Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York.
Disclosure: Dr. Kennedy is a consultant to Myriad; is on the speaker’s bureaus of Forest and Pfizer; and has received grant support from Forest, Myriad, Novartis, Pfizer, and Takeda.
Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: email@example.com.
Parkinson’s disease affects as many as 1 million Americans and with advanced age is complicated by dementia in a majority of cases. However, the recognition of cognitive impairment in Parkinson’s disease is made complicated by the predominance of motor symptoms and a neuropsychiatric profile that differs from the more common dementia of the Alzheimer’s type. Differentiating the decline in personal and social activities due to cognitive impairment rather than preexisting movement disorder is difficult. Several expert bodies have addressed the use of cholinesterase inhibitors for the dementia of Parkinson’s disease, but the evidence base is far less substantial than that which exists for Alzheimer’s disease. Although most patients with Parkinson’s disease dementia should be offered a trial of anti-cholinesterase therapy, particularly those experiencing hallucinations, dramatic benefits are not common. Temporary symptomatic relief rather than disease modification is the most that can be expected. As a result, treatment should be presented as an option rather than an imperative.
Parkinson’s disease has a mean age of onset of 57 years and a prevalence of 1% to 2% among adults ≥60 years of age. There may be as many as 1 million Americans with the illness.1 It is manifested by bradykinesia, rigidity, resting tremor, postural instability, frozen gait disorder, and flexed posture. The progression and severity of Parkinson’s disease varies widely and the associated motor disability may be substantially reduced by numerous medications singly or in combination. The goal is an increase in brain dopamine through either enhanced production or reduced breakdown of the molecule.2 The disease begins as a movement disorder, but with advancing age is complicated by dementia in as many as 80% of patients. The characteristic frozen facial expression, slowed cognition (bradyphrenia), fluctuation in attention, and motor impairment compounded by depression and hallucinations make the assessment of possible dementia challenging. In addition, dopaminergic medications precipitate hallucinations with recognized frequency. Although medication to treat the dementia of Parkinson’s disease is most often modestly effective for patients in aggregate, failure to recognize dementia means that the minority of individuals who might receive substantial benefit will not be offered a therapeutic trial. As a result, practitioners need guidance to efficiently assess cognitive decline among people with Parkinson’s disease as well as realistic expectations for the benefits of dementia treatment.
Similarities and Differences with Other Dementias
Loss of dopaminergic neurons in the substantia nigra is the hallmark of Parkinson’s disease and the basis for the use of dopamine agonists. In contrast, neuronal dropout in the entorhinal cortex and hippocampus are seen in Alzheimer’s disease. Yet, similar to Alzheimer’s disease, cholinergic deficits are common in Parkinson’s disease and parallel the decline in cognition. Hematoxilyn and eosin staining neuronal inclusions known as Lewy bodies occur in both Parkinson’s and Lewy body dementia but not in Alzheimer’s disease. However, amyloid plaques and neurofibrillary tangles thought to be the signature pathology of Alzheimer’s disease commonly occur in both Parkinson’s disease and Lewy body dementia as well, though less extensively. Differences between Alzheimer’s disease and the dementia of Parkinson’s and Lewy body disease detected by imaging studies, whether structural (magnetic resonance imaging [MRI], computerized axial tomography) or metabolic (positron emission tomography, single photon emission computed tomography, functional MRI), are too subtle for use in clinical diagnosis.
Clinical features of Alzheimer’s, Parkinson’s, and Lewy body dementia overlap as severity progresses but significant differences are apparent in the early stages (Table 1).3-5 In Alzheimer’s disease, memory impairment is prominent with executive dysfunction, aphasia, apraxia, and anomia often present but less obvious. Apathy is more common than depression, but one or the other will be present in ~25% of affected individuals. Hallucinations occur in 10% of cases most often at the mid- to later stage of the disease.6 Severe motor impairments in gait, balance, muscle strength, and swallowing occur in the later stages. In Parkinson’s dementia, the movement disorder precedes the onset of cognitive impairment. Inattention, executive dysfunction, bradyphrenia, and visuospatial deficits may be more noticeable than impaired memory. Hallucinations are four times more frequent and depressive symptoms somewhat less so than in Alzheimer’s disease. Irritability, anger, aggression, and delusions may be more prominent in Alzheimer’s disease. More severe postural instability and gait disorder predict the onset of dementia among people with Parkinson’s disease. Incident hallucinations also predict the subsequent emergence of dementia.3
Hallucinations are also a distinguishing feature of Lewy body dementia. Marked fluctuations in attentiveness and mild impairment in memory—both of which precede the appearance of rigidity, tremor, postural instability and gait disorder—distinguish Lewy body dementia from that of Parkinson’s disease. Unanticipated sensitivity to neuroleptic-induced extrapyramidal symptoms also indicates that Lewy body dementia, rather than Alzheimer’s disease with hallucinations, is the correct diagnosis.
Efficient Screening Procedures
Not every older adult should be screened for cognitive impairment. Screening in clinical practice is predicated on the recognition of cognitive decline interfering with personal or social activities by the patient, family, or clinician. However, Parkinson’s disease often impacts social and personal activities as a result of motor impairment. Thus, personal responsibilities may already have been abandoned before impaired cognition could have made noticeable contribution. Given the elevated frequency with which dementia emerges in Parkinson’s disease, the practitioner’s concern for impairment should be heightened. When hallucinations, apathy, or excessive daytime drowsiness appear after a period of stable treatment, dementia should be suspected.
In a 2007 review7 on the diagnosis and treatment of Parkinson’s disease dementia, the Movement Disorders Society’s taskforce recommended the Mini-Mental State Examination (MMSE) as a global measure of cognitive performance in which a score <26 indicates impairment. They also suggested a number of screening procedures to detect impairments in specific cognitive domains. These included domains of attention, visuo-constructive ability, executive function, and memory. Parkinson’s disease patients with impairments in more than one domain associated with deterioration in personal care or social activities would meet the criteria for dementia. Attention would be assessed with the serial seven subtraction task from the MMSE or by asking the patient to list months of the year in reverse order. In either test, two errors or omissions is considered evidence of impairment. For executive dysfunction, impairment is defined as failure to recite nine examples from the lexical category of words starting with the letter “S” in one minute or inability to draw a clock with the time set at 10 past 2. Visuo-constructional impairment is defined by inability to copy two intersecting pentagons from the MMSE. Impairment in memory is defined by failure to recall all three words from the MMSE’s registration and recall task. The review also provides a comprehensive listing of neuropsychological instruments that have been used to assess cognition among people with Parkinson’s disease.
However, busy practitioners may find the copyrighted MMSE and clock drawing cumbersome. As an alternative, the Memory Impairment Screen and the oral version of the Trail Making Test for executive function do not require paper and pencil, may be administered by phone, and are quite brief. Both have been validated as screening measures for use in population assessments of dementia.8 For the Memory Impairment Screen, the subject is tasked to repeat and remember four words (eg, apple, table, penny, spoon) given in sequence at 1-second intervals and then asked to recall each when prompted with a category cue (eg, fruit, furniture, money, utensil). The registration phase may be repeated up to five times before moving to the next test. Next, the subject is asked to recite the alphabet from “A to Z” and then to count from 1–25. The person is then asked to continue the sequence, which the examiner starts with “One A, Two B, Three C, Four ?” Subjects making two errors as they reach “M 13” are considered to exhibit executive impairment. Following the Trail Making test, the examiner returns to the Memory Impairment Screen by asking the subject to recall the four words that were previously rehearsed. Allowing 1 minute for free recall the examiner then provides the category cue for each word not remembered spontaneously. Words recalled freely receive a score of 2; those that required the cue for recall receive a score of 1. A total score of 4 is predictive of dementia. A free demonstration of the Trail Making Test, clock-drawing test, and other measures of executive dysfunction can be accessed on the Internet.6 Baseline assessment of cognition with simple screening procedures following the diagnosis of Parkinson’s disease will set the stage for detection of genuine impairment should warning signs of dementia emerge.
Responsiveness to Cholinesterase Inhibitors
The evidence base regarding the efficacy of pharmacotherapy for Parkinson’s disease dementia is limited9 but more extensive if one considers the illness to be part of a spectrum including dementia with Lewy bodies.10 In the largest randomized controlled trial to date, Emre and colleagues11 conducted a pivotal study of 541 people whose Parkinson’s disease was accompanied by mild-to-moderate dementia defined by MMSE score of 10–24. Patients were allocated to rivastigmine or placebo in a 2:1 ratio. Rivastigmine 1.5 mg was introduced and titrated to a maximum tolerated dose or 12 mg over 16 weeks. Exclusion criteria included a history of major depressive disorder, use of cholinesterase inhibitor or anticholinergic drug, or change in Parkinson’s disease medication within 4 weeks of enrollment. The initiation of a psychotropic medication during the study with the exception of an antipsychotic for an acute episode of psychosis was forbidden. The mean age of study participants was slightly >72 years and 66% were men. Forty percent were diagnosed with a mental disorder in addition to dementia.
Greater than 25% of participants were taking an antipsychotic at baseline, 25% were on an antidepressant, 20% were on a benzodiazepine or sedative hypnotic, and 95% were taking levodopa. The two primary efficacy measures were the Alzheimer’s Disease Assessment Scale (ADAS-cog) and the Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change (ADCS-CGIC). Each were separately assessed by trained raters blind to the assessment outcome. The ADAS-cog is a 70-point measure of cognitive performance. The ADCS-CGIC is a 7-point categorical scale anchored at baseline where “1” equals marked improvement, “7” equals marked worsening, and “4” denotes no change. Detectable changes that were not clinically meaningful were defined as minimal; changes associated with obvious clinical improvement were defined as moderate. Secondary efficacy measures included the ADCS measure of activities of daily living, the Neuropsychiatric Inventory, the MMSE, tests of attention and reaction time, and tests of executive function as measured by letter-category verbal fluency and clock-drawing.
At the end of dose titration, >50% of treated participants were taking rivastigmine 9–12 mg/day. Of those completing the study, 72% were in the rivastigmine group and 82% in placebo. Adverse events accounted for most of the premature withdrawals in both groups. Nausea (29%), vomiting (16.6%), and worsening tremor (10.2%) were significantly more frequent among the rivastigmine group. Of the efficacy measures comparing rivastigmine to placebo, at 24 weeks all were statistically significant. There was an 11.7% difference in cognitive performance (ADAS-cog) between drug and placebo groups. Clinically meaningful (marked to moderate) improvement was seen in 14.5% of placebo and 19.8% of the rivastigmine group. Clinically meaningful deterioration was seen in 23.1% of placebo and 13.0% of the rivastigmine group. Among the secondary measures of disability, neuropsychiatric symptoms, cognition, and executive functions all showed improvement with rivastigmine and decline with placebo with the differences being statistically significant. Of note, 34.6% of placebo and 45.4% of the rivastigmine group exhibited a ≥30% improvement in neuropsychiatric symptoms. Hallucinations disruptive enough to be considered adverse events occurred in 9.5% of placebo and 4.7% of rivastigmine participants, and the difference was significant.
Emre and colleagues11 conclude that their findings among patients with Parkinson’s disease and dementia are similar to those seen in studies of cholinesterase inhibitors for Alzheimer’s disease. Benefits are modest, representing a 6-month reprieve in the course of symptoms without genuine disease modification. However, close to one in five patients will show dramatic benefit obvious to the family and the clinician alike. Indeed, Press12 advocates the family’s impression of benefit over formal neuropsychological measures to assess the effectiveness of treatment. Given that benefits if apparent at all emerge within the first weeks of treatment, the most realistic expectation for patient and family is a 60–90-day trial of therapy rather than an open-ended course. Also noteworthy were the relatively more substantial benefits of rivastigmine for neuropsychiatric symptoms, including hallucinations, a finding similar to McKeith and colleagues’10 rivastigmine study of 120 patients with Lewy body dementia. The number of study participants receiving a neuroleptic during the Emre and colleagues11 study was considerable. Low doses of atypical antipsychotics such as olanzapine, quetiapine, and clozapine were initially used to control levodopa-induced hallucinations because they were less likely than typical antipsychotics to induce extrapyramidal symptoms.12
However, the 2005 Food and Drug Administration warning of increased mortality when prescribed to patients with dementia11 amplified by more recent reports14,15 raise the threshold at which these agents may be considered for psychosis in dementia nearly out of reach. Clearly, a trial of cholinesterase therapy should be recommended to reduce hallucinations of dementia in Parkinson’s disease before a neuroleptic is offered. The transdermal rivastigmine patch with less frequent gastrointestinal effects, not available at the time of Emre’s11 study, is an added advantage.16 It should be added that other cholinesterase inhibitors may be efficacious for the dementia of Parkinson’s disease but have not been subjected to large-scale trials. Nonetheless, the Cochrane Review and other sources17-20 find at least minimal evidence to support the use of donepezil as well (Table 2).
Dementia is such a frequent complication that every older patient with Parkinson’s disease should be screened for memory impairment and executive dysfunction, particularly if hallucinations emerge in the context of stable dopaminergic treatment. The impact of cholinesterase inhibitor therapy on cognition and activities of daily living will be obvious in only one patient in five. However, the reduction in hallucinations may be more robust. Consistent reports of elevated mortality associated with antipsychotics prescribed to people with dementia make cholinesterase inhibitor therapy preferable when hallucinations emerge. A 60–90-day trial of a cholinesterase inhibitor should be adequate to give the patient, family, and practitioner sufficient evidence on which to base a decision for ongoing treatment. In equivocal cases, the medication can be reinstituted if visible decline is observed following discontinuation.8 With adverse reactions and lack of efficacy taken into account, 40% to 60% of treated patients would withdraw from cholinesterase inhibitor therapy. However, lacking predictors of treatment responsiveness and balancing in the safety of cholinesterase inhibitor therapy, most patients with Parkinson’s disease dementia should be offered a trial of treatment. Practitioners’ zeal for treatment must be tempered by the realization that temporary symptomatic relief rather than disease modification is the most that can be expected. As a result, treatment should be presented as an option rather than an imperative. PP
1. Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson’s disease. Mov Disord. 2002;18(1):19-31.
2. LeWitt PA. Levodopa for the treatment of Parkinson’s disease. N Engl J Med. 2008;359(23):2468-2476.
3. Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with parkinson’s disease movement disorders. Mov Disord. 2007;22(12):1689-1707.
4. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
5. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005;65(12):1863-1872. Erratum in: Neurology. 2005 ;65(12):1992.
6. Lyketsos CG, Sheppard JM, Steinberg M, et al. Neuropychiatric disturbance in Alzheimer’s disease clusters into three groups: the Cache County study. Int J Geriat Psychiatry. 2001;16(11):1043-1053.
7. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the Movement Disorder Society Task Force. Mov Disord. 2007;22(16);2314-2324.
8. Kennedy GJ, Smyth CA. Screening older adults for executive dysfunction: an essential refinement in the assessment of cognitive impairment. American Journal of Nursing. 2008;108(12):60-69.
9. Poewe W, Gauthier S, Aarsland, et al. Diagnosis and management of Parkinson’s disease dementia. Int J Clin Pract. 2008;62(10);1581-1587.
10. McKeith I, Del Ser T, Spano P, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomized, double blind, placebo controlled international study. Lancet. 2000;356(9247):2031-2036.
11. Emre M, Aarsland, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Eng J Med. 2004;351(24):2509-2518.
12. Press DZ. Parkinson’s disease dementia–A first step? N Engl J Med. 2004;351:(24)2547-2549.
13. Kennedy GJ. Caution vs. closure: the use of atypical antipsychotics for the treatment of behavioral disturbances in dementia. Primary Psychiatry. 2005;12(9):16-19.
14. Ballard C, Hanney ML, Theodoulou M, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial. Lancet Neurol. 2009;8(2):151-157.
15. Ray WA, Chung CP, Murray KT, Hall K, Stein CM. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Eng J Med. 2009;360(3):225-235.
16. Lefèvre G, Pommier F, Sedek G, et al. Pharmacokinetics and bioavailability of the novel rivastigmine transdermal patch versus rivastigmine oral solution in healthy elderly subjects. J Clin Pharmacol. 2008;48(2):246-252.
17. Maidment I, Fox C, Boustani M. Cholinesterase inhibitors for Parkinson’s disease dementia. Cochrane Database Syst Rev. 2006;(1):CD004747.
18. Ravina B, Putt M, Siderowf A, et al. Donepezil for dementia in Parkinson’s disease: a randomised, double blind, placebo controlled crossover study. J Neurol Neurosurg Psychiatry. 2005;76(7):934-939.
19. Aarsland D, Laake K, Larsen JP, Janvin C. Donepezil for cognitive impairment in Parkinson’s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry. 2002;72(6):708-712.
20. Leroi I, Brandt J, Reich SG, et al. Randomized placebo-controlled trial of donepezil in cognitive impairment in Parkinson’s disease. Int J Geriatr Psychiatry. 2004;19(1):1-8.