4
colonoscopy. Of the 930 subjects, 832 completed both follow-up colonoscopies: 409 from the calcium group and 423 from the placebo group. At least one adenoma was diagnosed in 127 subjects receiving calcium supplement (3 1%) and in 159 subjects receiving placebo (38%). The adjusted risk ratio was 0.81 (95 % confidence internal, 0.67-0.99;p=0.04). Interestingly, it was noted that the ad- justed ratio of the average number of recurrent polyps in those receiving calcium compared with placebo was 0.76 This recent study opens up an important gate toward the use of calcium in colon polyp and cancer chemoprevention.The reported positive effect, however, although statistically significant, is nevertheless rather modest. The studies by both Holt et al.” and Baron et al.17 highlight the inherent difficulties in chemoprevention (which have been extensively reviewed by Lipkin and Newrnarkls) and indicate the need for long-term studies covering periods of 10-1 5 years and for recruitment of an adequate number of compliant subjects who are willing to take calcium for such a prolonged period of observation. Furthermore, it is essential to balance dietary supplemen- tation carefully, to avoid interactions between different dietary factors, as was observed by Alberts et a1.I6 4Fo.02). 1. 2. 3. 4. 5. 6. Potter JD. Reconciling the epidemiology, physiol- ogy, and molecular biology of colon cancer. JAMA Potter JD, Slattery ML, Bostick RM, Gapstur SM. Colon cancer: a review of epidemiology. Epidemiol Rev 1993;15:499-545 Willett WC, Stampfer MJ, Colditz GA, et al. Relation of meat, fat, and fiber intake to the risk of colon cancer in prospectivestudy among women. N Engl J Med 1990;323:1664-72 Kune S, Kune GA, Watson LF. Case-control study of dietary etiological factors: the Melbourne colorectal cancer study. Nutr Cancer 1987;9:21- 42 Negri E, La Vecchia C, D’Avanzo B, Franceschi S. Calciumdairy products and colorectal cancer. Nutr Cancer 1990;13:255-62 Wargovich MJ, Baer AR. Basic and clinical investi- gations of dietary calcium in the prevention of colorectal cancer. Prev Med 1989;18:672-9 1992;268:1573-7 7. 8. 9. 10. 11. 12. 13. 14. Newmark HL, Wargovich MJ, Bruce WR. Colon can- cer and dietary fat, phosphate, and calcium: a hy- pothesis. J Natl Cancer lnst 1984;72:1323-5 Wargovich MJ, Eng W, Newmark HL. Calcium in- hibits the damaging and compensatory prolifera- tive effects of fatty acids on mouse colon epithe- lium. Cancer Lett 1984;23:253-8 Welberg JW, Kleibeuker JH, van der Meer R, et al. Effects of oral calcium supplementationon intesti- nal bile acids and cytolytic activity of fecal water in patients with adenomatous polyps of the colon. Eur J Clin Invest 1993;23:63-8 Rozen FI Fireman Z, Fine N, et al. Oral calcium sup- presses increased rectal epithelial cell prolifera- tion in persons at risk of colorectal cancer. Gut Lipkin M, Newmark H. Effect of added dietary cal- cium on colonic epithelial cell proliferation in sub- jects at high risk for familial colonic cancer. N Engl J Med 1985;313:1381-4 Buset M, Lipkin M, Winawer S, et al. Inhibition of human colonic epithelial cell proliferation in vivo and in vitro by calcium. Cancer Res 1986;46:5426- 30 Lipkin M, Friedman E, Winawer SJ, Newmark H. Colonic epithelial cell proliferation in responders and nonresponders to supplemental dietary cal- cium. Cancer Res 1989;49:248-54 Bostick RM, Fosdick L, Wood JR, et al. Calcium and 1989;30:650-5 colorectal epithelial cell proliferation in sporadic adenoma patients: a randomized, double-blinded, placebo-controlledclinical trial. J Natl Cancer lnst Holt PR, Atillasoy EO, Gilman J, et al. Modulation of abnormal colonic epithelial cell proliferation and differentiation by low-fat dairy foods. JAMA Alberts DS, Ritenbaugh C, Story JA, et al. Random- ized, double-blinded, placebo-controlledstudy of effect of wheat bran fiber and calcium on fecal bile acids.in patients with resected adenomatous co- lon polyps. J Natl Cancer lnst 1996;88:81-92 Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal ad- enomas. N Engl J Med 1999;340:101-7 Lipkin M, Newmark H. Development of clinical chemoprevention trials. J Natl Cancer lnst 1995;87:1307-15 15. 1998;280:1074-9 16. 17. 18. 1995;87:1275-7 Homocysteine and Alzheimer’s Disease In a recent case-control study of 764 patients with clinically diagnosed Alzheimer’s disease (AD), in- cluding 76 patients with the AD diagnosis con- firmed postmortem, mean total serum homocys- teine concentration was found to be significantly This review was prepared by Joshua W. Miller, Ph.D., Assistant Adjunct Professor, University of California-Davis Medical Center, Department of Medical Pathology, Sacramento, CA 9581 7, USA. higher than that of a control group of elderly indi- viduals with no evidence of cognitive impairment. Because homocysteine is considered an indepen- dent risk factor for vascular disease, this finding is consistent with the emerging hypothesis that vas- cular disease is a contributing factor in the patho- genesis of AD. Dementia, defined as significant memory impairment and loss of intellectual functions, is a common and devastat- 126 NutritionReviews@, Vol. 57, No. 4

Homocysteine and Alzheimer's Disease

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Page 1: Homocysteine and Alzheimer's Disease

colonoscopy. Of the 930 subjects, 832 completed both follow-up colonoscopies: 409 from the calcium group and 423 from the placebo group. At least one adenoma was diagnosed in 127 subjects receiving calcium supplement (3 1%) and in 159 subjects receiving placebo (38%). The adjusted risk ratio was 0.81 (95 % confidence internal, 0.67-0.99;p=0.04). Interestingly, it was noted that the ad- justed ratio of the average number of recurrent polyps in those receiving calcium compared with placebo was 0.76

This recent study opens up an important gate toward the use of calcium in colon polyp and cancer chemoprevention. The reported positive effect, however, although statistically significant, is nevertheless rather modest. The studies by both Holt et al.” and Baron et al.17 highlight the inherent difficulties in chemoprevention (which have been extensively reviewed by Lipkin and Newrnarkls) and indicate the need for long-term studies covering periods of 10-1 5 years and for recruitment of an adequate number of compliant subjects who are willing to take calcium for such a prolonged period of observation. Furthermore, it is essential to balance dietary supplemen- tation carefully, to avoid interactions between different dietary factors, as was observed by Alberts et a1.I6

4Fo.02).

1.

2.

3.

4.

5.

6.

Potter JD. Reconciling the epidemiology, physiol- ogy, and molecular biology of colon cancer. JAMA

Potter JD, Slattery ML, Bostick RM, Gapstur SM. Colon cancer: a review of epidemiology. Epidemiol Rev 1993;15:499-545 Willett WC, Stampfer MJ, Colditz GA, et al. Relation of meat, fat, and fiber intake to the risk of colon cancer in prospective study among women. N Engl J Med 1990;323:1664-72 Kune S, Kune GA, Watson LF. Case-control study of dietary etiological factors: the Melbourne colorectal cancer study. Nutr Cancer 1987;9:21- 42 Negri E, La Vecchia C, D’Avanzo B, Franceschi S. Calcium dairy products and colorectal cancer. Nutr Cancer 1990;13:255-62 Wargovich MJ, Baer AR. Basic and clinical investi- gations of dietary calcium in the prevention of colorectal cancer. Prev Med 1989;18:672-9

1992;268:1573-7

7.

8.

9.

10.

11.

12.

13.

14.

Newmark HL, Wargovich MJ, Bruce WR. Colon can- cer and dietary fat, phosphate, and calcium: a hy- pothesis. J Natl Cancer lnst 1984;72:1323-5 Wargovich MJ, Eng W, Newmark HL. Calcium in- hibits the damaging and compensatory prolifera- tive effects of fatty acids on mouse colon epithe- lium. Cancer Lett 1984;23:253-8 Welberg JW, Kleibeuker JH, van der Meer R, et al. Effects of oral calcium supplementation on intesti- nal bile acids and cytolytic activity of fecal water in patients with adenomatous polyps of the colon. Eur J Clin Invest 1993;23:63-8 Rozen FI Fireman Z, Fine N, et al. Oral calcium sup- presses increased rectal epithelial cell prolifera- tion in persons at risk of colorectal cancer. Gut

Lipkin M, Newmark H. Effect of added dietary cal- cium on colonic epithelial cell proliferation in sub- jects at high risk for familial colonic cancer. N Engl J Med 1985;313:1381-4 Buset M, Lipkin M, Winawer S, et al. Inhibition of human colonic epithelial cell proliferation in vivo and in vitro by calcium. Cancer Res 1986;46:5426- 30 Lipkin M, Friedman E, Winawer SJ, Newmark H. Colonic epithelial cell proliferation in responders and nonresponders to supplemental dietary cal- cium. Cancer Res 1989;49:248-54 Bostick RM, Fosdick L, Wood JR, et al. Calcium and

1989;30:650-5

colorectal epithelial cell proliferation in sporadic adenoma patients: a randomized, double-blinded, placebo-controlled clinical trial. J Natl Cancer lnst

Holt PR, Atillasoy EO, Gilman J, et al. Modulation of abnormal colonic epithelial cell proliferation and differentiation by low-fat dairy foods. JAMA

Alberts DS, Ritenbaugh C, Story JA, et al. Random- ized, double-blinded, placebo-controlled study of effect of wheat bran fiber and calcium on fecal bile acids.in patients with resected adenomatous co- lon polyps. J Natl Cancer lnst 1996;88:81-92 Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal ad- enomas. N Engl J Med 1999;340:101-7 Lipkin M, Newmark H. Development of clinical chemoprevention trials. J Natl Cancer lnst

1995;87:1307-15 15.

1998;280:1074-9 16.

17.

18.

1995;87:1275-7

Homocysteine and Alzheimer’s Disease

In a recent case-control study of 764 patients with clinically diagnosed Alzheimer’s disease (AD), in- cluding 76 patients with the AD diagnosis con- firmed postmortem, mean total serum homocys- teine concentration was found to be significantly

This review was prepared by Joshua W. Miller, Ph.D., Assistant Adjunct Professor, University of California-Davis Medical Center, Department of Medical Pathology, Sacramento, CA 9581 7, USA.

higher than that of a control group of elderly indi- viduals with no evidence of cognitive impairment. Because homocysteine is considered an indepen- dent risk factor for vascular disease, this finding is consistent with the emerging hypothesis that vas- cular disease is a contributing factor in the patho- genesis of AD.

Dementia, defined as significant memory impairment and loss of intellectual functions, is a common and devastat-

126 Nutrition Reviews@, Vol. 57, No. 4

Page 2: Homocysteine and Alzheimer's Disease

b g public health problem, affecting an estimated 2-4 % of bdividuals over age 65.' Two pathologically distinct sub- types of dementia, vascular and Alzheimer's, constitute dx vast majority of cases. Vascular dementia results from significant cerebrovascular disease caused by repeated infarctions to the brain and is sometimes referred to as multi-infarct dementia. By contrast, the dementia of Alzheimer's disease (AD), with its characteristic amyloid plaques and neurofibrillary tangles in the brain, has long been considered to be independent of cerebrovascular involvement.

Currently, however, a potential vascular component in the etiology of AD is being considered. Although the two forms of dementia are pathologically distinct, it is not uncommon to find individuals with both the vascular and Alzheimer's dementia subtypes. Moreover, there is emerg- ing recognition that AD is often associated with athero- sclerosis,2 cerebral microvascular abnormalities,3 and high blood p r e ~ s u r e . ~ In addition, presence of the apolipoprotein E allele E4 (ApoE4) is thought to be an independent risk factor for both vascular disease and AD.2J

Research has shown an elevated blood level of the sulfur amino acid homocysteine, termed hyperhomo- cysteinemia, to be an independent risk factor for vascular disease.6 Accordingly, the hypothesis that hyperhomo- cysteinemia may also play a role in the pathogenesis of AD has been put forward. Evidence in support of a rela- tionship between plasma homocysteine concentration and brain h c t i o n has been accumulating during the 1990s. In 1992, Bell et al.' found a significant negative correlation between plasma homocysteine and cognitive function in a small group of elderly hospitalized patients with acute depression. In 1996, Eggs et a1.8 reported data from the Boston Veterans Affairs Normative Aging Study indicat- ing that plasma homocysteine concentration correlated negatively with spatial copying skills in 68 subjects 58 years old and older. In 1998, McCaddon et al.9 studied 30 individuals 65 years old and older with clinically diag- nosed AD and found a significant relationship between plasma homocysteine levels and scores on the Cambridge Cognitive Examination (CAMCOG), the cognitive assess- ment component of the Cambridge Examination of Mental Disorders of the Elderly (CAMDEX). In addition to these studies, several abstracts relating homocysteine to cog- nitive function were presented at the 2nd International Conference on Homocysteine Metabolism held at the Uni- versity of Nijmegen in The Netherlands in April 1998.1° Perhaps the most compelling of these studies has now been published by Clarke et a1.l' as a full report in the Archives of Neurology with an accompanying editorialk2 and is the strongest indication to date that hyperhomo- cysteinemia may contribute to cognitive impairment and AD.

The study by Clarke et al." was a case-control study of 164 patients 55 years old and older with a clinical diag- nosis of Alzheimer's-type dementia and 108 controls of similar age. An important feature of this study is that 76 of the patients were confirmed to have AD upon postmortem histologic analysis. The primary variables assessed for each participant were CAMCOG score, mini-mental state examination (MMSE) score, and total serum homocysteine. In addition, known determinants of serum homocysteine concentration were assessed, including serum and red blood cell folate, serum vitamin B,,, serum creatinine, and the frequency of a common homozygous mutation (C677T) in the gene encoding for a key folate metabolizing en- zyme, methylenetetrahydrofolate reductase (MTHFR). ApoE4 allele frequency was also determined.

CAMCOG and MMSE scores were significantly lower in the 164 AD patients than in the controls, whereas total homocysteine was significantly higher in the AD patients. Serum and red blood cell folate concentrations were sig- nificantly lower in the AD patients, whereas no significant difference between patients and controls was detected for serum vitamin BI2. The incidence of the ApoE4 allele was significantly higher in patients than controls, as ex- pected, whereas no significant difference in MTHFR ho- mozygous mutant frequency was detected.

As previously mentioned, a strength of this study was that the AD diagnosis for a large subset of the pa- tients was confirmed upon postmortem analysis. The clini- cal diagnosis of AD is somewhat difficult, with a misdiag- nosis rate as high as 20-30%. In the Clarke et al." study, postmortem histologic examination of the brain was con- ducted in 103 subjects, with only 76 (74%) found to actu- ally have the characteristics of AD pathology. Of impor- tance is that the differences in total homocysteine and serum and red blood cell folate between the 76 histologi- cally confirmed AD patients and the controls were more significant than those observed in the 164 clinically diag- nosed patients. Furthermore, a significant difference was detected for serum vitamin B,, between the confirmed AD patients and the controls, in contrast to the group of 164 clinically diagnosed patients. This dispels the notion that differences between AD patients and controls in the pa- rameters cited above might be the result of misdiagnosis of the disease.

The authors also carried out multiple logistic regres- sion analysis to determine the odds ratios for AD related to elevated total homocysteine, low serum folate, and low serum vitamin Bk2. For homocysteine, the odds ratio for histologically confirmed AD was 4.6 for those individuals in the highest tertile of homocysteine values (> 14.0 pM) compared with those in the lowest tertile (I1 1 .O pM). Simi- larly, high odds ratios were observed for those patients in the lowest tertiles for folate and vitamin B,, (I1 7.1 nM and 1199 pM, respectively) compared with those in the high-

Nutrition Reviews@, Vol. 57, No. 4 127

Page 3: Homocysteine and Alzheimer's Disease

est tertiles (> 24.2 nM and > 280 pM, respectively). These odds ratios were determined after adjustment for potential confounders, including age, gender, smoking, social class, and ApoE4 genotype. Of interest is that the increased odds ratios associated with low folate and vitamin BI2 status became insignificant when homocysteine was in- cluded in the equation. This suggests that homocysteine is not simply a surrogate for an effect of folate or vitamin B,, deficiency on brain function. It should be noted, how- ever, that it is likely that deficiency of B vitamins is the cause of the elevated homocysteine levels in the majority of cases.I3

An important consideration in any study relating fac- tors influenced by nutritional status to neurodegenerative disease is whether the disease itself is responsible for the nutritional deficits. The best way to assess this possibil- ity would be to gather dietary intake data. Obtaining di- etary records is often impractical, however, and such an undertaking was not carried out in the Clarke et al." study. The authors did provide some evidence, however, that suggests that the hyperhomocysteinemia in the AD pa- tients was not the result of poor nutrition caused by the disease. First, the researchers measured duration of memory impairment prior to collection of the blood samples in which homocysteine was measured (as reported by an informant, most likely a family member and/or care giver). No significant relationship between duration of memory impairment and homocysteine was found. The same held true for both folate and vitamin BIZ. If the disease was affecting nutritional intake, the expectation would be that the nutritional deficits would be worse with longer dura- tion of memory impairment. Second, the authors deter- mined replicate homocysteine levels in a subset (n=30) of the AD patients during annual follow-up visits over 3 years. In these patients, homocysteine values were rela- tively stable fkom visit to visit. The same was observed for 34 controls undergoing similar follow-up examinations. Again, if the disease was affecting nutritional intake, ho- mocysteine in the AD patients would be expected to in- crease with time as the disease progressed.

Perhaps the most intriguing aspect of this study is that the assessment of the AD patients also included a determination of medial temporal lobe thickness measured by X-ray cranial computed tomography. Atrophy of the medial temporal lobe is defined by the authors as an indi- cator of disease progression. Total homocysteine con- centrations and medial temporal lobe thickness were com- pared in a subset of the AD patients (n=43) at baseline and at annual follow-up visits over the next 3 years. At baseline, no correlation between homocysteine and medial tempo- ral thickness was observed. After 3 years, however, me- dial temporal lobe thickness was significantly lower in those patients in the two highest tertiles of homocysteine concentrations than those in the lowest tertile. Similar

analyses between folate and vitamin B,, and medial tern- poral lobe thickness showed a trend toward an associa- tion, but statistical significance was not reached. Because of the subjective nature of cognitive function assessments such as the CAMCOG and the MMSE, the finding that homocysteine correlates with physical pathology believed to be indicative of AD progression strengthens the hy- pothesis that hyperhomocysteinemia is associated with AD.

Three additional considerations would have enhanced the report by Clarke et al." First, no statistical analysis of the relationship between homocysteine and CAMCOG or MMSE scores was reported for the AD patients. It would have been interesting to see if the data were consistent with the finding of McCaddon et al.9 that homocysteine negatively correlates with CAMCOG scores. Second, vi- tamin B,, a known determinant of serum homocysteine concentration, was not assessed in this study. Some of the elevated homocysteine levels may have been due to low vitamin B, status, particularly because blood samples were not collected under fasting conditions. A relation- ship between vitamin B, status and homocysteine is usu- ally observed only under nonfasting conditions, i.e., after ingestion of protein containing methionine, the metabolic precursor of homocysteine. Along the same lines, identifi- cation of heterozygotes for deficiency of cystathionine R- synthase, a vitamin B,-dependent enzyme that initiates the catabolism of homocysteine through cystathionine synthesis, was not carried out. Perhaps future research that studies the relationship between homocysteine and AD should use methionine-load tests, which can indicate vitamin B, and cystathionine R-synthase deficiencies and associated hyperhomocysteinemia. Finally, serum creati- nine was measured by Clarke et al." but apparently was not considered as a potential confounder in the multiple regression analyses used to determine the odds ratios for AD related to homocysteine, folate, and vitamin BI2. Se- rum creatinine is an indicator of renal function, and im- paired renal function is a significant determinant of serum homocysteine levels. Because impaired renal function is prevalent in elderly populations, the hypothesis that the relationship between homocysteine and AD may simply be a surrogate for an effect of renal insufficiency on brain function independent of homocysteine cannot be ex- cluded. Arguing against this possibility, however, is that no significant difference in serum creatinine levels was found between the AD patients and the controls in the study by Clarke et al.'I

In conclusion, the paper by Clarke et al.lI strongly supports the hypothesis of a relationship between hyperhomocysteinemia and AD, and is consistent with the emerging hypothesis that vascular disease plays a significant role in the pathogenesis of this devastating and prevalent disorder. There is now a strong need for

128 Nutrition Reviews@, Vol. 57, No. 4

Page 4: Homocysteine and Alzheimer's Disease

prospective analysis of this relationship to establish cau- sality. Intervention trials designed to lower total homocys- teine concentrations with B vitamin supplementation are warranted. It is important to note that because the United States and other countries fortify the food supply with folic acid, the incidence of folate deficiency and its atten- dant complication^'^ is expected to diminish. Vitamin B,, deficiency, however, is still a major concern in elderly people,15 primarily because of malabsorption associated with atrophic gastritis and pernicious anemia. The pros- pect that supplements of these relatively innocuous and inexpensive nutrients may reduce the risk ofAD is stimu- lating.

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Nutrition Reviews@, Vol. 57, No. 4 129