Association of vitamin D metabolites with cognitive function and brain atrophy in elderly individuals - the Austrian stroke prevention study.

BACKGROUND: Vitamin D is a well-established regulator of calcium and phosphate metabolism that has neurotrophic and neuroprotective properties. Deficiency of vitamin D has been proposed to promote cognitive dysfunction and brain atrophy. However, existing studies provide inconsistent results. Here we aimed to investigate the association between vitamin D metabolites, cognitive function and brain atrophy in a cohort of well-characterized community-dwelling elderly individuals with normal neurological status and without history of stroke and dementia. METHODS: 25(OH)D3, 25(OH)D2 and 24,25(OH)2D3 were measured by liquid-chromatography tandem mass-spectrometry in serum samples from 390 community-dwelling elderly individuals. All participants underwent thorough neuropsychiatric tests capturing memory, executive function and visuopractical skills. In 139 of these individuals, MRI of the brain was performed in order to capture neurodegenerative and vascular changes. RESULTS: Total 25(OH)D (ß=0.003, 0.037), 24,25(OH)2D3 (ß=0.0456, p=0.010) and vitamin D metabolite ratio (VMR) (ß=0.0467, p=0.012) were significantly related to memory function. Adjustment for multiple testing weakened these relationships, but trends (p≤0.10) remained. 24,25(OH)2D3 and VMR showed similar trends also for visuopractical skills and global cognitive function. No significant relationships existed between vitamin D metabolites and MRI derived indices of neurodegeneration and vascular changes. Sub-group analyses of individuals with low concentrations of 25(OH)D and 24,25(OH)2D3 showed significantly worse memory function compared to individuals with normal or high concentrations. CONCLUSIONS: Vitamin D deficient individuals appear to have a modest reduction of memory function without structural brain atrophy. Future studies should explore if vitamin D supplementation can improve cognitive function.

Phenylalanine Effects on Brain Function in Adult Phenylketonuria.

OBJECTIVE: To evaluate the relationship between circulating phenylalanine and brain function as well as neuropsychiatric symptoms in adults with phenylketonuria. METHODS: In this prospective cross-sectional study, early-treated patients with phenylketonuria older than 30 years and age- and sex-matched controls were included. Extensive neurologic evaluation, neuropsychological and behavioral testing, sensory and motor evoked potentials, and MRI were performed. CSF concentrations of neurodegenerative markers were evaluated in addition in a subset of 10 patients. RESULTS: Nineteen patients with phenylketonuria (median age 41 years) with different phenylalanine levels (median 873 µmol/L) entered the study. They showed higher prevalence of neurologic symptoms, cognitive and behavioral abnormalities, autonomic dysfunction, alterations in neurophysiologic measures, and atrophy in putamen and right thalamus compared to controls. In CSF, patients with phenylketonuria exhibited higher ß-amyloid 1-42 (p = 0.003), total tau (p < 0.001), and phosphorylated tau (p = 0.032) levels compared to controls. Plasma phenylalanine levels highly correlated with the number of failed neuropsychological tests (r = 0.64, p = 0.003), neuropsychiatric symptoms (r = 0.73, p < 001), motor evoked potential latency (r = 0.48, p = 0.030), and parietal lobe atrophy. CONCLUSIONS: Our study provides strong evidence for a correlation between phenylalanine levels and clinical, neuropsychological, neurophysiologic, biochemical, and imaging alterations in adult patients with phenylketonuria.

Association of Methionine to Homocysteine Status With Brain Magnetic Resonance Imaging Measures and Risk of Dementia.

Importance: Impairment of methylation status (ie, methionine to homocysteine ratio) may be a modifiable risk factor for structural brain changes and incident dementia. Objective: To investigate the association of serum markers of methylation status and sulfur amino acids with risk of incident dementia, Alzheimer disease (AD), and the rate of total brain tissue volume loss during 6 years. Design, Setting, and Participants: This population-based longitudinal study was performed from March 21, 2001, to October 10, 2010, in a sample of 2570 individuals aged 60 to 102 years from the Swedish Study on Aging and Care in Kungsholmen who were dementia free at baseline and underwent comprehensive examinations and structural brain magnetic resonance imaging (MRI) on 2 to 3 occasions during 6 years. Data analysis was performed from March 1, 2018, to October 1, 2018. Main Outcomes and Measures: Incident dementia, AD, and the rate of total brain volume loss. Results: This study included 2570 individuals (mean [SD] age, 73.1 [10.4] years; 1331 [56.5%] female). The methionine to homocysteine ratio was higher in individuals who consumed vitamin supplements (median, 1.9; interquartile range [IQR], 1.5-2.6) compared with those who did not (median, 1.8; IQR, 1.3-2.3; P < .001) and increased per each quartile increase of vitamin B12 or folate. In the multiadjusted model, an elevated baseline serum total homocysteine level was associated with an increased risk of dementia and AD during 6 years: for the highest homocysteine quartile compared with the lowest, the hazard ratios (HRs) were 1.60 (95% CI, 1.01-2.55) for dementia and 2.33 (95% CI, 1.26-4.30) for AD. In contrast, elevated concentrations of methionine were associated with a decreased risk of dementia (HR, 0.54; 95% CI, 0.36-0.81) for the highest quartile compared with the lowest. Higher values of the methionine to homocysteine ratio were significantly associated with lower risk of dementia and AD: for the fourth methionine-homocysteine quartile compared with the first quartile, the HR was 0.44 (95% CI, 0.27-0.71) for incident dementia and 0.43 (95% CI, 0.23-0.80) for AD. In the multiadjusted linear mixed models, a higher methionine to homocysteine ratio was associated with a decreased rate of total brain tissue volume loss during the study period (ß [SE] per 1-SD increase, 0.038 [0.014]; P = .007). Conclusions and Relevance: The methionine to homocysteine status was associated with dementia development and structural brain changes during the 6-year study period, suggesting that a higher methionine to homocysteine ratio may be important in reducing the rate of brain atrophy and decreasing the risk of dementia in older adults.

Short term micronutrient-antioxidant supplementation has no impact on a serological marker of gastric atrophy in Zambian adults: retrospective analysis of a randomised controlled trial.

BACKGROUND: Gastric cancer is a major contributor to cancer deaths in Zambia but, as elsewhere, no preventive strategies have been identified. We set out to investigate the possibility of reducing gastric atrophy, a premalignant lesion, using micronutrient-antioxidant supplementation. METHODS: We analysed 215 archival samples from a randomised controlled trial of micronutrient-antioxidant supplementation carried out from 2003 to 2006. Participants were randomised to receive either the supplement or placebo and had been taking the allocated intervention for a mean of 18 (range 14-27) months when the samples used in this study were taken. We used low pepsinogen 1 to 2 (PEP1:2) ratio as a surrogate marker of gastric atrophy. A PEP 1:2 ratio of less than three was considered low. HIV serology, age, nutritional status, smoking, alcohol intake and gastric pH were also analysed. Ethical approval was obtained from the University of Zambia Biomedical Research Ethics Committee (011-04-12). The randomized trial was registered (ISRCTN31173864). RESULTS: The overall prevalence of low PEP 1:2 ratio was 15/215 (7%) and it did not differ between the placebo (8/103, 7.8%) and micronutrient groups (7/112, 6.3%; HR 1.24; 95% CI 0.47-3.3; P = 0.79). The presence of low PEP 1:2 ratio was not influenced by HIV infection (HR 1.07; 95% CI 0.37-3.2; P =0.89) or nutritional status but it inversely correlated with gastric pH (Spearman's rho = -0.34; P = 0.0001). Age above 40 years was associated with atrophy, but neither alcohol nor smoking had any influence. CONCLUSION: Short term micronutrient supplementation does not have any impact on PEP 1:2 ratio, a serological marker of gastric atrophy. PEP 1:2 ratio inversely correlates with gastric pH.

Significant reduction of homocysteine level with multiple B vitamins in atrophic glossitis patients.

OBJECTIVE: This study evaluated whether supplementations of different vitamins and iron could reduce the serum homocysteine levels in 91 atrophic glossitis (AG) patients. MATERIALS AND METHODS: Atrophic glossitis (AG) patients with concomitant deficiencies of vitamin B12 only (n = 39, group I), folic acid only (n = 10, group II), iron only (n = 9, group III), or vitamin B12 plus iron (n = 19, group IV) were treated with vitamin BC capsules plus deficient hematinics. AG patients without definite hematinic deficiencies (n = 14, group V) were treated with vitamin BC capsules only. The blood homocysteine and hematinic levels at baseline and after treatment till all oral symptoms had disappeared were measured and compared by paired t-test. RESULTS: Supplementations with vitamin BC capsules plus corresponding deficient hematinics for groups I, II, III, IV patients and with vitamin BC capsules only for group V patients could reduce the high serum homocysteine levels to significantly lower levels after a mean treatment period of 8.3-11.6 months (all P-values < 0.05). CONCLUSION: Supplementations with vitamin BC capsules plus corresponding deficient hematinics or with vitamin BC capsules only can reduce the high serum homocysteine levels to significantly lower levels in AG patients.

Plasma long-chain omega-3 fatty acids and atrophy of the medial temporal lobe.

OBJECTIVE: The long-chain ω-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are potential candidates for interventions to delay Alzheimer disease (AD), but evidence from clinical studies is mixed. We aimed at determining whether plasma levels of EPA or DHA predict atrophy of medial temporal lobe (MTL) gray matter regions in older subjects. METHODS: A total of 281 community dwellers from the Three-City Study, aged 65 years or older, had plasma fatty acid measurements at baseline and underwent MRI examinations at baseline and at 4 years. We studied the association between plasma EPA and DHA and MTL gray matter volume change at 4 years. RESULTS: Higher plasma EPA, but not DHA, was associated with lower gray matter atrophy of the right hippocampal/parahippocampal area and of the right amygdala (p < 0.05, familywise error corrected). Based on a mean right amygdala volume loss of 6.0 mm(3)/y (0.6%), a 1 SD higher plasma EPA (+0.64% of total plasma fatty acids) at baseline was related to a 1.3 mm(3) smaller gray matter loss per year in the right amygdala. Higher atrophy of the right amygdala was associated with greater 4-year decline in semantic memory performances and more depressive symptoms. CONCLUSION: The amygdala, which develops neuropathology in the early stage of AD and is involved in the pathogenesis of depression, may be an important brain structure involved in the association between EPA and cognitive decline and depressive symptoms.

Plasma amyloid beta protein 42 in non-demented persons aged 75 years: effects of concomitant medication and medial temporal lobe atrophy.

Plasma amyloid beta (Abeta42) levels increase with age and are elevated in some patients during the early stages of Alzheimer's disease (AD). Although plasma Abeta42 is not useful for diagnosis of AD, it might be a biological risk factor. In the elderly population a considerable variety of concomitant medication is used for the treatment of various disorders. How this co-medication might influence Abeta42 levels is still to be investigated. Through the Vienna Transdanube Aging study (VITA), the authors measured cross-sectional Abeta42 plasma levels during the initial examination of 526 individuals aged 75 years without dementia. The medication considered included: treatment with calcium channel blockers, digitalis, anticoagulants, antihistamines, ergotamine, histamine H(2) receptor antagonists, bronchodilators, pentoxyfilline, neuroleptics, insulin, oral antidiabetics, l-dopa, benzodiazepines, oestrogen, Gingko biloba, vitamins, piracetam, non-steroidal anti-inflammatory drugs (NSAIDs), and statins. Of the study population aged 75 years, 90% were users of some of the above-mentioned medication. Depending on their medial temporal lobe atrophy (MTA), users of insulin showed significantly increased levels of Abeta42, while users of gingko biloba for at least 2 years of drug intake had significantly decreased Abeta42 plasma levels, independent of their MTA. Users of NSAIDs showed a non-significant trend to reduced Abeta42 plasma levels, while users of biguanides showed an increase in Abeta42 plasma levels. In the multiple regression analysis considering possible interactions between various medications statin users showed a significant decrease of Abeta42; insulin users had again significantly higher and long-term gingko biloba users lower plasma Abeta42 levels. Persons with a low degree of MTA had significantly increased Abeta42 plasma levels. Considering the increase of Abeta42 plasma levels as a risk factor for AD, any changes induced by medication by long-term use in the peripheral and possibly also in the central compartment, could be of clinical relevance.

Clinical trials of vitamin B6 and proline supplementation for gyrate atrophy of the choroid and retina.

Five patients with gyrate atrophy of the choroid and retina were examined ophthalmologically, especially ophthalmoscopically, to evaluate trials of vitamin B6 (pyridoxine) or supplementary proline. The oral administration of vitamin B6 was tried in two patients. The vitamin did not alter the serum ornithine level and the progression of chorioretinal atrophy in one patient (case 2). Despite a reduced serum ornithine level following vitamin B6 administration, chorioretinal atrophy progressed gradually in another patient (case 3). Supplementary proline was tried in four patients. Despite the supplementation the serum proline level did not increase, and the chorioretinal atrophy progressed in one patient (case 2) who received both vitamin B6 and proline. Supplementary proline minimised the progression of gyrate atrophy in the youngest patient (case 1) and halted the progression in two others (cases 4 and 5). Supplementary proline may possibly lessen the progression of chorioretinal lesions in gyrate atrophy.