Survival in Parkinson's disease: the effect of dementia

In order to evaluate the effect of dementia on survival in Parkinson ’s disease (PD), we followed a series of 250 PD over a period of 5 years. Dementia was determined according to DSM-III-R criteria. Survival analysis of PD patients with dementia vs. without dementia was performed using entry date as starting point. Cox model was used for evaluation of variables associated with mortality in this sample. Upon inclusion to the study, dementia was diagnosed in 38% of our patients. At the end of the follow-up period, the cumulative death rates were 39% among the demented patients and 34% among the non-demented ones (χ²=3.2, df=1, p=0.07). Advanced age and, but marginally, cognitive deterioration were associated with reduced survival [Exp(β)=3.4, p=0.005 and Exp(β)=1.3, p=0.06, respectively].     

Treatment of dementia associated with Parkinson's disease

Dementia affects approximately one-third of all patients with Parkinson's disease. Currently there is no treatment to halt or reverse the disease progression. Symptomatic treatment approaches are based on substituting neurotransmitter deficits or ameliorating associated behavioral symptoms. The most prominent deficits are cholinergic, and treatment with cholinesterase inhibitors (ChE-I) has been shown to provide some benefits in cognitive and behavioral symptoms without undue worsening in motor symptoms. Based on a large, randomized, placebo controlled trial, the ChE-I rivastigmine has been approved for the treatment of dementia associated with PD.     

Hyperhomocysteinemia in levodopa‐treated patients with Parkinson's disease dementia

Dementia is a frequent non‐motor feature of Parkinson's disease (PD). Elevated plasma homocysteine (Hcy) levels have been associated with both cognitive impairment and dementia. Increased Hcy levels have been observed in levodopa‐treated patients with PD. The objective of our study was to evaluate the association between plasma Hcy levels and dementia in PD. We performed a multicenter cross‐sectional study on patients with PD with (PDD) and without (PDnD) dementia and age‐ and sex‐matched healthy controls. We compared Hcy levels in patients with PDD and PDnD and healthy controls, and we performed logistic regression analysis to search for an association between the presence of dementia and increased Hcy levels in PD. Patients with PD (121), PDD (42), and PDnD (79), and age‐ and sex‐matched controls (154) were enrolled. Hcy levels were higher in patients with PD compared to controls (17.5 μmol/L ± 10.2 vs. 11 ± 4.1; P < 0.00001). Among patients with PD, Hcy levels were higher in the PDD group compared to the PDnD group (20.7 μmol/L ± 12.1 vs. 15.8 ± 8.5; P = 0.002). In a multivariate logistic regression model, higher Hcy levels [Odds ratios comparing the top (>18.9 μmol/L) with the bottom tertile (<12.4 μmol/L): 3.68; 95% CI: 1.14–11.83] were significantly associated with dementia. These data support the association between elevated Hcylevels and the presence of dementia in PD. © 2009 Movement Disorder Society     

Rivastigmine in dementia associated with Parkinson's disease and Alzheimer's disease: similarities and differences

Parkinson's disease dementia (PDD) and Alzheimer's disease (AD) are both characterized by cognitive abnormalities, neuropsychiatric symptoms, and cholinergic deficits. We reviewed data from large, placebo-controlled clinical trials conducted with rivastigmine in patients with PDD and AD to evaluate similarities and differences in response to treatment. In placebo groups, AD patients appeared to show more rapid cognitive decline than those with PDD. Treatment effects (rivastigmine versus placebo) on cognitive performance over 6 months were quantitatively similar in both populations, but qualitatively different: in AD, cognitive abilities were stabilized by rivastigmine compared to declines in placebo groups, whereas in PDD symptomatic improvements above baseline drove treatment effects while placebo patients had limited change. On activities of daily living, stabilization (rather than improvement) was observed in both dementia types. A more aggressive course of placebo decline, and greater treatment differences (rivastigmine versus placebo), were seen in sub-populations of both PDD and AD patients with hallucinations at baseline. The safety and adverse event profiles were comparable in the two populations. In conclusion, the magnitude of effect with rivastigmine versus placebo is quantitatively comparable in patients with AD and PD, but the treatment effect tended to be one of stabilization in AD, while in PDD improvements over baseline were seen. In both populations, hallucinations may identify patients who are likely to be more treatment-responsive.     

Visual symptoms in Parkinson's disease and Parkinson's disease dementia

Visual symptoms are common in PD and PD dementia and include difficulty reading, double vision, illusions, feelings of presence and passage, and complex visual hallucinations. Despite the established prognostic implications of complex visual hallucinations, the interaction between cognitive decline, visual impairment, and other visual symptoms remains poorly understood. Our aim was to characterize the spectrum of visual symptomatology in PD and examine clinical predictors for their occurrence. Sixty-four subjects with PD, 26 with PD dementia, and 32 age-matched controls were assessed for visual symptoms, cognitive impairment, and ocular pathology. Complex visual hallucinations were common in PD (17%) and PD dementia (89%). Dementia subjects reported illusions (65%) and presence (62%) more frequently than PD or control subjects, but the frequency of passage hallucinations in PD and PD dementia groups was equivalent (48% versus 69%, respectively; P = 0.102). Visual acuity and contrast sensitivity was impaired in parkinsonian subjects, with disease severity and age emerging as the key predictors. Regression analysis identified a variety of factors independently predictive of complex visual hallucinations (e.g., dementia, visual acuity, and depression), illusions (e.g., excessive daytime somnolence and disease severity), and presence (e.g., rapid eye movement sleep behavior disorder and excessive daytime somnolence). Our results demonstrate that different "hallucinatory" experiences in PD do not necessarily share common disease predictors and may, therefore, be driven by different pathophysiological mechanisms. If confirmed, such a finding will have important implications for future studies of visual symptoms and cognitive decline in PD and PD dementia.     

Timing matters: Otological symptoms and Parkinson's disease

IntroductionOtological symptoms contribute to the disability of established Parkinson's disease (PD). We sought to evaluate whether prodromal onset may affect PD progression.MethodsA retrospective cohort design was used to compare time to advanced disease, defined as a Hoehn & Yahr stage ≥3 in consecutive PD patients with history of auditory and/or vestibular symptoms appearing before versus after PD onset. Time from PD onset to H&Y ≥ 3 was determined using Cox proportional hazards, with adjusted results summarized as hazards ratio (HR).ResultsAfter adjusting for age at PD onset, there was a lower risk of progression to advanced disease in patients with prodromal otological symptoms compared to those with otological symptoms after PD onset (HR = 0.34; 95%CI: 0.15–0.75, p = 0.008). This association remained significant after adjusting for age at PD onset and MDS-UPDRS III (HR = 0.25; 95% CI: 0.10–0.63, p = 0.003) and propensity score-adjusted analysis (HR = 0.46; 95% CI: 0.24–0.91, p = 0.025).ConclusionProdromal otological symptoms might be associated with a reduced risk of motor progression in PD.     

SCOPA‐cognition cutoff value for detection of Parkinson's disease dementia

The SCOPA‐Cognition is a reliable and valid test to evaluate cognitive functioning in Parkinson's disease and is widely used in clinical and research settings. Recently, the Movement Disorder Society introduced criteria for Parkinson's disease dementia. The objective of the present study was to use these criteria to determine SCOPA‐Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. A total of 282 patients with Parkinson's disease were assessed with the SCOPA‐Cognition and the Movement Disorder Society's Parkinson's disease dementia criteria. From the 275 patients with a complete assessment of the dementia criteria, 12% (n = 32) fulfilled the criteria. Data from 268 patients with complete assessments of both the dementia criteria and the SCOPA‐Cognition were used to determine cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. The area under the curve was 0.91 (95% confidence interval, 0.85–0.97), showing a strong association between the dementia criteria and the SCOPA‐Cognition. The cutoff for maximum accuracy was 22/23, based on the highest sum of sensitivity (0.80) and specificity (0.87), with positive and negative predictive values of 0.43 and 0.97, respectively. The optimal screening cutoff was 24/25, and the optimal diagnostic cutoff was 17/18. Using the recently published Parkinson's disease dementia criteria as a reference, the current study presents SCOPA‐Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. The availability of SCOPA‐Cognition cutoffs for Parkinson's disease dementia may contribute to the scale's usefulness and promote its further use in both clinical and research settings. © 2011 Movement Disorder Society     

Speech and gait in Parkinson's disease: When rhythm matters

IntroductionSpeech disturbances in Parkinson's disease (PD) are heterogeneous, ranging from hypokinetic to hyperkinetic types. Repetitive speech disorder has been demonstrated in more advanced disease stages and has been considered the speech equivalent of freezing of gait (FOG). We aimed to verify a possible relationship between speech and FOG in patients with PD.MethodsForty-three consecutive PD patients and 20 healthy control subjects underwent standardized speech evaluation using the Italian version of the Dysarthria Profile (DP), for its motor component, and subsets of the Battery for the Analysis of the Aphasic Deficit (BADA), for its procedural component. DP is a scale composed of 7 sub-sections assessing different features of speech; the rate/prosody section of DP includes items investigating the presence of repetitive speech disorder. Severity of FOG was evaluated with the new freezing of gait questionnaire (NFGQ).ResultsPD patients performed worse at DP and BADA compared to healthy controls; patients with FOG or with Hoehn-Yahr >2 reported lower scores in the articulation, intellibility, rate/prosody sections of DP and in the semantic verbal fluency test. Logistic regression analysis showed that only age and rate/prosody scores were significantly associated to FOG in PD. Multiple regression analysis showed that only the severity of FOG was associated to rate/prosody score.ConclusionsOur data demonstrate that repetitive speech disorder is related to FOG and is associated to advanced disease stages and independent of disease duration. Speech dysfluency represents a disorder of motor speech control, possibly sharing pathophysiological mechanisms with FOG.     

Rivastigmine in Parkinson's disease dementia

Dementia associated with Parkinson's disease (PD) ultimately develops in approximately 70% of patients with PD older than 80 years of age. The neuropathology of PD dementia (PDD) is likely multifactorial and affects several neuronal populations. There is evidence that PDD is associated with a cholinergic deficit, supporting the therapeutic role of cholinesterase inhibitors, which are already first-line agents in the treatment of Alzheimer's disease. Open-label and small controlled studies suggested a clinical efficacy of cholinesterase inhibitors in PDD. One large randomized placebo-controlled trial of 541 patients demonstrated that oral rivastigmine improved cognition, attention and executive functions, activities of daily living and behavioral symptoms after 6 months of treatment. Rivastigmine is a dual cholinesterase inhibitor, being effective on both acetylcholinesterase and butyrylcholinesterase. This paper reviews the pharmacokinetic and pharmacodynamic properties of rivastigmine (oral and transdermal administration). It also reviews evidence on clinical efficacy, safety and tolerability of the oral administration in PDD patients at doses of 3-12 mg/day.     

Psychosis in Parkinson's disease without dementia: Common and comorbid with other non‐motor symptoms

Psychosis in Parkinson's disease (PD) is common and associated with a range of negative outcomes. Dementia and psychosis are highly correlated in PD, but the frequency and correlates of psychosis in patients without cognitive impairment are not well understood. One hundred and ninety‐one non‐demented PD patients at two movement disorders centers participated in a study of neuropsychiatric complications in PD and completed a detailed neurological and neuropsychiatric assessment, including the rater‐administered Parkinson Psychosis Rating Scale for hallucinations, delusions, and minor symptoms of psychosis (illusions and misidentification of persons). Psychotic symptoms were present in 21.5% of the sample. Visual hallucinations were most common (13.6%), followed by auditory hallucinations (6.8%), illusions or misidentification of people (7.3%), and paranoid ideation (4.7%). Visual hallucinations and illusions or misidentification of people were the most common comorbid symptoms (3.1%). Depression (P = 0.01) and rapid eye movement behavior disorder symptoms (P = 0.03) were associated with psychosis in a multivariable model. The odds of experiencing psychotic symptoms were approximately five times higher in patients with comorbid disorders of depression and sleep‐wakefulness. Even in patients without global cognitive impairment, psychosis in PD is common and most highly correlated with other non‐motor symptoms. Screening for psychosis should occur at all stages of PD as part of a broad non‐motor assessment. In addition, these findings suggest a common neural substrate for disturbances of perception, mood, sleep‐wakefulness, and incipient cognitive decline in PD. © 2012 Movement Disorder Society     

PDD‐Short Screen: A brief cognitive test for screening dementia in Parkinson's disease

The diagnosis of Parkinson's disease with dementia (PDD) is currently based on clinical criteria (DSM‐IV, MDS–Task Force). In daily practice and research studies, these criteria still depend on the subjective impression of the examiner. Brief screening tests (BST) are helpful in identifying patients with PD with dementia, which can be difficult in patients with advanced PD. We aimed to develop a BST for PD, the PDD‐Short Screen (PDD‐SS), to accurately and quickly screen for PDD. In this prospective study, 70 patients with nondemented (age 73.8 ± 4.4) and 32 demented (age 73.8 ± 4.4) PD regularly attending a Movement Disorders Clinic were included. Diagnosis of dementia was based on DSM‐IV criteria, CDR score ≥1, and PD‐CRS total score ≤64. The PDD‐SS, Mattis Dementia Rating Scale (MDRS), and Mini‐Mental State Examination (MMSE) were administered to all participants. Validity, reliability, and discriminative power of the PDD‐SS were examined. The final version of the scale included the items immediate and delayed verbal memory, clock drawing, alternating verbal fluency, and a questionnaire covering cognitive and psychiatric (hallucinations, apathy) symptoms common in PDD. A cutoff score ≤11 on the PDD‐SS yielded high sensitivity (89.8%) and specificity (88.5%) for diagnosing PDD. The MDRS displayed similar accuracy, but the PDD‐SS administration time was significantly shorter (4.8–6.9 vs. 17.5–25.2 minutes). Diagnosis of dementia using the PDD‐SS was not influenced by age, education, or motor function. The PDD‐SS appears as the first BST for diagnosing PDD, displays an excellent diagnostic accuracy, and takes 5 to 7 minutes to be administered. © 2010 Movement Disorder Society     

Donepezil in Parkinson's disease dementia: A randomized,double‐blind efficacy and safety study

Parkinson's disease dementia (PDD) is associated with cholinergic deficits. This report presents an efficacy and safety study of the acetylcholinesterase inhibitor donepezil hydrochloride in PDD. PDD patients (n = 550) were randomized to donepezil (5 or 10 mg) or placebo for 24 weeks. Coprimary end points were the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS‐cog) and Clinician's Interview‐Based Impression of Change plus caregiver input (CIBIC+; global function). Secondary end points measured executive function, attention, activities of daily living (ADLs), and behavioral symptoms. Safety and tolerability were assessed. ADAS‐cog mean changes from baseline to week 24 (end point) were not significant for donepezil in the intent‐to‐treat population by the predefined statistical model (difference from placebo: ?1.45, P = .050, for 5 mg; ?1.45, P = .076, for 10 mg). Alternative ADAS‐cog analysis, removing the treatment‐by‐country interaction term from the model, revealed significant, dose‐dependent benefit with donepezil (difference from placebo: ?2.08, P = .002, for 5 mg; ?3.31, P < .001, for 10 mg). The 10‐mg group, but not the 5‐mg group, had significantly better CIBIC+ scores compared with placebo (3.7 vs 3.9, P = .113, for 5 mg; 3.6 vs 3.9, P = .040, for 10 mg). Secondary end points—Mini–Mental State Exam; Delis–Kaplan Executive Function System; Brief Test of Attention, representing cognitive functions particularly relevant to PDD—showed significant benefit for both donepezil doses (P ≤ .007). There were no significant differences in ADLs or behavior. Adverse events were more common with donepezil but mostly mild/moderate in severity. Although the study did not achieve its predefined primary end points, it presents evidence suggesting that donepezil can improve cognition, executive function, and global status in PDD. Tolerability was consistent with the known safety profile of donepezil. © 2012 Movement Disorder Society     

Randomized controlled trial of memantine in dementia associated with Parkinson's disease

The objective of this study is to investigate the safety and tolerability of memantine, a glutamatergic modulator, in patients suffering from dementia associated with Parkinson's disease (PDD), an increasingly common complication of PD. This was a 22‐week trial of 25 participants with a DSM‐IV diagnosis of PDD who were randomized to either placebo or 20 mg/day of memantine. Memantine was well tolerated by participants at 20 mg/day dosing. No participant was withdrawn due to memantine‐related adverse events. Six weeks after drug withdrawal, a significantly greater proportion (P = 0.04) of memantine‐treated participants deteriorated globally compared with those treated with placebo. These findings suggest that continued treatment with memantine may be needed to maintain global level of functioning over time. Based on the findings of this pilot study, memantine is safe and very well‐tolerated in PDD. © 2009 Movement Disorder Society