Mechanical Stretch Induces Senescence of Lung Epithelial Cells and Drives Fibroblast Activation by Paracrine Mechanisms.

Severe lung injury requiring mechanical ventilation may lead to secondary fibrosis. Senescence, a cell response characterized by cell cycle arrest and a shift towards a proinflammatory/profibrotic phenotype, is one of the involved mechanisms. Here, we explore the contribution of mechanical stretch as trigger of senescence of the respiratory epithelium and its link with fibrosis. Human lung epithelial cells and fibroblasts were exposed in vitro to mechanical stretch, and senescence assessed. In addition, fibroblasts were exposed to culture media preconditioned by senescent epithelial cells and their activation was studied. Transcriptomic profiles from stretched, senescent epithelial cells and activated fibroblasts were combined to identify potential activated pathways. Finally, the senolytic effects of digoxin were tested in these models. Mechanical stretch induced senescence in lung epithelial cells, but not in fibroblasts. This stretch-induced senescence has specific features compared to senescence induced by doxorubicin. Fibroblasts were activated after exposure to supernatants conditioned by epithelial senescent cells. Transcriptomic analyses revealed notch signaling as a potential responsible for the epithelial-mesenchymal crosstalk, as blockade of this pathway inhibits fibroblast activation. Treatment with digoxin reduced the percentage of senescent cells after stretch and ameliorated the fibroblast response to preconditioned media. These results suggest that lung fibrosis in response to mechanical stretch may be caused by the paracrine effects of senescent cells. This pathogenetic mechanism can be pharmacologically manipulated to improve lung repair.

Broad white matter impairment in multiple system atrophy.

Multiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by the widespread aberrant accumulation of α-synuclein (α-syn). MSA differs from other synucleinopathies such as Parkinson's disease (PD) in that α-syn accumulates primarily in oligodendrocytes, the only source of white matter myelination in the brain. Previous MSA imaging studies have uncovered focal differences in white matter. Here, we sought to build on this work by taking a global perspective on whole brain white matter. In order to do this, in vivo structural imaging and diffusion magnetic resonance imaging were acquired on 26 MSA patients, 26 healthy controls, and 23 PD patients. A refined whole brain approach encompassing the major fiber tracts and the superficial white matter located at the boundary of the cortical mantle was applied. The primary observation was that MSA but not PD patients had whole brain deep and superficial white matter diffusivity abnormalities (p < .001). In addition, in MSA patients, these abnormalities were associated with motor (Unified MSA Rating Scale, Part II) and cognitive functions (Mini-Mental State Examination). The pervasive whole brain abnormalities we observe suggest that there is widespread white matter damage in MSA patients which mirrors the widespread aggregation of α-syn in oligodendrocytes. Importantly, whole brain white matter abnormalities were associated with clinical symptoms, suggesting that white matter impairment may be more central to MSA than previously thought.

Reconstrucción de experiencias y percepciones propias de jóvenes habitantes de calle / Reconstruction of experiences and self-perceptions of homeless young people / Reconstrução da experiência e percepções próprias dos jovens em situação de rua

Resumen (analítico): En este artículo describimos los resultados de la investigación realizada en la Casa de Acogida para jóvenes de Medellín, trabajo en el que buscamos dar cuenta de la autopercepción de los individuos jóvenes en situación de calle que están en una etapa de recuperación, en relación con la forma en que los perciben los otros. Para ello, implementamos una metodología de investigación de tipo cualitativa, orientada por un enfoque fenomenológico que permitiera la reconstrucción de sus experiencias. En el diseño metodológico mezclamos técnicas experienciales con la realización de grupos focales, lo que nos permitió el levantamiento de la información. Entre los hallazgos presentamos las reflexiones que las personas jóvenes realizan sobre su proceso de resocialización, la estigmatización y las iniciativas relacionadas con el cambio de vida.

Abstract (analytical): This article describes the results of research carried out in the Medellin Youth Reception House. The study explored the self-perception of homeless youth who are now in the recovery phase, in terms of how they are perceived by others. A methodology of qualitative investigation using a phenomenological approach was applied and facilitated the reconstruction of their experiences. The information was gathered using a mix of experiential techniques and focus groups. The results of the study include the subjects' reflections on their process of re-socialization, stigmatization and initiatives related to how they changed their lives form. change of life are among the findings in this study.

Resumo (analítico): Neste artigo se descrevem os resultados da pesquisa realizada no Abrigo para jovens de Medellín, que procurou explicar a auto-percepção dos jovens moradores de rua que estão em uma fase de recuperação, em relação à forma como eles são percebidos pelos outros, para o qual foi implementada uma metodologia de pesquisa qualitativa guiada por uma abordagem fenomenológica que permitiria a reconstrução das suas experiências. No desenho metodológico foram misturadas técnicas experienciais com a realização de grupos focais que permitiram o levantamento da informação. Entre os resultados são apresentadas as reflexões que os jovens fizeram sobre o seu processo de ressocialização, a estigmatização e as iniciativas relacionadas com a mudança de vida.

Author Correction: Mental workload and neural efficiency quantified in the prefrontal cortex using fNIRS.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Effective translation of a type-2 diabetes primary prevention programme into routine primary care: The PreDE cluster randomised clinical trial.

AIMS: We assessed the effectiveness of a Type 2 diabetes mellitus (T2D) prevention programme in routine primary health care (PHC) in high-risk patients. METHODS: Phase IV cluster clinical trial involving 14 PHC centres in the Basque Health Service were randomised to the DE-PLAN educational healthy lifestyle promotion programme or standard care. All non-diabetic 45- to 70-year-old PHC attendees considered at high risk of T2D (FINDRISC ≥ 14 points) were eligible. The primary outcome was the 24-month cumulative incidence of T2D confirmed by oral glucose tolerance testing. Secondary outcomes were self-reported physical activity and dietary changes at 12 months in a subsample. RESULTS: Of the 4170 patients screened, 2128 (51%) were considered high risk, but 355 (33%) and 459 (43.6%) refused to participate in the control and intervention groups, respectively. Of all eligible non-diabetic patients, 634 and 454 were included in the control and intervention arms, 545 (85.9%) and 411 (90.5%) completed the follow-up. Intention-to-treat cumulative incidences of T2D were 12.1% (77/634) in the control group and 8.4% (38/454) in intervention group, with an absolute difference of 3.8% (95% CI: 0.18%-7.4%, p = 0.045) and a relative risk reduction of 32% (0.68; 95% CI: 0.47-0.99, p = 0.048) in favour of the intervention. Intervention patients were 1.83-fold more likely to meet recommended physical activity levels at 12 months (95% CI: 1.06-3.17, p = 0.03). CONCLUSIONS: The DE-PLAN programme was effective in reducing T2D incidence in PHC high-risk patients. Research on implementation strategies to improve its feasible and sustainable adoption, reach and public health impact is warranted.

Impact of diabetes on caregiver stress in patients with Alzheimer's disease: data from the ICTUS study.

ABSTRACTBackground:To estimate the impact of comorbid diabetes on caregiver stress in Alzheimer's disease (AD) patients from the Impact of Cholinergic Treatment Use (ICTUS) study. METHODS: Using the Data from the ICTUS study, diabetes mellitus (DM) was recorded at baseline and caregiver burden was assessed twice per year using the Zarit Burden Interview (ZBI) scale. The three-factorial model of ZBI (the effect on the social and personal life of caregivers, the psychological burden and the feelings of guilt) was adopted. Linear mixed models were used to examine the relation between DM and the scores of ZBI. RESULTS: The present analyses were conducted on 1,264 AD subjects. A total of 156 patients (12.3%) had DM with taking antidiabetic medication and/or self-report of a history. At baseline, the caregivers of patients with or without DM had similar ZBI global scores and similar scores of three different factors of ZBI. Unadjusted and adjusted models both indicated that ZBI global score increased over a 24-month follow-up without significant effect of DM. Similarly, unadjusted model showed that DM was not determining any significant difference in the score of any factor. However, adjusted model indicated that in diabetic patients, the scores of the social and personal life of caregivers and the psychological burden increased more slowly than those in non-diabetic patients (p = 0.04 and 0.01, respectively). CONCLUSIONS: DM may affect the caregivers' daily social and personal life and psychological burden in AD patients. It is necessary for further research.

Mental workload and neural efficiency quantified in the prefrontal cortex using fNIRS.

An improved understanding of how the brain allocates mental resources as a function of task difficulty is critical for enhancing human performance. Functional near infrared spectroscopy (fNIRS) is a field-deployable optical brain monitoring technology that provides a direct measure of cerebral blood flow in response to cognitive activity. We found that fNIRS was sensitive to variations in task difficulty in both real-life (flight simulator) and laboratory settings (tests measuring executive functions), showing increased concentration of oxygenated hemoglobin (HbO2) and decreased concentration of deoxygenated hemoglobin (HHb) in the prefrontal cortex as the tasks became more complex. Intensity of prefrontal activation (HbO2 concentration) was not clearly correlated to task performance. Rather, activation intensity shed insight on the level of mental effort, i.e., how hard an individual was working to accomplish a task. When combined with performance, fNIRS provided an estimate of the participants' neural efficiency, and this efficiency was consistent across levels of difficulty of the same task. Overall, our data support the suitability of fNIRS to assess the mental effort related to human operations and represents a promising tool for the measurement of neural efficiency in other contexts such as training programs or the clinical setting.

Cognitive Frailty: Mechanisms, Tools to Measure, Prevention and Controversy.

Physical frailty is often associated with cognitive impairment, possibly because of common underlying pathophysiologic mechanisms. To stimulate research in this field, the concept cognitive frailty was proposed, emphasizing the important role of brain aging. Cognitive frailty was defined as the presence of cognitive deficits in physically frail older persons without dementia. This subtype of frailty is deemed important, as it may represent a prodromal phase for neurodegenerative diseases and is potentially a suitable target for early intervention. The aim of this report is to refine the framework for the definition and mechanisms of cognitive frailty and relevant screening tools.

Refining Mild-to-Moderate Alzheimer Disease Screening: A Tool for Clinicians.

OBJECTIVES: Recent evidence suggests that a substantial minority of people clinically diagnosed with probable Alzheimer disease (AD) in fact do not fulfill the neuropathological criteria for the disease. A clinical hallmark of these phenocopies of AD is that these individuals tend to remain cognitively stable for extended periods of time, in contrast to their peers with confirmed AD who show a progressive decline. We aimed to examine the prevalence of patients clinically diagnosed with mild-to-moderate AD who do not experience the expected clinically significant cognitive decline and identify markers easily available in routine medical practice predictive of a stable cognitive prognosis in this population. DESIGN: Data were obtained from two independent, longitudinal, observational multicenter studies in patients with mild-to-moderate AD. SETTING: The two studies were the European "Impact of Cholinergic Treatment Use" (ICTUS) and the French "REseau sur la maladie d'Alzheimer FRançais" (REAL.FR). PARTICIPANTS: We used prospective data of 756 patients enrolled in ICTUS and 340 enrolled in REAL.FR. MEASUREMENTS: A prediction rule of cognitive decline was derived on ICTUS using classification and regression tree analysis and then cross-validated on REAL.FR. A range of demographic, clinical and cognitive variables were tested as predictor variables. RESULTS: Overall, 27.9% of patients in ICTUS and 20.9% in REAL.FR did not decline over 2 years. We identified optimized cut-points on the verbal memory items of the Alzheimer Disease Assessment Scale-Cognitive Subscale capable of classifying patients at baseline into those who went on to decline and those who remained stable or improved over the duration of the trial. CONCLUSION: The application of this simple rule would allow the identification of dementia cases where a more detailed differential diagnostic examination (eg, with biomarkers) is warranted. These findings are promising toward the refinement of AD screening in the clinic. For a further optimization of our classification rule, we encourage others to use our methodological approach on other episodic memory assessment tools designed to detect even small cognitive changes in patients with AD.

Predicting the Rate of Cognitive Decline in Alzheimer Disease: Data From the ICTUS Study.

BACKGROUND: Different rates of cognitive progression have been observed among Alzheimer disease (AD) patients. The present study aimed at evaluating whether the rate of cognitive worsening in AD may be predicted by widely available and easy-to-assess factors. METHODS: Mild to moderate AD patients were recruited in the ICTUS study. Multinomial logistic regression analysis was performed to measure the association between several sociodemographic and clinical variables and 3 different rates of cognitive decline defined by modifications (after 1 year of follow-up) of the Mini Mental State Examination (MMSE) score: (1) "slow" progression, as indicated by a decrease in the MMSE score ≤1 point; (2) "intermediate" progression, decrease in the MMSE score between 2 and 5 points; and (3) "rapid" progression, decrease in the MMSE score ≥6 points. RESULTS: A total of 1005 patients were considered for the present analyses. Overall, most of the study participants (52%) exhibited a slow cognitive course. Higher ADAS-Cog scores at baseline were significantly associated with both "intermediate" and "rapid" decline. Conversely, increasing age was negatively associated with "rapid" cognitive worsening. CONCLUSIONS: A slow progression of cognitive decline is common among AD patients. The influence of age and baseline cognitive impairment should always be carefully considered when designing AD trials and defining study populations.

Frailty Index and Cognitive Decline in Alzheimer's Disease: Data from the Impact of Cholinergic Treatment USe Study.

OBJECTIVES: To determine whether the Frailty Index (FI) was associated with short-term cognitive decline (according to changes in Mini Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores at 1-year follow-up) in individuals with Alzheimer's disease (AD). DESIGN: Prospective cohort study. SETTING: Impact of Cholinergic Treatment USe study. PARTICIPANTS: Individuals with mild-to-moderate AD (N = 973). MEASUREMENTS: Severity of dementia was assessed using the Clinical Dementia Rating (CDR). FI was calculated as the ratio of actual to potential deficits (deficits present divided by 30). Linear regression analyses were performed and stratified according to severity of dementia. RESULTS: A 1-unit (0.033 points) increase in FI corresponded to significant and clinically relevant cognitive decline, after adjustments for age, sex, and years of education (0.63-4.63 points on the MMSE, P = .01; 2.87-11.1 points on the ADAS-Cog, P = .001) after 1 year of follow-up. Differences in changes in MMSE and ADAS-Cog scores between nonfrail and frail individuals were 0.67 and 1.6 points, respectively. Although statistically significant, the clinical relevance of this finding remains to be further investigated. CONCLUSION: The FI may be a promising instrument for the assessment of the vulnerability of individuals with AD. Its implementation in clinical practice may support clinical decisions by identifying individuals at high risk of negative outcomes, specifically, short-term cognitive decline.

Type-2 diabetes primary prevention program implemented in routine primary care: a process evaluation study.

BACKGROUND: Process evaluation studies are recommended to improve our understanding of underlying mechanisms related to clinicians, patients, context and intervention delivery that may impact on trial or program results and on their potential transferability to practice. This paper aims to document the translation of a type-2 diabetes (T2D) prevention program into the routine context of several primary care centers, assessing process indicators related to clinician adoption, patient recruitment, exposure to the intervention components and baseline characteristics. METHODS: An observational descriptive process evaluation study was conducted of the 2.5-year implementation of the Prevention of Diabetes in Euskadi cluster randomized trial in 14 primary care centers of the Basque Health Service (Osakidetza). The clinical intervention consisted of three components: (1) risk screening, (2) an educational intervention promoting healthy lifestyles, and (3) remote support (follow-up). A passive dissemination strategy of providing training and materials was used to translate the intervention into practice. All non-diabetic patients aged 45 to 70 years who were identified as being at high risk of developing T2D were eligible for study inclusion. The RE-AIM framework guided the process evaluation. RESULTS: Overall, 31.4 % of family physicians and 57.6 % of nurses participated in the study, while 4170 out of 67,293 (6.2 %) targeted patients who attended the centers during the implementation period were reached through the screening. Around half of the screened patients were identified as being at high risk of developing T2D (FINDRISC score ≥14). The rate of refusal to participate and the proportion of women were higher in the intervention group. Finally, 634 and 454 non-diabetic 45- to 70-year-old patients who were at high risk of T2D were included in the control and intervention group centers (intervention reach = 48 %). Significant variability in most process indicators was observed at center level. CONCLUSION: The passive dissemination strategy has produced modest process indicators related to the adoption, reach and implementation of the intervention program, and reduced the possibility of its standardized application in heterogeneous contexts. The resulting different procedures and strategies used by the centers were associated with process outcomes. Context-specific variability and possible confounding will require rigorous procedures for analysis of the intervention effects. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov (identifier: NCT01365013 ). Registered on June 2011.

Adverse effects of pneumonia on physical functioning in nursing home residents: Results from the INCUR study.

BACKGROUND: Pneumonia is a very common infection in the nursing home, but little is known about its effects on levels of individual functioning. The aim of this study was to examine adverse effects of pneumonia events on physical functioning in nursing home residents. METHODS: Data were used from the INCUR study, a 1-year prospective cohort study of older residents from 13 nursing homes in France. The sample consisted of 716 residents, who were assessed at baseline, 6 and 12 months. Pneumonia diagnosis was based on clinical conditions documented in medical records. Physical functioning was measured by Activities of Daily Living (ADL). Longitudinal associations between pneumonia and physical functioning were explored using Generalized Estimating Equations (GEE). RESULTS: Of 716 participants, 145 (20%) had one or more pneumonia events during 12 months follow-up. Mean age of the participants was 86.0 (SD=7.4)years, and 76% of them were female. Overall, participants had relatively low levels of physical functioning at baseline (Mean ADL=2.4 out of 6, SD=1.8). The GEE analyses adjusted for age, gender, baseline physical functioning, and hospitalization during follow-up showed that pneumonia events had adverse effects on ADL functioning (B=-0.21, SE=0.08, p=0.008). Pneumonia events were mainly associated with loss of independence in transferring from bed to chair and bathing. CONCLUSIONS: In a population of nursing home residents where levels of physical functioning were already relatively low, pneumonia events were associated with loss of physical functioning. These results highlight the importance of preventive interventions aimed at reducing pneumonia in nursing home residents.

Brain Amyloid Deposition Is Associated With Lower Instrumental Activities of Daily Living Abilities in Older Adults. Results From the MAPT Study.

BACKGROUND: Brain amyloid deposition is one of the key pathological hallmarks underlying the cognitive changes associated with Alzheimer's disease. Growing interest has been given to the earliest clinical manifestations of amyloid plaques. However, the relationship between amyloid status and activities of everyday function remains largely unknown. In the present study, we examined the relationship between instrumental activities of daily living performance (using the ADL-PI score) and amyloid status in older adults. METHODS: Cross-sectional analyses of data from the Multidomain Alzheimer Preventive Trial (MAPT) were performed. Volunteers underwent a brain 18F-AV45 positron emission tomography examination. Bivariate analysis and regression models were conducted to study the relationships between brain amyloid deposition and the total ADL-PI score. RESULTS: We included 271 participants (women = 60%; age = 76±4 years). Amyloid positron emission tomography was positive (standard uptake value ≥1.17) for 103 participants (38%). The ADL-PI score was lower in amyloid positive participants than in their amyloid negative counterparts (38.8 vs 40.3, p = .007). This association was also confirmed in regression models adjusted for age, gender, and familial history of Alzheimer's disease (odds ratio = 0.94; 95% confidence interval 0.89-0.99; p = .02). This finding was consistent in cognitively normal individuals and in those with mild cognitive impairment, using the clinical dementia rating scale. CONCLUSIONS: This study highlighted an association between early functional limitations and brain amyloid deposition in elderly subjects. These symptoms could be the clinical manifestations of amyloid plaques even in the absence of overt dementia. Further prospective studies are warranted for examining the evolution of ADL-PI score over the course of Alzheimer's disease.

Relationship of regional brain ß-amyloid to gait speed.

OBJECTIVE: To investigate in vivo the relationship of regional brain ß-amyloid (Aß) to gait speed in a group of elderly individuals at high risk for dementia. METHODS: Cross-sectional associations between brain Aß as measured with [18F]florbetapir PET and gait speed were examined in 128 elderly participants. Subjects ranged from healthy to mildly cognitively impaired enrolled in the control arm of the multidomain intervention in the Multidomain Alzheimer Preventive Trial (MAPT). Nearly all participants presented spontaneous memory complaints. Regional [18F]florbetapir (AV45) standardized uptake volume ratios were obtained via semiautomated quantitative analysis using the cerebellum as reference region. Gait speed was measured by timing participants while they walked 4 meters. Associations were explored with linear regression, correcting for age, sex, education, body mass index (BMI), and APOE genotype. RESULTS: We found a significant association between Aß in the posterior and anterior putamen, occipital cortex, precuneus, and anterior cingulate and slow gait speed (all corrected p < 0.05). A multivariate model emphasized the locations of the posterior putamen and the precuneus. Aß burden explained up to 9% of the variance in gait speed, and significantly improved regression models already containing demographic variables, BMI, and APOE status. CONCLUSIONS: The present PET study confirms, in vivo, previous postmortem evidence showing an association between Alzheimer disease (AD) pathology and gait speed, and provides additional evidence on potential regional effects of brain Aß on motor function. More research is needed to elucidate the neural mechanisms underlying these regional associations, which may involve motor and sensorimotor circuits hitherto largely neglected in the pathophysiology of AD.

Brain health: the importance of recognizing cognitive impairment: an IAGG consensus conference.

Cognitive impairment creates significant challenges for patients, their families and friends, and clinicians who provide their health care. Early recognition allows for diagnosis and appropriate treatment, education, psychosocial support, and engagement in shared decision-making regarding life planning, health care, involvement in research, and financial matters. An IAGG-GARN consensus panel examined the importance of early recognition of impaired cognitive health. Their major conclusion was that case-finding by physicians and health professionals is an important step toward enhancing brain health for aging populations throughout the world. This conclusion is in keeping with the position of the United States' Centers for Medicare and Medicaid Services that reimburses for detection of cognitive impairment as part the of Medicare Annual Wellness Visit and with the international call for early detection of cognitive impairment as a patient's right. The panel agreed on the following specific findings: (1) validated screening tests are available that take 3 to 7 minutes to administer; (2) a combination of patient- and informant-based screens is the most appropriate approach for identifying early cognitive impairment; (3) early cognitive impairment may have treatable components; and (4) emerging data support a combination of medical and lifestyle interventions as a potential way to delay or reduce cognitive decline.

A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment.

Through the combined use of (18)F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case-control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.

Neural and behavioral endophenotypes in ADHD.

In recent years, descriptive symptom-based approaches of attention deficit hyperactivity disorder (ADHD) have been increasingly replaced by more sophisticated endophenotype-based strategies, better suited to investigate its pathophysiological basis, which is inherently heterogeneous. Measurements derived from neuroimaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) constitute endophenotypes of growing interest, capable of providing unprecedented windows on neurochemical and neuroanatomical components of psychiatric conditions. This chapter reviews the current state of knowledge regarding putative neural and behavioral endophenotypes of ADHD, across the lifespan. To this end, recent evidence drawn from molecular and structural neuroimaging studies are discussed in the light of widely accepted neuropsychological and pharmacological models of ADHD.

The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder.

Through neuromodulatory influences over fronto-striato-cerebellar circuits, dopamine and noradrenaline play important roles in high-level executive functions often reported to be impaired in attention-deficit/hyperactivity disorder (ADHD). Medications used in the treatment of ADHD (including methylphenidate, dextroamphetamine and atomoxetine) act to increase brain catecholamine levels. However, the precise prefrontal cortical and subcortical mechanisms by which these agents exert their therapeutic effects remain to be fully specified. Herein, we review and discuss the present state of knowledge regarding the roles of dopamine (DA) and noradrenaline in the regulation of corticostriatal circuits, with a focus on the molecular neuroimaging literature (both in ADHD patients and in healthy subjects). Recent positron emission tomography evidence has highlighted the utility of quantifying DA markers, at baseline or following drug administration, in striatal subregions governed by differential cortical connectivity. This approach opens the possibility of characterizing the neurobiological underpinnings of ADHD (and associated cognitive dysfunction) and its treatment by targeting specific neural circuits. It is anticipated that the application of refined and novel positron emission tomography methodology will help to disentangle the overlapping and dissociable contributions of DA and noradrenaline in the prefrontal cortex, thereby aiding our understanding of ADHD and facilitating new treatments.

Quantification of receptor-ligand binding potential in sub-striatal domains using probabilistic and template regions of interest.

Sub-striatal regions of interest (ROIs) are widely used in PET studies to investigate the role of dopamine in the modulation of neural networks implicated in emotion, cognition and motor function. One common approach is that of Mawlawi et al. (2001) and Martinez et al. (2003), where each striatum is divided into five sub-regions. This study focuses on the use of two spatial normalization-based alternatives to manual sub-striatal ROI delineation per subject: manual ROI delineation on a template brain and the production of probabilistic ROIs from a set of subject-specific manually delineated ROIs. Two spatial normalization algorithms were compared: SPM5 unified segmentation and ART. The ability of these methods to quantify sub-striatal regional non-displaceable binding potential (BP(ND)) and BP(ND) % change (following methylphenidate) was tested on 32 subjects (16 controls and 16 ADHD patients) scanned with the dopamine D(2)/D(3) ligand [(18)F]fallypride. Probabilistic ROIs produced by ART provided the best results, with similarity index values against subject-specific manual ROIs of 0.75-0.89 (mean 0.84) compared to 0.70-0.85 (mean 0.79) for template ROIs. Correlations (r) for BP(ND) and BP(ND) % change between subject-specific manual ROIs and these probabilistic ROIs of 0.90-0.98 (mean 0.95) and 0.98-1.00 (mean 0.99) respectively were superior overall to those obtained with template ROIs, although only marginally so for BP(ND) % change. The significance of relationships between BP(ND) measures and both behavioural tasks and methylphenidate plasma levels was preserved with ART combined with both probabilistic and template ROIs. SPM5 virtually matched the performance of ART for BP(ND) % change estimation but was inferior for BP(ND) estimation in caudate sub-regions. ART spatial normalization combined with probabilistic ROIs and to a lesser extent template ROIs provides an efficient and accurate alternative to time-consuming manual sub-striatal ROI delineation per subject, especially when the parameter of interest is BP(ND) % change.