N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder, involving psychiatric, cognitive and motor symptoms, caused by a CAG-repeat expansion encoding an extended polyglutamine tract in the huntingtin protein. Oxidative stress and excitotoxicity have previously been implicated in the pathogenesis of HD. We hypothesized that N-acetylcysteine (NAC) may reduce both excitotoxicity and oxidative stress through its actions on glutamate reuptake and antioxidant capacity. The R6/1 transgenic mouse model of HD was used to investigate the effects of NAC on HD pathology. It was found that chronic NAC administration delayed the onset and progression of motor deficits in R6/1 mice, while having an antidepressant-like effect on both R6/1 and wild-type mice. A deficit in the astrocytic glutamate transporter protein, GLT-1, was found in R6/1 mice. However, this deficit was not ameliorated by NAC, implying that the therapeutic effect of NAC is not due to rescue of the GLT-1 deficit and associated glutamate-induced excitotoxicity. Assessment of mitochondrial function in the striatum and cortex revealed that R6/1 mice show reduced mitochondrial respiratory capacity specific to the striatum. This deficit was rescued by chronic treatment with NAC. There was a selective increase in markers of oxidative damage in mitochondria, which was rescued by NAC. In conclusion, NAC is able to delay the onset of motor deficits in the R6/1 model of Huntington's disease and it may do so by ameliorating mitochondrial dysfunction. Thus, NAC shows promise as a potential therapeutic agent in HD. Furthermore, our data suggest that NAC may also have broader antidepressant efficacy.

N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease

Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington's disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system xc (-) In HD, the enzyme regulating cysteine (and subsequently cystine) production, cystathionine-γ-lygase, has recently been shown to be lowered. The aim of the present study was to establish whether cysteine supplementation, using N-acetylcysteine (NAC) could ameliorate glutamate pathology through the cystine-dependent transporters, system xc (-) and GLT-1. We demonstrate that the R6/1 transgenic mouse model of HD has lower basal levels of cystine, and showed depressive-like behaviors in the forced-swim test. Administration of NAC reversed these behaviors. This effect was blocked by co-administration of the system xc (-) and GLT-1 inhibitors CPG and DHK, showing that glutamate transporter activity was required for the antidepressant effects of NAC. NAC was also able to specifically increase glutamate in HD mice, in a glutamate transporter-dependent manner. These in vivo changes reflect changes in glutamate transporter protein in HD mice and human HD post-mortem tissue. Furthermore, NAC was able to rescue changes in key glutamate receptor proteins related to excitotoxicity in HD, including NMDAR2B. Thus, we have shown that baseline reductions in cysteine underlie glutamatergic dysfunction and depressive-like behavior in HD and these changes can be rescued by treatment with NAC. These findings have implications for the development of new therapeutic approaches for depressive disorders.

Satisfaction with services among people with progressive neurological illnesses and their careers in Australia

Abstract The current study investigated the types of support networks and services accessed by people with progressive neurological illness, as well as the assessment of the usefulness of these services. The participants were 25 people with multiple sclerosis, 15 people with motor neurone disease, 23 people with Parkinson's disease, and six people with Huntington's disease. Twenty-eight professionals who worked with people with these illnesses and 41 carers of people with these illnesses also were interviewed. The results demonstrate that all of the groups of respondents indicated a strong need for basic services (e.g. home help), as well as specialized services (e.g. support groups). These two services also were identified as the most useful services by all of the groups of respondents. The similarities and differences between the groups, as well as the patients and carers, are examined. These findings demonstrate the importance of providing basic services for people with progressive neurological illnesses.

The impact of neurological illness on marital relationships

The current study investigated the impact of neurological illness on marital relationship satisfaction. Participants numbered 423 patients and 335 carers from motor neurone disease (MND), Huntington's disease (HD), Parkinson's, and multiple sclerosis (MS). The results demonstrated that patients and carers with HD had a significantly lower level of relationship satisfaction and sex life satisfaction than the other three illness groups. Further, patients with HD indicated a significantly higher level of relationship satisfaction than their carers. For MS and MND patients, social support predicted marital relationship satisfaction, and for Parkinson's patients, social support and sex life satisfaction predicted marital relationship satisfaction.

A longitudinal study of economic pressure among people living with a progressive neurological illness

Objectives: Previous research has examined costs associated with progressive neurological illnesses, but has not examined predictors of economic pressure, or quality of life (QOL). The aim of the current study was to examine the predictors of both economic pressure and QOL among people with a range of progressive neurological illness.

Method: Participants were 257 people with motor neurone disease, Huntington’s disease, multiple sclerosis and Parkinson’s.

Results: High levels of cut backs in spending predicted economic pressure for all groups. Economic pressure predicted QOL at 12-month follow-up for all groups except Parkinson’s. For Parkinson’s, predictors of QOL were long duration of illness, illness-related expenses and cut backs in spending. Cut backs in spending, and not income or expenses, were the most important predictor of economic pressure. QOL was predicted by high levels of economic pressure for most of the illness groups.

Discussion: The implications of these findings are discussed. They suggest that cut backs in spending, as opposed to income and expenses, are important factors to focus on assisting people to adjust to the changes to their financial situation that frequently occurs after developing one of these progressive neurological illnesses.

A comparison of mood and quality of life among people with progressive neurological illnesses and their caregivers

The current study was designed to investigate differences in mood and a range of QOL domains among 423 patients and 335 caregivers of people with motor neurone disease (MND), Huntington’s disease (HD), Parkinson’s, and multiple sclerosis (MS). Patients and caregivers completed an anonymous questionnaire that evaluated their mood (anxiety, depression, fatigue, confusion) and QOL (physical, psychological, social, environment). The results demonstrated that caregivers of people with MND and HD experienced most problems with their mood and QOL compared to caregivers of people in the other illness groups. There were few differences in mood or QOL between patients and caregivers. Patients generally showed greater confusion, physical impairment, and psychological maladjustment. The findings suggest that educational and intervention programs need to be developed to help both patients and their caregivers to adjust and cope with these illnesses, particularly caregivers of people with MND and HD.

Marketing across cultures : an investigation into place specific dimensions of service quality in sport

Abstract The purpose of this study was to identify place-specific dimensions of service quality in spectator sport settings and determine if the importance of these dimensions differed across cultures. The study was limited to the soccer industry and involved the collection of responses from identified soccer spectators to a range of items presented in a survey instrument. The survey was distributed to respondents face-to-face on a match day of the club they supported, or mailed to their home address. Responses were obtained from spectators from two clubs from Australia (n=277), one club from the USA (n=199), one club from the Netherlands (n=245) and one federation from Malaysia (n= 100). Based on the findings of a number of authors, six categories of potential place-specific dimensions of service quality in spectator sport settings were created and the research instrument contained a number of items that could be categorised under one of these headings. These categories were Home, Religion, Social facilitation, Sensory, Uncertainty of outcome, and Personal attention. In this thesis it was assumed that place-specific service quality issues are similar for sport spectators of different cultures, although differences in degree of importance of these dimensions (etic approach) were likely to emerge. In other words, although it was expected dimensions per country to be similar, differences in degree of importance of these dimensions were expected. Given the lack of confirmatory statistical evidence pertaining to the specific country samples, it was concluded that differences per country are likely to be more than just differences in degree. Both the overall structure and structures per country could not be confirmed, and hence the conclusion was drawn that differences in nature between the countries were present. In other words, what is a dimension of place-specific service quality in one country is not necessarily a dimension in another country. The results of a content analysis of ‘core component’ structures per country compared with a (full sample) core component structure delivered six components (referred to as place-specific dimensions of service quality) that were defined as Home, Hedonist, Religious follower, Safe atmosphere, Hospitality and Personal Attention. It was found that in most cases the cultural orientation of soccer spectators reflects the cultural orientation of the country as a whole as proposed by Hofstede (1991). However, in line with Huntington (1997), it was also argued that grouping people based on their country of origin as a proxy for their cultural orientation, will increasingly lead to flawed and incomplete research findings. As noted by Yoo etal. (1999), the identification of a person's cultural orientation is likely to deliver more direct results when measured at the individual level In that regard it is concluded that it may seem prudent to view Hofstede's dimensions of culture with increased conceptual scrutiny. Although having been replicated in multiple studies, it becomes increasingly unlikely that Hofstede's dimensions cover the complete spectrum of an individual person's cultural orientation. In conclusion, this study identified that soccer spectators (from a number of clubs) from Australia, the USA, the Netherlands and to a lesser extent Malaysia, perceive a range of place-specific service quality dimensions in spectator spoil settings to be important when visiting a soccer match. Before research into satisfaction with and value of place-specific dimensions of the spectator sport service product is initiated, it is pertinent the identified dimensions are further explored and confirmed in different country (culture) settings. The confusion that still exists about the place of the value concept (in relation to quality and satisfaction), where Holbrook (1994) defines quality as a type of value and Chelladurai and Chang (2000) argue that value is a type of quality, further underpins this necessity. It needs to be clear what are the targets of service quality before this information is integrated in larger holistic research frameworks. In the final section of the thesis a conceptual model for international services marketing research in the sport industry was presented as a first attempt to integrate the findings of this research and other researchers.

Predictors of quality of life in carers for people with a progressive neurological illness: a longitudinal study

Purpose The aim of the present research was to determine the predictors of quality of life (QOL) among carers for people living with a chronic degenerative neurological illness, with comparisons of the differences in significant predictors of QOL between illness groups.
Methods Psychosocial and economic variables were examined among 192 carers for people living at home with motor neurone disease, Huntington’s disease, multiple sclerosis, and Parkinson’s, over a twelve-month period, to determine their contribution to the prediction of carer QOL.
Results Mood was the only consistent predictor of carer QOL across groups; however, marital relationship satisfaction, social support satisfaction, income, and economic pressure significantly predicted carer QOL for at least one of the illness groups, in addition to mood.
Conclusions The findings highlight the importance of recognising the varying roles that psychosocial and economic variables play on the prediction of carer QOL within each of these illness groups.

Why are some people with neurological illness more resilient than others?

The current qualitative study was designed to evaluate the coping strategies of people living with a chronic progressive neurological illness and their carers. The neurological illnesses were Huntington’s disease, motor neurone disease, multiple sclerosis and Parkinson’s disease. Participants included 15 people who showed high levels of adjustment and 15 who showed low levels of adjustment. Participants were selected from an earlier study, to ensure that they satisfied the inclusion criteria for the current study. Interviews were completed to determine the strategies used to cope with the demands of the illness. Participants who demonstrated good adjustment were more likely to draw on social support to provide them with the resources to deal with the illness. In contrast, those who evidenced poor adjustment were more likely to draw on external supports to complete tasks for them. The implications of these findings for people with chronic neurological illnesses and their families are discussed.

Depression's multiple comorbidities explained by (neuro)inflammatory and oxidative & nitrosative stress pathways

There is now evidence that depression, as characterized by melancholic symptoms, anxiety, and fatigue and somatic (F&S) symptoms, is the clinical expression of peripheral cell-mediated activation, inflammation and induction of oxidative and nitrosative stress (IO&NS) pathways and of central microglial activation, decreased neurogenesis and increased apoptosis. This review gives an explanation for the multiple “co-morbidities” between depression and a large variety of a) brain disorders related to neurodegeneration, e.g. Alzheimer’s, Parkinson’s and Huntington’s disease, multiple sclerosis and stroke; b) medical disorders, such as cardiovascular disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, irritable bowel syndrome, leaky gut, diabetes type 1 and 2, obesity and the metabolic syndrome, and HIV infection; and c) conditions, such as hemodialysis, interferon-α-based immunotherapy, the postnatal period and psychosocial stressors. The common denominator of all those disorders/conditions is the presence of microglial activation and/or activation of peripheral IO&NS pathways. There is evidence that shared peripheral and / or central IO&NS pathways underpin the pathophysiology of depression and the previously mentioned disorders and that activation of these IO&NS pathways contributes to shared risk. The IO&NS pathways function as a smoke sensor that detect threats in the peripheral and central parts of the body and signal these threats as melancholic, anxiety, and fatigue and somatic (F&S) symptoms. The presence of concomitant depression is strongly associated with a lower quality of life and increased morbidity and mortality in medical disorders. This may be explained since depression contributes to increased (neuro)inflammatory burden and may therefore drive the inflammatory and degenerative progression. It is concluded that the activation of peripheral and / or central IO&NS pathways may explain the co-occurrence of depression with the above disorders. This shows that depression belongs to the spectrum of inflammatory and degenerative disorders.