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Emerging Directions in Cholinergic Therapy

Accurate Diagnosis of Dementia with Lewy Bodies and Parkinson’s Disease Dementia

Ian G. McKeith, MD, FRCPsych, Professor of Old Age Psychiatry at the Institute for Ageing and Health at the University of Newcastle upon Tyne, in the United Kingdom, stated that dementia with Lewy bodies (DLB), which accounts for 15%–20% of all dementia in the elderly, is characterized by progressive cognitive decline, involving impairment of occupational and social functioning, attentional deficits, and visuospatial dysfunction. Approximately 75% of patients with DLB also experience extrapyramidal symptoms, which can be similar to the symptoms of Parkinson’s disease (PD).
Accurate diagnosis of DLB is critical because the specific management needs of patients with DLB or PD dementia (PDD) vary according to the

Criteria for Diagnosing Probable DLB
A diagnosis of DLB may be established if cognitive impairment is present in addition to at least two other features. These include fluctuating cognition with pronounced variations in attention and arousal, recurrent visual hallucinations, and spontaneous motor features of parkinsonism. Although features that are common in DLB, such as falls and systematized delusions, support a diagnosis of DLB, they lack specificity. Patients often do not have all of these features or may have additional pathologic conditions, such as Alzheimer’s disease (AD). Therefore, many patients with DLB are not recognized.

How Can We Improve Diagnosis of DLB?
An accurate differential diagnosis of DLB requires a comprehensive assessment of the patient, with informant history and physical and mental state examinations. Clinical experience with DLB is limited and a clear definition of the fluctuations in cognition is lacking. However, various assessment scales are available for improving the measurement of these fluctuations.

With the One-Day Fluctuation Assessment Scale, healthcare professionals question an informant about various features (e.g., falls, attention) that took place over the previous 24 hours (Walker, et al. Brit J Psychiatr. 2000;177:252). Alternatively, an experienced clinician may question an informant about the severity and frequency of fluctuations over the previous month (Walker, et al.). However, the best approach, Dr. McKeith believes, is to measure the fluctuations in cognition and attentional performance and how they vary. For example, in a test that records choice reaction over time passed, patients with DLB clearly were attentionally impaired compared with AD patients. Moreover, the fluctuations appeared to occur on a second-by-second basis.

Techniques Used for Differential Diagnoses
Neuroimaging may be used to differentiate among the various forms of dementia. For example, neuroimaging has demonstrated that AD patients have pronounced hippocampal atrophy, whereas individuals with DLB do not (Barber, et al. Neurology. 2000;54:1304). As determined by single photon emission computed tomography (SPECT), occipital hypoperfusion was markedly greater in patients with DLB than in AD patients (Lobotesis, et al. Neurology. 2001;56(5): 643). Furthermore, the SPECT ligand FP-CIT has shown that DLB and PD are associated with a profound loss of nigrostriatal dopaminergic enervation, whereas AD is not. This finding suggests that PD and DLB may share a common underlying disease process.

Relationship Between DLB and PDD
According to current understanding, progression to cortical dementia is thought to occur as a result of additional Alzheimer’s symptoms. However, Dr. McKeith believes this is incorrect, because the PDD rates have been shown to be cumulative with time: The cumulative prevalence rate of PDD is 78% after 8 years (Aarsland, et al. Presentation. IPA, 2001). Moreover, these patients experience cognitive fluctuations and visual hallucinations that typically are associated with DLB (Apaydin, et al. Arch Neurol. 2002;59:101). Indeed, cortical Lewy body disease is believed to be a primary pathologic substrate for PDD (Apaydin, et al).

Distinguishing between DLB and PDD depends arbitrarily on when dementia develops in the PD patient. “In practice,” Dr. McKeith suggested, “clinicians should use the diagnosis that best fits the patient’s current state.”

Treatment Choices in Dementia with Lewy Bodies and Parkinson’s Disease Dementia

In her review of treatment options for dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), Donna L. Masterman, MD, Assistant Clinical Professor of Neurology at the David Geffen School of Medicine at UCLA, and Clinical and Research Core Director of the UCLA Alzheimer’s Disease Research Center in Los Angeles, California, noted that patients with DLB and PDD have significant cholinergic deficits, which represent a potential target for treatment. Dr. Masterman focused on the use of cholinesterase inhibitors and atypical antipsychotics in treating DLB and PDD.

Use of Cholinesterase Inhibitors in Treatment of DLB
Donepezil is reported to substantially improve behavioral symptoms and cognition in patients with DLB (Samuel, et al. Int J Geriatr Psychiatr. 2000;15:794). Similarly, rivastigmine, which inhibits both butyrylcholinesterase and acetylcholinesterase, significantly (P < 0.01 vs placebo) improved behavioral symptoms, particularly apathy, anxiety, delusions, and hallucinations in patients with DLB (McKeith, et al. Lancet. 2000;356:2031) (Figure 1). Marked improvements in attention and memory also were observed, and parkinsonian features did not worsen. These effects were sustained for more than 52 weeks (Grace, et al. Int Psychogeriatr. 2001;13(2):199). However, behavioral problems, particularly psychosis, remained. Therefore, the role of antipsychotic therapies was examined.

Use of Atypical Antipsychotics in the Treatment of DLB
Data on the use of atypical antipsychotics in patients with DLB are equivocal. Olanzapine has been associated with
significant reductions in delusions and hallucinations, with no significant worsening of parkinsonian symptoms or Mini-Mental State Examination scores (Cummings, et al. Dement Geriatr Cogn Disord. 2002;13(2):67). However, in an open-label study, 3 of 8 patients with DLB were unable to tolerate olanzapine because of worsening motor symptoms, and only 2 of 8 patients showed improvement in psychotic and behavioral symptoms (Walker, et al. Int J Geriatr Psychiatry. 1999;14(6):459).

Quetiapine use was associated with significant improvement of psychosis in 80% of patients with PD and 90% of patients with DLB, but resulted in mild motor worsening in 32% of PD patients and in 27% of patients with DLB (Fernandez, et al. J Clin Psychiatry. 2002;63:513). Thus, Dr. Masterman recommends that atypical antipsychotics be used infrequently and with caution in patients with DLB, particularly because such patients may be hypersensitive to these agents.

Potential Drug Classes Available for Treatment of PDD Cholinesterase Inhibitors
Emerging evidence indicates that cholinesterase inhibitors may be useful in treating PDD. Donepezil was significantly (P<0.05) better than placebo in improving cognitive performance, with no increase in parkinsonian symptoms during treatment (Aarsland, et al. J Neurol Neurosurg Psychiatry. 2002;72: 708). Likewise, rivastigmine significantly improved Alzheimer’s Disease Assess-ment Scale subscores for recognition (P = 0.007), remembering instructions (P = 0.008), and concentration (P = 0.005) in patients with PDD at 12 and 26 weeks (Giladi, et al. Acta Neurol Scand. In press). Moreover, parkinsonian symptoms did not worsen, and mild to moderate improvements were noted by patients, caregivers, and neurologists in their global clinical impressions (Giladi, et al).

In a separate study, PDD patients who received rivastigmine showed significant improvements in Neuropsy-
chiatric Inventory subscores for hallucinations and sleep (P < 0.02, P < 0.015, respectively) (Reading, et al. Mov Disord. 2001;16:1171).

Atypical Antipsychotics
Clozapine treatment may be helpful in reducing motor symptoms in PD, but multiple small studies indicate that use of the drug requires stringent monitoring because of possible agranulocytosis. Quetiapine appears to be better tolerated but may be less effective than clozapine. Mixed results were obtained regarding the effects of olanzapine on motor symptoms, and risperidone is not recommended because it may exacerbate motor symptoms (Friedman, et al. J Geriatr Psychiatry Neurol. 2002;15:156; Friedman, et al. Mov Disord. 2000;15 (2):201; Aarsland, et al. J Neuropsychiatry Clin Neurosci. 1999;11(3):392).

Summarizing the treatment options for PDD, Dr. Masterman observed that preliminary data suggest that cholines-terase inhibitors improve cognition and neuropsychiatric symptoms without worsening Parkinson’s motor symptoms. The use of atypical antipsychotics remains equivocal, and more clinical data are needed to determine their usefulness. Similarly, selective serotonin reuptake inhibitors also may be useful, but data on their use are lacking.

Optimizing Diagnosis and Treatment of Vascular Dementia

Vascular dementia accounts for 15% of the dementia cases reported in North America (Fratiglioni, et al. Drugs
. 1999;15(5):365), stated Martin R. Farlow, MD, Professor and Vice Chairman for Research in the Department of Neurology at Indiana University School of Medicine, in Indianapolis.

Dr. Farlow noted that vascular dementia and Alzheimer’s disease (AD) share several pathologic vascular features, and the role of risk factors for cerebrovascular disease may be more prominent than previously thought for both types of dementia. Indeed, these risk factors may be involved in >50% of AD. Moreover, patients with vascular dementia are now known to exhibit cholinergic deficits that may be as prominent as the deficit in AD patients.

Vascular Dementia Associated with Cholinergic Deficits Similar to Those of AD
The symptomatology of AD and vascular dementia show considerable overlap. In vascular dementia, cholinergic deficits may be related to subcortical ischemic changes involving cholinergic pathways (Scheltens. Aging (Milano). 2001;13(3):203). Postmortem studies in patients with vascular dementia demonstrated decreased levels of both choline and muscarinic receptors in the brain, and these deficits may correlate with the severity of the dementia (Gottfries, et al. Dementia. 1994;5:163; Wallin, et al. Acta Neurol Scand. 1989;79:397). Noting these similarities between AD and vascular dementia, Dr. Farlow described various criteria used to diagnose vascular dementia.

Diagnostic Criteria for Vascular Dementia
The many diagnostic criteria that exist for vascular dementia define different frequencies and clusters of patients, and therefore are not interchangeable (Knopman, et al. Neurology. 2001;56: 1143; Pohjasvaara, et al. Stroke. 2000;31:2952). Some criteria require a time correlation between loss of cognitive functioning and a vascular event (Roman, et al. Neurology. 1993;43:250), whereas others consider cognitive deficits with evidence of cerebrovascular disease that cause functional impairment. Thus, an accurate diagnosis requires correlating clinical, imaging, and eventually neuropathologic findings.

Treatment Options for Vascular Dementia
Before July 2000, no trials had convincingly demonstrated efficacy of a drug in treating ischemic vascular dementia (AAN Practice Parameter. Neurology. 2001;56:1154). However, recent data strongly suggest that cholinesterase inhibitors are useful for treating cognitive symptoms of vascular dementia and may be even more effective in AD patients with vascular risk factors.

In a large, multicenter trial of vascular dementia, donepezil 5 mg/d and 10 mg/d were associated with
significant (P = 0.002 and P < 0.001, respectively, vs placebo) improvements in scores for the Alzheimer’s Disease Assessment Scale-cognitive component (ADAS-cog) at week 24 (Pratt, et al. Poster. Springfield-ATT Meeting, 2002). Interestingly, unlike AD patients, individuals with vascular dementia did not experience further deterioration when they were receiving appropriate treatment.

Patients with subcortical vascular dementia who received rivastigmine 3–6 mg/d exhibited improved cognition and behavior at 12 months (P < 0.05, P < 0.001, respectively, vs cardioaspirin) (Moretti, et al. Poster. 2nd Intl Conf Vascular Dementia, 2002). Considerable reduction in caregiver stress also was observed (P < 0.01, P < 0.05 vs cardioaspirin and baseline, respectively).

In AD patients with vascular risk factors, rivastigmine 6–12 mg/d was associated with significant (P<0.001 vs placebo) mean changes from baseline in ADAS-cog scores at week 26 (Kumar, et al. Eur J Neurol. 2000;7:159). The level of response was greater in patients who had a history of or current hypertension. Similar trends in mean changes from baseline were observed in Progressive Deterioration Scores with rivastigmine 6–12 mg/d (P < 0.05, P < 0.001 vs placebo in patients without and with vascular risk factors, respectively).

Likewise, galantamine 24 mg/d had a modest beneficial effect on ADAS-cog scores among AD patients with cerebrovascular disease (P = 0.0006 vs placebo) and patients with vascular dementia (Erkinjuntti, et al. Lancet. 2002;359: 1283). Again, patients with vascular dementia who received placebo exhibited little deterioration compared with AD patients.

Finally, Dr. Farlow mentioned that memantine, a partial antagonist at the NMDA receptor, has been associated with modest improvements in ADAS-cog scores among patients with vascular dementia (P = 0.0016 vs placebo) (Orgogozo, et al. Stroke. 2002;33:1834). These results suggest another novel mechanism exists by which the cognitive deficits of vascular dementia may be treated.

Current Practice and Future Trends in Cholinergic Therapy

George T. Grossberg, MD, Samuel W. Fordyce Professor and Director of Geriatric Psychiatry at St. Louis University School of Medicine, in St. Louis, Missouri, explained that in the cholinergic system, the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) metabolize acetylcholine in the synapse (Adem. Acta Neurol Scand. 1992;139:69). Inhibition of these enzymes with cholinesterase inhibitors may be beneficial in treating Alzheimer’s disease (AD), which is associated with significant depletion of acetylcholine.

Up-Regulation and Dosing of Cholinesterase Inhibitors
Cholinesterase inhibitors are effective in treating dementia symptoms, but some compounds, such as donepezil and galantamine, exhibit up-regulation: their ability to inhibit acetylcholinesterase decreases over time (Davidsson, et al. Neurosci Lett. 2001;300:157). According to laboratory data, higher doses of these compounds, particularly galantamine, are not associated with increased efficacy, and dosage adjustment of galantamine is required for renal or hepatic impairment (Physician’s Desk Reference, 2002).

In contrast, therapeutic doses of rivastigmine have a more sustained inhibitory effect on both BuChE and AChE, with higher doses producing greater AChE inhibition (Darreh-Shori, et al. Neurology. 2002;59:563). Rivastigmine also does not require dosage adjustment, because of its unique metabolism (Physician’s Desk Reference, 2002).

When to Consider Switching of Cholinesterase Inhibitor Therapy

Switching among cholinesterase inhibitor therapies is widely practiced and may be beneficial in individuals who are not responding to treatment, or patients who have safety (e.g., drug-drug interactions) or tolerability concerns (Emre. Int J Clin Pract. 2002;suppl127:64; Inglis. Prog Neurol Psychiatr. 2001;5:24).

In a large open-label study, patients with mild to moderate AD, 84% of whom had received donepzil 10 mg/d for at least 6 months, were switched to rivastigmine treatment for various reasons. These reasons included lack of efficacy (80%) and tolerability problems (11%) (Auriacombe, et al. Curr Med Res Opin. 2002;18:129).

Among the patients who had not responded to donepezil, ~ 55% showed a response with rivastigmine, with ~ 11% discontinuing rivastigmine because of adverse effects. Of the patients who were not able to tolerate donepezil, ~ 75% responded to rivastigmine and ~ 15% discontinued rivastigmine because of adverse events. Thus, in AD patients, lack of response to or tolerability of one cholinesterase inhibitor does not predict the efficacy and tolerability of another such agent.

Effects of Titration on Gastrointestinal Adverse Effects
A key difference among the cholinesterase inhibitors is dosing. Only donepezil may be administered once a day; the others require dosage titration. Weekly titration of cholinesterase inhibitors doses is associated with marked gastrointestinal adverse effects, such as nausea, vomiting, and diarrhea (Physician’s Desk Reference, 2002; Raskind, et al. Neurology. 2000;54:2261). A recent study with rivastigmine found that the frequency of these adverse effects could be greatly reduced if drug doses up to 6–12 mg/d were titrated slowly (minimum 4-week) and were taken with a full meal (Shua-Heim, et al. Presentation. Am Geriatr Soc, 2001).

Future Trends in Cholinesterase Inhibitor Therapy
Dr. Grossberg briefly reviewed the use of cholinesterase inhibitors in various disorders associated with cognitive decline. Donepezil has demonstrated promising but inconclusive results in treating Alzheimer’s type symptoms in persons with Down syndrome and may be useful in improving cognition in patients with traumatic brain injury. The drug has had mixed results in patients with schizophrenia, but may be effective in treating tardive dyskinesia.

Rivastigmine treatment has produced significant improvement in autistic children with limited side effects (Chez, et al. Poster. Annual Meeting Child Neurol Soc, 2002), and some cholinesterase inhibitors may improve behavioral symptoms, but not motor symptoms, in patients with Huntington’s disease. Preliminary anecdotal data suggest that cholinesterase inhibitors may be useful in attention-deficit hyperactivity disorder, bipolar disorder, and frontotemporal dementia, but larger placebo-controlled studies are needed.


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