The Dutch Parelsnoer Institute - Neurodegenerative diseases; methods, design and baseline results

Background: The is a collaboration between 8 Dutch University Medical Centers in which clinical data and biomaterials from patients suffering from chronic diseases (so called "Pearls") are collected according to harmonized protocols. The Pearl Neurodegenerative Diseases focuses on the role of biomarkers in the early diagnosis, differential diagnosis and in monitoring the course of neurodegenerative diseases, in particular Alzheimer's disease. Methods: The Pearl Neurodegenerative Diseases is a 3-year follow-up study of patients referred to a memory clinic with cognitive complaints. At baseline, all patients are subjected to a standardized examination, including clinical data and biobank materials, e.g. blood samples, MRI and cerebrospinal fluid. At present, in total more than 1000 patients have been included, of which cerebrospinal fluid and DNA samples are available of 211 and 661 patients, respectively. First descriptives of a subsample of the data (n = 665) shows that patients are diagnosed with dementia (45%), mild cognitive impairment (31%), and subjective memory complaints (24%). Discussion: The Pearl Neurodegenerative Diseases is an ongoing large network collecting clinical data and biomaterials of more than 1000 patients with cognitive impairments. The project has started with data analyses of the baseline characteristics and biomarkers, which will be the starting point of future specific research questions that can be answered by this unique dataset

Widespread disruption of functional brain organization in early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (AD) patients present a different clinical profile than late-onset AD patients. This can be partially explained by cortical atrophy, although brain organization might provide more insight. The aim of this study was to examine functional connectivity in early-onset and late-onset AD patients. Resting-state fMRI scans of 20 early-onset (<65 years old), 28 late-onset (≥65 years old) AD patients and 15 "young" (<65 years old) and 31 "old" (≥65 years old) age-matched controls were available. Resting-state network-masks were used to create subject-specific maps. Group differences were examined using a non-parametric permutation test, accounting for gray-matter. Performance on five cognitive domains were used in a correlation analysis with functional connectivity in AD patients. Functional connectivity was not different in any of the RSNs when comparing the two control groups (young vs. old controls), which implies that there is no general effect of aging on functional connectivity. Functional connectivity in early-onset AD was lower in all networks compared to age-matched controls, where late-onset AD showed lower functional connectivity in the default-mode network. Functional connectivity was lower in early-onset compared to late-onset AD in auditory-, sensory-motor, dorsal-visual systems and the default mode network. Across patients, an association of functional connectivity of the default mode network was found with visuoconstruction. Functional connectivity of the right dorsal visual system was associated with attention across patients. In late-onset AD patients alone, higher functional connectivity of the sensory-motor system was associated with poorer memory performance. Functional brain organization was more widely disrupted in early-onset AD when compared to late-onset AD. This could possibly explain different clinical profiles, although more research into the relationship of functional connectivity and cognitive performance is needed

The Influence of Co-Morbidity and Frailty on the Clinical Manifestation of Patients with Alzheimer's Disease

Item does not contain fulltextCo-morbidity and frailty are common in Alzheimer's disease (AD) and may contribute to the heterogeneity in clinical manifestations of the disease. We cross-sectionally investigated whether co-morbidity and frailty were independently associated with the clinical manifestation of AD in the 4C-Dementia study; a multicenter, longitudinal study in newly diagnosed AD patients. Clinical manifestation was operationalized using a composite of cognitive performance (neuropsychological assessment), activities of daily living (Disability Assessment for Dementia; DAD) and neuropsychiatric symptoms (Neuropsychiatric Inventory). As predictors of prime interest, co-morbidity was determined using the Cumulative Illness Rating Scale (CIRS-G) and frailty by the Fried criteria. In total, 213 AD patients participated (mean age 75 +/- 10 years; 58% females). In linear regression models adjusted for age, gender, education, and disease duration, CIRS-G (beta = -0.21, p < 0.01) and frailty (beta = -0.34, p < 0.001) were separately associated with clinical AD manifestation. However, CIRS-G (beta = -0.12, p = 0.12) lost statistical significance when both were combined (frailty: beta = -0.31, p < 0.001). Models with the individual components of clinical AD manifestation as dependent variables show significant associations between cognitive performance and CIRS-G (beta = -0.22, p = 0.01), and between DAD and frailty (beta = -0.37, p < 0.001). Our findings indicate that physical health and clinical AD manifestation are associated. This association may be responsible for part of the heterogeneity in the presentation of AD. This emphasizes the importance of adequate assessment of co-morbid medical conditions and frailty in patients with AD.9 p

Frozen-Ground Cartoons: An international collaboration between artists and permafrost scientists

This project started in October 2015 with a crazy idea: prepare and submit a funding application for an international, multidisciplinary and non-traditional scientific outreach project… within the next 48 hours. Well, it worked out. A group of highly motivated young researchers from Canada and Europe united to combine arts and science and produce a series of outreach comic strips about permafrost (frozen ground). The aim of the project is to present and explain scientific research conducted across the circumpolar Arctic, placing emphasis on field work and the rapidly changing northern environment. The target audience is kids, youth, parents and teachers, with the general goal of making permafrost science more fun and accessible to the public. Because guess what : permafrost represents an area of more than twenty million km2 in the Northern Hemisphere, a huge area. As the climate warms, permafrost thaws and becomes unstable for houses, roads and airports. This rapid thawing of previously frozen ground also disrupts plant and animal habitats, impacts water quality and the ecology of lakes, and releases carbon into the atmosphere as greenhouse gases, making climate change even stronger. Hence permafrost and its response to climate change concerns us all. The project received initial support from the International Permafrost Association (IPA) as a targeted ‘Action Group’, and since then several other sponsors have joined the project. Here we are, now, two years after this first idea. What you are about to read is the result of an iterative process of exchanging ideas between artists and scientists. We first made an application call and received 49 applications from artists in 16 countries. Through a formal review process, we then selected two artists to work on this project: Noémie Ross from Canada, and Heta Nääs from Finland. With input from scientists, Noémie and Heta created fantastic cartoons that explain some of the changes happening to the environment in permafrost areas, how they affect people and wildlife, and what scientists are doing to better understand these changes to help people find innovative ways to adapt. We wish everyone plenty of fun reading this booklet and we would like to thank all those who supported this project

Gray matter loss.

<p>Regions of decreased gray matter volume in early-onset AD (EOAD) patients when compared to age-matched young controls (A). Regions of decreased gray matter volume in late-onset AD (LOAD) patients when compared to age-matched old controls (B). Regions of decreased gray matter volume in early-onset AD patients when compared to late-onset AD (C). Regions of decreased gray matter volume in late-onset AD patients when compared to early-onset AD (D). Results are corrected for multiple comparisons (p<0.05) and are shown in radiological orientation on standard MNI space (MNI152 2 mm). Brighter colors represent most significant results. R = Right. L = Left.</p

Subject characteristics for early-onset Alzheimer’s disease (AD) patients (disease onset <65 years), late-onset AD patients (disease onset ≥65 years), young (<65 years) - and old (≥65 years) healthy age-matched controls (HC).

<p>Data are presented as means ± standard deviations.</p><p>Mini Mental State Examination (MMSE) score and Normalized Gray Matter Volume (NGMV) in litre (L). Level of education using Verhage’s classification <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102995#pone.0102995-Verhage1" target="_blank">[44]</a>. Not applicable (n.a.). Alzheimer’s disease (AD). Healthy controls (HC).</p><p>*All AD patients that were on AD medication used Reminyl, with exception of 1 early-onset AD patient, who used Exelon. Both are competitive and reversible cholinesterase inhibitors.</p>♦<p>significantly different from early-onset AD.</p>¶<p>significantly different from late-onset AD.</p>†<p>significantly different from young controls.</p>‡<p>significantly different from old controls.</p

Lowered functional connectivity in AD patients when compared to age-matched controls.

<p>Upper panel shows lower functional connectivity in early-onset AD patients when compared to ‘young’ age-matched controls. Lower panel shows decreased functional connectivity in late-onset AD patients (EOAD) when compared to ‘old’ age-matched controls. Standard maps of the Resting State Networks (RSNs) are shown in transparent blue. Upper panel: Lower functional connectivity was found in early-onset AD patients when compared to aged-matched young controls within the medial-visual system, lateral-visual system, auditory system, sensory-motor system, default mode network, the executive control network and bilateral dorsal-visual stream. Lower panel: late-onset AD patients (LOAD) show lower functional connectivity when compared to old age-matched controls within the default mode network only. Results are displayed in radiological orientation on standard MNI space (MNI152 2 mm), after correction for multiple comparisons across space (p<0.05). Gender and voxel-wise gray matter maps were used as covariates. Brighter colors represent most significant results. Abbreviations: R = right. L = left.</p

MNI-coordinates (MNI 152, 2 mm) of peak voxel and total number of voxels that showed significant lower functional connectivity within the resting-state networks (RSNs) when comparing early-onset AD (EOAD) patients with age-matched young healthy controls (HC), when comparing late-onset AD (LOAD) patients with age-matched old HC and in a direct comparison between early-onset AD and late-onset AD patients.

<p>Number of voxels are reported when using the FWE corrected p<0.05 and when correcting also for the number of tests (8 RSNs×4 groups) resulting in FWE corrected p<0.0016.</p

Spearman correlation coefficients of functional connectivity (mean z-score) within significant clusters within the resting-state network (RSNs) maps with performance on 5 cognitive domains (mean z-score).

<p>2-tailed Spearman correlation coefficients are reported (p-value) *p<0.05. Significant correlations are highlighted in bold.</p