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Atrophy is regarded a sensitive marker of neurodegenerative pathology. In addition to confirming the well-known presence of decreased global grey matter and hippocampal volumes in Alzheimer's disease, this study investigated whether deep grey matter structure also suffer degeneration in Alzheimer's disease, and whether such degeneration is associated with cognitive deterioration. In this cross-sectional correlation study, two groups were compared on volumes of seven subcortical regions: 70 memory complainers (MCs) and 69 subjects diagnosed with probable Alzheimer's disease. Using 3T 3D T1 MR images, volumes of nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen and thalamus were automatically calculated by the FMRIB's Integrated Registration and Segmentation Tool (FIRST)--algorithm FMRIB's Software Library (FSL). Subsequently, the volumes of the different regions were correlated with cognitive test results. In addition to finding the expected association between hippocampal atrophy and cognitive decline in Alzheimer's disease, volumes of putamen and thalamus were significantly reduced in patients diagnosed with probable Alzheimer's disease. We also found that the decrease in volume correlated linearly with impaired global cognitive performance. These findings strongly suggest that, beside neo-cortical atrophy, deep grey matter structures in Alzheimer's disease suffer atrophy as well and that degenerative processes in the putamen and thalamus, like the hippocampus, may contribute to cognitive decline in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Objective: Direct oral anticoagulants have been evaluated in the general population, but proper evidence for their safe use in the geriatric population is still missing. We compared the bleeding risk of a direct oral anticoagulant (rivaroxaban) and vitamin K antagonists (VKAs) among French geriatric patients with non-valvular atrial fibrillation (AF) aged ≥80 years., Methods: We performed a sequential observational prospective cohort study, using data from 33 geriatric centres. The sample comprised 908 patients newly initiated on VKAs between September 2011 and September 2014 and 995 patients newly initiated on rivaroxaban between September 2014 and September 2017. Patients were followed up for up to 12 months. One-year risks of major, intracerebral, gastrointestinal bleedings, ischaemic stroke and all-cause mortality were compared between rivaroxaban-treated and VKA-treated patients with propensity score matching and Cox models., Results: Major bleeding risk was significantly lower in rivaroxaban-treated patients (7.4/100 patient-years) compared with VKA-treated patients (14.6/100 patient-years) after multivariate adjustment (HR 0.66; 95% CI 0.43 to 0.99) and in the propensity score-matched sample (HR 0.53; 95% CI 0.33 to 0.85). Intracerebral bleeding occurred less frequently in rivaroxaban-treated patients (1.3/100 patient-years) than in VKA-treated patients (4.0/100 patient-years), adjusted HR 0.59 (95% CI 0.24 to 1.44) and in the propensity score-matched sample HR 0.26 (95% CI 0.09 to 0.80). Major lower bleeding risk was largely driven by lower risk of intracerebral bleeding., Conclusions: Our study findings indicate that bleeding risk, largely driven by lower risk of intracerebral bleeding, is lower with rivaroxaban than with VKA in stroke prevention in patients ≥80 years old with non-valvular AF., Competing Interests: Competing interests: OH received personal fees from Bayer Healthcare, Servier, Astra-Zeneca, Boston Scientific, Vifor, BMS, Pfizer and Boehringer Ingelheim. J-SV received fees from Bayer for non-profit medical association. SB received grant from Bayer. LF received personal fees from Bayer Healthcare, Boehringer Ingelheim, BMS – Pfizer, Medtronic and Novartis. PJ received personal fees from Pfizer. GS received fees from Smeka for non-profit medical association. FB received non-financial support from Bristol-Myers Squibb and Bayer Healthcare. JB received personal fees and non-financial support from Pfizer and Novartis. FP received personal fees from Bayer Healthcare, BMS – Pfizer, Boehringer Ingelheim, Daiichi Sankyo and Novartis. EP received personal fees from Bayer Healthcare, LeoPharma, BMS – Pfizer and received non-financial support from Nutrica. ML, J-PD, EC, GO, GP-D, NB, LWdJ, LC, PK-S, ASB and UV have nothing to disclose., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: The authors report no conflict of interest.

Place cell activity of hippocampal pyramidal cells has been described as the cognitive substrate of spatial memory. Replay is observed during hippocampal sharp-wave-ripple-associated population burst events (PBEs) and is critical for consolidation and recall-guided behaviors. PBE activity has historically been analyzed as a phenomenon subordinate to the place code. Here, we use hidden Markov models to study PBEs observed in rats during exploration of both linear mazes and open fields. We demonstrate that estimated models are consistent with a spatial map of the environment, and can even decode animals' positions during behavior. Moreover, we demonstrate the model can be used to identify hippocampal replay without recourse to the place code, using only PBE model congruence. These results suggest that downstream regions may rely on PBEs to provide a substrate for memory. Additionally, by forming models independent of animal behavior, we lay the groundwork for studies of non-spatial memory., Competing Interests: KM, EA, Ld, BP, DF, KD, CK No competing interests declared, (© 2018, Maboudi et al.)

There is growing evidence that sub-structures of the brain scale allometrically to total brain size, that is, in a non-proportional and non-linear way. Here, scaling of different volumes of interest (VOI) to intra-cranial volume (ICV) was examined. It was assessed whether scaling was allometric or isometric and whether scaling coefficients significantly differed from each other. We also tested to what extent allometric scaling of VOI was introduced by the automated segmentation technique. Furthermore, reproducibility of allometric scaling was studied different age groups and study populations. Study samples included samples of cognitively healthy adults from the community-based Age Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik Study) (N = 3,883), the Coronary Artery Risk Development in Young Adults Study (CARDIA) (N =709), and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 180). Data encompassed participants with different age, ethnicity, risk factor profile, and ICV and VOI obtained with different automated MRI segmentation techniques. Our analysis showed that (1) allometric scaling is a trait of all parts of the brain, (2) scaling of neo-cortical white matter, neo-cortical gray matter, and deep gray matter structures including the cerebellum are significantly different from each other, and (3) allometric scaling of brain structures cannot solely be explained by age-associated atrophy, sex, ethnicity, or a systematic bias from study-specific segmentation algorithm, but appears to be a true feature of brain geometry. Hum Brain Mapp 38:151-164, 2017. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors report no conflicts of interest., (© 2016 Wiley Periodicals, Inc.)

Objectives: Hypertension is a risk factor for cognitive impairment and dementia. Arterial stiffness could be involved in the mechanisms of vascular cognitive impairment and in Alzheimer's disease. We examined the association between arterial stiffness, assessed by carotid-femoral pulse wave velocity (PWV), and medial temporal lobe (MTL) atrophy, a biomarker of Alzheimer's disease., Methods: Elderly community-dwelling study participants (n = 149) with memory complaints were diagnosed with Alzheimer's disease (n = 62) or mild cognitive impairment (n = 87) at a memory clinic. PWV, peripheral and central blood pressure (SBP), and pulse pressure (PP) were measured. MTL was graded on MRI according to the Scheltens' scale., Results: Mean age was 79.5 (SD = 5) years old, 36% of study participants were men. MTL was absent or discrete in 23.5%, moderate in 53.0% and severe in 23.5% of study participants. PWV was 9.3 (2.2) m/s in none or discrete, 11.1 (2.8) in moderate and 13.5 (4.0) in severe MTL atrophy (P < 0.0001). PWV, central SBP, and central PP were overall associated with MTL atrophy after adjustment for age, sex, antihypertensive treatments and white matter lesions, and further adjusted for mean BP for PWV, whereas peripheral SBP and PP were not associated with MTL atrophy. PWV was significantly associated with severe MTL atrophy [odds ratio = 3.69 (95% confidence interval = 1.69-8.05), P = 0.001] and marginally associated with moderate MTL atrophy [1.80 (0.92-3.53), P = 0.09]. Furthermore PWV was significantly associated with severe MTL atrophy in Alzheimer's disease and mild cognitive impairment study participants separately., Conclusion: The result of this study suggests a role of arterial stiffness in the pathogenesis of Alzheimer's disease.

Atrophy of the medial temporal lobe (MTL) and basal ganglia (BG) are characteristic of various neurodegenerative diseases in older people. In search of potentially modifiable factors that lead to atrophy in these structures, we studied the association of vascular risk factors with atrophy of the MTL and BG in 368 nondemented men and women (born, 1907-1935) who participated in the Age, Gene/Environment, Susceptibility-Reykjavik Study. A fully automated segmentation pipeline estimated volumes of the MTL and BG from whole-brain magnetic resonance imaging performed at baseline and 2.4 years later. Linear regression models showed higher systolic and diastolic blood pressures and the presence of Apo E ε4 were independently associated with increased atrophy of the MTL but no association of vascular risk factors with atrophy of the BG. The different susceptibility of MTL and BG atrophy to the vascular risk factors suggests perfusion of the BG is relatively preserved when vascular risk factors are present., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: In dementia screening, most studies have focused on early cognitive impairment by comparing patients suffering from mild dementia or mild cognitive impairment with normal subjects. Few studies have focused on modifications over time of the cognitive function in the healthy elderly. The objective of the present study was to analyze the cognitive function changes of two different samples, born > 15 years apart., Method: A first sample of 204 cognitively normal participants was recruited in the memory clinic of Broca hospital between 1991 and 1997. A second sample of 177 cognitively normal participants was recruited in 2008-2009 in the same institution. Both samples were from the same districts of Paris and were assessed with the same neuropsychological test battery. Mean cognitive test scores were compared between 1991 and 2008 samples, between < 80 years old and ≥ 80 years old in 1991 and 2008 samples, and finally between subjects < 80 year old of 1991 sample and subjects ≥ 80 years old of the 2008 sample. Means were compared with T-tests stratified on gender, age-groups and educational level., Results: Cognitive scores were significantly higher in the 2008 sample. Participants < 80 years old outperformed those ≥ 80 in both samples. However, participants < 80 years old in 1991 sample and subjects ≥ 80 in the 2008 sample, born on average in 1923, performed mostly identically., Conclusion: This study showed a significant increase of cognitive scores over time. Further, contemporary octogenarians in the later sample performed like septuagenarians in the former sample. These findings might be consistent with the increase in life expectancy and life span in good health. The study highlights the necessity to take into account factors which may contaminate and artificially inflate the age-related differences in favor of younger to the older adults.

Striatal degeneration may contribute to cognitive impairment in older people. Here, we examine the relation of degeneration of the striatum and substructures to cognitive decline and dementia in subjects with a wide range of cognitive function. Data are from the prospective community-based Honolulu Asia Aging Study of Japanese American men born 1900-1919. Brain magnetic resonance imaging (MRI) (1.5 T) was acquired on a stratified subsample (n = 477) that included four groups defined by cognitive status relative to the scan date: subjects without dementia (n = 347), subjects identified as demented 2-3 years before brain scanning (n = 30), at the time of scanning (n = 58), and 3-5 years after scanning (n = 42). Volumes of the striatum, including the accumbens, putamen, and caudate nucleus were automatically estimated from T1 MR images. Global cognitive function was measured with the cognitive ability screening instrument (CASI), at four examinations spanning an 8-year interval. Trajectories of cognitive decline were estimated for each quartile of striatal volume using mixed models, controlling for demographic variables, measures of cerebro-vascular damage, global brain atrophy, and hippocampal volume. Diagnosis of dementia before, during, and after brain scanning was associated with smaller volumes of n. accumbens and putamen, but not with caudate nucleus volume. Subjects in the lowest quartile of n. accumbens volume, both in the total sample and in the subjects not diagnosed with dementia during the study, had a significantly (p < 0.0001) steeper decline in cognitive performance compared with those in the highest quartile. In conclusion, volumes of the n. accumbens and putamen are closely associated with the occurrence of dementia and n. accumbens volume predicts cognitive decline in older people. These associations were found independent of the magnitude of other pivotal markers of cognitive decline, i.e. cerebro-vascular damage and hippocampal volume. The present study suggests a role for the ventral striatum in the development of clinical dementia., (Published by Elsevier Inc.)

Rodent spatial navigation requires the dynamic evaluation of multiple sources of information, including visual cues, self-motion signals and reward signals. The nature of the evaluation, its dynamics and the relative weighting of the multiple information streams are largely unknown and have generated many hypotheses in the field of robotics. We use the framework of the traveling salesperson problem (TSP) to study how this evaluation may be achieved. The TSP is a classical artificial intelligence NP-hard problem that requires an agent to visit a fixed set of locations once, minimizing the total distance traveled. We show that after a few trials, rats converge on a short route between rewarded food cups. We propose that this route emerges from a series of local decisions that are derived from weighing information embedded in the context of the task. We study the relative weighting of spatial and reward information and establish that, in the conditions of this experiment, when the contingencies are not in conflict, rats choose the spatial or reward optimal solution. There was a trend toward a preference for space when the contingencies were in conflict. We also show that the spatial decision about which cup to go to next is biased by the orientation of the animal. Reward contingencies are also shown to significantly and dynamically modulate the decision-making process. This paradigm will allow for further neurophysiological studies aimed at understanding the synergistic role of brain areas involved in planning, reward processing and spatial navigation. These insights will in turn suggest new neural-like architectures for the control of mobile autonomous robots.

Objectives: The purpose of this work was to assess the long-term outcome of adolescents with chronic fatigue syndrome who received cognitive behavioral therapy and to determine the predictive value of fatigue severity and physical impairments of the adolescent and the fatigue severity of the mother at baseline for the outcome of the treatment at follow-up., Patients and Methods: Sixty-six adolescent patients with chronic fatigue syndrome who previously participated in a randomized, controlled trial that showed that cognitive behavioral therapy was more effective than a waiting-list condition in reducing fatigue and improving physical functioning were contacted for a follow-up assessment. Fifty participants of the follow-up study had received cognitive behavioral therapy for chronic fatigue syndrome (32 formed the cognitive behavioral therapy group in the original trial, and 18 patients received cognitive behavioral therapy after the waiting period). The remaining 16 patients had refused cognitive behavioral therapy after the waiting period. The main outcome measures were fatigue severity (Checklist Individual Strength), physical functioning (Short-Form General Health Survey), and school attendance., Results: Data were complete for 61 patients at follow-up (cognitive behavioral therapy group: 47 patients; no-treatment group: 14 patients). The mean follow-up time was 2.1 years. There was no significant change in fatigue severity between posttreatment and follow-up in the cognitive behavioral therapy group. There was a significant further increase in physical functioning and school attendance (10% increase). The adolescents in the cognitive behavioral therapy group were significantly less fatigued and significantly less functionally impaired and had higher school attendance at follow-up than those in the no-treatment group. Fatigue severity of the mother was a significant predictor of treatment outcome., Conclusions: The positive effects of cognitive behavioral therapy in adolescents with chronic fatigue syndrome are sustained after cognitive behavioral therapy. Higher fatigue severity of the mother predicts lower treatment outcome in adolescent patients.

In 2005, the Dutch College of General Practitioners revised their guideline on pelvic inflammatory disease (PID). It is difficult to diagnose PID because of the variability in the presentation of the disease. The revised guideline is a solid guide in the diagnostic process. History taking and physical examination are the most important diagnostic techniques, but require experience. Any diagnostic uncertainty justifies the consultation ofa specialist. The value ofsupplementary diagnostics in a specialist setting is limited. In case of suspected PID, cervical material should always be cultured for Chlamydia trackomatis and Neisseria gonorrhoeae, even if treatment has already been started. Laparoscopy is considered to be the gold standard in the diagnosis of PID. but is only performed if other methods do not suffice. Fast and adequate treatment considerably decreases the risk of serious complications, such as fertility disorders. Therefore, adequate antibiotic therapy covering at least the above-mentioned pathogens should be started if other causes of abdominal pain, such as ectopic pregnancy, appendicitis and torsion of the adnexal mass, have been excluded.

Objectives: Genetic factors appear to be important in the development of restenosis after percutaneous coronary intervention, as well as in the process of inflammation, a pivotal factor in restenosis. Caspase-1, interleukin-1-receptor and protein tyrosine phosphatase nonreceptor type 22 are important mediators in the inflammatory response and caspase-1 also in apoptosis. Therefore, we examined whether polymorphisms in these candidate genes are related to the risk of developing restenosis after percutaneous coronary intervention., Methods: The GENetic DEterminants of Restenosis-project is a multicenter prospective follow-up study. The 5352G/A (L235L) caspase-1-polymorphism, the 7464C/G (A124G) interleukin-1r-polymorphism and the 1858C/T (R620W) protein tyrosine phosphatase nonreceptor type 22-polymorphism were genotyped. To examine the functional effect of the caspase-1 polymorphism, mature plasma interleukin-1beta levels were measured by enzyme-linked immunosorbent assay in lipopolysaccharide-stimulated whole blood from a subpopulation of patients., Results: A total of 3104 patients, age 62.1+/-10.7 years, were included after successful percutaneous coronary intervention. A significant association between the 5352AA genotype of the caspase-1 gene and target vessel revascularization (relative risk 2.2, 95% confidence interval 1.32-3.76) was observed after correcting for clinical variables. Angiographic analysis of a subgroup of patients (N=478) also showed an increased risk for developing restenosis for patients having the 5352GA/AA genotype (P=0.001). The results were corroborated, although they were not statistically significant, by somewhat higher mature interleukin-1beta levels in patients with the 5352AA genotype., Conclusions: The present study shows that patients with the 5352AA genotype in the caspase-1 gene are at increased risk of developing restenosis. If confirmed by other studies, screening patients for this genotype can lead to better risk stratification and provide indications for improving individual treatment; for instance, by providing a new target for drug-eluting stents.

Objective: To evaluate the efficacy of cognitive behaviour therapy for adolescents aged 10-17 years with chronic fatigue syndrome., Design: Randomised controlled trial., Setting: Department of child psychology., Participants: 71 consecutively referred patients with chronic fatigue syndrome; 36 were randomly assigned to immediate cognitive behaviour therapy and 35 to the waiting list for therapy., Intervention: 10 sessions of therapy over five months. Treatment protocols depended on the type of activity pattern (relatively active or passive). All participants were assessed again after five months., Main Outcome Measures: Fatigue severity (checklist individual strength), functional impairment (SF-36 physical functioning), and school attendance., Results: 62 patients had complete data at five months (29 in the immediate therapy group and 33 on the waiting list). Patients in the therapy group reported significantly greater decrease in fatigue severity (difference in decrease on checklist individual strength was 14.5, 95% confidence interval 7.4 to 21.6) and functional impairment (difference in increase on SF-36 physical functioning was 17.3, 6.2 to 28.4) and their attendance at school increased significantly (difference in increase in percentage school attendance was 18.2, 0.8 to 35.5). They also reported a significant reduction in several accompanying symptoms. Self reported improvement was largest in the therapy group., Conclusion: Cognitive behaviour therapy is an effective treatment for chronic fatigue syndrome in adolescents.

Thirty patients with early and continuously treated phenylketonuria (PKU) between 8 and 20 years of age were compared with 30 controls, matched individually for age, sex, and educational level of both parents, on behaviour rating scales for parents and teachers as well as a school achievement scale. PKU patients, as a group, demonstrated more problems in task-oriented behaviour and average academic performance than did matched controls. Interestingly, whereas male PKU patients were rated significantly lower on introversion by their teachers, female patients were rated significantly higher on introversion and lower on extraversion than matched controls. This sex difference was also reflected in the relationship between measures of dietary control and the behaviour clusters, suggesting that male and female patients respond differently to elevated Phe levels or the stress associated with PKU. The teacher rating on average academic performance of the PKU patients was associated with recent level of dietary control, which suggests that it might be improved by more strict adherence to the diet. In addition, academic performance correlated negatively with the behaviour cluster negative task orientation. Further studies are recommended to obtain a more complete evaluation of this relationship and to replicate the current findings on larger samples. Over the years a number of studies have examined behaviour and school achievement in patients with early treated phenylketonuria (PKU; McKusick 261600). In general, these studies have found that despite early treatment with a phenylalanine (Phe)-restricted diet, PKU patients demonstrate more behavioural and school problems than do healthy controls. The behaviour problems include both internalizing symptoms (e.g. solitary, unresponsive, anxious, depressed mood: Pietz et al 1997; Smith et al 1988; Weglage et al 1992) and externalizing symptoms (e.g. hyperactive, talkative, impulsive, restless: Hendrikx et al 1994; Kalverboer et al 1994; Realmuto et al 1986; Smith et al 1988), but not antisocial or socially negative symptoms (e.g. lying, teasing, disobedience: Kalverboer et al 1994; Pietz et al 1997; Smith et al 1988). With respect to school achievement, studies have shown that patients with early treated PKU more often repeat classes or need special tutoring (Berry et al 1979; Brunner et al 1983; Koch et al 1987; Rey et al 1996; Verkerk 1995), have to work harder than healthy controls to achieve the same results (Weglage et al 1993), or have specific deficits in arithmetic achievement scores (Azen et al 1991; Berry et al 1979; Fishler et al 1987; Koch et al 1987; Weglage et al 1993). Nevertheless, many questions regarding the behavioural and school problems of patients with early treated PKU remain unanswered. For instance, the relationship between behavioural and school problems on the one hand and levels of dietary control on the other is still relatively unclear. The few studies that examined this relationship, have focused primarily on children in primary school (Azen et al 1991; Koch et al 1987; Smith et al 1988). Furthermore, although several psychological studies have shown that the pattern of behavioural problems varies by sex (see Prior et al 1999a for a discussion), so far very few studies have examined this issue in PKU patients and results are contradictory (Kalverboer et al 1994; Pietz et al 1997; Smith et al 1988; Weglage et al 1992). In addition, so far no study has actually examined whether there is a relationship between the behavioural problems and school difficulties of PKU patients, even though this relationship has been well documented in the psychological literature (Prior et al 1999b; Richards et al 1995). The aim of the present study is therefore to examine these issues in patients with early and continuously treated PKU over a wide age range and in relation to dietary control. More specifically, school achievement as well as social and task-oriented behaviour (at home

The prevalence of chronic fatigue syndrome (CFS) in teenagers is 10-20 per 100,000 inhabitants in the Netherlands. The natural course of the disorder is not favourable according to the literature. Proposed criteria for the diagnosis 'CFS' in adolescence are: absence of a physical explanation for the complaints, a disabling fatigue for at least six months and prolonged school absenteeism or severe motor and social disabilities. Exclusion criterion should be a psychiatric disorder. Factors that attribute to the persistence of fatigue are somatic attributions, illness enhancing cognitions and behaviour of parents as well as physical inactivity. The role of the physician and the role of parents can enhance the problems. The treatment should focus on decreasing the somatic attributions, on reinforcement by the parents of healthy adolescent behaviour, on the gradual increase of physical activity and on decreasing attention (including medical attention) for the somatic complaints.

This study addresses whether precocious puberty influences the child-rearing practices of parents. Three patients groups, girls with idiopathic precocious puberty, with premature thelarche and with premature pubarche were studied. These groups were compared with each other, and with reference groups of 'normal' school children and children referred for asthma or referred for behavioural problems. The results showed that the parents of the total group of patients did not experience more family stress and did not appraise their child-rearing situation as being more problematic than that of parents of normal school children, and they had significantly fewer problems than the parents of children referred for asthma of for behavioural problems. Within the group results suggested that parents of girls with premature pubarche experienced more family stress than those of the two other groups. Parents reported specific physical and educational concerns about their daughters. Therefore we recommend that specific attention should be given through a programme of relevant information.