Future perspectives on the treatment of cognitive deficits and negative symptoms in schizophrenia

Drug discovery based on classic models for cognitive impairment and negative symptoms of schizophrenia have met with only modest success. Because cognitive impairment and negative symptoms may result from disruptions in neurodevelopment, more complex developmental models that integrate environmental and genetic risk factors are needed. In addition, it has become clear that biochemical pathways involved in schizophrenia form complex, interconnected networks. Points at which risk factors converge, such as brain‐derived neurotrophic factor (BDNF) and protein kinase B (AKT), and from which processes involved in neuroplasticity diverge, are of particular interest for pharmacologic interventions. This paper reviews elements of neurodevelopmental models for cognitive deficits and negative symptoms of schizophrenia with the aim of identifying potential targets for interventions.     

Anatomical and functional deficits in patients with amnestic mild cognitive impairment

Background

Anatomical and functional deficits have been studied in patients with amnestic mild cognitive impairment (MCI). However, it is unclear whether and how the anatomical deficits are related to the functional alterations. Present study aims to characterize the association between anatomical and functional deficits in MCI patients.

Methods

Seventeen amnestic MCI patients and 18 healthy aging controls were scanned using a T1 Weighted MPRAGE sequence and a gradient-echo echo-planar imaging sequence. Clinical severity of MCI patients was evaluated by using Clinical Dementia Rating, Mini Mental State Examination (MMSE), Clock Drawing Test, Auditory Verbal Learning Test and Activities of Daily Living. VBM with DARTEL was used to characterize the gray matter deficits in MCI. Regional amplitude of low-frequency (0.01–0.08 Hz) fluctuations (ALFF) was used to evaluate regional functional alteration in MCI and fractional ALFF(fALFF) in slow 4 (0.027–0.073 Hz) and slow 5 (0.01–0.027 Hz) were also calculated.

Results

Significantly decreased gray matter volume (GMV) was observed in amnestic MCI group mainly in bilateral prefrontal, left temporal and posterior cingulate cortex. Significant positive correlation was observed between the GMV in left inferior frontal gyrus and MMSE scores. Interestingly, decreased ALFF/fALFF was revealed in MCI group compared to controls mainly in prefrontal, left parietal regions and right fusiform gyrus, while the increased ALFF/fALFF was found in limbic and midbrain. Furthermore, the changes of fALFF in MCI in the slow-5 band were greater than those in the slow-4. No significant correlation was found between the morphometric and functional results.

Conclusions

Findings from the study document that wide spread brain volume reduction accompanied with decreased and increased regional function in MCI, while the anatomical and functional changes were independently. Therefore, the combination of structural and functional MRI methods would provide complementary information and together advance our understanding of the pathophysiology underlying the symptoms of MCI.     

Compliance and the patient's perspective: Controlling symptoms in everyday life

Non-compliance with medical advice is poorly understood. Most of the existing literature considers the problem only from the doctor's point of view. We undertook a diachronic, qualitative study of the illness experiences of 19 women to try to understand non-compliance from the patient's perspective. Three-fourths of our study group had ceased to follow their doctor's recommendations by four months postdiagnosis. Their non-compliance could not be explained by the fact that the women held understandings of their illnessses which were incongruent with their physicians'; nor were they unable to understand the diagnosis they received A consideration of the roles that their diagnosis and treatments played in their daily lives proved more useful in explaining their failure to follow physicians' recommendations. Patients' use of treatments reflected their desire to control symptoms within the constraints of their daily routines.     

Oral health in institutionalised elderly people in Oslo, Norway and its relationship with dependence and cognitive impairment

doi: 10.1111/j.1741‐2358.2011.00490.x
Oral health in institutionalised elderly people in Oslo, Norway and its relationship with dependence and cognitive impairment Objective: Investigating oral health’s relationship with dependency and cognitive state. Background: Oral hygiene is poor in the institutionalised elderly. There are problems regarding the oral care of residents having poor mobility or cognitive impairment. Material and methods: Cross‐sectional study involving 135 participants (mean age 85.7, SD 8.8 years) in two categories: nurses doing tooth cleaning and residents doing tooth cleaning. Those cleaned by nurses were categorised as co‐operative or unco‐operative. The oral hygiene status, presence of caries, retained roots and denture‐related stomatitis were recorded. Results: Of the participants, 70% had only natural teeth. The prevalence of caries was 28%. A significant correlation showed that having more teeth gave a poorer Simplified Oral Hygiene Index (OHI‐S) (p = 0.018). The number of retained roots increased with the severity of cognitive impairment (p < 0.05). Significant differences were found between nurses or residents doing the tooth cleaning on the OHI‐S (p = 0.05) and percentage of dental plaque (p = 0.003). Unco‐operative residents had poorer oral hygiene (p = 0.028), more caries (p = 0.008) and were more often moderate–severe cognitive impaired (p = 0.016). Conclusions: A high percentage of participants had unacceptable oral hygiene. Residents whose teeth were cleaned by the nurses had poorer oral hygiene. Unco‐operative residents had the worst oral hygiene and more caries.     

Dopamine and glutamate in schizophrenia: biology,symptoms and treatment

Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.     

Socioeconomic and demographic diversity in the health status of elderly people in a transitional society, Kerala, India

Kerala State in India is the most advanced in terms of demographic and epidemiological transition and has the highest proportion of elderly population. The study examines the socio-demographic correlates of health status of elderly persons in Kerala in terms of three components: perceived health status, physical mobility and morbidity level. Overall health status was measured by combining the above three components of health status. Data from the 60th National Sample Survey Organization (NSSO) on Condition and Health Care of the Aged in Kerala in 2004 was used for the study. Significant socio-demographic differentials in health status were noted. While women report less morbidity, perceived well-being and physical mobility was better for men. This anomaly can be explained by variations in the components of socio-demographic factors. The findings call for urgent health care strategies for elderly persons in different socio-demographic groups in transitional Indian states like Kerala.     

Relationship between autonomic cardiovascular control,case definition,clinical symptoms,and functional disability in adolescent chronic fatigue syndrome: an exploratory study

Chronic Fatigue Syndrome (CFS) is characterized by severe impairment and multiple symptoms. Autonomic dysregulation has been demonstrated in several studies. We aimed at exploring the relationship between indices of autonomic cardiovascular control, the case definition from Centers for Disease Control and Prevention (CDC criteria), important clinical symptoms, and disability in adolescent chronic fatigue syndrome. 38 CFS patients aged 12–18 years were recruited according to a wide case definition (ie. not requiring accompanying symptoms) and subjected to head-up tilt test (HUT) and a questionnaire. The relationships between variables were explored with multiple linear regression analyses. In the final models, disability was positively associated with symptoms of cognitive impairments (p<0.001), hypersensitivity (p<0.001), fatigue (p=0.003) and age (p=0.007). Symptoms of cognitive impairments were associated with age (p=0.002), heart rate (HR) at baseline (p=0.01), and HR response during HUT (p=0.02). Hypersensitivity was associated with HR response during HUT (p=0.001), high-frequency variability of heart rate (HF-RRI) at baseline (p=0.05), and adherence to the CDC criteria (p=0.005). Fatigue was associated with gender (p=0.007) and adherence to the CDC criteria (p=0.04). In conclusion, a) The disability of CFS patients is not only related to fatigue but to other symptoms as well; b) Altered cardiovascular autonomic control is associated with certain symptoms; c) The CDC criteria are poorly associated with disability, symptoms, and indices of altered autonomic nervous activity.     

Tooth loss and caries prevalence in very old Swedish people: the relationship to cognitive function and functional ability

Objective: To analyse whether cognitive function and functional ability are related to oral health among community‐dwelling older people over the age of 80 years. Background: This cross‐sectional study is based on the Kungsholmen Elders Oral Health Survey (KEOHS). The study included oral examinations carried out in two local clinics by standardised examiners and interviews using structured questionnaires. Materials and Methods: Altogether 159 individuals were included in this study. Coronal caries and root caries were assessed using the National Institute of Dental and Craniofacial Research (NIDCR) diagnostic criteria. Cognitive function was assessed by the Mini‐Mental State Examination (MMSE) index and functional ability was assessed by a global measure of self‐reported changes. Results: Older adults with a low MMSE score (≤23) tended to have a higher risk of coronal caries than those with higher scores. Participants with mild cognitive decline (MMSE = 24–26) and with a decrease in functional ability had a significantly higher risk of root caries. These associations changed little when adjusted by the covariates. In addition, people with a low MMSE (0–23) had a four times higher risk of not using dental services regularly. This result was unchanged after adjusting for the variables studied. Conclusions: This study revealed associations between the cognitive and functional status of the individual and aspects of oral health, that may contribute to a deeper understanding of the background of oral health status in older adults.     

Relationship between behavioral and psychological symptoms of dementia and oral health status in the elderly with vascular dementia

doi: 10.1111/j.1741‐2358.2012.00664.x Relationship between behavioral and psychological symptoms of dementia and oral health status in the elderly with vascular dementia Objectives: The aim of this study was to clarify the relationship between behavioral and psychological symptoms of dementia (BPSD) and oral status in the elderly with vascular dementia. Background: There have been some reports of a relationship between disease symptoms and oral status in the elderly with Alzheimer’s disease, but few reports have been conducted in the elderly with vascular dementia. Until now, the relationship between BPSD and oral status has been unknown. Materials and methods: An investigation was conducted concerning BPSD and oral status among 57 subjects with vascular dementia (mean age, 85.7 ± 5.5 years). The wearing of dentures and oral activities of daily living (oral ADL) were examined. Results: Subjects with activity disturbances and those with aggressiveness had significantly lower rates of denture wearing than those without these two symptoms (p < 0.05). Significantly lower oral ADL scores were obtained from subjects with delusional ideas, hallucinations, activity disturbances and diurnal rhythm disturbances (p < 0.05), as well as those with affective disturbances (p < 0.01). Conclusion: This study indicated a relationship between BPSD and the wearing of dentures in the elderly with vascular dementia. The study also demonstrated relationships between BPSD and oral ADL.     

Astrogliosis in the hippocampus and cortex and cognitive deficits in rats with streptozotocin-induced diabetes: Effects of melatonin

We examined, using a Western blot technique, the contents and compositions of a specific neuronal protein, NCAM, and of an astrocyte marker, GFAP, in the hippocampus and cortex of rats with streptozotocin (STZ)-induced diabetes and compared these indices with those in control (intact) animals and STZ-diabetic rats treated with melatonin. Behavioral cognitive indices manifested in the passive avoidance test (PAT) and Morris water maze (MWM) learning performance were also estimated in the above groups of animals. As was found, STZ-diabetic rats demonstrated clear cognitive deficits according to the values of the retention latency in the PAT and time of reaching the escape platform in the MWM performance. In these animals, the GFAP content was elevated, and the amount of degraded products of this protein increased, as compared with the control. Simultaneously, considerable down-regulation of the NCAM expression and modifications of NCAM isoform composition were found in diabetic animals. In addition, significantly increased levels of lipid peroxidation (according to the amounts of malondialdehyde + 4-hydroxyalkenals) were measured in the cortex and hippocampus of rats with stable diabetic hyperglycemia. All the above-mentioned shifts were significantly smoothed or even nearly completely compensated in the case of treatment of STZ-diabetic rats with melatonin (10 mg/kg per day). The role of diabetes-related changes in the amount and composition of specific neural and glial proteins in the development of cognitive deficits, the involvement of oxidative stress in the mechanisms of the respective shifts, and possible mechanisms of the neuroprotective effect of melatonin with respect to diabetes-related pathological biochemical and behavioral shifts are discussed. Neirofiziologiya/Neurophysiology, Vol. 40, No. 2, pp. 105–111, March–April, 2008.     

Total antioxidant capacity and the severity of the pain in patients with fibromyalgia

The purpose of the study was to determine the oxidative and antioxidative status of plasma in patients with fibromyalgia. Total antioxidant capacity (TAC) of plasma was significantly lower in patients with fibromyalgia (n = 20) than in healthy controls (n = 20) [1.5 (SD 0.3) and 1.9 (SD 0.3) mmol Trolox equiv./l, P = 0.001]. In contrast, the total peroxide level of plasma was significantly higher in patients than in healthy controls [37.4 (SD 6.7) and 33.0 (SD 2.7) micromol H2O2/l; P = 0.01]. The oxidative stress index (OSI) level was significantly higher in patients with fibromyalgia than in healthy controls [2.5 (SD 1.0) and 1.8 (SD 0.4); P = 0.007]. A significant negative correlation between visual analogue scale (VAS) and TAC level was determined (r = -0.79, P < 0.001). The present results indicate that patients with fibromyalgia are exposed to oxidative stress and this increased oxidative stress may play a role in the etiopathogenesis of the disease. Supplementation of antioxidant vitamins such as vitamins C and E to the therapy may be indicated.     

Putative therapeutic agents for the learning and memory deficits of people with Down syndrome

Mental retardation is the most common and debilitating condition for individuals with Down syndrome (DS). The hyper-activation of DYRK1A by overexpression causes significant learning and memory deficits in DS-model mice. Thus far, no mechanism-based drug has been developed to address this. After a combination of in silico and in vitro screenings, two DYRK1A inhibitors were isolated that are active in a cell-based assay. Further optimization could lead to a novel drug discovery that could address DS learning and memory deficits.     

Neonatal asphyxia and hyperthermia and cognitive deficits in adult rats: Role of iron

We compared effects of a critical neonatal anoxia, applied in Wistar rats at body temperatures of 33, 37 and 39 °C, on memory performance in adulthood. Because hyperthermic–anoxic neonates suffer from hyperferremia an additional group of rats, exposed to anoxia at 39 °C, was injected with deferoxamine, a chelator of iron. At the age of 4 and 12 months all rats were examined in hole board, typical maze and Morris maze.     

Violent behaviour among people with schizophrenia: a framework for investigations of causes, and effective treatment, and prevention

Robust evidence has accumulated showing that individuals who develop schizophrenia are at elevated risk when compared to the general population to engage in violence towards others. This violence impacts negatively on victims as well as perpetrators and poses a significant financial burden to society. It is posited that among violent offenders with schizophrenia there are three distinct types defined by the age of onset of antisocial and violent behaviour. The early starters display a pattern of antisocial behaviour that emerges in childhood or early adolescence, well before illness onset, and that remains stable across the lifespan. The largest group of violent offenders with schizophrenia show no antisocial behaviour prior to the onset of the illness and then repeatedly engage in aggressive behaviour towards others. A small group of individuals who display a chronic course of schizophrenia show no aggressive behaviour for one or two decades after illness onset and then engage in serious violence, often killing, those who care for them. We hypothesize that both the developmental processes and the proximal factors, such as symptoms of psychosis and drug misuse, associated with violent behaviour differ for the three types of offenders with schizophrenia, as do their needs for treatment.     

Oral care of people with disability: a qualitative exploration of the views of nursing staff

This study aimed to identify influences, attitudes and actions of nursing staff in relation to oral care for people with disabilities. Individual in-depth interviews of twenty two nursing staff were conducted. Enabling and inhibiting factors in the reported attitudes, approaches and practices were identified. The main enabling factors were that nursing staff saw mouth care as part of their role and took an empathic and caring approach to its delivery. They aimed to make the residents socially acceptable, improve their self-esteem and make their mouths clean and breath fresher. Inhibiting factors were: a lack of training, time constraints associated with workload, and poor understanding of the processes causing dental disease. The study concludes that improvements in oral care by nursing staff can be encouraged by working with nurses'attitudes, values and beliefs. Once the desired behaviour change has occurred then the lack of knowledge can be addressed.