[en] Growing evidence supports the importance of immune processes in Parkinson's disease (PD). However, there is a need to improve the quality of observational clinical studies investigating the role of immunity in PD. In this context, an expert panel from the COST Action IMMUPARKNET (CA21117) aimed to develop guidance recommendations for conducting optimal immune profiling in PD. Firstly, criteria for inclusion and exclusion of participants, clinical data collection and participant stratification have been considered. Secondly, brain imaging of neuroinflammation has been reviewed. Finally, this review discusses sample collection, handling and storage of biological samples. In conclusion, this document aims to guide the scientific community in the optimal design of immune profiling studies in PD, so that we can generate robust and reliable data to advance our knowledge in this field.
Disciplines :
Neurology
Author, co-author :
Muñoz-Delgado, Laura ; Unidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. lmunoz-ibis@us.es ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. lmunoz-ibis@us.es
Williams-Gray, Caroline H ; Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0PY, UK
Garraux, Gaëtan ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie du système nerveux
Clemente, Diego ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain ; Neuroimmune-Repair group, National Hospital for Paraplegics, SESCAM, Toledo, Spain ; Health Research Institute of Castilla-La Mancha (IDISCAM), Toledo, Spain
Çakmak, Özgür Öztop ; Department of Neurology, School of Medecine, Koç University, Istanbul, Türkiye
Greenland, Julia C; Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0PY, UK
Figueira, Inês ; iNOVA4Health, NOVA Institute for Medical Systems Biology, NIMSB, Universidade Nova de Lisboa, 1099-085, Lisboa, Portugal ; iNOVA4Health, NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade Nova de Lisboa, 1169-056, Lisboa, Portugal
Machín-Díaz, Isabel; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain ; Neuroimmune-Repair group, National Hospital for Paraplegics, SESCAM, Toledo, Spain ; Health Research Institute of Castilla-La Mancha (IDISCAM), Toledo, Spain
Pirovano, Elenamaria; Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy
di Flora, Alessia ; Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy
Tournerie, Clotilde ; Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0PY, UK
Papoutsopoulou, Stamatia ; Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, Larissa, Greece
Ertan, Sibel ; Department of Neurology, School of Medecine, Koç University, Istanbul, Türkiye
Mir, Pablo ; Unidad de Trastornos del Movimiento, Servicio de Neurología, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain ; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain ; Departamento de Medicina, Facultad de Medicina, Universidad de Sevilla, Seville, Spain
Comi, Cristoforo ; Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale, Vercelli, Italy
ISCIII - Instituto de Salud Carlos III COST - European Cooperation in Science and Technology Junta de Andalucía. Consejería de Salud y Familias UKRI - UK Research and Innovation NIHR Cambridge BRC - NIHR Cambridge Biomedical Research Centre F.R.S.-FNRS - Fonds de la Recherche Scientifique ERC - European Research Council FEDER - Fondo Europeo de Desarrollo Regional Junta de Andalucía. Consejería de Economía, Conocimiento, Empresas y Universidad
Funding text :
of IMMUnity in tackling PARKinson’s disease through a Translational
NETwork [IMMUPARKNET], supported by COST (European Cooperation
in Science and Technology) (www.cost.eu). LauraMuñoz-Delgado is
financially supportedby the “JuanRodés” programme (JR23/00016) from
the Instituto de Salud Carlos III and receives funding support from the
Consejería de Salud y Consumo de la Junta de Andalucía (NEU-0005-
2022). CarolineWilliams-Grey receives financial support from the NIHR
Cambridge Biomedical Research Centre (NIHR203312) and the
Cambridge Centre for Parkinson-Plus, and grant funding from the UKRI
Medical Research Council (MR/W029235/1), Cure Parkinson’s,
Parkinson’sUK, and the Rosetrees Trust. Gaetan Garraux is supportedby
‘Fonds Rahier’, University of Liège and Fonds de la Recherche
Scientifique (F.R.S.-FNRS) de Belgique. Gaëtan Garraux has also
received support for travel or honorarium from AbbVie, Eurogenerics and
Zambon. Diego Clemente has received funding support from Instituto de
Salud Carlos III (PI18/00357, PI21/00302, PI24/00447, co-funded by the
European Union, CIBERNED CB22/05/00016, “INVESTIGO” programme
in theframeof thePlanpara laRecuperación,TransformaciónyResiliencia
(European Union Next Generation funds), and EMD Serono R&D R&D unit iNOVA4Health (LISBOA-01-0145-FEDER-007344; UIDB/
04462/2020), and LS4FUTURE Associated Laboratory (LA/P/0087/
2020).PabloMir has received financial support fromthe SpanishMinistry
of Science and Innovation (RTC2019-007150-1), the Instituto de Salud
Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER) (PI16/
01575, PI18/01898, PI19/01576, PI20/00613, PI21/01875, PI22/01704
and PI23/00512), the Consejería de Economía, Innovación, Ciencia y
Empleo de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería
de Salud y Bienestar Social de la Junta de Andalucía (PI-0471-2013, PE-
0210-2018, PI-0459-2018 and PE-0186-2019), the Consejería de
Transformación Económica, Industria,Conocimiento yUniversidades de
la Junta de Andalucía (PY20_00896). PabloMir has also received support
for attending meetings and/or travel or honorarium for lecturing from
Abbott, Allergan, AbbVie, Bial, Britannia, Italfarmaco,Merz, UCB, Teva
and Zambon. Cristoforo Comi is supported by the AGING PROJECT—
Department of Excellence—Università delPiemonteOrientale.Cristoforo
Comi has received travel grants for meeting participation from
Ecupharma, Bial and Novartis.
Agreement). Ines Figueira is supported by the the ERC—Grant No.
804229; through PeX—2022.02127.PTDC (PERCEPT) and through the
C. Roodveldt et al. The immune system in Parkinson’s disease: what we know so far Brain 147 3306 3324 38833182 11449148
Gugu, M. et al. IMMUnity unveiled: a translational NETwork for tackling PARKinson’s disease – IMMUPARKNET. Open Res. Eur.4, 119 (2025).
R.B. Postuma et al. MDS clinical diagnostic criteria for Parkinson’s disease Mov. Disord. 30 1591 1601 26474316
D. Berg et al. Movement disorder society criteria for clinically established early Parkinson’s disease Mov. Disord. 33 1643 1646 30145841
T. Simuni et al. A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research Lancet Neurol. 23 178 190 38267190
G.U. Höglinger et al. A biological classification of Parkinson’s disease: the SynNeurGe research diagnostic criteria Lancet Neurol. 23 191 204 38267191
H. Zhang et al. Plasma immune markers in an idiopathic REM sleep behavior disorder cohort Parkinsonism Relat. Disord. 78 145 150 32835920
K. Farmen et al. Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder Proc. Natl Acad. Sci. USA 118 33658371 7958435 e2020858118
S. Heinzel et al. Update of the MDS research criteria for prodromal Parkinson’s disease Mov. Disord. 34 1464 1470 31412427
A. Thaler et al. Mutations in GBA and LRRK2 are not associated with increased inflammatory markers J. Parkinsons Dis. 11 1285 1296 33998549 8461659
C. Koros et al. Peripheral Immune pattern in a genetic cohort of p.A53T alpha-synuclein carriers Parkinsonism Relat. Disord. 135 40328209 107853
G. Pawelec A. Larbi E. Derhovanessian Senescence of the human immune system J. Comp. Pathol. 142 S39 S44 19897208
S.L. Klein K.L. Flanagan Sex differences in immune responses Nat. Rev. Immunol. 16 626 638 27546235
S.K. Nissen et al. Alterations in blood monocyte functions in Parkinson’s disease Mov. Disord. 34 1711 1721 31449711
S.M. Carlisle et al. Sex-based differences in the activation of peripheral blood monocytes in early Parkinson disease NPJ Parkinsons Dis. 7 36 33850148 8044127
Y. Xiang M. Zhang D. Jiang Q. Su J. Shi The role of inflammation in autoimmune disease: a therapeutic target Front. Immunol. 14 37859999 10584158 1267091
Liu, W. et al. Immune and inflammatory mechanisms and therapeutic targets of gout: an update. Int. Immunopharmacol.121, 110466 (2023).
E.C. Shin P. Sung S.H. Park Immune responses and immunopathology in acute and chronic viral hepatitis Nat. Rev. Immunol. 16 509 523 27374637
N. Mac Giollabhui et al. To exclude or not to exclude: considerations and recommendations for C-reactive protein values higher than 10 mg/L Brain Behav. Immun. 87 898 900 7316621
I. Carrión-Barberà C. Lood Performance of the neutrophil-to-lymphocyte ratio as a prognostic tool for survival in solid cancers Front. Oncol. 15 40761253 12318771 1616477
A.J. Barrett B.N. Savani Does chemotherapy modify the immune surveillance of hematological malignancies? Leukemia 23 53 58 18830260
C. Moreno et al. Restoration of the immune function as a complementary strategy to treat chronic lymphocytic leukemia effectively J. Exp. Clin. Cancer Res. 40 321 34654437 8517318
A.M. Dąbrowska R. Słotwiński The immune response to surgery and infection Cent. Eur. J. Immunol. 39 532 537 26155175 4439968
A. Osuka H. Ogura M. Ueyama T. Shimazu J.A. Lederer Immune response to traumatic injury: harmony and discordance of immune system homeostasis Acute Med. Surg. 1 63 69 29930824 5997205
A. Berbudi N. Rahmadika A.I. Tjahjadi R. Ruslami Type 2 Diabetes and its Impact on the Immune System Curr. Diabetes Rev. 16 442 449 31657690 7475801
A.C. Wiseman Immunosuppressive medications Clin. J. Am. Soc. Nephrol. 11 332 343 26170177
W.T. Butler R.D. Rossen Effects of corticosteroids on immunity in man. I. Decreased serum IgG concentration caused by 3 or 5 days of high doses of methylprednisolone J. Clin. Invest. 52 2629 2640 4729056 302523
J. Sastre R. Mosges Local and systemic safety of intranasal corticosteroids J. Investig. Allergol. Clin. Immunol. 22 1 12 22448448
D. Pandya A. Puttanna V. Balagopal Systemic effects of inhaled corticosteroids: an overview Open Respir. Med. J. 8 59 65 25674175 4319197
D. Sakonlaya P. Tapanadechopone A. Poomkokruk S. Charoenvilaisiri Do NSAIDs inhibit growth of precancerous cervical cells in vitro? J. Med. Assoc. Thai 95 S65 S73 23964446
T. Morris et al. Effects of low-dose aspirin on acute inflammatory responses in humans J. Immunol. 183 2089 2096 19597002
A.J. Pollard E.M. Bijker A guide to vaccinology: from basic principles to new developments Nat. Rev. Immunol. 21 83 100 33353987
X. Yuan et al. Peripheral inflammatory and immune landscape in multiple system atrophy: a cross-sectional study Mov. Disord. 39 391 399 38155513
L. Muñoz-Delgado et al. Peripheral immune profile and neutrophil-to-lymphocyte ratio in progressive supranuclear palsy: case-control study and meta-analysis Eur. J. Neurol. 31 39162120 11555143 e16451
J. Doroszkiewicz I. Winkel B. Mroczko Comparative analysis of neuroinflammatory pathways in Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis: insights into similarities and distinctions Front. Neurosci. 19 40364858 12069400 1579511
Y. Zhu et al. Association between inflammatory bowel diseases and Parkinson’s disease: systematic review and meta-analysis Neural Regen. Res. 17 344 353 34269209
A. Witoelar et al. Genome-wide pleiotropy between Parkinson disease and autoimmune diseases JAMA Neurol. 74 780 792 28586827 5710535
L. Magistrelli et al. Relationship between circulating CD4+ T lymphocytes and cognitive impairment in patients with Parkinson’s disease Brain Behav. Immun. 89 668 674 32688028
K. Marder M.X. Tang L. Cote Y. Stern R. Mayeux The frequency and associated risk factors for dementia in patients with Parkinson’s disease Arch. Neurol. 52 695 701 7619026
R. Petty et al. Improving recruitment and retention of people with Parkinson’s disease to clinical studies: a scoping review J. Parkinson’s Dis. 15 6 18
S. Teague et al. Retention strategies in longitudinal cohort studies: a systematic review and meta-analysis BMC Med. Res. Methodol. 18 30477443 6258319 151
D.N. Weemering et al. Trial participation in neurodegenerative diseases: barriers and facilitators: a systematic review and meta-analysis Neurology 103 38830181 11244742 e209503
S. Jiang et al. Cell ratio differences in peripheral blood between early- and late-onset Parkinson’s disease: a case-control study Biomed. Res. Int. 2019 31781596 6874872 2072635
A. Freuchet A. Pinçon A. Sette C.S. Lindestam Arlehamn Inflammation and heterogeneity in synucleinopathies Front. Immunol. 15 1432342 39281666 11392857
B.D. Lyn-Cook et al. Increased expression of Toll-like receptors (TLRs) 7 and 9 and other cytokines in systemic lupus erythematosus (SLE) patients: ethnic differences and potential new targets for therapeutic drugs Mol. Immunol. 61 38 43 24865418
C.A. Martin et al. Ethnic differences in cellular and humoral immune responses to SARS-CoV-2 vaccination in UK healthcare workers: a cross-sectional analysis EClinicalMedicine 58 37034357 10071048 101926
A. Mamais A. Kaganovich K. Harvey Convergence of signalling pathways in innate immune responses and genetic forms of Parkinson’s disease Neurobiol. Dis. 169 35405260 105721
R.L. Wallings M.G. Tansey LRRK2 regulation of immune-pathways and inflammatory disease Biochem. Soc. Trans. 47 1581 1595 31769472 6925522
L. Muñoz-Delgado et al. Peripheral inflammatory immune response differs among sporadic and familial Parkinson’s disease NPJ Parkinsons Dis. 9 12 36720879 9889312
E. Kozina et al. Mutant LRRK2 mediates peripheral and central immune responses leading to neurodegeneration in vivo Brain 141 1753 1769 29800472 7190032
T.J.C. Collins et al. The influence of metabolic disorders on adaptive immunity Cell Mol. Immunol. 21 1109 1119 39134802 11442657
I. Fernandez-Ruiz Irene Immune system and cardiovascular disease Nat. Rev. Cardiol. 13 503 27516069
V. Grossmann et al. Profile of the immune and inflammatory response in individuals with prediabetes and type 2 diabetes Diabetes Care. 38 1356 1364 25877811
E.M. Kline et al. Genetic and environmental factors in Parkinson’s disease converge on immune function and inflammation Mov. Disord. 36 25 36 33314312
K. Kulcsarova C. Bang D. Berg E. Schaeffer Pesticides and the microbiome-gut-brain axis: convergent pathways in the pathogenesis of Parkinson’s disease J. Parkinsons Dis. 13 1079 1106 37927277 10657696
R.J. Smeyne A.J. Noyce M. Byrne R. Savica C. Marras Infection and risk of Parkinson’s disease J. Parkinsons Dis. 11 31 43 33361610 7990414
D. Wu E.D. Lewis M. Pae S.N. Meydani Nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance Front. Immunol. 9 3160 30697214 6340979
D.C. Nieman L.M. Wentz The compelling link between physical activity and the body’s defense system J. Sport Health Sci. 8 201 217 31193280
L. Besedovsky T. Lange J. Born Sleep and immune function Pflug. Arch. 463 121 137
M. Pinoli F. Marino M. Cosentino Dopaminergic regulation of innate iImmunity: a review J. Neuroimmune Pharmacol. 12 602 623 28578466
S. Thomas Broome et al. Dopamine: an immune transmitter Neural Regen. Res. 15 2173 2185 32594028 7749467
N. Kustrimovic E. Rasini M. Legnaro F. Marino M. Cosentino Expression of dopaminergic receptors on human CD4+ T lymphocytes: flow cytometric analysis of naive and memory subsets and relevance for the neuroimmunology of neurodegenerative disease J. Neuroimmune Pharmacol. 9 302 312 24682738
C.L. Tomlinson et al. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease Mov. Disord. 25 2649 2653 21069833
M. Lawton et al. Blood biomarkers with Parkinson’s disease clusters and prognosis: the Oxford discovery cohort Mov. Disord. 35 279 287 31693246
M. Reale et al. Peripheral cytokines profile in Parkinson’s disease Brain Behav. Immun. 23 55 63 18678243
C. Sun et al. Peripheral humoral immune response is associated with the non-motor symptoms of Parkinson’s disease Front Neurosci. 13 1057 31649497 6795918
C.H. Williams-Gray et al. Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD) Mov. Disord. 31 995 1003 26999434 4957620
R.S. Wijeyekoon et al. Peripheral innate immune and bacterial signals relate to clinical heterogeneity in Parkinson’s disease Brain Behav. Immun. 87 473 488 32006615 7613010
K.M. Scott et al. B lymphocyte responses in Parkinson’s disease and their possible significance in disease progression Brain Commun. 5 36993946 10042276 fcad060
K.M. Scott A. Kouli S.L. Yeoh M.R. Clatworthy C.H. Williams-Gray A systematic review and meta-analysis of alpha synuclein auto-antibodies in Parkinson’s disease Front. Neurol. 9 815 30333787 6176114
C.S. Lindestam Arlehamn et al. α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease Nat. Commun. 11 32313102 7171193 1875
R. Bhidayasiri P. Martinez-Martin Clinical assessments in Parkinson’s disease: scales and monitoring Int. Rev. Neurobiol. 132 129 182 28554406
C.G. Goetz et al. Movement Disorder Society UPDRS revision Task Force. Movement Disorder Society-sponsored revision of the unified Parkinson’s disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results Mov. Disord. 23 2129 2170 19025984
A. Kouli et al. Neuroinflammation is linked to dementia risk in Parkinson’s disease Brain 147 923 935 37757857
I. Litvan et al. Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society Task Force guidelines Mov. Disord. 27 349 356 22275317 3641655
M. Emre et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease Mov. Disord. 22 1689 1707 17542011
M. Skorvanek et al. Global scales for cognitive screening in Parkinson’s disease: Critique and recommendations Mov. Disord. 33 208 218 29168899
A.H. Miller C.L. Raison The role of inflammation in depression: from evolutionary imperative to modern treatment target Nat. Rev. Immunol. 16 22 34 26711676 5542678
Houser, M. C. & Tansey, M. G. The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis? NPJ Parkinsons Dis. 3, 3 (2017).
G.C. Brown M. Camacho C.H. Williams-Gray The endotoxin hypothesis of Parkinson’s disease Mov. Disord. 38 1143 1155 37157885 10947365
M. Camacho J.C. Greenland C.H. Williams-Gray The gastrointestinal dysfunction scale for Parkinson’s disease Mov. Disord. 36 2358 2366 34133059
M.C. Brumm et al. Updated percentiles for the University of Pennsylvania smell identification test in adults 50 years of age and older Neurology 100 e1691 e1701 36849448 10115503
C. Rumeau D.T. Nguyen R. Jankowski How to assess olfactory performance with the Sniffin’ Sticks test(®) Eur. Ann. Otorhinolaryngol. Head. Neck Dis. 133 203 206 26344139
K.R. Chaudhuri et al. The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: results from an international pilot study Mov. Disord. 22 1901 1911 17674410 Oct 15
Y. Lee Y. Park H. Nam J.W. Lee S.W. Yu Translocator protein (TSPO): the new story of the old protein in neuroinflammation BMB Rep. 53 20 27 31818362 6999824
W.C. Kreisl et al. PET imaging of neuroinflammation in neurological disorders Lancet Neurol. 19 940 950 33098803 7912433
S.S. Wijesinghe et al. Post-mortem validation of in vivo TSPO PET as a microglial biomarker Brain 148 1904 1910 40036275 12129730
P.F. Zhang F. Gao Neuroinflammation in Parkinson’s disease: a meta-analysis of PET imaging studies J. Neurol. 269 2304 2314 34724571
Y. Ouchi et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease Ann. Neurol. 57 168 175 15668962
A. Gerhard et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease Neurobiol. Dis. 21 404 412 16182554
T.A. Yacoubian et al. Brain and systemic inflammation in de novo Parkinson’s disease Mov. Disord. 38 743 754 36853618 11403348
M.G. Stokholm et al. Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case-control study Lancet Neurol. 16 789 796 28684245
S. Mullin et al. Brain microglial activation increased in glucocerebrosidase (GBA) mutation carriers without Parkinson’s disease Mov. Disord. 36 774 779 33278043
M. Li et al. Dopamine, a co-regulatory component, bridges the central nervous system and the immune system Biomed. Pharmacother. 145 34847478 112458
M.A. Peyronneau et al. 18F]DPA-714: effect of co-medications, age, sex, BMI and TSPO polymorphism on the human plasma input function Eur. J. Nucl. Med. Mol. Imaging 50 3251 3264 37291448
P. Jain et al. Neuroinflammation PET Imaging: current opinion and future directions J. Nucl. Med. 61 1107 1112 32620705 7413228
L.Y. Tan et al. Emergence of the brain-border immune niches and their contribution to the development of neurodegenerative diseases Front. Immunol. 15 38863704 11165048 1380063
P. Kanel G. Carli R. Vangel S. Roytman N.I. Bohnen Challenges and innovations in brain PET analysis of neurodegenerative disorders: a mini-review on partial volume effects, small brain region studies, and reference region selection Front. Neurosci. 17 38099203 10720329 1293847
M.G. Tansey et al. Inflammation and immune dysfunction in Parkinson disease Nat. Rev. Immunol. 22 657 673 35246670 8895080
Schroder et al. Immune cell activation in the cerebrospinal fluid of patients with Parkinson’s disease Front. Neurol. 9 1081 30619041 6305582
C. Pillny L. Nitsch S. Proske-Schmitz A. Sharma U. Wüllner Abnormal subpopulations of monocytes in the cerebrospinal fluid of patients with Parkinson’s disease Parkinsonism Relat. Disord. 84 144 145 33631553
X.Y. Qin S.P. Zhang C. Cao Y.P. Loh Y. Cheng Aberrations in peripheral inflammatory cytokine levels in Parkinson disease: a systematic review and meta-analysis JAMA Neurol. 73 1316 1324 27668667
Y. Qu et al. A systematic review and meta-analysis of inflammatory biomarkers in Parkinson’s disease NPJ Parkinsons Dis. 9 18 36739284 9899271
A.N. Coogan C.A. Wyse Neuroimmunology of the circadian clock Brain Res. 1232 104 112 18703032
Y.C. Chen W.S. Wang S.J.G. Lewis S.L. Wu Fighting against the clock: circadian disruption and Parkinson’s disease J. Mov. Disord. 17 1 14 37989149
T. Li et al. Peripheral clock system abnormalities in patients with Parkinson’s disease Front. Aging Neurosci. 13 34658839 8519399 736026
C. Scheiermann J. Gibbs L. Ince A. Loudon Clocking in to immunity Nat. Rev. Immunol. 18 423 437 29662121
R.S. Wijeyekoon et al. Cerebrospinal Fluid Cytokines and Neurodegeneration-Associated Proteins in Parkinson’s Disease Mov. Disord. 35 1062 1066 32413185 8629119
O. Kofanova et al. IL8 and EDEM3 gene expression ratio indicates peripheral blood mononuclear cell (PBMC) quality J. Immunol. Methods 465 13 19 30496732
K. Popko et al. Influence of blood sample storage and different types of anticoagulants on results of NK cytotoxicity tests Cent. Eur. J. Immunol. 48 267 273 38558558
A. Efthymiou et al. Isolation and freezing of human peripheral blood mononuclear cells from pregnant patients STAR Protoc. 3 35252886 8888982 101204
M. Zborowski Maciej L. Moore LeeR K. Melnik Kristie Y. Jing Ying Worked examples of cell sample preparation and magnetic separation procedures Lab. Tech. Biochem. Mol. Biol. 32 293 330
H. Chen et al. Functional comparison of PBMCs isolated by cell preparation tubes (CPT) vs. lymphoprep tubes BMC Immunol. 21 15 32228458 7106580
F. Betsou A. Gaignaux W. Ammerlaan P.J. Norris M. Stone Biospecimen science of blood for peripheral blood mononuclear cell (PBMC) functional applications Curr. Pathobiol. Rep. 7 17 27
P.C. Yi et al. Impact of delayed PBMC processing on functional and genomic assays J. Immunol. Methods 519 113514 37353001
W.C. Olson et al. Shipping blood to a central laboratory in multicenter clinical trials: effect of ambient temperature on specimen temperature, and effects of temperature on mononuclear cell yield, viability and immunologic function J. Transl. Med. 9 21385453 3063218 26
B. Thyagarajan et al. Effect of delayed cell processing and cryopreservation on immunophenotyping in multicenter population studies J. Immunol. Methods 463 61 70 30222961 6423980
L. Higdon et al. Impact on in-depth immunophenotyping of delay to peripheral blood processing Clin. Exp. Immunol. 217 119 132 38693758 11239563
S. Martire et al. The impact of pre-freezing storage time and temperature on gene expression of blood collected in EDTA tubes Mol. Biol. Rep. 49 4709 4718 35279776 9262796
A. Costantini et al. Effects of cryopreservation on lymphocyte immunophenotype and function J. Immunol. Methods 278 145 155 12957403
P.V. Jeurink Y.M. Vissers B. Rappard H.F. Savelkoul T cell responses in fresh and cryopreserved peripheral blood mononuclear cells: kinetics of cell viability, cellular subsets, proliferation, and cytokine production Cryobiology 57 91 103 18593572
L. Usero et al. Feasibility of using monocyte-derived dendritic cells obtained from cryopreserved cells for DC-based vaccines J. Immunol. Methods 498 34480950 113133
K.A. Reimann M. Chernoff C.L. Wilkening C.E. Nickerson A.L. Landay Preservation of lymphocyte immunophenotype and proliferative responses in cryopreserved peripheral blood mononuclear cells from human immunodeficiency virus type 1-infected donors: implications for multicenter clinical trials. The ACTG immunology advanced technology laboratories Clin. Diagn. Lab Immunol. 7 352 359 10799445 95878
D.F. Draxler M.T. Madondo G. Hanafi M. Plebanski R.L. Medcalf A flowcytometric analysis to efficiently quantify multiple innate immune cells and T Cell subsets in human blood Cytom. A. 91 336 350
M. Marino et al. Impact of 12-month cryopreservation on endogenous DNA damage in whole blood and isolated mononuclear cells evaluated by the comet assay Sci. Rep. 11 33432000 7801598 363
O. Ticha L. Moos I. Bekeredjian-Ding Effects of long-term cryopreservation of PBMC on recovery of B cell subpopulations J. Immunol. Methods 495 34048717 113081
B. Li et al. Comprehensive evaluation of the effects of long-term cryopreservation on peripheral blood mononuclear cells using flow cytometry BMC Immunol. 23 30 35672664 9175382
H. Barcelo J. Faul E. Crimmins B. Thyagarajan A Practical cryopreservation and staining protocol for immunophenotyping in population studies Curr. Protoc. Cytom. 84 30040214 6060642 e35
M.L. Disis et al. Maximizing the retention of antigen specific lymphocyte function after cryopreservation J. Immunol. Methods 308 13 18 16337957
T. Bogoslovsky et al. Cryopreservation and enumeration of human endothelial progenitor and endothelial cells for clinical trials J. Blood Disord. Transfus. 4 158 25309814 4193669
J. Yang et al. The effects of storage temperature on PBMC gene expression BMC Immunol. 17 6 26979060 4791795
K.R. Fowke J. Behnke C. Hanson K. Shea L.M. Cosentino Apoptosis: a method for evaluating the cryopreservation of whole blood and peripheral blood mononuclear cells J. Immunol. Methods 244 139 144 11033026
C.M. Hope et al. Optimization of blood handling and peripheral blood mononuclear cell cryopreservation of low cell number samples Int. J. Mol. Sci. 22 9129 34502038 8431655
A. Cossarizza et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) Eur. J. Immunol. 51 2708 3145 34910301 11115438
L.L. Chan et al. Accurate measurement of peripheral blood mononuclear cell concentration using image cytometry to eliminate RBC-induced counting error J. Immunol. Methods 388 25 32 23201386
K. Bagamery K. Kvell R. Landau J. Graham Flow cytometric analysis of CD41-labeled platelets isolated by the rapid, one-step OptiPrep method from human blood Cytom. A. 65 84 87
D.C. McFarland C. Zhang H.C. Thomas T.L. Ratliff Confounding effects of platelets on flow cytometric analysis and cell-sorting experiments using blood-derived cells Cytom. A. 69 86 94
B.E.J. Spurgeon M.D. Linden A.D. Michelson A.L. Frelinger 3rd. Immunophenotypic analysis of platelets by flow cytometry Curr. Protoc. 1 34170638 e178
J. Sroka A. Kordecka P. Włosiak Z. Madeja W. Korohoda Separation methods for isolation of human polymorphonuclear leukocytes affect their motile activity Eur. J. Cell Biol. 88 531 539 19560229
D.B. Kuhns D.A.L. Priel J. Chu K.A. Zarember Isolation and functional analysis of human neutrophils Curr ProtocImmunol 111 7.23.1 7.23.16
Y. Kuang U. Parthasarathy R. Martinelli Protocol for density gradient neutrophil isolation and flow cytometry-based characterization from human peripheral blood STAR Protoc. 4 37590147 10461015 102497
F. Alvieri et al. Methods of granulocyte isolation from human blood and labeling with multimodal superparamagnetic iron oxide nanoparticles Molecules 25 765 32053865 7070653
T. Mosca W.C. Forte Comparative efficiency and impact on the activity of blood neutrophils isolated by percoll, ficoll and spontaneous sedimentation methods Immunol. Invest. 45 29 37 26699845
C. Cui K.Q. Schoenfelt K.M. Becker L. Becker Isolation of polymorphonuclear neutrophils and monocytes from a single sample of human peripheral blood STAR Protoc. 2 34604813 8473578 100845
Y. Rosenberg-Hasson L. Hansmann M. Liedtke I. Herschmann H.T. Maecker Effects of serum and plasma matrices on multiplex immunoassays Immunol. Res. 58 224 233 24522699 4332596
A. Burska M. Boissinot F. Ponchel Cytokines as biomarkers in rheumatoid arthritis Mediators Inflamm. 2014 24733962 3964841 545493
C. Liu et al. Cytokines: from clinical significance to quantification Adv. Sci. 8 e2004433
A. Friebe H.D. Volk Stability of tumor necrosis factor alpha, interleukin 6, and interleukin 8 in blood samples of patients with systemic immune activation Arch. Pathol. Lab Med. 132 1802 1806 18976019
N. Aziz et al. Stability of cytokines, chemokines and soluble activation markers in unprocessed blood stored under different conditions Cytokine 84 17 24 27208752 4910822
A. Gottfried-Blackmore et al. Effects of processing conditions on stability of immune analytes in human blood Sci. Rep. 10 33060628 7566484 17328
J.A. Saugstad et al. Analysis of extracellular RNA in cerebrospinal fluid J. Extracell. Vesicles. 6 28717417 5505019 1317577
U. Fiszer E. Mix S. Fredrikson V. Kostulas H. Link Parkinson’s disease and immunological abnormalities: increase of HLA-DR expression on monocytes in cerebrospinal fluid and of CD45RO+ T cells in peripheral blood Acta Neurol. Scand. 90 160 166 7847055
Lepennetier, G. et al. Cytokine and immune cell profiling in the cerebrospinal fluid of patients with neuro-inflammatory diseases. J. Neuroinflammation. 16, 219 (2019).
M. Faizan et al. Cerebrospinal fluid protein biomarkers in Parkinson’s disease Clin. Chim. Acta 556 38417781 117848
C. Cantoni et al. A single-cell compendium of human cerebrospinal fluid identifies disease-associated immune cell populations J. Clin. Invest. 135 39744938 11684814 e177793
M.C. Kodali et al. Cryopreservation of cerebrospinal fluid cells preserves the transcriptional landscape for single-cell analysis J. Neuroinflammation 21 71 38521932 10960996
C.H. Lin et al. Altered gut microbiota and inflammatory cytokine responses in patients with Parkinson’s disease J. Neuroinflammation. 16 31248424 6598278 129
M.C. Houser et al. Stool immune profiles evince gastrointestinal inflammation in Parkinson’s disease Mov. Disord. 33 793 804 29572994 5992021
J.M. Boertien P.A.B. Pereira V.T.E. Aho F. Scheperjans Increasing comparability and utility of gut microbiome studies in Parkinson’s disease: a systematic review J. Parkinsons Dis. 9 S297 S312 31498131 6839453
M.I. De Bartolo et al. A systematic review of salivary biomarkers in Parkinson’s disease Neural Regen. Res. 19 2613 2625 38595280 11168506
Z. Szabo D.C. Slavish Measuring salivary markers of inflammation in health research: a review of methodological considerations and best practices Psychoneuroendocrinology 124 33316694 105069
