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author:("marsland, D")
1.  Age and diagnostic performance of Alzheimer disease CSF biomarkers 
Neurology  2012;78(7):468-476.
Core CSF changes in Alzheimer disease (AD) are decreased amyloid β1–42, increased total tau, and increased phospho-tau, probably indicating amyloid plaque accumulation, axonal degeneration, and tangle pathology, respectively. These biomarkers identify AD already at the predementia stage, but their diagnostic performance might be affected by age-dependent increase of AD-type brain pathology in cognitively unaffected elderly.
We investigated effects of age on the diagnostic performance of CSF biomarkers in a uniquely large multicenter study population, including a cross-sectional cohort of 529 patients with AD dementia (median age 71, range 43–89 years) and 304 controls (67, 44–91 years), and a longitudinal cohort of 750 subjects without dementia with mild cognitive impairment (69, 43–89 years) followed for at least 2 years, or until dementia diagnosis.
The specificities for subjects without AD and the areas under the receiver operating characteristics curves decreased with age. However, the positive predictive value for a combination of biomarkers remained stable, while the negative predictive value decreased only slightly in old subjects, as an effect of the high AD prevalence in older ages.
Although the diagnostic accuracies for AD decreased with age, the predictive values for a combination of biomarkers remained essentially stable. The findings highlight biomarker variability across ages, but support the use of CSF biomarkers for AD even in older populations.
PMCID: PMC3280049  PMID: 22302554
2.  White Matter Hyperintensities in Mild Lewy Body Dementia 
The objective of this study was to explore the load of white matter hyperintensities (WMH) in patients with Lewy body dementia (LBD) and compare to Alzheimer's disease (AD) and normal controls (NC).
Diagnosis of LBD and AD was made according to consensus criteria and cognitive tests were administered. MRI scans for 77 (61 AD and 16 LBD) patients and 37 healthy elderly control subjects were available for analysis. We segmented WMH from FLAIR images using an automatic thresholding technique and calculated the volume of WMH in several regions of the brain, using non-parametric tests to compare groups. Multivariate regression was applied.
There were no significant differences in WMH between AD and LBD. We found a significant correlation between total and frontal WMH and Mini-Mental State Examination (MMSE) and verbal fluency scores in the AD group, but not in the LBD group.
The WMH load in LBD was similar to that of AD. A correlation between WMH load and cognition was found in the AD group, but not in the LBD group, suggesting that vascular disease contributes to cognitive impairment in AD but not LBD.
PMCID: PMC3507264  PMID: 23189084
Cerebrovascular diseases; Cognition; Alzheimer's dementia; Lewy body dementia; Parkinson's disease; Magnetic resonance imaging; White matter hyperintensities
3.  MDS Task Force on Mild Cognitive Impairment in Parkinson’s disease: Critical Review of PD-MCI 
There is controversy regarding the definition and characteristics of mild cognitive impairment in Parkinson’s disease.
The Movement Disorders Society commissioned a Task Force to critically evaluate the literature and determine the frequency and characteristics of Parkinson’s disease-mild cognitive impairment and its association with dementia.
Comprehensive PubMed literature review using systematic inclusion and exclusion criteria.
A mean of 26.7% (range, 18.9–38.2%) of non-demented Parkinson’s disease patients have mild cognitive impairment. The frequency of Parkinson’s disease mild cognitive impairment increases with age, disease duration, and disease severity. Impairments occur in a range of cognitive domains, but single domain impairment is more common than multiple domain impairment, and within single domain impairment, non-amnestic is more common than amnestic impairment. A high proportion of patients with Parkinson’s disease-mild cognitive impairment progress to dementia in a relatively short period of time.
The primary conclusions of the Task Force are that: (1) Parkinson’s disease-mild cognitive impairment is common; (2) there is significant heterogeneity within Parkinson’s disease-mild cognitive impairment in the number and types of cognitive domain impairments; (3) Parkinson’s disease-mild cognitive impairment appears to place patients at risk of progressing to dementia; and (4) formal diagnostic criteria for Parkinson’s disease-mild cognitive impairment are needed.
PMCID: PMC3181006  PMID: 21661055
mild cognitive impairment; Parkinson’s disease; systematic review
4.  Mild cognitive impairment in Parkinson disease 
Neurology  2010;75(12):1062-1069.
In studies of mild cognitive impairment (MCI) in Parkinson disease (PD), patients without dementia have reported variable prevalences and profiles of MCI, likely to be due to methodologic differences between the studies.
The objective of this study was to determine frequency and the profile of MCI in a large, multicenter cohort of well-defined patients with PD using a standardized analytic method and a common definition of MCI.
A total of 1,346 patients with PD from 8 different cohorts were included. Standardized analysis of verbal memory, visuospatial, and attentional/executive abilities was performed. Subjects were classified as having MCI if their age- and education-corrected z score on one or more cognitive domains was at least 1.5 standard deviations below the mean of either control subjects or normative data.
A total of 25.8% of subjects (95% confidence interval [CI] 23.5–28.2) were classified as having MCI. Memory impairment was most common (13.3%; 11.6–15.3), followed by visuospatial (11.0%; 9.4–13.0) and attention/executive ability impairment (10.1%; 8.6–11.9). Regarding cognitive profiles, 11.3% (9.7–13.1) were classified as nonamnestic single-domain MCI, 8.9% (7.0–9.9) as amnestic single-domain, 4.8% (3.8–6.1) as amnestic multiple-domain, and 1.3% (0.9–2.1) as nonamnestic multiple-domain MCI. Having MCI was associated with older age at assessment and at disease onset, male gender, depression, more severe motor symptoms, and advanced disease stage.
MCI is common in patients with PD without dementia, affecting a range of cognitive domains, including memory, visual-spatial, and attention/executive abilities. Future studies of patients with PD with MCI need to determine risk factors for ongoing cognitive decline and assess interventions at a predementia stage.
= amnestic multiple-domain MCI;
= amnestic single-domain MCI;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= mild cognitive impairment;
= Mini-Mental State Examination;
= nonamnestic multiple-domain MCI;
= nonamnestic single-domain MCI;
= Parkinson disease;
= Parkinson's Disease Cognitive Rating Scale;
= Unified Parkinson's Disease Rating Scale.
PMCID: PMC2942065  PMID: 20855849
5.  Neuropsychiatric symptoms in Parkinson's disease 
Neuropsychiatric symptoms are common in Parkinson's disease, even at the earliest stages, and have important consequences for quality of life and daily functioning, are associated with increased carer burden and increased risk for nursing home admission. In addition to cognitive impairment, a wide range of neuropsychiatric symptoms have been reported. In this paper, the epidemiology, clinical course, diagnosis, and management of some of the most common neuropsychiatric symptoms in PD are discussed: depression, anxiety, apathy, fatigue and psychotic symptoms. Although much is known regarding the prevalence and course of these symptoms, the empirical evidence for how to manage these symptoms is limited at best. There is thus an urgent need for systematic studies for the pharmacological and non-pharmacological management of these symptoms.
PMCID: PMC2787875  PMID: 19768724
6.  Insomnia in Parkinson's disease: frequency and progression over time 
To examine the development of nocturnal sleeping problems in patients with Parkinson's disease (PD) over an 8‐year period and to study the clinical and demographic correlates of insomnia.
231 patients were included in a population‐based prevalence study in 1993, and re‐examined in 1997 and 2001. At all study visits, we applied semi‐structured interviews to obtain information on clinical and demographic data, as well as on nocturnal sleeping problems. Standardised rating scales of parkinsonism, depression and cognitive impairment were used. The relationship between insomnia and demographic and clinical variables was analysed using population‐averaged logistic regression models for correlated data. 231 patients were included at baseline, 142 were available for re‐evaluation in 1997 and 89 patients in 2001.
Most nocturnal sleeping problems varied little in prevalence over time, whereas problems related to turning in bed and vivid dreaming or nightmares increased. Insomnia was present in 54–60% of the patients at each of the three study visits and varied considerably in individual patients over time. The presence of insomnia was closely related to disease duration, higher Montgomery–Åsberg Depression Rating Scale scores and female sex.
Insomnia is a highly frequent complaint in patients with PD. It fluctuates over time in individual patients, and its origin seems to be multifactorial. Physicians should be aware of the high prevalence of insomnia in patients with PD and should examine their patients for a possible coexisting depression.
PMCID: PMC2117851  PMID: 17098844
7.  Neuropsychiatric symptoms in patients with Parkinson's disease and dementia: frequency, profile and associated care giver stress 
To explore the profile of neuropsychiatric symptoms in patients with dementia associated with Parkinson's disease (PDD).
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.
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.
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.
PMCID: PMC2117797  PMID: 16820421
8.  Attentional deficits affect activities of daily living in dementia‐associated with Parkinson's disease 
To investigate the effects of attentional deficits on activities of daily living (ADL) in patients with dementia associated with Parkinson's disease (PDD).
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.
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.
Impaired attention is an important determinant of ADL functions in patients with PDD.
PMCID: PMC2077544  PMID: 16801351
9.  Diagnosis and management of Parkinson's disease dementia 
Parkinson's disease (PD) has long been considered predominantly a motor disorder. However, its frequent association with dementia, which contributes significantly to the morbidity and mortality of the condition, is gaining increasing recognition. PD dementia (PDD) has a unique clinical profile and neuropathology, distinct from Alzheimer's disease (AD). Cholinergic deficits, a feature of both AD and PDD, underlie the rationale for cholinesterase inhibitor therapy in both conditions. In clinical practice, it is important that PDD should be recognised and appropriately treated. This review aims to outline the recently proposed clinical diagnostic criteria for PDD and to summarise the guidelines/recommendations published since 2006 on the use of cholinesterase inhibitors in the management of PDD. Although the cholinesterase inhibitor rivastigmine has recently been approved for the management of PDD, there remains a need for the development of novel therapies that can affect key mechanisms of the disease or prevent/delay patients with PD and mild cognitive impairment from progressing to PDD.
PMCID: PMC2658001  PMID: 18822028
10.  Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease 
Background: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown.
Objectives: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease).
Design: Survey of cognitive features.
Setting: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA.
Patients: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education.
Main outcome measures: Dementia rating scale subscores corrected for age.
Results: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001).
Conclusions: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.
PMCID: PMC1738667  PMID: 12933921
11.  Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study 
Objective: To study the safety and efficacy of the cholinesterase inhibitor donepezil in patients with Parkinson's disease (PD) and cognitive impairment.
Methods: This was a double blind, randomised and placebo controlled, crossover study in which 14 patients with PD and cognitive impairment received donepezil (5 or 10 mg per day) or matching placebo during two sequential periods lasting 10 weeks each. The primary outcome measures were the mini mental state examination (MMSE) score, the clinician's interview based impression of change plus caregiver input (CIBIC+) score, and the motor subscale of the unified Parkinson's disease rating scale (UPDRS).
Results: Two patients on donepezil (14%) dropped out after one and four weeks of the first treatment period because of peripheral cholinergic side effects, otherwise the adverse effects were few and not severe. Carryover or residual effects were not observed. Parkinsonism did not increase during donepezil treatment. After 10 weeks of treatment, the mean MMSE score was increased by 2.1(SD 2.7) points on donepezil and 0.3 (SD 3.2) points on placebo, and the CIBIC+ score was 3.3 (SD 0.9) on donepezil and 4.1 (SD 0.8) on placebo. Statistical analysis of the repeated measurements and crossover study design showed significant effects of donepezil compared with placebo for MMSE (p=0.013) and CIBIC+ (p=0.034). Five (42%) patients on donepezil and two (17%) on placebo were rated as improved on the basis of the CIBIC+ score.
Conclusions: Donepezil improves cognition, and seems to be well tolerated and not to worsen parkinsonism in patients with cognitive impairment.
PMCID: PMC1737925  PMID: 12023410

Results 1-12 (12)