Cognitive impairment secondary to cerebral circulation disturbances detected by transcranial doppler in patients with lupus systemic erythematosus
Authors: Carrillo Cecilia Sandoval 
Published: July 2024

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology with heterogeneous clinical manifestations including neuropsychiatric manifestations, the prevalence of which is unknown (14-75%). However, it is known that patients with SLE develop cognitive impairment even if they do not present other neurological manifestations clinically. In most patients, intellectual impairment is subclinical and is revealed by neuropsychological testing. The pathogenic factors associated with and triggering cognitive impairment in SLE are still unknown and it is very likely that it is multifactorial; essentially the following lines of research are being pursued (Figure 1): that it is a consequence of the production of autoantibodies directed to components of brain tissue, that inflammatory mechanisms are involved by cytokines in the presence of damage to the blood-brain barrier, or that cerebrovascular alterations associated mainly with microangiopathic processes participate. Although most studies are focused on demonstrating the autoimmune mechanism, there is evidence that allows us to support the participation of the vascular mechanism and currently there is transcranial Doppler technology that allows us the noninvasive evaluation of cerebral circulation in an easy, fast and economically accessible way. Therefore, it is essential to increase the knowledge about the pathogenic mechanisms responsible for cognitive alterations in SLE, so it is widely justified to carry out a research project to evaluate the state of cerebral circulation in patients with SLE and determine its potential involvement in the development of cognitive impairment associated with systemic lupus erythematosus. To evaluate the cerebral circulation, transcranial Doppler technology was selected to study in a simple, non-invasive and reproducible way, at low cost and in real time different parameters of the hemodynamics of the cerebral circulation including measurement of blood flow velocities and cerebrovascular reactivity (CVR) test that determines the state of the cerebral microcirculation. Objectives: To establish the prevalence of cognitive impairment in a cohort of SLE patients and to determine the frequency and magnitude of cerebral circulation alterations (blood flow velocities, pulsatility, and cerebrovascular reactivity) measured by TCD in patients with systemic lupus erythematosus and cognitive impairment, compared with SLE patients without intellectual impairment and with healthy control subjects. Methods: Case-control study nested in a cohort where patients with SLE belong to a cohort of 139 patients from the Department of Immunology and Rheumatology of INCMNSZ, cohort that is part of the protocol "Predictors of cognitive dysfunction in patients with generalized lupus erythematosus". Neuropsychological tests were applied in these patients to establish the presence of cognitive impairment. There were three study groups: (1) the problem group were patients with SLE and cognitive impairment; (2) control group 1 were patients with SLE without cognitive impairment; and (3) control group 2 were healthy controls assumed to have normal intellectual function. In all three groups, evaluation of the cerebral circulation was performed using transcranial Doppler technology, with recordings from the middle cerebral artery to obtain various parameters of the hemodynamics of the cerebral circulation including measurement of blood flow velocities and CVR; in this test the ability to increase blood flow velocities to hypercapnia by producing vasodilatation of the cerebral microcirculation is estimated (hypercapnia is provoked by inhalation of a mixture of CO2 at 8%, O2 at 21% and nitrogen balance for one minute - administered through a mask). Results: Of 67 patients with SLE included in the study, 29 were found to have alterations in the evaluation of cognitive functions for a prevalence of 43% in this cohort; cognitive impairment was categorized as mild in 16 patients (23.9%), moderate in 6 (9.0%) and severe in 7 patients (10.4%). When evaluating the hemodynamics of the cerebral circulation determined by transcranial Doppler in patients with SLE according to the presence of cognitive impairment and with healthy control subjects it was found that while the snguine flow velocities and pulsatility index showed no differences, significant alteration of cerebrovascular reactivity was found in patients with SLE and cognitive impairment (increase of only 13.1±9% to hypercapnia, compared to increase of 24.2±18.2% in patients without cognitive impairment; p=.01). When including in the analysis the group of healthy control subjects and stratifying the SLE patients according to cognitive performance in the neuropsychological tests, a gradient was found in the degree of alteration of cerebral vasomotor reactivity with greater deterioration of intellectual functions, such that the mean CVR±SD of increase to hypercapnea in the healthy control group was 32.6±16.5%, compared to 24.7±18.3%, 14.3±15.3% and 8.3±12.4 in patients with SLE and normal cognition, mild and moderate/severe impairment, respectively (p<0.001). When adjusting for cerebrovascular reactivity through multivariate analysis by binary logistic regression with other independent factors related to cognitive impairment, CVR was found to remain significant reaching the association estimate odds ratios of 9.8 (95% CI 2.9 - 32.8; p<0.001). Conclusions: The prevalence of cognitive impairment in this SLE cohort was 43% and was associated with significant alteration of cerebrovascular reactivity, suggesting that vascular mechanisms that damage cerebral microcirculation are involved in the development of cognitive impairment in SLE patients.