To date, there are no definitive biomarkers for Parkinson's disease (PD) diagnosis. The detection of cerebrospinal fluid (CSF) alpha (α)-synuclein in PD patients has yielded promising but inconclusive results. To determine the performance of CSF α-synuclein as a diagnostic biomarker of PD and whether CSF α-synuclein can discriminate PD from other neurodegenerative diseases, a systematic search of all relevant studies investigating reproducible CSF α-synuclein quantification methods was conducted in electronic databases. A total of 17 studies that included 3311 patients were included in this systemic review and meta-analysis. The mean CSF α-synuclein concentration was significantly lower in PD patients compared to normal/neurological controls [weighted mean difference (WMD) -0.31; 95% CI, -0.45, -0.16; p < 0.0001] and patients with Alzheimer's disease (AD) [WMD -0.15; 95% CI, -0.26, -0.04; p < 0.0001]. There was no significant difference between PD patients and dementia with Lewy bodies (DLB) patients [WMD -0.03; 95% CI, -0.16, 0.09; p = 0.58] or patients with multiple system atrophy (MSA) [WMD 0.05; 95% CI, -0.04, 0.13; p = 0.25]. Sensitivity and specificity of CSF α-synuclein in the diagnosis of PD was 0.88 (95% CI, 0.84-0.91) and 0.40 (95% CI, 0.35-0.45), respectively. The positive and negative likelihood ratios of CSF α-synuclein in the diagnosis of PD were 1.41 (95% CI, 1.24-1.60), and 0.29 (95% CI, 0.15-0.56), respectively. The corresponding summary receiver operating characteristic (SROC) curve showed an area under the curve (AUC) of 0.73. The concentration of CSF α-synuclein may be a biomarker for the diagnosis of PD. The use of α-synuclein alone however is not sufficient as a single biomarker and it must therefore be used in conjunction with other documented and reliable biomarkers.

Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of Parkinson’s disease (PD). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects in PD by regulating the phenotype of microglia. Recent studies suggest that TREM2 regulates high glucose-induced microglial inflammation through the NLRP3 signaling pathway. This study aimed to investigate the effect of TREM2 on NLRP3 inflammasome activation and neuroinflammation in PD. Mice were injected with AAV-TREM2-shRNA into both sides of the substantia nigra using a stereotactic injection method, followed by intraperitoneal injection of MPTP to establish chronic PD mouse model. Behavioral assessments including the pole test and rotarod test were conducted to evaluate the effects of TREM2 deficiency on MPTP-induced motor dysfunction. Immunohistochemistry of TREM2 and tyrosine hydroxylase (TH), immunohistochemistry and immunofluorescence Iba1, Western blot of NLRP3 inflammasome and its downstream inflammatory factors IL-1β and IL-18, and the key pyroptosis factors GSDMD and GSDMD-N were performed to explore the effect of TREM2 on NLRP3 inflammasome and neuroinflammation. In an in vitro experiment, lentivirus was used to interfere with the expression of TREM2 in BV2 microglia, and then lipopolysaccharide (LPS) and adenopterin nucleoside triphosphate (ATP) were used to stimulate inflammation to construct a cellular inflammation model. The expression differences of NLRP3 inflammasome and its components were detected by qPCR and Western blot. In vivo, TREM2 knockdown aggravated the loss of dopaminergic neuron and the decline of motor function. After TREM2 knockdown, the number of activated microglia was significantly increased, and the expression of cleaved caspase-1, NLRP3 inflammasome, IL-1β, GSDMD, and GSDMD-N was increased. In vitro, TREM2 knockdown aggravated the inflammatory response of BV2 cells stimulated by LPS and promoted the activation of NLRP3 inflammasome through the NF-κB pathway. In addition, TREM2 knockdown also promoted the expression of TLR4/MyD88, an upstream factor of the NF-κB pathway. Our vivo and vitro data showed that TREM2 knockdown promoted NLRP3 inflammasome activation and downstream inflammatory response, promoted pyroptosis, and aggravated dopaminergic neuron loss. TREM2 acts as an anti-inflammatory in PD through the TLR4/MyD88/NF-κB pathway, which extends previous findings and supports the notion that TREM2 ameliorates neuroinflammation in PD.

Aims: The aim of the study was to evaluate the glymphatic function and its related factors in patients with Parkinson's disease (PD) and patients with PD of different ages using the diffusion tensor image analysis along the perivascular space (DTI‐ALPS) method.Methods: Medical records and imaging data of 93 patients with idiopathic PD and 42 age‐ and sex‐matched healthy controls (HCs) were retrospectively reviewed and analyzed. The diffusivity along the perivascular spaces, projection fibers, and association fibers were calculated on diffusion tensor imaging (DTI) to acquire the analysis along the perivascular space (ALPS) index.Results: PD patients exhibited a reduced ALPS index compared with the HCs. Negative correlations between the ALPS index and clinical information including age, age at disease onset, Parkinson's disease sleep scale 2nd version (PDSS‐2) scores, and history of diabetes mellitus were revealed in the PD group. Besides, a negative correlation between the ALPS index and the severity of motor symptoms was identified in the subgroup aged 65 and above, rather than in the younger ones.Conclusions: The results demonstrate that reduced ALPS index, a potential noninvasive measure of compromised glymphatic activity, is involved in the pathophysiology of PD, especially in the aged ones and those with sleep disorders.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine. Chronic inflammation induced by amyloid β proteins (Aβ) is one prominent neuropathological feature in Alzheimer’s disease (AD) brain. Elisa, Western blot, and immunohistochemical staining analysis were performed to examine the level of MIF protein in CSF and brain tissues. MTT and LDH assays were used to examine the neurotoxicity, and the Morris Water Maze test was performed to examine the cognitive function in the MIF+/−/APP23 transgenic mice. MIF expression was upregulated in the brain of AD patients and AD model mice. Elevated MIF concentration was detected in the cerebrospinal fluid of AD patients but not in that of the patients suffering from mild cognitive impairment and vascular dementia. Reduced MIF expression impaired learning and memory in the AD model mice. MIF expression largely associates with Aβ deposits and microglia. The binding assay revealed a direct association between MIF and Aβ oligomers. Neurons instead of glial cells were responsible for the secretion of MIF upon stimulation by Aβ oligomers. In addition, overexpression of MIF significantly protected neuronal cells from Aβ-induced cytotoxicity. Our study suggests that neuronal secretion of MIF may serve as a defense mechanism to compensate for declined cognitive function in AD, and increased MIF level could be a potential AD biomarker.