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October 1986, Vol 43, No. 10 >
Article | October 1986

Cerebrospinal Fluid Biopterin Is Decreased in Alzheimer's Disease

Arthur D. Kay, MD; Sheldon Milstien, PhD; Seymour Kaufman, PhD; Helen Creasey, MBBS; James V. Haxby, PhD; Neal R. Cutler, MD; Stanley I. Rapoport, MD
[+] Author Affiliations

Accepted for publication May 7, 1986.

Reprint requests to the Laboratory of Neurosciences, National Institute on Aging, Bldg 10, Room 6C103, National Institutes of Health, Bethesda, MD 20892 (Dr Rapoport).


Arch Neurol. 1986;43(10):996-999. doi:10.1001/archneur.1986.00520100018008
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Comments

• Tetrahydrobiopterin is the cofactor in the hydroxylation of phenylalanine, tyrosine, and tryptophan leading to the eventual synthesis of the monoaminergic neurotransmitters, dopamine, norepinephrine, and serotonin, respectively. Total biopterin (90% of which is in the tetrahydro form) was measured in cerebrospinal fluid (CSF) and plasma of 30 patients with Alzheimer's disease and of 19 healthy controls. Plasma and CSF biopterin concentrations were not significantly correlated, but the mean CSF biopterin concentration in patients with Alzheimer's disease was significantly less than in age-matched controls, 13.5 pmol/mL as compared with 18.9 pmol/mL. The CSF biopterin concentration was not correlated with ventricular volume, as estimated by quantitative computed tomography, nor with the severity of dementia, as measured by various cognitive tests. The results suggest that a central biopterin deficiency exists in Alzheimer's disease.

REFERENCES

1 +
Kaufman S:  The structure of the phenylalanine-hydroxylation cofactor . Proc Natl Acad Sci USA 1963;;50:1085-1093.
2 +
Shiman R, Akino M, Kaufman S:  Solubilization and partial purification of tyrosine hydroxylase from bovine adrenal medulla . J Biol Chem 1971;;246:1330-1340.
3 +
Friedman PA, Kappelman AH, Kaufman S:  Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain . J Biol Chem 1972;;247:4165-4173.
4 +
Levitt M, Spector S, Sjoerdsma A, et al:  Elucidation of the rate-limiting step in norepinephrine biosynthesis in the perfused guinea pig heart . J Pharmacol Exp Ther 1965;;148:1-8.
5 +
Kaufman S, Fisher DB:  Pterin-requiring aromatic amino acid hydroxylases , in Hayaishi O (ed): Molecular Mechanisms of Oxygen Activation . Orlando, Fla, Academic Press Inc, 1974;, pp 285-369.
6 +
Lovenberg W, Jequier E, Sjoerdsma A:  Tryptophan hydroxylation measurement in pineal gland, brainstem, and carcinoid tumor . Science 1967;;155:217-219.
7 +
Nagatsu T:  Biopterin cofactor and regulation of monoamine-synthesizing mono-oxygenases . Trends Pharmacol Sci 1981;;2:276-279.
8 +
Kettler R, Bartholini G, Pletscher A:  In vivo enhancement of tyrosine hydroxylation in rat striatum by tetrahydrobiopterin . Nature 1974;;249:476-478.
9 +
Levine RA, Miller LP, Lovenberg W:  Tetrahydrobiopterin in striatum: Localization in dopamine nerve terminal and role in catecholaminergic synthesis . Science 1981;;214:919-921.
10 +
Lovenberg W, Ames MM, Lerner P:  Mechanisms of short-term regulation of tyrosine hydroxylase , in Lipton MA, DiMascio A, Killiam KF (eds): Psychopharmacology: A Generation of Progress . New York, Raven Press, 1978;, pp 247-259.
11 +
Kaufman S, Berlow S, Summer GK, et al:  Hyperphenylalaninemia due to a deficiency of biopterin: A variant form of phenylketonuria . N Engl J Med 1978;;299:673-679.
12 +
Schaub J, Däumling S, Curtius H-Ch, et al:  Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis . Arch Dis Child 1978;;53:674-676.
13 +
Curtius H-Ch, Niederwieser A, Viscontini M, et al:  Atypical phenylketonuria due to tetrahydrobiopterin deficiency: Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin, and sepiapterin . Clin Chim Acta 1979;;93:251-262.
14 +
Rey F, Harpey J-P, Leeming RJ, et al:  Les hyperphenylalaninemies avec activite normale de la phenylalanine hydroxylase: Le deficit en tetrahydro bipterine et la deficit en dihydropteridine reductase . Arch Fr Pediatr 1977;;34( (suppl) ):1099-1120.
15 +
Kaufman S, Holtzman NA, Milstien S, et al:  Phenylketonuria due to a deficiency of dihydropteridine reductase . N Engl J Med 1975;;293:785-790.
16 +
Brewster TG, Moskowitz MA, Kaufman S, et al:  Dihydropteridine reductase deficiency associated with severe neurologic disease and mild hyperphenylalaninemia . Pediatrics 1979;;63:94-99.
17 +
Gröbe H, Bartholome K, Milstien S, et al:  Hyperphenylalaninaemia due to dihydropteridine reductase deficiency . Eur J Pediatr 1978;;129:93-98.
18 +
Kaufman S:  Studies on the mechanism of the enzymatic conversion of phenylalanine to tyrosine . J Biol Chem 1959;;234:2677-2682.
19 +
Craine JE, Hall ES, Kaufman S:  The isolation and characterization of dihydropteridine reductase from sheep liver . J Biol Chem 1972;;247:6082-6091.
20 +
Nagatsu T, Yamaguchi T, Kato T, et al:  Biopterin in human brain and urine from controls and parkinsonian patients: Application of a new radioimmunoassay . Clin Chim Acta 1981;;109:305-311.
21 +
Levine RA, Williams AC, Robinson DS, et al:  Analysis of hydroxylase cofactor activity in the cerebrospinal fluid of patients with Parkinson's disease . Adv Neurol 1979;;24:303-307.
22 +
LeWitt PA, Miller LP, Newman RP, et al:  Tyrosine hydroxylase cofactor (tetrahydrobiopterin) in parkinsonism . Adv Neurol 1984;;40:459-462.
23 +
Lovenberg W, Levine RA, Robinson DS, et al:  Hydroxylase cofactor activity in cerebrospinal fluid of normal subjects and patients with Parkinson's disease . Science 1979;;204:624-626.
24 +
Williams AC, Levine RA, Chase TN, et al:  CSF hydroxylase cofactor levels in some neurological diseases . J Neurol Neurosurg Psychiatry 1980;;43:735-738.
25 +
Bernheimer H, Birkmayer W, Hornykiewicz O, et al:  Brain dopamine and the syndromes of Parkinson and Huntington: Clinical, morphological, and neurochemical correlations . J Neurol Sci 1973;;20:415-455.
26 +
Adolfsson R, Gottfries CG, Oreland L, et al:  Reduced levels of catecholamines in the brain and increased activity of monoamine oxidase in platelets in Alzheimer's disease: Therapeutic implications , in Katzman R, Terry RD, Bick KL (eds): Alzheimer's Disease: Senile Dementia and Related Disorders . New York, Raven Press, 1978;, vol 7, pp 441-451.
27 +
Argentiero V, Tavolato B:  Dopamine (DA) and serotonin metabolic levels in the cerebrospinal fluid (CSF) in Alzheimer's presenile dementia under basic conditions and after stimulation with cerebral cortex phospholipids (BC-PL) . J Neurol 1980;;224:53-58.
28 +
Bareggi SR, Franceschi M, Bonini L, et al:  Decreased CSF concentrations of homovanillic acid and γ-aminobutyric acid in Alzheimer's disease: Age- or disease-related modifications? Arch Neurol 1982;;39:709-712.
29 +
Bondareff W, Mountjoy CQ, Roth M:  Selective loss of neurones of origin of adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia . Lancet 1981;;1:783-784.
30 +
Bondareff W, Mountjoy CQ, Roth M:  Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia . Neurology 1982;;32:164-168.
31 +
Bowen DM, White P, Flack RHA, et al:  Brain-decarboxylase activities as indices of pathological change in senile dementia . Lancet 1974;;1:1247-1249.
32 +
Bowen DM, White P, Spillane JA, et al:  Accelerated ageing or selective neuronal loss as an important cause of dementia? Lancet 1979;;1:11-14.
33 +
Cross AJ, Crow TJ, Perry EK, et al:  Reduced dopamine β-hydroxylase activity in Alzheimer's disease . Br Med J 1981;;282:93-94.
34 +
Cross AJ, Crow TJ, Johnson JA, et al:  Monoamine metabolism in senile dementia of Alzheimer type . J Neurol Sci 1983;;60:383-392.
35 +
Gottfries CG, Gottfries I, Roos BE:  Disturbances of monoamine metabolism in the brains from patients with dementia senilis and Mb Alzheimer . Excerpta Med Int Congr Ser 1969;;180:310-312.
36 +
Gottfries CG, Gottfries I, Roos BE:  The investigation of homovanillic acid in the human brain and its correlation to senile dementia . Br J Psychiatry 1969;;115:563-574.
37 +
Gottfries CG, Gottfries I, Roos BE:  Homovanillic acid and 5-hydroxyindoleacetic acid in the cerebrospinal fluid of patients with senile dementia, presenile dementia, and parkinsonism . J Neurochem 1969;;16:1341-1345.
38 +
Gottfries CG, Gottfries I, Roos BE:  Homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid related to rated mental and motor impairment in senile and presenile dementia . Acta Psychiatr Scand 1970;;46:99-105.
39 +
Gottfries CG, Roos BE:  Acid monoamine metabolites in cerebrospinal fluid from patients with presenile dementia (Alzheimer's disease) . Acta Psychiatr Scand 1973;;49:257-263.
40 +
Gottfries CG, Kjällquist Å, Pontén U, et al:  Cerebrospinal fluid pH and monoamine and glucolytic metabolites in Alzheimer's disease . Br J Psychiatry 1974;;124:280-287.
41 +
Gottfries CG:  Biochemistry of dementia and normal ageing . Trends Neurol Sci 1980;;3:55-57.
42 +
Gottfries CG, Adolfsson R, Aquilonius SM, et al:  Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT) . Neurobiol Aging 1983;;4:261-271.
43 +
Guard O, Renaud B, Chazot G:  Métabolisme cérébral de la dopamine et de la sérotonine au cours des maladies d'Alzheimer et de Pick: Étude dynamique par le test au probenecide . Encephale 1976;;2:293-303.
44 +
Mann DMA, Lincoln J, Yates PO, et al:  Changes in the monoamine containing neurones of the human CNS in senile dementia . Br J Psychiatry 1980;;136:533-541.
45 +
Palmer AM, Sims NR, Bowen DM, et al:  Monoamine metabolite concentrations in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer's dementia . J Neurol Neurosurg Psychiatry 1984;;47:481-484.
46 +
Perry EK, Tomlinson BE, Blessed G, et al:  Neuropathological and biochemical observations on the noradrenergic system in Alzheimer's disease . J Neurol Sci 1981;;51:279-287.
47 +
Reisine TD, Yamamura HI, Bird ED, et al:  Pre- and postsynaptic neurochemical alterations in Alzheimer's disease . Brain Res 1978;;159:477-481.
48 +
Soininen H, MacDonald E, Rekonen M, et al:  Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with senile dementia of Alzheimer type . Acta Neurol Scand 1981;;64:101-107.
49 +
Tomlinson BE, Irving D, Blessed G:  Cell loss in the locus coeruleus in senile dementia of Alzheimer type . J Neurol Sci 1981;;49:419-428.
50 +
Aziz AA, Leeming RJ, Blair JA:  Tetrahydrobiopterin metabolism in senile dementia of Alzheimer type . J Neurol Neurosurg Psychiatry 1983;;46:410-413.
51 +
Leeming RJ, Blair JA, Melikian V:  Biopterin derivatives in senile dementia . Lancet 1979;;1:215.
52 +
Leeming RJ, Blair JA:  The effects of pathological and normal physiological processes on biopterin derivative levels in man . Clin Chim Acta 1980;;108:103-111.
53 +
Morar C, Whitburn SB, Blair JA, et al:  Tetrahydrobiopterin metabolism in senile dementia of Alzheimer type . J Neurol Neurosurg Psychiatry 1983;;46:582.
54 +
Barford PA, Blair JA, Eggar C, et al:  Tetrahydrobiopterin metabolism in the temporal lobe of patients dying with senile dementia of Alzheimer type . J Neurol Neurosurg Psychiatry 1984;;47:736-738.
55 +
American Psychiatric Association Task Force on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Disorders (DSM-III) , ed 3. Washington, DC, American Psychiatric Association, 1980;, pp 124-126.
56 +
Duara R, Grady CL, Haxby JV, et al:  Human brain glucose utilization and cognitive function in relation to age . Ann Neurol 1984;;16:702-713.
57 +
Folstein MF, Folstein SE, McHugh PR:  'Mini-mental state': A practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res 1975;;12:189-198.
58 +
Blessed G, Tomlinson BE, Roth M:  The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects . Br J Psychiatry 1968;;114:797-811.
59 +
Wechsler D: The Wechsler Adult Intelligence Scale . New York, Psychological Corp, 1955;.
60 +
Mattis S:  Mental status examination for organic mental syndrome in the elderly patient , in Bellak L, Karasu TB (eds): Geriatric Psychiatry . New York, Grune & Stratton, 1976;, pp 77-121.
61 +
Creasey H, Schwartz M, Cohen S, et al:  CT estimation of brain atrophy in dementia of Alzheimer type . Neurology 1984;;34( (suppl) ):88.
62 +
Schwartz M, Creasey H, Grady CL, et al:  CT analysis of brain morphometrics in 30 healthy men aged 21 to 81 years . Ann Neurol 1985;;17:146-157.
63 +
Lake CR, Ziegler MG, Kopin IJ:  Use of plasma norepinephrine for evaluation of sympathetic neuronal function in man . Life Sci 1976;;18:1315-1326.
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Bulat M, Žiković  B: Origin of 5-hydroxyindoleacetic acid in the spinal fluid . Science 1971;;173:738-740.
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Dhondt JL, Farriaux JP:  La tétrahydrobioptérine: Métabolisme physiologique et pathologique des ptéridines non conjuguées . Pathol Biol 1980;;28:397-405.
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Hoganson G, Berlow S, Kaufman S, et al:  Biopterin synthesis defects: Problems in diagnosis . Pediatrics 1984;;74:1004-1011.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Kaufman S:  The structure of the phenylalanine-hydroxylation cofactor . Proc Natl Acad Sci USA 1963;;50:1085-1093.
2 +
Shiman R, Akino M, Kaufman S:  Solubilization and partial purification of tyrosine hydroxylase from bovine adrenal medulla . J Biol Chem 1971;;246:1330-1340.
3 +
Friedman PA, Kappelman AH, Kaufman S:  Partial purification and characterization of tryptophan hydroxylase from rabbit hindbrain . J Biol Chem 1972;;247:4165-4173.
4 +
Levitt M, Spector S, Sjoerdsma A, et al:  Elucidation of the rate-limiting step in norepinephrine biosynthesis in the perfused guinea pig heart . J Pharmacol Exp Ther 1965;;148:1-8.
5 +
Kaufman S, Fisher DB:  Pterin-requiring aromatic amino acid hydroxylases , in Hayaishi O (ed): Molecular Mechanisms of Oxygen Activation . Orlando, Fla, Academic Press Inc, 1974;, pp 285-369.
6 +
Lovenberg W, Jequier E, Sjoerdsma A:  Tryptophan hydroxylation measurement in pineal gland, brainstem, and carcinoid tumor . Science 1967;;155:217-219.
7 +
Nagatsu T:  Biopterin cofactor and regulation of monoamine-synthesizing mono-oxygenases . Trends Pharmacol Sci 1981;;2:276-279.
8 +
Kettler R, Bartholini G, Pletscher A:  In vivo enhancement of tyrosine hydroxylation in rat striatum by tetrahydrobiopterin . Nature 1974;;249:476-478.
9 +
Levine RA, Miller LP, Lovenberg W:  Tetrahydrobiopterin in striatum: Localization in dopamine nerve terminal and role in catecholaminergic synthesis . Science 1981;;214:919-921.
10 +
Lovenberg W, Ames MM, Lerner P:  Mechanisms of short-term regulation of tyrosine hydroxylase , in Lipton MA, DiMascio A, Killiam KF (eds): Psychopharmacology: A Generation of Progress . New York, Raven Press, 1978;, pp 247-259.
11 +
Kaufman S, Berlow S, Summer GK, et al:  Hyperphenylalaninemia due to a deficiency of biopterin: A variant form of phenylketonuria . N Engl J Med 1978;;299:673-679.
12 +
Schaub J, Däumling S, Curtius H-Ch, et al:  Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis . Arch Dis Child 1978;;53:674-676.
13 +
Curtius H-Ch, Niederwieser A, Viscontini M, et al:  Atypical phenylketonuria due to tetrahydrobiopterin deficiency: Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin, and sepiapterin . Clin Chim Acta 1979;;93:251-262.
14 +
Rey F, Harpey J-P, Leeming RJ, et al:  Les hyperphenylalaninemies avec activite normale de la phenylalanine hydroxylase: Le deficit en tetrahydro bipterine et la deficit en dihydropteridine reductase . Arch Fr Pediatr 1977;;34( (suppl) ):1099-1120.
15 +
Kaufman S, Holtzman NA, Milstien S, et al:  Phenylketonuria due to a deficiency of dihydropteridine reductase . N Engl J Med 1975;;293:785-790.
16 +
Brewster TG, Moskowitz MA, Kaufman S, et al:  Dihydropteridine reductase deficiency associated with severe neurologic disease and mild hyperphenylalaninemia . Pediatrics 1979;;63:94-99.
17 +
Gröbe H, Bartholome K, Milstien S, et al:  Hyperphenylalaninaemia due to dihydropteridine reductase deficiency . Eur J Pediatr 1978;;129:93-98.
18 +
Kaufman S:  Studies on the mechanism of the enzymatic conversion of phenylalanine to tyrosine . J Biol Chem 1959;;234:2677-2682.
19 +
Craine JE, Hall ES, Kaufman S:  The isolation and characterization of dihydropteridine reductase from sheep liver . J Biol Chem 1972;;247:6082-6091.
20 +
Nagatsu T, Yamaguchi T, Kato T, et al:  Biopterin in human brain and urine from controls and parkinsonian patients: Application of a new radioimmunoassay . Clin Chim Acta 1981;;109:305-311.
21 +
Levine RA, Williams AC, Robinson DS, et al:  Analysis of hydroxylase cofactor activity in the cerebrospinal fluid of patients with Parkinson's disease . Adv Neurol 1979;;24:303-307.
22 +
LeWitt PA, Miller LP, Newman RP, et al:  Tyrosine hydroxylase cofactor (tetrahydrobiopterin) in parkinsonism . Adv Neurol 1984;;40:459-462.
23 +
Lovenberg W, Levine RA, Robinson DS, et al:  Hydroxylase cofactor activity in cerebrospinal fluid of normal subjects and patients with Parkinson's disease . Science 1979;;204:624-626.
24 +
Williams AC, Levine RA, Chase TN, et al:  CSF hydroxylase cofactor levels in some neurological diseases . J Neurol Neurosurg Psychiatry 1980;;43:735-738.
25 +
Bernheimer H, Birkmayer W, Hornykiewicz O, et al:  Brain dopamine and the syndromes of Parkinson and Huntington: Clinical, morphological, and neurochemical correlations . J Neurol Sci 1973;;20:415-455.
26 +
Adolfsson R, Gottfries CG, Oreland L, et al:  Reduced levels of catecholamines in the brain and increased activity of monoamine oxidase in platelets in Alzheimer's disease: Therapeutic implications , in Katzman R, Terry RD, Bick KL (eds): Alzheimer's Disease: Senile Dementia and Related Disorders . New York, Raven Press, 1978;, vol 7, pp 441-451.
27 +
Argentiero V, Tavolato B:  Dopamine (DA) and serotonin metabolic levels in the cerebrospinal fluid (CSF) in Alzheimer's presenile dementia under basic conditions and after stimulation with cerebral cortex phospholipids (BC-PL) . J Neurol 1980;;224:53-58.
28 +
Bareggi SR, Franceschi M, Bonini L, et al:  Decreased CSF concentrations of homovanillic acid and γ-aminobutyric acid in Alzheimer's disease: Age- or disease-related modifications? Arch Neurol 1982;;39:709-712.
29 +
Bondareff W, Mountjoy CQ, Roth M:  Selective loss of neurones of origin of adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia . Lancet 1981;;1:783-784.
30 +
Bondareff W, Mountjoy CQ, Roth M:  Loss of neurons of origin of the adrenergic projection to cerebral cortex (nucleus locus ceruleus) in senile dementia . Neurology 1982;;32:164-168.
31 +
Bowen DM, White P, Flack RHA, et al:  Brain-decarboxylase activities as indices of pathological change in senile dementia . Lancet 1974;;1:1247-1249.
32 +
Bowen DM, White P, Spillane JA, et al:  Accelerated ageing or selective neuronal loss as an important cause of dementia? Lancet 1979;;1:11-14.
33 +
Cross AJ, Crow TJ, Perry EK, et al:  Reduced dopamine β-hydroxylase activity in Alzheimer's disease . Br Med J 1981;;282:93-94.
34 +
Cross AJ, Crow TJ, Johnson JA, et al:  Monoamine metabolism in senile dementia of Alzheimer type . J Neurol Sci 1983;;60:383-392.
35 +
Gottfries CG, Gottfries I, Roos BE:  Disturbances of monoamine metabolism in the brains from patients with dementia senilis and Mb Alzheimer . Excerpta Med Int Congr Ser 1969;;180:310-312.
36 +
Gottfries CG, Gottfries I, Roos BE:  The investigation of homovanillic acid in the human brain and its correlation to senile dementia . Br J Psychiatry 1969;;115:563-574.
37 +
Gottfries CG, Gottfries I, Roos BE:  Homovanillic acid and 5-hydroxyindoleacetic acid in the cerebrospinal fluid of patients with senile dementia, presenile dementia, and parkinsonism . J Neurochem 1969;;16:1341-1345.
38 +
Gottfries CG, Gottfries I, Roos BE:  Homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid related to rated mental and motor impairment in senile and presenile dementia . Acta Psychiatr Scand 1970;;46:99-105.
39 +
Gottfries CG, Roos BE:  Acid monoamine metabolites in cerebrospinal fluid from patients with presenile dementia (Alzheimer's disease) . Acta Psychiatr Scand 1973;;49:257-263.
40 +
Gottfries CG, Kjällquist Å, Pontén U, et al:  Cerebrospinal fluid pH and monoamine and glucolytic metabolites in Alzheimer's disease . Br J Psychiatry 1974;;124:280-287.
41 +
Gottfries CG:  Biochemistry of dementia and normal ageing . Trends Neurol Sci 1980;;3:55-57.
42 +
Gottfries CG, Adolfsson R, Aquilonius SM, et al:  Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT) . Neurobiol Aging 1983;;4:261-271.
43 +
Guard O, Renaud B, Chazot G:  Métabolisme cérébral de la dopamine et de la sérotonine au cours des maladies d'Alzheimer et de Pick: Étude dynamique par le test au probenecide . Encephale 1976;;2:293-303.
44 +
Mann DMA, Lincoln J, Yates PO, et al:  Changes in the monoamine containing neurones of the human CNS in senile dementia . Br J Psychiatry 1980;;136:533-541.
45 +
Palmer AM, Sims NR, Bowen DM, et al:  Monoamine metabolite concentrations in lumbar cerebrospinal fluid of patients with histologically verified Alzheimer's dementia . J Neurol Neurosurg Psychiatry 1984;;47:481-484.
46 +
Perry EK, Tomlinson BE, Blessed G, et al:  Neuropathological and biochemical observations on the noradrenergic system in Alzheimer's disease . J Neurol Sci 1981;;51:279-287.
47 +
Reisine TD, Yamamura HI, Bird ED, et al:  Pre- and postsynaptic neurochemical alterations in Alzheimer's disease . Brain Res 1978;;159:477-481.
48 +
Soininen H, MacDonald E, Rekonen M, et al:  Homovanillic acid and 5-hydroxyindoleacetic acid levels in cerebrospinal fluid of patients with senile dementia of Alzheimer type . Acta Neurol Scand 1981;;64:101-107.
49 +
Tomlinson BE, Irving D, Blessed G:  Cell loss in the locus coeruleus in senile dementia of Alzheimer type . J Neurol Sci 1981;;49:419-428.
50 +
Aziz AA, Leeming RJ, Blair JA:  Tetrahydrobiopterin metabolism in senile dementia of Alzheimer type . J Neurol Neurosurg Psychiatry 1983;;46:410-413.
51 +
Leeming RJ, Blair JA, Melikian V:  Biopterin derivatives in senile dementia . Lancet 1979;;1:215.
52 +
Leeming RJ, Blair JA:  The effects of pathological and normal physiological processes on biopterin derivative levels in man . Clin Chim Acta 1980;;108:103-111.
53 +
Morar C, Whitburn SB, Blair JA, et al:  Tetrahydrobiopterin metabolism in senile dementia of Alzheimer type . J Neurol Neurosurg Psychiatry 1983;;46:582.
54 +
Barford PA, Blair JA, Eggar C, et al:  Tetrahydrobiopterin metabolism in the temporal lobe of patients dying with senile dementia of Alzheimer type . J Neurol Neurosurg Psychiatry 1984;;47:736-738.
55 +
American Psychiatric Association Task Force on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Disorders (DSM-III) , ed 3. Washington, DC, American Psychiatric Association, 1980;, pp 124-126.
56 +
Duara R, Grady CL, Haxby JV, et al:  Human brain glucose utilization and cognitive function in relation to age . Ann Neurol 1984;;16:702-713.
57 +
Folstein MF, Folstein SE, McHugh PR:  'Mini-mental state': A practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res 1975;;12:189-198.
58 +
Blessed G, Tomlinson BE, Roth M:  The association between quantitative measures of dementia and of senile change in the cerebral grey matter of elderly subjects . Br J Psychiatry 1968;;114:797-811.
59 +
Wechsler D: The Wechsler Adult Intelligence Scale . New York, Psychological Corp, 1955;.
60 +
Mattis S:  Mental status examination for organic mental syndrome in the elderly patient , in Bellak L, Karasu TB (eds): Geriatric Psychiatry . New York, Grune & Stratton, 1976;, pp 77-121.
61 +
Creasey H, Schwartz M, Cohen S, et al:  CT estimation of brain atrophy in dementia of Alzheimer type . Neurology 1984;;34( (suppl) ):88.
62 +
Schwartz M, Creasey H, Grady CL, et al:  CT analysis of brain morphometrics in 30 healthy men aged 21 to 81 years . Ann Neurol 1985;;17:146-157.
63 +
Lake CR, Ziegler MG, Kopin IJ:  Use of plasma norepinephrine for evaluation of sympathetic neuronal function in man . Life Sci 1976;;18:1315-1326.
64 +
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Compression-Only CPR: Pushing the Science Forward
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AAM 2010;304:1493-1495.
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BMJ 2010;341:c5893-c1494.
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