Multiple system atrophy (MSA) is a fatal α-synucleinopathy characterized by progressive parkinsonism, cerebellar ataxia, and autonomic dysfunction. While white matter degeneration is a pathological hallmark, the molecular mechanisms driving neuroinflammation and oligodendrocyte loss remain poorly understood. Here, we identify astrocytic fatty acid-binding protein 5 (FABP5) as a critical mediator of this non-cell-autonomous injury through a multi-dimensional study involving human tissues, transgenic mice, and in vitro models. Transcriptomic profiling of MSA cerebellar white matter revealed a robust activation of inflammatory and ferroptotic pathways, with FABP5 upregulation strongly correlated with these pathogenic signatures (GSVA). We confirmed that FABP5 is upregulated in reactive astrocytes in the PLP-α-syn mouse model. Critically, using an MSA-specific α-synuclein (α-syn) pre-formed fibrils (PFFs) model, we demonstrate that PFFs uptake directly triggers FABP5-dependent inflammation and lipid peroxidation in astrocytes, recapitulating the phenotype observed with LPS stimulation. Mechanistically, we show that astrocytic FABP5 drives a TNF-α-mediated paracrine assault that depletes the antioxidant enzyme GPX3 and triggers apoptosis in neighboring oligodendrocytes. Importantly, silencing astrocytic Fabp5 effectively rescued oligodendrocytes from this oxidative injury and cell death. These findings establish astrocytic FABP5 as a central regulator linking glial inflammation to oligodendrocyte susceptibility, highlighting it as a promising therapeutic target for MSA.

Purpose:To develop implementable confocal multispectral imaging (MSI) by adapting data capture and developing novel analysis on a commercially available device. Using an aging mouse model as proof-of-principle confocal MSI was compared against current reference-standard flood-illuminated hyperspectral imaging (HSI). Methods:Mice aged three, five, and eight months old (n = 14-19/group) underwent confocal scanning laser ophthalmoscopy retinal imaging (MultiColor module on Spectralis OCT) at three laser wavelengths returning: blue (BR, 486 nm), green (GR, 518 nm), and infrared reflectance (IR, 815 nm). Images were focused in 2D steps over a range of 20D. Average retinal reflectance was calculated for wavelengths across the dioptric range and corrected for chromatic aberration. Flood-illuminated HSI from 320 to 680 nm was also conducted. Results:MSI post-chromatic aberration correction found a significant interaction effect with age and retinal depth in IR, GR and BR (P < 0.05). The reflectance ratio of short/long wavelength shows a significant interaction effect (BR/IR, P < 0.01; average (BR,GR)/IR, P < 0.05) or trend GR/IR, P = 0.13 with advancing age and retinal depth. HSI also found a decrease in reflectance ratio with age (P < 0.0001), consistent with MSI. The effect size (Cohen's d) between HSI and MSI in the middle retina were comparable (P < 0.05). Conclusions:Confocal MSI can be achieved on a common commercial optical coherence tomography (OCT) device with off the shelf add-on features, and after chromatic aberration correction, enables depth-resolved spectral analysis. This offers advances over flood-illuminated HSI, which does not return depth information and requires custom made or dedicated equipment. Both MSI and HSI detect similar age-related retinal reflectivity changes. This development conceptually parallels the transition from two-dimensional fundus photography to three-dimensional OCT, offering potential enhancements for selected wavelengths.

Purpose: This study aimed to compare outer retinal thickness and reflectivity using directional OCT between people living with Parkinson's disease (PD) and age-matched controls. Methods: Fourteen neurologist-confirmed people living with PD and 18 age-matched healthy controls participated. To measure the true outer nuclear layer (ONL) (composed of photoreceptor cell bodies) rather than the conventional presumed or standard ONL (ONL plus Henle fiber layer [HFL], which includes photoreceptor processes), off-axis (directional) OCT scans were acquired by altering the incident beam angle. Combined with on-axis (standard) line scans to yield HFL, true ONL and HFL thicknesses as well as ellipsoid zone (EZ) reflectivity were measured and compared between groups using a mixed-effects analysis. Results: Directional OCT revealed that true ONL comprises 63% of the presumed ONL thickness. Compared with healthy controls, the PD group showed a thicker true ONL and a thinner HFL (P < 0.05), whereas the combined ONL and HFL thickness was not different (P > 0.05). The EZ band exhibited lower reflectance in PD participants than healthy controls at the fovea and parafoveal regions (P < 0.05). Conclusions: Directional OCT reveals that people with PD have a thicker photoreceptor nuclear layer and a thinner layer of photoreceptor processes. These opposing effects are not detectable using standard on-axis OCT alone. The EZ band is rich in mitochondria, and a lower reflectivity in PD participants may be indicative of metabolic changes in PD. These detailed examinations of the outer retina facilitate a deeper understanding of PD-related photoreceptor changes.

Objectives To evaluate the proportion, demographic characteristics, and care needs of people with Parkinson’s disease (PD) in Australian residential aged care facilities (RACFs). Design Retrospective observational study (2012-2022) and cross-sectional study (2022). Setting and Participants Permanent residents with PD living in Australian RACF during 2012 to 2022. Methods Annual data, including demographic and clinical characteristics between 2012 and 2022, were obtained from the Australian Institute of Health and Welfare National Aged Care Databases. The Aged Care Funding Instrument assessed care needs as high, medium, or low across 3 domains. Trends in the proportion and profile of residents with PD over time were reported descriptively, together with cross-sectional data from residents in 2022. Joinpoint regression analysis was used to explore changes in the proportion of PD over time. The associations between demographic and clinical factors and high care needs and the associations between sex and dementia, depression, and anxiety were examined in the 2022 cohort using logistic regression. Results From 2012 to 2022, the number of residents with PD increased from 8962 to 10,024, representing a within-RACF proportion of 5.5% in 2022. The percentage of residents with high care needs increased over this period in all Aged Care Funding Instrument domains (activities of daily living: 63%-85%; behavior: 55%-68%; and complex health care: 39%-68%). In 2022, 51% of residents with PD were male, and 66% were aged ≥80 years. The proportion of PD was higher among males (8.4% vs 4.1% females), and they were more likely to have dementia compared with females (odds ratio, 1.6; 95% CI, 1.5-1.7). Age was not associated with high activities of daily living or complex health care needs. Conclusions and Implications The population of residents with PD in RACFs is growing, with increasing levels of disability and comorbid health conditions. These findings highlight the need for evolving care models, workforce development, and planning to meet the growing demand for services.

Gut dysfunction commonly precedes motor symptoms in Parkinson’s disease (PD), but the mechanistic sequence of gut versus brain pathology remains unclear. This work aimed to define the timing of intestinal barrier dysfunction relative to central nervous system (CNS) changes in the A53T α-synuclein transgenic mouse model of PD. Functional and molecular assessments of the gastrointestinal tract (ileum and colon) were conducted at 12 and 36 weeks. We measured in vivo and ex vivo intestinal permeability, nutrient absorption, histomorphology, goblet cell density, and expression of MUC2 and Claudin-1. Inflammatory markers (CRP, TNF-α, CD45) were quantified in plasma and gut tissues. A53T mice exhibited increased intestinal permeability at 12 and 36 weeks, with transiently elevated ex vivo transepithelial electrical resistance (TER) at 12 weeks. Nutrient absorption remained intact. Morphological changes included widened villi and crypts, altered mucin expression, and early reductions in Claudin-1 in the ileum and the colon while inflammatory markers remained largely unchanged. These findings suggest that gut dysfunction precedes known central pathology in A53T mice, supporting further investigation into the gut as an early site of pathology and a potential therapeutic target in PD.

AIMS:The accumulation of α-synuclein in astrocytes in Parkinson's disease is considered to be secondary to neuronal accumulation. The aim of this study to identify whether astrocytes accumulate small α-synuclein aggregates before or after neurons in the nigrostriatal pathway. METHODS:Fixed serial midbrain and striatal sections from M83 A53T transgenic mouse model of Parkinson's disease and wild-type controls were histologically processed for multiplex labelling of α-synuclein and astrocytic markers and astrocyte quantitation performed on digital images using QuPath software. RESULTS:The density of astrocytes within the substantia nigra pars compacta was approximately 30% greater compared with other sampled regions (p < 0.005). Small aggregates of α-synuclein were observed in astrocytic processes, including in wild-type mice where a quarter of all astrocytes had an obvious α-synuclein aggregate. Compared to wild-type, A53T transgenic astrocytes had significantly enlarged somas (p < 0.001) with more processes (p < 0.001) consistent with a reactive phenotype. The A53T transgenic mice had more than double the numbers of astrocytes (p < 0.001) and 2.5 times more astrocytes with α-synuclein aggregates compared to wild-type mice (p < 0.001). CONCLUSIONS:These data suggest that small α-synuclein aggregates are normally cleared by astrocytes and that the substantia nigra pars compacta requires more astrocytic support for this function than other midbrain dopaminergic regions or the striatum. This adds another vulnerability factor to those already known for the substantia nigra with early deficits in clearance of small α-synuclein aggregates by astrocytes associated with increased astrocytic reactivity in the A53T transgenic mouse model.

Parkinsons disease is considered biologically a neuronal alpha synuclein disease, largely ignoring the more widespread alpha synuclein deposition that occurs in astrocytes. Recent single cell transcriptomics have identified early astrocytic differences in both Parkinsons disease and mouse models with an increase in reactive astrocytes associated with proteostasis. To identify whether astrocytes accumulate alpha synuclein before or after neurons, the present study histologically assessed astrocytes and alpha synuclein accumulation in the M83 A53T transgenic mouse model of Parkinsons disease prior to significant neuronal alpha synuclein accumulation. The brains of M83 A53T transgenic and wild-type mice were perfusion fixed and serial sections of the midbrain and striatum processed for multiplex labelling. Digital images were captured from standardised sampling regions and astrocyte quantitation performed using QuPath software. Multivariate linear region models with Turkey posthoc tests were used to evaluate the effects of genotype on regional astrocyte morphology and numbers. The density of astrocytes within the substantia nigra pars compacta was approximately thirty percent greater compared with other sampled regions. Small aggregates of alpha synuclein were observed in astrocytic processes, including in wild-type mice where a quarter of all astrocytes had an obvious alpha synuclein aggregate. Compared to wild-type, A53T transgenic astrocytes had significantly enlarged somas with more processes consistent with a reactive phenotype. The expression of vascular endothelial growth factor A was present in analysed astrocytes, but not the synthesising enzyme for vitamin D CYP27B1. The A53T transgenic mice had more than double the numbers of astrocytes and 2.5 times more astrocytes with alpha synuclein aggregates compared to wild-type mice. These data suggest that alpha synuclein is normally cleared by astrocytes and that the substantia nigra pars compacta requires more astrocytic support than other midbrain dopaminergic regions or the striatum. This adds another vulnerability factor to those already known for the substantia nigra. In the A53T transgenic mouse model, astrocytes have an early upregulation of their clearance of alpha synuclein aggregates. While speculative, a loss of this ability to take up alpha synuclein in these regions may precipitate the selective neuronal degeneration and pathologies observed in Parkinsons disease. As we move to a biological definition for this disease, understanding this early role astrocytes needs to be considered further. ### Competing Interest Statement The authors have declared no competing interest.

Gastrointestinal (GI) dysfunctions, including constipation and delayed stomach emptying, are prevalent and debilitating non-motor symptoms of Parkinson’s disease (PD). These symptoms have been associated with damage in the enteric nervous system (ENS) and the accumulation of pathogenic alpha-synuclein (α-Syn) within the GI tract. While motor deficits and dopaminergic neuron loss in the central nervous system (CNS) of the A53T mouse model are well-characterised, the temporal relationship between GI dysfunction, ENS pathology, and motor symptoms remains unclear. This study aimed to investigate functional alterations in the GI tract at the early stages of the disease, before the appearance of motor deficits, both in vivo and ex vivo. Early colonic motility deficits observed in A53T mice, measured via bead expulsion, preceded motor impairments emerged at 36 weeks. Although whole-gut transit remained unchanged, reduced faecal output was concurrent with marked colonic dysmotility at 36 weeks. Despite a lack of significant neuronal loss, a greater number of enteric neurons in A53T mice showed signs of neuronal hypertrophy and increased nuclear translocation of HuC/D proteins indicative of neuronal stress at 12 and 36 weeks. Calcium imaging revealed differential enteric neuron activity, characterised by exaggerated calcium transients at 12 weeks that normalized by 36 weeks. Furthermore, a reduction in enteric glial populations was observed as early as 12 weeks in both the ileum and colon of A53T mice. These findings provide compelling evidence that ENS pathology, including neuronal stress, disrupted calcium signalling, and glial cell loss, precedes the onset of motor symptoms and may contribute to early GI dysfunction in PD.

Over the last two decades, visual symptoms and retinal changes in Parkinson's disease (PD) have emerged as important biomarkers. Color vision deficiency, which begins in the outer retina, has been increasingly investigated, but a focused review of these papers has not recently been conducted. Similarly, thinning of the outer retina as measured using optical coherence tomography (OCT) holds potential as a screening marker for PD, particularly as these devices are already commonplace in community and hospital settings. Moreover, outer retinal thinning may be more specific for Parkinson's disease as inner retinal changes also occur in more common neurodegenerative diseases like glaucoma and Alzheimer's disease. This review summarizes contemporary evidence on two outer retina focused measures, color vision and outer retinal thickness, which can be readily quantified using non-invasive approaches and thus examines their potential as biomarkers for screening, detection, and progression in PD.

Hyposmia is one of the most prevalent non-motor symptoms of Parkinson’s disease and antecedes motor dysfunction by up to a decade. However, the underlying pathophysiology remains poorly understood. In this study, we investigated the mechanisms of dopamine metabolism in post-mortem olfactory bulbs from ten Parkinson’s disease and ten neurologic control subjects. In contrast to the loss of dopaminergic neurons in the midbrain, we observed an increase in tyrosine hydroxylase-positive neurons in the Parkinson’s disease olfactory bulb, suggesting a potential role for dopamine in the hyposmia associated with the condition. Using immunohistochemistry, high-performance liquid chromatography, western blot, and enzyme-linked immunosorbent assays, we demonstrate a reduction in catechol-O-methyltransferase catabolism of dopamine to homovanillic acid, potentially due to a depletion of the methyl donor substrate S-adenosyl methionine. We hypothesized that reduction in catechol-O-methyltransferase activity would result in increased dopamine occupation of the D2 receptor, and consequent inhibition of olfactory processing. Next, we conducted pharmacological interventions to modify dopamine dynamics in hyposmic tau knockout mice, which exhibit altered dopamine metabolism. Our hypothesis was supported by the observation that the D2 receptor antagonist haloperidol temporarily alleviated olfactory deficits in these tau knockout mice. This study implicates a potential role of catechol-O-methyltransferase-mediated dopamine metabolism in the early olfactory impairments associated with Parkinson’s disease.

Understanding the intricate role of dopamine D1–D5 receptors is pivotal in addressing the challenges posed by the aging global population, as well as by social stress and advancing therapeutic interventions. Central to diverse brain functions such as movement, cognition, motivation, and reward, dopamine receptors are ubiquitously distributed across various brain nuclei. This comprehensive review explores the nuanced functions of each dopamine receptor, D1, D2, D3, D4, and D5, in distinct brain regions, elucidating the alterations witnessed in several neurological and psychiatric disorders. From the substantia nigra and ventral tegmental area, crucial for motor control and reward processing, to the limbic system influencing emotional responses, motivation, and cognitive functions, each brain nucleus reveals a specific involvement of dopamine receptors. In addition, genetic variations in dopamine receptors affect the risk of developing schizophrenia and parkinsonism. The review further investigates the physiological significance and pathogenic impacts of dopamine receptors in critical areas like the prefrontal cortex, hypothalamus, and striatum. By unraveling the complexities of dopamine receptor biology, especially those focused on different brain nuclei, this review provides a foundation for understanding their varied roles in health and disease, which is essential for the development of targeted therapeutic strategies aimed at mitigating the impact of aging and mental health on neurological well-being.

The quest for new and improved therapies for Parkinson's disease (PD) remains of paramount importance, despite previous trial failures. There is a current debate regarding the potential of stem cell research as a therapeutic approach for PD. The studies of dopaminergic fetal stem cells for PD treatment, their design, and the results of the initial surgical placebo-controlled trials were reviewed in this study. Some of the fundamental methodological challenges and possible strategies to resolve them were proposed. In this article, we argue that the most important impact lies in the proof-of-principle demonstrated by clinical trials for cell replacement strategies in reconstructing the human brain. While some researchers argue that the considerable technical challenges associated with cell therapies for PD warrant the discontinuation of further development using stem cells, we believe that the opposing viewpoints are instrumental in identifying a series of methodological misunderstandings. Here, we propose to expose key challenges to ensure the advancement of the field and unlock the potential of stem cell therapies in PD treatment. Overall, this review underscores the need for further research and innovation to overcome the hurdles in realizing the potential of stem cell-based therapies for PD.

Retinal hyperspectral imaging (HSI) is a non-invasive in vivo approach that has shown promise in Alzheimer’s disease. Parkinson’s disease is another neurodegenerative disease where brain pathobiology such as alpha-synuclein and iron overaccumulation have been implicated in the retina. However, it remains unknown whether HSI is altered in in vivo models of Parkinson’s disease, whether it differs from healthy aging, and the mechanisms which drive these changes. To address this, we conducted HSI in two mouse models of Parkinson’s disease across different ages; an alpha-synuclein overaccumulation model (hA53T transgenic line M83, A53T) and an iron deposition model (Tau knock out, TauKO). In comparison to wild-type littermates the A53T and TauKO mice both demonstrated increased reflectivity at short wavelengths ~ 450 to 600 nm. In contrast, healthy aging in three background strains exhibited the opposite effect, a decreased reflectance in the short wavelength spectrum. We also demonstrate that the Parkinson’s hyperspectral signature is similar to that from an Alzheimer’s disease model, 5xFAD mice. Multivariate analyses of HSI were significant when plotted against age. Moreover, when alpha-synuclein, iron or retinal nerve fibre layer thickness were added as a cofactor this improved the R2 values of the correlations in certain groups. This study demonstrates an in vivo hyperspectral signature in Parkinson’s disease that is consistent in two mouse models and is distinct from healthy aging. There is also a suggestion that factors including retinal deposition of alpha-synuclein and iron may play a role in driving the Parkinson’s disease hyperspectral profile and retinal nerve fibre layer thickness in advanced aging. These findings suggest that HSI may be a promising translation tool in Parkinson’s disease.

Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Studies have demonstrated that the retina in patients with Parkinson’s disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson’s disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson’s disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells—a sensitive neuron in the retina—at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson’s disease and retinal ganglion cell injury.

Background: Visual biomarkers of Parkinson’s disease (PD) are attractive as the retina is an outpouching of the brain. Although inner retinal neurodegeneration in PD is well-established this has overlap with other neurodegenerative diseases and thus outer retinal (photoreceptor) measures warrant further investigation. Objective: To examine in a cross-sectional study whether clinically implementable measures targeting outer retinal function and structure can differentiate PD from healthy ageing and whether these are sensitive to intraday levodopa (L-DOPA) dosing. Methods: Centre-surround perceptual contrast suppression, macular visual field sensitivity, colour discrimination, light-adapted electroretinography and optical coherence tomography (OCT) were tested in PD participants ( n = 16) and controls ( n = 21). Electroretinography and OCT were conducted before and after midday L-DOPA in PD participants, or repeated after ∼2 hours in controls. Results: PD participants had decreased center-surround contrast suppression ( p < 0.01), reduced macular visual field sensitivity ( p < 0.05), color vision impairment ( p < 0.01) photoreceptor dysfunction (a-wave, p < 0.01) and photoreceptor neurodegeneration (outer nuclear layer thinning, p < 0.05), relative to controls. Effect size comparison between inner and outer retinal parameters showed that photoreceptor metrics were similarly robust in differentiating the PD group from age-matched controls as inner retinal changes. Electroretinography and OCT were unaffected by L-DOPA treatment or time. Conclusions: We show that outer retinal outcomes of photoreceptoral dysfunction (decreased cone function and impaired color vision) and degeneration (i.e., outer nuclear layer thinning) were equivalent to inner retinal metrics at differentiating PD from healthy age-matched adults. These findings suggest outer retinal metrics may serve as useful biomarkers for PD.

Parkinson’s disease (PD) is an increasingly common neurodegenerative disease. It has been suggested that the etiology of idiopathic PD is complex and multifactorial involving environmental contributions, such as viral or bacterial infections and microbial dysbiosis, in genetically predisposed individuals. With advances in our understanding of the gut-brain axis, there is increasing evidence that the intestinal microbiota and the mammalian immune system functionally interact. Recent findings suggest that a shift in the gut microbiome to a pro-inflammatory phenotype may play a role in PD onset and progression. While there are links between gut bacteria, inflammation, and PD, the bacterial products involved and how they traverse the gut lumen and distribute systemically to trigger inflammation are ill-defined. Mechanisms emerging in other research fields point to a role for small, inherently stable vesicles released by Gram-negative bacteria, called outer membrane vesicles in disease pathogenesis. These vesicles facilitate communication between bacteria and the host and can shuttle bacterial toxins and virulence factors around the body to elicit an immune response in local and distant organs. In this perspective article, we hypothesize a role for bacterial outer membrane vesicles in PD pathogenesis. We present evidence suggesting that these outer membrane vesicles specifically from Gram-negative bacteria could potentially contribute to PD by traversing the gut lumen to trigger local, systemic, and neuroinflammation. This perspective aims to facilitate a discussion on outer membrane vesicles in PD and encourage research in the area, with the goal of developing strategies for the prevention and treatment of the disease.