RESUMEN

Cognitive impairment and major depressive disorder (MDD) are common HIV-1 central nervous system (CNS) complications. Their frequencies in AIDS patients are 36% and 45%, respectively. The diagnoses of HIV cognitive impairment are made by clinical criteria, no single laboratory test or biomarker establishes the diagnosis. Factors of indirect neuronal injury related with the pathophysiology of the HIV infection in the CNS, are the factors studied as biomarkers. In the present no biomarker is established to the diagnosis of HIV cognitive impairment, much still needs to be done. We review in this paper some biomarkers in cerebrospinal fluid that could be valuable to the diagnosis of HIV cognitive impairment. Diagnosing depression in the context of HIV can be challenging, to identify a biomarker that could help in the diagnosis would be very important, although MDD risks and neurobiology are still poorly understood.

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RESUMEN

Cognitive impairment and major depressive disorder (MDD) are common HIV-1 central nervous system (CNS) complications. Their frequencies in AIDS patients are 36% and 45%, respectively. The diagnoses of HIV cognitive impairment are made by clinical criteria, no single laboratory test or biomarker establishes the diagnosis. Factors of indirect neuronal injury related with the pathophysiology of the HIV infection in the CNS, are the factors studied as biomarkers. In the present no biomarker is established to the diagnosis of HIV cognitive impairment, much still needs to be done. We review in this paper some biomarkers in cerebrospinal fluid that could be valuable to the diagnosis of HIV cognitive impairment. Diagnosing depression in the context of HIV can be challenging, to identify a biomarker that could help in the diagnosis would be very important, although MDD risks and neurobiology are still poorly understood.

A alteração cognitiva e a desordem depressiva maior (MDD) são complicações comuns da AIDS no sistema nervoso central (CNS). Suas frequências, em pacientes com AIDS são 36 % e 45 %, respectivamente. O diagnósticos de alteração cognitiva pelo HIV é feito por critérios clínicos, não há nenhum teste único de laboratório ou biomarcador que estabeleçam o diagnóstico. Os fatores inflamatórios relacionados com dano neuronal indireto e com a patofisiologia da infecção do HIV no CNS, são os fatores estudados como biomarcadores. No presente nenhum biomarcador é estabelecido para o diagnóstico de alteração cognitiva pelo HIV, muito ainda tem para ser feito. Nesta revisão abordaremos alguns biomarcadores no líquido cefalorraquidiano que podem auxiliar no diagnóstico da alteração cognitiva e HIV. Da mesma forma o diagnostico de depressão no contexto da aids pode ser desafiante, identificar um biomarcador que possa ajudar no diagnóstico seria muito importante, embora os riscos de desenvolvimento de MDD e a neurobiologia ainda sejam pobremente entendidos.

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Preliminary findings suggest that abnormalities in matrix metalloproteinase (MMP) activity may be found in the cerebrospinal fluid (CSF) of patients with Creutzfeldt-Jakob disease (CJD). In this study of 16 subjects with CJD and 16 age-, and sex-matched controls, we determined the presence of MMP-2 and MMP-9 in their active and proenzyme forms, the relative levels of MMP-3 and four inhibitors of MMP activity (TIMP-1, TIMP-2, TIMP-3 and TIMP-4), and the concentration of 4-3-3 protein. The methodology used involved zymography and immunological techniques. The results indicate that, compared with controls, CJD patients have a significantly higher positive frequency of pro-MMP-9 and of the active form of MMP-2, along with significantly higher levels of TIMP-1 and TIMP-2, classical inhibitors of MMP-9 and MMP-2, respectively. We also found a positive correlation between 14-3-3 protein concentration and that of TIMP-1 and TIMP-2 levels (correlation coefficients of 0.793 and 0.798, respectively). These results suggest that abnormalities in MMP and TIMP profiles may be helpful in the biochemical characterisation of CJD.

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The tropical spastic paraparesis or human T-cell lymphotropic virus associated myelopathy (TSP/HAM), has been related with an overexpression of matrix metalloproteinases (MMPs), especially MMP-9. Initial studies of reverse zymography with cerebrospinal fluid (CSF) from TSP/HAM patients, and controls showed the presence of TIMPs, endogenous MMP inhibitors. We determined in CSF the levels of TIMPs by immunoanalysis in 25 patients with TSP/HAM, and compared with two groups: controls and patients with acute and subacute inflammatory neurological diseases. We found that TIMP-2, TIMP-3 and TIMP-4 levels were significantly higher than in controls in both TSP/HAM and inflammatory patients, while TIMP-1 was increased only in the inflammatory group. Levels of MMP-3 and MMP-9 from the two groups of patients showed a significant upregulation in CSF. In the CSF of around the 70% of TSP-HAM and inflammatory patients the presence MMP-9 was detected by zymography, but not in controls. MMP-2 was only overexpressed in the acute inflammatory group. The active form of MMP-2 was observed in both groups of patients with a similar high frequency (60%). MMPs overexpressions are independent of the evolution time of the disease in TSP/HAM. The chronic overexpression of these extracelullar matrix proteins detected in CSF of TSP/HAM should be indirectly produced by secreted viral proteins being responsible for the progression of this disease, accounting for the observed differences with acute inflammatory patients. Our results support the existence of an imbalance between MMPs and their endogenous tissue inhibitors, which could be a pathogenic factor in the chronicity of TSP/HAM.

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BACKGROUND: Proteolytic modifications of neuronal surfaces and the surrounding extracellular matrix are very important in neuronal development and regeneration. Increased activity of matrix metalloproteinases (MMPs) and their tissue inhibitors, due to secretion by macrophages and lymphocytes, occur in inflammatory processes that disrupt the blood brain barrier. However, neurons and microglia can also secrete these enzymes. AIM: To identify the type of MMP present in the cerebrospinal fluid (CSF) and changes in the expression of tissue inhibitors of metalloproteinases (TIMPs) in patients with HTLV-1 associated tropical spastic paraparesis. PATIENTS AND METHODS: CSF samples from 12 patients with HTLV-1 associated tropical spastic paraparesis and 12 healthy controls were obtained by an atraumatic lumbar puncture. The presence of MMPs was measured by zymography and the relative amounts of TIMPs were measured by immunowestern blot. RESULTS: In the CSF of both controls and patients, a similar gelatinolytic band corresponding to proMMP-2 (latent form) was observed. In 83.3% of patients with HTLV 1 associated tropical spastic paraparesis, the MMP-9 was also present. TIMP-1, TIMP-2 and TIMP-3 were elevated 2.24 +/- 0.72, 3.85 +/- 1.38 and 5.89 +/- 3.4 fold, respectively, in the CSF of patients as compared to controls. CONCLUSIONS: Patients with HTLV-1 associated tropical spastic paraparesis have elevated activity of MMP-9 and levels of TIMPs in the CSF, when compared to healthy controls.

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