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Alexopoulos P.,TU Munich | Alexopoulos P.,University of Patras | Kriett L.,TU Munich | Haller B.,TU Munich | And 11 more authors.
Alzheimer's and Dementia | Year: 2014

New diagnostic criteria for Alzheimer's disease (AD) treat different biomarkers of neuronal injury as equivalent. Here, we quantified the degree of agreement between hippocampal volume on structural magnetic resonance imaging, regional glucose metabolism on positron emission tomography, and levels of phosphorylated tau in cerebrospinal fluid (CSF) in 585 subjects from all phases of the AD Neuroimaging Initiative. The overall chance-corrected agreement was poor (Cohen κ, 0.24-0.34), in accord with a high rate of conflicting findings (26%-41%). Neither diagnosis nor APOE ε4 status significantly influenced the distribution of agreement between the biomarkers. The degree of agreement tended to be higher in individuals with abnormal versus normal CSF β-amyloid (Aβ1-42) levels. Prospective diagnostic criteria for AD should address the relative importance of markers of neuronal injury and elaborate a way of dealing with conflicting biomarker findings. © 2014 The Alzheimer's Association. All rights reserved.


Ortner M.,TU Munich | Kurz A.,TU Munich | Alexopoulos P.,TU Munich | Auer F.,TU Munich | And 10 more authors.
Biological Psychiatry | Year: 2015

BACKGROUND: There is controversy concerning whether Alzheimer's disease (AD) with early onset is distinct from AD with late onset with regard to amyloid pathology and neuronal metabolic deficit. We hypothesized that compared with patients with early-onset AD, patients with late-onset AD have more comorbid small vessel disease (SVD) contributing to clinical severity, whereas there are no differences in amyloid pathology and neuronal metabolic deficit. METHODS: The study included two groups of patients with probable AD dementia with evidence of the AD pathophysiologic process: 24 patients with age at onset <60 years old and 36 patients with age at onset >70 years old. Amyloid deposition was assessed using carbon-11-labeled Pittsburgh compound B positron emission tomography, comorbid SVD was assessed using magnetic resonance imaging, and neuronal metabolic deficit was assessed using fluorodeoxyglucose positron emission tomography. Group differences of global and regional distribution of pathology were explored using region of interest and voxel-based analyses, respectively, carefully controlling for the influence of dementia severity, apolipoprotein E genotype, and in particular SVD. The pattern of cognitive impairment was determined using z scores of the subtests of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery. RESULTS: Patients with late-onset AD showed a significantly greater amount of SVD. No statistically significant differences in global or regional amyloid deposition or neuronal metabolic deficit between the two groups were revealed. However, when not controlling for SVD, subtle differences in fluorodeoxyglucose uptake between early-onset AD and late-onset AD groups were detectable. There were no significant differences regarding cognitive functioning. CONCLUSIONS: Age at onset does not influence amyloid deposition or neuronal metabolic deficit in AD. The greater extent of SVD in late-onset AD influences the association between neuronal metabolic deficit and clinical symptoms. © 2015 Society of Biological Psychiatry.


Li R.,TU Munich | Perneczky R.,Imperial College London | Perneczky R.,TU Munich | Perneczky R.,West London Cognitive Disorders Treatment and Research Unit | And 2 more authors.
Journal of Intelligent Information Systems | Year: 2015

Subgroup discovery is a task at the intersection of predictive and descriptive induction, aiming at identifying subgroups that have the most unusual statistical (distributional) characteristics with respect to a property of interest. Although a great deal of work has been devoted to the topic, one remaining problem concerns the redundancy of subgroup descriptions, which often effectively convey very similar information. In this paper, we propose a quadratic programming based approach to reduce the amount of redundancy in the subgroup rules. Experimental results on 12 datasets show that the resulting subgroups are in fact less redundant compared to standard methods. In addition, our experiments show that the computational costs are significantly lower than the costs of other methods compared in the paper. © 2013, Springer Science+Business Media New York.


Ritchie C.W.,Imperial College London | Ritchie C.W.,West London Cognitive Disorders Treatment and Research Unit | Wells K.,Imperial College London | Ritchie K.,Imperial College London | Ritchie K.,French Institute of Health and Medical Research
International Review of Psychiatry | Year: 2013

It is clear that the neurodegenerative disease processes which cause dementias are initiated many years before the onset of symptoms. In people with mild cognitive impairment there is already good evidence available to suggest that many of the key pathologies are well established. The PREVENT research programme seeks to understand the origin point and sequence of pathological changes which lead to dementia. It also aims to determine what clinical, environmental and genetic factors increase (or decrease) the risk of these changes initiating and developing. From this data we will be able to develop risk models that can be applied both in clinical practice and research which illustrate the chances a given individual has of developing clinical symptoms of neurodegenerative disease. Once these risks are identified and the sequence of pathological events are characterized; interventions to remove risk or reduce the impact of a risk can be undertaken, as can studies of agents which specifically target the earliest or most up-stream pathological processes. This paper provides the conceptual framework for the PREVENT programme and other similar studies interrogating people in midlife with a view to providing empirical evidence to inform intervention studies and better clinical practice. © 2013 Institute of Psychiatry.


Perneczky R.,Imperial College London | Perneczky R.,West London Cognitive Disorders Treatment and Research Unit | Perneczky R.,TU Munich | Alexopoulos P.,TU Munich | Kurz A.,TU Munich
Trends in Molecular Medicine | Year: 2014

Recently revised diagnostic guidelines for Alzheimer's disease (AD) emphasise the use of biomarkers, heralding a paradigm shift towards a more biological definition of the disorder. Currently available biomarkers offer added diagnostic accuracy in certain situations, but their performance in terms of early diagnostic sensitivity and specificity does not fully live up to the desired standards. One feasible approach to improve the diagnostic and prognostic performance of AD biomarkers is to measure upstream events of amyloid precursor protein (APP) processing, which are at the core of the initial phase of AD pathogenesis. Here we review evidence on the APP processing enzymes and their cleavage products and discuss possible applications and limitations in their use as AD biomarkers. © 2013 Elsevier Ltd.


Wilson D.,Imperial College London | Peters R.,West London Cognitive Disorders Treatment and Research Unit | Ritchie K.,Imperial College London | Ritchie C.W.,Imperial College London
Therapeutic Advances in Chronic Disease | Year: 2011

Objectives: In this paper we aim to: (1) identify and review midlife risk factors that may contribute to the development of dementia and that may be amenable to intervention; (2) review advances made in our understanding of the most common cause of dementia, Alzheimer's disease (AD), where current pharmacological studies have aimed to modify the disease course; and (3) explore other interventions that may slow cognitive decline in those with AD. Methods: A review of the literature was conducted to look for interventions that may modify the risk of incident dementia or that may modify symptom progression in those with diagnosed dementia. Results: (1) Midlife risks identified as amenable to intervention include blood pressure, diabetes, elevated cholesterol, poor psychosocial and lifestyle factors. (2) The leading drugs in development can be grouped by their principal target: anti-amyloid, anti-tau and mitochondrial stability. However to date, there have been no successes in late stage Phase III trials of putative disease-modifying drugs for AD. (3) Once the diagnosis of dementia has been made there is little that can slow the rate of decline. Possible exceptions include the use of exercise and antihypertensive medication with some nootropic medication showing promise in small trials. Conclusion: (1) It is clear that there are several risk factors in midlife that may lead to a greater likelihood of developing dementia. However, there is no simple intervention to modify these risks. It seems sensible to conclude from the data that avoiding high blood pressure, controlling cholesterol and diabetes as well as maintaining a healthy diet and lifestyle may lower the risk of developing dementia. (2) The need for better outcome measures in clinical trials is evident and may, in part, explain the numerous failures in late-stage clinical trials of disease-modifying drugs. Improved diagnostic test batteries to reduce population heterogeneity in early intervention studies will be required for robust clinical trials in the future. (3) Current research indicates that there is little that can delay decline; however, future trials may wish to focus on nootropics. © The Author(s), 2011.


Bronner K.,TU Munich | Perneczky R.,TU Munich | Perneczky R.,Imperial College London | Perneczky R.,West London Cognitive Disorders Treatment and Research Unit | And 3 more authors.
BMC Research Notes | Year: 2016

Background: The relevance of early decision making will rise with increasing availability of early detection of Alzheimer's disease (AD) using brain imaging or biomarkers. Results: Five people with mild AD, six relatives and 13 healthcare professionals with experience in the management of AD were interviewed in a qualitative study regarding medical and social decision topics that emerge after early diagnosis of Alzheimer's disease. Medical treatment, assistance in everyday life and legal issues emerged as the main decision topics after an early diagnosis of AD. People with AD mostly got in contact with the health and social care system through the initiative of their spouses. They were usually aware of their illness and most received antidementia drugs and/or behavioural interventions. Following diagnosis people with AD received support by their spouses. Healthcare professionals were aware of the risk of excessive demand on relatives due to supporting their family member with AD. In the opinion of healthcare professionals legal issues should be arranged in time before patients lose their decisional capacity. In addition, people with AD and spouses reported various coping strategies, in particular "carry on as normal" after diagnosis but mostly are reluctant to actively plan for future stages of the disease. Conclusions: Due to the common desire to "carry on as usual" after a diagnosis of AD, many people with AD and spouses may miss the opportunity to discuss and decide on important medical and social topics. A structured approach e.g. a decision aid might support people with AD and spouses in their decision making process and thereby preserve persons' with AD autonomy before they lose the capacity in decision-making. © 2016 Bronner et al.


Guo L.-H.,TU Munich | Alexopoulos P.,TU Munich | Perneczky R.,TU Munich | Perneczky R.,Imperial College London | Perneczky R.,West London Cognitive Disorders Treatment and Research Unit
European Archives of Psychiatry and Clinical Neuroscience | Year: 2013

The main objective of the study was to validate the findings of previous cerebrospinal fluid (CSF) proteomic studies for the differentiation between Alzheimer's disease (AD) dementia and physiological ageing. The most consistently significant proteins in the separation between AD dementia versus normal controls using CSF proteomics were identified in the literature. The classification performance of the four pre-selected proteins was explored in 92 controls, 149 patients with mild cognitive impairment (MCI), and 69 patients with AD dementia. Heart-type fatty acid binding protein (hFABP) and vascular endothelial growth factor (VEGF) CSF concentrations distinguished between healthy controls and patients with AD dementia with a sensitivity and specificity of 57 and 35 %, and 76 and 84 %, respectively. The optimal classification was achieved by a combination of the two additional CSF biomarker candidates in conjunction with the three established markers Amyloid-β (Aβ)1-42, total-Tau (tTau), and phosphorylated-Tau (pTau) 181, which resulted in a sensitivity of 83 % and a specificity of 86 %. hFABP also predicted the progression from MCI to AD dementia. The present study provides evidence in support of hFABP and VEGF in CSF as AD biomarker candidates to be used in combination with the established markers Aβ1-42, tTau, and pTau181. © 2013 Springer-Verlag Berlin Heidelberg.


Perneczky R.,Imperial College London | Perneczky R.,West London Cognitive Disorders Treatment and Research Unit | Perneczky R.,TU Munich | Alexopoulos P.,TU Munich
Alzheimer's and Dementia | Year: 2014

Methods BACE1 activity and protein concentrations were measured and analyzed in 342 participants of the Alzheimer's Disease Neuroimaging Initiative, including 99 normal control, 75 stable mild cognitive impairment (MCI), 87 progressive MCI, and 79 AD dementia cases. All statistical analyses were Bonferroni corrected for multiple comparisons.Results No significant differences between controls and any of the three patient groups were detected for BACE1 activity and soluble APPβ (sAPPβ) concentrations in CSF. Significant correlations with BACE1 activity were found for CSF APPβ and total tau in all four groups and for CSF phosphorylated tau181 in all groups but the progressive MCI group. There were no correlations for CSF amyloid β (Aβ)1-42 or for plasma Aβ1-42 and Aβ1-40.Conclusions The consistent correlation between BACE1 activity and sAPPβ supports their role as biomarkers of target engagement in clinical trials on BACE1 inhibition.Objective The objective of this study was to assess cerebrospinal fluid (CSF) β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) activity in relation to Alzheimer's disease (AD) and to correlate the enzyme activity with protein markers of APP metabolism and axonal degeneration. © 2014 The Alzheimer's Association.


PubMed | West London Cognitive Disorders Treatment and Research Unit
Type: Journal Article | Journal: International psychogeriatrics | Year: 2013

Connecting willing patients with dementia to suitable clinical research studies has been historically challenging. The United Kingdom Dementia and Neurodegenerative Research Network (DeNDRoN) was established to link patients into high-quality studies. One component is DemReg, a register of dementia patients and their carers who have agreed to be approached regarding future research studies. The limited literature highlights the predominance of altruism mediating research register participation. The objective of this study was to understand the motivations of patients and carers to participate in DemReg.There were 107 participants in the study, interviewed using a questionnaire to determine which factors were important in their decision to be on the register. The study compared the proportion of the altruistic motivations articulated with the proportion of the other answers offered.The two most important motivators for registering on DemReg were to help others (44%; p < 0.001) or themselves (29%; p < 0.001) and altruistic motives took precedence over those for personal benefit. Participants were not motivated by the prospect of payment or by concern that they would be letting down their clinician if they did not register.There are currently major projects within the United Kingdom to increase the number of patients on dementia registers and to further involvement in dementia research. This study, to the best of our knowledge, is the first to assess the motivations of patients and carers for joining a dementia research register in the United Kingdom, and the findings highlight the importance of altruistic motives.

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