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Late-onset Alzheimer's disease is the most common cause of dementia in western societies. Despite remarkable achievements in human genetics over the years, in particular, technological advances in gene mapping and in statistical methods, to date only a small proportion of the genetic contribution to Alzheimer's disease can be explained. One reason for the difficulty in gene identification is that Alzheimer's disease is a complex disorder in which multiple genes with small individual effects as well as environmental factors are likely to contribute to disease risk as well as the various quantitative traits associated with the disease such as age-of-onset, cognition, neuropsychiatric symptoms, amyloid/tau pathology, or structural brain changes. Identifying the genetic factors modulating changes in these individual endophenotypes would help elucidate disease pathogenesis. In this special issue on genetics and genomics of Alzheimer's disease and its endophenotypes, we have invited a few papers that address this issue. The first two articles address the impact of APOE genotype, the best established Alzheimer's disease susceptibility gene, on neuropsychiatric endophenotypes associated with Alzheimer's disease including psychosis, late-life depression, anxiety, apathy, hallucinations, agitation, and aggressiveness. The third paper examines the effect of an intron 7 polymorphism in the amyloid precursor protein (APP) on the age of onset of Alzheimer's disease in persons with Down syndrome. The fourth and fifth papers explore mechanisms modulating components of the amyloid cascade pathway, focusing, in particular, on the APP intracellular domain (AICD), which is an end product of the proteolytic cleavage of APP by β- and γ-secretase. In the first of these two papers, Ansaloni et al. evaluated the effect of NTRK2 which encodes the TrkB receptor on APP metabolism and AICD levels. TrkB is a member of the tyrosine kinase receptor family and binds specifically to brain-derived neurotrophic factor (BDNF). The paper reports on the effects of different TrkB isoforms on APP metabolism in the human neuroblastoma cell line. In the other paper, Raychaudhuri et al. examined the impact of overexpression of AICD on expression of proteins that are part of pathways involved in neurodegeneration and neuroregeneration. Finally, the sixth paper reviews the findings of genome-wide association studies (GWAS) that tested whether SNPs in the top-ranked Alzheimer's disease-related candidate genes were associated with various brain imaging endophenotypes including the volumes of the temporal lobe, hippocampus, amygdale, and frontal lobe, as well as grey matter density, entorhinal cortex thickness, and white matter integrity. In addition, this article discusses multigene and more complex genetic models as a means to identify genetic contributions to Alzheimer's disease. Christiane Reitz Ekaterina Rogaeva Tatiana Foroud Lindsay A. Farrer

The objective of this paper is to summarize current knowledge on the possible advantages of lifestyle interventions, with particular attention to physical fitness, cognitive activity, leisure and social activity as well as nutrition. There is a large amount of published papers providing partial evidence and asserting the need for immediate, appropriate preventive lifestyle measures against dementia and AD development. Nevertheless, there are currently great difficulties in drafting effective guidelines in this field. This depends mainly upon lack of randomized controlled trials assessing benefits versus risks of particular lifestyle interventions strategies. However, due to the rapid increase of dementia burden, lifestyle factors and their amelioration should be already made part of decision making in light of their health-maintaining effects while awaiting for results of well-designed large prospective cohort studies in dementia.

In view of the availability of drugs that may slow or even halt the progression of Alzheimer's disease (AD), the possibility to routinely discriminate individuals carrying incipient AD is utmost important. The CSF biomarkers beta-amyloid and tau are increasingly used in several countries in Europe for their high diagnostic accuracy in detecting early or even prodromal AD. Up till now, thousands of subjects have been studied either in research or routine setting, giving sensitivity and specificity values invariably above 80%. Despite these clinically relevant results, CSF analysis is still considered only a supportive exam in AD diagnostic work-up. We think there is a great need to improve the medical awareness about the importance to perform lumbar puncture as a routine procedure in the diagnostic assessment of cognitive deterioration. In line with this belief, the first paper of this special issue addresses the usefulness of cerebrospinal fluid analysis for diagnostic definition of cognitive deficits, and the second one further focuses on the ethical issues related to early diagnosis of Alzheimer's disease. As a corollary, the third paper reports some reflections about the actual need in clinical practice of guidelines for diagnosis and management of incipient AD. The fourth paper illustrates what is known about CSF biomarkers for diagnosing AD, and the fifth paper gives a different perspective according to the Canadian guidelines for dementia diagnosis. An up-dated and comprehensive view of crucial issues emerged from large multicentre studies (which have clearly highlighted the inter-centre variability of these determinations) on CSF biomarkers for AD diagnosis is reported in the sixth paper. Accordingly, the seventh paper nicely describes the efforts done for standardization of assay procedures and the eighth paper further goes into details about the many factors inducing variation of amyloid beta concentration, which heavily hampers, at present, a good inter-centre reliability. Besides the state of art about what is known on classical CSF biomarkers for early diagnosis in routine clinical practice, there also are impressive international research initiatives aimed at identifying new biomarkers for neurodegenerative diseases. This issue is thoroughly addressed by the ninth paper, which gives an overview of the EU-funded consortium cNEUPRO. The issue of the role of CSF biomarkers in non-AD dementias is also partly addressed in this special issue. An overview on CSF biomarkers in dementia with Lewy bodies (DLB) is given in the tenth paper, and in the eleventh paper the discriminative power of classical and putative CSF biomarkers for differentiating AD, DLB, and Parkinson's disease with dementia (PDD) is accurately described; finally, the usefulness of classical CSF biomarkers in characterizing CADASIL, a genetic model of subcortical vascular dementia, is also reported. Lucilla Parnetti Jens Wiltfang Kaj Blennow

In the last decade, the fundamental role of the microtubule-associated protein tau in neurodegeneration and dementia has been widely accepted. The generation of various transgenic models for tau pathology, varying in expressed mutations and driving promoters with either permanent (constitutive) or inducible expression, as well as the use of alternative animal models (fly, zebra fish, and rat) provided tools for studying mechanistic aspects of tau pathology and developing therapeutic approaches. It is now well established that pathological forms of tau (hyperphosphorylated, aggregated, and truncated) are a major cause of dementia, rather than being only a secondary effect to the amyloid pathology in Alzheimer's disease (AD). There is a link between these two AD pathologies, tau and amyloid, with tau pathology being downstream to amyloid pathology, yet tau pathology can develop and respond independently of amyloid plaques. The direct evidence for tau pathology developing independently of amyloid, being sufficient to cause dementia and neurodegeneration, is the fact that there are various diseases with isolated tau pathology (frontotemporal dementia, Pick's disease, etc.), one disease with both pathologies (AD), while there is no dementia disease with isolated amyloid pathology without tau pathology present. These findings supported the concept that amyloid toxicity is tau dependent and that blocking/reducing the pathological effects of tau may be protective against the harmful effects of amyloid pathology, a concept that has indeed proven feasibility in various studies. Much evidence has been accumulated pointing to the contribution of tau to AD pathology by two mechanisms: loss of function (such as stabilization of microtubules) as well as gain of toxic function (aggregation and deposition as neurofibrillary tangles). Recently, new concepts emerge contributing to our understanding of the pathogenesis of tau pathology, particularly the identification of toxic soluble oligomers of tau, arguing for these isoforms being the main toxic forms of the taupathology; and the concept that tau pathology may spread in the brain by a prion-like mechanism, possibly involving a transsynaptic mechanism of spreading along anatomically connected networks. These accumulating data provide a better understanding of tau pathogenesis, and given the disappointing clinical outcomes of antiamyloid therapeutic approaches, led the scientific community to devote much more effort into studying tau pathology, and into developing tau-targeted therapeutic approaches, such as tau immunotherapy, kinase inhibitors, or microtubule stabilizers. In this Special issue of International Journal of Alzheimer's Disease, the investigators contributed review articles as well as original research articles that stimulate the continuing efforts towards understanding tau pathology in AD and other tauopathies as well as unravel the physiological functions of tau, in an effort to develop new treatments. The paper by the F. Van Leuven's group: “Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer's disease,” which discusses the relevance of tau in Alzheimer's disease and frontotemporal dementias. This concise and clear review covers the major discoveries and the many still remaining questions in the field. The L. M. Ittner group contributed an excellent review paper: “Lessons from tau-deficient mice.” This paper takes you through the under-reported part of the tau story; it summarizes the consequences for tau loss of function and its possible role in neurodegeneration. The authors thoroughly reviewed the different tau knockout models and addressed the pathophysiology of various tau models. Tau mediates Aβ toxicity and perhaps the toxicity of other amyloidogenic proteins, hence, the characterization of tau knockout animal models is critical for our understanding of the complex molecular signaling pathways in Alzheimer's Disease. S. S. Hebert and his colleagues, review in their article: “MicroRNAs and the regulation of tau metabolism” what is known about the transcriptional and posttranscriptional regulation of tau. They discussed clearly the role of micro RNAs (miRNAs) in this process, with a focus on miR-16 and miR-132 as putative endogenous modulators of neuronal tau phosphorylation and tau exon 10 splicing, respectively. They speculated that miRNAs may contribute to sporadic forms of tauopathies. The review from M. Gistenlinck and collaborators, entitled “Drosophila models of tauopathies: what have we learned?” is focused on how and why Drosophila is helpful to modelize Tau pathology. Further, contributors explain why such simple models are important to unravel new pathophysiological hypothesis from genetic screening. Finally, authors describe clearly how Drosophila models are unvaluable tools to reconcile genome wide association studies with pathophysiology. The group of Gozes in the paper: “Tau and caspase 3 as targets for neuroprotection” shows clearly that in an in vitro model for ischemia, in primary neuronal cultures subjected to oxygen-glucose deprivation that causes an increase in the levels of active caspase-3 and hyperphosphorylated tau, both processes are prevented by either the NAP peptide or caspase-inhibitor treatment. This group suggests that caspase activation may be an upstream event to tau hyperphosphorylation. M. Kolarova and colleagues, in their contribution entitled “Structure and pathology of tau protein in Alzheimer disease” give us a comprehensive overview of what tau is and how tau can be modified. This contribution particularly emphasized that posttranductional modifications of Tau are important regulatory steps of its aggregation. Also, authors point out importance of Tau truncation which may additionally play an important role in AD-related pathophysiology. The final paper of this special issue entitled: “Tau phosphorylation by GSK3 in different conditions” J. Avila et al. review comprehensively the complex consequences for tau of being a phosphoprotein. Focusing on serine/threonine phosphorylation they discuss that depending on the modified residue in tau molecule, phosphorylation could be protective, like in processes like hibernation, or toxic like in development of tauopathies, characterized by a hyperphosphorylation and aggregation of tau. Hanna Rosenmann David Blum Rakez Kayed Lars M. Ittner

For many years, it has been accepted that the etiology of early-onset Alzheimer's disease (AD) is genetic in nature, with the relevant mutations involving genes encoding products that function in pathways dealing with processing of β-amyloid. The etiology of the far more prevalent late-onset AD is not primarily genetic in origin even though research over the last two decades has identified one or more genetic risk factors that predispose their bearers to development of the disease. Studies of late-onset AD have been strongly influenced by the amyloid cascade hypothesis. This influential hypothesis posits that plaques of β-amyloid (i.e., neuritic senile plaques, NSP) accumulate in the neuropil, where they eventually initiate a neuropathogenic process that engenders production of insoluble tangles of modified tau protein (i.e., neurofibrillar tangles, NFT), the ultimate result of which is progressive cognitive dysfunction. Firm and final diagnosis of the disease remains dependent on postmortem quantitation of the density and character of NSP and NFT in specific regions (e.g., hippocampus) of the affected brain. In addition, inflammation in the late-onset AD brain has been well documented, but this potentially important aspect of pathogenesis has not found a major place in the suite of factors thought to play primary roles in the neuropathogenic process. Substantial evidence derived from clinical trials, animal model studies, and other sources indicates that late-onset AD cannot be explained solely or primarily by accumulating NSP and NFT despite the fact that these are the most obvious and consistent pathological features of this disease. Rather, the evidence strongly suggests that late-onset AD results from a complex interplay between genetic and environmental factors, most of which remain to be elucidated. In this special issue, we were interested particularly in papers that present alternative viewpoints concerning the complex etiology and pathogenic processes underlying late-onset AD. The solicitation targeted reports of primary research from different fields, including new genome sequence or structure data that shed light on the complex genetic background giving increased susceptibility to disease induction, new insights regarding relevant environmental influences that may contribute to that induction, and new studies focusing on the biochemistry and molecular genetics of AD. Further, we wanted review articles that summarized recent research developments that engender new views on the etiology and/or neuropathogenic mechanisms of AD as well as hypothesis-driven but evidence-based arguments regarding etiology and neuropathogenesis. The first paper included in this special issue presents an interesting, and we think cogent, argument for a reconsideration of the amyloid cascade hypothesis. The authors of this review conclude that current evidence indicates that the production of NFT and NSP is independent of one another and that these are probably the products, not the cause, of the neurodegeneration that characterizes late-onset AD. The article presents a modified version of the hypothesis that provides a reasonable explanation of the pathogenesis of the disease. Since firm diagnosis of late-onset AD depends on postmortem examination of the brain of affected individuals, a pressing need exists for identification of markers that can reliably indicate the presence of AD in individuals at much earlier stages of the disease induction process. The second paper included in this special issue presents new research indicating that delineation of certain aspects of the IL-10 genotype and expression of one membrane-located adenosine receptor might prove useful in identifying individuals with the early signs of dementia who are at high risk of progressing to incipient late-onset AD. The final three papers accept the amyloid cascade hypothesis as a mechanistic explanation for the characteristic neuropathogenesis of late-onset AD, but each develops an interesting new idea concerning how the accumulation of β-amyloid at high levels might be initiated and maintained. The first of the three papers reviews the biochemical roles of the transglutaminase enzymes, the long-standing hypothesis that the activity of these enzymes contributes to oligomerization and accumulation of β-amyloid, and posits that specific inhibitors of the enzymes found in the CNS may prove to be effective therapeutic targets to ameliorate disease progression. The next paper reports that when Aβ1-42 is infused into mice, the activity of a particular ABC transport system is impaired, leading to attenuated removal of β-amyloid from the brain. This intriguing observation suggests that the documented age-related decrease in the expression of that transporter may contribute to the accumulation of β-amyloid in the brain and thus of NSP formation. The final paper in this special issue is a study of the function(s) of a noncoding transcript from the BACE1-encoding gene, using a transgenic mouse model in which Aβ production is excessive. Previous work from this group had demonstrated that these noncoding transcripts stabilize the mRNA specifying BACE1, thereby increasing the production of insoluble β-amyloid. In the present study, knockdown-based inhibition of either the noncoding or BACE1-encoding transcript engendered decreased β-amyloid production and attenuated neuronal degeneration. These last three papers point to new ways of reducing the burden of NSPs in the brains of transgenic mice. The challenge now is to determine if these approaches can be applied to the brains of aging primates, and if so, whether reducing the burden of NSPs will be sufficient to slow the rate of cognitive decline. AD and stroke together account for the bulk of cognitive impairment and mortality worldwide. As the risk factors and causes of stroke are becoming better understood, interventions have started to decrease the incidence of stroke (see, e.g., [1]). By contrast, despite three decades of intense research, the etiology of late-onset AD remains to be elucidated, and the incidence of this disease is steadily increasing (see, e.g., [2]). The present collection of papers illustrates that progress is being made on several fronts and indicates that many avenues of enquiry remain to be explored. We hope that these papers will stimulate new lines of thinking and experimentation, thereby hastening our understanding of this cruel and insidious disease. Alan P. Hudson Brian J. Balin Keith Crutcher Stephen Robinson

Caring for a person with dementia burdens family caregivers, and there is a close negative relationship between this burden and their quality of life (QoL). Research suggests that caregivers’ main needs are information and training about the disease and support from others experiencing the same situation, and Internet interventions hold considerable promise for meeting these needs. Virtual communities of practice (VCoPs) are Internet frameworks to share knowledge where members collaborate and achieve a sense of trust in the community. This paper seeks to evaluate the impact of participating in a VCoP (developed through an App) on the QoL of caregivers to people with Alzheimer’s. Results show QoL before and after the intervention changed significantly. The impact of VCoP on caregivers’ overall QoL is moderated by age and relation with the person with Alzheimer’s, specifically those over 65, and spouses. VCoPs allow interaction and knowledge sharing among caregivers which provide them mainly with information and support from peers helping them to meet their needs. Furthermore, caregivers’ QoL did not decrease when their relative deteriorated functionally, which could be due to the participation in VCoP. Although we found significant pre- and post differences in caregivers’ health literacy, we must report the ambiguous result that this variable only impacts on QoL’s physical domain. Participants also reported that they had a positive experience because the App was perceived to be a useful tool, because they could manage their own participation and they met peers and felt less lonely. Results suggest that participation in a VCoP impacts positively on caregivers’ QoL.

Purpose. Alzheimer’s disease (AD) and dementia with Lewy Bodies (DLB) constitute two of the most common forms of dementia in North America. Driving is a primary means of mobility among older adults and the risk of dementia increases with advanced age. The purpose of this paper is to describe the cognitive profile of licensed drivers with mild AD and mild DLB.Method. Licensed drivers with mild AD, mild DLB, and healthy controls completed neuropsychological tests measuring general cognition, attention, visuospatial/perception, language, and cognitive fluctuations.Results. The results showed differences between healthy controls and demented participants on almost all neuropsychological measures. Participants with early DLB were found to perform significantly worse on some measures of attention and visuospatial functioning in comparison with early AD.Discussion. Future research should examine the relationship between neuropsychological measures and driving outcomes among individuals with mild AD and mild DLB.

Prevalence of Alzheimer’s disease (AD) will reach epidemic proportions in the United States and worldwide in the coming decades, and with substantially higher rates in African Americans (AAs) than in Whites. Older age, family history, low levels of education, and ɛ4 allele of the apolipoprotein E (APOE) gene are recognized risk factors for the neurodegeneration in AD and related disorders. In AAs, the contributions of APOE gene to AD risk continue to engender a considerable debate. In addition to the established role of cardiovascular disease (CVD) risk in vascular dementia, it is now believed that CVD risk and its endophenotype may directly comediate AD phenotype. Given the pleiotropic effects of APOE on CVD and AD risks, the higher rates of CVD risks in AAs than in Whites, it is likely that CVD risks contribute to the disproportionately higher rates of AD in AAs. Though the advantageous effects of aerobic exercise on cognition is increasingly recognized, this evidence is hardly definitive, and data on AAs is lacking. In this paper, we will discuss the roles of CVD risk factors in the development of AD and related dementias, the susceptibility of these risk factors to physiologic adaptation, and fitness-related improvements in cognitive function. Its relevance to AD prevention in AAs is emphasized.

Alzheimer’s disease (AD) is the most common form of dementia, and the pathological changes of senile plaques (SPs) and neurofibrillary tangles (NFTs) in AD brains are well described. Clinically, a diagnosis remains a postmortem one, hampering both accurate and early diagnosis as well as research into potential new treatments. Visual deficits have long been noted in AD patients, and it is becoming increasingly apparent that histopathological changes already noted in the brain also occur in an extension of the brain; the retina. Due to the optically transparent nature of the eye, it is possible to image the retina at a cellular level noninvasively and thus potentially allow an earlier diagnosis as well as a way of monitoring progression and treatment effects. Transgenic animal models expressing amyloid precursor protein (APP) presenilin (PS) and tau mutations have been used successfully to recapitulate the pathological findings of AD in the brain. This paper will cover the ocular abnormalities that have been detected in these transgenic AD animal models.

The problems and needs of older people are often associated with mental illness, characterized by a set of clinical manifestations, which constitute important domains for investigation and clinical practice. This paper presents the results of a pilot study whose main purpose was to identify met and unmet needs and to analyze the relationship between those needs, psychopathology and functionality in older people with mental health problems. A sample of 75 patients aged 65 or over, of both sexes, diagnosed with mental illness using ICD-9. The main diagnoses were depression (36%) and dementia (29.3%). Most patients had cognitive impairment (MMSE, 52%; CDT, 66.7%), depression (GDS, 61.3%), anxiety (ZAS, 81.3%), and moderate dependence (BI, 49.3% and LI, 77.3%). The main unmet needs found were daytime activities (40%), social benefits (13.3%), company (10.7%), psychological distress (9.3%), and continence (8%). The majority of these unmet needs occur with dementia patients. The majority of the carers of these patients had global needs (met and unmet) in terms of psychological distress. Findings also reveal that a low level of functionality is associated with dementia diagnoses. The association analyses suggest that dementia is an important determinant of the functional status and needs.

Since 1992, the amyloid cascade hypothesis has played the prominent role in explaining the etiology and pathogenesis of Alzheimer's disease (AD). It proposes that the deposition of β-amyloid (Aβ) is the initial pathological event in AD leading to the formation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs), neuronal cell death, and ultimately dementia. While there is substantial evidence supporting the hypothesis, there are also limitations: (1) SP and NFT may develop independently, and (2) SPs and NFTs may be the products rather than the causes of neurodegeneration in AD. In addition, randomized clinical trials that tested drugs or antibodies targeting components of the amyloid pathway have been inconclusive. This paper provides a critical overview of the evidence for and against the amyloid cascade hypothesis in AD and provides suggestions for future directions.

Most MRI studies of Alzheimer's disease (AD) and frontotemporal dementia (FTD) have assessed structural, perfusion and diffusion abnormalities separately while ignoring the relationships across imaging modalities. This paper aimed to assess brain gray (GM) and white matter (WM) abnormalities jointly to elucidate differences in abnormal MRI patterns between the diseases. Twenty AD, 20 FTD patients, and 21 healthy control subjects were imaged using a 4Tesla MRI. GM loss and GM hypoperfusion were measured using high-resolution T1 and arterial spin labeling MRI (ASL-MRI). WM degradation was measured with diffusion tensor imaging (DTI). Using a new analytical approach, the study found greater WM degenerations in FTD than AD at mild abnormality levels. Furthermore, the GM loss and WM degeneration exceeded the reduced perfusion in FTD whereas, in AD, structural and functional damages were similar. Joint assessments of multimodal MRI have potential value to provide new imaging markers for improved differential diagnoses between FTD and AD. Copyright © 2011 Yu Zhang et al.

Alzheimer’s disease (AD) is a neurodegenerative disorder whose clinical onset is mainly characterized by memory loss. During AD progression, behavioral and psychological symptoms of dementia (BPSD) frequently occur. In this paper we evaluated the association between AD and the short/long (S/L) functional polymorphism of the promoter region of the 5-hydroxytryptamine (5-HT) transporter gene (SLC6A4). The S-allele shows a 2-fold reduced transcriptional rate, causing an imbalance in 5-HT intracellular availability that might in turn trigger behavioral and cognitive alterations. We also genotyped theSLC6A4promoter functional variantrs25531(A→G). By comparing the genotypic and allelic frequencies in an Italian population of 235 AD and 207 controls, we found an association between5-HTTLPRand AD (odds ratio for the L-allele versus the S-allele: 0.74, associatedPvalue = .03), while no difference was found for thers25531. A meta-analysis of studies in Italy assessing5-HTTLPRand AD risk gave an estimation of odds ratio for the L-allele versus the S-allele of 0.85 (associatedPvalue = .08). Overall, our findings are not supportive of a large genetic effect of the explored polymorphisms on AD risk.

Current research is aiming to push the boundaries of the point at which a diagnosis of Alzheimer Disease (AD) can be made. Clinical syndromes such as Mild Cognitive Impairment (MCI) and various clinical and biological markers of AD may help to identify people in the early stage of AD, before a full dementia syndrome is present. In the first part of this paper, we discuss whether MCI represents incipient AD, and examine some of the methods currently used in research to identify AD patients in the preclinical phase. In the second part, we discuss whether specific guidelines are needed for the diagnosis and management of MCI and incipient AD, and consider the potential impact of this on clinical practice and public health from the perspective of patients, caregivers, and healthcare providers.

Patients suffering from Alzheimer's disease (AD) are typified and diagnosed postmortem by the combined accumulations of extracellular amyloid plaques and of intracellular tauopathy, consisting of neuropil treads and neurofibrillary tangles in the somata. Both hallmarks are inseparable and remain diagnostic as described by Alois Alzheimer more than a century ago. Nevertheless, these pathological features are largely abandoned as being the actual pathogenic or neurotoxic factors. The previous, almost exclusive experimental attention on amyloid has shifted over the last 10 years in two directions. Firstly, from the "concrete" deposits of amyloid plaques to less well-defined soluble or pseudosoluble oligomers of the amyloid peptides, ranging from dimers to dodecamers and even larger aggregates. A second shift in research focus is from amyloid to tauopathy, and to their mutual relation. The role of Tau in the pathogenesis and disease progression is appreciated as leading to synaptic and neuronal loss, causing cognitive deficits and dementia. Both trends are incorporated in a modified amyloid cascade hypothesis, briefly discussed in this paper that is mainly concerned with the second aspect, that is, protein Tau and its associated fundamental questions. ispartof: International journal of Alzheimer's disease vol:2010 pages:573138- ispartof: location:United States status: published

Alzheimer's disease (AD) is the most common form of dementia that affects several million people worldwide. The major neuropathological hallmarks of AD are the presence of extracellular amyloid plaques that are composed of Aβ40 and Aβ42 and intracellular neurofibrillary tangles (NFT), which is composed of hyperphosphorylated protein Tau. While the amyloid plaques and NFT could define the disease progression involving neuronal loss and dysfunction, significant cognitive decline occurs before their appearance. Although significant advances in neuroimaging techniques provide the structure and physiology of brain of AD cases, the biomarker studies based on cerebrospinal fluid (CSF) and plasma represent the most direct and convenient means to study the disease progression. Biomarkers are useful in detecting the preclinical as well as symptomatic stages of AD. In this paper, we discuss the recent advancements of various biomarkers with particular emphasis on CSF biomarkers for monitoring the early development of AD before significant cognitive dysfunction.

Dementia is one of the most disabling conditions. Alzheimer’s disease and vascular dementia (VaD) are the most frequent causes. Subcortical VaD is consequent to deep-brain small vessel disease (SVD) and is the most frequent form of VaD. Its pathological hallmarks are ischemic white matter changes and lacunar infarcts. Degenerative and vascular changes often coexist, but mechanisms of interaction are incompletely understood. The term mild cognitive impairment defines a transitional state between normal ageing and dementia. Pre-dementia stages of VaD are also acknowledged (vascular mild cognitive impairment, VMCI). Progression relates mostly to the subcortical VaD type, but determinants of such transition are unknown. Variability of phenotypic expression is not fully explained by severity grade of lesions, as depicted by conventional MRI that is not sensitive to microstructural and metabolic alterations. Advanced neuroimaging techniques seem able to achieve this. Beside hypoperfusion, blood-brain-barrier dysfunction has been also demonstrated in subcortical VaD. The aim of the Vascular Mild Cognitive Impairment Tuscany Study is to expand knowledge about determinants of transition from mild cognitive impairment to dementia in patients with cerebral SVD. This paper summarizes the main aims and methodological aspects of this multicenter, ongoing, observational study enrolling patients affected by VMCI with SVD.

Alzheimer's disease (AD) is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.

Clinicians and researchers alike are in need of quantitative and robust measurement tools to assess medial temporal lobe atrophy (MTA) due to Alzheimer’s disease (AD). We recently proposed a morphological metric, extracted from T1-weighted magnetic resonance images (MRI), to track and estimate MTA in cohorts of controls, AD, and mild cognitive impairment subjects, at high-risk of progression to dementia. In this paper, we investigated its reliability through analysis of within-session scan/repeat images and scan/rescans from large multicenter studies. In total, we used MRI data from 1051 subjects recruited at over 60 centers. We processed the data identically and calculated our metric for each individual, based on the concept of distance in a high-dimensional space of intensity and shape characteristics. Over 759 subjects, the scan/repeat change in the mean was 1.97% (SD: 21.2%). Over three subjects, the scan/rescan change in the mean was 0.89% (SD: 22.1%). At this level, the minimum trial size required to detect this difference is 68 individuals for both samples. Our scan/repeat and scan/rescan results demonstrate that our MTA assessment metric shows high reliability, a necessary component of validity.

This paper introduces Functional Analytic Multisensory Environmental Therapy (FAMSET) for use with elders with dementia while using a multisensory environment/snoezelen room. The model introduces behavioral theory and practice to the multisensory environment treatment, addressing assessment, and, within session techniques, integrating behavioral interventions with emotion-oriented care. A modular approach is emphasized to delineate different treatment phases for multisensory environment therapy. The aim of the treatment is to provide a safe and effective framework for reducing the behavioral disturbance of the disease process, increasing elder well-being, and to promote transfer of positive effects to other environments outside of the multisensory treatment room.

Alzheimer's disease (AD), which is characterized by a degeneration of neurons and their synapses, is one of the most common forms of dementia. CSF levels of amyloid 𝛽 4 2 (A 𝛽 4 2 ) have been recognized as a strong candidate to serve as an AD biomarker. There are a number of commercial assays that are routinely employed for measuring A 𝛽 4 2 ; however, these assays give diverse ranges for the absolute levels of CSF A 𝛽 4 2 . In order to employ CSF A 𝛽 4 2 as a biomarker across multiple laboratories, studies need to be performed to understand the relationship between the different platforms. We have analyzed CSF samples from both diseased and nondiseased subjects with two different widely used assay platforms. The results showed that different values for the levels of CSF A 𝛽 4 2 were reported, depending on the assay used. Nonetheless, both assays clearly demonstrated statistically significant differences in the levels of A 𝛽 4 2 in CSF from AD relative to age-matched controls (AMC). This paper provides essential data for establishing the relationship between these assays and provides an important step towards the validation of A 𝛽 4 2 as a biomarker for AD.

Corticobasal degeneration (CBD) is an uncommon, sporadic, neurodegenerative disorder of mid- to late-adult life. We describe a further example of the pathologic heterogeneity of this condition. A 71-year-old woman initially presented dysarthria, clumsiness, progressive asymmetric bradykinesia, and rigidity in left arm. Rigidity gradually involved ipsilateral leg; postural instability with falls, blepharospasm, and dysphagia subsequently developed. She has been previously diagnosed as unresponsive Parkinson's Disease. At our clinical examination, she presented left upper-arm-fixed-dystonia, spasticity in left lower limb and pyramidal signs (Babinski and Hoffmann). Brain MRI showed asymmetric cortical atrophy in the right frontotemporal cortex. Neuropsychological examination showed an impairment in visuospatial functioning, frontal-executive dysfunction, and hemineglect. This case demonstrates that association of asymmetrical focal cortical and subcortical features remains the clinical hallmark of this condition. There are no absolute markers for the clinical diagnosis that is complicated by the variability of presentation involving also cognitive symptoms that are reviewed in the paper. Despite the difficulty of diagnosing CBD, somatosensory evoked potentials, motor evoked potentials, long latency reflexes, and correlations between results on electroencephalography (EEG) and electromyography (EMG) provide further support for a CBD diagnosis. These techniques are also used to identify neurophysiological correlates of the neurological signs of the disease.

The spatial correlations between the brain's default mode network (DMN) and the brain regions known to develop pathophysiology in Alzheimer's disease (AD) have recently attracted much attention. In this paper, we compare results of different functional and structural imaging modalities, including MRI and PET, and highlight different patterns of anomalies observed within the DMN. Multitracer PET imaging in subjects with and without dementia has demonstrated that [C-11]PIB- and [F-18]FDDNP-binding patterns in patients with AD overlap within nodes of the brain's default network including the prefrontal, lateral parietal, lateral temporal, and posterior cingulate cortices, with the exception of the medial temporal cortex (especially, the hippocampus) where significant discrepancy between increased [F-18]FDDNP binding and negligible [C-11]PIB-binding was observed. [F-18]FDDNP binding in the medial temporal cortex—a key constituent of the DMN—coincides with both the presence of amyloid and tau pathology, and also with cortical areas with maximal atrophy as demonstrated by T1-weighted MR imaging of AD patients.

Alzheimer's disease (AD), the most common type of dementia among older people, is characterized by the accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles composed of hyperphosphorylated tau in the brain. Despite major advances in understanding the molecular etiology of the disease, progress in the clinical treatment of AD patients has been extremely limited. Therefore, new and more effective therapeutic approaches are needed. Accumulating evidence from human and animal studies suggests that the long-term consumption of caffeine, the most commonly used psychoactive drug in the world, may be protective against AD. The mechanisms underlying the suggested beneficial effect of caffeine against AD remain to be elucidated. In recent studies, several potential neuroprotective effects of caffeine have been proposed. Interestingly, a recent study in rats showed that the long-term consumption of caffeine increased cerebrospinal fluid (CSF) production, associated with the increased expression of Na+-K+ATPase and increased cerebral blood flow. Compromised function of the choroid plexus and defective CSF production and turnover, with diminished clearance of Aβ, may be one mechanism implicated in the pathogenesis of late-onset AD. If reduced CSF turnover is a risk factor for AD, then therapeutic strategies to improve CSF flow are reasonable. In this paper, we hypothesize that long-term caffeine consumption could exert protective effects against AD at least in part by facilitating CSF production, turnover, and clearance. Further, we propose a preclinical experimental design allowing evaluation of this hypothesis.

Alzheimer's Disease (AD) is the most common dementia in the elderly and is estimated to affect tens of millions of people worldwide. AD is believed to have a prodromal stage lasting ten or more years. While amyloid deposits, tau filaments, and loss of brain cells are characteristics of the disease, the loss of dendritic spines and of synapses predate such changes. Popular preclinical detection strategies mainly involve cerebrospinal fluid biomarkers, magnetic resonance imaging, metabolic PET scans, and amyloid imaging. One strategy missing from this list involves neurophysiological measures, which might be more sensitive to detect alterations in brain function. The Magnetoencephalography International Consortium of Alzheimer's Disease arose out of the need to advance the use of Magnetoencephalography (MEG), as a tool in AD and pre-AD research. This paper presents a framework for using MEG in dementia research, and for short-term research priorities. Copyright © 2011 Edward Zamrini et al.

Alzheimer's disease (AD)—the most common type of dementia among the elderly—represents one of the most challenging and urgent medical mysteries affecting our aging population. Although dominant inherited mutation in genes involved in the amyloid metabolism can elicit familial AD, the overwhelming majority of AD cases, dubbed sporadic AD, do not display this Mendelian inheritance pattern. Apolipoprotein E (APOE), the main lipid carrier protein in the central nervous system, is the only gene that has been robustly and consistently associated with AD risk. The purpose of the current paper is thus to highlight the pleiotropic roles and the structure-function relationship of APOE to stimulate both the functional characterization and the identification of novel lipid homeostasis-related molecular targets involved in AD.

SPECT allows registration of regional cerebral blood flow (rCBF) which is altered in a characteristic temporoparietal pattern in Alzheimer's Dementia. Numerous studies have shown the diagnostic value of reduced cerebral blood flow and metabolic changes using perfusion SPECT and FDG-PEPT in AD diagnosis as well as in differential diagnosis against frontotemporal dementia, dementia with Lewy bodies and vascular disease. Recently more pathophysiology-based biomarkers in CSF and Amyloid-PET tracers have been developed that probably have a higher diagnostic accuracy than the more indirect rCBF changes seen in perfusion SPECT. In the paper review, we describe recent advances in AD biomarkers as well as improvements in the SPECT technique.