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Zonneveld H.I.,Alzheimer Center | Goos J.D.C.,Neurology | Wattjes M.P.,Alzheimer Center | Prins N.D.,Neurology | And 5 more authors.
Neurology | Year: 2014

Objective: To determine prevalence, topography, and severity of cortical superficial siderosis (SS), a recently recognized manifestation of cerebral amyloid angiopathy, and its possible association with Alzheimer disease (AD) in a memory clinic patient cohort. Methods: We included 809 patients (56% men, aged 66 6 10 years) from the Amsterdam Dementia Cohort between November 2010 and November 2012 scanned on a 3-tesla MRI system. We analyzed prevalence and topography of cortical SS according to demographic, clinical, and MRI data. Agreement for SS detection between 2 neuroradiologists was calculated by using Cohen k. Results: Agreement for detection of SS was excellent (unweighted k of 0.81). In 17 patients (2.1%), cortical SS was found without a known cause. The prevalence of idiopathic SS differed according to diagnostic groups (p , 0.001): nearly 5% (95% confidence interval [CI] 2.8%- 8.2%) in patients with AD (n 5 168) vs 2% (95%CI 0.7%-6.0%) in patients with mild cognitive impairment (n 5 143) and 2.5% (95% CI 0.7%-8.7%) in other types of dementia (n 5 80). By contrast, SS was not found in patients with subjective complaints (n 5 168) or in those with other disorders (n5157). Presence of SS was associated with APOE e4, microbleeds, and white matter hyperintensities (all p , 0.05) independent of diagnosis. Conclusion: The prevalence of cortical SS in a memory clinic setting is higher than reported in the general population but lower than reported in cerebral amyloid angiopathy. The relatively high prevalence of SS in AD suggests that SS is a relevant radiologic manifestation of amyloid pathology in AD. Presence of SS does not seem to predict severity of AD. Further longitudinal research is needed to investigate clinical relevance.


Van Der Vlies A.E.,Alzheimer Center | Goos J.D.C.,Alzheimer Center | Barkhof F.,Image Analysis Center and Alzheimer Center | Scheltens P.,Alzheimer Center | And 2 more authors.
Neurology | Year: 2012

Objective: To investigate the relationship between brain microbleeds (MBs) and the rate of cognitive decline in Alzheimer disease (AD). Methods: In this cohort study, we studied 221 patients with AD with available baseline MRI scans (1.0 or 1.5 T) and at least 2 Mini-Mental State Examinations (MMSE) scores obtained more than 1 year apart from our memory clinic. Mean ± SD follow-up time was 3 ± 1 years, and patients had a median of 4 MMSE scores (range 2-17). We used linear mixed models with sex and age as covariates to investigate whether MBs influenced the rate of cognitive decline. Results: Mean age was 68 ± 9 years, 109 (49%) patients were female, and the baseline MMSE score was 22 ± 4. There were 39 patients (18%) with MBs (median 2, range 1-27) and 182 without. Linear mixed models showed that overall patients declined 2 MMSE points per year. We found no association of the presence of MBs with baseline MMSE or change in MMSE. Adjustment for atrophy, white matter hyperintensities, lacunes, and vascular risk factors did not change the results nor did stratification for MB location, APOE ε4 carriership, or age at onset (≤65 years vs >65 years). Repeating the analyses with number of MBs as predictor rendered similar results. Conclusion: MBs did not influence the rate of cognitive decline in patients with AD. The formerly reported increased risk of mortality in patients with MBs seems not to be attributable to a steeper rate of decline per se but might be due to vascular events, including (hemorrhagic) stroke. Copyright © 2012 by AAN Enterprises, Inc.


Elias-Sonnenschein L.S.,Maastricht University | Bertram L.,Max Planck Institute for Molecular Genetics | Visser P.J.,Maastricht University | Visser P.J.,Alzheimer Center
Biomarkers in Medicine | Year: 2012

Alzheimers disease (AD) is a neurodegenerative disorder characterized by neuritic plaques (main constituent: -amyloid [A]) and neurofibrillary tangles (hyperphosphorylated tau protein) in the brain. Abnormalities in A and tau can be measured upon neuropathological examination, in cerebrospinal fluid or by PET. Etiologically, a growing body of evidence suggests that susceptibility to AD is genetically controlled. However, the precise nature of the underlying risk genes and their relation to AD biomarkers remains largely elusive. To this end, we performed a qualitative review of 17 studies (covering 47 polymorphisms in 26 genes) and investigated the potential relation between the most compelling AD risk genes and markers for A and tau in cerebrospinal fluid, PET imaging and neuropathological examination. Of all covered genes, only APOE and PICALM showed consistent effects on A but not on tau, while no obvious effects were observed for CLU, CR1, ACE, SORL and MAPT. © 2012 Future Medicine Ltd.


Bertens D.,Alzheimer Center | Knol D.L.,Medical Center | Scheltens P.,Alzheimer Center | Visser P.J.,Alzheimer Center | Visser P.J.,Maastricht University
Alzheimer's and Dementia | Year: 2015

Background We investigated the pattern of disease progression in the asymptomatic, mild cognitive impairment (MCI), and dementia stage of Alzheimer's disease (AD). Methods We selected 284 subjects with AD pathology, defined as abnormal levels of amyloid beta 1-42 (Aβ1-42) in cerebrospinal fluid (CSF). Disease outcome measures included six biomarkers and five cognitive markers. We compared differences in baseline measures and decline over 4 years between the AD stages and tested whether these changes differed from subjects, without AD pathology (N = 132). Results CSF Aβ1-42 reached the maximum abnormality level in the asymptomatic stage and tau in the MCI stage. The imaging and cognitive markers started to decline in the asymptomatic stage, and decline accelerated with advancing clinical stage. Conclusion This study provides further evidence for a temporal evolution of AD biomarkers. Our findings may be helpful to determine stage specific outcome measures for clinical trials. © 2015 The Alzheimer's Association.


HALLE (SAALE), Germany,  8 December  2016 - Probiodrug AG (Euronext Amsterdam: PBD), a biopharmaceutical company developing novel therapeutic solutions to treat Alzheimer's disease (AD), announced today that the study design of the ongoing Phase IIa SAPHIR trial comparing PQ912 to placebo will be presented as a poster on Thursday, December 8, 2016 at the  9th Clinical Trials on Alzheimer's disease (CTAD) meeting in San Diego, USA. The SAPHIR study is a 3 month study in treatment naïve patients with early AD. PQ912 targets the inhibition of the Glutaminylcyclase (QC) resulting in a reduction of the production of neurotoxic pyroGlu-Abeta (pGlu-Abeta) and related oligomers. PQ912 has been extensively investigated in Phase 1 Multiple ascending dose studies (MAD) showing good tolerability and a dose dependent QC-inhibition in the spinal fluid. The SAPHIR study has been designed and is conducted in collaboration with Philip Scheltens, M.D., Ph.D., the VUmc Amsterdam (NL) and the CRO Julius Clinical ( NL). The primary objective of the SAPHIR study is to investigate the safety of PQ912 in the target population and the secondary objective is to assess the pharmacodynamic profile. The publication at CTAD reveals that the study applies a series of methodological innovations which in this combination has not been executed before in an early AD study. Specific in and exclusion criteria based on diagnostic biomarkers of Abeta and tau were required to be met by all patients to ensure a high confidence of the diagnosis of early AD. Mini-Mental State Examination (MMSE) and Cogstate test battery assessments at baseline are monitored blindly every 30 patients to ensure consistency and reliability of ratings. A number of exploratory endpoints like EEG, fMRI and a series of CSF based biomarkers including QC-activity, pGlu-Abeta, Abeta oligomers, neurogranin as well as  inflammation markers are centrally analysed. Based on an exploratory analysis of 86 randomised patients, a low standard deviation for the Neuro-psychological test battery and functional EEG at baseline has been observed. Prof Philip Scheltens, Director of the Alzheimer Center at the VUmc  in Amsterdam and Chairman of the SAPHIR study, said: "The combination of in and exclusion criteria together with the primary and innovative exploratory outcome parameter in the SAPHIR study is unique for an early AD study. We are excited to see the full results in the second quarter of 2017." For more information, please contact: Notes to Editors: About Probiodrug AG Headquartered in Halle (Saale), Germany, Probiodrug AG (Euronext Amsterdam: PBD) is a biopharmaceutical company focused on the development of new therapeutic products for the treatment of Alzheimer's disease. Founded in 1997, the company successfully developed a novel therapeutic concept for diabetes - the DP4 inhibitors - which provided the basis for a novel class of antidiabetics - the gliptins. Its core capabilities are based on its long-standing expertise in the elucidation of the structure and function of enzymes involved in the modification of proteins and peptides, which play a central role in pathological conditions. Today Probiodrug's aim is to become a leading company in the development of Alzheimer's disease treatments and to thereby provide a better life for Alzheimer's disease patients. It has identified a new therapeutic concept linked to disease initiation and progression. The development approaches are targeting pyroglutamate-Abeta (pGlu-Abeta) as a therapeutic strategy to fight Alzheimer's disease. The Company has medical use and composition of matter patents related to the inhibition of Glutaminyl Cyclase (QC) and anti-pGlu-Abeta- specific monoclonal antibodies, providing it, in the Company's view, with a leading position in this field of research. Probiodrug's lead product candidate, PQ912, is a highly specific and potent inhibitor of Glutaminyl Cyclase (QC), which has shown therapeutic effects in Alzheimer's animal models. PQ912 is currently in a Phase 2a study, the SAPHIR trial. In a preceding Phase 1 study with healthy young and elderly volunteers, PQ912 has shown to be safe and well tolerated and also revealed high QC-inhibition. About Alzheimer's disease Alzheimer's disease is a neurological disorder, which is the most common form of dementia, and ultimately leads to death. Because Alzheimer's disease cannot be cured and is degenerative, the affected patients must increasingly rely on others for assistance. . Today, 47 million people live with dementia worldwide, and this number is projected to treble to more than 131 million by 2050, as populations age. Dementia also has a huge economic impact. Alzheimer's has an estimated, global societal cost of US$ 818 billion, and it will become a trillion dollar disease by 2018. (World Alzheimer Report 2016). Forward Looking Statements Information set forth in this press release contains forward-looking statements, which involve a number of risks and uncertainties. The forward-looking statements contained herein represent the judgment of Probiodrug AG as of the date of this press release. Such forward-looking statements are neither promises nor guarantees, but are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in these forward-looking statements. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any such statements to reflect any change in our expectations or any change in events, conditions or circumstances on which any such statement is based.


Ramakers I.H.G.B.,Maastricht University | Verhey F.R.J.,Maastricht University | Scheltens P.,Alzheimer Center | Hampel H.,Goethe University Frankfurt | And 10 more authors.
Psychological Medicine | Year: 2013

Background Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI. Method Subjects with MCI (n=268) were selected from the 'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease' (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid β(1-42) protein (Aβ42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory. Results Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aβ42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.3] and t-tau (OR 2.6, 95% CI 1.9-3.6) concentrations and with the combination of abnormal concentrations of both Aβ42 and t-tau (OR 3.1, 95% CI 2.0-4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aβ42 (agitation: OR 1.6, 95% CI 1.1-2.3; irritability: OR 2.2, 95% CI 1.5-3.3). Symptoms of depression and apathy were not related to any of the CSF markers. Conclusions In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not. © 2012 Cambridge University Press.


Fiala M.,University of California at Los Angeles | Veerhuis R.,Alzheimer Center
Experimental Gerontology | Year: 2010

The ultimate goal of diagnostic research is a blood test detecting the risk of Alzheimer disease (AD) before neuronal damage develops. Current amyloid-β (Aβ) tests do not detect the process leading to neurodegeneration. Novel immunologic and proteomics tests are based on aberrant appearance of inflammatory cytokines in the CSF and other protein biomarkers in the CSF or blood, and immune biomarkers of peripheral blood mononuclear cells (PBMC's). Cytokines, chemokines, complement factors, serum amyloid P component, and signaling proteins in the CSF or blood may be a rich source of diagnostic biomarkers, but the power of these tests will need to be examined in prospective studies. Recently-described flow cytometric test of defective Aβ phagocytosis detects patients with AD with a high sensitivity and specificity in distinct populations (confirmed AD patients vs. active University professors), but further experience is necessary for its use in general population at risk of AD. The analysis of the transcriptome of peripheral blood mononuclear cells "stressed" by Aβ is beginning to unravel the relations between specific pathways and AD. Thus novel diagnostic tests may provide biomarkers for pre-clinical detection, clarification of progression from MCI to AD, and follow-up of patients in clinical trials of immunostimulating therapies. © 2009 Elsevier Inc. All rights reserved.


Bakker C.,Center for Specialized Care in Early Onset Dementia | Bakker C.,Radboud University Nijmegen | De Vugt M.E.,Maastricht University | Van Vliet D.,Maastricht University | And 6 more authors.
American Journal of Geriatric Psychiatry | Year: 2013

Objective: Early onset dementia (EOD) poses specific challenges and issues for both the patient and (in)formal care. This study explores the use of (in)formal care prior to institutionalization, and its association with patient and caregiver characteristics. Design/Setting: Participants were part of a community-based prospective longitudinal study of 215 patients and their informal caregivers. Participants: Baseline data of a subsample of 215 patient-caregiver dyads were analyzed. Measurements: Analyses of covariance were performed to determine correlates of (in)formal care use assessed with the Resource Utilization in Dementia (RUD)-Lite questionnaire. Results: Informal care had a 3:1 ratio with formal care. Supervision/surveillance constituted the largest part of informal care. In more than half of cases, patients had only one informal caregiver. The amount of informal care was associated with disease severity, showing more informal care hours in advanced disease stages. Fewer informal care hours were related to more caregiver working hours, especially in younger patients. The amount of formal care was related to disease severity, behavioral problems, and initiative for activities of daily living. Conclusion: In EOD, it appears that family members provide most of the care. However, other social roles still have to be fulfilled. Especially in spousal caregivers of younger patients in advanced disease stages, there is a double burden of work and care responsibilities. This finding also indicates that even within the EOD group there might be important age-related differences. The relatively higher amount of formal care use during advanced disease stages suggests a postponement in the use of formal care. © 2013 American Association for Geriatric Psychiatry.


Perez G.,Technical University of Ambato | Perez G.,Rey Juan Carlos University | Conci A.,Federal University of Fluminense | Moreno A.B.,Rey Juan Carlos University | Hernandez-Tamames J.A.,Alzheimer Center
Integrated Computer-Aided Engineering | Year: 2014

Preprocessing stage for denoising is a crucial task in image analysis in general, and in computer-aided diagnosis using medical images in particular. Standard acquisition of Magnetic Resonance Images (MRI) presents statistical Rician noise which degrades the performance of the image analysis. This paper presents a new technique to reduce Rician noise of brain MRI. The new method for noise filtering is achieved in the discrete Wavelet Packets Transform (WPT) domain. Four methodologies for thresholding the detail coefficients in the same 2D WPT domain have been experimented considering two scenarios (with and without a previous adaptive Wiener filtering in the spatial domain). Best quantitative and qualitative results have been obtained by the new method presented in this work (specifically tailored for brain MRI), which is adaptive to each subband and dependent on the data. It has been compared with other traditional methods considering the Signal to Noise Ratio (SNR), Normalized Cross Correlation (NCC) and execution time ( 0.1 s/slice). A complete dataset of structural (T1-w) brain MRI of the BrainWeb database has been used for experiments. An important aspect is that these experiments with synthetic images proved that the common prior adaptive Wiener filtering often used by many authors is a dispensable procedure. © 2014 IOS Press.


Hooghiemstra A.M.,VU University Amsterdam | Hooghiemstra A.M.,Alzheimer Center | Eggermont L.H.P.,VU University Amsterdam | Scheltens P.,Alzheimer Center | And 3 more authors.
Alzheimer Disease and Associated Disorders | Year: 2015

Background: A substantial part of elderly persons with dementia show rest-activity rhythm disturbances. The rest-activity rhythm is important to study in people with early-onset dementia (EOD) for rest-activity rhythm disturbances are predictive of institutionalization, and caregivers of young patients suffer from high distress. Objective: The aim of this study was to study (1) whether EOD patients have more rest-activity rhythm disturbances compared with cognitively intact adults; and (2) which factors contribute to a disturbed rhythm. Methods: We included 61 patients with EOD [mean age 61.9 (4.9) y, 41 (67%) men] and 68 cognitively intact adults [mean age 61.6 (4.5) y, 28 (41%) men]. Rest-activity rhythm was assessed by actigraphy. Results: EOD patients tended to have higher intradaily variability [0.46 (0.16) and 0.39 (0.10), P=0.03]. EOD patients also lay for a longer time in bed [time in bed: 08:49 (0:51) h and 08:07 (0:47) h, P<0.001] and needed more time to fall asleep [sleep onset latency: 23 (22) min and 15 (15) min, P=0.02]. Disturbances in the restactivity rhythm were predicted by a low level of physical activity, use of antidepressants and central nervous system neurological medications, and being male. Conclusions: EOD patients showed more variability in the restactivity rhythm compared with cognitively intact adults. The main predictor for rest-activity rhythm disturbances was a low level of physical activity. © 2014 Wolters Kluwer Health, Inc. All rights reserved.

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