelin staining, and two-dimensional laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging. In vivo iron-related MRI was performed on five healthy controls, five patients with Parkinson’s disease (PD), and five patients with PSP. In the postmortem examination, excessive iron deposition along the myelinated fiber at the anterior SN and third cranial nerve (oculomotor nerve) fascicles of the PSP brain was verified by LA-ICP-MS. This region corresponded to those with high R2* values and positive susceptibility from quantitative susceptibility mapping (QSM), but was less sensitive in Perls’ Prussian blue staining. In in vivo susceptibility-weighted imaging, hypointense pixels were observed in the region between the SN and red nucleus (RN) in patients with PSP, but not in healthy controls and patients with PD. R2* and QSM values of such region were significantly higher in patients with PSP compared to those in healthy controls and patients with PD as well (vs. healthy control: p = 0.008; vs. PD: p = 0.008). Thus, excessive iron accumulation along the myelinated fibers at the anterior SN and oculomotor nerve fascicles may be a pathological characteristic and crucial MR biomarker in a brain with PSP.

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The Course of AαVal541 as a Proteinase 3 Specific Neo-Epitope after Alpha-1-Antitrypsin Augmentation in Severe Deficient Patients

International Journal of Molecular Sciences ◽

10.3390/ijms22158031 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8031

Author(s):

Iris G. M. Schouten ◽

Richard A. Mumford ◽

Dirk Jan A. R. Moes ◽

Pieter S. Hiemstra ◽

Jan Stolk

Keyword(s):

Plasma Level ◽

Serine Proteases ◽

Population Pharmacokinetic ◽

Proteinase 3 ◽

Healthy Controls ◽

Population Pharmacokinetic Modeling ◽

Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin

In alpha-1-antitrypsin deficiency (AATD), neutrophil serine proteases such as elastase and proteinase 3 (PR3) are insufficiently inhibited. A previous study in AATD patients showed a higher plasma level of the specific PR3-generated fibrinogen-derived peptide AαVal541, compared with healthy controls. Here, we analyzed the course of AαVal541 plasma levels during 4 weeks after a single iv dose of 240 mg/kg AAT in ten patients with genotype Z/Rare or Rare/Rare. To this end, we developed an immunoassay to measure AαVal541 in plasma and applied population pharmacokinetic modeling for AAT. The median AαVal541 plasma level before treatment was 140.2 nM (IQR 51.5–234.8 nM)). In five patients who received AAT for the first time, AαVal541 levels decreased to 20.6 nM (IQR 5.8–88.9 nM), and in five patients who already had received multiple infusions before, it decreased to 26.2 nM (IQR 22.31–35.0 nM). In 9 of 10 patients, AαVal541 levels were reduced to the median level of healthy controls (21.4 nM; IQR 16.7–30.1 nM). At 7–14 days after treatment, AαVal541 levels started to increase again in all patients. Our results show that fibrinopeptide AαVal541 may serve as a biochemical footprint to assess the efficacy of in vivo inhibition of PR3 activity in patients receiving intravenous AAT augmentation therapy.

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