As the need to develop a successful disease-modifying treatment for Alzheimer’s disease (AD) becomes more urgent, imaging is increasingly used in therapeutic trials. We provide an overview of how the different imaging modalities are used in AD studies and the current regulatory guidelines for their use in clinical trials as endpoints. We review the current literature for results of imaging endpoints of efficacy and safety in published clinical trials. We start with trials in mild to moderate AD, where imaging (largely magnetic resonance imaging (MRI)) has long played a role in inclusion and exclusion criteria; more recently, MRI has been used to identify adverse events and to measure rates of brain atrophy. The advent of amyloid imaging using positron emission tomography has led to trials incorporating amyloid measurements as endpoints and incidentally to the recognition of the high proportion of amyloid-negative individuals that may be recruited into these trials. Ongoing and planned trials now commonly include multimodality imaging: amyloid positron emission tomography, MRI and other modalities. At the same time, the failure of recent large profile trials in mild to moderate AD together with the realisation that there is a long prodromal period to AD has driven a push to move studies to earlier in the disease. Imaging has particularly important roles, alongside other biomarkers, in assessing efficacy because conventional clinical outcomes may have limited ability to detect treatment effects in these early stages.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0087-9) contains supplementary material, which is available to authorized users.
Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by impaired higher visual processing skills; however, motor features more commonly associated with corticobasal syndrome may also occur. We investigated the frequency and clinical characteristics of motor features in 44 PCA patients and, with 30 controls, conducted voxel-based morphometry, cortical thickness, and subcortical volumetric analyses of their magnetic resonance imaging. Prominent limb rigidity was used to define a PCA-motor subgroup. A total of 30% (13) had PCA-motor; all demonstrating asymmetrical left upper limb rigidity. Limb apraxia was more frequent and asymmetrical in PCA-motor, as was myoclonus. Tremor and alien limb phenomena only occurred in this subgroup. The subgroups did not differ in neuropsychological test performance or apolipoprotein E4 allele frequency. Greater asymmetry of atrophy occurred in PCA-motor, particularly involving right frontoparietal and peri-rolandic cortices, putamen, and thalamus. The 9 patients (including 4 PCA-motor) with pathology or cerebrospinal fluid all showed evidence of Alzheimer's disease. Our data suggest that PCA patients with motor features have greater atrophy of contralateral sensorimotor areas but are still likely to have underlying Alzheimer's disease.
•We investigated motor features and their neuroimaging correlates in 44 posterior cortical atrophy (PCA) patients.•A total of 30% had asymmetrical left upper limb rigidity and were termed the “PCA-motor” group.•Limb apraxia was more frequent and asymmetrical in PCA-motor, as was myoclonus.•PCA-motor had greater asymmetry of atrophy, involving the right sensorimotor areas.•The subgroup with pathology or cerebrospinal fluid all showed evidence of Alzheimer's disease.
Posterior cortical atrophy; Corticobasal syndrome; Alzheimer's disease; Phenotype; Asymmetric atrophy
La Substance Use Risk Profile Scale (SURPS) est un instrument de dépistage des caractéristiques de personnalité qui représentent un risque pour le développement d’une consommation problématique de substances. La SURPS comporte 23 items évaluant 4 dimensions et permet aux intervenants en santé mentale de mieux cibler la prévention. La SURPS a été validée au Canada anglais, au Royaume-Uni, en Chine et au Sri Lanka; l’objectif de cette étude est de valider une traduction française de la SURPS pour des adolescents francophones québécois, en plus d’en tester la sensibilité dans une population clinique.
Deux cent deux jeunes de 15 ans d’un échantillon communautaire ont répondu à la SURPS et à des mesures de la personnalité et de l’utilisation de substances. La cohérence interne, la solution factorielle et la validité concomitante de l’échelle ont été évaluées. Quarante adolescents (âge moyen de 15,7 ans) présentant un diagnostic psychiatrique ont également répondu à la SURPS et les scores ont été comparés aux normes de l’échantillon communautaire.
La traduction française de la SURPS démontre une bonne cohérence interne ainsi qu’une solution factorielle à 4 facteurs semblable à la version originale. Ses 4 souséchelles ont une bonne validité concomitante. De plus, 3 de ses souséchelles sont corrélées avec des mesures relatives à la consommation de substances psychoactives. Finalement, 95 % des participants de l’échantillon clinique ont été identifiés à risque selon les scores limites de la SURPS.
La version française de la SURPS paraît être une mesure valide et sensible pouvant être utilisée auprès d’une population adolescente, québécoise et francophone.
PMID: 24099502 CAMSID: cams3463
adolescents; alcool; drogues; personnalité; programme de prévention sélectif
Most research linking early pubertal development to substance use has focused on the effects of pubertal timing (age at which a certain stage of pubertal development is reached or pubertal status at a particular age—related to the maturation disparity hypothesis), but little research has focused on pubertal tempo (rate of growth through pubertal stages—related to the maturation compression hypothesis). However, both timing and tempo have not only been identified as important components of pubertal development, with different predictors, but have also been shown to be independently associated with other adolescent psychopathologies. Using latent growth-curve modeling, this study examined how pubertal status at age 12 and pubertal tempo (between 11 and 13 years) related to substance use from 15 to 16 years in boys from low socioeconomic backgrounds (N = 871). Results showed that both pubertal status at age 12 and tempo were significant predictors of increased levels of substance use and problems in mid to late adolescence. In an attempt to identify mechanisms that may explain the association between pubertal development and substance use it was found that sensation seeking partially mediated the association between pubertal status at age 12 and substance use behaviors. Impulse control was found to moderate the association sensation seeking had with marijuana use frequency, with high sensation-seeking scores predicting higher marijuana use frequency only at low levels of impulse control. These findings highlight the importance of considering multiple sources of individual variability in the pubertal development of boys and provide support for both the maturational disparity and compression hypotheses.
PMID: 24016016 CAMSID: cams3462
adolescence; puberty; substance use; impulsivity; sensation seeking
Adolescent substance use is associated with both earlier childhood behavioural problems and serious lifetime addiction problems later in life.
To examine whether, and through which mechanisms, targeting risk factors in early childhood prevents substance use across adolescence.
Disruptive kindergarten boys (n = 172) living in Montreal were randomly allocated to a preventive intervention and a control condition. The intervention was delivered over 2 years (7–9 years of age) with two main components: (a) social and problem-solving skills training for the boys; and (b) training for parents on effective child-rearing skills.
Adolescent substance use, up to 8 years post-intervention, was reduced in those who received the intervention (d = 0.48–0.70). Of most interest, the intervention effects were explained partly by reductions in impulsivity, antisocial behaviour and affiliation with less deviant peers during pre-adolescence (11–13 years).
Adolescent substance use may be indirectly prevented by selectively targeting childhood risk factors that disrupt the developmental cascade of adolescent risk factors for substance use.
Declaration of interest
PMID: 23929441 CAMSID: cams3461
Alzheimer's disease (AD) causes devastating cognitive impairment and an intense research effort is currently devoted to developing improved treatments for it. A minority of cases occur at a particularly young age and are caused by autosomal dominantly inherited genetic mutations. Although rare, familial AD provides unique opportunities to gain insights into the cascade of pathological events and how they relate to clinical manifestations. The phenotype of familial AD is highly variable and, although it shares many clinical features with sporadic AD, it also possesses important differences. Exploring the genetic and pathological basis of this phenotypic heterogeneity can illuminate aspects of the underlying disease mechanism, and is likely to inform our understanding and treatment of AD in the future.
amyloid precursor protein; dominantly inherited Alzheimer's disease; early-onset dementia; familial Alzheimer's disease; presenilins
Associating with substance using peers is generally considered as one of the most important predictors of adolescent substance use. However, peer association does not affect all adolescents in the same way. To better understand when and under what conditions peer association is most linked with adolescent substance use (SU), this review focuses on the factors that may operate as moderators of this association. The review highlighted several potential moderators reflecting adolescents’ individual characteristics (e.g., pubertal status, genes and personality), peer and parental factors (e.g., nature of relationships and parental monitoring), and contextual factors (e.g., peer, school and neighborhood context). As peer association is a broad concept, important methodological aspects were also addressed in order to illustrate how they can potentially bias interpretation. Taking these into account, we suggest that, while the effects of some moderators are clear (e.g., parental monitoring and sensation seeking), others are less straightforward (e.g., neighborhood) and need to be further examined. This review also provides recommendations for addressing different methodological concerns in the study of moderators, including: the use of longitudinal and experimental studies and the use of mediated moderation. These will be key for developing theory and effective prevention.
PMID: 24183303 CAMSID: cams3491
Peers; substance use; alcohol use; adolescence; moderation effect
A compulsivity spectrum has been hypothesized to exist across Obsessive-Compulsive disorder (OCD), Eating Disorders (ED), substance abuse (SA) and binge-drinking (BD). The objective was to examine the validity of this compulsivity spectrum, and differentiate it from an externalizing behaviors dimension, but also to look at hypothesized personality and neural correlates.
A community-sample of adolescents (N=1938; mean age 14.5 years), and their parents were recruited via high-schools in 8 European study sites. Data on adolescents’ psychiatric symptoms, DSM diagnoses (DAWBA) and substance use behaviors (AUDIT and ESPAD) were collected through adolescent- and parent-reported questionnaires and interviews. The phenotypic structure of compulsive behaviors was then tested using structural equation modeling. The model was validated using personality variables (NEO-FFI and TCI), and Voxel-Based Morphometry (VBM) analysis.
Compulsivity symptoms best fit a higher-order two factor model, with ED and OCD loading onto a compulsivity factor, and BD and SA loading onto an externalizing factor, composed also of ADHD and conduct disorder symptoms. The compulsivity construct correlated with neuroticism (r=0.638; p≤0.001), conscientiousness (r=0.171; p≤0.001), and brain gray matter volume in left and right orbitofrontal cortex, right ventral striatum and right dorsolateral prefrontal cortex. The externalizing factor correlated with extraversion (r=0.201; p≤0.001), novelty-seeking (r=0.451; p≤0.001), and negatively with gray matter volume in the left inferior and middle frontal gyri.
Results suggest that a compulsivity spectrum exists in an adolescent, preclinical sample and accounts for variance in both OCD and ED, but not substance-related behaviors, and can be differentiated from an externalizing spectrum.
To assess regional patterns of gray and white matter atrophy in familial Alzheimer disease (FAD) mutation carriers.
A total of 192 participants with volumetric T1-weighted MRI, genotyping, and clinical diagnosis were available from the Dominantly Inherited Alzheimer Network. Of these, 69 were presymptomatic mutation carriers, 50 were symptomatic carriers (31 with Clinical Dementia Rating [CDR] = 0.5, 19 with CDR > 0.5), and 73 were noncarriers from the same families. Voxel-based morphometry was used to identify cross-sectional group differences in gray matter and white matter volume.
Significant differences in gray matter (p < 0.05, family-wise error–corrected) were observed between noncarriers and mildly symptomatic (CDR = 0.5) carriers in the thalamus and putamen, as well as in the temporal lobe, precuneus, and cingulate gyrus; the same pattern, but with more extensive changes, was seen in those with CDR > 0.5. Significant white matter differences between noncarriers and symptomatic carriers were observed in the cingulum and fornix; these form input and output connections to the medial temporal lobe, cingulate, and precuneus. No differences between noncarriers and presymptomatic carriers survived correction for multiple comparisons, but there was a trend for decreased gray matter in the thalamus for carriers closer to their estimated age at onset. There were no significant increases of gray or white matter in asymptomatic or symptomatic carriers compared to noncarriers.
Atrophy in FAD is observed early, both in areas commonly associated with sporadic Alzheimer disease and also in the putamen and thalamus, 2 regions associated with early amyloid deposition in FAD mutation carriers.
An expanded hexanucleotide repeat in the C9orf72 gene is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). We now report the first description of a homozygous patient and compare it to a series of heterozygous cases. The patient developed early-onset frontotemporal dementia without additional features. Neuropathological analysis showed c9FTD/ALS characteristics, with abundant p62-positive inclusions in the frontal and temporal cortices, hippocampus and cerebellum, as well as less abundant TDP-43-positive inclusions. Overall, the clinical and pathological features were severe, but did not fall outside the usual disease spectrum. Quantification of C9orf72 transcript levels in post-mortem brain demonstrated expression of all known C9orf72 transcript variants, but at a reduced level. The pathogenic mechanisms by which the hexanucleotide repeat expansion causes disease are unclear and both gain- and loss-of-function mechanisms may play a role. Our data support a gain-of-function mechanism as pure homozygous loss of function would be expected to lead to a more severe, or completely different clinical phenotype to the one described here, which falls within the usual range. Our findings have implications for genetic counselling, highlighting the need to use genetic tests that distinguish C9orf72 homozygosity.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1147-0) contains supplementary material, which is available to authorized users.
C9orf72; ALS; FTD
The primary progressive aphasias (PPA) are a heterogeneous group of language-led neurodegenerative diseases resulting from large-scale brain network degeneration. White matter (WM) pathways bind networks together, and might therefore hold information about PPA pathogenesis. Here we used diffusion tensor imaging and tract-based spatial statistics to compare WM tract changes between PPA syndromes and with respect to Alzheimer's disease and healthy controls in 33 patients with PPA (13 nonfluent/agrammatic PPA); 10 logopenic variant PPA; and 10 semantic variant PPA. Nonfluent/agrammatic PPA was associated with predominantly left-sided and anterior tract alterations including uncinate fasciculus (UF) and subcortical projections; semantic variant PPA with bilateral alterations in inferior longitudinal fasciculus and UF; and logopenic variant PPA with bilateral but predominantly left-sided alterations in inferior longitudinal fasciculus, UF, superior longitudinal fasciculus, and subcortical projections. Tract alterations were more extensive than gray matter alterations, and the extent of alteration across tracts and PPA syndromes varied between diffusivity metrics. These WM signatures of PPA syndromes illustrate the selective vulnerability of brain language networks in these diseases and might have some pathologic specificity.
Primary progressive aphasia; DTI; Networks; White matter
Amyloid imaging studies of presymptomatic familial Alzheimer’s disease have revealed the striatum and thalamus to be the earliest sites of amyloid deposition. This study aimed to investigate whether there are associated volume and diffusivity changes in these subcortical structures during the presymptomatic and symptomatic stages of familial Alzheimer’s disease. As the thalamus and striatum are involved in neural networks subserving complex cognitive and behavioural functions, we also examined the diffusion characteristics in connecting white matter tracts. A cohort of 20 presenilin 1 mutation carriers underwent volumetric and diffusion tensor magnetic resonance imaging, neuropsychological and clinical assessments; 10 were symptomatic, 10 were presymptomatic and on average 5.6 years younger than their expected age at onset; 20 healthy control subjects were also studied. We conducted region of interest analyses of volume and diffusivity changes in the thalamus, caudate, putamen and hippocampus and examined diffusion behaviour in the white matter tracts of interest (fornix, cingulum and corpus callosum). Voxel-based morphometry and tract-based spatial statistics were also used to provide unbiased whole-brain analyses of group differences in volume and diffusion indices, respectively. We found that reduced volumes of the left thalamus and bilateral caudate were evident at a presymptomatic stage, together with increased fractional anisotropy of bilateral thalamus and left caudate. Although no significant hippocampal volume loss was evident presymptomatically, reduced mean diffusivity was observed in the right hippocampus and reduced mean and axial diffusivity in the right cingulum. In contrast, symptomatic mutation carriers showed increased mean, axial and in particular radial diffusivity, with reduced fractional anisotropy, in all of the white matter tracts of interest. The symptomatic group also showed atrophy and increased mean diffusivity in all of the subcortical grey matter regions of interest, with increased fractional anisotropy in bilateral putamen. We propose that axonal injury may be an early event in presymptomatic Alzheimer’s disease, causing an initial fall in axial and mean diffusivity, which then increases with loss of axonal density. The selective degeneration of long-coursing white matter tracts, with relative preservation of short interneurons, may account for the increase in fractional anisotropy that is seen in the thalamus and caudate presymptomatically. It may be owing to their dense connectivity that imaging changes are seen first in the thalamus and striatum, which then progress to involve other regions in a vulnerable neuronal network.
familial Alzheimer’s disease; presenilin 1 (PSEN1, PS1); presymptomatic; diffusion tensor imaging; subcortical atrophy
The current paper aims to review findings from developmental research that are related to adolescent substance-use and are considered key for improving theory and developing effective prevention.
A selective literature review of relevant developmental studies on adolescent substance-use was conducted.
Studies in epidemiology and developmental science focusing on developmental onset, developmental transitions, comorbidity among disorders, and endophenotypes have identified important trends, risk-factors for and consequences of adolescent substance-use, which have informed theoretical models of addiction. Furthermore, they have informed clinical practice by identifying childhood disorders and personality characteristics that can be targeted preventatively before substance-use problems have their onset.
Developmental research has contributed significantly to the understanding of aetiology and treatment of substance-use disorders. By targeting early liability factors rather than substance-use problems later in adolescence, interventions could reduce the adverse impact substance-use has on the developing brain as well as other associated harms.
substance-use; adolescence; development; aetiology; prevention; utilisation de substances; adolescence; développement; étiologie; prévention
Tract-based spatial statistics (TBSS) is a popular method for the analysis of diffusion tensor imaging data. TBSS focuses on differences in white matter voxels with high fractional anisotropy (FA), representing the major fibre tracts, through registering all subjects to a common reference and the creation of a FA skeleton. This work considers the effect of choice of reference in the TBSS pipeline, which can be a standard template, an individual subject from the study, a study-specific template or a group-wise average. While TBSS attempts to overcome registration error by searching the neighbourhood perpendicular to the FA skeleton for the voxel with maximum FA, this projection step may not compensate for large registration errors that might occur in the presence of pathology such as atrophy in neurodegenerative diseases. This makes registration performance and choice of reference an important issue. Substantial work in the field of computational anatomy has shown the use of group-wise averages to reduce biases while avoiding the arbitrary selection of a single individual. Here, we demonstrate the impact of the choice of reference on: (a) specificity (b) sensitivity in a simulation study and (c) a real-world comparison of Alzheimer's disease patients to controls. In (a) and (b), simulated deformations and decreases in FA were applied to control subjects to simulate changes of shape and WM integrity similar to what would be seen in AD patients, in order to provide a “ground truth” for evaluating the various methods of TBSS reference. Using a group-wise average atlas as the reference outperformed other references in the TBSS pipeline in all evaluations.
Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
With the prospect of prevention trials for familial Alzheimer's disease on the horizon, understanding the natural history of the illness has never been so important. Earlier this year in The Lancet Neurology, Acosta-Baena and colleagues published the results of the largest and longest retrospective study of pre-dementia clinical stages in familial Alzheimer's disease to date. By reviewing serial neuropsychological assessments of individuals from a large Colombian kindred affected by the E280A mutation in the Presenilin 1 gene, they defined three stages of pre-dementia cognitive impairment. Using survival analyses, the authors estimated the median age at onset and rate of progression through each of these stages towards dementia and ultimately death. Their study provides valuable insights into the time course of cognitive decline associated with this mutation. Furthermore, the study highlights some of the challenges of defining pre-dementia clinical stages in familial Alzheimer's disease and the need for the field to develop a consistent terminology.
Medial temporal lobe atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), however, it can be prominent in frontotemporal lobar degeneration (FTLD). There is an increasing awareness that posterior atrophy (PA) is important in AD and may aid the differentiation of AD from FTLD. Visual rating scales are a convenient way of assessing atrophy in a clinical setting. In this study, 2 visual rating scales measuring MTA and PA were used to compare atrophy patterns in 62 pathologically-confirmed AD and 40 FTLD patients. Anatomical correspondence of MTA and PA was assessed using manually-delineated regions of the hippocampus and posterior cingulate gyrus, respectively. Both MTA and PA scales showed good inter- and intrarater reliabilities (kappa > 0.8). MTA scores showed a good correspondence with manual hippocampal volumes. Thirty percent of the AD patients showed PA in the absence of MTA. Adding the PA to the MTA scale improved discrimination of AD from FTLD, and early-onset AD from normal aging. These results underline the importance of considering PA in AD diagnosis, particularly in younger patients where medial temporal atrophy may be less conspicuous.
Visual rating scales; Posterior atrophy; Medial temporal lobe atrophy; MRI; Dementia; Pathology; Manual volumes
Amyloid precursor protein gene (APP) duplications have been identified in screens of selected probands with early onset familial Alzheimer's disease (FAD). A causal role for copy number variation (CNV) in the prion protein gene (PRNP) in prion dementias is not known. We aimed to determine the prevalence of copy number variation in APP and PRNP in a large referral series, test a screening method for detection of the same, and expand knowledge of clinical phenotype. We used a 3-tiered screening assay for APP and PRNP duplication (exonic real-time quantitative polymerase chain reaction [exon-qPCR], fluorescent microsatellite quantitative PCR [fm-q-PCR], and Illumina array [Illumina Inc., San Diego, CA, USA]) for analysis of a heterogeneous referral series comprising 1531 probands. Five of 1531 probands screened showed APP duplication, a similar prevalence to APP missense mutation. Real-time quantitative PCR and fluorescent microsatellite quantitative PCR were similar individually but are theoretically complementary; we used Illumina arrays as our reference assay. Two of 5 probands were from an autosomal dominant early onset Alzheimer's disease (familial Alzheimer's disease) pedigree. One extensive, noncontiguous duplication on chromosome 21 was consistent with an unbalanced translocation not including the Down's syndrome critical region. Seizures were prominent in the other typical APP duplications. A range of imaging, neuropsychological, cerebrospinal fluid, and pathological findings are reported that extend the known phenotype. APP but not PRNP duplication is a significant cause of early onset dementia in the UK. The recognized phenotype may be expanded to include the possibility of early seizures and apparently sporadic disease which, in part, may be due to different mutational mechanisms. The pros and cons of our screening method are discussed.
APP; Duplication; PRNP; Prion; Chromosome 21; Dementia
Cohesin-mediated sister chromatid cohesion is essential for chromosome segregation and post-replicative DNA repair1,2. In addition, evidence from model organisms3-6 and from human genetics7 suggests that cohesin plays a role in the control of gene expression8,9. This non-canonical role has recently been rationalized by the findings that mammalian cohesin complexes are recruited to a subset of DNase I hypersensitive sites (HSS) and to conserved non-coding sequences by the DNA binding protein CTCF10-13. CTCF functions at insulators (which control interactions between enhancers and promoters) and at boundary elements (which demarcate regions of distinct chromatin structure)14, and cohesin contributes to CTCF’s enhancer blocking activity10,11. The underlying mechanisms remain unknown, and the full spectrum of cohesin functions remains to be elucidated. Here we show that cohesin forms the topological and mechanistic basis for cell type-specific long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG. Hence, cohesin’s ability to constrain chromosome topology is utilized not only for the purpose of sister chromatid cohesion1,2, but also to dynamically define the spatial conformation of specific loci. This novel aspect of cohesin function is likely of importance to normal development3-6 and to disease7.
Differentiated cells can be reprogrammed through the formation of heterokaryons and hybrid cells when fused with embryonic stem (ES) cells. Here, we provide evidence that conversion of human B-lymphocytes towards a multipotent state is initiated much more rapidly than previously thought, occurring in transient heterokaryons before nuclear fusion and cell division. Interestingly, reprogramming of human lymphocytes by mouse ES cells elicits the expression of a human ES-specific gene profile, in which markers of human ES cells are expressed (hSSEA4, hFGF receptors and ligands), but markers that are specific to mouse ES cells are not (e.g., Bmp4 and LIF receptor). Using genetically engineered mouse ES cells, we demonstrate that successful reprogramming of human lymphocytes is independent of Sox2, a factor thought to be required for induced pluripotent stem (iPS) cells. In contrast, there is a distinct requirement for Oct4 in the establishment but not the maintenance of the reprogrammed state. Experimental heterokaryons, therefore, offer a powerful approach to trace the contribution of individual factors to the reprogramming of human somatic cells towards a multipotent state.
One of the most pressing objectives of medical research today is the development of approaches to restore the function of tissues damaged by accident or disease. An important goal for this work is the isolation of stem cell populations to replace missing or nonfunctioning cells. Because problems of immune rejection are likely to occur unless the recipient and donor stem cells are very closely matched, a desirable strategy is to convert differentiated cells (such as white blood cells) from patients into immature tailored stem cell populations. Here, we have experimentally fused human white blood cells and mouse embryonic stem cells and shown that this reprograms them to become stem-like. This kind of “differentiation reversal” is shown to be rapid and stable. It requires the stem cell–specific factor Oct4, but does not require Sox2. This approach allows the identification of factors that are required to reprogram human blood cells with the long-term perspective to eventually generate patient-specific stem cells.
It has been reported that mania may be associated with superior cognitive performance. In this study, we test the hypothesis that manic symptoms in youth separate along two correlated dimensions and that a symptom constellation of high energy and cheerfulness is associated with superior cognitive performance.
We studied 1755 participants of the IMAGEN study, of average age 14.4 years (SD = 0.43), 50.7% girls. Manic symptoms were assessed using the Development and Wellbeing Assessment by interviewing parents and young people. Cognition was assessed using the Wechsler Intelligence Scale For Children (WISC-IV) and a response inhibition task.
Manic symptoms in youth formed two correlated dimensions: one termed exuberance, characterized by high energy and cheerfulness and one of undercontrol with distractibility, irritability and risk-taking behavior. Only the undercontrol, but not the exuberant dimension, was independently associated with measures of psychosocial impairment. In multivariate regression models, the exuberant, but not the undercontrolled, dimension was positively and significantly associated with verbal IQ by both parent- and self-report; conversely, the undercontrolled, but not the exuberant, dimension was associated with poor performance in a response inhibition task.
Our findings suggest that manic symptoms in youth may form dimensions with distinct correlates. The results are in keeping with previous findings about superior performance associated with mania. Further research is required to study etiological differences between these symptom dimensions and their implications for clinical practice.
Mania; bipolar; intelligence; adolescents; creativity