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Dementia in Huntington's disease is associated with neurochemical deficits in the caudate nucleus, not the cerebral cortex
Neuroscience Letters, 113 (1990) 95-100
95
Elsevier Scientific Publishers Ireland Ltd.
NSL 06847
Dementia in Huntington's disease is associated with neurochemical deficits in the caudate nucleus, not the cerebral cortex Gavin P. Reynolds, Sally J. Pearson and Kenneth W.G. Heathfield* Department of Pathology, University of Nottingham Medical School, Queen's Medical Centre, Nottingham (U.K.) (Received 9 December 1989; Accepted 18 January 1990)
Key words: Huntington's disease; Dementia; Human brain; ~,-Aminobutyric acid; Glutamic acid; Choline acetyltransferase; Neurotransmitter Choline acetyltransferase (CHAT) and the neurotransmitter amino acids ~,-aminobutyric acid (GABA) and glutamic acid were measured in brain tissue taken post-mortem frbm control subjects and from patients with Huntington's disease (HD). Two subgroups of HD patients were defined with either severe dementia or no dementia. It was found that ChAT exhibited no greater decrease in cortical tissue from severely demented patients. While there were also no significant deficits associated with dementia in cortical concentrations of the amino acids, a substantial and regionally-specific decrease in both GABA and glutamate was observed in the caudate nucleus of severely demented HD patients.
Huntington's disease (HD) is an autosomal dominant hereditary disorder characterised typically by an insidious development of choreiform movements in middle age. In addition to the movement disorder, psychiatric symptoms ranging from personality changes to severe schizophreniform psychosis or depression may also develop prior to, or concurrent with, the movement disorder. More consistently, most cases of HD show a progressive dementing process, particularly in the later stages of the disease. The major neuropathological finding in HD is an atrophy of the structures ofthe basal ganglia which reflects a profound neuronal loss; typically the caudate nucleus, putamen and pallidum are shrunken by over 50% [4, 5]. It is this atrophy of the brain regions involved in the control of automatic movement which is considered to relate to the dyskinetic symptoms. There is, however, a more generalised tissue loss in the brain which in the cortex reflects a substantial neuronal loss [4, 5]. It seems likely
*Present address: The London and Whipp's Cross Hospitals, London, U.K. Correspondence: G.P. Reynolds, Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, U.K. 0304-3940/90/$ 03.50 © 1990 Elsevier Scientific Publishers Ireland Ltd.
96 that these cortical deficits could contribute to some of the psychiatric and cognitive symptoms of HD. A loss of the cortical cholinergic innervation has in the past been particularly associated with memory loss and dementia. Thus the activity of choline acetyltransferase (CHAT, a marker for cholinergic neurons) measured after autopsy in several cortical regions of patients with Alzheimer's disease has been found to correlate inversely with clinical measures of dementia and cognitive impairment [6]. Similarly, patients with dementia in Parkinson's disease have temporal and frontal cortical ChAT activity reduced below the levels found in undemented Parkinson's disease or in control subjects [7], the reduction being equivalent to that observed in Alzheimer's disease but often in the absence of the characteristic neuropathological signs of the latter disorder. The present study was initially undertaken to investigate whether such a deficit of the cholinergic marker enzyme in the cortex was associated with the presence of dementia in HD, as part of a major study of neurotransmitter abnormalities and their correlation with the clinical symptoms in HD. We have investigated tissue samples taken post-mortem from several brain regions in a series of 47 neuropathologically-confirmed H D cases and 27 age-matched control subjects who had no known history of neurological or psychiatric disease (Table I). Using medical and nursing case records, it proved possible to obtain a global impression of the severity of dementia in 35 of the H D patients. This employed a fourpoint scale in which dementia was described as absent, mild, moderate or severe. Recognising that this retrospective assessment can provide no more than an approximate indication of dementia severity, in this study we have investigated only the two extreme subgroups in which dementia was determined as being either absent (n = 5) or severe (n = 12). These would be approximately equivalent to points 1 and 6/7, respectively on the Global Deterioration Scale of Reisberg et al. [8]. Samples were supplied by the Cambridge Brain Bank Laboratory which houses a national collection of brain tissue taken post-mortem from patients dying with HD. Tissue samples, dissected from brain hemispheres according to previously published procedures [9], were stored at - 7 0 ° C until assay. Temporal cortex was taken from Brodmann area 38, and frontal cortex from area 10. The other hemisphere from each H D brain was used for neuropathological confirmation of diagnosis. TABLE I DETAILS OF SUBJECTSINVESTIGATED
Controls Huntington's disease Not demented Severelydemented
Age (yr)
Sex
Disease duration
57 + 14 56+ 12 67+ 10" 54_ 12
24M 3F 23M 24F 3M 2F 5M 7F
12.0+ 5.6 14.2+__3.6 14,0+ 3.9
Values are mean _ SD in years. *P < 0.05 vs. severelydementedcases.
97
ChAT activity was determined using a modification of the method of Fonnum [3]. Briefly, this involved the incubation of brain enzyme (prepared from the supernatant of a 20 vols homogenate at pH 7.4 in phosphate-buffered saline containing EDTA and Triton X-100) with 0.2 mM [3H]acetyl CoA and 8 mM choline in a volume of 100/zl at 37°C. Eserine at 0.1 mM was used to inhibit cholinesterase activity. Labelled acetylcholine was extracted with tetraphenylboron into toluene-based scintillant and the radioactivity determined by liquid scintillation counting. Activities were calculated using the differences between product formation at 5 and 15 min incubation. Statistical differences were assessed by the t-test of logarithmically transformed data. GABA and glutamate concentrations were measured using a liquid chromatography technique with electrochemical detection after o-phthalaldehyde derivatisation [10]. The deficit of ChAT in striatal regions of the HD brain is well established; we observed a decrease of 60% in caudate tissue from this series (HD: 2.2___1.8; controls: 5.5 + 2.0/tmol/h/g tissue; mean + SD) which is consistent with previous reports [13]. ChAT also demonstrated significant differences in two of the three cortical areas studied (Table II), a small deficit being found in the frontal cortex and a deficit of over 30% in the hippocampus. However, these deficits did not appear to be related to the severity of dementia; in fact a tendency to lower ChAT activity was apparent in the neocortical regions of the undemented HD cases, reaching significance in the temporal cortex. This difference between the HD subgroups may well be related to the greater age of the undemented patients since a decrease with age of ChAT in the frontal cortex has been reported in control subjects [12]. We have also found no difference between the two groups in the cortical concentrations of two transmitters affected in Alzheimer's disease, 5-hydroxytryptamine and noradrenaline (results not shown). It is notable that the deficits of ChAT in HD are small in comparison with those observed in Alzheimer's disease, typically 40-50% of control values [11, 12] or in dementia in Parkinson's disease in which similar or greater losses are reported [7]. Thus dementia in HD does not share the severe losses of cortical cholinergic projections that occur in these other two dementing conditions and that have been presumed to contribute to the cognitive symptoms. In a previous study of this series of brain tissues we have shown that GABA is
T A B L E II C H O L I N E A C E T Y L T R A N S F E R A S E A C T I V I T Y IN C O R T I C A L B R A I N TISSUE IN H U N T I N G T O N ' S DISEASE
Controls H u n t i n g t o n ' s disease N o t demented (4-5) Severely demented (10-12)
Hippocampus
Temporal cortex
Frontal cortex
1.04 + 0.42 0.72 + 0.42* ** 0.75 + 0.37 0.63+0.30
0.38 + 0.06 0.34 + 0.11 0.26 + 0.05 tt 0.41 +0.10
0.34 + 0.09 0.30 + 0.10* 0.26 + 0.05 0.31 +0.10
Values are m e a n s + SD in g m o l / h / g tissue. Nos. o f cases in parentheses. * P < 0.05, ***P<0.001 vs. controls, t t p < 0.01 vs. severely demented cases.
98 decreased in H D not only in the areas of the basal ganglia, a well-established finding [14, 16], but also in the hippocampus and neocortex [10]. Glutamate too was shown to be significantly reduced in the putamen and cortical regions in H D [10]. In the present work we have determined whether these deficits might be related to the dementia of HD. The results, shown in Table III, indicate that no difference in G A B A concentrations between the undemented and severely demented H D cases is apparent in the hippocampus and frontal cortex, which contrasts with the losses observed in Alzheimer's disease [12]. However, a significant and substantially greater loss of caudate G A B A occurs in the most demented cases. This result is consistent with the interpretation that dementia in H D is related to neuronal degeneration within the caudate nucleus. Glutamate shows similar results. While in H D dementia the hippocampus, frontal cortex and putamen demonstrate minor deficits of 10-17%, the caudate nucleus exhibits a significant decrease of 42% below the results in undemented patients. As we have discussed previously [10], this size of deficit is likely to account for a loss of the major proportion of transmitter glutamate, the remainder representing primarily the metabolic pool of the amino acid. Thus a further substantial and relatively specific loss of caudate glutamate also appears to be associated with dementia in HD. It is unlikely that these changes are artifactual reflections of other differences between the two H D subgroups, particularly since the results are so regionally specific. There is little difference between the duration of disease in each group indicating that, in general, the disease process is not more advanced in the demented patients. The effect, if any, of the lower age of this group would be to increase G A B A concentrations, not to lower them as is apparent here. Post-mortem delay, agonal state and TABLE IIl GABA AND GLUTAMATEIN BRAIN TISSUE IN HUNTINGTON'S DISEASE Caudate nucleus
Putamen
Hippocampus Frontal cortex
GABA
Controls Huntington's disease Not demented (4-5) Severely demented (10-12) Glutamate Controls Huntington's disease
Not demented (4-5) Severelydemented (10-12)
314 + 90 100+40"** 146__26m 81 +23
1694__.219 1127+ 384*** 1628+559t 942 ___301
461 ___62 165+52"** 186+49
196+ 55 140+43"** 133+62
196+ 37 140+37"** 131+44
149+ 14
139_+24
138_+39
21604-272 1638_+397*** 1842+527
1232+ 166 1082-t-298** 1228+381
1507+ 272 1366+ 407* 1436+736
1535+ 287
1104+ 280
1267+ 430
Values are mean + SD in #g/g tissue. Nos. of cases in parentheses. *P < 0.05, **P< 0.01, ***P< 0.001 vs. controls, t p < 0.05, rap< 0.001 vs. severelydemented cases.
99 gender are other factors that are important to consider as potential sources o f artifact in the investigation o f h u m a n autopsy tissue; however, as we have discussed [10], they are most unlikely to be responsible for any substantial differences in amino acid concentrations in this series. While this is the first report providing direct neurochemical evidence implicating the caudate in the dementia of H D , there have been other studies indicating the caudate nucleus and not the cerebral cortex to be the site o f the lesion involved in this cognitive deficit. Several computerised t o m o g r a p h y studies have shown cognitive deficits in H D to be correlated with various measures o f caudate, but not cortical, atrophy [1, 15]. Positron emission tomography, used to measure regional metabolic activity, has also demonstrated that there is no hypometabolism in the neocortex in H D , contrary to that in Alzheimer's disease, and that a decrease in the energy metabolism o f the caudate is related to impaired cognitive function [2]. The innervation of the caudate nucleus by the cortex is glutamatergic and thus the decrease in caudate glutamate that we observe here is consistent with a loss of this cortical output pathway. As Weinberger et al. [17] have shown, H D does not show the expected deficit in cerebral blood flow associated with a measurable deterioration of a function mediated by intrinsic frontal cortical systems. Thus the additional neuronal damage of the caudate nucleus that is reflected by further amino acid losses in dementing H D patients can lead to this disruption of cognitive behaviour that is essentially cortical in origin. We wish to thank the staff of the Cambridge Brain Bank L a b o r a t o r y for the supply of brain tissue and Dr. L. Carrasco, Runwell Hospital, for neuropathological diagnosis. The work was supported by the Association to C o m b a t Huntington's Chorea and the Wellcome Trust. 1 Bamford, K.A., Caine, E.D., Kido, D.K., Plassche, W.M. and Shoulson, I., Clinical-pathologic correlation in Huntington's disease: a neuropsychologicaland computed tomography study, Neurology, 39 (1989) 796-801. 2 Berent, S., Giordani, B., Lehteinen, S., Markel, D., Penney, J.B., Buchtel, H.A., Starosta-Rubinstein, S., Hichwa, R. and Young, A.B., Positron emission tomographic scan investigations of Huntington's disease: cerebral metabolic correlates of cognitive function, Ann. Neurol., 23 (1988) 541-546. 3 Fonnum, F., A rapid radiochemical method for the determination of choline acetyltransferase, J. Neurochem., 24 (1975) 407-409. 4 Lange, H., Thrrner, G., Hopf, A. and Schrrder, K.F., Morphometric studies of the neuropathological changes in choreatic diseases, J. Neurol. Sci., 28 (1976) 401-425. 5 De la Monte, S.M., Vonsattel, J.P. and Richardson, E.P., Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington's disease, J. Neuropath. Exp. Neurol., 47 (1988) 516-525. 6 Mountjoy, C.Q., Rossor, M.N., Iversen, L.L. and Roth, M., Correlation of cortical cholinergic and GABA deficits with quantitative neuropathological findings in senile dementia, Brain, 107 (1984) 507-518. 7 Perry, R.H., Tomlinson, B.E., Candy, J.M., Blessed, G., Foster, J.F., Bloxham, C.A. and Perry, E.R., Cortical cholinergic deficit in mentally impaired Parkinsonian patients, Lancet, ii (1983) 789-790. 8 Reisberg, B., Ferris, S.H., de Leon, M.J. and Crook, T., Global deterioration scale for age-associated cognitive decline and Alzheimer'sdisease, Am. J. Psychiat., 139 (1982) 1136-1139.
100 9 Reynolds, G.P., Neurochemical studies in human post-mortem brain tissue. In: A.A. Boulton and G.B. Baker (Eds.), Neuromethods, Vol. 1, Humana Press, New Jersey, 1985, pp. 477 496. 10 Reynolds, G.P. and Pearson, S.J., Decreased glutamate and increased serotonin in Huntington's disease, Neurosci. Lett., 78 (1987) 233 238. 11 Rossor, M.N., Iversen, L.L., Johnson, A.L., Mountjoy, C.Q. and Roth, M., A post-mortem study of the cholinergic and GABA systems in senile dementia, Brain, 105 (1982) 313-330. 12 Rossor, M.N., Iversen, L.L., Reynolds, G.P., Mountjoy, C.Q. and Roth, M., Neurochemical characteristics of early and late onset types of Alzheimer's disease, Br. Med. J., 288 (1984)961-964. 13 Spokes, E.G.S., Neurochemical alterations in Huntington's chorea, Brain, 103 (1980) 179-180. 14 Spokes, E.G.S., Garrett, N.J., Rossor, M.N. and Iversen, L.L., Distribution of GABA in post-mortem brain tissue from control, psychotic and Huntington's chorea subjects, J. Neurol. Sci., 48 (1980) 303-313. 15 Starkstein, S.E., Brandt, J., Folstein, S., Strauss, M., Berthier, M.L., Pearlson, G.D., Wong, D., McDonnell, A. and Folstein, M., Neuropsychological and neuroradiological correlates in Huntington's disease, J. Neurol. Neurosurg. Psychiatr., 51 (1988) 1259--1263. 16 Urquhart, N., Perry, T.L., Hansen, S. and Kennedy, J., GABA content and glutamic acid decarboxylase activity in brain of Huntington's chorea patients and control subjects, J. Neurochem., 24 (1975) 1071-1075. 17 Weinberger, D.R., Berman, K.F., ladarola, M., Driesen, N. and Zec, R.F., Prefrontal cortical blood and cognitive function in Huntington's disease, J. Neurol. Neurosurg. Psychiatr., 51 (1988) 94-104.
95
Elsevier Scientific Publishers Ireland Ltd.
NSL 06847
Dementia in Huntington's disease is associated with neurochemical deficits in the caudate nucleus, not the cerebral cortex Gavin P. Reynolds, Sally J. Pearson and Kenneth W.G. Heathfield* Department of Pathology, University of Nottingham Medical School, Queen's Medical Centre, Nottingham (U.K.) (Received 9 December 1989; Accepted 18 January 1990)
Key words: Huntington's disease; Dementia; Human brain; ~,-Aminobutyric acid; Glutamic acid; Choline acetyltransferase; Neurotransmitter Choline acetyltransferase (CHAT) and the neurotransmitter amino acids ~,-aminobutyric acid (GABA) and glutamic acid were measured in brain tissue taken post-mortem frbm control subjects and from patients with Huntington's disease (HD). Two subgroups of HD patients were defined with either severe dementia or no dementia. It was found that ChAT exhibited no greater decrease in cortical tissue from severely demented patients. While there were also no significant deficits associated with dementia in cortical concentrations of the amino acids, a substantial and regionally-specific decrease in both GABA and glutamate was observed in the caudate nucleus of severely demented HD patients.
Huntington's disease (HD) is an autosomal dominant hereditary disorder characterised typically by an insidious development of choreiform movements in middle age. In addition to the movement disorder, psychiatric symptoms ranging from personality changes to severe schizophreniform psychosis or depression may also develop prior to, or concurrent with, the movement disorder. More consistently, most cases of HD show a progressive dementing process, particularly in the later stages of the disease. The major neuropathological finding in HD is an atrophy of the structures ofthe basal ganglia which reflects a profound neuronal loss; typically the caudate nucleus, putamen and pallidum are shrunken by over 50% [4, 5]. It is this atrophy of the brain regions involved in the control of automatic movement which is considered to relate to the dyskinetic symptoms. There is, however, a more generalised tissue loss in the brain which in the cortex reflects a substantial neuronal loss [4, 5]. It seems likely
*Present address: The London and Whipp's Cross Hospitals, London, U.K. Correspondence: G.P. Reynolds, Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, U.K. 0304-3940/90/$ 03.50 © 1990 Elsevier Scientific Publishers Ireland Ltd.
96 that these cortical deficits could contribute to some of the psychiatric and cognitive symptoms of HD. A loss of the cortical cholinergic innervation has in the past been particularly associated with memory loss and dementia. Thus the activity of choline acetyltransferase (CHAT, a marker for cholinergic neurons) measured after autopsy in several cortical regions of patients with Alzheimer's disease has been found to correlate inversely with clinical measures of dementia and cognitive impairment [6]. Similarly, patients with dementia in Parkinson's disease have temporal and frontal cortical ChAT activity reduced below the levels found in undemented Parkinson's disease or in control subjects [7], the reduction being equivalent to that observed in Alzheimer's disease but often in the absence of the characteristic neuropathological signs of the latter disorder. The present study was initially undertaken to investigate whether such a deficit of the cholinergic marker enzyme in the cortex was associated with the presence of dementia in HD, as part of a major study of neurotransmitter abnormalities and their correlation with the clinical symptoms in HD. We have investigated tissue samples taken post-mortem from several brain regions in a series of 47 neuropathologically-confirmed H D cases and 27 age-matched control subjects who had no known history of neurological or psychiatric disease (Table I). Using medical and nursing case records, it proved possible to obtain a global impression of the severity of dementia in 35 of the H D patients. This employed a fourpoint scale in which dementia was described as absent, mild, moderate or severe. Recognising that this retrospective assessment can provide no more than an approximate indication of dementia severity, in this study we have investigated only the two extreme subgroups in which dementia was determined as being either absent (n = 5) or severe (n = 12). These would be approximately equivalent to points 1 and 6/7, respectively on the Global Deterioration Scale of Reisberg et al. [8]. Samples were supplied by the Cambridge Brain Bank Laboratory which houses a national collection of brain tissue taken post-mortem from patients dying with HD. Tissue samples, dissected from brain hemispheres according to previously published procedures [9], were stored at - 7 0 ° C until assay. Temporal cortex was taken from Brodmann area 38, and frontal cortex from area 10. The other hemisphere from each H D brain was used for neuropathological confirmation of diagnosis. TABLE I DETAILS OF SUBJECTSINVESTIGATED
Controls Huntington's disease Not demented Severelydemented
Age (yr)
Sex
Disease duration
57 + 14 56+ 12 67+ 10" 54_ 12
24M 3F 23M 24F 3M 2F 5M 7F
12.0+ 5.6 14.2+__3.6 14,0+ 3.9
Values are mean _ SD in years. *P < 0.05 vs. severelydementedcases.
97
ChAT activity was determined using a modification of the method of Fonnum [3]. Briefly, this involved the incubation of brain enzyme (prepared from the supernatant of a 20 vols homogenate at pH 7.4 in phosphate-buffered saline containing EDTA and Triton X-100) with 0.2 mM [3H]acetyl CoA and 8 mM choline in a volume of 100/zl at 37°C. Eserine at 0.1 mM was used to inhibit cholinesterase activity. Labelled acetylcholine was extracted with tetraphenylboron into toluene-based scintillant and the radioactivity determined by liquid scintillation counting. Activities were calculated using the differences between product formation at 5 and 15 min incubation. Statistical differences were assessed by the t-test of logarithmically transformed data. GABA and glutamate concentrations were measured using a liquid chromatography technique with electrochemical detection after o-phthalaldehyde derivatisation [10]. The deficit of ChAT in striatal regions of the HD brain is well established; we observed a decrease of 60% in caudate tissue from this series (HD: 2.2___1.8; controls: 5.5 + 2.0/tmol/h/g tissue; mean + SD) which is consistent with previous reports [13]. ChAT also demonstrated significant differences in two of the three cortical areas studied (Table II), a small deficit being found in the frontal cortex and a deficit of over 30% in the hippocampus. However, these deficits did not appear to be related to the severity of dementia; in fact a tendency to lower ChAT activity was apparent in the neocortical regions of the undemented HD cases, reaching significance in the temporal cortex. This difference between the HD subgroups may well be related to the greater age of the undemented patients since a decrease with age of ChAT in the frontal cortex has been reported in control subjects [12]. We have also found no difference between the two groups in the cortical concentrations of two transmitters affected in Alzheimer's disease, 5-hydroxytryptamine and noradrenaline (results not shown). It is notable that the deficits of ChAT in HD are small in comparison with those observed in Alzheimer's disease, typically 40-50% of control values [11, 12] or in dementia in Parkinson's disease in which similar or greater losses are reported [7]. Thus dementia in HD does not share the severe losses of cortical cholinergic projections that occur in these other two dementing conditions and that have been presumed to contribute to the cognitive symptoms. In a previous study of this series of brain tissues we have shown that GABA is
T A B L E II C H O L I N E A C E T Y L T R A N S F E R A S E A C T I V I T Y IN C O R T I C A L B R A I N TISSUE IN H U N T I N G T O N ' S DISEASE
Controls H u n t i n g t o n ' s disease N o t demented (4-5) Severely demented (10-12)
Hippocampus
Temporal cortex
Frontal cortex
1.04 + 0.42 0.72 + 0.42* ** 0.75 + 0.37 0.63+0.30
0.38 + 0.06 0.34 + 0.11 0.26 + 0.05 tt 0.41 +0.10
0.34 + 0.09 0.30 + 0.10* 0.26 + 0.05 0.31 +0.10
Values are m e a n s + SD in g m o l / h / g tissue. Nos. o f cases in parentheses. * P < 0.05, ***P<0.001 vs. controls, t t p < 0.01 vs. severely demented cases.
98 decreased in H D not only in the areas of the basal ganglia, a well-established finding [14, 16], but also in the hippocampus and neocortex [10]. Glutamate too was shown to be significantly reduced in the putamen and cortical regions in H D [10]. In the present work we have determined whether these deficits might be related to the dementia of HD. The results, shown in Table III, indicate that no difference in G A B A concentrations between the undemented and severely demented H D cases is apparent in the hippocampus and frontal cortex, which contrasts with the losses observed in Alzheimer's disease [12]. However, a significant and substantially greater loss of caudate G A B A occurs in the most demented cases. This result is consistent with the interpretation that dementia in H D is related to neuronal degeneration within the caudate nucleus. Glutamate shows similar results. While in H D dementia the hippocampus, frontal cortex and putamen demonstrate minor deficits of 10-17%, the caudate nucleus exhibits a significant decrease of 42% below the results in undemented patients. As we have discussed previously [10], this size of deficit is likely to account for a loss of the major proportion of transmitter glutamate, the remainder representing primarily the metabolic pool of the amino acid. Thus a further substantial and relatively specific loss of caudate glutamate also appears to be associated with dementia in HD. It is unlikely that these changes are artifactual reflections of other differences between the two H D subgroups, particularly since the results are so regionally specific. There is little difference between the duration of disease in each group indicating that, in general, the disease process is not more advanced in the demented patients. The effect, if any, of the lower age of this group would be to increase G A B A concentrations, not to lower them as is apparent here. Post-mortem delay, agonal state and TABLE IIl GABA AND GLUTAMATEIN BRAIN TISSUE IN HUNTINGTON'S DISEASE Caudate nucleus
Putamen
Hippocampus Frontal cortex
GABA
Controls Huntington's disease Not demented (4-5) Severely demented (10-12) Glutamate Controls Huntington's disease
Not demented (4-5) Severelydemented (10-12)
314 + 90 100+40"** 146__26m 81 +23
1694__.219 1127+ 384*** 1628+559t 942 ___301
461 ___62 165+52"** 186+49
196+ 55 140+43"** 133+62
196+ 37 140+37"** 131+44
149+ 14
139_+24
138_+39
21604-272 1638_+397*** 1842+527
1232+ 166 1082-t-298** 1228+381
1507+ 272 1366+ 407* 1436+736
1535+ 287
1104+ 280
1267+ 430
Values are mean + SD in #g/g tissue. Nos. of cases in parentheses. *P < 0.05, **P< 0.01, ***P< 0.001 vs. controls, t p < 0.05, rap< 0.001 vs. severelydemented cases.
99 gender are other factors that are important to consider as potential sources o f artifact in the investigation o f h u m a n autopsy tissue; however, as we have discussed [10], they are most unlikely to be responsible for any substantial differences in amino acid concentrations in this series. While this is the first report providing direct neurochemical evidence implicating the caudate in the dementia of H D , there have been other studies indicating the caudate nucleus and not the cerebral cortex to be the site o f the lesion involved in this cognitive deficit. Several computerised t o m o g r a p h y studies have shown cognitive deficits in H D to be correlated with various measures o f caudate, but not cortical, atrophy [1, 15]. Positron emission tomography, used to measure regional metabolic activity, has also demonstrated that there is no hypometabolism in the neocortex in H D , contrary to that in Alzheimer's disease, and that a decrease in the energy metabolism o f the caudate is related to impaired cognitive function [2]. The innervation of the caudate nucleus by the cortex is glutamatergic and thus the decrease in caudate glutamate that we observe here is consistent with a loss of this cortical output pathway. As Weinberger et al. [17] have shown, H D does not show the expected deficit in cerebral blood flow associated with a measurable deterioration of a function mediated by intrinsic frontal cortical systems. Thus the additional neuronal damage of the caudate nucleus that is reflected by further amino acid losses in dementing H D patients can lead to this disruption of cognitive behaviour that is essentially cortical in origin. We wish to thank the staff of the Cambridge Brain Bank L a b o r a t o r y for the supply of brain tissue and Dr. L. Carrasco, Runwell Hospital, for neuropathological diagnosis. The work was supported by the Association to C o m b a t Huntington's Chorea and the Wellcome Trust. 1 Bamford, K.A., Caine, E.D., Kido, D.K., Plassche, W.M. and Shoulson, I., Clinical-pathologic correlation in Huntington's disease: a neuropsychologicaland computed tomography study, Neurology, 39 (1989) 796-801. 2 Berent, S., Giordani, B., Lehteinen, S., Markel, D., Penney, J.B., Buchtel, H.A., Starosta-Rubinstein, S., Hichwa, R. and Young, A.B., Positron emission tomographic scan investigations of Huntington's disease: cerebral metabolic correlates of cognitive function, Ann. Neurol., 23 (1988) 541-546. 3 Fonnum, F., A rapid radiochemical method for the determination of choline acetyltransferase, J. Neurochem., 24 (1975) 407-409. 4 Lange, H., Thrrner, G., Hopf, A. and Schrrder, K.F., Morphometric studies of the neuropathological changes in choreatic diseases, J. Neurol. Sci., 28 (1976) 401-425. 5 De la Monte, S.M., Vonsattel, J.P. and Richardson, E.P., Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington's disease, J. Neuropath. Exp. Neurol., 47 (1988) 516-525. 6 Mountjoy, C.Q., Rossor, M.N., Iversen, L.L. and Roth, M., Correlation of cortical cholinergic and GABA deficits with quantitative neuropathological findings in senile dementia, Brain, 107 (1984) 507-518. 7 Perry, R.H., Tomlinson, B.E., Candy, J.M., Blessed, G., Foster, J.F., Bloxham, C.A. and Perry, E.R., Cortical cholinergic deficit in mentally impaired Parkinsonian patients, Lancet, ii (1983) 789-790. 8 Reisberg, B., Ferris, S.H., de Leon, M.J. and Crook, T., Global deterioration scale for age-associated cognitive decline and Alzheimer'sdisease, Am. J. Psychiat., 139 (1982) 1136-1139.
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