Cystatin C expression in ischemic white matter lesions.

Department of Internal Medicine III, University Hospital, Shimane University, Izumo, Japan.
Acta Neurologica Scandinavica (Impact Factor: 2.44). 07/2008; 118(1):60-7. DOI: 10.1111/j.1600-0404.2007.00984.x
Source: PubMed

ABSTRACT To study the involvement of cystatin C in the progression of ischemic white matter lesions (WMLs).
Cystatin C levels in the cerebrospinal fluid (CSF) of patients with cerebrovascular disease, and also in primary and established human neural cell cultures were investigated. For pathologic analysis, cystatin C immunoreactivity was investigated in the white matter of patients with severe WMLs, mild WMLs or controls.
Cystatin C levels in the CSF of patients with Fazekas WML grade 3 [14 with hypertension; W/HT(+) and nine without hypertension; W/HT(-)] were lower than those in 38 patients with grade 0-1 (P = 0.0022 and P < 0.0001 respectively). Immunohistochemical study showed that the cystatin C immunoreactivity was found in astrocytes, and the number of astrocytes in the white matter in the severe WML group was decreased when compared with that in controls (P = 0.0027) and in the mild WML group (P = 0.0024). In human neural cell cultures, treatments with thrombin, matrix metalloproteinases and interleukin 1 beta increased the expression of cystatin C mRNA in human astrocytes and hybrid neurons, but an enzyme-linked immunosorbent assay revealed that only thrombin significantly increased the production and secretion of cystatin C in astrocytes.
These results suggest that low levels of CSF cystatin C in ischemic WMLs might be due to the decreased number of astrocytes that secrete cystatin C in response to the stimuli of proteases and inflammatory cytokines.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective damage of motor neurons in the brain and spinal cord. The aim of the current study was to reveal new specific markers of neurodegeneration in the cerebrospinal fluid (CSF) of ALS patients. We measured the activities of substances that modulate the activity of cysteine proteases (calpain, caspase, and cathepsin B) in the CSF of ALS patients. The CSF of ALS patients, in contrast to the CSF of patients with multiple sclerosis, inhibits calpain and cathepsin B significantly more strongly, as compared to the control CSF. The LDH activity and the concentration of neuron-specific enolase (NSE) in the CSF of control patients and ALS patients did not differ. The concentration of neurofilament heavy chains in the CSF was significantly higher in the ALS patients as compared to the control group. The albumin index increased in 50% of all ALS patients. We also have shown a correlation between the cathepsin inhibitor activity, the concentration of neurofilament heavy chains, and the albumin index and the clinical findings of the disease. According to our data, the concentration of neurofilament heavy chains is a sensitive marker of neurodegenerative process during ALS. An increase in the CSF inhibiting activity with respect to cathepsin B and calpain is specific for ALS and may confirm the role of an imbalance of proteolytic systems in the pathogenesis of this disease.
    Neurochemical Journal 06/2009; 3(2):133-138. · 0.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Extracellular vesicles (EVs) and their protein levels have been identified as a potential risk marker for the development of vascular disease. In the present study, we assessed whether levels of four previously identified EV proteins (cystatin C, serpin G1, serpin F2 and CD14) are associated with cerebral white matter lesions (WMLs) and brain atrophy. Cohort study; cross-sectional and prospective. Single centre, secondary and tertiary setting. 1309 patients with manifest vascular disease from the Second Manifestations of ARTerial disease-MR (SMART-MR) study, of which 994 had successful brain MRI and EV protein level measurements. WML and brain parenchymal fraction (BPF), as parameter for brain atrophy, at baseline and follow-up. The relationship between EV protein levels and WML volume (expressed as log transformed percentage of intracranial volume) and BPF (expressed percentage of intracranial volume) on 1.5 T brain MRI was assessed with multivariable linear regression modelling. Subsequently, the relationship between baseline EV protein levels and progression of atrophy and WML was analysed in 534 patients, in whom a follow-up MRI was obtained after 4 years. Higher EV-cystatin C and EV-CD14 were significantly associated with larger WML volume (linear regression coefficient (95% CI) 0.10 log %/SD (0.04 to 0.17) and 0.14 log %/SD (0.07 to 0.20), respectively. Higher EV-CD14 was associated with more brain atrophy (-0.14%/SD; -0.27 to -0.01). Baseline EV-CD14 was significantly associated with increase of WMLs (0.11 log %/SD (0.04 to 0.18)). No relationship with EV-serpins was observed at baseline or at follow-up. EV proteins cystatin C and CD14 are related to cerebral WMLs and the progression of brain atrophy in patients with manifest vascular disease, potentially identifying EVs in the aetiology of structural brain changes.
    BMJ Open 01/2014; 4(1):e003824. · 2.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the changes of cerebrospinal fluid (CSF) cystatin C (CC) levels associated with the postoperative ischemic conditions and prognostic outcome in patients with aneurysmal subarachnoid hemorrhage (SAH). MATERIAL and
    Turkish neurosurgery. 01/2014; 24(3):391-7.