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Abstract

Introduction

Inflammatory processes and neurodegeneration are common features of Alzheimer's disease (AD). The systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) are easily accessible, cost-effective prognostic indicators of inflammation status. We assessed the diagnostic value of SII and compared the efficacies of NLR, PLR, and SII in predicting AD severity.

Materials and Methods

Between January 2021 and December 2022, this prospective, cross-sectional clinical study included 175 patients with AD and 61 controls. SII, NLR, and PLR were calculated.

Results

Age, white blood cell and lymphocyte counts, and NLR and PLR values were significantly different between the patient and control groups (P <.05). Age, hemoglobin, neutrophil, NLR, and SII values were significantly different among dementia severity subgroups (P <.05). Compared with PLR and SII, NLR was more strongly correlated with dementia severity. In the analysis of adjusted data by gender, it was found that hemoglobin level is significantly negatively associated with dementia severity in males, while in females, age and PLR are significantly positively associated with dementia severity, and lymphocyte count and SII are negatively associated.

Conclusion

SII, a novel inflammatory marker, was associated with dementia severity in patients with AD. Compared with PLR and SII, NLR was more strongly correlated with dementia severity. In future studies with larger populations, SII and NLR values can be used to determine dementia severity and establish follow-up plans for patients with high dementia risk.

Keywords

Alzheimer’s disease systemic immune-inflammation index neutrophil-to-lymphocyte ratio platelet-to-lymphocyte ratio

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia, responsible for up to 80% of all dementia diagnoses worldwide, and its prevalence increases with age.¹ β-amyloid plaque deposits and neurofibrillary tangles comprising hyperphosphorylated tau are the classic neuropathological hallmarks of AD.¹ These pathological markers are positively correlated with neuronal degeneration, neuroinflammation, microglia activation, blood–brain barrier dysfunction, and cognitive decline.²

Neuroinflammation is a prevalent and key component of AD. Microglia, resident macrophage-like immune cells in the brain, play important roles in the inflammatory response and the progression of neurodegenerative disease. Previous studies have shown that the presence of activated microglia and astrocytes surrounding Aβ plaques is correlated with elevated levels of inflammatory cytokines, including interleukins 1 and 6, as well as tumor necrosis factor-α.^3,4 Peripheral inflammatory changes during AD include neutrophil hyperactivation and increased lymphocyte migration into the central nervous system across the compromised blood–brain barrier.⁵ Because inflammation plays an important role in multiple neurological conditions, including Parkinson’s disease, multiple sclerosis, and stroke, as well as various systemic diseases (eg, atherosclerosis, cancer, cardiovascular disease, and metabolic disorders), recent studies have focused on hematological biomarkers and indexes to determine the risk of inflammation.^6-9

Epidemiological data suggest that neuroinflammation is an independent predictor of early death in AD.¹⁰ Thus, it is important to identify patients with high risks of morbidity and mortality. Although the core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aβ42), CSF NFL, and plasma T-tau are strongly associated with Alzheimer’s disease,¹¹ they are not very useful markers. However, the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) are useful, cost-effective, and commonly used indicators of peripheral systemic inflammation.^12-16 Several studies have shown that NLR and PLR are prognostic indicators of cognitive impairment and disease progression in AD.^12,17,18

The SII, a novel, cost-effective inflammation marker calculated from hemogram parameters (platelet count × neutrophil count/lymphocyte count) indicates simultaneous immune and inflammatory status; it is a more accurate indicator of overall inflammatory status, compared with NLR and PLR.¹⁵ Furthermore, the SII can predict severity and prognosis in conditions such as stroke, cardiovascular diseases, atherosclerotic diseases, and cancers.^6-9,12,14,17

Alzheimer’s disease is highly prevalent in rural areas. However, in these regions, the disease is either not diagnosed or diagnosed only based on cognitive tests. This is due to the lack of resources for amyloid beta or tau pathology testing. Therefore, simple blood tests and more accessible peripheral markers for the diagnosis of Alzheimer’s disease are needed in these areas.

However, the role of SII in AD is not fully understood. Here, we assessed the role of SII in AD pathophysiology and explored the ability of SII to predict disease severity (compared with NLR or PLR) in patients with AD.

Materials and Methods

Study Design

This prospective, cross-sectional, clinical study included all patients consecutively admitted to the neurology outpatient clinic of the Inonu University Faculty of Medicine between January 2021 and December 2022. The study protocol was approved by the Ethics Committee of Inonu University Faculty of Medicine (protocol number: 2022/32), and the study was conducted in accordance with the Declaration of Helsinki. All patients and control participants provided written informed consent after receiving a detailed explanation of the study.

Participants and Eligibility Criteria

Patients who had symptoms consistent with dementia underwent detailed assessments including clinical history, neuropsychological tests including the Mini-Mental Status Examination, and neuroradiological imaging (cranial magnetic resonance imaging or cranial computed tomography). All participants underwent a neurological examination. Alzheimer’s-type dementia was diagnosed in accordance with the criteria of the American Society of Neurology, Language Disorder and Stroke-Alzheimer’s Disease and Related Diseases Working Group.¹⁹ To ensure that the study included patients who only had AD, we excluded patients with secondary dementia and patients in whom SII processes may have played a role, including patients with a history of ischemic or hemorrhagic stroke, possible disease that may affect laboratory results (leukemia, lymphoma, or thrombocytopenia); active infection (pneumonia supported by imaging examination, urinary tract infection by urine examination, chronic active viral hepatitis, etc.) or systemic disease including malignant tumor, uremia, liver cirrhosis, chronic heart, disease, and chronic lung disease. autoimmune or chronic inflammatory disease, organ failure (kidney, liver, lung), endocrine system diseases that may affect routine blood indicators, treatment with immunomodulatory drugs or chronic use of anti-inflammatory drugs, as well as patients with incomplete diagnostic examinations. We also excluded patients with thyroid disease, vitamin B12 deficiency, and acute/chronic psychiatric disease because the corresponding symptoms may be confused with AD.

The control group consisted of healthy older adults with normal cognitive status based on Mini-Mental Status Examination scores.²⁰ The controls were frequency-matched to patients with AD on the basis of age, sex, education level, and comorbidities. AD severity was classified as mild, moderate, or severe according to neuropsychological test scores and Clinical Dementia Rating scale scores.²¹ Patients with a CDR score of 1 or higher were included in the study. A CDR score of 1 is defined as Mild Dementia, 2 as Moderate Dementia, and 3 as Severe Dementia. We are aware that there is a deficiency in our study regarding the definitive diagnosis of Alzheimer’s diseases. But we could not diagnose our patients with cerebrospinal fluid (CSF) biomarkers like amyloid β 42 or hyperphosphorylated tau. Because these tests are performed in only one labarotory in our country and the accessibility of the tests is very difficult.

Biochemical and Hematological Blood Sample Analysis

Fasting peripheral blood samples were collected from all patients. Hematological parameters, including levels of hemoglobin and platelets, as well as counts of white blood cells (WBCs), neutrophils, lymphocytes, and platelets, were measured using an automated hematology analyzer system (Sysmex Corporation, Kobe, Japan) with kits (Sysmex Corporation) that utilized a fully automatic nephelometric method. Absolute cell counts were used in subsequent analyses. The SII was calculated as platelet count × neutrophil count/lymphocyte count. The NLR and PLR were also calculated.

Statistical Analysis

Statistical analyses were performed using SPSS for Windows version 26.0 (IBM Corp., Armonk, NY, USA). All statistical tests were two-tailed and P-values < .05 were assumed to indicate statistical significance. The normality of continuous variables was verified using the Shapiro–Wilk test (n < 50) and Kolmogorov-Smirnov test (n ≥ 50). Differences between patients with AD and healthy controls were assessed using the Mann–Whitney U test for independent non-normally distributed variables and independent t-tests for normally distributed variables. Dementia severity subgroups were compared using the Kruskal–Wallis test or analysis of variance, depending on data distribution normality. Receiver operating characteristic (ROC) curves were used to determine optimal cutoff values for NLR and SII in terms of predicting disease severity among patients with AD. Spearman’s correlation analysis was used to determine correlations among NLR, PLR, and SII values. The comparison of variables between the dementia severity was conducted using analysis of variance (linear regression), adjusting for age and sex.

Results

Baseline Characteristics

The study included 175 patients (92 men and 83 women) with a mean age of 75.31 ± 9.62 years, (minimum-maximum, 49-102 years) who met all AD diagnostic criteria. AD dementia severity was classified as mild in 61 (35.8%), moderate in 57 (32.6%), and severe in 57 (32.6%) patients. The control group consisted of 61 healthy people (31 men and 30 women) with a mean age of 73.87 ± 7.49 years (minimum-maximum, 60-98 years).

Comparison of Demographic and Hematological Parameters

Age, WBC and lymphocyte counts, and NLR and PLR values were significantly different between patient and control groups (P < .05). The mean age, mean NLR, and mean PLR were significantly higher among patients than among controls, whereas the WBC and lymphocyte counts were significantly lower in the patient group (P < .05, Table 1). Gender distribution and SII values did not significantly differ between groups (P > .05) (Supplemental Material).

Table 1.

Demographic and Biochemical Variables According to AD.

	Controls (n = 61) (25.8%)	Patients with AD (n = 175) (74.2%)	P
	(mean ± SD/min–max)	(mean ± SD/min–max)	P
Age (years)**	73.87 ± 7.49/60-98	75.31 ± 9.62/49-102	.364
Hemoglobin (g/dL)	15.79 ± 16.93/8.9-145	13.4 ± 1.97/4.5-19.1	.489
WBC count (10⁹/L)	8.23 ± 2.75/4.57-17.53	7.34 ± 2.27/1.79-15.3	.032*
Neutrophils (10⁹/L)	4.65 ± 1.52/2.12-8.44	4.56 ± 1.79/1.68-12	.411
Lymphocytes (10⁹/L)	2.34 ± .88/.85-6.52	1.9 ± .83/.56-8.76	.000*
Platelets (10⁹/L)	247.99 ± 77.52/106-447	255.02 ± 77.89/101-536	.458
NLR	2.13 ± .77/.67-4.33	2.71 ± 1.49/1-9.44	.042*
PLR	118.17 ± 47.08/23.8-272.9	145.98 ± 65.44/43.4-465	.004*
SII (10⁹/L)	549.53 ± 259.31/104.8-1300	67.24 ± 429.14/153-3193	.118
Gender (female (n)/male (n))	30/31	83/92	.814

*Statistically significant (P < .05). **t-test; all other variables were assessed using the Mann–Whitney U test. AD, Alzheimer's disease; WBC, white blood cell; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic immune-inflammatory index.

Age, hemoglobin level, neutrophil count, NLR, and SII value significantly differed among dementia subgroups (P < .05, Table 2). The mean age, mean neutrophil count, mean NLR, and mean SII value were significantly higher, and hemoglobin values were significantly lower, in patients with severe dementia than in patients with mild or moderate dementia (P < .05, Table 2). There are significant differences in neutrophil count, NLR, and SII values between mild and moderate dementia; in age, hemoglobin, neutrophil count, NLR, and SII values between mild and severe dementia; and in age and hemoglobin between moderate and severe dementia (P < .05, Table 2). (Supplemental Material).

Table 2.

Biochemical Variables According to Dementia Severity (Mean ± Standard Deviation/Minimum–Maximum).

	Mild dementia (n = 61) (35.8%)	Moderate dementia (n = 57) (32.6%)	Severe dementia (n = 57) (32.6%)	Mild vs Moderate	Mild vs Severe	Moderate vs Severe
	Mild dementia (n = 61) (35.8%)	Moderate dementia (n = 57) (32.6%)	Severe dementia (n = 57) (32.6%)	P	P	P
Age (years)**	72.36 ± 10.54	73.74 ± 9.13	8.04 ± 7.1	.863	.003*	.009*
Hemoglobin (g/dL)	13.62 ± 2.02	13.6 ± 2.18	12.97 ± 1.64	.751	.035*	.011*
WBC count (10⁹/L)	7.02 ± 1.82	7.86 ± 2.42	7.17 ± 2.5	.059	.987	.136
Neutrophil (10⁹/L)	3.93 ± 1.13	4.91 ± 1.87	4.89 ± 2.12	.004*	.036*	.685
Lymphocyte (10⁹/L)	1.95 ± .71	1.89 ± .57	1.85 ± 1.13	.979	.114	.154
Platelet (10⁹/L)	247.96 ± 72.44	261.47 ± 91.2	256.12 ± 69.36	.616	.563	.823
NLR	2.17 ± .99	2.79 ± 1.35	3.2 ± 1.86	.002*	.000*	.35
PLR	135.18 ± 55.62	144.32 ± 65.76	159.2 ± 73.2	.516	.072	.225
SII (10⁹/L)	537.94 ± 272.99	705.81 ± 424.48	776.26 ± 529.53	.027*	.005*	.495

*Statistically significant (P < .05). **t-test; all other variables were assessed using the Mann–Whitney U test. WBC, white blood cell; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic immune-inflammatory index.

In the comparison between gender, hemoglobin and WBC were higher in male compared to female, while platelet count was lower (Table 3). (Supplemental Material).

Table 3.

Biochemical Variables According to Gender (Mean ± Standard Deviation/Minimum–Maximum).

	Male (n = 113) (47.9%)	Female (n = 123) (52.1%)	P
Age (years)**	73.46 ± 9.26/48-98	75 ± 10.7/53-102	.328
Hemoglobin (g/dL)**	14.01 ± 1.91/8.6-19.1	12.97 ± 1.68/7-16.5	.000*
WBC count (10 B/L)	7.88 ± 2.61/1.79-17.53	7.23 ± 2.18/3.43-17.4	.038*
Neutrophil (10 B/L)	4.68 ± 1.75/1.68-12	4.49 ± 1.7/1.95-10.79	.405
Lymphocyte (10 B/L)	1.99 ± 1/.8-8.76	2.03 ± .68/.56-4.2	.727
Platelet (10 B/L)	236.56 ± 73.48/101-448	271.32 ± 78.4/107-536	.001*
NLR	2.62 ± 1.34/.67-9.44	2.5 ± 1.38/.9-8.37	.513
PLR	132.39 ± 57.58/23.8-372.5	145.77 ± 66.69/51.2-465	.100
SII (10 B/L)	611.58 ± 384.8/104.8-3193	7 ± 7.88/7.42-8.35	.267

In the analysis of adjusted data by gender, it was found that hemoglobin level is significantly negatively associated with dementia severity in males, while in females, age and PLR are significantly positively associated with dementia severity, and lymphocyte count and SII are negatively associated (Table 4).

Table 4.

Association Between Biochemical Variables and Dementia Severity, Adjusted for Gender.

	Male		Female
	Unstandardized coefficients (B)	P	Unstandardized coefficients (B)	P
Age (years)	.002	.870	.023**	.019**
Hemoglobin (g/dL)	−.114*	.022*	.086	.172
WBC count (10 B/L)	−.065	.137	−.039	.638
Neutrophil (10 B/L)	−.011	.924	.160	.256
Lymphocyte (10 B/L)	−.045	.646	−.343***	.043***
Platelet (10 B/L)	.003	.084	−.001	.744
NLR	.273	.062	.298	.088
PLR	−.003	.431	.010**	.012**
SII (10 B/L)	−.001	−.943	−.002***	.047***

Linear Regression is used. *Hemoglobin level is significantly negative associatied with dementia severity for male. **Age and PLR are significantly positive associated with dementia severity for female. ***Lymphocyte and SII are significantly negative associated with dementia severity for female.

In the analysis of age-adjusted data, NLR, PLR, and SII are significantly positively associated with dementia severity (Table 5).

Table 5.

Association Between Biochemical Variables and Dementia Severity, Adjusted for Age.

	Unstandardized coefficients (B)	P
Hemoglobin (g/dL)	−.052	.184
WBC count (10 B/L)	−.049	.100
Neutrophil (10 B/L)	.069	.100
Lymphocyte (10 B/L)*	−.241	.004
Platelet (10 B/L)	.001	.222
NLR**	.248	.000
PLR**	.004	.000
SII (10 B/L)**	.001	.000

*Lymphocyte is significantly negative associated with dementia severity. **NLR, PLR and SII are significantly positive associated with dementia severity.

Among the inflammatory markers, the NLR had the strongest correlation with dementia severity (r = .286; P < .001), followed by PLR (r = .138; P = .069) and SII (r = .217; P = .004; Table 6).

Table 6.

Correlations of NLR. PLR. and SII with Dementia Severity.

	NLR		PLR		SII
	r	P	r	P	r	P
Dementia severity	.286	.000*	.138	.069	.217	.004*

*Statistically wsignificant (P < .05). NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SII, systemic immune-inflammatory index.

ROC curve analysis and the Youden index were used to determine the optimal serum NLR for distinguishing mild dementia from moderate and severe types of dementia. The area under the ROC curve for NLR was 71.90 (95% confidence interval [CI], .552-.700; Figure 1). ROC curve analysis for moderate-severe dementia revealed that the optimal NLR cutoff value was 2.89 with sensitivity, specificity, and accuracy values of 56.1%, 75.4%, and 62.8%, respectively (Table 7). Furthermore, ROC curve analysis and the Youden index were used to determine the SII value that distinguished mild dementia from moderate and severe types of dementia. The area under the ROC curve for SII was 63.4 (95% CI, .623-.764; Figure 2). ROC curve analysis for moderate-severe dementia showed that the optimal SII cutoff value was 335.15 with sensitivity, specificity, and accuracy values of 90.4%, 31.1%, and 69.7%, respectively (Table 8).

Figure 1.

ROC curve analysis of NLR to predict mild and moderate-severe dementia. ROC: receiver operating characteristic; NLR: neutrophil-to-lymphocyte ratio.

Table 7.

ROC Curve Analysis of NLR Cutoff for Mild and Moderate-Severe Dementia.

Cutoff	2.39
Specificity	75.4%
Sensitivity	56.1%
Accuracy	62.8%
Area under the curve	67.8%
95% CI	.552-.700
P-value	.001*

*Statistically significant (P < .05). ROC, receiver operating characteristic; NLR, neutrophil-to-lymphocyte ratio.

Figure 2.

ROC curve analysis of SII to predict mild and moderate-severe dementia. ROC: receiver operating characteristic; SII: systemic immune-inflammation index.

Table 8.

ROC Curve Analysis of SII Cutoff for Mild and Moderate-Severe Dementia.

Cutoff	335.15
Specificity	31.1%
Sensitivity	9.4%
Accuracy	69.7%
Area under the curve	63.4%
95% CI	.623-.764
P-value	.000*

*Statistically significant (P < .05). ROC, receiver operating characteristic; SII, systemic immune-inflammation index.

Discussion

We found that SII and NLR values were significantly lower in patients with mild dementia than in patients with moderate or severe dementia. Furthermore, compared with PLR and SII, NLR was a better predictor of dementia. To our knowledge, this study is one of the first to investigate the prognostic values of inflammatory markers in patients with dementia.

Inflammatory processes and neurodegeneration are common features of AD.²² Serum NLR and PLR,^13,23-25 as well as SII,²⁶ are easily accessible, cost-effective prognostic indicators of inflammation status. The NLR integrates information from two distinct leukocyte subtypes, thereby avoiding the use of misleading information from a single leukocyte subtype, which may be affected by infection or dehydration; thus, it has greater clinical significance than other independent inflammatory biomarkers.²⁷ The NLR, derived from a widely available complete blood count laboratory test,¹⁸ has been studied as a prognostic factor in diseases such as coronary artery disease,^28,29 cancer,^30,31 and inflammatory diseases.³² Kuyumcu et al.³³ reported that the NLR was higher in patients with AD than in controls. By measuring NLR and neocortical amyloid load in patients with AD, Rembach et al.³⁴ found that the NLR was significantly elevated and was correlated with neocortical amyloid load. In another study, the NLR was significantly elevated among patients with AD and patients with mild cognitive impairment.¹⁷ Another study revealed that the NLR was elevated in patients with AD and mild cognitive impairment, whereas the PLR was not significantly different.¹³ Li et al.²⁶ found that the NLR, but not the PLR, was significantly elevated in patients aged > 60 years who had cognitive impairment. Moreover, individuals with an elevated NLR had greater risk of dementia during a 5.9-year follow-up period. Our findings are consistent with previous reports of an association between the NLR and AD. We also found that the NLR significantly increased with increasing dementia severity. In contrast to previous studies, we found that the PLR significantly differed between AD and control groups. The most notable finding in the present study was that the NLR could more reliably predict dementia severity, compared with PLR and SII, suggesting that the platelet count does not provide additional prognostic information.

It is well known that the primary function of platelets is related to the coagulation system and hemostasis. However, they also play a role in inflammatory processes and the proliferation of megakaryocytes, which results in an increase in platelet count. Chemokines, cytokines, and procoagulant molecules released from platelets activated by inflammation are reported to play a role in the immune response as acute phase reactants. Dağıstan et al, Yeşil et al, Chen et al, and Koç et al have shown that an increase in mean platelet volume (MPV) is associated with Alzheimer’s disease (AD),^35-38 while Dong et al¹⁷ have found it to be associated with mild cognitive impairment (MCI). Additionally, Liang et al and Dong et al have demonstrated that a decrease in platelet distribution volume (PDV) is significant for AD.^17,39 In our study, consistent with the literature, we found that the platelet-lymphocyte ratio (PLR) significantly differed between the AD and control groups. Another result obtained in our study, which differs from other studies in the literature, is that, when the correlation analyzes of the markers are examined, the neutrophil-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) values were more correlated with dementia levels compared to PLR.

Sex differences in dysregulation of glial cell-mediated neuro-immune responses have been implicated in AD⁴⁰ It has been revealed that Alzheimer’s disease is more common in women and the severity of the disease is more severe.⁴¹ Women usually have stronger immune responses to stimulations than men involving different pathways and immune cells, correlating to higher susceptibility to infections in male. In a preclinical study where experimental AD was induced in male and female mice, it was demonstrated that female mice exhibited increased expression of pro-inflammatory cytokines and an enhanced microglial response.⁴² In our study, we found that in female patients, age and PLR are significantly positively associated with dementia severity, while lymphocyte count and SII are negatively associated. In contrast, no association was found between peripheral immune system markers and dementia in male patients. These results suggest that, as highlighted in the literature, the differences in immune responses between males and females may contribute to these findings, with immune responses being more pronounced in females compared to males.

Several previous studies have utilized ROC curve analysis to determine diagnostic accuracy for AD. Kuyumcu et al.³³ reported sensitivity of 70% and specificity of 80% for AD diagnosis, whereas another study revealed that the specificity and sensitivity for AD diagnosis were 54% and 83%, respectively.¹⁷ In the present study, ROC curve analysis showed that the sensitivity and specificity of NLR for mild and moderate-severe types of dementia were 56.1% and 75.4%, respectively. Although previous studies utilized ROC curve analyses to distinguish patients with dementia and control participants, we believe that our ROC curve analysis of dementia severity provides novel information.

The SII is an easily measurable, inexpensive novel inflammatory index that can be calculated using the neutrophil, platelet, and lymphocyte counts obtained from routine peripheral blood tests. This biomarker was first proposed by Hu et al.⁴³ in 2014 to predict the prognosis of hepatocellular carcinoma. A previous study revealed a significant correlation between increased carotid intima-media thickness and SII value in patients with hypertension¹⁵; another study showed a positive correlation between SII value and poor prognosis in patients with coronary artery disease.⁴⁴ Furthermore, the SII is correlated with disease activity in patients with ankylosing spondylitis and ulcerative colitis.^14,45 Li et al.²⁶ reported that the SII was significantly higher in patients aged > 60 years who had cognitive impairment. In the present study, the SII did not significantly differ between the dementia and control groups; however, SII values differed among dementia severity subgroups. We found that the SII had a diagnostic accuracy of 69.7% for dementia severity. Although this diagnostic accuracy is not high, we found no previous investigations related to SII and diagnostic accuracy for dementia severity; therefore, we present our findings as a contribution to the literature.

Our study had several limitations including the small number of cases, the single-center and cross-sectional study design, and the inability to exclude other factors potentially involved in inflammation. Our study has a cross-sectional design, therefore future studies with longitudinal design are needed to confirm the findings of study.

In conclusion, SII was associated with dementia severity in patients with AD; however, compared with PLR and SII, NLR was more strongly correlated with dementia severity. In future studies with larger populations, SII and NLR values can be used to determine dementia severity and establish follow-up plans for patients with high dementia risk. Moreover, changes in neutrophil and lymphocyte ratios may constitute specific markers of dementia severity.

Supplemental Material

Supplemental Material - Increased Systemic Immune-Inflammation Index as a Novel Indicator of Alzheimer’s Disease Severity

Supplemental Material for Increased Systemic Immune-Inflammation Index as a Novel Indicator of Alzheimer’s Disease Severity by Fatma E. Algul and Yuksel Kaplan in Journal of Geriatric Psychiatry and Neurology

Footnotes

Author Contributions

F.E.A., Y.K.: conceptualized the study. F.E.A.: analyzed the data. Y.K.: inferential statistics; language editing; provided expert advice in clinical pharmacology. F.E.A., Y.K.: provided expert advice inpsychiatry and psychopharmacology. F.E.A.: interpreted the study results, drafted the firstversion of the manuscript, created the tables and figures. F.E.A., Y.K.: assisted with the preparationof the manuscript. Y.K.: supervised the project. All authors: commented on previous versions of the manuscript; read and approved the final manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Fatma E. Algul

Supplemental Material

Supplemental material for this article is available online.

Appendix

References

Crous-Bou

Minguillón

Gramunt

Molinuevo

. Alzheimer’s disease prevention: from risk factors to early intervention. Alzheimer's Res Ther. 2017;9(1):71.

Hachinski

Lassen

Marshall

. Multi-infarct dementia. A cause of mental deterioration in the elderly. Lancet. 1974;2:207-210.

Suri

Topiwala

Mackay

, et al. Using structural and diffusion magnetic resonance imaging to differentiate the dementias. Curr Neurol Neurosci Rep. 2014;14:475.

Villeneuve

Reed

Madison

, et al. Vascular risk and Ab interact to reduce cortical thickness in AD vulnerable brain regions. Neurology. 2014;83:40-47.

Zenaro

Pietronigro

Bianca

, et al. Neutrophils promote Alzheimer's disease–like pathology and cognitive decline via LFA-1 integrin. Nat Med. 2015;21:880-886.

Akıl

Bulut

Kaplan

, et al. The increase of carcinoembryonic antigen (CEA), high-sensitivity C-reactive protein, and neutrophil/lymphocyte ratio in Parkinson' disease. Neurol Sci. 2015;36(3):423-428.

Gharagozloo

Gris

Mahvelati

, et al. NLR dependent regulation of inflammation in Multiple Sclerosis. Front Immunol. 2018;8:2012.

Hou

Ding

, et al. Prognostic value of neutrophil-to-lymphocyte ratio in stroke: a systematic review and metanalysis. Front Neurol. 2021;2:686983.

Afari

Bhat

. Neutrophil-to-Lymphocyte ratio and cardiovascular diseases: an update. Expert Rev Cardiovasc Ther. 2016;14:573-577.

10.

Serrano-Pozo

Muzikansky

Gomez-Isla

, et al. Differential relationships ofnreactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease. J Neuropathol Exp Neurol. 2013;72:462-471.

11.

Olsson

Lautner

Andreasson

, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15(7):673-684.

12.

Sayed

Bahbah

Kamel

, et al. The neutrophil-to-lymphocyte ratio in Alzheimer’s disease: current understending and potential applications. J Neuroimmunol. 2020;349:577398.

13.

Kalelioglu

Akkus

Karamustafalioglu

, et al. Neutrophil, lymphocyte and platelet-lymphocyte ratios in people with subjective, mild cognitive impairment and early Alzheimers’s disease. Psychogeriatrics Note. 2017;17:506-508.

14.

Yan

Chai

. Systemic immune-inflammation index is associated with disease activity in patients with ankylosing spondylitis. J Clin Lab Anal. 2021;35:e23964.

15.

Çırakoğlu

Yılmaz

. Systemic immune-inflammation index is associated with increased carotid intima-media thickness in hypertensive patients. Clinical and Experimental Hypertansion. 2021;6:565-571.

16.

Liu

Chen

, et al. Systemic immune-inflammation index predicts the severity of coronary stenosis in patients with coronary heart disease. Coron Artery Dis. 2021;32:715-720.

17.

Dong

Nao

Shi

Zheng

. Predictive value of routine peripheral blood biomarkers in Alzheimer’s disease. Front Aging Neurosci. 2019;11:332.

18.

Ramos-Cejuda

Johnson

Beiser

, et al. The neutrophil-to-lymphocyte ratio is associated with the risk of subsequent dementia in the Framingham heart study. Front Aging Neurosci. 2021;13:773984.

19.

McKhann

Drachman

Folstein

, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of department ofHealth and human services task force on Alzheimer’s disease. Neurology. 1984;34:939-944.

20.

Cupp

Cariolou

Tzoulaki

, et al. Neutrophil to lymphocyte ratio and cancerprognosis: an umbrella review of systematic reviews and meta-analyses of observational studies. BMC Med. 2020;18:360.

21.

Hughes

Berg

Danziger

, et al. A new clinical scale for the staging ofdementia. Br J Psychiatry: J Ment Sci. 1982;140:566-572. doi:10.1192/bjp.140.6.566

22.

Vergallo

Megret

Lista

, et al. Plasma amyloid beta 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer’s disease. Alzheimers Dement. 2019;15:764-775.

23.

Ucar

Gokce

Unal

, et al. Comparison of neutrophil-lymphocyte ratio (NLR) in Parkinson’s disease subtypes. Neurol Sci. 2017;38:287-293.

24.

Kotfis

Bott-Olenjik

Szylinska

Rotter

. Could neutrophil-lymphocyte ratio (NLR) serve as a potential marker for delirium prediction in patients with acute ischemic stroke? A prospective observational study. J Clin Med. 2019;8:1075.

25.

Tak

AZA

Sengul

. Evaluation neutrophil-lymphocyte ratio (NLR) and platelet-tolymphocyte ratio in essential tremor. Ideggyogy Sz. 2019;72:33-38.

26.

Shang

, et al. Associations between dietary and blood inflammatory indices and their effects on cognitive function in elderly Americans. Front Neurosci. 2023;17:1117056.

27.

Petrone

Eisenman

Steele

, et al. Temporal dynamics of peripheral neutrophil and lymphocytes following acute ischemic stroke. Neurol Sci. 2019;40:1877-1885. doi:10.1007/s10072-019-03919-y

28.

Uthamalingam

Patvardhan

Subramanian

, et al. Utility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failure. Am J Cardiol. 2011;107:433-438.

29.

Tamhane

Aneja

Montgomery

, et al. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol. 2008;102:653-657.

30.

Kishi

Kopetz

Chun

, et al. Blood neutrophil-to-lymphocyte ratio predicts survival in patients with colorectal liver metastases treated with systemic chemotherapy. Ann Surg Oncol. 2009;16:614-622.

31.

Sato

Tsubosa

Kawano

. Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. World J Surg. 2012;36:617-622.

32.

Azab

Jaglall

Atallah

, et al. Neutrophil-lymphocyte ratio as a predictor of adverse outcomes of acute pancreatitis. Pancreatology. 2011;11:445-452.

33.

Kuyumcu

Yesil

Ozturk

, et al. The evaluation of neutrophil-lymphocyte ratio in Alzheimer's disease. Dement Geriatr Cogn Disord. 2012;34:69-74.

34.

Rembach

Watt

Wilson

, et al. An increased neutrophil-lymphocyte ratio in Alzheimer’s disease is a function of age and is weakly correlated with neocortical amyloid accumulation. J Neuroimmunol. 2014;273:65-71. doi:10.1016/j.jneuroim.2014.05

35.

Chen

Jin

, et al. Altered peripheral profile of blood cells in Alzheimer disease: a hospital-based case-control study. Medicine. 2017;96:e6843. doi:10.1097/MD.0000000000006843

36.

Dagistan

Cosgun

. Could hemogram parameters be predictors of dementia in elderly patients? Aging Male. 2019;22:192-197. doi:10.1080/13685538.2019.1618821

37.

Yesil

Kuyumcu

Cankurtaran

, et al. Increased mean platelet volume (MPV) indicating the vascular risk in Alzheimer’s disease (AD). Arch Gerontol Geriatr. 2012;55:257-260. doi:10.1016/j.archger.2011.09.016

38.

Koc

Uzar

Cirak

Parlak

Ilhan

. The increase of mean platelet volume in patients with Alzheimer disease. Turk J Med Sci. 2014;44:1060-1066. doi:10.3906/sag-1212-1215

39.

Liang

Jin

Wang

. Mean platelet volume and platelet distribution width in vascular dementia and Alzheimer’s disease. Platelets. 2014;25:433-438. doi:10.3109/09537104.2013.831064

40.

Dzamba

Harantova

Butenko

Anderova

. Glial cells—the key elements of Alzheimer’s disease. Curr Alzheimer Res. 2016;13(8):894-911.

41.

Zhu

Montagne

Zhao

. Alzheimer’s pathogenic mechanisms and underlying sex diference. Cell Mol Life Sci. 2021;78:4907-4920.

42.

Kodama

Guzman

Etchegaray

, et al. Microglial micro RNAs mediate sex-specific responses to tau pathology. Nat Neurosci. 2020;23(2):16.

43.

Yang

, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin Cancer Res. 2014;20:6212-6222.

44.

Liua

Yea

Chena

, et al. Systemic immune-inflammation index predicts the severity of coronary stenosis in patients with coronary heart disease. Coron Artery Dis. 2021;32:715-720.

45.

Zhang

Wang

, et al. Effective immune-inflammation index for ulcerative colitis and activity assessments. World J Clin Cases. 2021;9(2):334-343.

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