Obsessive–compulsive disorder and spectrum across the life span

An obsessive–compulsive disorder (OCD) spectrum has been proposed, which includes a group of disorders that share certain features with OCD including clinical symptoms (repetitive behaviours and thoughts), neurobiology (e.g. neurotransmitters) and preferential response to anti-obsessional treatments, such as the selective serotonin reuptake inhibitors (SSRIs). Three distinct clusters have been identified within the OCD spectrum, i.e. disorders concerning preoccupations with bodily sensations or appearance, impulsive disorders, and neurologically based disorders, and these share phenotypic features. Using one example from each of these clusters, body dysmorphic disorder (BDD), pathological gambling (PG) and autism, respectively, the phenomenology, neurobiology and pharmacotherapy indicates that specific biological factors are shared by OCD and by these disorders and correlate with the severity of repetitive behaviours. Thus, in common with OCDs, in BDD there is increased activity in the limbic regions; in PG there is evidence of deficiencies in 5-HT function and receptors; and in autism there are restricted interests and repetitive behaviours which may be influenced by serotonergic mechanisms. Our findings support the notion that targeted treatments, for example using SSRIs, for the behaviours associated with these disorders are effective. Our review considers one SSRI treatment in particular, fluvoxamine, and conclusions should be drawn in light of this. Further testing of our hypothesis would be prudent to confirm its validity.     

Neonatal 192 IgG-saporin lesion of forebrain cholinergic neurons: focus on the life span?

The cholinergic immunotoxin 192 IgG-saporin can be used to effect selective, substantial and permanent lesions of basal forebrain neurons in the neonatal rat. Human neurodevelopmental disorders such as Rett and Down syndromes are characterized by early cholinergic dysfunction and cognitive impairment. Hence, the study of the neonatal 192 IgG-saporin lesioned rat should illuminate the role of cholinergic dysfunction in these human disorders. To date, we and others have failed to observe notable effects of this neonatal lesion on learning and memory, even when combined with a severe lesion of noradrenergic forebrain innervation. As well, attention seems not to be affected. However, complex problem solving (intelligence?) is compromised by the cholinergic lesion. There also appears to be reduced cortical dendritic branching indicative of synapse loss but further research is needed to characterize this. Even if the synapse loss due to neonatal cholinergic lesion is modest and thus insufficient to cause a significant neurodevelopmental dysfunction, its consequences may be devastating during old age.     

Imaging hippocampal function across the human life span: Is memory decline normal or not?

Memory function commonly declines in later life. Whether memory decline represents a disease process or whether it is part of normal aging remains unknown. Here we answer this question by assessing the function of multiple subregions that make up the hippocampal circuit across the human life span. A newly developed MRI approach--designed to detect functional changes in individual hippocampal subregions--was used to assess the hippocampal circuit in 70 subjects between 20 and 88 years of age. Using strict parametric criteria, analysis revealed that function in two hippocampal subregions--the subiculum and the dentate gyrus--decline normally with age. In contrast, function in the entorhinal cortex declines pathologically. Single-subject analysis revealed that hippocampal dysfunction, found in 60% of elders was selectively correlated with memory decline. These results show that memory decline is caused by different mechanisms and suggests how memory decline should be approached clinically.     

Autism and ADHD across the life span. Differential diagnoses or comorbidity?

Exclusion criteria of the DSM-IV-TR and ICD-10 do prevent dual diagnoses of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). However, inattention, impulsivity and hyperactivity are amongst the most frequent associated symptoms of ASD. Psychopathological, neuropsychological, brain imaging and genetic studies suggest possible pathophysiological links between ASD and ADHD. Thus, standard diagnostic procedures for both disorders should assess the presence of potential comorbid symptoms of the other disorder. Treatment strategies for ADHD symptoms in the context of ASD overlap with those for patients with ADHD, but lower dosages and slower titration might be recommendable.     

Quantifying creativity: can measures span the spectrum?

Because the cognitive neuroscientists have become increasingly interested in the phenomenon of creativity, the issue arises of how creativity is to be optimally measured. Unlike intelligence, which can be assessed across the full range of intellectual ability creativity measures tend to concentrate on different sections of the overall spectrum. After first defining creativity in terms of the three criteria of novelty, usefulness, and surprise, this article provides an overview of the available measures. Not only do these instruments vary according to whether they focus on the creative process, person, or product, but they differ regarding whether they tap into "little-c" versus "Big-C" creativity; only productivity and eminence measures reach into genius-level manifestations of the phenomenon. The article closes by discussing whether various alternative assessment techniques can be integrated into a single measure that quantifies creativity across the full spectrum.     

Changes in the solubility and phosphorylation of ��-synuclein over the course of Parkinson��s disease

Lewy bodies are made from insoluble, phosphorylated α-synuclein, but the earliest changes that precipitate such pathology still remain conjecture. In this study, we quantify and identify relationships between the levels of the main pathologic form of phosphorylated α-synuclein over the course of Parkinson's disease in regions affected early through to end-stage disease. Brain tissue samples from 33 cases at different disease stages and 13 controls were collected through the Australian Network of Brain Banks. 500 mg of frozen putamen (affected preclinically) and frontal cortex (affected late) was homogenized, fractionated and α-synuclein levels evaluated using specific antibodies (syn-1, BD Transduction Laboratories; S129P phospho-α-synuclein, Elan Pharmaceuticals) and quantitative western blotting. Statistical analyses assessed the relationship between the different forms of α-synuclein, compared levels between groups, and determined any changes over the disease course. Soluble S129P was detected in controls with higher levels in putamen compared with frontal cortex. In contrast, insoluble α-synuclein occurred in Parkinson's disease with a significant increase in soluble and lipid-associated S129P, and a decrease in soluble frontal α-synuclein over the disease course. Increasing soluble S129P in the putamen correlated with increasing S129P in other fractions and regions. These data show that soluble non-phosphorylated α-synuclein decreases over the course of Parkinson's disease, becoming increasingly phosphorylated and insoluble. The finding that S129P α-synuclein normally occurs in vulnerable brain regions, and in Parkinson's disease has the strongest relationships to the pathogenic forms of α-synuclein in other brain regions, suggests a propagating role for putamenal phospho-α-synuclein in disease pathogenesis.     

Progressive grey matter alterations in bipolar disorder across the life span – A systematic review

Objectives

To elucidate the relationship between the course of bipolar disorder (BD) and structural brain changes across the life span, we conducted a systematic review of longitudinal imaging studies in adolescent and adult BD patients.

Methods

Eleven studies with 329 BD patients and 277 controls met our PICOS criteria (participants, intervention, comparison, outcome and study design): BD diagnosis based on DSM criteria, natural course of disease, comparison of grey matter changes in BD individuals over ≥1-year interval between scans.

Results

The selected studies yielded heterogeneous findings, partly due to varying patient characteristics, data acquisition and statistical models. Mood episodes were associated with greater grey matter loss in frontal brain regions over time. Brain volume decreased or remained stable in adolescent patients, whereas it increased in healthy adolescents. Adult BD patients showed increased cortical thinning and brain structural decline. In particular, disease onset in adolescence was associated with amygdala volume reduction, which was not reported in adult BD.

Conclusions

The evidence collected suggests that the progression of BD impairs adolescent brain development and accelerates structural brain decline across the lifespan. Age-specific changes in amygdala volume in adolescent BD suggest that reduced amygdala volume is a correlate of early onset BD. Clarifying the role of BD in brain development across the lifespan promises a deeper understanding of the progression of BD patients through different developmental episodes.     

Absence of the ��v��3 integrin dictates the time-course of angiogenesis in the hypoxic central nervous system: accelerated endothelial proliferation correlates with compensatory increases in ��5��1 integrin expression

Cerebral angiogenesis is an important adaptive response to hypoxia. As the αvβ3 integrin is induced on angiogenic vessels in the ischemic central nervous system (CNS), and the suggested angiogenic role for this integrin in other systems, it is important to determine whether the αvβ3 integrin is an important mediator of cerebral angiogenesis. αvβ3 integrin expression was examined in a model of cerebral hypoxia, in which mice were subject to hypoxia (8% O₂) for 0, 4, 7, or 14 days. Immunofluorescence and western blot analysis revealed that in the hypoxic CNS, αvβ3 integrin was strongly induced on angiogenic brain endothelial cells (BEC), along with its ligand vitronectin. In the hypoxia model, β3 integrin-null mice showed no obvious defect in cerebral angiogenesis. However, early in the angiogenic process, BEC in these mice showed an increased mitotic index that correlated closely with increased α5 integrin expression. In vitro experiments confirmed α5 integrin upregulation on β3 integrin-null BEC, which also correlated with increased BEC proliferation on fibronectin. These studies confirm hypoxic induction of αvβ3 integrin on angiogenic vessels, but suggest distinct roles for the BEC integrins αvβ3 and α5β1 in cerebral angiogenesis, with αvβ3 having a nonessential role, and α5β1 promoting BEC proliferation.     

Quality of life measures in epilepsy: how well can they detect change over time?

OBJECTIVE: To evaluate the ability of health-related quality of life (HRQOL) measures to detect change over time in persons with epilepsy. BACKGROUND: The application of HRQOL measures in clinical trials has been limited by a dearth of information regarding their abilities to measure change over time (i.e., their responsiveness). To calculate responsiveness, one must categorize subjects as "changed" or "unchanged" by a priori criteria. METHODS: The authors analyzed data collected at baseline and at 28-week follow-up from an antiepileptic drug trial. Two different criteria for classifying subjects as changed or unchanged-one based on seizure frequency (where changed = attainment of seizure freedom) and one based on self-reported overall condition (where changed = improvement in overall condition)-were used. We compared responsiveness indices for two generic (Short Form [SF]-36 and SF-12) and two epilepsy-targeted (Quality of Life in Epilepsy [QOLIE]-89 and QOLIE-31) HRQOL measures. Two scoring procedures for the SF-36, one based on classic test theory and the other on item response theory (IRT), were compared. RESULTS: Effect sizes of the most responsive HRQOL measures were medium to large. The shorter epilepsy-targeted measure had similar responsiveness indices to those of the longer measure. Epilepsy-targeted measures were consistently more responsive than generic measures under the overall condition criterion, but for the seizure freedom criterion, IRT scoring of the SF-36 yielded responsiveness indices comparable to those of the epilepsy-targeted measures. CONCLUSION: Epilepsy-targeted health-related quality of life measures may be preferable to generic ones in longitudinal studies. Selection of a shorter epilepsy-targeted measure does not compromise responsiveness. Item response theory scoring should be applied to epilepsy-targeted HRQOL measures.     

How parkinsonism influences life: the patients’ point of view

To explore the experience of living with parkinsonism, a survey form was sent to the members of a patients’ association; 1,256 forms were analysed. The mean age was 65.75 ± 9.29 years; 64.4% males. A family history was reported by 19.2%. Basic abilities were preserved in 75% of the responders; the ability to do indoor and outdoor activities was preserved in 42 and 28%, respectively. 70% of the responders liked to meet other people and about 50% liked discussing their condition. 80.3% of the responders lived with partner, while 7.8% did not live with family. Of the patients’ partners, 38.9% took drugs, and 9.4% themselves needed assistance. Care programmes for parkinsonians should take into account the disease duration, the degree of disability, the presence of caregiver/s, and the level of caregiver burden; but it should also be appreciated that social habits, need of help, and severity of symptoms influence disability.     

Postconcussional disorder: Are the DSM-IV criteria an improvement over the ICD-10?

Little is known about the characteristics and outcomes of patients diagnosed with postconcussional disorder (PCD) under the provisionally proposed criteria in the DSM-IV and how they differ from patients diagnosed with postconcussional syndrome (PCS) under the International Classification of Diseases, 10th edition clinical (ICD-10) criteria. This study investigated differences in outcome based on a diagnosis of PCD (DSM-IV) versus PCS (ICD-10 clinical criteria) as to which criteria set might be preferred for clinical practice. A consecutive series of adult patients with mild (N = 319) to moderate (N = 21) traumatic brain injury was assessed at 3 months postinjury with a brief neuropsychological battery and measures of specific outcome domains. In two separate series of analyses, patients with PCD were compared with those without PCD, and those with PCS were compared with those without PCS. Although the two criteria sets resulted in markedly different incidence rates, there was no substantial pattern of differences between the DSM-IV and ICD-10 in the outcome domains of psychiatric symptoms and disorders, social and community integration, health-related quality of life, or global outcome as measured by the Glasgow Outcome Scale-Extended. In spite of significant differences between the two diagnostic criteria sets and different incidence rates for PCD/PCS, outcome in all measured domains was very similar at 3 months postinjury. There is no compelling evidence, based on these outcome domains, to suggest which of the two diagnostic criteria sets should be clinically preferred.