Chronic Neurodegenerative Conditions Research Articles

Traumatic MicroRNAs: Deconvolving the Signal After Severe Traumatic Brain Injury.

History of traumatic brain injury (TBI) represents a significant risk factor for development of dementia and neurodegenerative disorders in later life. While histopathological sequelae and neurological diagnostics of TBI are well defined, the molecular events linking the post-TBI signaling and neurodegenerative cascades remain unknown. It is not only due to the brain's inaccessibility to direct molecular analysis but also due to the lack of well-defined and highly informative peripheral biomarkers. MicroRNAs (miRNAs) in blood are promising candidates to address this gap. Using integrative bioinformatics pipeline including miRNA:target identification, pathway enrichment, and protein-protein interactions analysis we identified set of genes, interacting proteins, and pathways that are connected to previously reported peripheral miRNAs, deregulated following severe traumatic brain injury (sTBI) in humans. This meta-analysis revealed a spectrum of genes closely related to critical biological processes, such as neuroregeneration including axon guidance and neurite outgrowth, neurotransmission, inflammation, proliferation, apoptosis, cell adhesion, and response to DNA damage. More importantly, we have identified molecular pathways associated with neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, based on purely peripheral markers. The pathway signature after acute sTBI is similar to the one observed in chronic neurodegenerative conditions, which implicates a link between the post-sTBI signaling and neurodegeneration. Identified key hub interacting proteins represent a group of novel candidates for potential therapeutic targets or biomarkers.

Neuromuscular Complications of SARS-CoV-2 and Other Viral Infections.

In this article we review complications to the peripheral nervous system that occur as a consequence of viral infections, with a special focus on complications of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We discuss neuromuscular complications in three broad categories; the direct consequences of viral infection, autoimmune neuromuscular disorders provoked by viral infections, and chronic neurodegenerative conditions which have been associated with viral infections. We also include discussion of neuromuscular disorders that are treated by immunomodulatory therapies, and how this affects patient susceptibility in the current context of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 is associated with direct consequences to the peripheral nervous system via presumed direct viral injury (dysgeusia/anosmia, myalgias/rhabdomyolysis, and potentially mononeuritis multiplex) and autoimmunity (Guillain Barré syndrome and variants). It has important implications for people receiving immunomodulatory therapies who may be at greater risk of severe outcomes from COVID-19. Thus far, chronic post-COVID syndromes (a.k.a: long COVID) also include possible involvement of the neuromuscular system. Whether we may observe neuromuscular degenerative conditions in the longer term will be an important question to monitor in future studies.

Investigating White Matter Inflammatory Cells and their Relationship with Beta‐Amyloid in Alzheimer's Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative condition affecting millions of people worldwide. With an aging population, it is predicted that by 2050 the number of individuals living with AD will triple, resulting in an increased social and economic burden. Previous research has demonstrated that the pathological process leading to AD occurs years before a positive diagnosis. Therefore, identifying biomarkers that co‐occur within the early stage of AD progression and that predict worsening cognitive outcomes are critically needed. AD is characterized by the presence of beta‐amyloid plaques, neurofibrillary tangles and neuroinflammation. Clinically, being unable to recall new information is the most common outcome of AD. White matter inflammation is mediated by microglial activation and astrocytosis and are thought to be important underlying mechanisms involved in the pathogenesis of AD progression, while also being predictive of future cognitive decline. In a transgenic rat model of AD, it has been previously found that microglial activation within the white matter tracts was strongly associated with impairments in executive function. Age‐related differences in inflammatory cells have also been identified. One study found a significant increase in age‐associated white matter inflammatory cells in amyloid‐plaque negative rats at 7‐and‐8‐months of age. Sex‐and‐age related differences in inflammatory cells and amyloid‐beta have been identified, however, they remain poorly understood in the white matter. The purpose of this study was to investigate the sex‐specific‐age trajectory of white matter inflammatory cells in a wildtype rat model of normal aging and in two transgenic rat models of AD: one in an amyloid‐plaque negative, and one in an amyloid‐plaque positive environment. We hypothesized that microglial activation increases with normal aging and is further exacerbated by the presence of beta‐amyloid deposition. Male (n=5) and female (n=5) Fischer 344 wildtype, transgenic APP21 (amyloid‐plaque negative) and APP/PS1 (amyloid‐plaque positive) rats at 3, 9 and 15‐months of age were included in the experimental design. Immunohistochemical analyses were conducted to detect the presence of microglial activation, pro‐inflammatory M1 microglial activation, astrocytosis and beta‐amyloid. Results demonstrate unique age‐dependant trajectories in microglial activation, particularly in the corpus callosum, supraventricular corpus callosum and internal capsule of the wildtype, transgenic APP/21 and APP/PS1 rat genotypes. Given that only the APP/PS1 rats demonstrated age‐dependant plaque deposition, our results indicate that microglial activation within the white matter is associated with changes in amyloid‐plaque deposition. Future work will aim to better understand the mechanisms related to the relationship between white matter microglial activation, amyloid‐plaque deposition and cognitive impairment. A better understanding of this relationship can aid in the development of an earlier method of detecting AD, which in turn can better define a new therapeutic window of opportunity to target microglial activation and prevent neurodegeneration and cognitive decline associated with AD.

Exogenous Ketones and Lactate as a Potential Therapeutic Intervention for Brain Injury and Neurodegenerative Conditions.

Metabolic dysfunction is a ubiquitous underlying feature of many neurological conditions including acute traumatic brain injuries and chronic neurodegenerative conditions. A central problem in neurological patients, in particular those with traumatic brain injuries, is an impairment in the utilization of glucose, which is the predominant metabolic substrate in a normally functioning brain. In such patients, alternative substrates including ketone bodies and lactate become important metabolic candidates for maintaining brain function. While the potential neuroprotective benefits of ketosis have been recognized for up to almost a century, the majority of work has focused on the use of ketogenic diets to induce such a state, which is inappropriate in cases of acute disease due to the prolonged periods of time (i.e., weeks to months) required for the effects of a ketogenic diet to be seen. The following review seeks to explore the neuroprotective effects of exogenous ketone and lactate preparations, which have more recently become commercially available and are able to induce a deep ketogenic response in a fraction of the time. The rapid response of exogenous preparations makes their use as a therapeutic adjunct more feasible from a clinical perspective in both acute and chronic neurological conditions. Potentially, their ability to globally moderate long-term, occult brain dysfunction may also be relevant in reducing lifetime risks of certain neurodegenerative conditions. In particular, this review explores the association between traumatic brain injury and contusion-related dementia, assessing metabolic parallels and highlighting the potential role of exogenous ketone and lactate therapies.

Crossed cerebellar diaschisis in Alzheimer's disease.

Crossed cerebellar diaschisis (CCD) is characterized by hypometabolism and hypoperfusion on molecular imaging in the cerebellum due to a supratentorial lesion on the contralateral side. CCD is a well-established phenomenon in acute or subacute conditions such as infarction but it has been less well described in chronic conditions such as neurodegenerative dementias. Here, we investigate CCD in a large sample of 830 people meeting research criteria for Alzheimer's disease (AD) using [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET). This study is based on FDG-PET data collected at baseline as part of two large-scale Phase III clinical trials of a novel tau aggregation inhibitor medication, methylthioninium in mild to moderate AD participants. Quantification of FDG-PET hypometabolism was carried out using standardized uptake value ratio (SUVR), with the pons as the comparison region. SUVR was compared in different regions of interest between the right and left hemispheres of the brain and cerebellum in people with mild AD (Mini-Mental State Examination score ≥ 20). Comparison of SUVR in different brain regions demonstrated significant differences in the temporal, occipital and cerebellar cortices. Right and left asymmetry was noted with lower SUVR in the left temporal and occipital regions, whereas SUVR was lower in the right side of the cerebellum. Here, we found robust evidence of CCD in a large sample of people with AD, a chronic neurodegenerative condition. The presence of this phenomenon in AD opens up a new avenue of research in AD pathogenesis and has the potential to change future diagnostic and therapeutic strategies.

A NARRATIVE REVIEW OF THE MANAGEMENT OF BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA

Dementia is a chronic or progressive neurodegenerative condition which is organic in origin. There will be impairment of thinking, memory orientation, comprehension, language, calculation, and judgement. Alzheimer's disease facts and gures in 2021 according to Alzheimer's association shows Alzheimer's disease accounts for 60% to 80% of the total cases. Behavioural and psychological symptoms of dementia also known as neuropsychiatric symptoms are a group of symptoms with behavioural and psychological manifestations. Disturbances include behavioural symptoms like wandering, hoarding, physical aggression, sexually disinhibition, culturally inappropriate behaviour, agitation and psychological symptoms like apathy, depression, anxiety, delusions, and hallucinations, sundowning, elation. Scales like the Neuropsychiatric Inventory, the Behavioural Pathology in Alzheimer Disease rating scale, the Consortium to Establish a Registry for Alzheimer Disease Behaviour Rating Scale for Dementia, Dementia Behaviour Disturbance scale, and the Neurobehavioral Rating Scale can be utilized to recognise BPSD.Neuropsychological assessment also have an important role. Non-pharmacological methodologies contain different sorts of treatment: tactile stimulation, pressure point massage, fragrant healing, light treatment, garden exercises, music therapy, dance therapy, and Snoezelen multisensory therapy, psychological strategies of multicomponent treatment strategies. Broadly focussing on sensory stimulation, social activities, structural activities, behavioural activities, environmental activities, and training programmes. Pharmacological treatment includes antipsychotics, mood stabilizers and antidepressants in treating BPSD, and cholinesterase inhibitors and memantine for the situation of Alzheimer's dementia sedative/hypnotics for sleep issues. Treatment can be further categorized based on individual NPS like agitation, psychosis, apathy, depression, sleep problems and other symptoms. Future treatment which has less evidence as of now includes rTMS, TDCS and Photo biomodulation therapy

Effects of bee venom and dopamine-loaded nanoparticles on reserpine-induced Parkinson\u2019s disease rat model

Parkinson’s disease (PD) is a progressive chronic neurodegenerative condition characterized by the loss of dopaminergic neurons within the substantia nigra. Current PD therapeutic strategies are mainly symptomatic and can lead to motor complications overtime. As a result, alternative medicine may provide an effective adjuvant treatment for PD as an addition to or as a replacement of the conventional therapies. The aim of this work was to evaluate the effects of Bee Venom (BV) and dopamine (DA)-loaded nanoparticles in a reserpine-induced animal model of PD. After inducing PD with reserpine injection, different groups of male rats were treated with L-Dopa, BV, DA-nanoparticles. Our findings showed that BV and DA-nanoparticles administration restored monoamines, balanced glutamate/GABA levels, halted DNA fragmentation, decreased pro-inflammatory mediators (IL-1β and TNF-α), and elevated anti-inflammatory mediators (PON1) and neurotropic factor (BDNF) levels in comparison with conventional therapy of PD. Furthermore, in a reserpine-induced PD rat model, the ameliorative effects of BV were significantly superior to that of DA-nanoparticles. These findings imply that BV and DA-nanoparticles could be useful as adjuvant treatments for PD.

Deciphering the focal role of endostatin in Alzheimer's disease.

Alzheimer's disease (AD) is a paramount chronic neurodegenerative condition that has been affecting elderly people since the 1900s. It causes memory loss, disorientation, and poor mental function. AD is considered to be one of the most serious problems that dementia sufferers face. Despite extensive investigation, the pathological origin of Alzheimer's disease remains a mystery. The amyloid cascade theory and the vascular hypothesis, which stresses the buildup of Aβ plaques, have dominated research into dementia and aging throughout history. However, research into this task failed to yield the long-awaited therapeutic miracle lead for Alzheimer's disease. Perhaps a hypothetical fragility in the context of Alzheimer's disease was regarded as a state distinct from aging in general, as suggested by the angiogenesis hypothesis, which suggests that old age is one state associated with upregulation of angiogenic growth factors, resulting in decreased microcirculation throughout the body. There has also been evidence that by controlling or inhibiting the components involved in the sequence of events that cause angiogenesis, there is a visible progression in AD patients. In Alzheimer's disease, one such antiangiogenic drug is being used.

Plasma Membrane and Organellar Targets of STIM1 for Intracellular Calcium Handling in Health and Neurodegenerative Diseases.

Located at the level of the endoplasmic reticulum (ER) membrane, stromal interacting molecule 1 (STIM1) undergoes a complex conformational rearrangement after depletion of ER luminal Ca2+. Then, STIM1 translocates into discrete ER-plasma membrane (PM) junctions where it directly interacts with and activates plasma membrane Orai1 channels to refill ER with Ca2+. Furthermore, Ca2+ entry due to Orai1/STIM1 interaction may induce canonical transient receptor potential channel 1 (TRPC1) translocation to the plasma membrane, where it is activated by STIM1. All these events give rise to store-operated calcium entry (SOCE). Besides the main pathway underlying SOCE, which mainly involves Orai1 and TRPC1 activation, STIM1 modulates many other plasma membrane proteins in order to potentiate the influxof Ca2+. Furthermore, it is now clear that STIM1 may inhibit Ca2+ currents mediated by L-type Ca2+ channels. Interestingly, STIM1 also interacts with some intracellular channels and transporters, including nuclear and lysosomal ionic proteins, thus orchestrating organellar Ca2+ homeostasis. STIM1 and its partners/effectors are significantly modulated in diverse acute and chronic neurodegenerative conditions. This highlights the importance of further disclosing their cellular functions as they might represent promising molecular targets for neuroprotection.

Experiences of healthcare for people living with multiple sclerosis and their healthcare professionals.

BackgroundMultiple sclerosis (MS) is a chronic inflammatory and neurodegenerative condition of the central nervous system that commonly strikes in young adulthood and has no cure. Many people living with MS (PwMS) will have significant contact with a range of healthcare professionals (HCPs). To achieve optimal health outcomes in MS, it is important to understand factors that contribute to positive or negative healthcare experiences. Previous studies have shown that PwMS want clear communication and in‐depth relationships with their HCPs. However, many studies have lacked qualitative feedback from HCPs.ObjectiveThis study aimed to investigate healthcare experiences of PwMS and HCPs and identify areas that are working well and areas that could be improved.MethodsSemistructured interviews with 15 PwMS and 11 HCPs (seven neurologists, four MS nurses) from across Australia were conducted. Interviews were transcribed verbatim and analysed thematically.ResultsBoth PwMS and HCPs valued clear communication, recognized uncertainties associated with MS and highlighted the importance of rapport. PwMS focused on decision‐making, understanding roles and expectations, self‐directed management and their needs for support. HCPs discussed issues related to medical management, providing hope and reassurance, barriers to healthcare and multidisciplinary care.ConclusionGreater transparency and communication, particularly around the approach to care and the roles played by HCPs, is likely to enhance healthcare experiences and contribute to better health outcomes for PwMS.Public ContributionPwMS and HCPs volunteered to be interviewed, and PwMS assisted with the development of interview content and structure.

Stressed axons craving for glial sugar: links to regeneration?

Stressed axons craving for glial sugar: links to regeneration?

Therapeutic Potential of α-Crystallins in Retinal Neurodegenerative Diseases.

The chaperone and anti-apoptotic activity of α-crystallins (αA- and αB-) and their derivatives has received increasing attention due to their tremendous potential in preventing cell death. While originally known and described for their role in the lens, the upregulation of these proteins in cells and animal models of neurodegenerative diseases highlighted their involvement in adaptive protective responses to neurodegeneration associated stress. However, several studies also suggest that chronic neurodegenerative conditions are associated with progressive loss of function of these proteins. Thus, while external supplementation of α-crystallin shows promise, their potential as a protein-based therapeutic for the treatment of chronic neurodegenerative diseases remains ambiguous. The current review aims at assessing the current literature supporting the anti-apoptotic potential of αA- and αB-crystallins and its potential involvement in retinal neurodegenerative diseases. The review further extends into potentially modulating the chaperone and the anti-apoptotic function of α-crystallins and the use of such functionally enhanced proteins for promoting neuronal viability in retinal neurodegenerative disease.

Multimodal Classification of Parkinson's Disease in Home Environments with Resiliency to Missing Modalities.

Parkinson’s disease (PD) is a chronic neurodegenerative condition that affects a patient’s everyday life. Authors have proposed that a machine learning and sensor-based approach that continuously monitors patients in naturalistic settings can provide constant evaluation of PD and objectively analyse its progression. In this paper, we make progress toward such PD evaluation by presenting a multimodal deep learning approach for discriminating between people with PD and without PD. Specifically, our proposed architecture, named MCPD-Net, uses two data modalities, acquired from vision and accelerometer sensors in a home environment to train variational autoencoder (VAE) models. These are modality-specific VAEs that predict effective representations of human movements to be fused and given to a classification module. During our end-to-end training, we minimise the difference between the latent spaces corresponding to the two data modalities. This makes our method capable of dealing with missing modalities during inference. We show that our proposed multimodal method outperforms unimodal and other multimodal approaches by an average increase in -score of 0.25 and 0.09, respectively, on a data set with real patients. We also show that our method still outperforms other approaches by an average increase in -score of 0.17 when a modality is missing during inference, demonstrating the benefit of training on multiple modalities.

Proteome Profiling Identified Amyloid-β Protein Precursor as a Novel Binding Partner and Modulator of VGLUT1.

The toxicity of excessive glutamate release has been implicated in various acute and chronic neurodegenerative conditions. Vesicular glutamate transporters (VGLUTs) are the major mediators for the uptake of glutamate into synaptic vesicles. However, the dynamics and mechanism of this process in glutamatergic neurons are still largely unknown. This study aimed to investigate the candidate protein partners of VGLUT1 and their regulatory roles in the vesicles in rat brain. Pull down assay, co-immunoprecipitation assay, or split-ubiquitin membrane yeast two hybrid screening coupled with nanoRPLC-MS/MS were used to identify the candidate protein partners of VGLUT1 in the vesicles in rat brain. The in vitro and in vivo models were used to test effects of AβPP, Atp6ap2, Gja1, and Synataxin on VGLUT1 expression. A total of 255 and 225 proteins and 172 known genes were identified in the pull down assay, co-immunoprecipitation assay, or split-ubiquitin yeast two-hybrid screening respectively. The physiological interactions of SV2A, Syntaxin 12, Gja1, AβPP, and Atp6ap2 to VGLUT1 were further confirmed. Knockdown of Atp6ap2, Gja1, and Synataxin increased VGLUT1 mRNA expression and only knockdown of AβPP increased both mRNA and protein levels of VGLUT1 in PC12 cells. The regulatory function of AβPP on VGLUT1 expression was further confirmed in the in vitro and in vivo models. These results elucidate that the AβPP and VGLUT1 interacts at vesicular level and AβPP plays a role in the regulation of VGLUT1 expression which is essential for maintaining vesicular activities.

Precision health in Alzheimer disease: Risk assessment‐based strategies

AbstractAlzheimer disease (AD) is a chronic neurodegenerative condition that affects an individual's cognitive function over an extended period. Treatment and prevention for AD have long been sought after; however, no strategy has yet been successful, as individuals with cognitive impairment usually present to the clinic when they have reached an advanced stage of the disease. The disease is progressive and multifactorial in its pathogenesis. Precision medicine (PM) is the new era of medicine comprising a holistic approach in dealing with diseases. With scientific innovations, PM has improved our disease knowledge, altered diagnoses and therapy approaches resulting in a more precise, predictive, preventative and personalized patient care. PM in AD focuses, among other things, on stratifying individuals according to their risk factors of developing the disease and applying preventative strategies and personalized treatment approaches for a better outcome. In this mini‐review, we have focused on a few modifiable and non‐modifiable risk factors and presented recommendations for future consideration to implement.

Symptom management of patients with multiple sclerosis in primary care: focus on overlooked symptoms.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative condition of the central nervous system. Its prevalence varies from 50–300 per 100 000 people, and it is estimated that around 2.3 million people worldwide live with MS.1 In 2020, Public Health England released new MS prevalence data from GP records. This revealed that the number of adults with MS in the UK has risen to 131 720.2 Each year there are on average 4950 new cases of MS diagnosed and recorded in UK primary care records.2 Treatment of MS comprises disease-modifying drugs (DMDs) that reduce the inflammation and management of MS relapses and symptoms. The clinical decisions about DMDs and their complex monitoring dominate consultations with MS specialists, leaving less time for the management of patients’ daily symptoms. Therefore, GPs currently have a unique role in managing patients’ symptoms in primary care. This article focuses on the most under-recognised symptoms of MS. Cognitive dysfunction, fatigue, and depression are often overlooked by healthcare professionals.3–8 These symptoms are linked and profoundly affect patients’ quality of life, especially at the early stages of the disease.3–8 ### Cognitive dysfunction Cognitive impairment is prevalent in up to 65% of patients with MS.4 The most common cognitive domains affected are processing speed and memory.4 Other cognitive symptoms include deficits in attention, executive functioning, and verbal fluency.4,5 There is a robust correlation between cognitive deficits and quality of life, including employment status in patients with MS.4,5 Patients’ self-reported cognitive function is not considered a reliable measure, as it correlates with depression, rather than cognition.4 An informant report about patients’ cognition correlates better with objectively measured cognitive function …

Histamine in the Crosstalk Between Innate Immune Cells and Neurons: Relevance for Brain Homeostasis and Disease.

Histamine is a biogenic amine playing a central role in allergy and peripheral inflammatory reactions and acts as a neurotransmitter and neuromodulator in the brain. In the adult, histamine is produced mainly by mast cells and hypothalamic neurons, which project their axons throughout the brain. Thus, histamine exerts a range of functions, including wakefulness control, learning and memory, neurogenesis, and regulation of glial activity. Histamine is also known to modulate innate immune responses induced by brain-resident microglia cells and peripheral circulating monocytes, and monocyte-derived cells (macrophages and dendritic cells). In physiological conditions, histamine per se causes mainly a pro-inflammatory phenotype while counteracting lipopolysaccharide-induced inflammation both in microglia, monocytes, and monocyte-derived cells. In turn, the activation of the innate immune system can profoundly affect neuronal survival and function, which plays a critical role in the onset and development of brain disorders. Therefore, the dual role of histamine/antihistamines in microglia and monocytes/macrophages is relevant for identifying novel putative therapeutic strategies for brain diseases. This review focuses on the effects of histamine in innate immune responses and the impact on neuronal survival, function, and differentiation/maturation, both in physiological and acute (ischemic stroke) and chronic neurodegenerative conditions (Parkinson's disease).

Early Stage Detection of Parkinson Disease

Parkinson’s disease is a chronic neurodegenerative condition that demonstrate the progressive loss of the ability to correlate movements mainly occurs in the elderly. For the purpose of monitoring tremors in Parkinson’s disease, a system has to be designed and developed. For coordination of movements, people with Parkinson’s, deprive of a chemical called dopamine which behaves as the messenger between the brain parts and the nervous system .Detecting Parkinson’s disease is a very arduous task as there is no evidence currently present to do this. Therefore, the main intention of our work is the designing of a system for recognizing Parkinson’s disease at an initial stage. An Android application is being designed that allows the status of PD patients to be assessed based on the tests found on the Unified Parkinson’s Disease Rating Scale approved by the Movement Disorders Society (MDS-UPDRS).

Parkinson’s Disease: Possible Mechanisms for Nutritional Approaches

Parkinson’s disease (PD) is among the most common chronic neurodegenerative conditions, affecting 1% of those over 60 years of age, and involves motor and non-motor impairments. Alterations in normal physiology may become apparent years – in some cases, 10–20 years – before established diagnostic criteria are met. Thus, better clinical outcomes may result when practitioners utilize nutritional and supplement interventions that support reductions in neuroinflammation and neurodegeneration as early as possible. PD is a devastating, progressive neurodegenerative condition that has both hereditary and environmental components to its pathogenesis, and early identification of risk factors and onset is critical. The purpose of this review is to highlight various nutrition and supplement interventions that may positively affect disease onset and progression, and that warrant further research.

High fat diet-induced obesity causes a reduction in brain tyrosine hydroxylase levels and non-motor features in rats through metabolic dysfunction, neuroinflammation and oxidative stress

ABSTRACT Obesity is a health problem that has been associated with neuroinflammation, decreased cognitive functions and development of neurodegenerative diseases. Parkinson’s disease (PD) is a chronic neurodegenerative condition characterized by motor and non-motor abnormalities, increased brain inflammation, α-synuclein protein aggregation and dopaminergic neuron loss that is associated with decreased levels of tyrosine hydroxylase (TH) in the brain. Diet-induced obesity is a global epidemic and its role as a risk factor for PD is not clear. Herein, we showed that 25 weeks on a high-fat diet (HFD) promotes significant alterations in the nigrostriatal axis of Wistar rats. Obesity induced by HFD exposure caused a reduction in TH levels and increased TH phosphorylation at serine 40 in the ventral tegmental area. These effects were associated with insulin resistance, increased tumor necrosis factor-α levels, oxidative stress, astrogliosis and microglia activation. No difference was detected in the levels of α-synuclein. Obesity also induced impairment of locomotor activity, total mobility and anxiety-related behaviors that were identified in the open-field and light/dark tasks. There were no changes in motor coordination or memory. Together, these data suggest that the reduction of TH levels in the nigrostriatal axis occurs through an α-synuclein-independent pathway and can be attributed to brain inflammation, oxidative/nitrosative stress and metabolic disorders induced by obesity.