View Of Alzheimer Research Articles

Astrocytes and Adenosine A2A Receptors: Active Players in Alzheimer's Disease.

Astrocytes, through their numerous processes, establish a bidirectional communication with neurons that is crucial to regulate synaptic plasticity, the purported neurophysiological basis of memory. This evidence contributed to change the classic “neurocentric” view of Alzheimer’s disease (AD), being astrocytes increasingly considered a key player in this neurodegenerative disease. AD, the most common form of dementia in the elderly, is characterized by a deterioration of memory and of other cognitive functions. Although, early cognitive deficits have been associated with synaptic loss and dysfunction caused by amyloid-β peptides (Aβ), accumulating evidences support a role of astrocytes in AD. Astrocyte atrophy and reactivity occurring at early and later stages of AD, respectively, involve morphological alterations that translate into functional changes. However, the main signals responsible for astrocytic alterations in AD and their impact on synaptic function remain to be defined. One possible candidate is adenosine, which can be formed upon extracellular catabolism of ATP released by astrocytes. Adenosine can act as a homeostatic modulator and also as a neuromodulator at the synaptic level, through the activation of adenosine receptors, mainly of A1R and A2AR subtypes. These receptors are also present in astrocytes, being particularly relevant in pathological conditions, to control the morphofunctional responses of astrocytes. Here, we will focus on the role of A2AR, since they are particularly associated with neurodegeneration and also with memory processes. Furthermore, A2AR levels are increased in the AD brain, namely in astrocytes where they can control key astrocytic functions. Thus, unveiling the role of A2AR in astrocytes function might shed light on novel therapeutic strategies for AD.

Alzheimer’s Disease Prevention and Treatment: Case for Optimism

A paradigm shift is under way in the Alzheimer's field. A view of Alzheimer's disease, AD, prevailing until now, the old paradigm, maintains that it is initiated and driven by the overproduction and extracellular accumulation of beta-amyloid, Aβ; a peptide assumed to be derived, both in health and disease, solely by proteolysis of its large precursor, βAPP. In AD, according to this view, Aβ overproduction-associated neurodegeneration begins early, accumulates throughout the lifespan, and manifests symptomatically late in life. A number of drugs, designed within the framework of exceptionality of the βAPP proteolytic/secretory pathway in Aβ production in Alzheimer's disease, achieved spectacular successes in treatment, even the reversal, of AD symptoms in animal models. Without exception, they all exhibited equally spectacular failures in human clinical trials. This paradigm provides few causes for optimism with regard to prevention and treatment of AD. In its context, the disease is considered untreatable in the symptomatic phase; even prodromal cases are assumed too advanced for treatment because Aβ-triggered damages have been accumulating for preceding decades, presumably starting in the early twenties and, to be effective, this is when therapeutic intervention should commence and continue for life. The new paradigm does not dispute the seminal role of Aβ in AD but posits that beta-amyloid produced in the βAPP proteolytic/secretory pathway causes AD in humans no more than it does in non-human mammals that share this pathway with humans, accumulate Aβ as they age, but do not develop the disease. Alzheimer's disease, according to this outlook, is driven by the AD-specific pathway of Aβ production, independent of βAPP and absent in animals. Its activation, late in life, occurs through accumulation, via both cellular uptake of secreted Aβ and neuronal retention of a fraction of beta-amyloid produced in the βAPP proteolytic pathway, of intraneuronal Aβ, which triggers mitochondrial dysfunction. Cellular stresses associated with mitochondrial dysfunction, or, probably, the integrated stress response, ISR, elicited by it, activate an AD-specific Aβ production pathway. In it, every conventionally produced βAPP mRNA molecule potentially serves repeatedly as a template for production of severely 5'-truncated mRNA encoding C99 fragment of βAPP, the immediate precursor of Aβ that is processed in a non-secretory pathway, apparently in a neuron-specific manner. The resulting intraneuronally retained Aβ augments mitochondrial dysfunction, which, in turn, sustains the activity of the βAPP mRNA amplification pathway. These self-propagating Aβ overproduction/mitochondrial dysfunction mutual feedback cycles constitute the engine that drives AD and ultimately triggers neuronal death. In this paradigm, preventive treatment can be initiated any time prior to commencement of βAPP mRNA amplification. Moreover, there are good reasons to believe that with a drug blocking the amplification pathway, it would be possible not only to preempt the disease but also stop and reverse it even when early AD symptoms are already manifested. Thus, the new paradigm introduces a novel theory of Alzheimer's disease. It explains the observed discordances, determines defined therapeutic targets, provides blueprints for a new generation of conceptually distinct AD models and specifies design of a reporter for the mRNA amplification pathway. Most importantly, it offers detailed guidance and tangible hope for prevention of the disease and its treatment at the early symptomatic stages.

Unraveling the potential co-contributions of cerebral small vessel vasculopathy to the pathogenesis of Alzheimer's dementia.

Emerging evidence for the potential co-contributions of small vessel vasculopathy to dementia has resulted in a more nuanced view of Alzheimer’s disease (AD) pathogenesis. Although cerebral small vessel disease, visualized on magnetic resonance imaging as hyperintense signal abnormalities, independently predicts the incidence and clinical progression of dementia, the relationships between AD pathology, white matter hyperintensity volume, genotype, and cognitive decline in AD remain unclear. The study by Morgen and colleagues, recently published in Alzheimer’s Research & Therapy, presents important new findings on the associations between apolipoprotien E ε4 genotype, white matter hyperintensities, and cognition, independent of vascular risk, in a cohort of AD patients.

Pseudodémence, de quoi parle-t-on ? Partie II : de Stertz à Alzheimer : une maladie psychogène après traumatisme

The aim of this work is to give a new anchorage for the initial concept of pseudodementia, its basic definitions and actual clinical implications. The original definition and framework of the concept are misidentified and therefore need to be reintroduced and analysed here. This approach, beyond its heuristic and epistemological goal, has a practical aim: to adjust the psychopathological point of view on pseudodementia.In addition to a conventional survey based on search engines (Medline, PsychINFO and google book), we conducted a systematic review of the concomitant papers related to the rise of the concept.Three moments of conceptualization are identified and linked to Wernicke's successors at the university of Breslau. Firstly, Stertz (1910) has described pseudodementia as a psychogenic illness that could occur after any trauma. According to our research, it is probably the first written use of the term pseudodementia in its psychogenic meaning. Secondly, we present Bonhoeffer's approach based on psychogenic reactions (1911). Finally, the views of Alzheimer and his student Schuppius are described: their understanding of pseudodementia is open to psychoanalytic concepts (1914).The concept of pseudodementia (Pseudodemenz) takes shape in a particular period of German history: the promulgation of laws settling railway (1871) and industrial accidents (1884) but also the law of compensation of the traumatic neurosis (1889), the nosological specificity of which was debated. German psychiatry of the beginning of the 20th century was strongly imbued with a moralizing sense of national duty. The disqualification of traumatic neurosis has been followed by a unanimous recognition of traumatic hysteria and its psychogenic hypothesis. As a consequence, traumatic events were rarely taken into consideration and the issue was moved into the private sphere (Privatsache) by questioning patients' morbid wishes. Breslau's psychiatrists analyzed the cognitive disorders of pseudodementia with regard to an ideogenic model of the trauma, which emphasized the subjectivity but which was still facing the primacy of the consciousness. It is in this context, and by reducing the question of the pseudodementia to the situations of detention (Gansersche Syndrom) and pension neuroses (Rentenneurosen), that Bonhoeffer promoted the notion of "wishing to be sick" (Wille zur Krankheit). This conception gave a social component to mental disorders but placed in the foreground a suggestive phenomenon, which Raecke included as secondary to the primary symptom of hysterical inhibition. Thus, Schuppius's article under the tutoring of Aloïs Alzheimer offers a double testimony. On one hand, it shows how neuropsychiatry was, by then, at least partially open to the notion of an unconscious causality. On the other hand, it exposes a hidden aspect of Aloïs Alzheimer: a brilliant histopathologist capable of interest for psychodynamic mechanisms.In his famous study of 1961, Leslie Gordon Kiloh argues that the concept of pseudodementia does not belong to any nosological system, is purely descriptive and does not imply an accurate diagnosis. The present work shows a very different conclusion. Initially, the term was introduced in German psychiatry to describe cases of hysterical psychogenic illness after trauma (psychogene Erkrankungen nach Trauma) in which the mechanism of inhibition was discussed. Topologically, we can even define its emergence in the Breslau's university and psychiatric clinic in which Wernicke, Stertz, Bonhoeffer and Alzheimer himself, promoted it. One should also note that the category of hysteria referred to an array of functional mental disorders, including "hysterical psychosis" (hysterische Psychosen).

CSF Biomarkers of Alzheimer’s Disease: Impact on Disease Concept, Diagnosis, and Clinical Trial Design

Data from clinicopathologic and biomarker studies have converged to support the view of Alzheimer’s disease (AD) as a continuum, with pathology developing decades prior to the onset of cognitive symptoms which culminate as dementia at the end stage of the disease. This concept is impacting disease nomenclature, diagnostic criteria, prognostic potential, and clinical trial design. Revisions to diagnostic criteria to incorporate biomarker results have recently been proposed in order to increase the confidence of AD as the underlying etiology of a clinical impairment and to permit a diagnosis of AD across the disease continuum, eventually perhaps in the asymptomatic period. Individuals in this preclinical stage are receiving intense focus as a targeted population for secondary prevention trials aimed at identifying disease-modifying therapies that have the best chance of preserving normal cognitive function. The goal is to bring validated biomarkers to clinical practice for the purpose of disease diagnosis, prognosis, and evaluation of therapeutic efficacy once disease-modifying treatments become available. Realization of this goal requires worldwide biomarker standardization efforts, consensus among researchers and clinicians regarding the clinical utility of assessing biomarkers in patient care settings, and eventually the endorsement and adoption of such procedures and practices into global health care systems.

Alzheimer’s as a metabolic disease

Empirical evidence indicates that impaired mitochondrial energy metabolism is the defining characteristic of almost all cases of Alzheimer's disease (AD). Evidence is reviewed supporting the general hypothesis that the up-regulation of OxPhos activity, a metabolic response to mitochondrial dysregulation, drives the cascade of events leading to AD. This mode of metabolic alteration, called the Inverse Warburg effect, is postulated as an essential compensatory mechanism of energy production to maintain the viability of impaired neuronal cells. This article appeals to the inverse comorbidity of cancer and AD to show that the amyloid hypothesis, a genetic and neuron-centric model of the origin of sporadic forms of AD, is not consistent with epidemiological data concerning the age-incidence rates of AD. A view of Alzheimer's as a metabolic disease-a condition consistent with mitochondrial dysregulation and the Inverse Warburg effect, will entail a radically new approach to diagnostic and therapeutic strategies.

Are Alzheimer's Disease and Aging Evolutionary?

The Origin of Everything, by D.B. Kelley, 345 p, ISBN 978-0-9854625-1-2 http://www.universalselection.com/Origin-ofEverything.html What does evolution have to do with Alzheimer’s disease? Prevailing views of Alzheimer’s disease and aging are that post-reproductive life is on autopilot, genes having already moved on to the next generation. So half our life is then directed by genes of youth, in keeping with the common, but incorrect, view that people lived only half as long just a century ago. So are aging and Alzheimer’s disease left to chance? Kelley’s book brings these concepts to the natural world in all scales—atoms to chemicals, mountains to galaxies—by demonstrating that the properties Darwin observed for life’s evolution transform the natural world to a more stable state due to survival of the fittest systems, or the preservation of stable phenomena, biological and non-biological. Fundamentally, the entire natural world is in competition between various forms, and evolution works to retain those that are most stable at any given point. Existence is a balance between staying where you are and potential for transformation. Absolute stability blocks transformation and leads to its own failure to adapt. This dynamic supports the spectrum of life forms from differentiated euryakotes to individual molecules. Could aging then be the change we experience as we balance stability and adaptation, and could lifespan per se be the result? Indeed, altering lifespan in either direction would require a transformation of stability and adaptability. In our own species, increasing lifespan would increase human population if generation time was maintained, transforming population dynamics. The same can be said for atoms, molecules, largescale systems, and more. Kelley’s thesis embraces the changes of aging as creating greater stability, and raises the possibility of lifespan and age-related decrement as being actively selected, and for aging, senescence, and death, as integral to the processes.

An insider’s view of Alzheimer: cinematic portrayals of the struggle for personhood

This article looks at three recent films in which a person with dementia is the principal character. These films have been chosen according to the following criteria: representing different stages of dementia (early, moderate and advanced); films where the demented is the protagonist; and films challenging the biomedical view of dementia. Two of the characters are diagnosed with Alzheimer’s disease: the protagonist of Cortex (2008) is at a moderate stage, the one in Pandora’s Box (2008) is diagnosed when already in advanced stage and the third, the protagonist of Old Cats (2010), while not officially diagnosed, is in early onset of dementia. While the number of dementia films has significantly increased during the past decade, only a few access the subjective world and acknowledge the personhood of people with dementia. Made outside the mainstream film industry, making elaborate use of cinematic image and metaphor, these films, each in its own particular cinematic idiom, succeed in conveying the psychological, social and spiritual realities of dementia as they are experienced from within the protagonist’s psyche. While not denying the often bleak and painful aspects of dementia, these recent productions go against the grain, inspiring a complex, richly nuanced picture of dementia that centres around the protagonist’s stubbornly courageous struggle to forge a meaningful existence even in the direst of circumstances. These films, we believe, offer a richer and profound understating of the human aspects embedded in the phenomena of dementia.

A holistic approach to caring for people with Alzheimer’s disease

This article adopts a holistic view of Alzheimer's disease. Biomedical, psychological and social aspects of the condition are discussed, and aetiology, epidemiology, diagnosis and treatment explored. A range of approaches to working with people with Alzheimer's disease, based on a psychological model of dementia, is described including reminiscence and cognitive stimulation therapy.

Commentary: Integrative Narrative Evolutionary Health: Toward a Wiser View of Alzheimer's Disease

Commentary: Integrative Narrative Evolutionary Health: Toward a Wiser View of Alzheimer's Disease

A neurologist's view of Alzheimer's disease and dementia

Senile dementia was the third most common admission diagnosis for New York psychiatric hospitals at the start of the twentieth century and the distinction between vascular and senile dementia was understood by psychiatrists even then. The term Alzheimer's disease (AD) was originally introduced to distinguish a pre-senile dementia from the common general paresis, but Alzheimer raised the possibility that pre-senile AD might not be distinguishable in clinical or histological terms from senile dementia. By the late 1970s it had become clear that the most common disorder producing dementia in elderly people was clinically and pathologically identical to pre-senile AD. AD is malignant, reducing remaining life expectancy by almost half and raising the risk of death over five years threefold (cancer raises it fourfold). Synapse loss associated with beta amyloid oligomers is a strong determinant of cognitive decline in patients with AD. Tau-containing neurofibrillary tangles usefully track disease severity. Unmodifiable risk factors include mutations in three genes which affect the production or metabolism of beta amyloid, the risk factor gene for Apolipoprotein [see symol in text]4 and female gender. The overriding risk factor is age, the prevalence of AD doubling with every five years of age until 90. Low education, head injury and low folate levels are examples of potentially modifiable risk factors. Since a delay of onset of five years would halve the number of patients with the disease, clinical trials for such putative protective factors as estrogens, folic acid, vitamin E, statins, and NSAIDs have begun. Cognitive and leisure activity may be protective against the development of AD but any protective function can only be confirmed by clinical trials.

What evidence would prove the amyloid hypothesis? Towards rational drug treatments for Alzheimer's disease

Department of Pharmacology and Biochemistry, University of South Florida College of Medicine, Tampa FL33612-4799, USAAs one of us (DM) listened intently to the debatespresented at the meeting on Challenging Views ofAlzheimer’s Disease, I was struck by the strong desireby some in attendance to find fault with the amyloidhypothesis of Alzheimer’s disease (AD). Argumentswere presented in multiple discussions leading to theconclusion that the relationship between amyloid andAD was so tenuous that we should not even waste timedeveloping drugs directed at reducing amyloid.What was most surprising was the level of proof towhich the amyloid hypothesis was being held by thoseattempting to refute it. I was left with the impressionthat if every symptomin every patient regardless of pa-tient age, gender, state of disease progression or con-current disorders, did not correlate linearly with theamyloid burden, then the assumption was the amyloidhypothesis must be false. For example, some patientsdie with brains loaded with enough amyloid to reachthe criterion for AD, yet they are cognitively fit as fid-dles. Alternatively,patientsdie withfull blowndemen-tia, diagnosed as AD, yet they have little or no amyloidpathology.The animal models are argued to be failures becausenot all aspects of the AD phenotypeare manifest. Theyhavebrainsfilledwithamyloid,yetthereislittleneuronloss or tangle formation. Thus, the amyloid hypothe-sis must be wrong or the mice should recapitulate the

Successful Strategies for Serving Diverse Populations

SUMMARY Unique insights of key delivery staff and successful delivery strategies used to overcome cultural barriers were obtained through intensive interviews with fifty staff members. Participants in the study were identified as knowledgeable staff members by project coordinators. An open-ended qualitative methodology was used to interview staff members about barriers they faced in delivering services to new populations and strategies that were used to address these barriers. Fifty interviews were completed. Of those, forty-two interviewees were frontline staff members and eight were “hands-on” administrators. Fifteen of these staff members worked in programs that were targeted to urban dwelling Latino families and ten served urban African-Americans. Of the twenty-five staff members who worked in programs targeted to rural populations, eight worked to provide respite to African-American families while four served rural Latinos. The remaining thirteen interviewees served rural families of all ethnic groups. Interviews were tape recorded for accuracy and later transcribed. Emergent themes include: successful vs. unsuccessful service efforts, diversity of caregivers within ethnic groups, staff members' perceptions of their clients, staffing patterns, cultural views of Alzheimer's disease, service use in general, and government assistance. Concrete examples from staff members' experiences are used to illustrate these themes.