Joshua W. Miller

Plasma homocysteine levels and risk of Alzheimer disease

Objective: To explore the association between high homocysteine levels and risk of Alzheimer disease (AD) in the Washington Heights-Inwood Columbia Aging Project (WHICAP). Methods: The authors obtained fasting plasma samples in 909 elderly subjects chosen at random from a cohort of Medicare recipients; there was longitudinal data in 679 subjects without dementia at baseline who were followed for 3,206 person-years. Prevalent and incident dementia and its subtypes were diagnosed using standard methods. Results: There were 128 persons with prevalent AD and 109 with incident AD in 3,206 person-years of follow-up. The adjusted OR of prevalent AD for the highest quartile of homocysteine compared to the lowest was 1.3 (95% CI = 0.7, 2.3; p for trend = 0.25). In longitudinal analyses, the authors found that the adjusted hazard ratio of AD for the highest quartile of homocysteine was 1.4 (95% CI = 0.8, 2.4; p for trend = 0.31). The authors also found that high homocysteine levels were not related to a decline in memory scores over time. Age was a significant confounder in all the analyses. The study had 80% power to detect a hazard ratio of 1.3 in the longitudinal analyses. Conclusion: High homocysteine levels were not associated with AD and were not related to a decrease in memory scores over time.

Homocysteine, vitamin B6, and vascular disease in AD patients.

BackgroundCerebrovascular disease is a cause of dementia and is associated with elevated plasma levels of homocysteine. Patients with AD tend to have unexplained elevations of homocysteine concentrations vs healthy control subjects. Vitamin B6 status, a potential determinant of plasma homocysteine, has not been characterized in patients with AD. ObjectiveTo investigate plasma homocysteine, vitamin B6 status, and the occurrence of vascular disease in patients with AD. MethodsForty-three patients with AD and 37 control subjects without AD were studied for homocysteine, B vitamin status (folate, vitamin B12, pyridoxal-5′-phosphate [PLP]), kidney function (creatinine), and thyroid function (thyroid-stimulating hormone, thyroxin). In addition, the presence of vascular disease was assessed by reviewing both medical histories and brain imaging data provided by CT and MRI. ResultsThe OR for elevated plasma homocysteine (>12 &mgr;mol/L) was only 2.2 (not significant) for subjects with AD. In contrast, the OR was 10.0 (p = 0.03) for subjects with vascular disease (n = 26). The OR for low plasma PLP (<25 nmol/L) was 12.3 (p = 0.01) for patients with AD. No significant relationship was observed between vascular disease and PLP level or between plasma homocysteine and PLP concentrations. ConclusionsElevated plasma homocysteine in patients with AD appears related to vascular disease and not AD pathology. In addition, low vitamin B6 status is prevalent in patients with AD. It remains to be determined if elevated plasma homocysteine or low vitamin B6 status directly influences AD pathogenesis or progression.

Oxidative damage caused by free radicals produced during catecholamine autoxidation: Protective effects of O-methylation and melatonin

Catecholamine autoxidation produces reactive oxygen species that have been implicated in the loss of dopaminergic neurons in the nigrostriatal region of the brain that occurs during normal aging and in Parkinsons disease. In the present study, the potential protective effects of catecholamine O-methylation and of melatonin against catecholamine autoxidation-induced protein damage were assessed in vitro using the oxygen radical absorbance capacity (ORAC) assay. The rate of oxidation of the fluorescent protein porphyridium cruentum beta-phycoerythrin (beta-PE) caused by the oxidizing agent CuSO4 was shown to be accelerated by addition of the catecholamines dopamine and L-dopa. Replacement of dopamine and L-dopa in the assay with their O-methylated metabolites 3-O-methyldopamine and 3-O-methyldopa significantly decreased the rate of beta-PE oxidation. When melatonin was added to the ORAC assay in combination with dopamine or L-dopa, the rate of beta-PE oxidation was decreased as well. These findings were consistent with the following interpretations: (1) O-methylated catecholamines are less susceptible to autoxidation than their nonmethylated precursors, and (2) melatonin, which has recently been shown to be a powerful antioxidant, is capable of scavenging free radicals produced during catecholamine autoxidation. These findings suggest that O-methylation and melatonin may be important components of the brains antioxidant defenses against catecholamine autoxidation and may protect against consequent dopaminergic neurodegeneration.

Identifying polyglutamine protein species in situ that best predict neurodegeneration

SUMMARY Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function on proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies (IBs), IB formation may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that monoclonal antibody (mAb) 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular weight conformational states expanded polyQ assumes and disappears in higher molecular-weight aggregated forms, such as IBs. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species.

Helicobacter pylori Infection Is Associated With an Increased Rate of Diabetes

OBJECTIVE Chronic infections could be contributing to the socioeconomic gradient in chronic diseases. Although chronic infections have been associated with increased levels of inflammatory cytokines and cardiovascular disease, there is limited evidence on how infections affect risk of diabetes. RESEARCH DESIGN AND METHODS We examined the association between serological evidence of chronic viral and bacterial infections and incident diabetes in a prospective cohort of Latino elderly. We analyzed data on 782 individuals aged >60 years and diabetes-free in 1998–1999, whose blood was tested for antibodies to herpes simplex virus 1, varicella virus, cytomegalovirus, Helicobacter pylori, and Toxoplasma gondii and who were followed until June 2008. We used Cox proportional hazards regression to estimate the relative incidence rate of diabetes by serostatus, with adjustment for age, sex, education, cardiovascular disease, smoking, and cholesterol levels. RESULTS Individuals seropositive for herpes simplex virus 1, varicella virus, cytomegalovirus, and T. gondii did not show an increased rate of diabetes, whereas those who were seropositive for H. pylori at enrollment were 2.7 times more likely at any given time to develop diabetes than seronegative individuals (hazard ratio 2.69 [95% CI 1.10–6.60]). Controlling for insulin resistance, C-reactive protein and interleukin-6 did not attenuate the effect of H. pylori infection. CONCLUSIONS We demonstrated for the first time that H. pylori infection leads to an increased rate of incident diabetes in a prospective cohort study. Our findings implicate a potential role for antibiotic and gastrointestinal treatment in preventing diabetes.

Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats) of the fragile X (FMR1) gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS.

Effect of L-dopa and the catechol-O-methyltransferase inhibitor Ro 41-0960 on sulfur amino acid metabolites in rats

L-Dopa is the most effective drug known for the treatment of Parkinsons disease. However, the large doses required to treat this neurodegenerative disorder can significantly affect tissue concentrations of sulfur amino acid metabolites due to peripheral and central O-methylation. These effects include decreases in tissue concentrations of the biochemical methyl donor S-adenosylmethionine (SAM), increases in tissue concentrations of the methylation inhibitor S-adenosylhomocysteine (SAH), and increases in plasma concentrations of homocysteine, recently identified as an independent risk factor for vascular disease. In the present study, the ability of the catechol-O-methyltransferase inhibitor Ro 41-0960 to prevent L-Dopa-induced changes in SAM, SAH, and homocysteine concentrations was determined in rats. Rats were injected intraperitoneally with Ro 41-0960 or vehicle 30 min prior to an intraperitoneal injection of L-Dopa or vehicle. One hour after the second injection, the rats were killed and their brains, livers, spleens, kidneys, and plasma collected. SAM and SAH concentrations were then determined in discrete brain regions and peripheral tissues, and total homocysteine concentrations were determined in plasma. In the rats treated with only L-Dopa, decreased SAM concentrations and increased SAH concentrations were found in all brain regions and peripheral tissues measured, and increased homocysteine concentrations were found in plasma, consistent with previous reports. In rats pretreated with Ro 41-0960, however, these L-Dopa-induced effects on sulfur amino acid metabolite concentrations were attenuated or prevented entirely. It remains to be determined if this sparing effect of Ro 41-0960 on sulfur amino acid metabolites has clinical significance.

Vitamin B 12 deficiency

Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12-containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency.

Heterogeneity of cognitive trajectories in diverse older persons.

This study examined trajectories of cognitive change in psychometrically matched measures of episodic memory, semantic memory, and executive function in an ethnically, demographically, and cognitively diverse sample of older persons. Individual rates of change showed considerable heterogeneity in each domain. Baseline clinical diagnosis predicted differential change in semantic memory and executive function, dementia > mild cognitive impairment (MCI) > normal, but average decline in verbal episodic memory was similar across all 3 diagnostic groups. There was substantial overlap of distributions of cognitive change across baseline diagnostic groups for all 3 measures. Cognitive change was strongly related to change in clinical diagnosis. Rapid and similar change was present for all 3 cognitive measures in patients with dementia and in those with normal cognition and those with MCI who progressed clinically. In cognitively normal patients, verbal episodic memory change was greater than change in the other two domains. Global status, measured by the Clinical Dementia Rating scale (Morris, 1993), predicted change in semantic memory and executive function, whereas APOE genotype predicted change in verbal episodic memory, and age had no effect on rates of change in any domain independent of global status and APOE. Results show important limitations in using cross-sectional diagnosis to predict prognosis and suggest that research to identify robust predictors of cognitive change across the full spectrum from normal to dementia is needed for better early identification of diseases that cause progressive decline.

Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin, is more pronounced in older adults with elevated plasma folate

BACKGROUND An analysis of data from the National Health and Nutrition Examination Survey indicated that in older adults exposed to folic acid fortification, the combination of low serum vitamin B-12 and elevated folate is associated with higher concentrations of homocysteine and methylmalonic acid and higher odds ratios for cognitive impairment and anemia than the combination of low vitamin B-12 and nonelevated folate. These findings await confirmation in other populations. OBJECTIVE The purpose was to compare metabolic indicators of vitamin B-12 status, cognitive function, and depressive symptoms among elderly Latinos with elevated and nonelevated plasma folate. DESIGN Cross-sectional data were analyzed for 1535 subjects (age: >or=60 y) from the Sacramento Area Latino Study on Aging. Subjects were divided into 4 groups on the basis of plasma vitamin B-12 (< or >or=148 pmol/L) and folate (<or= or >45.3 nmol/L). Homocysteine, methylmalonic acid, holotranscobalamin, ratio of holotranscobalamin to vitamin B-12, Modified Mini-Mental State Examination, delayed recall, and depressive symptom scores were compared between the groups. RESULTS Individuals with low vitamin B-12 and elevated folate (n = 22) had the highest concentrations of homocysteine and methylmalonic acid and the lowest concentration of holotranscobalamin and ratio of holotranscobalamin to vitamin B-12 when compared with all other groups (P <or= 0.003). No differences in Modified Mini-Mental State Examination, delayed recall, and depressive symptom scores were observed between the low vitamin B-12 and elevated-folate group compared with other groups. CONCLUSIONS Low vitamin B-12 is associated with more pronounced metabolic evidence of vitamin B-12 deficiency when folate is elevated than when folate is not elevated. These data should be considered when assessing the potential costs, risks, and benefits of folic acid and vitamin B-12 fortification programs.