Plasma homocysteine and cerebrospinal fluid neurodegeneration biomarkers in mild cognitive impairment and dementia

4. Rodman DP, Stevenson TL, Ray TR. Phenytoin malabsorption after jejunos- This study illustrated a lack of awareness among doctors tomy tube delivery. Pharmacotherapy 1995;15:801–805.
5. Healy DP, Brodbeck MC, Clendening CE. Ciprofloxacin absorption is im- and nurses in the general hospital setting of the complexities paired in patients given enteral feedings orally and via gastrostomy and jeju- of administering a number of common medications through nostomy tubes. Antimicrob Agents Chemother 1996;40:6–10.
enteral tubes. This was most marked with regard to mod- 6. Mitchell JF, Pawlicki KS. Oral solid dosage forms that should not be crushed: ified-release preparations but also was common for other 1994 revision. Hosp Pharm 1994;29:666–665.
7. Schier JG, Howland MA, Hoffman RS et al. Fatality from administration of labetalol and crushed extended-release nifedipine. Ann Pharmacother 2003; There is a paucity of structured research in this area, consistent with knowledge deficits among the medical and 8. Estoup M. Approaches and limitations of medication delivery in patients with nursing professions.8 The findings of the current study are enteral feeding tubes. Crit Care Nurse 1994;14:68–69.
9. Seifert CF, Johnston BA. A nationwide survey of long-term care facilities to compatible with studies showing lack of awareness among determine the characteristics of medication administration through enteral nurses in nursing homes and intensive care units.9 There is a feeding catheters. Nutr Clin Pract 2005;20:354–362.
need to highlight this lack of awareness and to institute 10. Joint Formulary Committee. British National Formulary, 56th Ed. London: British clear standardized guidelines and training, not only in the Medical Association and Royal Pharmaceutical Society of Great Britain, 2008.
acute hospital setting, but also in extended care and com-munity settings, where increasing numbers of patients arereceiving medications through enteral tubes.
The results of this study also point to the need for greater awareness among pharmaceutical regulatory bodies of the complexities of prescribing for older people, the group who are the most likely to receive medicationsthrough enteral tubes.1 The American Geriatrics Society To the Editor: The clinical and scientific interest surround- and the European Union Geriatric Medicine Society have ing homocysteine has progressively increased because of initiated a dialogue with medication regulation agencies in homocysteine’s significance in a variety of clinical condi- the United States and Europe on the importance of incor- tions. Homocysteine is considered to exert a direct or ad- porating specific gerontological and geriatric medicine ditional contribution to cognitive decline and pathogenesis knowledge into the licensing of medicines that older peo- of dementia.1 Positive associations have been observed not ple are likely to use. In addition, major prescribing guides, only between plasma homocysteine and plasma b-amyloid such as the British National Formulary,10 might consider 40 and b-amyloid 42 (b42) in neurodegenerative diseases,2 adding a separate section on prescribing and enteral tubes in but also between cerebrospinal fluid (CSF) homocysteine the same way that they include sections on prescribing and and CSF phosphorylated Tau protein (p-Tau) in patients pregnancy, liver disease, and renal disease.
with different neurological disorders.3 The aim of this studywas to test the hypothesis that plasma homocysteine cor- relates with CSF biomarkers of neurodegeneration.
Study participants were recruited at the departments of psychiatry of the universities of Erlangen, Bonn, and Go¨ttingen, Germany, cooperating within the national De- Desmond O. Neill, MA, MD, FRCPI, AGSF, FRCP (Glasg) mentia Competence Network.4 The study comprised pa- tients with mild cognitive impairment (MCI), early Alzheimer’s disease (AD), and mild dementias of other eti- ologies (D-o). Exclusion criteria were ongoing vitamin sub-stitution, alcohol abuse or alcoholism, serum vitamin B12levels less than 200 or greater than 3,000 pg/mL, and serumfolate levels less than 2 or greater than 20 ng/mL. AD was diagnosed according to the International Classification of Conflict of Interest: The editor in chief has reviewed Diseases, Tenth Revision, criteria for dementia and the Na- the conflict of interest checklist provided by the authors tional Institute of Neurological and Communicative Disor- and has determined that the authors have no finan- ders and Stroke and the Alzheimer’s Disease and Related cial or any other kind of personal conflicts with this Disorders Association criteria for probable AD. D-o ful- filled internationally accepted criteria for the respective Author Contributions: MTL, TC, DRC, and DON: disorders (e.g., frontotemporal degeneration, Lewy body literature review, study design, analysis, and writing. MTL disease).4 The diagnosis of MCI was based on criteria pre- and JB: data collection and collation.
viously developed.5 The clinical examination included psy- chiatric and neurological status, neuropsychological testing(including the Consortium to Establish A Registry for Alz- heimer’s Disease neuropsychological battery), assessment 1. Lonergan MT, Coughlan T, O’Neill D. Majority of tube fed patients are pre- of basic and instrumental activities of daily living, magnetic scribed medications which require special instructions. J Nutr Health Ageing resonance imaging, laboratory screening, and lumbar punc- 2. Farrell Z, O’Neill D. Towards better screening and assessment of oropharyn- Blood samples were drawn in the morning and pro- geal swallow disorders in the general hospital. Lancet 1999;354:355–356.
3. Cogen R, Weinryb J, Pomerantz C et al. Complications of jejunostomy tube cessed within 1 hour of collection. The mean interval be- feeding in nursing facility patients. Am J Gastroenterol 1991;86:1610–1613.
tween blood and CSF sample collection was 13 days.
Table 1. Summary of the Characteristics and Clinical and Biochemical Data of the Study Sample Mini-Mental State Examination score, mean Æ SD Interval between blood and cerebrospinal sample collection, days, Homocysteine was determined using high-pressure liquid correlation between CSF and plasma homocysteine3,7 can be chromatography in Erlangen, immunephelometry in Bonn, attributed to the fact that a large portion of CSF b-amyloid and Abbott AxSYM immunoassay in Go¨ttingen. These originates in the brain rather than the plasma.8 The results of methods correlate well with each other.6 Vitamin B12 and the current study are consistent with findings from a previous folate plasma concentrations were measured using radio- study that did not detect an association between homocy- steine and b42 in CSF.3 It was expected that homocysteine immunosorbent assays were used for amyloid b-peptide would correlate with p-tau because of the positive associa- (The Genetics Co, Zu¨rich, Switzerland) and tau protein tion between p-tau and CSF homocysteine in patients with determination (Innogenetics, Ghent, Belgium).
different neurological disorders.3 This discrepancy might re- The Spearman correlation test was employed for the sult from sample differences in the diseases of the partici- examination of possible correlations. The simultaneous pants, because our sample comprised mainly patients with effects of different parameters on homocysteine concentra- AD and MCI, most of whom had an overproduction of p- tions were investigated using a multiple linear regression analysis. Po.05 was considered statistically significant.
Two shortcomings of the study concern the long inter- The characteristics and data of the sample are summa- val between blood and CSF collection and the fact that rized in Table 1. Plasma homocysteine levels correlated homocysteine was not measured only in fasting conditions.
significantly with folate, vitamin B12, and creatinine (cor- However, homocysteine concentration is relatively constant relation coefficients: À 0.408, À 0.358, 0.230, Po.001, over at least 1 month,9 and the interval between sample .001, .03, respectively) but not with CSF parameters in the collections in this study was shorter. Furthermore, post- whole sample or in the MCI or AD subgroups (the D-o prandial and fasting homocysteine blood levels do not differ group was not analyzed separately because of its limited significantly within 4 to 7 hours after breakfast.10 Because number of patients). Moreover vitamin B12 correlated sig- blood was collected in the present study within 4 hours after breakfast, it is unlikely that it biased the findings.
Age, sex, vitamin B12, creatinine, clinical diagnosis, These results suggest that blood homocysteine levels homocysteine determination method, p-Tau, and b42 were are not associated with CSF biomarkers of neurodegener- fed into a multiple linear regression analysis to find factors that predict blood homocysteine concentrations. Consistentwith previous observations,1 vitamin B12 and creatininewere shown to have a significant effect on homocysteine (Po.001 and .001, b 5 À 0.006 and 6.283, standard error Department of Psychiatry and Psychotherapy 5 0.002 and 1.790, respectively). Neither CSF parameters Friedrich-Alexander-Universita¨t Erlangen-Nu¨rnberg nor the method of homocysteine measurement affected Department of Psychiatry and Psychotherapy The lack of correlation between CSF b-amyloid and ho- mocysteine, despite their association in plasma,2 and the PL is a consultant to Innogenetics. This study was sup- Department of Psychiatry and Psychotherapy ported by a grant from the German Federal Ministry of Friedrich-Alexander-Universita¨t Erlangen-Nu¨rnberg Education and Research (BMBF): Kompetenznetz Demen- Author Contribution: Initial study concept: PA and JK.
Acquisition of data: PA, JK, FG, JP, FJ, OP, SW, TRS, JW, PL. Analysis and interpretation data: PA, JK, FG, TK.
Department of Psychiatry and Psychotherapy Preparation of the manuscript: PA, FG, JP, FJ, OP, SW, TK, Rheinische Friedrich-Wilhelms-Universita¨t Bonn Sponsor’s Role: The sponsor was not involved in the study design, methods, subject recruitment, data collection, analysis, or preparation of the letter.
1. Kessler H, Bleich S, Falkai P et al. Homocysteine and dementia. Fortschr 2. Irizarry MC, Gurol ME, Raju S et al. Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative disease. Neurology 3. Obeid R, Kasoha M, Knapp JP et al. Folate and methylation status in relation to phosphorylated tau protein(181P) and beta-amyloid(1-42) in cerebrospinalfluid. Clin Chem 2007;53:1129–1136.
4. Kornhuber J, Schmidtke K, Fro¨lich L et al. Early and differential diagnosis of dementia and MCI: Design and cohort baseline characteristics of the GermanDementia Competence Network. Dement Geriatr Cogn Disord 2009; in press.
Ludwig-Maximilian-Universita¨t Mu¨nchen 5. Petersen RC, Doody R, Kurz A et al. Current concepts in mild cognitive im- pairment. Arch Neurol 2001;58:1985–1892.
6. Zappacosta B, Persichilli S, Schribano D et al. Comparing different methods for homocysteine determination. Clin Chem Lab Med 2002;40:1139–1142.
Department of Psychiatry and Psychotherapy 7. Selley ML, Close DR, Stern SE. The effect of increased concentrations of ho- mocysteine on the concentration of (E)-4-hydroxy-2-nonenal in the plasma and the cerebrospinal fluid of patients with Alzheimer’s disease. NeurobiolAging 2002;3:383–388.
8. Mehta PD, Pirttila T, Patrick BA et al. Amyloid beta protein 1-40 and 1-42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci Lett 2001;304:102–106.
Department of Psychiatry and Psychotherapy 9. Clarke R, Woodhouse P, Ulvik A et al. Variability and determinants of total Friedrich-Alexander-Universita¨t Erlangen-Nu homocysteine concentrations in plasma in an elderly population. Clin Chem 10. Thirup P, Ekelund S. Day-to-day, postprandial, and orthostatic variation of total plasma homocysteine. Clin Chem 1999;45:1280–1283.
Department of Psychiatry and Psychotherapy Friedrich-Alexander-Universita¨t Erlangen-Nu¨rnberg SENATOR JOHN MCCAIN’S HEALTH STATUS AND Department of Psychiatry, Socialpsychiatry and To the Editor: Health problems related to the 72-year-old U.S. Senator and presidential candidate John McCain werea great concern in the 2008 presidential race.1 Senator McCain had a high-risk cutaneous melanoma Department of Psychiatry and Psychotherapy removed approximately 8 years ago, and it has been pointed out how great might be his mortality risk due to melanoma.2 In fact, a closer look at McCain’s health records3 might call into question the wisdom of modern preventive med- icine; although McCain has no evidence of heart or other Department of Psychiatry and Psychotherapy cardiovascular disease, he has been taking the cholesterol- Friedrich-Alexander-Universita¨t Erlangen-Nu¨rnberg lowering drug simvastatin because of slightly abnormal Accumulating evidence suggests that, in the routine treatment of elderly subjects with statins, an increase in cancer incidence and mortality may exceed in magnitude Conflict of Interest: The editor in chief has reviewed the any decrease in cardiovascular disease morbidity and mor- conflict of interest checklist provided by the authors and has tality.4 This might be particularly striking in subjects who determined that the authors have no financial or any other already have cancer. In fact, statin drugs have been shown kind of personal conflicts with this letter.
to modulate the immune system through coordinated ac-


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