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In the present study, a comparison was made of the fatty acid composition of the grey and white matter of the frontal, parietal and parahippocampal regions of ...

Brain (1993), 116, 717-725

Differences in the fatty acid composition of the grey and white matter of different regions of the brains of patients with Alzheimer's disease and control subjects Departments of ^Molecular and Cell Biology, Cental Health and ^Pathology, University of Aberdeen, Aberdeen, Scotland

SUMMARY

In the present study, a comparison was made of the fatty acid composition of the grey and white matter of the frontal, parietal and parahippocampal regions of post-mortem brains of patients who had died with Alzheimer's disease (n = 15) and control postmortem subjects (n = 10). Diagnosis of Alzheimer-type disease was based on the presence of senile plaques and neurofibrillary tangles in post-mortem sections. Several highly significant and specific differences were observed between the two groups. Adrenic acid (22 : 4 n-6) was three to four times higher in the grey matter but lower in the white matter in each of the three regions in the Alzheimer brains than in the control group. These alterations were compensated by reciprocal changes in 18 : 0 in the grey matter and 16 : 1 fatty acids in the white matter. There was no significant difference in the proportion of other fatty acids, including those of the n-6 and n-3 series, in either the grey or the white matter of any of the three regions of the two groups, except for a higher proportion of 22 : 6 n-3 in the parietal white matter in the Alzheimer patients. There was no significant relationship between the levels of the individual fatty acids and age at death. It is suggested that the alterations in the fatty acid composition observed in the brains of Alzheimer patients may be caused by an aberration in the system by which essential fatty acids are transported into the brain.

INTRODUCTION

Between 50 and 60% of the solid matter of the brain consists of membrane lipids of which phospholipids are quantitatively the most significant components (O'Brien, 1965; Crawford and Sinclair, 1972). These constituents are assembled into a bilayer which forms the basic structure of all biological membranes and contains appreciable quantities of polyunsaturated fatty acids of the n-3 and n-6 series (O'Brien etal., 1964; Crawford etal., 1976). The parent fatty acids of the two series, linoleic acid (18:2 n-6) and linolenic acid Correspondence to: Dr E. R. Skinner, Department of Molecular and Cell Biology, University of Aberdeen, Marischal College, Aberdeen AB9 IAS, Scotland. © Oxford University Press 1993

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E. R. Skinner,1 C. Watt,1 J. A. O. Besson2 and P. V. Best3

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MATERIALS AND METHODS Subjects and collections of samples The 15 patients studied had a clinical diagnosis of dementia (probably Alzheimer-type) and were long-stay residents in the psychogeriatric service of the Royal Cornhill Hospital, Aberdeen. At autopsy, as soon as the brain had been removed, samples were taken from cerebral cortex and white matter in the following sites: anterior frontal near the pole, parahippocampal gyrus, superolateral parietal. These portions of tissue were immediately placed in a refrigerator at — 80°C. The brain was fixed by suspension in neutral-buffered formalin for at least 3 weeks. Blocks selected for histological examination included the hippocampus, amygdaloid region and at least two neocortical areas. The staining methods used were haematoxylin—eosin, modified Bielschowsky and methenamine silver. The diagnosis of Alzheimer-type disease was based on the presence of numerous senile plaques and neurofibrillary tangles (well above the diagnostic frequency limits proposed by Khachaturian, 1985) in the hippocampus, amygdaloid complex and neocortex. The mean age of the patients was 79.1, range 65 — 87 years. Control samples were obtained from 10 routine autopsy cases in which there had been no history of dementia or neurological disorder and in which the histopathological features of Alzheimer's disease were absent. Apart from one man aged 47 years, the age range was 59—87 years and the overall mean 67.7 years. Biochemical analysis The frozen tissues were thawed at room temperature and treated as soon as they became soft (within 15—20 min after removal from the freezer). Total lipids were extracted by a modification (Hanson and Olley, 1963) of the Bligh and Dyer (1959) method. Between 0.3 and 0.5 g of tissue [to which two crystals of BHT (2,6-di-rm-butyl-4-methylphenol) were added to prevent the oxidation of fatty acids] was homogenized for 1 min, using an 'Ultra-Turrax' homogenizer (Janke and Kunkel Gmb H, Ika-werk, D-7813 Staufen,

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(18:3 n-3) cannot be synthesized in the human body and are therefore essential dietary components. These acids, which are not interconvertible, can be further elongated and desaturated by the same enzyme systems to form a large number of acids which form important membrane components (Sinclair, 1990). In most membranes, linoleic acid accounts for between 15 and 25% of the total fatty acids present, but in nervous tissue it forms only ~ 2.5 % or less of the fatty acid composition (Svennerholm et al., 1978), while 22-carbon fatty acids of the n-6 series are found in higher concentrations in the brain than in most other tissues. The same is also true for acids of the n-3 series. This suggests that the n-6 desaturase is of particular significance in the brain; this enzyme provides a rate-limiting step in the formation of n-3 and n-6 metabolites and is inhibited by several substances including saturated fats, cholesterol and ethanol (Sprecher, 1981). Several recent studies have shown that dietary supplementation of essential fatty acids or their metabolites may have a therapeutic effect on mental disorders, for example schizophrenia (Rudin, 1981). Polyunsaturated fatty acids serve two basic functions: (i) they are precursors of the prostanoids, vital regulatory factors whose activities affect every tissue of the body (Moncada and Vane, 1978); (ii) they contribute to determining the fluidity of the membranes containing them. This, in turn, influences the behaviour of membrane-associated enzymes and receptors (Spector and Yorek, 1985). Little is known, however, of the changes that occur in the fatty acid composition of the brain in the development of Alzheimer's disease (Embree et al., 1972; Bowen et al., 1973). The present study was therefore carried out to determine the fatty acid compositions of the cerebral cortex and white matter in various regions of the brains of Alzheimer patients and control subjects.

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RESULTS

A comparison of the fatty acid composition of corresponding regions of the brains taken from Alzheimer's patients and control subjects revealed some highly specific differences between the two groups of subjects (Tables 1,2). Most notable was the distribution of adrenic acid (22 : 4 n-6) which was three to four times higher in each of the three regions of the grey matter from the Alzheimer's patients than from the control subjects. This was balanced by a corresponding decrease in the proportion of the saturated acid, 18 :0, in each of the three regions of the brains from the Alzheimer patients. Conversely, adrenic acid was significantly lower in the white matter of the frontal and parahippocampal regions from the Alzheimer patients; that in the parietal regions was also lower in the

TABLE 1. FATTY ACID COMPOSITION OF THE GREY MATTER OF DIFFERENT REGIONS OF THE BRAINS OF PATIENTS WHO HAD ALZHEIMER'S DISEASE AND CONTROL SUBJECTS Fatty

acid 14:0 16:0 16:1 18:0 18:1 20:4 n-6 22:4 n-6 22:6 n-3 Total n-6 Total n-3 + n-6

AD (13)

Parietal Control (10)

0.35 ±0.45 24.66±4.52 0.52 ±0.63 20.31 ±1.69 25.80±4.36 8.42±3.27 2.78±2.49 17.10±4.07 11.20±2.88 28.30±3.28

0.39 ±0.26 24.91 ±0.83 0.56±0.38 22.93 ±1.00** 24.20±2.32 8.70 ±2.96 0.74 ±1.60* 17.57±1.34 9.44±2.28 27.01 ±1.96

AD (9)

0.52 ±0.30 25.09 ±1.43 0.54±0.40 20.45 ±1.33 22.61 ±1.62 9.78 ±0.64 3.65 ±1.92 17.33±0.86 13.43 ±1.28 30.76 ±1.14

Frontal Control (10)

0.59 ±0.09 26.48±3.87 0.66 ±0.50 22.54 ±1.114*** 22.01 ±3.80 8.43 ±3.96 0.89 ±1.70** 18.64 ±2.06 9.32±2.83**** 27.97±2.57

Parahippocampal AD (12) Control (10)

0.51 ±0.38 25.67±3.51 0.51 ±0.47 19.24 ±5.47 24.43 ±2.07 9.82±3.26 3.45 ±2.45 16.55 ±2.70 13.27±2.57 29.82 ±2.88

0.33±0.27 25.96 ±1.69 0.40±0.33 23.67 ±0.80* 19.72±3.83*** 12.11 ±1.33 0.87±1.64*** 16.91 ±1.37 12.98 ±1.50 29.89 ±1.44

Values represent percentage composition (±SD) for Alzheimer's disease brains (AD) and control brains. *P < 0.05; **P < 0.01; ***P < 0.002; ****P < 0.001 for differences between Alzheimer's disease brains and control brains.

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Germany) with 5 ml methanol, 2.5 ml chloroform and 2 ml water. The volume of water added was inclusive of the water content of the sample. A further 2.5 ml of chloroform was added and the mixture homogenized for 30 s. Finally, 2.5 ml of water was added and the mixture again homogenized for 30 s. After centrifugation for 20 min at 4°C and 800 g, the top layer was withdrawn and the solvents removed by rotary evaporation. The lipids were saponified by heating under reflux for 20 min with 3 ml of 0.05 M NaOH in methanol, to which two crystals of BHT, two anti-bump granules and 10 drops of benzene had been added. The reaction mixture was allowed to cool for 1 min before the addition of BF3 (14% in methanol; 3 ml). After a further 20 min reflux, the mixture was allowed to cool to room temperature and the methyl esters separated by two extractions of the aqueous medium with n-hexane. After removal of traces of inorganic salt by two washes with water, the final solution was dehydrated by the addition of Na2SO4 and adjusted to a concentration of 0.1 mg/ml of methyl esters for analysis. The composition of methyl esters of fatty acids was determined by gas chromatography using an oncolumn injector fitted in a Hewlett-Packard 588A gas chromatograph equipped with a 30 m x 0.253 mm (inner diameter) fused silica column coated with DB-wax. The temperature was set at 40°C and was programmed to increase at 25cC/min to a temperature of 140°C and then at 3°C/min to a final temperature of 230°C at which it was held for a further 10 min. Identification of fatty acid methyl esters was made by comparison with authentic standards and by low resolution electron impact or chemical ionization mass spectrometry.

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E. R. SKINNER AND OTHERS TABLE 2. FATTY ACID COMPOSITION OF THE WHITE MATTER OF DIFFERENT REGIONS OF THE BRAINS OF PATIENTS WITH ALZHEIMER'S DISEASE AND CONTROL SUBJECTS

Fatty AD (8)

Parietal Control (8)

0.53 ±0.41 19.95 ±4.21 1.03 ±0.34 19.64±4.91 39.62 ±6.47 6.78±1.05 6.89±3.08 5.60 ±1.94 13.67±2.06 19.27±2.02

0.21 ±0.27 16.82 ±1.25 0.71±0.14 21.19±0.93 42.65 ±1.85 6.30±0.43 8.80±0.76 3.33 ±1.08* 15.10±0.60 18.43 ±0.76

AD (7)

0.43 ±0.27 17.58±1.85 1.01±0.11 20.95±l.ll 41.86±2.57 6.34±0.75 7.23 ±0.57 4.58 ±1.60 13.57dbl.66 18.15±0.97

Frontal Control (8)

0.22 ±0.28 16.95 ±1.20 0.81 ±0.14* 21.05 ±0.97 42.23 ±1.56 6.63 ±0.41 8.53 ±0.78**** 3.59±0.78 15.16±0.59* 18.75 ±0.66

Parahippocampal AD (7) Control (8)

0.50±0.33 18.83 ±1.55 1.04±0.14 20.01 ±2.04 40.32±3.08 7.33 ±1.56 6.93 ±1.02 5.01 ±1.75 14.26 ±1.29 19.27 ±1.42

0.43 ±0.21 18.40 ±1.77 0.79 ±0.009*** 20.76 ±0.91 38.38±2.79 7.58±1.10 8.53 ±0.58** 5.12 ±1.49 16.11 ±0.84** 21.23 ±1.06

Values represent percentage composition (±SD) for Alzheimer's disease brains (AD) and control brains. *P < 0.05; **P < 0.01; ***/> < 0.002; ****/> < 0.001 for differences between Alzheimer's disease brains and control brains.

Alzheimer group, though the difference did not reach statistical significance. In the frontal and parahippocampal regions in the white matter, these decreases were associated with significant increases in the mono-unsaturated acid, 16:1, together with a modest increase in this fatty acid in the parietal white matter of the Alzheimer's patients. There was no significant difference between the groups in the proportions of other n-6 fatty acids (20:4 n-6) in any of the three regions of either the grey or the white matter. No differences were shown in fatty acids of the n-3 series (22 : 6 n-3) between the two groups in any of the regions examined, except for parietal white matter in which this acid was higher in the Alzheimer group. The relationship between age at death and the level of those fatty acid components that showed significant differences between the two groups are shown in Table 3. No association was observed for any of the fatty acids within either group considered separately except for 22 : 6 n-3 in the parietal white region of the Alzheimer's patients, but not in the control group, in spite of the wider age distribution of the latter. When the association was measured in the combined groups of subjects, only that for 22 : 4 n-6 in the white matter of the parahippocampus was significant, reflecting the large difference in the level of this constituent between the two groups. Terminal status had essentially no effect on the fatty acid composition of the different regions of the brain. The percentage composition of each of the eight fatty acids in all six tissues examined from the Alzheimer group and the control group who died suddenly (e.g. myocardial infarction) did not differ significantly from those of subjects who died from prolonged causes (e.g. bronchopneumonia), except in one instance. In this case, the 22 : 6 n-3 acid in the parahippocampal white matter of the control group was higher (P < 0.05) in the sudden death group than in the subjects who died of prolonged causes. The percentage composition of this fatty acid in this region of the brain did not, however, differ between the Alzheimer patients and the control group. In addition, differences in the time interval between death and autopsy in the two

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acid 14:0 16:0 16:1 18:0 18:1 20:4 n-6 22:4 n-6 22:6 n-3 Total n-6 Total n-3 + n-6

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TABLE 3. THE RELATIONSHIP BETWEEN AGE AT DEATH AND FATTY ACID COMPOSITION (C) 10 (AD) 13 (T) 23

16:1

18:0 0.37 0.21 -0.27

Frontal grey

(C) 10 (AD) 9 (T) 19

0.14 0.44 -0.06

Parahippo grey

(C) 10 (AD) 12 (T) 22

0.02 -0.27 -0.24

Parietal white

(C) 8 (AD) 8 (T) 16

Frontal white

(C) 8 (AD) 7 (T) 15

0.35 0.25 0.51

Parahippo white

(C) 8 (AD) 7 (T) 15

-0.18 -0.60 0.25

18:1

22:4 n-6 0.53 0.25 0.11

22:6 n-3

0.11 0.31 0.27 0.09 0.07 0.42

-0.52 0.02 0.31 0.19 -0.78** 0.18 -0.36 0.05 -0.40 -0.38 -0.55 -0.616*

Values represent correlation coefficients for different regions of the brains of control subjects (C), brains of Alzheimer's disease subjects (AD) and the two groups combined (T). *P < 0.02; **P < 0.001.

subject groups appear to be unlikely to have influenced the values for the fatty acids obtained in this study. This period ranged from 8 to 71 h (except for one subject at 93 h). The brain region fatty acid composition of the patients and control subjects for whom the time interval between death and autopsy was less than the mean value of 31 h was compared with that when the time interval was greater than 31 h. Of the 96 possible comparisons (i.e. of the eight fatty acids in each of the six tissues of the two subject groups), only 78 could be compared with reliability, as the remainder involved the use of less than two subjects. Only two of the comparisons (20: 4 n-6 in the parietal white tissue and 22 : 4 n-6 in the parietal grey tissue of the Alzheimer group) showed differences at the P < 0.05 level of significance and are therefore likely to represent false positive results, particularly in view of the small numbers of subjects involved. DISCUSSION

The normal functioning of the brain depends upon the activity of the membrane-bound proteins which produce the transmitter functions or provide the mechanism for the passage of ions and molecules into and out of the brain cells. Optimal activity of these regulatory proteins depends on the maintenance of the appropriate level of fluidity within the membrane and this, in turn, is dependent upon the degree of unsaturation of the fatty acids associated with the phospholipids that form the bilayer (Ho and Cox, 1982; Goodfriend and Ball, 1986). In addition, certain polyunsaturated acids (20 : 3 n-6, 20:4 n-6 and 20: 5 n-3) are also precursors of prostaglandins, thromboxanes and leukotrienes

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Parietal grey

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which have been shown to have major effects on neuronal function (Horrobin et al., 1977). The above considerations demand the presence of a constant lipid composition within the cell membranes of the brain, yet brain phospholipids are known to be metabolically active in vivo (Dawson and Richter, 1950; Ansell and Dohmen, 1957) and undergo rapid exchange of their fatty acyl moieties (Corbin and Sun, 1978; Fisher and Rowe, 1980). It has been demonstrated recently, that cerebral cortex (Connor et al., 1990) as well as isolated synaptosomes and myelin subfractions (Youyou et al., 1986) have a remarkable capacity to change their fatty acid composition and thereby to correct for any deficiencies within a few weeks. This raises the question as to whether abnormalities in the fatty acid composition of the brain and an inability to correct this defect, due to a fault in the mechanism by which fatty acids are exchanged, may be associated with some forms of mental disorder. To explore this possibility, the fatty acid composition of the grey and white matter of different regions of the brains taken post-mortem from patients with Alzheimer's disease and control subjects was compared. It was shown that the frontal, parietal and parahippocampal regions of the grey matter and those of the white matter each had fatty acid compositions that were very uniform, though very significant differences occurred between the grey and the white matter. Of the polyunsaturated fatty acids, 22 : 4 n-6 was —10 times more abundant in the white matter than in the grey matter, while the proportion of 22 : 6 n-3 was three to five times higher in the grey matter. The differences observed between the Alzheimer patients and the control subjects displayed a remarkable degree of specificity with respect to certain fatty acids. Thus the Alzheimer's patients had significantly higher levels of adrenic acid (22 : 4 n-6) in the grey matter in all three regions, yet lower levels of this fatty acid in the white matter of each of the three regions compared with control subjects. There was no difference between the two groups in the proportion of the other n-6 acid, arachidonic acid (20: 4 n-6), in any of the regions investigated and the n-3 acid, 22 : 6 n-3 differed only in the white matter of the parietal region in the Alzheimer group in which it was found in elevated concentrations. These alterations in fatty acid composition observed in patients with Alzheimer's disease may arise either through a defect in the metabolism of essential fatty acids or in the delivery of these components or their precursors to the brain. The observation that the brain, in contrast to most other mammalian tissues, contains low concentrations of linoleic acid (Svennerholm et al., 1978), suggests that this tissue has effective desaturase/elongase enzyme systems to supply the needs of the tissue. Although the activities of these enzymes are modulated by many factors, an alteration in their activities in Alzheimer patients would appear unlikely as no changes in any of their precursors were observed and only adrenic acid was affected. This may indicate that there is an aberration in the mechanism by which either linoleic acid or its metabolites, possibly formed in the liver (Li et al., 1992), are delivered to the brain of patients with Alzheimer's disease. At the present time, it is not clearly understood how fatty acids are delivered to the brain, but it is likely to occur through the action of lipoprotein lipase on triglyceride-rich lipoproteins (Ben-Zeev et al., 1990) or by receptor-mediated uptake of circulating low density or high density lipoproteins (Langan et al., 1987). It may be relevant that apo E which is implicated in the uptake of high-density lipoprotein (HDL), is synthesized by nervous tissue and has been suggested to preserve local concentrations of lipid in regenerating

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nerve tissue since apo E has a strong affinity for cholesterol (Ignatius et al., 1986). In a recent study, it was shown that the feeding of oils rich in n-6 fatty acids to patients with Alzheimer's disease resulted in a decrease in the plasma concentration of a subfraction of HDL that was rich in apo E and that this reduction correlated with a decreased score on the Hamilton Depression Rating Scale, indicative of improved mood (Van Rhijn etal, 1990). It has been observed recently (Yates et al., 1990) that homogenates of brains from patients either with or without brain disorders who die after a terminal illness are more acidic than those from patients with no brain disorder who die suddenly. This arises as a result of changes in lactate concentration, probably due to alterations in ante-mortem anaerobic glycolysis resulting from cerebral hypoxia (Hardy et al., 1985) and therefore raises the question as to whether the results observed in this study may have been due to differences in the agonal status of the Alzheimer's patients and control subjects. It would appear unlikely that this difference would affect the recovery of polyunsaturated fatty acids, since the extraction of phospholipids and cerebrosides from brain is not affected by changes in pH (Spence, 1969). Although that of brain gangliosides is pH dependent, there is no difference over the pH range of 6.3—6.7 which covers the values observed in post-mortem brains from patients with different agonal status. Furthermore, negligible differences occur in the activity of desaturase enzymes in the pH region 6.5—7.5 (Oshino et al., 1966) suggesting that differences in the pH of the brains of the two patient groups are not responsible for differences in the formation of polyunsaturated fatty acids from their less unsaturated precursors by desaturases. These observations are borne out by the findings in the present study that there was effectively no difference in the level of any fatty acids measured in either the patients who had Alzheimer's disease or the subjects who died a sudden death and those with prolonged deaths. Furthermore, the results do not appear to be influenced by difference in the time-lag between death and body refrigeration and subsequent freezing of the samples, as the fatty acid compositions were independent of the time between death and autopsy and all samples were frozen immediately after removal at autopsy. The possibility that the above findings are related to differences in diet between the two subject groups should be considered since hospitalized patients with dementia are reported to show a weight loss in comparison with patients living in the community or control subjects; such a correlation, however, could not be identified in the study by Burns et al. (1989) who also considered that malabsorption was an unlikely factor. A further possible explanation for the fatty acid differences observed in this study is that it reflects the altered population of neuron and glial cells in the brain of Alzheimer patients. This possibility is not supported by the high degree of specificity of the fatty acids involved in the change. A consideration of the composition of the neurons, glial cells (oligodendrocytes and astrocysts) and myelin (Bourre et al., 1984) demonstrates that a change in the proportion of cell types would, rather, result in broad changes in fatty acid composition. The fatty acid composition of the major brain lipids varies with age, and acids of the n-6 species, predominantly 22 :4 n-6 (which is largely associated with sphingomyelin of the white matter), have been shown to diminish throughout life into old age (Svennerholm et al., 1978). In addition, it has been reported that the desaturase activity of the brain decreases with age (Hrelia et al., 1990). In the present study, the mean age of the

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Alzheimer group was higher than that of the control subjects, though this was strongly influenced by the inclusion of one younger subject in the control group and there was a considerable overlap in the age distribution of the two groups. The lack of any significant association between the levels of individual fatty acids and age (Table 3) provides strong evidence that the differences observed reflect genuine group differences and are not a function of age differences between the groups. ACKNOWLEDGEMENTS

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We wish to thank Dr C. Moffat who carried out the analysis of methyl esters of fatty acids at the Torry Research Station, Aberdeen, Scotland.

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