Additive effect of metabolic syndrome on brain atrophy in people living with HIV – magnetic resonance volumetry study

doi:10.21203/rs.3.rs-3107995/v1

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Additive effect of metabolic syndrome on brain atrophy in people living with HIV – magnetic resonance volumetry study

https://doi.org/10.21203/rs.3.rs-3107995/v1

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published 13 Jun, 2024

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With people living with HIV (PLWH) reaching senium, the importance of aging-related comorbidities such as metabolic syndrome (MS) becomes increasingly important. The aim of this study was to determine the additive effect of MS on brain atrophy in PLWH.

This prospective study included 43 PLWH, average age 43.02 ± 10.93 years and 24 healthy controls, average age 36.87 ± 8.89 years. PLWH were divided into two subgroups: without MS and with MS, according to NCEP-ATP-III criteria. All patients underwent brain magnetic resonance (MR)imaging on 3T clinical scanner with MR volumetry, used for defining volumes of cerebrospinal fluid (CSF) spaces and white and grey matter structures, including basal ganglia. ANOVA was used to determine differences in brain volumes between subject subgroups. Binary classification was performed to determine sensitivity and specificity of volumetry findings and cut-off values. Statistical significance was set at p < 0.05.

PLWH presented with significantly lower volumes of gray matter, putamen, thalamus, globus pallidus and nc. accumbens compared to healthy controls; cut-off values were: for gray matter 738.130 cm³, putamen 8.535cm³, thalamus 11.895 cm³, globus pallidus 2.252 cm³ nc. accumbens 0.715 cm³. Volumes of CSF and lateral ventricles were higher in PLWH with MS compared to those without MS- with specificity of 0.310 and sensitivity of 0.714 it can be assumed that PLWH with CSF volume above 212.83cm³ will also have MS.

There seems to be an important connection between MS and brain volume reduction in PLWH with MS, which may add to accurate identification of persons at risk of developing HIV-associated cognitive impairment.

Biological sciences/Neuroscience

Health sciences/Diseases/Infectious diseases

Health sciences/Diseases/Metabolic disorders

The main result of the introduction of cART (combined antiretroviral therapy) is effective peripheral suppression of viral replication and the consequent prolongation of life expectancy in patients with HIV infection. However, latency of HIV in its reservoirs - adypocites, microglia and macrophages, induces a persistent systemic low-level inflammation and immune activation, leading to a series of comorbidities [1–3]. Adypocite latency is reflected through an intensive process of lipolysis, hyperglycaemia and hypertriglyceridaemia, which results in redistribution of adipose tissue in the body and accumulation of visceral fat [4, 5]. Visceral fat itself is the source of many inflammatory proteins and together with HIV infection it contributes to a number of complications at the cardiometabolic, neurocognitive and many other levels [6].

A number of studies have shown that patients with HIV infection presented lower brain volumes compared to healthy controls [7]. The degree of brain tissue atrophy in HIV infection is variable, with recent studies showing the presence of brain atrophy even in neuroasymptomatic patients [8]. In addition, people with metabolic syndrome, steatosis, elevated cardiovascular risk, etc. also have significantly lower brain volumes than healthy controls [9–13]. The additive effect of HIV infection and metabolic syndrome as comorbidity, on the reductive changes in central nervous system has not been evaluated to the date.

The aim of this study was to determine whether there was a significant additive effect of metabolic syndrome as comorbidity on brain atrophy in patients with HIV infection.

2.1 Subject selection

This prospective study included a total 24 healthy subjects, average age 36.87 ± 8.89, and 43 HIV-positive male subjects, average age 43.02 ± 10.93 years. HIV positive subjects were further divided into subgroups of HIV-positive patients without the presence of metabolic syndrome, and HIV-positive patients with diagnosed metabolic syndrome, according to NCEP ATP III criteria [14]. All HIV-positive patients were stable on cART for at least 6 months, with undetectable viral loads. At the time of study, all patients included were on the old fashion cART, that did not include integrase strand transfer inhibitors (INSTI).

Inclusion criteria for the group of healthy subjects was age over 18, absence of any pathological condition confirmed by clinical examination and laboratory tests.

In the groups of HIV-positive patients inclusion criteria included: the presence of HIV infection confirmed by Western–Blot analysis, and:

Absence of any pathological findings in clinical examination and laboratory results for the subgroup of patients with HIV infection without comorbidities.
Confirmed metabolic syndrome using NCEP ATP III criteria, and the absence of any other pathological findings on clinical examination and laboratory results for the group of patients with HIV infection with metabolic syndrome.

The criteria for exclusion from the study were: the presence of active opportunistic CNS infection (toxoplasmosis, cytomegalovirus, tuberculosis, PML (progressive multifocal leukoencephalopathy), cryptococcosis), the presence of focal or diffuse white mass lesions (brain tumors, metastases, vascular malformations), history of brain irradiation, active substance abuse and alcohol abuse, co-infections with Hepatitis C and Hepatitis B, and contraindications for MR imaging. The study was approved by the institutional ethical committee and all subjects signed informed consent to participate in the study.

2.2 Clinical and laboratory data

Blood glucose, high density lipoprotein (HDL), low density lipoprotein (LDL) and triglycerides (TG) levels were obtained from each patient. Body height (BH), waist (WC) and hip circumference (HC), waist-to-hip ratio (WHR), BMI (body mass index) and blood pressure were also measured for each patient.

2.3 MR imaging

All patients underwent conventional MRI on a 3T magnetic resonance unit (Trio Tim, Siemens, Erlangen, Germany) using an 8-channel head coil. Conventional MR imaging consisted of T1-weighted sagittal spin echo (TR/TE 440ms/3.8 ms, section thickness 5 mm, duration 2:00 min), T2-weghted turbo spin echo axial (TR/TE 5150 ms/105 ms, section thickness 5 mm, duration 2:57 min), FLAIR (Fluid Attenuation Inversion Recovery) axial tomograms (TR/TE 8000 ms /101 ms, 5 mm section thickness, duration 3:30 min), diffusion-weighted imaging (DWI) (TR /TE4100 ms/91 ms, 5 mm section thickness, duration 2:07 min), coronal T2-weighted turbo spin echo tomograms (TR/TE 7150 ms/111 ms, section thickness 5 mm, duration 2:17 min), and 3D T1W MP-RAGE (magnetization prepared rapid acquisition gradient echo) sagittal tomograms (TR/TE 1530 ms / 2.97 ms, section thickness 1 mm, duration 5:12 min).

Volumetric measures of the brain structures for all subjects were obtained using an online automatic analysis system called: “VolBrain”, available through the website: www.volbrain.upv.es. Raw data were converted to NIFTI (the neuroimaging informatics technology initiative) format from DICOM (digital imaging and communications in medicine) using a dcm2nii program (part of the MRICRON software), available at: http://people.cas.sc.edu/rorden/mricron/index.html. The VolBrain system displays volumes and percentages of structural asymmetry at the levels of intracranial cavity [ICC defined as the sum of all white and gray mass andcerebrospinal fluid (CSF)], tissue volumes: white mass, gray mass, and CSF volume, volumes of cerebrum, cerebellum and brain stem (with separation of right and left cerebral and cerebellar hemispheres), lateral ventricles, and subcortical structures of gray matter (putamen, nucleus caudatus, globus pallidus, thalamus, hippocampus, amygdala and nucleus accumbens).

2.4 Statistical analysis

Statistical data processing was done in the software program SPSS v23.0. The normality of the distribution and the homogeneity of the variance were checked for each group, and afterwards appropriate statistical analyses were performed. To determine the effects of metabolic syndrome on volumetric findings in patients with HIV infection and metabolic syndrome compared to patients with HIV infection only, an ANOVA variance analysis was performed, with post hoc significance testing between subgroups. For every statistically significant result, binary classification analysis was performed in order to determine the sensitivity and specificity of volumetry and cut off values were defined. The values of p < 0.05 were considered statistically significant.

2.5 Ethic Committee Approval Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethical Board of the Oncology Institute of Vojvodina, Sremska Kamenica (protocol code 01–39/192/1).

Demographic and clinical data of the subjects patients are summarized in Table 1. Average age of healthy subjects was 36.87 ± 8.89. Average age of all HIV-positive patients was 43.02 ± 10.93 years, average duration of infection was 6.40 ± 4.75, and average duration of therapy was 5.98 ± 4.28. Average values of immunological parameters of all HIV-positive patients are also summarized in Table 1. Furthermore, patiens with chronic HIV infection were divided into two groups – patiens with and without metabolic syndrome. Their clinical and demographic characteristics are summarized in Table 2. In the group of HIV-positive patients with MS, average age was 48.36 ± 8.44, average duration of infection 10.64 ± 6.67, and average duration of therapy was 9.00 ± 4.50. In the group of HIV positive patients without metabolic syndrome, average age was 43.68 ± 9.00, average duration of infection 9.55 ± 4.49, and average duration of therapy was 8.41 ± 3.51. Independent T test showed that there were no statistically significant differences between any of the characteristics in two subgroups of HIV-positive patients (Table 2). According to the results, there were no significant differences in duratoin of HIV infection and cART therapy in two subgroups of HIV-positive patients.

First part of analysis was directed towards examination of brain MR volumetry differences between healthy subjects and HIV-positive patients. In the goal of determining differences in volumetry findings between healthy controls and patients with HIV infection, a series of T test for independent samples has been conducted. HIV-positive patients presented with significantly lower volumes of gray matter, putamen, thalamus, globus pallidus and nc. accumbens (Table 3). ROC curve analysis showed that all of the values were highly specific and sensitive (Table 4, Column 4). Area below the curve had the value from 0.654 to 0.750 which is considered as satisfying (as shown). Cut off value based on ROC curve values of volumetry findings in gray matter are 738.130 cm³, in putamen (total) 8.535cm³, in thalamus (total) 11.895 cm³, in globus pallidus (total) 2.252 cm³and for nc. accumbens (total) 0.715 cm³ (Fig. 1).

The second part of analysis was directed towards examination of brain MR volumetry differences between HIV-positive patients with and without metabolic syndrome. For this purpose, variance analysis has been conducted. Results showed that the volumes of cerebrospinal fluid (CSF) and lateral ventriculi were higher in patients with metabolic syndrome (Table 5.). Due to previous, variance analysis has been conducted to determine differences in volumetry findings between left and right ventricle. The left ventricle was of significantly higher volume (Table 6).

Binary classification analysis used to determine specificity and sensitivity of volumetry findings of the left ventricle and volume of CSF showed that a cut off value could not be identified, considering that ROC curve value is 0.671 (Table 7, Fig. 2). However, based on the results, with high specificity and sensitivity it can be assumed that patients with CSF volume above 212.83cm³ will also have metabolic syndrome (sensitivity − 0.714, specificity − 0.310) (Table 8, Fig. 3).

The introduction of combined antiretroviral therapy and effective suppression of the virus in the peripheral compartment led to a decrease in the incidence of AIDS-related diseases. However, the incidence of HIV-associated neurocognitive disorder remains stable [14]. Number of studies so far have illustrated reduction of brain volume tissues in PLWH [15, 16]. Although the processes of neurodegeneration in PLWH are diffuse, the most affected areas in which brain tissue reduction has been registered are the gray matter, as well as the basal ganglia [17, 18]. In our study, people living with HIV compared to healthy subjects had decreased volumes of gray matter, putamen, thalamus, globus pallidus and nc. accumbens which are the results consistent to many previous studies [7, 15, 17, 19]. Bearing in mind that HAND is considered to be subcortical dementia characterized by disorders of attention and memory, verbal and motor abilities, as well as sensory modalities, perception and abstract thinking [14], the verified reduction of brain tissue in the above mentioned regions in our research is expected. Underlying mechanism of brain injury in PLWH refers to the mechanism of continuous low-level inflammation and immune activation that takes place despite the effective suppression of the virus. The etiological background is dual and it implies continuous inflammation that leads to increased permeability of the blood brain barrier, and on the other hand, persistent inflammation at the level of brain tissue that potentiates the damage [2, 12, 20]. A growing number of recent studies focused on neurodegenerative processes in chronic HIV infection are directed towards the assumption that PLWH have accentuated aging, which implies a third contributing factor to development and progress of neurocognitive disorders associated with HIV infection [21–23].

As already mentioned, the early introduction of cART (practically immediately after seropositivity confirmation) resulted in the prolonged lifespan of PLWH and more prevalent non-HIV related disorders in this population. Among those, the most important are those associated with systemic inflammation - metabolic syndrome, hepatic steatosis/non-alcoholic liver disease, and cardiovascular disorders [3–6, 24].

The incidence of metabolic syndrome (MS) in patients living with HIV (PLWH) compared to general population is not clearly defined, probably due to overlapping of host, viral, and antiretroviral therapy factors that solely or in synergy contribute to the components of this syndrome. Recent studies reported the prevalence of MetS in PLWH from 10% to over 50%, depending on the studied population and region [25–28].

However, the relationship between MS and brain atrophy is a recently recognized issue that is not clearly understood and explained. Our results showed a significant increase in the volume of CSF and lateral ventricle in HIV-positive patients with MS compared to HIV-positive subjects without defined metabolic syndrome. There was no significant difference in the mean age of patients in observed cohorts, so the effect on age on brain reductive changes can be neglected. Additionally, no significant differences in duration of HIV infection or the time from the cART initiation were present between two subgroups of HIV-positive patients, which is important fact given that chronically HIV-infected individuals on stable cART undergo progressive loss of brain tissue and present with changes on MR volumetry of the brain [18].

Despite the undetectable plasma viral load in HIV-positive patients on cART, HIV remains latent in several cell types, among which the adipocytes play an important role. Adipocytes continuously secrete adipokines – inflammation mediators – that have systemic activity both in peripheral and central nervous system compartments [29]. Activated adipocytes via chemokines and cytokines induce monocyte activation that reach the brain. Recent studies showed continuous microglia receptor expression in the chronic HIV infection. This activation is induced by inflammatory cytokines and chemokines released from adipose tissue that further induce secretion of correspondent mediators in the central nervous system. Furthermore, this induces the astrocyte activation and neuronal apoptosis [29, 30].

Regarding previously said, it is clear that HIV-induced neurodegeneration and astrocyte activation in metabolic syndrome can have synergistic effect, but to which point these processes are additive, remains to be explained. The results of our study showed that the volume of CSF spaces in HIV-positive patients with MS was significantly higher than in HIV-positive patients without MS. This might speak in favor of additive effect of HIV infection and MS on the brain of HIV-positive patients. Moreover, our results showed that in patients with CSF volumes over 2012.82 cm³, the presence of concomitant metabolic syndrome can be assumed with high specificity. This finding should induce additional evaluation of the patient in order to reduce potential complications of both disorders. Timely evaluation of these subgroup of patients is important from the aspect of treatment and prevention of complications that significantly degrade the quality of life of these patients.

One interesting result of our study was significant reduction of the volume of the left ventricle. Li et al in their recent study showed that lower CD4+/CD8 + ratio was associated with higher volumes of the left ventricle and the whole ventricular system [20]. However, in our study, no obvious correlations were found with the serological parameters of the HIV infection (31). In a paper from CHARTER study, higher CSF ventricular volumes were associated with the presence of diabetes, which is in line with our results [32]. However, over a third of subjects involved in CHARTER study were cognitively impaired; to the contrary, our study group did not include patients with Internation HIV Dementia Scale score lower than 10 [33].

This study has some limitations. First of all, the study sample is relatively small and the study is conducted in a cross-sectional manner. However, the exclusion criteria were strict and the selection of subjects was carefully performed, meaning that a certain number of patients were excluded. Longitudinal studies would aid to the understanding of pathophysiological mechanism of HIV and metabolic syndrome synergy in the development of neurocognitive impairment and brain atrophy. Finally, type of cART is important for the interpretation of the results. In our study sample, at the time of study, a significant number of patients were on an cART regimen not including INSTI. A follow-up study might be a reasonable solution, with exploring the findings in these patients now converted to the modern cART.

Neurodegenerative processes in HIV infection are diffuse and constant, despite early introduction of cART and effective peripherial suppresion of viral replication. Due to that, the incidence of HAND remains stable and, along with comorbidities that are now the leading cause of death in PLWH, represent emerging problem in the treatment of people living with HIV. Brain volumetric analysis can reliably point to the presence of metabolic syndrome in HIV-positive patients and vice versa. This result is expected since many factors associated with the infection itself and application of cART contribute to the development of metabolic syndrome, in addition to the classical risk factors. There seems to be an important connection between metabolic syndrome and the presence of volume reduction in the brain. The global volume reduction in the brain is associated with the enlarged CSF spaces (and lateral ventricles) and is more prominent in HIV-positive patients with metabolic syndrome, according to the results of our study. This identifies these persons as those in risk of development of HIV-associated cognitive impairment, and may point to the elevated risk of impairment in executive, cognitive and emotional functioning. That way, after diagnosing metabolic syndrome in an HIV-positive patient, the clinician should prompt detailed neurocognitive evaluation of the patient in order to exclude signs of cognitive disorder on time.

Author Contributions

All the authors have seen and approved the final version and have contributed significantly to the work in the means of conception and design (S.B., J.B.), acquisition of the data (V.A., A.B., J.B., D.K.), data analysis and interpretation (V.A., S.B., J.B.), as well as drafting the article (V.A., J.B.) or revising it (S.B., D.K., J.B).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

This research was funded by Merck Investigators Study Programme, No. MISP59574 (No. Of the clinical trial NCT04887675).

Data availability statement

The data that support the findings of this study are available on request from the corresponding author, VA. The data are not publicly available due to containing information that could compromise the privacy of research participants.

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Table 1

Demographic and clinical characteristics of participants
Category	N	X ± SD	min	max
Age (HIV-positive patients)	43	43.02 ± 10.93	26	65
Age (healthy subjects)	24	36.87 ± 8.89	22	58
Duration of infection (in years)	43	6.40 ± 4.75	1	16
Duration of therapy (in years)	43	5.98 ± 4.28	0,5	16
nadirCD4+ (cells/mm³)	43	293.82 ± 189.79	11	772
CD4+ (cells /mm³)	43	580.20 ± 227.65	239	1122
CD8+ (cells /mm³)	43	943.69 ± 502.93	217	2412
CD4+/CD8 + index	43	0.47 ± 0.43	0,05	1.98
IL-6 (pg/ml)	43	2.91 ± 2.44	0,49	10.12
TNFα (pg/ml)	43	3.28 ± 1.02	1,01	5.81

Table 2

Demographic and clinical characteristics of PLWH
Category	N	X ± SD	Min	Max	P
Age (HIV+, MS-)	29	43.68 ± 9.00	29	58	0.22
Age (HIV+, MS+)	14	48.36 ± 8.44	31	62	0.22
Duration of infection (HIV+, MS-)	29	9.55 ± 4.49	9	18	0.61
Duration of infection (HIV+, MS+)	14	10.64 ± 6.67	4	24	0.61
Duration of therapy (HIV+, MS-)	29	8.41 ± 3.51	8	16	0.74
Duration of therapy (HIV+, MS+)	14	9.00 ± 4.50	4	19	0.74

Table 3

Volumetry findings between healthy subjects and PLWH
Volume (cm³)	HIV	N	M	SD	t	df	p
White matter	positive	43	580.92	116.83	.107	65	> 0.05
White matter	negative	24	578.24	52.09	.107	65	> 0.05
Gray matter	positive	43	706.19	99.77	-2.091	65	< 0.05
Gray matter	negative	24	752.89	59.44	-2.091	65	< 0.05
Cerebrum total	positive	43	1118.49	116.95	-1.355	65	> 0.05
Cerebrum total	negative	24	1155.54	87.04	-1.355	65	> 0.05
CSF	positive	43	211.18	69.26	.733	65	> 0.05
CSF	negative	24	200.08	34.84	.733	65	> 0.05
Intracranial cavity	positive	43	1498.30	143.30	− .967	65	> 0.05
Intracranial cavity	negative	24	1530.84	108.57	− .967	65	> 0.05
Cerebellum	positive	43	262.70	799.83	.689	65	> 0.05
Cerebellum	negative	24	149.89	9.81	.689	65	> 0.05
Lateral ventriculi total	positive	43	14.9000	10.98	.440	65	> 0.05
Lateral ventriculi total	negative	24	13.74	8.83	.440	65	> 0.05
Caudatus - total	positive	43	6.96	1.88	-1.678	65	> 0.05
Caudatus - total	negative	24	7.64	0.85	-1.678	65	> 0.05
Putamen – total	positive	43	8.17	1.99	-2.855	65	< 0.01
Putamen – total	negative	24	9.40	0.87	-2.855	65	< 0.01
Thalamus - total	positive	43	11.06	3.14	-2.059	65	< 0.05
Thalamus - total	negative	24	12.42	0.98	-2.059	65	< 0.05
Globus pallidus - total	positive	43	2.29	0.59	-2.502	65	< 0.05
Globus pallidus - total	negative	24	2.62	0.29	-2.502	65	< 0.05
Hippocampus - total	positive	43	7.58	2.09	-1.924	65	> 0.05
Hippocampus - total	negative	24	8.44	0.72	-1.924	65	> 0.05
Amygdala - total	positive	43	1.66	0.46	-1.469	65	> 0.05
Amygdala - total	negative	24	1.81	0.15	-1.469	65	> 0.05
Accumbens - total	positive	43	0.63	0.20	-2.579	65	< 0.05
Accumbens - total	negative	24	0.74	0.10	-2.579	65	< 0.05

Table 4

Sensitivity and specificity of the test for healthy subjects and HIV positive patients
Region	Area	Std.Error	Asymptotic Sig.	Asymptotic 95% Confidence Interval
Region	Area	Std.Error	Asymptotic Sig.	Lower Bound	Upper Bound
Gray matter	0.654	0.069	0.038	0.519	0.788
Putamen total	0.750	0.062	0.001	0.630	0.871
Thalamus total	0.677	0.067	0.017	0.546	0.808
Globus pallidus total	0.706	0.065	0.005	0.580	0.833
Accumbens total	0.688	0.064	0.011	0.562	0.813

Table 5

Differences in volumetry findings relative to presence of metabolic syndrome
Volume (cm³)	Met.syndrome	M	SD	F	p
CSF	no	191.164	63.251	8.823	0.005
CSF	yes	252.643	64.341	8.823	0.005
Lateral ventriculi total	no	12.565	9.580	4.343	0.043
Lateral ventriculi total	yes	19.736	12.447	4.343	0.043

Table 6

Differences in volumetry findings between left and right ventricule in patients with HIV infection and metabolic syndrome
Volume (cm³)	Met.syndrome	M	SD	F	P
Right lateral ventricule	no	6.219	5.600	3.456	0.070
Right lateral ventricule	yes	9.645	5.792	3.456	0.070
Left lateral ventricule	no	6.345	4.347	4.827	0.034
Left lateral ventricule	yes	10.091	6.773	4.827	0.034

Table 7

Specificity and sensitivity of the volumetry values of left ventricule in patients with HIV infection and metabolic syndrome
Structure	Area	Std.Error	Asymptotic Sig.	Asymptotic 95% Confidence Interval
Structure	Area	Std.Error	Asymptotic Sig.	Lower Bound	Upper Bound
Left lateral ventricule	0.671	0.085	0.072	0.504	0.838

Table 8

Specificity and sensitivity of the volumetry values of CSF in patients with HIV infection and metabolic syndrome
Structure	Area	Std.Error	Asymptotic Sig.	Asymptotic 95% Confidence Interval
Structure	Area	Std.Error	Asymptotic Sig.	Lower Bound	Upper Bound
CSF	0.756	0.074	0.007	0.612	0.901

No competing interests reported.

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Journal Publication

published 13 Jun, 2024

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Additive effect of metabolic syndrome on brain atrophy in people living with HIV – magnetic resonance volumetry study

Status:

Journal Publication

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Abstract

Figures

1 Introduction

2 Methods

2.1 Subject selection

2.2 Clinical and laboratory data

2.3 MR imaging

2.4 Statistical analysis

2.5 Ethic Committee Approval Statement

3 Results

4 Discussion

5 Conclusion

Declarations

Author Contributions

Conflict of Interest

Funding

Data availability statement

References

Tables

Additional Declarations

Status:

Journal Publication

Version 1