Specific treatments for cognitive impairment

Cholinesterase inhibitors

Evidence suggests that cholinergic deficit is a major biochemical substrate of cognitive dysfunction in PD-D and DLB [11]. ChE-Is inhibit the enzyme acetylcholinesterase, which breaks down acetylcholine in the synaptic cleft, terminating its post-synaptic effects. The synaptic half-life of acetylcholine is prolonged through this inhibition and cholinergic transmission is enhanced. The first report of a ChE-I in PD-D was of a small, open-label study with tacrine, the first ChE-I which became available for clinical use [12]; this suggested favourable effects on mental symptoms without worsening of motor functions. All available ChE-Is, including donepezil, rivastigmine, and galantamine, have subsequently been tested in PD-D and DLB. Despite open-label designs and small sample sizes in most of these studies, a consistent pattern was seen, with improvements in cognitive and behavioural symptoms [3]. Worsening of motor symptoms, usually a dose-related increase in tremor, was seen in only a few cases. These preliminary findings prompted the initiation of one large-scale, placebo-controlled randomized trial with rivastigmine in DLB, and two studies in PD-D, one with rivastigmine and the other with donepezil. The first [13] to be conducted assessed the effect of rivastigmine in DLB patients over a period of 20 weeks, followed by a 3-week withdrawal period. A total of 120 patients with a clinical diagnosis of probable DLB and a Mini-Mental State Examination (MMSE) score between 10 and 23 were treated with up to 12 mg per day of rivastigmine (mean dose 9.4 mg/day) or placebo. A four-item subscore of the Neuropsychiatric Inventory (NPI), comprising delusions, hallucinations, apathy, and depression, was used as the primary efficacy criterion [14]. Approximately twice as many patients on rivastigmine (63.4%) as on placebo (30.0%) showed at least a 30% improvement from baseline on their NPI-4 scores (p = 0.001), these symptoms re-emerged during a 3-week washout period. Statistically non-significant improvements were also seen at 20 weeks in MMSE score and Clinical Global Impression of Change (CGIC)-plus rating in favour of the rivastigmine-treated group. Parkinsonian signs did not worsen on treatment, although emergent tremor was noted in four rivastigmine- treated patients. Predominant adverse effects were cholinergic in nature and the frequency of nausea (37%), vomiting (25%), anorexia (19%), and somnolence (9%) was significantly higher in the rivastigmine-treated patients. Most adverse events were rated as either mild or moderate, but 7 of 59 patients receiving rivastigmine withdrew for this reason. Long-term follow-up of some of the study participants [15] found MMSE and NPI scores to be stable over the first 12 months of treatment, then to gradually worsen, although not significantly so, even 2 years after baseline.

Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores tended to improve, probably because some antiparkinsonian treatment was initiated during this time.

In the EXPRESS study 541 patients with mild to moderate PD-D were assigned to rivastigmine or placebo over 24 weeks [16r]. Rivastigmine was slowly titrated in monthly increments of 3 mg/ day over the first 16 weeks up to 12 mg/day and then maintained at the highest tolerated dose for another 8 weeks; the mean dose at the end of the study was 8.6 mg/day. Primary efficacy parameters included the Alzheimer’s Disease Assessment Scale—Cognition subscale (ADAS-COG) for the assessment of cognitive functions and a CGIC scale for the assessment of changes in the overall state from baseline. Both primary end points showed statistically significant improvements on rivastigmine treatment compared with placebo. Patients on rivastigmine showed an improvement of 2.1 points in ADAS-COG score at week 24, whereas patients on placebo deteriorated by 0.7 points (p < 0.001). The mean score for the CGIC at week 24 was 3.8 in the rivastigmine group and 4.3 in the placebo group (a score of 4 indicating no change, lower scores indicating improvement, and higher scores indicating worsening from baseline). More patients on rivastigmine showed any degree of improvement (40.8% on rivastigmine versus 29.7% on placebo) and more patients on placebo had any degree of deterioration (42.5% on placebo versus 33.7% on rivastigmine) (p = 0.007). Similarly, all secondary efficacy measures revealed statistically significant differences in favour of rivastigmine, including neuropsychiatric symptoms (NPI), the clock-drawing test, verbal fluency, computer-based attention tests, and MMSE score. ADL scores showed a minimal worsening from baseline in patients on rivastigmine, whereas those on placebo worsened significantly more. Adverse events were significantly more frequent with rivastigmine, mainly nausea (29.0% on rivastigmine versus 11.2% on placebo) and vomiting (16.6.% on rivastigmine versus 1.7% on placebo). Worsening of parkinsonian symptoms was more frequently reported on rivastigmine (27.3% versus 15.6% on placebo); this was principally driven by worsening of tremor (10.2% on rivastigmine versus 3.9% on placebo). UPDRS motor scores did not, however, reveal any significant differences between the groups.

In order to assess the long-term effects of rivastigmine, the EXPRESS study had a further 6-month extension during which all patients received active treatment [17]. The results demonstrated that the beneficial effects seen during the first 6 months were largely maintained, although treatment effects started to decline. Patients who initially received placebo and then switched to rivastigmine showed similar benefits to those who had been on rivastigmine for the entire duration of the study, but not in all parameters, suggesting that there may be potential benefits to starting treatment earlier. Importantly, there was no evidence of worsening motor function over the course of 1 year of treatment [18].

The second large randomized, double-blind, placebo-controlled study in PD-D used donepezil [19]. In this study 550 patients with mild to moderate PD-D were randomized into three groups to receive either placebo, donepezil 5 mg, or donepezil 10 mg for 24 weeks. The primary efficacy parameters were ADAS-COG and a global measure of change from baseline (CIBIC-plus). At week 24, there was a 0.3-point improvement in ADAS-COG on placebo, a 2.45-point improvement on 5 mg, and a 3.72-point improvement on 10 mg. These differences did not reach statistical significance in the primary analysis because of a country interaction, but did so when this was controlled for (p < 0.001). In the latter analysis the CIBIC-plus showed statistically significant superiority for the 10 mg dose but not for 5 mg. Statistically significant differences in favour of donepezil were also found on some secondary measures including MMSE, Brief Test of Attention, and the Verbal Fluency Test, whereas there were no statistically significant differences from placebo on the ADL scale Disability Assessment in Dementia and the behavioural scale NPI. UPDRS motor scores did not reveal any significant worsening of motor functions on donepezil.

In a later trial of donepezil in DLB [20], 140 patients recruited from 48 specialty centres in Japan were randomly assigned to receive placebo, 3, 5, or 10 mg of donepezil daily for 12 weeks. Effects on cognitive function were assessed using the MMSE and several domain-specific neuropsychological tests. Changes in behaviour were evaluated using the NPI, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician’s Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the UPDRS part III. Donepezil at 5 and 10 mg/day was significantly superior to placebo on both the MMSE (5 mg, mean difference 3.8; 10 mg, mean difference 2.4) and on CIBIC-plus (p < 0.001 for each); 3 mg/day was significantly superior to placebo on CIBIC-plus but not on the MMSE. Significant improvements were also found in behavioural measures at 5 and 10 mg/day and caregiver burden at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups. A subsequent open-label follow-up study suggested that benefits lasted at 52 weeks. [21].

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