The Role of the Dopamine D1 Receptor in Cognition

The dopamine D1 receptor (DD1R) has been linked to cognitive functioning in various human and animal studies using diverse methods from pharmacological manipulations to brain imaging. Moreover, suboptimal or supraoptimal functioning of the DD1R has been linked to cognitive dysfunction. However, the previous research on this topic has mainly relied on correlational evidence, or the use of drugs that are not selective to the DD1R. Therefore, the current study investigated whether cognitive dysfunction is due to suboptimal functioning of the DD1R. The DD1R mutant rat (Smits et al., 2006) provides an opportunity to examine the role of the DD1R in cognitive functioning. The performance of the DD1R mutant rats was compared to that of littermate control rats (wildtypes). Across five experiments we found tentative evidence to suggest that the DD1R is necessary for normal cognitive ability. First, the DD1R mutant rats were unable to improve their performance when an egocentric strategy was required in the starmaze, using both positive and negative reinforcement. Second, compared to wildtype rats, the DD1R mutants were impaired in learning an allocentric strategy in the starmaze with positive reinforcement when they had been previously trained in an egocentric task. Third, the mutants were unable to improve when an egocentric strategy was required in the Y-maze. Finally, the DD1R mutant rats took longer than the wildtypes to reverse their learning when a baited arm was switched after two weeks of training with a different arm as the baited arm in the T-maze. Despite some of the limitations of the experiments, these initial findings suggest an impairment in cognition. Ideas for future research and applications are discussed

MARC1 variant rs2642438 increases hepatic phosphatidylcholines and decreases severity of non-alcoholic fatty liver disease in humans

Non peer reviewe

The PNPLA3-I148M Variant Confers an Antiatherogenic Lipid Profile in Insulin-resistant Patients

Context: The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat. Objective: To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients. Design: Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR. Setting: Tertiary referral center. Patients: A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49 +/- 9 years, body mass index [BMI] 43.2 +/- 6.8 kg/m(2)), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45 +/- 14 years, BMI 29.7 +/- 5.7 kg/m(2)). Main Outcome Measures: Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition. Results: In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than noncarriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles and their constituents, and increased high-density lipoprotein particles and their constituents, compared with noncarriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese than in the obese cohort. Conclusions: PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.Peer reviewe

Assessment of Lifestyle Factors Helps to Identify Liver Fibrosis Due to Non-Alcoholic Fatty Liver Disease in Obesity

Only some individuals with obesity develop liver fibrosis due to non-alcoholic fatty liver disease (NAFLD-fibrosis). We determined whether detailed assessment of lifestyle factors in addition to physical, biochemical and genetic factors helps in identification of these patients. A total of 100 patients with obesity (mean BMI 40.0 ± 0.6 kg/m2) referred for bariatric surgery at the Helsinki University Hospital underwent a liver biopsy to evaluate liver histology. Physical activity was determined by accelerometer recordings and by the Modifiable Activity Questionnaire, diet by the FINRISK Food Frequency Questionnaire, and other lifestyle factors, such as sleep patterns and smoking, by face-to-face interviews. Physical and biochemical parameters and genetic risk score (GRS based on variants in PNPLA3, TM6SF2, MBOAT7 and HSD17B13) were measured. Of all participants 49% had NAFLD-fibrosis. Independent predictors of NAFLD-fibrosis were low moderate-to-vigorous physical activity, high red meat intake, low carbohydrate intake, smoking, HbA1c, triglycerides and GRS. A model including these factors (areas under the receiver operating characteristics curve (AUROC) 0.90 (95% CI 0.84–0.96)) identified NAFLD-fibrosis significantly more accurately than a model including all but lifestyle factors (AUROC 0.82 (95% CI 0.73–0.91)) or models including lifestyle, physical and biochemical, or genetic factors alone. Assessment of lifestyle parameters in addition to physical, biochemical and genetic factors helps to identify obese patients with NAFLD-fibrosis

Käypä hoito -suosituksen fibroosilaskureiden toimivuus lihavien rasvamaksatautipotilaiden edenneen fibroosin selvittelyssä

JOHDANTO : Rasvamaksatautipotilaiden edenneen fibroosin tunnistaminen on tärkeää vakavien maksakomplikaatioiden ehkäisyssä. Käypä hoito -suosituksessa käytetään Fibrosis-4- (FIB-4) ja NAFLD Fibrosis Score (NFS) -fibroosilaskureita kaksiportaisesti. Selvitimme, miten Käypä hoito -algoritmin kaksiportainen seulonta toimii edenneen fibroosin selvittelyssä verrattuna yleisesti suositellun pelkän FIB-4:n käyttöön. MENETELMÄT : Tutkimukseen osallistui 401 lihavaa potilasta, joille tehtiin kliinisen tutkimuksen lisäksi maksabiopsia. Potilaille laskettiin FIB-4- ja NFS-riskipisteet, ja niiden osuvuutta tunnistaa maksabiopsialla varmistettu edennyt fibroosi arvioitiin. TULOKSET : Maksabiopsiassa ilmeni rasvamaksatauti 64 %:lla ja edennyt fibroosi 5 %:lla potilaista. Käypä hoito -algoritmi ohjasi jatkotutkimuksiin 76 potilasta eli merkitsevästi vähemmän kuin pelkkä FIB-4 (129 potilasta, p < 0,001). Algoritmi ja pelkkä FIB-4 tunnistivat edenneen fibroosin yhtä hyvin (18/20 vs 15/20 potilasta, p = 0,41). PÄÄTELMÄT : Käypä hoito -algoritmin mukainen lihavien potilaiden edenneen fibroosin kaksiportainen seulonta vähentää turhia lähetteitä jatkotutkimuksiin verrattuna pelkän FIB-4:n käyttöön.Peer reviewe

Synergistic associations of cognitive and motor impairments with functional outcome in covert cerebral small vessel disease

Background Cognitive and motor impairments are the key clinical manifestations of cerebral small vessel disease (SVD), but their combined effects on functional outcome have not been elucidated. This study investigated the interactions and mediating effects of cognitive and motor functions on instrumental activities of daily living (IADL) and quality of life in older individuals with various degrees of white matter hyperintensities (WMH). Methods Participants of the Helsinki Small Vessel Disease Study (n = 152) were assessed according to an extensive clinical, physical, neuropsychological and MRI protocol. Volumes of WMH and gray matter (GM) were obtained with automated segmentation. Results Cognitive (global cognition, executive functions, processing speed, memory) and motor functions (gait speed, single-leg stance, timed up-and-go) had strong interrelations with each other, and they were significantly associated with IADL, quality of life as well as WMH and GM volumes. A consistent pattern on significant interactions between cognitive and motor functions was found on informant-evaluated IADL, but not on self-evaluated quality of life. The association of WMH volume with IADL was mediated by global cognition, whereas the association of GM volume with IADL was mediated by global cognition and timed up-and-go performance. Conclusion The results highlight the complex interplay and synergism between motor and cognitive abilities on functional outcome in SVD. The combined effect of motor and cognitive disturbances on IADL is likely to be greater than their individual effects. Patients with both impairments are at disproportionate risk for poor outcome. WMH and brain atrophy contribute to disability through cognitive and motor impairment.Peer reviewe

Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease

Background & aims: Recent experimental models and epidemiological studies suggest that specific environmental contaminants (ECs) contribute to the initiation and pathology of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms linking EC exposure with NAFLD remain poorly understood and there is no data on their impact on the human liver metabolome. Herein, we hypothesized that exposure to ECs, particularly perfluorinated alkyl substances (PFAS), impacts liver metabolism, specifically bile acid metabolism. Methods: In a well-characterized human NAFLD cohort of 105 individuals, we investigated the effects of EC exposure on liver metabolism. We characterized the liver (via biopsy) and circulating metabolomes using 4 mass spectrometry-based analytical platforms, and measured PFAS and other ECs in serum. We subsequently compared these results with an exposure study in a PPARa-humanized mouse model. Results: PFAS exposure appears associated with perturbation of key hepatic metabolic pathways previously found altered in NAFLD, particularly those related to bile acid and lipid metabolism. We identified stronger associations between the liver metabolome, chemical exposure and NAFLD-associated clinical variables (liver fat content, HOMA-IR), in females than males. Specifically, we observed PFAS-associated upregulation of bile acids, triacylglycerols and ceramides, and association between chemical exposure and dysregulated glucose metabolism in females. The murine exposure study further corroborated our findings, vis-a-vis a sex-specific association between PFAS exposure and NAFLD-associated lipid changes. Conclusions: Females may be more sensitive to the harmful impacts of PFAS. Lipid-related changes subsequent to PFAS exposure may be secondary to the interplay between PFAS and bile acid metabolism. Lay summary: There is increasing evidence that specific environmental contaminants, such as perfluorinated alkyl substances (PFAS), contribute to the progression of non-alcoholic fatty liver disease (NAFLD). However, it is poorly understood how these chemicals impact human liver metabolism. Here we show that human exposure to PFAS impacts metabolic processes associated with NAFLD, and that the effect is different in females and males. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.Peer reviewe

Distinct contributions of metabolic dysfunction and genetic risk factors in the pathogenesis of non-alcoholic fatty liver disease

Background & Aims: There is substantial inter-individual variability in the risk of non-alcoholic fatty liver disease (NAFLD). Part of which is explained by insulin resistance (IR) ('MetComp') and part by common modifiers of genetic risk ('GenComp'). We examined how IR on the one hand and genetic risk on the other contribute to the pathogenesis of NAFLD. Methods: We studied 846 individuals: 492 were obese patients with liver histology and 354 were individuals who underwent intrahepatic triglyceride measurement by proton magnetic resonance spectroscopy. A genetic risk score was calculated using the number of risk alleles in PNPLA3, TM6SF2, MBOAT7, HSD17B13 and MARC1. Substrate concentrations were assessed by serum NMR metabolomics. In subsets of participants, non-esterified fatty acids (NEFAs) and their flux were assessed by D-5-glycerol and hyperinsulinemic-euglycemic clamp (n = 41), and hepatic de novo lipogenesis (DNL) was measured by D2O (n = 61). Results: We found that substrate surplus (increased concentrations of 28 serum metabolites including glucose, glycolytic intermediates, and amino acids; increased NEFAs and their flux; increased DNL) characterized the 'MetComp'. In contrast, the 'GenComp' was not accompanied by any substrate excess but was characterized by an increased hepaticmitochondrial redox state, as determined by serum beta-hydroxybutyrate/acetoacetate ratio, and inhibition of hepatic pathways dependent on tricarboxylic acid cycle activity, such as DNL. Serum beta-hydroxybutyrate/acetoacetate ratio correlated strongly with all histological features of NAFLD. IR and hepatic mitochondrial redox state conferred additive increases in histological features of NAFLD. Conclusions: These data show that the mechanisms underlying 'Metabolic' and 'Genetic' components of NAFLD are fundamentally different. These findings may have implications with respect to the diagnosis and treatment of NAFLD. Lay summary: The pathogenesis of non-alcoholic fatty liver disease can be explained in part by a metabolic component, including obesity, and in part by a genetic component. Herein, we demonstrate that the mechanisms underlying these components are fundamentally different: the metabolic component is characterized by hepatic oversupply of substrates, such as sugars, lipids and amino acids. In contrast, the genetic component is characterized by impaired hepatic mitochondrial function, making the liver less able to metabolize these substrates. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.Peer reviewe

Neurofilament light level correlates with brain atrophy, and cognitive and motor performance

Peer reviewe