Background: The role of both microglial activation and alpha-synuclein deposition in Parkinson's disease remain unclear. We have tested the hypothesis that if microglia play a primary role in Parkinson's disease pathogenesis, the microglial "activated" phenotype should be associated with histopathological and/or clinical features of the disease.

The concept of gliodegenerative diseases has not been widely established although there is accumulating evidence that glial cells may represent a primary target of degenerative disease processes. In the central nervous system (CNS), examples that provide a "proof of concept" include at least one alpha-synucleinopathy, multiple system atrophy (MSA), but this disease is conventionally discussed under the heading of "neurodegeneration". Additional evidence in support of primary glial affection has been reported in neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and transmissible spongiform encephalopathies. Based on biochemical, genetic and transcriptomic studies it is also becoming increasingly clear that the molecular changes measured in whole tissue extracts, e.g. obtained from Parkinson's disease brain, are not based on a purely neuronal contribution. This important evidence has been missed in cell culture or laser capture work focusing on the neuronal cell population. Studies of animal and in vitro models of disease pathogenesis additionally suggest glial accountability for some CNS degenerative processes. This review provides a critical analysis of the evidence available to date in support of the concept of gliodegeneration, which we propose to represent an essential although largely disregarded component of the spectrum of classical "neurodegeneration". Examples from the spectrum of alpha-synucleinopathies are presented.

Immunohistochemistry for alpha-synuclein has become the histological technique of choice for the diagnosis for Parkinson's disease, Dementia with Lewy bodies and Multiple System Atrophy (www.ICDNS.org). Nevertheless, no standardised protocol has been proposed. We have reviewed 242 of the 270 studies published until June 2005 that mentioned immunohistochemistry for anti-alpha synuclein on human tissue and we found that only 75 (31%) used commercial antibodies. We also noted that protocols, particularly dilution and antigen unmasking, varied between studies, even when the same antibody was employed. In order to establish a standardised protocol for alpha-synuclein immunohistochemistry, which can be applied in diagnostic neuropathology we tested seven commercial monoclonal antibodies in brains of subjects with Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, multiple sclerosis with incidental Lewy bodies and aged-matched normal brain and determined for each antibody the best suited protocol for antigen unmasking. We evaluated the intensity of immunolabelling in Lewy bodies, neuropil threads, dendrites, presynaptic terminals, granular cytoplasmic positivity, peri-axonal positivity, glial inclusions and non-specific immunolabelling. Although our results showed that all the antibodies detected alpha-synuclein inclusions, differences were noted between antibodies, particularly with regard to the detection of glial inclusions. From our study, the best antibodies of the seven tested appeared to be those directed against amino acids 116-131 and 15-123 and we suggest them to be used in routine diagnostic practice for alpha-synucleinopathies. Keywords : alpha-synuclein ; immunohistochemistryAlpha-synuclein (αSN) is a highly conserved, natively unfolded 18 kDa protein [1] which represents the major component of Lewy bodies (LBs) [2], and the glial cytoplasmic inclusions (GCIs) associated with Multiple System Atrophy (MSA) [3]. The increased sensitivity of αSN immunohistochemistry over conventional histological stains has established the technique as a standard tool in the diagnosis of Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and MSA [4], and led to new insights regarding the extent and variation of αSN-containing structures and their formation. αSN aggregations vary throughout the brain, with brainstem pathology characterized by compact LBs and neuropil threads. Pigmented neurones of the substantia nigra may also contain diffuse fine or coarse granules, which likely represent the state of aggregation preceding LBs [5,6]. Cortical pathology consists of more diffuse LBs and punctate granular positivity that corresponds to pre-synaptic terminals [7].Despite the growing frequency with which immunohistochemistry is used as a diagnostic tool for PD, DLB and MSA, a standardized protocol for αSN has not been established. Pretreatment with proteinase K or formic acid has been reported to increase the immunoreactivity of αSN; however, the only studies to investigate this systematically ...

The identification of mutations that cause familial Parkinson's disease (PD) provides a framework for studies into pathways that may be perturbed also in the far more common, non-familial form of the disorder. Following this hypothesis, we have examined the gene regulatory network that links alpha-synuclein and parkin pathways with dopamine metabolism in neuropathologically verified cases of sporadic PD. By means of an in silico approach using a database of eukaryotic molecular interactions and a whole genome transcriptome dataset validated by qRT-PCR and histological methods, we found parkin and functionally associated genes to be upregulated in the lateral substantia nigra (SN). In contrast, alpha-synuclein and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) gene expression levels were significantly reduced in both the lateral and medial SN in PD. Gene expression for Septin 4, a member of the GTP-binding protein family involved in alpha-synuclein metabolism was elevated in the lateral parkinsonian SN. Additionally, catalase and mitogen-activated protein kinase 8 and poly (ADP-ribose) polymerase family member 1 (PARP1) known to function in DNA repair and cell death induction, all members of the dopamine synthesis pathway, were up-regulated in the lateral SN. In contrast, two additional PD-linked genes, glucocerebrosidase and nuclear receptor subfamily 4, group A, member 2 (NR4A2) showed reduced expression. We show that in sporadic PD, parkin, alpha-synuclein and dopamine pathways are co-deregulated. Alpha-synuclein is a member of all three gene regulatory networks. Our analysis results support the view that alpha-synuclein has a central role in the familial as well as the non-familial form of the disease and provide steps towards a pathway definition of PD.

Breakfast cereal improves overall diet quality yet is under constant scrutiny with assertions that the category has not improved over time. This study aimed to comprehensively analyse the category of breakfast cereals, the nutritional values, and health claims across eight distinct sub-categories at four time points (2013, 2015, 2018, and 2020). An audit of products from four major supermarkets in metropolitan Sydney (Aldi, Coles, IGA, and Woolworths) collected ingredient lists, nutrition information, claims and Health Star Rating (HSR) for biscuits and bites; brans; bubbles, puffs, and flakes; granola and clusters; hot cereal flavoured; hot cereal plain; muesli; breakfast biscuits. The median (IQR) were calculated for energy, protein, fat, saturated fat, carbohydrate, sugars, dietary fibre, and sodium for comparisons over time points by nutrient. Data from 2013 was compared with 2020 (by sub-category and then for a sub-section of common products available at each time point). Product numbers between 2013 (n = 283) and 2020 (n = 543) almost doubled, led by granola and clusters. Whole grain cereals ≥ 8 g/serve made up 67% of products (↑114%). While there were positive changes in nutrient composition over time within the full data set, the most notable changes were in the nutrition composition of cereals marketed as the same product in both years (n = 134); with decreases in mean carbohydrate (2%), sugar (10%) and sodium (16%) (p < 0.000), while protein and total fat increased significantly (p = 0.036; p = 0.021). Claims regarding Dietary Fibre and Whole Grain doubled since 2013. Analysis of sub-categories of breakfast cereal assisted in identifying some changes over time, but products common to both timeframes provided a clearer analysis of change within the breakfast category, following introduction of HSR. Whole grain products were lower in the two target nutrients, sodium and sugars, and well-chosen products represent a better choice within this category.

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Aim: There is scarcity of research for the nutritional management of pelvic radiotherapy in gynaecological malignancies and delivery of specialised nutrition care is limited due to the current knowledge gap in guidelines. This study aimed to better understand the nutritional risk, weight changes and pattern of nutrition impact symptoms occurring at various treatment timepoints in this population, to inform an effective model of care. Methods: This retrospective, observational study included women with gynaecological cancers receiving pelvic radiotherapy at a tertiary hospital from January 2017 to December 2018 (n = 104). Information was collected on: first day of radiotherapy; weekly during treatment; acute-phase post-treatment (0-6 weeks); and intermediate-phase post-treatment (6 weeks to 6 months). This study reported on incidence of clinically significant weight change (±5%), documented nutrition impact symptoms and the current nutrition care model (nutrition screening, referral, assessment and interventions). Results: Clinically significant weight loss was experienced by 38% (n = 40/104) of patients prior to commencing treatment and 19% (n = 14/73) during treatment. Diarrhoea (n = 40/79), fatigue (n = 54/79), nausea (n = 38/79) and pain (n = 31/79) were frequently reported during treatment, and fatigue (n = 33/92) and pain (n = 25/92) continued acutely post-treatment. Despite high rates of weight loss and prevalence of nutrition impact symptoms, only 38% (n = 40/104) of patients were referred to a dietitian.Conclusions: A considerable proportion of patients with gynaecological cancers are at nutrition risk before and during treatment due to clinically significant weight loss and prevalence of nutrition impact symptoms experienced.