Higher levels of proinflammatory cytokines are found in Parkinson's disease (PD) patient's brains and inflammation is thought to be a major contributor to the neurodegeneration. During the inflammatory process, microglial release of proinflammatory cytokines act on the endothelium of blood-brain barrier (BBB) cells to stimulate upregulation of adhesion molecules. Consequently, this upregulation leads to the recruitment of passing T cells and monocytes, which express the counter receptors, that then go on to release more cytokines [Whitton, P.S., 2007. Inflammation as a causative factor in the aetiology of Parkinson's disease, Br. J. Pharmacol. 50, 963-976; Kortekaas, R., Leenders, K.L., Van Oostrom, J.C., Vaalburg, W., Bart, J., Willemsen, A.T., Hendrikse, N.H., 2005. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo, Ann. Neurol. 57, 176-179]. In addition, a systemic inflammatory response results in the production of cytokines which circulate in the blood and communicate with neurons within the brain. Thus, a central inflammatory reaction interacts with peripheral blood mononuclear cells (PBMCs) modulating immune activity. The present study investigates levels of production and expression of cyto/chemokines by PBMCs in PD patients. Basal and LPS-induced levels of MCP-1, RANTES, MIP-1alpha, IL-8, IFNgamma, IL-1beta and TNFalpha were significantly higher in PD patients than in HC subjects (p<0.001), as determined by RT-PCR and Elisa methods. Cyto/chemokine levels were significantly correlated with UPDRS III and H/Y stage (p<0.001). The Pearson's correlation coefficient (R) was also used to assess the strength of the relationship between NF-kappaBp65 levels and all studied cyto/chemokines and between NF-kappaBp65, UPDRS III and H/Y score in PD patients. The overall results strengthen and extend the knowledge of the peripheral dysregulation in the cytokine network associated with PD.

Peripheral cytokines profile in Parkinson's disease

Alzheimer’s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer’s disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer’s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer’s disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer’s disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer’s disease to two separate Epstein–Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer’s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration. An integrated analysis of several cohorts shows that clonal, antigen-experienced T cells are found in the cerebrospinal fluid of patients with Alzheimer’s disease, suggesting that the adaptive immune system has a role in age-related neurodegeneration.

Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease

Neuroinflammation, oxidative stress, and the pathogenesis of Parkinson’s disease

An inflammatory review of Parkinson's disease

The role of TNF and its receptors in Alzheimer’s disease

Blood platelet monoamine oxidase activity, as well as other platelet enzyme activities, have been studied in several neuropsychiatric disorders in an attempt to identify biochemical markers of altered brain function. In this study, we determined both total and molecular monoamine oxidase activity in platelets derived from demented patients, which showed significantly greater enzyme activity than those of the controls. It therefore seems that the high degree of monoamine oxidase activity depends on the increased intrinsic activity of individual enzyme molecules. A significant positive correlation was found between monoamine oxidase activity and the severity of illness, which suggests that monoamine oxidase activity may be a state-dependent marker of neurodegeneration. These findings are discussed with reference to the central nervous system biochemical abnormalities of demented subjects: it may be that Alzheimer-type dementia involves some central biochemical changes that are reflected in certain peripheral tissues (e.g. platelets), or a systemic derangement that also affects the brain.

Platelet monoamine oxidase molecular activity in demented patients

Monoamine oxidase molecular activity in platelets of parkinsonian and demented patients.

Dementia of Alzheimer type (DAT) is a neurodegenerative disease of the central nervous system (CNS), in which an unbalanced cytokine network may lead to an altered immunoregulation. Tumour necrosis factor (TNF)-α is a cytokine with manifold effects on the neuroimmune system. Specific TNF-α receptors have been found on human peripheral blood lymphocytes. The aim of the present study has been to assay TNF-α binding on T cells from DAT patients and healthy sex- and age-matched controls. We found that T lymphocytes from demented patients bear significantly more p60 and p80 TNF-α receptors than those from controls (Bmax: 705, 29 vs 131, 6 (mean, SEM) receptors/cell). Such TNF-α binding sites, of the same type in DAT patients and healthy subjects (Kd: 67.6, 5.0 vs 70.7, 5.6 (mean, SEM) pM), are functional, since they are able to mediate in vitro NF-κB activation. These results are discussed in terms of DAT pathogenesis. Since it has been reported that activated T cells have more TNF-α receptors than resting cells, an increased number of lymphocyte TNF-α receptors might indicate a systemic immune activation in DAT patients as compared with healthy controls.

T-cell tumour necrosis factor-α receptor binding in demented patients

T-lymphocyte tumor necrosis factor-α receptor binding in patients with Parkinson's disease

Objective: To investigate some aspects of T-cell‐ dependent immune function in patients with dementia of the Alzheimer type (DAT). Design: Assay of interleukin 6 binding on T lymphocytes from patients with DAT, compared with that in healthy controls. Setting: The study included ambulatory patients in a tertiary care center who were diagnosed as having DAT according to the criteria of the National Institute of Neurologic and Communicative Disorders and Stroke. Subjects: Thirty-five patients with DAT without depression (15 women and 20 men; mean ± SD age, 68.6 ± 15.8 years) were selected consecutively. They had not taken any medication for at least 3 weeks and did not smoke. Illness severity was evaluated according to the Clinical Dementia Rating Scale. Thirty-five age- and sexmatched healthy nonsmoking subjects with no family history of neuropsychiatric disorders formed the control group. Results: A significant (P,.001) increase in Tlymphocyte interleukin 6 binding was found in patients with DAT compared with healthy controls (mean ± SE receptors per cell, 30 5±7v s 276 ±6 ,respectively), whereas the ligand-receptor affinity values were similar in the 2 groups (mean ± SE, 25.9 ± 0.9 and 25.3 ± 0.6 nmol/L). Conclusion: These data indicate a derangement of the immune response in patients with DAT since cellsurface interleukin 6 receptors seem to be related to Tlymphocyte immune function. Arch Neurol. 1998;55:1305-1308

https://jamanetwork.com/journals/jamaneurology/articlepdf/774306/noc7277.pdf

B. Boccardi

Papers

Platelet monoamine oxidase molecular activity in demented patients

Monoamine oxidase molecular activity in platelets of parkinsonian and demented patients.

T-cell tumour necrosis factor-α receptor binding in demented patients

T-lymphocyte tumor necrosis factor-α receptor binding in patients with Parkinson's disease

T-Lymphocyte Interleukin 6 Receptor Binding in Patients With Dementia of Alzheimer Type