Dementia in Parkinson's disease.
The psychiatric complications of Parkinson's disease have attracted attention for two reasons: first, they are of practical importance in the management of patients suffering from this disease and, second, their study provides insight into a range of psychiatric conditions.
The nature of dementia in Parkinson's disease
There have been numerous reports of the impairment of specific cognitive functions in patients with Parkinson's disease. Some of the impairments described are often only identifiable by specially designed methods of assessment, but some are revealed by tests of cognitive function that are in widespread use. Mortimer and his colleagues have reported a very high prevalence of cognitive impairment—93 per cent in a substantial group of patients with Parkinson's disease. (1)
Examination of their data showed neither a clear distinction between impaired groups nor the presence of subtypes of Parkinson's disease in which cognitive impairment was a more frequent occurrence. Their findings led them to propose that cognitive impairment in Parkinson's disease lies on a continuum of severity, rather than arising as a feature of particular subgroups. The impairments identified include deficits in memory, language, visuospatial functioning, abstract reasoning, slowness in intellectual tasks, and difficulty in shifting from task to task. Not only are these deficits widespread among patients with Parkinson's disease but they have been shown to occur at a very early stage of the disorder. (2,3)
A proportion of patients with Parkinson's disease show impairment of a range of cognitive functions, which is more akin to the global impairment seen in dementing disorders such as Alzheimer's disease. (4) However, the pattern of this impairment is frequently less severe than that seen in Alzheimer's disease where the pathological changes in the brain are known to be widespread. This observation, together with the occurrence of cognitive impairment in a range of movement disorders where the main neuropathological changes reside in the subcortical region of the brain, has led to the concept of ‘subcortical dementia'—a form of intellectual impairment of lesser degree than in Alzheimer's disease, but affecting several cognitive functions and associated with a disorder of movement. In 1974 Albert and his colleagues gave a description of the syndrome in which the main features were listed as emotional or personality changes, impaired memory, defective ability to manipulate acquired knowledge, and a striking slowness in the rate of information processing. (5)
This concept has carried some conviction, as the impairment seen in many subjects with disease in the subcortical region of the brain shows a pattern of cognitive impairment distinctly different from that of Alzheimer's disease. However, many issues have arisen as to the nature of ‘subcortical dementia'. Is subcortical dementia a clinical or a pathological concept? Is the difference between this and other forms of dementia simply one of degree? Do the pathological changes occur in the subcortical region of the brain alone? Is the syndrome of cognitive impairment distinctly different from other dementias or does the presence of motor features of the disorder simply give the intellectual impairment a distinct character? Is subcortical dementia a stable condition or a transitional state leading eventually to global dementia? Opinion has ranged from full acceptance of ‘subcortical dementia' as a distinct form of cognitive impairment to scepticism. (6,7 and 8)
McHugh( 9) has gone further than Albert et al.,(5) suggesting that the subcortical region subserves functions not only in motor control and cognitive function but also in the control and display of mood. He suggests that some syndromes arising from subcortical disease represent a ‘subcortical triad' of symptoms. This combination of symptoms is most convincingly seen in Huntington's disease. A notable difference between this concept and that of Albert and his colleagues is that the pathological disturbance of mood is only intermittently present, whereas the motor and cognitive changes are persistent.
Cummings (10) has suggested a useful development of the concept of ‘subcortical dementia'. He believes that the concept is applicable to disorders of movement to varying degrees. He suggests that cognitive impairment in Parkinson's disease takes three forms: a form which is relatively mild and meets the criteria for subcortical dementia, a more severe form showing wider impairment of cognitive function but neuropathologically distinct from senile dementia Alzheimer type ( SDAT), and a severe form which shows neuropathological changes in both the subcortical region of the brain and in the cortex, the latter of Alzheimer type. This proposal does not resolve some of the questions that have arisen over the nature of subcortical dementia, but it does provide a basis for viewing cognitive changes in Parkinson's disease, albeit provisional.
Many reports have suggested that global dementia occurs in Parkinson's disease. Whether such a severe change in cognitive function can be regarded as an intrinsic feature of this disease, whether it implies an extension of a neuropathological process more widely in the brain, or whether it suggests a different neuropathology from the outset which initially presented with disordered movement is, as yet, uncertain.
The methodology of studies of dementia in Parkinson's disease
Research to establish the status of dementia in Parkinson's disease has confronted a range of methodological issues. (11)
A major problem in research on dementia in Parkinson's disease has been in the diagnosis of Parkinson's disease itself. The original description of paralysis agitans by Parkinson was, in fact, the identification of a syndrome rather than of a disease. The part played by such agents as heavy metals, infection, and vascular disease was recognized more than 50 years ago. More recently, the importance of drug-induced parkinsonism, where patients generally recover following withdrawal of the drug, has been recognized. The term Parkinson's disease had come to be regarded as synonymous with idiopathic Parkinson's disease and paralysis agitans, and to be a degenerative disease of unknown cause. In spite of the use of standardized methods of diagnosis, recent studies have shown that a substantial proportion of patients diagnosed as suffering from Parkinson's disease in life do not show the expected findings in the brain postmortem. (12,13) In the study by Hughes et al., (12) 80 per cent of cases were shown to have neuropathological changes of Parkinson's disease after death and over 20 per cent were diagnosed as having suffered from progressive supranuclear palsy, multiple system atrophy, or Alzheimer's disease. Furthermore, some dementing illnesses may show movement disorder as a clinical feature, often late in the course of the disease, but further confusing the issue of diagnosis.
Studies of dementia in Parkinson's disease
Cases of dementia in Parkinson's disease have been reported for over a hundred years. Frequently, the relationship between dementia and this disease in reported cases is impossible to discern.
A number of cross-sectional or prevalence studies of dementia in Parkinson's disease have been carried out. The frequency of dementia reported ranges from zero to 81 per cent. In a review of 17 studies Brown and Marsden found that, overall, 35 per cent of subjects were regarded as demented. (14) However, if more stringent criteria for dementia were applied then the proportions demented fell to between 15 and 20 per cent. The authors regarded these figures to be more realistic, and this level has proved to be in keeping with more recent cross-sectional studies.
Follow-up studies have great advantages in studying the frequency of dementia in Parkinson's disease: they allow the diagnosis of Parkinson's disease to be checked; repeated assessment reduces errors in the recognition of dementia; the pattern of evolution of dementia may be followed; the underestimation of dementia by selective loss through death is avoided; and they reveal the incidence rather than the prevalence of the condition. The problems of follow-up studies include the difficulties in the choice of those methods of diagnosis and assessment that will remain appropriate throughout the period of the follow-up.
No prospective controlled study of the incidence of dementia in Parkinson's disease has been entirely satisfactory in its methodology. Probably the most satisfactory is that reported by Biggins et al., (15) and subsequently after a longer period of follow-up by Hughes et al.(16) Although this study employed satisfactory methods in most respects, its greatest weakness was in the selection of the original samples of both patients and controls. Biggins et al. (15) reported an incidence of dementia of 19 per cent after 4.5 years observation, or 48 per 1000 person-years of observation. A later report on the same cohorts of subjects showed an incidence of dementia of 47.8 per cent after 10 years of observation, or 46.9 cases per 1000 person-years of observation. The study shows a substantial incidence of dementia in Parkinson's disease increasing with the passage of the years. The control group showed cases of cognitive impairment but none amounting to dementia, thereby demonstrating a substantial excess risk in those subjects with Parkinson's disease.
Prediction of dementia in Parkinson's disease
There is a consensus from a number of studies as to which of those subjects with Parkinson's disease are most likely to suffer from dementia: older people, patients with Parkinson's disease of longer duration, subjects who have a greater severity of motor symptoms and signs of Parkinson's disease, and those who show greater physical disability. (15,16) Some studies have shown that Parkinson's disease in men or of late onset is more likely to be associated with dementia. (19) In parkinsonism, as distinct from Parkinson's disease, the likelihood of dementia is closely related to the pathological changes that underlie the symptoms of parkinsonism, which include diseases in which dementia is a leading feature, such as Alzheimer's disease. The explanation of an apparent association between the treatment of Parkinson's disease with levodopa and dementia is probably that successful treatment of the motor symptoms of Parkinson's disease prolongs life and thereby increases the risk of dementia.
The characteristic neuropathological changes of Parkinson's disease were described before the Second World War. The basic lesion is the degeneration of the pigmented neurone cells in the pars compacta of the substantia nigra in the brainstem, the presence of Lewy bodies, and accompanying gliosis. There is also a degeneration of neurones in the striatum and globus pallidus, but these changes may be secondary. (20) Clinical Parkinson's disease does not appear until about 80 per cent of the nigro striatal dopaminergic neurones have died. A correlation between the extent of cell loss in the pars compacta and the severity and duration of Parkinson's disease has been demonstrated. Lewy bodies had come to be regarded as pathognomonic of Parkinson's disease, but are now known to be present in other diseases (see: Lewy body dementia).
Although the degenerative changes in the substantia nigra are known to be closely linked with decreased dopaminergic neurotransmission in the brain, and that it is this deficiency which leads to the main motor features of the disease, other neurotransmitters are also deficient. Some of these deficiencies are of a type that has been associated with cognitive impairment in other disorders, including a deficiency in acetylcholinesterase in the cortex, a deficiency of noradrenaline in the cortex, and a deficiency of serotonin (5-hydroxytryptamine) in the striatum and cortex. The concentration of a range of neuropeptides may also be altered.
The neuropathology of cases of Parkinson's disease showing dementia is inconsistent; some show neuropathological changes extending to parts of the brain beyond the subcortical region, whereas in others the changes are similar to those seen in patients with Parkinson's disease without dementia and with neuropathological changes restricted to the subcortical region. In some patients with dementia the neuropathological diagnosis is of Alzheimer's disease or of other recognized degenerated conditions of the brain. (21) An interesting case is that of Lewy body disease, which is dealt with here: Lewy body dementia.
Just as there are difficulties in isolating Parkinson's disease from other conditions which closely resemble it, there are problems in understand the interrelationships of dementing disorders. At present, the aetiology of Parkinson's disease is unknown. Parkinson's disease shares this situation with a number of ‘neurodegenerative' disorders, including Alzheimer's disease. Several distinct neurodegenerative diseases share some aetiological factors, which may represent an interaction between environmental factors and the ageing process but with differing end results arising from specific factors in the process. (22,23) Problems in the diagnosis of Parkinson's disease, the shrinking category of idiopathic Parkinson's disease, and the difficulties encountered in explaining the occasional development of dementia in this disease, suggests that the interrelationship between causative agents, the clinical features of disorders of movement, the occurrence of cognitive impairment, and the neuropathology of this group of disorders requires substantial further work before it is understood.
The influence of dementia on mortality
Dementia of any origin is associated with an increased risk of premature death. A number of studies have shown an increased mortality in Parkinson's disease to be associated with age, late age of onset of this disease, cognitive impairment, dementia, and, in some studies, male sex. Certain medications have been associated with increased mortality. Many of the studies that have been carried out have been methodologically faulty, making comparisons between studies and the identification of the effect of particular factors, including dementia, problematic. A study, meeting most of the requirements for an accurate assessment of mortality, showed a hazard ratio for Parkinson's disease compared with controls of 1.64, in general, and of 1.94 for Parkinson's disease with dementia. (24) The occurrence of depression with Parkinson's disease led to increased mortality even more than dementia, with a hazard ratio of 2.66.
Clinical aspects of Parkinson's disease with dementia
The recognition of cognitive impairment in patients with Parkinson's disease has major implications for their management. Although prospective studies of patients with Parkinson's disease show that the illness usually follows a course extending over many years, dementia brings with it important changes in the care a patient will require and in their life expectancy. These needs will progressively increase and will place an increasing burden upon the patient's immediate family and carers. The timing of wills and other legal procedures may be affected.
The most important step in the recognition of dementia in Parkinson's disease is to suspect its presence. There are many features of Parkinson's disease that tend to activity, slowness in movement may conceal intellectual slowness, and sadness may suggest that morbid depression of mood is the reason for a reduction in liveliness. These clinical features may seem to account for increasing disability. The clinical picture can usually be clarified by careful examination of the mental state. Examination of cognitive functions by more extensive standardized psychological tests may be useful in some cases.
The clinical importance of dementia in Parkinson's disease is that there is a marked increase in disability, with problems arising in areas of functioning not previously affected by motor impairment alone. The development of drug treatments for dementia makes its recognition in Parkinson's disease especially important. Dementia may be accompanied by an increased liability to confusional episodes from the toxic effects of drugs and other causes.
Management of dementia is similar to that for patients suffering from other dementing disorders, but with attention to the presence of a movement disorder.
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