Sylvie Slaets

Cerebrospinal Fluid Aβ1-40 Improves Differential Dementia Diagnosis in Patients with Intermediate P-tau181P Levels

It is assumed that the concentration of amyloid-β1-40 (Aβ1-40) in cerebrospinal fluid (CSF) reflects the total amount of Aβ protein in the brain and thus allows a better interpretation of inter-individual differences in Aβ quantity than the Aβ1-42 concentration. In this study, Aβ1-40 was added to the existing CSF biomarker panel of Aβ1-42, total tau (T-tau), and phosphorylated tau (P-tau181P) in order to test whether the accuracy of the differential dementia diagnosis improved. The concentration of Aβ1-40 (INNOTEST® β-amyloid(1-40) prototype version, Innogenetics NV, Belgium) and the other biomarkers (INNOTEST®) was determined in CSF samples from 80 Alzheimers disease (AD) patients, 75 non-AD dementia patients, and 30 controls. A large proportion of the study population had autopsy-confirmed neurodegeneration (AD: 73/80 = 91%; non-AD: 38/75 = 51%). The levels of Aβ1-40 were decreased in AD (10856 ± 4745 pg/mL) and non-AD patients (10519 ± 4491 pg/mL) when compared to controls (14760 ± 7846 pg/mL) (p = 0.002 and p = 0.001). The Aβ1-42/Aβ1-40 ratio was significantly decreased in AD (0.043 ± 0.021) as compared to non-AD patients (0.064 ± 0.027; p < 0.001) and controls (0.053 ± 0.023; p < 0.001). In order to differentiate AD from non-AD patients, a decision tree was constructed. The diagnostic accuracy of the decision tree that contained Aβ1-42, Aβ1-40, P-tau181P, and the Aβ1-42/Aβ1-40 ratio was significantly better than the diagnostic accuracy (80% versus 74%) of the decision tree without Aβ1-40 and the Aβ1-42/Aβ1-40 ratio (p < 0.001). In conclusion, no difference in Aβ1-40 CSF levels was found between AD and non-AD patients, but adding CSF Aβ1-40 and the CSF Aβ1-42/Aβ1-40 ratio to a biomarker-based decision tree, might have an added value for discriminating AD from non-AD patients in case of intermediate CSF P-tau181P values.

Increased CSF α-synuclein levels in Alzheimer's disease: Correlation with tau levels

Given the difficult clinical differential diagnosis between Alzheimers disease (AD) and dementia with Lewy bodies (DLB), growing interest resulted in research on α‐synuclein as a potential cerebrospinal fluid biomarker (CSF) for synucleinopathies.

Amyloid pathology influences aβ1-42 cerebrospinal fluid levels in dementia with lewy bodies.

A significant proportion of patients with dementia with Lewy bodies (DLB) show Alzheimers disease (AD) pathology like senile plaques and neurofibrillary tangles. Biomarkers in cerebrospinal fluid (CSF), such as amyloid-β1-42 (Aβ1-42), total tau (T-tau), and hyperphosphorylated tau (P-tau181P), are linked to the different pathological hallmarks of AD. We set up a study to investigate the influence of AD co-pathology on CSF biomarker concentrations and profiles in autopsy-confirmed DLB. DLB patients with senile plaques showed significantly lower CSF Aβ1-42 concentrations than DLB patients without senile plaques, but not compared to the AD patients. There were no significant differences in CSF T-tau or P-tau181P concentrations between DLB patients with and without neurofibrillary tangles. A correlation was found between the number of APOE ε4 alleles and Aβ1-42 CSF levels in DLB patients with senile plaques. Although the CSF biomarkers Aβ1-42, T-tau, and P-tau181P have an added diagnostic value for the differential dementia diagnosis, concomitant amyloid pathology in DLB limits the use of CSF Aβ1-42 for the differential diagnosis of AD versus DLB.

Diagnostic value of MIBG cardiac scintigraphy for differential dementia diagnosis.

Iodine‐123 metaiodobenzylguanidine (MIBG) cardiac scintigraphy has shown the potential to discriminate dementia with Lewy bodies (DLB) from Alzheimers disease (AD). However, these studies did not reflect clinical practice, as patients with ischemic heart disease, heart failure, diabetes mellitus, arterial hypertension, and hyperlipidemia and patients treated with antidepressants like trazodone were excluded.

Diffusion Kurtosis Imaging: A Possible MRI Biomarker for AD Diagnosis?

Abstract The purpose of this explorative study was to investigate whether diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) parameter changes are reliable measures of white matter integrity changes in Alzheimer’s disease (AD) patients using a whole brain voxel-based analysis (VBA). Therefore, age- and gender-matched patients with mild cognitive impairment (MCI) due to AD (n = 18), dementia due to AD (n = 19), and age-matched cognitively healthy controls (n = 14) were prospectively included. The magnetic resonance imaging protocol included routine structural brain imaging and DKI. Datasets were transformed to a population-specific atlas space. Groups were compared using VBA. Differences in diffusion and mean kurtosis measures between MCI and AD patients and controls were shown, and were mainly found in the splenium of the corpus callosum and the corona radiata. Hence, DTI and DKI parameter changes are suggestive of white matter changes in AD.

Influence of AD pathology on CSF biomarkers in autopsy-confirmed Dementia With Lewy Bodies patients

20 electrode placement system) with a Bluetooth enabled telemetric headset. Proprietary BCI software (BCiLab Clinic) both (i) activates brain circuits (beyond resting state conditions) with auditory stimulation, photic stimulation and/ or cognitive tasks from the CogState computer cognition battery or the Paced Arithmetic Serial Assessment Test (PASAT)while (ii) simultaneously recording the raw EEG data and subject responses for post-acquisition spectral analysis. Bench top assessment of the hardware/software system was conducted by BCI under a US Army Phase 1 SBIR contract. After IRB approval, preliminary assessment of MindScope was conducted in subjects (N 1⁄4 10 in each of 20, 40, 60, 70, 80 years of age) and mild to moderate dementia patients, as assessed byMini-mental State Exam.Results:Analytical testing showed excellent signal to noise ratio of greater than 20 db as well as low intra subject variation. Preliminary studies with CNS active compounds have shown statistically significant differences pre versus post compound administration. Preliminary data in humans from the Palm Drive Hospital Aging study and the Alzheimer study will be presented. Conclusions: A physiologically focused battery of tasks to functionally activate EEG is able to probe elements of brain circuits not presently assessed with standard resting state quantitative EEG. TheMindScope offers a convenient and novel alternative to rapidly, portably and non-invasively assess brain health and functionwith no requirement for technical EEG training. Further work is required to develop the necessary activated EEG signatures to map the brain for its physiological defects.

Resting state functional MRI as a possible biomarker for Alzheimer’s disease: An innovative approach for robust extraction of the default mode network

P4-248 RESTING STATE FUNCTIONAL MRI AS A POSSIBLE BIOMARKER FOR ALZHEIMER’S DISEASE: AN INNOVATIVE APPROACH FOR ROBUST EXTRACTION OF THE DEFAULT MODE NETWORK Hanne Struyfs, Dirk Smeets, Vasilis Terzopoulos, Sylvie Slaets, Laura Wuyts, Benjamin Peters, Frank De Belder, Paul M. Parizel, Wim Van Hecke, Sebastiaan Engelborghs, Reference Center for Biological Markers of Dementia (BIODEM), Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; icoMetrix, Leuven, Belgium; icoMetrix, Leuven, Belgium; University of Antwerp, Antwerp, Belgium; Antwerp University Hospital & University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp, Middelheim and Hoge Beuken, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Hospital Network Antwerp (ZNA), Antwerp, Belgium. Contact e-mail: hanne.struyfs@uantwerpen.be

THE DIAGNOSTIC VALUE OF MIBG CARDIAC SCINTIGRAPHY FOR DIFFERENTIAL DEMENTIA DIAGNOSIS

on a presentation of the information gathered during the clinical diagnostic work-up at enrollment in the study, a panel of three neurologists experienced with dementia made a consensus clinical dementia diagnosis. The panel was provided with clinical information, such as date of birth, age and gender, history of past illnesses, social history, onset and history of presenting complaint, familial history, medication, physical examination, clinical neurological examination, neuropsychological examination including (amongst others) Mini-Mental State Examination scores (MMSE), brain CT and/or MRI scan. Clinical diagnosis was based on standard clinical diagnostic criteria, allowing the panel to label each clinical diagnosis as probable or possible depending on the likelihood of it being the cause of dementia. All pathological diagnoses were established by the same neuropathologist, who was blinded for the clinical diagnostic results, according to standard neuropathological criteria. Results: Forty-two patients in the population (59%) appeared to have definite AD, whereas 29 (41%) patients had a non-AD dementia The panel clinically diagnosed possible or probable VaD in 27 out of 71 (38%) patients (with or without a concomitant neurodegenerative dementia like AD). Of those 27 patients, diagnosis of VaD was neuropathologically confirmed in only five (19%) patients (p1⁄40.017). Conclusions: In this study, patients with vascular lesions observed with structural brain imaging were often misdiagnosed as a dementia with a presumed clinically significant vascular component as compared to the neuropathological dementia diagnosis. After neuropathological confirmation, the majority of these patients were diagnosed with other dementia types than VaD.

DIFFUSION KURTOSIS IMAGING: A BIOMARKER FOR EARLY DIAGNOSIS OF ALZHEIMER'S DISEASE?

O2-03-05 HYPOMETABOLISM AND CORTICAL ATROPHY IN [18F]FLORBETAPIR ACCUMULATORS AND NON-ACCUMULATORS Sara Mohades, Sulantha Sanjeewa Mathotaarachchi, Maxime Parent, Monica Shin, Seqian Wang, Andrea Lessa Benedet, Antoine Leuzy, Thomas Beaudry, Eduardo Rigon Zimmer, Laksanun Cheewakriengkrai, Daliah Farajat, Vladmir Fonov, Simon Eskildsen, Serge Gauthier, Pedro Rosa-Neto, McGill Center for Studies in Aging, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; McGill Centre for Studies in Aging, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; McGill University, Montreal, Quebec, Canada; Aarhus University, Aarhus, Denmark; McGill Center for Studies in Aging, Montreal, Quebec, Canada; MCSA, Montreal, Quebec, Canada. Contact e-mail: sara.mohades@gmail.com

The CSF Aβ1-40/Aβ1-42 ratio for differential dementia diagnosis

and others recently discovered that BACE1 activity was significantly increased in sporadic AD brains and that the concentrations of both CSF BACE1 enzymatic activity and protein were significantly increased in subjects with amnestic mild cognitive impairment (MCI).We have hypothesized that by using BACE1 as a biomarker candidate in CSF, it may aid in early detection and prediction of AD in the at-risk predementia MCI stage. Lumbar punctures, however, are considered an invasive procedure. It may be difficult to obtain the sample size necessary for biomarker validation studies, or for a broad clinical screening with a diagnostic indicator. Therefore, potential biomarkers from a more accessible source, such as blood plasma, are critical for advancement. In this study,wewanted to understandwhetherBACE in the blood fromMCI andADpatients would be changed.Methods: Therewere at least 100 patients in each group. Clinically, the MCI subjects met Petersen criteria for amnestic MCI and the AD subjects met NINDS-ADRDA criteria for the diagnosis. Control group is composed by age-matched healthy individuals. We used BACE enzymatic activity assay, BACE ELISA, Ab1-x and sAPPb tomeasure BACE enzyme activity, expression levels and reaction product.Results: Both BACE enzyme activity and expression levels are significantly changed in MCI and AD patients compared to healthy agematched controls.Conclusions:To our knowledge, this is the first time blood from MCI and AD patients has been systematically examined for BACE1 functional proteins and enzyme activity, as well as the enzymatic product, sAPPb and total Ab1-x. Here, we report significant changes of BACE1 functional proteins in the blood among subjects with MCI or AD compared to age-matched cognitively normal controls. These finding are highly relevant for the improved hypothesis-driven generation of biomarkers for AD, regarding early detection and prediction, as well as for assessment of mechanisms for amyloid lowering compounds currently in phase II-III clinical trials.