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Cystatin C in cerebrospinal fluid as a biomarker of ALS
Sachiko Tsuji-Akimotoa,
, 
,
Ichiro Yabea,
1,
Masaaki Niinoa,
1,
Seiji Kikuchib,
2
and Hidenao Sasakia,
1
Received 15 August 2008;
revised 9 January
2009;
accepted 9 January 2009.
Available online 14
January 2009.
Abstract
Amyotrophic lateral sclerosis (ALS) is diagnosed on the basis of progressive symptoms in both the upper and lower motor neurons. Because there are no specific biomarkers for ALS, it is difficult to diagnose this disease in its early stages. Cerebrospinal fluid (CSF) samples were obtained from 14 patients in the early stages of ALS, from 13 with polyneuropathy, and from 16 with other neurological disorders. The concentration of cystatin C in the CSF was measured using a sandwich enzyme-linked immunosorbent assay (ELISA) kit. The concentration of cystatin C in the CSF was significantly lower in ALS patients than in the control subjects who were patients with polyneuropathy or other neurological diseases (patients with ALS, polyneuropathy, and other diseases exhibited 5.5 ± 0.3, 6.7 ± 0.4, and 6.9 ± 0.3 mg/L cystatin C, respectively; ALS patients vs. control subjects: p = 0.014 and ALS patients vs. polyneuropathy patients: p = 0.024). Cystatin C may be a useful biomarker of ALS and can be used to distinguish between ALS and polyneuropathy.
Keywords: Amyotrophic lateral sclerosis; Cystatin C;
Diagnosis; Biomarker
Article Outline
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder
characterized by the specific degeneration of motor neurons. The
following are critical points that are considered for the clinical
diagnosis of ALS: (1) progressive course, (2) enlarging lesions (3)
involvement of both the upper and lower motor neurons, and (4) exclusion
of other diseases. According to the revised El Escorial Criteria
(rEEC), which are the international criteria for the diagnosis of ALS,
diagnostic accuracy is determined on the basis of the distribution and
combination of symptoms of the disease in the upper and lower motor
neurons [7]. According to rEEC, ALS is
divided into five categories: definite, probable, clinically probable or
laboratory supported, possible, and suspected. Currently, these are the
most reliable criteria for diagnosis when specific biomarkers are not
frequently detected, and as recommended by the World Federation of
Neurology, many clinical trials are performed on individuals diagnosed
with definite, probable, and clinically probable cases of ALS.
However, it is often difficult to diagnose ALS. In many patients, the first symptoms occur in a single area and remain restricted there for months. Such patients are diagnosed with possible ALS, and they do not participate in clinical trials unless their condition deteriorates. Indeed, the mean intervals from the time of the first symptom to the time of diagnosis in three population-based studies were 8 [34], 10.6 [3] and 14.4 months [36]. Among the 34 cases of ALS that were diagnosed on the basis of the autopsy findings, the average duration between the onset of ALS symptoms and the diagnosis of definite ALS was 21 months [6]. Thus, it is important to determine the correct stage at which ALS should be diagnosed. Furthermore, when symptoms are widely distributed, 16% of ALS patients diagnosed by clinical physicians exhibited only lower motor neuron symptoms throughout their life, which satisfies the definition of clinically suspected ALS alone [34]. It is often difficult to differentiate ALS from other diseases. Two clinically instructive cohort studies demonstrated that 7–8% of patients diagnosed with ALS could be re-diagnosed with other diseases such as cervical spondylotic myeloradiculopathy, multifocal motor neuropathy (MMN), and spinobulbar muscular atrophy [9] and [33]. The rEEC permitted electromyography and gene analysis in addition to routine laboratory data and neuroradiological examinations. However, cases with poor electromyographic findings in nonsymptomatic muscles are frequently observed. In a retrospective electromyographic study in 82 patients suspected with ALS, the specificity was 0.97 and the sensitivity was 0.57 [18]. Gene analysis also has a low sensitivity, and it can be applied only to approximately 2% of all ALS patients, who have a mutation in the Cu2+, Zn2+-superoxide dismutases, which is the most frequent familial ALS [28]. Powerful diagnostic tools are required for the accurate diagnosis of possible or suspected ALS with a high sensitivity.
No specific biomarkers have yet been universally confirmed for ALS. However, a recent proteomic analysis revealed that cystatin C, transthyretin, and other protein species (4.8 and 6.7 kDa) in the cerebrospinal fluid (CSF) were possible biomarkers of ALS [25] and [26]. In particular, cystatin C may be a specific biomarker since it is specific for Bunina bodies, a characteristic feature of ALS [21]. Although ubiquitin-positive inclusions are a disease-specific pathology in various neurodegenerative disorders such as Parkinson's disease and multiple system atrophy [35], Bunina bodies are characteristic indicators of ubiquitin-negative protein accumulation. The process by which they are formed remains unknown; however, cystatin C and ferritin [19] have been recently identified using immunohistological methods.
In this study, we demonstrate that the presence of cystatin C in the CSF could be used as a clinical marker for the diagnosis of ALS in its early stages, especially to distinguish ALS from polyneuropathy.
CSF samples were obtained from 14 ALS patients who had undergone lumbar puncture at the Hokkaido University Hospital from April 2006 to March 2007. The controls were patients with polyneuropathy and other diseases and who were of the same sex and age as the ALS subjects. Meningitis and other acute inflammatory disorders that cause increases in the CSF cell count were excluded. Thirteen patients with polyneuropathy and 16 with other diseases were the control subjects; these patients were definitely diagnosed with polyneuropathy or other diseases. CSF samples from cases of neuropathy were obtained before medication. In the control group, the disease phase at the time of CSF collection varied. Patients who were categorized under the “suspect” group of ALS according to the rEEC were excluded from our study; however, patients from this group and those with possible ALS were included if the progressive course was confirmed after several months. Two patients with ALS symptoms only in the lower motor neurons underwent repetitive nerve conduction tests and intravenous immunoglobulin therapy (IVIg), but they did not show any improvement in the symptoms. Since the rEEC for the diagnosis of ALS is stringent, 16% of the patients were not diagnosed with ALS until the final stages of the disease. In Ireland, suspected and possible patients were included if the typical clinical course was confirmed prospectively, and other diseases were excluded [23]. International scales of the symptom, such as revised ALS functional rating scale (ALSFRS-R), were not available on all subjects at the lumber puncture; therefore correlation to clinical severity cannot be addressed. Informed consent was obtained from all the subjects for research purposes, and the study was approved by the ethical committee of Hokkaido University.
The collected CSF samples were kept in 4 °C for several hours at longest, and after division into 1-mL of aliquots without centrifugation, they were preserved at −80 °C until they were used for analysis. The concentration of cystatin C was measured using sandwich enzyme-linked immunosorbent assay (ELISA) with a human cystatin C ELISA kit (Quantikine, R and D systems, Mckinley Place, NE, USA). A 40-fold dilution of the samples was prepared, and ELISA was performed according to the instructions provided in the kit. All samples were measured at single time. After colorization with tetramethylbenzidine, the absorbance was determined at 450 nm by using a microplate reader, and the wavelength used for correction was 570 nm. The results were analyzed using KaleidaGraph 4.0 software. Statistical analysis was performed using the Student–Newman–Keuls test when one-factorial analysis of variance (ANOVA) showed significance (Fig. 1).
However, it is often difficult to diagnose ALS. In many patients, the first symptoms occur in a single area and remain restricted there for months. Such patients are diagnosed with possible ALS, and they do not participate in clinical trials unless their condition deteriorates. Indeed, the mean intervals from the time of the first symptom to the time of diagnosis in three population-based studies were 8 [34], 10.6 [3] and 14.4 months [36]. Among the 34 cases of ALS that were diagnosed on the basis of the autopsy findings, the average duration between the onset of ALS symptoms and the diagnosis of definite ALS was 21 months [6]. Thus, it is important to determine the correct stage at which ALS should be diagnosed. Furthermore, when symptoms are widely distributed, 16% of ALS patients diagnosed by clinical physicians exhibited only lower motor neuron symptoms throughout their life, which satisfies the definition of clinically suspected ALS alone [34]. It is often difficult to differentiate ALS from other diseases. Two clinically instructive cohort studies demonstrated that 7–8% of patients diagnosed with ALS could be re-diagnosed with other diseases such as cervical spondylotic myeloradiculopathy, multifocal motor neuropathy (MMN), and spinobulbar muscular atrophy [9] and [33]. The rEEC permitted electromyography and gene analysis in addition to routine laboratory data and neuroradiological examinations. However, cases with poor electromyographic findings in nonsymptomatic muscles are frequently observed. In a retrospective electromyographic study in 82 patients suspected with ALS, the specificity was 0.97 and the sensitivity was 0.57 [18]. Gene analysis also has a low sensitivity, and it can be applied only to approximately 2% of all ALS patients, who have a mutation in the Cu2+, Zn2+-superoxide dismutases, which is the most frequent familial ALS [28]. Powerful diagnostic tools are required for the accurate diagnosis of possible or suspected ALS with a high sensitivity.
No specific biomarkers have yet been universally confirmed for ALS. However, a recent proteomic analysis revealed that cystatin C, transthyretin, and other protein species (4.8 and 6.7 kDa) in the cerebrospinal fluid (CSF) were possible biomarkers of ALS [25] and [26]. In particular, cystatin C may be a specific biomarker since it is specific for Bunina bodies, a characteristic feature of ALS [21]. Although ubiquitin-positive inclusions are a disease-specific pathology in various neurodegenerative disorders such as Parkinson's disease and multiple system atrophy [35], Bunina bodies are characteristic indicators of ubiquitin-negative protein accumulation. The process by which they are formed remains unknown; however, cystatin C and ferritin [19] have been recently identified using immunohistological methods.
In this study, we demonstrate that the presence of cystatin C in the CSF could be used as a clinical marker for the diagnosis of ALS in its early stages, especially to distinguish ALS from polyneuropathy.
CSF samples were obtained from 14 ALS patients who had undergone lumbar puncture at the Hokkaido University Hospital from April 2006 to March 2007. The controls were patients with polyneuropathy and other diseases and who were of the same sex and age as the ALS subjects. Meningitis and other acute inflammatory disorders that cause increases in the CSF cell count were excluded. Thirteen patients with polyneuropathy and 16 with other diseases were the control subjects; these patients were definitely diagnosed with polyneuropathy or other diseases. CSF samples from cases of neuropathy were obtained before medication. In the control group, the disease phase at the time of CSF collection varied. Patients who were categorized under the “suspect” group of ALS according to the rEEC were excluded from our study; however, patients from this group and those with possible ALS were included if the progressive course was confirmed after several months. Two patients with ALS symptoms only in the lower motor neurons underwent repetitive nerve conduction tests and intravenous immunoglobulin therapy (IVIg), but they did not show any improvement in the symptoms. Since the rEEC for the diagnosis of ALS is stringent, 16% of the patients were not diagnosed with ALS until the final stages of the disease. In Ireland, suspected and possible patients were included if the typical clinical course was confirmed prospectively, and other diseases were excluded [23]. International scales of the symptom, such as revised ALS functional rating scale (ALSFRS-R), were not available on all subjects at the lumber puncture; therefore correlation to clinical severity cannot be addressed. Informed consent was obtained from all the subjects for research purposes, and the study was approved by the ethical committee of Hokkaido University.
The collected CSF samples were kept in 4 °C for several hours at longest, and after division into 1-mL of aliquots without centrifugation, they were preserved at −80 °C until they were used for analysis. The concentration of cystatin C was measured using sandwich enzyme-linked immunosorbent assay (ELISA) with a human cystatin C ELISA kit (Quantikine, R and D systems, Mckinley Place, NE, USA). A 40-fold dilution of the samples was prepared, and ELISA was performed according to the instructions provided in the kit. All samples were measured at single time. After colorization with tetramethylbenzidine, the absorbance was determined at 450 nm by using a microplate reader, and the wavelength used for correction was 570 nm. The results were analyzed using KaleidaGraph 4.0 software. Statistical analysis was performed using the Student–Newman–Keuls test when one-factorial analysis of variance (ANOVA) showed significance (Fig. 1).
 | Full-size image (24K) |
Details of the patients are described in Table 1, Table 2 and Table 3. The mean age of ALS patients and the control subjects with polyneuropathy and other diseases were 62 ± 10, 56 ± 18, and 64 ± 15 years, respectively. The period between the onset of ALS and lumbar puncture was 9.9 months (range, 3–24 months). The female/male ratio of the 3 groups was 2/12, 2/11, and 2/14, respectively. After obtaining the CSF samples from the 8 patients who were diagnosed with possible and suspected ALS, 3 died from respiratory failure within 2 years after the lumbar puncture and 4 progressed to probable or definite ALS. The muscular atrophy and weakness of the remaining one patient who belonged to the “suspect” ALS category marked deteriorated though he was received repetitive IVIg therapies. The mean concentration of cystatin C was 5.5 ± 0.3 mg/L in the ALS group, 6.7 ± 0.4 mg/L in the polyneuropathy group, and 6.9 ± 0.3 mg/L in the other disease group. The concentration was found to be significantly lower in the ALS group than in the other two groups (ALS patients vs. other disease controls: p = 0.014 and ALS patients vs. polyneuropathy patients: p = 0.024).
Table 2. Detail
of each group.
Detailed
diagnoses of control groups were shown.
| Polyneuropathy | Number of patients |
|---|---|
| Chronic inflammatory demyelinating polyneuropathy | 5 |
| Multifocal motor neuropathy | 3 |
| Churg-Strauss syndrome | 2 |
| Charcot-Marrie-tooth disese | 2 |
| Cisplatin neuropathy | 1 |
| Other disease control | |
| Normal pressure hydrocephalus | 7 |
| Cervical spondylotic myelopathy | 3 |
| Post-cerebral infarction | 2 |
| Post-cerebral hemorrage | 1 |
| Ideopathic intracranial hypertension | 1 |
| Phenytoin toxication | 1 |
| Psychogenic reaction | 1 |
Of the two control groups, no correlation was observed between the age and cystatin C concentration. In the ALS group, there was no correlation between the cystatin C concentration and the duration of the disease (Fig. 2). In the ALS group, 5 patients showed bulbar symptoms at the onset of ALS and 3 patients were classified as having progressive bulbar palsy. A slight reduction in the concentration of cystatin C was observed in these patients. Analysis of the CSF samples showed that the extent of the affected region, and the duration of the disease were not correlated with the concentration of cystatin C.
 | Full-size image (21K) |
Three patients with cervical spondylotic myelopathy (CSM) and 3 with MMN were included in the control groups. These patients were frequently misdiagnosed with ALS. Although the sample size is small, their concentrations were not lower than the average concentration observed in ALS (individual concentrations of CSM: 8.8, 7.6, and 8.8 mg/L and individual concentrations of MMN: 6.8, 8.9, and 7.5 mg/dL). Two CSM patients were on pre-operation, and one had a sequela, although it had been operated.
Although several medications have been reported to prolong the lifespan in murine ALS models, only a few clinical trials achieved good treatment outcomes [8], [11] and [31]. One of the critical reasons for this discrepancy is the delay in clinical diagnosis [32]. According to the rEEC, diagnosis of ALS should be withheld until deterioration occurs in two or more affected regions and until several motor neurons are irreversibly damaged. In the present study, we found that cystatin C in the CSF could be a useful biomarker for the diagnosis of ALS in its early stages. Our subjects included eight patients who were diagnosed with possible and suspected ALS. We obtained CSF from these patients, and when their condition subsequently deteriorated, it was found to be similar to that occurring in ALS. The results of our present study may facilitate the early diagnosis of probable ALS before further progression to probable ALS. It is necessary to verify our results in a study with a larger sample size of patients and normal controls. Our samples were collected clinically; therefore, normal controls were absent. In two previous studies, the cystatin C concentration in the CSF was measured among normal controls and patients with minor neurological symptoms. These results showed a concentration of 5.8 ± 2.20 mg/L, which is 5.5 times greater than the concentration in plasma [14] and [17]. As compared to these studies, our data might indicate that cystatin C was upregulated in the case of polyneuropathy and the other disease controls. However, we consider that the concentration of cystatin C in ALS was reduced as reported in proteomics studies, while that in polyneuropathy and other diseases was near the normal range. This error may have resulted from the difference in the assay methods used, which should be eliminated in studies using larger sample sizes.
Cystatin C is an extracellular cysteine proteinase inhibitor that belongs to the cysteine superfamily [27]. It consists of 120 amino acids and is encoded by CST3, which has a leader sequence of 26 amino acids and is associated with the secreted protein. Cystatin C is expressed in various tissues [2], and it is present in all biological fluids. It is produced by the choroid plexus and secreted into the CSF, which contains the highest concentration of cystatin C as compared to the serum, urine, and saliva [1]. A missense mutation in the gene encoding cystatin C can lead to a hereditary human disease known as cerebral amyloid angiopathy (human cystatin C amyloid angiopathy, HCCAA) [24]. Pathological mutation of L68Q leads to the formation of dimers [4], whose conformational changes by three-dimensional domain swapping are amyloidogenic [15]. In this hereditary disease, there is abundant deposition of cystatin C along the vascular walls [22]. However, the concentration of cystatin C in the CSF is low [12]. Further, a cell line that expressed mutant cystatin C secreted it at lower levels than those of wild-type cystatin C; and the high levels of cystatin C aggregated within cells instead of being secreted from the cells [5]. This may imply that the mutation may have caused a breakdown in the protein transport mechanism. The deposition of Bunina bodies and the relatively low cystatin C concentration in the CSF in ALS patients might indicate that the mechanism underlying ALS may be similar to that of HCCAA.
Proteomics analysis of the CSF is a promising method for identifying biomarkers in neurological diseases. Thus far, alterations in several types of protein have been reported in various diseases. Alteration of cystatin C is found in several neurological disorders such as Creutzfeldt–Jakob disease [30], frontotemporal dementia [29], multiple sclerosis [20], and lumbar disk herniation [16]. However, recent articles have reported that cystatin C is truncated during storage at −20 °C [10] and [13]. This information indicates that care should be taken during the storage and treatment of the samples containing cystatin C. Therefore, it is better to use fresh CSF aspirates when determining the levels of cystatin C to avoid an alteration in the concentration of this protein due to storage or treatment methods.
Analysis of CSF samples revealed that cystatin C can be used as a supplementary biomarker for the diagnosis of ALS in its early stages.
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Corresponding author. Tel.: +81 11 706 6028; fax:
+81 11 700 5356.1 Tel.: +81 11 706 6028; fax: +81 11 700 5356.
2 Tel.: +81 11 596 2211; fax: +81 11 596 3122.
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