Sibel Tekin

Neuropsychiatric symptoms in patients with Parkinson’s disease and dementia: frequency, profile and associated care giver stress

Objective: To explore the profile of neuropsychiatric symptoms in patients with dementia associated with Parkinson’s disease (PDD). Methods: 537 patients with PDD drawn from an international multicentre clinical trial of rivastigmine were assessed using the 10-item Neuropsychiatric Inventory (NPI). A cluster analysis was used to investigate the inter-relationship of NPI items. Associations between the clusters and demographic and clinical variables were analysed. Results: 89% of the patients presented at least one symptom on the NPI, 77% had two or more symptoms and 64% had at least one symptom with a score ⩾4. The most common symptoms were depression (58%), apathy (54%), anxiety (49%) and hallucinations (44%). Patients with more severe dementia and advanced Parkinson’s disease had more neuropsychiatric symptoms. Nearly 60% of the care givers reported at least one NPI symptom to be of at least moderate severe distress. Five NPI clusters were identified: one group with few and mild symptoms (52%); a mood cluster (11%, high scores on depression, anxiety and apathy); apathy (24%; high apathy and low scores on other items); agitation (5%, high score on agitation and high total NPI score); and a psychosis cluster (8%; high scores on delusions and hallucinations). The psychosis and agitation clusters had the lowest Mini-Mental State Examination score and the highest Unified Parkinson’s Disease Rating Scale and care giver distress scores. Conclusion: Neuropsychiatric symptoms are common in patients with PDD. The profile of these symptoms differs from that in other types of dementia. Subgroups with different neuropsychiatric profiles were identified. These subgroups may be associated with distinct neurobiological changes, which should be explored in future studies.

Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study

OBJECTIVE To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimers disease (AD) and the rate of cognitive decline. METHODS The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

Behavioral symptoms in mild cognitive impairment

The authors investigated neuropsychiatric symptoms in mild cognitive impairment (MCI) from baseline data of the Investigation in the Delay to Diagnosis of AD with Exelon (InDDEx) study (n = 1,010). Neuropsychiatric symptoms were reported in 59% of subjects (Neuropsychiatric Inventory [NPI]). NPI+ subjects had significantly greater impairment on global, cognitive, and functional scores than NPI− subjects. The presence of neuropsychiatric symptoms appears to be a marker of MCI severity.

Impact of APOE in mild cognitive impairment

Objective: The authors aimed to use baseline data of an ongoing large, prospective study in subjects with mild cognitive impairment (MCI) to investigate the impact of APOE genotype on the symptom profile of the condition. Methods: Cognitive assessments included the AD Assessment Scale cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and a cognitive battery for assessment of memory, attention, and executive function. Behavioral assessments included the Neuropsychiatric Inventory and Beck Depression Inventory. Activities of daily living were assessed by the AD Cooperative Study Activities of Daily Living (ADCS-ADL) scale. Hippocampal volumes were measured with MRI. Results: A total of 494 of 1,018 study subjects provided APOE data. Approximately 40% of the subjects were APOE ε4 carriers. APOE ε4 carriers had lower MMSE (p = 0.01) and higher ADAS-cog (p < 0.0001) scores than noncarriers, indicating worse cognitive impairment. APOE ε4 carriers also had greater deficits on New York University delayed paragraph recall and Buschke free and cued selective reminding tests, and on the ADCS-ADL scale (p < 0.001). They also had smaller hippocampal volumes (p = 0.002). Behavioral scores were similar across the subgroups. Conclusion: MCI subjects carrying the APOE ε4 allele showed distinct cognitive and imaging profiles, which appeared to resemble those of early Alzheimer patients. APOE ε4 genotype was associated with greater impairments in memory and functional activities as well as hippocampal atrophy.

Attentional deficits affect activities of daily living in dementia‐associated with Parkinson's disease

Objective: To investigate the effects of attentional deficits on activities of daily living (ADL) in patients with dementia associated with Parkinson’s disease (PDD). Method: 461 patients were assessed neuropsychologically. Factor analyses were used to differentiate attention from other cognitive functions and to differentiate different aspects of ADL functions. The effects of the attentional measure on ADL were examined using sequential multiple regression, controlling for age, sex, education, severity of motor symptoms and other cognitive functions. Results: Three cognitive factors were identified, with one factor emerging as a measure of vigilance and focused attention. This factor predicted different aspects of ADL status even after controlling for motor functions and other cognitive factors. The attention factor was the single strongest cognitive predictor of ADL status, matching the strength of the effects of motor functions on ADL status. Conclusion: Impaired attention is an important determinant of ADL functions in patients with PDD.

Long‐term benefits of rivastigmine in dementia associated with Parkinson's disease: An active treatment extension study

In patients with dementia associated with Parkinsons disease (PD), the efficacy and safety of rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase, were previously demonstrated in a 24‐week double‐blind placebo‐controlled trial. Our objective was to determine whether benefits were sustained over the long term. Following the double‐blind trial, all patients were permitted to enter an active treatment extension study, during which they received rivastigmine 3–12 mg/day. Standard safety assessments were performed. Efficacy assessments included the Alzheimers Disease Assessment Scale cognitive subscale (ADAS‐cog) and other measures of cognition, daily function, neuropsychiatric symptoms, and executive function. Of 433 patients who completed the double‐blind trial, 334 entered and 273 completed the active treatment extension. At 48 weeks, the mean ADAS‐cog score for the whole group improved by 2 points above baseline. Placebo patients switching to rivastigmine for the active treatment extension experienced a mean cognitive improvement similar to that of the original rivastigmine group during the double‐blind trial. The adverse event profile was comparable to that seen in the double‐blind trial. Long‐term rivastigmine treatment appeared well tolerated and may provide sustained benefits in dementia associated with PD patients who remain on treatment for up to 48 weeks.

Profile of cognitive impairment in dementia associated with Parkinson’s disease compared with Alzheimer’s disease

Objective: To compare the profile of cognitive impairment in Alzheimer’s disease (AD) with dementia associated with Parkinson’s disease (PDD). Methods: Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini-Mental State Examination (MMSE) and the Alzheimers Disease Assessment Scale-cognitive subscale (ADAS-cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen’s d). Results: Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS-cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients. Conclusion: The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.

Effects of Rivastigmine on Tremor and Other Motor Symptoms in Patients with Parkinson's Disease Dementia A Retrospective Analysis of a Double-Blind Trial and an Open-Label Extension

AbstractBackground and aim: Rivastigmine is now widely approved for the treatment of mild to moderately severe dementia in Parkinson’s disease (PDD). However, since anticholinergic drugs have a role in the management of tremor in patients with Parkinson’s disease (PD), concerns have been raised that the use of cholinergic drugs might worsen PD. The current analyses were performed to examine the potential of rivastigmine to affect tremor and other motor symptoms in patients with PDD. Methods: The safety profile of rivastigmine was evaluated using a database from a 24-week, randomized, double-blind, placebo-controlled trial in 541 PDD patients (362 randomized to rivastigmine, 179 to placebo), and 334 PDD patients who subsequently entered an open-label 24-week extension on rivastigmine. Results: During the double-blind trial, the adverse event (AE) of emerging or worsening tremor was reported in 10.2% of patients in the rivastigmine group, compared with 3.9% in the placebo group (p = 0.012). Tremor was most frequently reported during the titration phase of rivastigmine treatment, although this was not reflected in total motor Unified Parkinson’s Disease Rating Scale (UPDRS) part III scores. Dose dependence of this AE was not observed. At the end of the double-blind phase, six (1.7%) rivastigmine-treated patients had discontinued the study because of tremor. In the open-label extension in which all patients received rivastigmine, tremor was reported by 6.9% of patients: 3.8% and 12.2% of whom had previously received double-blind rivastigmine and placebo, respectively (p = 0.006), suggesting that first exposure to rivastigmine leads to a transient increase in tremor. Three (0.9%) of the 334 patients who entered the open-label extension phase discontinued because of tremor. Incidences of worse ning parkinsonism, bradykinesia and rigidity were all <5% in both treatment groups (all p-values not statistically significant, rivastigmine vs placebo). In the 48-week observation of rivastigmine treatment, there was no evidence of adverse long-term motor outcomes. Posthoc analysis showed that similar improvements in the symptoms of dementia, including the ability to perform activities of daily living, were seen regardless of whether exacerbation of tremor was reported during the study. Conclusion: Rivastigmine did not induce clinically significant exacerbation of motor dysfunction in patients with PDD. Rest tremor incidence as an AE was a transient phenomenon during dose titration of rivastigmine. There was no indication that exposure to long-term rivastigmine was associated with a worsening of PD.

Rivastigmine Transdermal Patch Skin Tolerability: Results of a 1-Year Clinical Trial in Patients with Mild-to-Moderate Alzheimer's Disease

AbstractBackground and Objectives: Transdermal patches provide non-invasive, continuous drug delivery, and offer significant potential advantages over oral treatments. With all transdermal treatments a proportion of patients will experience some form of skin reaction. The rivastigmine patch has been approved for the treatment of mild-to-moderate Alzheimer’s disease (AD) since July 2007 in the US. The aim of the component of the trial reported here was to evaluate the skin tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate AD. Methods: The pivotal IDEAL trial was a 24-week, randomized, double-blind, placebo-controlled, multicentre trial of the efficacy and tolerability of the rivastigmine transdermal patch in 1195 patients with mild-to-moderate AD. This was followed by a 28-week open-label extension. Although not prospectively defined as a secondary assessment, during both phases of the study the condition of the patients’ skin at the application site was evaluated. These data are reviewed in this article. Results: During the 24-week, double-blind phase of the study, 89.6% of patients in the target 9.5 mg/24 h patch treatment group had recorded ‘no, slight or mild’ signs or symptoms for their most severe application-site reaction. Erythema and pruritus were the most commonly reported reactions. No patient in any patch treatment group experienced a skin reaction that was reported as a serious adverse event. In the 9.5 mg/24 h treatment group, 2.4% of patients discontinued treatment due to an application-site reaction. During the 28-week open-label extension, the skin tolerability profile was similar to that seen in the double-blind phase. Overall, 3.7% of patients discontinued treatment due to application-site skin reactions. There was no indication that the severity of the skin reactions increased over time. Conclusion: Overall, the data support a favourable skin tolerability profile for the rivastigmine transdermal patch, and provide reassurance that the benefits of rivastigmine patch therapy for patients with AD are not confounded by significant skin irritation problems. Nevertheless, care should be taken to follow manufacturer’s advice about patch application, such as daily rotation of the application site, to minimize the risk of skin reactions.

Cognitive correlates of visual hallucinations in dementia associated with Parkinson's disease.

There may be a relationship between cognitive impairment and visual hallucinations (VHs) in patients with Parkinsons disease (PD). The objective of this study was to compare the cognitive profile of hallucinating vs. nonhallucinating patients with Parkinsons disease dementia (PDD).