The relationship between chronic anemia caused by hematologic disease and cognitive impairment

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The relationship between chronic anemia caused by hematologic disease and cognitive impairment

https://doi.org/10.21203/rs.3.rs-3231589/v1

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Patients with hematology disease ( such as aplastic anemia, primary myelofibrosis, and myelodysplastic syndrome) always in the condition of moderate and severe anemia for a long time. However, this chronic anemia condition impact on cognitive function was not well studied. We aim to explore the relationship between chronic anemia and cognitive function. We conducted a cross-sectional study. Collecting patients’ clinical dates and demographic characteristics from blood routine examination and self report. Objective cognition function was assessed by Chinese versions of Montreal Cognitive Assessment ( MoCA), total score of cognitive function and subscores of cognitive domains were calculated for each. Associations with chronic anemia and cognitive function were estimated using logistic regression. A total of 214 people including 70 chronic anemia and 144 non-anemia. Chronic anemia was independent factor for overall cognitive impairment, visual space and execution, attention, abstract and delayed recall (P < 0.05). The longer time of chronic anemia, the more possibility to have cognitive decline (P < 0.05). 36.5 months is a cutoff line for cognitive impairment among patients with chronic anemia. Chronic anemia can cause cognitive impairment; the longer time of chronic anemia, the easier to have cognitive decline.

Biological sciences/Neuroscience/Cognitive neuroscience

Biological sciences/Neuroscience/Social behaviour

Biological sciences/Neuroscience

Health sciences/Diseases

Health sciences/Neurology

Health sciences/Risk factors

chronic anemia

aplastic anemia

primary myelofibrosis

myelodysplastic syndrome

cognitive impairment

Chronic anemia usually refers to hemoglobin (Hb) concentrations less than 13 g/dL in men and less than 12 g/dL in women according to WHO standard for a least 6 months. [1] A number of diseases can induce chronic anemia such as chronic kidney disease, malignant tumors, bone marrow failure, chronic infections and non-infectious inflammation. [2–4] In addition, we found patients who have aplastic anemia, primary myelofibrosis and myelodysplastic syndrome always in the condition of moderate and severe anemia for a long time. [5–7] Although, they can survive for longer time relying on occasionally transfusion. However, their Hb concentrations were difficult to reach to normal range. As a result, patients have one of these three blood system disease always in the condition of chronic anemia.

Prevalence of cognitive impairment increases exponentially with increasing age, and doubles every five years of age after age 65. One the other hand, anemia has long been considered to be associated with cognitive impairment and dementia. [8–9] Cognitive impairment including mild, moderate and severe cognitive decline. [10] Existing studies have shown that anemia is closely related to cognitive impairment. [9.11]. Anemia usually found among children, gravida, elderly people and groups have chronic disease. [12–15] However, researches about chronic anemia caused by blood disease impact on cognitive function were limited.

Anemia impact on cognitive function was controversial. Some researches found that anemia was independant factor for cognitive decline. [16] However, other studies shown that anemia has no impact on cognitive dysfunction. [17] Whether chronic anemia due to blood system disease can cause cognitive impairment is unknow. Therefore, we conducted this study to explore the relationship between chronic anemia and cognitive impairment.

Study design and participants

The study was approved by the Ethics Committee of Lianyungang First People's Hospital ( No. LW-20230621001-01) and was in line with the Declaration of Helsinki. After a detailed description of the study, participants gave written informed consent. 70 patients with chronic anemia were selected from September 2021 to September 2022, and 144 healthy people were selected as the comparing group. The inclusion criteria: 1) Patients with aplastic anemia, myelodysplastic syndrome or primary myelofibrosis; 2) Hb concentrations below WHO standards ( Hb concentrations less than 13 g/dL in men and less than 12 g/dL in women); [18] 3) Time of anemia ≥ 6 months;[1] 4) Being able to complete cognitive function assessments. Exclusion criteria: 1) Performed adiotherapy, chemotherapy, and targeted therapy; 2) Performed bone marrow transplantation; 3) Had cerebral infarction and cerebral hemorrhage and related history; 4) Had neurological damage caused by non-cerebrovascular disease (e.g. primary and metastatic tumors, post-seizure paralysis, head trauma, etc.); 5) Being diagnosed subarachnoid hemorrhage; 6) Already have cognitive impairment or dementia before admission. The inclusion criteria for non-anemic patients: Hb concentrations in normal range according to the WHO criterion. [18] Exclusion criteria: 1) Had hematological diseases, stroke, subarachnoid hemorrhage; 2) Had neurological damage caused by non-cerebrovascular diseases (such as primary and metastatic tumors, post-seizure paralysis, head trauma, etc.) and central nervous system infections.

Clinical Measurement

The demographic characteristics as well as clinical dates were obtained through standardized questionnaires interviewed by trained neurologists and routine examination of blood. Demographic datas consisted of age, gender, body mass index (BMI) and years of education. We also collected information including hypertension, hyperlipidemia, diabetes mellitus, smoke and alcohol drinking state according to ask patients directly or the medicine they are taking.

Cognitive function assessment

Cognitive function was assessed by a training neurologist who blinded to subjects. Cognitive impairment was evaluated using Chinese version Montreal Cognitive Assessment (MoCA), a simple, stand-alone cognitive screening tool with superior sensitivity. It covers important cognitive domains, can be administered in 10 minutes, and fits on one page.[19] When the education years of the participants were no more than 12 years, 1 point was added on their MoCA total score (if < 30).[20] A higher score indicates better cognitive function. Cognitive impairment was identified from MoCA: ≤13 for illiterate individuals, ≤ 19 for individuals with 1– 6 years of education, and ≤ 24 for those with 7 or more years of education.

Statistical analyses

Using SPSS 26.0 for the statistical analysis. Datas that conformed to continuous variables were summarized as mean (standard deviation, SD) and the independent sample t-test was used for the groups comparison. Datas that did not conform to the continuous variables are represented by median (quartile) and using Mann-Whitney U test for groups comparison. χ2 test was used for the comparison of categorical variables, and using Mann-Whitney U test for non-categorical variables comparison. Logistic regression was used to analyze factors affecting cognitive dysfunction. GraphPad prism 7 software was used to plot the ROC curve of anemia time to evaluate cognitive dysfunction. P < 0.05 was considered have statistically significance.

Baseline characteristics

Age, BMI and glomerular filtration rate (GFR) of chronic anemia group were lower than non-anemia group (P＜0.05) ( Table 1) The proportion of hypertension, hyperlipidemia, smoking and drinking in the chronic anemia group was significantly lower than that in the non-anemia group (P<0.05)( Table 1) .

Table 1 Comparision of baseline characteristics

characteristics	total (n=214)	Non-anemia(n=144)	Chronic anemia(n=70)	t/Z/χ2	P
Age（average）(year)SD	56.02±16.65	56.50±16.68	55.04±16.65	0.600	0.549
Sex				0.616	0.433
Male n（%）	111(51.9)	72(50.0)	39(55.7)
Female n（%）	103(48.1)	72(50.0)	31(44.3)
education				-1.524	0.128
≤ 6 year n（%）	71(33.2)	43(29.9)	28(40.0)
6-9 year n（%）	77(36.0)	53(36.8)	24(34.3)
>9 year n（%）	66(30.8)	48(33.3)	18(25.7)
BMI(kg/m2)（average）SD	24.90±3.64	25.36±3.54	23.95±3.69	2.705	0.007
Diabetes n（%）	30(14.0)	23(16.0)	7(10.0)	1.394	0.238
hypertension n（%）	79(36.9)	75(52.1)	4(5.7)	43.488	<0.001
Hyperlipidemia n（%）	46(21.5)	37(25.7)	9(12.9)	4.600	0.032
Smoke n（%）	41(19.2)	33(22.9)	8(11.4)	4.014	0.045
Drink n（%）	42(19.6)	34(23.6)	8(11.4)	4.432	0.035
GFR (ml/min)（average）SD	89.69±18.99	94.98±25.30	87.12±14.44	2.414	0.018

Continuous variables are presented as mean ± SD, or median (interquartile range, 25th–75th percentile). BMI = body mass index; GFR = glomerular fifiltration rate.

Cognitive function and anemia

There was no significant difference in named, language, and rotation cognitive impairment of the fields of cognitive function in the two groups (P>0.05).( Table 2) However, chronic anemia group was more likely to have lower overall cognitive function, visual space and execution, attention, abstraction and delayed recall than non-anemia group (P<0.05).( Table 2) After further adjust related variables, chronic anemia is independant factor affecting global cognitive dysfunction, visual space and execution, attention, and abstraction (OR>1, P<0.05).( Table 2)

Table 2 Cognitive function and anemia

Cognitive function	total (n=214)	Non-anemia (n=144)	Chronic anemia (n=70)	t/Z/χ²	Non-conditioning model			Conditioning model
Cognitive function	total (n=214)	Non-anemia (n=144)	Chronic anemia (n=70)	t/Z/χ²	OR(95% CI)	Waldχ²	P	OR(95% CI)	Waldχ²	P
Cognitive impairment n（%）	103(48.1)	60(41.7)	43(61.4)	7.368	2.230(1.243~3.999)	7.235	0.007	5.394(2.517~11.558)	18.788	<0.001
Specific areas of cognitive function
Visual space and execution n（%）	56(26.2)	14(9.7)	42(60.0)	61.628	13.929(6.714~28.897)	50.039	<0.001	14.305(5.717~35.791)	32.332	<0.001
Named n（%）	64(29.9)	42(29.2)	22(31.4)	0.115	1.113(0.599~2.068)	0.115	0.735	1.236(0.655~2.330)	0.428	0.513
Attention n（%）	58(27.1)	10(6.9)	48(68.6)	90.545	29.236(12.916~66.181)	65.573	<0.001	31.535(11.033~90.139)	41.479	<0.001
Language n（%）	50(23.4)	33(22.9)	17(24.3)	0.049	1.079(0.552~2.109)	0.049	0.824	1.584(0.758~3.309)	1.498	0.221
Abstraction n（%）	64(29..9)	18(12.5)	46(65.7)	63.630	13.417(6.675~26.969)	53.128	<0.001	53.280(16.652~170.483)	44.883	<0.001
Delayed recall n（%）	50(23.4)	18(12.5)	32(45.7)	29.021	5.895(2.981~11.658)	25.998	<0.001	-	-	-
Rotation n（%）	24(11.2)	12(8.3)	12(17.1)	3.671	2.276(0.965~5.366)	3.532	0.060	-	-	-

Note:

Cognitive impairment multiple logistic regression after controlling for anemia, age, glomerular filtration rate;

Visual space and executive capacity multiple logistic regression after controlling for anemia, age, alcohol consumption, hypertension;

Named multiple logistic regression after controlling for anemia, smoking;

Attention multiple logistic regression after controlling for anemia, BMI, smoking, hypertension, and hyperlipidemia;

Language multiple logistic regression after controlling for anemia, age, gender, smoking;

Abstractions multiple logistic regression after controlling for anemia, age, education, and hypertension.

Time of anemia and cognitive impairment

The incidence of cognitive impairment in anemia, time ≤ 15, 16-45, and ≥ 46 months was 42.9%, 50.0%, and 85.2% respectively (P<0.05).(Table 3) It can be seen from the ROC curve (Figure 1) indicates that time of anemia can forecast cognitive impairment and cutoff time was 36.5 months (sensitivity was 67.4% and specificity was 85.2%).

Table 3 Time of anemia and cognitive impairment

Time of anemia (months)	Number	Cognitive impairment
≤15	21	9(42.9)
16-45	22	11(50.0)
≥46	27	23(85.2)^ab
χ²	-	10.701
P	-	0.005
a: compared with ≤ 15 months; b: compared with 16-45 months (P<0.05).

Logistic regression of anemia and cognitive impairment

Participants with cognitive impairment group have lower GFR than participants without cognitive dysfunction (P<0.05). ( Table 4) From logistic regression, there is a significant correlation between age, glomerular filtration rate, anemia and cognitive impairment (P<0.05). ( Table 4) Further taking age, GFR and anemia as independent variables, and establish a binary logistic regression model. The results showed that age and anemia can cause cognitive impairment(P <0.05; OR>1 ).( Table 4) In addition, the risk of cognitive impairment increased 0.102 times when age be one year older and people with chronic anemia has 4.394 times to have cognitive impairment than without anemia.( Table 4)

Table 4 Logistic regression of anemia and cognitive impairment

characteristics	Non-cognitive impairment (n=111)	Cognitive impairment (n=103)	χ²	P	Single factor			Single factor
characteristics	Non-cognitive impairment (n=111)	Cognitive impairment (n=103)	χ²	P	OR(95% CI)	Waldχ²	P	OR(95% CI)	Waldχ²	P
Age（average） (year) SD	49.80±15.67	62.73±15.05	6.146	<0.001	1.085(1.055~1.115)	32.694	0.000	1.102(1.066~1.139)	32.584	<0.001
Sex（average）SD			2.207	0.137	1.504(0.877~2.579)	2.199	0.138	-	-	-
Male n（%）	63(56.8)	48(46.6)
Female n（%）	48(43.2)	55(53.4)
Education			-1.481	0.139	0.777(0.554~1.089)	2.149	0.143	-	-	-
≤ 6 year n（%）	30(27.0)	41(39.8)
6-9 year n（%）	45(40.5)	32(31.1)
>9 year n（%）	36(32.4)	30(29.1)
BMI(kg/m²)（average）SD	25.26±3.86	24.51±3.37	1.503	0.134	0.944(0.875~1.018)	2.222	0.136	-	-	-
Diabetes n（%）	13(11.7)	17(16.5)	1.018	0.313	1.490(0.684~3.244)	1.010	0.315	-	-	-
Hypertension n（%）	39(35.1)	40(38.8)	0.314	0.575	1.172(0.672~2.043)	0.314	0.575	-	-	-
Hyperlipidemia n（%）	28(25.2)	18(17.5)	1.901	0.168	0.628(0.323~1.220)	1.884	0.170	-	-	-
Smoke n（%）	19(17.1)	22(21.4)	0.621	0.431	1.315(0.665~2.603)	0.619	0.432	-	-	-
Drink n（%）	25(22.5)	17(16.5)	1.226	0.268	0.680(0.343~1.349)	1.218	0.270	-	-	-
GFR (ml/min)（average）SD	93.68±18.85	85.39±18.29	3.260	0.001	0.975(0.960~0.991)	9.616	0.002	0.998(0.977~1.018)	0.050	0.823
Anemia n（%）	27(24.3)	43(41.7)	7.368	0.007	2.230(1.243~3.999)	7.235	0.007	5.394(2.517~11.558)	18.788	<0.001

To the best of our knowledge, this is the first study to explore the relationship between chronic anemia caused by blood system disease and cognitive impairment. Our study demonstrated that chronic anemia can cause a decline in overall cognitive function, visual space and executive ability, attention, abstraction, and delayed recall function. The longer time of chronic anemia, the greater the possibility of cognitive impairment.

Chronic anemia can cause global cognitive decline, with effects on the four aspects of visual space and executive ability, attention, abstraction, and delayed recall, which is consistent with the results of Qin et al. study of anemia induced global cognitive decline and scene memory decline.[21] In addition, one study also showed that long-term anemia status will damage to the nervous system, which can greatly affect cognitive function.[22] However, different to studies reported before, our study focus on exploring chronic anemia caused by blood system disease was associated with cognitive impairment. Our study showed that chronic anemia affect cognitive function in specific domains, which was also limited in the current study.

Interestingly, some studies had opposite conclusion to our study, which showed anemia can not induce cognitive impairment.[17] The reason of this result may be because healthy people can regulate Hb concentration in the short term so that they avoided cognitive impairment. As reported in relevant literature, anemia was indeed related to memory loss.[23] However, it does not have particular effect on the executive function within a certain time window.[24] Chronic anemia caused was different, on the one hand, because the time of chronic anemia usuallt longer, which easy cause dysfunction of Hb concentration for a long time. As a result, cognitive impairment will follow up. In addition, as Atti et al. implied that anemia and cognitive impairment have a dose-response relationship,[25] a slight decrease in Hb concentration, may not have much effect on cognitive function. However, most of the people with chronic anemia are more intend in the condition of moderate or severe anemia.[26] That was to say people with chronic anemia have lower Hb concentration, as a result they are easier have cognitive dysfunction. [27] In addition, it also can explain the longer chronic anemia, the easier cognitive impairment have.

Several pathological mechanisms on anemia-induced cerebral injury may elucidate the effect of chronic anemia on cognitive impairment.[25] Studies found that anemia can lead to subcortical ischemia, and patients with anemia had severe white matter hyper signal perform, which induce worse in performing function[28] Insufficient cerebral blood oxygen supply, β deposition of amyloid and tau protein lead brain hypoxia and iron deficiency in the brain may affect neurotransmitter metabolism.[29,30] Therefore, we hypothesize that people with chronic anemia, due to low hemoglobin levels in the blood for a long time, lead to cerebral oxygen deficiency, repeat cerebral insults and cannot carry out effective physiological functions, resulting in cognitive decline, but it requires further research.

The reasons why aplastic anemia, primary myelofibrosis, and myelodysplastic syndrome are chosen as the source of chronic anemia: chronic anemia, refers to hematopoietic dysfunction of the human body and it is a common clinical syndrome.[31] People have these three diseases always in the condition of chronic anemic for a long time. We found that people with these three diseases gradually have cognitive decline. Therefore our study fucus on these people and further evidence whether chronic anemia caused by blood system disease will pose cognitive impairment.

Strengths and limitations

Our study also has certain shortcomings, as it fails to demonstrate effective interventions to prevent cognitive impairment caused by chronic anemia, and further research is needed to find possible methods to alleviate cognitive decline caused by chronic anemia. In addition, our study of chronic anemia had a small number of people and needed a larger sample size to further confirm our findings. Our research advantage is to explore new areas of research on chronic anemia and cognitive impairment and has certain clinical diagnosis and treatment reference value. On the other hand, we exclude other factors to make our results more reliable.

Declarations of interest: none

Acknowledgments

Thank you for all authors’ contribution to this paper. This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. SJCX23_1417). The funder played no role in any aspect of the manuscript, including the review idea, design, analysis, or interpretation.

Funding sources

This work was supported by the Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. SJCX23_1417).

Consent statement

All participants provided informed consent.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author contribution

Liaoyang Xu: Analysis and interpretation of data and drafting the article.

Hang Zhou: The conception and design of the study and acquisition of data.

Xinyu Zhou: Revising it critically for important intellectual content and final approval of the version to be submitted.

Jifeng Wei: Revising it critically for important intellectual content.

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No competing interests reported.

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The relationship between chronic anemia caused by hematologic disease and cognitive impairment

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Abstract

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Background

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Study design and participants

Clinical Measurement

Cognitive function assessment

Statistical analyses

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