Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand 11C-PIB

Early Detection of Alzheimer's Disease Beta-amyloid Pathology -Applicability of Positron Emission Tomography with the Amyloid Radioligand 11C-PIB Accumulation of beta amyloid (Abeta) in the brain is characteristic for Alzheimer’s disease (AD). Carbon-11 labeled 2-(4’-methylaminophenyl)-6-hydroxybenzothiazole (11C-PIB) is a novel positron emission tomography (PET) amyloid imaging agent that appears to be applicable for in vivo Abeta plaque detection and quantitation. The biodistribution and radiation dosimetry of 11C-PIB were investigated in 16 healthy subjects. The reproducibility of a simplified 11C-PIB quantitation method was evaluated with a test-retest study on 6 AD patients and 4 healthy control subjects. Brain 11C-PIB uptake and its possible association with brain atrophy rates were studied over a two-year follow-up in 14 AD patients and 13 healthy controls. Nine monozygotic and 8 dizygotic twin pairs discordant for cognitive impairment and 9 unrelated controls were examined to determine whether brain Abeta accumulation could be detected with 11C-PIB PET in cognitively intact persons who are at increased genetic risk for AD. The highest absorbed radiation dose was received by the gallbladder wall (41.5 mjuGy/MBq). About 20 % of the injected radioactivity was excreted into urine, and the effective whole-body radiation dose was 4.7 mjuSv/MBq. Such a dose allows repeated scans of individual subjects. The reproducibility of the simplified 11C-PIB quantitation was good or excellent both at the regional level (VAR 0.9-5.5 %) and at the voxel level (VAR 4.2-6.4 %). 11C-PIB uptake did not increase during 24 months’ follow-up of subjects with mild or moderate AD, even though brain atrophy and cognitive decline progressed. Baseline neocortical 11C-PIB uptake predicted subsequent volumetric brain changes in healthy control subjects (r = 0.725, p = 0.005). Cognitively intact monozygotic co-twins – but not dizygotic co-twins – of memory-impaired subjects exhibited increased 11C-PIB uptake (117-121 % of control mean) in their temporal and parietal cortices and the posterior cingulate (p11C-PIB PET may be a useful method for patient selection and follow-up for early-phase intervention trials of novel therapeutic agents. AD might be detectable in high-risk individuals in its presymptomatic stage with 11C-PIB PET, which would have important consequences both for future diagnostics and for research on disease-modifying treatments.Alzheimerin taudin beta-amyloidipatologian varhainen toteaminen. 11C-PIB-amyloidimerkkiaineella tehtävän positroniemissiotomografian soveltuvuus Beeta-amyloidin (Abeta) kertyminen aivoihin on tyypillistä Alzheimerin taudille (AT). Hiili-11-isotoopilla leimattu 2-(4’-metyyliaminofenyyli)-6-hydroksibentsotiatsoli (11C-PIB) on uusi positroniemissiotomografiassa (PET) käytettävä merkkiaine, joka vaikuttaa soveltuvan amyloidiplakkien toteamiseen ja niiden määrän arvioimiseen. 11C-PIB:n jakautumista kehossa ja sen aiheuttamaa säderasitusta tutkittiin 16 terveellä henkilöllä. Yksinkertaistettujen 11C-PIB-analyysimenetelmien toistettavuutta selvitettiin toistomittausasetelmalla 6 AT-potilaalla ja 4 terveellä verrokilla. 11C-PIB-kertymän muutosta sekä 11C-PIB-kertymän ja aivojen kutistumisnopeuden välistä suhdetta mitattiin kahden vuoden seurantatutkimuksella, jossa oli 14 AT-potilasta ja 13 tervettä verrokkia. Tutkimalla 9 samanmunaista ja 8 erimunaista muistihäiriön suhteen toisistaan poikkeavaa kaksosparia sekä 9 iäkästä verrokkihenkilöä 11C-PIB PET:lla selvitettiin, voisiko aivoamyloidia olla havaittavissa sellaisilla kognitiivisesti terveillä henkilöillä, joilla on suurentunut riski sairastua AT:iin. Sappirakon seinämä sai elimistä suurimman määrän säteilyä, 41.5 mjuGy/MBq. Noin 20 % annetusta radioaktiivisuusannoksesta erittyi virtsaan. Efektiivinen sädeannos oli 4.7 mjuSv/MBq. Tämä annos mahdollistaa toistetut tutkimukset samoilla henkilöillä. Yksinkertaistettujen 11C-PIB PET –analyysimenetelmien toistettavuus oli hyvää tai erinomaista sekä alueittain (VAR 0.9-5.5%) että kuva-alkioittain (VAR 4.2-6.4%) tarkasteltuna. 11C-PIB-kertymä ei lisääntynyt AT-potilailla seuranta-ajan kuluessa, vaikka aivojen kutistuminen ja kognitiivinen heikentyminen etenivät. Alkutilanteen 11C-PIB-kertymä vaikutti ennustavan terveiden verrokkien aivojen tilavuusmuutoksia seuranta-aikana (r = 0.725, p = 0.005). Kognitiivisesti terveillä muistihäiriöisten samanmunaisilla kaksosilla – mutta ei erimunaisilla kaksosilla - oli suurentuneita 11C-PIB-kertymiä (117-121% verrokkien keskiarvosta) ohimo- ja päälakialueen aivokuorella sekä posteriorisessa cingulumissa (p11C-PIB PET voi olla käypä menetelmä tutkittavien valinnassa ja seurannassa, kun tehdään varhaisen sairausvaiheen tutkimuksia uusilla lääkkeillä. AT saatetaan voida todeta 11C-PIB PET:n avulla täysin oireettomassa vaiheessa sellaisilla henkilöillä, joilla on suurentunut riski sairastua. Tällä voisi olla merkittäviä vaikutuksia taudinmääritykselle ja sellaisten hoitojen tutkimiselle, jotka tähtäävät taudin kulun muuttamiseen.Siirretty Doriast

Negative C-11-PIB PET Predicts Lack of Alzheimer's Disease Pathology in Postmortem Examination

Our aim was to assess whether in vivo C-11-PIB negative memory-impaired subjects may nonetheless exhibit brain Alzheimer's disease (AD) pathology. We re-evaluated the PET images and systematically characterized the postmortem neuropathology of six individuals who had undergone clinically indicated amyloid PET. The single case with negligible amyloid-beta (A beta) pathology had Lewy body disease, where concomitant AD changes are often seen. Further, the subject's plaques were predominantly diffuse. The predictive value of a negative C-11-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic A beta plaque pathology in the absence of specific/cortical C-11-PIB binding upon PET is unlikely

Education is the strongest socio-economic predictor of smoking in pregnancy

First published: 14 January 2018Aims To investigate socio-economic disparities in smoking in pregnancy (SIP) by the mother's education, occupational class and current economic conditions. Design Cross-sectional analysis with linked survey and register data. Setting South-western Finland. Participants A total of 2667 pregnant women [70% of the original sample (n=3808)] from FinnBrain, a prospective pregnancy cohort study. Measurements The outcome was smoking during the first pregnancy trimester, measured from the Finnish Medical Birth Register. Education and occupational class were linked from population registers. Income support recipiency and subjective economic wellbeing were questionnaire-based measures of current economic conditions. These were adjusted for age, partnership status, residential area type, parental separation, parity, childhood socio-economic background, childhood adversities (the Trauma and Distressing Events During Childhood scale) and antenatal stress (Edinburgh Postnatal Depression Scale). Logistic regressions and attributable fractions (AF) were estimated. Findings Mother's education was the strongest socio-economic predictor of SIP. Compared with university education, adjusted odds ratios (aORs) of SIP were: 2.2 [95% confidence interval (CI)=1.2-3.9; P=0.011] for tertiary vocational education, 4.4 (95% CI=2.1-9.0; P<0.001) for combined general and vocational secondary education, 2.9 (95% CI=1.4-6.1; P=0.006) for general secondary education, 9.5 (95% CI 5.0-18.2; P<0.001) for vocational secondary education and 14.4 (95% CI=6.3-33.0; P<0.001) for compulsory schooling. The total AF of education was 0.5. Adjusted for the other variables, occupational class and subjective economic wellbeing did not predict SIP. Income support recipiency was associated positively with SIP (aOR=1.8; 95% CI=1.1-3.1; P=0.022). Antenatal stress predicted SIP (aOR=2.0; 95% CI=1.4-2.8 ; P<0.001), but did not attenuate its socio-economic disparities. Conclusions In Finland, socio-economic disparities in smoking in pregnancy are attributable primarily to differences in the mother's educational level (low versus high) and orientation (vocational versus general).Academy of Finland [287908,134950, 253270]Signe and Ane Gyllenberg Foundatio

Educational differences in prenatal anxiety and depressive symptoms and the role of childhood circumstances

Despite interest in unequal maternal and child health, previous research has not focused on educational differences in anxiety and depressive symptoms during pregnancy, although they threaten maternal and child wellbeing. Using the prospective FinnBrain Cohort Study data on 2763 pregnant women over the three pregnancy trimesters and Finnish register data, we estimated multilevel regressions to describe educational differences in prenatal anxiety and depressive symptoms and to analyze whether they can be explained by socioeconomic background, parental mental disorders and adverse experiences during childhood. Prenatal anxiety was measured by the Symptom Checklist (SCL-90-anxiety subscale) and depressive symptoms by the Edinburgh Postnatal Depression Scale (EPDS). The results showed less anxiety and depressive symptoms among more educated pregnant women. In accounting for the educational differences, we found support for both the social selection and the social causation perspectives. Adverse childhood experiences partly explained the educational differences, highlighting the role of an undisturbed childhood environment in prenatal mental health disparities. Results from the regression models as well as sensitivity analyses also suggested that education is likely to buffer against prenatal distress.</p

Healthy full-term infants' brain responses to emotionally and linguistically relevant sounds using a multi-feature mismatch negativity (MMN) paradigm

We evaluated the feasibility of a multi-feature mismatch negativity (MMN) paradigm in studying auditory processing of healthy newborns. The aim was to examine the automatic change-detection and processing of semantic and emotional information in speech in newborns. Brain responses of 202 healthy newborns were recorded with a multi-feature paradigm including a Finnish bi-syllabic pseudo-word/ta-ta/as a standard stimulus, six linguistically relevant deviant stimuli and three emotionally relevant stimuli (happy, sad, angry). Clear responses to emotional sounds were found already at the early latency window 100-200 ms, whereas responses to linguistically relevant minor changes and emotional stimuli at the later latency window 300-500 ms did not reach significance. Moreover, significant interaction between gender and emotional stimuli was found in the early latency window. Further studies on using multi-feature paradigms with linguistic and emotional stimuli in newborns are needed, especially those containing of follow-ups, enabling the assessment of the predictive value of early variations between subjects.Peer reviewe

Education is the strongest socio-economic predictor of smoking in pregnancy

Aims To investigate socio-economic disparities in smoking in pregnancy (SIP) by the mother’s education, occupational class and current economic conditions. Design Cross-sectional analysis with linked survey and register data. Setting South-western Finland. Participants A total of 2667 pregnant women [70% of the original sample (n = 3808)] from FinnBrain, a prospective pregnancy cohort study. Measurements The outcome was smoking during the first pregnancy trimester, measured from the Finnish Medical Birth Register. Education and occupational class were linked from population registers. Income support recipiency and subjective economic wellbeing were questionnairebased measures of current economic conditions. These were adjusted for age, partnership status, residential area type, parental separation, parity, childhood socio-economic background, childhood adversities (the Trauma and Distressing EventsDuring Childhood scale) and antenatal stress (Edinburgh Postnatal Depression Scale). Logistic regressions and attributable fractions (AF) were estimated. Findings Mother’s education was the strongest socio-economic predictor of SIP. Compared with university education, adjusted odds ratios (aORs) of SIP were: 2.2 [95% confidence interval (CI) = 1.2–3.9; P = 0.011] for tertiary vocational education, 4.4 (95% CI = 2.1–9.0; P disparities. Conclusions In Finland, socio-economic disparities in smoking in pregnancy are attributable primarily to differences in the mother’s educational level (low versus high) and orientation (vocational versus general). </p

Successful suppression of musical hallucinations with low-frequency rTMS of the left temporo-parietal junction: A case report

Background: Inhibitory low frequency repetitive transcranial magnetic stimulation (rTMS) of the temporo-parietal area has been applied to treat both auditory verbal hallucinations as well as tinnitus.Objective: We hypothesized that 1 Hz rTMS to the left temporoparietal junction (TPJ) may be beneficial in alleviating musical hallucinations (MH), another condition with auditory experiences in the absence of an external source.Methods: Here we describe a patient with almost insufferable life-long MH with comorbid depression, who received inhibitory rTMS to the left TPJ as well as the right dorsolateral prefrontal cortex (DLPFC).Results: The intrusiveness and frequency of her MH as well as her depressive symptoms alleviated quickly and substantially, and once-a-week maintenance therapy with rTMS seemed to preserve this amelioration. Future studies will hopefully reveal whether this is a viable treatment approach for other patients suffering from MH with or without comorbid depression.(c) 2021 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).</p

Association between parental alexithymic traits and self-reported postnatal reflective functioning in a birth cohort population Findings from the FinnBrain Birth Cohort Study

Parental reflective functioning (PRF) refers to a parent's effort to see his/her child as a separate individual person from early on, and to be curious of the child's own thoughts and feelings. Parenting abilities are affected by the parent's emotion regulation and emotional availability. Alexithymia as a personality construct with emotional deficits and poor imagination could potentially affect also PRF, but studies on parental alexithymia are still scarce. The aim of the present study was to examine the association between parental alexithymic traits and PRF, which to date has not been explored. As most of the parenting research concern only mothers, an additional aim was to study also fathers. The 20-item Toronto Alexithymia Scale (TAS-20) and the 14-item Parental Reflective Functioning Questionnaire (PRFQ-Fi) were filled by 1882 mothers and 994 fathers at six months postpartum as part of the FinnBrain Birth Cohort Study. A significant negative association between TAS-20 total score and PRFQ-Fi total score among both genders was found. The main alexithymia dimension responsible for this association was Externally Oriented Thinking. The results suggest that alexithymic traits indeed are related to parental reflective functioning, but more studies are needed to explore the direction of this relation

Maternal prenatal hair cortisol is associated with prenatal depressive symptom trajectories

Maternal prenatal cortisol levels have been inconsistently associated with self-reports of prenatal psychological distress (PD). Previous research has linked hair cortisol concentration (HCC) evaluating cumulatively the previous months with cross-sectional PD measures that usually cover the past week(s), which may lead to misleading conclusions on their relations. We aimed to investigate how maternal HCC relates to cumulative PD measures across pregnancy. Maternal prenatal cortisol levels have been inconsistently associated with self-reports of prenatal psychological distress (PD). Previous research has linked hair cortisol concentration (HCC) evaluating cumulatively the previous months with cross-sectional PD measures that usually cover the past week(s), which may lead to misleading conclusions on their relations. We aimed to investigate how maternal HCC relates to cumulative PD measures across pregnancy. Methods Subjects (N = 595) were drawn from the FinnBrain Birth Cohort Study. Maternal HCC was measured from hair samples collected at gestational week (gwk) 24 (HCC1, n = 467) and at delivery (HCC2, n = 222). As HCC1 and HCC2 comprised mostly of different subjects, they were considered as independent populations. Maternal PD assessments at gwks 14, 24, and 34 were the Edinburgh Postnatal Depression Scale (EPDS), the anxiety subscale of the Symptom Checklist (SCL-90), the Pregnancy-Related Anxiety Questionnaire -Revised2 (PRAQ-R2), and a daily hassles scale. Cumulative PD comprised of the mean scores of two consecutive assessments (mean1 = gwks 14 and 24; mean2 = gwks 24 and 34). In addition, EPDS and SCL scores were modelled by using growth mixture modelling to identify symptom trajectory categories. Regression models were adjusted for age, body mass index, education and use of selective serotonin/serotonin-norepinephrine reuptake inhibitor medication. Results In the adjusted regression model, higher HCC2 was related to the “consistently elevated” prenatal depressive symptoms trajectory in comparison to “consistently low” (β =.71, p =.021) and “low and increasing” (β =.82, p = .011) symptom trajectories. Additionally, the cumulative mean (mean 1) of daily hassles in relationships was associated with HCC1 (β = 0.25, p = .004). General or pregnancy-related anxiety symptoms were unrelated to HCC after adjustment for the covariates. Conclusions The assessment of cumulative or trajectory measures of PD can reveal important associations with maternal prenatal HCC, even though the associations are generally weak. Of the different dimensions of PD, prenatal trajectories of depressive symptoms were most consistently linked with end-pregnancy HCC levels.Academy of Finland (grant #134950 to HK and grant #308176 to LK), Jane and Aatos Erkko Foundation, Signe and Ane Gyllenberg Foundation, and State Research Grants. Preparation of the manuscript has been funded by Juho Vainio Foundation (PM), Finnish Brain Foundation (PM), and Yrjö Jahnsson Foundation (LK, grants #6976 and #6847). AJR is an FCT Investigator Fellow (IF/00883/2013) and is funded by projects POCI-01-0145-FEDER-016428; POCI-01-0145-FEDER-029071 and POCI-01-0145-FEDER-00703

Parental divorce in childhood does not independently predict maternal depressive symptoms during pregnancy

Background: This study sought to investigate if parental divorce in childhood increases the risk for depressive symptoms in pregnancy.Methods: Women were recruited during their ultrasound screening in gestational week (gwk) 12. The final study sample consisted of 2,899 pregnant women. Questionnaires (including the Edinburgh Postnatal Depression Scale) were completed at three measurement points (gwk 14, 24 and 34). Prenatal depressive symptoms were defined as Edinburgh Postnatal Depression Scale score ≥ 13. Parental divorce and other stressful life events in childhood were assessed at gwk 14. Parental divorce was defined as separation of parents who were married or cohabiting. Questionnaire data was supplemented with data from Statistics Finland and the Finnish Medical Birth Register.Results: Parental divorce in childhood increased the risk for depressive symptoms during pregnancy (OR 1.47; 95% CI 1.02–2.13), but the connection was no longer significant after adjusting for socioeconomic status, family conflicts and witnessing domestic violence in the childhood family (OR 0.80; 95% CI 0.54–1.18).Conclusions: Parental divorce alone does not predict depressive symptoms during pregnancy.Keywords: prenatal depression, depression, parental divorce, family conflicts, domestic violence</p