Journal of Alzheimer’s Disease 81 (2021) 629–640 629 DOI 10.3233/JAD-201565 IOS Press Different Inflammatory Signatures in Alzheimer’s Disease and Frontotemporal Dementia Cerebrospinal Fluid Gustaf Boströma,∗ , Eva Freyhultb , Johan Virhammarc , Daniel Alcolead,e , Hayrettin Tumanif , Markus Ottof , Rose-Marie Brundina , Lena Kilandera , Malin Löwenmarka , Vilmantas Giedraitisa , Alberto Lleód,e , Christine A.F. von Arnimf,g , Kim Kultimah,1 and Martin Ingelssona,1 a Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden b Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden c Department of Neuroscience, Neurology, Uppsala University Hospital, Uppsala, Sweden d Memory Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain e Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain f Department of Neurology, Ulm University Hospital, Ulm, Germany g Department of Geriatric Medicine, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany h Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden Accepted 1 March 2021 Pre-press 1 April 2021 Abstract. Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 control subjects, correcting for age, gender, collection unit, and multiple testing. Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14–1.53, q = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20–1.94, q = 0.045; and FTD: FC = 1.42, 95% CI 1.10–1.83, q = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q < 0.05). Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders. Keywords: Alzheimer’s disease, frontotemporal dementia, mild cognitive impairment, neuroinflammation, proteomics 1 Theseauthors contributed equally to this work. ∗ Correspondence to: Gustaf Boström, Department of Public 564, SE-751 22 Uppsala, Sweden. Tel.: +46 18 471 4107; Fax: +46 Health and Caring Sciences, Geriatrics, Uppsala University, Box 18 471 6675; E-mail: gustaf.bostrom@pubcare.uu.se. ISSN 1387-2877 © 2021 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0). 630 G. Boström et al. / Different Inflammatory Signatures in AD and FTD INTRODUCTION astrocytosis are typically seen also in the FTD brain [13]. Mixed results have been presented regarding Alzheimer’s disease (AD) and frontotemporal de- CSF levels of inflammatory proteins in FTD. Some mentia (FTD) are two of our most common neu- studies have shown increased CSF levels of the pro- rodegenerative disorders. Whereas both diseases are inflammatory proteins TNF, MCP-1, IL-8, IL-11, and characterized by neuroinflammatory processes, we YKL-40 in FTD compared with healthy controls, have limited knowledge of how these are mirrored as well as neuroinflammatory signaling on TSPO- in the cerebrospinal fluid (CSF). PET [13–18]. In contrast, decreased CSF levels of AD is characterized by cerebral accumulation of pro-inflammatory IL-12 and increased levels of anti- amyloid-␤ (A␤) into plaques, aggregation of hyper- inflammatory transforming growth factor-␤ (TGF␤) phosphorylated tau into neurofibrillary tangles, and have also been reported in FTD [18, 19]. neuroinflammation associated with activation of mic- The primary aim of this study was to investigate the roglia and astrocytes [1]. During the disease develop- CSF signature of inflammatory proteins in AD and ment, patients pass through a stage of mild cognitive FTD, using a multiplex proximity extension assay impairment (MCI), which may occur several years (PEA). To that end, we quantified 92 such proteins, before the onset of dementia [2]. However, only preselected by the manufacturer. A secondary aim about 50% of all MCI cases progress to AD demen- was to assess if any of these proteins were altered tia, whereas the other half remains cognitively stable already at an early stage of AD. even after several years of follow-up [3]. It is today largely unknown what molecular features, other than METHODS A␤ and tau mismetabolism, that distinguish MCI patients with incipient AD from non-progressors. Participants Among different theories, neuroinflammation has been hypothesized to be such a disease determinant. This study included CSF samples from 135 pat- More specifically, temporary inflammatory reactions ients and 49 healthy controls from biobanks of three have been proposed to be beneficial in early AD medical centers (Uppsala, Sweden; Ulm, Germany; stages but may contribute to an accelerated neurode- Barcelona, Spain). The spinal taps were performed generative process if becoming chronic [4]. Further- during 2005–2018 and the following diagnoses more, many AD risk gene variants (e.g., TREM2, were represented among the patients: AD dementia CD33, and APOE) have been associated with mic- (n = 42), MCI due to AD (MCI/AD, n = 29), stable roglia dysfunction, which in turn may be implicated MCI (MCI, n = 22), and FTD (n = 42). in chronic inflammation [4]. However, current knowl- edge of inflammatory protein involvement in AD Diagnostic procedures development is limited. Several studies have evaluated neuroinflammatory All patients were subjected to a standardized inves- features in AD CSF or plasma, with diverse findings tigation at a memory disorder unit, including clinical such as decreased levels of IL-8 or increased levels assessments, caregiver interviews, neuroimaging, ne- of GFAP [5, 6]. A recent review described increases uropsychological evaluation, laboratory assessments, in eleven inflammatory proteins in AD in at least two and CSF sampling. Diagnoses of AD dementia and CSF studies, whereas only one was decreased [7]. Of MCI/AD were made according to the National Insti- the studies reviewed, only two included MCI patients, tute on Aging and Alzheimer’s Association (NIA- none of which made distinction between MCI due to AA) criteria for “probable AD dementia with AD and stable MCI [8, 9]. evidence of AD pathophysiological process” and As the second most common neurodegenerative “MCI due to AD – high likelihood”, respectively, disorder before the age of 65 [10], FTD includes while stable MCI patients fulfilled the NIA-AA “MCI the behavioral variant of frontotemporal dementia – core clinical criteria” [20, 21]. Furthermore, stable (bvFTD) as well as forms characterized by various MCI patients did not convert to AD or any other neu- degrees of language dysfunction, e.g., primary prog- rodegenerative disorder during the follow-up period ressive aphasia (PPA) and its subtypes nonfluent of 4–9 years. variant (nfvPPA), semantic variant (svPPA), and log- The FTD diagnosis was based on clinical crite- openic variant (lvPPA) [11, 12]. Similar to cel- ria in combination with characteristic patterns in lular changes in the AD brain, microgliosis and neuroimaging, resulting in an imaging supported G. Boström et al. / Different Inflammatory Signatures in AD and FTD 631 diagnosis of svPPA or “probable bvFTD” in 39 of Protein levels were measured with PEA, at 42 FTD participants [12, 22]. Of the remaining three Olink Proteomics’ laboratory in Uppsala, using the FTD patients, two were unable to undergo any imag- Olink® Inflammation panel (Olink Proteomics AB, ing examination. One of them fulfilled the clinical Uppsala, Sweden; https://www.olink.com/products/ criteria of “possible bvFTD”, while the other could inflammation/, accessed 26 September 2019) accord- not be subclassified [22]. The last FTD patient could ing to the manufacturer’s instructions. The PEA not be subclassified despite having imaging results. technology is a validated immunoassay with high sen- In summary, 35 FTD patients were diagnosed with sitivity and specificity that enables 92 analytes to be the bvFTD phenotype, five with svPPA, and two measured simultaneously, using 1 ␮L of each sample with non-specified FTD. The two non-specified FTD [24]. In brief, pairs of oligonucleotide-labeled anti- patients were classified as FTD patients rather than body probes bind to their targeted protein and, if the unspecified dementia since they showed signs and two probes are brought in close proximity to each symptoms of significant frontal lobe dysfunction, other, the oligonucleotides will hybridize in a pair- such as personality and behavioral changes together wise manner, enabling amplification with PCR. Data with loss of insight at an early stage. is quality controlled and normalized using internal The control group consisted of individuals free extension and inter-plate controls, to adjust for intra- from neurocognitive disorders, recruited at the three and inter-run variation. The final assay read-out is medical centers. Control subjects from Uppsala were presented as a Normalized Protein eXpression (NPX) cognitively healthy elderly recruited through adver- value, which is an arbitrary unit on a log2-scale tisements in a local newspaper. The controls from where a high value corresponds to a higher protein Ulm were headache patients (most commonly of the expression (i.e., an increase with 1 NPX is a doubled tension-type) without any signs of systemic inflam- value of the detectable quantity). All assay validation mation, neoplasia, or neurodegenerative disease, who data (detection limits, intra- and inter-assay precision obtained a lumbar puncture during the clinical work- data, etc.) are available on the manufacturer’s website up. The controls from Barcelona were spouses and (http://www.olink.com). children of patients from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort with normal CSF Statistical analyses markers, normal results on cognitive tests, and no signs of cognitive decline during a four-year follow- Principal component analysis (PCA) was used to up period [23]. evaluate patterns of clusters related to the different patient groups, medical centers and plates. Only pro- Standard protocol approvals, registrations, and teins detected in at least 75% of the samples were patients consents included in the analyses. Samples where the inter- nal controls deviated more than 0.3 NPX from their The collection and analyses of CSF samples were median value were excluded at this point. Linear approved by ethical review boards at the three centers regression analyses were performed using ANOVA involved (Uppsala: 2005-244, Ö 48-2005, 2013/187 F-tests, comparing mean NPX-values of AD versus and 2018/168; Ulm: 20/10; Barcelona: Colección controls, MC/AD versus controls, MCI/AD versus 16/2013). Written informed consent was collected MCI, and FTD versus controls, respectively. For the from all patients or their next of kin at the time of AD and FTD analyses, samples from all three cen- lumbar puncture. ters were included, whereas for the MCI analyses only samples from the Uppsala cohort were avail- Sample handling and measurements able. Age, sex, collection site, and plate numbers were included as confounders in the analyses. The A volume of 40–50 ␮l of each participant’s CSF Benjamini-Hochberg method was used to control the was thawed, aliquoted into microtubes and refrozen false discovery rate (FDR) caused by multiple testing. at –70◦ C. The samples were stratified according to An FDR below 5% (q-value below 0.05) was consid- research site, age, sex, and diagnosis. Next, they ered significant. A post hoc sample size calculation were allocated, using the randomization generator of was made based on a power of 95% and a signif- Microsoft Excel (v.16, Microsoft Corporation, Red- icance level of 0.05/60 (adjusting for 60 multiple mond, WA), to a position on one of three hypothetical tests, assuming 60 of 92 detectable analytes) in a two- plates with 8 × 11 wells. sample t-test, resulting in 41 samples required per 632 G. Boström et al. / Different Inflammatory Signatures in AD and FTD group to detect a between group difference beta of 0.4 deviated more than 0.3 NPX from the median of the (corresponding to a fold change [FC] of 20.4 = 1.32) internal quality control samples (supplied by the man- with a standard deviation (SD) of 0.35. The statisti- ufacturer) and were therefore excluded from further cal analyses were conducted using R version 3.6.3 analyses. (R Core Team, 2020) and the R-package ropls to The control group and the MCI/AD group had a perform the PCA analyses [25]. very similar distribution pattern of protein levels in the PCA (Fig. 1). The MCI and FTD groups deviated most from the control group, while the AD group RESULTS displayed a pattern between those of the control and FTD groups. The PCA did not reveal any major differ- The 184 study participants consisted of 90 women ences between the three medical centers, or between (48.9%) and 94 men (51.1%) with a mean ± SD age the plate IDs (Fig. 1). of 69.5 ± 9.1 years (Table 1). Women were slightly When assessing the individual analytes separately, overrepresented in the AD and MCI/AD group matrix metalloproteinase-10 (MMP-10) was signif- (59.5% and 58.6%, respectively), while the FTD icantly increased in AD compared with controls group consisted of more men (69.0%) with a slightly (FC = 1.32, 95% confidence interval [CI] 1.14–1.53, lower mean ± SD age of 64.6 ± 9.0 years (Table 1). q = 0.018, Fig. 2A), as well as between MCI/AD Amyloid-␤42 (A␤42 ) CSF levels (mean ng/L±SD) patients and controls (FC = 1.53, 95% CI 1.20–1.94, were roughly 50% lower in the AD and MCI/AD q = 0.045, Fig. 2A). It was also significantly higher group compared with the controls (AD: 415 ± 82, in the MCI/AD group compared with the MCI group MCI/AD: 439 ± 108, Controls: 899 ± 289), while the (FC = 1.38, 95% CI 1.16–1.65, q = 0.011, Fig. 2B), total-tau (t-tau) levels (mean ng/L±SD) were approx- as well as in the FTD group compared with controls imately 55–85% higher (AD: 725 ± 296, MCI/AD: (FC = 1.42, 95% CI 1.10–1.83, q = 0.020, Fig. 2C). 608 ± 235, Controls: 392 ± 233, Table 1). Com- Upon stratification by patient group and medical pared with the controls, the FTD group had similar center a trend toward higher levels of MMP-10 A␤42 and t-tau levels (FTD versus Controls, A␤42 : was observed in all three neurodegenerative disease 1025 ± 508 versus 899 ± 289, t-tau: 346 ± 156 ver- groups (AD, MCI/AD and FTD), but with varying sus 392 ± 233, Table 1), while the stable MCI group distributions among the different centers and a higher had similar A␤42 levels but roughly one third lower variability in the FTD group (Fig. 3). t-tau levels (MCI versus Controls, A␤42 : 826 ± 203 We found eleven additional proteins to be signif- versus 899 ± 392; t-tau: 265 ± 86 versus 392 ± 233, icantly increased in MCI/AD compared with MCI Table 1). Of the 92 proteins included in the assay, (q < 0.05, Table 3, Fig. 2B), six of which were growth 56 (61%) were detected in at least 75% of the CSF factors; tumor necrosis factor ligand superfamily samples. All proteins, their abbreviations, and their member 12 (TNFSF12, also known as TWEAK; 46% detectability are available in Supplementary Table 1, higher), hepatocyte growth factor or scatter factor while the type and function of the detected pro- (HGF/SF, 36% higher), programmed death-ligand 1 teins are listed in Table 2. Two of the AD samples (PD-L1, 38% higher), vascular endothelial growth Table 1 Demographics of the participants Total AD MCI/AD MCI FTD Controls Number 184 42 29 22 42 49 Age, mean (SD) 69.5 (9.1) 71.0 (6.9) 69.8 (5.0) 72.0 (5.3) 64.6 (9.0) 71.2 (12.3) Women, n (%) 90 (48.9) 25 (59.5) 17 (58.6) 11 (50) 13 (31.0) 24 (49) T-tau (ng/L), mean (SD) 482 (281) 725 (296) 608 (235) 265 (86) 346 (156) 392 (233) (n = 35) (n = 48) A␤42 (ng/L), mean (SD) 730 (389) 415 (82) 439 (108) 826 (203) 1025 (508) 899 (289) (n = 39) (n = 48) Study site, n (%) Uppsala, Swe 98 (53.3) 21 (50.0) 21 (72.4) 22 (100) 13 (31.0) 21 (42.9) Ulm, Ger 43 (23.4) 14 (33.3) 0 0 15 (35.7) 14 (28.6) Barcelona, Spa 43 (23.4) 7 (16.7) 8 (27.6) 0 14 (33.3) 14 (28.6) A␤, amyloid-␤; AD, Alzheimer’s disease; FTD, frontotemporal dementia; MCI, mild cognitive impairment, cognitively stable at the MCI level; MCI/AD, mild cognitive impairment due to Alzheimer’s disease; SD, standard deviation; T-tau, total tau. G. Boström et al. / Different Inflammatory Signatures in AD and FTD 633 Table 2 Type and function of cerebrospinal fluid proteins differing between groups Protein Type Function ADAb Enzyme, Purine metabolism, T cell differentiation. Deaminase Beta-NGFa,b Growth factor Nerve growth factor. CCL4b Chemokine Attracts NK cells, monocytes, and other immune cells. CCL19b Chemokine Attracts B and T cells. CCL23b Chemokine Highly chemotactic for resting T cells and monocytes and slightly chemotactic for neutrophils. CD5b T cell receptor Stimulation mitigate activating signals. CD6b T cell receptor T cell activation and proliferation. CD8Ab T cell receptor MHC receptor on cytotoxic T cells and a subset of NK cells. CD40b TNF-receptor Stimulates Th1 cells to induce Ig-switch and ROS-production. CD244b NK-cell receptor Mediates non-MHC-killing. CDCP1a,b Transmembrane glycoprotein, Involved in cell adhesion, cell matrix association, T cell receptor ligand and T cell activation, migration and chemotaxis. CSF-1a,b Growth factor Induces macrophage, monocyte, and microglia proliferation. CX3CL1b Chemokine Involved in adhesion, migration, and synapse pruning. CXCL1b Chemokine Involved in mitosis, inflammation, and neutrophil attraction. CXCL6b Chemokine Attracts neutrophils. CXCL10b Chemokine Attracts microglia, monocytes and T cells. CXCL11b Chemokine Attracts activated T cells. DNERb Growth factor Involved in proliferation and neurogenesis. FGF-5a,b Growth factor Regulates cell proliferation and differentiation. FGF-19b Growth factor Glucose regulator. Flt3Lb Growth factor Involved in dendritic cell proliferation. HGFa,b Growth factor Involved in angiogenesis, tumorigenesis, and tissue regeneration. IL8b Chemokine Attracts neutrophils, basophils, and T cells. IL-10RBb Cytokine receptor Forms a receptor with IFNLR1. Activates antiviral pathway upon stimulation. IL-12Bb Growth factor Stimulates T and NK cells. LIF-Ra,b Polyfunctional cytokine Induces neuronal and leukocytic differentiation. Also involved in cell survival, and proliferation. MCP-2b Chemokine Attracts monocytes, lymphocytes, basophils, and eosinophils. MMP-10a,c Matrix metalloproteinase Breakdown of extracellular matrix. PD-L1a,b B7 Family Ligand, Immunoregulator. Inhibits T cell activation and induces self-tolerence. Immune inhibitor SCFa,b Growth factor Regulates cell survival and proliferation of lymphocytes, melanocytes, mast cells and microglia. SIRT2a Sirtuin, Deacetylase Involved in cell cycle control, microtubule regulation and autophagy. Blockage promotes inflammation by NF-κB acetylation. TGF-alphab Growth factor Involved in cell proliferation, differentiation and mitosis. TNFRSF9b TNF-receptor Costimulatory receptor present in T cells, NK cells, dendritic cells, eosinophils, mast cells, and endothelial cells. TNFSF14b TNF-ligand Costimulatory ligand, activates proliferation of B and T cells. TRAILb TNF-ligand Induces apoptosis and promotes inflammation. TWEAKa,b TNF-ligand Induces apoptosis, angiogenesis, and proliferation of endothelial cells. uPAb Serine protease Mediates fibrinolysis. VEGFAa,b Growth factor Induces proliferation and migration of vascular endothelial cells. Promotes angiogenesis. Proteins are presented in alphabetical order. a Increased in patients with mild cognitive impairment due to Alzheimer’s disease (MCI/AD) compared with cognitively stable patients with mild cognitive impairment (MCI); b Decreased in patients with frontotemporal dementia (FTD) compared with healthy controls; c Increased in patients with FTD, AD dementia, and MCI/AD compared with healthy controls. factor A (VEGFA, 34% higher), nerve growth factor 1 (CSF-1, 22% higher), and sirtuin 2 (SIRT2, 34% beta (NGF, 23% higher), stem cell factor (SCF, 37% higher). higher), fibroblast growth factor 5 (FGF5, 34% hig- Thirty-six of the proteins were decreased in FTD her), leukemia inhibitory factor receptor (LIFR, 27% compared with controls (q < 0.05, Table 3, Fig. 2C), higher), CUB domain-containing protein 1 (CDCP1, including all the eleven proteins increased in MCI/ 29% higher), macrophage colony stimulating factor AD compared with MCI, except SIRT2, whereas only 634 G. Boström et al. / Different Inflammatory Signatures in AD and FTD Fig. 1. Principal component analysis (PCA) of cerebrospinal fluid protein levels. The PCA is divided into (A) patient groups, (B) medical centers, and (C) number of plate sent for analysis. Each ellipse represents 95% of respective group’s samples. D) The detected proteins’ contribution to principal component 1 (PC1) and 2 (PC2). AD, Alzheimer’s disease dementia; C, healthy controls; FTD, frontotemporal dementia; MCI, mild cognitive impairment, cognitively stable at the MCI level; MCI/AD, mild cognitive impairment due to Alzheimer’s disease. Fig. 2. Volcano plots of group differences in cerebrospinal fluid proteins. The plots show fold change and p-values of inflammatory proteins in cerebrospinal fluid from (A) patients with AD and MCI/AD compared with healthy controls, (B) patients with MCI/AD compared with patients with MCI, and (C) patients with FTD compared with healthy controls. The proteins were analyzed using ANOVA F-tests, adjusting for age, sex, plate ID, and study site (A, C), and age, sex, and plate ID (B), respectively. Proteins with a false discovery rate below 0.05 are labeled. AD, Alzheimer’s disease dementia; C, healthy controls; FTD, frontotemporal dementia; MCI, mild cognitive impairment, cognitively stable at the MCI level; MCI/AD, mild cognitive impairment due to Alzheimer’s disease. MMP-10 was increased. Of the 36 decreased proteins, DISCUSSION eleven were growth factors, ten chemokines, and five related to TNF-signaling. In addition, several of the In this study, we have compared CSF levels of decreased proteins were related to T cell function, 56 different inflammation-related proteins between including T cell receptors, T cell receptor ligands, groups of patients with AD, MCI/AD, MCI, FTD, growth factors and chemokines (Table 2). and healthy controls. Several findings emerge. Firstly, G. Boström et al. / Different Inflammatory Signatures in AD and FTD 635 Table 3 Differentially expressed cerebrospinal fluid proteins, in addition to MMP-10 Comparison Protein Beta Fold change p q (95% CI) MCI/AD Beta-NGF 0.293 1.23 (1.08, 1.39) 0.00268 0.0250 versus MCIa CDCP1 0.369 1.29 (1.08, 1.54) 0.00640 0.0359 CSF-1 0.283 1.22 (1.06, 1.40) 0.00706 0.0359 FGF-5 0.417 1.34 (1.10, 1.62) 0.00471 0.0330 HGF 0.446 1.36 (1.16, 1.61) 0.000511 0.0109 LIF-R 0.347 1.27 (1.07, 1.50) 0.00590 0.0359 PD-L1 0.469 1.38 (1.16, 1.66) 0.00078 0.0109 SCF 0.453 1.37 (1.11, 1.68) 0.00400 0.0320 SIRT2 0.426 1.34 (1.08, 1.67) 0.00842 0.0393 TWEAK 0.549 1.46 (1.21, 1.76) 0.000187 0.0105 VEGFA 0.426 1.34 (1.22, 1.61) 0.00199 0.0223 FTD versus Cb ADA –0.334 0.793 (0.657, 0.957) 0.0163 0.0305 Beta-NGF –0.306 0.809 (0.722, 0.907) 0.000393 0.00550 CCL4 –0.363 0.777 (0.660, 0.916) 0.00305 0.0122 CCL19 –0.944 0.520 (0.385, 0.703) 0.0000438 0.00245 CCL23 –0.280 0.824 (0.706, 0.960) 0.0140 0.0279 CD5 –0.246 0.843 (0.733, 0.970) 0.0175 0.0306 CD6 –0.226 0.855 (0.747, 0.978) 0.0233 0.0384 CD8A –0.377 0.770 (0.622, 0.954) 0.0172 0.0306 CD40 –0.288 0.819 (0.722, 0.930) 0.00236 0.0112 CD244 –0.245 0.844 (0.750, 0.949) 0.00528 0.0164 CDCP1 –0.256 0.837 (0.721, 0.973) 0.0210 0.0357 CSF-1 –0.273 0.827 (0.743, 0.921) 0.000745 0.00695 CX3CL1 –0.391 0.763 (0.648, 0.898) 0.00140 0.00784 CXCL1 –0.433 0.741 (0.601, 0.913) 0.00545 0.0164 CXCL6 –0.535 0.690 (0.557, 0.855) 0.000929 0.00702 CXCL10 –0.603 0.658 (0.505, 0.858) 0.00239 0.0112 CXCL11 –0.483 0.715 (0.566, 0.904) 0.00557 0.0164 DNER –0.054 0.963 (0.932, 0.955) 0.0260 0.0415 FGF-5 –0.362 0.778 (0.675, 0.897) 0.000724 0.00695 FGF-19 –0.374 0.772 (0.630, 0.945) 0.0129 0.0278 Flt3L –0.189 0.877 (0.792, 0.971) 0.0124 0.0278 HGF –0.304 0.810 (0.702, 0.935) 0.00440 0.0154 IL8 –0.336 0.792 (0.659, 0.952) 0.0136 0.0279 IL-10RB –0.225 0.856 (0.756, 0.969) 0.0145 0.0281 IL-12B –0.212 0.863 (0.756, 0.986) 0.0308 0.0466 LIF-R –0.226 0.855 (0.758, 0.965) 0.0117 0.0273 MCP-2 –0.397 0.759 (0.624, 0.923) 0.00631 0.0177 PD-L1 –0.439 0.738 (0.629, 0.865) 0.000274 0.00550 SCF –0.318 0.802 (0.693, 0.929) 0.00361 0.0135 TGF-alpha –0.275 0.827 (0.731, 0.935) 0.00282 0.0121 TNFRSF9 –0.331 0.795 (0.673, 0.938) 0.00728 0.0194 TNFSF14 –0.187 0.878 (0.782, 0.987) 0.0292 0.0454 TRAIL –0.173 0.887 (0.809, 0.973) 0.0115 0.0273 TWEAK –0.360 0.779 (0.671, 0.904) 0.00129 0.00784 uPA –0.326 0.798 (0.699, 0.910) 0.00100 0.00702 VEGFA –0.400 0.758 (0.654, 0.878) 0.000342 0.00550 Proteins are presented in alphabetical order. A false discovery rate, q < 0.05 was considered significant. a Analyzed using ANOVA F-tests, adjusted for age, sex and plate ID; b Analyzed using ANOVA F-tests, adjusting for age, sex, plate ID, and Study site; AD, Alzheimer’s disease dementia; C, healthy controls; MCI, patients with mild cognitive impairment, cognitively stable at the MCI level; MCI/AD, mild cognitive impairment due to Alzheimer’s disease; FTD, frontotemporal dementia. levels of MMP-10 were found to be increased in AD, remained cognitively stable after several years of MCI/AD, and FTD patients, compared with healthy follow-up. Notably, none of the proteins analyzed controls. Secondly, MMP-10 and eleven other inflam- were found at decreased levels in the AD or the matory proteins were elevated in CSF from patients MCI/AD group. Thirdly, and in stark contrast to the with MCI/AD, as compared with MCI subjects that pattern in the AD and MCI/AD groups, 36 of the 636 G. Boström et al. / Different Inflammatory Signatures in AD and FTD the BBB may lead to the influx of plasma proteins into CNS, which in turn may increase the level of neurotoxicity and accelerate the neurodegenerative process [30]. As for the increase of the eleven other inflam- mation-related proteins in MCI/AD compared with stable MCI subjects, several have previously been implicated in AD or in other neurodegenerative dis- eases. After reviewing the putative functions of these eleven proteins, we have divided them into pro- or anti-inflammatory proteins (Table 2). The pro-inflammatory proteins include tumor Fig. 3. Box plot of MMP-10 levels stratified by patient group and necrosis factor (TNF)-related weak inducer of apop- medical center. AD, Alzheimer’s disease dementia; C, healthy tosis (TWEAK), vascular endothelial growth factor controls; FTD, frontotemporal dementia; MCI, mild cognitive impairment, cognitively stable at the MCI level; MCI/AD, mild A (VEGFA, or VEGF), fibroblast growth factor 5 cognitive impairment due to Alzheimer’s disease; MMP-10, matrix (FGF5), CUB domain-containing protein 1 (CDCP1, metalloproteinase-10; NPX, normalized protein expression. also known as CD318) and macrophage colony stim- ulating factor (M-CSF, also known as CSF-1). Many inflammatory proteins were found at decreased lev- of these are involved in regulation of blood vessel els in the FTD group, compared with healthy controls. permeability, induction of angiogenesis and/or mobi- Apart from MMP-10, none of the markers were found lization or activation of pro-inflammatory cells or at increased levels in the FTD patients. cytokines. In models of multiple sclerosis and amy- Increased CSF levels of MMP-10 have previously otrophic lateral sclerosis, endothelial cells respond been reported in AD and have also been found to cor- to stimulation by TWEAK through neuroinflamma- relate with increased levels of tau and p-tau [26]. A tion and BBB-disruption by upregulating MMP-9, recently published study, using the same panel, also increasing the level of pro-inflammatory cytokines found increased levels of MMP-10 in CSF samples and attracting monocytes [31]. Increased levels of of AD and MCI/AD patients compared with healthy VEGFA have been associated with neurogenesis, controls [27]. To our knowledge, the current study learning, and neuroprotective effects, but may also is the first to show increased CSF levels of MMP- increase vascular permeability and be neurotoxic in 10 in FTD patients. The MMPs comprise a group of high concentrations [32]. FGF5 may be involved in enzymes that help to increase cell motility by degrad- reactive astrocytes, as FGF5 knock-out mice have ing parts of the extracellular matrix. Increased activity been shown to have a reduced number of GFAP- of these enzymes has previously been associated with positive astrocytes in midbrain tegmentum [33]. the disruption of the blood-brain barrier (BBB) [26]. Blockage of the T cell receptor CD6 and its ligands, The levels of MMPs are regulated by tissue inhibitors such as CDCP1, have shown protection from disease of metalloproteinases (TIMPs), which may in turn in mouse models of psoriasis and multiple sclerosis be reduced by cerebral microbleeds [26]. Cerebral [34]. M-CSF, or CSF-1, binds to a receptor (CSF-1R) microbleeds are common in neurocognitive disorders that is located on microglia. In a mouse model, block- and have been found to increase the risk of dementia, ing the CSF-1R has led to a blockage of microglial including AD, possibly by activating a neuroinflam- activation and a shift from pro-inflammatory to anti- matory and neurodegenerative process in microglia inflammatory microglia [35]. through fibrinogen-induced spine elimination [28]. The remaining six anti-inflammatory proteins Previously, a combination of eight proteins, includ- with increased CSF levels in MCI/AD compared ing TIMP-1, MMP-9, and MMP-2, but not MMP-10, with MCI include hepatocyte growth factor (HGF), was shown to discriminate patients with subcortical programmed death-ligand 1 (PD-L1), nerve growth vascular disease from patients with AD, with a sensi- factor (NGF), stem cell factor (SCF), leukemia inhibi- tivity of 89% and a specificity of 90% [29]. MMP-10 tory factor (LIF), and sirtuin 2 (SIRT2). Many of these was also increased in both of these patient groups proteins are involved in tissue regeneration, immune compared with controls [29]. Thus, the increased CSF cell inhibition, or alterations of immune cells to anti- levels of MMP-10 may be a result of a disrupted BBB inflammatory phenotypes (Table 2). Previous studies in the AD, MCI/AD, and FTD brain. Disruption of have found increased levels of HGF in astrocytes and G. Boström et al. / Different Inflammatory Signatures in AD and FTD 637 microglia surrounding senile plaques in the AD brain Both our results and previous studies indicate [36]. Blockage of PD-L1, or its receptor (PD-1), has that elevated CSF levels of inflammatory proteins been used in cancer therapy to activate the T cell is an early feature in AD pathogenesis [27]. In mediated immune response, which in a mouse model postmortem studies as well as in studies of neu- of tauopathy has led to an increased recruitment of roinflammatory translocator protein (TSPO) positron circulating monocytes to the brain and the rescue of emission tomography (PET), inflammation has been neurons [37]. Previous studies have implicated a mis- implicated at early AD stages [44, 45]. Moreover, match in NGF metabolism in AD, where higher levels it has been suggested to be involved in the propa- of MMPs have been associated with an increased gation of tau pathology in AD, increasing linearly degradation of NGF and an increase in loss of cholin- throughout the disease and reaching the highest lev- ergic neurons [38]. Microglia exposed for SCF have els in late stages [44, 45]. Some TSPO PET studies shown an anti-inflammatory phenotype in vitro [39]. have noted an early inflammatory peak in MCI/AD, Intracellular signaling cascades in neurons and oligo- with a subsequent decline before the inflammation dendrocytes, caused by LIF, leads to neurosurvival. It reaches even higher levels in AD dementia [45, 46]. also alters immune cells to anti-inflammatory pheno- In our study, there was a tendency toward higher types [40]. Several studies have observed a positive levels of inflammatory proteins in MCI/AD than in effect of blocking SIRT2, both in models of Parkin- AD dementia CSF (Fig. 2A), indicating that the dif- son’s disease and AD, which stabilizes microtubules ferent methods might measure different aspects of and increases the autophagic breakdown of accu- neuroinflammation. This contrast seems to be espe- mulated proteins [41]. Which of these mechanisms cially prominent in FTD, where increased levels of that are relevant in the pathogenesis of early AD inflammation has been found with TSPO PET, while and their internal interactions remain to be deter- the levels of inflammatory proteins were dramatically mined. It is noticeable that more proteins differed lower in the present study [13]. As discussed in other when comparing MCI/AD with MCI than when com- studies, TSPO PET may not be able to differ between paring MCI/AD with controls. These results seem to activated microglia of pro- or anti-inflammatory phe- be partly caused by a general decrease in CSF inflam- notype [45, 46]. It seems that more than one pro- or matory proteins in stable MCI patients. However, as anti-inflammatory phenotype of microglia may exist the MCI groups were rather small, it may be a coinci- and that the current measurements focusing on the dental observation and larger studies are thus needed morphology or the activity of microglia may miss to to confirm these data. differentiate between those phenotypes. Another main finding of this study is the general A limitation of this study is the small sample sizes decrease of inflammatory markers in CSF of FTD in the MCI/AD and MCI groups, which may have brains, including almost all of the proteins found to be affected the precision of the results in these groups. increased in MCI/AD compared with MCI. This find- Still, the sample sizes in the AD, FTD, and control ing indicates that the pathogenic processes involved groups were robust and, although sample sizes from in FTD may affect microglial function, inflammation the individual study sites were too small to be inves- and neurodegeneration in a different manner than in tigated separately, the general trends of increased AD. An interesting observation is that several of the MMP-10 levels in AD and FTD, as well as the dec- decreased proteins were related to T cell function, reased levels of inflammatory proteins in FTD, were a research area that has not been much explored in similar between the study sites. Whereas the methods FTD. to diagnose AD and FTD were the same between the A combination of CSF t-tau and A␤42 has been sites, the control groups were recruited differently, shown to have a sensitivity of 95% and a specificity which affects comparability and generalizability of of 83% for detection of incipient AD in patients with the results. However, all subjects in the control group MCI [42]. In addition, the ratio of t-tau/A␤42 gives a were cognitively healthy and represent a group free high sensitivity and specificity when comparing AD of neurocognitive disease. As another limitation we to FTD [43]. However, this ratio is not as useful in dis- did not have access to genetic information of the tinguishing FTD from healthy controls [43]. The use AD or FTD patients. Since FTD is a heteroge- of inflammatory biomarkers in CSF can potentially neous disease where 30–50% have a familial form, aid clinicians in predicting which MCI cases will it would be of interest to see if the observed dif- progress to AD dementia, as well as distinguishing ferences relate to mutations in specific genes, such patients with FTD from AD. as microtubule-associated protein tau (MAPT), pro- 638 G. Boström et al. / Different Inflammatory Signatures in AD and FTD granulin (PGRN), or C9orf72 [47]. In general, the AD SUPPLEMENTARY MATERIAL and FTD groups had higher levels of MMP-10, but the within-group variation was large, indicating that The supplementary material is available in the different phenotypes or subgroups may exist within electronic version of this article: https://dx.doi.org/ these diseases, which could be attributable to disease 10.3233/JAD-201565. specific mutations. 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