Predictors of long-term change in adult cognitive performance: systematic review and data from the Northern Finland Birth Cohort 1966

Objective: Several social life events and challenges have an impact on cognitive development. Our goal was to analyze the predictors of change in cognitive performance in early midlife in a general population sample. Additionally, systematic literature review was performed. Method: The study sample was drawn from the Northern Finland Birth Cohort 1966 at the ages of 34 and 43 years. Primary school performance, sociodemographic factors and body mass index (BMI) were used to predict change in cognitive performance measured by the California Verbal Learning Test, Visual Object Learning Test, and Abstraction Inhibition and Working Memory task. Analyses were weighted by gender and education, and p-values were corrected for multiple comparisons using Benjamini–Hochberg procedure (B–H). Results: Male gender predicted decrease in episodic memory. Poor school marks of practical subjects, having no children, and increase in BMI were associated with decrease in episodic memory, though non-significantly after B–H. Better school marks, and higher occupational class were associated with preserved performance in visual object learning. Higher vocational education predicted preserved performance in visual object learning test, though non-significantly after B-H. Likewise, having children predicted decreased performance in executive functioning but non-significantly after B-H. Conclusions: Adolescent cognitive ability, change in BMI and several sociodemographic factors appear to predict cognitive changes in early midlife. The key advantage of present study is the exploration of possible predictors of change in cognitive performance among general population in the early midlife, a developmental period that has been earlier overlooked

Pharmacoperones for misfolded gonadotropin receptors

The gonadotropin receptors (luteinising hormone receptor; LHR and follicle-stimulating hormone receptor; FSHR) are G protein-coupled receptors (GPCRs) that play an important role in the endocrine control of reproduction. Thus genetic mutations that cause impaired function of these receptors have been implicated in a number of reproductive disorders. Disease-causing genetic mutations in GPCRs frequently result in intracellular retention and degradation of the nascent protein through misfolding and subsequent recognition by cellular quality control machinery. The discovery and development of novel compounds termed pharmacological chaperones (pharmacoperones) that can stabilise misfolded receptors and restore trafficking and plasma membrane expression are therefore of great interest clinically, and promising in vitro data describing the pharmacoperone rescue of a number of intracellularly retained mutant GPCRs has provided a platform for taking these compounds into in vivo trials. Thienopyrimidine small molecule allosteric gonadotropin receptor agonists (Org 42599 and Org 41841) have been demonstrated to have pharmacoperone activity. These compounds can rescue cell surface expression and in many cases, hormone responsiveness, of a range of retained mutant gonadotropin receptors. Should gonadotropin receptor selectivity of these compounds be improved, they could offer therapeutic benefit to subsets of patients suffering from reproductive disorders attributed to defective gonadotropin receptor trafficking.https://www.springer.com/series/1642018-12-01hj2018Immunolog

Change in cognitive performance and its predictors in general population and schizophrenia in early midlife:the Northern Finland Birth Cohort 1966 Study

Abstract The aim of this study was to provide novel information on the change of cognitive performance and its predictors in early midlife between ages of 34 and 43 years. The change in verbal episodic memory between non-psychotic and schizophrenia samples was compared in the Northern Finland Birth Cohort 1966. In the non-psychotic sample, associations between primary school performance, sociodemographic factors and body mass index (BMI), and in the schizophrenia sample, between premorbid school performance and severity of illness with the change in cognitive performance were evaluated. There was no evidence of greater decline in verbal episodic memory in the schizophrenia sample, compared to the non-psychotic sample, though the schizophrenia sample had an overall lower cognitive performance at the baseline. In the non-psychotic sample, male gender, poorer school performance, increases in BMI and having no children predicted a decline in verbal episodic memory; poorer school performance and low vocational education and occupational class predicted a decline in visual episodic memory; and having children predicted a decline in executive function. In the schizophrenia sample, poorer premorbid school performance, but not the later course of illness, was related to a decline in cognitive performance. This study is one of the few studies to investigate the predictors of change in cognitive performance in the early middle-aged general population, and the first to investigate the predictors of cognitive change in early midlife schizophrenia. To summarize; poor cognitive performance in adolescence may be considered as a vulnerability marker for a later impairment in cognitive functioning. In schizophrenia, cognitive ability possibly declines mostly in a normative fashion with aging at the same rate as in the general population rather than as a result of neurodegenerative processes. These results might improve our understanding of midlife change in cognitive functioning and may also help to develop effective interventions of cognitive impairment in schizophrenia.Tiivistelmä Tutkimuksen tavoitteena oli tuoda uutta tietoa kognitiivisen suoriutumisen muutoksesta sekä siihen liittyvistä tekijöistä varhaisessa keski-iässä ikävuosien 34 ja 43 välillä. Tutkimuksessa verrattiin kielellisessä muistisuoriutumisessa tapahtuvaa muutosta yleisväestön ja skitsofrenia-aineiston välillä Pohjois-Suomen vuoden 1966 syntymäkohortissa. Lisäksi yleisväestössä tutkittiin koulumenestyksen, sosiodemografisten tekijöiden ja painoindeksin yhteyttä ja skitsofrenia-aineistossa koulumenestyksen ja sairauden varhaisen kulun yhteyttä kognitiivisen suoriutumisen muutokseen. Kielellisen muistisuoriutumisen heikentyminen ei ollut skitsofrenia-aineistossa suurempaa verrattuna yleisväestöön, joskin kognitiivisen suoriutumisen lähtötaso oli skitsofrenia-aineistossa alempi. Yleisväestössä miessukupuoli, heikompi koulumenestys peruskoulussa, painoindeksin nousu ja lapsettomuus olivat yhteydessä kielellisen muistisuoriutumisen heikkenemiseen, heikompi koulumenestys peruskoulussa ja matala ammatillinen koulutus ja sosioekonominen asema näönvaraisen muistisuoriutumisen heikkenemiseen ja vanhemmuus toiminnanohjauksellisten taitojen laskuun. Skitsofrenia-aineistossa heikompi menestys peruskoulussa ennusti kognitiivisen suoriutumisen heikkenemistä kielellisen ja näönvaraisen muistin sekä toiminnanohjauksellisten taitojen osa-alueilla. Oireiden vakavuus ja toimintakyky sairastumisen jälkeen eivät liittyneet kognitiivisen suoriutumisen muutokseen. Tämä on yksi harvoista tutkimuksista, joissa on selvitetty kognitiivisen suoriutumisen muutosta ennustavia tekijöitä varhaisessa keski-iässä yleisväestössä, ja ensimmäinen, jossa on tutkittu kognitiivisen suoriutumisen muutosta ennustavia tekijöitä skitsofrenia-aineistossa varhaisessa keski-iässä. Yhteenvetona voidaan todeta, että heikko nuoruusiän koulumenestys voi ennustaa kognitiivisen suoriutumisen heikkenemistä varhaisessa keski-iässä. Kognitiivinen suorituskyky näyttää heikkenevän skitsofreniassa enemmänkin tavanomaisella tavalla ikääntymisen myötä kuin neurodegeneratiivisen prosessin seurauksena. Tämän tutkimuksen tulokset tuovat uutta tietoa kognitiivisen suoriutumisen muutoksesta keski-ikäisessä väestössä. Tuloksia voidaan myös hyödyntää kehitettäessä kognitiivisten häiriöiden hoitoa skitsofreniassa

Stable transfection of the rat follicle-stimulating hormone receptor complementary DNA into an immortalized murine Sertoli cell line

A plasmid expressing the rat FSH receptor (R) cDNA under the Simian virus (SV) 40 promoter/enhancer was stably transfected into a mouse Sertoli cell (SC) line (MSC-1) established from transgenic mice carrying a fusion gene of the human anti-Müllerian hormone (AMH) promoter sequences linked to the SV40 T-antigen gene (Peschon et al., 1992). The original cell line has numerous SC characteristics, but it was reported not to express the inhibin-alpha and follicle-stimulating hormone (FSH)R genes. The new FSHR expressing cell line possessed approximately 2000 per cell with equilibrium association constant (Ka) of 1.5 x 10(9) l/mol. In Northern blots, an FSHR mRNA species of 2.6 kb was found. The cells responded to recombinant human FSH (recFSH) and pertussis toxin (PT) with stimulated cAMP production. Moreover, PT enhanced the FSH-stimulated cAMP production in these cells, indicating the presence of a functional Gi protein. 12-O-tetradecanoylphorbol-13-acetate (TPA) suppressed the FSH-stimulated cAMP production of the cells, which effect was similar to that observed previously upon protein kinase C (PKC) activation in rat seminiferous tubules in vitro. Hence, the FSHR signalling, and its modulatory pathways, were intact in the FSHR expressing MSC-1 cell line. RT-PCR with inhibin-alpha specific oligonucleotide primers. followed by Southern hybridization, indicated that, unlike previously shown, the original and the FSHR expressing MSC-1 cells do express the inhibin alpha gene. FSH stimulation of the cells decreased their proliferation and, unexpectedly, the inhibin-alpha mRNA levels. The cells have functional features both from neonatal and mature SC. A feature of the former cells is the lack of FSH-stimulated up-regulation of inhibin-alpha expression; in fact FSH decreased this message. The antiproliferative, and apparently differentiating, effect of FSH on these cells resembled mature SC functions. Since adult SC do not proliferate in vitro, the new FSHR expressing and proliferating cell line provides a useful in vitro model for studying some facets of SC functions, though keeping in mind that these transformed cells do not behave identically with adult SC in vivo. The constitutive expression of FSHR in these cells allows the study of posttranscriptional events in the FSHR regulation

Lifetime use of psychiatric medications and cognition at 43 years of age in schizophrenia in the Northern Finland Birth Cohort 1966

Background: Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia. Methods: Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43 years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression. Results: Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11 months) before the cognitive examination was associated with better cognitive performance (P = 0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P = 0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition. Conclusions: Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia. (C) 2017 Elsevier Masson SAS. All rights reserved.Peer reviewe