Inflamatory Rol

GeroScience
https://doi.org/10.1007/s11357-022-00556-w
1
REVIEW
2 Role of inflammatory markers in the diagnosis of vascular

3 contributions to cognitive impairment and dementia:
4 a systematic review and meta‑analysis
5 Carlo Custodero · Alessandro Ciavarella · Francesco Panza · Davide Gnocchi ·
6 Gennaro M. Lenato · Juhan Lee · Antonio Mazzocca · Carlo Sabbà ·
7 Vincenzo Solfrizzi
F
O
8 Received: 6 September 2021 / Accepted: 23 March 2022
9 © The Author(s) 2022, corrected publication 2022
O
Abstract Vascular contribution to cognitive impair- in differential diagnosis between VaD and Alzhei-
PR
10 20
11 ment and dementia (VCID) is a clinical label encom- mer’s disease (AD), and assessed their prognostic 21
12 passing a wide range of cognitive disorders progress- value on predicting VaD incidence. We collected 22
13 ing from mild to major vascular cognitive impairment literature until January 31, 2021, assessing three 23
14 (VCI), which is also defined as vascular dementia inflammatory markers [interleukin(IL)-6, C-reactive 24
ED
15 (VaD). VaD diagnosis is mainly based on clinical protein (CRP), tumor necrosis factor (TNF)-α] from 25
16 and imaging findings. Earlier biomarkers are needed blood or cerebrospinal fluid (CSF) samples. Thirteen 26
17 to identify subjects at risk to develop mild VCI and cross-sectional and seven prospective studies were 27
18 VaD. In the present meta-analysis, we comprehen- included. Blood IL-6 levels were cross-sectionally 28
IS
19 sively evaluated the role of inflammatory biomarkers significantly higher in people with VaD compared to 29
AD patients (SMD: 0.40, 95% CI: 0.18 to 0.62) with 30
low heterogeneity (I2: 41%, p = 0.13). Higher IL-6
EV
31
A1 Supplementary Information The online version levels were also associated to higher risk of incident 32
contains supplementary material available at https://doi.
A2
org/10.1007/s11357-022-00556-w.
VaD (relative risk: 1.28, 95% CI: 1.03 to 1.59, I2: 33
A3
0%). IL-6 in CSF was significantly higher in people 34
C. Custodero · A. Ciavarella · D. Gnocchi · G. M. Lenato · with VaD compared to healthy subjects (SMD: 0.77,
R
A4 35
A5 A. Mazzocca · C. Sabbà · V. Solfrizzi (*) 95% CI: 0.17 to 1.37, I2: 70%), and not compared to 36
Dipartimento Interdisciplinare di Medicina, Clinica
A6 AD patients, but due to limited evidence and high 37
A7 Medica e Geriatria “Cesare Frugoni”, University of Bari
A8 Aldo Moro, Bari, Italy inconsistency across studies, we could not draw defi- 38
A9 e-mail: vincenzo.solfrizzi@uniba.it nite conclusion. Higher blood IL-6 levels might rep- 39
resent a useful biomarker able to differentiate people 40
A. Ciavarella
A10 with VaD from those with AD and might be corre- 41
A11 Fondazione IRCCS Ca’ Granda—Ospedale Maggiore
A12 Policlinico, A. Bianchi Bonomi Hemophilia lated with higher risk of future VaD. 42
A13 and Thrombosis Center, Milan, Italy

Keywords Vascular contributions to cognitive 43
F. Panza
A14 impairment and dementia · Alzheimer’s disease · 44
A15 Population Health Unit—“Salus In Apulia Study”,
A16 National Institute of Gastroenterology “Saverio de Bellis”, Interleukin-6 · C-reactive protein · Tumor necrosis 45
A17 Research Hospital, Castellana Grotte, Bari, Italy factor-α 46
A18 J. Lee
A19 Department of Psychiatry, Yale University School
A20 of Medicine, New Haven, CT, USA
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Journal : Medium 11357 Article No : 556 Pages : 20 MS Code : 556 Dispatch : 22-7-2022
GeroScience
47 Introduction To date, no specific circulating biomarker is availa- 95

ble in the diagnosis of VCID [9]. Over the last several 96
48 Vascular contributions to cognitive impairment and years, there has been growing interest in addressing 97
49 dementia (VCID) are conditions arising from vascular the relationship between inflammation, cardiovas- 98
50 diseases or abnormalities that result in a wide range cular diseases, and cognitive dysfunction [10]. It is 99
51 of cognitive disorders progressing from mild to major becoming clear that inflammation may have a role in 100
52 vascular cognitive impairment (VCI), which is also the pathogenesis of dementia. As already reviewed, 101
53 defined as vascular dementia (VaD) [1, 2]. Among the promising perspectives came from inflammatory bio- 102
54 different forms of dementia, VaD is considered the markers in predicting risk of overall dementia [11]. 103
55 second most common cause after Alzheimer’s disease Previous meta-analyses showed that increased circu- 104
56 (AD), accounting approximately the 20% of dementia lating interleukin(IL)-6 and C-reactive protein (CRP) 105
57 cases [2]. Its prevalence is estimated to be 0.6–2.1% levels were associated to higher risk of dementia from 106
in subjects aged over 65 years [3], and it increases all causes, but not to AD [12, 13]. These studies did
F
58 107
59 with age, up to 4.8% in those over 85 years [4]. Cer- not test the role of inflammatory biomarkers in dif- 108
O
60 ebrovascular disease is the main etiological feature ferential diagnosis between VaD and AD, and did 109
61 of VCID, independent of the underlying mechanism not include inflammatory markers from cerebrospi- 110
nal fluid (CSF). We hypothesized that inflammatory
O
62 (e.g., multiple or single territorial or small infarcts, 111
63 strategic infarcts) and the occurrence of stroke symp- biomarkers may be increased to a greater extent in 112
toms [5]. However, it is becoming clear that white VCID compared to AD; thus, the goal of this review
64
65
66
matter damage and cognitive impairment occur also
in absence of stroke symptoms, suggesting that often
PR was to examine the diagnostic and predictive power
of selected inflammatory biomarkers for VCID.
113
114
115
67 there is a silent and slow progression of the disease
68 due to involvement of cerebral small vessels [6]. For
ED
69 example, VCID can be detected in subjects suffer- Methods 116

70 ing from arrhythmias (e.g., atrial fibrillation) or other
71 vascular risk factors (e.g., tobacco use, hypertension, Search strategy and study selection 117
72 obesity, hyperlipidemia, diabetes, hyper-coagulation),
IS
73 but without stroke history. In addition, vascular mani- The present systematic literature review and meta- 118
74 festations in older adults often fluctuate over time, analysis followed the requirements of the PRISMA 119
resulting in diagnostic delay and ineffective treat- statement [14]. An a priori protocol was established
EV
75 120
76 ments [7]. and registered on PROSPERO, an international pro- 121
77 The main cerebrovascular signs of VCID are spective register of systematic reviews (http://www. 122
78 brain atrophy, white matter hyperintensities (WMH) crd.york.ac.uk/PROSPERO; registration number: 123
lesions, infarctions, and hemorrhages. Indeed, imag- CRD42021268548).
R
79 124
80 ing techniques (e.g., magnetic resonance imaging or Two study authors (C.C. and A.C.) independently 125
81 computed tomography) represent an essential step in conducted a systematic search of the databases MED- 126
82 the diagnosis and evaluation of disease progression. LINE, PubMed, Scopus, Web of Science, and Google 127
83 However, evidence at neuroimaging is already a sign Scholar until January 31, 2021. Search terms included 128
84 of advanced stage of disease and non-reversible brain combinations of the following keywords: (“C-reac- 129
85 damage. As for the definition of AD with introduc- tive protein” OR “interleukin-6” OR “tumor necro- 130
86 tion of amyloid, tau, neurodegeneration (AT[N]) sys- sis factor-α” OR “inflammation” OR “inflammatory 131
87 tem [8], also for VCID, there is a need to change the marker”) AND ((“blood” AND “vessels”) OR “blood 132
88 paradigm traditionally based on clinical history and vessels” OR “vascular”)) AND (“cognitive impair- 133
89 signs and symptoms of the disease, toward a biologi- ment” OR “dementia”). To be included in the present 134
90 cal framework founded on early biomarkers able to meta-analysis, studies had to be observational with 135
91 predict development of VCID. This approach could either cross-sectional or longitudinal design. Studies 136
92 allow the recognition of subjects at risk in a preclini- were required to meet the following inclusion crite- 137
93 cal phase and timely the implementation of potential ria: (1) conducted in humans; (2) assessed at least 138
94 preventive strategies. one specific inflammatory marker in serum, plasma 139
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140 or CSF; (3) including subjects with some form of by revision and consultation with a senior author 185
141 VCID; (4) written in the English language. In addi- (V.S.). 186
142 tion, studies with the following characteristics were
143 excluded: (1) interventional studies; (2) with not clear Statistical analysis 187
144 differentiation among dementia subtypes; (3) lack of
145 comparison group; (4) prospective studies including For studies with cross-sectional design, each study’s 188
146 subjects with dementia at baseline; (5) autoptic stud- effect size, or standardized mean difference (SMD), 189
147 ies. Articles were initially screened based on title and was calculated by comparing mean and standard devi- 190
148 abstract by two study authors (C.C., and A.C.), with ation of inflammatory biomarkers, between VaD and 191
149 the full text sought if the abstract did not provide control or AD groups [16]. If the data were reported 192
150 sufficient information. Reference lists of the articles as median and interquartile range, the correspondent 193
151 were reviewed to identify additional relevant articles. mean and standard deviation were estimated using 194
Disagreement was resolved by discussion or in con- the method developed by Wan and colleagues [17].
F
152 195
153 sultation with a senior author (V.S.). We contacted In accordance with convention, effect sizes were clas- 196
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154 the authors of primary studies to obtain any missing sified as small (0.2), moderate (0.5), and large (0.8) 197
155 information. [18]. For studies with longitudinal design, study-spe- 198
cific risk estimates were extracted from each article,
O
199
156 Data extraction and log risk estimates were weighted by the inverse of 200
their variances to obtain a pooled risk estimate. The
PR
201
157 The following details were extracted from each study: primary analyses combined ln RR associated with 202
158 first author’s name, publication year and country, one-unit change in inflammatory markers. Studies 203
159 sample size, details of study population (mean age, were combined using the DerSimonian and Laird ran- 204
160 health status), study duration, study design, assessed dom-effects model, which considers both within- and 205
ED
161 inflammatory markers, definition of dementia diagno- between-study variations [16]. Heterogeneity across 206
162 sis, potential confounders that were considered in the studies was estimated by I2 statistic. It measures per- 207
163 analysis and main results. For prospective studies, we centage of variation that is caused by heterogeneity 208
164 extracted the reported effect estimates (relative risk between studies, and is larger when heterogeneity 209
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165 (RR) or hazard ratio (HR)) and the corresponding increases [16]. Sensitivity analyses were performed to 210
166 95% confidence interval (CI) derived from the most investigate the influence of each individual study on 211
fully adjusted model for potential confounders if stud- the overall meta-analysis summary estimate and the
EV
167 212
168 ies reported several multivariable-adjusted RRs. validity of the effect size. Further sensitivity analysis 213
was performed to determine the robustness of find- 214
169 Risk of bias assessment ings by excluding studies with poor-quality assess- 215
ment (NOS score < 7). Funnel plots and Egger’s tests
R
216
170 The quality of the studies was assessed using appro- were utilized to detect bias in meta-analyses [16]. 217
171 priate tool for observational studies: the Newcas- Statistical analyses were performed in RevMan 5.4 218
172 tle–Ottawa Quality Assessment Scale (NOS) [15]. (The Cochrane Collaboration, Oxford, England) and 219
173 Two study authors (A.C. and D.G.) assigned a rat- STATA 14.0 software (StataCorp LP, College Sta- 220
174 ing, using stars, based on three domains: selection of tion, TX, USA). Each p value is based on two-sided 221
175 study population (0–4 stars), comparability of study alternative hypothesis, and a level of 0.05 or below 222
176 groups (0–2 stars), ascertainment of outcome (for was considered statistically significant. 223
177 cohort studies) or exposure (for case–control stud-
178 ies) (0–3 stars). The final NOS score for each study
179 ranges from 0 stars (lowest quality) to 9 stars (highest Results 224
180 quality), with studies scoring 0–3 stars judged as low
181 quality, those between 4 and 6 as medium quality, and Search results and study selection 225
182 those between 7 and 9 considered to be of high qual-
183 ity. Discrepancies in the evaluation were solved by Details about the study selection process are shown 226
184 discussion. The reliability of assessment was ensured in Fig. 1. A total of 2,657 articles were identified and 227
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Fig. 1 PRISMA flowchart

Records identified through
of identification and selec-
Identification
MEDLINE, Scopus, Web of
tion of eligible studies Science, Google Scholar searching
(n= 4,811)
Records duplicates removed

(n= 2,154)
Screening
Records excluded:
Records screened Irrelevant articles (n= 2,032)
(n= 2,657) Reviews (n= 183)
Preclinical studies (n= 166)
Intervention studies (n= 39)
F
O
Full-text articles excluded with
Eligibility
Full-text articles assessed for reasons:

eligibility No inflammatory markers (n= 71)
No VCID data (n= 95)
O
(n= 237)
No control group/not free of dementia
at baseline (n= 29)
Post-mortem studies (n= 6)
PR Missing data (n= 11)

No full text (n= 5)
Included
Studies included in quantitative

synthesis (meta-analysis)
(n= 20)
ED
228 screened. Two thousand four hundred twenty papers studies as the major concerns for potential sources of 248
IS
229 were excluded on the basis of titles and abstracts bias (Supplementary Table 1). 249
230 and full text of 237 papers were reviewed. Other 217
studies were excluded for absence of investigated Blood inflammatory markers
EV
231 250
232 inflammatory markers, lack of information about any
233 form of VCID, absence of comparison group, inclu- Interleukin‑6 and vascular dementia 251
234 sion of subjects with dementia in prospective cohort
studies, missing data, or not availability of full text. Six studies investigated serum or plasma IL-6 levels
R
235 252
236 Overall, 20 studies were eligible for meta-analysis, in 311 subjects with VaD compared to 355 healthy 253
237 13 case–control studies [19–31] (Table 1), and seven controls [19–21, 27–29]. IL-6 levels were sig- 254
238 cohort studies [32–38] (Table 2). Seventeen articles nificantly higher in people with VaD compared to 255
239 analyzed inflammatory biomarkers on sera or plasma healthy subjects (SMD: 0.75, 95% CI: 0.38 to 1.13) 256
240 [19–22, 25–27, 29–38], two on CSF [23, 24], and one with evidence of high heterogeneity across the studies 257
241 on both blood and CSF [28]. (I2 = 78%, p < 0.001) (Fig. 2A). No small study effect 258
was detected at Egger’s test (p = 0.475) (Supplemen- 259
tary Fig. 1). In a sensitivity analysis, we excluded the 260
242 Quality assessment study by Zhang and colleagues [19], which deter- 261
mined asymmetry at funnel plot. The levels of IL-6 262
243 We evaluated distribution of the risk of bias across remained still significantly higher in VaD patients 263
244 the 20 studies included in the quantitative synthe- compared to controls (SMD: 0.57, 95% CI: 0.33 to 264
245 sis. The quality of the included studies ranged from 0.81), but the heterogeneity was reduced (I2 = 42%, 265
246 medium to high, with comparability for case–con- p = 0.14). Results were confirmed also removing the 266
247 trol study and ascertainment of outcome for cohort studies with low-quality assessment at NOS [19, 20, 267
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Table 1 Characteristics of cross-sectional studies investigating relationship between inflammatory markers and vascular dementia
Study (country) Population Sample size Mean age Inflammatory bio- Covariates Diagnostic criteria Main results
markers
GeroScience
Zhang, 2017 (China) Subjects with VCI VaD: 30 65.7 y CRP, IL-6, TNF-α - VaD: MoCA, CDR, Higher CRP, IL-6 and
with no dementia, Mild VCI: 30 [serum] ADL and HIS TNF-α in VaD vs
VaD and cog- CON: 30 MRI scan mild VCI or CON
Journal : Medium 11357

nitively healthy (p < 0.05)
(CON)
Dukic, 2016 (Croatia) Patients older than VaD: 67 73.0 y CRP, IL-6 [serum] - VaD: NINDS- Higher IL-6 in VaD vs
60 years with MCI: 48 AIREN criteria AD, MCI or CON
AD, VaD, MCI or AD: 70 AD: NIA-AA 2011 (p = 0.014)
cognitively healthy CON: 50 criteria Lower CRP in AD
Article No : 556
(CON) MCI: Petersen’s
criteria
R CT scan
Uslu, 2012 (Turkey) Newly diagnosed, VaD: 16 68.4 y IL-6, TNF-α [serum] - AD: NINCDS- IL-6 and TNF-α levels
randomly chosen AD: 28 ADRDA criteria did not differ sig-
Pages : 20
AD, VaD patients CON: 23 VaD: NINDS- nificantly across AD,
and or cognitively AIREN criteria VaD and CON
EV
healthy (CON)
Li, 2010 (Germany) Community dwelling VaD: 16 78.5 y hs-CRP [serum] - AD: NINCDS- Trend toward higher
subjects with AD, MCI: 17 ADRDA criteria hs-CRP in all disease
VaD, cognitive AD: 28 VaD: NINDS- groups (AD, VaD,
IS
impairment, or CON: 22 AIREN criteria MCI) vs CON
MS Code : 556
cognitively healthy MCI: Petersen’s
(CON) criteria
Jia, 2005 (China) Hospitalized patients VaD: 38 64.2 y IL-1α, IL-1β, IL-2, - AD: NINCDS- Higher CSF IL-6 in
ED
with AD, VaD, or AD: 39 IL-6, TNF-α, T-tau, ADRDA criteria AD and VaD vs
cognitively healthy CON: 35 P-tau, Aβ1–42 VaD: NINDS- CON (p < 0.01), no
cases with periph- [CSF] AIREN criteria significant difference
eral nerve diseases between AD and
(CON) VaD
Higher CSF TNF-α
PR
in AD vs CON
(p < 0.01), and lower
O
O vs VaD (p < 0.01)
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Table 1 (continued)
markers
13
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Wada-Isoe, 2004 Patients with AD, VaD: 11 69.0 y IL-6 [CSF] - AD: DSM-III-R, Higher CSF IL-6

(Japan) VaD, CVND, and AD: 26 NINCDS-ADRDA in VaD vs AD
other neurological CVND: 11 criteria and HIS ≤ 4 (p < 0.01) or CON
disorders without CON: 21 VaD: DSM-III-R, (p < 0.01)
cognitive impair- ADDTC criteria
ment (CON) and HIS ≥ 7
CT scan or MRI and
R
Article No : 556
SPECT
Paganelli, 2002 Community dwelling VaD: 18 76.7 y IL-1β, TNFα [serum] - AD: NINCDS- Lower TNF-α in
(Italy) subjects with AD, AD: 36 (25 mild AD, ADRDA criteria mild-moderate
VaD or mixed 11 severe AD) VaD: NINDS- AD vs severe AD
EV
dementia MIX: 16 AIREN criteria (p < 0.001), VaD
CT or MRI scan (p < 0.001) and MIX
Pages : 20
(p < 0.001)
Lower TNF-α/IL-1β
IS
ratio in mild-moder-
ate AD vs VaD and
MIX
De Luigi, 2001 (Swit- Patients with dif- VaD: 7 Not reported TNF-α, IL-1β, sTNF- - VaD: modified Higher TNF-α, sTNF-
ED
zerland) ferent types of AD: 44 RI, IL-1Ra, IL-10 HIS > 4 RI in VaD vs CON
MS Code : 556
dementia, cognitive MIX: 10 [plasma] AD: NINCDS- (p < 0.001)
impairment, or Uncertain dementia: ADRDA criteria After LPS stimulus
cognitively healthy 18 reduced produc-
(CON) MCI: 12 tion of TNF-α in all
CON: 42 dementia groups and
PR
of IL-10 in VaD
Zuliani, 2007 (Italy) Patients with AD, VaD: 80 76.4 y IL-6, TNF-α, IL-1β, Age, gender, coro- AD: NINCDS- Higher IL-1β in VaD,
O
VaD, CDND, and AD: 60 IL-10 [serum] nary heart disease, ADRDA criteria AD, and CDND vs
cognitively healthy CVND: 40 diabetes, hyperten- VaD: NINDS- CON (p < 0.005)
(CON) CON: 42 sion, smoking, and AIREN criteria Higher TNF-α in
O
alcohol consump- CT scan VaD and AD vs
tion CON (p < 0.05),
and in VaD vs AD
F
(p < 0.03)
Higher IL-6 in VaD vs
AD (p < 0.03)
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Table 1 (continued)
markers
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Tarkowski, 1999 Patients with AD, AD: 34 66.7 y TNF-α, IL-1β, IL-6 - AD: according Higher TNF-α in
(Sweden) VaD or cognitively VaD: 33 [serum and CSF] definition of “pure” the CSF of AD
healthy (CON) CON: 55 (25 with AD by Wallin et al. (p = 0.006) and VaD

CSF assessment) (1994) patients (p = 0.001)
VaD: NINDS- vs CON
AIREN criteria No difference in
CT scan TNF-α serum level
between AD, VaD
and CON
Article No : 556
Higher TNF-α in CSF
than in the sera in
patients with AD
R
(p = 0.039) and with
VaD (p = 0.007)
Higher serum IL-6
Pages : 20
in VaD vs CON
(p < 0.0001) and vs
EV
CSF IL-6 (p = 0.002)
No difference in CSF
and serum IL-6 and
IL-1β levels between
IS
AD and VaD
MS Code : 556
Wehr, 2019 (Poland) Patients with differ- AD: 166 73.3 y IL-6, hs-CRP, chito- - AD: NINCDS- Higher IL-6 in the
ent types of demen- VaD: 85 triosidase activity, ADRDA criteria whole dementia
tia, or cognitively MIX: 149 paraoxonase-1 VaD: NINDS- group and in the
ED
healthy (CON) CON: 180 [serum] AIREN criteria VaD, MIX groups vs
CT or MRI scan CON
Higher hs-CRP in the
VaD group
Higher chitotriosidase
PR
activity in VaD and
MIX but not in AD
Vishnu, 2017 (India) Patients with differ- AD: 41 - Fibrinogen, D-dimer, - AD: Dubois criteria, No difference in IL-6
O
ent types of demen- VaD: 11 IL-6, CRP [plasma] VaD: DSM IV and CRP between
tia or cognitive MCI: 11 criteria AD and VaD
O
impairment Mild VCI: 5 MCI/mild VCI: NIA- Higher fibrinogen in
AA criteria VaD
MRI, FDG-PET and Higher D-dimer levels
F
CSF biomarkers in VaD
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28] (SMD: 0.56, 95% CI: 0.24 to 0.88), with low het-
positron emission tomography, IL interleukin, HIS Hachinski Ischemic Scale, hs-CRP high sensitive c-reactive protein, MCI mild cognitive impairment, MIX mixed dementia,
Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences, SCI subjective cognitive impairment, SPECT single photon emission computed tomog-
MoCA montreal cognitive assessment, MRI magnetic resonance imaging, NIA-AA National Institute on Aging-Alzheimer’s Association, NINCDS-ADRDA National Institute of
Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and related Disorders Association, NINDS-AIREN National Institute of Neurological Disorders and
controls, CRP c-reactive protein, CSF cerebrospinal fluid, CT computed tomography, CVND cerebrovascular disease but without dementia, FDG-PET 18fluoro-2-deoxyglucose
Abbreviations: AD Alzheimer’s disease, ADDTC Alzheimer’s Disease Diagnostic and Treatment Centers, ADL activities of daily living scale, CDR clinical dementia rating, CON
268
erogeneity (I2 = 48%, p = 0.14).
dementia group vs
control and in AD
269
Higher hs-CRP in Six studies investigated difference in serum or 270

plasma IL-6 levels between 289 subjects with VaD
Main results
271
and 385 subjects affected by AD [20, 21, 27–30].
vs VaD
272
IL-6 levels were significantly higher in subjects with 273
VaD compared to those with AD (SMD: 0.40, 95% 274
CI: 0.18 to 0.62), with low heterogeneity (I2 = 41%, 275
Diagnostic criteria
ADRDA criteria
p = 0.13) (Fig. 2B) and no evidence of small study

AIREN criteria
276
CT or MRI scan
raphy, sTNF-RI soluble tumor necrosis factor receptor type I, TNF tumor necrosis factor, VaD vascular dementia, VCI vascular cognitive impairment
AD: NINCDS-
effect at Egger’s test (p = 0.662) (Supplementary

VaD: NINDS-
277
Fig. 2). Findings were confirmed by a sensitiv- 278
ity analysis including only high-quality studies 279
(NOS ≥ 7) [21, 27, 29] (SMD: 0.50, 95% CI: 0.22 to
F
280
0.78, I2 = 41%, p = 0.18). 281
O
Four studies explored the risk of incident VaD 282
among 3,345 cognitive healthy subjects over a mean 283
follow-up of 8.6 years (range: 4–17 years) [32–35].
O
284
Covariates
Out of the four studies, one was nested case–control 285

[35], and the other three were cohort studies [32–34].
PR Median IL-6 levels at baseline ranged from 1.17
286
-
287
to 2.20 pg/ml [33]. For one-unit increase in ln IL-6
Fibrinogen, hs-CRP
288
Inflammatory bio-
levels, the rate of VaD rose by 28% (RR: 1.28, 95% 289
CI: 1.03 to 1.59) with no evidence of heterogene- 290
ED
[plasma]
ity (I2 = 0%, p = 0.83) (Fig. 2C) or small study effect 291
markers
(p = 0.739) across the studies (Supplementary Fig. 3). 292

Results were consistent after removing one study with 293
low-quality assessment [33] (RR: 1.31, 95% CI: 1.04 294
IS
to 1.65, I2 = 0%, p = 0.78).

Mean age
295
83.5 y
EV
C‑reactive protein and vascular dementia 296
Five studies analyzed differences in CRP levels 297

Sample size
between a total of 261 subjects with VaD and 381

R
298
CON: 99
ent types of demen- VaD: 64
healthy controls [19, 20, 22, 29, 31]. CRP levels did
AD: 35
299
not significantly differ compared to healthy controls 300
(SMD: − 0.14, 95% CI: − 1.56 to 1.27) with high 301
heterogeneity across the study (I2 = 98%, p < 0.001)
Patients with differ-
tia, or cognitively
302
healthy (CON)
(Fig. 3A), but no small study effect (p = 0.829) (Sup- 303

plementary Fig. 4). Removing the study by Man- 304
Population
cinella and colleagues [31] that, at visual inspec- 305

tion of funnel plot, led to marked asymmetry, levels 306
of CRP in VaD compared to controls were still not 307
significantly different (SMD: 0.59, 95% CI: − 0.06
Table 1 (continued)
308
to 1.25), with a modest reduction of heterogeneity
Mancinella, 2009
309
Study (country)
(I2 = 89%, p < 0.001). We also performed sensitivity 310

analysis excluding low-quality studies [19, 20], but 311
(Italy)
the inconsistency across the studies was not reduced 312

(I2 = 99%, p < 0.001), suggesting presence of other 313
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Table 2 Characteristics of longitudinal studies investigating relationship between inflammatory markers and vascular dementia
Study (country) Mean follow-up Population Sample size Mean age at Inflammatory bio- Covariates Diagnostic criteria Main results
baseline markers
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Miwa, 2016 7.5 y Participants form 803 67.0 y IL-6, CRP [serum] Age, sex, AD: NINCDS- Higher IL-6 signifi-
(Japan) Osaka Follow- APO-Eε4, ADRDA criteria cantly associated
up Study for education, VaD: NINDS- with VaD (RR:

Carotid Ath- variants of IL-6 AIREN criteria 1.95, 95% CI:
erosclerosis, Part receptor gene MRI scan 1.15–3.19,
2 (OSACA2) (rs2228145) p = 0.017), but
on high CV this association
risk subjects in disappeared when
primary and sec- further adjusting
Article No : 556
ondary preven- for IL-6 recep-
tion with MMSE tor gene variant
score ≥ 24 and 0 rs2228145
R
on the CDR
Gallacher, 2010 17.3 y Men free 865 From 45 to 59 y hs-CRP, IL-6, Age, social AD: NINCDS- Higher fibrino-
(England) of vascular disease fibrinogen, plasma class, systolic ADRDA criteria gen associated
Pages : 20
and not taking viscosity, WBC, pressure, BMI, VaD: NINDS- with VaD (HR:
EV
anticoagulants at α2-macroglobulin, smoking status, AIREN criteria 1.68, 95% CI:
baseline α1-antitrypsin total cholesterol, Rosen-modified 1.02–2.76)
[plasma] and alcohol HIS Other inflammatory
consumption markers not asso-
IS
ciated with VaD
MS Code : 556
Ravaglia, 2007 3.7 y Participants aged 804 73.6 y hs-CRP, IL-6 [serum] Age, gender, AD: NINCDS- Higher CRP associ-
(Italy) 65 years and α1-antichymotrypsin education, ADRDA criteria ated with VaD
older free of [plasma] APO-E genotype, VaD: NINDS- (HR: 2.93, 95%
ED
dementia from history of stroke AIREN criteria CI: 1.39–6.18)
the Conselice and cardiovas- CT scan Combination of
Study of Brain cular disease, high CRP and
Ageing physical activity, high IL6 associ-
and BMI ated with risk
of VaD (HR:
PR
2.56, 95% CI:
1.21–5.50)
O
O
F
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Table 2 (continued)
Study (country) Mean follow-up Population Sample size Mean age at Inflammatory bio- Covariates Diagnostic criteria Main results
baseline markers
13
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Engelhart, 2004 6–9 y Participants aged 727 71.7 y ACT, CRP, IL-6, Age, gender, edu- AD: NINCDS- ACT (RR: 2.48)

(Netherlands) 55 years and sICAM-1, and cation, smoking, ADRDA criteria and CRP (RR:
older free of sVCAM-1 [plasma] BMI, diabetes VaD: NINDS- 1.31) associated
dementia from mellitus, use of AIREN criteria with increased
Rotterdam Study anti-inflamma- risk of Va
tory medication, Levels of IL-6,
and atheroscle- sICAM-1 and
R
Article No : 556
rosis sVCAM-1 not
associated with
VaD
Schmidt, 2002 25 y Nested case–con- 1,050 29.2 y hs-CRP [serum] Education, smok- AD: NINCDS- Compared with
EV
(United States) trol study from ing, midlife ADRDA criteria lowest hs-
Honolulu-Asia average choles- VaD: California CRP quartile
Pages : 20
Aging Study in terol, midlife Alzheimer’s (< 0.34 mg/L),
Japanese Ameri- blood pressure, Disease Diag- men in the upper
IS
can men age, years of nostic and Treat- three quartiles
follow-up, ment Centers had a threefold
APO-Eε4, BMI, criteria higher risk for all
stroke, coronary dementias,
ED
heart disease, AD, and VaD. For
MS Code : 556
left ventricular VaD, the risk
hypertrophy, increased with
atrial fibrillation, increasing quartile
diabetes mel-
litus, ABI at the
PR
time of dementia
assessment
O
Hsu, 2017 (Tai- 11 y Participants aged 1,436 73.2 y CRP [serum] Age, gender, Not specified Higher CRP associ-
wan) 65 years and education, BMI, (review of ICD- ated with higher
older free of use of sleep 9-CM code from risk of VaD (HR:
O
dementia from medication, medical records) 2.09; 95% CI:
the Elderly alcohol con- 1.01–4.32) but
Nutrition and sumption, and not AD
F
Health Survey diastolic blood
in Taiwan pressure
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potential sources of heterogeneity (e.g., CRP assess-
c-reactive protein, CT computed tomography, IL interleukin, HIS Hachinski Ischemic Scale, HR hazard ratio, hs-CRP high sensitive c-reactive protein, MRI magnetic resonance
imaging, NINCDS-ADRDA National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and related Disorders Association, NINDS-AIREN
Abbreviations: ABI ankle-brachial index, ACT α1-antichymotrypsin, AD Alzheimer’s disease, APOE apolipoprotein E, BMI body mass index, CI confidence interval, CRP
National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences, RR relative risk, sICAM-1 soluble
314
risk of dementia
ated with higher
ated with higher

CRP not associ-
ment method).
risk of both AD
(HR: 1.25, 95%
CI: 1.04–1.49)
315
and VaD (HR:
Higher levels of
High fibrinogen
1.76, 95% CI:

levels associ-
Four studies compared CRP levels between 316
1.34–2.30)
Diagnostic criteria Main results
231 patients with VaD and 298 AD patients [20, 317

22, 29, 31]. No significant difference was found 318
(SMD: − 1.24, 95% CI: − 2.95 to 0.46), with evidence 319
of high heterogeneity across the studies (I2 = 98%, 320
ADRDA criteria
AIREN criteria
p < 0.001) (Fig. 3B). No small study effect was

AD: NINCDS-
321
VaD: NINDS-
detected at Egger’s test (p = 0.096) (Supplemen- 322

tary Fig. 5). In a sensitivity analysis, we removed 323
the study by Mancinella and colleagues [31], which 324
determined remarkable asymmetry at funnel plot, but 325
ous stroke, white
blood cell count,
results did not change (SMD: 0.34, 95% CI: − 0.16 to
F
326
apoEε4, previ-
and fibrinogen
Cardiovascular
0.83, I2 = 80%, p = 0.006). Also removing the study

risk factors,
327
presence of
O
with poorer quality assessment [20] did not reduced
Covariates
328
the very high heterogeneity (I2 = 99%, p < 0.001). 329
Six high-quality studies with an overall population
O
330
of 11,679 cognitive healthy subjects explored the risk 331
Fibrinogen, hs-CRP
of incident VaD during a mean follow-up of 10 years
PR
forms of intercellular adhesion molecule-1, sVCAM-1 vascular cell adhesion molecule-1, VaD vascular dementia
332
Inflammatory bio-
(range: 4–25 years) [32, 34–38]. Two were nested 333

case–control studies [35, 36] and four were cohort 334
[plasma]
studies [32, 34, 37, 38]. All but two studies [32, 37]
markers
335
measured high-sensitivity CRP; three studies used 336
ED
immunonephelometry [34, 35, 38], and the remain- 337
ing studies used ELISA methodology [36] or immu- 338
noturbidimetric assay [32, 37]. Median CRP levels 339
Sample size Mean age at
at baseline ranged from 0.57 [36] to 17.2 mg/l [35]. 340

IS
baseline
No significant increase of VaD risk was observed for

69.5 y
341
one-unit change in ln CRP (RR: 1.22, 95% CI: 1.00 342
to 1.48) with significant heterogeneity between the
EV
343
studies (I2 = 64%, p = 0.02) (Fig. 3C), and evidence of 344
small study effect at Egger’s test (p = 0.009) (Supple-
Participants aged 6,713
345
mentary Fig. 6). 346
R
Rotterdam Study
dementia from
Tumor necrosis factor‑α and vascular dementia 347

55 years and
older free of
Mean follow-up Population
Five studies analyzed differences in tumor necrosis 348

factor (TNF)-α levels between a total of 166 subjects 349
with VaD and 167 healthy controls [19, 21, 26–28]. 350
TNF-α levels were more elevated in VaD patients 351
compared to healthy controls (SMD: 1.73, 95% CI: 352
0.42 to 3.05) with evidence of high heterogeneity 353
across the studies (I2 = 96%, p < 0.001) (Fig. 4A),
5.7 y
354
and no small study effect (p = 0.06) (Supplementary
Table 2 (continued)
355
Fig. 7). Excluding the studies by Zhang and col- 356
Van Oijen, 2005
Study (country)
(Netherlands)
leagues [19] and De Luigi and colleagues [26] that, at 357

visual inspection of funnel plot, led to marked asym- 358
metry, the higher levels of TNF-α in VaD compared 359
to controls were still confirmed (SMD: 0.36, 95% 360
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F
O
O
PR
ED
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EV
Fig. 2 Difference in blood interleukin-6 levels between subjects with vascular dementia and controls (A) or those with Alzheimer’s
disease (B); pooled hazard ratios for interleukin-6 and incident vascular dementia (C)
R
361 CI: 0.09 to 0.63), but the heterogeneity was reduced heterogeneity (SMD: 0.30, 95% CI: − 0.04 to 0.65, 375
362 (I2 = 0%, p = 0.97). These findings were further con- I2 = 0%, p = 0.43). No study analyzed correlation 376
363 firmed performing sensitivity analysis with the exclu- between blood TNF-α levels and incident VaD. 377
364 sion of all low-quality studies [19, 26, 28] (SMD:
365 0.38, 95% CI: 0.05 to 0.70, I2 = 0%, p = 0.99). Interleukin‑6 in cerebrospinal fluid and vascular 378
366 Moreover, four studies compared circulating con- dementia 379
367 centration of TNF-α between 147 VaD and 158 AD
368 patients [21, 25, 27, 28]. No significant difference For quantitative synthesis, only three studies were eli- 380
369 was detected among these two subgroups (SMD: gible which compared IL-6 levels in the CSF between 381
370 0.30, 95% CI: − 0.04 to 0.65), with low heterogeneity 82 patients with VaD, 99 with AD, and 81 healthy 382
371 across the studies (I2 = 49%, p = 0.12) (Fig. 4B) and subjects [23, 24, 28]. IL-6 was significantly higher 383
372 no evidence of small study effect (p = 0.507) (Sup- in people with VaD compared to healthy subjects 384
373 plementary Fig. 8). Removing low-quality studies (SMD: 0.73, 95% CI: 0.12 to 1.34) (Fig. 5A), but not 385
374 [25, 28], the results were confirmed, also reducing the compared to AD patients (SMD: 0.14, 95% CI: − 0.65 386
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F
O
O
PR
ED
IS
EV
Fig. 3 Difference in blood C-reactive protein levels between subjects with vascular dementia and controls (A) or those with Alzhei-
mer’s disease (B); pooled hazard ratios for C-reactive protein and incident vascular dementia (C)
R
387 to 0.93) (Fig. 5B). Despite no evidence of small found that, compared to healthy subjects, a moder- 399
388 study effect (p = 0.830 for VaD vs healthy controls, ate to large elevation of both blood IL-6 and TNF-α 400
389 p = 0.800 for VaD vs AD) (Supplementary Figs. 9 and levels was associated with VaD diagnosis. How- 401
390 10), high heterogeneity (I2 = 70%, p = 0.04 for VaD ever, only blood IL-6 concentrations significantly 402
391 vs healthy controls, I2 = 84%, p = 0.002 for VaD vs differed between VaD and AD subjects such that 403
392 AD) (Fig. 5A and B, respectively), together with poor patients with VaD had small to moderate elevation 404
393 overall quality of the studies, limited the reliability of of IL-6 compared to those with AD. Moreover, we 405
394 these findings. found that each unit increase of IL-6 levels pre- 406
dicted 28% higher risk of VaD. In the CSF of VaD 407
patients, IL-6 levels were significantly higher than 408
395 Discussion in healthy subjects, but no difference was detected 409
compared to AD patients. Data from CSF should be 410
396 In the present systematic review and meta-analysis, taken with caution due to high inconsistency related 411
397 we investigated the usefulness of blood and CSF to the still limited number of studies with relatively 412
398 inflammatory biomarkers for VaD diagnosis. We small sample size. 413
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O
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PR
Fig. 4 Difference in blood tumor necrosis factor-α levels between subjects with vascular dementia and controls (A) or those with
Alzheimer’s disease (B)
ED
IS
EV
R
Fig. 5 Difference in cerebrospinal fluid interleukin-6 levels between subjects with vascular dementia and controls (A) or those with
Alzheimer’s disease (B)
414 Present findings might suggest that among inflam- studies highlight that higher IL-6 levels are related 422
415 matory markers, circulating IL-6 levels could be a with poorer cognitive performance [40, 41] and faster 423
416 useful biomarker able to differentiate across healthy, cognitive decline [42, 43]. The relationship between 424
417 VaD, and AD subjects. A recent meta-analysis by cognitive impairment and inflammation in VCID 425
418 Ng and colleagues showed that blood inflammatory is partly explained by the existence of a clear asso- 426
419 markers, including IL-6, were not significantly differ- ciation between inflammatory status, atherosclerosis, 427
420 ent between AD patients and controls [39]. However, and prothrombotic conditions [44]. Compared to pre- 428
421 evidence from both cross-sectional and prospective vious meta-analytic findings that did not evidence any 429
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430 significant association between circulating CRP and muscle cells, there occurs an overexpression of genes 479
431 IL-6 levels and future risk of AD [12, 13], we found coding for inflammatory cytokines, chemokines, 480
432 a positive linear relationship between blood IL-6 and adhesion molecules, and other proinflammatory 481
433 risk of incident VaD. mediators, leading to the development of a proinflam- 482
434 In the present meta-analysis, among CSF inflammatory microenvironment that promotes vascular 483
435 matory biomarkers, only IL-6 had enough studies to dysfunction [53, 54]. Moreover, higher inflamma- 484
436 be included in quantitative synthesis. However, other tory markers may underlie a damage of neurovas- 485
437 inflammatory markers in CSF are under investigation. cular unit [55]. Indeed, inflammatory and oxidative 486
438 For example, few reports showed that TNF-α levels injuries may alter neurons and white matter function 487
439 in the CSF were higher than in sera among subjects by interfering with neurovascular coupling [56]. This 488
440 with dementia, suggesting an intrathecal synthesis of process exacerbates tissue hypoxia, by contrasting 489
441 this cytokine [28]. Assessment of the soluble forms proliferation, migration, and differentiation of oligo- 490
of TNF-α receptors (sTNFR1 and 2) which may pro- dendrocyte stem cells and by compromising mecha-
F
442 491
443 vide more accurate information about activation of nisms of reparation of damage in the white matter 492
O
444 the TNF-α system revealed that patients with mild [57]. In addition, the activation of leukocytes and the 493
445 cognitive impairment (MCI) who converted to VaD release of inflammatory cytokines and cell adhesion 494
had higher concentrations of these biomarkers com- molecules, which have been observed in patients with
O
446 495
447 pared to those who converted in AD [45]. Biomarkers hypertension, may induce a dysregulation of the sign- 496
of microglial activation in CSF, which are related to aling of angiotensin II [58]. This dysregulation may
PR
448 497
449 neuroinflammation (i.e., YKL-40 and calcium bind- lead to the impairment of the modulation of cerebral 498
450 ing protein B), were not able to differentiate between perfusion in response to blood pressure variations 499
451 AD and VaD patients [46]. However, Olsson and col- [59]. Specifically, IL-6 is involved in atherosclerosis 500
452 leagues showed that in subjects with MCI followed through a large variety of pathways leading to plaque 501
ED
453 over 5.7 years, higher levels of YKL-40 and sCD14 formation, from the stimulation of the acute-phase 502
454 in CSF predicted conversion to VaD but not to AD reactants and coagulation factors synthesis in the liver 503
455 [47]. Further well-conducted studies are warranted to to the promotion of proliferation and differentiation of 504
456 draw conclusion on reliability of inflammatory mark- leukocytes and the activation of endothelial cells [60]. 505
IS
457 ers from CSF in VaD diagnosis. The latter respond to the IL-6 stimuli by releasing 506
458 Our findings might suggest that systemic inflam- chemokines and increasing the expression of cellular 507
mation contributes to VCID. Studies on brain biop- adhesion molecules as the intercellular adhesion mol-
EV
459 508
460 sies showed controversial results on the contribution ecule 1 (ICAM-1), which is involved in the adhesion 509
461 of inflammatory mechanisms in the pathogenesis of and transmigration of circulating leukocytes [61]. 510
462 VaD [48–50]. It has been hypothesized that different Promising perspectives come from other blood proin- 511
types of cerebral small vessel disease (SVD) might be flammatory biomarkers as midregional proenkephalin
R
463 512
464 mechanistically linked to different forms of inflam- A (MR-PENK A), mainly associated with pain sensa- 513
465 mation [51]. Cerebral SVD represents one of the most tion, cardiac function, and immunity, which has been 514
466 common neuropathological features of VCID [52]. It positively associated with increased risk of VaD [62]. 515
467 has been shown that biomarkers of systemic inflam- Despite data from randomized controlled trials are 516
468 mation, like IL-6, may be associated with a specific still scarce, targeting proinflammatory pathways may 517
469 form of SVD, the cerebral amyloid angiopathy (CAA) be a promising approach for the prevention of car- 518
470 also known as type 2 SVD, which involves lobar diovascular diseases and potentially VCID. Among 519
471 regions and the centrum semiovale [51]. Conversely, eligible pharmacological strategies geared toward 520
472 sustained elevation over time of biomarkers of sys- systemic inflammation, the inhibition of TNF-α sign- 521
473 temic inflammation is longitudinally associated with aling or the treatment with the IL-6 inhibitor tocili- 522
474 SVD progression [51]. zumab determined an improvement of endothelial 523
475 Among different inflammatory biomarkers, we function assessed by means of flow-mediated dila- 524
476 found a preeminent role of IL-6 in the diagnosis of tation [63, 64]. Also findings from COLCOT trial 525
477 VaD. Preclinical and clinical studies have demon- demonstrated the effectiveness of the colchicine in 526
478 strated that during aging, in endothelial and smooth secondary cardiovascular prevention after myocardial 527
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528 infarction [65]. On the other hand, the administration across the studies, due to potential several reasons: (a) 577
529 of low-dose methotrexate did not result in fewer car- different measurement platforms, (b) small sample size 578
530 diovascular events compared to placebo [66]. Great per each study, (c) different case adjudication meth- 579
531 interest has been aroused by the effect of a therapeutic ods, (d) presence of subjects in different VCID stages 580
532 monoclonal antibody targeting IL-1β, canakinumab, in cross-sectional studies, or (e) different lengths of 581
533 whose administration led, in a large cohort of patients follow-up in longitudinal studies. Second, several stud- 582
534 with previous myocardial infarction, to a significantly ies had relatively small sample sizes that could poten- 583
535 lower rate of recurrent cardiovascular events [67]. tially lead to overestimation of effects. Nevertheless, 584
536 Nevertheless, canakinumab was not approved for we performed sensitivity analysis excluding the stud- 585
537 cardiovascular disease prevention, due to increased ies at higher risk of publication bias, and we did not 586
538 risk of fatal infections. Also, the statins, beyond their detect any significant change in the results. Third, for 587
539 lipid-lowering effect, have well-characterized anti- most of the studies, the assessment of inflammatory 588
inflammatory properties including the inhibition of state was based only on a single value of the biomarker
F
540 589
541 the formation of isoprenoids and proinflammatory which could lead to a misclassification of exposure. 590
O
542 mediators, and the subsequent reduction of asym- Fourth, although we included only studies in which 591
543 metrical dimethylarginine, implicated in endothelial VaD and AD diagnosis were based on internationally 592
dysfunction [68, 69]. Noteworthy, several randomized validated criteria, misclassification of outcome should
O
544 593
545 controlled trials demonstrated that patients taking be accounted given the different methods used for diag- 594
statins had a significant reduction of CRP levels [70, nosis and the few studies including a confirmation of
546
547
548
71], but evidence of a protective role of statins against
VCID are still insufficient [72].
PR diagnosis by imaging techniques. In this regard, it is
worthy of mention that whenever specified, subjects
595
596
597
549 A few preclinical studies explored the effective- with mixed dementia were excluded. Fifth, the included 598
550 ness of other compounds with anti-inflammatory studies adjusted the analysis for different factors; there- 599
ED
551 properties for VCID prevention. The angioten- fore, there could be unmeasured confounders associated 600
552 sin-(1–7) glycosylated mas receptor agonist demon- with inflammation and dementia. Sixth, results on CSF 601
553 strated the ability to restore visual-spatial memory biomarkers should be considered with caution due to 602
554 in a murine model of VCID [73]. Another molecule, limited number of included studies. Finally, the assays 603
IS
555 the N-palmitoylethanolamide-oxazoline, reduced for biochemical measurements of serum or plasma 604
556 in mice the histological alterations typical of VCID IL-6, CRP, and TNF-α varied across the studies. 605
and improved behavioral disorders through neuro- In conclusion, blood IL-6 levels might represent
EV
557 606
558 protective and anti-inflammatory activity [74]. Fur- a useful biomarker of VCID, able to differentiate 607
559 thermore, treatment with resveratrol which has well- people with VaD from those with AD and to predict 608
560 known anti-inflammatory and antioxidant properties future VaD risk in healthy subjects. Further prospec- 609
was associated, in a rodent model of VaD, to better tive, high-quality studies are warranted to test oppor-
R
561 610
562 vascular reactivity and reduction of cognitive decline tune IL-6 cutoffs for VCID diagnosis alone or in 611
563 [75]. Future preclinical and clinical studies should combination with other inflammatory biomarkers, the 612
564 test if strategies targeting chronic inflammation and, association of IL-6 levels with different stages across 613
565 in particular, blood IL-6 could have a role in reducing the VCID spectrum, and finally the usefulness in bet- 614
566 incidence of VCID or slow down its progression. ter characterization of mixed dementia. Ultimately, 615
567 To the best of our knowledge, this is the first meta- present findings should encourage promotion of pre- 616
568 analysis exploring the reliability of few well-accepted ventive strategies targeting systemic inflammation in 617
569 inflammatory biomarkers (IL-6, CRP, and TNF-α) for subjects with high cardiovascular risk. 618
570 differential diagnosis between VaD and AD. This dis-
571 tinguishes our findings from those of other previous Author contribution Conception and design of the work: 619
C.C.; acquisition of data: C.C, A.C., and D.G.; analysis: C.C. 620
572 systematic reviews and meta-analyses that assessed and J.L.; interpretation of data: C.C., A.C., G.M.L., and V.S.; 621
573 only the association between inflammation and overall drafting of manuscript: C.C., A.C., and V.S.; critical revision: 622
574 dementia or AD [12, 13]. The present study has also F.P., A.M., and C.S. All authors approved the submitted ver- 623
575 some limitations. First, despite the strict inclusion/ sion and agreed to be personally accountable for the author’s 624
own contributions. 625
576 exclusion criteria, there is wide heterogeneity observed
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626 Funding Open access funding provided by Università degli 8. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn 678
627 Studi di Bari Aldo Moro within the CRUI-CARE Agreement. B, Haeberlein SB, et al. NIA-AA research framework: 679
toward a biological definition of Alzheimer’s disease. Alz- 680
628 Declarations heimers Dement J Alzheimers Assoc. 2018;14(4):535–62. 681
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629 Conflict of interest The authors declare no competing inter- 9. Wallin A Kapaki E Boban M Engelborghs S Hermann 683
630 ests. DM Huisa B et al. Biochemical markers in vascular cogni- 684
tive impairment associated with subcortical small vessel 685
Open Access This article is licensed under a Creative Com- disease - a consensus report. BMC Neurology. 2017;17(1). 686
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mons Attribution 4.0 International License, which permits https://doi.org/10.1186/s12883-017-0877-3. 687
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use, sharing, adaptation, distribution and reproduction in any 10. Ferrucci L, Fabbri E. Inflammageing: chronic inflam- 688
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2 Role of inflammatory markers in the diagnosis of vascular

A13 and Thrombosis Center, Milan, Italy

A17 Research Hospital, Castellana Grotte, Bari, Italy factor-α 46

47 Introduction To date, no specific circulating biomarker is availa- 95

69 example, VCID can be detected in subjects suffer- Methods 116

Fig. 1 PRISMA flowchart

Records duplicates removed

Full-text articles assessed for reasons:

PR Missing data (n= 11)

Studies included in quantitative

Journal : Medium 11357

Journal : Medium 11357

Journal : Medium 11357

Higher hs-CRP in Six studies investigated difference in serum or 270

p = 0.13) (Fig. 2B) and no evidence of small study

effect at Egger’s test (p = 0.662) (Supplementary

Out of the four studies, one was nested case–control 285

(p = 0.739) across the studies (Supplementary Fig. 3). 292

to 1.65, I2 = 0%, p = 0.78).

C‑reactive protein and vascular dementia 296

Five studies analyzed differences in CRP levels 297

between a total of 261 subjects with VaD and 381

(Fig. 3A), but no small study effect (p = 0.829) (Sup- 303

cinella and colleagues [31] that, at visual inspec- 305

(I2 = 89%, p < 0.001). We also performed sensitivity 310

the inconsistency across the studies was not reduced 312

Journal : Medium 11357

Journal : Medium 11357

potential sources of heterogeneity (e.g., CRP assess-

ated with higher

and VaD (HR:

1.76, 95% CI:

231 patients with VaD and 298 AD patients [20, 317

p < 0.001) (Fig. 3B). No small study effect was

detected at Egger’s test (p = 0.096) (Supplemen- 322

results did not change (SMD: 0.34, 95% CI: − 0.16 to

0.83, I2 = 80%, p = 0.006). Also removing the study

of incident VaD during a mean follow-up of 10 years

(range: 4–25 years) [32, 34–38]. Two were nested 333

at baseline ranged from 0.57 [36] to 17.2 mg/l [35]. 340

No significant increase of VaD risk was observed for

Tumor necrosis factor‑α and vascular dementia 347

Five studies analyzed differences in tumor necrosis 348

leagues [19] and De Luigi and colleagues [26] that, at 357

652 2. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg 711

660 dementia in developing countries: prevalence, manage- 719

775 erosclerosis and dementia – inflammatory markers and jstro​kecer​ebrov​asdis.​2005.​08.​009. 834

893 Journal of Molecular Sciences. 2020;21(3). https://​doi.​ ather​oscle​rosis.​2011.​09.​015. 951

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775 erosclerosis and dementia – inflammatory markers and jstrokecerebrovasdis.2005.08.009. 834

893 Journal of Molecular Sciences. 2020;21(3). https://doi. atherosclerosis.2011.09.015. 951