patients who were undergoing diagnostic lumbar puncture. Thirty-three patients had Alzheimer-type dementia (ATD); 16 patients had other dementing illnesses ...
Cerebrospinal fluid trace element content in dementia: Clinical, radiologic, and pathologic correlations Charles O. Hershey, Linda A. Hershey, Arthur Varnes, et al. Neurology 1983;33;1350 DOI 10.1212/WNL.33.10.1350 This information is current as of October 1, 1983
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/33/10/1350.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1983 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
a n d r a t s treated with dipropylacetate. Biochem Med 1980;24(2):153-61.
11. Mortensen PB. Inhibition of fatty acid oxidation by valproate. Lancet 1980;2,18:856-7. 12. Shumate JB, Dodson WE, Brooke MH, Santiago J. Suppres-
Cerebrospinal fluid trace element content in dementia: Clinical, radiologic, and pathologic correlations
sion of fatty acid oxidation by valproic acid. Ann Neurol 1981;10:88. 13. Haas R, Stumpf DA, Parks JK, Eguren L. Inhibitory effects of
sodium valproate on oxidative phosphorylation. Neurology (NY) 1981;3 1:1473-6.
Article abstract-Using inductively coupled argon plasma emission spectroscopy, we measured 19 trace elements in cerebrospinal fluid of 265 patients who were undergoing diagnostic lumbar puncture. Thirty-three patients had Alzheimer-type dementia (ATD); 16 patients had other dementing illnesses; and 20 had no neurologic disease. There were seven cases of autopsy-proven Alzheimer's disease (AD) and eight autopsy controls. We found elevated CSF silicon in 24%of ATD and 71% of AD patients. We found no relationship between CSF aluminum, arsenic, lead, or manganese and ATD, AD, or other dementing illnesses.
1 NEUROLOGY (Cleveland) 1983;33:1350-3
Charles 0. Hershey, MD; Linda A. Hershey, MD, PhD; Arthur Varnes, PhD; Shardul D. Vibhakar, MD; Patrick Lavin, MD; and William H. Strain, PhD
Alzheimer-type dementia (ATD) affects 11%of people over age 65l and is the fourth or fifth most common cause of death in the United S t a t e s 2 Dementing illnesses have been characterized clinically and pathologically, but most etiologies are not known. Silicon and aluminum have been linked to Alzheimer's disease (AD) by studies of senile plaque^.^.^ Aluminum has been found in elevated concentrations in brain by Crapper et al,5but not by other^.^,^ Manganese toxicity causes a syndrome resembling parkinsonism,s and elevation has been reported in one case of dementia with extrapyramidal signs.gZinc deficiency has also been suggested as a cause of ATD.'" We measured multiple trace elements in the CSF of patients having a variety of neurologic and medical diseases to study the elemental composition of CSF. Methods. From January 1981 to March 1982, we obtained CSF with informed consent from 265 hospitalized patients undergoing lumbar puncture for medical indications. Milliliter aliquots of CSF were collected directly into polystyrene or polypropylene tubes after the medically indicated samples had been obtained. The specimens were stored at - 20 "C until analyzed. Samples containing greater than 500 RBC or 10 WBC were excluded. We selected patients with ATD and two groups of controls. Demented patients were those who had experienced deterioration of memory and other intellectual functions, of sufficient severity to interfere with social or occupational functioning. In 33 patients, the dementia showed a chronically progressive downhill course, and other diseases or conditions causing dementia were excluded these patients were classified as ATD (mean age, 75). A control group (control I) was composed of 20 patients in
1360 NEUROLOGY 33 October 1983
whom neurologic investigation yielded no organic disease of the nervous system (mean age, 39). Control I1 (mean age, 70) consisted of demented patients with Parkinson's disease (n = 9), normal pressure hydrocephalus (n = 2), alcoholic dementia (n = 4), or olivopontocerebellar degeneration (n = 1). Patients with significant renal impairment (serum creatinine 2.7 mg/dl) were excluded from analysis because of known trace element abnorma1ities."J2 A few patients came to autopsy and were grouped according to histologic evidence of Alzheimer's disease. They were not included in the clinical groups. Trace element analyses were performed with an inductively coupled argon plasma spectrometer (Jarrell-Ash Atom Comp Model 975). The procedure is based upon that proposed by the US Environmental Protection Agency for measurement of trace elements in water and wastes,13 and has been used to study element content of CSF, blood, urine, and human brains.12J4J5The principles of plasma emission spectrometry have been critically reviewed by Fassel.16Our limits of detection were derived according to the method described by FasseP and are (in mg/L) Al, 0.045; As, 0.030; Ba, 0.003; Be, 0.001; Cd, 0.015; Co, 0.003; Cr, 0.015; Cu, 0.005; Fe, 0.015; Mn, 0.003; Mo, 0.030; Ni, 0.045; Pb, 0.030; Se, 0.030; Si, 0.030; Sn, 0.500; Ti, 0.003; V, 0.015; and Zn, 0.009. Statistical analysis was performed, using the twotailed Student's t test and Welche's t test. Data analysis used the BMDP Biomedical Computer Programs, P series, program package~.'~
Results. We found no elevations of aluminum, arsenic, or manganese in any group (table 1).Copper and zinc were within the ranges reported by othersIs and in exact agreement with results of McCall et al.19 Silicon was significantly higher in ATD patients than in control I (p < 0.05). The difference in silicon
Table 1. Trace element concentrations in the CSF of ATD patients and controls
Age (yr) Element (mg/L) Cr
ATD N = 33
Control I N = 20
75.8 k 1.84
38.5 f 4.12
*
0.028 0.017* 0.059 i 0.013 0.036 0.009 0.081 i 0.025' 0.025 2 0.0031
cu Si Zn
70.4
* 2.68
ND
ND
ND 0.014 i 0.003
0.027 ? 0.010 0.016 0.002 0.035 0.009 0.014 0.003
0.031 0.032
*
Fe
Control I1 N = 16
* 0.012 * 0.009
* * *
*
Values expressed as mean ? SEM. p < 0.05 versus control I. p < 0.025 versus control I, and p < 0.05 versus control 11. ND Not detectable. The following were analyzed and not detected Al, As, Ba, Be, Cd, Co, Mn, Mo, Ni, Pb, Se, Sn, Ti, and V.
Table 2. Trace element concentrations in the CSF of individual ATD patients (mg/L) Patient
A1
Elevated silicon 78 WF 56 WF 95WM 95 B F 81 WF 84WM 88 WF 76 WF
-
Mn
0.037
Elevated zinc 60 WF 83 WF 80 BF 70 BF 74 WM 78 WF Normal silicon and zinc 61 WF 76 BM 81 RF 87 BF 71 WF 75WM 98 BF 67 BF 58 WF 76RM 79BM 65BM 78WM 81 HF 64 WF 74 WF 69 WF 71 WM 78WM
As
0.036
Si
Zn
0.147* 0.724* 0.205* 0.395' 0.233* 0.172* 0.131* 0.093*
0.019 0.031 0.015 0.022 0.010 0.019 0.027 0.042*
0.084 0.068 0.032
0.045 0.054* 0.082*
0.005* 0.089* 0.059
.
0.060 0.075 0.084*
0.082' 0.067* 0.038* 0.041* 0.049* 0.085*
0.014 0.036 0.011 0.013 0.011 0.019 0.013 0.028
0.010 0.020 0.019
0.078
0.051
0.010 0.015 0.023 0.024
Dot indicates levels below the limit of detection. *Indicates levels greater than 2 SDs above the mean of control I.
October 1983 NEUROLOGY 33 1361
levels between ATD patients and control I1 was not significant by Welche’s t test. Our control levels of silicon were less than 0.030 mg/L, values identical with those of Austin et a1.20 Zinc levels in ATD patients were significantly higher than both control groups (p < 0.025 for control I and p < 0.05 for control 11). Using two standard deviations above the mean of control group I as upper limit of normal, we found three subgroups of ATD, patients: one with elevated silicon, one with elevated zinc, and one with neither abnormality (table 2). None of the patients in either control group had elevations of zinc, and one patient in each control group had minimally elevated silicon. Sporadic elevations of aluminum, arsenic, and manganese were found in the ATD group, but in neither control group. Analysis of computerized tomography of the head by a radiologist blind to the clinical and chemical data showed no relationship between trace element elevations and degree of cortical atrophy, ventricular enlargement, or calcifications. Table 3 shows that five of the seven autopsyverified Alzheimer patients and none of the eight autopsy controls had high CSF silicon levels (p < 0.05). One AD patient and three autopsy controls had high CSF zinc content. No autopsiedpatient had measurable CSF aluminum. Sporadic elevations of manganese and arsenic were found.
Discussion. Our data suggest an association between ATD/AD and elevated CSF silicon levels. Twenty-four percent of ATD patients and 71% of AD patients had elevated CSF silicon. We cannot exclude the possibility that elevations in AD patients may require a second process, ie, an infarct, although infarction alone is insufficient. Others have noted a relationship between AD and silicon. Silicon has been found with aluminum in the senile plaques and neurofibrillary tangles of AD brain.3,4Silicon has been found in nonaffected neurons of Alzheimer brains by x-ray spectrometry by some investigators3but not by others4Whole brain content of silicon does not appear to be elevated, and Austin et alZosuggest that the silicon abnormality is associated strictly with senile plaques and neurofibrillary tangles. They2(’studied silicon in CSF of one autopsy-proven familial AD patient and three clinically diagnosed ATD patients, but did not find elevations. We attribute the disparity of their results and ours to their small sample size; also, we found elevated CSF silicon in only 24% of our ATD patients. Austin et alZO found no relationship of CSF silicon to age, a finding we have repeated. Evidence of silicon toxicity is accumulating. Best described in pulmonary silicosis, it causes a fibrogenic response.21Renal toxicity has been described in humans in relation to occupational exposure,zz~23 pulmonary silicosis,24or endemic n e p h r ~ p a t h yas ,~~
Table 3. Trace element concentrations in the CSF of autopsy-verified Alzheimer’s disease and neurologic controls (mg/L) Autopsy-verified Alzheimer’s disease Patient
Additional autopsy diagnoses
69 WF 69WM 63 WM 80 WF 76 BF 67 BM 84 WM
Multiple remote cerebral infarctions Acute and remote infarctions Intracerebral hemorrhage Acute hemorrhagic infarction Anoxic encephalopathy Cervical spondylosis Multiple remote infarctions and spinocerebellar degeneration
A1
AS
-.
Mn
Si
Zn 0.025 0.020
0.013*
0.794* 0.563* 0.404* 0.122* 0.054
0.052
NV 0.011 0.010
0.177*
0.012 0.088*
Si
Zn
0.047 0.043
0.030
Autopsied controls Patient
Autopsy diagnoses
62 WF 64WM 78 BM 87 BF 82WM 24 BF 40 WM 67WM
Acute and remote cerebral infarctions Alcoholic cerebellar degeneration and subdural Corticospinal tract degeneration Parkinson’s disease with Alzheimer’s changes Acute hemorrhagic infarction Acute focal encephalomalacia (sepsis) Acute multiple cerebral infarctions Acute multiple hemorrhagic infarctions
Dot indicates levels below the limit of detection. * Indicates levels greater than 2 SDs above the mean of control I. NV lndicates no value was measured.
1362 NEUROLOGY 33 October 1983
A1
..
AS
0.048
0.095*
Mn
0.032 0.051’
well as in experimental animal~.~6.*~ Silicon is a common contaminant of water, with values as high as 33.6 mg/L and a mean of 3.4 mg/L, as tested in 100 US cities.28 Environmental exposure must be frequent and extensive. We found CSF zinc elevations in one group of ATD patients, but in only one AD patient. Our data do not support the hypothesis of zinc deficiencyas an etiology of ATD.l0 We did not find elevations of CSF aluminum. Our limit of detection for aluminum (0.045 mg/L) is relatively high, and we are able to detect gross but not modest elevations. Our data do not support aluminum as an etiologic agent in Alzheimer’s disease, but cannot exclude it. Similarly, we did not find elevations of arsenic, lead, or manganese in ATD patients or demented Parkinson patients. The finding of elevated CSF silicon and zinc in some patients with ATD suggests several hypotheses. ATD may be a mixed syndrome; elevated CSF silicon could be a marker of one lesion, zinc of another. A second is that ATD patients have an inherited disorder of silicon metabolism, which is manifest as dementia according to the exposure of the patient to silicon. A third hypothesis is that CSF silicon becomes elevated only after sufficient progression of the disease. Finally, CSF silicon elevations may be more likely in ATD patients who experience a subsequent cerebral infarction. Our study supports the work of other authors linking silicon to Alzheimer’s disease. Prospective clinical studies of silicon in brain and CSF will aid in understanding the relationship of silicon to human pathophysiology and dementing illness.
Acknowledgments The Frackelton Memorial Fund and Andrew W. Mellon Foundation are to be acknowledged for their generous support of Dr. L.A. Hershey. We thank Dr. Robert B. Daroff for his helpful comments. Donald Eisenstadt provided computer systems analysis, and Pat Hyla prepared the manuscript. From the Departments of Medicine (Dr. C.O. Hershey). Neurology (Drs. L.A. Hershey a n d L a v i n ) , Surgery (Dr. S t r a i n ) , a n d Radiology (Dr. Vihhakar), Case Western Reserve University School of Medicine, Cleveland, OH, and the Sohio Research and Development Center (Dr. Varnes), Cleveland, OH. Presented in part at the thirty-fourth annual meeting of the American Academy of Neurology, Washington, DC, April 1982. Accepted for publication January 31,1983. Address correspondence and reprint requests to Dr. Charles 0. Hershey, Department of Medicine, Cleveland Metropolitan General Hospital, 3395 Scranton Road, Cleveland, OH 44109.
References 1. Terry RD. Dementia: a brief and selective review. Arch Neurol 1976;33:1-3. 2. Katzman R. The prevalence and malignancy of Alzheimer disease: a major killer. Arch Neurol 1976;33:217-8. 3. Nikaido T , Austin J , Trueb L, Rinehart R. Studies in agingof the brain: microchemical analysis of the nervous system in
Alzheimer patients. Arch Neurol 1972;27:549-54. 4. Per1 DP, Brody AR. Alzheimer’s disease: x-ray spectrometric evidence of aluminum accumulation in neurofibrillary tanglebearing neurons. Science 1980;208:297-9. 5. Crapper DR, Krishnan SS, Dalton AJ. Brain aluminum distribution in Alzheimer’s disease and experimental neurofibrillary degeneration. Science 1973;180:511-3. 6. Markesbery WR, Ehmann WD, Hossain TIM, Alaudin M, Goodin DT. Instrumental neutron activation analysis of brain aluminum in Alzheimer disease and aging. Ann Neurol 1981;10:511-6. 7. McDermott J R , Smith AI, Wisniewski HM. Brain aluminum i n aging a n d Alzheimer disease. Neurology ( N Y ) 1979;29:804-14. 8. Mena I, Marin 0,Fuenzalida S, Cotzias GC. Chronic manganese poisoning. Neurology (Minneap) 1976;17:128-36. 9. Banta RG, Markesbery WR. Elevated manganese levels associated with dementia and extrapyramidal signs. Neurology (Minneap) 1977;27:213-6. 10. Burnet RM. A possible role of zinc in thepathologyof dementia. Lancet 1981;1:186-8. 11. Hershey LA, Lavin PJ, Hershey CO, Varnes AW, Strain WH. Elevated CSF silicon levels in Alzheimer’s-type and dialysis dementia. Neurology (NY) 1982;32(2):A227. 12. Mauras Y, Riberi P, Cartier F, Allain P. Increase in blood silicon concentration in patients with renal failure. Biomedicine 1980;33:228-30. 13. Guidelines establishing test procedures for the analysis of pollutants: proposed regulations. Appendix IV. Inductively coupled plasma optical emission spectrometric method (ICP) for trace element analysis of water and wastes. Federal Register 1979;44:69464-564. 14.Allain P, Yves M. Determination of aluminum in blood, urine, and water by inductively coupled plasma emission spectrometry. Anal Chem 1979;51:2089-91. 15. Craelius W, Jacobs RM, Jones AOL. Mineral composition of brains of normal and multiple sclerosis victims. Proc Soc Exp Biol Med 1980;165:327-9. 16. Fassel VA. Quantitative elemental analyses by plasma emission spectroscopy. Science 1978;202:182-91. 17. Dixon WJ, Brown MB, eds. BMDP Biomedical Computer Programs: P-series 1979. Berkeley, CA: Universityof California Press, 1979. 18. Bogden JD, Troiano RA, Joselow MW. Copper, zinc, magnesium, and calcium in plasma and cerebrospinal fluid of p a t i e n t s with neurological diseases. Clin Chem 1977;23:485-9. 19. McCall J T , Goldstein NP, Smith LH. Implications of trace metals in human diseases. Fed Proc 1971;30:1011-5. 20. Austin J H , Rinehart R, Williamson T, et al. Studies in ageing of the brain. 111. Silicon levels in postmortem tissues and body fluids. Prog Brain Res 1973:40:485-95. 21. Underwood E. Silicon. In: Trace elements in human and animal nutrition, 4th ed. New York: Academy Press, 1977~398-409. 22. Hauglustaine D, Van Damme B, Daenens P, Michielson P. Silicon neDhroDathv: a Dossible occuDationa1 hazard. Nephron 1980;26:219124. 23. Saldanha LF. Rosen V, Gonick HC. Silicon nephropathv. _ _ _ Am J Med 1975;59:95-103. 24. Bolton WK, Suratt PM, Sturgill BC. Rapidly progressive silicon nephropathy. Am J Med 1981;71:823-8. 25. Markovic BL, Arambasic MD. Experimental chronic interstitial nephritis compared with endemic human nephrolgy. J Pathol 1971;103:35-40. 26. Newborne PM, Wilson RB. Renal damage associated with silicon compounds in dogs. Proc Natl Acad Sci USA 1970~65~872-5. 27. Dobbie JW, Smith MJB. Silicate nephrotoxicity in the experimental animal: t h e missing factor in analgesic nephropathy. Scott Med J 1982;27:10-6. 28. Durfor CN, Becker E. Public water supplies of the 100 largest cities in the United States, 1962. Geological Supply Paper 1812. Government Printing Office, Washington, DC, 1964.
October 1963 NEUROLOGY 33 1363
Cerebrospinal fluid trace element content in dementia: Clinical, radiologic, and pathologic correlations Charles O. Hershey, Linda A. Hershey, Arthur Varnes, et al. Neurology 1983;33;1350 DOI 10.1212/WNL.33.10.1350 This information is current as of October 1, 1983 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/33/10/1350.full.h tml
Citations
This article has been cited by 6 HighWire-hosted articles: http://www.neurology.org/content/33/10/1350.full.h tml##otherarticles
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permis sions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprint sus
