Increased cerebrospinal fluid pyruvate levels in Alzheimer's disease

doi:10.1016/0304-3940(95)12058-C

Neuroscience Letters

Volume 199, Issue 3, 27 October 1995, Pages 231-233

https://doi.org/10.1016/0304-3940(95)12058-C Get rights and content

Abstract

Impaired energy metabolism is an early, predominant feature in Alzheimer's disease. In order to find out simple, reliable ‘in vivo’ markers for the clinical-biological typization of the disorder, we measured cerebrospinal fluid (CSF) glucose, lactate and pyruvate levels in patients suffering from dementia of Alzheimer type (DAT) and in healthy elderly controls. DAT group showed remarkably higher levels of pyruvate (P = 0.01), with no overlap with the values obtained in controls. CSF pyruvate levels were also significantly associated with the severity of dementia. Therefore, CSF pyruvate levels neatly separate DAT patients from controls, having also pathogenetic value.

References (20)

M.F. Folstein et al.
‘Mini Mental State’: a practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975)
E.X. Perry et al.
Coenzyme-A-acetylating enzymes in Alzheimer's disease: possible cholinergic ‘compartment’ of pyruvate dehydrogenase
Neurosci. Lett.
(1980)
B. Szelies et al.
Quantitative EEG mapping and PET in Alzheimer's disease
J. Neurol. Sci.
(1992)
American Psychiatric Association
Diagnostic and Statistical Manual of Mental Disorders
(1987)
M.F. Beal
Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?
Ann. Neurol.
(1992)
J.P. Blass et al.
Consequences of mild, graded hypoxia
Adv. Neurol.
(1979)
J.P. Blass et al.
Non-neural markers in Alzheimer's disease
Alzheimer Dis. Assoc. Dis.
(1993)
M. Browning et al.
Phosphorilation-mediated changes in pyruvate dehydrogenase activity influence pyruvate-supported calcium accumulation by brain mitochondria
J. Neurochem.
(1981)
S.T. De Kosky et al.
Assessing utility of single photon emission computed tomography (SPECT) scan in Alzheimer disease: correlation with cognitive severity
Alzheimer Dis. Assoc. Dis.
(1990)
C.G. Gottfries et al.
A new rating scale for dementia syndromes
Gerontologist
(1982)

There are more references available in the full text version of this article.

Cited by (46)

Optimization of measurement of mitochondrial electron transport activity in postmortem human brain samples and measurement of susceptibility to rotenone and 4-hydroxynonenal inhibition
2022, Redox Biology
Mitochondrial function is required to meet the energetic and metabolic requirements of the brain. Abnormalities in mitochondrial function, due to genetic or developmental factors, mitochondrial toxins, aging or insufficient mitochondrial quality control contribute to neurological and psychiatric diseases. Studying bioenergetics from postmortem human tissues has been challenging due to the diverse range of human genetics, health conditions, sex, age, and postmortem interval. Furthermore, fresh tissues that were in the past required for assessment of mitochondrial respiratory function were rarely available. Recent studies established protocols to use in bioenergetic analyses from frozen tissues using animal models and cell cultures. In this study we optimized these methods to determine the activities of mitochondrial electron transport in postmortem human brain. Further we demonstrate how these samples can be used to assess the susceptibility to the mitochondrial toxin rotenone and exposure to the reactive lipid species 4-hydroxynonenal. The establishment of such an approach will significantly impact translational studies of human diseases by allowing measurement of mitochondrial function in human tissue repositories.
Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease
2022, Acta Pharmaceutica Sinica B
Citation Excerpt :
Pre-clinical models of both diabetic and non-diabetic rats with increased β-amyloid exposure in the hippocampus show significant decreases in energy intake, activity, and fat oxidation but increases in carbohydrate oxidation and energy expenditure (resulting in negative energy balance and weight loss)72. Assessments of in vivo metabolism through various indirect methods have shown that, in patients with AD, cerebrospinal fluid (CSF) concentrations of lactate and pyruvate were higher, while succinate, fumarate, and glutamine were lower than controls, suggesting an impairment of mitochondrial oxidative metabolism of glucose73–75. A proposed deficit in cerebral glucose metabolism is further confirmed by in vivo imaging [e.g., FDG-PET and magnetic resonance imaging (MRI)] of tissue atrophy and lower glucose metabolism, including specific metabolic deficits in the precuneus, posterior cingulate, and temporal-parietal, as well as the hippocampus and default mode network brain regions, which vary by age at onset and disease progression74,76–81.
Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.
Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias
2021, Neurobiology of Aging
Citation Excerpt :
Indeed, lactate is fully ionized at physiological pH levels and thus crosses the blood-brain barrier very slowly (Cunnane et al., 2020; Magistretti and Allaman, 2018; Posner and Plum, 1967), meaning that CSF Lactate should resent of neither plasma lactate nor glucose levels and merely reflect primary brain production. Taking into account previous works that identified higher CSF lactate levels in patients with AD (Parnetti et al., 1995), we first measured CSF lactate levels in patients with either AD, FTD or dementia with Lewy body (DLB), to assess the presence of differences in mean values with respect to a population of healthy controls. Then—focusing on updates from the most recent NIA-AA research framework (Jack et al., 2018)—we stratified patients within the Alzheimer's continuum into subgroups according to the ATN system, to investigate potential differences due to biological substrates.
Mitochondrial dysfunction is pivotal in the development of neurodegenerative dementias, causing cellular death alongside disease-specific pathogenic cascades. Holding cerebrospinal fluid (CSF) lactates as an indirect measure of brain metabolic activity, we first compared CSF lactate levels from patients with Alzheimer's disease (AD)—stratified according to the ATN system and epsilon genotype—frontotemporal dementia (FTD) and dementia with Lewy body (DLB) to findings from healthy controls. With respect to controls, we detected lower CSF lactates in patients with AD and FTD but comparable levels in patients with DLB. Second, a correlation analysis between CSF lactates and biomarkers of neurodegeneration identified an inverse correlation between lactates and levels of t-tau and p-tau only in the Alzheimer's continuum. The reduction of CSF lactate correlates to the advent of tauopathy and cellular death in AD, implying that Aβ pathology alone is not sufficient to induce neuronal metabolic impairment. The metabolic impairment in FTD patients has a similar explanation, as it is likely due to fast neuronal degeneration in the disease. The absence of CSF lactate reduction in patients with DLB may be related to the prevalent subcortical localization of the pathology.
An integrated approach to unravel a putative crosstalk network in Alzheimer's disease and Parkinson's disease
2020, Neuropeptides
Integration of multiple profiling data and construction of functional regulatory networks provide a powerful approach to uncover functional relationships and significant molecular entities from transcriptomic data, highlighting the molecular mechanisms of complex diseases. Despite having an overlap in the neuropathologies of AD and PD, the molecular entities overlapped and mechanisms behind them are less known. Here we used an integrated strategy to analyze miRNA and gene transcriptomic data to understand the role of miRNAs and genes in regulatory activities taking place in cells, and find transcriptomic signatures linking AD and PD. We preprocessed and analyzed publicly available microarray datasets and identified 97 DEGs and 21 DEmiRs that may be involved in the overlapped mechanisms between these two disorders. Among the DEGs, we found HSPA9, PGK1, SDHC, FH, DLD, YWHAZ and ACLY as the major protein-coding genes involved in the crosstalk for AD-PD pathogenesis. Further we integrated these DEGs and DEmiRs with regulatory TFs to construct an overlapped dysregulated network of AD and PD. In the network, miR-27a-3p, miR-148a-3p and miR-15a-5p were found to be the most relevant with maximum interactions, describing their significance in the potential crosstalk. We also looked into the dysregulated biological processes and pathways overlapped in AD and PD. In conclusion, we highlighted the DEGs, DEmiRs, their interactions and related pathways overlapped in AD and PD pathogenesis, also describing a potential crosstalk at molecular level. Besides, our findings can further be used for molecular studies to reveal an assured AD-PD crosstalk.
Negative correlation between CSF lactate levels and MoCA scores in male Chinese subjects
2017, Psychiatry Research
Citation Excerpt :
To summarize, the present study showed the negative correlation between CSF lactate levels and MoCA scores in male Chinese subjects. Previous studies demonstrated that elevated CSF lactate levels were correlated with the cognitive impairment in patients with Alzheimer's disease (Parnetti et al., 1995, 2000; Pugliese et al., 2005; Liguori et al., 2015), which is in line with our findings. Increased evidences supported the view that mitochondrial dysfunction may contribute to cognitive function decline (Pugliese et al., 2005; Manczak et al., 2004).
Lactate is a product of glycolysis by astrocytes and can be generated as a primary metabolic energy source by neurons. Lactate plays multifunctional role in human brain energy metabolism and cognitive function. However, no direct evidence demonstrated the link between lactate and cognition in normal condition. In the present study, concentrations of lactate in cerebrospinal fluid (CSF) and peripheral blood were measured to investigate the association of lactate with cognitive ability, which was assessed by Montreal Cognitive Assessment (MoCA), in 99 male Chinese subjects. Correlation analyses revealed that serum lactate levels were negatively correlated with age, and CSF lactate levels were negatively correlated with MoCA scores after Box-Cox transformations. But no correlation was found between serum lactate levels and MoCA scores after Box-Cox transformations. In conclusion, the results indicate that CSF lactate levels were negatively correlated with MoCA scores in male Chinese subjects.
Metabolite profiling for the identification of altered metabolic pathways in Alzheimer's disease
2015, Journal of Pharmaceutical and Biomedical Analysis
Gas chromatography coupled to mass spectrometry is the most frequent tool for metabolomic profiling of low molecular weight metabolites. Its suitability in health survey is beyond doubt, given that primary metabolites involved in central pathways of metabolism are usually altered in diseases. The objective of this work is to investigate metabolic differences in serum between Alzheimer's disease patients and healthy controls in order to elucidate pathological mechanisms underlying to disease. Alterations in levels of 23 metabolites were detected, including increased lactic acid, α-ketoglutarate, isocitric acid, glucose, oleic acid, adenosine and cholesterol, as well as decreased urea, valine, aspartic acid, pyroglutamate, glutamine, phenylalanine, asparagine, ornithine, pipecolic acid, histidine, tyrosine, palmitic and uric acid, tryptophan, stearic acid and cystine. Metabolic pathway analysis revealed the involvement of multiple affected pathways, such as energy deficiencies, oxidative stress, hyperammonemia, and others. Moreover, it is noteworthy that some of these compounds have not been previously described in AD research, such as α-ketoglutarate, isocitrate pipecolic acid, pyroglutamate and adenosine, confirming the potential of this metabolomic approach in the search of novel potential markers for early detection of Alzheimer's disease.

View all citing articles on Scopus

View full text

Increased cerebrospinal fluid pyruvate levels in Alzheimer's disease

Abstract

J. Psychiatr. Res.

Neurosci. Lett.

J. Neurol. Sci.

Diagnostic and Statistical Manual of Mental Disorders

Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses?

Ann. Neurol.

Consequences of mild, graded hypoxia

Adv. Neurol.

Non-neural markers in Alzheimer's disease

Alzheimer Dis. Assoc. Dis.

Phosphorilation-mediated changes in pyruvate dehydrogenase activity influence pyruvate-supported calcium accumulation by brain mitochondria

J. Neurochem.

Assessing utility of single photon emission computed tomography (SPECT) scan in Alzheimer disease: correlation with cognitive severity

Alzheimer Dis. Assoc. Dis.

A new rating scale for dementia syndromes

Gerontologist