Psychopharmacotogy(1992) 106:S 137-S 139
Psychopharmacology O Springer-Verlag 1992
Depression and senile dementia of the Alzheimer type: a role for moclobemide V. Chan-Palay Neurology Clinic, University Hospital, CH-8091 Zurich, Switzerland
Abstract. Depression is common in patients with senile dementia of the Alzheimer type (SDAT) and may precede the onset of the dementia; the underlying biological and neurotransmitter mechanisms may be common to both diseases, so far as norepinephrine lesions are concerned. The major routes of metabolism of amines in the brain utilize the monoamine oxidase (MAO) enzymes. Due to the consistent severity of norepinephrine lesions in the locus coeruleus of patients with pre-senile dementia or SDAT and the fact that MAO-A enzyme is the major metabolizing enzyme present in the locus coeruleus in man, the new specific, reversible M A O ~ inhibitors may have a place in the treatment of depression associated with SDAT. Key words: Norepinephrine - Mood - Monoamine oxidase - Presenile dementia - Immunocytochemistry
Depression has been reported to occur in between approximately one-quarter and one-third of patients with senile dementia of the Alzheimer type (SDAT) (Hasegawa 1979; Reifler et al. 1982). Other studies have corroborated the co-occurrence of affective and cognitive disorders, but differ in respect of actual incidence figures (Rubin et al. 1988; Smith and Kiloch 1981). In some cases, severe chronic depression precedes the onset of SDAT by a number of years, causing speculation that at least in a proportion of these cases - the biological mechanisms underlying one disease may co-exist or overlap with those of the second. Understanding these mechanisms in relation to the dementing disorders of SDAT remains a major medical research endeavour. In collaboration with scientists and clinicians, present-day pharmaceutical research is attempting to develop credible pharmacological treatments based on such fundamental information. The treatment of depression, unlike that of dementia, has progressed over the last few decades, with the development of several lines of antidepressant therapy based on the regulation of altered levels of va-
rious monoamines in the brain, including serotonin and the catecholamines, particularly norepinephrine. In the difficult field of co-existent disease, in which a depressive disorder occurs with or precedes and then co-occurs with the dementing disorder, elucidation of the basic neuronal mechanisms is particularly challenging. Cognitive and intellectual declines are the hallmarks of SDAT. These are related to a failure of neuron systems particularly in the frontal, temporal and parietal cortices and hippocampus, and in several key regions of the brain in the basal nucleus of Meynert and assoc,iated regions, the locus coeruleus (LC) and raphe, and hypothalamic nuclei. Eventually, in the terminal disorientation, overall brain weight may be reduced by as much as one-third, along with much brain function. Classically, SDAT is characterized clinically by progressive decline of memory and cognitive abilities over years, without the sporadic attacks more commonly seen with dementJias of ischaemic origins. Neuropathologically, severe cortical atrophy and cell loss occur, as well as high numbers of neurofibrillary tangles and neuritic plaques. With the application of more sophisticated neurobiological methods to the investigation of the SDAT brain, aided by the attention accorded recently to more careful selection of clinically defined cases and to short post-mortem delays, it has been possible to show clearly that other important subcortical centres in the brain are also seriously and characteristically affected. Neuronal systems based on acetylcholine, norepinephrine and serotonin, and peptides such as galanin and somatostatin are variously involved. Related to this, there have been recent reports of studies of the LC the major collections of norepinephrine neurons within the brain stem, which are responsible for the afferent innervation of the cerebral cortices, hippocampus, and practically all of the neuraxes (Chan-Palay and Asan 198%, b for review). These studies have attempted to correlate cellular neuropathological findings and measurements of norepinephrine content in the various cortical projection areas. Using immunocytochemistry and antibodies directed against the catecholamine syn-
$138
thesizing enzymes tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), it has been demonstrated that norepinephrine neurons are lost progressively in normal ageing (Chan-Palay and Asan 1989a). However, there is a pathological increase in this rate of norepinephrine neuron loss in SDAT, and most seriously in Parkinson's disease (Chan-Palay and Asan 1989b) when it is complicated by dementia or depression (Chan-Palay 1990, 1991). We had reported recently (Chan Palay 1990) that in SDAT with coexistent depression, a loss of norepinephrine neurons (along with other neurotransmitter changes in the brain) occurs throughout the nucleus, but more in the rostral parts in patients with SDAT; the severity of the cell loss was in proportion to the approximate severity of the clinical disease. Since the neurons in the rostral region of the LC are believed to provide the afferent norepinephrine innervation to the cerebral cortices, the importance of this brain region in the cortically based lesions in SDAT is emphasized (Chan-Palay and Asan 1989b). A loss of LC norepinephrine neurons has also been observed in Parkinson's disease patients, particularly in the caudal parts of the nuclei. A more recent report discusses the correlation of the paucity of LC neurons and low levels of TH and of norepinephrine synthesis with the occurrence of depression in some patients with Parkinson disease (Chan-Palay 1991). There exists a correlation between the loss of LC norepinephrine neurons and SDAT [as well as with presenile dementia of the Alzheimer type (PDAT)], in that the severity of this neuronal loss is in approximate proportion to the severity of the clinical disease. Regardless of the patient's age, the more decompensated the condition and the more rapid the progression of the disease, the worse is the cell loss in the LC. The morphological changes in the LC neurons in SDAT and PDAT are as described above in that the norepinephrine neurons are typically enlarged in somata and have short distorted neuronal processes, possibly secondary to other concurrent cytoskeletal changes. Two features are common to the following groups of patients: those who are depressed without cognitive defect, those with Parkinson's disease and depression, and those suffering from SDAT with depression. Firstly, there is the norepinephrine neuron loss in the LC above the normal age-related range of cell loss, which is mildest in cases of simple depression, and worst in those of SDAT with depression. Secondly, there are similarities in the chemical morphology of LC neurons. The norepinephrine neurons have reduced norepinephrine synthesizing enzymes, as detected by TH and DBH antigenantibody immunocytochemistry, both in depressed states, with or without cognitive defect, and in Parkinson's disease. Thus, the presence of LC neurons with low norepinephrine levels may have a direct correlation with that of depressive disorders. It appears that low norepinephrine synthesis in LC neurons may predispose to or underlie depressive disorders alone, or may co-exist with other complex symptoms such as Parkinson's disease or dementia. A natural consequence of these studies would be to
question what therapeutic strategies might be developed to deal with reduced norepinephrine levels in patients with SDAT or PDAT, particularly since some proportion of these patients may exhibit the depressive symptoms for a decade or more, and well before the cognitive defects become evident. Clearly, the depressive symptoms need to be treated with antidepressants, perhaps preferably with those whose pharmacological activity is aimed more directly at treating the reduced norepinephrine levels. In the last decade, monoamine oxidase (MAO) inhibitors have shown interesting developments in the treatment of depression and dementia (Anand and Wesnes 1989; Sunderland et al. 1987). The major routes of metabolism of amines in the brain utilize MAO enzymes, both of which show separate and different distributions in human brain tissue (Benedetti and Dostert 1989; Westlund et al. 1989). The M A O - A subtype is found mainly in the LC, while only 10% of substantia nigra neurons exhibit detectable MAO-A. Dopamine is known to be a substrate for MAO-B in man (Glover et al. 1977). MAO-B, on the other hand, is found in raphe serotonin neurons, which have only minor amounts of MAO-A. MAO-B is increased in advanced age, SDAT and senile dementia (Gottfries 1985). Since the late 1970s, MAO-B inhibitors have increasingly been developed for supplementary use to L-dopa in antiparkinsonian therapy, with considerable success (Birkmayer and Yahr 1978; for review, see Kabins and Gershon, in press). Another approach to the use of MAO-B inhibitors has been in the exploration of their use in SDAT (Agnoli et al. 1990; Sandler and Glover 1988; Sunderland et al. 1987). The new generation of specific, reversible M A O - A inhibitors such as moclobemide, which are without the tyramine dietary and circulatory problems of the old, irreversible mixed MAO inhibitors, has been successfully developed for use in antidepressant therapy (for review, see Priest 1989 and this supplement). Due to the consistent severity of these norepinephrine lesions in the LC and the fact that the M A O - A enzyme is the major metabolizing enzyme present in the LC, new, specific, reversible M A O - A inhibitors may have a place in the treatment of depression not only in Parkinson's disease (Chan-Palay 1991), but possibly also in depression with early SDAT or early PDAT. It is clear that the dementing disorders in SDAT and PDAT are associated with multiple risk factors and are multi-factorial in terms of changes in the brain, while the changes described above are only one such factor. However, these changes have the advantage of being tangible in terms of a possible therapeutic strategy, to be used in an enrichment strategy in conjunction with other pharmacological manipulations for the management of dementia.
References Agnoli A, Martucci N, Fabbrini G, Buckley AE, Fioravanti M (1990) Monoamine oxidase and dementia: treatment with an inhibitor of M A O - B activity. Dementia 1 : 109-114
S139 Anand R, Wesnes KA (1989) Moclobemide, a reversible MAO inhibitor possesses cognition enhancing effect in humans. In: Wurtman R J, Corkin SH, Growdon JH, Ritter-Walker E (eds) Alzheimer's disease: advances in basic research and therapies. Center for Brain Science and Metabolism Charitable Trust, Cambridge, Mass., pp 607-701 Benedetti MS, Dostert P (1989) Monoamine oxidase, brain ageing and degenerative disease. Biochem Pharmacol 38:555-561 Birkmayer W, Yahr M (1978) Deprenyl, an inhibitor of MAO-type B in the treatment of parkinsonism. J Neural Transm 43:3-4 Chan-Palay V (1990) Depression and senile dementia of the Alzheimer type; catecholamine changes in the locus coeruleus basis for therapy. Dementia 1:253-262 Chan-Palay V (1991) Depression and dementia in Parkinson's disease-catecholamine changes in the locus coeruleus basis for therapy. Dementia 2:7-17 Chan-Palay V, Asan E (1989a) Quantitation of catecholamine neurons in the locus coeruleus in human brains or normal young and older adults and in depression. J Comp Neurol 287:357-372 Chan-Palay V, Asan E (1989b) Alterations in Catecholamine Neurons of the Locus Coeruleus in Senile Dementia of the Alzheimer Type and in Parkinson's Disease With and Without Dementia and Depression. J Comp Neurol 287:373-392 Glover V, Sandler M, Owen F, Riley GJ (1977) Dopamine is a monoamine oxidase B substrate in man. Nature 265:80-81 Gottfries CG (1985) Alzheimer's disease and senile dementia:
biochemical characteristics and aspects of treatment. Psychopharmacology 86: 245-252 Hasegawa K (1979) Aspects of community health care of the elderly in Japan. Int J Ment Health 8 : 36-49 Kabins D, Gershon S (1990) Potential applications for MAO-B inhibitors. Dementia 1: 323-348 Priest RG (ed) (1989) Depression and reversible monoamine oxidase inhibitors - new perspectives. Br J Psychiatry 155:4.84 Reifler BV, Larson E, Hanlet R (1982) Co-existence of cognitive impairment and depression in geriatric outpatients. Am J Psychiatry 139 : 623-626 Rubin EH, Zorumski CF, Burke WJ (1988) Overlapping symptoms of geriatric depression and Alzheimer type dementia. Hosp Community Psychiatry 39:1074-1079 Sandler M, Glover V (1988) Monoamine oxidase inhibitors in Parkinson's disease In: Calne DB (ed) Drugs for the treatment of Parkinson's disease. Springer, Berlin Heidelberg New York Smith JS, Kiloch LG (1981) The investigation of dementia: results in 200 consecutive admissions. Lancet I:824-827 Sunderland T, Tariot PN, Cohen RM, Newhouse PA, Mellow PA, Mueller EA, Murphy DL (1987) Dose-dependent effects of deprenyl on CSF monoamine metabolites in patients with Alzheimer's disease. Psychopharmacology 91:293 296 Westlund KN, Denney RN, Rosa RM, Abell CW (1989) Localization of distinct monoaminooxidase A and monoaminooxidase B cell populations in human brainstem. Neuroscience 25 : 439-456
Psychopharmacology O Springer-Verlag 1992
Depression and senile dementia of the Alzheimer type: a role for moclobemide V. Chan-Palay Neurology Clinic, University Hospital, CH-8091 Zurich, Switzerland
Abstract. Depression is common in patients with senile dementia of the Alzheimer type (SDAT) and may precede the onset of the dementia; the underlying biological and neurotransmitter mechanisms may be common to both diseases, so far as norepinephrine lesions are concerned. The major routes of metabolism of amines in the brain utilize the monoamine oxidase (MAO) enzymes. Due to the consistent severity of norepinephrine lesions in the locus coeruleus of patients with pre-senile dementia or SDAT and the fact that MAO-A enzyme is the major metabolizing enzyme present in the locus coeruleus in man, the new specific, reversible M A O ~ inhibitors may have a place in the treatment of depression associated with SDAT. Key words: Norepinephrine - Mood - Monoamine oxidase - Presenile dementia - Immunocytochemistry
Depression has been reported to occur in between approximately one-quarter and one-third of patients with senile dementia of the Alzheimer type (SDAT) (Hasegawa 1979; Reifler et al. 1982). Other studies have corroborated the co-occurrence of affective and cognitive disorders, but differ in respect of actual incidence figures (Rubin et al. 1988; Smith and Kiloch 1981). In some cases, severe chronic depression precedes the onset of SDAT by a number of years, causing speculation that at least in a proportion of these cases - the biological mechanisms underlying one disease may co-exist or overlap with those of the second. Understanding these mechanisms in relation to the dementing disorders of SDAT remains a major medical research endeavour. In collaboration with scientists and clinicians, present-day pharmaceutical research is attempting to develop credible pharmacological treatments based on such fundamental information. The treatment of depression, unlike that of dementia, has progressed over the last few decades, with the development of several lines of antidepressant therapy based on the regulation of altered levels of va-
rious monoamines in the brain, including serotonin and the catecholamines, particularly norepinephrine. In the difficult field of co-existent disease, in which a depressive disorder occurs with or precedes and then co-occurs with the dementing disorder, elucidation of the basic neuronal mechanisms is particularly challenging. Cognitive and intellectual declines are the hallmarks of SDAT. These are related to a failure of neuron systems particularly in the frontal, temporal and parietal cortices and hippocampus, and in several key regions of the brain in the basal nucleus of Meynert and assoc,iated regions, the locus coeruleus (LC) and raphe, and hypothalamic nuclei. Eventually, in the terminal disorientation, overall brain weight may be reduced by as much as one-third, along with much brain function. Classically, SDAT is characterized clinically by progressive decline of memory and cognitive abilities over years, without the sporadic attacks more commonly seen with dementJias of ischaemic origins. Neuropathologically, severe cortical atrophy and cell loss occur, as well as high numbers of neurofibrillary tangles and neuritic plaques. With the application of more sophisticated neurobiological methods to the investigation of the SDAT brain, aided by the attention accorded recently to more careful selection of clinically defined cases and to short post-mortem delays, it has been possible to show clearly that other important subcortical centres in the brain are also seriously and characteristically affected. Neuronal systems based on acetylcholine, norepinephrine and serotonin, and peptides such as galanin and somatostatin are variously involved. Related to this, there have been recent reports of studies of the LC the major collections of norepinephrine neurons within the brain stem, which are responsible for the afferent innervation of the cerebral cortices, hippocampus, and practically all of the neuraxes (Chan-Palay and Asan 198%, b for review). These studies have attempted to correlate cellular neuropathological findings and measurements of norepinephrine content in the various cortical projection areas. Using immunocytochemistry and antibodies directed against the catecholamine syn-
$138
thesizing enzymes tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), it has been demonstrated that norepinephrine neurons are lost progressively in normal ageing (Chan-Palay and Asan 1989a). However, there is a pathological increase in this rate of norepinephrine neuron loss in SDAT, and most seriously in Parkinson's disease (Chan-Palay and Asan 1989b) when it is complicated by dementia or depression (Chan-Palay 1990, 1991). We had reported recently (Chan Palay 1990) that in SDAT with coexistent depression, a loss of norepinephrine neurons (along with other neurotransmitter changes in the brain) occurs throughout the nucleus, but more in the rostral parts in patients with SDAT; the severity of the cell loss was in proportion to the approximate severity of the clinical disease. Since the neurons in the rostral region of the LC are believed to provide the afferent norepinephrine innervation to the cerebral cortices, the importance of this brain region in the cortically based lesions in SDAT is emphasized (Chan-Palay and Asan 1989b). A loss of LC norepinephrine neurons has also been observed in Parkinson's disease patients, particularly in the caudal parts of the nuclei. A more recent report discusses the correlation of the paucity of LC neurons and low levels of TH and of norepinephrine synthesis with the occurrence of depression in some patients with Parkinson disease (Chan-Palay 1991). There exists a correlation between the loss of LC norepinephrine neurons and SDAT [as well as with presenile dementia of the Alzheimer type (PDAT)], in that the severity of this neuronal loss is in approximate proportion to the severity of the clinical disease. Regardless of the patient's age, the more decompensated the condition and the more rapid the progression of the disease, the worse is the cell loss in the LC. The morphological changes in the LC neurons in SDAT and PDAT are as described above in that the norepinephrine neurons are typically enlarged in somata and have short distorted neuronal processes, possibly secondary to other concurrent cytoskeletal changes. Two features are common to the following groups of patients: those who are depressed without cognitive defect, those with Parkinson's disease and depression, and those suffering from SDAT with depression. Firstly, there is the norepinephrine neuron loss in the LC above the normal age-related range of cell loss, which is mildest in cases of simple depression, and worst in those of SDAT with depression. Secondly, there are similarities in the chemical morphology of LC neurons. The norepinephrine neurons have reduced norepinephrine synthesizing enzymes, as detected by TH and DBH antigenantibody immunocytochemistry, both in depressed states, with or without cognitive defect, and in Parkinson's disease. Thus, the presence of LC neurons with low norepinephrine levels may have a direct correlation with that of depressive disorders. It appears that low norepinephrine synthesis in LC neurons may predispose to or underlie depressive disorders alone, or may co-exist with other complex symptoms such as Parkinson's disease or dementia. A natural consequence of these studies would be to
question what therapeutic strategies might be developed to deal with reduced norepinephrine levels in patients with SDAT or PDAT, particularly since some proportion of these patients may exhibit the depressive symptoms for a decade or more, and well before the cognitive defects become evident. Clearly, the depressive symptoms need to be treated with antidepressants, perhaps preferably with those whose pharmacological activity is aimed more directly at treating the reduced norepinephrine levels. In the last decade, monoamine oxidase (MAO) inhibitors have shown interesting developments in the treatment of depression and dementia (Anand and Wesnes 1989; Sunderland et al. 1987). The major routes of metabolism of amines in the brain utilize MAO enzymes, both of which show separate and different distributions in human brain tissue (Benedetti and Dostert 1989; Westlund et al. 1989). The M A O - A subtype is found mainly in the LC, while only 10% of substantia nigra neurons exhibit detectable MAO-A. Dopamine is known to be a substrate for MAO-B in man (Glover et al. 1977). MAO-B, on the other hand, is found in raphe serotonin neurons, which have only minor amounts of MAO-A. MAO-B is increased in advanced age, SDAT and senile dementia (Gottfries 1985). Since the late 1970s, MAO-B inhibitors have increasingly been developed for supplementary use to L-dopa in antiparkinsonian therapy, with considerable success (Birkmayer and Yahr 1978; for review, see Kabins and Gershon, in press). Another approach to the use of MAO-B inhibitors has been in the exploration of their use in SDAT (Agnoli et al. 1990; Sandler and Glover 1988; Sunderland et al. 1987). The new generation of specific, reversible M A O - A inhibitors such as moclobemide, which are without the tyramine dietary and circulatory problems of the old, irreversible mixed MAO inhibitors, has been successfully developed for use in antidepressant therapy (for review, see Priest 1989 and this supplement). Due to the consistent severity of these norepinephrine lesions in the LC and the fact that the M A O - A enzyme is the major metabolizing enzyme present in the LC, new, specific, reversible M A O - A inhibitors may have a place in the treatment of depression not only in Parkinson's disease (Chan-Palay 1991), but possibly also in depression with early SDAT or early PDAT. It is clear that the dementing disorders in SDAT and PDAT are associated with multiple risk factors and are multi-factorial in terms of changes in the brain, while the changes described above are only one such factor. However, these changes have the advantage of being tangible in terms of a possible therapeutic strategy, to be used in an enrichment strategy in conjunction with other pharmacological manipulations for the management of dementia.
References Agnoli A, Martucci N, Fabbrini G, Buckley AE, Fioravanti M (1990) Monoamine oxidase and dementia: treatment with an inhibitor of M A O - B activity. Dementia 1 : 109-114
S139 Anand R, Wesnes KA (1989) Moclobemide, a reversible MAO inhibitor possesses cognition enhancing effect in humans. In: Wurtman R J, Corkin SH, Growdon JH, Ritter-Walker E (eds) Alzheimer's disease: advances in basic research and therapies. Center for Brain Science and Metabolism Charitable Trust, Cambridge, Mass., pp 607-701 Benedetti MS, Dostert P (1989) Monoamine oxidase, brain ageing and degenerative disease. Biochem Pharmacol 38:555-561 Birkmayer W, Yahr M (1978) Deprenyl, an inhibitor of MAO-type B in the treatment of parkinsonism. J Neural Transm 43:3-4 Chan-Palay V (1990) Depression and senile dementia of the Alzheimer type; catecholamine changes in the locus coeruleus basis for therapy. Dementia 1:253-262 Chan-Palay V (1991) Depression and dementia in Parkinson's disease-catecholamine changes in the locus coeruleus basis for therapy. Dementia 2:7-17 Chan-Palay V, Asan E (1989a) Quantitation of catecholamine neurons in the locus coeruleus in human brains or normal young and older adults and in depression. J Comp Neurol 287:357-372 Chan-Palay V, Asan E (1989b) Alterations in Catecholamine Neurons of the Locus Coeruleus in Senile Dementia of the Alzheimer Type and in Parkinson's Disease With and Without Dementia and Depression. J Comp Neurol 287:373-392 Glover V, Sandler M, Owen F, Riley GJ (1977) Dopamine is a monoamine oxidase B substrate in man. Nature 265:80-81 Gottfries CG (1985) Alzheimer's disease and senile dementia:
biochemical characteristics and aspects of treatment. Psychopharmacology 86: 245-252 Hasegawa K (1979) Aspects of community health care of the elderly in Japan. Int J Ment Health 8 : 36-49 Kabins D, Gershon S (1990) Potential applications for MAO-B inhibitors. Dementia 1: 323-348 Priest RG (ed) (1989) Depression and reversible monoamine oxidase inhibitors - new perspectives. Br J Psychiatry 155:4.84 Reifler BV, Larson E, Hanlet R (1982) Co-existence of cognitive impairment and depression in geriatric outpatients. Am J Psychiatry 139 : 623-626 Rubin EH, Zorumski CF, Burke WJ (1988) Overlapping symptoms of geriatric depression and Alzheimer type dementia. Hosp Community Psychiatry 39:1074-1079 Sandler M, Glover V (1988) Monoamine oxidase inhibitors in Parkinson's disease In: Calne DB (ed) Drugs for the treatment of Parkinson's disease. Springer, Berlin Heidelberg New York Smith JS, Kiloch LG (1981) The investigation of dementia: results in 200 consecutive admissions. Lancet I:824-827 Sunderland T, Tariot PN, Cohen RM, Newhouse PA, Mellow PA, Mueller EA, Murphy DL (1987) Dose-dependent effects of deprenyl on CSF monoamine metabolites in patients with Alzheimer's disease. Psychopharmacology 91:293 296 Westlund KN, Denney RN, Rosa RM, Abell CW (1989) Localization of distinct monoaminooxidase A and monoaminooxidase B cell populations in human brainstem. Neuroscience 25 : 439-456
