Wasim Khan

Alterations in brain leptin signalling in spite of unchanged CSF leptin levels in Alzheimer's disease

Several studies support the relation between leptin and Alzheimers disease (AD). We show that leptin levels in CSF are unchanged as subjects progress to AD. However, in AD hippocampus, leptin signalling was decreased and leptin localization was shifted, being more abundant in reactive astrocytes and less in neurons. Similar translocation of leptin was found in brains from Tg2576 and apoE4 mice. Moreover, an enhancement of leptin receptors was found in hippocampus of young Tg2576 mice and in primary astrocytes and neurons treated with Aβ1‐42. In contrast, old Tg2576 mice showed decreased leptin receptors levels. Similar findings to those seen in Tg2576 mice were found in apoE4, but not in apoE3 mice. These results suggest that leptin levels are intact, but leptin signalling is impaired in AD. Thus, Aβ accumulation and apoE4 genotype result in a transient enhancement of leptin signalling that might lead to a leptin resistance state over time.

No Differences in Hippocampal Volume between Carriers and Non-Carriers of the ApoE ε4 and ε2 Alleles in Young Healthy Adolescents

Alleles of the apolipoprotein E (ApoE) gene are known to modulate the genetic risk for developing late-onset Alzheimers disease (AD) and have been associated with hippocampal volume differences in AD. However, the effect of these alleles on hippocampal volume in younger subjects has yet to be clearly established. Using a large cohort of more than 1,400 adolescents, this study found no hippocampal volume or hippocampal asymmetry differences between carriers and non-carriers of the ApoE ε4 or ε2 alleles, nor dose-dependent effects of either allele, suggesting that regionally specific effects of these polymorphisms may only become apparent in later life.

A Subset of Cerebrospinal Fluid Proteins from a Multi-Analyte Panel Associated with Brain Atrophy, Disease Classification and Prediction in Alzheimer’s Disease

In this exploratory neuroimaging-proteomic study, we aimed to identify CSF proteins associated with AD and test their prognostic ability for disease classification and MCI to AD conversion prediction. Our study sample consisted of 295 subjects with CSF multi-analyte panel data and MRI at baseline downloaded from ADNI. Firstly, we tested the statistical effects of CSF proteins (n = 83) to measures of brain atrophy, CSF biomarkers, ApoE genotype and cognitive decline. We found that several proteins (primarily CgA and FABP) were related to either brain atrophy or CSF biomarkers. In relation to ApoE genotype, a unique biochemical profile characterised by low CSF levels of Apo E was evident in ε4 carriers compared to ε3 carriers. In an exploratory analysis, 3/83 proteins (SGOT, MCP-1, IL6r) were also found to be mildly associated with cognitive decline in MCI subjects over a 4-year period. Future studies are warranted to establish the validity of these proteins as prognostic factors for cognitive decline. For disease classification, a subset of proteins (n = 24) combined with MRI measurements and CSF biomarkers achieved an accuracy of 95.1% (Sensitivity 87.7%; Specificity 94.3%; AUC 0.95) and accurately detected 94.1% of MCI subjects progressing to AD at 12 months. The subset of proteins included FABP, CgA, MMP-2, and PPP as strong predictors in the model. Our findings suggest that the marker of panel of proteins identified here may be important candidates for improving the earlier detection of AD. Further targeted proteomic and longitudinal studies would be required to validate these findings with more generalisability.

A Multi-Cohort Study of ApoE ɛ4 and Amyloid-β Effects on the Hippocampus in Alzheimer’s Disease

The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk of Alzheimer’s disease (AD). Here, using an AD and normal aging dataset primarily consisting of three AD multi-center studies (n = 1,781), we compared the effect of APOE and amyloid-β (Aβ) on baseline hippocampal volumes in AD patients, mild cognitive impairment (MCI) subjects, and healthy controls. A large sample of healthy adolescents (n = 1,387) was also used to compare hippocampal volumes between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI) scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In the AD and normal aging dataset, hippocampal comparisons were performed in each APOE group and in ɛ4 carriers with positron emission tomography (PET) Aβ who were dichotomized (Aβ+/Aβ–) using previous cut-offs. We found a linear reduction in hippocampal volumes with ɛ4 carriers possessing the smallest volumes, ɛ3 carriers possessing intermediate volumes, and ɛ2 carriers possessing the largest volumes. Moreover, AD and MCI ɛ4 carriers possessed the smallest hippocampal volumes and control ɛ2 carriers possessed the largest hippocampal volumes. Subjects with both APOE ɛ4 and Aβ positivity had the lowest hippocampal volumes when compared to Aβ- ɛ4 carriers, suggesting a synergistic relationship between APOE ɛ4 and Aβ. However, we found no hippocampal volume differences between APOE groups in healthy 14-year-old adolescents. Our findings suggest that the strongest neuroanatomic effect of APOE ɛ4 on the hippocampus is observed in AD and groups most at risk of developing the disease, whereas hippocampi of old and young healthy individuals remain unaffected.

Tract Based Spatial Statistic Reveals No Differences in White Matter Microstructural Organization between Carriers and Non-Carriers of the APOE ɛ4 and ɛ2 Alleles in Young Healthy Adolescents

The apolipoprotein E (APOE) ɛ4 allele is the best established genetic risk factor for Alzheimers disease (AD) and has been previously associated with alterations in structural gray matter and changes in functional brain activity in healthy middle-aged individuals and older non-demented subjects. In order to determine the neural mechanism by which APOE polymorphisms affect white matter (WM) structure, we investigated the diffusion characteristics of WM tracts in carriers and non-carriers of the APOE ɛ4 and ɛ2 alleles using an unbiased whole brain analysis technique (Tract Based Spatial Statistics) in a healthy young adolescent (14 years) cohort. A large sample of healthy young adolescents (n = 575) were selected from the European neuroimaging-genetics IMAGEN study with available APOE status and accompanying diffusion imaging data. MR Diffusion data was acquired on 3T systems using 32 diffusion-weighted (DW) directions and 4 non-DW volumes (b-value = 1,300 s/mm² and isotropic resolution of 2.4×2.4×2.4  mm). No significant differences in WM structure were found in diffusion indices between carriers and non-carriers of the APOE ɛ4 and ɛ2 alleles, and dose-dependent effects of these variants were not established, suggesting that differences in WM structure are not modulated by the APOE polymorphism. In conclusion, our results suggest that microstructural properties of WM structure are not associated with the APOE ɛ4 and ɛ2 alleles in young adolescence, suggesting that the neural effects of these variants are not evident in 14-year-olds and may only develop later in life.

DISTINCT NEURAL SIGNATURES OF DIFFERENT APOE GENE POLYMORPHISMS ON HIPPOCAMPAL VOLUME: A LARGE SCALE STUDY IN ALZHEIMER'S DISEASE AND NORMAL HEALTHY AGEING

neuropsychological tests. Patients were classified as aMCI according to which test showed a deficit, the cutoff for objective impairment as well as the number of tests used to seek a deficit. Five tests were applied: Logical Memory (LM), Verbal Paired Associates (VPA) and Rey Auditory Verbal Learning Test (RAVLT) including 3 parts: learning, delayed recall and recognition.We compared the following groups : G1with only one test evaluated and showing deficit (1/1), G2 with two tests evaluated and deficit in two (2/2), G3 and G4 with deficit in at least one or two of the five tests respectively (1/5 and 2/5). Finally, we stratified the groups according to the cutoff applied in each case (1 SD, 1.5 SD and 2 SD). Results: Mean age was 71.28 years, 57% female. In G1 considering only LM, the cases included as aMCI were : 1SD1⁄4 75 %, 1.5 SD1⁄462 % and 2 SD1⁄4 53% but in G2 considering LM and VPA were : 1 SD1⁄434 %, 1.5 SD1⁄422 % and 2 SD1⁄417 % .In G3 (1/5) the cases included as aMCI were: 1 SD1⁄4100 %; 1.5 SD1⁄4 86 %; and 2 SD1⁄471 % but in G4 were: 1 SD1⁄477 %, 1.5 SD1⁄452 % and 2 SD1⁄438 %. The percentage differences between the different criteria were significant. Conclusions: A consensus on the criteria is needed, because the heterogeneity of aMCI evidenced in this study would impact on the nosological interpretation of this entity.

TRACT-BASED SPATIAL STATISTIC REVEALS NO DIFFERENCES IN WHITE MATTER BETWEEN CARRIERS AND NON-CARRIERS OF THE APOE E4 AND E2 ALLELES IN YOUNG HEALTHY ADOLESCENTS

Andr ea Benedet, Philippe Lemay, Sulantha Sanjeewa Mathotaarachchi, Sara Mohades, Eduardo Rigon Zimmer, Alexandre Dionne-Laporte, Cynthia Picard, Monica Shin, Seqian Wang, Maxime Parent, Lucas Porcello Schilling, Thomas Beaudry, Felix Carbonnell, Vladmir Fonov, Serge Gauthier, Guy Rouleau, Judes Poirier, Pedro Rosa-Neto, McGill University, Montreal, Quebec, Canada; Universit e de Montr eal, Montreal, Quebec, Canada; McGill Centre for Studies in Aging, Montreal, Quebec, Canada; McGill Center for Studies in Aging, Montreal, Quebec, Canada; Douglas Mental Health University Institute, Montreal, Quebec, Canada; McGill Centre for Studies in Aging, Montreal, Quebec, Canada; McGill Centre for Studies in Aging/Translational Neuroimaging Laboratory, Montreal, Quebec, Canada; Biospective Inc., Montreal, Quebec, Canada; Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada; Montreal Neurological Institute and Hospital, Montreal, Quebec, Canada; Montreal Neurological Institute and Hospital, Porto Alegre, Brazil. Contact e-mail: andrea.benedet@mail.mcgill.ca

Identifying novel CSF markers of brain atrophy in Alzheimer's disease and mild cognitive impairment using a multiplex panel of analytes

P1-204 IDENTIFYING NOVEL CSF MARKERS OF BRAIN ATROPHY IN ALZHEIMER’S DISEASE AND MILD COGNITIVE IMPAIRMENT USING A MULTIPLEX PANEL OFANALYTES Steven Kiddle, Wasim Khan, Carlos Aguilar, Madhav Thambisetty, Martina Sattlecker, Stephen Newhouse, Richard Dobson, Andy Simmons, King’s College London, London, United Kingdom; Karonlinska Institute, Stockholm, Sweden; King’s College London, London, United Kingdom; King’s College, London, London, United Kingdom; KCL, London, United Kingdom; King’s College London, Institute of Psychiatry, London, United Kingdom. Contact e-mail: wasim. khan@kcl.ac.uk