Increased CSF Pyruvate Levels as a Marker of Impaired Energy Metabolism in Alzheimer's Disease

To the Editor: Reduction of the cerebral metabolic rate of glucose is one of the most predominant abnormalities generally found in the Alzheimer brain, whereas the cerebral metabolic rate of oxygen is only slightly or not at all diminished at the beginning of this dementing disorder.1 This metabolic abnormality may induce functional disturbances preceding morphobiological changes. Recently, it has been claimed that a reduction in cerebral energy metabolism could be a primary event in the pathophysiological chain leading to excitotoxic neuronal death in neurodegenerative illnesses, with special emphasis for Alzheimer's disease.2 Cerebrospinal fluid (CSF) lactate and pyruvate levels provide a reliable measure of cerebral glucose metabolism. Lactate is mainly derived from glycolysis and removed by mitochondrial metabolism; therefore, increased CSF lactate concentration may be due to increased glycolysis, decreased respiration, or both, and elevation of both lactate and pyruvate has been considered as implying mitochondrial metabolic failure.3 We measured CSF levels of lactate, pyruvate and glucose in patients suffering from dementia of Alzheimer type (DAT) and in age- and sex-matched controls. The DAT group included 16 patients 68 ± 6.6 years old, with diagnosis of probable Alzheimer's disease according to the DSM III and the NINCDS-ADRDA criteria.4 The psychobehavioral assessment of demented patients was carried out by means of Mini-Mental State Exam (MMSE)5 for grading cognitive impairment and by means of GBS (Gottfries, Brane, and Steen) Rating Scale for Dementia.6 The control group consisted of 12 subjects 67 ± 4.2 years old, with no evidence of mental deterioration as shown by a MMSE score above 26, admitted to the orthopedic department for a suspected discus prolapse and subjected to lumbar puncture for diagnostic purpose (myelography). No subject had a history of psychiatric illness or alcohol abuse. Blood cell count, urinalysis, and blood chemistry tests using 12-factor automated chemical analysis (SMA-12) were within the normal range for all subjects. No subjects were taking drugs. In both controls and demented patients, lumbar punctures were performed between 8:00 and 10:00 AM, after informed consent, with the subject in sitting position after an overnight bedrest. Twelve mL of CSF were collected on ice, vortexed, divided in 1 mL aliquots, and immediately stored at −85°C until the analysis. Routine proteins analysis in serum and CSF and cytological investigations showed neither signs of acute inflammatory reaction nor blood brain barrier damage in any of the subjects studied. CSF glucose, lactate, and pyruvate concentrations were determined by means of quantitative enzymatic determination (SIGMA Diagnostics, St. Louis, MO). For lactate and pyruvate determinations, CSF samples were added 1:1 with 8% perchloric acid, then centrifuged at 12,000 rpm for 5 minutes and the supernatant taken for analysis. During the handling, samples were kept on ice. The DAT group showed significantly higher mean levels of lactate (P = 0.04) and pyruvate (P = 0.01) (Table 1), the latter being more than four times that of controls (Figure 1). Simple regression analysis showed no association between CSF lactate and pyruvate. CSF levels of lactate and pyruvate in controls and in Alzheimer's patients. These data suggest a defective utilization of pyruvate as substrate for mitochondrial oxidative phosphorylation in DAT. The oxidation of pyruvate to acetyl-coenzyme A, i.e., the step which connects glycolysis to the Krebs tricarboxylic acid cycle, is catalyzed by pyruvate dehydrogenase complex (PDHC). In Alzheimer's disease, PDHC activity is reduced, as postmortem studies7,8 have found, and evidence for an uncoupling of mitochondrial energy metabolism has also been found.9 CSF pyruvate levels above 5 mg/L could then represent a simple and inexpensive method in clinical practice to substantiate the diagnosis of Alzheimer's disease.