Parkinson's Disease Dementia — A First Step?
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《新英格兰医药杂志》
The hallmark of Parkinson's disease is involvement of the motor system, causing tremor, rigidity, and slowness of movement. But cognitive symptoms are frequently present at the time of diagnosis,1 contribute heavily to disability,2 and progress to dementia at an alarming rate. Dementia will develop in 40 to 70 percent of patients with Parkinson's disease during the course of their illness.3 The term "Parkinson's disease dementia" refers to dementia that develops at least two years after the diagnosis of Parkinson's disease. If dementia develops before or within two years after the onset of motor symptoms, then the criteria are met for the related condition, diffuse Lewy-body disease. Risk factors for Parkinson's disease dementia include advanced age, treatment-induced visual hallucinations, and more severe motor symptoms.4 The cognitive profile is similar to that of Alzheimer's disease, but patients with Parkinson's disease dementia generally have more severe visuospatial deficits, large fluctuations in attention, frequent visual hallucinations, and less severe memory problems.5
Parkinson's disease dementia and diffuse Lewy-body disease share a common neuropathological pattern, cognitive profile, and clinical course. The two conditions lie on the same disease spectrum, with the system that is initially involved — motor in Parkinson's disease dementia and cognitive in diffuse Lewy-body disease — artificially splitting them. Both can be considered subtypes of the more inclusive diagnosis of dementia with Lewy bodies. This larger category probably accounts for 10 to 15 percent of cases of dementia, making it the second most common cause of dementia after Alzheimer's disease.6 The pathological hallmark of both Parkinson's disease dementia and diffuse Lewy-body disease is the presence of Lewy bodies — intracytoplasmic neuronal inclusions containing -synuclein — in neocortical and paralimbic regions. By contrast, Lewy bodies are generally restricted to subcortical structures such as the substantia nigra in patients who have Parkinson's disease without dementia. The majority of patients who have dementia with Lewy bodies also have pathological findings characteristic of Alzheimer's disease, which adds to the nosologic challenge.7
The care of patients who have dementia with Lewy bodies is extremely challenging. Dopaminergic agents frequently worsen hallucinations and cognitive symptoms, whereas the older antipsychotic agents, or typical neuroleptics, can precipitate a profound, even fatal worsening in the motor symptoms of patients with parkinsonism.8 In general, the goal of therapy is to achieve acceptable motor function with the use of the lowest dose of levodopa and to control troubling hallucinations by adding low doses of atypical neuroleptics such as olanzapine, quetiapine, or clozapine. Evidence from a number of lines of study suggests that increasing cholinergic function can be particularly beneficial for both cognitive and behavioral symptoms in patients with Parkinson's disease dementia, since it has already been found to be effective for these symptoms in a smaller study of patients with diffuse Lewy-body disease.9 Patients with Parkinson's disease dementia have a greater cholinergic deficit than those with Alzheimer's disease, and the extent of the deficit correlates with the severity of cognitive symptoms; patients with Parkinson's disease dementia also have less devastation in the number of neocortical neurons, which can benefit from cholinergic repletion.10
In this issue of the Journal, Emre et al. report the first large, multicenter comparison of the cholinesterase inhibitor rivastigmine in a double-blind, placebo-controlled trial of patients with Parkinson's disease dementia.11 The results are not as impressive as one would have hoped. Patients receiving rivastigmine had a mean improvement of 2.1 points in the score for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), which has a 70-point range, whereas control subjects had a 0.7-point worsening. This degree of improvement closely mirrors that seen in patients with Alzheimer's disease.12 To put this into context, patients with Alzheimer's disease generally have a worsening in the score of 6 to 7 points per year, so the difference between the groups of 2.8 points would represent an average relative improvement of about six months' time.
The ADAS-cog is specifically designed to measure the cognitive deficits in patients with Alzheimer's disease and may have underestimated the clinical improvement in patients with Parkinson's disease dementia because of a lack of sensitivity to the impairments seen in these patients. In fact, some of the secondary measures used by Emre et al. that one would expect to be more sensitive, such as the Computerized Assessment System power of attention tests and the Verbal Fluency test, did show a more substantial improvement. Still, the overall measure of the Clinical Global Impression of Change showed only a moderate benefit. The benefit may actually have been inflated because of the higher dropout rate in the rivastigmine group than in the placebo group (27.3 percent vs. 17.9 percent), since in studies of patients with progressive degenerative disorders, the use of an earlier observation for those who discontinue the trial owing to a side effect of medication artificially benefits the treatment group. For those who dropped out, it is as though the medication completely halted disease progression. The question of the appropriate correction for this bias has not been settled, but efforts have been made in other studies to correct for it.13
As in other trials, the side effects of rivastigmine were primarily cholinergic, with the most frequent being nausea (affecting 29.0 percent of patients, as compared with 11.2 percent of those in the placebo group) and vomiting (affecting 16.6 percent, as compared with 1.7 percent of those in the placebo group). Tremor was also more frequent in the rivastigmine group, which concurs with the observation that anticholinergic agents are quite effective in reducing tremor. Although tremor was more common in the rivastigmine group, the overall motor function in this group did not decline. Interestingly, hallucinations were reported more frequently in the placebo group than in the rivastigmine group (9.5 percent vs. 4.7 percent), giving additional weight to the suggestion that cholinesterase inhibitors can lessen visual hallucinations in this population.
What role do cholinesterase inhibitors have in the management of Parkinson's disease dementia? One key point that clinicians should keep in mind is that this class of medications offers only a symptomatic benefit and probably does not modify the course of the disease. Just as with any other symptomatic treatment, if the clinical improvement is very small or the side effects are bothersome, then the medication should be tapered and discontinued. Families need to be made aware of the fact that although these medications will not slow the progress of the underlying dementia, they can offer moderate improvements in memory, attention, and behavior. The amount of improvement varies, and both clinicians and families should expect the patient's condition to decline again, but from a potentially higher baseline level.
The challenge lies in the ability to detect the clinical response, since the amount of improvement that can be expected in terms of cognition amounts to about 1 point on the 30-point Mini–Mental State Examination. One option would be to use a more detailed battery of cognitive tests that can be performed in the office before and after treatment is initiated. Observant family members can also assist in judging the patient's response, in terms of both cognition and especially behavior. A subgroup of patients can have a fairly dramatic response, but there is as yet no test to determine a priori who will have such a response. If neither the family nor the clinician notices a clear response after a trial period of 8 to12 weeks, then the medication should be tapered and discontinued.
Another challenge is to determine how long to continue treatment in patients who have a response. If the disease has progressed to advanced dementia or to the point that placement in a long-term care facility is required, then tapering followed by a trial period off the medicine is a reasonable next step. If there is subsequently a clinically relevant decline that is temporally related to the discontinuation of treatment, then the medication can be reintroduced.
Finally, the question often arises as to which cholinesterase inhibitor to choose. To date, there is no convincing evidence that one is more effective than another. It is reasonable to use tolerability, ease of use, and cost to help select a treatment.
Until medications that are clearly disease-modifying are available, treatment for Parkinson's disease dementia, as well as other dementias, will remain focused on symptomatic improvements in cognition, behavior, and mood. As our knowledge of the pathophysiology of Parkinson's disease advances, it is to be hoped that medications that arrest the progression of motor symptoms will also avert dementia. As exemplified by the study by the Parkinson Study Group,14 which also appears in this issue of the Journal, the optimal approach to the management of the motor symptoms of Parkinson's disease remains controversial, but our ability to treat these symptoms far exceeds our ability to treat the cognitive deficits. We must increase our efforts to understand the cognitive aspects of these disorders, since many of the newest treatments for the motor symptoms of Parkinson's disease, such as subthalamic stimulation, can worsen cognition and behavior. Although cholinesterase inhibitors such as rivastigmine offer a moderate improvement in only a portion of patients with Parkinson's disease dementia, such agents offer the potential for clinically significant benefits in cognition. Such agents can now be added to the list of medications that may benefit these patients.
Source Information
From the Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
References
Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive ability of an incident cohort of Parkinson's patients in the UK: the CamPaIGN study. Brain 2004;127:550-560.
Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Effect of psychiatric and other nonmotor symptoms on disability in Parkinson's disease. J Am Geriatr Soc 2004;52:784-788.
Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 2003;60:387-392.
Hobson P, Meara J. Risk and incidence of dementia in a cohort of older subjects with Parkinson's disease in the United Kingdom. Mov Disord 2004;19:1043-1049.
Calderon J, Perry RJ, Erzinclioglu SW, Berrios GE, Dening TR, Hodges JR. Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer's disease. J Neurol Neurosurg Psychiatry 2001;70:157-164.
McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB international workshop. Neurology 1996;47:1113-1124.
Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 2003;60:1586-1590.
Ballard C, Grace J, McKeith I, Holmes C. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's disease. Lancet 1998;351:1032-1033.
McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000;356:2031-2036.
Bohnen NI, Kaufer DI, Ivanco LS, et al. Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol 2003;60:1745-1748.
Emre M, Aarsland D, Albanese A, et al. Rivastigmine for the dementia associated with Parkinson's disease. N Engl J Med 2004;351:2509-2518.
Cummings JL. Alzheimer's disease. N Engl J Med 2004;351:56-67.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.
The Parkinson Study Group. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351:2498-2508.(Daniel Z. Press, M.D.)
Parkinson's disease dementia and diffuse Lewy-body disease share a common neuropathological pattern, cognitive profile, and clinical course. The two conditions lie on the same disease spectrum, with the system that is initially involved — motor in Parkinson's disease dementia and cognitive in diffuse Lewy-body disease — artificially splitting them. Both can be considered subtypes of the more inclusive diagnosis of dementia with Lewy bodies. This larger category probably accounts for 10 to 15 percent of cases of dementia, making it the second most common cause of dementia after Alzheimer's disease.6 The pathological hallmark of both Parkinson's disease dementia and diffuse Lewy-body disease is the presence of Lewy bodies — intracytoplasmic neuronal inclusions containing -synuclein — in neocortical and paralimbic regions. By contrast, Lewy bodies are generally restricted to subcortical structures such as the substantia nigra in patients who have Parkinson's disease without dementia. The majority of patients who have dementia with Lewy bodies also have pathological findings characteristic of Alzheimer's disease, which adds to the nosologic challenge.7
The care of patients who have dementia with Lewy bodies is extremely challenging. Dopaminergic agents frequently worsen hallucinations and cognitive symptoms, whereas the older antipsychotic agents, or typical neuroleptics, can precipitate a profound, even fatal worsening in the motor symptoms of patients with parkinsonism.8 In general, the goal of therapy is to achieve acceptable motor function with the use of the lowest dose of levodopa and to control troubling hallucinations by adding low doses of atypical neuroleptics such as olanzapine, quetiapine, or clozapine. Evidence from a number of lines of study suggests that increasing cholinergic function can be particularly beneficial for both cognitive and behavioral symptoms in patients with Parkinson's disease dementia, since it has already been found to be effective for these symptoms in a smaller study of patients with diffuse Lewy-body disease.9 Patients with Parkinson's disease dementia have a greater cholinergic deficit than those with Alzheimer's disease, and the extent of the deficit correlates with the severity of cognitive symptoms; patients with Parkinson's disease dementia also have less devastation in the number of neocortical neurons, which can benefit from cholinergic repletion.10
In this issue of the Journal, Emre et al. report the first large, multicenter comparison of the cholinesterase inhibitor rivastigmine in a double-blind, placebo-controlled trial of patients with Parkinson's disease dementia.11 The results are not as impressive as one would have hoped. Patients receiving rivastigmine had a mean improvement of 2.1 points in the score for the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), which has a 70-point range, whereas control subjects had a 0.7-point worsening. This degree of improvement closely mirrors that seen in patients with Alzheimer's disease.12 To put this into context, patients with Alzheimer's disease generally have a worsening in the score of 6 to 7 points per year, so the difference between the groups of 2.8 points would represent an average relative improvement of about six months' time.
The ADAS-cog is specifically designed to measure the cognitive deficits in patients with Alzheimer's disease and may have underestimated the clinical improvement in patients with Parkinson's disease dementia because of a lack of sensitivity to the impairments seen in these patients. In fact, some of the secondary measures used by Emre et al. that one would expect to be more sensitive, such as the Computerized Assessment System power of attention tests and the Verbal Fluency test, did show a more substantial improvement. Still, the overall measure of the Clinical Global Impression of Change showed only a moderate benefit. The benefit may actually have been inflated because of the higher dropout rate in the rivastigmine group than in the placebo group (27.3 percent vs. 17.9 percent), since in studies of patients with progressive degenerative disorders, the use of an earlier observation for those who discontinue the trial owing to a side effect of medication artificially benefits the treatment group. For those who dropped out, it is as though the medication completely halted disease progression. The question of the appropriate correction for this bias has not been settled, but efforts have been made in other studies to correct for it.13
As in other trials, the side effects of rivastigmine were primarily cholinergic, with the most frequent being nausea (affecting 29.0 percent of patients, as compared with 11.2 percent of those in the placebo group) and vomiting (affecting 16.6 percent, as compared with 1.7 percent of those in the placebo group). Tremor was also more frequent in the rivastigmine group, which concurs with the observation that anticholinergic agents are quite effective in reducing tremor. Although tremor was more common in the rivastigmine group, the overall motor function in this group did not decline. Interestingly, hallucinations were reported more frequently in the placebo group than in the rivastigmine group (9.5 percent vs. 4.7 percent), giving additional weight to the suggestion that cholinesterase inhibitors can lessen visual hallucinations in this population.
What role do cholinesterase inhibitors have in the management of Parkinson's disease dementia? One key point that clinicians should keep in mind is that this class of medications offers only a symptomatic benefit and probably does not modify the course of the disease. Just as with any other symptomatic treatment, if the clinical improvement is very small or the side effects are bothersome, then the medication should be tapered and discontinued. Families need to be made aware of the fact that although these medications will not slow the progress of the underlying dementia, they can offer moderate improvements in memory, attention, and behavior. The amount of improvement varies, and both clinicians and families should expect the patient's condition to decline again, but from a potentially higher baseline level.
The challenge lies in the ability to detect the clinical response, since the amount of improvement that can be expected in terms of cognition amounts to about 1 point on the 30-point Mini–Mental State Examination. One option would be to use a more detailed battery of cognitive tests that can be performed in the office before and after treatment is initiated. Observant family members can also assist in judging the patient's response, in terms of both cognition and especially behavior. A subgroup of patients can have a fairly dramatic response, but there is as yet no test to determine a priori who will have such a response. If neither the family nor the clinician notices a clear response after a trial period of 8 to12 weeks, then the medication should be tapered and discontinued.
Another challenge is to determine how long to continue treatment in patients who have a response. If the disease has progressed to advanced dementia or to the point that placement in a long-term care facility is required, then tapering followed by a trial period off the medicine is a reasonable next step. If there is subsequently a clinically relevant decline that is temporally related to the discontinuation of treatment, then the medication can be reintroduced.
Finally, the question often arises as to which cholinesterase inhibitor to choose. To date, there is no convincing evidence that one is more effective than another. It is reasonable to use tolerability, ease of use, and cost to help select a treatment.
Until medications that are clearly disease-modifying are available, treatment for Parkinson's disease dementia, as well as other dementias, will remain focused on symptomatic improvements in cognition, behavior, and mood. As our knowledge of the pathophysiology of Parkinson's disease advances, it is to be hoped that medications that arrest the progression of motor symptoms will also avert dementia. As exemplified by the study by the Parkinson Study Group,14 which also appears in this issue of the Journal, the optimal approach to the management of the motor symptoms of Parkinson's disease remains controversial, but our ability to treat these symptoms far exceeds our ability to treat the cognitive deficits. We must increase our efforts to understand the cognitive aspects of these disorders, since many of the newest treatments for the motor symptoms of Parkinson's disease, such as subthalamic stimulation, can worsen cognition and behavior. Although cholinesterase inhibitors such as rivastigmine offer a moderate improvement in only a portion of patients with Parkinson's disease dementia, such agents offer the potential for clinically significant benefits in cognition. Such agents can now be added to the list of medications that may benefit these patients.
Source Information
From the Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.
References
Foltynie T, Brayne CE, Robbins TW, Barker RA. The cognitive ability of an incident cohort of Parkinson's patients in the UK: the CamPaIGN study. Brain 2004;127:550-560.
Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Effect of psychiatric and other nonmotor symptoms on disability in Parkinson's disease. J Am Geriatr Soc 2004;52:784-788.
Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 2003;60:387-392.
Hobson P, Meara J. Risk and incidence of dementia in a cohort of older subjects with Parkinson's disease in the United Kingdom. Mov Disord 2004;19:1043-1049.
Calderon J, Perry RJ, Erzinclioglu SW, Berrios GE, Dening TR, Hodges JR. Perception, attention, and working memory are disproportionately impaired in dementia with Lewy bodies compared with Alzheimer's disease. J Neurol Neurosurg Psychiatry 2001;70:157-164.
McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB international workshop. Neurology 1996;47:1113-1124.
Merdes AR, Hansen LA, Jeste DV, et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 2003;60:1586-1590.
Ballard C, Grace J, McKeith I, Holmes C. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's disease. Lancet 1998;351:1032-1033.
McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000;356:2031-2036.
Bohnen NI, Kaufer DI, Ivanco LS, et al. Cortical cholinergic function is more severely affected in parkinsonian dementia than in Alzheimer disease: an in vivo positron emission tomographic study. Arch Neurol 2003;60:1745-1748.
Emre M, Aarsland D, Albanese A, et al. Rivastigmine for the dementia associated with Parkinson's disease. N Engl J Med 2004;351:2509-2518.
Cummings JL. Alzheimer's disease. N Engl J Med 2004;351:56-67.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105-2115.
The Parkinson Study Group. Levodopa and the progression of Parkinson's disease. N Engl J Med 2004;351:2498-2508.(Daniel Z. Press, M.D.)