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Background: Neuropsychiatric symptoms are common in dementia and linked to adverse outcomes. Inflammation is increasingly recognized as playing a role as a driver of early disease progression in Alzheimer's disease (AD) and related dementias. Inflammation has also been linked to primary psychiatric disorders, however its association with neuropsychiatric symptoms in neurodegenerative dementias remains uncertain. Methods: We conducted a systematic literature review investigating associations between inflammation and neuropsychiatric symptoms in neurodegenerative dementias, including AD, Lewy body, Frontotemporal, Parkinson's (PD) and Huntington's disease dementias. Results: Ninety-nine studies met our inclusion criteria, and the majority (n = 59) investigated AD and/or mild cognitive impairment (MCI). Thirty-five studies included PD, and only 6 investigated non-AD dementias. Inflammation was measured in blood, CSF, by genotype, brain tissue and PET imaging. Overall, studies exhibited considerable heterogeneity and evidence for specific inflammatory markers was inconsistent, with lack of replication and few longitudinal studies with repeat biomarkers. Depression was the most frequently investigated symptom. In AD, some studies reported increases in peripheral IL-6, TNF-a associated with depressive symptoms. Preliminary investigations using PET measures of microglial activation found an association with agitation. In PD, studies reported positive associations between TNF-a, IL-6, CRP, MCP-1, IL-10 and depression. Conclusion: Central and peripheral inflammation may play a role in neuropsychiatric symptoms in neurodegenerative dementias; however, the evidence is inconsistent. There is a need for multi-site longitudinal studies with detailed assessments of neuropsychiatric symptoms combined with replicable peripheral and central markers of inflammation. [ABSTRACT FROM AUTHOR]

Deposition of amyloid-β (Aβ) in the brain can impair neuronal function and contribute to cognitive decline in Alzheimer's disease (AD). Here, we found that dopamine and the dopamine precursor levodopa (also called l-DOPA) induced Aβ degradation in the brain. Chemogenetic approaches in mice revealed that the activation of dopamine release from ventral tegmental area (VTA) neurons increased the abundance and activity of the Aβ-degrading enzyme neprilysin and reduced the amount of Aβ deposits in the prefrontal cortex in a neprilysin-dependent manner. Aged mice had less dopamine and neprilysin in the anterior cortex, a decrease that was accentuated in AD model mice. Treating AD model mice with levodopa reduced Aβ deposition and improved cognitive function. These observations demonstrate that dopamine promotes brain region–specific, neprilysin-dependent degradation of Aβ, suggesting that dopamine-associated strategies have the potential to treat this aspect of AD pathology. Editor's summary: The accumulation of amyloid-β in the brain is associated with progressive cognitive impairment in Alzheimer's disease. Watamura et al. found that a treatment commonly used to treat a symptom of Parkinson's disease also induced the breakdown of amyloid-β. In mice, dopamine release in the brain increased the abundance and activity of the enzyme neprilysin, which degraded amyloid-β specifically in the working memory center of the brain. Levodopa induced these effects and improved cognitive function in aged and Alzheimer's disease model mice, suggesting that the approach might be explored for patients with Alzheimer's disease. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by numerous motor and non-motor symptoms. Recent data highlight a potential interplay between the gut microbiota and the pathophysiology of PD. The degeneration of dopaminergic neurons in PD leads to motor symptoms (tremor, rigidity, and bradykinesia), with antecedent gastrointestinal manifestations, most notably constipation. Consequently, the gut emerges as a plausible modulator in the neurodegenerative progression of PD. Key molecular changes in PD are discussed in the context of the gut–brain axis. Evidence suggests that the alterations in the gut microbiota composition may contribute to gastroenteric inflammation and influence PD symptoms. Disturbances in the levels of inflammatory markers, including tumor necrosis factor-α (TNF α), interleukin -1β (IL-1β), and interleukin-6 (IL-6), have been observed in PD patients. These implicate the involvement of systemic inflammation in disease pathology. Fecal microbiota transplantation emerges as a potential therapeutic strategy for PD. It may mitigate inflammation by restoring gut homeostasis. Preclinical studies in animal models and initial clinical trials have shown promising results. Overall, understanding the interplay between inflammation, the gut microbiota, and PD pathology provides valuable insights into potential therapeutic interventions. This review presents recent data about the bidirectional communication between the gut microbiome and the brain in PD, specifically focusing on the involvement of inflammatory biomarkers. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disorder with a complicated etiology and pathogenesis. α-Synuclein aggregation, dopaminergic (DA) neuron loss, mitochondrial injury, oxidative stress, and inflammation are involved in the process of PD. Neuroinflammation has been recognized as a key element in the initiation and progression of PD. In this review, we summarize the inflammatory response and pathogenic mechanisms of PD. Additionally, we describe the potential anti-inflammatory therapies, including nod-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome inhibition, nuclear factor κB (NF-κB) inhibition, microglia inhibition, astrocyte inhibition, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibition, the peroxisome proliferator-activated receptor γ (PPARγ) agonist, targeting the mitogen-activated protein kinase (MAPK) pathway, targeting the adenosine monophosphate-activated protein kinase (AMPK)-dependent pathway, targeting α-synuclein, targeting miRNA, acupuncture, and exercise. The review focuses on inflammation and will help in designing new prevention strategies for PD. [ABSTRACT FROM AUTHOR]

To investigate whether glial fibrillary acidic protein (GFAP), neurofilament light chain (NFL), and 12 cytokines can serve as serum biomarkers of olfactory identification dysfunction in patients with Parkinson's disease (PD). GFAP and NFL levels were measured in 75 patients with PD and 36 healthy controls (HCs). The levels of 12 cytokines were assayed in 41 patients with PD. The 16-item Sniffin' Sticks test and the Mini-Mental State Examination (MMSE) were used to assess olfactory identification ability and cognitive function, respectively. Linear regression models were applied to control for confounding effects. Receiver operating characteristic curves were used to examine the diagnostic accuracy of serum NFL, GFAP, and interleukin-6 (IL-6) levels. The cut-off value for the SS-16 test in diagnosing dysosmia was equal to 9.5 points. Serum GFAP levels were higher in patients with PD with olfactory identification dysfunction than in those without. GFAP, NFL, and IL-6 levels were correlated with SS-16 scores. Moreover, combining these three biomarkers yielded the best-fitting model for distinguishing patients with PD with or without dysosmia. We found a prominent indirect effect of GFAP on MMSE scores through its contribution to SS-16 scores. GFAP, NFL, and IL-6 can serve as serum biomarkers for olfactory identification dysfunctions in PD. We inferred that astrogliosis might promote the occurrence of dysosmia by releasing proinflammatory factors and causing neuronal damage and may indirectly impair cognition through its effect on olfactory function. [ABSTRACT FROM AUTHOR]

An altered immune response has been identified as a pathophysiological factor in Parkinson's disease (PD). We aimed to identify blood immunity-associated proteins that discriminate PD from controls and that are associated with long-term disease severity in PD patients. Immune response-derived proteins in blood plasma were measured using Proximity Extension Technology by OLINK in a cohort of PD patients (N = 66) and age-matched healthy controls (N = 52). In a selection of 30 PD patients, we evaluated changes in protein levels 7–10 years after the baseline and assessed correlations with motor and cognitive assessments. Data from the Parkinson's Disease Biomarkers Program (PDBP) cohort and the Parkinson's Progression Markers Initiative (PPMI) cohort were used for independent validation. PD patients showed an altered immune response compared to controls based on a panel of four proteins (IL-12B, OPG, CXCL11, and CSF-1). The expression levels of five inflammation-associated proteins (CCL23, CCL25, TNFRSF9, TGF-alpha, and VEGFA) increased over time in PD and were partially associated with more severe motor and cognitive symptoms at follow-up. Increased CCL23 levels were associated with cognitive decline and the APOE4 genotype. Our findings provide further evidence for an altered immune response in PD that is associated with disease severity in PD over a long period of time. [ABSTRACT FROM AUTHOR]

Abstract—This review describes the role of peripheral blood biomarkers involved in neurodegeneration and neuroregeneration in Parkinson's disease: BDNF, Cathepsin D, NSAM, myeloperoxidase, plasminogen activator inhibitor-1 (PAI-1), platelet-derived growth factor (PDGF), a chemokine that is regulated upon activation, normal T cell expression and secreted (RANTES), and intercellular adhesion molecules (sICAM-1). These biomarkers are important indicators of biological processes and are promising for early diagnosis, the prognosis of the disease, and the development of new possibilities for modifying therapy for Parkinson's disease, as they are associated with neuroprotective and neurotrophic systems. [ABSTRACT FROM AUTHOR]

The worldwide prevalence of Parkinson's disease (PD) has been constantly increasing in the last decades. With rising life expectancy, a longer disease duration in PD patients is observed, further increasing the need and socioeconomic importance of adequate PD treatment. Today, PD is exclusively treated symptomatically, mainly by dopaminergic stimulation, while efforts to modify disease progression could not yet be translated to the clinics. New formulations of approved drugs and treatment options of motor fluctuations in advanced stages accompanied by telehealth monitoring have improved PD patients care. In addition, continuous improvement in the understanding of PD disease mechanisms resulted in the identification of new pharmacological targets. Applying novel trial designs, targeting of pre-symptomatic disease stages, and the acknowledgment of PD heterogeneity raise hopes to overcome past failures in the development of drugs for disease modification. In this review, we address these recent developments and venture a glimpse into the future of PD therapy in the years to come. [ABSTRACT FROM AUTHOR]

Emerging evidence implicates intestinal involvement in the onset and/or progression on the selective degeneration of dopaminergic neurons characterizing Parkinson's disease (PD). On the one hand, there are studies supporting the Braak hypothesis that holds that pathologic α-synuclein, a hallmark of PD, is secreted by enteric nerves into intestinal tissue and finds its way to the central nervous system (CNS) via retrograde movement in the vagus nerve. On the other hand, there is data showing that cells bearing leucine-rich repeat kinase 2 (LRRK2), a signaling molecule with genetic variants associated with both PD and with inflammatory bowel disease, can be activated in intestinal tissue and contribute locally to intestinal inflammation, or peripherally to PD pathogenesis via cell trafficking to the CNS. Importantly, these gut-centered factors affecting PD development are not necessarily independent of one another: they may interact and enhance their respective pathologic functions. In this review, we discuss this possibility by analysis of studies conducted in recent years focusing on the ability of LRRK2 to shape immunologic responses and the role of α-synuclein in influencing this ability. [ABSTRACT FROM AUTHOR]

Parkinson's Disease (PD) is the second most common neurodegenerative disorder seen, especially in the elderly. Tremor, shaking, movement problems, and difficulty with balance and coordination are among the hallmarks, and dopaminergic neuronal loss in substantia nigra pars compacta of the brain and aggregation of intracellular protein α-synuclein are the pathological characterizations. Neuroinflammation has emerged as an involving mechanism at the initiation and development of PD. It is a complex network of interactions comprising immune and non-immune cells in addition to mediators of the immune response. Microglia, the resident macrophages in the CNS, take on the leading role in regulating neuroinflammation and maintaining homeostasis. Under normal physiological conditions, they exist as "homeostatic" but upon pathological stimuli, they switch to the "reactive state". Pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes are used to classify microglial activity with each phenotype having its own markers and released mediators. When M1 microglia are persistent, they will contribute to various inflammatory diseases, including neurodegenerative diseases, such as PD. In this review, we focus on the role of microglia mediated neuroinflammation in PD and also signaling pathways, receptors, and mediators involved in the process, presenting the studies that associate microglia-mediated inflammation with PD. A better understanding of this complex network and interactions is important in seeking new therapies for PD and possibly other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common inflammatory neurodegenerative disorder after dementia. Preclinical and epidemiological data strongly suggest that chronic neuroinflammation slowly induces neuronal dysfunction. Activated microglia secrete several neurotoxic substances, such as chemokines and proinflammatory cytokines, which may promote blood–brain barrier (BBB) permeabilization. CD4+ T cells comprise proinflammatory cells such as T helper (Th) 1 and Th17 cells, as well as anti-inflammatory cells such as Th2 and T regulatory cells (Tregs). Th1 and Th17 cells can be detrimental to dopamine neurons, whereas Th2 and Tregs are neuroprotective. The results of studies on the serum levels of cytokines such as IFN-γ and TNF-α secreted by Th1 T cells, IL-8 and IL-10 secreted by Th2 T cells, and IL-17 secreted by Th17 cells in PD patients are not uniform. In addition, the relationships between serum cytokine levels and motor and non-motor symptoms of PD are controversial. Surgical stress and anesthesia induce inflammatory responses by disturbing the balance between pro- and anti-inflammatory cytokines, which may exacerbate the neuroinflammatory response in PD patients. Here we review studies on blood inflammatory biomarkers in PD patients and discuss the roles of surgery and anesthesia in PD progression. [ABSTRACT FROM AUTHOR]

Dysfunction of the immune system and mitochondrial metabolism has been associated with Parkinson's disease (PD) pathology. Mutations and increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) are linked to both idiopathic and familial PD. However, the function of LRRK2 in the immune cells under inflammatory conditions is contradictory. Our results showed that lipopolysaccharide (LPS) stimulation increased the kinase activity of LRRK2 in parental RAW 264.7 (WT) cells. In addition to this, LRRK2 deletion in LRRK2 KO RAW 264.7 (KO) cells altered cell morphology following LPS stimulation compared to the WT cells, as shown by an increase in the cell impedance as observed by the xCELLigence measurements. LPS stimulation caused an increase in the cellular reactive oxygen species (ROS) levels in both WT and KO cells. However, WT cells displayed a higher ROS level compared to the KO cells. Moreover, LRRK2 deletion led to a reduction in interleukin-6 (IL-6) inflammatory cytokine and cyclooxygenase-2 (COX-2) expression and an increase in lactate production after LPS stimulation compared to the WT cells. These data illustrate that LRRK2 has an effect on inflammatory processes in RAW macrophages upon LPS stimulation. [ABSTRACT FROM AUTHOR]

One of the major mediators of neuroinflammation in PD is tumour necrosis factor alpha (TNF-α), which, similar to other cytokines, is produced by activated microglia and astrocytes. Although TNF-α can be neuroprotective in the brain, long-term neuroinflammation and TNF release can be harmful, having a neurotoxic role that leads to death of oligodendrocytes, astrocytes, and neurons and, therefore, is associated with neurodegeneration. Apart from cytokines, a wide family of molecules with homologous structures, namely chemokines, play a key role in neuro-inflammation by drawing cytotoxic T-lymphocytes and activating microglia. The objective of the current study was to examine the levels of the serum TNF-α and CCL2 (Chemokine (C-C motif) ligand 2), also known as MCP-1 (Monocyte Chemoattractant Protein-1), in PD patients compared with healthy controls. We also investigated the associations between the serum levels of these two inflammatory mediators and a number of clinical symptoms, in particular, disease severity and cognition. Such an assessment may point to their prognostic value and provide some treatment hints. PD patients with advanced stage on the Hoehn–Yahr scale showed an increase in TNF-α levels compared with PD patients with stages 1 and 2 (p = 0.01). Additionally, the UPDRS score was significantly associated with TNF-α levels. CCL2 levels, however, showed no significant associations. [ABSTRACT FROM AUTHOR]

Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson's disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with LRRK2 mutations indicate a varied pathology, and the molecular functions of LRRK2 and its relationship to PD pathogenesis are largely unknown. Recently, non-autonomous neurodegeneration associated with glial cell dysfunction has attracted attention as a possible mechanism of dopaminergic neurodegeneration. Molecular studies of LRRK2 in astrocytes and microglia have also suggested that LRRK2 is involved in the regulation of lysosomal and other organelle dynamics and inflammation. In this review, we describe the proposed functions of LRRK2 in glial cells and discuss its involvement in the pathomechanisms of PD. [ABSTRACT FROM AUTHOR]

Given the clear role of inflammation in the pathogenesis of Parkinson's disease (PD) and its impact on incidence and phenotypical characteristics, this review provides an overview with focus on inflammatory biofluid markers in blood and cerebrospinal fluid (CSF) in PD patient cohorts. In preparation for clinical trials targeting the immune system, we specifically address the following questions: 1) What evidence do we have for pro-inflammatory profiles in blood and in CSF of sporadic and genetic PD patients? 2) Is there a role of anti-inflammatory mediators in blood/CSF? 3) Do inflammatory profiles in blood reflect those in CSF indicative of a cross-talk between periphery and brain? 4) Do blood/CSF inflammatory profiles change over the disease course as assessed in repeatedly taken biosamples? 5) Are blood/CSF inflammatory profiles associated with phenotypical trajectories in PD? 6) Are blood/CSF inflammatory profiles associated with CSF levels of neurodegenerative/PD-specific biomarkers? Knowledge on these questions will inform future strategies for patient stratification and cohort enrichment as well as suitable outcome measures for clinical trials. [ABSTRACT FROM AUTHOR]

Multiple lines of clinical and pre-clinical research support a pathogenic role for neuroinflammation and peripheral immune system dysfunction in Parkinson's disease. In this paper, we have reviewed and summarised the published literature reporting evidence of neuroinflammation and peripheral immune changes in cohorts of patients with isolated REM sleep behaviour disorder and non-manifesting carriers of GBA or LRRK2 gene mutations, who have increased risk for Parkinsonism and synucleinopathies, and could be in the prodromal stage of these conditions. Taken together, the findings of these studies suggest that the early stages of pathology in Parkinsonism involve activation of both the central and peripheral immune systems with significant crosstalk. We consider these findings with respect to those found in patients with clinical Parkinson's disease and discuss their possible pathological roles. Moreover, those factors possibly associated with the immune response, such as the immunomodulatory role of the affected neurotransmitters and the changes in the gut-brain axis, are also considered. [ABSTRACT FROM AUTHOR]

The clinical presentation of Parkinson's disease (PD) is both complex and heterogeneous, and its precise classification often requires an intensive work-up. The differential diagnosis, assessment of disease progression, evaluation of therapeutic responses, or identification of PD subtypes frequently remains uncertain from a clinical point of view. Various tissue- and fluid-based biomarkers are currently being investigated to improve the description of PD. From a clinician's perspective, signatures from blood that are relatively easy to obtain would have great potential for use in clinical practice if they fulfill the necessary requirements as PD biomarker. In this review article, we summarize the knowledge on blood-based PD biomarkers and present both a researcher's and a clinician's perspective on recent developments and potential future applications. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is one of the most common long-term degenerative disorders of the CNS that primarily affects the human locomotor system. Owing to the heterogeneity of PD etiology and the lack of appropriate diagnostic tests, blood-based biomarkers became the most promising method for diagnosing PD. Even though various biomarkers for PD have been found, their specificity and sensitivity are not optimum when used alone. Therefore, the aim of this study was directed to evaluate changes in a group of sensitive blood-based biomarkers in the same PD patients compared to healthy individuals. Serum samples were collected from 20 PD patients and 15 age-matched healthy controls. We analyzed serum levels of cytokines (IL10, IL12, and TNF-α), α-synuclein proteins, miRNAs (miR-214, miR-221, and miR-141), and antioxidants (UA, PON1, ARE). Our results showed an increase in sera levels of cytokines in PD patients as well as a positive correlation among them. Also, we found a significant increase in sera levels of α-synuclein protein associated with a decrease in miR-214 which regulates its gene expression. Lastly, we observed a decrease in sera levels of miR-221, miR-141, UA, PON1, and ARE, which have a prominent role against oxidative stress. Because of the many etiologies of PD, a single measure is unlikely to become a useful biomarker. Therefore, to correctly predict disease state and progression, a mix of noninvasive biomarkers is required. Although considerable work has to be done, this study sheds light on the role of certain biomarkers in the diagnosis of PD. [ABSTRACT FROM AUTHOR]

Dysfunction of neurons in the central nervous system is the primary pathological feature of Parkinson's disease (PD). Despite different triggering, emerging evidence indicates that neuroinflammation revealed through microglia activation is critical for PD. Moreover, recent investigations sought a potential relationship between Lrrk2 genetic mutation and microglia activation. In this paper, neuroinflammation in sporadic PD, Lrrk2-PD and unaffected Lrrk2 mutation carriers were investigated. The principal component analysis (PCA) and the subject's residual profile (SRP) techniques were performed on multiple groups and regions of interest in 22 brain-regions. The 11C-PBR28 binding profiles were compared in four genotypes depending on groups, i.e., HC, sPD, Lrrk2-PD and UC, using the PCA and SPR scores. The genotype effect was found as a principal feature of group-dependent 11C-PBR28 binding, and preliminary evidence of a MAB-Lrrk2 mutation interaction in manifest Parkinson's and subjects at risk was found. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is widely considered to be a disabling neurodegenerative disorder, which has been ranked second worldwide just after Alzheimer's disease. Until present, a wide range of studies has focused on the role of circulating inflammatory cytokines in the development of PD. However, the causal relationship between circulating inflammatory cytokines and the risk and age at the onset of PD has not been elucidated. Hence, to evaluate the effects of circulating inflammatory cytokines on the risk or age at the onset of PD more accurately, we conducted this two-sample Mendelian randomization (MR) study involving summary statistics from genome-wide association studies (GWASs). Totally, we included a GWAS for inflammatory cytokines (8,293 participants), a meta-analysis of GWASs for PD risk (482,730 participants), and a GWAS dataset for age at the onset of PD (17,996 patients with PD). A total of 149 and 131 polymorphisms for exploring relationships between 19 inflammatory cytokines and the risk and age at the onset of PD were obtained as instrumental variants. Then, we used a total of five MR methods, including inverse-variance weighted (IVW), Wald ratio, MR Egger regression, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Finally, we found a causal association between circulating levels of macrophage inflammatory protein-1 beta (MIP1b) and PD risk in the IVW method (OR: 1.06; 95% CI: 1.02–1.10; P = 0.001). Meanwhile, other MR estimates by weighted median and MR-PRESSO methods yielded similar effect estimates. Besides, we identified a suggestive association of interleukin-16 (IL-16) levels with PD risk (OR: 1.08; 95% CI: 1.00–1.17; P = 0.037). For age at PD onset, there was no evidence supporting its correlation with inflammatory cytokines. Our findings implied that MIP1b and IL-16 may be novel biomarkers and promising therapeutic targets for PD development. [ABSTRACT FROM AUTHOR]

Background: An involvement of the central-nervous and peripheral, innate and adaptive immune system in the pathogenesis of Parkinson's disease (PD) is nowadays well established. Objectives: We face several open questions in preparation of clinical trials aiming at disease-modification by targeting the immune system: Do peripheral (blood) inflammatory profiles reflect central (CSF) inflammatory processes? Are blood/CSF inflammatory markers associated with CSF levels of neurodegenerative/PD-specific biomarkers? Methods: Using a multiplex assay we assessed 41 inflammatory markers in CSF/serum pairs in 453 sporadic PD patients. We analyzed CSF/serum correlation as well as associations of inflammatory markers with clinical outcome measures (UPDRS-III, H&Y, MoCA) and with CSF levels of α-synuclein, Aβ1−42, t- Tau, p181-Tau and NFL. All analyses were stratified by sex as the immune system shows relevant sex-specific differences. Results: Correlations between CSF and serum were sparse and detected in only 25% (9 out of 36) of the analysable inflammatory markers in male PD patients and in only 38% (12 out of 32) of female PD patients. The most important pro-inflammatory mediators associated with motor and cognitive decline as well as with neurodegenerative/PD-specific biomarkers were FABP, ICAM-1, IL-8, MCP-1, MIP-1-beta, and SCF. Results were more robust for CSF than for serum. Interpretation: Levels of central-nervous and peripheral inflammatory markers might be regulated independently of each other with CSF inflammatory markers reflecting CNS pathology more accurately than peripheral markers. These findings along with sex-specific characteristics have to be considered when designing clinical trials aiming at disease-modification by targeting the immune system. [ABSTRACT FROM AUTHOR]