Milica G. Kramberger

EuroInf: A multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease

Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinsons disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open‐label, prospective, observational, 6‐month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 ± 10.6 years; disease duration: 14 ± 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3‐4) and 44 on IJLI (56.8% males, age 62.7 ± 9.1 years; disease duration: 16.1 ± 6.7 years; median H & Y stage 4; IQR, 3‐4). Cohens effect sizes (≥0.8 considered as large) were “large” with both therapies with respect to total motor, nonmotor, and quality‐of‐life scores. The Non‐Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy‐five percent on IJLI improved in their quality‐of‐life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open‐label, nonrandomized, comparative study, we report that, in advanced Parkinsons patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality‐of‐life, and some NMS. Controlled, randomized studies are required.

Mild cognitive impairment and deficits in instrumental activities of daily living: a systematic review

IntroductionThere is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia.MethodsThe databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review.ResultsIn 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer’s disease and healthy controls.ConclusionIADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.

Health economic evaluation of treatments for Alzheimer's disease : impact of new diagnostic criteria

The socio‐economic impact of Alzheimer′s disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost‐effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimers Association workgroups in combination with the goal of effective disease‐modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost‐effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD‐dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end‐points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long‐term effects. To improve cost‐effectiveness studies, long‐term population‐based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end‐points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered.

Cerebrospinal Fluid Alzheimer Markers in Depressed Elderly Subjects with and without Alzheimer’s Disease

Background: The aim of this study was to explore the relationship between cerebrospinal fluid Alzheimer’s disease (AD) markers and depression in elderly people. Method: We included subjects with AD as well as persons with subjective cognitive impairment and normal cognition. Depression was assessed with the Cornell Scale for Depression in Dementia, and a cut-off score of >6 was used to define depression. Cerebrospinal fluid was analyzed using commercially available assays for β-amyloid 1–42, total tau, and phosphorylated tau 181. Results: A total of 183 participants (66.7% female) were included (92 with AD and 91 with subjective cognitive impairment), with a mean age (±SD) of 67.6 ± 7.4 years, a Mini-Mental State Examination score of 26.0 ± 4.0, and a median Cornell Scale for Depression in Dementia score of 5 (range 0–19). Depression scores were not associated with higher phosphorylated tau 181 and total tau or reduced β-amyloid 1–42 in AD or non-demented subjects. Conclusions: These results suggest that AD pathology does not contribute to depression, indicating that other factors may be more important. Further studies of the aetiology of depression in elderly people with and without AD are warranted.

Multivariate classification of patients with Alzheimer’s and dementia with Lewy bodies using high-dimensional cortical thickness measurements: an MRI surface-based morphometric study

ContextAlzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the most common neurodegenerative dementia types. It is important to differentiate between them because of the differences in prognosis and treatment approaches.ObjectiveInvestigate if sparse partial least squares (SPLS) classification of cortical thickness measurements could differentiate between AD and DLB.MethodsTwo independent cohorts without MR-protocol alignment in Norway and Slovenia with 97 AD and DLB subjects were enrolled. Cortical thickness measurements acquired with Freesurfer were used in subsequent SPLS classification runs. The cohorts were analyzed separately and afterwards combined. The models were trained with leave-one-out cross validation and test datasets where used when available. To study the impact of MR-protocol alignment, the classifiers were additionally tested on sets drawn exclusively from the independent cohorts.ResultsThe obtained sensitivity/specificity/AUC values were 94.4/88.89/0.978 and 88.2/94.1/0.969 in the Norwegian and Slovenian cohorts, respectively. Both cohorts showed AD-associated pattern of thinning in mid-anterior temporal, occipital and subgenual cingulate cortex, whereas the pattern supportive for DLB included thinning in dorsal cingulate, posterior temporal and lateral orbitofrontal regions. When combining the cohorts, sensitivity/specificity/AUC were 82.1/85.7/0.948 for the training and 77.8/75/0.731 for the testing datasets with the same pattern-of-difference. The models tested on datasets drawn exclusively from the independent cohorts did not produce adequate accuracy.ConclusionSPLS classification of cortical thickness is a good method for differentiating between AD and DLB, relatively stable even for mixed data, but not when tested on completely independent data drawn from different cohorts (without MR-protocol alignment).

Biological confounders for the values of cerebrospinal fluid proteins in Parkinson's disease and related disorders

Cerebrospinal fluid (CSF) has been extensively studied to explore biochemical alterations in subjects with neurodegenerative disorders. In Alzheimers disease, levels of increased CSF tau protein and decreased levels of β‐amyloid 1–42 (Aβ42) have been shown to correlate with brain plaque formation and tangle pathology. Intracellular Lewy inclusions containing aggregated α‐synuclein (α‐syn) represent a pathological hallmark of Parkinsons disease (PD). In most – but not all – studies published to date total CSF α‐syn concentrations have been found to be decreased in disorders related to α‐syn pathology, that is, PD, dementia with Lewy bodies and multiple system atrophy. However, these reports show extensive signal overlap among tested individuals, thereby diminishing its potential for routine use in clinical practice.

Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid‐β1–42, tau, and phosphorylated tau in the diagnostic evaluation of patients with dementia. The recommendations were developed by a multidisciplinary working group based on the available evidence and consensus from focused discussions for (i) identification of Alzheimers disease (AD) as the cause of dementia, (ii) prediction of rate of decline, (iii) cost‐effectiveness, and (iv) interpretation of results. The working group found sufficient evidence to support a recommendation to use CSF AD biomarkers as a supplement to clinical evaluation, particularly in uncertain and atypical cases, to identify or exclude AD as the cause of dementia. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Operational recommendations for the interpretation of ambiguous CSF biomarker results were also provided.

Recommendations for cerebrospinal fluid Alzheimer's disease biomarkers in the diagnostic evaluation of mild cognitive impairment

This article presents recommendations, based on the Grading of Recommendations, Assessment, Development, and Evaluation method, for the clinical application of cerebrospinal fluid (CSF) amyloid‐β1–42, tau, and phosphorylated tau in the diagnostic evaluation of patients with mild cognitive impairment (MCI). The recommendations were developed by a multidisciplinary working group and based on the available evidence and consensus from focused group discussions for 1) prediction of clinical progression to Alzheimers disease (AD) dementia, 2) cost‐effectiveness, 3) interpretation of results, and 4) patient counseling. The working group recommended using CSF AD biomarkers in the diagnostic workup of MCI patients, after prebiomarker counseling, as an add‐on to clinical evaluation to predict functional decline or conversion to AD dementia and to guide disease management. Because of insufficient evidence, it was uncertain whether CSF AD biomarkers outperform imaging biomarkers. Furthermore, the working group provided recommendations for interpretation of ambiguous CSF biomarker results and for pre‐ and post‐biomarker counseling.

Alzheimer's disease cerebrospinal fluid biomarkers predict cognitive decline in lewy body dementia

Alzheimers disease pathologies are common in dementia with Lewy bodies, but their clinical relevance is not clear. CSF biomarkers amyloid beta 1‐42, total tau, and tau phosphorylated at threonine 181 reflect Alzheimers disease neuropathology antemortem. In PD, low CSF amyloid beta 1‐42 predict long‐term cognitive decline, but little is known about these biomarkers as predictors for cognitive decline in Lewy body dementia. The aim of this study was to assess whether Alzheimers disease CSF biomarkers predict cognitive decline in Lewy body dementia.

Neuropsychiatric Symptoms in Parkinson's Disease.

Parkinsons disease (PD) is characterized by motor symptoms, but focused and extensive research in the last years has provided new knowledge in the field of non-motor symptoms. Non-motor symptoms include neuropsychiatric symptoms such as depression, anxiety, psychosis, apathy, impulse control disorders, and occur in the majority of patients with PD. They are associated with impaired quality of life for patients and relatives, additional deterioration of function and increased use of health resources. Medical and surgical therapies commonly used for treatment of PD can induce or worsen such symptoms. This paper discusses the epidemiology, clinical features and treatment approaches for neuropsychiatric symptoms (NPS) in PD in the perspective of clinical practice and management. The prevalence rates of various NPS are high, various demographic, clinical and treatment related variables have shown to be associated with higher risk of NPS. Randomized controlled trials of pharmacological and non-pharmacological treatments of NPS in PD are sparse. Current evidence supports tricyclic antidepressants as efficacious treatment of depression in PD and antipsychotic clozapine as efficacious choice for psychosis. Further studies to evaluate various other management strategies of NPS in PD are required. Neuropsychiatric symptoms in PD should be considered an integral part of the disease; hence a multidisciplinary approach is essential to improve the overall outcome of PD also through raised awareness and enriched knowledge on NPS.