%0 Journal Article %J J Alzheimers Dis %D 2021 %T B Vitamins Prevent Iron-Associated Brain Atrophy and Domain-Specific Effects of Iron, Copper, Aluminum, and Silicon on Cognition in Mild Cognitive Impairment. %A Jakubowski, Hieronim %A Zioła-Frankowska, Anetta %A Frankowski, Marcin %A Perła-Kaján, Joanna %A Refsum, Helga %A de Jager, Celeste A %A Smith, A David %B J Alzheimers Dis %V 84 %P 1039-1055 %8 2021 Nov 23 %G eng %N 3 %R 10.3233/JAD-215085 %0 Journal Article %J J Alzheimers Dis %D 2021 %T Paraoxonase 1, B Vitamins Supplementation, and Mild Cognitive Impairment. %A Perła-Kaján, Joanna %A Włoczkowska, Olga %A Zioła-Frankowska, Anetta %A Frankowski, Marcin %A David Smith, A %A de Jager, Celeste A %A Refsum, Helga %A Jakubowski, Hieronim %X

BACKGROUND: Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer's disease.

OBJECTIVE: We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI).

METHODS: Individuals with MCI (n = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) (n = 95) or placebo (n = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates.

RESULTS: In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N-Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition.

CONCLUSION: PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI.

%B J Alzheimers Dis %V 81 %P 1211-1229 %8 2021 Jun 01 %G eng %N 3 %R 10.3233/JAD-210137 %0 Journal Article %J J Alzheimers Dis %D 2018 %T Homocysteine and Dementia: An International Consensus Statement. %A Smith, A David %A Refsum, Helga %A Bottiglieri, Teodoro %A Fenech, Michael %A Hooshmand, Babak %A McCaddon, Andrew %A Miller, Joshua W %A Rosenberg, Irwin H %A Obeid, Rima %K Cognition %K Cognitive Dysfunction %K Consensus %K Dementia %K Dietary Supplements %K Homocysteine %K Humans %K Meta-Analysis as Topic %K Review Literature as Topic %K Risk Factors %K Vitamin B Complex %X

Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for development of cognitive decline, dementia, and Alzheimer's disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia.

%B J Alzheimers Dis %V 62 %P 561-570 %8 2018 %G eng %U https://content.iospress.com/download/journal-of-alzheimers-disease/jad171042?id=journal-of-alzheimers-disease%2Fjad171042 %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/29480200?dopt=Abstract %R 10.3233/JAD-171042 %0 Journal Article %J J Alzheimers Dis %D 2017 %T Kynurenine Pathway Metabolites in Alzheimer's Disease. %A Giil, Lasse Melvaer %A Midttun, Øivind %A Refsum, Helga %A Ulvik, Arve %A Advani, Rajiv %A Smith, A David %A Ueland, Per Magne %X

BACKGROUND: Metabolites of tryptophan, produced via the kynurenine pathway (kynurenines), have been linked to Alzheimer's disease (AD) in small cohorts with conflicting results.

OBJECTIVE: To compare differences in plasma kynurenine levels between AD and controls and identify potential associations with cognition.

METHODS: The study included 65 histopathologically-confirmed AD patients and 65 cognitively-screened controls from the Oxford Project to Investigate Memory and Ageing (OPTIMA) cohort. Cognition was assessed using the Cambridge Cognitive Examination (CamCog). Tryptophan, kynurenines, neopterin, and vitamin B6 forms were measured in plasma by liquid chromatography-tandem mass spectrometry. Non-parametric statistics, logistic regression and standardized robust regressions were applied with a false discovery rate of 0.05.

RESULTS: Tryptophan, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid were lower in AD (Odds ratios (ORs) 0.24 -0.47; p-values <0.001 -0.01). Pyridoxal 5'phosphate did not differ between AD and controls. Kynurenine, anthranilic acid, quinolinic acid, and markers of immune activation (neopterin, kynurenine/tryptophan ratio, and the PAr index (Pyridoxic acid/(Pyridoxal 5'phosphate + Pyridoxal)) increased with age (β 0.31 -0.51; p-values <0.001 -0.006). Xanthurenic acid decreased with age (β: -0.42, p < 0.001). Elderly AD patients with high quinolinic acid performed worse on the CamCog test, indicated by a significant age*quinolinic acid interaction (β 0.21, p < 0.001).

CONCLUSION: Plasma concentrations of several kynurenines were lower in patients with AD compared to controls. Low xanthurenic acid occurred in both AD and with aging. Inflammation-related markers were associated with age, but not AD. However, elevated QA was associated with poor cognition in older AD patients.

%B J Alzheimers Dis %V 60 %P 495-504 %8 2017 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/28869479?dopt=Abstract %R 10.3233/JAD-170485 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Omega-3 Fatty Acid Status Enhances the Prevention of Cognitive Decline by B Vitamins in Mild Cognitive Impairment. %A Oulhaj, Abderrahim %A Jernerén, Fredrik %A Refsum, Helga %A Smith, A David %A de Jager, Celeste A %K Aged %K Aged, 80 and over %K Cognition %K Cognitive Dysfunction %K Disease Progression %K Fatty Acids, Omega-3 %K Female %K Humans %K Male %K Neuropsychological Tests %K Treatment Outcome %K Vitamin B Complex %X

A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.

%B J Alzheimers Dis %V 50 %P 547-57 %8 2016 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26757190?dopt=Abstract %R 10.3233/JAD-150777