Elles Konijnenberg

Functional and effective whole brain connectivity using magnetoencephalography to identify monozygotic twin pairs

Resting-state functional connectivity patterns are highly stable over time within subjects. This suggests that such ‘functional fingerprints’ may have strong genetic component. We investigated whether the functional (FC) or effective (EC) connectivity patterns of one monozygotic twin could be used to identify the co-twin among a larger sample and determined the overlap in functional fingerprints within monozygotic (MZ) twin pairs using resting state magnetoencephalography (MEG). We included 32 cognitively normal MZ twin pairs from the Netherlands Twin Register who participate in the EMIF-AD preclinAD study (average age 68 years). Combining EC information across multiple frequency bands we obtained an identification rate over 75%. Since MZ twin pairs are genetically identical these results suggest a high genetic contribution to MEG-based EC patterns, leading to large similarities in brain connectivity patterns between two individuals even after 60 years of life or more.

Assessing Amyloid Pathology in Cognitively Normal Subjects using [18F]Flutemetamol PET: Comparing Visual Reads and Quantitative Methods

Our objective was to determine the optimal approach for assessing amyloid disease in a cognitively normal elderly population. Methods: Dynamic 18F-flutemetamol PET scans were acquired using a coffee-break protocol (a 0- to 30-min scan and a 90- to 110-min scan) on 190 cognitively normal elderly individuals (mean age, 70.4 y; 60% female). Parametric images were generated from SUV ratio (SUVr) and nondisplaceable binding potential (BPND) methods, with cerebellar gray matter as a reference region, and were visually assessed by 3 trained readers. Interreader agreement was calculated using κ-statistics, and semiquantitative values were obtained. Global cutoffs were calculated for both SUVr and BPND using a receiver-operating-characteristic analysis and the Youden index. Visual assessment was related to semiquantitative classifications. Results: Interreader agreement in visual assessment was moderate for SUVr (κ = 0.57) and good for BPND images (κ = 0.77). There was discordance between readers for 35 cases (18%) using SUVr and for 15 cases (8%) using BPND, with 9 overlapping cases. For the total cohort, the mean (±SD) SUVr and BPND were 1.33 (±0.21) and 0.16 (±0.12), respectively. Most of the 35 cases (91%) for which SUVr image assessment was discordant between readers were classified as negative based on semiquantitative measurements. Conclusion: The use of parametric BPND images for visual assessment of 18F-flutemetamol in a population with low amyloid burden improves interreader agreement. Implementing semiquantification in addition to visual assessment of SUVr images can reduce false-positive classification in this population.

ASSESSMENT OF EARLY AMYLOID PATHOLOGY USING [18F]FLUTEMETAMOL POSITRON EMISSION TOMOGRAPHY: COMPARING VISUAL READ, SEMI-QUANTITATIVE AND QUANTITATIVE METHODS

of disease modifying treatment. Unconditional benefits were reported less frequently but include the potential for positive lifestyle changes (e.g. improved diet and exercise) and future planning. Conclusions:Physicians’ perceptions demonstrated a risk-benefit assessment of amyloid imaging in preclinical individuals. Frequently cited risks to employment and insurability highlight the need for legal protections specifically for biomarkers. The reported riskbenefit assessment will contribute to the development of standardized counseling and informed consent methods for amyloid PET imaging.

AMYLOID AGGREGATION IS ASSOCIATED WITH DECLINE ON DIGIT SPAN BACKWARD IN COGNITIVELY NORMAL ELDERLY MONOZYGOTIC TWINS

Figure 1. Association baseline CSF Ab42/40 ratio and Digit Span Backwards. Jori Tomassen, Anouk den Braber, Elles Konijnenberg, Mara ten Kate, Sandra D. Mulder, Charlotte E. Teunissen, Dorret I. Boomsma, Philip Scheltens, Pieter Jelle Visser, Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; Department of Biological Psychology, VU University, Amsterdam, Netherlands; Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, Netherlands; Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands. Contact e-mail: j.tomassen@vumc.nl

WHITE MATTER MICROSTRUCTURE AND AMYLOID AGGREGATION IN COGNITIVELY HEALTHY, ELDERLY IDENTICAL TWINS

Background: Lack of effective predictive models and/or treatments for Alzheimers Disease (AD) has led a growing movement towards better characterization of pre-clinical stages. One currently established biomarker is positron emission tomography (PET) measured amyloid beta load. Here, in a genetically informative population of cognitively healthy, elderly identical twins, we compared this biomarker to a promising new candidate; white matter (WM) integrity measured by diffusion tensor imaging (DTI). Method(s): Eighty-eight genetically identical twin-pairs and 14 individual twins (n=190, mean age(SD)= 70 (7.5)) were selected from the EMIF-AD PreclinAD study. Abeta load, as a measure for amyloid aggregation, was quantified from [18F] Flutemetamol PET scans. Regional measurements of fractional anisotropy (FA) and mean diffusivity (MD), obtained with tract-based spatial statistics (TBSS) from FMRIBs Software Library (FSL), were used as measures for WM integrity. Within-subject associations between amyloid aggregation and WM integrity were estimated using generalized estimating equations, correcting for twin dependency. A possible shared etiology between amyloid aggregation and WM integrity was further explored using a cross-twin cross-trait (CTCT) design, testing whether amyloid aggregation in a twin could predict WM integrity in the co-twin. Analyses were adjusted for age, sex and intracranial volume. Result(s): Amyloid aggregation predicted trends in increased FA and decreased MD. Regions of interest (ROIs) that met p

CORRELATION OF GREY MATTER NETWORK MEASURES IN COGNITIVELY HEALTHY ELDERLY MONOZYGOTIC TWIN PAIRS

pattern with 4 different quadrants shown for 3 s (sample). After a brief delay (simultaneous condition, 0 s, 4 s, and 12 s) four similar patterns appeared for the subject tomatchwith the sample (Fig.1). Five trials of each DMS condition were administered interspersed with visual fixation baseline. Six right-handed adults performed DMS during fMRI at 3T. The Pronto Toolkit was used to optimize preprocessing pipelines (Churchill PloSone-2015); Z-scored maps of each trial vs. baseline were obtained using a Gauss Na€ıve Base (GNB) model. Principal Component Analysis (PCA) was performed on the 6 Z-scored maps to obtain brain patterns that explained the most variance across subjects.Results:Fig. 2 depicts group brain maps for the 4 s and 12 s delay conditions. Increased brain activity is observed in medial temporal lobe (MTL) structures during performance with 12 s delay compared to 4 s delay, including recruitment of left hippocampus, as well as increased activity in superior, middle, and inferior frontal gyri and the anterior cingulate. The differences in brain activity patterns are consistent with increased memory demands with increasing time delay. Activity is also observed inmotor, premotor, and ventral premotor cortex consistent with fine motor control of the hand. Conclusions: Results suggest that the tablet with VFHP provides brain activity consistent with performing ecologically valid computerized DMS. This intuitive setup and analysis helps to accurately map activity in the MTL associated with different memory demands.

Correlation of cortical thickness in cognitively healthy elderly monozygotic twin pairs

components. The model detected statistically significant association with pathological markers (MMSE: p1⁄4 3.8e-2, time to conversion: p1⁄44.9e-3, and hippocampal volume: p1⁄41.5e-4) when independently tested on 553 patients with mild cognitive impairment (Figure 4). Conclusions: This study links AD-related brain measures to several biological regulatory functions mediated by common genetic variants. Most importantly, the identified metabolic and cellular pathways are linked to known biochemical mechanisms of AD, and highlight potential targets for developing novel therapeutic agents. IC-02-04 CORRELATION OF CORTICALTHICKNESS IN COGNITIVELY HEALTHY ELDERLY MONOZYGOTIC TWIN PAIRS Anouk den Braber, Elles Konijnenberg, Mara ten Kate, BettyM. Tijms, Frederik Barkhof, Dorret I. Boomsma, Philip Scheltens, Pieter Jelle Visser, Department of Biological Psychology, VUUniversity, Amsterdam, Netherlands; Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands; 3 Department of Radiology and NuclearMedicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands; Alzheimer Center, Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands; VU University Medical Center, Amsterdam, Netherlands; Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands. Contact e-mail: a.den.braber@vu.nl

CONCORDANCE OF [18F]FLUTEMETAMOL AMYLOID DEPOSITION IN COGNITIVELY HEALTHY ELDERLY MONOZYGOTIC TWIN PAIRS

Elles Konijnenberg, Anouk den Braber, Mara ten Kate, Sofie Adriaanse, Maqsood M. Yaqub, Dorret I. Boomsma, Philip Scheltens, Bart N.M. van Berckel, Pieter Jelle Visser, Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands; 2 Department of Biological Psychology, VU University, Amsterdam, Netherlands; Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, Netherlands; VU University Medical Center, Amsterdam, Netherlands; 5 Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands. Contact e-mail: e.konijnenberg@vumc.nl

Prevalence and diagnostic procedures in early-onset dementia in tertiary referral center patients in denmark, sweden, and the netherlands

neuropsychiatric symptoms, apathy was significantly higher (p1⁄40.001) in EOD, whereas motor disturbances (p1⁄40.03) & night time behaviours (p<0.001) was more in LOD. Similar results were observed for AD, apathy, anxiety and depression was more in early-onset AD, whereas agitation, motor disturbances and night time behaviours was higher in late-onset AD (p<0.05). We did not find significant differences between early and late-onset FTD. Regarding treatment history, more number of LOD (66%) compared to EOD (37%)were seeking help for the first time, however the mean duration of illness before seeking any professional helpwas similar in both groups (23-25 months). Conclusions:Presence of non-cognitive symptoms such as apathy differentiated the early from late onset group, though they were similar in co-morbidity, cognition and disease severity. The longer duration of illness at presentation in EOD could be probably due to the delay in diagnoses. Biological and genetic basis for the differences in non-cognitive aspects could be explored in future studies.