[Show abstract][Hide abstract] ABSTRACT: This chapter questions the prevailing "implicit" assumption that molecular mechanisms and the biological phenotype of dominantly inherited early-onset alzheimer's disease (EOAD) could serve as a linear model to study the pathogenesis of sporadic late-onset alzheimer's disease (LOAD). Now there is growing evidence to suggest that such reductionism may not be warranted; these suppositions are not adequate to explain the molecular complexities of LOAD. For example, the failure of some recent amyloid-centric clinical trials, which were largely based on the extrapolations from EOAD biological phenotypes to the molecular mechanisms in the pathogenesis of LOAD, might be due to such false assumptions. The distinct difference in the biology of LOAD and EOAD is underscored by the presence of EOAD cases without evidence of familial clustering or Mendelian transmission and, conversely, the discovery and frequent reports of such clustering and transmission patterns in LOAD cases. The primary thesis of this chapter is that a radically different way of thinking is required for comprehensive explanations regarding the distinct complexities in the molecular pathogenesis of inherited and sporadic forms of Alzheimer's disease (AD). We propose using longitudinal analytical methods and the paradigm of systems biology (using transcriptomics, proteomics, metabolomics, and lipidomics) to provide us a more comprehensive insight into the lifelong origin and progression of different molecular mechanisms and neurodegeneration. Such studies should aim to clarify the role of specific pathophysiological and signaling pathways such as neuroinflammation, altered lipid metabolism, apoptosis, oxidative stress, tau hyperphosphorylation, protein misfolding, tangle formation, and amyloidogenic cascade leading to overproduction and reduced clearance of aggregating amyloid-beta (Aβ) species. A more complete understanding of the distinct difference in molecular mechanisms, signaling pathways, as well as comparability of the various forms of AD is of paramount importance. The development of knowledge and technologies for early detection and characterization of the disease across all stages will improve the predictions regarding the course of the disease, prognosis, and response to treatment. No doubt such advances will have a significant impact on the clinical management of both EOAD and LOAD patients. The approach propped here, combining longitudinal studies with the systems biology paradigm, will create a more effective and comprehensive framework for development of prevention therapies in AD.
[Show abstract][Hide abstract] ABSTRACT: There is a growing body of evidence that subtle deficits in instrumental activities of daily living (IADL) may be present in mild cognitive impairment (MCI). However, it is not clear if there are IADL domains that are consistently affected across patients with MCI. In this systematic review, therefore, we aimed to summarize research results regarding the performance of MCI patients in specific IADL (sub)domains compared with persons who are cognitively normal and/or patients with dementia.
The databases PsycINFO, PubMed and Web of Science were searched for relevant literature in December 2013. Publications from 1999 onward were considered for inclusion. Altogether, 497 articles were retrieved. Reference lists of selected articles were searched for potentially relevant articles. After screening the abstracts of these 497 articles, 37 articles were included in this review.
In 35 studies, IADL deficits (such as problems with medication intake, telephone use, keeping appointments, finding things at home and using everyday technology) were documented in patients with MCI. Financial capacity in patients with MCI was affected in the majority of studies. Effect sizes for group differences between patients with MCI and healthy controls were predominantly moderate to large. Performance-based instruments showed slight advantages (in terms of effect sizes) in detecting group differences in IADL functioning between patients with MCI, patients with Alzheimer’s disease and healthy controls.
IADL requiring higher neuropsychological functioning seem to be most severely affected in patients with MCI. A reliable identification of such deficits is necessary, as patients with MCI with IADL deficits seem to have a higher risk of converting to dementia than patients with MCI without IADL deficits. The use of assessment tools specifically designed and validated for patients with MCI is therefore strongly recommended. Furthermore, the development of performance-based assessment instruments should be intensified, as they allow a valid and reliable assessment of subtle IADL deficits in MCI, even if a proxy is not available. Another important point to consider when designing new scales is the inclusion of technology-associated IADL. Novel instruments for clinical practice should be time-efficient and easy to administer.
Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0099-0 · 3.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of common diseases such as Alzheimer’s disease (AD) and cancer are
currently poorly understood. Inflammation is a common risk factor for cancer and AD. Recent
data, provided by our group and from others, demonstrate that increased pressure and
inflammation are synonymous. There is a continuous increase in pressure from inflammation to
fibrosis and then cancer. This in line with the numerous papers reporting high interstitial pressure
in cancer. But most authors focus on the role of pressure in the lack of delivery of chemotherapy
in the center of the tumor. Pressure may also be a key factor in carcinogenesis. Increased
pressure is responsible for oncogene activation and cytokine secretion. Accumulation of
mechanical stress plays a key role in the development of diseases of old age such as
cardiomyopathy, atherosclerosis and osteoarthritis. Growing evidence suggest also a possible
link between mechanical stress in the pathogenesis of AD. The aim of this review is to describe
environmental and endogenous mechanical factors possibly playing a pivotal role in the
mechanism of chronic inflammation, AD and cancer.
[Show abstract][Hide abstract] ABSTRACT: Identification of blood-based biomarkers of Alzheimer's disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C(11)]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker.
[Show abstract][Hide abstract] ABSTRACT: The clinical differential diagnosis of Alzheimer's disease (AD) and behavioral-variant frontotemporal dementia (bvFTD) can no longer rely only on episodic memory impairment or executive dysfunctions, as highlighted by recent findings showing that both diseases could present with similar impairments. Objective cognitive tests assessing specific symptoms, such as impulsivity in bvFTD, are thus crucially needed. The aim of this study was to evaluate the differences in impulsivity between bvFTD and AD using a delay-discounting paradigm.
An ecological delay-discounting test was administrated to 70 participants including 30 ADs, 20 bvFTD and 20 controls. AD patients were divided according to the severity of the disease into mild or moderate group. The delay-discounting score, reflecting the total percentage of impulsive choice across the entire task, was analyzed for each group.
This score showed that bvFTD patients were significantly more impulsive than controls and AD patients at mild or moderate stage. AD patients, regardless of disease stage, did not differ from controls. ROC analyses revealed high and significant area under the curve (AUC, 95% confidence interval) for this score to differentiate bvFTD from AD (0.704) or controls (0.904), or both group (AD + controls; AUC = 0.791).
The total delay-discounting score provided by our task showed that it could accurately differentiate bvFTD patients from AD and controls. These results support the relevancy of using tests inspired by experimental psychoeconomics and taping into reward processing to increase the distinction between both diseases. (PsycINFO Database Record
(c) 2015 APA, all rights reserved).
[Show abstract][Hide abstract] ABSTRACT: Hippocampus volumetry based on magnetic resonance imaging (MRI) has not yet been translated into everyday clinical diagnostic patient care, at least in part due to limited availability of appropriate software tools. In the present study, we evaluate a fully-automated and computationally efficient processing pipeline for atlas based hippocampal volumetry using freely available Statistical Parametric Mapping (SPM) software in 198 amnestic mild cognitive impairment (MCI) subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI1). Subjects were grouped into MCI stable and MCI to probable Alzheimer's disease (AD) converters according to follow-up diagnoses at 12, 24, and 36 months. Hippocampal grey matter volume (HGMV) was obtained from baseline T1-weighted MRI and then corrected for total intracranial volume and age. Average processing time per subject was less than 4 minutes on a standard PC. The area under the receiver operator characteristic curve of the corrected HGMV for identification of MCI to probable AD converters within 12, 24, and 36 months was 0.78, 0.72, and 0.71, respectively. Thus, hippocampal volume computed with the fully-automated processing pipeline provides similar power for prediction of MCI to probable AD conversion as computationally more expensive methods. The whole processing pipeline has been made freely available as an SPM8 toolbox. It is easily set up and integrated into everyday clinical patient care.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) represents an increasing worldwide healthcare epidemic. Secondary preventive disease-modifying treatments under clinical development are considered most effective when initiated as early as possible in the pathophysiological course and progression of the disease. Major targets are to enhance clearance and to reduce cerebral accumulation of amyloid, decrease hyperphosphorylation of tau and the generation of neurofibrillary tangles, reduce inflammation, and finally progressive neurodegeneration. Comprehensive sets of biological markers are needed to characterize the pathophysiological mechanisms, indicate effects of treatment and to facilitate early characterisation and detection of AD during the prodromal or even at asymptomatic stages. No primary or secondary preventive treatments for AD have been approved. Epidemiological research, however, has provided evidence of specifically modifiable risk and protective factors. Among them are vascular, lifestyle and psychological risk factors that may act both independently and by potentiating each other. These factors may be substantially impacted by single or multi-domain strategies to prevent or postpone the onset of AD-related pathophysiology. Researchers have recently started the European Dementia Prevention Initiative (EDPI), an international consortium to improve strategies for preventing dementia. EDPI, in particular, includes the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) which aims at optimizing the early identification of subjects at increased risk of late-life cognitive deterioration, and at the evaluation of multi-domain intervention strategies. The ongoing discussion on new diagnostic criteria provided by the International Working Group (IWG), as well as by the recommendations summoned by the National Institute on Aging and Alzheimer's Association (NIA-AA) initiative, has inspired the creation of novel study designs and the definition of earlier target populations for trials in pre- and asymptomatic at-risk and prodromal stages of AD. As a result, a number of promising international prevention trials are currently ongoing. In this review, we critically discuss the main paths to AD prevention through control of modifiable risk factors and lifestyle changes. We will also review the role of biomarkers to identify subgroups of patients who would most likely benefit from secondary prevention strategies, and to evaluate the benefit of treatment in such patients.
The Journal of Nutrition Health and Aging 02/2015; 19(2):154-63. DOI:10.1007/s12603-014-0515-3 · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Posterior cortical atrophy (PCA) is characterized by progressive visuoperceptual and visuospatial deficits and commonly considered to be an atypical variant of Alzheimer disease. Mutations of the GRN gene are responsible for a large phenotypic spectrum, but, to our knowledge, the association of PCA with GRN mutations has never been described.
We studied a patient presenting with insidious impairment of basic visuoperceptual skills and apperceptive visual agnosia with predominant posterior atrophy corresponding to a visual/ventral variant of PCA. A heterozygous p.Arg110* (c.328C>T) GRN mutation was identified in this patient.
This study extends the clinical spectrum of GRN mutations that may be responsible for a PCA phenotype. The GRN phenotypes overlap other degenerative dementias and highlight the limits of actual nosologic boundaries in dementias. The GRN gene should be analyzed in patients with PCA, particularly when the damage progresses to anterior cerebral regions and a family history of dementia is present.
[Show abstract][Hide abstract] ABSTRACT: Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD.
[Show abstract][Hide abstract] ABSTRACT: The extent to which social cognitive changes reflect a discrete constellation of symptoms dissociable from general cognitive changes in Alzheimer's disease (AD) is unclear. Moreover, whether social cognitive symptoms contribute to disease severity and progression is unknown. The current multicenter study investigated cross-sectional and longitudinal associations between social cognition measured with six items from the Blessed Dementia Rating Scale, general cognition, and dependence in 517 participants with probable AD. Participants were monitored every 6 months for 5.5 years. Results from multivariate latent growth curve models adjusted for sex, age, education, depression, and recruitment site revealed that social cognition and general cognition were unrelated cross-sectionally and throughout time. However, baseline levels of each were related independently to dependence, and change values of each were related independently to change in dependence. These findings highlight the separability of social and general cognition in AD. Results underscore the relevance of considering social cognition when modeling disease and estimating clinical outcomes related to patient disability.
Alzheimer's & dementia: the journal of the Alzheimer's Association 11/2014; 10(6). DOI:10.1016/j.jalz.2013.12.021 · 17.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Objective: To define a practice guideline for biological treatment of dementias for general practitioners in primary care. Methods: This paper is a short and practical summary of the World Federation of Biological Psychiatry (WFSBP) guidelines for the Biological treatment of Alzheimer's disease and other dementias for treatment in primary care. The recommendations were developed by a task force of international experts in the field and are based on randomized controlled studies. Results: Anti-dementia medications neither cure, nor arrest, or alter the course of the disease. The type of dementia, the individual symptom constellation and the tolerability and evidence for efficacy should determine what medications should be used. In treating neuropsychiatric symptoms, psychosocial intervention should be the treatment of first choice. For neuropsychiatric symptoms, medications should only be considered when psychosocial interventions are not adequate and after cautious risk-benefit analysis. Conclusions: Depending on the diagnostic entity and clinical presentation different anti-dementia drugs can be recommended. These guidelines provide a practical approach for general practitioners managing dementias.
International Journal of Psychiatry in Clinical Practice 09/2014; 19(1):1-11. DOI:10.3109/13651501.2014.961931 · 1.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Allais Paradox represents one of the earliest empirical challenges to normative models of decision-making, and suggests that choices in one part of a gamble may depend on the possible outcome in another, independent, part of the gamble—a violation of the so-called "independence axiom." To account for Allaisian behavior, one well-known class of models propose that individuals' choices are influenced not only by possible outcomes resulting from one's choices, but also the anticipation of regret for foregone options. Here we test the regret hypothesis using a population of patients with behavioral variant frontotemporal dementia (bvFTD), a clinical population known to present ventromedial prefrontal cortex dysfunctions and associated with impaired regret processing in previous studies of decision-making. Compared to matched controls and Alzheimer's disease (AD) patients, we found a striking diminution of Allaisian behavior among bvFTD patients. These results are consistent with the regret hypothesis and furthermore suggest a crucial role for prefrontal regions in choices that typically stands in contradiction with a basic axiom of rational decision-making.
Frontiers in Neuroscience 09/2014; 8. DOI:10.3389/fnins.2014.00287 · 3.70 Impact Factor