dimethylarginine and Alzheimer-Disease

Renal disease is a risk factor for vascular diseases and for dementia, and renal insufficiency can be a feature of Alzheimer's disease (AD). Evidence has suggested that vascular mechanisms mediate the link between renal disease and dementia. Our study sought to test this hypothesis by examining renal and vascular functioning in AD by investigating estimated glomerular filtration rates (eGFR), calculated from serum creatinine concentrations, and established biomarkers of vascular functioning, asymmetrical dimethylarginine (ADMA) and plasma homocysteine (Hcy), in individuals with mild to moderate AD (n = 34) and a group of older adult controls (n = 34). We found significantly reduced eGFR, indicative of impaired renal functioning, in individuals with AD (M = 62.9, SD = 15.2) compared with controls (M = 73.6, SD = 11.8). However, concentrations of ADMA and Hcy did not differ between patient and control groups (ADMA: M = 0.47; M = 0.50; Hcy: M = 17.2; M = 14.9; patients and controls). The criteria for a mediation analysis were not met, as concentrations of ADMA and Hcy did not predict AD, indicating that these biomarkers of vascular functioning did not mediate a relationship between renal functioning and AD. This study indicated that renal insufficiency may independently contribute to AD pathology, and other vascular mechanisms may influence a relationship between renal impairment and AD.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Arginine; Biomarkers; Case-Control Studies; Creatinine; Female; Glomerular Filtration Rate; Homocysteine; Humans; Kidney Diseases; Male; Mental Status Schedule; Multivariate Analysis; Risk Factors; Vascular Diseases

Increasing evidence suggest that Alzheimer's disease (AD) is a heterogeneous disorder that includes several subtypes with different etiology and progression. Cerebrospinal fluid (CSF) is being used to find new biomarkers reflecting the complexity of the pathological pathways within this disease. We used CSF and clinical data from patients to investigate the status of asymmetric dimethyl-L-arginine, creatine, suberylglycine, and L-carnitine along AD progression. These molecules play important roles in mitochondrial function and dysfunction in mitochondrial metabolism are involved in AD pathology. We found that non-APOE4 carriers show lower levels of L-carnitine in CSF early in AD. L-carnitine levels correlate with amyloid-β (Aβ) levels and Mini-Mental State Examination score, but do not add to the specificity or sensitivity of the classical AD CSF biomarkers, Aβ42, phospho-tau, and total-tau. Our results suggest APOE genotype-dependent differences in L-carnitine synthesis or metabolism along AD, and insinuate that L-carnitine treatments would be more beneficial for AD patients not carrying the APOE4 isoform.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoprotein E4; Arginine; Biomarkers; Carnitine; Cognition Disorders; Cognitive Dysfunction; Creatine; Dicarboxylic Acids; Female; Glycine; Heterozygote; Humans; Male; Middle Aged; Neuropsychological Tests; Peptide Fragments; Sensitivity and Specificity; tau Proteins

Alzheimer's disease (AD) is the most common type of dementia accounting for 60-80% of the reported cases. The aim of this study was to evaluate levels of certain parameters of oxidative stress and markers of endothelial dysfunction in the blood of 21 AD patients under standard treatment compared with 10 controls, in an attempt to elucidate the contribution of AD to the total oxidative stress status of the patients. Results indicate that IL-6, TNF-α, ADMA and homocysteine levels were significantly elevated in AD patients. Protein carbonyls levels were higher in AD group, while glutathione reductase and total antioxidant capacity were lower, depicting decreased defense ability against reactive oxygen species. Besides, a higher level of advanced glycation end-products was observed in AD patients. Depending on the treatment received, a distinct inflammatory and oxidative stress profile was observed: in Rivastigmine-treated group, IL6 levels were 47% lower than the average value of the remaining AD patients; homocysteine and glutathione reductase were statistically unchanged in the Rivastigmine and Donepezil-Memantine, respectively Donepezil group. Although the study is based on a limited population, the results could constitute the basis for further studies regarding the effect of medication and diet on AD patients.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Antioxidants; Arginine; Biomarkers; Case-Control Studies; Endothelium, Vascular; Female; Glutathione; Homocysteine; Humans; Inflammation; Interleukin-6; Male; Oxidative Stress; Protein Carbonylation; Tumor Necrosis Factor-alpha

Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and dimethylarginine metabolism (plasma and CSF asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, L-arginine) as well as CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alzheimer Disease; Arginine; Biomarkers; Female; Homocysteine; Humans; Male; Middle Aged; S-Adenosylmethionine; Young Adult

Increased circulating concentrations of homocysteine may be a risk factor for Alzheimer's disease and cognitive dysfunction in normal aging. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (NOS). ADMA is metabolized in neurons by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Nitric oxide plays an important role in synaptic events involved in learning and memory. We determined the effect of L-homocysteine on ADMA accumulation and nitric oxide production in cultured rat neuronal granule cells. The incubation of neuronal granule cells with L-homocysteine for 24 hr caused a dose-dependent accumulation of ADMA and a dose-dependent decrease in nitric oxide production. The addition of the sulfhydryl antioxidant pyrrolidine dithiocarbamate (PDTC) attenuated the effect of homocysteine on ADMA accumulation and nitric oxide production. DDAH activity had a decreasing dose-response relationship with increasing L-homocysteine concentrations. The addition of PDTC caused a dose-dependent increase in DDAH activity. The addition of the N-methyl-D-aspartate receptor antagonists (+/-)-2-amino-5-phosphopentanoic acid and 7-chlorokynurenate had no effect on the inhibition of DDAH by homocysteine. It is concluded that L-homocysteine inhibits DDAH activity, thereby causing ADMA accumulation and decreasing nitric oxide production in cultured neurons. The protective effect of PDTC suggests that L-homocysteine inactivates DDAH in neurons by reacting with the cysteine residue in its active site. The preservation of DDAH activity and the reduction of ADMA accumulation in neurons may be a new strategy for the treatment of Alzheimer's disease and cognitive impairment in normal aging.

Topics: Alzheimer Disease; Amidohydrolases; Animals; Antioxidants; Arginine; Brain; Cells, Cultured; Cognition Disorders; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Feedback, Physiological; Homocysteine; Neurons; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase; Proline; Rats; Thiocarbamates; Up-Regulation