In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD ...psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors - for example, autonomic dysfunction - that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis.
Neuropsychiatric symptoms (NPS), such as depression, apathy, agitation, and psychotic symptoms are common in mild cognitive impairment (MCI) and dementia in Alzheimer's disease (AD). Subgroups of NPS ...have been reported. Yet the relationship of NPS and their subgroups to different stages of cognitive impairment is unclear. Most previous studies are based on small sample sizes and show conflicting results. We sought to examine the frequency of NPS and their subgroups in MCI and different stages of dementia in AD.
This was a cross-sectional study using data from a Norwegian national registry of memory clinics. From a total sample of 4,571 patients, we included those with MCI or AD (MCI 817, mild AD 883, moderate-severe AD 441). To compare variables across groups ANOVA or χ 2-test was applied. We used factor analysis of Neuropsychiatric Inventory Questionnaire (NPI-Q) items to identify subgroups of NPS.
The frequency of any NPS was 87.2% (AD 91.2%, MCI 79.5%; p < 0.001) and increased with increasing severity of cognitive decline. The most frequent NPS in MCI was depression. Apathy was the most frequent NPS in AD across different stages of severity. The factor analysis identified three subgroups in MCI and mild AD, and a fourth one in moderate-severe AD. We labelled the subgroups "depression," "agitation," "psychosis," and "elation."
The frequency of NPS is high in MCI and AD and increases with the severity of cognitive decline. The subgroups of NPS were relatively consistent from MCI to moderate-severe AD. The subgroup elation appeared only in moderate-severe AD.
Summary Background Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment ...licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB. Methods We did a parallel-group, 24-week, randomised controlled study of memantine (20 mg per day) versus placebo at four psychiatric and neurological outpatient clinics in Norway, Sweden, and the UK during 2005–08. Patients were included if they fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's disease (PD) and developed dementia according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM IV) criteria at least 1 year after the onset of motor symptoms (PDD) or met the revised consensus operationalised criteria for DLB. Patients were assigned to a computer-generated randomisation list. All physicians who had contact with patients were masked to treatment allocation. The primary outcome measure was clinical global impression of change (CGIC), which ranged from 1 to 7 points, and a low score means a better outcome. Analysis was by intention to treat based on the last observation carried forward. This trial is registered, number ISRCTN89624516. Findings 72 patients with PDD or DLB were randomly assigned and started treatment: 34 with memantine and 38 with placebo. 56 (78%) completed the study. All withdrawals were owing to adverse events, but the proportion of withdrawals was similar in both groups. At week 24 the patients in the memantine group had better CGIC scores than those taking placebo (mean difference 0·7, 95% CI 0·04–1·39; p=0·03). With the exception of improved speed on attentional tasks in the memantine group (a quick test of cognition AQT form: difference 12·4, 95% CI 6·0–30·9; p=0·004), there were no significant differences between the groups in secondary outcome measures. Interpretation Patients with DLB or PDD might benefit from treatment with memantine, which was well tolerated. Large-scale studies are now required to confirm our preliminary findings. Funding The Western Norway Regional Health Authority; H Lundbeck A/S.
Objective To determine whether a systematic approach to the treatment of pain can reduce agitation in people with moderate to severe dementia living in nursing homes.Design Cluster randomised ...controlled trial.Setting 60 clusters (single independent nursing home units) in 18 nursing homes within five municipalities of western Norway.Participants 352 residents with moderate to severe dementia and clinically significant behavioural disturbances randomised to a stepwise protocol for the treatment of pain for eight weeks with additional follow-up four weeks after the end of treatment (33 clusters; n=175) or to usual treatment (control, 27 clusters; n=177).Intervention Participants in the intervention group received individual daily treatment of pain for eight weeks according to the stepwise protocol, with paracetamol (acetaminophen), morphine, buprenorphine transdermal patch, or pregabaline. The control group received usual treatment and care.Main outcome measures Primary outcome measure was agitation (scores on Cohen-Mansfield agitation inventory). Secondary outcome measures were aggression (scores on neuropsychiatric inventory-nursing home version), pain (scores on mobilisation-observation-behaviour-intensity-dementia-2), activities of daily living, and cognition (mini-mental state examination).Results Agitation was significantly reduced in the intervention group compared with control group after eight weeks (repeated measures analysis of covariance adjusting for baseline score, P<0.001): the average reduction in scores for agitation was 17% (treatment effect estimate −7.0, 95% confidence interval −3.7 to −10.3). Treatment of pain was also significantly beneficial for the overall severity of neuropsychiatric symptoms (−9.0, −5.5 to −12.6) and pain (−1.3, −0.8 to −1.7), but the groups did not differ significantly for activities of daily living or cognition.Conclusion A systematic approach to the management of pain significantly reduced agitation in residents of nursing homes with moderate to severe dementia. Effective management of pain can play an important part in the treatment of agitation and could reduce the number of unnecessary prescriptions for psychotropic drugs in this population.Trial registration ClinicalTrials.gov NCT01021696 and Norwegian Medicines Agency EudraCTnr 2008-007490-20.
Objective
Depression is associated with accelerated aging and age‐related diseases. However, mechanisms underlying this relationship remain unclear. The aim of this study was to longitudinally assess ...the link between depressive symptoms, brain atrophy, and cortisol levels.
Method
Participants from the Betula prospective cohort study (mean age = 59 years, SD = 13.4 years) underwent clinical, neuropsychological and brain 3T MRI assessments at baseline and a 4‐year follow‐up. Cortisol levels were measured at baseline in four saliva samples. Cortical and hippocampal atrophy rates were estimated and compared between participants with and without depressive symptoms (n = 81) and correlated with cortisol levels (n = 49).
Results
Atrophy in the left superior frontal gyrus and right lingual gyrus developed in parallel with depressive symptoms, and in the left temporal pole, superior temporal cortex, and supramarginal cortex after the onset of depressive symptom. Depression‐related atrophy was significantly associated with elevated cortisol levels. Elevated cortisol levels were also associated with widespread prefrontal, parietal, lateral, and medial temporal atrophy.
Conclusion
Depressive symptoms and elevated cortisol levels are associated with atrophy of the prefrontal and limbic areas of the brain.
Computer-aided diagnosis of Alzheimer's disease (AD) is a rapidly developing field of neuroimaging with strong potential to be used in practice. In this context, assessment of models' robustness to ...noise and imaging protocol differences together with post-processing and tuning strategies are key tasks to be addressed in order to move towards successful clinical applications. In this study, we investigated the efficacy of Random Forest classifiers trained using different structural MRI measures, with and without neuroanatomical constraints in the detection and prediction of AD in terms of accuracy and between-cohort robustness. From The ADNI database, 185 AD, and 225 healthy controls (HC) were randomly split into training and testing datasets. 165 subjects with mild cognitive impairment (MCI) were distributed according to the month of conversion to dementia (4-year follow-up). Structural 1.5-T MRI-scans were processed using Freesurfer segmentation and cortical reconstruction. Using the resulting output, AD/HC classifiers were trained. Training included model tuning and performance assessment using out-of-bag estimation. Subsequently the classifiers were validated on the AD/HC test set and for the ability to predict MCI-to-AD conversion. Models' between-cohort robustness was additionally assessed using the AddNeuroMed dataset acquired with harmonized clinical and imaging protocols. In the ADNI set, the best AD/HC sensitivity/specificity (88.6%/92.0% - test set) was achieved by combining cortical thickness and volumetric measures. The Random Forest model resulted in significantly higher accuracy compared to the reference classifier (linear Support Vector Machine). The models trained using parcelled and high-dimensional (HD) input demonstrated equivalent performance, but the former was more effective in terms of computation/memory and time costs. The sensitivity/specificity for detecting MCI-to-AD conversion (but not AD/HC classification performance) was further improved from 79.5%/75%-83.3%/81.3% by a combination of morphometric measurements with ApoE-genotype and demographics (age, sex, education). When applied to the independent AddNeuroMed cohort, the best ADNI models produced equivalent performance without substantial accuracy drop, suggesting good robustness sufficient for future clinical implementation.
Behavioral disturbances and pain are common in nursing home (NH) patients with dementia. An association between pain and increased agitation has been suggested, and recently a significant reduction ...of agitation has been demonstrated by pain treatment in patients with moderate to severe dementia. We now examined which specific agitated behaviors respond to individualized pain treatment.
Cluster randomized clinical trial.
60 clusters (i.e., clusters defined as single independent NH units) in 18 NHs within five municipalities of Western Norway.
352 patients with moderate to severe dementia and clinically significant behavioral disturbances.
The control group received usual treatment and care. According to a predefined scheme for 8 weeks, all patients in the intervention group received individual daily pain treatment with acetaminophen, extended release morphine, buprenorphine transdermal patch, and/or pregabaline.
Cohen-Mansfield Agitation Inventory subscales and items.
Analyses demonstrated that Factor 3 (Verbally agitated behaviors) showed the largest significant difference (DF = 1204.0, t = -4.308, p <0.001), followed by Factor 2 (Physically non-aggressive behaviors) (DF = 1198.0, t = -2.672, p = 0.008), and Factor 1 (Aggressive behaviors) (DF = 1196.0, t = -2.093, p = 0.037) after 8 weeks, by a linear random intercept mixed model in two-way repeated-measures configuration with adjustment for heteroscedasticity.
We found that verbal agitation behaviors such as complaining, negativism, repetitious sentences and questions, constant request for attention, and cursing or verbal aggression responded to pain treatment. In addition, restlessness and pacing were sensible to analgesics. Such behaviors should therefore lead to an assessment of pain, and pain treatment. Further studies comparing how pain treatment should be balanced against other strategies including psychotropic drugs are needed.
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