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The purpose of this study was to investigate if the concentration of lactate can provide additional information for pathologies that need examination of the cerebrospinal fluid (CSF) in their diagnostic controls or protocols.
A prospective study carried out in the year 2001 at the University Hospital of Bellvitge (Barcelona), on 92 samples of CSF f...
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... values in group C are comparable with the normal values obtained in other similar studies (2). Within the MS group, the decrease in lactate concentration is more marked in RRMS and CIS, which show values lower than those obtained in PPMS (Table 2), in agreement with other publications (5), suggesting that PPMS constitutes a separate disease entity different from RRMS. The decrease in lactate concentration in the CSF of patients with MS, may explain the alterations in sensitivity in some of these patients. ...
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Citations
... It can be concluded that there is an elevation in extra-mitochondrial glucose metabolism in MS patients, which could also be associated with impaired mitochondrial function [117]. Taking into account the aforementioned data, the fluctuations in lactate levels have the potential to serve as diagnostic criteria as they could indicate the progression of the disease [118]. ...
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration. Oligodendrocytes play a vital role in maintaining the integrity of myelin, the protective sheath around nerve fibres essential for efficient signal transmission. However, in MS, oligodendrocytes become dysfunctional, leading to myelin damage and axonal degeneration. Emerging evidence suggests that metabolic changes, including mitochondrial dysfunction and alterations in glucose and lipid metabolism, contribute significantly to the pathogenesis of MS. Mitochondrial dysfunction is observed in both immune cells and oligodendrocytes within the CNS of MS patients. Impaired mitochondrial function leads to energy deficits, affecting crucial processes such as impulse transmission and axonal transport, ultimately contributing to neurodegeneration. Moreover, mitochondrial dysfunction is linked to the generation of reactive oxygen species (ROS), exacerbating myelin damage and inflammation. Altered glucose metabolism affects the energy supply required for oligodendrocyte function and myelin synthesis. Dysregulated lipid metabolism results in changes to the composition of myelin, affecting its stability and integrity. Importantly, low levels of polyunsaturated fatty acids in MS are associated with upregulated lipid metabolism and enhanced glucose catabolism. Understanding the intricate relationship between these mechanisms is crucial for developing targeted therapies to preserve myelin and promote neurological recovery in individuals with MS. Addressing these metabolic aspects may offer new insights into potential therapeutic strategies to halt disease progression and improve the quality of life for MS patients.
... In contrary, other data showed a diminished CSF lactate level or comparable levels. Those results were mainly in the initial phases of MS [21][22][23]. ...
... The overproduced lactate in MS stay in the CSF transiently and quickly passes into the circulation. This step of the transients overproduction of lactate in CSF clarify the controversial data of literature, and explain why the increment in CSF lactate level was not showed to be linked to EDSS or the subtypes of MS [17][18][19][20][21][22][23]. ...
... MS is characterized by metabolic disturbance caused by impaired mitochondrial functions, so it is expected that MS may lead to overproduction of the neuronal lactate. Information related to conceivable alterations in lactate level in MS patients are conflicting due to either increment [17,20] or no alter [23] in serum lactate levels has been determined. Also, information accessible in literature has basically been gotten in generally limited cohorts of MS patients and no relationship with the progression of MS or with the disease subtype (RR MS, SP MS, and PP MS) has been illustrated (19,17,20]. ...
Objective: To study the serum lactate level in MS and to explore its correlation with the progression and disability in multiple sclerosis (MS), and the important role of mitochondrial dysfunction in the pathogenesis of MS.
Methods: This case-control study included 80 participants, involved 50 MS patients and 30 normal healthy controls. Detailed history taking, complete neurological examination, and clinical evaluation of the disability using the Expanded Disability Status Scale (EDSS) were done for all patients. Level of serum lactate was measured in both groups and was correlated with EDSS, MS subtypes, MRI brain, and MRS findings.
Results: Serum lactate in MS patients was about three and half times higher than serum lactate levels of healthy controls (22.87 ± 5.92 mg/dl versus 6.39 ± 0.9 6.39 ± 0.91, p < 0.001). Importantly, serum lactate values were increased in MS cases with a progressive course compared with MS cases with RR course. Also, there were linearly correlations linking serum lactate levels and the duration of MS (r = 0.342, P = 0.015), relapses numbers (r = 0.335, P = 0.022), and EDSS (r = 0.483, P < 0.001). Also, there were strong positive correlations between serum lactate and Lipid/Lactate (r = 0.461, P = 0.001), periventricular lesion (r = 0.453, P = 0.005), and moderate positive correlations between serum lactate and juxtacortical lesion (r = 0.351, P = 0.02), and infratentorial lesion (r = 0.355, P = 0.02).
Conclusion: Measurement of serum lactate may be helpful in MS and this supports the hypothesis of the critical role of mitochondrial dysfunction and axonal damage in MS.
... Nonetheless, a study by Amorini el al. has reported a threefold elevation in serum lactate levels in MS patients [24]. Although this study supports evidence of mitochondrial dysfunction in MS, previous studies assessing both serum [25] and CSF (cerebral spinal fluid) [26] lactate levels in this disorder have failed to show any evidence of an increase in the level of this metabolite. Importantly, lactate levels may not necessarily be raised as a consequence of MRC dysfunction as evidenced in patients with primary mitochondrial disorders [27]. ...
Objectives:
Evidence of mitochondrial respiratory chain (MRC) dysfunction and oxidative stress has been implicated in the pathophysiology of multiple sclerosis (MS). However, at present, there is no reliable low invasive surrogate available to evaluate mitochondrial function in these patients. In view of the particular sensitivity of MRC complex IV to oxidative stress, the aim of this study was to assess blood mononuclear cell (BMNC) MRC complex IV activity in MS patients and compare these results to age matched controls and MS patients on β-interferon treatment.
Methods:
Spectrophotometric enzyme assay was employed to measure MRC complex IV activity in blood mononuclear cell obtained multiple sclerosis patients and aged matched controls.
Results:
MRC Complex IV activity was found to be significantly decreased (p< 0.05) in MS patients (2.1 ± 0.8 k/nmol × 10-3; mean ± SD] when compared to the controls (7.2 ± 2.3 k/nmol × 10-3). Complex IV activity in MS patients on β-interferon (4.9 ± 1.5 k/nmol × 10-3) was not found to be significantly different from that of the controls.
Conclusions:
This study has indicated evidence of peripheral MRC complex IV deficiency in MS patients and has highlighted the potential utility of BMNCs as a potential means to evaluate mitochondrial function in this disorder. Furthermore, the reported improvement of complex IV activity may provide novel insights into the mode(s) of action of β-interferon.
... In another study performed by Albanese et al., the oxidative stress-induced mitochondrial abnormality has been reported to raise CSF lactate levels as a result of impaired energy metabolism (anaerobic metabolism) as well as disrupted neuro-axonal homeostasis (Albanese et al., 2016). Contrarily, some other studies suggest, however, that CSF lactate levels fell in the early stages of MS or that no significant difference was found in the serum lactate levels compared to the control group (Aasly et al., 1997;Fonalledas-Perelló et al., 2008). However, it should be noted that contradictory results of the aforementioned studies may be due to the fact that the present study's sample size was restricted (Mähler et al., 2012). ...
... reported lower levels. 16 Lactate is the final cytoplasmic product of the glycolysis pathway and represents quantitatively the most important monocarboxylate. Indeed, during glycolysis in the Krebs cycle, glucose breaks down to pyruvate, which is subsequently reversibly converted to lactate by the enzyme lactate dehydrogenase. ...
Melatonin has a beneficial role in adult rat models of multiple sclerosis (MS). In this study, melatonin treatment (10 mg/kg/d) was investigated in young age (5-6 weeks old) Lewis rat model of acute experimental autoimmune encephalomyelitis (EAE) followed by assessing serum levels of lactate and melatonin. Results showed that clinical outcomes were exacerbated in melatonin- (neurological score=6) versus PBS-treated EAE rats (score=5). Melatonin caused a significant increase in serum IFN-γ, in comparison to PBS-treated EAE rats whereas no considerable change in IL-4 levels were found, although they were significantly lower than those of controls. The ratio of IFN-γ/IL-4, an indicator of Th-1/Th-2, was significantly higher in PBS- and melatonin- treated EAE rats, in comparison to controls. Moreover, results showed increased lymphocyte infiltration, activated astrocytes (GFAP+ cells) but also higher demyelinated plaques (MBP-deficient areas) in the lumbar spinal cord of melatonin-treated EAE rats. Finally, serum levels of lactate, but not melatonin, significantly increased in the melatonin group, compared to untreated EAE and normal rats. In conclusion, our results indicated a relationship between age and the development of EAE since a negative impact was found for melatonin on EAE recovery of young rats by enhancing IFN-γ, the ratio of Th1/Th2 cells, and astrocyte activation, which seems to delay the remyelination process. While melatonin levels decline in MS patients, lactate might be a potential diagnostic biomarker for prediction of disease progression. Early administration of melatonin in the acute phase of MS might be harmful and needs further investigations.
... MRI studies showed a correlation between CSF lactate concentration and the number of inflammatory plaques [8,11]. In contrast, data reporting decreased CSF lactate levels in the early stages of MS or comparable concentration have also been published [9,10,25]. In our study, carried out in a large cohort of RRMS patients, we noted a significant increase of CSF lactate levels, possibly due to the deranged use of energetic substrates caused by the impairment of oxidative phosphorylation cycle. ...
Altered cerebrospinal fluid (CSF) levels of lactate have been described in neurodegenerative diseases and related to mitochondrial dysfunction and neuronal degeneration. We investigated the relationship between CSF lactate levels, disease severity, and biomarkers associated with neuroaxonal damage in patients with multiple sclerosis (MS).
One-hundred eighteen subjects with relapsing-remitting multiple sclerosis (RRMS) were included, along with one-hundred fifty seven matched controls. CSF levels of lactate, tau protein, and neurofilament light were detected at the time of diagnosis. Patients were followed-up for a mean of 5 years. Progression index (PI), multiple sclerosis severity scale (MSSS), and Bayesian risk estimate for multiple sclerosis (BREMS) were assessed as clinical measures of disease severity and progression. Differences between groups and correlation between CSF lactate, disease severity and CSF biomarkers of neuronal damage were explored.
CSF lactate was higher in RRMS patients compared to controls. A negative correlation was found between lactate levels and disease duration. Patients with higher CSF lactate concentration had significantly higher PI, MSSS, and BREMS scores at long-term follow-up. Furthermore, CSF lactate correlated positively and significantly with CSF levels of both tau protein and neurofilament light protein.
Measurement of CSF lactate may be helpful, in conjunction with other biomarkers of tissue damage, as an early predictor of disease severity in RRMS patients. A better understanding of the alterations of mitochondrial metabolic pathways associated to RRMS severity may pave the way to new therapeutic targets to contrast axonal damage and disease severity.
... A correlation between lactate concentration in the CSF and the number of inflammatory plaques reinforced the indication of increased glycolysis in MS due to mitochondrial malfunctioning [23,24]. Notwithstanding, data reporting decrease in CSF lactate in the early stages of MS have also been published [25], casting doubts over the role of this compound and, therefore, over the importance of its measurements. Furthermore, to compound this uncertainty, further 1 H MRS studies indicated either elevated [26] or no change [27] of brain lactate in MS patients. ...
... According to this strong indication that MS is characterized by metabolic imbalance due to compromised mitochondrial functions, it is conceivable to expect that MS may cause an increase in neuronal lactate production through compensatory mechanisms. Data referring to possible changes in lactate in MS patients are controversial, since either increase [22][23][24] or decrease [25] in CSF lactate has been reported. To compound the uncertainty about changes of lactate in relation to MS, it should be remembered that both elevated [26] and no change [27] of brain lactate have been reported. ...
... To compound the uncertainty about changes of lactate in relation to MS, it should be remembered that both elevated [26] and no change [27] of brain lactate have been reported. In addition, data available in literature have mainly been obtained in relatively restricted cohorts of MS patients [22][23][24][25]. However, when lactate was found elevated in the CSF of MS patients [22][23][24] no correlation with the disease progression on EDSS or with the clinical subtype (RR, SP, PP) has been demonstrated, thus raising questions as to the usefulness of monitoring this molecule in MS. ...
Multiple sclerosis (MS) is a primary inflammatory demyelinating disease associated with a probably secondary progressive neuronegenerative component. Impaired mitochondrial functioning has been hypothesised to drive neurodegeneration and to cause increased anaerobic metabolism in MS. The aim of our multicentre study was to determine whether MS patients had values of circulating lactate different from those of controls. Patients (n=613) were recruited, assessed for disability and clinically classified (relapling-remitting, secondary progressive, primary progressive) at the Catholic University of Rome, Italy (n=281), at the MS Centre Amsterdam, The Netherlands (n=158) and at the S. Camillo Forlanini Hospital, Rome, Italy (n=174). Serum lactate levels were quantified spectrophotometrically with the analyst being blinded to all clinical information. In patients with MS serum lactate was three times higher (3.04±1.26mmol/l) than that of healthy controls (1.09±0.25mmol/l, p<0.0001) and increased across clinical groups, with higher levels in cases with a progressive than with a relapsing-remitting disease course. In addition, there was a linear correlation between serum lactate levels and the EDSS (R2=0.419; p<0.001). These data support the hypothesis that mitochondrial dysfunction is an important feature in MS and of particular relevance to the neurodegenerative phase of the disease. Measurement of serum lactate in MS might be a relative inexpensive test for longitudinal monitoring of "virtual hypoxia" in MS. and also a secondary outcome for treatment trials aimed to improve mitochondrial function in patients with MS.
... A correlation between lactate concentration in the CSF and the number of inflammatory plaques reinforced the indication of increased glycolysis in MS due to mitochondrial malfunctioning [23,24]. Notwithstanding, data reporting decrease in CSF lactate in the early stages of MS have also been published [25], casting doubts over the role of this compound and, therefore, over the importance of its measurements. Furthermore, to compound this uncertainty, further 1 H MRS studies indicated either elevated [26] or no change [27] of brain lactate in MS patients. ...
... According to this strong indication that MS is characterized by metabolic imbalance due to compromised mitochondrial functions, it is conceivable to expect that MS may cause an increase in neuronal lactate production through compensatory mechanisms. Data referring to possible changes in lactate in MS patients are controversial, since either increase [22][23][24] or decrease [25] in CSF lactate has been reported. To compound the uncertainty about changes of lactate in relation to MS, it should be remembered that both elevated [26] and no change [27] of brain lactate have been reported. ...
... To compound the uncertainty about changes of lactate in relation to MS, it should be remembered that both elevated [26] and no change [27] of brain lactate have been reported. In addition, data available in literature have mainly been obtained in relatively restricted cohorts of MS patients [22][23][24][25]. However, when lactate was found elevated in the CSF of MS patients [22][23][24] no correlation with the disease progression on EDSS or with the clinical subtype (RR, SP, PP) has been demonstrated, thus raising questions as to the usefulness of monitoring this molecule in MS. ...
Multiple sclerosis (MS) is a primary inflammatory demyelinating disease associated with a probably secondary progressive neurodegenerative component. Impaired mitochondrial functioning has been hypothesized to drive neurodegeneration and to cause increased anaerobic metabolism in MS. The aim of our multicentre study was to determine whether MS patients had values of circulating lactate different from those of controls. Patients (n = 613) were recruited, assessed for disability and clinically classified (relapsing–remitting, secondary progressive, primary progressive) at the Catholic University of Rome, Italy (n = 281), at the MS Centre Amsterdam, The Netherlands (n = 158) and at the S. Camillo Forlanini Hospital, Rome, Italy (n = 174). Serum lactate levels were quantified spectrophotometrically with the analyst being blinded to all clinical information. In patients with MS serum lactate was three times higher (3.04 ± 1.26 mmol/l) than that of healthy controls (1.09 ± 0.25 mmol/l, p < 0.0001) and increased across clinical groups, with higher levels in cases with a progressive than with a relapsing–remitting disease course. In addition, there was a linear correlation between serum lactate levels and the expanded disability scale (EDSS) (R2 = 0.419; p < 0.001). These data support the hypothesis that mitochondrial dysfunction is an important feature in MS and of particular relevance to the neurodegenerative phase of the disease. Measurement of serum lactate in MS might be a relative inexpensive test for longitudinal monitoring of “virtual hypoxia” in MS and also a secondary outcome for treatment trials aimed to improve mitochondrial function in patients with MS.
Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS), which is characterized by demyelination and neurodegeneration. Oligodendrocytes have an essential role in maintaining the integrity of myelin, the protective sheath that surrounds nerve fibers and is indispensable for efficient signal transmission. Nevertheless, in multiple sclerosis, oligodendrocytes become dysfunctional, leading to myelin deterioration and axonal degeneration. Recent research suggests that metabolic changes, including mitochondrial dysfunction and alterations in glucose and lipid metabolism, contribute significantly to the pathogenesis of MS. Mitochondrial dysfunction is observed in both immune cells and CNS oligodendrocytes of MS patients. Impaired mitochondrial function leads to energy deficits, affecting crucial processes such as impulse transmission and axonal transport, ultimately contributing to neurodegeneration. Understanding the complex relationship between these mechanisms is crucial to the development of an effective treatment for MS.
Multiple sclerosis (MS) is a complicated autoimmune disease characterized by inflammatory and demyelinating events in the central nervous system. The exact etiology and pathogenesis of MS have not been elucidated. However, a set of metabolic changes and their effects on immune cells and neural functions have been explained. This review highlights the contribution of carbohydrates and lipids metabolism to the etiology and pathogenesis of MS. Then, we have proposed a hypothetical relationship between such metabolic changes and the immune system in patients with MS. Finally, the potential clinical implications of these metabolic changes in diagnosis, prognosis, and discovering therapeutic targets have been discussed. It is concluded that research on the pathophysiological alterations of carbohydrate and lipid metabolism may be a potential strategy for paving the way toward MS treatment.
