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Prenatal environment reportedly affects the programming of developmental trajectories in offspring and the modification of risks for later morbidity. Among the increasingly studied prenatal exposures are maternal psychological distress (PD) and altered maternal hypothalamus-pituitary-adrenal (HPA) axis functioning. Both prenatal PD and maternal short-term cortisol concentrations as markers for HPA axis activity have been linked to adverse child outcomes and it has been assumed that maternal PD affects the offspring partially via altered cortisol secretion patterns. Yet, the existing literature on the interrelations between these two measures is conflicting. The assessment of cortisol levels by using hair cortisol concentration (HCC) has gained interest, as it offers a way to assess long-term cortisol levels with a single non-invasive sampling. According to our review, 6 studies assessing the associations between maternal HCC during pregnancy and various types of maternal PD have been published so far. Measures of prenatal PD range from maternal symptoms of depression or anxiety to stress related to person's life situation or pregnancy. The aim of this systematic review is to critically evaluate the potential of HCC as a biomarker for maternal PD during pregnancy. We conclude that HCC appears to be inconsistently associated with self-reported symptoms of prenatal PD, especially in the range of mild to moderate symptom levels. Self-reports on PD usually cover short time periods and they seem to depict partly different phenomena than HCC. Thus, methodological aspects are in a key role in future studies evaluating the interconnections across different types of prenatal PD and maternal HPA axis functioning. Further, studies including repetitive measurements of both HCC and PD during the prenatal period are needed, as timing of the assessments is one important source of variation among current studies. The significance of prenatal HCC in the context of offspring outcomes needs to be further investigated., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Caressing touch is an effective way to communicate emotions and to create social bonds. It is also one of the key mediators of early parental bonding. The caresses are generally thought to represent a social form of touching and indeed, slow, gentle brushing is encoded in specialized peripheral nerve fibers, the C-tactile (CT) afferents. In adults, areas such as the posterior insula and superior temporal sulcus are activated by affective, slow stroking touch but not by fast stroking stimulation. However, whether these areas are activated in infants, after social tactile stimulation, is unknown. In this study, we compared the total hemoglobin responses measured with diffuse optical tomography (DOT) in the left hemisphere following slow and fast stroking touch stimulation in 16 2-month-old infants. We compared slow stroking (optimal CT afferent stimulation) to fast stroking (non-optimal CT stimulation). Activated regions were delineated using two methods: one based on contrast between the two conditions, and the other based on voxel-based statistical significance of the difference between the two conditions. The first method showed a single activation cluster in the temporal cortex with center of gravity in the middle temporal gyrus where the total hemoglobin increased after the slow stroking relative to the fast stroking (p = 0.04 uncorrected). The second method revealed a cluster in the insula with an increase in total hemoglobin in the insular cortex in response to slow stroking relative to fast stroking (p = 0.0005 uncorrected; p = 0.04 corrected for multiple comparisons). These activation clusters encompass areas that are involved in processing of affective, slow stroking touch in the adult brain. We conclude that the infant brain shows a pronounced and adult-like response to slow stroking touch compared to fast stroking touch in the insular cortex but the expected response in the primary somatosensory cortex was not found at this age. The results imply that emotionally valent touch is encoded in the brain in adult-like manner already soon after birth and this suggests a potential for involvement of touch in bonding with the caretaker., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Studies on the subjective effects of antidepressants suggest that they may not only improve depressed mood, but as an adverse effect also cause "emotional blunting." This phenomenon is poorly understood and little studied. The aim of this study was to examine the association of serotonergic antidepressant use and subjective emotional awareness. Emotional awareness was assessed using the Difficulty Identifying Feelings subscale from the 20-Item Toronto Alexithymia Scale. Fifty-seven individuals on antidepressant medication and 441 controls were compared. The effects of sex, age, education, as well as current depressive symptoms were controlled for. After controlling for selected variables, the antidepressant group scored higher in subjective difficulty identifying feelings, compared to controls. (p = .043, Adjusted means by Group 14.2 vs. 15.5, 95% confidence interval for mean difference between Groups 0.04-2.5). Serotonergic antidepressant use may be associated with difficulty identifying feelings. Future studies with a longitudinal setting are warranted to clarify causality. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Our aim was to assess whether in vivo11C-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-β (Aβ) 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 11C-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic Aβ plaque pathology in the absence of specific/cortical 11C-PIB binding upon PET is unlikely.

A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G > A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This variant prompted us to consider this gene as a putative candidate for DD. The RNA expression pattern of the NCAN gene in human tissues was highly correlated (R > 0.8) with that of the previously suggested DD susceptibility genes KIAA0319, CTNND2, CNTNAP2 and GRIN2B. We investigated the association of common variation in NCAN to brain structures in two data sets: young adults (Brainchild study, Sweden) and infants (FinnBrain study, Finland). In young adults, we found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. In infants, this same variant was found to be associated with cingulate and prefrontal grey matter volumes. Our results suggest NCAN as a new candidate gene for DD and indicate that NCAN variants affect brain structure.

Background: Alexithymia is a personality construct involving difficulties identifying and verbalizing feelings, and an externally oriented thinking style. There is preliminary evidence for alexithymia subtypes that may carry different risk profiles for psychiatric illness. The aim of this study was to gain support for the existence of alexithymia subtypes and further characterize their clinical relevance., Methods: To identify possible subtypes, a cluster analysis was conducted for individuals with high alexithymic traits (N=113). Current depressive and anxiety symptoms, self-reported psychiatric medical history, and self-reported early life adversity were compared between subtypes. The cluster analysis was replicated with the low (N=2471) and moderate (N=290) alexithymia groups., Results: We identified two alexithymia subtypes. Compared to type A, type B alexithymia was associated with higher levels of difficulties in identifying feelings, and was more strongly associated with current depressive (Cohen's d=0.77, p<0.001) and anxiety symptoms (Cohen's d=0.82, p<0.001), and self-reported early life adversity (Cohen's d 0.42, p=0.048). Compared to type A, type B alexithymia was also associated with a higher prevalence of self-reported diagnosis of major depressive- (30.2% vs. 8.3%) and anxiety disorder (18.9% vs. 3.3%)., Conclusions: The results of this study support the hypothesis of alexithymia subtypes, and add support to the growing evidence showing that alexithymia is likely a heterogeneous and dimensional phenomenon. The subtype (type B) with most pronounced difficulties in identifying feelings may be associated with a higher risk for psychiatric illness compared to type A alexithymia, and may exhibit a more severe history of early life adversity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Maternal prenatal psychological symptoms are associated with child health outcomes, e.g., atopic diseases. Altered prenatal functioning of the immune system is a potential mechanism linking maternal symptoms with child health. Research on prenatal distress and cytokines is warranted. The study population comprised consecutive N = 139 women from a general population-based FinnBrain Birth Cohort Study. Standardized questionnaires for depressive, overall anxiety, and pregnancy-related anxiety symptoms were used. Serum concentrations of selected cytokines were analyzed using Multiplex bead arrays from samples drawn at the gestational week 24. The concentrations of T helper (Th)2-related interleukins (IL)-9 and IL-13 and Th1-related IL-12 correlated positively with prenatal depressive and overall anxiety symptom scores (p values, range 0.011-0.029). Higher interferon (IFN)-γ/IL-4 ratio (p = 0.039) and Th2-related IL-5 (p = 0.007) concentration correlated positively with depressive symptoms. Pregnancy-related anxiety score correlated positively with IL-12 (p = 0.041), IL-13 (p = 0.025), and anti-inflammatory IL-10 (p = 0.048) concentrations. IL-6 and TNF-α concentrations were unrelated to prenatal symptoms. As a novel finding, we observed positive correlations between concentrations of potentially proallergenic cytokines and maternal prenatal psychological symptoms. Different symptom measures may yield distinct cytokine responses. This provides hypotheses for studies on mechanisms bridging prenatal stress and child health.

The 10-item Pregnancy-Related Anxiety Questionnaire-Revised (PRAQ-R) is a widely used instrument to assess and identify pregnancy-specific anxiety in nulliparous women. It has good psychometric values and predictive validity for birth and childhood outcomes. Nonetheless, the PRAQ-R is not designed for use in parous women, as particularly one item of the questionnaire is not relevant for women who gave birth before. We tested the factorial and scalar invariance of a modified PRAQ-R2 across nulliparous and parous women with an adapted item to fit both groups of pregnant women. A longitudinal study among 1144 pregnant women (n = 608 nulliparous and n = 536 parous) with two repeated measures of the PRAQ-R2 was used to test for measurement invariance of the instrument. Results show metric and scalar invariance, indicating that the PRAQ-R2 measures similar constructs on the same scale for all pregnant women at two different times during pregnancy. We conclude that the PRAQ-R2 can be used, compared, or combined in a sample of nulliparous and parous women.

Early stress would seem to be associated with alterations in certain structures of the brain, such as the amygdala and hippocampus, cerebral cortex and white matter, in structures of pathways essential to emotional control. Furthermore, a tendency to have higher levels of stress hormone, i.e. cortisol, as well as hormonal responses to stress has been shown in individuals exposed to early stress. Early stress, already experienced in utero, may in fact program the central nervous system to become more susceptible to later-onset disturbances of regulation of stress and emotions. Prevention and treatment of stress during pregnancy and its consequences would thus require more investments than at present.

The aim of this longitudinal positron emission tomography (PET) study was to evaluate the interrelationship between brain metabolism and amyloid accumulation during the disease process from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Nine MCI patients, who converted to AD between two and five years, and nine healthy subjects underwent [11C]PIB and [18F]FDG PET scans at baseline and at 5 years. [11C]PIB uptake was clearly higher in MCI patients at baseline compared to controls and spread extensively to the cerebral cortex during the conversion to AD. [18F]FDG uptake was reduced especially in the temporal-parietal regions in MCI compared to controls at baseline, and widely over the cortex at the 5-year follow-up. The reduction in metabolism during the follow-up was significant in the posterior brain regions. In addition, brain amyloid load was positively associated with metabolism in posterior brain regions in MCI, but not after conversion to AD. The results suggest that there are interactions between brain amyloid accumulation and metabolism during the AD process, including a possible compensatory upregulation of posterior brain metabolism in the early phase.

Purpose: The aim of this study was to evaluate the longitudinal changes in [(11)C]PIB uptake in mild cognitive impairment (MCI) and Alzheimer's disease (AD) over a long-term follow-up., Methods: Six AD patients, ten MCI patients and eight healthy subjects underwent a [(11)C]PIB PET scan at baseline and at 2 and 5 years. The clinical status of the MCI patients was evaluated every 6 months., Results: The MCI group showed a significant increase in [(11)C]PIB uptake over time (p < 0.001), with a similar increase from baseline to 2 years (4.7% per year) and from 2 to 5 years (5.0% per year). Eight MCI patients (80%) converted to AD, and two of these patients showed a normal [(11)C]PIB scan at baseline but increased uptake later. There was an increase in [(11)C]PIB uptake with time in the AD group (p = 0.02), but this did not significantly differ from the change in the control group., Conclusion: Our results revealed a significant increase in amyloid load even at the time of AD diagnosis in some of the MCI patients who converted. A positive [(11)C]PIB scan at baseline in MCI patients strongly predicted future conversion to AD but a negative PIB scan in MCI patients did not exclude future conversion. The results suggest that there is wide individual variation in the brain amyloid load in MCI, and in the course of amyloid accumulation in relation to the clinical diagnosis of AD.

Background/objective: Our aim was to elucidate factors that contribute to amyloid-β (Aβ) accumulation in the brains of the seemingly healthy elderly population, and whether there is interplay between those factors., Methods: We conducted a cross-sectional positron emission tomography (PET) study with the amyloid tracer 11C-PIB, in 64 cognitively healthy subjects (54-89 years). In addition to PET, magnetic resonance imaging, neuropsychological testing, and APOE genotyping was performed. The results were assessed with a statistical general linear model as well as with Statistical Parametric Mapping (SPM)., Results: The effects of age (p < 0.001), APOE ε4 carrier status (p = 0.003), and gender (p = 0.001) on composite cortical 11C-PIB uptake were all significant. The effect of educational level was non-significant (p = 0.37). No significant interactions were found between any of the factors. Cortical 11C-PIB uptake increased, on the average, by 0.015 cortex/cerebellar cortical ratio unit, with every year of age. APOE ε4 positive subjects exhibited higher cortical 11C-PIB uptake than APOE ε4 negative subjects (unadjusted means 1.49 ± 0.34 versus 1.29 ± 0.26) and males had higher uptake than females (1.49 ± 0.39 versus 1.29 ± 0.22), irrespective of age. The results of the voxel-based (SPM) analysis were similar. In addition, SPM analysis showed that lower CERAD score was associated with higher 11C-PIB uptake in the frontal cortex., Conclusions: Age and APOE ε4 genotype were associated with higher 11C-PIB uptake. In this sample of cognitively healthy elderly individuals, men exhibited higher 11C-PIB uptake than women. Possible gender differences in Aβ accumulation have not been addressed in detail in previous studies, and deeper evaluation in the future is warranted.

Purpose: Cortical glucose metabolism, brain amyloid β accumulation and hippocampal atrophy imaging have all been suggested as potential biomarkers in predicting which patients with mild cognitive impairment (MCI) will convert to Alzheimer's disease (AD). The aim of this study was to compare the prognostic ability of [(11)C]PIB PET, [(18)F]FDG PET and quantitative hippocampal volumes measured with MR imaging in predicting conversion to AD in patients with MCI., Methods: The study group comprised 29 patients with MCI who underwent [(11)C]PIB PET and MR imaging. Of these, 22 also underwent [(18)F]FDG PET. All subjects were invited back for clinical evaluation after 2 years., Results: During the follow-up time 17 patients had converted to AD while 12 continued to meet the criteria for MCI. The two groups did not differ in age, gender or education level, but the converter group tended to have lower MMSE and Word List learning than the nonconverter group. High [(11)C]PIB retention in the frontotemporal regions and anterior and posterior cingulate (p < 0.05) predicted conversion to AD. Also reduced [(18)F]FDG uptake in the left lateral temporal cortex (LTC) predicted conversion (p < 0.05), but quantitative hippocampal volumes did not (p > 0.1). In receiver operating characteristic (ROC) analysis the measurements that best predicted the conversion were [(11)C]PIB retention in the lateral frontal cortex and [(18)F]FDG uptake in the left LTC. Both PET methods resulted in good sensitivity and specificity and neither was significantly superior to the other., Conclusion: The findings indicate that [(11)C]PIB and [(18)F]FDG are superior to hippocampal volumes in predicting conversion to AD in patients with MCI.

Background/aims: The relationship between baseline (11)C-Pittsburgh compound B ((11)C-PIB) uptake and cognitive decline during a 2-year follow-up was studied in 9 patients with mild cognitive impairment (MCI) who converted to Alzheimer's disease (AD) and 7 who remained with MCI., Methods: (11)C-PIB PET scan was conducted at baseline and cognitive assessment both at baseline and at follow-up. To obtain quantitative regional values of (11)C-PIB uptake, automated region of interest analysis was done using spatially normalized parametric ratio (region-to-cerebellar cortex) images., Results: At baseline, there were statistically significant differences in (11)C-PIB uptake, but not in cognitive test performances between the converters and nonconverters. Memory and executive function declined only in the converters during follow-up. In the converters, lower baseline frontal (11)C-PIB uptake was associated with faster decline in verbal learning. Higher baseline uptake in the caudate nucleus was related to faster decline in memory consolidation, and higher temporal uptake was associated with decline in executive function., Conclusion: Higher (11)C-PIB uptake in the caudate nucleus and temporal lobe was related to decline in memory and executive functions, whereas lower frontal uptake was related to decline in verbal learning. The results indicate that in prodromal AD, frontal amyloid accumulation reaches its maximum in the MCI stage, characterized by memory problems without full-blown dementia., (Copyright © 2012 S. Karger AG, Basel.)

New treatments against Alzheimer's disease (AD) may be just around the corner. A common approach in developing these disease-modifying treatments is to target beta-amyloid (Aβ). Aβ is excessively present in the AD brain and it likely starts to accumulate long before clinical symptoms become apparent. As Aβ is hypothesized to be the causative agent in the pathophysiological cascade leading to progressive neurodegeneration in AD, efforts to e.g. prevent its formation, to promote its clearance from brain tissue, and to inhibit its toxicity, are warranted. This quest for an effective AD treatment needs valid biomarker outcome measures, for instance because clinical benefit takes long to present itself and is difficult to measure, and also because treatment would likely be most efficacious if administered already before symptoms occur. In vivo amyloid imaging has evolved in the past decade to be a feasible means to monitor brain Aβ deposits in the human brain. It effectively differentiates AD patients from healthy age-matched controls, and also shows promise in the early, even presymptomatic, detection of AD. Amyloid imaging will likely also broaden and deepen our understanding of AD and other neurodegenerative disorders. It could prove valuable e.g. in subject selection and stratification for clinical trials, in safety and proof-of-concept assessments, and in monitoring of treatment effects. This article aims to review the motives, prerequisites, potential, and challenges of using amyloid imaging as a surrogate marker in clinical therapeutic trials in AD.

Purpose: Positron emission tomography (PET) with 11C-labelled Pittsburgh compound B ([11C]PIB) enables the quantitation of beta-amyloid accumulation in the brain of patients with Alzheimer's disease (AD). Voxel-based image analysis techniques conducted in a standard brain space provide an objective, rapid and fully automated method to analyze [11C]PIB PET data. The purpose of this study was to evaluate both region- and voxel-level reproducibility of automated and simplified [11C]PIB quantitation when using only 30 min of imaging data., Methods: Six AD patients and four healthy controls were scanned twice with an average interval of 6 weeks. To evaluate the feasibility of short scanning (convenient for AD patients), [11C]PIB uptake was quantitated using 30 min of imaging data (60 to 90 min after tracer injection) for region-to-cerebellum ratio calculations. To evaluate the reproducibility, a test-retest design was used to derive absolute variability (VAR) estimates and intraclass correlation coefficients at both region-of-interest (ROI) and voxel level., Results: The reproducibility both at the region level (VAR 0.9-5.5%) and at the voxel level (VAR 4.2-6.4%) was good to excellent. Based on the variability estimates obtained, power calculations indicated that 90% power to obtain statistically significant difference can be achieved using a sample size of five subjects per group when a 15% change from baseline (increase or decrease) in [11C]PIB accumulation in the frontal cortex is anticipated in one group compared to no change in another group., Conclusion: Our results showed that an automated analysis method based on an efficient scanning protocol provides reproducible results for [11C]PIB uptake and appears suitable for PET studies aiming at the quantitation of amyloid accumulation in the brain of AD patients for the evaluation of progression and treatment effects.

Unlabelled: We investigated the biodistribution and radiation dosimetry of the PET amyloid imaging agent (11)C-PIB ((11)C-6-OH-BTA-1) (where BTA is benzothiazole) in humans. Previous radiation exposure estimates have been based on animal experiments. A dosimetry study in humans is essential for a balanced risk-benefit assessment of (11)C-PIB PET studies., Methods: We used data from 16 different (11)C-PIB PET scans on healthy volunteers to estimate radiation exposure. Six of these scans were dynamic imaging over the abdominal region: 3 covering the upper abdomen and 3 covering the middle abdomen. On average, 489 MBq of (11)C-PIB (range, 416-606 MBq) were injected intravenously, and dynamic emission scans were recorded for up to 40 min. Two subjects had whole-body imaging over the entire body to illustrate the biodistribution. PET brain scans and blood and urine radioactivity measurements from our previous (11)C-PIB studies were also analyzed. Thirteen source organs and the remainder of the body were studied to estimate residence times and mean radiation-absorbed doses. The MIRD method was used to calculate the radiation exposure of selected target organs and the body as a whole., Results: There is a high degree of consistency between our human data and previous biodistribution information based on baboons. In our study, the highest radiation-absorbed doses were received by the gallbladder wall (41.5 microGy/MBq), liver (19.0 microGy/MBq), urinary bladder wall (16.6 microGy/MBq), kidneys (12.6 microGy/MBq), and upper large intestine wall (9.0 microGy/MBq). The hepatobiliary and renal systems were the major routes of clearance and excretion, with approximately 20% of the injected radioactivity being excreted into urine. The effective radiation dose was 4.74 microSv/MBq., Conclusion: The established clinical dose of (11)C-PIB required for 3-dimensional PET amyloid imaging has an acceptable effective radiation dose. This dose is comparable with the average exposure expected in other PET brain receptor tracer studies. (11)C-PIB is rapidly cleared from the body, largely by the kidneys. From the viewpoint of radiation safety, these results support the use of (11)C-PIB in clinical PET studies.