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Cognitive Disturbances in Parkinson’s Disease
Cognitive Disturbances in Parkinson’s Disease Zoran Grujic, MD Introduction Cognitive changes are common in Parkinson’s disease (PD), even in the early stages of the illness.1 Most of these early cognitive changes involve impairments in executive functioning (defined as the ability to plan, organize, and regulate goal-directed behavior). Unfortunately, many PD patients experience a progressive cognitive decline into a dementia stage, Parkinson’s disease dementia (PDD). Like Alzheimer’s patients, PD patients may spend several years in a transition zone between normal cognitive function and dementia called mild cognitive impairment (MCI). The cognitive impairment in MCI, although objectively noted on neuropsychological testing, is not severe enough to sufficiently impair activities of daily living and normal social functioning (see Fig 1). Dementia in Parkinson’s disease has been difficult to define. DSM IV criteria for diagnosing a dementia require that the cognitive impairment be severe enough to interfere with social or occupational functions. However, in PD it is often difficult to differentiate how much the motor disability rather than the cognition is contributing to the functional decline. For example, bradykinesia and other motor deficits may interfere with timed neuropsychological tasks or functional abilities at home, like writing checks. In addition, it is often difficult to control for the effects that PD medications and co-morbid mood disturbances have on neuropsychological tests. For example, anxiety, depression, and apathy which can appear in PD will interfere with thinking. The diagnosis of dementia in PD is further complicated if one tries to differentiate between PDD and another disease entity known as dementia with Lewy bodies (DLB). There is some controversy whether DLB and PDD are unique syndromes or are in fact part of a continuum of disease. Currently, accepted criteria for differentiating the two disorders state that patients who have had the typical Parkinsonian motor signs for at least 1 year before the onset of their dementia would be labeled with PDD. If the Dis Mon 2007;53:302-308 0011-5029/2007 $32.00 ⫹ 0 doi:10.1016/j.disamonth.2007.02.007 302
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FIG 1. Hypothetical disease course in a PD patient who developed dementia at age of 80.
dementia preceded or occurred simultaneously with the onset of the Parkinsonism, then the dementia would be diagnosed as DLB. Thus, one can see the difficulties in interpreting the PDD prevalence data.
Prevalence of Dementia in Parkinson’s Disease Depending on the sample population and criteria used, the prevalence rate of PDD ranges from 10 to 40%.1,2 Risk factors for PDD have included: advanced age, severity of motor disease (especially bradykinesia), early levodopa associated confusion, and depression. Atypical neurological features at presentation were also found to be risk factors for developing dementia. For example, patients with early orthostatic hypotension or a symmetric presentation were at an increased risk of developing PDD.2 The association with age is consistently found in many studies. One study suggested that the prevalence of PDD in patients below the age of 50 was 0%, whereas in patients above the age of 80 it approached 70%.3 Another study found the prevalence of PDD in patients below the age of 70 to be 9%, whereas above the age of 70 the prevalence was 37%.4
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303
TABLE 1. Characteristics of cortical versus subcortical dementia
Cognitive
Executive dysfunction Personality Insight Mood disturbances
Cortical
Subcortical
Memory impairment Aphasia Apraxia Agnosia Visuospatial Dysfunction Late Preserved early Preserved until late Less common early Depression may occur
Memory impairment
Hallmark Early changes Can be impaired Depression Apathy Anxiety Emotional lability
Clinical, Neuropsychological, and Imaging Characteristic of Parkinson’s Disease Dementia Parkinson’s disease dementia is a subcortical dementia. The cardinal feature is a dysexecutive syndrome characterized by impaired problem solving, planning, concept formation, and set shifting (knowing when to stop one task and move to a different task). In addition, psychomotor slowing, memory retrieval deficits, and alterations in personality and mood are present. These characteristics are different from the cortical dementias like Alzheimer’s disease (AD), where cortical deficits such as aphasia, apraxia, amnesia, or agnosia are salient features (see Table 1). Disruption of the frontal–subcortical (fronto-striatal) circuits in PD is the likely cause for many of these behavioral and cognitive changes. For example, the dorsolateral prefrontal circuits (which project to the caudate and globus pallidus) are involved in executive function (planning, problem solving, organizing, and retrieving memories). The dorsolateral prefrontal circuits can be disrupted early in PD. Thus, even non-demented PD patients often have trouble with maintaining sets, planning, and retrieving memories.5 The anterior cingulate circuit is another circuit that is often disrupted early. This circuit originates in the anterior cingulate gyrus and projects to the ventral striatum. Its disruption leads to apathy and decreased motivation, which are common behavioral symptoms noted in PD. Functional imaging studies such as single photon emission CT (SPECT) which reveals how various regions of the brain take up blood flow have been used to help in the diagnosis of PDD. SPECT studies have shown either frontal hypoperfusion or bilateral temporoparietal deficits6 in PDD. 304
DM, May 2007
TABLE 2. Diagnostic criteria for Lewy Body Dementia A. Dementia B. At least two of the following major characteristics 1. Parkinsonism 2. Fluctuations in alertness and cognition 3. Presence of fully formed visual hallucinations 4. Rapid eye movement sleep behavior disorder C. Minor criteria supportive of the diagnosis 1. Neuroleptic hypersensitivity 2. Syncope 3. Delusions 4. Repeated falls The diagnostic criteria are based on the Consortium on Dementia with Lewy Bodies and the Mayo clinic adaptation.
PET scanning has shown more global deficits in glucose metabolism with the most severe hypometabolism in the temporoparietal areas (very similar to AD). A more recent study using PET scans7 suggested that hypometabolism in the visual association areas (occipital lobes) helps differentiate PDD from AD.
Dementia With Lewy Bodies (DLB) The most commonly used clinical criteria for the diagnosis of probable DLB are noted in Table 2. One of the key clinical characteristics in DLB is a change in alertness/arousal. Many DLB patients exhibit severe excessive daytime sleepiness. They experience wide fluctuations in their attention and concentration. Because of these fluctuations, families will often comment that the patient has very obvious “good and bad days.” Another important clinical feature is the association of DLB with rapid eye movement sleep behavior disorder (RBD). RBD may be present in greater than 50% of DLB patients. In fact, RBD is often a precursor of DLB.8 As noted previously, there is increasing controversy as to whether DLB and PDD are separate illnesses or part of a continuum of disease. The hallmark neuropathologic feature for both dementias involves the presence of alpha-synuclein positive cortical Lewy bodies.9 The amount of concomitant AD pathology in PDD is typically less than that in classic DLB. The clinical features of PDD are similar to those of DLB, with attentional deficits, executive abnormalities, and frequent concomitant neuropsychiatric disturbances, including visual hallucinations and delusions. The neuropsychological deficits of DLB are usually distinct from those DM, May 2007
305
of Alzheimer’s disease. The typical DLB patient performs better on confrontational naming and memory tests than does the AD patient. DLB patients have worse executive functions than AD patients. DLB patients are also significantly more apathetic than AD patients.
Treatment Non-Pharmacological Therapy Education of the caregiver regarding the realities of disease progression is important. Providing the caregiver and patient with locally available community resources such as respite care and daycare centers, support groups, etc. can result in immeasurable benefits including stress reduction. Furthermore, the elimination of non-essential medications, especially those that are sedating may improve overall functioning. Notably, although anticholinergics are sometimes used early in the course of PD for tremor control, they should be eliminated as soon as possible since they can negatively impact cognition. A recent study by Perry et al. found that amyloid plaque densities were more than 2.5-fold higher in PD patients who were chronically treated with anticholinergic medications versus those whose exposure was limited.10 In addition, neurofibrillary tangle densities were also the greatest in chronic users of anticholinergic medications. Amyloid plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer’s disease. Based on these data, one can speculate as to whether anticholinergic drugs should be used at all in PD patients since they may increase the possibility of AD changes in the brain.
Pharmacological Therapy Levodopa probably has very little benefit for cognition in PDD. Some early dementia patients may note mild improvements in attention, mood, and arousal with levodopa. However, in the more advanced dementia patients, levodopa may worsen cognition by promoting hallucinations, delusions, and confusion. There is some evidence that the ascending cholinergic pathways are damaged in PDD. In autopsy studies, severe cell loss has been noted in the nucleus basalis of Meynert (which is the area that provides cholinergic innervation of the cerebral cortex).11 Additionally, choline acetyltransferase (ChAT) activity is decreased to 40 to 60% of control values in frontal, temporal, and hippocampal cortex.12 The loss of ChAT activity and cells in basal nucleus of Maynert correlates with the level of cognitive impairment and the presence of dementia.12 Animal and human studies 306
DM, May 2007
have shown that the cholinergic networks are involved in many cognitive functions; especially attention and memory. Therefore, based on the finding of cholinergic deficits in PD, there is good rationale for using acetylcholinesterase inhibitors in individuals with PDD. A 10-week double blind, placebo controlled study using donepezil in PDD patients revealed an increase in the MMSE by almost 2 points in the treated group versus the placebo.13 A recent placebo controlled study using rivastigmine did also find improvements in cognition and neuropsychiatric features in PDD patients.14 There were also improvements noted on a global impression scale suggesting “real world” practical benefits and not just improvements on paper and pencil tests. There is only one published double-blind placebo controlled study using a cholinesterase inhibitor in LBD.15 This study used 120 patients with probable LBD. The patients on rivastigmine did significantly better than the placebo patients on four measures on the Neuropsychiatric inventory (NPI): apathy, anxiety, delusions, and hallucinations. Although mental speed also improved, there was no differences noted on the MMSE between the 2 groups.
Conclusion Parkinson’s disease dementia is an important risk factor for nursing home placement and does increase mortality independent of the severity of motor symptoms.16 Therefore, early recognition and treatment of the cognitive deficits in Parkinson’s disease is important in order to improve quality of life for the patient, decrease the caregiver burden, and potentially delay nursing home placement.
REFERENCES 1. 2. 3.
4. 5. 6. 7.
Cummings JL. Intellectual impairment in Parkinson’s disease: clinical, pathologic, and biochemical correlates. J Geriatr Psychiatry Neurol 1988;1:24-36. Aarsland D, Andersen K, Larsen JP, et al. Risk of dementia in Parkinson’s disease: a community based prospective study. Neurology 2001;56:730-6. Mayeux R, Denaro J, Hemenegildo N, et al. A population-based investigation of Parkinson’s disease with and without dementia: relationship to age and gender. Arch Neurol 1992;49:492-7. Reid WG, Hely MA, Morris JG, et al. A longitudinal study of Parkinson’s disease: clinical and neuropsychological correlates of dementia. J Clin Neuroci 1996;3:327-33. Rashkin SA, Borod JC, Tweedy J. Neuropsychological aspects of Parkinson’s disease. Neuropsychol Rev 1990;1:185-219. Bissesser S, Tissingh G, Wolters EC. CBF SPECT in Parkinson’s disease patients with mental dysfunction. J Neural Transm Suppl 1997;50:25-30. Firbank MJ, Colloby SJ, Burn DJ, et al. Regional Cerebral blood flow in Parkinson’s disease with and without dementia. Neuroimage 2003;20:1309-19.
DM, May 2007
307
8. 9. 10. 11. 12.
13.
14. 15.
16.
308
Boeve BF, Silber MH, Ferman TJ. REM sleep behavior disorder in Parkinson’s disease and dementia with Lewy bodies. J Geriatr Psychiatry Neurol 2004;17(3):146-57. Hurtig HI, Trojanowski JQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 2000;54:1916-21. Perry EK, Kilford L, Lees AJ, et al. Increased Alzheimer Pathology in Parkinson’s Disease related to antimuscarinic drugs. Ann Neurol 2003;54(2):144-6. Candy JM, Perry RH, Perry EK, et al. Pathological changes in the nucleus of Maynert in Alzheimer’s and Parkinson’s disease. J Neurol Sci 1983;59:277-89. Mattila PM, Roytta M, Lonnberg P, et al. Choline acetyltransferase activity and striatal dopamine receptors in Parkinson’s disease in relation to cognitive impairment. Acta Neuropathol 2001;102:160-6. Aarsland D, Larsen JP, Janvin C, et al. Donepezil treatment in Pakinson’s disease with dementia; a double blind, placebo-controlled crossover study. J Neurol Neurosurg Psychiatry 2002;72:708-12. Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004;351(24):2547-9. McKeith I, Del Ser T, Spano P-F, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomized, double blind, placebo controlled international study. Lancet 2000;356:2031-6. Levy G, Tang MX, Cote LJ, et al. Motor impairment in PD: relationship to incident dementia and age. Neurology 2000;55:539-44.
DM, May 2007
DM, May 2007
FIG 1. Hypothetical disease course in a PD patient who developed dementia at age of 80.
dementia preceded or occurred simultaneously with the onset of the Parkinsonism, then the dementia would be diagnosed as DLB. Thus, one can see the difficulties in interpreting the PDD prevalence data.
Prevalence of Dementia in Parkinson’s Disease Depending on the sample population and criteria used, the prevalence rate of PDD ranges from 10 to 40%.1,2 Risk factors for PDD have included: advanced age, severity of motor disease (especially bradykinesia), early levodopa associated confusion, and depression. Atypical neurological features at presentation were also found to be risk factors for developing dementia. For example, patients with early orthostatic hypotension or a symmetric presentation were at an increased risk of developing PDD.2 The association with age is consistently found in many studies. One study suggested that the prevalence of PDD in patients below the age of 50 was 0%, whereas in patients above the age of 80 it approached 70%.3 Another study found the prevalence of PDD in patients below the age of 70 to be 9%, whereas above the age of 70 the prevalence was 37%.4
DM, May 2007
303
TABLE 1. Characteristics of cortical versus subcortical dementia
Cognitive
Executive dysfunction Personality Insight Mood disturbances
Cortical
Subcortical
Memory impairment Aphasia Apraxia Agnosia Visuospatial Dysfunction Late Preserved early Preserved until late Less common early Depression may occur
Memory impairment
Hallmark Early changes Can be impaired Depression Apathy Anxiety Emotional lability
Clinical, Neuropsychological, and Imaging Characteristic of Parkinson’s Disease Dementia Parkinson’s disease dementia is a subcortical dementia. The cardinal feature is a dysexecutive syndrome characterized by impaired problem solving, planning, concept formation, and set shifting (knowing when to stop one task and move to a different task). In addition, psychomotor slowing, memory retrieval deficits, and alterations in personality and mood are present. These characteristics are different from the cortical dementias like Alzheimer’s disease (AD), where cortical deficits such as aphasia, apraxia, amnesia, or agnosia are salient features (see Table 1). Disruption of the frontal–subcortical (fronto-striatal) circuits in PD is the likely cause for many of these behavioral and cognitive changes. For example, the dorsolateral prefrontal circuits (which project to the caudate and globus pallidus) are involved in executive function (planning, problem solving, organizing, and retrieving memories). The dorsolateral prefrontal circuits can be disrupted early in PD. Thus, even non-demented PD patients often have trouble with maintaining sets, planning, and retrieving memories.5 The anterior cingulate circuit is another circuit that is often disrupted early. This circuit originates in the anterior cingulate gyrus and projects to the ventral striatum. Its disruption leads to apathy and decreased motivation, which are common behavioral symptoms noted in PD. Functional imaging studies such as single photon emission CT (SPECT) which reveals how various regions of the brain take up blood flow have been used to help in the diagnosis of PDD. SPECT studies have shown either frontal hypoperfusion or bilateral temporoparietal deficits6 in PDD. 304
DM, May 2007
TABLE 2. Diagnostic criteria for Lewy Body Dementia A. Dementia B. At least two of the following major characteristics 1. Parkinsonism 2. Fluctuations in alertness and cognition 3. Presence of fully formed visual hallucinations 4. Rapid eye movement sleep behavior disorder C. Minor criteria supportive of the diagnosis 1. Neuroleptic hypersensitivity 2. Syncope 3. Delusions 4. Repeated falls The diagnostic criteria are based on the Consortium on Dementia with Lewy Bodies and the Mayo clinic adaptation.
PET scanning has shown more global deficits in glucose metabolism with the most severe hypometabolism in the temporoparietal areas (very similar to AD). A more recent study using PET scans7 suggested that hypometabolism in the visual association areas (occipital lobes) helps differentiate PDD from AD.
Dementia With Lewy Bodies (DLB) The most commonly used clinical criteria for the diagnosis of probable DLB are noted in Table 2. One of the key clinical characteristics in DLB is a change in alertness/arousal. Many DLB patients exhibit severe excessive daytime sleepiness. They experience wide fluctuations in their attention and concentration. Because of these fluctuations, families will often comment that the patient has very obvious “good and bad days.” Another important clinical feature is the association of DLB with rapid eye movement sleep behavior disorder (RBD). RBD may be present in greater than 50% of DLB patients. In fact, RBD is often a precursor of DLB.8 As noted previously, there is increasing controversy as to whether DLB and PDD are separate illnesses or part of a continuum of disease. The hallmark neuropathologic feature for both dementias involves the presence of alpha-synuclein positive cortical Lewy bodies.9 The amount of concomitant AD pathology in PDD is typically less than that in classic DLB. The clinical features of PDD are similar to those of DLB, with attentional deficits, executive abnormalities, and frequent concomitant neuropsychiatric disturbances, including visual hallucinations and delusions. The neuropsychological deficits of DLB are usually distinct from those DM, May 2007
305
of Alzheimer’s disease. The typical DLB patient performs better on confrontational naming and memory tests than does the AD patient. DLB patients have worse executive functions than AD patients. DLB patients are also significantly more apathetic than AD patients.
Treatment Non-Pharmacological Therapy Education of the caregiver regarding the realities of disease progression is important. Providing the caregiver and patient with locally available community resources such as respite care and daycare centers, support groups, etc. can result in immeasurable benefits including stress reduction. Furthermore, the elimination of non-essential medications, especially those that are sedating may improve overall functioning. Notably, although anticholinergics are sometimes used early in the course of PD for tremor control, they should be eliminated as soon as possible since they can negatively impact cognition. A recent study by Perry et al. found that amyloid plaque densities were more than 2.5-fold higher in PD patients who were chronically treated with anticholinergic medications versus those whose exposure was limited.10 In addition, neurofibrillary tangle densities were also the greatest in chronic users of anticholinergic medications. Amyloid plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer’s disease. Based on these data, one can speculate as to whether anticholinergic drugs should be used at all in PD patients since they may increase the possibility of AD changes in the brain.
Pharmacological Therapy Levodopa probably has very little benefit for cognition in PDD. Some early dementia patients may note mild improvements in attention, mood, and arousal with levodopa. However, in the more advanced dementia patients, levodopa may worsen cognition by promoting hallucinations, delusions, and confusion. There is some evidence that the ascending cholinergic pathways are damaged in PDD. In autopsy studies, severe cell loss has been noted in the nucleus basalis of Meynert (which is the area that provides cholinergic innervation of the cerebral cortex).11 Additionally, choline acetyltransferase (ChAT) activity is decreased to 40 to 60% of control values in frontal, temporal, and hippocampal cortex.12 The loss of ChAT activity and cells in basal nucleus of Maynert correlates with the level of cognitive impairment and the presence of dementia.12 Animal and human studies 306
DM, May 2007
have shown that the cholinergic networks are involved in many cognitive functions; especially attention and memory. Therefore, based on the finding of cholinergic deficits in PD, there is good rationale for using acetylcholinesterase inhibitors in individuals with PDD. A 10-week double blind, placebo controlled study using donepezil in PDD patients revealed an increase in the MMSE by almost 2 points in the treated group versus the placebo.13 A recent placebo controlled study using rivastigmine did also find improvements in cognition and neuropsychiatric features in PDD patients.14 There were also improvements noted on a global impression scale suggesting “real world” practical benefits and not just improvements on paper and pencil tests. There is only one published double-blind placebo controlled study using a cholinesterase inhibitor in LBD.15 This study used 120 patients with probable LBD. The patients on rivastigmine did significantly better than the placebo patients on four measures on the Neuropsychiatric inventory (NPI): apathy, anxiety, delusions, and hallucinations. Although mental speed also improved, there was no differences noted on the MMSE between the 2 groups.
Conclusion Parkinson’s disease dementia is an important risk factor for nursing home placement and does increase mortality independent of the severity of motor symptoms.16 Therefore, early recognition and treatment of the cognitive deficits in Parkinson’s disease is important in order to improve quality of life for the patient, decrease the caregiver burden, and potentially delay nursing home placement.
REFERENCES 1. 2. 3.
4. 5. 6. 7.
Cummings JL. Intellectual impairment in Parkinson’s disease: clinical, pathologic, and biochemical correlates. J Geriatr Psychiatry Neurol 1988;1:24-36. Aarsland D, Andersen K, Larsen JP, et al. Risk of dementia in Parkinson’s disease: a community based prospective study. Neurology 2001;56:730-6. Mayeux R, Denaro J, Hemenegildo N, et al. A population-based investigation of Parkinson’s disease with and without dementia: relationship to age and gender. Arch Neurol 1992;49:492-7. Reid WG, Hely MA, Morris JG, et al. A longitudinal study of Parkinson’s disease: clinical and neuropsychological correlates of dementia. J Clin Neuroci 1996;3:327-33. Rashkin SA, Borod JC, Tweedy J. Neuropsychological aspects of Parkinson’s disease. Neuropsychol Rev 1990;1:185-219. Bissesser S, Tissingh G, Wolters EC. CBF SPECT in Parkinson’s disease patients with mental dysfunction. J Neural Transm Suppl 1997;50:25-30. Firbank MJ, Colloby SJ, Burn DJ, et al. Regional Cerebral blood flow in Parkinson’s disease with and without dementia. Neuroimage 2003;20:1309-19.
DM, May 2007
307
8. 9. 10. 11. 12.
13.
14. 15.
16.
308
Boeve BF, Silber MH, Ferman TJ. REM sleep behavior disorder in Parkinson’s disease and dementia with Lewy bodies. J Geriatr Psychiatry Neurol 2004;17(3):146-57. Hurtig HI, Trojanowski JQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 2000;54:1916-21. Perry EK, Kilford L, Lees AJ, et al. Increased Alzheimer Pathology in Parkinson’s Disease related to antimuscarinic drugs. Ann Neurol 2003;54(2):144-6. Candy JM, Perry RH, Perry EK, et al. Pathological changes in the nucleus of Maynert in Alzheimer’s and Parkinson’s disease. J Neurol Sci 1983;59:277-89. Mattila PM, Roytta M, Lonnberg P, et al. Choline acetyltransferase activity and striatal dopamine receptors in Parkinson’s disease in relation to cognitive impairment. Acta Neuropathol 2001;102:160-6. Aarsland D, Larsen JP, Janvin C, et al. Donepezil treatment in Pakinson’s disease with dementia; a double blind, placebo-controlled crossover study. J Neurol Neurosurg Psychiatry 2002;72:708-12. Emre M, Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004;351(24):2547-9. McKeith I, Del Ser T, Spano P-F, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomized, double blind, placebo controlled international study. Lancet 2000;356:2031-6. Levy G, Tang MX, Cote LJ, et al. Motor impairment in PD: relationship to incident dementia and age. Neurology 2000;55:539-44.
DM, May 2007