Intern. J. Neuroscience, 1992. Vol. 64, pp. 209-212 Reprints available directly from the publisher Photocopying permitted by license only
0 1992 Gordon and Breach Science Publishers S.A. Printed in the United States of America
Letter to the Editor THE ASSOCIATION OF DIABETES MELLITUS WITH DEMENTIA IN PARKINSON’S DISEASE (Received April I I , 1991; in final form F e b r u a v 7 , 1992)
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 05/30/15 For personal use only.
Keywords: Diabetes mellitus, dementia, Parkinson’s disease
To The Editor: It has long been recognized that Parkinson’s disease (PD) is associated with an increased incidence of diabetes mellitus (DM). Barbeau et al. (1961) evaluated oral glucose tolerance in 30 Parkinsonian patients and found decreased glucose tolerance in 17 patients (56.7%), which was attributed to their increased incidence of liver disease. Van Woert and Mueller (1971) also found increased incidence of glucose intolerance in patients with PD and proposed defective release of pancreatic insulin to explain these findings. Lipman et al. (1974) found a 52.4% incidence of abnormal glucose tolerance in a sample of 56 patients with PD and speculated that “hypothalamic involvement might be logically suspected as explaining the abnormal glucose metabolism in these cases.” Finally, Barbeau and Pourcher (1983) noted that patients with early onset PD exhibited diabetes more often than expected. It has been suggested that the high incidence of diabetes in patients with PD results from decreased insulin release due to reduced dopaminergic stimulation of the pancreatic beta-cells (Van Woert & Mueller 1971). However, with the detection of an insulin-sensitive hypothalamic glucoregulatory system, which is involved in the regulation of peripheral glucose metabolism (Szabo & Szabo, 1974; 1975), it was postulated that hypothalamic dopamine deficiency may alter the activity of this system and ultimately decrease peripheral glucose tolerance (Sandyk, 1984). The presence of abundant Lewy bodies in the hypothalamus of PD patients (Hirano & Zimmerman, 1962; Langston & Forno, 1978; cf. Sandyk et al., 1987) supports this hypothesis. At present it remains unexplored whether abnormal glucose metabolism affects the severity of the motor and cognitive aspects of PD and whether control of the diabetic state influences the symptoms and progression of the disease. In a series of 800 Parkinsonian patients, including postencephalitic cases, Schwab (1960) suggested that diabetes was a factor contributing to rapid progression of the disease. We recently investigated the relationship of diabetes and Parkinsonism in 44 chronic schizophrenic inpatients, of which 16 (36.4%) were diabetic. We found that the diabetic schizophrenic patients had a significantly more severe global Parkinsonism, including akinesia, rigidity, and gait impairment as compared to nondiabetic schizophrenics (Sandyk et al., in press). These findings suggest that diabetes may be a risk factor for drug-induced Parkinsonism in schizophrenia. To investigate whether this association also occurs in patients with idiopathic PD, we surveyed the incidence of dementia, postural instability (which reflects a poor prognostic sign), CT scan and electroencephalographic (EEG) abnormalities in a sample of 12 Parkinsonian patients (8 men; 4 women; mean age: 74.3 years, SD = 8.2, Correspondence to: Prof. Reuven Sandyk, P. 0. Box 203, Bedford Hills NY 10507, USA. 209
R . SANDYK AND G.I. AWERBUCH
210
TABLE I Sample characteristics (N
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 05/30/15 For personal use only.
Age
Sex
Diabetes
Dementia
=
12)
Postural instability
CT scan
EEG
range = 60-87) who were admitted consecutively to the Department of Neurology, Bay City Medical Center, Michigan. The mean age of onset of PD was 68.1 years (SD = 7.0) and the mean duration of illness was 6.2 (SD = 2.8). Ten of the patients were diagnosed de novo and the remaining two had been receiving antiparkinsonian medication during the study. Clinical assessments were undertaken by a research neurologist who was blind to the patient’s data and hypothesis of the study. The diagnosis of dementia was established on the basis of a bedside Mini-Mental status examination which included orientation to time, person, and space, ability to perform serial 3 substractions, ability to spell forwards and backwards, general judgment and insight, and retention and recall of simple tasks. None of the patients had dementia related to secondary causes such as metabolic, endocrine, traumatic, or infectious. A patient was judged to have postural instability when he or she exhibited imbalanced gait and a tendency to fall. The CT scan was considered abnormal if the patient had cerebral atrophy which was disproportionate to his age. A standard EEG recording was rated as abnormal if it showed evidence of generalized slowing and/ or diffuse disorganization. Five patients (41.6%) had type I1 DM which was controlled with diet and/or oral hypoglycemic drugs. Diabetes was unrelated to the patient’s age ( t = 42), sex (X2 = .68), age of onset of illness ( t = 79), and antiparkinsonian therapy (X2 = 3.36). However, the diabetic patients had a significantly longer duration of illness as compared to the nondiabetic patients (p < .005). These findings suggest that chronicity of illness may be associated with an increased risk for diabetes in PD patients. As can be seen from Table I, all diabetic patients had some degree of dementia as well as postural instability and abnormal CT scan and EEG findings. In contrast, none of the nondiabetic patients had dementia, abnormal CT scan, or postural instability. Only one of these patients had an abnormal EEG recording. These findings indicate that elderly diabetic Parkinsonian patients have a higher incidence of dementia, postural instability, and abnormal CT scan and EEG findings as compared to nondiabetic patients. The data concur with our previous investigation in which we found a more severe degree of drug-induced Parkinsonism in diabetic schizophrenic patients as compared to nondiabetic patients (Sandyk et al., in press). There is now a consensus that intellectual impairment is a common feature of PD. In a group of 520 PD patients seen over eight years, Lieberman et al. (1979) found 169 (32%) with moderate to marked dementia. They suggested that dementia is re-
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 05/30/15 For personal use only.
DIABETES, DEMENTIA AND PARKINSON’S DISEASE
21 1
lated to PD more than to age and that the incidence of dementia in PD was ten times higher than that of their spouses who were of similar age and educational status. Benson (1984) suggested that almost all patients with PD eventually show some degree of intellectual impairment and that this is of subcortical type, similar to the dementia seen in patients with Huntington’s disease, Wilson’s disease, and progressive supranuclear palsy (PSP). Mortimer et al. (1982) found a significant correlation between the severity of Parkinsonian akinesia and impaired performance in tests of psychomotor speed and visuospatial reasoning and suggested that both cortical and subcortical lesions may be implicated in Parkinsonian dementia. Alvord (197 l ) , however, suggested that demented Parkinsonian patients may have a coexisting Alzheimer’s disease. Likewise, on the basis of neuropathological studies in 34 autopsy-proven cases of PD, Hakim and Mathieson (1 979) proposed that Parkinsonian dementia may be related to the presence of simultaneous Alzheimer’s disease. Boller et al. (1980) found histological changes consistent with the dementia of Alzheimer’s disease in the brains of 33% of 36 patients with autopsy-confirmed idiopathic PD. In contrast, such changes were found in only 5.1% of the brains of an age-matched population. Based on these findings it has been suggested that there may be two types of PD: one with a severe dementia characterized by the presence of cortical Alzheimer’s pathology associated with subcortical changes of PD, and the other without dementia with neuropathological lesions confined to the basal ganglia and substantia nigra (Boller et al., 1980). The higher incidence of dementia in the diabetic Parkinsonian patients suggests that type I1 diabetes may be a feature of Parkinsonism which coexists with Alzheimer’s disease. Whether the presence of Alzheimer’s pathology facilitates the development of diabetes in these patients remains unknown. Perhaps a more extensive hypothalamic pathology in this subtype of PD may account for the higher incidence of diabetes in these patients. Alternatively, it is also possible that diabetes may contribute to the development of dementia in these patients. Whatever the mechanisms may be, the occurrence of diabetes in Parkinsonian patients may indicate the presence of a more malignant form of the disease potentially leading to the development of dementia and severe motor disability.
REFERENCES Alvord, E. C. (1971). The pathology of Parkinsonism: Part 11. An interpretation with special reference to other changes in the aging brain. In F. H. McDowell & C. H. Markham (Eds.). Recent advances in Parkinson’s disease. Philadelphia: Davis. Barbeau, A. (1961). Experience clinique avec le tolbutamide dans la maladie de Parkinson. Union Medicale Cannada, 90, 147-151. Barbeau, A. & Pourcher, E. (1983). Genetics of early onset Parkinson’s disease. In M. D. Yahr (Ed.). Current concepts of Parkinson disease and related disorders. Amsterdam: Excerpta Medica. Benson, D. F. (1984). Parkinsonian dementia: cortical or subcortical? In R. G. Hassler & J. F. Christ (Eds.). Advances in neurology, vol. 40. New York: Raven Press, pp. 235-240. Boller, F., Mizutani, T. & Roessmann, U. (1980). Parkinson’s disease, dementia and Alzheimer’s disease: Clinico-pathological correlations. Annals of Neurology, 7 , 329-335. Hakim, A. M. & Mathieson, G. (1979). Dementia in Parkinson disease: A neuropathologic study. Neurology, 29, 1209-1214. Hirano, A. & Zimmerman, H. M. (1962). Alzheimer’s neurofibrillary changes. Archives of Neurology, 7, 227-243. Langston, J . W. & Forno, L. S. (1978). The hypothalamus in Parkinson disease. Annals ofNeurology, 3, 129-133.
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 05/30/15 For personal use only.
212
R. SANDYK AND G.I. AWERBUCH
Lieberman, A., Dziatolowski, M . , Kupersmith, M . , Serby, M., Goodgold, A , , Korien, J. & Goldstein, M. (1979). Dementia in Parkinson disease. Annuls ofNeurology, 6, 355-359. Lipman, I. J., Boykin, M . E. & Flora, R . E. (1974). Glucose intolerance in Parkinson's disease. Journal of Chronic Diseases, 27, 573-579. Mortimer, J. A , , Pirozzolo, F. J. & Hansch, E. C . (1982). Relationship of motor symptoms to intellectual deficits in Parkinson's disease. Neurology, 3 2 , 133- 137. Sandyk, R. (1984). The effects of dopamine hydrochloride on insulin action in isolated rat adipocytes. M.Sc. Dissertation, University of the Witwatersrand, Johannesburg. South Africa. Sandyk, R., Iacono, R. P. & Bamford, C. R. (1987). The hypothalamus in Parkinson disease. Italiun Journal of Neurological Sciences, 8 , 227-234. Sandyk, R., Awerbuch, G. I. & Iacono, R. P. (1991). Diabetes mellitus as a risk factor for drug-induced Parkinsonism in schizophrenia. Inrernarional Journal of Neuroscience, 61, 149- 188. Szabo, 0. & Szabo, A. J. (1974). Effects of autonomic neurotransmitter and inhibitor drugs on the insulin sensitive CNS glucoregulatory center. Diabetes, 23, 342. Szabo, A. J. & Szabo, 0. (1975). Influence of the insulin sensitive CNS regulator receptor on hepatic glucose metabolism. Journal of Physiology, 253, 121-133. Schwab, R. S . (1960). Progression and prognosis in Parkinson's disease. Journal of Nervous and Mental Disease, 130, 556-566. Van Woert, M. H. & Mueller, P. S . (1971). Glucose, insulin, and free fatty acid metabolism in Parkinson's disease treated with levodopa. Clinical fharmucology & Therapeutics, 12, 360-367. REUVENSANDYK Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461. U.S.A. GAVIN I. AWERBUCH Department of Neurology, Bay Medical Center, Bay City, Michigan 48708, U.S.A.
0 1992 Gordon and Breach Science Publishers S.A. Printed in the United States of America
Letter to the Editor THE ASSOCIATION OF DIABETES MELLITUS WITH DEMENTIA IN PARKINSON’S DISEASE (Received April I I , 1991; in final form F e b r u a v 7 , 1992)
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 05/30/15 For personal use only.
Keywords: Diabetes mellitus, dementia, Parkinson’s disease
To The Editor: It has long been recognized that Parkinson’s disease (PD) is associated with an increased incidence of diabetes mellitus (DM). Barbeau et al. (1961) evaluated oral glucose tolerance in 30 Parkinsonian patients and found decreased glucose tolerance in 17 patients (56.7%), which was attributed to their increased incidence of liver disease. Van Woert and Mueller (1971) also found increased incidence of glucose intolerance in patients with PD and proposed defective release of pancreatic insulin to explain these findings. Lipman et al. (1974) found a 52.4% incidence of abnormal glucose tolerance in a sample of 56 patients with PD and speculated that “hypothalamic involvement might be logically suspected as explaining the abnormal glucose metabolism in these cases.” Finally, Barbeau and Pourcher (1983) noted that patients with early onset PD exhibited diabetes more often than expected. It has been suggested that the high incidence of diabetes in patients with PD results from decreased insulin release due to reduced dopaminergic stimulation of the pancreatic beta-cells (Van Woert & Mueller 1971). However, with the detection of an insulin-sensitive hypothalamic glucoregulatory system, which is involved in the regulation of peripheral glucose metabolism (Szabo & Szabo, 1974; 1975), it was postulated that hypothalamic dopamine deficiency may alter the activity of this system and ultimately decrease peripheral glucose tolerance (Sandyk, 1984). The presence of abundant Lewy bodies in the hypothalamus of PD patients (Hirano & Zimmerman, 1962; Langston & Forno, 1978; cf. Sandyk et al., 1987) supports this hypothesis. At present it remains unexplored whether abnormal glucose metabolism affects the severity of the motor and cognitive aspects of PD and whether control of the diabetic state influences the symptoms and progression of the disease. In a series of 800 Parkinsonian patients, including postencephalitic cases, Schwab (1960) suggested that diabetes was a factor contributing to rapid progression of the disease. We recently investigated the relationship of diabetes and Parkinsonism in 44 chronic schizophrenic inpatients, of which 16 (36.4%) were diabetic. We found that the diabetic schizophrenic patients had a significantly more severe global Parkinsonism, including akinesia, rigidity, and gait impairment as compared to nondiabetic schizophrenics (Sandyk et al., in press). These findings suggest that diabetes may be a risk factor for drug-induced Parkinsonism in schizophrenia. To investigate whether this association also occurs in patients with idiopathic PD, we surveyed the incidence of dementia, postural instability (which reflects a poor prognostic sign), CT scan and electroencephalographic (EEG) abnormalities in a sample of 12 Parkinsonian patients (8 men; 4 women; mean age: 74.3 years, SD = 8.2, Correspondence to: Prof. Reuven Sandyk, P. 0. Box 203, Bedford Hills NY 10507, USA. 209
R . SANDYK AND G.I. AWERBUCH
210
TABLE I Sample characteristics (N
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 05/30/15 For personal use only.
Age
Sex
Diabetes
Dementia
=
12)
Postural instability
CT scan
EEG
range = 60-87) who were admitted consecutively to the Department of Neurology, Bay City Medical Center, Michigan. The mean age of onset of PD was 68.1 years (SD = 7.0) and the mean duration of illness was 6.2 (SD = 2.8). Ten of the patients were diagnosed de novo and the remaining two had been receiving antiparkinsonian medication during the study. Clinical assessments were undertaken by a research neurologist who was blind to the patient’s data and hypothesis of the study. The diagnosis of dementia was established on the basis of a bedside Mini-Mental status examination which included orientation to time, person, and space, ability to perform serial 3 substractions, ability to spell forwards and backwards, general judgment and insight, and retention and recall of simple tasks. None of the patients had dementia related to secondary causes such as metabolic, endocrine, traumatic, or infectious. A patient was judged to have postural instability when he or she exhibited imbalanced gait and a tendency to fall. The CT scan was considered abnormal if the patient had cerebral atrophy which was disproportionate to his age. A standard EEG recording was rated as abnormal if it showed evidence of generalized slowing and/ or diffuse disorganization. Five patients (41.6%) had type I1 DM which was controlled with diet and/or oral hypoglycemic drugs. Diabetes was unrelated to the patient’s age ( t = 42), sex (X2 = .68), age of onset of illness ( t = 79), and antiparkinsonian therapy (X2 = 3.36). However, the diabetic patients had a significantly longer duration of illness as compared to the nondiabetic patients (p < .005). These findings suggest that chronicity of illness may be associated with an increased risk for diabetes in PD patients. As can be seen from Table I, all diabetic patients had some degree of dementia as well as postural instability and abnormal CT scan and EEG findings. In contrast, none of the nondiabetic patients had dementia, abnormal CT scan, or postural instability. Only one of these patients had an abnormal EEG recording. These findings indicate that elderly diabetic Parkinsonian patients have a higher incidence of dementia, postural instability, and abnormal CT scan and EEG findings as compared to nondiabetic patients. The data concur with our previous investigation in which we found a more severe degree of drug-induced Parkinsonism in diabetic schizophrenic patients as compared to nondiabetic patients (Sandyk et al., in press). There is now a consensus that intellectual impairment is a common feature of PD. In a group of 520 PD patients seen over eight years, Lieberman et al. (1979) found 169 (32%) with moderate to marked dementia. They suggested that dementia is re-
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 05/30/15 For personal use only.
DIABETES, DEMENTIA AND PARKINSON’S DISEASE
21 1
lated to PD more than to age and that the incidence of dementia in PD was ten times higher than that of their spouses who were of similar age and educational status. Benson (1984) suggested that almost all patients with PD eventually show some degree of intellectual impairment and that this is of subcortical type, similar to the dementia seen in patients with Huntington’s disease, Wilson’s disease, and progressive supranuclear palsy (PSP). Mortimer et al. (1982) found a significant correlation between the severity of Parkinsonian akinesia and impaired performance in tests of psychomotor speed and visuospatial reasoning and suggested that both cortical and subcortical lesions may be implicated in Parkinsonian dementia. Alvord (197 l ) , however, suggested that demented Parkinsonian patients may have a coexisting Alzheimer’s disease. Likewise, on the basis of neuropathological studies in 34 autopsy-proven cases of PD, Hakim and Mathieson (1 979) proposed that Parkinsonian dementia may be related to the presence of simultaneous Alzheimer’s disease. Boller et al. (1980) found histological changes consistent with the dementia of Alzheimer’s disease in the brains of 33% of 36 patients with autopsy-confirmed idiopathic PD. In contrast, such changes were found in only 5.1% of the brains of an age-matched population. Based on these findings it has been suggested that there may be two types of PD: one with a severe dementia characterized by the presence of cortical Alzheimer’s pathology associated with subcortical changes of PD, and the other without dementia with neuropathological lesions confined to the basal ganglia and substantia nigra (Boller et al., 1980). The higher incidence of dementia in the diabetic Parkinsonian patients suggests that type I1 diabetes may be a feature of Parkinsonism which coexists with Alzheimer’s disease. Whether the presence of Alzheimer’s pathology facilitates the development of diabetes in these patients remains unknown. Perhaps a more extensive hypothalamic pathology in this subtype of PD may account for the higher incidence of diabetes in these patients. Alternatively, it is also possible that diabetes may contribute to the development of dementia in these patients. Whatever the mechanisms may be, the occurrence of diabetes in Parkinsonian patients may indicate the presence of a more malignant form of the disease potentially leading to the development of dementia and severe motor disability.
REFERENCES Alvord, E. C. (1971). The pathology of Parkinsonism: Part 11. An interpretation with special reference to other changes in the aging brain. In F. H. McDowell & C. H. Markham (Eds.). Recent advances in Parkinson’s disease. Philadelphia: Davis. Barbeau, A. (1961). Experience clinique avec le tolbutamide dans la maladie de Parkinson. Union Medicale Cannada, 90, 147-151. Barbeau, A. & Pourcher, E. (1983). Genetics of early onset Parkinson’s disease. In M. D. Yahr (Ed.). Current concepts of Parkinson disease and related disorders. Amsterdam: Excerpta Medica. Benson, D. F. (1984). Parkinsonian dementia: cortical or subcortical? In R. G. Hassler & J. F. Christ (Eds.). Advances in neurology, vol. 40. New York: Raven Press, pp. 235-240. Boller, F., Mizutani, T. & Roessmann, U. (1980). Parkinson’s disease, dementia and Alzheimer’s disease: Clinico-pathological correlations. Annals of Neurology, 7 , 329-335. Hakim, A. M. & Mathieson, G. (1979). Dementia in Parkinson disease: A neuropathologic study. Neurology, 29, 1209-1214. Hirano, A. & Zimmerman, H. M. (1962). Alzheimer’s neurofibrillary changes. Archives of Neurology, 7, 227-243. Langston, J . W. & Forno, L. S. (1978). The hypothalamus in Parkinson disease. Annals ofNeurology, 3, 129-133.
Int J Neurosci Downloaded from informahealthcare.com by Nyu Medical Center on 05/30/15 For personal use only.
212
R. SANDYK AND G.I. AWERBUCH
Lieberman, A., Dziatolowski, M . , Kupersmith, M . , Serby, M., Goodgold, A , , Korien, J. & Goldstein, M. (1979). Dementia in Parkinson disease. Annuls ofNeurology, 6, 355-359. Lipman, I. J., Boykin, M . E. & Flora, R . E. (1974). Glucose intolerance in Parkinson's disease. Journal of Chronic Diseases, 27, 573-579. Mortimer, J. A , , Pirozzolo, F. J. & Hansch, E. C . (1982). Relationship of motor symptoms to intellectual deficits in Parkinson's disease. Neurology, 3 2 , 133- 137. Sandyk, R. (1984). The effects of dopamine hydrochloride on insulin action in isolated rat adipocytes. M.Sc. Dissertation, University of the Witwatersrand, Johannesburg. South Africa. Sandyk, R., Iacono, R. P. & Bamford, C. R. (1987). The hypothalamus in Parkinson disease. Italiun Journal of Neurological Sciences, 8 , 227-234. Sandyk, R., Awerbuch, G. I. & Iacono, R. P. (1991). Diabetes mellitus as a risk factor for drug-induced Parkinsonism in schizophrenia. Inrernarional Journal of Neuroscience, 61, 149- 188. Szabo, 0. & Szabo, A. J. (1974). Effects of autonomic neurotransmitter and inhibitor drugs on the insulin sensitive CNS glucoregulatory center. Diabetes, 23, 342. Szabo, A. J. & Szabo, 0. (1975). Influence of the insulin sensitive CNS regulator receptor on hepatic glucose metabolism. Journal of Physiology, 253, 121-133. Schwab, R. S . (1960). Progression and prognosis in Parkinson's disease. Journal of Nervous and Mental Disease, 130, 556-566. Van Woert, M. H. & Mueller, P. S . (1971). Glucose, insulin, and free fatty acid metabolism in Parkinson's disease treated with levodopa. Clinical fharmucology & Therapeutics, 12, 360-367. REUVENSANDYK Department of Psychiatry, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10461. U.S.A. GAVIN I. AWERBUCH Department of Neurology, Bay Medical Center, Bay City, Michigan 48708, U.S.A.
