Increased YKL-40 But Not C-Reactive Protein Levels in Patients With Alzheimer’s DiseaseⅢ

3. Results 

3.1. Associations with Demographic 

Data Demographic and clinical data are shown in Table 1 for further characterization of the study cohort. A total of 34 subjects were clinically diagnosed with AD, 22 subjects were grouped as MCI and 30 subjects were diagnosed with PD. Individuals diagnosed with AD were slightly older than the rest of the cohort, including PD, MCI, and healthy subjects. 

Click to cistanche tubulosa capsules for Alzheimer's disease and Parkinson's disease

The female sex was overrepresented in the AD and MCI groups, while males represented around 60% of controls and PD subjects. APOE ε4 carriers were more prevalent in the MCI/AD group than in controls, according to previous publications [49]. Most AD patients had clinically mild dementia (74% scored 1 on the CDR scale), and none of the PD patients reached the dementia stage. Furthermore, the majority of individuals diagnosed with PD exhibited mild motor impairment (73% of them were in Hoehn & Yahr stage 1 or 2).

3.2. YKL-40 and CRP Levels in Different Diagnostic Groups 

YKL-40 and CRP levels across all clinical groups are illustrated in Figure 1. In CSF, YKL-40 levels were different among groups and were found to increase in AD dementia subjects compared with healthy controls (Figure 1A). No differences were found in YKL40 levels between healthy controls and MCI or PD groups in CSF (Figure 1A). Nevertheless, a trend toward reduced levels was observed in PD patients, which were significantly lower compared to AD and MCI patient groups (Figure 1A). In plasma, YKL-40 levels remained unchanged across all clinical groups (Figure 1B).

A nonparametric trend test did not show any statistically significant rising tendency of CSF (p = 0.48) or plasma (p = 0.053) YKL-40 levels along with MCI or mild and moderate AD. When adjusting for age, sex, and APOE ε4 status, levels of CSF YKL-40 remained high in AD dementia patients when compared with controls (b = 125.5 ng/mL, 95% CI = 19.1 to 232.0 ng/mL, p < 0.05).

Regarding CRP levels in CSF and plasma, we did not find significant differences between healthy subjects and AD, MCI, and PD patients (Figure 1C, D). Our results are consistent with previous studies indicating no differences in CRP levels from CSF comparing healthy subjects and PD patients [26] or in serum CRP levels between patients with AD and healthy subjects [30]. 

To analyze the discriminative ability of both biomarkers for the diagnosis of PD and AD, we performed a logistic regression analysis and calculated the corresponding ROC curve for each CSF biomarker and diagnosis. CSF YKL-40 differentiated AD patients from the rest of the cohort, including PD, MCI, and healthy subjects, with 65.6% sensitivity and 66.3% specificity (AUC = 0.69, 95%CI = 0.58 to 0.80, cutoff point = 316.5 ng/mL) (Figure 2A). 

The combination with CSF CRP did not improve the performance. Nevertheless, for the diagnosis of PD, the combination of CSF YKL-40 and CRP yielded the best results, showing a moderate discriminative ability (AUC = 0.82, 95% CI =0.73 to 0.89, cutoff point of the model = 0.300), with 79.2% sensitivity and 82.1% specificity (Figure 2B).

3.3. Correlations between YKL-40 and CRP Levels in Plasma and CSF 

Both CSF YKL-40 (r = 0.39, p < 0.001; Figure 3A) and CRP (r = 0.56, p < 0.0001; Figure 3B) correlated significantly with their respective plasma concentrations in the whole cohort. A stronger positive correlation was found in AD patients (YKL-40: r = 0.69, CRP: r = 0.84).

In the whole cohort, plasma and CSF YKL-40 levels positively correlated with age (CSF YKL-40: r = 0.38, p < 0.0001; Figure 3C; plasma YKL-40: r = 0.57, p < 0.0001; Figure 3D). This correlation was especially stronger for the control group (CSF YKL-40: r = 0.46, p < 0.01; plasma YKL-40: r = 0.84, p < 0.0001). No statistically significant correlation with age was found in the plasma and CSF CRP analysis. Furthermore, the time since symptom onset did not correlate with any biomarker level in any group. Plasma and CSF YKL-40 and CRP levels did not differ by sex or by the presence of an APOE ε4 allele.

3.4. YKL-40 Levels in AD Brain 

Upon inflammation, YKL-40 is produced and secreted by many cells including vascular smooth muscle cells and macrophages [50]. In the brain, YKL-40 is mainly expressed in reactive astrocytes [20,25]. Thus, we investigated if the observed increase in YKL-40 levels in CSF from AD patients could be associated with higher YKL-40 levels in cerebral parenchyma. 

To explore this hypothesis, we examined the YKL-40 cellular levels in human brain tissue from AD patients and healthy subjects. Immunoblotting showed that YKL-40 levels in cerebral orbitofrontal cortex samples were significantly increased in AD patients compared with healthy subjects (Figure 4A). 

To determine if increased levels of YKL-40 in the cerebral orbitofrontal cortex were associated with astrocyte reactivity, the levels of GFAP were also analyzed. Western blotting showed that GFAP levels were also higher in AD samples compared to those observed in control subjects (Figure 4B) in parallel with the observed rise in YKL-40 levels, proving that AD astrogliosis increases YKL-40 levels.

4. Discussion 

In this cross-sectional study, we showed a variable pattern of the inflammatory biomarkers YKL-40 and CRP in AD and PD patients. We confirmed that YKL-40 levels are significantly increased in CSF from AD patients compared to healthy controls, indicating an inflammatory response at the dementia stage. Such an increase was not seen in MCI or PD patients, where CSF YKL-40 levels remained unchanged. 

These results were also extended to the cerebral orbitofrontal cortex where we found that YKL-40 expression was augmented in AD patients, suggesting glial activation, thus corroborating our hypothesis. Another finding in this study was related to CRP levels in CSF and plasma. We found lower CRP levels in CSF from PD patients compared with other groups (AD, MCI, and healthy subjects), but this change did not reach statistical significance. 

Furthermore, we did not find evidence of significant alterations in plasma for YKL-40 or CRP. Inflammation is increasingly recognized as part of the pathology of neurodegenerative conditions, including AD and PD. Evidence proposes that neurodegeneration occurs in part because the CNS environment is affected by a cascade of events collectively named neuroinflammation [51]. 

Despite biomarkers of neuroinflammation being useful for monitoring disease diagnosis, progression, and response to therapy, accurate and reliable biomarkers for many neurological diseases are scarce. In recent years, the interest in new neuroinflammatory biomarkers has grown at the early and symptomatic stages of these diseases. Blood and CSF are commonly used to monitor biomarkers of neuroinflammation, with many of them being the consequence of CNS pathology. Some examples are the levels of cytokines and chemokines, the loss of blood–brain barrier integrity, and neuronal damage indicators [52]. 

Only a few studies have shown the possibility of analyzing YKL-40 levels in CSF and blood from patients with AD and predementia stages. One of these studies found that YKL-40 concentration in CSF from AD patients was significantly elevated compared to cognitively normal subjects, with an AUC = 0.88 pointing to the potential value of YKL-40 levels in CSF for AD diagnosis [53]. Increased YKL-40 levels were observed not only in AD dementia but also in the prodromal phase of AD when compared to cognitively normal controls [54]. 

Similar observations were found in patients with AD, where YKL-40 concentration in CSF was increased in very mild and mild dementia subjects in comparison with cognitively normal individuals [16]. In our study, we found a trend of increased YKL-40 levels in CSF from MCI subjects compared with healthy controls, and this increase was evident in AD patients. However, the resulting AUC in our study was lower; thus, we propose that YKL-40 might only be a modest AD biomarker candidate. Significantly increased chitinase-3-like 3 (CHI3L3) mRNA expression, a mouse homolog of YKL-40, was found in the brains of AD mice models when compared to age-matched controls [55]. 

Similarly, in autopsied human brain samples from pathologically confirmed AD subjects, YKL-40 mRNA levels were significantly increased in comparison with non-demented controls [55]. Although there is no clear explanation regarding which factors modulate YKL-40 levels in AD, it has been suggested that elevated YKL-40 expression and protein levels might result from increased astrocytic reactivity and release in the brain [21]. 

It was shown that astrocytes in the close vicinity of amyloid plaques were immunoreactive for YKL-40, which confirms the involvement of this protein in the neuroinflammatory response to Aβ deposition [16]. It is known that insoluble Aβ aggregates may induce inflammatory reactions and activation of microglia, resulting in increased proinflammatory mediator production. The relationship between YKL-40 and amyloid-related pathways in AD development was further discussed [17,25]. 

It seems that the YKL-40 concentration in CSF may be linked to AD pathology, particularly astrogliosis. Indeed, it has been shown that YKL-40 is expressed by reactive astrocytes GFAP+ in AD [25]. Thus, increased expression of YKL-40 and protein levels in reactive astrocytes may be reflected in the CSF, indicating that astrocyte-associated metabolites may be utilized as potential biomarkers. Although data regarding elevated YKL-40 levels in CSF from early stages of AD are contradictory [16,17,22–24,54], our results support the increase in YKL-40 levels in CSF from AD subjects, as well as the increased astrocytic YKL-40 levels associated with astrocytosis. 

Interestingly, we found that YKL-40 levels in CSF from PD patients were significantly lower compared with those levels in AD subjects suggesting that YKL-40, a marker of astroglial activation, is downregulated in PD. It was reported that YKL-40 levels were decreased in synucleinopathies when compared with tauopathies, suggesting that glial activation may be lower in the brains of PD patients and other synucleinopathies in comparison with patients who have tauopathies or healthy controls [26,56]. 

These data may suggest that CSF YKL-40, as a marker of astroglial activation, is downregulated in PD. Despite astrocytes exerting protection against the inflammatory response in PD [57,58], astroglial dysfunction due to α-syn inclusions may occur simultaneously. In vitro evidence showed that astrocytes can efficiently degrade the α-syn aggregates from the extracellular space [59]. 

More recently, it was shown that primary rat astrocytes receive α-syn aggregates from neurons in mixed cell culture and efficiently transfer them from astrocyte to astrocyte [60].  The increase in α-syn levels in astrocytes may be a consequence of an endocytic mechanism upon high α-syn levels from the extracellular space, leading to the typical α-syn astrocytic inclusions in PD brains [61]. 

This accumulation could then lead to the dysregulation of other astrocytic functions, including YKL-40 production/secretion. Our study yielded no significant changes in CRP levels in CSF or plasma from AD and PD subjects, although others have described contradictory results [30–32,34]. Pathological studies have demonstrated that CRP is present in the senile plaques and neurofibrillary tangles in AD brains, suggesting that this protein may play a role in the neuropathological processes in AD [62–64]. 

In PD, aggregated α-syn can promote microglial activation and stimulate the secretion of inflammatory molecules, including CRP [65], thus evoking neuroinflammation [66]. CRP is primarily produced in the liver but is also generated in neurons to a lesser extent [41]. Such residual production of CRP in the CNS does not appear to contribute significantly to CSF levels [39]. 

In summary, our present study revealed a different inflammatory biomarker profile in individuals with AD and PD. CSF YKL-40 levels were significantly elevated in the AD group, and this increment corroborated the analysis of the YKL-40 protein levels in the cerebral orbitofrontal cortex from pathologically confirmed AD subjects. 

In PD individuals, plasma and CSF CRP and YKL-40 levels remained unchanged. Notwithstanding, we identified a moderate discriminative ability by combining both biomarkers in CSF for PD diagnosis. Together, our data support the involvement of both inflammatory proteins in the pathogenesis of neurodegenerative diseases.

The mechanism of Cistanche treats Alzheimer's disease & Parkinson's disease

Cistanche is an herb that has been traditionally used in Chinese medicine to treat a variety of health conditions, including neurological disorders like Alzheimer's disease (AD) and Parkinson's disease (PD).  Cistanche contains several bioactive compounds, including phenylethanoid glycosides and iridoid glycosides, which have antioxidant, anti-inflammatory, and neuroprotective effects. These compounds help to protect neuronal cells from damage caused by free radicals and inflammatory processes, which are believed to contribute to the development and progression of AD and PD.

Additionally, Cistanche has been shown to increase the levels of certain neurotransmitters in the brain, including dopamine and acetylcholine, which are important for normal brain function. By increasing these neurotransmitter levels, Cistanche may help to improve cognitive function and reduce the symptoms of AD and PD.

Overall, the mechanisms of Cistanche in treating AD and PD involve its antioxidant, anti-inflammatory, and neuroprotective effects, as well as its ability to enhance neurotransmitter levels in the brain.

References 

1 Heneka, M.T.; Carson, M.J.; El Khoury, J.; Landreth, G.E.; Brosseron, F.; Feinstein, D.L.; Jacobs, A.H.; Wyss-Coray, T.; Vitorica, J.; Ransohoff, R.M.; et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015, 14, 388–405. [CrossRef] 

2. Calsolaro, V.; Edison, P. Neuroinflammation in Alzheimer’s disease: Current evidence and future directions. Alzheimer’s Dement. 2016, 12, 719–732. [CrossRef] [PubMed] 

3. McGeer, P.L.; McGeer, E.G. Inflammation and neurodegeneration in Parkinson’s disease. Park. Relat. Disord. 2004, 10, S3–S7. [CrossRef]

4. Hirsch, E.C.; Hunot, S. Neuroinflammation in Parkinson’s disease: A target for neuroprotection? Lancet Neurol. 2009, 8, 382–397. [CrossRef] 

5. Tansey, M.G.; Goldberg, M.S. Neuroinflammation in Parkinson’s disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiol. Dis. 2010, 37, 510–518. [CrossRef] 

6. Maccioni, R.B.; Rojo, L.; Fernández, J.A.; Kuljis, R. The Role of Neuroimmunomodulation in Alzheimer’s Disease. Ann. N. Y. Acad. Sci. 2009, 1153, 240–246. [CrossRef] [PubMed] 

7. Swardfager, W.; Lanctot, K.L.; Rothenburg, L.; Wong, A.; Cappell, J.; Herrmann, N. A Meta-Analysis of Cytokines in Alzheimer’s Disease. Biol. Psychiatry 2010, 68, 930–941. [CrossRef] [PubMed] 

8. Brosseron, F.; Krauthausen, M.; Kummer, M.; Heneka, M.T. Body Fluid Cytokine Levels in Mild Cognitive Impairment and Alzheimer’s Disease: A Comparative Overview. Mol. Neurobiol. 2014, 50, 534–544. [CrossRef] 

9. Létuvé, S.; Kozhich, A.; Arouche, N.; Grandsaigne, M.; Reed, J.; Dombret, M.-C.; Kiener, P.A.; Aubier, M.; Coyle, A.J.; Pretolani, M. YKL-40 Is Elevated in Patients with Chronic Obstructive Pulmonary Disease and Activates Alveolar Macrophages. J. Immunol. 2008, 181, 5167–5173. [CrossRef] [PubMed] 

10. Sharif, M.; Granell, R.; Johansen, J.; Clarke, S.; Elson, C.; Kirwan, J.R. Serum cartilage oligomeric matrix protein and other biomarker profiles in tibiofemoral and patellofemoral osteoarthritis of the knee. Rheumatol. 2005, 45, 522–526. [CrossRef] 

11. Johansen, J.S.; Christoffersen, P.; Møller, S.; A Price, P.; Henriksen, J.H.; Garbarsch, C.; Bendtsen, F. Serum YKL-40 is increased in patients with hepatic fibrosis. J. Hepatol. 2000, 32, 911–920. [CrossRef] 

12. Shao, R.; Hamel, K.; Petersen, L.; Cao, Q.J.; Arenas, R.B.; Bigelow, C.; Bentley, B.; Yan, W. YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene 2009, 28, 4456–4468. [CrossRef] 

13. Rathcke, C.N.; Vestergaard, H. YKL-40—An emerging biomarker in cardiovascular disease and diabetes. Cardiovasc. Diabetol. 2009, 8, 61. [CrossRef] [PubMed] 

14. Rehli, M.; Niller, H.-H.; Ammon, C.; Langmann, S.; Schwarzfischer, L.; Andreesen, R.; Krause, S. Transcriptional Regulation of CHI3L1, a Marker Gene for Late Stages of Macrophage Differentiation. J. Biol. Chem. 2003, 278, 44058–44067. [CrossRef] [PubMed] 

15. Bonneh-Barkay, D.; Wang, G.; Starkey, A.; Hamilton, R.L.; A Wiley, C. In vivo CHI3L1 (YKL-40) expression in astrocytes in acute and chronic neurological diseases. J. Neuroinflamm. 2010, 7, 34. [CrossRef] [PubMed] 

16. Craig-Schapiro, R.; Perrin, R.J.; Roe, C.M.; Xiong, C.; Carter, D.; Cairns, N.J.; Mintun, M.A.; Peskind, E.R.; Li, G.; Galasko, D.R.; et al. YKL-40: A Novel Prognostic Fluid Biomarker for Preclinical Alzheimer’s Disease. Biol. Psychiatry 2010, 68, 903–912. [CrossRef] 

17. Alcolea, D.; Vilaplana, E.; Pegueroles, J.; Montal, V.; Sánchez-Juan, P.; González-Suárez, A.; Pozueta, A.; Rodriguez-Rodríguez, E.; Bartrés-Faz, D.; Vidal-Piñeiro, D.; et al. Relationship between cortical thickness and cerebrospinal fluid YKL-40 in predementia stages of Alzheimer’s disease. Neurobiol. Aging 2015, 36, 2018–2023. [CrossRef] 

18. Janelidze, S.; Mattsson, N.; Stomrud, E.; Lindberg, O.; Palmqvist, S.; Zetterberg, H.; Blennow, K.; Hansson, O. CSF biomarkers of neuroinflammation and cerebrovascular dysfunction in early Alzheimer disease. Neurol. 2018, 91, e867–e877. [CrossRef] 

19. Verkhratsky, A.; Olabarria, M.; Noristani, H.; Yeh, C.-Y.; Rodriguez, J.J. Astrocytes in Alzheimer’s disease. Neurother. 2010, 7, 399–412. [CrossRef] 

20. Querol-Vilaseca, M.; Colom-Cadena, M.; Pegueroles, J.; Martín-Paniello, C.S.; Clarimon, J.; Belbin, O.; Fortea, J.; Lleó, A. YKL-40 (Chitinase 3-like I) is expressed in a subset of astrocytes in Alzheimer’s disease and other tauopathies. J. Neuroinflamm. 2017, 14, 1–10. [CrossRef] 

21. Bonneh-Barkay, D.; Bissel, S.J.; Kofler, J.; Starkey, A.; Wang, G.; Wiley, C.A. Astrocyte and Macrophage Regulation of YKL-40 Expression and Cellular Response in Neuroinflammation. Brain Pathol. 2011, 22, 530–546. [CrossRef] 

22. Zhang, H.; Initiative, T.A.D.N.; Ng, K.P.; Therriault, J.; Kang, M.S.; Pascoal, T.A.; Rosa-Neto, P.; Gauthier, S. Cerebrospinal fluid phosphorylated tau, visinin-like protein-1, and chitinase-3-like protein 1 in mild cognitive impairment and Alzheimer’s disease. Transl. Neurodegener. 2018, 7, 1–12. [CrossRef] 

23. Nordengen, K.; Kirsebom, B.-E.; Henjum, K.; Selnes, P.; Gísladóttir, B.; Wettergreen, M.; Torsetnes, S.B.; Grøntvedt, G.R.; Waterloo, K.K.; Aarsland, D.; et al. Glial activation and inflammation along the Alzheimer’s disease continuum. J. Neuroinflamm. 2019, 16, 1–13. [CrossRef] 

24. Wang, L.; Gao, T.; Cai, T.; Li, K.; Zheng, P.; Liu, J. Cerebrospinal fluid levels of YKL-40 in prodromal Alzheimer’s disease. Neurosci. Lett. 2020, 715, 134658. [CrossRef] 

25. Llorens, F.; Thüne, K.; Tahir, W.; Kanata, E.; Diaz-Lucena, D.; Xanthopoulos, K.; Kovatsi, E.; Pleschka, C.; Garcia-Esparcia, P.; Schmitz, M.; et al. YKL-40 in the brain and cerebrospinal fluid of neurodegenerative dementias. Mol. Neurodegener. 2017, 12, 83. [CrossRef] [PubMed] 

26. Hall, S.; Janelidze, S.; Surova, Y.; Widner, H.; Zetterberg, H.; Hansson, O. Cerebrospinal fluid concentrations of inflammatory markers in Parkinson’s disease and atypical parkinsonian disorders. Sci. Rep. 2018, 8, 1–9. [CrossRef] [PubMed] 27. Gabay, C.; Kushner, I. Acute-Phase Proteins and Other Systemic Responses to Inflammation. New Engl. J. Med. 1999, 340, 448–454. [CrossRef] 

28. Luan, Y.-Y.; Yao, Y.-M. The Clinical Significance and Potential Role of C-Reactive Protein in Chronic Inflammatory and Neurodegenerative Diseases. Front. Immunol. 2018, 9, 1302. [CrossRef] [PubMed] 

29. Koyama, A.; O’Brien, J.; Weuve, J.; Blacker, D.; Metti, A.L.; Yaffe, K. The Role of Peripheral Inflammatory Markers in Dementia and Alzheimer’s Disease: A Meta-Analysis. J. Gerontol. Ser. A Boil. Sci. Med Sci. 2012, 68, 433–440. [CrossRef]

30. Gong, C.; Wei, D.; Wang, Y.; Ma, J.; Yuan, C.; Zhang, W.; Yu, G.; Zhao, Y. A Meta-Analysis of C-Reactive Protein in Patients With Alzheimer’s Disease. Am. J. Alzheimer’s Dis. Other Dementias 2016, 31, 194–200. [CrossRef] [PubMed] 

31. Schuitemaker, A.; Dik, M.G.; Veerhuis, R.; Scheltens, P.; Schoonenboom, N.S.; Hack, C.E.; Blankenstein, M.A.; Jonker, C. Inflammatory markers in AD and MCI patients with different biomarker profiles. Neurobiol. Aging 2009, 30, 1885–1889. [CrossRef] [PubMed] 

32. Brosseron, F.; Traschütz, A.; Widmann, C.N.; Kummer, M.P.; Tacik, P.; Santarelli, F.; Jessen, F.; Heneka, M.T. Characterization and clinical use of inflammatory cerebrospinal fluid protein markers in Alzheimer’s disease. Alzheimer’s Res. Ther. 2018, 10, 1–14. [CrossRef] [PubMed] 

33. Andican, G.; Konukoglu, D.; Bozluolcay, M.; Bayulkem, K.; Firtiına, S.; Burçak, G.; Konukoglu, D. Plasma oxidative and ˇ inflammatory markers in patients with idiopathic Parkinson’s disease. Acta Neurol. Belg. 2012, 112, 155–159. [CrossRef] 

34. Song, I.-U.; Cho, H.-J.; Kim, J.-S.; Park, I.-S.; Lee, K.-S. Serum hs-CRP Levels are Increased in de Novo Parkinson’s Disease Independently from Age of Onset. Eur. Neurol. 2014, 72, 285–289. [CrossRef] 

35. Williams-Gray, C.; Wijeyekoon, R.; Yarnall, A.; Lawson, R.A.; Breen, D.P.; Evans, J.R.; Cummins, G.A.; Duncan, G.W.; Khoo, T.K.; Burn, D.; et al. S serum immune markers and disease progression in an incident Parkinson’s disease cohort ( ICICLE-PD ). Mov. Disord. 2016, 31, 995–1003. [CrossRef] 

36. Qiu, X.; Xiao, Y.; Wu, J.; Gan, L.; Huang, Y.; Wang, J. C-Reactive Protein and Risk of Parkinson’s Disease: A Systematic Review and Meta-Analysis. Front. Neurol. 2019, 10, 384. [CrossRef] 

37. Yasojima, K.; Schwab, C.; McGeer, E.G.; McGeer, P.L. Human neurons generate C-reactive protein and amyloid P: Upregulation in Alzheimer’s disease. Brain Res. 2000, 887, 80–89. [CrossRef] 

38. Wight, R.D.; Tull, C.A.; Deel, M.W.; Stroope, B.L.; Eubanks, A.G.; Chavis, J.A.; Drew, P.D.; Hensley, L.L. Resveratrol effects on astrocyte function: Relevance to neurodegenerative diseases. Biochem. Biophys. Res. Commun. 2012, 426, 112–115. [CrossRef] 

39. Mulder, S.D.; Hack, C.E.; van der Flier, W.M.; Scheltens, P.; Blankenstein, M.A.; Veerhuis, R. Evaluation of Intrathecal Serum Amyloid P (SAP) and C-Reactive Protein (CRP) Synthesis in Alzheimer’s Disease with the Use of Index Values. J. Alzheimer’s Dis. 2011, 22, 1073–1079. [CrossRef] [PubMed] 

40. McGeer, P.L.; Yasojima, K.; McGeer, E.G. Inflammation in Parkinson’s disease. Adv. Neurol. 2001, 86, 83–89. [PubMed] 

41. Di Napoli, M.; Godoy, D.A.; Campi, V.; Masotti, L.; Smith, C.; Jones, A.R.P.; Hopkins, S.; Slevin, M.; Papa, F.; Mogoanta, L.; et al. C-reactive protein in intracerebral hemorrhage: Time course, tissue localization, and prognosis. Neurol. 2012, 79, 690–699. [CrossRef] 

42. Di Napoli, M.; Parry-Jones, A.R.; Smith, C.; Hopkins, S.; Slevin, M.; Masotti, L.; Campi, V.; Singh, P.; Papa, F.; Popa-Wagner, A.; et al. C-Reactive Protein Predicts Hematoma Growth in Intracerebral Hemorrhage. Stroke 2014, 45, 59–65. [CrossRef] 

43. Albert, M.S.; DeKosky, S.; Dickson, D.W.; Dubois, B.; Feldman, H.; Fox, N.; Gamst, A.; Holtzman, D.M.; Jagust, W.J.; Petersen, R.C.; et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement. 2011, 7, 270–279. [CrossRef] 

44. McKhann, G.M.; Knopman, D.S.; Chertkow, H.; Hyman, B.T.; Jack, C.R., Jr.; Kawas, C.H.; Klunk, W.E.; Koroshetz, W.J.; Manly, J.J.; Mayeux, R.; et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s Dement. 2011, 7, 263–269. [CrossRef] 

45. Winblad, B.; Palmer, K.; Kivipelto, M.; Jelic, V.; Fratiglioni, L.; Wahlund, L.-O.; Nordberg, A.; Backman, L.J.; Albert, M.S.; Almkvist, O.; et al. Mild cognitive impairment—Beyond controversies, towards a consensus: Report of the International Working Group on Mild Cognitive Impairment. J. Intern. Med. 2004, 256, 240–246. [CrossRef] 

46. Morris, J.C. The Clinical Dementia Rating (CDR): Current version and scoring rules. Neurology 1993, 43, 2412–2414. [CrossRef] 

47. Postuma, R.B.; Berg, D.; Stern, M.; Poewe, W.; Olanow, C.W.; Oertel, W.; Obeso, J.; Marek, K.; Litvan, I.; Lang, A.E.; et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov. Disord. 2015, 30, 1591–1601. [CrossRef] [PubMed] 

48. Hyman, B.T.; Phelps, C.H.; Beach, T.G.; Bigio, E.H.; Cairns, N.J.; Carrillo, M.C.; Dickson, D.W.; Duyckaerts, C.; Frosch, M.P.; Masliah, E.; et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s Dement. 2012, 8, 1–13. [CrossRef] [PubMed] 

49. Heffernan, A.; Chidgey, C.; Peng, P.; Masters, C.; Roberts, B.R. The Neurobiology and Age-Related Prevalence of the ε4 Allele of Apolipoprotein E in Alzheimer’s Disease Cohorts. J. Mol. Neurosci. 2016, 60, 316–324. [CrossRef] [PubMed] 

50. Rathcke, C.N.; Vestergaard, H. YKL-40, a new inflammatory marker with relation to insulin resistance and with a role in endothelial dysfunction and atherosclerosis. Inflamm. Res. 2006, 55, 221–227. [CrossRef] [PubMed] 

51. Ransohoff, R.M. How neuroinflammation contributes to neurodegeneration. Science 2016, 353, 777–783. [CrossRef] [PubMed] 

52. Kothur, K.; Wienholt, L.; Brilot, F.; Dale, R.C. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: A systematic review. Cytokine 2016, 77, 227–237. [CrossRef] [PubMed] 

53. Andersson, C.-H.; Andreasson, U.; Bjerke, M.; Rami, L.; Blennow, K.; Zetterberg, H.; Rosén, C.; Molinuevo, J.L.; Lladó, A. Increased Levels of Chitotriosidase and YKL-40 in Cerebrospinal Fluid from Patients with Alzheimer’s Disease. Dement. Geriatr. Cogn. Disord. Extra 2014, 4, 297–304. [CrossRef] 

54. Antonell, A.; Mansilla, A.; Rami, L.; Lladó, A.; Iranzo, A.; Olives, J.; Balasa, M.; Sánchez-Valle, R.; Molinuevo, J.L. Cerebrospinal Fluid Level of YKL-40 Protein in Preclinical and Prodromal Alzheimer’s Disease. J. Alzheimer’s Dis. 2014, 42, 901–908. [CrossRef]

55. A Colton, C.; Mott, R.T.; Sharpe, H.; Xu, Q.; E Van Nostrand, W.; Vitek, M.P. Expression profiles for macrophage alternative activation genes in AD and mouse models of AD. J. Neuroinflamm. 2006, 3, 27. [CrossRef] [PubMed] 

56. Olsson, B.; Constantinescu, R.; Holmberg, B.; Andreasen, N.; Blennow, K.; Zetterberg, H. The glial marker YKL-40 is decreased in synucleinopathies. Mov. Disord. 2013, 28, 1882–1885. [CrossRef] 

57. Sofroniew, M.V.; Vinters, H.V. Astrocytes: Biology and pathology. Acta Neuropathol. 2010, 119, 7–35. [CrossRef] 

58. Gray, M.T.; Woulfe, J.M. Striatal Blood–Brain Barrier Permeability in Parkinson’S Disease. Br. J. Pharmacol. 2015, 35, 747–750. [CrossRef] 

59. Li, J.-Y.; Englund, E.; Holton, J.L.; Soulet, D.; Hagell, P.; Lees, A.J.; Lashley, T.; Quinn, N.P.; Rehncrona, S.; Björklund, A.; et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 2008, 14, 501–503. [CrossRef] 

60. Loria, F.; Vargas, J.Y.; Bousset, L.; Syan, S.; Salles, A.; Melki, R.; Zurzolo, C. α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol. 2017, 134, 789–808. [CrossRef] 

61. Stevenson, T.; Murray, H.; Turner, C.; Faull, R.L.M.; Dieriks, B.V.; Curtis, M.A. α-synuclein inclusions are abundant in nonneuronal cells in the anterior olfactory nucleus of the Parkinson’s disease olfactory bulb. Sci. Rep. 2020, 10, 1–10. [CrossRef] [PubMed] 

62. McGeer, E. The pentraxins: Possible role in Alzheimer’s disease and other innate inflammatory diseases. Neurobiol. Aging 2001, 22, 843–848. [CrossRef] 

63. Duong, T.; Nikolaeva, M.; Acton, P.J. C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer’s disease. Brain Res. 1997, 749, 152–156. [CrossRef] 

64. Iwamoto, N.; Nishiyama, E.; Ohwada, J.; Arai, H. Demonstration of CRP immunoreactivity in brains of Alzheimer’s disease: Immunohistochemical study using formic acid pretreatment of tissue sections. Neurosci. Lett. 1994, 177, 23–26. [CrossRef] 

65. Sarkar, S.; Dammer, E.; Malovic, E.; Olsen, A.L.; Raza, S.A.; Gao, T.; Xiao, H.; Oliver, D.L.; Duong, D.; Joers, V.; et al. Molecular Signatures of Neuroinflammation Induced by αSynuclein Aggregates in Microglial Cells. Front. Immunol. 2020, 11, 33. [CrossRef] 

66. Surendranathan, A.; Rowe, J.B.; O’Brien, J.T. Neuroinflammation in Lewy body dementia. Park. Relat. Disord. 2015, 21, 1398–1406. [CrossRef]